ASE GUIDELINES AND STANDARDS

Recommendations for Noninvasive Evaluation of Native Valvular Regurgitation

A Report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance

William A. Zoghbi, MD, FASE (Chair), David Adams, RCS, RDCS, FASE, Robert O. Bonow, MD, Maurice Enriquez-Sarano, MD, Elyse Foster, MD, FASE, Paul A. Grayburn, MD, FASE, Rebecca T. Hahn, MD, FASE, Yuchi Han, MD, MMSc,* Judy Hung, MD, FASE, Roberto M. Lang, MD, FASE, Stephen H. Little, MD, FASE, Dipan J. Shah, MD, MMSc,* Stanton Shernan, MD, FASE, Paaladinesh Thavendiranathan, MD, MSc, FASE,* James D. Thomas, MD, FASE, and

Neil J. Weissman, MD, FASE, Houston and Dallas, Texas; Durham, North Carolina; Chicago, Illinois; Rochester, Minnesota; San Francisco, California; New York, New York; Philadelphia, Pennsylvania; Boston, Massachusetts; Toronto, Ontario, Canada; and Washington, DC

TABLE OF CONTENTS

I. Introduction 305

• II. Evaluation of Valvular Regurgitation: General Considerations 305 A. Identifying the Mechanism of Regurgitation 305 B. Evaluating Valvular Regurgitation with Echocardiography 305 1. General Principles 305 a. Comprehensive imaging 306 b. Integrative interpretation 306 c. Individualization 306 d. Precise language 306

• 2. Echocardiographic Imaging 306 a. Valve structure and severity of regurgitation 306 b. Impact of regurgitation on cardiac remodeling 307
• 3. Color Doppler Imaging 307 a. Jet characteristics and jet area 308

• b. Vena contracta 309 c. Flow convergence 309

• 4. Pulsed Doppler 310 a. Forward flow 310 b. Flow reversal 310
• 5. Continuous Wave Doppler 310 a. Spectral density 310 b. Timing of regurgitation 310 c. Time course of the regurgitant velocity 310
• 6. Quantitative Approaches to Valvular Regurgitation 311 a. Quantitative pulsed Doppler method 311 b. Quantitative volumetric method 312 c. Flow convergence method (proximal isovelocity surface area [PISA] method) 312

From Houston Methodist Hospital, Houston, Texas (W.A.Z., S.H.L., D.J.S.); Duke University Medical Center, Durham, North Carolina (D.A.); Northwestern University, Chicago, Illinois (R.O.B., J.D.T.); Mayo Clinic, Rochester, Minnesota (M.E.-S.); University of California, San Francisco, California (E.F.); Baylor University Medical Center, Dallas, Texas (P.A.G.); Columbia University Medical Center, New York, New York, (R.T.H.); Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (Y.H.); Massachusetts General Hospital, Boston, Massachusetts (J.H.); University of Chicago, Chicago, Illinois (R.M.L.); Brigham and Women’s Hospital, Boston, Massachusetts (S.S.); Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada (P.T.); and MedStar Health Research Institute, Washington, DC (N.J.W.).

The following authors reported no actual or potential conflicts of interest in relation to this document: David Adams, RCS, RDCS, FASE; Robert O. Bonow, MD; Judy Hung, MD, FASE; Stephen H. Little, MD, FASE; Paaladinesh Thavendiranathan, MD, MSc; and Neil J. Weissman, MD, FASE. The following authors reported relationships with one or more commercial interests: Maurice Enriquez-Sarano, MD, received research support from Edwards LLC; Elyse Foster, MD, FASE, received grant support from Abbott Vascular Structural Heart and consulted for Gilead; Paul A. Grayburn, MD, FASE, consulted for Abbott Vascular, Neochord, and Tendyne and received research support from Abbott Vascular, Tendyne, Valtech, Edwards, Medtronic, Neochord, and Boston Scientific; Rebecca T. Hahn, MD, FASE, is a speaker for Philips Healthcare, St. Jude’s Medical, and Boston Scientific; Yuchi Han, MD, MMSc, received research support from Gilead and GE; Roberto M.

Lang, MD, FASE, is on the advisory board of and received grant support from Phillips Medical Systems; Dipan Shah, MD, MMSc, received research grant support from Abbott Vascular and Guerbet; Stanton Shernan, MD, FASE, is an educator for Philips Healthcare, Inc.; James D. Thomas, MD, FASE, received honoraria from Edwards and GE, and honoraria, research grant, and consultation fee from Abbott; and William A. Zoghbi, MD, FASE, has a licensing agreement with GE Healthcare and is on the advisory board for Abbott Vascular.

Reprint requests: American Society of Echocardiography, 2100 Gateway Centre Boulevard, Suite 310, Morrisville, NC 27560 (E-mail: ase@asecho.org).

Attention ASE Members:

The ASE has gone green! Visit www.aseuniversity.org to earn free continuing medical education credit through an online activity related to this article. Certificates are available for immediate access upon successful completion of the activity. Nonmembers will need to join the ASE to access this great

*Society for Cardiovascular Magnetic Resonance Representative. 0894-7317/$36.00

Copyright 2017 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2017.01.007

303

304 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Abbreviations 2D = Two-dimensional 3D = Three-dimensional

ACC/AHA = American College of Cardiology/American Heart Association

ARO = Anatomic regurgitant orifice

AR = Aortic regurgitation

ASE = American Society of Echocardiography

CMR = Cardiovascular magnetic resonance

CSA = Cross-sectional area

CWD = Continuous wave Doppler

EROA = Effective regurgitant orifice area

LA = Left atrium, atrial

LV = Left ventricle, ventricular

LVEF = Left ventricular ejection fraction

LVOT

MR = Mitral regurgitation MV = Mitral valve

MVP = Mitral valve prolapse PA = Pulmonary artery PISA = Proximal isovelocity surface area PR = Pulmonary regurgitation PRF = Pulse repetition frequency PV = Pulmonary valve RF = Regurgitant fraction RV = Right ventricle, ventricular RVol = Regurgitant volume RVOT = Right ventricular outflow tract SSFP = Steady-state free precession SV = Stroke volume TEE = Transesophageal echocardiography TR = Tricuspid regurgitation TTE = Transthoracic echocardiography TV = Tricuspid valve Va = Aliasing velocity VC = Vena contracta VCA = Vena contracta area VCW = Vena contracta width VTI = Velocity time integral

• C. Evaluating Valvular Regurgitation with Cardiac Magnetic Resonance 314

1. Cardiac Morphology, Function, and Valvular Anatomy 314 a. Ventricular volumes 314

• b. Correct placement of the basal ventricular short-axis slice is critical 314

• c. Planimetry of LV epicardial contour 315 d. Left atrial volume 315

• 2. Assessing Severity of Regurgitation with CMR 315 a. Phase-contrast CMR 315 b. Quantitative methods 315 c. Technical considerations 317 d. Thresholds for regurgitation severity 317
• 3. Strengths and Limitations of CMR 317 4. When Is CMR Indicated? 317

• D. Grading the Severity of Valvular Regurgitation 318

• III. Mitral Regurgitation 318 A. Anatomy of the Mitral Valve and General Imaging Considerations 318

• B. Identifying the Mechanism of MR: Primary and Secondary MR 319 1. Primary MR 319 2. Secondary MR 320 3. Mixed Etiology 321

• C. Hemodynamic Considerations in Assessing MR Severity 323 1. Acute MR 323 2. Dynamic Nature of MR 323 a. Temporal variation of MR during systole 323 b. Effect of loading conditions 323 c. Systolic anterior MV motion 324

• 3. Pacing and Dysrhythmias 324

• D. Doppler Methods of Evaluating MR Severity 324 1. Color Flow Doppler 324 a. Regurgitant jet area 324 b. Vena contracta (width and area) 328 c. Flow convergence (PISA) 328

• 2. Continuous Wave Doppler 330 3. Pulsed Doppler 330 4. Pulmonary Vein Flow 330

• E. Assessment of LV and LA Volumes 330 F. Role of Exercise Testing 330

• G. Role of TEE in Assessing Mechanism and Severity of MR 330 H. Role of CMR in the Assessment of MR 331 1. Mechanism of MR 331 2. Methods of MR Quantitation 331 3. LV and LA Volumes and Function 331 4. When Is CMR Indicated? 331

• I. Concordance between Echocardiography and CMR 331 J. Integrative Approach to Assessment of MR 332 1. Considerations in Primary MR 334 2. Considerations in Secondary MR 334

• IV. Aortic Regurgitation 334

A. Anatomy of the Aortic Valve and Etiology of Aortic Regurgitation 334

• B. Classification and Mechanisms of AR 335 C. Assessment of AR Severity 336 1. Echocardiographic Imaging 336 2. Doppler Methods 336 a. Color flow Doppler 336 b. Pulsed wave Doppler 336 c. Continuous wave Doppler 336

• D. Role of TEE 340 E. Role of CMR in the Assessment of AR 340 1. Mechanism 340 2. Quantifying AR with CMR 340 3. LV Remodeling 342 4. Aortopathy 342 5. When Is CMR Indicated? 342

• F. Integrative Approach to Assessment of AR 343

• V. Tricuspid Regurgitation 345 A. Anatomy of the Tricuspid Valve 345

Zoghbi et al 305

Journal of the American Society of Echocardiography Volume 30 Number 4

B. Etiology and Pathology of Tricuspid	Regurgitation	Regurgitation	Regurgitation	345
C. Role of Imaging in Tricuspid Regurgitation			345
1. Evaluation of the Tricuspid Valve		345
a. Echocardiographic imaging		345
b. CMR imaging 345
2. Evaluating Right Heart Chambers		345
D. Echocardiographic Evaluation of TR		Severity	350
1. Color Flow Imaging 350
a. Jet area 350
b. Vena contracta 350
c. Flow convergence 350
2. Regurgitant Volume 352
3. Pulsed and Continuous Wave Doppler			352
E. CMR Evaluation of TR Severity	353
F. Integrative Approach in the Evaluation of TR			353
VI. Pulmonary Regurgitation 353
A. Anatomy and General Imaging Considerations				353
B. Etiology and Pathology 355
C. Right Ventricular Remodeling 355
D. Echocardiographic Evaluation of PR		Severity	355
1. Color Flow Doppler 355
2. Pulsed and Continuous Wave Doppler			356
3. Quantitative Doppler 356
E. CMR Methods in Evaluating PR	358
F. Integrative Approach to Assessment		of PR	358
VII. Considerations in Mulitivalvular Disease		360
A. Impact of Multivalvular Disease on	Echocardiographic Parame-
ters of Regurgitation 360
1. Color Jet Area 360
2. Regurgitant Orifce Area 360
3. Proximal Convergence and Vena		Contracta		360
4. Volumetric Methods 360
B. CMR Approach to Quantitation of	Regurgitation			in Multivalvu-
lar Disease 360
VIII. Integrating Imaging Data with Clinical Information				362
IX. Future Directions 363
Reviewers 363
Notice and Disclaimer 363

I. INTRODUCTION

Valvular regurgitation continues to be an important cause of morbidity and mortality. While a careful history and physical examination remain essential in the overall evaluation and management of patients with suspected valvular disease, diagnostic methods are often needed and are crucial to assess the etiology and severity of valvular regurgitation, the associated remodeling of cardiac chambers in response to the volume overload, and the characterization of longitudinal changes for optimal timing of intervention. In 2003, the American Society of Echocardiography along with other endorsing organizations provided, for the first time, recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional (2D) and Doppler echocardiography. Advances in threedimensional (3D) echocardiography and cardiovascular magnetic resonance (CMR) have occurred in the interim that provide additional tools to further delineate the pathophysiology and mechanisms of regurgitation and supplement current methods for assessing regurgitation severity. Furthermore, within this time frame, critical information linking Doppler echocardiographic measures of regurgitation severity to clinical outcome has been published. This update on the evaluation of valvular regurgitation is a

comprehensive review of the noninvasive assessment of valvular regurgitation with echocardiography and CMR in the adult. It provides recommendations for the assessment of the etiology and severity of valvular regurgitation based on the literature and a consensus of a panel of experts. This guideline is accompanied by a number of tutorials and illustrative case studies on evaluation of valvular regurgitation, posted on the following website (www. asecho.org/vrcases), which will build gradually over time. Issues regarding medical management and timing of surgical interventions are beyond the scope of this document and have been recently updated.

II. EVALUATION OF VALVULAR REGURGITATION: GENERAL CONSIDERATIONS

A. Identifying the Mechanism of Regurgitation

Valvular regurgitation or insufficiency results from a variety of etiologies that prevent complete apposition of the valve leaflets or cusps. These are grossly divided into organic valve regurgitation (primary regurgitation) with structural alteration of the valvular apparatus and functional regurgitation (secondary regurgitation), whereby cardiac chamber remodeling affects a structurally normal valve, leading to insufficient coaptation. Etiologies of primary valve regurgitation are numerous and include degeneration, inflammation, infection, trauma, tissue disruption, iatrogenic, or congenital. Doppler techniques are very sensitive, and thus trivial or physiologic valve regurgitation, even in a structurally normal valve, can be detected and occurs frequently in right-sided valves.

It is not sufficient to only note the presence of regurgitation. One is obligated to describe the mechanism and possible etiologies, particularly in clinically significant regurgitation, as these affect the severity of regurgitation, cardiac remodeling, and management. The mechanism of regurgitation is not necessarily synonymous with the cause. For example, endocarditis can cause either perforation or valvular prolapse. The resolution (spatial and temporal) of imaging modalities have markedly improved, resulting in identification of the underlying mechanism of regurgitation in the majority of cases. Transthoracic echocardiography (TTE) is usually the first-line imaging modality to investigate valvular regurgitation (etiology, severity, and impact). However, if the TTE is suboptimal, reliance on transesophageal echocardiography (TEE) or CMR would be the next step in evaluating the etiology or severity of regurgitation. Three-dimensional echocardiography has significantly enhanced our understanding of the mechanism of regurgitation and provides a real-time display of the valve in the 3D space. This is particularly evident when imaging the mitral, aortic, and tricuspid valves (TVs) with TEE.

B. Evaluating Valvular Regurgitation with Echocardiography

1. General Principles. TTE with Doppler provides the core of the evaluation of valvular regurgitation severity. Additional methods, echocardiographic (TEE) and nonechocardiographic (computed tomography, CMR, angiography), can be useful at the discretion of examining physicians based on the combination of the potential for these methods to be informative versus their potential risk. This could be particularly important for patients with suboptimal image quality

306 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 1 Echocardiographic parameters in the comprehensive evaluation of valvular regurgitation

	Parameters
Clinical information	Symptoms and related clinical fndings
	Height/weight/body surface area
	Blood pressure and heart rate
Imaging of the valve	Motion of leafets: prolapse, fail, restriction, tenting of atrioventricular valves, valve coaptation
	Structure: thickening, calcifcations, vegetations
	Annular size/dilatation
Doppler echocardiography of the valve	Site of origin of regurgitation and its direction in the receiving chamber by color Doppler
	The three color Doppler components of the jet: fow convergence, VC, and jet area
	Density of the jet velocity signal, CW
	Contour of the jet in MR and TR, CW
	Deceleration rate or pressure half-time in AR and PR, CW
	Flow reversal in pulmonary/hepatic veins (MR, TR); in aorta/PA branches (AR, PR)
	LV and RV flling dynamics (MR, TR)
Quantitative parameters for regurgitation	PISA optimization for calculation of RVol and EROA
	Valve annular diameters and corresponding pulsed Doppler for respective SV calculations and
	derivation of RVol and RF
	Optimization of LV chamber quantitation (contrast when needed)
3D echocardiography*	Localization of valve pathology, particularly with TEE
	LV/RV volumes calculation
	Measured EROA
	Automated quantitation of fow and RVol by 3D color fow Doppler†
Other echocardiographic data	LV and RV size, function, and hypertrophy
	Left and right atrial size
	Concomitant valvular disease
	Estimation of PA pressure

*If available in a laboratory. †Needs further clinical validation.

and/or whenever there is a discrepancy between the clinical presentation/symptoms and the evaluation by echocardiography. When TTE provides a complete array of good quality data on the regurgitation, little or no additional information may be needed for the clinical care of patients. However, when the quality of the data is in question, or more precise/accurate measurements are required for clinical decision making, advanced imaging has an important role.

There are a number of principles to apply in the evaluation of valvular regurgitation with echocardiography:

a. Comprehensive imaging. All modalities included in the standard TTE evaluation inclusive of M-mode, 2D, and 3D where applicable, pulsed, color, continuous wave Doppler (CWD), and combined qualitative and quantitative assessment contribute to valve regurgitation assessment.

b. Integrative interpretation. While the predictive power for outcome of all the measurements is not equal and is dominated by a few powerful quantitative measures, interpretation should not rely on a single parameter. Single measures are subject to variability (anatomic, physiologic, and operator); a combination of measures and signs should be comprehensively used to describe and report the final assessment of valve regurgitation.

c. Individualization. Recent data show that valve regurgitation measures and signs that appear similar may have different implications in

different etiologies, so that measures and signs require individualized interpretation, taking into account body size, cause of regurgitation, cardiac compliance and function, acuteness or chronicity of the regurgitation, regurgitation dynamics, and hemodynamic conditions at measurement, among others.

d. Precise language. Avoiding imprecision and including detailed and comprehensive observations of the cause, mechanism, severity, location, associated lesions, and cardiac response are required. This language should be standardized and concise. Table 1 summarizes the essential parameters needed in the evaluation of valvular regurgitation with echocardiography.

2. Echocardiographic Imaging. The main goal of echocardiographic imaging is to define the etiology, mechanism, severity, and impact of the regurgitant lesion on remodeling of the cardiac chambers.

a. Valve structure and severity of regurgitation. Competent leaflets are characterized by a sufficient coaptation surface, which approximates 8-10 mm for the mitral valve (MV), 4-9 mm for the TV, and a few millimeters for semilunar valves. Measurement of leaflet coaptation surface is not accurate with TTE. Three-dimensional TEE or other imaging modalities may allow a prediction of regurgitation severity based on leaflet coaptation. Severe regurgitant lesions when noted represent direct signs of large regurgitant orifices. Such

Zoghbi et al 307

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 1 Depiction of the three components of a color flow regurgitant jet of MR: flow convergence (FC), VC, and jet area.

lesions occur in various etiologies: large perforations, large flail segments, profound retraction of leaflets leaving a coaptation gap, or marked tenting of leaflets with tethering and loss of coaptation. All of these findings predict severe valve regurgitation with a high positive predictive value but low sensitivity. Hence, these specific signs are useful when present, but their absence does not exclude severe regurgitation. TTE is the main modality to assess valvular structure usually with the 2D approach, with TEE reserved for inconclusive studies, and to assess eligibility and suitability for transcatheter or surgical procedures. Three-dimensional applications in evaluating valve morphology have had a significant impact on the accuracy of localization of valvular lesions mostly from the transesophageal approach, particularly for the atrioventricular valves. The current lower spatial and temporal resolution of 3D TTE limits its evaluation of valvular structure, however, this is improving.

b. Impact of regurgitation on cardiac remodeling. As blood is incompressible, the regurgitant volume (RVol) must be contained in the cardiac cavities affected, implying that some degree of cavity dilation is proportional to the severity and chronicity of regurgitation. Despite this obligatory remodeling, the dilatation of cardiac cavities is considered in general a supportive sign of valvular regurgitation severity and not a specific sign (unless some conditions are met) because of multiple factors affecting cardiac remodeling. Acute severe regurgitation is characterized by a large regurgitant orifice, but cavity dilatation is minimized. The kinetic energy transmitted through the regurgitant orifice is affected by low cavity compliance, whereby the regurgitant energy is transformed into potential energy (elevated pressure in the receiving chamber) so that rapid equalization of pressure occurs with a low driving force for regurgitation. Consequently, acute severe regurgitation may be brief, with low RVol (low kinetic energy) and little cavity dilatation. In chronic regurgitation, however, cavity dilatation should reflect the regurgitation severity and duration. Cavity dilatation may be specific for significant regurgitation when ventricular function is preserved but loses specificity in conditions such as cardiomyopathy or ischemic ventricular dysfunction. A component of intrinsic dilatation (e.g., cardiomyopathy, atrial dilata-

tion due to atrial fibrillation) may exaggerate the apparent ‘‘consequences’’ of regurgitation. Conversely, in patients with small cavities prior to the onset of regurgitation, an increase in cavity size may be underestimated if preregurgitation cavity size is unknown. Anatomic variability and technical issues may limit the ability to detect cavity dilatation. Measuring cavity diameters rather than volumes has inherent limitations as the diameter-volume relationship is nonlinear. Furthermore, the proposed range of normal values currently available is based on a limited number of subjects, so that for patients with small or very large body size, normalcy is difficult to define. The small body size limitation is of particular concern in evaluating valve regurgitation in females, where normalizing ventricular and regurgitant measurements to body size may provide a more accurate assessment of outcomes. Nevertheless, in a patient with regurgitation, an enlarged ventricle is consistent with significant regurgitation in the chronic setting and in the absence of other modulating factors, particularly when ventricular function is normal. Once a diagnosis of significant regurgitation is established, serial echocardiography with TTE is currently the method of choice to assess the progression of the impact of regurgitation on cardiac chamber structure and function. Careful attention to consistency of measurements and individualized interpretation of results are critical to the assessment of cardiac remodeling as a sign of regurgitation severity. Contrast echocardiography should be used in technically difficult studies for better endocardial visualization, as it enhances overall accuracy of ventricular volume measurements. Three-dimensional TTE can also be used for an overall more accurate assessment of volumes and ejection fraction, as it avoids foreshortening of the left ventricle (LV).

Echocardiography in general tends to underestimate measurements of LV volumes compared to other techniques when the traced endocardium includes ventricular trabeculations; the use of contrast to better visualize the endocardial borders excludes trabeculations and provides larger measurements of cavity size, closer to those by computed tomography and CMR.

3. Color Doppler Imaging. Color flow Doppler is widely used for the detection of regurgitant valve lesions and is the primary method

308 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 2 Factors that increase or reduce the color Doppler jet area

Increases jet area	Reduces jet area
Higher momentum	Lower momentum
Larger regurgitant orifce area	Smaller regurgitant orifce area
Higher velocity (greater pressure gradient)	Lower velocity (lower pressure gradient)
Higher entrainment of fow	Chamber constraint/wall-impinging jet
Lower Nyquist limit	Higher Nyquist limit
Higher Doppler gain	Lower Doppler gain
Far-feld beam widening	Far-feld attenuation/attenuation by an interposed ultrasound-refecting structure
Slit-like regurgitant orifce, imaged along
the thin, long shape of the orifce
Multiple orifces

for assessment of regurgitation severity. This technique provides visualization of the origin of the regurgitant jet and its size (VC), the spatial orientation of the regurgitant jet area in the receiving chamber, and, in cases of significant regurgitation, flow convergence into the regurgitant orifice (Figure 1). Experience has shown that attention to these three components of the regurgitation lesion by color Doppler—as opposed to the traditional regurgitant jet area alone with its inherent limitations—significantly improves the overall accuracy of assessment of regurgitation severity. The following are important considerations for color Doppler imaging of regurgitant jets:

a. Jet characteristics and jet area. Since color Doppler visualization of regurgitant jets plays such a significant role in the assessment of valvular regurgitation, it is useful to discuss the underlying basis of color jet formation and display and factors that affect it. A more detailed exposition on color jet formation has been described elsewhere. First, it is important to understand that simply knowing the orifice flow rate is not enough to predict jet size, since the jet will entrain additional flow as it propagates into the receiving chamber and this entrainment strongly depends on the orifice velocity (which in turn is affected by the orifice driving pressure). Rather, jet flow is governed mainly by conservation of momentum. Cardiologists are likely less familiar with momentum as opposed to the other two conserved quantities in fluid flow: mass (manifest in the continuity equation) and energy (found in the Bernoulli equation); but momentum is a critical concept for understanding regurgitant jets. For a jet originating through a regurgitant orifice with effective orifice area A and velocity v, the flow Q is equal to Av, and the momentum M is given by Qv or Av. (By extension, energy is given by Qv or Av). The amount of momentum that is within a jet at its orifice remains constant throughout the jet. Thus, a 5 m/sec mitral regurgitation (MR) jet with a flow rate of 100 mL/sec should appear the same by color Doppler as a 2.5 m/ sec tricuspid regurgitation (TR) jet with a flow rate of 200 mL/sec. For a free turbulent jet, the centerline velocity in the jet drops off inversely with distance from the regurgitant orifice.

To understand how large a jet will appear in color Doppler, one needs to know the minimum velocity that can be detected by the instrument. This is not specifically defined on the echocardiogram but typically is a fraction (around 10%) of the full Nyquist velocity. The jet will appear anywhere the jet velocity is greater than this minimally detectible velocity. The situation is somewhat more complicated in that no jets inside the heart are completely free but are constrained by the chamber walls, causing the velocity to fall off earlier than it would otherwise. The effect of the interplay among momentum, chamber constraint, and minimal displayed velocity on jet area is

complex, but for clinical purposes, it suffices to know the following determinants of jet size (Table 2):

• Jet momentum (Av): a major overall determinant of jet size.

• Jet constraint/wall impingement: eccentric wall-hugging jets lose momentum rapidly, thus appearing smaller than nonconstrained jets of the same RVol.

• Nyquist limit (velocity scale): reducing the velocity scale emphasizes lower velocities and makes the jet appear larger. In addition, blood cells within the receiving chamber that move in response to or are entrained by the regurgitant jet may reach the minimal velocity and thus appear part of the regurgitant jet.

• Orifice geometry: slit-like orifices (particularly imaged along the long axis of the orifice) and multiple separate orifices lead to larger jets than single, relatively round orifices.

• Pulse repetition frequency (PRF): affects jet area inversely

• Doppler gain: jet size is quite sensitive and proportional to gain.

• Ultrasound attenuation: attenuation in the far field, from body habitus, or from an interposing highly reflectant structure such as calcium or metal (interferes with both imaging and Doppler) will decrease jet size.

• Transducer frequency: this has a dual effect. The higher frequency experiences a significant Doppler shift at lower velocities, making jets larger, such as in TEE. On the other hand, these higher frequency beams suffer excessive attenuation and jets may appear smaller in the far field, during TTE.

• Angle of interrogation: since color Doppler is sensitive only to the component of flow in the direction of the transducer, jets interrogated orthogonally may appear smaller than the same jet imaged axially. This effect actually is lessened as the turbulence within jets leads to high-velocity flow in all directions, thus making the jet visible even when imaged from the side.

• Color versus tissue threshold: if the tissue priority is set too high, structures may encroach on the color Doppler signal.

Thus, a larger area of a jet that is central in the cavity may imply more regurgitation, but as discussed, sole reliance on this parameter can be misleading. Figure 2 illustrates examples of modifiers of jet size. Standard technique is to use a Nyquist limit (aliasing velocity [Va]) of 50-70 cm/sec and a high color gain that just eliminates random color speckle from nonmoving regions (Figure 2). Eccentric wall-impinging jets appear significantly smaller than centrally directed jets of similar hemodynamic severity. Their presence however, should also alert to the possibility of structural valve abnormalities (e.g., prolapse, flail, or perforation), frequently situated in the leaflet or cusp opposite to the direction of the jet. A jet may appear larger by increasing the driving pressure across the valve (higher momentum); hence the importance of measuring blood pressure for left heart lesions at the time of the study, particularly in the intraoperative setting or in a sedated patient. Lastly, it is important to note that in cases of very large regurgitant

Zoghbi et al 309

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 2 Effect of color gain, Nyquist limit, and transducer frequency on color jet area. Color gain should be optimized high, just below clutter noise level, otherwise the jet will be much smaller. A low Nyquist limit will emphasize lower velocities, and thus the jet will be larger; Nyquist should be between 50 and 70 cm/sec. A higher transducer frequency, as used in TEE, will also depict a slightly larger jet.

orifice areas, such as in cases of massive TR with a wide, noncoapting valve, a distinct jet may not be seen with color Doppler because of laminar flow and very low blood velocity.

b. Vena contracta. The vena contracta (VC) is the narrowest portion of the regurgitant flow that occurs at or immediately downstream of the regurgitant orifice (Figure 1). It is characterized by high-velocity laminar flow and is slightly smaller than the anatomic regurgitant orifice (ARO). Thus, the cross-sectional area (CSA) of the VC represents a measure of the effective regurgitant orifice area (EROA), a true parameter of lesion severity. The size of the hydraulic VC is independent of flow rate and driving pressure for a fixed orifice. However, if the regurgitant orifice is dynamic, the VC may change during the cardiac cycle. In general, the VC by color Doppler significantly overestimates the hydraulic VC and is dependent on flow rate, likely because of entrainment. Despite these limitations, it remains a helpful semiquantitative measure of valve regurgitation severity. The VC by color Doppler is considerably less dependent on technical factors (e.g., PRF) compared with the jet extent. Imaging of the VC can be achieved using 2D or 3D color-flow Doppler, each presenting different challenges. For 2D VC measurement, it is indispensable to have a linear view of the three components of regurgitant flow (flow convergence, VC, jet area)

and to orient the ultrasonic beam as perpendicular to the flow as possible to take advantage of axial measurement accuracy. Hence, it is often necessary to angulate the transducer out of the conventional echocardiographic imaging planes. Proper beam-flow orientation is best achieved for aortic or pulmonary regurgitation (PR), less for MR, and even less for TR. A zoomed view is also indispensable to minimize the measurement inaccuracies for a width of a few millimeters. VCA tracing requires 3D imaging and is achieved offline by reorienting images and using cropping planes to locate the VC. The color flow sector should also be as narrow as possible, to maximize lateral and temporal resolution. Achieving reasonable certainty that the smallest flow area is traced is a tedious process and may be difficult and lengthy; automated processes are being developed to this end. Because of the small values of the width of the VC (usually <1 cm), small errors in its measurement may lead to a large percent error and misclassification of the severity of regurgitation, hence the importance of accurate acquisition of the primary data and measurements.

c. Flow convergence. Locating the flow convergence proximal to the regurgitant orifice provides qualitative information on both the location of the lesion causing the regurgitation and the magnitude of the regurgitant flow. A well-defined small flow convergence combined with a

310 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 3 M-mode color images depict timing of MR: classic holosystolic MR, late systolic MR due to MVP, and early systolic MR in a patient with cardiomyopathy and left bundle branch block. Single-frame measurements of EROA or VC (width or area) will overestimate MR severity when it is not holosystolic.

small jet is specific for mild regurgitation,while a large flow convergence recorded at the minimum 50-70 cm/sec range, persisting throughout the duration of flow is specific for severe regurgitation. Flow convergence is amenable to quantitation of regurgitant flow (see below).

4. Pulsed Doppler. Pulsed Doppler is used combined with multiple measures of flow velocity as part of the quantitative assessment of valve regurgitation (see below). However, alterations in forward flow and reversed flow detected with pulsed Doppler associated with regurgitation can also be used as qualitative measures of valve regurgitation severity.

a. Forward flow. Valve regurgitation implies that the forward stroke volume (SV) across the affected valve during the cardiac cycle is increased. For atrioventricular valves, increased forward flow is characterized by increased early E velocity and E/A ratio, generally associated with a short E deceleration time in the absence of stenosis. This supportive sign is mired by the multiple factors affecting ventricular filling including diastolic function, ventricular inflow obstruction (e.g., annular calcification), or alterations in cardiac output. For semilunar valves, ejection velocity is slightly increased with severe regurgitation, but the velocity time integral (VTI) of forward flow at the annulus is generally increased along with a prolongation in ejection time. This supportive sign is nonspecific but is a useful part of the constellation of findings in severe regurgitation.

b. Flow reversal. The RVol, when significant, may cause flow reversal in the receiving or proximal chamber, depending on the valve. In atrioventricular valves, valve regurgitation may result in pulmonary systolic venous flow reversal with MR or hepatic venous systolic flow reversal in cases of TR. Such systolic reversals are considered specific (>85% probability of severe regurgitation when present) but insensitive. Care should be taken to exclude other causes of flow reversal such as atrioventricular dissociation or pacemakers with ventriculoatrial conduction. For aortic regurgitation (AR), reversal of flow is diastolic, noted in the aortic arch and abdominal aorta, and is influenced by multiple factors, particularly peripheral vascular resistance and aortic compliance. Hence, prominent holodiastolic aortic flow reversal is a specific sign of severe AR but insensitive. Other causes of diastolic flow reversal should be sought in the absence of AR such as

arteriovenous fistulas, ruptured sinus of Valsalva, or patent ductus arteriosus.

5. Continuous Wave Doppler. Recording of jet velocity with continuous wave Doppler (CWD) provides valuable information as to the velocity and gradient between the two cardiac chambers involved in the regurgitation, its time course, and timing of the regurgitation. The density of the signal is also helpful, provided the Doppler waveform is not overgained.

a. Spectral density. The intensity (amplitude) of the returned Doppler signal is proportional to the number of red blood cells reflecting the signal. Hence, the signal density of the CWD of the regurgitant jet should reflect the regurgitant flow. Thus a faint, incomplete, or soft signal is indicative of trace or mild regurgitation. A dense signal may not be able to differentiate moderate from severe regurgitation. Signal density also depends on spectral recording of the jet throughout the relevant portion of the cardiac cycle. Therefore, a central jet well aligned with the ultrasound beam may appear denser than an eccentric jet of much higher severity, if not well aligned.

b. Timing of regurgitation. The duration and timing of regurgitation can be valuable in the overall assessment of the physiology and hemodynamics of regurgitation. While the majority of regurgitant lesions are holosystolic or holodiastolic, some may occur during a brief period (Figure 3). In patients with MV prolapse (MVP), the regurgitation may be limited to late systole and is rarely severe when not holosystolic, with infrequent cardiac remodeling. MR and TR may be limited to isovolumic contraction and relaxation phases or both, particularly in functional regurgitation, which correspond to mild or trivial regurgitation.

c. Time course of the regurgitant velocity. The spectral velocity profile of a regurgitant jet is determined by the pressure difference between the upstream and downstream chambers, with a general parabolic shape during systole for atrioventricular valves and a trapezoid shape during diastole for semilunar valves. For atrioventricular valves, an early peaking or cutoff sign denotes a large regurgitant wave in the respective atrium and significant regurgitation. A rapid decay of the diastolic slope in semilunar valve

Zoghbi et al 311

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 4 Echo-Doppler calculations of SV at the LVOT and MV annulus sites. In this example of severe MR, SVMV was 183 mL (d = 3.5 cm, VTI = 19 cm) and SVLVOT was 58 mL (d = 2.3 cm, VTI = 14 cm). This yielded an RVol of 125 mL and an RF of 125/183 or 68%. d, Diameter of the annulus; PW, pulsed wave Doppler.

regurgitation also can denote significant regurgitation but is exaggerated in cases of poor ventricular compliance and thus may not be specific. Pulmonic regurgitation (PR) may end prior to end diastole and may be related to poor ventricular compliance and/or severe regurgitation. Premature termination of diastolic flow is rarely seen in AR and usually denotes acute severe regurgitation.

