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Research Article
Originally Published 2 March 2012
Free Access

Mitral Valve Prolapse With Mid-Late Systolic Mitral Regurgitation: Pitfalls of Evaluation and Clinical Outcome Compared With Holosystolic Regurgitation

Abstract

Background—

Mitral regurgitation (MR) of mitral valve prolapse predominates in late systole but may be holosystolic or purely mid-late systolic, but the impact of MR timing on MR left ventricular and left atrial consequences and outcome is unknown. Whether effective regurgitant orifice (ERO) by the flow convergence method is similarly linked to outcome in mid-late systolic MR and holosystolic MR is uncertain.

Methods and Results—

We comprehensively and prospectively quantified MR in 111 patients with mitral valve prolapse and mid-late systolic MR and matched them to 90 patients with mitral valve prolapse and holosystolic MR for age, gender, atrial fibrillation, ejection fraction, and ERO (flow convergence). Mid-late systolic MR versus holosystolic MR groups were well matched, including for comorbidity, blood pressure, and heart rate (all P>0.10). Mid-late systolic MR versus holosystolic MR caused similar color jet area, midsystolic regurgitant flow, and peak velocity (P>0.40). Despite identical ERO (0.25±0.15 versus 0.25±0.15 cm2; P=0.53), the shorter duration of mid-late systolic MR (233±56 versus 426±50 ms; P<0.0001) yielded lower regurgitant volume (24.8±13.4 versus 48.6±25.6 mL; P<0.0001). MR consequences, systolic pulmonary pressure, and left ventricular and left atrial volume index (all P<0.001) were more benign in mid-late systolic MR versus holosystolic MR. Under medical management, fewer cardiac events (5 years: 15.8±4.6% versus 40.4±6.1%; P<0.0001) occurred in mid-late systolic MR versus holosystolic MR, requiring less mitral surgery. Multivariable analysis confirmed the independent association of mid-late systolic MR with benign consequences and outcomes (all P<0.01). Absolute ERO was not linked to outcome, in contrast to regurgitant volume.

Conclusions—

MR of mitral valve prolapse that is purely mid-late systolic causes more benign consequences and outcomes than holosystolic MR. Assessment may be misleading because jet area and ERO by flow convergence appear similar to those of holosystolic MR. However, shorter MR yields lower regurgitant volume, consequences, and benign outcomes. Instantaneous ERO by flow convergence should be interpreted in context, and in mid-late systolic MR, regurgitant volume provides information more reflective of MR severity. Therefore, for clinical management and surgical referral, clinicians should carefully take into account the timing and consequences of MR.

Introduction

Epidemiological data show that mitral regurgitation (MR) is the most frequent valve disease in the US population.1 The major cause of MR requiring surgical correction is degenerative, characterized primarily by mitral valve prolapse (MVP).24 The association between aging and higher MR prevalence leads to a rapidly increasing population burden of this valve disease.1 Despite the high feasibility of valve repair and the marked decline in operative mortality,5 the timing of surgery in asymptomatic patients with MVP remains controversial,6,7 as shown also by divergences between US and European guidelines.8,9A critical element of the clinical decision-making process is MR severity, which in patients with MVP is an essential marker of survival after diagnosis.10 Furthermore, quantitative MR assessment has taken a central role in the evaluation of patients with MR and MVP. Indeed, these methods are sensitive in detecting MR progression,11 and effective regurgitant orifice (ERO) has been shown in several large prospective series to be independently and strongly associated with outcome under medical management.1214An ERO ≥40 mm2 is now recognized by most scientific societies as the threshold for defining severe MR8,15 and is associated with high mortality (in excess of that expected in the population) and with frequent cardiac events.12,16
Clinical Perspective on p 1651
However, despite the coherence of outcome studies and the wide consensus on the markers of MR severity, some areas of uncertainty may have important clinical consequences. MR associated with MVP is dynamic17,18 predominantly or purely in the later phase of systole (mid-late systolic MR). Patients with MR that is not holosystolic were not represented in outcome studies,12 and it is not possible to determine whether such patients incur the same consequences (ventricular, atrial, hemodynamic, outcome) as their counterparts with holosystolic MR and whether the measured ERO carries similar implications in mid-late systolic MR and holosystolic MR. From the theoretical physiological point of view, there is relative equipoise in that regard. On one hand, the MR of MVP predominates in late systole, with the largest phasic ERO, whereas the largest regurgitant volume is delivered in mid-late systole18 so that the lack of an early systolic phase to the MR may be negligible and mid-late systolic MR may carry severe consequences.19 Indeed, our measurements showed that <10% of the regurgitant volume occurs in the first 25% of systole in MVP.18 On the other hand, amputation of a substantial part of systole in generating regurgitant volume may affect overall MR severity and lead to overestimation of MR by using the ERO measured at peak MR velocity as the main marker of MR severity. These 2 opposite concepts are possible and cannot be resolved by review of previous data.
Thus, to fill these gaps of knowledge and verify the hypothesis that MVP with mid-late systolic MR causes left ventricular (LV), left atrial (LA), and outcome consequences similar to those of MVP with holosystolic MR, we prospectively enrolled patients with MVP and mid-late systolic MR and quantified the MR by the proximal isovelocity surface area (PISA) method. We then matched these patients to those with MVP and holosystolic MR for age, gender, ejection fraction (EF), presence of atrial fibrillation (AF), and measured ERO.