6. Quantitative Approaches to Valvular Regurgitation. There

are few methods using echo Doppler techniques to quantitate valvular regurgitation. All these methods derive three measures of regurgitation severity:

• The EROA, the fundamental measure of lesion severity.

• The RVol per beat, which provides a measure of the severity of the volume overload.

• The regurgitant fraction (RF) provides a ratio of the RVol to the forward SV specific to the patient.

Prior studies suggest that the absolute measurements of EROA and RVol provide the strongest predictors of outcome. It is uncertain whether normalization of these measures to body size (body surface area or body mass index) is superior to absolute values, particularly in women. Careful attention should be paid to assess whether the regurgitation covers its entire period (systole for atrioventricular, diastole for semilunar valves); for regurgitations limited to part of their flow period, the EROA should be normalized to the entire period of potential regurgitation or ignored, as it would overestimate the severity of regurgitation. Overall, in such partial regurgitations, the RVol is a better measure of regurgitation severity.

a. Quantitative pulsed Doppler method. Doppler recording of VTI can be combined with 2D or 3D measurement of flow area to derive SVs at different sites. The difference between inflow and outflow SVs of the same ventricle is caused by the RVol in single valvular regurgitation. This method is simple in principle, however, accurate results require individual training (e.g., practice in normal patients where SVs at different sites are equal). Briefly, forward SV at any valve annulus—the least variable anatomic area of a valve apparatus—is derived as the product of CSA and the VTI, measured by pulsed Doppler at the annulus. Overall, assumption of a circular geometry has worked well clinically. In this case,

where d is the diameter of the annulus in centimeters, VTI in centimeters, and SV in milliliters.

Calculations of SV can be made at two or more different sites: left ventricular outflow tract (LVOT), mitral annulus and right ventricular outflow tract (RVOT). In the absence of regurgitation, SV determinations at these sites are equal. In the presence of regurgitation of one valve, without the presence of any intracardiac shunt, the SV through the affected valve is larger than through the other competent valves. The difference between the two represents the RVol (Figure 4). RF is then derived as the RVol divided by the SV through the regurgitant valve. Thus,

There are three methods for quantitative assessment of valvular regurgitation:

RF ¼ RVol=SVRegValv;

312 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

where SVRegValv is the SV derived at the annulus of the regurgitant valve and SVCompValv is the SV at the competent valve.

EROA can be calculated using the VTI of the regurgitant jet (VTIRegJet) recorded by CWD as

EROA ¼ RVol=VTIRegJet;

All measurements are expressed in centimeters or milliliters, leading to the calculation of EROA in square centimeters.

The most common errors encountered in determining these parameters are (1) failure to measure the valve annulus accurately (error is squared in the formula), (2) failure to trace the modal velocity (brightest signal representing the velocity of the majority of blood cells) of the pulsed Doppler tracing, and (3) failure to position the sample volume correctly, and with minimal angulation, at the level of the annulus. Furthermore, in the case of significant calcifications of the mitral annulus and valve, quantitation of flow at the mitral site is less accurate and more prone to errors.

A major challenge with all volumetric methods is that each of the component SVs has intrinsic error, in part due to the multiple parameters that must be combined into each one. These errors increase (as the root sum square) when the SVs are subtracted, with the relative error increasing even more as one subtracts one large number from another to get a small RVol. For example, a recent study of 3D color flow quantitation demonstrated 95% confidence limits of mitral flow (relative to CMR) of 618.9 mL and 617.8 mL for the aortic valve. When these SVs are subtracted, the confidence intervals rise to 626 mL, emphasizing the critical need for meticulous attention to technique with these methods.

b. Quantitative volumetric method. Because blood is incompressible, the total SV ejected by the ventricle in single-valve regurgitation is equal to the SVat the regurgitant valve (SVRegValv). If the forward SV (SVForward) is measurable simultaneously by Doppler or by any other method, the RVol can be calculated. Most use of this method has been for single left-sided regurgitant valves and the LV SV has been calculated using 2D echocardiography measurement of LV volumes. In such cases SVForward is measured on the nonregurgitant valve (aortic valve for MR or MV for AR). Hence calculations are the following:

Methods for calculation of LV volumes by echocardiography have been previously detailed. The limitation of the method is the potential pitfall of underestimating true LV volume as noted above and therefore underestimating regurgitation severity. This can be improved with avoidance of foreshortening and use of contrast echocardiography. Assessment of ventricular volumes based on M- mode measurements has important limitations and is not recommended. The use of 3D echocardiography may improve the accuracy of LV volume determinations.

c. Flow convergence method (proximal isovelocity surface area [PISA] method). In valvular regurgitation, blood flow converges towards the regurgitant orifice forming concentric, roughly hemispheric shells of increasing velocity and decreasing surface area. Color flow mapping offers the ability to image one of these hemispheres that corresponds to the first aliasing threshold (where the displayed color changes from red to yellow) as one moves out from the regurgitant orifice. This is generally done by shifting the baseline of the color scale in the direction of the regurgitant jet (i.e., down for MR into the LA on TTE and up for MR on TEE) to highlight an aliasing contour where flow convergence has a roughly hemispheric shape; it may appear more teardrop-shaped because lateral flows, perpendicular to the ultrasound beam, cannot be detected by Doppler. Alternatively, one could reduce the PRF to decrease the Nyquist (and aliasing) velocity, although most echocardiographers prefer shifting the baseline. The radius of the PISA is measured from the point of color Doppler aliasing (abrupt change in color from blue to yellow if jet direction is away from transducer) to the VC. Regardless, the aliasing contour is better detected if variance color mapping is turned off. For a hemispheric proximal convergence zone with radius r, the regurgitant flow rate (RFlow, in mL/sec) is calculated as the product of the surface area of the hemisphere (2pr) and the Va as

Assuming that the selected PISA radius occurs at the time of peak regurgitant velocity, the EROA at that specific time is derived as

where PeakVRegJet is the peak velocity of the regurgitant jet by CWD. The radius is expressed in centimeters and velocities in centimeters per second, allowing the EROA to be expressed in square centimeters. The RVol can be calculated as

where VTIRegJet is the VTI of the regurgitant jet expressed in centimeters.

The PISA method is simple conceptually and in its practical calculation (Figure 5). It allows a qualitative and a quantitative assessment of the severity of the regurgitation and has become the main method of quantification of regurgitation, particularly on the mitral and TVs. However, there are several core principles to pay attention to in order to maintain quality control:

• Timing of measurements: since the PISA calculation provides an instantaneous peak flow rate, the EROA calculated by this approach may not be equivalent to the average regurgitant orifice throughout the regurgitant phase. Previous studies using timed measurement in MR have shown that the regurgitation is often dynamic; two important precautions were highlighted: first, measurement of flow and velocity should be performed at simultaneous moments of the regurgitant phase (Figure 5; e.g., not combining a late-systolic flow convergence with a midsystolic velocity). Second, the PISA measurement most representative of the mean EROA is that performed simultaneously with the peak velocity of the regurgitation (Figure 5). Hence it is essential to follow these rules without aiming for the largest flow convergence, while also remembering that the dynamic nature of the jets may lead to underestimation in the case of typically bimodal secondary MR or overestimation in the case of late systolic primary MR.

Zoghbi et al 313

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 5 Schematic representation of the flow convergence method (PISA). The example on the right shows the measurement of the PISA radius and the timing of the selection of the color frame for measurement (solid yellow arrow), corresponding to the maximal jet velocity by CWD (dashed arrow). Reg, Regurgitation; PKV, peak velocity of regurgitant flow by CWD; VTI, velocity time integral of the regurgitant jet by CWD.

• Duration of regurgitation: the issue of instantaneous versus average measurement comes particularly into play for ‘‘partial’’ regurgitation (e.g., myxomatous MR confined to mid-late systole or functional MR in early systole and isovolumic relaxation). For such partial regurgitation, the RVol can be approximated by multiplying the maximal EROA by the VTI from the densest part of the CWD tracing. When reporting the EROA, however, it is best to use the ‘‘mean’’ EROA, where the maximal EROA is normalized by the proportion of systole during which significant regurgitation occurs; preferably, the RVol should be retained as the most appropriate index. Where feasible, volumetric methods can yield these regurgitant parameters without needing to make assumptions about variation in the EROA.

• Shape of PISA: the standard method assumes that the valvular plane from which the regurgitant orifice arises is planar and that the flow convergence is homogeneous, but this is not always the case. First, the plane of the regurgitant orifice may be conical rather than flat or planar (180[]), as seen in TR and MV leaflet tenting. This conical angle should be accounted for, as the flow convergence covers more than a hemisphere. Second, the shape of the flow convergence may be inconsistent with a hemisphere, which may require adjustment of the Va such that a well-defined hemisphere is shown. If the flow convergence does not fulfill the criteria of a hemisphere due to constraint, the initial approach is to attempt avoiding the constraint by increasing the Va, making the flow convergence smaller and less prone to constraint. However, if the constraint persists, the echocardiographer should decide whether a simple angle correction for the truncation of the flow convergence is possible, and if not, the method should not be reported.

• Shape of the regurgitant orifice: a factor that complicates PISA calculations is the shape of the regurgitant orifice itself. While organic disease (e.g., leaflet flail) usually causes a roughly circular orifice, the regurgitant orifice area in functional disease is often elongated throughout the coaptation line. Application of the standard PISA formula to such an elliptical orifice will lead predictably to flow underestimation. Recent computational fluid dynamics simulations have shown that this underestimation may not be as severe as might be feared, depending on the shape of the ellipse, since the flow

contours rapidly become hemispheric as one moves away from the orifice. For a 3:1 ellipse, use of the standard PISA formula (with 40 cm/ sec Va and 5 m/sec orifice velocity) only results in 8% underestimation relative to a circular orifice. However, a 5:1 ratio leads to a 17% underestimation, and a 10:1 ratio to a 35% underestimation.

A few additional limitations of PISA should be noted. Central jets allow an easy alignment of the ultrasound beam and the centerline of the flow convergence. In contrast, eccentric jets may present a challenge, for both flow convergence and CWD recording (angulation or inability to record jet despite multiple windows). It is generally easy to identify the aliasing line of the hemispheric contour, but deciding on the position of the regurgitant orifice is more challenging. The presence of dark zones indicating horizontal flow perpendicular to the beam of ultrasound represents the best marker of the position of the regurgitant orifice (Figure 5). In cases where this is not obvious, a display of simultaneous color and noncolor 2D images or turning off the color-flow imaging may be helpful. In cases where the regurgitant orifice is noncircular, as frequently is seen in functional MR (crescent shape), the PISA shape is also modified and no longer hemispheric. Three-dimensional color flow would provide a better assessment of the PISA surface (likely underestimated with 2D PISA), although with additional limitations of lower spatial and temporal resolution. Lastly, in patients with multiple jets, the PISA method can be applied to each orifice, with flows and EROA added together; if one lesion is very mild, it can be neglected. Overall, the PISA method by the combination of both qualitative visual assessment and full calculation is the most used method for quantitation of valvular regurgitation in routine clinical practice.

314 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 6 Example CMR study for assessment of LV function. Sequential short-axis slices are acquired from the mitral annular plane (base) to the apex of the LV. LV end-diastolic volume (LVEDV) is calculated by summation of the volume (area thickness) of each short-axis slice during diastole. LV end-systolic volume (LVESV) is calculated by summation of the volume of each short-axis slice during systole. Note, this methodology requires no geometric assumptions.

C. Evaluating Valvular Regurgitation with Cardiac Magnetic Resonance

While echocardiography remains the first line modality for assessment of valvular regurgitation, in some situations, it may be suboptimal. In these instances, CMR can play a useful role because of a number of unique advantages: it provides a view of the entire heart without limitations of imaging windows or body habitus, allows free choice of imaging planes as prescribed by the scan operator, is free of ionizing radiation, and does not require contrast administration. In addition to assessing the severity of the regurgitant lesion, a comprehensive CMR study is able to quantitate cardiac remodeling and provide insight into the mechanism of regurgitation.

1. Cardiac Morphology, Function, and Valvular Anatomy. The typical CMR study for evaluating valvular regurgitation involves the performance of a complete set of short-axis and long-axis (two-, three-, and four-chamber views) cine images using a steady-state free precession (SSFP) pulse sequence, which provides excellent signal-to-noise ratio and high blood-to-myocardium contrast. The typical spatial resolution is 1.5-2.0 mm per pixel with 6- to 8-mm slice thickness and 2- to 4-mm interslice gap to produce a short-axis image every 10 mm from base to apex. Some CMR laboratories have adopted a strategy of utilizing no interslice gap to theoretically improve the accuracy of SV quantification, especially for the RV with its unique geometry. Using this fast pulse

sequence, temporal resolution of #45 msec (frame rates of 20-25/ sec) can be achieved within a 5- to 8-second breath hold that is generally tolerable for most patients. In individuals who have significant difficulty with breath holding, a nonbreath-held ‘‘real-time’’ pulse sequence has been shown to provide comparable assessment of LV and RV volumes and ejection fraction with only a modest compromise in spatial and temporal resolution.

An example of a typical series of cine images is shown in Figure 6. In addition to providing a comprehensive assessment of regional LV and RV function, this data set can be used to perform planimetry of LV and RV volumes at end diastole and end systole, thus determining ventricular SV and ejection fraction with the method of discs. While full details on performing planimetry of ventricular volumes can be found at the Society for Cardiovascular Magnetic Resonance position statement on standardized image interpretation and post processing, there are a few key points worth mentioning:

a. Ventricular volumes. When performing planimetry, it is important to draw the LV and RV end-diastolic and end-systolic contours on the phases with the largest and smallest blood volume, respectively.

b. Correct placement of the basal ventricular short-axis slice is critical. It is recommended that the most basal slice be located immediately on the myocardial side of the atrioventricular junction at end

Zoghbi et al 315

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 3 CMR methods for valvular regurgitation

Approach	MR	AR	TR	PR
Preferred method for	(LV SV)(AO total	Direct diastolic reverse	(RV SV)(PA total	Direct diastolic reverse
quantitation*	forward SV)	volume at AO root	forward SV)	volume at PA
Secondary methods for	(LV SV)(PA forward	(AO total forward	(RV SV)(AO total	(RV SV)(LV SV)
quantitation†	SV)	SV)(PA total forward	forward SV)	(RV SV)(AO total
	(LV SV)(RV SV)	SV)	(RV SV)(LV SV)	forward SV)
	(Mitral infow SV)(AO	(LV SV)(RV SV)
	total forward SV)
Corroborating signs of	LV dilation, LA dilation	LV dilation	RV dilation, right atrium	RV dilation
signifcant			dilation
regurgitation

AO, Aortic.

*Preferred method for quantitation is generally not affected by the presence of concomitant valvular regurgitant lesions. †Secondary methods are most reliable in the absence of concomitant valvular regurgitation, or as long as the severity of other valvular regurgitant lesions can be accounted for.

diastole. As a result of systolic motion of the MV toward the apex, a slice containing LV blood volume at end diastole may include only left atrium (LA) without LV blood volume at end systole. The LA can be identified when less than 50% of the blood volume is surrounded by myocardium and the blood volume cavity is seen to be expanding during systole. It can be helpful to use analysis software that allows adjustment for systolic atrioventricular ring descent using cross-referencing from long-axis locations. The RV contouring is performed in an analogous manner, with the RVOT volume included in the RV end-diastolic volume. Because of the tomographic nature of the technique, CMR can provide these volumetric measures in a 3D fashion without the need for geometric assumptions—in fact, it is considered the gold standard, with demonstrated accuracy and high reproducibility.

c. Planimetry of LV epicardial contour. This can be performed to derive LV mass.

d. Left atrial volume. LA volume can be derived by performance of multiple short-axis slices through the LA or by utilizing the biplane area-length method as in echocardiography.

It is important to note that normal reference ranges for left and right cardiac chamber volumes by CMR are higher than for echocardiography and that correlation between the two modalities is improved with use of 3D echocardiography and/or administration of echocardiographic contrast. The ability to image in any plane makes CMR robust for assessment of valvular anatomy and aids in assessment of mechanism of regurgitation. This can be especially useful for assessment of right-sided valves, which may be difficult to visualize by echocardiography. Assessment of valve anatomy is accomplished by performing a series of contiguous (no gap) parallel thin slice (4-5 mm) SSFP cine acquisitions in the plane of interest. The exact planes to be chosen for each valve will be described in detail in subsequent sections.

2. Assessing Severity of Regurgitation with CMR. Assessing

the severity of valvular regurgitation can be performed via a variety of methods: (1) visual assessment of the extent of signal loss due to spin dephasing on cine CMR acquisitions, (2) planimetry of the ARO area from the cine CMR acquisitions of the valve, or (3) quantitation of the RVol. While the first

two methods can be used to obtain a qualitative assessment of regurgitant severity, the last method is the most robust and the crux of CMR assessment of valvular regurgitation. The following are approaches and considerations for quantitation of valvular regurgitation (Table 3):

a. Phase-contrast CMR. This is the imaging sequence of choice in quantifying flow and calculating velocities. Protons moving along a magnetic field gradient acquire a phase shift relative to stationary spins. The phase shift is directly proportional to the velocity of the moving protons in a linear gradient. Phase-contrast CMR produces two sets of images: magnitude images and phase velocity maps (Figure 7). The magnitude image is used for anatomic orientation of the imaging slice and to identify the boundaries of the vessel imaged. The phase map encodes the velocities within each pixel. Using both images, a region of interest can be traced at each time frame of the data set. The region of interest must be drawn carefully for each frame of the cardiac cycle because of movement and deformation of the vessel. Flow is derived by integrating the velocity of each pixel and its area over the cardiac cycle, allowing for calculation of anterograde and retrograde flows through a region of interest (Figure 7). CMR flow measurements have extensive validation in both in vitro and in vivo studies.

b. Quantitative methods. Methods for quantification of valvular regurgitation can be broadly divided into direct and indirect methods. The direct method employs use of through-plane phase-contrast CMR to quantify blood flow at any given location. This method has been shown to be very accurate for assessing anterograde and retrograde flow across semilunar valves and therefore is the preferred technique used for assessing aortic or pulmonic insufficiency. Phase contrast for direct assessment of flow in the mitral or TVs is more difficult because of significant motion of the annulus during systole. For this reason, quantification of mitral or tricuspid RVol is performed using an alternative, indirect approach by comparing ventricular SV (derived by planimetry of short-axis cines) to forward flow (derived by phase-contrast CMR) across the aortic or pulmonary valves (PVs; Figure 8). In addition to the preferred methods for each valve lesion described above, multiple additional indirect methods such as comparison of LV and RV SVs or use of mitral

316 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 7 CMR technique for assessment of great vessel forward and retrograde flow. Left side of the figure demonstrates a phasecontrast acquisition performed in the aortic root. This produces a set of two cine images at matched anatomic locations that provide differing information: a magnitude image that provides anatomic reference (A) and velocity or phase map with pixel values linearly related to velocity and direction of flow (B). On postprocessing, via drawing a region of interest around the aortic root (red circles), a flow versus time graph is generated (C), which can be used to compute forward (red arrow) and reverse flow (yellow arrow). In this example of AR, the reverse flow represents the directly measured volume of AR. The right side of the figure demonstrates the same, performed at the PA trunk to derive PA flow.

Figure 8 Example CMR method for quantification of MR. The volume of the LV is calculated during end-diastole (LVEDV) and during end-systole (LVESV) via the methodology demonstrated in Figure 6. The total volume of blood ejected from the LV, LV SV, is computed as the difference between LV end-diastolic volume and LV end-systolic volume. In this example LV SV is 150 mL. The volume of blood crossing the aortic (AO) valve is measured by performance of a phase-contrast acquisition in the aorta (as detailed in Figure 6); in this example, 80 mL. The mitral RVol (M RVol) is computed as the difference between the LV SV and aortic forward SV; in this example, 70 mL.

Zoghbi et al 317

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 4 Strengths and limitations of CMR in evaluation of valvular regurgitation

Strengths	Limitations
No limitations from acoustic windows or body habitus	Not widely available. Claustrophobia in some patients. Cannot be
(except inability to ft in scanner).	performed at bedside.
Free choice of imaging planes.	Unable to perform in patients with certain implanted devices (e.g.,
	pacemakers, defbrillators) except in specialized centers.
High signal-to-noise ratio and high blood pool to myocardium	Requires good breath holding to achieve optimal image quality.
contrast
Accurate and reproducible measures of cardiac remodeling	Need to acquire images over several cardiac cycles can lead to
(i.e., ventricular volumes, function, and mass) without	compromised quality in setting of arrhythmias (i.e., atrial fbrillation or
geometric assumptions.	premature ventricular contractions), and current widely available phase-
	contrast sequences can fail in frequent arrhythmias.
Ability to provide information about myocardial viability and	Diffculty to image small or chaotically mobile objects (e.g., vegetations) due
scarring if gadolinium contrast is administered.	to averaging over multiple cardiac cycles and inadequate spatial and
	temporal resolution.
Phase-contrast imaging derives fow using velocities from entire	For through-plane phase-contrast imaging, the imaging plane needs to be
orifce (without needing to assume fat transorifce fow	perpendicular to the blood fow, and diffculty can exist especially in
profle or certain geometric shape).	dilated PAs. Adjacent sternal wires and stented valve prosthesis can
	create susceptibility artifact compromising image quality.
Allows quantitation of fow through each ventricle (LV/RV) and	Phase-contrast acquisitions have lower temporal resolution than echo
great vessel (aorta/PA).	Doppler–based methods, which may lead to underestimation of peak
	velocity. Inadequate spatial resolution may lead to underestimation due
	to partial volume averaging.
Severity assessment based on quantitation of RVol or fraction	In case of turbulence when there is mixed stenosis and regurgitation, phase
(no hemodynamic or shape assumptions; not affected	contrast can underestimate volume due to intravoxel dephasing and loss
by jet direction or presence of multiple jets).	of signal
	For mitral and TVs there is no established direct method to quantify
	regurgitation severity
	Limited data on RVol and fraction cutoffs for severity grading, and limited
	outcome data available based on the grading.

or tricuspid diastolic inflow can be employed to serve as an internal check.

c. Technical considerations. When performing flow measurements a few technical aspects need to be kept in mind. The velocity encoding should be set to the lowest velocity feasible without aliasing. It is important that the imaging plane be (1) centered in the vessel of interest, (2) aligned orthogonally to the expected main blood flow direction in two spatial directions, and (3) centered in the isocenter of the magnetic field. Despite these steps, phase offset errors due to eddy currents in the magnetic field can still occur, and it is important to consider the use of phantom or background correction in every case if possible.

d. Thresholds for regurgitation severity. There is a paucity of data on specific CMR thresholds of RVol or fraction that define severe regurgitation based on outcomes. An earlier study suggested using a RF threshold of 48% by CMR to define severe regurgitation of the aortic or MVs, based on achieving the best correlation with limited echocardiographic assessment. One study in MR and another in AR have focused on RVol/fraction thresholds for prognosis. Progression to symptoms and need for valve surgery were seen with a RF of >40% for MR and >33% for AR (or >55 mL). Due to the paucity of data and absence of other recommendations, the general cutoffs for RVols and RFs recommended by echocardiography and the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines are used.

3. Strengths and Limitations of CMR. CMR has a number of unique strengths, which make it ideal for assessment of valvular disease (Table 4). Specifically, the free choice of imaging planes allows for a comprehensive assessment of all four cardiac valves without limitations of acoustic windows. In addition, volumetric assessment by CMR has been shown to have high interstudy reproducibility and therefore may be ideal for serial assessment.

The limitations of CMR are listed in Table 4 and include its inability to be performed in patients with certain implanted devices. A comprehensive review of all contraindicated devices is beyond the scope of this document, but it is essential that all CMR laboratories perform careful screening on all patients referred for imaging. Since most CMR acquisitions are performed in a segmented fashion (obtained over multiple cardiac cycles), arrhythmias such as atrial fibrillation or premature ventricular contractions may pose a challenge for standard breath-held phase-contrast CMR sequences. CMR is also not as readily available as echocardiography, cannot be performed at the bedside or in some patients with claustrophobia, and is generally a more expensive modality. There are no uniform thresholds for grading severity of regurgitation, and there is a paucity of outcome data available regarding specific thresholds. Lastly, CMR is unable to assess pressures inside a vessel or cardiac chamber.

4. When Is CMR Indicated? While echocardiography remains the first-line modality for assessment of valvular regurgitation, CMR is generally indicated when (1) echocardiographic images are

318 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Key Points

A comprehensive evaluation of valvular regurgitation should include identifying the mechanism and the severity of valvular regurgitation, along with adaptation of the heart to the volume overload. Height, weight, body surface area, heart rate, rhythm, and blood pressure are required clinical parameters in the assessment of regurgitation. Echocardiography with Doppler is the primary modality for evaluation of native valvular regurgitation. Color Doppler is the primary method for detection of regurgitation. In evaluating severity of regurgitation with color Doppler, the three components of the regurgitant jet need to be assessed: flow convergence, VC, and the regurgitant jet direction and area into the receiving chamber. While color Doppler is important, pulsed and CWD are also essential in providing flow characteristics and dynamics. An integrative interpretation of valvular structure, cardiac size and function, and all Doppler parameters is crucial for assessing regurgitation severity, since each of these parameters has advantages and limitations. CMR is an excellent modality for evaluating native valvular regurgitation. While echocardiography remains the first-line modality, CMR is indicated when: B Echo images are suboptimal B Discordance exists between 2D echocardiographic features and Doppler findings B Discordance exists between clinical assessment and severity of regurgitation by echocardiography In addition to quantifying the severity of regurgitation, a comprehensive CMR study will also quantitate cardiac remodeling (both atrial and ventricular) and provides insights into the mechanism of regurgitation. Regurgitation severity may be difficult to assess, as it lacks a true gold standard and is influenced by hemodynamic conditions. Quantitative parameters include RVol, RF, and regurgitant orifice area. Recommendations for grading severity of regurgitation are those of mild, moderate, and severe.

suboptimal, (2) when there is discordance between 2D echocardiographic features and Doppler findings (e.g., ventricular enlargement greater than expected on the basis of Doppler measures of valvular regurgitation), or (3) when there is discordance between clinical assessment and severity of valvular regurgitation by echocardiography. Specific scenarios when CMR may be indicated will be described in further detail in subsequent sections for individual valvular lesions.

The direct method described above for quantification of aortic or PR and the indirect method described for mitral and TR are independent of other coexisting valvular lesions, and therefore CMR may be especially useful in the setting of multiple valvular lesions when echocardiographic assessment is challenged. This will be presented in more detail in the section on multivalvular disease.

D. Grading the Severity of Valvular Regurgitation

Characterization of the severity of regurgitant lesions is among the most difficult problems in valvular heart disease. Such a determination is important since mild regurgitation does not lead to remodeling of cardiac chambers and has a benign clinical course, whereas severe regurgitation is associated with significant remodeling, morbidity and mortality. Contributing to the difficulty of assessment of regurgitation is the lack of a true gold standard and the dependence of regurgitation severity on the hemodynamic conditions at the time of evaluation. Although angiography has been used historically to define the degree of regurgitation based on opacification of the receiving chamber, it is also dependent on several technical factors and hemodynamics. For example, an increase in blood pressure will increase all parameters of aortic or MR, be it assessed as RF or angiographic grade. Furthermore, the angiographic severity grades, which have ranged between three and five grades, have only modest correlations with quantitative indices of regurgitation.

Doppler and CMR methods for valvular regurgitation have been validated in animal models against independent flow parameters, and clinically, against the angiographic standard and each other. The majority of these studies have involved left-sided cardiac valves. For Doppler echocardiography, and as discussed above, there are several qualitative and quantitative parameters that can provide assessment of valvular regurgitation. Although this adds to the complexity of evaluation, the availability of these different parameters provides an internal check and corroboration of the severity of the lesion, particularly when technical or physiologic conditions preclude the use of one or the other of these indexes. For CMR, the

evaluation involves fewer parameters, is mostly quantitative, but is still influenced by technical and physiologic factors. In order to mitigate the effect of these factors within each individual exam, quantitative internal checks within the CMR exam should be employed. For example, in patients with isolated MR, the difference between the LV SV and aortic total forward flow should be the same as the difference between the LV SV and the pulmonary artery (PA) total forward flow or RV SV. Thus, an integrative, comprehensive approach is essential. In echocardiography, if there are signs suggesting that the regurgitation is significant and the quality of the data lends itself to quantitation, it is desirable for echocardiographers with experience in quantitative methods to determine quantitatively the degree of regurgitation, particularly for left-sided lesions. Ultimately, the interpreter of either echocardiography or CMR must integrate the information and disregard ‘‘outlying’’ data (because of poor quality or a physiologic condition that alters accuracy of a certain parameter), making a best estimate of regurgitation severity. The consensus of the writing group is to classify grading of severity of regurgitation into mild, moderate, and severe. ‘‘Trace’’ regurgitation is used in the event that regurgitation is barely detected. Usually this is physiologic, particularly in right heart valves and MV, and may not produce an audible murmur. Since the severity of regurgitation may be influenced by hemodynamic conditions, it is essential to record the patient’s blood pressure, heart rate, and rhythm at the time of the study and note the patient’s medications whenever possible. When following a patient with serial examinations, these factors need to be considered in comparing the severity of regurgitation and its hemodynamic consequences and actual studies reviewed and compared because of inherent variability of techniques and measurements.

III. MITRAL REGURGITATION

A. Anatomy of the Mitral Valve and General Imaging Considerations

The MVapparatus includes the anterior and posterior mitral leaflets, the mitral annulus, chordae tendinae, papillary muscles, and the underlying LV myocardium. Echocardiographic views and their relation to mitral anatomy and the three scallops of each leaflet have been reviewed in detail. Typically, a 2D long-axis view runs through the middle portion of the anterior leaflet (A2) and the middle scallop of the posterior leaflet (P2). A short-axis view is

Zoghbi et al 319

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 9 Three-dimensional echocardiographic frames of MVs from the LA view depicting a normal valve with delineation of the anterior and posterior scallops, a patient with fibroelastic deficiency and a flail P2 segment, as well as a patient with Barlow’s disease.

useful in defining the exact location of pathology because it allows imaging of both leaflets and the commissures. The four-chamber view can cut through the leaflets at different locations. A crosscommissural view (typically by TEE but approximated by the transthoracic apical two-chamber view) is good at identifying the lateral (P1) and medial (P3) scallops of the posterior leaflet and the middle (A2) anterior leaflet. The optimal view of the coaptation line is a 3D en face view by either TTE or TEE. Threedimensional echocardiography can provide detailed views of the complex structure of the MV apparatus, either from the LA or the LV. This facilitates both anatomic and functional interpretation, allowing precise localization of abnormal MV anatomy, particularly with TEE (Figure 9).

B. Identifying the Mechanism of MR: Primary and Secondary MR

The mechanism of MR can be divided broadly into two categories, based on whether the mitral leaflets exhibit significant pathological abnormality or not (Table 5). In primary MR, an intrinsic abnormality of the leaflets causes the MR, whereas secondary MR results from distortion of the MV apparatus due to LV and/or LA remodeling. Hence, most secondary MR is a disease of the LV. It is important to distinguish primary from secondary MR as therapeutic approaches and outcomes differ. It is also useful to consider whether leaflet motion is intrinsically normal or abnormal according to the Carpentier classification (Figure 10). Type I leaflet motion is normal but can be associated with MR if there is annular dilation (secondary MR) or a leaflet perforation. Type II leaflet motion is excessive and is most commonly due to MVP or flail leaflet. Type III leaflet motion is restrictive, commonly seen in the presence of LV dilation (secondary MR) or rheumatic MV disease or other postinflammatory conditions such as collagen vascular disease, radiation injury, carcinoid syndrome, or drug-induced inflammatory changes. Table 6 compares the MV apparatus, cardiac remodeling, and jet characteristics in primary and secondary MR.

1. Primary MR. The most common cause of primary MR is myxomatous degeneration, most frequently MVP. MVP is a spectrum of disease ranging from a focal abnormality of a mitral leaflet to

Table 5 Etiology of primary and secondary MR

Primary MR (leafet abnormality)
MVP myxomatous	Prolapse, fail, ruptured or
changes	elongated chordae
Degenerative changes	Calcifcation, thickening
Infectious	Endocarditis vegetations,
	perforations, aneurysm
Infammatory	Rheumatic, collagen
	vascular disease,
	radiation, drugs
Congenital	Cleft leafet, parachute MV
Secondary MR (ventricular remodeling)
Ischemic etiology
secondary to coronary
artery disease
Nonischemic
cardiomyopathy
Annular dilation	Atrial fbrillation, restrictive
	cardiomyopathy

diffuse involvement of both leaflets. Fibroelastic deficiency refers to focal segmental pathology with thin leaflets, while Barlow’s disease refers to diffuse thickening and redundancy, typically affecting multiple segments of both leaflets and chordae (Figure 9). Characteristically, the MR occurs during mid-late systole when the laxity resulting in leaflet malcoaptation is greatest. In such cases, failure to recognize that MR is not holosystolic can lead to overestimation of MR severity by methods that rely on single-frame color Doppler measurements acquired when MR is at its maximum (Figure 11).

Using echocardiography, MVP is diagnosed ideally in the parasternal long-axis window as systolic displacement of the mitral leaflet into the LA of at least 2 mm from the mitral annular plane. If parasternal windows are of poor quality, the apical long-axis view can also be used, although the latter is less standardized and thus more variable. Diagnosis of MVP should be avoided in the apical four- or two-chamber windows as these windows image the MV annulus along the low

320 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 10 Depiction of mechanisms of MR as per the Carpentier classification.

Table 6 MV apparatus, cardiac remodeling, and jet characteristics in primary and secondary MR

Primary MR*	Secondary MR* Regional LV dysfunction Global LV dysfunction
Etiology Myxomatous or calcifc leafet degeneration	Inferior myocardial infarction Nonischemic cardiomyopathy, large anterior or multiple myocardial infarctions
LV remodeling Global, if severe chronic MR	Primarily inferior wall Global dilation with increased sphericity
LA remodeling Moderate to severe if chronic MR	Variable Usually severe
Annulus Dilated, preserved dynamic function	Mild to no dilation, less dynamic Dilated, fattened, nondynamic
Leafet morphology: Thickening Prolapse or fail Calcifcation Yes/moderate, severe Usually present Variable	No/mild No No/mild No/mild No No/mild
Tethering pattern None	Asymmetric Symmetric
Systolic tenting None	Increased Markedly increased
Papillary muscle distance Normal	Increased posterior papillary- intervalvular fbrosa distance Increased interpapillary muscle distance
MR jet direction Eccentric or central	Posterior Usually central
CWD May be late systolic (if MVP) or uniform if fail or with calcifc degeneration	Density usually uniform throughout systole Biphasic pattern, with increased density in early- and late-systolic fow and midsystolic dropout
PISA Often hemispheric	Often not hemispheric Often not hemispheric; may be biphasic

*Primary and secondary MR may coexist.

points of the saddle-shaped MV annulus, falsely making the leaflets appear to be displaced into the LA from the annular plane.

A flail leaflet is part of the MVP spectrum and occurs when the leaflet edge, not just the leaflet body, is located in the LA with free motion. It occurs most commonly from rupture of the marginal chords. A flail leaflet almost always denotes severe MR and is clearly associated with adverse outcomes. An extreme of flail MV is

papillary muscle rupture. Other etiologies of primary MR are listed in Table 5.

2. Secondary MR. The leaflets are intrinsically normal in secondary MR, although minor leaflet thickening and annular calcification can be present. With adverse LV remodeling, one or both of the mitral leaflets are pulled apically into the LV as a result of the outward

Zoghbi et al 321

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 11 Late systolic MR in MVP. (A) Midsystolic frame shows no MR by color Doppler. LA volume index was normal (26 mL/m). (B) Late-systolic frame shows an eccentric MR jet with a large flow convergence. (C) CWD profile of MR jet demonstrates that MR is confined to late systole (onset at yellow arrow, small VTI of jet, dotted contour). (D) Pulsed wave Doppler of mitral inflow shows an E wave velocity of 75 cm/sec with normal E/e ratio consistent with normal LA pressure. Calculation of EROA will overestimate regurgitation severity: EROA = 2pr * Va/PkVreg = 2 3.14 1 29.9/527 = 0.36 cm. Quantitation of regurgitation should rely on RVol by either PISA or volumetric measures. RVol by PISA = EROA * VTIreg = 0.36 76 = 27 mL.

displacement of the papillary muscles. This results in incomplete mitral leaflet closure. The leaflets are apically displaced, tethered, and may have restricted mobility, especially the posterior leaflet. Leaflet tethering is often asymmetric, particularly in ischemic as opposed to dilated cardiomyopathies, where the P3 scallop is tethered more apically than is P1. In such cases, the regurgitant orifice tends to be largest at the posteromedial scallop (P3), it may be irregularly shaped, and there may be two separate MR jets, which sometimes cross each other in the LA (Figures 12 and 13). Additional echocardiographic features of tethering include a bend in the body of the anterior leaflet from tethering of the basal or strut chordae (‘‘seagull’’ or ‘‘hockey stick’’ sign), with a posteriorly directed jet. This should not be confused with MVP.

Several methods have been proposed to quantify the degree of tethering. The most common is a simple area measurement from the leaflet tips to the annular plane (tenting area) performed at midsystole where the area is at a minimum. Another measure is coaptation height or depth, which measures the maximal distance from the leaflet tips to the annular plane and appears to correlate with the presence and severity of ischemic MR. More recently, 3D echocardiography has been applied to quantify leaflet tethering by measuring the tethering distance from papillary muscle tip to the mitral annulus and measuring the tenting volume (volume from leaflets to annular plane). While there is a general correlation between

tenting area or height and severity of secondary MR, these measurements are not precise in discriminating mild, moderate, or severe MR, particularly since the leaflets may vary in size and thus accommodate the outward tethering. Mitral annular dilation also plays a role in the development of functional MR by increasing the area needed for the mitral leaflets to cover. However, annular dilation alone without leaflet tethering is an uncommon cause of significant secondary MR, such as in patients with severe LA dilatation from long-standing atrial fibrillation.

3. Mixed Etiology. Occasionally, patients may present with mixed etiologies of MR that include both primary and secondary MR. For example, a patient with long-standing ischemic or nonischemic cardiomyopathy and secondary MR may rupture a chord and develop a flail leaflet. Conversely, a patient with mild or moderate MR from primary leaflet pathology may have a myocardial infarction and develop worse MR from tethering of the already abnormal leaflets. Although most cases of MR fall into the primary or secondary classification scheme, it should be recognized that mixed etiology can and does occur. It is important to emphasize that a severely restricted posterior leaflet due to ischemic wall motion abnormality may result in anterior leaflet override. In such cases, the anterior leaflet is not prolapsed and this does not represent a mixed etiology.

322 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 12 (A) An example of significant secondary MR in a dilated cardiomyopathy with marked tenting (arrows) of the MV. (B) Parasternal short-axis color Doppler showing regurgitation along the entire length of the valve coaptation. (C) PW Doppler at tips of the MV leaflets with high E velocity. (D) Triangular shape to the CW spectral in the setting of significant MR. (E and F) PISA from apical three- and two- (commissural) chamber views showing the different shapes of the flow convergence (nonhemispheric) and VC (noncircular). Assumption of a hemispheric flow convergence or circular VC would underestimate MR.

Zoghbi et al 323

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 13 Short-axis views of MR in four different patients. (A) Relatively round orifice in myxomatous MV with flail P2 scallop. (B) Patient with secondary MR and two separate MR jets (arrows). (C) Noncircular MR located at P3 and P2 scallops in a patient with ischemic cardiomyopathy and a large inferoposterior wall motion abnormality. (D) Elliptical MR jet extending from commissure to commissure in a patient with ischemic cardiomyopathy.

C. Hemodynamic Considerations in Assessing MR Severity

1. Acute MR. Acute MR is far less common than chronic MR and usually results in hemodynamic compromise. It occurs most commonly due to ruptured papillary muscle after acute myocardial infarction, ruptured chordae tendinae resulting in a flail leaflet, or leaflet destruction due to endocarditis and less frequently due to rapid onset of cardiomyopathy (e.g., Takotsubo, myocarditis, or postpartum cardiomyopathy). Patients often present with pulmonary edema from elevated LA pressure, tachycardia, and severe hypotension from loss of forward SV. The combination of hypotension and high LA pressure results in a low driving pressure and therefore lower MR jet velocity across the MV. Accordingly, color Doppler imaging often will not show a large turbulent flow disturbance, and thus MR may be underestimated or not appreciated at all. The color Doppler jet is usually markedly eccentric, which again can underestimate MR severity. Anatomic imaging of flail leaflet or ruptured papillary muscle and the finding of a hyperdynamic LV with low Doppler systemic output along with clinical findings should be enough to substantiate the diagnosis, even if color Doppler does not show a large MR jet. Systolic flow reversal in the pulmonary veins is usually present and is helpful. TEE may be better at identifying acute severe MR. The Doppler methods for assessing MR severity in the remainder of this section apply to chronic and not to acute severe MR.

2. Dynamic Nature of MR. a. Temporal variation of MR during systole. The regurgitant orifice area in MR is often a variable quantity during the cardiac cycle, whether holosystolic or not. The measured

EROA as described earlier differs from the dynamic regurgitant orifice area in that it is usually derived from static, maximal values from single systolic frames. Although MR is classically holosystolic, patients with MVP often have no MR in early systole, with a relatively large EROA limited to mid- or late systole. Compared with patients with holosystolic MR, those with late systolic MR yield lower RVols, despite similar EROA and jet areas. In such patients, RVol has been shown to be superior to EROA in predicting cardiac death, admission for congestive heart failure, or new-onset atrial fibrillation. On the other hand, patients with secondary MR often exhibit a biphasic pattern of MR, with an initial EROA peak in early systole, a decline in midsystole, and a second peak in late systole and isovolumic relaxation. Occasionally, transient MR limited to early systole is seen, particularly with bundle branch block. Thus, duration and timing of MR should be carefully evaluated. EROA to grade MR severity (Figure 3) should be used only if adjusted for the duration of MR, where feasible. Volumetric methods for assessing MR would forgo the above limitations and are preferred in nonholosystolic MR.

b. Effect of loading conditions. Grading of MR severity can be significantly impacted by hemodynamic changes, particularly blood pressure. Figure 14 shows an example of the dynamic nature of MR. Hemodynamic variation could be seen with conscious sedation (during TEE) but is particularly challenging in the operating room, brought about by anesthesia and vasoactive agents. In general, the commonly encountered intraoperative decrease in loading conditions or contractility is more likely to result in an underestimation of the MR grade compared with ambulatory conditions.

324 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 14 Importance of MR jet velocity in MR. The images are from two patients with functional ischemic MR due to posterior leaflet restriction, LVEF 30%, and similar appearance of eccentric MR jets directed laterally. The patient in the top panels has a low MR velocity (4.1 m/sec) consistent with low blood pressure and/or elevated LA pressure. His blood pressure (BP) was 105/76 mmHg. EROA by PISA is 0.3 cm with an RVol of 42 mL. The patient in the lower panels has a similar MR jet appearance but has a peak MR velocity of 6.4 m/sec due to hypertension (178/94 mmHg). EROA is 0.08 cm with an RVol of 17 mL. Despite similar MR jet appearance on color Doppler, the patient in the top panel has moderate MR; the patient in the bottom panel has mild MR.

Consequently, the preoperative MR grade may be preferred to guide therapeutic decisions. Intraoperative optimization of loading conditions may be used to guide surgical decision making. Patients with secondary MR may demonstrate significant variation in severity from one occasion to the next, depending on volume status and other hemodynamic variables.

c. Systolic anterior MV motion. Dynamic changes in MR severity can also occur with systolic anterior motion of the MV and LVOT obstruction, most commonly associated with either hypertrophic obstructive cardiomyopathy or following valve repair with a ring annuloplasty. This phenomenon has also been described in some patients with LV dysfunction and a hyperdynamic base following acute myocardial infarction or Takotsubo cardiomyopathy. Anterior MV leaflet motion exceeds that of the posterior leaflet, thereby creating malcoaptation with a posteriorly directed jet.

3. Pacing and Dysrhythmias. The severity of MR can also be influenced by cardiac dysrhythmias and pacing. RV pacing has been associated with development of functional MR, and cardiac resynchronization therapy has been shown to improve functional MR; the response, however, is not uniform. Atrial fibrillation is commonly experienced by patients with MR and may confound its grading due to rapid ventricular response or variable cycle lengths. In patients with a prolonged PR interval due to atrioventricular conduction abnormalities, atrial systole can induce premature ineffective valve closure, accompanied by varying degrees of diastolic MR. Careful attention to heart rhythm and pacing is therefore important in evaluating MR.

D. Doppler Methods of Evaluating MR Severity

There are several methods for evaluating the severity of MR with Doppler echocardiography. The various methods, their optimization, advantages, and limitations are hereby discussed and highlighted in Table 7.

1. Color Flow Doppler. Color Doppler flow mapping is the primary modality to screen for MR (Figure 15). There are three methods of evaluating MR severity by color flow Doppler: regurgitant jet area, VC, and flow convergence. Although jet area was the first method used for assessing MR severity, its sole use is less accurate than the latter two methods.

a. Regurgitant jet area. Although jet area is excellent for excluding MR, it is not reliable for grading MR severity, even when indexed for LA area. Patients with acute severe MR, in whom blood pressure is low and LA pressure is elevated, may have a small color flow jet area, whereas hypertensive patients with mild MR may have a large jet area. Jet area is also dependent on the mechanism of MR. With flail leaflet, the MR jet is often very eccentric; jet area is small, underestimating MR severity as the jet spreads out along the wall and loses energy. In secondary MR, central jets with a slit-like orifice can appear large, particularly in the two-chamber view, along the line of MV coaptation, even when the EROA is small. Therefore, MR grade should not be determined by ‘‘eyeballing’’ the color flow area of the MR jet alone, without considering the origin of the jet (VC) and its flow convergence. However, a small noneccentric jet with a narrow VC (<0.3 cm) and no visible flow convergence region usually indicates mild MR (Table 7). Conversely, a large jet with a wide VC

Zoghbi et al 325

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 7 Doppler echocardiography in evaluating severity of MR

Modality	Optimization	Example	Advantages	Pitfalls
Color fow Doppler 2D:
Proximal fow convergence	Align direction of fow		Rapid qualitative	Multiple jets
	with insonation beam		assessment	Eccentric jets
	to avoid distortion of		Absence of proximal	Constrained jet
	hemisphere from		fow convergence	(LV wall)
	noncoaxial imaging		usually a sign of mild	Nonhemispheric
	Zoomed view		MR	shape,
	Variance off			particularly
	Change baseline of			functional MR
	Nyquist limit in the			Overestimation
	direction of the jet			when MR not
	Adjust lower Nyquist			holosystolic
	limit to obtain the
	most hemispheric
	fow convergence
	(typically 30-40 cm/
	sec)
	Measure the radius
	from the point of
	color aliasing to
	the VC
VCW	Parasternal long-axis		Surrogate for	Problematic in the
	view		regurgitant orifce	presence of
	Zoomed view		size	multiple jets
	Imaging plane for		Independent of fow	Convergence
	optimal VC		rate and driving	zone needs to be
	Best measured when		pressure for a fxed	visualized for
	proximal fow		orifce	adequate
	convergence, VC,		Can be applied in	measurement
	and MR jet aligned in		eccentric jets	Overestimation
	same plane		Less dependent on	when MR not
			technical factors	holosystolic
			Good at separating
			mild (<0.3 cm) from
			severe MR ($0.7 cm)
Jet area or jet area/LA area	Apical view		Easy to measure	Shown to be
ratio	Zoom view			imprecise in
	Measure largest			multiple studies,
	jet alone or as ratio to			particularly in
	LA area in same view			eccentric, wall-
				impinging jets
				Dependent on
				hemodynamic
				(especially LV
				systolic pressure)
				and technical
				variables
				Overestimation
				when MR not
				holosystolic
				(Continued)

326 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 7 (Continued)

Modality	Optimization	Example	Advantages	Pitfalls
Color fow Doppler 3D:	Color fow sector		Multiple jets of	Subject to color
3D VCA	should be as narrow		differing directions	Doppler blooming
	as possible to		may be measured	Limited temporal
	improve volume rates		Can identify severe	and spatial
	and line density		functional MR in	resolution
	Align orthogonal		some cases where	Overestimation
	cropping planes		PISA underestimates	when MR not
	along the axis of the		EROA	holosystolic
	jet			Multiple jets may
	Planimeter the high			be in different
	velocity aliased signal			planes, must be
	of VC, avoiding low			analyzed
	velocity (dark color)			separately and
	signals			then added
				Cumbersome,
				often requires
				offine analysis
Pulsed wave Doppler:
Mitral infow velocity	Align insonation beam		E velocity$1.2 m/	Depends on LV
	with the fow across		sec a simple	relaxation and
	the MV at leafet tips		supportive sign of	flling pressures
	in apical four-		severe MR (volume	High E velocity
	chamber view		load)	not specifc for
			Dominant A-wave	severe MR in
			infow pattern	secondary MR,
			virtually excludes	atrial fbrillation
			severe MR	and mitral infow
			Can be obtained with	stenosis
			both TTE and TEE
Pulmonary vein fow pattern	Use small sample		Systolic fow reversal	Eccentric MR of
	volume (3-5 mm)		in more than one	mild or moderate
	placed 1 cm into		pulmonary vein is	severity directed
	pulmonary vein		specifc for severe	into a pulmonary
			MR	vein alters fow
			Normal pulmonary	pattern
			vein pattern suggests	Systolic blunting
			low LA pressure and	is not specifc for
			hence nonsevere MR	signifcant MR
				(common in
				secondary MR
				and present in
				elevated LA
				pressure, atrial
				fbrillation)
				(Continued)

Zoghbi et al 327

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 7 (Continued)

Modality	Optimization	Example	Advantages	Pitfalls
CWD
Density and contour of	Align insonation beam		Simple	Qualitative
regurgitant jet	with the fow		Density is	Perfectly central
			proportional to the	jets may appear
			number of red blood	denser than
			cells refecting the	eccentric jets of
			signal	higher severity
			Faint or incomplete	Density is gain
			jet is compatible with	dependent
			mild MR	A contour with an
			A triangular contour	early peak
			(early MR peak	velocity is not
			velocity; see arrow)	sensitive for
			denotes a large	severe MR
			regurgitant pressure
			wave and
			hemodynamic
			signifcance
Quantitative Doppler: EROA,
RVol, and fraction
Flow convergence	Align insonation		Rapid quantitative	May not be
method (PISA):	beam with the fow,		assessment of lesion	accurate in
	usually in apical		severity (EROA) and	multiple jets
	views; zoomed view		volume overload	Less accurate in
	Lower the color		(RVol)	eccentric jets or
	Doppler baseline in		Shown to predict	markedly
	the direction of the jet		outcomes in	crescent-shaped
	Look for the		degenerative and	orifces
	hemispheric shape to		functional MR	Small errors in
	guide the best low			radius
	Nyquist limit			measurement can
	Look for need for			lead to substantial
	angle correction if			errors in EROA
	fow convergence			due to squaring of
	zone is nonplanar			error. This is less
	Measure PISA radius			likely to
	at roughly the same			misclassify
	time as CW jet peak			patients at very
	velocity			large ($1.0 cm) or
				very small radii
				(#0.4 cm)

(Continued)

328 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 7 (Continued)

	Modality	Optimization	Example	Advantages	Pitfalls
SV	method	LVOT diameter	Mitral annulus	Quantitative, valid	Not valid for
		measured at the		with multiple jets and	combined MR
		annulus in systole		eccentric jets.	and AR, unless
		and pulsed Doppler		Provides both lesion	pulmonic site is
		from apical views at		severity (EROA, RF)	used
		same site		and volume overload	Cumbersome,
		Mitral annulus		(RVol)	needs training;
		measured at		Validated against	small errors in
		middiastole; pulsed		CMR in isolated MR	each different
RVol	= SVMVSVLVO	Doppler at the annulus level in			measurement can combine to
		diastole			magnify error in
		Total LV SV can be			fnal results
		measured by pulsed			Pulsed Doppler
		Doppler technique at	LVOT		method (mitral
		mitral annulus or by			SV) and LV
		the difference			volume method
		between LV end-			may give different
		diastolic volume and			results.
		end-systolic volume.
		LV volumes are best
		measured by 3D.
		Contrast may be
		needed to better
		trace endocardial
		borders. If 3D not
		feasible, use 2D
		method of disks.

($0.7 cm) and where the jet wraps around the LA and penetrates into the pulmonary veins is almost always severe MR. Anything else should alert the observer to use the methods below.

b. Vena contracta (width and area). The VC is a measure of the effective regurgitant orifice. For MR, the VC width (VCW) should be imaged preferably in a parasternal long-axis view (axial resolution) and measured using zoom mode at the narrowest portion of the jet as it emerges from the orifice (Figure 1). AVC < 0.3 cm usually denotes mild MR; $ 0.7 cm is specific for severe MR. Intermediate values overlap substantially between MR grades, so additional methods should be used for confirmation. VCW works equally well for central and eccentric jets, however, it is dependent on orifice geometry, underestimating MR severity if there are multiple jets or if there is a markedly elliptical (noncircular) orifice shape, as often seen in secondary MR.

The development of 3D echocardiography has allowed direct measurement of VC area (VCA). Multiplanar reconstruction tools are used to orient orthogonal imaging planes (x and y) through the long axis of the MR jet, and the z plane is adjusted perpendicularly through the narrowest CSA of the VC (Figure 16). VCA can then be measured by manual planimetry of the color Doppler signal. If there are multiple jets, the imaging plane should be oriented through each jet separately for tracing. Care should be taken to only measure the highest velocity, aliased signal so as not to include low-velocity (dark color) eddies that are not part of the jet core. Limitations include technically difficult images, dynamic variation in the regurgitant orifice over the cardiac cycle, and the color Doppler blooming effect, in which the color Doppler signal is larger than the jet core itself.

Three-dimensional echocardiography has shown that the regurgitant orifice is often crescent shaped in secondary MR (Figure 16). In such cases, the assumption of circular orifice geometry inherent to VCW may result in underestimation of secondary MR. In a recent study, 3D VCA > 0.4 cm denoted severe MR. However, studies relating 3D VCA to outcomes have not been performed yet.

c. Flow convergence (PISA). In MR, PISA is more accurate for central regurgitant jets than eccentric jets and for circular orifices than noncircular orifices. It is usually easy to identify the aliasing line of the hemisphere; however, it can be difficult to judge the exact location of the orifice. Optimization of acquisition and measurement of PISA are essential and have been discussed earlier, as any error in radius is subsequently squared in the derivation of EROA. Errors of 10%-25% are common even among expert readers and are the smallest for central jets; therefore, PISA should always be considered in the context of the other echo/Doppler findings. The dynamic nature of the orifice in MR can also lead to errors with the PISA formula. The regurgitant orifice is often crescent shaped in secondary MR. In such cases, the assumption of circular orifice geometry inherent to 2D PISA may result in underestimation of secondary MR. This may partly explain the finding that lower values of EROA by 2D PISA are associated with worsened prognosis in secondary MR. Also, it should be remembered that PISA EROA, like VCW or VCA, is calculated from a single-frame image. These parameters therefore will overestimate MR severity when MR is not holosystolic (Figure 11). Finally, poor alignment of the CWD beam

Zoghbi et al 329

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 15 Color Doppler panel of mild and severe MR (central and eccentric). In the eccentric, wall-impinging jet case, the jet area is small, but the flow convergence and VC are large and alert to the severity of regurgitation.

Figure 16 Two cases showing evaluation and quantitation of VCA with 3D echocardiography and multiplanar reconstruction. A case of primary MR (upper panels) with a circular VCA and hemispheric PISA and another with secondary MR (lower panels) with elliptical VCA and nonhemispheric PISA.

with an eccentric jet will lead to an underestimation of velocity and an overestimation of the EROA.

A simplified approach to PISA quantitation has been validated. Assuming a 5 m/sec MR jet (100 mmHg pressure difference between LV and LA in systole), baseline shifting the color Doppler display to a Va of around 40 cm/sec and measuring the aliasing radius r yields a

simplified estimate of EROA = r /2. This simplification does not hold at extremes of blood pressure, but the vast majority of patients have jets between 4 and 6 m/sec for which this approximation is reasonable. Generally, in primary MR, an EROA $ 0.4 cm is consistent with severe MR, 0.20-0.39 cm with moderate, and < 0.20 cm with mild MR.

330 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

2. Continuous Wave Doppler. In most patients, maximum MR velocity is 4-6 m/sec due to the high systolic pressure gradient between the LV and LA. The velocity itself does not provide useful information about the volumetric severity of MR, but it does provide clues to the hemodynamic consequences of MR. A low MR peak velocity (e.g., 4 m/sec) suggests hemodynamic compromise (low blood pressure/elevated LA pressure). In addition to peak velocity, the contour of the velocity profile and its density are useful. A truncated, triangular jet contour with early peaking of the maximal velocity indicates elevated LA pressure or a prominent regurgitant pressure wave (Figure 12). The density of the CWD signal is a qualitative index of MR severity; a dense signal suggests significant MR, whereas a faint signal is likely to be mild or trace MR. CWD should also be used to interrogate the TR jet to estimate PA systolic pressure, another indirect clue as to MR severity and compensation for the volume overload.

3. Pulsed Doppler. Pulsed Doppler methods can be used to calculate SVs at the LVOT and MV level and determine RVol and RF (Figure 4; Table 7). RVol can also be calculated by comparing Doppler LVOT SV to total LV SV derived from LV volumes. Because 2D echocardiography tends to underestimate LV volumes, 3D LV volumes are preferable, and ultrasound contrast should be used if needed to identify endocardial borders.

Pulsed Doppler tracings at the mitral leaflet tips are commonly used to evaluate LV diastolic function but can be helpful in MR. Patients with severe MR have a dominant early filling (increased E velocity) due to increased diastolic flow across the MV (E velocity is usually $1.2 m/sec). An impaired relaxation pattern with a low E velocity and A wave dominance virtually excludes severe MR. Because of the effect of relaxation on mitral inflow indices, these observations are more applicable in individuals older than 50 years of age or in conditions of impaired myocardial relaxation. The mitral inflow pattern is also more reliable for assessing primary MR because, in secondary MR, it is difficult to determine whether E dominance is due to significant MR or elevated LV filling pressures. The peak E velocity is also affected by even mild degrees of mitral stenosis in the presence of rheumatic disease, mitral annular calcification, or a mitral annular ring.

4. Pulmonary Vein Flow. Pulsed Doppler of pulmonary venous flow is a useful adjunct to evaluating the hemodynamic consequences of MR. With increasing severity of MR, there is a diminution of the systolic velocity, culminating with systolic flow reversal in severe MR. Since the MR jet may selectively enter a vein, sampling more than one vein is recommended, especially during TEE. One limitation of the pulmonary venous pattern is that elevation in LA pressure of any etiology as well as atrial fibrillation may also result in a blunted systolic forward flow. Thus, systolic blunting is less valuable in secondary MR than in primary MR. As a result, the pulmonary venous flow pattern should be used adjunctively with other parameters. Nevertheless, the finding of systolic flow reversal in more than one pulmonary vein is specific for severe MR. If the MR is confined to late systole, flow reversal may be present only during late systole. It is also important to distinguish true systolic flow reversal from contamination by the MR jet itself, a more difficult task during TTE compared with during TEE.

E. Assessment of LV and LA Volumes

Primary significant MR imposes a pure volume overload on the LV. If chronic, such a condition would result in chamber dilation and ultimate LV dysfunction if untreated. It is important to consider body size in evaluating LV size, particularly in patients with small body surface area such as women. On the other hand, in secondary MR, the relation between LV dilation and MR severity is complicated because MR results from LV dysfunction but also may contribute to it. In either case, it is important to measure both LV chamber size and function for determining the need for surgical or percutaneous intervention and for measuring any reverse LV remodeling after therapy. Threedimensional echocardiography is now recommended for evaluation of LV volumes because it offers improved accuracy and precision compared to 2D echocardiography. Echocardiographic measurements of global longitudinal strain may become useful in evaluating earlier myocardial dysfunction in MR that could be masked by volume-based measurements, such as LV ejection fraction (LVEF).

LA dilation is also an expected consequence of severe MR. A normal LA size generally excludes severe chronic MR. LA volumes are superior to LA diameters in evaluating LA dilation and in predicting outcomes and atrial fibrillation. However, LA dilatation can occur in many disease states including hypertension and atrial fibrillation. Therefore, a dilated LA does not necessarily imply severe MR.

F. Role of Exercise Testing

Exercise echocardiography can be useful in evaluating patients with both primary MR and ischemic functional MR. Exercise may unmask the presence of symptoms and establish functional capacity in patients who are sedentary or have equivocal symptoms. Failure of LVEF to increase normally with exercise predicts worse postoperative LV function in primary MR. Color Doppler inclusive of changes in EROA derived with PISA during exercise can be technically difficult to capture due to tachypnea and tachycardia and may be best performed during supine bicycle exercise. Increases in EROA ($13 mm) during exercise have been shown to be associated with symptoms and adverse outcome in secondary MR. Lastly, increased PA pressure during exercise ($60 mmHg) may be important in asymptomatic severe primary MR. There is currently no role for pharmacologic stress echocardiography to evaluate severity of MR or direct its management.

G. Role of TEE in Assessing Mechanism and Severity of MR

TEE is indicated to evaluate MR severity in patients in whom TTE is inconclusive or technically difficult. In addition, TEE is particularly well suited to identify the underlying mechanism of MR and for planning MV surgery or percutaneous valve procedures and provides overall a better accuracy in localizing MV pathology. The majority of the above methods of quantifying MR can be used during TEE. In particular, the higher resolution of TEE, multiplane and 3D capabilities, and proximity to the MV makes VC imaging and PISA easier and probably more accurate. Furthermore, interrogation of all pulmonary veins is generally feasible and better than with TTE. A few cautionary points are worth mentioning regarding TEE. Since jet size is affected by transducer frequency, PRF, and signal strength, the same jet may appear larger on TEE compared with on TTE. Because sedatives are used, careful attention to blood pressure is important; secondary MR may appear less severe if the blood pressure is significantly lowered. Quantitative pulsed Doppler is more

Zoghbi et al 331

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 17 Examples of primary and secondary MR evaluated with CMR. There is flail of the posterior MV leaflet (red arrow) with highly eccentric anteriorly directed jet of MR. Volumetric calculations showed an LV end-diastolic volume of 235 mL, end-systolic volume of 75 mL, and thus a total LV SV of 160 mL. The systemic aortic SV was 94 mL. Thus, the mitral RVol was 66 mL and the RF was 66/160 or 41%. In the case of secondary MR, the mitral leaflets are seen tethered apically with the jet of MR (red arrow). The total LV SV was 77 mL with an RVol of 32 mL and an RF of 42%. Late gadolinium enhancement (LGE) showed localization of a previous infarction in the posterior wall. This is consistent with moderate MR.

challenging and is the most affected quantitative MR parameter with TEE: acquisition of pulsed Doppler in the LVOT is usually hampered by angulation issues, leading to underestimation of systemic output.

H. Role of CMR in the Assessment of MR

CMR offers several important advantages in the assessment of MR. This includes identifying the mechanism of MR, quantifying MR severity, and determining its consequences on cardiac remodeling.

1. Mechanism of MR. Like echocardiography, CMR can provide information about the mechanism of MR by identifying morphologic abnormalities of the MVapparatus. The presence of billowing, prolapse, or flail segments can be identified by dedicated cine imaging performed through the different scallops of the MV leaflets (Figure 17). In secondary MR, CMR offers accurate assessment of LV dilation and function in addition to identification of myocardial and papillary muscle scar (Figure 17).

2. Methods of MR Quantitation. MR can be assessed using several techniques by CMR. This includes qualitative or semiquantitative visual assessment of MR jet based on spin dephasing in the LA, measurement of the VCA or anatomical regurgitant orifice area on short-axis cine of phase-contrast images, and quantification of RVol and RF. Among these techniques, quantification of RVol and fraction is recommended (Figures 8 and 17). The suggested preference order for calculation of RVols is the use of

• The difference between LV SV using planimetry of short-axis cine images and aortic SV obtained by phase-contrast images

• The difference in LV and RV SV by endocardial contouring of LV and RV cine images

• The difference between the mitral inflow SVand aortic SV by phase-contrast imaging

The RF can be calculated by dividing the RVol by the LV SV for the first two methods and by the mitral inflow SV for the third method.

3. LV and LA Volumes and Function. CMR provides the most accurate and reproducible assessment of LV volume and ejection fraction and LA volume. All measurements should be indexed to BSA, and remodeling can be assessed based on existing reference values.

4. When Is CMR Indicated? The primary indication of CMR is the evaluation of MR severity when assessment by echocardiography is felt to be unsatisfactory or when there is a discrepancy between MR severity and clinical findings. CMR may provide additional information about the mechanism of MR and myocardial viability, both of which may have implications for surgical intervention, and CMR importantly provides quantitative evaluation of chamber size, RVol, and fraction.

I. Concordance between Echocardiography and CMR

As CMR is increasingly used in evaluating MR and is usually performed after an initial echocardiogram, it is important to review the concordance of evaluating MR severity between these two modalities and what to expect clinically, even with technical adequacy of both studies. There is a paucity of comparative studies, and the majority have shown a modest concordance in the qualitative or quantitative evaluation of MR. This is expected in view of the various factors that affect evaluation of regurgitation by each modality. Reproducibility of quantitation has been consistently higher with CMR. In a recent study, echocardiographic grading of MR severity was higher, and 2D PISA-derived RVols were larger than by CMR. More recently, however, using volumetric pulsed Doppler flow quantitation, a modest correlation was seen between RVol/fraction by echo and CMR, without a consistent over estimation by either

332 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 8 Grading the severity of chronic MR by echocardiography

	MR severity* Mild Moderate Severe
Structural
MV morphology	None or mild leafet abnormality (e.g., mild thickening, calcifcations or prolapse, mild tenting) Moderate leafet abnormality or moderate tenting Severe valve lesions (primary: fail leafet, ruptured papillary muscle, severe retraction, large perforation; secondary: severe tenting, poor leafet coaptation)
LV and LA size†	Usually normal Normal or mild dilated Dilated‡
Qualitative Doppler
Color fow jet area§	Small, central, narrow, often brief Variable Large central jet (>50% of LA) or eccentric wall-impinging jet of variable size
Flow convergencek	Not visible, transient or small Intermediate in size and duration Large throughout systole
CWD jet	Faint/partial/parabolic Dense but partial or parabolic Holosystolic/dense/triangular
Semiquantitative
VCW (cm)	<0.3 Intermediate $0.7 (>0.8 for biplane){
Pulmonary vein fow#	Systolic dominance(may be blunted in LV dysfunction or AF) Normal or systolic blunting# Minimal to no systolic fow/ systolic fow reversal
Mitral infow**	A-wave dominant Variable E-wave dominant (>1.2 m/sec)
Quantitative††,‡‡
EROA, 2D PISA (cm2)	<0.20 0.20-0.29 0.30-0.39 $0.40 (may be lower in secondary MR with elliptical ROA)
RVol (mL)	<30 30-44 45-59†† $60 (may be lower in low fow conditions)
RF (%)	< 30 30-39 40-49 $50

ROA, Regurgitant orifice area. Bolded qualitative and semiquantitative signs are considered specific for their MR grade. *All parameters have limitations, and an integrated approach must be used that weighs the strength of each echocardiographic measurement. All signs and measures should be interpreted in an individualized manner that accounts for body size, sex, and all other patient characteristics. †This pertains mostly to patients with primary MR. ‡LV and LA can be within the ‘‘normal’’ range for patients with acute severe MR or with chronic severe MR who have small body size, particularly women, or with small LV size preceding the occurrence of MR. §With Nyquist limit 50-70 cm/sec. kSmall flow convergence is usually <0.3 cm, and large is $ 1 cm at a Nyquist limit of 30-40 cm/sec. {For average between apical two- and four-chamber views. #Influenced by many other factors (LV diastolic function, atrial fibrillation, LA pressure). **Most valid in patients >50 years old and is influenced by other causes of elevated LA pressure. ††Discrepancies among EROA, RF, and RVol may arise in the setting of low or high flow states. ‡‡Quantitative parameters can help subclassify the moderate regurgitation group.

modality, similar to previous studies. Exact concordance of semiquantitative grading of MR (four-grade scale) was seen in 50% of patients, increasing to 90% when allowing for a one grade difference in MR severity. The majority of the discrepancies in assessing MR occurred in secondary MR, where RVols are small and more subject to errors. It is important to note that while CMR is more reproducible, each modality has its potential errors and limitations and is technically demanding. In the 10%-20% where a significant discrepancy in assessment of MR between these modalities occurs and may be important clinically, further assessment would be required with either TEE or invasive means if reconciliation of findings (e.g., problem with

one technique or the other, interim physiologic changes, rhythm disturbance, etc.) cannot be achieved.