Methods

Study Population

Between 2004 and 2006, we enrolled consecutive patients with MVP with mid-late systolic MR (by continuous-wave Doppler) with eligibility criteria identical to those in our prospective study of holosystolic MR.12 Thus, all patients had at least mild (by color flow imaging jet), isolated (without aortic valve disease), and pure (without stenosis) MR quantified by the PISA method. High-quality flow convergence imaging excluded constrained flow convergences. Patients were excluded if they had functional MR, particularly with pseudoprolapse (leaflet overshoot) with restricted motion or structurally normal valves. MR limited to isovolumic relaxation was excluded, and in all cases peak MR velocity was easily discernible and measurable. We excluded patients with annular calcification and mean gradient ≥5 mm Hg, associated organic aortic or tricuspid disease, previous valve repair or replacement, congenital or pericardial disease, or decreased EF (<50%) for any reason. Age, sex, and cardiac rhythm were not considered eligibility criteria.

Study Design

At enrollment, we performed prospective MR quantification followed by retrospective frequency matching of the cases (mid-late systolic MR group) to the control group with MVP and similarly prospectively quantified holosystolic MR (by continuous-wave Doppler) as reported previously.12 Gender- and AF-specific means of age (±5 years), EF (±5%), and ERO (±5 mm2) were used (as known major predictors of outcome) to define target matching criteria for the control population for holosystolic MR. This frequency-matching process provides groups with identical distribution of matching criteria but without specific 1-to-1 case-control matching. Thus, all patients had MVP with MR classified as mild or greater (by color flow imaging jet) and quantification of ERO and regurgitant volume by Doppler echocardiography. The study was powered (80%; 0.05; for a minimum total of 48 events for both groups combined) to detect at least a 30% difference in cardiac events (cardiac death, heart failure, or new-onset AF under medical management) between patients with mid-late systolic MR versus holosystolic MR. The study was approved by the Mayo Clinic institutional review board and was judged to be low risk, requiring only oral consent.

Clinical Assessment and Management

History and clinical examination were recorded at baseline by patients' personal physicians at our institution. Coexisting conditions were evaluated by the Charlson comorbidity index.20 Congestive heart failure was diagnosed on the basis of Framingham Heart Study criteria.21 New AF was diagnosed in patients in sinus rhythm at baseline with the use of ECG tracings. Clinical management was determined independently by the patients' personal physicians using all information available. Follow-up information was collected in 2010 after enrollment ended and all baseline data had been obtained. Events used as end points were all-cause mortality, cardiac events (cardiac mortality including sudden death,22 congestive heart failure, new onset of AF), and need for mitral valve surgery.

Doppler Echocardiography

Complete Doppler echocardiography was performed. Quantitative data promptly stored in a database were not altered throughout the study.
MR quantification used the PISA method as validated previously.15,23,24Briefly, color Doppler images of MR proximal flow convergence used a zoom of the region of interest. We optimized the position of the transducer to minimize the angle between regurgitant flow and ultrasonic beam, color flow scale, and baseline shift until flow convergence was visualized clearly. Flow convergences that were constrained or deformed were not considered acceptable so that correction by constraint angle was not necessary. Radial distance between first red/blue interface and mitral orifice allowed calculation of regurgitant flow. Using continuous-wave Doppler, we measured MR peak velocity, regurgitant time-velocity integral, total systolic duration (including preejection, ejection, and relaxation) from mitral closure to opening, and MR effective duration from regurgitation from beginning to end (mitral opening), and we calculated MR normalized duration as ratio of MR effective duration to total systolic duration. Absolute ERO area was calculated as regurgitant flow/MR velocity, and regurgitant volume was calculated as ERO×regurgitant time-velocity integral (Figure 1). A time-normalized ERO was calculated as absolute ERO×MR normalized duration. Regurgitant volume was also measured by quantitative Doppler (measurement of mitral and aortic stroke volumes) in 117 patients as described previously.25 Interobserver and intraobserver variability of MR Doppler echocardiographic quantification was analyzed in 15 randomly selected patients.
Figure 1. Example of quantitative and qualitative estimation of mitral regurgitation (MR) in a patient with holosystolic MR (A, B, and C) and with mid-late systolic MR (D, E, and F). A and D show the timing of MR signal, peak velocity, and time-velocity integral (marked by the white line) with the use of continuous-wave Doppler. Note the holosystolic signal (A) contrasting with a mid-late systolic signal (D). Flow convergence imaging is shown in B and E, demonstrating a similarly large zone of flow convergence, allowing calculation of similar midsystolic regurgitant flow and effective regurgitant orifice. The color flow jet in the 2-chamber view is shown in C and F and appears quite similar in the patients with holosystolic (C) and mid-late systolic (F) MR.
LV diameters, volumes, EF, and mass were measured as recommended.26 LA volume was calculated with the biplane area-length method as described previously.27

Statistical Analysis

Continuous normally distributed parameters are presented as mean±SD and were compared with the Student t test. Ordinal and/or nonnormally distributed variables are presented as median and first and third quartiles and were compared with the nonparametric Wilcoxon rank-sum test. Categorical data were compared between groups with a χ2 test or Fisher exact test when appropriate. Comparison of measurements (PISA versus quantitative Doppler or intraobserver and interobserver comparisons) relied on linear regression, paired t tests, and Bland-Altman plotting of differences versus mean values. To analyze the effect of mid-late systolic MR versus holosystolic MR (independent variable) on echocardiographic measures of MR severity and consequences (regurgitant volume, LV size index, LA volume index, right ventricular systolic pressure, continuous and dichotomous), univariable and multivariable analyses adjusted for age, gender, EF, AF, ERO, and systolic blood pressure were performed. Clinical outcome end points were ascertained while patients were under medical management (from diagnosis to surgery or death). Event rates (presented ±SE) were calculated according to the Kaplan-Meier method and compared by log-rank test. Unadjusted and adjusted analyses of time to events were performed with Cox proportional hazards models. To avoid overfitting of the model, we restricted the independent variables to the presence of mid-late systolic MR as the main variable of interest and age, sex, symptoms, EF, presence of AF, and ERO as main adjusting variables with Charlson comorbidity index and systolic blood pressure added to the adjusting variables in a verification model. All P values were 2-sided, and values <0.05 indicated statistical significance. All authors participated in designing the study, collecting and analyzing the data, and drafting and revising the manuscript.

Results

Baseline Characteristics

Table 1 shows the baseline characteristics of the 201 patients enrolled in the study, overall and stratified by presence of mid-late systolic MR. Comparison between mid-late systolic MR and holosystolic MR verified that the matching process was successful because age, sex, EF, AF, and ERO were equally distributed. Although not part of the matching process, blood pressure, heart rate, prevalence of diabetes mellitus, and Charlson comorbidity index showed no difference between mid-late systolic MR and holosystolic MR groups. Thus, the matching process achieved groups (mid-late systolic MR and holosystolic MR) with similar comorbidities, ERO, and AF prevalence that differed essentially by the timing of MR. These characteristics, particularly age, are well within the general presentation of patients with MR in the current era.12
Table 1. Baseline Characteristics of Patients With MR Overall and Stratified by the Presence or Absence of End-Systolic MR
 All Patients (n=201)Mid-Late Systolic MR (n=111)Holosystolic MR (n=90)P
Matching variables    
    Age, y64.2±15.764.0±16.964.4±14.40.86
    Atrial fibrillation, n (%)19 (9.5)12 (10.8)7 (7.8)0.46
    Male sex, n (%)96 (48)51 (46)45 (50)0.56
    Ejection fraction, %64.4±6.564.4±6.764.4±6.30.96
    Absolute ERO, mm20.26±0.150.25±0.150.26±0.150.53
Nonmatching variables    
    Heart rate, bpm67±1266±1368±110.31
    SBP, mm Hg132±17130.5±16.4134.5±18.40.10
    Diabetes mellitus, n (%)7 (3.5)5 (4.5)2 (2.2)0.37
    Charlson comorbidity index*2.2 (0.8, 3.7)2.2 (0.8, 3.9)2.1 (0.8, 3.9)0.75
MR indicates mitral regurgitation; absolute ERO, effective regurgitant orifice of MR calculated from measurements at peak regurgitant velocity; and SBP, systolic blood pressure.
*
The comorbidity index is presented as median (25th, 75th percentile).