J. Integrative Approach to Assessment of MR

Evaluation of MR severity ideally integrates multiple parameters because all methods have intrinsic limitations and lack precision. It is also important to distinguish between the amount of MR and its hemodynamic consequences. For example, a modest RVol that develops acutely into a small, noncompliant LA may cause severe pulmonary congestion and systemic hypotension.

Zoghbi et al 333

Journal of the American Society of Echocardiography Volume 30 Number 4

Chronic Mitral Regurgitation by Doppler Echocardiography

----- Start of picture text ----- Yes, mild Does MR meet specific criteria for Yes, severe * mild or severe MR? ** Intermediate Values: Specific Criteria for Mild MR Specific Criteria for Severe MR • Small, narrow central jet MR Probably Moderate • Flail leaflet •• VCW ≤ 0.3 cm PISA radius absent or ≤ 0.3 cm at criteria2-3 ** criteria2-3 •• VCW ≥ 0.7 cm PISA radius ≥ 1.0 cm at Nyquist 30- • Mitral A wave dominant inflowNyquist 30-40 cm/s Perform quantitative methods whenever possible • Central large jet > 50% of LA area 40 cm/s • Soft or incomplete jet by CW Doppler • Pulmonary vein systolic flow reversal • Normal LV and LA size • Enlarged LV with normal function Definitely mild≥4 Criteria EROA < 0.2 cmRVol < 30 ml EROA 0.2-0.29 cmRVol 30-44 ml EROA 0.30-0.39 cmRVol 45-59 ml EROA ≥ 0.4 cmRVol ≥ 60 ml ¶ ≥4 CriteriaDefinitely severe RF < 30% RF 30-39% RF 40-49% RF ≥ 50% MR Grade I MR Grade II MR Grade III MR Grade IV 3 specific criteria for severe MR or elliptical orifice Mild Moderate Severe MR MR MR • Poor TTE quality or low confidence in measured Doppler parameters Indeterminate MR • Discordant quantitative and qualitative parameters and/or clinical data Consider further testing: TEE or CMR for quantitation * Beware of underesmaon of MR severity in eccentric, wall impinging jets; quantaon is advised ** All values for EROA by PISA assume holosystolic MR; single frame EROA by PISA and VCW overesmate non-holosystolic MR ¶ Regurgitant volume for severe MR may be lower in low flow conditions. ----- End of picture text -----

Figure 18 Algorithm for the integration of multiple parameters of MR severity. Good-quality echocardiographic imaging and complete data acquisition are assumed. If imaging is technically difficult, consider TEE or CMR. MR severity may be indeterminate due to poor image quality, technical issues with data, internal inconsistency among echo findings, or discordance with clinical findings.

Conversely, some patients with chronic severe MR remain asymptomatic owing to compensatory mechanisms and a dilated, compliant LA. It is important to consider primary and secondary MR separately, as the etiology, mechanism, underlying cardiac structures, and hemodynamics differ significantly and may modulate echo/Doppler parameters assessing MR. However, regardless of etiology, if there is a small central jet, normal leaflet morphology, a VCW < 0.3 cm, no proximal flow convergence, and an A-wave dominant mitral inflow pattern, then MR is mild and further quantitation is not necessary. Conversely, if there is a large jet, with a prominent flow convergence, large VCW > 0.7 cm, flow reversal in the pulmonary veins, then MR is severe; quantitation would substantiate the severity of the regurgitation.

The qualitative, semiquantitative, and quantitative parameters used in grading primary MR are summarized in Table 8, along with a suggested algorithm for the assessment of MR severity (Figure 18) that incorporates these various parameters. In applying this scheme, the writing committee wishes to emphasize that specific signs have inherently a high positive predictive value for the severity of regurgitation and are thus highlighted in bold in Table 8. The supportive signs or clues may be helpful in consolidating the impression of the degree of MR, although their predictive value is more modest. It is the consensus of the committee mem-

bers that the process of grading MR should be comprehensive, using a combination of clues, signs, and measurements obtained by Doppler echocardiography. If the MR is definitely determined as mild or less using these signs, no further measurement is required. If there are signs suggesting that the MR is more than mild and the quality of the data lends itself to quantitation, it is desirable for echocardiographers with experience in quantitative methods to determine quantitatively the degree of MR, including the RVol and fraction as descriptors of volume overload and the EROA as a descriptor of the lesion severity. Quantitation of regurgitation can further subclassify regurgitation into four grades, with grade III having some overlap with characteristics of severe MR (Figure 18 and Table 8), hence the need for an integrative approach. Finally, it is important to stress that when there is congruent evidence from different parameters, it is easy to grade MR severity with confidence. When different parameters are contradictory, one must look carefully for technical and physiologic reasons to explain the discrepancies and rely on components with the highest quality of the primary data that are the most accurate, considering the underlying physiologic condition. There will be times when MR severity and/or mechanism is uncertain by TTE and further testing is needed with TEE or CMR. The following are some considerations in the assessment of severity of primary and secondary MR:

334 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Key Points

1. Considerations in Primary MR. Severe valve lesions on 2D or 3D imaging, such as flail leaflet, ruptured papillary muscle, severe leaflet retraction, or a large perforation, are specific for severe MR. Similarly, a properly measured VCW $ 0.7 cm is specific for severe MR, as is systolic flow reversal in more than one pulmonary vein. In contrast, failure to identify a proximal flow convergence region or the presence of an A-wave dominant mitral filling pattern are specific for nonsevere MR. Proper integration of the many echocardiographic findings include appropriate discounting of measurements that may not be considered accurate for technical reasons. As noted earlier, it is critical to pay attention to the duration of MR as late systolic MR is rarely severe. The hemodynamic consequences of MR are reflected in several parameters including LA and LV volumes, the contour of the CWD profile, and pulmonary venous flow pattern. Finally, clinical presentation and hemodynamic state should also be considered in making a final judgment of MR severity.

2. Considerations in Secondary MR. Secondary MR can be much more challenging to grade than primary MR. The challenge arises from several situations as alluded to earlier in Section II, General Considerations: the total LV forward SV may be reduced and thus RVol is usually lower than in primary MR (below 60 mL for severe MR if total SV is reduced). Although RF would account for comparative lower flows, its derivation has higher errors because of the small numbers involved. The regurgitant orifice is frequently semilunar or elliptical, affecting measurements of VCW and possibly leading to underestimating EROA by the 2D PISA method. EROA may also vary with LV size and LVEF. Thus while EROA $ 0.4 cm still denotes severe MR, a lower cutoff of EROA $ 0.3 cm may still be likely severe MR by 2D PISA due to the above considerations. Adding to the challenges of secondary MR, adjunctive findings are less helpful because they are often rendered abnormal by the underlying cardiomyopathy. For example, most patients with cardiomyopathy have systolic blunting of the pulmonary venous flow pattern due to elevated LA pressure. Because of a combination of elevated LA pressure, a dilated and compliant LA, and depressed LV systolic function, systolic flow reversal is not commonly seen, even though it remains specific for severe secondary MR when present. Another confounding problem is that secondary MR is notoriously dynamic (Figure 15). It is important to consider volume status, blood pressure, and other clinical variables, as in primary MR.

Several studies have shown that EROA $ 0.2 cm portends a worse prognosis in secondary MR. Considerable controversy has arisen regarding whether EROA $ 0.2 cm by 2D PISA should redefine severe secondary MR based on prognosis alone. In fact, this criterion has been incorporated in the last ACC/AHA guidelines. This issue and how to address secondary MR was deliberated on and discussed extensively among the writing committee members. The rationale for the current recommendations regarding EROA is as follows. If association with adverse prognosis warrants labeling a lesion as severe, then any degree of secondary MR should be considered clinically significant, since there is evidence that even mild MR is associated with adverse prognosis. It is not clear whether the prognostic value of EROA $ 0.2 cm is primarily due to the MR itself or to the underlying LV dysfunction or degree of myocardial scarring and irreversible damage. Importantly, there is no evidence that surgical correction of secondary MR improves

When MR is detected, the evaluation starts with an assessment of the anatomy of the MV to determine the mechanism of the regurgitation, classified as primary or secondary (functional), especially when MR is more than mild (Table 5 and Figures 9 and 10). The mechanism should be specified and reported. No single Doppler and echocardiographic parameter is precise enough to quantify MR in individual patients. Integration of multiple parameters is required for a more accurate assessment of MR severity (Tables 7 and 8, and Figure 18). When multiple parameters are concordant, MR severity can be determined with high probability, especially for mild or severe MR. Assessing LV/LA volumes, indexed to body surface area, is important. Chronic severe MR almost always leads to dilated LV and LA, and thus normal chamber volumes are unusual with chronic severe MR. (Tables 6 and 8). In individuals with small body surface areas (inclusive of women), normalization of cardiac chambers to body surface area is important in accurately identifying enlarged chambers. In evaluating severity of MR by color Doppler, always evaluate the three components of the jet (flow convergence, VC, and jet area) and the direction of the MR jet. Beware of very eccentric jets hugging the atrial wall, as jet area will underestimate severity and cannot be used. Duration of MR is important. MR limited to late systole (MVP) or early systole (ventricular dyssynchrony) is usually not severe but may be misinterpreted as severe when based only on single-color frame measurements such as VC or PISA (Figures 3 and 11). Perform quantitative measurements of MR severity when qualitative and semiquantitative parameters do not establish clearly the severity of the MR, provided that the quality of the data is good. Pay attention to systemic blood pressure and MR jet velocity. Color flow jets are proportional to Av. A high velocity (e.g., > 6 m/sec) MR jet can look large by color Doppler although EROA or RVol are small (Figure 14). This is often seen with hypertension, severe aortic stenosis, or significant LVOT obstruction. Acute severe MR due to flail MV or ruptured papillary muscle is more challenging to diagnose than chronic severe MR, particularly with color Doppler (very eccentric MR, short duration, tachycardia, low MR velocity). A high index of suspicion should be maintained if conventional echo/Doppler parameters point to significant MR, with a low threshold for performance of TEE. Additional testing with TEE or CMR is indicated when the TTE examination is suboptimal in patients with suspected MR, the mechanism for significant MR is not elucidated, the echo/Doppler parameters are discordant or inconclusive regarding the severity of MR, or in the presence of a discrepancy between TTE findings and the clinical setting.

outcomes, and there is concern that calling lesser degrees of MR as severe might lead to unnecessary intervention. In fact, recent data have shown that MV repair of moderate ischemic MR (using an integrative approach, inclusive of EROA 0.2-0.39 cm) did not improve outcome and was associated with an increased hazard of neurologic events and supraventricular arrhythmias. Finally, in patients with severe MR treated with the MitraClip, reduction of MR severity was associated with favorable LV and LA remodeling and improved functional class, even when residual MR was moderate. Redefining such MR as severe based on EROA is problematic, unless improvement in remodeling and outcome can be shown for catheter-based interventions on traditional moderate MR. Further research is needed to refine severity criteria in secondary MR using 2D and 3D echocardiography, address the role of CMR, and assess whether LV and LA reverse remodeling occurs, along with improved clinical outcome when intervening on patients with various cutoff values of regurgitation severity. This will likely be facilitated by the advent of catheter-based techniques of MV repair and replacement.

IV. AORTIC REGURGITATION

A. Anatomy of the Aortic Valve and Etiology of Aortic Regurgitation

The aortic valve is composed of three semilunar cusps attached to the aortic wall and forming in part, the sinuses of Valsalva. The highest point of attachment at the leaflet commissures defines the sinotubular

Zoghbi et al 335

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 9 Etiology and mechanisms of AR

Mechanism	Specifc etiology
Congenital/leafet abnormalities	Bicuspid, unicuspid, or quadricuspid aortic valve
	Ventricular septal defect
Acquired leafet abnormalities	Senile calcifcation
	Infective endocarditis
	Rheumatic disease
	Radiation-induced valvulopathy
	Toxin-induced valvulopathy: anorectic drugs, 5-hydroxytryptamine (carcinoid)
Congenital/genetic aortic	Annuloaortic ectasia
root abnormalities	Connective tissue disease: Loeys Deitz, Ehlers-Danlos, Marfan syndrome, osteogenesis imperfecta
Acquired aortic root	Idiopathic aortic root dilatation
abnormalities	Systemic hypertension
	Autoimmune disease: systemic lupus erythematosis, ankylosing spondylitis, Reiter’s syndrome
	Aortitis: syphilitic, Takayasu’s arteritis
	Aortic dissection
	Trauma

Figure 19 Suggested classification of AR morphology, depicting the various mechanisms of AR. Type Ia depicts sinotubular junction enlargement and dilatation of the ascending aorta. Type Ib depicts dilatation of the sinuses of Valsalva and sinotubular junction. Type Ic depicts dilatation of the ventriculoarterial junction (annulus). Type Id denotes aortic cusp perforation.

junction, and the most ventricular point (i.e., the nadir of the cusps) defines the annular plane. The coaptation zone of the leaflets (lunulae) are more uniform in thickness except for a slightly more fibrous region at the anatomic midpoint of each cusp or nodules of Arantius. Given the anatomy of the aortic valve, AR results from disease of either the aortic leaflets and/or the aortic root (Table 9) that results in valve malcoaptation.

In congenital bicuspid aortic valve, all combinations of conjoined cusps can be identified by TTE; visualization of the raphe is key to classification of bicuspid valve types. Because of the increased stress on the typically larger conjoined cusp, these valves may become stenotic, regurgitant, or both. In addition, AR may be seen secondary to the associated dilatation of the aorta. TTE has up to a 92% sensitivity and 96% specificity for detecting bicuspid valve anatomy.

B. Classification and Mechanisms of AR

Identifying the mechanism responsible for AR is essential in determining the reparability of the aortic valve. Several functional classifications can be used. Adaptation of the Carpentier classification originally designed for the MV have been described for AR and can be helpful to understand the mechanism of AR, guide valve repair technique, and predict recurrence of AR (Figure 19). This scheme classifies dysfunction based on the aortic root and leaflet morphology. Type I is associated with normal leaflet motion and can be subcategorized based on the exact pathology of either the aortic root or valve. Type Ia occurs in the setting of sinotubular junction enlargement and dilatation of the ascending aorta, type Ib is a result of dilatation of the sinuses of Valsalva and the sinotubular junction, type Ic is the result of dilatation of the ventriculoarterial junction (i.e., the annulus), and type Id results from cusp perforation or

336 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

fenestration without a primary functional aortic annular lesion. Type II is associated with excessive leaflet motion from leaflet prolapse as a result of either excessive leaflet tissue or commissural disruption. Type III is associated with restricted leaflet motion seen with congenitally abnormal valves, degenerative calcification, or any other cause of thickening/fibrosis or calcification of the valve leaflets.

C. Assessment of AR Severity

1. Echocardiographic Imaging. Echocardiography plays an important role in the overall assessment of AR and in the timing of surgical intervention. While ‘‘physiologic’’ or mild degrees of tricuspid and PR are commonly noted in normal exams, AR is not. When AR is detected, the evaluation starts with an assessment of the anatomy of the aortic valve and root to determine the etiology of the regurgitation followed by an assessment of LV size, geometry, and function. Similar to MR, the hemodynamics and cardiac adaptation to acute versus chronic AR are quite different. In severe acute AR, the LV is not dilated and the sudden rise in LV end-diastolic pressure may cause the MV to close prematurely, best documented with an M-mode. In chronic AR, echocardiography is essential in tracking the changes in LV geometry (progressive increase in LV volume) and function (progressive worsening) due to the protracted LV volume overload. LV dilatation, particularly with preserved LV function, is a supportive sign of significant AR and becomes more specific with exclusion of other causes of LV volume overload (e.g., athlete, anemia). Stress echocardiography can be utilized in both asymptomatic and symptomatic patients to assess functional capacity, the presence of coronary disease, and response of LV size and function to exercise.

2. Doppler Methods. Doppler echocardiography is essential in the evaluation of AR severity. The underlying principles for color flow Doppler, pulsed, and CWD in the assessment of valve regurgitation have been discussed earlier under Section II, General Considerations. The various methods in assessing AR, their advantages and limitations are detailed in Table 10. Table 11 summarizes the parameters involved in grading the severity of AR.

a. Color flow Doppler. AR in most patients is easily seen with color flow Doppler as a mosaic blend of colors originating from the aortic valve during diastole. Although the apical approach is the most sensitive for detection, the parasternal long and short axis are essential in evaluating the origin of the jet and its semiquantitative characteristics. It is important to visualize the three components of the color jet (flow convergence, VC, and jet area) for a better assessment of the origin and direction of the jet and its overall severity (Figure 20). Because the length of the AR jet into the LV chamber is so dependent on the driving pressure (diastolic blood pressure), it is not a reliable parameter of AR severity. Lastly, AR usually lasts throughout diastole except in acute AR, where it may be brief and of lower velocity, making detection and assessment with color Doppler more difficult.

Jet width in LVOT: the width of the AR jet compared with the LVOT diameter in centrally directed jets can be used to assess the severity of regurgitation semiquantitatively. This ratio is obtained in the parasternal long-axis view, just apical to the aortic valve. A ratio <25% generally indicates mild, 25%-64% indicates moderate, and $65% indicates severe AR. Similarly, a ratio of the area of the jet in cross section (short-axis view) to LVOT area is a measure of AR severity (Tables 10 and 11). However, both the width and area

ratios are not valid in eccentric jets, directed towards the septum or anterior MV, or in multiple jets.

Vena contracta: the VC is best visualized and measured in a zoomed, parasternal long-axis view. Since it is the narrowest area of the jet, it is smaller than the jet width in the LVOT. It can be measured in most patients with good echocardiographic images. A VC < 0.3 cm indicates mild, 0.3-0.6 cm indicates moderate, and > 0.6 cm indicates severe AR. If optimized, VC can still be measured in most eccentric jets. The VCW is small, so errors in measurement of 2 mm or more can influence AR grading.

Flow convergence (PISA): flow convergence can be used qualitatively and quantitatively for evaluation of AR severity (Figure 21), similar to MR. Zooming on the LVOT in either the parasternal or apical long-axis views is the best approach to record the proximal flow convergence area, with a baseline shift of the Nyquist limit to measure the flow convergence radius. Measurement of the AR peak velocity and VTI by CWD allows calculation of the EROA and RVol (see earlier and Table 10). The threshold for severe AR is an EROA $ 0.30 cm and an RVol greater than 60 mL (Table 11). Clinically, PISA quantitation of AR is used less often than in MR, as the flow convergence is in the far field and may be shadowed by aortic valve thickening and calcifications. Imaging from the right parasternal window may be helpful.

b. Pulsed wave Doppler. Aortic diastolic flow reversal: pulsed wave Doppler from the suprasternal window in the descending aorta often shows a brief early diastolic flow reversal in normals. Holodiastolic flow reversal is an abnormal finding (Figure 22) and indicates at least moderate AR; when present in the abdominal aorta, it is consistent with severe AR. However, in the absence of AR, holodiastolic retrograde aortic flow can also be seen in other conditions such as a left-to-right shunt across a patent ductus arteriosus, reduced compliance of the aorta in the elderly, an upper extremity arteriovenous fistula, a ruptured sinus of Valsalva, or when there is an aortic dissection with diastolic flow into the false lumen. Note that in acute severe AR or bradycardia, there may be equilibration of pressure between the aorta and ventricle before the end of diastole leading to flow reversal that is not holodiastolic. The ratio of the VTI of the reverse flow to the forward flow provides a rough assessment of RF. Variation in aortic size during the cardiac cycle limits this from being a truly quantitative measure.

Flow calculations: quantitation of flow with pulsed Doppler for the assessment of AR is based on comparison of measurements of aortic SV at the LVOT with mitral or pulmonic SV, provided there is no significant MR or PR. Grading of AR severity with RVol and RF is shown in Table 11. EROA can also be calculated by dividing the RVol by the VTI from AR CWD jet recording. Total LV SV (equal to SVat LVOT in isolated AR) can also be obtained from the difference between LV diastolic and systolic volumes. The use of 3D echocardiography and contrast enhances the accuracy of this measurement and decreases the underestimation of total LV SV by echocardiography. As noted in the general section, meticulous attention to accuracy is needed throughout this process, and even then, the confidence intervals may remain wide.

c. Continuous wave Doppler. The best window for the evaluation of AR with CWD is the apical window. However, in very eccentric jets, identified by color Doppler, a parasternal window may give a better ultrasound alignment and recording of the jet.

Zoghbi et al 337

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 10 Doppler echocardiography in evaluating severity of AR

Modality	Optimization	Example	Advantages	Pitfalls
Color fow Doppler 2D
Jet width/	Long-axis view		Simple sensitive	Underestimates AR in
LVOT diameter	Zoomed view		screen for AR	eccentric jets
	Imaging plane for		Rapid qualitative	May overestimate AR
	optimal VC		assessment	in central jets as AR
	measurement may be			jet may expand
	different from PISA			unpredictably below
	Measure in LVOT			the orifce
	within 1 cm of the VC			Is affected by the size
				of the LVOT
Jet area/LVOT area	Short-axis view		Estimate of	Direction and shape
	Zoom view		regurgitant orifce	of jet may
	Measure within 1 cm		area	overestimate or
	of the VC			underestimate jet
				area
VC	Parasternal long-axis		Surrogate for	Problematic in the
	view		regurgitant orifce	presence of multiple
	Zoomed view		size	jets or bicuspid
	Imaging plane for		May be used in	valves
	optimal VC		eccentric jets	Convergence zone
	measurement may be		Independent of fow	needs to be
	different from that for		rate and driving	visualized
	PISA		pressure	The direction of the
	Narrowest area of jet		Less dependent on	jet (in relation to the
	at or just apical to the		technical factors	insonation beam) will
	valve		Good at identifying	infuence the
			mild or severe AR	appearance of the jet
Proximal fow	Align direction of fow Apical view		Rapid qualitative	Multiple jets
convergence	with insonation beam		assessment	Constrained jet
	to avoid distortion of			(aortic wall)
	hemisphere from			Nonhemispheric
	noncoaxial imaging			shape
	Zoomed view			Timing in early
	Change baseline of			diastole
	Nyquist limit in the
	direction of the jet
	Adjust lower Nyquist
	limit to obtain the most hemispheric	Parasternal view
	fow convergence
				(Continued)

338 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 10 (Continued)

Modality	Optimization	Example	Advantages	Pitfalls
Color fow Doppler 3D:	Color fow sector		Multiple jets of	Dynamic jets may be
3D VC	should be narrow		differing directions	over- or
	Align orthogonal		may be measured	underestimated
	cropping planes
	along the axis of the
	jet
	Choose a
	middiastolic cycle
	Noncoaxial jets or
	aliased fow may
	appear ‘‘laminar’’ but
	still represent
	regurgitant fow
Pulsed wave Doppler:	Align insonation		Simple supportive	Depends on
Flow reversal in	beam with the fow in		sign of severe AR	compliance of the
proximal descending	the proximal		More specifc sign if	aorta; less reliable in
aorta	descending or		seen in abdominal	older patients
	abdominal aorta		aorta	Brief velocity reversal
			Can be obtained with is normal
			both TTE and TEE	Can be present in
				arteriovenous fstula
				in upper extremity,
				ruptured sinus of
				Valsalva
				May not be
				holodiastolic in acute
				AR
CWD
Density of	Align insonation		Simple	Qualitative
regurgitant jet	beam with the fow		Density is	Perfectly central jets
	Adjust overall gain		proportional to the	may appear denser
			number of red blood	than eccentric jets of
			cells refecting the	higher severity
			signal	Overlap between
			Faint or incomplete	moderate and severe
			jet is compatible with	AR
			mild or trace AR
Jet deceleration rate	Align insonation		Simple	Qualitative
(pressure half-	beam with the fow		Specifc sign of	Poor alignment of
time)	Usually best from		pressure relation	Doppler beam may
	apical windows		between aorta and	result in lower
	In eccentric jets, may		LV	pressure half-time
	be best from		If long, excludes	Affected by changes
	parasternal window,		severe AR	that modify LV-aorta
	helped by color			pressure gradient (if
	Doppler			short, implies
				signifcant AR or high
				LV flling pressure)
				(Continued)

Zoghbi et al 339

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 10 (Continued)

Modality	Optimization	Example	Advantages	Pitfalls
Quantitative Doppler:
EROA, regurgitation
volume and fraction
	Align insonation		Rapid quantitative	Feasibility is limited
	beam with the fow		assessment of lesion	by aortic valve
	Lower the color		severity (EROA) and	calcifcations
	Doppler baseline in		volume overload	Not valid for multiple
	the direction of the jet		(RVol)	jets, less accurate in
	Look for the			eccentric jets
	hemispheric shape to			Limited experience
	guide the best lower			Small errors in radius
	Nyquist limit			measurement can
	CWD of regurgitant			lead to substantial
	jet for peak velocity			errors in EROA due to
	and VTI			squaring of error.
SV method	LVOT diameter		Quantitative, valid	Diffculties measuring
	measured at the		with multiple jets and	mitral annulus
	annulus in systole		eccentric jets.	diameter, particularly
	and pulsed Doppler		Provides both lesion	with annular
	from apical views at		severity (EROA, RF)	calcifcation
	same site		and volume overload	Not valid for
	Mitral annulus		(RVol)	combined MR and
	measured at		Verify results using	AR, unless pulmonic
	middiastole; pulsed		LV end-diastolic	site is used
RVol = SVLVOTSVMV	Doppler at the		volume and LV end-
	annulus level in		systolic volume
	diastole
	Total LV SV can also
	be measured by the
	difference between
	LV end-diastolic
	volume and end-
	systolic volume.
	LV volumes are best
	measured by 3D.
	Contrast may be
	needed to better
	trace endocardial
	borders. If 3D not
	feasible, use 2D
	method of disks.

Signal density: the density of the CWD signal reflects the volume of regurgitation, particularly when compared to the density of the forward flow. A faint or incomplete jet indicates mild or trace regurgitation, while a dense jet may be compatible with more significant regurgitation but cannot differentiate between moderate and severe AR.

Pressure half-time: the pressure half-time of the AR spectral Doppler slope can be a parameter of severity. The CW signal has to be adequate with a clear visualization of the decrease in diastolic AR velocity for this measurement to be performed. A steep slope indicates a more rapid equalization of pressures between the aorta and

LV during diastole (Figure 22). A pressure half-time >500 msec suggests mild AR, and <200 msec suggests severe AR. However, since this parameter is affected by compliance of the LV, patients with severe chronic regurgitation with well compensated ventricular function may have a pressure half-time in the ‘‘moderate’’ range. In contrast, mild AR in patients with severe diastolic dysfunction may have short pressure half-time. The pressure half-time reflects reduction in the transvalvular gradient, which can also be accomplished by vasodilator therapy (reduces diastolic blood pressure independent of the AR). Thus, this method is less useful for monitoring AR in patients being treated medically.

340 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 11 Grading the severity of chronic AR with echocardiography

	AR severity Mild Moderate Severe
Structural parameters
Aortic leafets	Normal or abnormal Normal or abnormal Abnormal/fail, or wide coaptation defect
LV size	Normal* Normal or dilated Usually dilated†
Qualitative Doppler
Jet width in LVOT, color fow	Small in central jets Intermediate Large in central jets; variable in eccentric jets
Flow convergence, color fow	None or very small Intermediate Large
Jet density, CW	Incomplete or faint Dense Dense
Jet deceleration rate, CW (PHT, msec)‡	Incomplete or faint Slow, >500 Medium, 500-200 Steep, <200
Diastolic fow reversal in descending aorta, PW	Brief, early diastolic reversal Intermediate Prominent holodiastolic reversal
Semiquantitative parameters§
VCW (cm)	<0.3 0.3-0.6 >0.6
Jet width/LVOT width, central jets (%)	<25 25-45 46-64 $65
Jet CSA/LVOT CSA, central jets (%)	<5 5-20 21-59 $60
Quantitative parameters§
RVol (mL/beat)	<30 30-44 45-59 $60
RF (%)	<30 30-39 40-49 $50
EROA (cm2)	<0.10 0.10-0.19 0.20-0.29 $0.30

PHT, Pressure half-time; PW, pulsed wave Doppler. Bolded qualitative and semiquantitative signs are considered specific for their AR grade. Color Doppler usually performed at a Nyquist limit of 50-70 cm/sec. *Unless there are other reasons for LV dilation. †Specific in normal LV function, in absence of causes of volume overload. Exception: acute AR, in which chambers have not had time to dilate. ‡PHT is shortened with increasing LV diastolic pressure and may be lengthened in chronic adaptation to severe AR. §Quantitative parameters can subclassify the moderate regurgitation group.

D. Role of TEE

TTE is an essential first diagnostic test and is frequently sufficient to evaluate the presence and severity of AR. TEE is usually reserved for more detailed assessment, if needed, of the morphology of the valve and aorta, mechanism of AR, and measurements of color flow parameters. Both 2D and 3D TEE have proven utility, improving diagnostic accuracy of TTE in a number of disease processes causing AR: infectious or inflammatory endocarditis, isolated aortic root dilatation, or acute aortic dissection. The diagnostic value of 2D and 3D TEE in defining the mechanisms of AR is particularly important for presurgical evaluation of patients undergoing aortic root surgery, valve-sparing aortic surgery, or valve repair.[192-] 194 Understanding leaflet as well as aortic root morphology will likely be more important in the planning of transcatheter repair or replacement devices.

(Figure 23). An imaging plane is prescribed to produce a standard three-chamber long-axis view and additionally an LVOT coronal view. These views are then used to prescribe a parallel series of at least 3 thin (4-5 mm) slices in short axis and provide a comprehensive assessment of aortic valve and aortic root anatomy and can aid in identifying congenital leaflet anomalies (i.e., bicuspid), acquired leaflet abnormalities (i.e., vegetations), or aortic root or ascending aortic abnormalities (Figure 23).

There are limitations of cine CMR that need to be mentioned. Specifically, while the in-plane resolution is high (typically 1.5 mm), the slice thickness is 4-5 mm, which can lead to some partial volume effects. Additionally, since cine CMR images are acquired over multiple cardiac cycles, there may be difficulty in visualizing highly mobile objects such as small mobile vegetations. Nonetheless, CMR can still provide useful insights into the mechanism of AR in most cases.

E. Role of CMR in the Assessment of AR

There are four main roles for CMR in the assessment of AR: identification of the mechanism of AR, quantification of its severity, evaluation of LV remodeling, and potential associated aortopathy:

1. Mechanism. Anatomic assessment of the aortic valve and aortic root is typically performed with the use of cine SSFP sequences

2. Quantifying AR with CMR. Thereare several methods for quantifying AR by CMR, broadly categorized as direct and indirect methods (see Section II, General Considerations). The direct method involves performing phase-contrast velocity mapping in a plane perpendicular to the aorta; most operators recommend positioning in the aortic root (just above the aortic valve) (Figures 7 and 24). Forward and reverse flow is derived by integrating the velocity of each pixel and its

Zoghbi et al 341

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 20 Color flow Doppler of AR in the parasternal long- and short-axis views. The three components of the jet are shown with arrows: flow convergence (FC), VC, and jet height (or width) in the LV outflow.

Figure 21 Flow convergence or PISA can be performed for obtaining the EROA in patients with AR. Zooming in on the LVOT in either the parasternal or apical long-axis views is the best way to record the proximal flow convergence area. Adjust the Nyquist limit using the baseline shift control to obtain and measure the flow convergence radius (red arrow). Regurgitant flow rate is calculated as 2p r VAlias (r = the radius of the flow convergence in early diastole [red arrow], and VAlias is the Va in cm/sec). EROA and RVol can then be calculated as EROA = regurgitant flow rate/peak AR velocity in early diastole in cm/sec. RVol = EROA VTI of the AR. For the aortic valve, severe regurgitation is an EROA greater than 0.30 cm and an RVol greater than 60 mL.

area over the cardiac cycle. This information can then be used to calculate RF (reverse volume/forward volume * 100%). In most instances this direct method is the preferred technique for assessment of AR as it is the most validated and is not affected by coexisting valvular regurgitant lesions.