MR Characteristics

MR characteristics and associated LV, LA, and hemodynamic and clinical characteristics are compared between mid-late systolic MR and holosystolic MR groups in Table 2, showing similarities but also marked differences between the 2 types of MR. Indeed, in addition to similar ERO by design, jet area (in both the 4-chamber and 2-chamber views), regurgitant peak velocity (driving pressure), and regurgitant flow rate were similar in mid-late systolic MR and holosystolic MR groups. Conversely, regurgitant duration and the ratio of MR duration to total systolic time were shorter in the mid-late systolic MR group (Figure 1). Shorter MR duration resulted in smaller regurgitant time-velocity integral and thus smaller regurgitant volume in mid-late systolic MR despite similar ERO and driving pressure. Thus, despite the large and similar MR jet, the prevalence of severe MR (regurgitant volume ≥60 mL per beat) was much lower in mid-late systolic MR (1% versus 33%; P<0.0001). The adequacy of regurgitant volume measurement was confirmed in 117 patients in whom we also measured regurgitant volume simultaneously by quantitative Doppler. The correlation between Doppler and flow convergence regurgitant volume was r=0.93, P<0.001, with slope not different from 1.0 (P=0.80), and values of regurgitant volume by Doppler and flow convergence regurgitant volume showed no difference by paired analysis (45±25 and 44±25 mL per beat; P=0.17) and by Bland-Altman analysis (difference of methods not different from 0 throughout range of values). Mean differences for intraobserver and interobserver differences for ERO were 0.13 and 1.9 mm2 and for regurgitant volume were 2.4 and 2.2 mL per beat, respectively (not different from 0) (all P>0.24). Thus, no evidence for measurement errors appeared as a source of difference in regurgitant volume between mid-late systolic MR and holosystolic MR.
Table 2. Clinical and Echocardiographic Characteristics in Mid-Late Systolic and Holosystolic MR
 Mid-Late Systolic MR (n=111)Holosystolic MR (n=90)P
MR characteristics   
    ERO, mm20.25±0.150.25±0.150.53
    Jet area, 4-chamber view, cm28.3±3.68.0±5.20.63
    Jet area, 2-chamber view, cm28.2±4.08.3±5.10.93
    Aliasing velocity, cm/s37.7±7.635.6±9.50.08
    Flow convergence radius, cm0.74±0.20.78±0.20.20
    Regurgitant flow rate, mL/s139.4±80.1148.6±80.40.42
    Regurgitant peak velocity, m/s5.7±0.65.7±0.50.96
    Regurgitant TVI, cm105.5±21190.2±29.5<0.0001
    MR duration, ms233±56426±50<0.0001
    MR duration/systolic time ratio, %54.9±10.599.7±3.1<0.0001
    Regurgitant volume, mL per beat25.2±13.548.5±25.6<0.0001
LV and LA characteristics   
    LVEDD, mm51.3±6.453.9±6.60.005
    LVESD, mm32.1±5.133.5±5.40.06
    LA volume index, mL/m239±1454±21<0.0001
    LV diastolic volume index, mL/m272±22102±22<0.0001
    LV systolic volume index, mL/m225±1030±120.0005
    LV mass index, g/m2103±31112±250.02
    End-systolic mitral annulus diameter, cm3.7±0.53.8±0.40.56
Hemodynamics   
    Deceleration time, ms219.5±52207.6±450.09
    E-wave velocity, m/s0.78±0.220.87±0.250.01
    A-wave velocity, m/s0.69±0.240.69±0.220.96
    E/A ratio1.24±0.501.36±0.610.17
    PV systolic flow reversal, n (%)4 (3.6)12 (18.2)0.001
    RVSP, mm Hg29±736±10<0.0001
    Cardiac index, L/min per m22.93±0.72.78±0.60.1
Clinical characteristics   
    NYHA class I, %9269<0.0001
    NYHA class II, %729 
    NYHA class III, %12 
    β-blocker use, %30370.3
    Diuretic use, %8200.01
    Digoxin use, %223<0.0001
MR indicates mitral regurgitation; ERO, effective regurgitant orifice; TVI, time-velocity integral; LV, left ventricular; EDD, end-diastolic diameter; ESD, end-systolic diameter; LA, left atrial; PV, pulmonary vein; RVSP, right ventricular systolic pressure; and NYHA, New York Heart Association.
In terms of MR consequences, smaller regurgitant volume in mid-late systolic MR was associated with smaller LV dimension and mass and LA volume (Table 2). Hemodynamic consequences of MR were also markedly different between mid-late systolic MR and holosystolic MR. Mid-late systolic MR was associated with lower E-wave diastolic velocity, consistent with lower regurgitant volume and possibly lower LV filling pressure, as suggested by lower systolic pulmonary pressure. Less frequent systolic reversal in pulmonary veins is also consistent with lower regurgitant volume. Clinically, lower severity at presentation with less frequent symptoms in mid-late systolic MR was mirrored by lower intensity of medical treatment by diuretics or digoxin in mid-late systolic MR versus holosystolic MR.
These overall differences between mid-late systolic MR and holosystolic MR were confirmed after stratification according to measured instantaneous ERO (ERO ≥0.20 or <0.20 cm2). In both strata, the differences in echocardiographic measurements between mid-late systolic MR and holosystolic MR remained highly significant (Figure 2). Thus, the lower severity and consequences of MR in mid-late systolic MR are not related to a different response to a given ERO but are observed irrespective of instantaneous ERO range.
Figure 2. Comparison of regurgitant volume, left atrial (LA) volume index, right ventricular (RV) systolic pressure, and left ventricular (LV) end-diastolic volume index between patients with mid-late systolic mitral regurgitation (MR) (mid-late MR) and holosystolic MR (holo-MR) stratified by measured effective regurgitant orifice (ERO) (ERO <0.2 cm2, top; ERO ≥0.2 cm2, bottom). For all strata and all variables represented, mid-late systolic MR was associated with fewer consequences than holosystolic MR.
In multivariable analyses, association of mid-late systolic MR with lower severity and consequences of MR was tested with adjustment for age, sex, EF, systolic blood pressure, AF, and measured ERO. Indeed, mid-late systolic MR remained independently associated with smaller regurgitant volume as a continuous variable (P<0.0001) and with lower odds of regurgitant volume ≥60 mL (odds ratio, 0.02 [0.001–0.08]; P<0.0001). Mid-late systolic MR was independently associated with lower LV end-diastolic volume index as a continuous variable (P<0.0001) and with lower odds of a value ≥100 mL/m2 (0.09 [0.03–0.19]; P<0.0001). It was also independently associated with lower LV end-systolic volume index (P<0.001) and with lower odds of a value ≥35 mL/m2 (0.29 [0.13–0.62]; P=0.001). Mid-late systolic MR was independently associated with lower LA volume index (P<0.0001) and lower odds of LA index ≥60 mL/m2 (0.16 [0.06–0.39); P<0.0001). It was also independently associated with lower systolic pulmonary pressure (P<0.0001).

Clinical Outcome

All-Cause Mortality

There were 20 deaths under medical management among the entire series, with survival rates of 98±1% at 1 year and 90±3% at 5 years. The 5-year survival rate tended to be lower in the holosystolic MR versus the mid-late systolic MR group, but the difference did not reach statistical significance (84±5% versus 94±3%; P=0.10). Multivariable analysis with limited adjustment for age and ERO did not affect the results, and the trend toward lower mortality in patients with mid-late systolic MR did not reach statistical significance (P=0.10). Among the entire cohort, 55 underwent mitral valve surgery; this percentage was lower in patients with mid-late systolic MR than in those with holosystolic MR (19.8% versus 36.7%; P=0.008). Thus, the combined event of death or need for surgery was more often observed in patients with holosystolic MR than in those with mid-late systolic MR (24±5% versus 6±2% at 1 year and 44±6% versus 31±6% at 5 years; P=0.02).

Cardiac Events

After diagnosis, there were 52 cardiac events (death from cardiac causes, admission for congestive heart failure, or new-onset AF) while patients were medically treated, including 16 patients who presented with heart failure and 28 with new AF. The 5-year cardiac event rate was 26±4% overall and was significantly lower in patients with mid-late systolic MR than in those with holosystolic MR (15.9±4.7% versus 42.4±6.2%; P<0.0001) (Figure 3). Each individual event, besides death, was less frequent (at 5 years: heart failure, 5.8±3.4% versus 17.0±4.7%; P=0.002; new onset of AF, 7.0±2.5% versus 21.5±5.2%; P=0.009) in mid-late systolic MR. Mid-late systolic MR was strongly associated with lower cardiac event rates in Cox proportional hazards analysis (Table 3), showing a hazard ratio of 0.25 for mid-late systolic MR versus holosystolic MR that was almost unaffected by any adjustment.
Figure 3. Cardiac events (cardiac death, congestive heart failure, or new-onset atrial fibrillation) under medical management in patients with mid-late systolic mitral regurgitation (mid-late MR) compared with holosystolic MR (holo-MR). The values indicated for each line are cardiac event rates (±SE) at 5 years. Note that there are significantly fewer cardiac events in patients with mid-late systolic MR compared with patients with holosystolic MR with the same effective regurgitant orifice.
Table 3. Cox Proportional Hazards Unadjusted and Adjusted Analysis of MR Timing (Mid-Late Systolic vs Holosystolic MR) Linked to Cardiovascular Events
 Hazard Ratio for Mid-Late Systolic MR95% CIP
Cardiac events   
    Univariable analysis0.250.12–0.48<0.0001
    Adjustment*0.260.13–0.52<0.0001
    Comprehensive adjustment0.250.12–0.50<0.0001
MR indicates mitral regurgitation; CI, confidence interval.
*
Adjustment was for age, ejection fraction, symptoms (New York Heart Association class ≥II), and presence of atrial fibrillation.
Adjustment was for age, ejection fraction, symptoms (New York Heart Association class ≥II), presence of atrial fibrillation, systolic blood pressure, and comorbidity index.
Examining the objective echocardiographic variables associated with outcome measured by cardiac events, we tested the absolute ERO, regurgitant volume, LA volume index, and ERO normalized for relative regurgitant time. In this setting, absolute instantaneous ERO nonnormalized to regurgitant time was not associated with cardiac events (hazard ratio, 1.2 [0.5–2.5] for ERO ≥0.40 cm2; P=0.64), a lack of association unaffected by any adjustment (all P>0.36). Conversely, regurgitant volume was associated with cardiac events univariably (hazard ratio, 3.42 [1.74–6.32]; P=0.0007 unadjusted for regurgitant volume ≥60 mL per beat) and in multivariable analysis (hazard ratio, 3.85 [1.94–7.23]; P=0.0003 adjusted for age, sex, symptoms, AF, and EF; and hazard ratio, 3.91 [1.93–7.48]; P=0.0004 with additional adjustment for systolic blood pressure and comorbidity index). The ERO normalized to relative regurgitant time was also associated with cardiac events univariably (hazard ratio for normalized ERO ≥40 mm2, 3.29 [1.34–6.92]; P=0.01) and in multivariable analysis with similar adjustments (hazard ratio, 4.28 [1.63–9.9]; P=0.005; and hazard ratio, 4.38 [1.65–10.3]; P=0.005 for comprehensive adjustment). LA volume index ≥60 mL/m2 was also associated with high event rates univariably (hazard ratio, 3.28 [1.75–5.90]; P<0.001) and in multivariable Cox proportional hazards analysis (hazard ratio, 2.98 [1.49–5.77]; P=0.003 and hazard ratio, 3.18 [1.57–6.26]; P=0.002 for comprehensive adjustment). Thus, even in the presence of mid-late systolic MR, there are measures of MR severity and consequences that are strongly linked to outcome once it is realized that the nonnormalized ERO is not useful under such circumstances.