Occasionally in the setting of arrhythmias or atrial fibrillation, the data obtained from the direct method may be compromised (specifically the diastolic reverse flow assessment). In these instances, multiple indirect methods can be employed to determine AR severity. In the absence of significant PR, aortic RVol can be

342 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 22 (A) Still frame of a patient with moderate eccentric AR due to aortic valve prolapse. Note the area of flow convergence and VC. (B) Early closure of the MV (before the R wave of the electrocardiogram) in a patient with acute AR due to bacterial endocarditis. (C) Pulsed Doppler in the descending aorta in a patient with severe AR depicting holodiastolic aortic flow reversal. (D) CWD of a patient with severe and acute AR. Note the steep deceleration slope and similar density of the antegrade and retrograde flows.

derived by subtracting the pulmonic forward flow from the aortic forward flow. Another indirect method involves comparing the RV and LV SVs obtained by planimetry; however, it will not be reliable if there is significant coexisting mitral or right-sided regurgitant lesions.

In addition to volumetric quantification, a number of features have been evaluated as corroborating signs of severe AR. The ARO can be determined by obtaining an ‘‘en face’’ view of the aortic valve using sequential SSFPs cines. The smallest diastolic regurgitant orifice in middiastole is traced. An ARO $ 0.48 cm was found to have a sensitivity and specificity of 83% and 97%, respectively, in detecting severe AR. In a separate study, the presence of holodiastolic flow reversal in the mid descending aorta predicted severe AR with high sensitivity (100%) and specificity (93%).

3. LV Remodeling. LV remodeling could be a consequence of chronic severe AR and may be a specific marker of regurgitation severity. CMR provides the most accurate measurement of LV volumes. This is accomplished using the acquisition of short-axis SSFP cine images from the base to the apex of the ventricle followed by endocardial contouring with commercially available software. Recently a study focused on prognosis demonstrated that an LV volume of >246 mL (unindexed) predicted progression to symptoms or the need for aortic valve replacement over a mean follow-up of 2.6 years.

4. Aortopathy. The presence of aortopathy can be a cause of AR or associated with AR. It is reliably assessed using contrast and noncontrast magnetic resonance angiography techniques.

5. When Is CMR Indicated? While echocardiography remains the first line modality for assessment of AR, CMR is indicated in the following situations: (1) suboptimal echocardiographic images; (2) discordance between echocardiographic and Doppler findings (i.e., discordance between LV enlargement and Doppler measures of AR severity); or (3) discordance between clinical assessment and severity of AR by echocardiography; (4) patients with moderate or severe AR and suboptimal echocardiography for assessment of LV volumes and systolic function and measurement of AR severity; (5) patients with bicuspid aortic valves, when the morphology of aortic sinuses, sinotubular junction, or ascending aorta (to at least 4 cm above the valve plane) cannot be assessed accurately or fully by echocardiography. Lastly, the direct method for AR quantification described in this section is independent of other coexisting valvular lesions, and therefore CMR may be used in the setting of multiple valvular lesions when echocardiographic assessment may be challenged. This will be presented in more detail in the section on multivalvular disease.

CMR measurement of regurgitant severity of AR and accompanying LV remodeling is less variable than with echocardiography and may therefore be ideally suited for longitudinal follow up in individual patients. Furthermore, patients with bicuspid aortic valves,

Zoghbi et al 343

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 23 Examples of various etiologies of AR identified with CMR: bicuspid aortic valve (A), vegetation on the aortic valve (B), aortic root dilation (C), and type A aortic dissection (D).

concomitant AR, and ascending aortic dilatation may be best followed with CMR, depending on the severity of AR and size of the aorta.

F. Integrative Approach to Assessment of AR

The evaluation of AR by Doppler echocardiography should be a comprehensive and an integrative process based on all the information collected during the examination, since each of the parameters used in this evaluation has advantages and limitations (Tables 10 and 11). In all cases one should routinely perform an evaluation of the aortic valve and LV size and function and an assessment of the jet characteristics by color flow imaging. The LV outflow velocity and the velocity in the proximal descending aorta and/or abdominal aorta should be recorded by pulsed Doppler. CWD of the AR jet should also be routinely recorded but only utilized if a complete signal is obtained.

Based on data in the literature and a consensus of the committee members, the writing committee proposes a scheme for evaluation of patients with AR (Figure 25). In applying this scheme, it is the consensus of the committee members that the process of grading AR should be comprehensive using a combination of these signs,

clues, and measurements obtained by Doppler echocardiography. If the AR is definitely determined as mild or severe using these specific signs, no further measurement is required, particularly for mild lesions. If there are only few parameters consistent with mild or severe AR, and the quality of the primary data lends itself to quantitation, it is desirable for echocardiographers with experience in quantitative methods to measure quantitatively the degree of AR, including the RVol and fraction as descriptors of volume overload and the effective regurgitant orifice as a descriptor of the lesion severity. Similar to MR, quantitation of regurgitation can further subclassify regurgitation into four grades, with grade III having some overlap with characteristics of severe AR (Figure 25), hence the need for an integrative approach. Similar to MR, when the evidence from the different parameters is congruent, it is easy to grade AR severity. When different parameters are contradictory, one must look carefully for technical and physiologic reasons to explain these discrepancies and rely on the components that have the best quality of the primary data and that are the most accurate considering the underlying clinical condition. In situations where the assessment is difficult and indeterminate, provides contradicting echo/Doppler data that cannot be resolved, or conflicts with the clinical presentation, further testing is advised with either TEE or CMR.

344 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 24 Phase-contrast CMR for assessment of aortic valve flow. (A) Phase-contrast CMR acquisition is prescribed in a plane perpendicular to the aortic root, just above the aortic valve (yellow dashed line). This produces two sets of images on which contours of the aortic wall are planimetered (red contours in panels B and C): magnitude images that provide anatomic location information (B) and phase image that encodes velocity in each pixel (C). A flow-time curve is generated (D) by integration of velocity and area data at each phase in the cardiac cycle. The reverse (regurgitant) volume is 70 mL, and the RF is 70 mL/138 mL or 51%.

----- Start of picture text ----- Chronic Aortic Regurgitation by Doppler Echocardiography Yes, mild Yes, severe * Does AR meet specific criteria of * mild or severe AR? Specific Criteria for Mild AR Specific Criteria for Severe AR • VC width < 0.3 cm Intermediate Values: • Flail Valve • Central Jet, width < 25% of AR Probably moderate • VC width > 0.6 cm LVOT • Central Jet, width ≥ 65% of LVOT • Small or no flow convergence 2-3 criteria 2-3 criteria • Large flow convergence • Soft or incomplete jet by CW Perform quantitative methods whenever possible to • PHT < 200 ms • PHT > 500 ms refine assessment • Prominent holodiastolic flow • Normal LV size reversal in the descending aorta • Enlarged LV with normal function ≥ 4 criteria ≥ 4 criteria Definitively mild Definitively severe (quantitation not needed) RVol < 30 mL RVol 30-44 mL RVol 45-59 mL RVol ≥ 60 mL (may still quantitate) RF < 30% RF 30-39% RF 40-49% RF ≥ 50% EROA <0.1 cm EROA 0.10-0.19 cm EROA 0.20-0.29 cm EROA ≥0.3 cm AR Grade I AR Grade II AR Grade III AR Grade IV 3 specific criteria for severe AR Mild Moderate Severe AR AR AR • Poor TTE quality or low confidence in measured Doppler parameters Indeterminate AR • Discordant quantitative and qualitative parameters and/or clinical data Consider further testing: TEE or CMR for quantitation * Beware of limitaons of color flow assessment in eccentric AR jets; volumetric quantaon and integraon of other parameters is advised ----- End of picture text -----

Figure 25 Algorithm for the integration of multiple parameters of AR severity. Good-quality echocardiographic imaging and complete data acquisition are assumed. If imaging is technically difficult, consider TEE or CMR. AR severity may be indeterminate due to poor image quality, technical issues with data, internal inconsistency among echo findings, or discordance with clinical findings. PHT, Pressure half-time.

Zoghbi et al 345

Journal of the American Society of Echocardiography Volume 30 Number 4

Key Points

• When AR is detected, the evaluation starts with an assessment of the anatomy of the aortic valve and aortic root to determine the etiology and mechanism of the regurgitation, followed by an assessment of LV size, geometry, and function.

• No single measurement or Doppler parameter is precise enough to quantify AR in individual patients. Integration of multiple parameters is required (Tables 10 and 11 and Figures 20-22).

• The severity of AR can be graded using a combination of structural, qualitative Doppler, and semiquantitative parameters (Table 11 and Figure 25). When multiple parameters are concordant, AR severity can be determined with high probability, especially for mild or severe AR.

• It is important to assess LV size/volume, indexed to body surface area. Chronic severe AR almost always leads to dilated LV, and thus, normal chamber volumes are unusual with chronic severe AR (Table 11).

• In assessing AR by color Doppler, always evaluate the three components of the jet (flow convergence, VC, jet size in LV outflow) and jet direction. Beware of very eccentric AR directed at the septum or anterior MV, as AR severity parameters of jet size become less reliable.

• Perform quantitative measurements of AR severity when qualitative and semiquantitative parameters do not establish clearly the severity of AR, provided that the quality of the data is good.

• Acute severe AR may be more challenging to diagnose than chronic severe AR, particularly with color Doppler (short duration, tachycardia, low AR velocity, eccentric jet). A high index of suspicion should be maintained if conventional echo/Doppler parameters point to significant AR, with a low threshold for performance of TEE.

• Additional testing with TEE or CMR is indicated when TTE is suboptimal in patients with suspected AR, the mechanism for significant AR is not identified, the echo/ Doppler parameters are discordant or inconclusive regarding the severity of AR, the aortic root and ascending aorta need better assessment, or a discrepancy is present between the TTE findings and the clinical setting.

V. TRICUSPID REGURGITATION

A small degree of TR is present in the majority of normal individuals. Hemodynamically significant TR may be responsible for significant morbidity and possibly mortality, independent of underlying conditions. TR may be difficult to detect on clinical examination because the murmur is often soft. It is important for the echocardiographer not only to recognize severe TR but also to try to elucidate its mechanism.

A. Anatomy of the Tricuspid Valve

The TV is the largest and most apically positioned valve and its functional anatomy, similar to the MV, can be divided into four components: the fibrous annulus, the three leaflets, the papillary muscles, and the chordal attachments. The tricuspid annulus is complex and dynamic, allowing it to change with varying loading conditions. Unlike the MV, there is no fibrous continuity with the corresponding semilunar valve. Three-dimensional echocardiography has been integral in our understanding of TV anatomy. A normal annulus is triangular as well as saddle shaped (Figure 26). When functional dilatation occurs, the annulus becomes more circular and planar, dilating in the septal to lateral direction.

B. Etiology and Pathology of Tricuspid Regurgitation

The most common cause of TR is secondary or functional regurgitation, due to annular dilatation from either right atrial or RV enlargement. Table 12 lists the common etiologies of TR. Annular dilation, papillary muscle displacement, or a combination can cause significant TR. This can occur in the setting of RV dysfunction, pulmonary hypertension, or left heart disease. In these conditions, the increased tethering forces result in leaflet malcoaptation and leaflet tethering and tenting.

The most common cause of primary TR is myxomatous degeneration. Although some degree of prolapse is common for the

nonplanar TV, actual ‘‘TV prolapse’’ is typically reserved for excessive billowing into the right atrium associated with redundancy of the tricuspid leaflets. This abnormality is seen in 20% of patients with concomitant MVP. Flail leaflets are not typically associated with myxomatous TV disease but rather with closed chest trauma or RV endomyocardial biopsy. Pacemaker leads can result in significant TR by interfering with closure of the TV but rarely cause a flail leaflet or a perforation of

C. Role of Imaging in Tricuspid Regurgitation

1. Evaluation of the Tricuspid Valve. a. Echocardiographic imaging. A comprehensive TTE examination of the TV requires a methodical approach to identify the pathology associated with TR. With 2D echocardiography, the three leaflets cannot be visualized simultaneously, and there is a great deal of variability as to which leaflets are visualized in a given view. The parasternal RV inflow view will always image the anterior leaflet in the near field, but in the far field, the leaflet may be the septal or the posterior leaflet. On short axis, the leaflet adjacent to the aorta is either the septal or anterior leaflet, and the leaflet adjacent to the RV free wall is usually the posterior leaflet. In the apical four-chamber view, there is more certainty, with the anterior leaflet on the free wall and the septal leaflet adjacent to the septum. Significant annular dilatation is defined by an end-diastolic diameter $40 mm or >21 mm/ m in the four-chamber transthoracic view and is the main imaging criterion used to indicate severe TR in the current the ACC/AHA guidelines. Compared with TTE, TEE is in general more limited in permitting optimal views due to off-angle imaging planes and the greater distance of the probe from the TV. Three-dimensional echocardiography provides unique en face views of the TV that enable simultaneous visualization of all three leaflets and the entire annulus (Figure 26). The addition of color flow Doppler to a full volume acquisition not only provides the ability to analyze the mechanism and locate the TR jet but also to quantify the size of the effective regurgitant orifice size by using cropping planes to display and measure the VCA.

b. CMR imaging. The normal TV with a thickness of <1 mm is difficult to visualize clearly with routine CMR cine SSFP imaging (Figure 27). The strengths of CMR in defining tricuspid anatomy include its ability to display the valve in any imaging plane. When the valve is thickened in pathological situations, the valve and TR are more readily visualized by CMR. In a study comparing echocardiography with CMR in patients with Ebstein’s anomaly, the posterior leaflets and TV fenestrations were better visualized by CMR. A limitation of CMR that can compromise visualization of TV leaflets is that flow cannot be separated from 2D structural imaging unlike color Doppler in echocardiography. In case of turbulent flow, the turbulence creates flow disturbance, which is of low signal intensity and can obscure the valve and make it difficult to visualize (Figure 28).

2. Evaluating Right Heart Chambers. The RV is usually dilated in the presence of hemodynamically significant TR. The position of the septum produces a D-shaped LV predominantly in diastole (RV volume overload pattern). When TR is due to pulmonary hypertension, septal flattening is present throughout the cardiac cycle, reflecting the diastolic and systolic overload of the RV (RV pressure overload pattern).

346 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 26 Three-dimensional echocardiography provides the only echocardiographic approach to visualize the three leaflets of the TV simultaneously. A, Anterior leaflet; P, posterior; S, septal.

Table 12 Etiology of TR

Morphologic
classifcation	Disease subgroup	Specifc abnormality
Primary leafet	Acquired disease	Degenerative, myxomatous
abnormality		Rheumatic
		Endocarditis
		Carcinoid
		Endomyocardial fbrosis
		Toxins
		Trauma
		Iatrogenic (pacing leads, RV biopsy)
		Other (e.g., ischemic papillary muscle rupture)
	Congenital	Ebstein’s anomaly
		TV dysplasia
		TV tethering associated with perimembranous ventricular septal defect and ventricular
		septal aneurysm
		Repaired tetralogy of Fallot
		Congenitally corrected transposition of the great arteries
		Other (giant right atrium)
Secondary	Left heart disease	LV dysfunction or valve disease
(functional)
	RV dysfunction	RV ischemia
		RV volume overload
		RV cardiomyopathy
	Pulmonary	Chronic lung disease
	hypertension	Pulmonary thromboembolism
		Left-to-right shunt
	Right atrial	Atrial fbrillation
	abnormalities

Zoghbi et al 347

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 27 TV normal anatomy visualized by CMR. (A) Basal short-axis view when the tips of the three leaflets can be seen on the same plane (outlined by the black triangle). The relationship with the four-chamber view and RV inflow view are illustrated by the dotted lines. (B) Four-chamber view where the septal and anterior leaflets are seen. (C) The RV inflow (two-chamber) view where the anterior and posterior leaflets are seen. (D) RV inflow and outflow view (three-chamber view) can visualize posterior and septal leaflets.

Figure 28 CMR cine SSFP visualization of mild (A) and severe (B) TR. Arrows point to the dephasing jet of TR. Severe TR may be more difficult to visualize, and the leaflet morphology may be obscured.

Parameters of RV systolic function are important in following the effects of chronic primary TR to detect deterioration of RV muscle function. RV systolic function is challenging in this setting as these parameters are load dependent. A tricuspid annular excursion measurement <1.6 cm and an RV fractional area change <35% are suggestive of RV dysfunction, although tricuspid annular excursion in particular may yield both false-positive and -negative results. In the presence of an anatomically normal valve, abnormal RV function is more likely the cause rather than the effect of TR. Significant chronic TR also causes

enlargement of the right atrium and inferior vena cava. Lastly, right atrial enlargement in patients with permanent atrial fibrillation and concomitant TV annular dilatation (>35 mm) may result in secondary TR.

CMR is currently the reference standard for the quantitation of RV size and function. RV volume and function can be measured using the short-axis stack cine SSFP at the same time when the LV is assessed based on existing recommendations. Dedicated axial orientation cine is not necessary in evaluating the RV in the absence of complex congenital disease. In general,

348 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 13 Doppler echocardiography in evaluating severity of TR

Modality	Optimization	Example	Advantages	Pitfalls
Color fow Doppler 2D
Proximal fow	Align direction of	Apical four color view	Rapid qualitative	Multiple jets
convergence	fow with		assessment	Nonhemispheric
	insonation beam			shape
	to avoid distortion
	of hemisphere
	from noncoaxial
	imaging
	Zoomed view
	Change baseline
	of Nyquist limit in
	the direction of
	the jet
	Adjust lower
	Nyquist limit to
	obtain the most
	hemispheric fow
	convergence
VC	Zoomed view		Surrogate for	Problematic in the
	Apical four		regurgitant orifce	presence of
	chamber view		size	multiple jets
	RV infow view		Independent of fow	In order to
			rate and driving	measure it,
			pressure for a fxed	convergence
			orifce	zone needs to be
			Less dependent on	visualized
			technical factors
			Good at identifying
			severe TR
Jet area	Four chamber, RV		Qualitative	Dependent on the
	infow or			driving pressure
	subcostal views			and jet direction
				Direction and
				shape of jet may
				overestimate
				(central
				entrainment) or
				underestimate
				(eccentric, wall-
				impinging) jet area
Color fow Doppler 3D:	Color fow sector		Multiple jets of	Dynamic jets may
3D VC	should be narrow		differing directions	be over- or
	Align orthogonal		may be measured	underestimated
	cropping planes			Time consuming
	along the axis of			Limited spatial
	the jet			resolution will
	Choose a			lead to
	midsystolic cycle			overestimation
	Noncoaxial jets or
	aliased fow may
	appear ‘‘laminar’’
	but still represent
	regurgitant fow
				(Continued)

Zoghbi et al 349

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 13 (Continued)

Modality	Optimization	Example	Advantages	Pitfalls
Pulsed wave Doppler:	Align insonation		Simple supportive	Depends on
Hepatic vein fow	beam with the		sign of severe TR	compliance of the
reversal	fow in the hepatic		Can be obtained with	right atrium
	vein		both TTE and TEE	May not be
				reliable in patients
				with atrial
				fbrillation, paced
				rhythm with
				retrograde atrial
				conduction
CWD
Density of	Align insonation		Simple	Qualitative
regurgitant jet	beam with the		Density is	Perfectly central
	fow		proportional to the	jets may appear
			number of red blood	denser than
			cells refecting the	eccentric jets of
			signal	higher severity
			Faint or incomplete	Overlap between
			jet is compatible with	moderate and
			mild TR	severe TR
Jet contour	Align insonation		Simple	Qualitative
	beam with the		Specifc sign of	Affected by
	fow		pressure equalization	changes that
			in low velocity, early	modify RV and RA
			peaking dense TR jet	pressures
Quantitative Doppler:
EROA, regurgitation
volume:
PISA	Align insonation		Quantitative	Not valid for
	beam with the		assessment of lesion	multiple jets, less
	fow		severity (EROA) and	accurate in
	Lower the color		volume overload	eccentric jets
	Doppler baseline		(RVol)	Limited
	in the direction of			experience and
	the jet			evidence
	Look for the			Typically lower RV
	hemispheric			pressures (than
	shape to guide			LV) lead to greater
	the best lower			contour fattening
	Nyquist limit			and
	CWD of			underestimation
	regurgitant jet for			in proportion to
	peak velocity and			Va/Vjet
	VTI

350 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 14 Grading the severity of chronic TR by echocardiography

Parameters	Mild	Moderate	Severe
Structural
TV morphology	Normal or mildly abnormal leafets	Moderately abnormal leafets	Severe valve lesions(e.g., fail
			leafet, severe retraction, large
			perforation)
RV and RA size	Usually normal	Normal or mild dilatation	Usually dilated*
Inferior vena cava diameter	Normal < 2 cm	Normal or mildly dilated 2.1- 2.5 cm	Dilated > 2.5 cm
Qualitative Doppler
Color fow jet area†	Small, narrow, central	Moderate central	Large central jetor eccentric wall-
			impinging jet of variable size
Flow convergence zone	Not visible, transient or small	Intermediate in size and duration	Large throughout systole
CWD jet	Faint/partial/parabolic	Dense, parabolic or triangular	Dense, often triangular
Semiquantitative
Color fow jet area (cm2)†	Not defned	Not defned	>10
VCW (cm)†	<0.3	0.3-0.69	$0.7
PISA radius (cm)‡	#0.5	0.6-0.9	>0.9
Hepatic vein fow§	Systolic dominance	Systolic blunting	Systolic fow reversal
Tricuspid infow§	A-wave dominant	Variable	E-wave >1.0 m/sec
Quantitative
EROA (cm2)	<0.20	0.20-0.39k	$0.40
RVol (2D PISA) (mL)	<30	30-44k	$45

RA, Right atrium. Bolded signs are considered specific for their TR grade. *RV and RA size can be within the ‘‘normal’’ range in patients with acute severe TR. †With Nyquist limit >50-70 cm/sec. ‡With baseline Nyquist limit shift of 28 cm/sec. §Signs are nonspecific and are influenced by many other factors (RV diastolic function, atrial fibrillation, RA pressure). kThere are little data to support further separation of these values.

right atrial and RV size measurements are larger by CMR than by echocardiography due to different handling of trabeculations.

D. Echocardiographic Evaluation of TR Severity

1. Color Flow Imaging. Color flow Doppler evaluation of TR severity involves a critical assessment of the components of the jet: jet area, VC, and flow convergence (Tables 13 and 14).

a. Jet area. Jet area is one of the color Doppler parameters of regurgitation severity. However, there can be considerable overlap of jet areas in patients with mild versus moderate TR. Furthermore, and similar to MR, regurgitant jets that are eccentric and wall impinging appear smaller than centrally directed jets with similar RVol (Figure 29). In general, a color Doppler jet area of >10 cm is consistent with severe TR; however, since several hemodynamic and anatomic factors affect the appearance of a central jet, jet area is often considered a semiquantitative parameter only. In wide-open, severe TR with no TV coaptation, the TR velocity may be so low that there is no aliasing of the jet velocity and TR may lose its appearance as a distinct jet.

b. Vena contracta. Visualization of the VCW is technically less demanding than the PISA method and can be utilized either semi-

quantitatively or qualitatively. When acquired from the apical four-chamber and RV inflow parasternal views, a TR VCW >0.7 cm identifies severe TR and is a marker of worse prognosis. Three-dimensional color Doppler methods can be used to measure VCA and VCW; however, it is important to note that the imaging planes acquired by 2D and those displayed by 3D may not be identical. In comparing 2D and 3D color Doppler measures of the VC, maximal VC diameter is often larger by 3D Doppler imaging. The 3D VCA correlates well with EROA, moderately well with VC diameter, and weakly with jet area/right atrial area ratio and was best for organic TR and in patients in sinus rhythm. From current available data, a VCA > 0.4 cm is a reasonable cutoff value for severe TR.

c. Flow convergence. The proximal convergence method is applicable in TR, but there is less experience with TR than with MR. Quantitation of TR using the PISA method has been validated in small studies but is not commonly used clinically (Figure 30). The general application is similar to MR. The TR PISA method is subject to all the limitations of its application in MR. In particular, the contour flattening as blood gets closer to the orifice may be exaggerated with TR, since the peak TR velocity is generally less than in MR, thus producing more flattening and regurgitant flow underestimation. To the extent that the orifice is noncircular (as often happens in TR), the usual PISA approach will produce

Zoghbi et al 351

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 29 Echocardiographic examples of TR cases. In mild TR, a small narrow jet is seen with a narrow VC, no flow convergence, and a ‘‘faint’’ TR jet on CWD. In severe eccentric TR, there is a wide VC and the color flow jet entrains the lateral wall of the right atrium in this patient with a flail septal leaflet; a dense parabolic jet with early peaking is seen. In the severe central TR, the VC is > 7 mm, with a large flow convergence; CWD demonstrates dense triangulated jet with low velocity (2 m/sec) consistent with severe TR and ventricularization of right atrial pressure.

Figure 30 Measurement of EROA and RVol in a patient with severe TR associated with pulmonary hypertension. Severe right atrial enlargement and atrial septal deviation to the left is seen in addition to systolic reversal of hepatic vein flow. D, Diastolic velocity; S, systolic velocity. Calculations are consistent with severe TR.

352 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

----- Start of picture text ----- Chronic Tricuspid Regurgitation by Doppler Echocardiography Yes, mild Does TR meet most specific criteria Yes, severe for mild or severe TR? No Specific Criteria for Mild TR Specific Criteria for Severe TR • Thin, small central color jet Minority of criteria or Intermediate Values: • Dilated annulus with no valve coaptation or • VC width <0.3 cm flail leaflet • PISA Radius <0.4 cm at Nyquist 30-40 cm/s TR Probably Moderate • Large central jet > 50% of RA • Incomplete or faint CW jet • VC width > 0.7 cm • Systolic dominant Hepatic vein flow • PISA radius > 0.9 cm at Nyquist 30-40cm/s • Tricuspid A-wave dominant inflow Perform VC measurement, and May perform • Dense, triangular CW jet or sine wave pattern. • Normal RV/RA quantitative PISA method, whenever possible* • Systolic reversal of Hepatic vein flow • Dilated RV with preserved function VC width < 0.3 cm VC width 0.3-0.69 cm VC width > 0.7 cm * EROA < 0.2 cm * EROA 0.2 - 0.4 cm * EROA > 0.4 cm * RVol < 30 mL * RVol = 30 - 44 mL * RVol ≥ 45 mL Mild TR Moderate TR Severe TR • Poor TTE quality or low confidence in measured Doppler parameters Indeterminate TR • Discordant quantitative and qualitative parameters and/or clinical data Consider further testing: TEE or CMR for quantitation * Clinical experience in quantaon of TR is much less than that with mitral and aorc regurgitaon ----- End of picture text -----

Figure 31 Algorithm for the integration of multiple parameters of TR severity. Good-quality echocardiographic imaging and complete data acquisition are assumed. If imaging is technically difficult, consider TEE or CMR. TR severity may be indeterminate due to poor image quality, technical issues with data, internal inconsistency among echo findings, or discordance with clinical findings.

further underestimation. On the other hand, if the TR arises eccentrically, then the proximal convergence zone will be constrained, producing flow overestimation. Using TTE, the 2D PISA method was compared to a single-beat 3D PISA method and to VCA and volumetric derivation of orifice area; EROA derived with 2D PISA underestimated regurgitant orifice area by the other methods.

2. Regurgitant Volume. In theory, TR volume can be calculated by subtracting the flow across a nonregurgitant valve from the antegrade flow across the TV annulus. In contrast to MR and AR, this approach is rarely utilized for TR, partly because of difficulty in accurately estimating the noncircular annular inflow area and the lack of velocity uniformity across the annulus.

The threshold value of RVol for severe TR is unclear. A comparative study in patients with severe MR and TR observed that for the same 2D PISA EROA of $0.4 cm, RVols cutoffs were different for TR ($45 mL/beat) than for MR ($60 mL/ beat), an obvious consequence of the typically lower TR velocity than MR, suggesting that in clinical practice different thresholds for severe TR and MR may need to be used for RVol, whereas a similar grading scheme can be employed for EROA cutoff. Further confirmation of these findings is needed using volumetric techniques.

3. Pulsed and Continuous Wave Doppler. It is important to note that TR jet velocity is not related to the volume of regurgitant flow. In fact, very severe TR is often associated with a low jet velocity (2 m/sec), with near equalization of RV and right atrial systolic pressures (Figure 29). Similar to MR, the features of the CWD TR jet that help in evaluating severity of regurgitation are the signal intensity and the contour of the velocity curve. With severe TR, a dense spectral recording is seen. A truncated, triangular jet contour with early peaking of the maximal velocity indicates elevated right atrium pressure and a prominent regurgitant pressure wave (‘‘V wave’’) in the right atrium (Figure 29). It should be noted that this pattern may be present in patients with milder degrees of TR and severe elevation of right atrium pressure (reduced right atrial compliance). With severe TR and normal RV systolic pressure, the antegrade and retrograde CW flow signals across the valve can appear qualitatively very similar with a ‘‘sine wave’’ appearance, corresponding to the ‘‘to-and-fro’’ flow across the severely incompetent valve.

Pulsed wave Doppler examination of the hepatic veins helps corroborate the assessment of TR severity. With increasing severity of TR, the normally dominant systolic wave is blunted. With severe TR, systolic flow reversal occurs (Figure 30). However, hepatic vein flow patterns are also affected by right atrial and RV compliance, respiration, preload, pacemaker rhythms, complete heart block, and

Zoghbi et al 353

Journal of the American Society of Echocardiography Volume 30 Number 4

atrial fibrillation and flutter. Systolic flow reversal is a specific sign of severe TR, provided that the modulating conditions mentioned above are accounted for during interpretation.

E. CMR Evaluation of TR Severity

CMR assessment of TR is less established compared with other regurgitant valvular lesions. Few indirect quantitative techniques have been used since direct measurement of tricuspid inflow is of limited value (substantial through-plane motion of the TV). RVol can be calculated by subtracting pulmonic forward volume from the RV SV and deriving a RF. Alternatively, in the absence of AR, aortic forward volume can be subtracted from the RV SV. Lastly, in the absence of other regurgitant lesions, LV SV can also be subtracted from RV SV to obtain TR RVol. There are no specific thresholds of RVol for TR severity by CMR. Instead, thresholds for RF have been borrowed from MR classification to grade TR severity (#15% mild, 16%-25% moderate, 25%-48% moderate to severe, and >48% severe).

Additional qualitative methods to assess TR have been reported using CMR. Visual assessment based on spin dephasing in the right atrium has been used previously. However, newer SSFP sequences, unlike the early spoiled gradient echo sequences, tend to minimize spin dephasing; this is even less appreciated in severe TR and is therefore not recommended to grade regurgitation severity. Time-resolved imaging of contrast kinetics angiography and retrograde hepatic vein contrast appearance have also been used.

The strength of CMR is its ability to quantitatively assess RVol, fraction, and ventricular and atrial remodeling. The limitations of CMR result both from errors in the RV volume assessment and issues in the acquisition of accurate phase-contrast images in the PA. It may be difficult to trace the enlarged trabeculated RV, which can extend above the tricuspid annulus into the atrial plane. Pulmonary outflow and aortic outflow were assessed in patients without an intracardiac shunt and the calculated Qp:Qs was found to be within 0.8-1.2. Therefore a 20% error can exist in either direction in the phase-contrast flow assessment of the PA. In addition, background phase, partial volume average from low spatial resolution and nonperpendicular plane selection, and complex jet flow pattern causing intravoxel dephasing and loss of phase coherence can all lead to inaccurate phase-contrast assessment. Indirect quantification of TR can amplify errors and lead to significant underor overestimation. In addition, to date, categorization of TR severity by CMR has not been validated due to lack of adequate reference standards.

F. Integrative Approach in the Evaluation of TR

The ideal approach to evaluation of TR severity is to integrate multiple parameters of TR severity rather than emphasize or depend on a single measurement. This approach helps to mitigate the effects of technical or measurement errors, which are inherent to each method previously discussed. It is also important to distinguish between the volume of TR and its hemodynamic consequences, particularly when considering acute versus more chronic regurgitation.

The consensus of the committee is to propose an approach to TR evaluation that would first assess the severity of valve regurgitation by evaluating whether there is a majority of specific signs that would point towards either mild or severe regurgitation (Figure 31). If most of the signs and indices are concordant, then there is confidence in the interpretation and no further quantitation is needed. If the signs

or values of the qualitative or semiquantitative parameters are in the intermediate range between mild and severe, most likely the severity of TR is moderate. Although quantitation may be feasible, it is more challenging than in MR and AR; echocardiographers with experience in quantitation may quantitate RVols and EROA to further refine assessment of intermediate lesions; however, clinical experience with these measurements is far less than with MR and AR. Furthermore, in contrast to MR and AR, further subclassifying TR severity into four grades according to quantitative criteria has not been validated in the literature. In the cases where there is difficulty in the evaluation of regurgitation by TTE, significant internal inconsistency (signs of mild and severe TR that cannot be resolved) or discordant findings with the clinical presentation, further evaluation by other modalities may be warranted to more accurately assess the mechanism and severity of TR.

Key Points

Physiologic mild TR is common in normal individuals. In patients with more than mild TR, identifying the mechanism of TR is important. TR is classified as primary or secondary (functional), and the precise mechanism of TR should be specified and reported (Table 12). No single Doppler and echocardiographic measurement or parameter is precise enough to quantify TR severity. Integration of multiple parameters is required (Tables 13 and 14). When multiple parameters are concordant, TR grade can be determined with high probability (especially for mild or severe TR). There is less experience with quantitation of TR severity with PISA or volumetric flow compared with MR and AR. Severe, wide-open TR may have low velocity, without aliasing or turbulence, and thus may be difficult to see as a distinct jet by color Doppler. The size of the right atrium and RV should be considered. Chronic severe TR almost always leads to dilated RV and right atrium. Conversely, normal chamber volumes are unusual with chronic severe TR. CMR assessment of TR is less established compared with other regurgitant valvular lesions. Few indirect quantitative techniques can be used. Additional testing with TEE or CMR is indicated when the TTE examination does not provide a mechanism for significant TR, the echo/Doppler parameters are discordant or inconclusive regarding the severity of TR, or there is discrepancy of echocardiographic findings with the clinical setting.