Discussion

In patients with MVP, the dynamic nature of MR during the cardiac cycle is well documented,17,18 but little attention has been directed toward MVP with mid-late systolic MR.19 Previous outcome studies of organic MR either included exclusively holosystolic MR12 or did not address the specific outcome of mid-late systolic MR.10,11,14,2830 We report herein the first sizable series of patients with mid-late systolic MR due to MVP with prospective, quantitative assessment and analysis of long-term outcome. Our study shows that purely mid-late systolic MR due to MVP can be particularly misleading. Indeed, compared with holosystolic MR, mid-late systolic MR presents with a similar jet extent, similar large flow convergence, and similar regurgitant flow and velocity. Therefore, a less than comprehensive assessment may lead clinicians to erroneously consider it as severe as holosystolic MR, particularly if the measured instantaneous ERO is the only quantitative variable considered. However, our study shows that despite the late predominance of MR in MVP, comprehensive assessment reveals the lesser degree and consequences of purely mid-late systolic MR. With MR involving purely mid-late systole, lower regurgitant volume with less LV and LA enlargement, lower pulmonary pressures, and fewer symptoms due to MR are observed. In turn, our study shows that lower volume overload translates into clinical outcomes with markedly lower rates of cardiac events and need for surgical treatment. Hence, the mid-late systolic nature of MR has critical importance in the interpretation of qualitative or quantitative measures of MR severity. In this setting, the measured instantaneous ERO is not independently associated with outcome, in contrast to observations of holosystolic MR. Hence, other measures of MR severity, particularly regurgitant volume, should be used in the clinical management of patients with MVP and MR. Therefore, for clinical management, clinicians should carefully take into account the timing and consequences of MR and interpret the ERO measurement in context.

Pathophysiology and Clinical Presentation

The historic seminal report on MVP linked late-systolic murmurs to billowing mitral valves31; this was later confirmed by echocardiography.32 Doppler echocardiography subsequently demonstrated the dynamic MR of MVP,17,18 with MVP progression throughout systole even in patients with holosystolic MR. Pathophysiologically, as systole progresses, LV volume decreases, causing increasing mitral billowing,33 which, compounded by the dysfunctional enlarging mitral annulus,34leads to wider ERO, so that most of the regurgitant volume penetrates the LA in mid-late systole.17,18 With dynamic ERO measured by the instantaneous flow convergence method, concerns in regard to accuracy were raised, but ERO measured at peak MR velocity closely reflects average holosystolic ERO18 and determines outcome.12 Mid-late systolic MR has not been well studied, and the observation that it may have serious clinical consequences19 raised the issue that marked late-systolic MR predominance17,18 makes the differentiation of MR presence in early systole an academic consideration of little clinical significance. This concept is supported by the fact that in MVP, <10% of regurgitant volume is regurgitated in the first one quarter of systole.18 However, our study shows that in regard to MR timing, the differentiation between mid-late systolic and holosystolic MR matters a great deal. Mid-late systolic MR of MVP causes less volume overload with much lower regurgitant volume than holosystolic MR of similar measured instantaneous ERO. This observation is confirmed by the smaller LV, lower LV mass, and smaller LA in mid-late systolic MR versus holosystolic MR. Furthermore, the pulmonary pressures are also lower in mid-late systolic MR despite similar ERO, so that an alternative hypothesis of lower regurgitant volume due to higher LA pressure is highly unlikely. All forms of adjustment and stratification confirm lower volume overload of mid-late systolic MR consistent with lower E-wave velocity, less frequent systolic reversal in pulmonary veins, and less frequent symptoms. Consequently, highly dynamic MR of MVP with late predominance should not mislead clinicians and hinder the importance of distinguishing mid-late systolic MR from holosystolic MR and recognizing its lesser volume overload and clinical consequences.

MR Assessment and Clinical Outcome

MR assessment is based on guidelines that combine specific qualitative criteria and quantitative criteria.15 Despite these guidelines, assessment of mid-late systolic MR may be particularly misleading. Indeed, among the specific qualitative criteria of severe MR are prominently large jets and large flow convergences. Our study shows that, in regard to these criteria, mid-late systolic MR and holosystolic MR have a similar appearance by color Doppler, and recognizing that these characteristics are only present for part of systole is not easy. Because of the pitfalls of color Doppler, quantitative assessment is recommended,15 and a large ERO is now recognized in clinical guidelines as a major marker of severe MR.8 This recognition is based on the association of ERO with the physiological consequences of MR35 and the clinical outcome in several prospective studies of organic MR.1214,16 The power of ERO as a determinant of outcome is related to the fact that LV energy is transmitted to the LA36 not just as regurgitant volume but also as potential energy (pressure), so that ERO is associated with subsequent heart failure and cardiac events.12 ERO and regurgitant volume are measurable by several methods,15 and the flow convergence method has been validated24,37 with excellent correlations to quantitative Doppler.35 Thus, ERO ≥40 mm2 is widely considered a marker of severe MR.8 However, these validation and outcome studies were conducted in holosystolic MR12 and have not addressed the issue of mid-late systolic MR due to MVP.
Our study shows that use of a single measurement at peak velocity applied indiscriminately to mid-late systolic MR provides measured EROs that are not associated with outcome and inappropriate for patient management. Indeed, in mid-late systolic MR there is considerable discrepancy between uncorrected ERO ≥40 mm2 categorizing 15% of patients with severe MR, whereas regurgitant volume ≥60 mL per beat is detected in only 1%. Furthermore, with matched ERO between mid-late systolic MR and holosystolic MR as well as matched age, sex, and EF and similar blood pressure, heart rate, and comorbidity, the outcome of mid-late systolic MR is much more benign than that of holosystolic MR, and surgery is indicated less frequently. This difference in outcome is confirmed for each specific event (heart failure and new AF) and in all multivariable models. Additionally, ERO uncorrected to normalized regurgitant time is not associated with outcome, in contrast to previous data in holosystolic MR.12 Thus, patients with MVP and mid-late systolic MR have a generally benign outcome, which is congruent with the seminal work on MVP32 and population-based MVP with minimal MR.10 Undetected inclusion of patients with mid-late systolic MR may explain the benign outcome observed in some degenerative MR series.38 Conversely, irrespective of MR timing, large regurgitant volume or large LA index39 predicts outcome and reflects unbiased severity of MR. It is also possible to correct the ERO for the normalized regurgitant time (fraction of systole occupied by MR) and to obtain information strongly linked to outcome.
Thus, in a very misleading situation with large regurgitant jet, large flow convergence, and large ERO in mid-late systolic MR, it is essential to conform to the comprehensive MR assessment recommended in the present guidelines.15 Low E-wave velocity and absence of pulmonary venous reversal attract attention but are not decisive. Interpretation in the context (brief MR duration) of ERO values and a comprehensive assessment of MR with regurgitant volume measurement allow appropriate interpretation of the severity of the condition. Although we favor early surgery in patients with organic, severe MR and reparable mitral valve,7 we believe that, in patients with mid-late systolic MR who generally have a benign outcome for several years after diagnosis, prudent rather than aggressive surgical consideration is in order. However, patients with MVP and mid-late systolic MR should be monitored carefully because progression of MR11,40 and its transformation in holosystolic MR may lead to a more somber outlook. Therefore, in patients with MVP, MR timing is of critical importance in interpreting ERO measured by the flow convergence method (or other color Doppler–based approaches), so that for clinical management and the surgical referral generally reserved for severe MR, clinicians should carefully take into account the timing and consequences of MR.

Limitations

The study was not powered to assess differences in mortality, which is a rare occurrence in patients with mid-late systolic MR, and therefore the analysis of this end point was prudent with limited adjustment. Therefore, we focused on cardiac events as measures of outcome because these events are associated with poor survival,41 even after surgery,42 and represent crucial end points. The retrospective frequency matching of the holosystolic MR group to the prospectively examined mid-late systolic MR group may be discussed, but this is the only approach that allows identical baseline characteristics in these different types of MVP. The PISA method to quantify MR may be criticized but has been validated and confirmed by our institution and others.12,14,25We included only patients with appropriate flow convergence shape so that constrained flow convergence application of constraint-related correction factors cannot explain differences between mid-late systolic and holosystolic MR. Furthermore, the correlation between flow convergence and quantitative Doppler, based on mitral and aortic stroke volumes, was of high quality so that the low regurgitant volume observed in mid-late systolic MR is not a technical error but reflects an intrinsically lower volume overload. For outcome, diagnosis of AF by ECG may ignore some paroxysmal arrhythmias but provides specific event ascertainment.

Conclusions

Mid-late systolic MR compared with holosystolic MR of similar ERO yields smaller volume overload and a more benign outcome with smaller regurgitant volume, less enlargement of LV and LA, fewer hemodynamic consequences, and fewer cardiac events. As opposed to holosystolic MR, risk stratification in mid-late systolic MR should not rely on jet extent or uncorrected instantaneous ERO, which may be misleading. Conversely, comprehensive assessment, with attention paid to regurgitation timing and quantitation of regurgitant volume, is linked to outcome and provides appropriate clinical management tools.