VI. PULMONARY REGURGITATION

Trace to mild PR, similar to TR, is a common finding and reported to occur in almost 75% of the population and is of little hemodynamic significance. The primary goal of imaging is to identify and assess abnormal degrees of PR, its etiology, and effect on cardiac structure and function.

A. Anatomy and General Imaging Considerations

The PVis a semilunar valve with three cusps, located anterior and superior to the aortic valve. The PV cusps are thinner than those of the aortic valve. In the normal heart, the PA arises from a muscular infundibulum and therefore lacks fibrous continuity with the TV. The plane of the PVisorthogonal tothatoftheaorticvalve.Awarenessofthisspatialrelationship is useful when the operator is attempting to define the optimal imaging window for PV imaging. Because the PV is an anterior structure, it offers challenges to imaging, particularly with TEE.

In addition to visualizing the valvular anatomy, the aims of imaging should include inspection of the RVOT, pulmonary annulus, main PA and proximal branches. The annulus and main PA may be dilated in patients with pulmonary hypertension and connective tissue disorders and in some patients with congenital heart disease. The RVOT is often dilated in patients with tetralogy of Fallot whose surgery involved enlargement of the RVOT, usually with a patch. Branch pulmonary stenosis may also contribute to more significant PR.

354 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 15 Doppler echocardiography in evaluating severity of PR

Modality	Optimization	Example	Advantages	Pitfalls
Color fow Doppler 2D
VC	Parasternal short-		Surrogate for	Not usable with
	axis or subcostal		effective regurgitant	multiple jets
	views		orifce size	The direction of the
	Zoomed view		Independent of fow	jet (in relation to the
	Should visualize		rate and driving	insonation beam) will
	proximal fow		pressure for a fxed	infuence the
	convergence, distal		orifce	appearance of the jet
	jet, and the ‘‘narrow’’		Less dependent on	Cutoffs for various
	neck in a single view		technical factors	grades of PR not
	Measured in diastole			validated.
	immediately below			Not easy to perform
	PV
VCW/PV annular	Parasternal short-		Simple sensitive	Underestimates PR in
diameter ratio	axis view		screen for PR	eccentric jets
	Zoomed view		Rapid qualitative	Overestimates PR in
	Optimize		assessment	central jets
	visualization of			PR jet may expand
	proximal PA			unpredictably below
				the orifce
Pulsed wave Doppler:	Align insonation		Simple supportive	Depends on
fow reversal in the	beam with the fow in		sign of severe PR	compliance of the PA
branch PA	the RPA and LPA			Brief velocity reversal
	Obtain pulsed wave			is normal
	Doppler from both
	branch PAs
CWD
Density of regurgitant jet	Align insonation	Severe PR with dense jet	Simple	Qualitative
	beam with the fow		Density is	Perfectly central jets
	PSAX view or		proportional to the	may appear denser
	subcostal views		number of red blood	than eccentric jets of
			cells refecting the	higher severity
			signal	Overlap between
			Faint or incomplete	moderate and severe
			jet is compatible with	PR
			mild PR
		Mild PR
				(Continued)

Zoghbi et al 355

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 15 (Continued)

Modality	Optimization	Example	Advantages	Pitfalls
Jet deceleration rate	Align insonation		Simple	Poor alignment of
(pressure half-time)	beam with the fow		Specifc sign of	Doppler beam may
	PSAX view or		pressure equalization	result in eccentric jets
	subcostal views		Values < 100 msec	providing low PHT
			consistent with	Affected by RV and
			severe PR	PA pressure
				difference, e.g., RV
				diastolic dysfunction.
The PR index	Align insonation		Uses combination of	Affected by RV
(A/B)	beam with the fow		PR duration and	diastolic dysfunction
	PSAX view or		duration of diastole	and RV diastolic
	subcostal views		Accounts for	pressures.
	Ensure complete		pressure differences
	forward and		between PA and RV
	regurgitant fow
	spectral Doppler
Quantitative Doppler:
RVol and fraction
RVol = SVRVOTSVLVOT	Pulmonic annulus		Quantitative, valid	Diffculties measuring
RF = RVol/SVRVOT	from PSAX view,		with multiple jets and	RVOT diameter
	measured during		eccentric jets.	In case of AR, would
	early ejection just		Provides lesion	need to use the mitral
	below PV		severity (RF) and	annulus site.
	Pulsed Doppler in		volume overload	Experience is scant
	RVOT from PSAX		(RVol); EROA not
	Aortic annulus		validated
	measured in early
	systole from PLA
	Pulsed Doppler in
	LVOT from apical
	window.

LPA, Left pulmonary artery; PHT, Pressure half-time; PSAX, Parasternal short axis; RPA, Right pulmonary artery.

B. Etiology and Pathology

Primary PR due to abnormal PV leaflets is more common in congenital heart disease and after balloon valvuloplasty for pulmonic stenosis than acquired valve disease. Significant acquired PR is rare, occurring in <1% of patients, and is present in adults with pathologies such as rheumatic heart disease, endocarditis, carcinoid valve disease, or pergolide-induced disease. Rarely blunt chest trauma can lead to leaflet disruption and prolapse. Secondary PR is most common in patients with elevated PA pressure, although the volume of regurgitation is usually small. By definition, the PV leaflets are normal with secondary PR.

C. Right Ventricular Remodeling

Significant primary PR leads to an enlargement of the RV with preserved RV function and a volume overload pattern of the septum. Chronic severe PR may lead to RV dysfunction. However, RV dilation by itself is not a specific sign of significant PR since it can result

from a number of conditions, so it is important to correlate RV dilation with the severity of PR by Doppler. Dilation may also be localized to the RVOT as can be seen after a tetralogy repair. In secondary PR, RV dilation and function as well as septal motion relate more to the underlying disease state (e.g., pulmonary hypertension severity) than to the degree of PR, which is usually at most moderate.

D. Echocardiographic Evaluation of PR Severity

There is a paucity of data regarding the quantification of PR. This stems partly from the difficulty in visualizing PR, the fact that minor degrees of PR are common and have no clinical impact, and the low incidence of clinically significant PR in the adult. Most of the concepts for quantifying AR are applied to PR. The various parameters used and their advantages and limitations are listed in Table 15.

1. Color Flow Doppler. Color Doppler assessment of PR severity includes proximal jet width, color jet area, and jet length (Figure 32).

356 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Figure 32 Examples of mild and severe PR depicting the difference in color jet, jet height (between arrows), and spectral density and deceleration of the PR jet by CWD. In severe PR, there is frequently early termination of the diastolic regurgitant flow (green arrow) with early equalization of RV and PA diastolic pressures.

A jet length of <10 mm is considered to represent insignificant PR, particularly if narrow at the origin; however, as in the case of AR, jet length is sensitive to driving pressure. The jet area has been related to various degrees of PR at angiography; however, significant overlap is seen, and it can be difficult to measure reproducibly. The proximal jet width (VC) is probably the most widely used semiqualitative color Doppler method. This parameter is less dependent on driving pressures and is simple and more reproducible. The VCW of the PR is commonly expressed as a ratio relative to the PV annulus diameter. A ratio of >0.5 is correlated with severe PR measured by CMR. It is important to note that in severe PR with normal PA pressures (e.g., primary PR), the color jet can be difficult to detect as the PR jet velocities are low, laminar, and brief in duration due to rapid equilibration of pressures across the PV. In secondary PR with pulmonary hypertension, the jet is aliased, of high velocity, and usually holodiastolic. There are limited data on the role of 3D echocardiography in assessing PR.

2. Pulsed and Continuous Wave Doppler. The density of the CW signal provides a qualitative measure of regurgitation. The CW pattern seen in mild PR shows a soft or faint signal with slow deceleration. In contrast, severe PR has a dense jet with rapid deceleration of the velocity due to the rapid equilibration of the diastolic pressure gradient between the PA and RV (Figures 32 and 33). This ‘‘to-andfro’’ flow across the PV shows a characteristic ‘‘sine wave’’ shape. It is important to note that rapid deceleration by itself is not specific for severe PR and can be seen in conditions with decreased RV compliance. Judging the severity of PR in these situations will

depend on color Doppler characteristics of the PR jet and comparative flow considerations.

Few indices have been proposed to quantitate the deceleration of the PR velocity and its premature diastolic termination. A pressure half-time of <100 msec (or deceleration time of < 260 msec) has been shown to be consistent with severe PR. A PR index has also been suggested, calculated as the ratio of PR duration by CWD to total diastolic time (Figure 33). A PR index of <0.77 was shown to correlate well with severe PR by CMR. However, these indices, as noted, are not specific for severe PR and have to be integrated with other findings in evaluating PR severity.

An additional sign of severe PR by pulsed Doppler is the presence of reverse flow in the PA. The presence of diastolic flow reversal in the branch pulmonary arteries had a sensitivity and specificity of 87% for severe PR compared with CMR. It is important to visualize and sample flow in the branch pulmonary arteries and not just in the main PA, as the specificity dropped to 39%.

3. Quantitative Doppler. Quantitative pulsed Doppler methods can be used to measure PR RVol and fraction. The RVOT, however, is probably the most difficult site to measure SV because of its poor visualization and the changing size of the RVOT during the cardiac cycle. The RVOT is measured during early ejection (two to three frames after the R wave on the electrocardiogram) just below the PV in the parasternal short-axis view. Although not validated for quantitation of PR, flows in the RVOT can be compared to other sites to derive RVol and fraction.

Zoghbi et al 357

Journal of the American Society of Echocardiography Volume 30 Number 4

Figure 33 CWD of pulmonic flow. Calculation of pulmonic regurgitation index (PR index = A/B) is shown, an index of PR severity, quantitating early termination of diastolic regurgitant flow.

Figure 34 An example of severe PR (arrow) assessed by CMR. The red circles depict the magnitude image of the pulmonary artery (upper left panel) and the respective phase contrast image (lower left panel). Forward SV by phase contrast was 129 mL, and reverse (regurgitant) volume was 78 mL, yielding an RF of 60% (lower right panel).

358 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Table 16 Echocardiographic and Doppler parameters useful in grading PR severity

Parameter	Mild	Moderate	Severe
Pulmonic valve	Normal	Normal or abnormal Abnormal and may not be visible
RV size	Normal*	Normal or dilated	Dilated†
Jet size, color Doppler‡	Thin (usually <10 mm in length) with a	Intermediate	Broad origin; variable depth of
	narrow origin		penetration
Ratio of PR jet width/pulmonary			>0.7§
annulus
Jet density and contour (CW)	Soft	Dense	Dense; early termination of diastolic
			fow
Deceleration time of the PR spectral			Short, <260 msec
Doppler signal
Pressure half-time of PR jet			<100 msecjj
PR index{		<0.77	<0.77
Diastolic fow reversal in the main or			Prominent
branch PAs (PW)
Pulmonic systolic fow (VTI)	Slightly increased	Intermediate	Greatly increased
compared to systemic fow (LVOT
VTI) by PW#
RF**	<20%	20%-40%	>40%

PW, Pulsed wave Doppler. *Unless there are other reasons for RV enlargement. †Exception: acute PR. ‡At a Nyquist limit of 50-70 cm/sec. §Identifies a CMR-derived PR fraction $40%. {Defined as the duration of the PR signal divided by the total duration of diastole, with this cutoff identifying a CMR-derived PR fraction > 25%. jjNot reliable in the presence of high RV end diastolic pressure. #Cutoff values for RVol and fraction are not well validated. §Steep deceleration is not specific for severe PR. **RF data primarily derived from CMR with limited application with echocardiography.

E. CMR Methods in Evaluating PR

CMR is currently the best method to quantitate PR and serially evaluate RV remodeling and function in patients with significant PR and congenital heart disease. Several approaches can be used to quantify PR by CMR. These can be classified into two broad categories as direct and indirect methods resulting in calculations of RVol and fraction. The methodology of these approaches and their clinical use have been discussed earlier and previously detailed. There is some evidence that pulmonic RVol may better reflect the physiological consequence to the RV than RF. Other CMR techniques such as visual assessment of the degree of signal loss due to spin dephasing from the regurgitation can be used but are less validated and provide only a qualitative assessment.

The direct method based on the use of phase-contrast imaging with acquisition obtained from above the PV (Figure 34) is the preferred method, as it allows direct measurement of total pulmonic forward SVand RVol. The indirect methods are based on SV quantification by ventricular endocardial contouring with or without additional phase-contrast imaging. One method is to use the difference in RV and LV SVs. This technique is only valid in the absence of any other concomitant valvular regurgitation. A second indirect method is to use the difference between RV SV by endocardial contouring and aortic forward SV by phase-contrast imaging to calculate pulmonic RVol. This method is only valid in the absence

of TR. Other indirect techniques can be used but are less reliable. The best use of these indirect techniques is to confirm the findings of the direct technique.

There are no specific thresholds for PR severity by CMR; as in other regurgitant valves, these have been borrowed from the echo literature. One recommendation for PR severity uses a RF <20% to define mild PR, 20%-40% for moderate, and >40% for severe PR. RVol categories for PR severity by CMR have not been

F. Integrative Approach to Assessment of PR

Trivial and mild PR is clinically very common and easily diagnosed. On the other hand, clinically significant PR is uncommon and is usually secondary to pulmonary hypertension and congenital heart disease. Echocardiography is the primary modality for assessment of PR. An integrative approach combining color, pulsed wave Doppler, and CWD methods should be used in the grading of PR. The simplest and most robust method is PR jet width, and VC. Other Doppler measures have limitations, high variability, or limited validation. Table 16 summarizes the parameters for grading PR. Using these criteria, an algorithm was developed for the assessment of PR and separating mild from severe PR (Figure 35). If the majority or all criteria point to either mild or severe PR, the evaluation of the severity of PR is confident. If intermediate criteria or an overlap among them is present, the

Zoghbi et al 359

Journal of the American Society of Echocardiography Volume 30 Number 4

Chronic Pulmonic Regurgitation by Color Doppler

----- Start of picture text ----- Yes, mild Does PR meet most specific criteria Yes, severe for mild or severe PR? No Specific Criteria for mild PR Specific Criteria for Severe PR • Small Jet, with narrow width Minority of criteria or Intermediate Values: • Jet width/Annulus ≥ 70% • Soft or faint CW jet • Dense jet, PHT < 100 ms • Slow deceleration time PR Probably Moderate • Early termination of PR flow • Normal RV Size • Diastolic flow reversal in PA branches • Dilated RV with NL function May Perform volumetric quantitative methods, if possible, whenever significant PR is suspected* RF <20% RF 20-40% RF >40% Mild PR Moderate PR Severe PR Poor TTE quality or discordant parameters with clinical data, Indeterminate PR particularly when significant PR may be suspected Consider CMR for quantitation * Clinical experience in quantaon of PR is sparse. ----- End of picture text -----

Figure 35 Algorithm for the integration of multiple parameters of PR severity. Good-quality echocardiographic imaging and complete data acquisition are assumed. If imaging is technically difficult, consider CMR or TEE. PR severity may be indeterminate due to poor image quality, technical issues with data, internal inconsistency among echo findings, or discordance with clinical findings. PHT, Pressure half-time.

Key Points

• Physiologic, mild PR is common in normal individuals.

• In patients with more than mild PR, identifying the mechanism of PR is important. PR is classified as primary or secondary (functional); primary PR is more common in congenital heart disease.

• No single Doppler and echocardiographic parameter is precise enough to quantify PR severity. Integration of multiple parameters is required (Tables 15 and 16 and Figure 35). When multiple parameters are concordant, PR grade can be determined with high probability (especially for mild or severe PR).

• There is little experience with quantitation of PR severity with Doppler echocardiography.

• Severe, primary PR with normal pulmonary pressures may be of very short duration and has low velocity; thus it may be difficult to see as a distinct jet by color Doppler.

• The size of the RV should be always considered. Chronic severe PR almost always leads to a dilated RV. Conversely, normal chamber volumes are unusual with chronic severe PR. In patients with PR secondary to pulmonary hypertension, the size and function of the RV are variable.

• CMR is an excellent modality for evaluation of the PV, PA and for quantitation of PR severity, using the direct phase-contrast method. It is the preferred method for quantitation of RV volume and function.

• Additional testing with CMR is indicated when the TTE examination does not provide a mechanism for significant PR, the echo/Doppler parameters are discordant or inconclusive regarding the severity of PR, or there is discrepancy of echocardiographic findings with the clinical setting. This indication is particularly relevant in patients with suspected or known congenital heart disease. TEE is not a preferred modality when information beyond TTE is needed.

severity of PR is likely moderate. Although quantitation may be feasible, it is more challenging than in MR and AR; echocardiographers may quantitate RVols and fractions to further refine assessment of intermediate lesions; however, clinical experience with these measurements is far less than with MR and AR and likely better obtained with CMR. Furthermore, in contrast to MR and AR, further subclassifying PR severity into four grades according to quantitative criteria has not been validated in the literature. CMR is indicated when there is concern for clinically significant

PR that cannot be reliably assessed by echocardiography, when the mechanism for PR is not clear, or when there is a discrepancy between severity by echocardiography and other clinical findings (e.g., only moderate PR with dilating RV). In adolescents and adults with congenital heart disease (e.g., repaired tetralogy, after pulmonary valvotomy) and when there is concern for more than moderate PR, CMR is indicated for quantification and follow-up of PR and RV size and function, especially when intervention such as PV replacement is being considered.

360 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

VII. CONSIDERATIONS IN MULITIVALVULAR DISEASE

The presence of multivalvular disease makes the assessment of valvular regurgitation more complex. When evaluating the impact of a second valve lesion on a regurgitant lesion, one must consider in addition to the impact on outcomes, whether the additional lesion modifies the actual severity of the primary lesion and whether it affects the quantitation and grading of the primary lesion. Table 17 indicates a few of the ways that the assessment of a given regurgitant lesion by Doppler echocardiography or CMR can be impacted by another concomitant valve lesion.

A. Impact of Multivalvular Disease on Echocardiographic Parameters of Regurgitation

1. Color Jet Area. A lesion or condition that results in a higher pressure gradient will affect color jet area as detailed earlier under general considerations. For example, the addition of aortic stenosis to MR will increase the RVol in proportion to the square root of the rise in LV pressure, assuming that the EROA remains the same (since jet velocity is related to the square root of the driving pressure gradient). The jet area, however, will be expected to increase more than this, since jet momentum is proportional to regurgitant orifice area Dp and thus is increased above and beyond the increase in flow. Similarly, any lesion that increases pulmonary arterial pressure will worsen TR by similar amounts, with an exaggerated impact on jet area.

2. Regurgitant Orifice Area. Beyond the predictable changes in jet flow with driving pressure, one should also consider whether the second lesion will increase the size of the regurgitant orifice area. Functional MR is particularly prone to this, as the degree of coaptation can vary considerably with LV volume. For example, the further LV dilation from severe AR might increase the regurgitant orifice area in secondary MR and dramatically worsen the RVol. In contrast, one could imagine that a Barlow’s-type MV might see a reduction in regurgitant orifice area when AR dilates the LV, making the mitral prolapse less pronounced.

3. Proximal Convergence and Vena Contracta. PISA and VC methods should generally not be influenced by another regurgitant jet, such as AR. Even in severe MR, the flow convergence region, from which PISA calculations are made, is usually within 1.5 cm of the mitral orifice. Unless AR is markedly eccentric directed posteriorly (e.g., a flail right coronary cusp), the AR jet is not likely to interfere with the flow convergence of the MR. One exception would be if the AR flow is severe enough that the forward flow through the LVOT ‘‘contaminates’’ the proximal convergence flow, pushing the aliasing radius outward. A potential solution for this is to increase the Va, so that the MR PISA is clearly separated from the LVOT flow. The same general observation applies to VC methods, whether using a simple long-axis VCW or the more elegant 3D planimetry of the VCA described previously. There should be little direct impact on VC from a second valvular lesion.

4. Volumetric Methods. All the volumetric methods for quantifying valvular regurgitation require a reference SV against which flow through regurgitant valves can be compared. For example, in isolated MR, LVOT flow could be used as the reference SV. The forward plus mitral RVol could be obtained by either the difference in

LV end-diastolic volume and LV end-systolic volume obtained from 2D or 3D echo or by using PW Doppler to measure the SV through the mitral annulus. Subtracting LVOT SV from either of these ‘‘mitral’’ SVs will yield the mitral RVol. However, if AR ensues, then there is no measurement in the left heart that reflects pure systemic flow, as the LV SV includes both the AR and MR RVols. In such a case, one should seek a reference volume in the right heart, most commonly the RVOT, as the TV annulus site is challenging. Unfortunately, if all four valves have important regurgitation, or a shunt is present from an atrial or ventricular septal defect, then there may simply be no reference systemic SV to use. In such cases, direct measurement of forward and reversed flow through a given valve is the best option. Currently, this is most reliably performed with velocity encoded magnetic resonance imaging (see below), although there is hope that 3D echo could do this as well.

B. CMR Approach to Quantitation of Regurgitation in Multivalvular Disease

CMR methods for the quantification of valvular regurgitation can offer advantages over other methods in the setting of multivalvular disease. For example, the direct method of AR volume assessment via forward andreverseflowmeasurementsintheaorticrootisgenerallynotaffected by aortic stenosis, mitral stenosis or regurgitation, or right-sided valvular lesions. It is important to note that in the settingofconcomitant aortic stenosis, the aortic forward flow may be underestimated (due to intravoxel dephasing from the stenotic jet). Although the aortic reverse volume assessment would not be affected, it will be useful to utilize the forward flow proximal to the lesion (i.e., LVOT) for the purposes of calculating RF. The principles discussed would also apply to the assessment of PR in the setting of concomitant valvular lesions. Table 17 highlights conditions where acquisition or quantitation of RVol and fraction would be different than discussed earlier.

The preferred indirect method for deriving mitral RVol (LV SV - aortic forward SV) will be unaffected by coexisting AR (as both LV SV and aortic forward SV will be increased by the amount of AR). However, calculation of mitral RF will require subtracting the AR RVol from the LV SV. Therefore mitral RF in combined MR and AR would be derived by the following: MR RVol/(LVSV - AR RVol) * 100. As the preferred method for TR assessment is analogous, the principles discussed would also apply to TR assessment in the setting of concomitant valvular lesions.

It is important to note, however, that alternative methods for quantifying regurgitation (aside from the preferred methods detailed above) that are often used as confirmatory checks may not be valid in the setting of multiple valvular lesions. Furthermore, assessments of regurgitant severity could be affected in the setting of intracardiac shunt lesions.

As there is a paucity of data on indications for CMR in the setting of multiple valvular lesions, it is reasonable to consider CMR for scenarios as outlined. Owing to the fact that CMR methods are generally independent of other valvular lesions, it may in fact be the preferred method in these situations. Additionally, CMR may be especially useful in the setting of mixed valve disease to fully determine the consequences of multiple lesions on cardiac morphology and function.

Key Points

• The presence of multivalvular disease makes the assessment of valvular regurgitation more complex.

• When evaluating the impact of a second valve lesion on a regurgitant lesion, one must consider, in addition to the impact on outcomes, whether the lesion (stenosis or regurgitation) modifies the actual severity of the primary regurgitant lesion and whether it affects the quantitation and grading of the primary lesion (Table 17).

Zoghbi et al 361

Journal of the American Society of Echocardiography Volume 30 Number 4

Table 17 Impact of multivalvular disease on assessment of valvular regurgitation with Doppler echocardiography and CMR

By this Valvular Lesion	Impact on this Regurgitant Lesion
	AR MR PR TR
AS	Little impact, although hemodynamically signifcant AR will increase AS gradient. For CMR: phase-contrast plane better in LVOT For constant ROA, RVol increases in proportion to square root of excess pressure; jet area exaggerated beyond this. ROA may increase if LV dilates. Little impact unless PH ensues. Little impact unless PH ensues.
AR	NA LV dilation may increase ROA (especially in secondary MR). Mixed regurgitant lesions render volumetric methods challenging, as one must fnd some location refective of net forward fow (e.g., RVOT). For CMR: MV RVol = LVSV - aortic forward fow; MR Reg fraction = MR RVol/ (LVSV - AR Rvol). Little impact unless PH ensues. Little impact unless PH ensues.
MS	Little direct impact, although the delayed LV flling might theoretically lengthen AR pressure half-time. If MV is heavily calcifed, may shadow and decrease jet area and appearance of jet. Lesion most likely to increase PAP and thus worsen RVol and jet area. Lesion most likely to increase PAP and thus worsen RVol and jet area. If RV dysfunction occurs, may increase ROA.
MR	Little direct impact, but mixed regurgitant lesions render volumetric methods challenging, as one must fnd some location refective of net forward fow (e.g., RVOT). Rapid early flling may decrease AR pressure half-time NA Likely to increase PAP and thus worsen RVol and jet area. Likely to increase PAP and thus worsen RVol and jet area. If RV dysfunction occurs, may increase ROA.
PS	Little direct impact Little direct impact Little impact, although PR will exacerbate PS gradient. For CMR: phase-contrast plane better in RVOT. Increased RVSP will worsen RVol and jet area. If RV dysfunction occurs, may increase ROA.
PR	Little direct impact Little direct impact NA Increased RV volume may increase ROA, which will worsen RVol and jet area. For CMR: TV RVol = RVSV - pulmonic forward fow. TR Reg fraction = TR RVol/ (RVSV - PR RVol).
TS	Little direct impact Little direct impact Little direct impact Little direct impact, although TR will exacerbate TS gradient.
TR	Little direct impact Little direct impact Rapid RV flling from TR may further shorten PR pressure half-time, and color PR jet more brief. NA

AS, Aortic stenosis; MS, mitral stenosis; NA, not applicable; PAP, pulmonary artery pressure; PH, pulmonary hypertension; PS, pulmonic stenosis; Reg, regurgitant; ROA, regurgitant orifice area; RVSP, right ventricular systolic pressure; TS, tricuspid stenosis. CMR-related considerations are in bold.

362 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Key Points

VIII. INTEGRATING IMAGING DATA WITH CLINICAL INFORMATION

The optimal management of patients with valvular regurgitation requires excellent clinical judgment as well as excellent imaging skills. As irreversible LV or RV dysfunction can develop with these lesions before the onset of significant symptoms, it is possible to wait too long before referring patients for surgery or, in some cases, transcatheter intervention. It is also possible to overestimate severity of regurgitation and operate too early in the natural history, thus subjecting patients to the short-term risks of surgical complications and longterm risks of prosthetic valves when they otherwise might have done well without surgery for many years. Thus, accurate quantification of RVols and their hemodynamic impact are of paramount importance.

Data regarding the presence and severity of valvular regurgitation, whether obtained by echocardiography or CMR, need to be interpreted in context with the clinical presentation. Common scenarios include asymptomatic patients with newly diagnosed heart murmurs, patients with known valve disease undergoing serial imaging studies to assess severity of regurgitation and its hemodynamic impact, and patients with heart failure undergoing imaging to assess LV function in whom secondary MR may be suspected or unsuspected. Valvular regurgitation is also often identified as an incidental finding when imaging is performed for other purposes, such as patients after myocardial infarction or patients receiving chemotherapy, in whom previously undetected MR may result from LV systolic dysfunction or be unrelated. Significant but previously unrecognized TR is often detected during evaluation of patients with chronic MR and will require attention if MV surgery is recommended. Similarly, severe PR may be relatively silent for many years in patients following repair of tetralogy of Fallot and other congenital diseases. The indications for and frequency of imaging vary depending on the stages of the disease process as defined in the 2014 AHA/ACC guidelines for management of valvular heart disease: stage A, individuals without known disease but at risk for valvular regurgitation (such as patients with bicuspid aortic valves, MVP, previous rheumatic fever, previous myocardial infarction or dilated cardiomyopathy, previous repair of congenital heart disease); stage B, patients with asymptomatic mild to moderate valvular regurgitation with preserved LVor RV function; stage C, patients with asymptomatic severe valvular regurgitation (C1, normal ventricular systolic function; and C2, depressed ventricular systolic function); and stage D, symptomatic patients with severe valvular regurgitation.

Clinically significant MR almost always produces a systolic murmur, and the characteristics of the murmur should be taken into consideration in image interpretation. For example, a mitral murmur that is late systolic in timing rather than holosystolic suggests that the MR is not severe, in which case the timing of the Doppler signal may be more important than the magnitude of the VC and the calculated EROA by PISA in assessing overall severity of MR. An MR murmur that radiates to the posterior thorax is almost always indicative of severe MR; in such cases an eccentric MR jet may be difficult to quantify but the physical findings may prompt additional ancillary imaging findings such as LA dilation and reversal of systolic flow in the pulmonary veins. Symptomatic patients with apparently mild or moderate MR on resting echocardiographic studies, in whom the MR murmur changes dramatically with interventions such as the Valsalva maneuver or standing from a squatting position, may be candidates for exercise Doppler interrogation to determine

The optimal management of patients with valvular regurgitation requires both excellent clinical judgment as well as excellent imaging skills. Irreversible LV or RV dysfunction can develop with valvular regurgitation before the onset of clinical symptoms, hence the need for careful serial observations and periodic stress testing in patients with asymptomatic significant regurgitation. It is possible to overestimate severity of regurgitation and operate too early in the natural history, thus subjecting patients to the short-term risks of surgical complications and long-term risks of prosthetic valves when they otherwise might have done well without surgery for many years. Thus, accurate assessment and quantification of regurgitation severity parameters and their hemodynamic impact are of paramount importance. If TTE results are inconclusive or discordant with the clinical assessment, one should not hesitate to proceed to TEE, CMR, or possibly invasive hemodynamic evaluation for further assessment and clarification.

whether exercise-induced symptoms correlate with worsening of MR. Patients with LV dysfunction and secondary MR often have very soft murmurs even when the MR is severe, and an apical systolic murmur of any magnitude on physical exam in a patient with known LV systolic dysfunction should raise the possibility of clinically significant secondary MR. It is also important to recognize that even mild degrees of MR, which would be well tolerated for years in patients with primary MR, identify patients at considerable risk of heart failure and death in the setting of LV dysfunction and secondary MR.

In contrast, the diastolic murmur of AR is often barely audible or may be completely absent, and the only appreciable murmur may be a systolic outflow murmur related to the high SV. Additional physical findings such as a wide pulse pressure or bounding carotid pulses point toward significant AR rather than AS. AR is often first identified on echocardiograms performed to investigate a systolic murmur.

Similarly, TR is also often not identified clinically prior to echocardiography but identified as an important concomitant lesion in patients with MR. When TR results from primary disease of the TV, there are often no clinical manifestations when the TR is mild. However, severe TR caused by primary disorders is almost invariably associated with a systolic murmur with respiratory variation, elevated V waves in the jugular venous pulse, and an RV heave as evidence of RV volume overload. PR in the setting of normal PA pressure, such as following repair of tetralogy of Fallot, can go unrecognized as the murmur is usually soft and low pitched, whereas PR related to pulmonary hypertension creates a higher pitched murmur that is difficult to distinguish from AR.

As the clinical management of patients with severe MR or AR continues to evolve toward early surgical intervention, it is important that early preemptive surgery be performed only in those with truly severe regurgitation. Similarly, surgery in symptomatic patients is recommended only when AR or MR is considered severe enough to be the cause of symptoms. Thus, quantifying severity of regurgitation with echocardiography or CMR is of paramount importance in determining whether asymptomatic or symptomatic patients are candidates for surgical or percutaneous intervention. In such cases, however, patient symptoms and all of the skills of the clinician such as meticulous physical examination and history taking are of equal importance to the results of the imaging itself to identify those with truly severe disease.

In patients with secondary TR associated with MV disease, surgical repair of severe TR is indicated at the time of MV surgery whether or not there are clinical signs of severe TR. In such situations, the decision for concomitant TVrepair is driven principally by imaging evidence of severe TR or severe dilation of the tricuspid annulus. In contrast, in patients with primary TR, the clinical presentation is also of great

Zoghbi et al 363

Journal of the American Society of Echocardiography Volume 30 Number 4

importance, as the indications for surgical tricuspid repair or replacement are strongest in those with symptoms, declining exercise tolerance, or evidence of RV failure. However, TV surgery may also be considered in asymptomatic patients when there is evidence of severe TR associated with progressive RV dilation or systolic dysfunction. Diagnosing the etiology of primary TR is often challenging. Expert imaging with echocardiography or CMR is the key to reduce misdiagnoses.

Isolated PR in adults is usually innocuous and rarely severe. A highpitched murmur of PR, however, may be an important clinical marker of primary or secondary pulmonary hypertension. In addition, PR following repair of tetralogy of Fallot is a common late complication of previous surgical repair with important clinical implications. Patients with previous tetralogy repair should be considered for surgery if severe PR is present in the setting of symptoms, declining effort tolerance, RV dilation/dysfunction, atrial or ventricular arrhythmias, or moderate to severe TR. As the murmur of PR may itself be unimpressive, awareness of the high frequency of this late complication following otherwise successful repair, with appropriate referral for imaging, is essential. Similarly, hemodynamically important PR in the absence of pulmonary hypertension is a possible late outcome in patients who have undergone transcatheter or surgical PV repair or replacement for pulmonic stenosis and in patients with a pulmonary homograft following a Ross procedure. This emphasizes the need for long-term follow-up of such patients.

In asymptomatic patients with known valvular disease who are being followed serially, the timing of imaging studies changes when there are changes in the clinical situation. Exercise stress testing is used to assess functional capacity and equivocal symptoms. The onset of possible or definite symptoms or changes in the timing or intensity of the murmur should trigger repeat echocardiography or CMR. In patients with bicuspid aortic valves, a new murmur of AR could reflect an increase in severity or dilatation of the aortic sinuses or ascending aorta and is an indication for comprehensive imaging with echocardiography, CMR or both.

increased reproducibility of quantification, reduced dependency on shape and size assumptions, and improvement in work flow, allowing easier integration into routine clinical practice. In CMR, further improvements in quantitation of flow across mitral and TVs, taking into account annular motion, would further enhance the power of the technique to quantitate individual and multiple valve lesions.

REVIEWERS

This document was reviewed by members of the 2016-2017 ASE Guidelines and Standards Committee, ASE Board of Directors, ASE Executive Committee, and a representative for the Society for Cardiovascular Magnetic Resonance.

Reviewers included Deborah A. Agler, RCT, RDCS, FASE, Federico M. Asch, MD, FASE, Merri L. Bremer, EdD, RN, EDCS, ACS, FASE, Benjamin Byrd, MD, FASE, Hollie D. Carron, RDCS, FASE, Joao L. Cavalcante, MD, FASE, Scott D. Choyce, RDCS, RVT, RDMS, FASE, Frederick C. Cobey, MD, FASE, Meryl Cohen, MD, FASE, Patrick H. Collier, MD, PhD, FASE, Keith A. Collins, MS, RDCS, FASE, Mary C. Corretti, MD, FASE, Benjamin Eidem, MD, FASE, Mark K. Friedberg, MD, FASE, Neal Gerstein, MD, FASE, Edward A. Gill, MD, FASE, Yvonne E. Gilliland, MD, FASE, Robi Goswami, MD, FASE, Stephen Heitner, MD, FASE, Lanqi Hua, RDCS, FASE, Soo H. Kim, MD, MPH, RPVI, FASE, James N. Kirkpatrick, MD, FASE, Allan L. Klein, MD, FASE, Jonathan R. Lindner, MD, FASE, Rick Meece, ACS, RDCS, RCIS, FASE, Carol Mitchell, PhD, RDMS, RDCS, RVT, RT(R), ACS, FASE, Tasneem Naqvi, MD, FASE, Maryellen H. Orsinelli, RN, RDCS, FASE, Andy Pellett, PhD, RCS, RDCS, FASE, Patricia A. Pellikka, MD, FASE, Sue D. Phillip, RCS, FASE, Juan Carlos Plana, MD, FASE, Vera H. Rigolin, MD, FASE, Vandana Sachdev, MD, FASE, Anita Sadeghpour, MD, FASE, Liza Y. Sanchez, RCS, FASE, Elaine Shea, ACS, RCS, RCCS, FASE, Roman M. Sniecinski, MD, FASE, Raymond F. Stainback, MD, FASE, Cynthia Taub, MD, FASE, Seth Uretsky, MD, Steven Walling, RCS, RDCS, FASE, Neil J. Weissman, MD, FASE, Susan E. Wiegers, MD, FASE, and David H. Wiener, MD, FASE.

IX. FUTURE DIRECTIONS

NOTICE AND DISCLAIMER

Cardiovascular imaging has had a major impact in the diagnosis, prognosis, and management of patients with valvular heart disease. In general, regurgitation may present a challenge for most diagnostic techniques because of the dynamic nature of the lesion and its dependence on various hemodynamic and physiologic conditions. For all valvular regurgitation, irrespective of the modality, an integrative approach is recommended to achieve an accurate evaluation of the severity of the lesion and its clinical significance. This takes into account physiologic conditions that could alter the accuracy of certain parameters, emphasizes the quality of the primary data, and allows internal verification of the interpretation. Future developments should aim for advances in ultrasound and CMR techniques, more automation in quantitation to reduce variability, and more data on quantitation and grading of right heart lesions in relation to outcomes. In real-time 3D imaging, improvements in temporal and spatial resolution to enhance display of valve regurgitation and improve automation of flow convergence, VC, and the regurgitant jet would be welcome. Recent advances have included the use of 3D volume color Doppler acquisition followed by use of the velocity information intrinsic to color Doppler data to quantify SVand PISA in mitral, aortic, and TR. The important potential strengths of these methods include the

This report is made available by ASE as a courtesy reference source for members. This report contains recommendations only and should not be used as the sole basis to make medical practice decisions or for disciplinary action against any employee. The statements and recommendations contained in this report are primarily based on the opinions of experts, rather than on scientifically verified data. ASE makes no express or implied warranties regarding the completeness or accuracy of the information in this report, including the warranty of merchantability or fitness for a particular purpose. In no event shall ASE be liable to you, your patients, or any other third parties for any decision made or action taken by you or such other parties in reliance on this information. Nor does your use of this information constitute the offering of medical advice by ASE or create any physicianpatient relationship between ASE and your patients or anyone else.

REFERENCES

1. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al. 2014 AHA/ACC guideline for the management of

364 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438-88.

2. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777-802.

3. Lang RM, Badano LP, Tsang W, Adams DH, Agricola E, Buck T, et al. EAE/ASE recommendations for image acquisition and display using three-dimensional echocardiography. J Am Soc Echocardiogr 2012;25: 3-46.

4. Lang RM, Tsang W, Weinert L, Mor-Avi V, Chandra S. Valvular heart disease. The value of 3-dimensional echocardiography. J Am Coll Cardiol 2011;58:1933-44.

5. American College of Cardiology Foundation Task Force on Expert Consensus, Hundley WG, Bluemke DA, Finn JP, Flamm SD, Fogel MA, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol 2010;55:2614-62.

6. Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG, et al. Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. J Cardiovasc Magn Reson 2013;15:35.

7. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, Detaint D, Capps M, Nkomo V, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352:875-83.

8. Detaint D, Messika-Zeitoun D, Maalouf J, Tribouilloy C, Mahoney DW, Tajik AJ, et al. Quantitative echocardiographic determinants of clinical outcome in asymptomatic patients with aortic regurgitation: a prospective study. JACC Cardiovasc Imaging 2008;1:1-11.

9. Topilsky Y, Nkomo VT, Vatury O, Michelena HI, Letourneau T, Suri RM, et al. Clinical outcome of isolated tricuspid regurgitation. JACC Cardiovasc Imaging 2014;7:1185-94.

10. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759-64.

11. Sandler H, Dodge HT, Hay RE, Rackley CE. Quantitation of valvular insufficiency in man by angiocardiography. Am Heart J 1963;65:501-13.

12. Ben Zekry S, Nagueh SF, Little SH, Quinones MA, McCulloch ML, Karanbir S, et al. Comparative accuracy of two- and three-dimensional transthoracic and transesophageal echocardiography in identifying mitral valve pathology in patients undergoing mitral valve repair: initial observations. J Am Soc Echocardiogr 2011;24:1079-85.

13. Mantovani F, Clavel MA, Michelena HI, Suri RM, Schaff HV, EnriquezSarano M. Comprehensive imaging in women with organic mitral regurgitation: implications for clinical outcome. JACC Cardiovasc Imaging 2016;9:388-96.

14. Thomson HL, Basmadjian AJ, Rainbird AJ, Razavi M, Avierinos JF, Pellikka PA, et al. Contrast echocardiography improves the accuracy and reproducibility of left ventricular remodeling measurements: a prospective, randomly assigned, blinded study. J Am Coll Cardiol 2001; 38:867-75.

15. Mor-Avi V, Jenkins C, Kuhl HP, Nesser HJ, Marwick T, Franke A, et al. Real-time 3-dimensional echocardiographic quantification of left ventricular volumes: multicenter study for validation with magnetic resonance imaging and investigation of sources of error. JACC Cardiovasc Imaging 2008;1:413-23.

16. Tribouilloy C, Shen WF, Quere JP, Rey JL, Choquet D, Dufosse H, et al. Assessment of severity of mitral regurgitation by measuring regurgitant jet width at its origin with transesophageal Doppler color flow imaging. Circulation 1992;85:1248-53.

17. Thomas JD, Liu CM, Flachskampf FA, O’Shea JP, Davidoff R, Weyman AE. Quantification of jet flow by momentum analysis. An in vitro color Doppler flow study. Circulation 1990;81:247-59.

18. Blevins R. Applied Fluid Dynamics Handbook. New York: Van Nostrand Reinhold; 1984.

19. Chen CG, Thomas JD, Anconina J, Harrigan P, Mueller L, Picard MH, et al. Impact of impinging wall jet on color Doppler quantification of mitral regurgitation. Circulation 1991;84:712-20.

20. Enriquez-Sarano M, Bailey KR, Seward JB, Tajik AJ, Krohn MJ, Mays JM. Quantitative Doppler assessment of valvular regurgitation. Circulation 1993;87:841-8.

21. Stewart WJ, Currie PJ, Salcedo EE, Lytle BW, Gill CC, Schiavone WA, et al. Intraoperative Doppler color flow mapping for decision-making in valve repair for mitral regurgitation. Technique and results in 100 patients. Circulation 1990;81:556-66.

22. Mascherbauer J, Rosenhek R, Bittner B, Binder J, Simon P, Maurer G, et al. Doppler echocardiographic assessment of valvular regurgitation severity by measurement of the vena contracta: an in vitro validation study. J Am Soc Echocardiogr 2005;18:999-1006.

23. Grayburn PA, Appleton CP, DeMaria AN, Greenberg B, Lowes B, Oh J, et al. Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST). J Am Coll Cardiol 2005;45:1064-71.

24. Hall SA, Brickner ME, Willett DL, Irani WN, Afridi I, Grayburn PA. Assessment of mitral regurgitation severity by Doppler color flow mapping of the vena contracta. Circulation 1997;95:636-42.

25. Enriquez-Sarano M, Seward JB, Bailey KR, Tajik AJ. Effective regurgitant orifice area: a noninvasive Doppler development of an old hemodynamic concept. J Am Coll Cardiol 1994;23:443-51.

26. Baumgartner H, Schima H, Kuhn P. Value and limitations of proximal jet dimensions for the quantitation of valvular regurgitation: an in vitro study using Doppler flow imaging. J Am Soc Echocardiogr 1991;4: 57-66.

27. Kizilbash AM, Willett DL, Brickner ME, Heinle SK, Grayburn PA. Effects of afterload reduction on vena contracta width in mitral regurgitation. J Am Coll Cardiol 1998;32:427-31.

28. Tribouilloy CM, Enriquez-Sarano M, Bailey KR, Seward JB, Tajik AJ. Assessment of severity of aortic regurgitation using the width of the vena contracta: a clinical color Doppler imaging study. Circulation 2000;102:558-64.

29. Tribouilloy CM, Enriquez-Sarano M, Bailey KR, Tajik AJ, Seward JB. Quantification of tricuspid regurgitation by measuring the width of the vena contracta with Doppler color flow imaging: a clinical study. J Am Coll Cardiol 2000;36:472-8.

30. Zeng X, Levine RA, Hua L, Morris EL, Kang Y, Flaherty M, et al. Diagnostic value of vena contracta area in the quantification of mitral regurgitation severity by color Doppler 3D echocardiography. Circ Cardiovasc Imaging 2011;4:506-13.

31. Little SH, Pirat B, Kumar R, Igo SR, McCulloch M, Hartley CJ, et al. Threedimensional color Doppler echocardiography for direct measurement of vena contracta area in mitral regurgitation: in vitro validation and clinical experience. JACC Cardiovasc Imaging 2008;1:695-704.

32. Yosefy C, Hung J, Chua S, Vaturi M, Ton-Nu TT, Handschumacher MD, et al. Direct measurement of vena contracta area by real-time 3- dimensional echocardiography for assessing severity of mitral regurgitation. Am J Cardiol 2009;104:978-83.

33. Shanks M, Siebelink HM, Delgado V, van de Veire NR, Ng AC, Sieders A, et al. Quantitative assessment of mitral regurgitation: comparison between three-dimensional transesophageal echocardiography and magnetic resonance imaging. Circ Cardiovasc Imaging 2010;3:694-700.

34. Bargiggia GS, Tronconi L, Sahn DJ, Recusani F, Raisaro A, De Servi S, et al. A new method for quantitation of mitral regurgitation based on color flow Doppler imaging of flow convergence proximal to regurgitant orifice. Circulation 1991;84:1481-9.

35. Tribouilloy C, Shen WF, Rey JL, Adam MC, Lesbre JP. Mitral to aortic velocity-time integral ratio. A non-geometric pulsed-Doppler regurgitant index in isolated pure mitral regurgitation. Eur Heart J 1994; 15:1335-9.

36. Tribouilloy C, Avinee P, Shen WF, Rey JL, Slama M, Lesbre JP. End diastolic flow velocity just beneath the aortic isthmus assessed by pulsed

Zoghbi et al 365

Journal of the American Society of Echocardiography Volume 30 Number 4

• Doppler echocardiography: a new predictor of the aortic regurgitant fraction. Br Heart J 1991;65:37-40.

37. Enriquez-Sarano M, Dujardin KS, Tribouilloy CM, Seward JB, Yoganathan AP, Bailey KR, et al. Determinants of pulmonary venous flow reversal in mitral regurgitation and its usefulness in determining the severity of regurgitation. Am J Cardiol 1999;83: 535-41.

38. Klein AL, Obarski TP, Stewart WJ, Casale PN, Pearce GL, Husbands K, et al. Transesophageal Doppler echocardiography of pulmonary venous flow: a new marker of mitral regurgitation severity. J Am Coll Cardiol 1991;18:518-26.

39. Pennestri F, Loperfido F, Salvatori MP, Mongiardo R, Ferrazza A, Guccione P, et al. Assessment of tricuspid regurgitation by pulsed Doppler ultrasonography of the hepatic veins. Am J Cardiol 1984;54:363-8.

40. Chen M, Luo H, Miyamoto T, Atar S, Kobal S, Rahban M, et al. Correlation of echo-Doppler aortic valve regurgitation index with angiographic aortic regurgitation severity. Am J Cardiol 2003;92:634-5.

41. Schwammenthal E, Chen C, Benning F, Block M, Breithardt G, Levine RA. Dynamics of mitral regurgitant flow and orifice area. Physiologic application of the proximal flow convergence method: clinical data and experimental testing. Circulation 1994;90:307-22.

42. Grose R, Strain J, Cohen MV. Pulmonary arterial V waves in mitral regurgitation: clinical and experimental observations. Circulation 1984;69: 214-22.

43. Pizzarello RA, Turnier J, Padmanabhan VT, Goldman MA, Tortolani AJ. Left atrial size, pressure, and V wave height in patients with isolated, severe, pure mitral regurgitation. Cathet Cardiovasc Diagn 1984;10: 445-54.

44. Ishii M, Jones M, Shiota T, Yamada I, Heinrich RS, Holcomb SR, et al. What is the validity of continuous wave Doppler grading of aortic regurgitation severity? A chronic animal model study. J Am Soc Echocardiogr 1998;11:332-7.

45. Topilsky Y, Michelena H, Bichara V, Maalouf J, Mahoney DW, EnriquezSarano M. Mitral valve prolapse with mid-late systolic mitral regurgitation: pitfalls of evaluation and clinical outcome compared with holosystolic regurgitation. Circulation 2012;125:1643-51.

46. Rokey R, Sterling LL, Zoghbi WA, Sartori MP, Limacher MC, Kuo LC, et al. Determination of regurgitant fraction in isolated mitral or aortic regurgitation by pulsed Doppler two-dimensional echocardiography. J Am Coll Cardiol 1986;7:1273-8.

47. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation 1984;70:425-31.

48. Thavendiranathan P, Liu S, Datta S, Walls M, Nitinunu A, Van Houten T, et al. Automated quantification of mitral inflow and aortic outflow stroke volumes by three-dimensional real-time volume color-flow Doppler transthoracic echocardiography: comparison with pulsed-wave Doppler and cardiac magnetic resonance imaging. J Am Soc Echocardiogr 2012; 25:56-65.

49. Blumlein S, Bouchard A, Schiller NB, Dae M, Byrd BF 3rd, Ports T, et al. Quantitation of mitral regurgitation by Doppler echocardiography. Circulation 1986;74:306-14.

50. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1-3914.

51. Hundley WG, Kizilbash AM, Afridi I, Franco F, Peshock RM, Grayburn PA. Administration of an intravenous perfluorocarbon contrast agent improves echocardiographic determination of left ventricular volumes and ejection fraction: comparison with cine magnetic resonance imaging. J Am Coll Cardiol 1998;32:1426-32.

52. Vandervoort PM, Rivera JM, Mele D, Palacios IF, Dinsmore RE, Weyman AE, et al. Application of color Doppler flow mapping to calculate effective regurgitant orifice area. An in vitro study and initial clinical observations. Circulation 1993;88:1150-6.

53. Enriquez-Sarano M, Miller FA Jr., Hayes SN, Bailey KR, Tajik AJ, Seward JB. Effective mitral regurgitant orifice area: clinical use and pitfalls of the proximal isovelocity surface area method. J Am Coll Cardiol 1995; 25:703-9.

54. Tribouilloy CM, Enriquez-Sarano M, Fett SL, Bailey KR, Seward JB, Tajik AJ. Application of the proximal flow convergence method to calculate the effective regurgitant orifice area in aortic regurgitation. J Am Coll Cardiol 1998;32:1032-9.

55. Rivera M, Vandervoort PM, Mele D, Siu S, Morris E, Weyman AE, et al. Quantification of tricuspid regurgitation by means of the proximal flow convergence method: a clinical study. Am Heart J 1994;127:1354-62.

56. Rivera JM, Vandervoort PM, Thoreau DH, Levine RA, Weyman AE, Thomas JD. Quantification of mitral regurgitation with the proximal flow convergence method: a clinical study. Am Heart J 1992;124: 1289-96.

57. Buck T, Plicht B, Kahlert P, Schenk IM, Hunold P, Erbel R. Effect of dynamic flow rate and orifice area on mitral regurgitant stroke volume quantification using the proximal isovelocity surface area method. J Am Coll Cardiol 2008;52:767-78.

58. Hung J, Otsuji Y, Handschumacher MD, Schwammenthal E, Levine RA. Mechanism of dynamic regurgitant orifice area variation in functional mitral regurgitation: physiologic insights from the proximal flow convergence technique. J Am Coll Cardiol 1999;33:538-45.

59. Enriquez-Sarano M, Sinak LJ, Tajik AJ, Bailey KR, Seward JB. Changes in effective regurgitant orifice throughout systole in patients with mitral valve prolapse. A clinical study using the proximal isovelocity surface area method. Circulation 1995;92:2951-8.

60. Pu M, Vandervoort PM, Griffin BP, Leung DY, Stewart WJ, Cosgrove DM 3rd, et al. Quantification of mitral regurgitation by the proximal convergence method using transesophageal echocardiography. Clinical validation of a geometric correction for proximal flow constraint. Circulation 1995;92:2169-77.

61. Matsumura Y, Fukuda S, Tran H, Greenberg NL, Agler DA, Wada N, et al. Geometry of the proximal isovelocity surface area in mitral regurgitation by 3-dimensional color Doppler echocardiography: difference between functional mitral regurgitation and prolapse regurgitation. Am Heart J 2008;155:231-8.

62. Iwakura K, Ito H, Kawano S, Okamura A, Kurotobi T, Date M, et al. Comparison of orifice area by transthoracic three-dimensional Doppler echocardiography versus proximal isovelocity surface area (PISA) method for assessment of mitral regurgitation. Am J Cardiol 2006;97: 1630-7.

63. Mitter SS, Wagner GJ, Barker AJ, Markl M, Thomas JD. Impact of assuming a circular orifice on flow error through elliptical regurgitant orifices: a computational fluid dynamics (CFD) analysis. Circulation 2015; 132:A16560.

64. Simpson IA, Shiota T, Gharib M, Sahn DJ. Current status of flow convergence for clinical applications: is it a leaning tower of ‘‘PISA’’? J Am Coll Cardiol 1996;27:504-9.

65. Yosefy C, Levine RA, Solis J, Vaturi M, Handschumacher MD, Hung J. Proximal flow convergence region as assessed by real-time 3- dimensional echocardiography: challenging the hemispheric assumption. J Am Soc Echocardiogr 2007;20:389-96.

66. Little SH, Igo SR, Pirat B, McCulloch M, Hartley CJ, Nose Y, et al. In vitro validation of real-time three-dimensional color Doppler echocardiography for direct measurement of proximal isovelocity surface area in mitral regurgitation. Am J Cardiol 2007;99:1440-7.

67. Thavendiranathan P, Liu S, Datta S, Rajagopalan S, Ryan T, Igo SR, et al. Quantification of chronic functional mitral regurgitation by automated 3-dimensional peak and integrated proximal isovelocity surface area and stroke volume techniques using realtime 3-dimensional volume color Doppler echocardiography: in vitro and clinical validation. Circ Cardiovasc Imaging 2013;6: 125-33.

68. Carr JC, Simonetti O, Bundy J, Li D, Pereles S, Finn JP. Cine MR angiography of the heart with segmented true fast imaging with steady-state precession. Radiology 2001;219:828-34.

366 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

69. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E, the Society for Cardiovascular Magnetic Resonance Board of Trustees Task Force on Standardized Protocols. Standardized cardiovascular magnetic resonance (CMR) protocols 2013 update. J Cardiovasc Magn Reson 2013;15:91.

70. Hori Y, Yamada N, Higashi M, Hirai N, Nakatani S. Rapid evaluation of right and left ventricular function and mass using real-time true-FISP cine MR imaging without breath-hold: comparison with segmented true-FISP cine MR imaging with breath-hold. J Cardiovasc Magn Reson 2003;5: 439-50.

71. Hudsmith LE, Petersen SE, Francis JM, Robson MD, Neubauer S. Normal human left and right ventricular and left atrial dimensions using steady state free precession magnetic resonance imaging. J Cardiovasc Magn Reson 2005;7:775-82.

72. Maceira AM, Cosin-Sales J, Roughton M, Prasad SK, Pennell DJ. Reference left atrial dimensions and volumes by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2010; 12:65.

73. Gleeson TG, Mwangi I, Horgan SJ, Cradock A, Fitzpatrick P, Murray JG. Steady-state free-precession (SSFP) cine MRI in distinguishing normal and bicuspid aortic valves. J Magn Reson Imaging 2008;28:873-8.

74. Evans AJ, Blinder RA, Herfkens RJ, Spritzer CE, Kuethe DO, Fram EK, et al. Effects of turbulence on signal intensity in gradient echo images. Invest Radiol 1988;23:512-8.

75. Krombach GA, Kuhl H, Bucker A, Mahnken AH, Spuntrup E, Lipke C, et al. Cine MR imaging of heart valve dysfunction with segmented true fast imaging with steady state free precession. J Magn Reson Imaging 2004;19:59-67.

76. Debl K, Djavidani B, Buchner S, Heinicke N, Fredersdorf S, Haimerl J, et al. Assessment of the anatomic regurgitant orifice in aortic regurgitation: a clinical magnetic resonance imaging study. Heart 2008;94:e8.

77. Buchner S, Debl K, Poschenrieder F, Feuerbach S, Riegger GA, Luchner A, et al. Cardiovascular magnetic resonance for direct assessment of anatomic regurgitant orifice in mitral regurgitation. Circ Cardiovasc Imaging 2008;1:148-55.

78. Chatzimavroudis GP, Oshinski JN, Franch RH, Walker PG, Yoganathan AP, Pettigrew RI. Evaluation of the precision of magnetic resonance phase velocity mapping for blood flow measurements. J Cardiovasc Magn Reson 2001;3:11-9.

79. Hundley WG, Li HF, Hillis LD, Meshack BM, Lange RA, Willard JE, et al. Quantitation of cardiac output with velocity-encoded, phase-difference magnetic resonance imaging. Am J Cardiol 1995;75:1250-5.

80. Sondergaard L, Lindvig K, Hildebrandt P, Thomsen C, Stahlberg F, Joen T, et al. Quantification of aortic regurgitation by magnetic resonance velocity mapping. Am Heart J 1993;125:1081-90.

81. Sondergaard L, Thomsen C, Stahlberg F, Gymoese E, Lindvig K, Hildebrandt P, et al. Mitral and aortic valvular flow: quantification with MR phase mapping. J Magn Reson Imaging 1992;2:295-302.

82. Gatehouse PD, Rolf MP, Graves MJ, Hofman MB, Totman J, Werner B, et al. Flow measurement by cardiovascular magnetic resonance: a multi-centre multi-vendor study of background phase offset errors that can compromise the accuracy of derived regurgitant or shunt flow measurements. J Cardiovasc Magn Reson 2010;12:5.

83. Wilkoff BL, Bello D, Taborsky M, Vymazal J, Kanal E, Heuer H, et al. Magnetic resonance imaging in patients with a pacemaker system designed for the magnetic resonance environment. Heart Rhythm 2011; 8:65-73.

84. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:e521-643.

85. Gelfand EV, Hughes S, Hauser TH, Yeon SB, Goepfert L, Kissinger KV, et al. Severity of mitral and aortic regurgitation as assessed by cardiovascular magnetic resonance: optimizing correlation with Doppler echocardiography. J Cardiovasc Magn Reson 2006;8:503-7.

86. Myerson SG, d’Arcy J, Mohiaddin R, Greenwood JP, Karamitsos TF, Francis JM, et al. Aortic regurgitation quantification using cardiovascular magnetic resonance: association with clinical outcome. Circulation 2012; 126:1452-60.

87. Myerson SG, d’Arcy J, Christiansen JP, Dobson LE, Mohiaddin R, Francis JM, et al. Determination of clinical outcome in mitral regurgitation with cardiovascular magnetic resonance quantification. Circulation 2016; 133:2287-96.

88. Expert Panel on MR Safety, Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG Jr, et al. ACR guidance document on MR safe practices: 2013. J Magn Reson Imaging 2013;37:501-30.

89. Honey M, Gough JH, Katsaros S, Miller GA, Thuraisingham V. Left ventricular cine-angio-cardiography in the assessment of mitral regurgitation. Br Heart J 1969;31:596-602.

90. Baron MG. Angiocardiographic evaluation of valvular insufficiency. Circulation 1971;43:599-605.

91. McCarthy KP, Ring L, Rana BS. Anatomy of the mitral valve: understanding the mitral valve complex in mitral regurgitation. Eur J Echocardiogr 2010;11:i3-9.

92. Silbiger JJ. Novel pathogenetic mechanisms and structural adaptations in ischemic mitral regurgitation. J Am Soc Echocardiogr 2013;26: 1107-17.

93. Chikwe J, Adams DH, Su KN, Anyanwu AC, Lin HM, Goldstone AB, et al. Can three-dimensional echocardiography accurately predict complexity of mitral valve repair? Eur J Cardiothorac Surg 2012;41: 518-24.

94. Carpentier A. Cardiac valve surgery—the ‘‘French correction’’. J Thorac Cardiovasc Surg 1983;86:323-37.

95. Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 1999;341:1-7.

96. Levine RA, Handschumacher MD, Sanfilippo AJ, Hagege AA, Harrigan P, Marshall JE, et al. Three-dimensional echocardiographic reconstruction of the mitral valve, with implications for the diagnosis of mitral valve prolapse. Circulation 1989;80:589-98.

97. Ling LH, Enriquez-Sarano M, Seward JB, Tajik AJ, Schaff HV, Bailey KR, et al. Clinical outcome of mitral regurgitation due to flail leaflet. N Engl J Med 1996;335:1417-23.

98. Grigioni F, Enriquez-Sarano M, Ling LH, Bailey KR, Seward JB, Tajik AJ, et al. Sudden death in mitral regurgitation due to flail leaflet. J Am Coll Cardiol 1999;34:2078-85.

99. Levine HJ, Gaasch WH. Vasoactive drugs in chronic regurgitant lesions of the mitral and aortic valves. J Am Coll Cardiol 1996;28:1083-91.

100. Grigioni F, Tribouilloy C, Avierinos JF, Barbieri A, Ferlito M, Trojette F, et al. Outcomes in mitral regurgitation due to flail leaflets a multicenter European study. JACC Cardiovasc Imaging 2008;1:133-41.

101. Otsuji Y, Handschumacher MD, Liel-Cohen N, Tanabe H, Jiang L, Schwammenthal E, et al. Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation. J Am Coll Cardiol 2001;37:641-8.

102. Godley RW, Wann LS, Rogers EW, Feigenbaum H, Weyman AE. Incomplete mitral leaflet closure in patients with papillary muscle dysfunction. Circulation 1981;63:565-71.

103. Levine RA, Schwammenthal E. Ischemic mitral regurgitation on the threshold of a solution: from paradoxes to unifying concepts. Circulation 2005;112:745-58.

104. Gorman JH 3rd, Jackson BM, Gorman RC, Kelley ST, Gikakis N, Edmunds LH Jr. Papillary muscle discoordination rather than increased annular area facilitates mitral regurgitation after acute posterior myocardial infarction. Circulation 1997;96(9 Suppl):II124-7.

105. Tibayan FA, Rodriguez F, Zasio MK, Bailey L, Liang D, Daughters GT, et al. Geometric distortions of the mitral valvular-ventricular complex in chronic ischemic mitral regurgitation. Circulation 2003;108(Suppl 1):II116-21.

106. Kwan J, Shiota T, Agler DA, Popovic ZB, Qin JX, Gillinov MA, et al. Geometric differences of the mitral apparatus between ischemic and dilated

Zoghbi et al 367

Journal of the American Society of Echocardiography Volume 30 Number 4

• cardiomyopathy with significant mitral regurgitation: real-time threedimensional echocardiography study. Circulation 2003;107:1135-40.

107. Carabello BA. Ischemic mitral regurgitation and ventricular remodeling. J Am Coll Cardiol 2004;43:384-5.

108. Golba K, Mokrzycki K, Drozdz J, Cherniavsky A, Wrobel K, Roberts BJ, et al. Mechanisms of functional mitral regurgitation in ischemic cardiomyopathy determined by transesophageal echocardiography (from the Surgical Treatment for Ischemic Heart Failure Trial). Am J Cardiol 2013;112:1812-8.

109. Kaji S, Nasu M, Yamamuro A, Tanabe K, Nagai K, Tani T, et al. Annular geometry in patients with chronic ischemic mitral regurgitation: threedimensional magnetic resonance imaging study. Circulation 2005; 112(9 Suppl):I409-14.

110. Boltwood CM, Tei C, Wong M, Shah PM. Quantitative echocardiography of the mitral complex in dilated cardiomyopathy: the mechanism of functional mitral regurgitation. Circulation 1983;68:498-508.

111. Gertz ZM, Raina A, Saghy L, Zado ES, Callans DJ, Marchlinski FE, et al. Evidence of atrial functional mitral regurgitation due to atrial fibrillation: reversal with arrhythmia control. J Am Coll Cardiol 2011;58:1474-81.

112. van Rosendael PJ, Katsanos S, Kamperidis V, Roos CJ, Scholte AJ, Schalij MJ, et al. New insights on Carpentier I mitral regurgitation from multidetector row computed tomography. Am J Cardiol 2014;114: 763-8.

113. Khoury AF, Afridi I, Quinones MA, Zoghbi WA. Transesophageal echocardiography in critically ill patients: feasibility, safety, and impact on management. Am Heart J 1994;127:1363-71.

114. Yoran C, Yellin EL, Becker RM, Gabbay S, Frater RW, Sonnenblick EH. Dynamic aspects of acute mitral regurgitation: effects of ventricular volume, pressure and contractility on the effective regurgitant orifice area. Circulation 1979;60:170-6.

115. Gisbert A, Souliere V, Denault AY, Bouchard D, Couture P, Pellerin M, et al. Dynamic quantitative echocardiographic evaluation of mitral regurgitation in the operating department. J Am Soc Echocardiogr 2006;19: 140-6.

116. Shiran A, Merdler A, Ismir E, Ammar R, Zlotnick AY, Aravot D, et al. Intraoperative transesophageal echocardiography using a quantitative dynamic loading test for the evaluation of ischemic mitral regurgitation. J Am Soc Echocardiogr 2007;20:690-7.

117. Mihalatos DG, Gopal AS, Kates R, Toole RS, Bercow NR, Lamendola C, et al. Intraoperative assessment of mitral regurgitation: role of phenylephrine challenge. J Am Soc Echocardiogr 2006;19:1158-64.

118. Nagueh SF, Bierig SM, Budoff MJ, Desai M, Dilsizian V, Eidem B, et al. American Society of Echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with hypertrophic cardiomyopathy: endorsed by the American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography. J Am Soc Echocardiogr 2011;24: 473-98.

119. Grigg LE, Wigle ED, Williams WG, Daniel LB, Rakowski H. Transesophageal Doppler echocardiography in obstructive hypertrophic cardiomyopathy: clarification of pathophysiology and importance in intraoperative decision making. J Am Coll Cardiol 1992;20:42-52.

120. Sherrid MV, Wever-Pinzon O, Shah A, Chaudhry FA. Reflections of inflections in hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54: 212-9.

121. Mark JB, Chetham PM. Ventricular pacing can induce hemodynamically significant mitral valve regurgitation. Anesthesiology 1991;74: 375-7.

122. Alizadeh A, Sanati HR, Haji-Karimi M, Yazdi AH, Rad MA, Haghjoo M, et al. Induction and aggravation of atrioventricular valve regurgitation in the course of chronic right ventricular apical pacing. Europace 2011;13: 1587-90.

123. Sutton MG, Plappert T, Hilpisch KE, Abraham WT, Hayes DL, Chinchoy E. Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: quantitative Doppler echocardiographic evidence from the Multicenter In-

• Sync Randomized Clinical Evaluation (MIRACLE). Circulation 2006; 113:266-72.

124. Di Biase L, Auricchio A, Mohanty P, Bai R, Kautzner J, Pieragnoli P, et al. Impact of cardiac resynchronization therapy on the severity of mitral regurgitation. Europace 2011;13:829-38.

125. Onishi T, Onishi T, Marek JJ, Ahmed M, Haberman SC, Oyenuga O, et al. Mechanistic features associated with improvement in mitral regurgitation after cardiac resynchronization therapy and their relation to longterm patient outcome. Circ Heart Fail 2013;6:685-93.

126. van Bommel RJ, Marsan NA, Delgado V, Borleffs CJ, van Rijnsoever EP, Schalij MJ, et al. Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation 2011;124:912-9.

127. Panidis IP, Ross J, Munley B, Nestico P, Mintz GS. Diastolic mitral regurgitation in patients with atrioventricular conduction abnormalities: a common finding by Doppler echocardiography. J Am Coll Cardiol 1986;7: 768-74.

128. Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease). Eur J Echocardiogr 2010;11:307-32.

129. Diebold B, Delouche A, Delouche P, Guglielmi JP, Dumee P, Herment A. In vitro flow mapping of regurgitant jets. Systematic description of free jet with laser Doppler velocimetry. Circulation 1996;94:158-69.