Clinical Perspective

Mitral valve prolapse (MVP) is frequent, and its outcome is highly dependent on the severity of mitral regurgitation (MR) it causes. MR of MVP is predominant and often is limited to the mid or later part of systole, but the impact of such MR timing on MR assessment, on the volume overload it causes, and on outcome is unknown. To address this issue, we prospectively quantified MR in patients with MVP and mid-late systolic MR and compared them with matched patients with MVP and holosystolic MR. The study shows that mid-late systolic MR can be misleading because it presents with similar jet area, velocity, and effective regurgitant orifice but has less regurgitant volume because of its shorter duration. Furthermore, mid-late systolic MR causes less volume overload with smaller left ventricles and atria, lower pulmonary pressure, and less frequent flow reversal in the pulmonary veins. In regard to outcome, mid-late systolic MR was benign in comparison to holosystolic MR, with much fewer cardiac events during follow-up, independently of any baseline characteristics. This event rate was independently linked to the regurgitant volume (not orifice), which is smaller in mid-late systolic MR. Therefore, for clinical management and surgical referral of patients with MVP, clinicians should carefully take into account the timing and consequences of MR.

Sources of Funding

The study was funded exclusively by the Mayo Clinic Foundation.

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Circulation
Pages: 1643 - 1651
PubMed: 22388325

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History

Received: 11 July 2011
Accepted: 22 February 2012
Published online: 2 March 2012
Published in print: 3 April 2012

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Keywords

  1. echocardiography
  2. mitral regurgitation
  3. valvular regurgitation

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Yan Topilsky, MD
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo College of Medicine, Mayo Clinic, Rochester, MN.
Hector Michelena, MD
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo College of Medicine, Mayo Clinic, Rochester, MN.
Valentina Bichara, MD
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo College of Medicine, Mayo Clinic, Rochester, MN.
Joseph Maalouf, MD
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo College of Medicine, Mayo Clinic, Rochester, MN.
Douglas W. Mahoney, MS
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo College of Medicine, Mayo Clinic, Rochester, MN.
Maurice Enriquez-Sarano, MD
From the Division of Cardiovascular Diseases and Internal Medicine, Mayo College of Medicine, Mayo Clinic, Rochester, MN.

Notes

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Correspondence to Maurice Enriquez-Sarano, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail [email protected]

Disclosures

Dr Enriquez-Sarano discloses a research grant from Abbott Vascular and being a member of the scientific advisory board of Valtech, Inc. All other authors report no conflicts.

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  1. Echocardiographic Assessment of Mitral Valve Prolapse Prevalence before and after the Year 1999: A Systematic Review, Journal of Clinical Medicine, 13, 20, (6160), (2024).https://doi.org/10.3390/jcm13206160
    Crossref
  2. Left Ventricular Fibrosis by Cardiac Magnetic Resonance Tissue Characterization in Chronic Mitral Regurgitation Patients, Journal of Clinical Medicine, 13, 13, (3877), (2024).https://doi.org/10.3390/jcm13133877
    Crossref
  3. The Role of Cardiovascular Magnetic Resonance Imaging in the Assessment of Mitral Regurgitation, Diagnostics, 14, 6, (644), (2024).https://doi.org/10.3390/diagnostics14060644
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  4. Automatic Segmentation and Evaluation of Mitral Regurgitation Using Doppler Echocardiographic Images, Bioengineering, 11, 11, (1131), (2024).https://doi.org/10.3390/bioengineering11111131
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  5. Quantification of Mitral Valve Regurgitation in Cavalier King Charles Spaniels and Chihuahuas Using Radius of Proximal Isovelocity Surface Area, Animals, 14, 19, (2805), (2024).https://doi.org/10.3390/ani14192805
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  6. EasyPISA: Automatic Integrated PISA Measurements of Mitral Regurgitation From 2-D Color-Doppler Using Deep Learning, Ultrasound in Medicine & Biology, 50, 11, (1628-1637), (2024).https://doi.org/10.1016/j.ultrasmedbio.2024.06.008
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  7. Tele-, Proto-, or Holosystolic Mitral Regurgitation . . . Time to Learn From Physical Examination and Go Beyond PISA, Journal of the American Society of Echocardiography, 37, 3, (325-327), (2024).https://doi.org/10.1016/j.echo.2024.01.007
    Crossref
  8. The Pixel Variation Score: An Echocardiographic Index to Assess Temporal Variation of Mitral Regurgitant Flow, Journal of the American Society of Echocardiography, 37, 3, (316-324), (2024).https://doi.org/10.1016/j.echo.2023.10.012
    Crossref
  9. Echocardiography vs. CMR in the Quantification of Chronic Mitral Regurgitation: A Happy Marriage or Stormy Divorce?, Journal of Cardiovascular Development and Disease, 10, 4, (150), (2023).https://doi.org/10.3390/jcdd10040150
    Crossref
  10. Arrhythmic Mitral Valve Prolapse: A Comprehensive Review, Diagnostics, 13, 18, (2868), (2023).https://doi.org/10.3390/diagnostics13182868
    Crossref
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Mitral Valve Prolapse With Mid-Late Systolic Mitral Regurgitation
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