130. Altiok E, Hamada S, van Hall S, Hanenberg M, Dohmen G, Almalla M, et al. Comparison of direct planimetry of mitral valve regurgitation orifice area by three-dimensional transesophageal echocardiography to effective regurgitant orifice area obtained by proximal flow convergence method and vena contracta area determined by color Doppler echocardiography. Am J Cardiol 2011;107:452-8.

131. Kahlert P, Plicht B, Schenk IM, Janosi RA, Erbel R, Buck T. Direct assessment of size and shape of noncircular vena contracta area in functional versus organic mitral regurgitation using real-time three-dimensional echocardiography. J Am Soc Echocardiogr 2008;21:912-21.

132. Matsumura Y, Saracino G, Sugioka K, Tran H, Greenberg NL, Wada N, et al. Determination of regurgitant orifice area with the use of a new three-dimensional flow convergence geometric assumption in functional mitral regurgitation. J Am Soc Echocardiogr 2008;21:1251-6.

133. Marsan NA, Westenberg JJ, Ypenburg C, Delgado V, van Bommel RJ, Roes SD, et al. Quantification of functional mitral regurgitation by realtime 3D echocardiography: comparison with 3D velocity-encoded cardiac magnetic resonance. JACC Cardiovasc Imaging 2009;2:1245-52.

134. Biner S, Rafique A, Raf F, Tolstrup K, Noorani O, Shiota T, et al. Reproducibility of proximal isovelocity surface area, vena contracta, and regurgitant jet area for assessment of mitral regurgitation severity. JACC Cardiovasc Imaging 2010;3:235-43.

135. Grigioni F, Detaint D, Avierinos JF, Scott C, Tajik J, Enriquez-Sarano M. Contribution of ischemic mitral regurgitation to congestive heart failure after myocardial infarction. J Am Coll Cardiol 2005;45:260-7.

136. Lancellotti P, Troisfontaines P, Toussaint AC, Pierard LA. Prognostic importance of exercise-induced changes in mitral regurgitation in patients with chronic ischemic left ventricular dysfunction. Circulation 2003;108:1713-7.

137. Rossi A, Dini FL, Faggiano P, Agricola E, Cicoira M, Frattini S, et al. Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy. Heart 2011;97: 1675-80.

138. Pu M, Prior DL, Fan X, Asher CR, Vasquez C, Griffin BP, et al. Calculation of mitral regurgitant orifice area with use of a simplified proximal convergence method: initial clinical application. J Am Soc Echocardiogr 2001;14:180-5.

139. Kizilbash AM, Hundley WG, Willett DL, Franco F, Peshock RM, Grayburn PA. Comparison of quantitative Doppler with magnetic resonance imaging for assessment of the severity of mitral regurgitation. Am J Cardiol 1998;81:792-5.

368 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

140. Dujardin KS, Enriquez-Sarano M, Bailey KR, Nishimura RA, Seward JB, Tajik AJ. Grading of mitral regurgitation by quantitative Doppler echocardiography: calibration by left ventricular angiography in routine clinical practice. Circulation 1997;96:3409-15.

141. Pu M, Griffin BP, Vandervoort PM, Stewart WJ, Fan X, Cosgrove DM, et al. The value of assessing pulmonary venous flow velocity for predicting severity of mitral regurgitation: a quantitative assessment integrating left ventricular function. J Am Soc Echocardiogr 1999;12:736-43.

142. Grayburn PA, Foster E, Sangli C, Weissman NJ, Massaro J, Glower DG, et al. Relationship between the magnitude of reduction in mitral regurgitation severity and left ventricular and left atrial reverse remodeling after MitraClip therapy. Circulation 2013;128:1667-74.

143. Lancellotti P, Cosyns B, Zacharakis D, Attena E, Van Camp G, Gach O, et al. Importance of left ventricular longitudinal function and functional reserve in patients with degenerative mitral regurgitation: assessment by two-dimensional speckle tracking. J Am Soc Echocardiogr 2008;21: 1331-6.

144. Witkowski TG, Thomas JD, Debonnaire PJ, Delgado V, Hoke U, Ewe SH, et al. Global longitudinal strain predicts left ventricular dysfunction after mitral valve repair. Eur Heart J Cardiovasc Imaging 2013;14:69-76.

145. Messika-Zeitoun D, Bellamy M, Avierinos JF, Breen J, Eusemann C, Rossi A, et al. Left atrial remodelling in mitral regurgitation—methodologic approach, physiological determinants, and outcome implications: a prospective quantitative Doppler-echocardiographic and electron beam-computed tomographic study. Eur Heart J 2007;28:1773-81.

146. Leung DY, Griffin BP, Stewart WJ, Cosgrove DM 3rd, Thomas JD, Marwick TH. Left ventricular function after valve repair for chronic mitral regurgitation: predictive value of preoperative assessment of contractile reserve by exercise echocardiography. J Am Coll Cardiol 1996;28: 1198-205.

147. Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, et al. Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28:230-68.

148. Buchner S, Poschenrieder F, Hamer OW, Jungbauer C, Resch M, Birner C, et al. Direct visualization of regurgitant orifice by CMR reveals differential asymmetry according to etiology of mitral regurgitation. JACC Cardiovasc Imaging 2011;4:1088-96.

149. Gabriel RS, Kerr AJ, Raffel OC, Stewart FA, Cowan BR, Occleshaw CJ. Mapping of mitral regurgitant defects by cardiovascular magnetic resonance in moderate or severe mitral regurgitation secondary to mitral valve prolapse. J Cardiovasc Magn Reson 2008;10:16.

150. Han Y, Peters DC, Salton CJ, Bzymek D, Nezafat R, Goddu B, et al. Cardiovascular magnetic resonance characterization of mitral valve prolapse. JACC Cardiovasc Imaging 2008;1:294-303.

151. Chinitz JS, Chen D, Goyal P, Wilson S, Islam F, Nguyen T, et al. Mitral apparatus assessment by delayed enhancement CMR: relative impact of infarct distribution on mitral regurgitation. JACC Cardiovasc Imaging 2013;6:220-34.

152. Srichai MB, Grimm RA, Stillman AE, Gillinov AM, Rodriguez LL, Lieber ML, et al. Ischemic mitral regurgitation: impact of the left ventricle and mitral valve in patients with left ventricular systolic dysfunction. Ann Thorac Surg 2005;80:170-8.

153. Aurigemma G, Reichek N, Schiebler M, Axel L. Evaluation of mitral regurgitation by cine magnetic resonance imaging. Am J Cardiol 1990; 66:621-5.

154. Pflugfelder PW, Sechtem UP, White RD, Cassidy MM, Schiller NB, Higgins CB. Noninvasive evaluation of mitral regurgitation by analysis of left atrial signal loss in cine magnetic resonance. Am Heart J 1989; 117:1113-9.

155. Hundley WG, Li HF, Willard JE, Landau C, Lange RA, Meshack BM, et al. Magnetic resonance imaging assessment of the severity of mitral regurgitation. Comparison with invasive techniques. Circulation 1995;92:1151-8.

156. Kon MW, Myerson SG, Moat NE, Pennell DJ. Quantification of regurgitant fraction in mitral regurgitation by cardiovascular magnetic resonance: comparison of techniques. J Heart Valve Dis 2004;13:600-7.

157. Fujita N, Chazouilleres AF, Hartiala JJ, O’Sullivan M, Heidenreich P, Kaplan JD, et al. Quantification of mitral regurgitation by velocityencoded cine nuclear magnetic resonance imaging. J Am Coll Cardiol 1994;23:951-8.

158. Maceira AM, Prasad SK, Khan M, Pennell DJ. Reference right ventricular systolic and diastolic function normalized to age, gender and body surface area from steady-state free precession cardiovascular magnetic resonance. Eur Heart J 2006;27:2879-88.

159. Maceira AM, Prasad SK, Khan M, Pennell DJ. Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2006;8: 417-26.

160. Cawley PJ, Hamilton-Craig C, Owens DS, Krieger EV, Strugnell WE, Mitsumori L, et al. Prospective comparison of valve regurgitation quantitation by cardiac magnetic resonance imaging and transthoracic echocardiography. Circ Cardiovasc Imaging 2013;6:48-57.

161. Uretsky S, Gillam L, Lang R, Chaudhry FA, Argulian E, Supariwala A, et al. Discordance between echocardiography and MRI in the assessment of mitral regurgitation severity: a prospective multicenter trial. J Am Coll Cardiol 2015;65:1078-88.

162. Lopez-Mattei JC, Ibrahim H, Shaikh KA, Little SH, Shah DJ, Maragiannis D, et al. Comparative assessment of mitral regurgitation severity by transthoracic echocardiography and cardiac magnetic resonance using an integrative and quantitative approach. Am J Cardiol 2016;117:264-70.

163. Grayburn PA, Carabello B, Hung J, Gillam LD, Liang D, Mack MJ, et al. Defining ‘‘severe’’ secondary mitral regurgitation: emphasizing an integrated approach. J Am Coll Cardiol 2014;64:2792-801.

164. Cioffi G, Tarantini L, De Feo S, Pulignano G, Del Sindaco D, Stefenelli C, et al. Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure. Eur J Heart Fail 2005;7:1112-7.

165. Marwick TH, Zoghbi WA, Narula J. Redrawing the borders: considering guideline revision in functional mitral regurgitation. JACC Cardiovasc Imaging 2014;7:333-5.

166. Beigel R, Siegel RJ. Should the guidelines for the assessment of the severity of functional mitral regurgitation be redefined? JACC Cardiovasc Imaging 2014;7:313-4.

167. Trichon BH, Felker GM, Shaw LKL, Cabell CH, O’Connor CM. Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol 2003;91:538-43.

168. Deja MA, Grayburn PA, Sun B, Rao V, She L, Krejca M, et al. Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial. Circulation 2012;125:2639-48.

169. Michler RE, Smith PK, Parides MK, Ailawadi G, Thourani V, Moskowitz AJ, et al. Two-year outcomes of surgical treatment of moderate ischemic mitral regurgitation. N Engl J Med 2016;374: 1932-41.

170. Anderson RH. Clinical anatomy of the aortic root. Heart 2000;84:670-3.

171. Carr JA, Savage EB. Aortic valve repair for aortic insufficiency in adults: a contemporary review and comparison with replacement techniques. Eur J Cardiothorac Surg 2004;25:6-15.

172. Shapira N, Fernandez J, McNicholas KW, Serra AJ, Hirschfeld K, Spagna PM, et al. Hypertrophy of nodules of Arantius and aortic insufficiency: pathophysiology and repair. Ann Thorac Surg 1991; 51:969-72.

173. Bekeredjian R, Grayburn PA. Valvular heart disease: aortic regurgitation. Circulation 2005;112:125-34.

174. Michelena HI, Prakash SK, Della Corte A, Bissell MM, Anavekar N, Mathieu P, et al. Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon). Circulation 2014;129:2691-704.

175. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133: 1226-33.

Zoghbi et al 369

Journal of the American Society of Echocardiography Volume 30 Number 4

176. Hahn RT, Roman MJ, Mogtader AH, Devereux RB. Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves. J Am Coll Cardiol 1992;19:283-8.

177. Detaint D, Michelena HI, Nkomo VT, Vahanian A, Jondeau G, Sarano ME. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy. Heart 2014;100:126-34.

178. Roberts WC, Vowels TJ, Ko JM, Filardo G, Hebeler RF Jr., Henry AC, et al. Comparison of the structure of the aortic valve and ascending aorta in adults having aortic valve replacement for aortic stenosis versus for pure aortic regurgitation and resection of the ascending aorta for aneurysm. Circulation 2011;123:896-903.

179. Chan KL, Stinson WA, Veinot JP. Reliability of transthoracic echocardiography in the assessment of aortic valve morphology: pathological correlation in 178 patients. Can J Cardiol 1999;15:48-52.

180. El Khoury G, Glineur D, Rubay J, Verhelst R, d’Acoz Y, Poncelet A, et al. Functional classification of aortic root/valve abnormalities and their correlation with etiologies and surgical procedures. Curr Opin Cardiol 2005;20:115-21.

181. Boodhwani M, de Kerchove L, Glineur D, Poncelet A, Rubay J, Astarci P, et al. Repair-oriented classification of aortic insufficiency: impact on surgical techniques and clinical outcomes. J Thorac Cardiovasc Surg 2009; 137:286-94.

182. Shiota T, Jones M, Agler DA, McDonald RW, Marcella CP, Qin JX, et al. New echocardiographic windows for quantitative determination of aortic regurgitation volume using color Doppler flow convergence and vena contracta. Am J Cardiol 1999;83:1064-8.

183. Griffin BP, Flachskampf FA, Siu A, Weyman AE, Thomas JD. The effects of regurgitant orifice size, chamber compliance, and systemic vascular resistance on aortic regurgitant velocity slope and pressure half-time. Am Heart J 1991;122:1049-56.

184. Griffin BP, Flachskampf FA, Reimold SC, Lee RT, Thomas JD. Relationship of aortic regurgitant velocity slope and pressure half-time to severity of aortic regurgitation under changing haemodynamic conditions. Eur Heart J 1994;15:681-5.

185. Reynolds HR, Jagen MA, Tunick PA, Kronzon I. Sensitivity of transthoracic versus transesophageal echocardiography for the detection of native valve vegetations in the modern era. J Am Soc Echocardiogr 2003;16:67-70.

186. Roldan CA, Qualls CR, Sopko KS, Sibbitt WL Jr. Transthoracic versus transesophageal echocardiography for detection of Libman-Sacks endocarditis: a randomized controlled study. J Rheumatol 2008;35:224-9.

187. La Canna G, Maisano F, De Michele L, Grimaldi A, Grassi F, Capritti E, et al. Determinants of the degree of functional aortic regurgitation in patients with anatomically normal aortic valve and ascending thoracic aorta aneurysm. Transoesophageal Doppler echocardiography study. Heart 2009;95:130-6.

188. Keane MG, Wiegers SE, Yang E, Ferrari VZ, St John Sutton MG, Bavaria JE. Structural determinants of aortic regurgitation in type A dissection and the role of valvular resuspension as determined by intraoperative transesophageal echocardiography. Am J Cardiol 2000;85:604-10.

189. Thorsgard ME, Morrissette GJ, Sun B, Eales F, Kshettry V, Flavin T, et al. Impact of intraoperative transesophageal echocardiography on acute type-A aortic dissection. J Cardiothorac Vasc Anesth 2014;28:1203-7.

190. Otani K, Takeuchi M, Kaku K, Sugeng L, Yoshitani H, Haruki N, et al. Assessment of the aortic root using real-time 3D transesophageal echocardiography. Circ J 2010;74:2649-57.

191. Gallego Garcia de Vinuesa P, Castro A, Barquero JM, Araji O, Brunstein G, Mendez I, et al. Functional anatomy of aortic regurgitation. Role of transesophageal echocardiography in aortic valve-sparing surgery. Rev Esp Cardiol 2010;63:536-43.

192. le Polain de Waroux JB, Pouleur AC, Goffinet C, Vancraeynest D, Van Dyck M, Robert A, et al. Functional anatomy of aortic regurgitation: accuracy, prediction of surgical repairability, and outcome implications of transesophageal echocardiography. Circulation 2007;116(11 Suppl):I264-9.

193. Movsowitz HD, Levine RA, Hilgenberg AD, Isselbacher EM. Transesophageal echocardiographic description of the mechanisms of aortic

regurgitation in acute type A aortic dissection: implications for aortic valve repair. J Am Coll Cardiol 2000;36:884-90.

194. Vanoverschelde JL, van Dyck M, Gerber B, Vancraeynest D, Melchior J, de Meester C, et al. The role of echocardiography in aortic valve repair. Ann Cardiothorac Surg 2013;2:65-72.

195. Roy DA, Schaefer U, Guetta V, Hildick-Smith D, Mollmann H, Dumonteil N, et al. Transcatheter aortic valve implantation for pure severe native aortic valve regurgitation. J Am Coll Cardiol 2013;61:1577-84.

196. Seiffert M, Bader R, Kappert U, Rastan A, Krapf S, Bleiziffer S, et al. Initial German experience with transapical implantation of a secondgeneration transcatheter heart valve for the treatment of aortic regurgitation. JACC Cardiovasc Interv 2014;7:1168-74.

197. Chatzimavroudis GP, Oshinski JN, Franch RH, Pettigrew RI, Walker PG, Yoganathan AP. Quantification of the aortic regurgitant volume with magnetic resonance phase velocity mapping: a clinical investigation of the importance of imaging slice location. J Heart Valve Dis 1998;7: 94-101.

198. Fratz S, Chung T, Greil GF, Samyn MM, Taylor AM, Valsangiacomo Buechel ER, et al. Guidelines and protocols for cardiovascular magnetic resonance in children and adults with congenital heart disease: SCMR expert consensus group on congenital heart disease. J Cardiovasc Magn Reson 2013;15:51.

199. Chatzimavroudis GP, Walker PG, Oshinski JN, Franch RH, Pettigrew RI, Yoganathan AP. Slice location dependence of aortic regurgitation measurements with MR phase velocity mapping. Magn Reson Med 1997; 37:545-51.

200. Kilner PJ, Gatehouse PD, Firmin DN. Flow measurement by magnetic resonance: a unique asset worth optimising. J Cardiovasc Magn Reson 2007;9:723-8.

201. Dulce MC, Mostbeck GH, O’Sullivan M, Cheitlin M, Caputo GR, Higgins CB. Severity of aortic regurgitation: interstudy reproducibility of measurements with velocity-encoded cine MR imaging. Radiology 1992;185:235-40.

202. Honda N, Machida K, Hashimoto M, Mamiya T, Takahashi T, Kamano T, et al. Aortic regurgitation: quantitation with MR imaging velocity mapping. Radiology 1993;186:189-94.

203. Ley S, Eichhorn J, Ley-Zaporozhan J, Ulmer H, Schenk JP, Kauczor HU, et al. Evaluation of aortic regurgitation in congenital heart disease: value of MR imaging in comparison to echocardiography. Pediatr Radiol 2007; 37:426-36.

204. Iwamoto Y, Inage A, Tomlinson G, Lee KJ, Grosse-Wortmann L, Seed M, et al. Direct measurement of aortic regurgitation with phase-contrast magnetic resonance is inaccurate: proposal of an alternative method of quantification. Pediatr Radiol 2014;44:1358-69.

205. Sechtem U, Pflugfelder PW, Cassidy MM, White RD, Cheitlin MD, Schiller NB, et al. Mitral or aortic regurgitation: quantification of regurgitant volumes with cine MR imaging. Radiology 1988;167: 425-30.

206. Neuhold A, Globits S, Frank H, Glogar D, Mayr H, Stiskal M, et al. CineMR for the quantification of regurgitation defects by a volume method. Rofo 1990;153:627-32.

207. Globits S, Mayr H, Frank H, Neuhold A, Glogar D. Quantification of regurgitant lesions by MRI. Int J Card Imaging 1990;6:109-16.

208. Bolen MA, Popovic ZB, Rajiah P, Gabriel RS, Zurick AO, Lieber ML, et al. Cardiac MR assessment of aortic regurgitation: holodiastolic flow reversal in the descending aorta helps stratify severity. Radiology 2011; 260:98-104.

209. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2014;148:e1-132.

210. Hendel RC, Patel MR, Kramer CM, Poon M, Hendel RC, Carr JC, et al. ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee

370 Zoghbi et al

Journal of the American Society of Echocardiography April 2017

Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology. J Am Coll Cardiol 2006;48: 1475-97.

211. Behm CZ, Nath J, Foster E. Clinical correlates and mortality of hemodynamically significant tricuspid regurgitation. J Heart Valve Dis 2004;13: 784-9.

212. Nath J, Foster E, Heidenreich PA. Impact of tricuspid regurgitation on long-term survival. J Am Coll Cardiol 2004;43:405-9.

213. Antunes MJ, Barlow JB. Management of tricuspid valve regurgitation. Heart 2007;93:271-6.

214. Shah PM, Raney AA. Tricuspid valve disease. Curr Probl Cardiol 2008; 33:47-84.

215. Martinez RM, O’Leary PW, Anderson RH. Anatomy and echocardiography of the normal and abnormal tricuspid valve. Cardiol Young 2006; 16(Suppl 3):4-11.

216. Kostucki W, Vandenbossche JL, Friart A, Englert M. Pulsed Doppler regurgitant flow patterns of normal valves. Am J Cardiol 1986;58: 309-13.

217. Anwar AM, Geleijnse ML, Soliman OI, McGhie JS, Frowijn R, Nemes A, et al. Assessment of normal tricuspid valve anatomy in adults by real-time three-dimensional echocardiography. Int J Cardiovasc Imaging 2007;23: 717-24.

218. Fukuda S, Saracino G, Matsumura Y, Daimon M, Tran H, Greenberg NL, et al. Three-dimensional geometry of the tricuspid annulus in healthy subjects and in patients with functional tricuspid regurgitation: a real-time, 3- dimensional echocardiographic study. Circulation 2006;114(1 Suppl): I492-8.

219. Rogers JH, Bolling SF. The tricuspid valve: current perspective and evolving management of tricuspid regurgitation. Circulation 2009;119: 2718-25.

220. Mahmood F, Kim H, Chaudary B, Bergman R, Matyal R, Gerstle J, et al. Tricuspid annular geometry: a three-dimensional transesophageal echocardiographic study. J Cardiothorac Vasc Anesth 2013;27: 639-46.

221. Spinner EM, Shannon P, Buice D, Jimenez JH, Veledar E, Del Nido PJ, et al. In vitro characterization of the mechanisms responsible for functional tricuspid regurgitation. Circulation 2011;124:920-9.

222. Chandraratna PN, Lopez JM, Fernandez JJ, Cohen LS. Echocardiographic detection of tricuspid valve prolapse. Circulation 1975;51: 823-6.

223. Rippe JM, Angoff G, Sloss LJ, Wynne J, Alpert JS. Multiple floppy valves: an echocardiographic syndrome. Am J Med 1979;66:817-24.

224. Schlamowitz RA, Gross S, Keating E, Pitt W, Mazur J. Tricuspid valve prolapse: a common occurrence in the click-murmur syndrome. J Clin Ultrasound 1982;10:435-9.

225. Emine BS, Murat A, Mehmet B, Mustafa K, Gokturk I. Flail mitral and tricuspid valves due to myxomatous disease. Eur J Echocardiogr 2008; 9:304-5.

226. van Son JA, Danielson GK, Schaff HV, Miller FA Jr. Traumatic tricuspid valve insufficiency. Experience in thirteen patients. J Thorac Cardiovasc Surg 1994;108:893-8.

227. Choi JS, Kim EJ. Simultaneous rupture of the mitral and tricuspid valves with left ventricular rupture caused by blunt trauma. Ann Thorac Surg 2008;86:1371-3.

228. Reddy VK, Nanda S, Bandarupalli N, Pothineni KR, Nanda NC. Traumatic tricuspid papillary muscle and chordae rupture: emerging role of three-dimensional echocardiography. Echocardiography 2008;25:653-7.

229. Braverman AC, Coplen SE, Mudge GH, Lee RT. Ruptured chordae tendineae of the tricuspid valve as a complication of endomyocardial biopsy in heart transplant patients. Am J Cardiol 1990;66:111-3.

230. Mielniczuk L, Haddad H, Davies RA, Veinot JP. Tricuspid valve chordal tissue in endomyocardial biopsy specimens of patients with

• significant tricuspid regurgitation. J Heart Lung Transplant 2005;24: 1586-90.

231. Sloan KP, Bruce CJ, Oh JK, Rihal CS. Complications of echocardiography-guided endomyocardial biopsy. J Am Soc Echocardiogr 2009;22:324.e1-4.

232. Christogiannis Z, Korantzopoulos P, Pappas K, Pitsis A. Flail septal leaflet of the tricuspid valve due to rupture of chordae tendineae ten years after pacemaker implantation. Int J Cardiol 2014;176:e41-6.

233. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685-713. quiz 786–8.

234. Chan K-L, Veinot JP. Anatomic Basis of Echocardiographic Diagnosis. London: Springer; 2011.

235. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 2001;104: 2525-32.

236. Attenhofer Jost CH, Edmister WD, Julsrud PR, Dearani JA, Savas Tepe M, Warnes CA, et al. Prospective comparison of echocardiography versus cardiac magnetic resonance imaging in patients with Ebstein’s anomaly. Int J Cardiovasc Imaging 2012;28:1147-59.

237. Shiran A, Najjar R, Adawi S, Aronson D. Risk factors for progression of functional tricuspid regurgitation. Am J Cardiol 2014;113:995-1000.

238. Pennell DJ. Ventricular volume and mass by CMR. J Cardiovasc Magn Reson 2002;4:507-13.

239. James SH, Wald R, Wintersperger BJ, Jimenez-Juan L, Deva D, Crean M, et al. Accuracy of right and left ventricular functional assessment by short-axis vs axial cine steady-state free-precession magnetic resonance imaging: intrapatient correlation with main pulmonary artery and ascending aorta phase-contrast flow measurements. Can Assoc Radiol J 2013;64:213-9.

240. Alfakih K, Plein S, Thiele H, Jones T, Ridgway JP, Sivananthan MU. Normal human left and right ventricular dimensions for MRI as assessed by turbo gradient echo and steady-state free precession imaging sequences. J Magn Reson Imaging 2003;17:323-9.

241. Sugeng L, Weinert L, Lang RM. Real-time 3-dimensional color Doppler flow of mitral and tricuspid regurgitation: feasibility and initial quantitative comparison with 2-dimensional methods. J Am Soc Echocardiogr 2007;20:1050-7.

242. Chen TE, Kwon SH, Enriquez-Sarano M, Wong BF, Mankad SV. Threedimensional color Doppler echocardiographic quantification of tricuspid regurgitation orifice area: comparison with conventional twodimensional measures. J Am Soc Echocardiogr 2013;26:1143-52.

243. de Agustin JA, Viliani D, Vieira C, Islas F, Marcos-Alberca P, Gomez de Diego JJ, et al. Proximal isovelocity surface area by single-beat threedimensional color Doppler echocardiography applied for tricuspid regurgitation quantification. J Am Soc Echocardiogr 2013;26:1063-72.

244. Tribouilloy CM, Enriquez-Sarano M, Capps MA, Bailey KR, Tajik AJ. Contrasting effect of similar effective regurgitant orifice area in mitral and tricuspid regurgitation: a quantitative Doppler echocardiographic study. J Am Soc Echocardiogr 2002;15:958-65.

245. van der Hulst AE, Westenberg JJ, Kroft LJ, Bax JJ, Blom NA, de Roos A, et al. Tetralogy of fallot: 3D velocity-encoded MR imaging for evaluation of right ventricular valve flow and diastolic function in patients after correction. Radiology 2010;256:724-34.

246. Reddy ST, Shah M, Doyle M, Thompson DV, Williams RB, Yamrozik J, et al. Evaluation of cardiac valvular regurgitant lesions by cardiac MRI sequences: comparison of a four-valve semi-quantitative versus quantitative approach. J Heart Valve Dis 2013;22:491-9.

247. Speiser U, Abas A, Henke C, Sandfort V, Jellinghaus S, Sievers B, et al. Time-resolved magnetic resonance imaging of contrast kinetics

Zoghbi et al 371

Journal of the American Society of Echocardiography Volume 30 Number 4

to identify severe tricuspid valve regurgitation. Acta Cardiol 2013;68: 247-53.

248. Norton KI, Tong C, Glass RB, Nielsen JC. Cardiac MR imaging assessment following tetralogy of Fallot repair. Radiographics 2006;26:197-211.

249. Powell AJ, Maier SE, Chung T, Geva T. Phase-velocity cine magnetic resonance imaging measurement of pulsatile blood flow inchildren andyoung adults: in vitro and in vivo validation. Pediatr Cardiol 2000;21:104-10.

250. Choong CY, Abascal VM, Weyman J, Levine RA, Gentile F, Thomas JD, et al. Prevalence of valvular regurgitation by Doppler echocardiography in patients with structurally normal hearts by two-dimensional echocardiography. Am Heart J 1989;117:636-42.

251. Takao S, Miyatake K, Izumi S, Okamoto M, Kinoshita N, Nakagawa H, et al. Clinical implications of pulmonary regurgitation in healthy individuals: detection by cross sectional pulsed Doppler echocardiography. Br Heart J 1988;59:542-50.

252. Martinez RM, Anderson RH. Echocardiographic features of the morphologically right ventriculo-arterial junction. Cardiol Young 2005;15(Suppl 1):17-26.

253. Iung B, Vahanian A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol 2011;8:162-72.

254. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Barwolf C, Levang OW, et al. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231-43.

255. Renella P, Aboulhosn J, Lohan DG, Jonnala P, Finn JP, Satou GM, et al. Two-dimensional and Doppler echocardiography reliably predict severe pulmonary regurgitation as quantified by cardiac magnetic resonance. J Am Soc Echocardiogr 2010;23:880-6.

256. Puchalski MD, Askovich B, Sower CT, Williams RV, Minich LL, Tani LY. Pulmonary regurgitation: determining severity by echocardiography and magnetic resonance imaging. Congenit Heart Dis 2008;3:168-75.

257. Mori Y, Rusk RA, Jones M, Li XN, Irvine T, Zetts AD, et al. A new dynamic three-dimensional digital color Doppler method for quantification of pulmonary regurgitation: validation study in an animal model. J Am Coll Cardiol 2002;40:1179-85.

258. Silversides CK, Veldtman GR, Crossin J, Merchant N, Webb GD, McCrindle BW, et al. Pressure half-time predicts hemodynamically significant pulmonary regurgitation in adult patients with repaired tetralogy of Fallot. J Am Soc Echocardiogr 2003;16:1057-62.

259. Li W, Davlouros PA, Kilner PJ, Pennell DJ, Gibson D, Henein MY, et al. Doppler-echocardiographic assessment of pulmonary regurgitation in adults with repaired tetralogy of Fallot: comparison with cardiovascular magnetic resonance imaging. Am Heart J 2004;147:165-72.

260. Zoghbi WA, Farmer KKL, Soto JG, Nelson JG, Quinones MA. Accurate noninvasive quantification of stenotic aortic valve area by Doppler echocardiography. Circulation 1986;73:452-9.

261. Valente AM, Cook S, Festa P, Ko HH, Krishnamurthy R, Taylor AM, et al. Multimodality imaging guidelines for patients with repaired tetralogy of fallot: a report from the American Society of Echocardiography: developed in collaboration with the Society for Cardiovascular Magnetic Resonance and the Society for Pediatric Radiology. J Am Soc Echocardiogr 2014;27:111-41.

262. Spiewak M, Biernacka EK, Malek LA, Misko J, Kowalski M, Milosz B, et al. Quantitative assessment of pulmonary regurgitation in patients with and without right ventricular tract obstruction. Eur J Radiol 2011;80:e164-8.

263. Wald RM, Redington AN, Pereira A, Provost YL, Paul NS, Oechslin EN, et al. Refining the assessment of pulmonary regurgitation in adults after

• tetralogy of Fallot repair: should we be measuring regurgitant fraction or regurgitant volume? Eur Heart J 2009;30:356-61.

264. Johansson B, Babu-Narayan SV, Kilner PJ. The effects of breath-holding on pulmonary regurgitation measured by cardiovascular magnetic resonance velocity mapping. J Cardiovasc Magn Reson 2009;11:1.

265. Rebergen SA, Chin JG, Ottenkamp J, van der Wall EE, de Roos A. Pulmonary regurgitation in the late postoperative follow-up of tetralogy of Fallot. Volumetric quantitation by nuclear magnetic resonance velocity mapping. Circulation 1993;88:2257-66.

266. Mercer-Rosa L, Yang W, Kutty S, Rychik J, Fogel M, Goldmuntz E. Quantifying pulmonary regurgitation and right ventricular function in surgically repaired tetralogy of Fallot: a comparative analysis of echocardiography and magnetic resonance imaging. Circ Cardiovasc Imaging 2012;5:637-43.

267. Klein AL, Burstow DJ, Tajik AJ, Zachariah PK, Taliercio CP, Taylor CL, et al. Age-related prevalence of valvular regurgitation in normal subjects: a comprehensive color flow examination of 118 volunteers. J Am Soc Echocardiogr 1990;3:54-63.

268. Muzzarelli S, Monney P, O’Brien K, Faletra F, Moccetti T, Vogt P, et al. Quantification of aortic flow by phase-contrast magnetic resonance in patients with bicuspid aortic valve. Eur Heart J Cardiovasc Imaging 2014;15:77-84.

269. Nordmeyer S, Riesenkampff E, Messroghli D, Kropf S, Nordmeyer J, Berger F, et al. Four-dimensional velocity-encoded magnetic resonance imaging improves blood flow quantification in patients with complex accelerated flow. J Magn Reson Imaging 2013;37:208-16.

270. O’Brien KR, Gabriel RS, Greiser A, Cowan BR, Young AA, Kerr AJ. Aortic valve stenotic area calculation from phase contrast cardiovascular magnetic resonance: the importance of short echo time. J Cardiovasc Magn Reson 2009;11:49.

271. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease). Developed in Collaboration with the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e143-263.

272. Thavendiranathan P, Liu S, Datta S, Walls M, Calleja A, Nitinunu A, et al. Automated 3D quantification of mitral regurgitation by real-time volume color flow Doppler: comparison with cardiac magnetic resonance imaging. J Am Soc Echocardiogr 2011;24:B3.

273. de Agustin JA, Marcos-Alberca P, Fernandez-Golfin C, Goncalves A, Feltes G, Nunez-Gil IJ, et al. Direct measurement of proximal isovelocity surface area by single-beat three-dimensional color Doppler echocardiography in mitral regurgitation: a validation study. J Am Soc Echocardiogr 2012;25:815-23.

274. Choi J, Heo R, Hong GR, Chang HJ, Sung JM, Shin SH, et al. Differential effect of 3-dimensional color Doppler echocardiography for the quantification of mitral regurgitation according to the severity and characteristics. Circ Cardiovasc Imaging 2014;7:535-44.

275. Choi J, Hong GR, Kim M, Cho IJ, Shim CY, Chang HJ, et al. Automatic quantification of aortic regurgitation using 3D full volume color doppler echocardiography: a validation study with cardiac magnetic resonance imaging. Int J Cardiovasc Imaging 2015;31:1379-89.