The Evolution of Mitral Valve Prolapse: Insights from the Framingham Heart Study

Abstract

Background

Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with non-diagnostic MVP morphologies (NDM), are lacking.

Methods and Results

We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation (MR) jet height in 261 Framingham Offspring participants at Examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (N=63), NDM - ‘minimal systolic displacement’ or MSD (N=50) and the ‘abnormal anterior coaptation’ (AAC) phenotype (N=10, with coaptation height >40% of the annulus similar to posterior MVP), plus 138 healthy referents without MVP or NDM. At follow-up, individuals with MVP (52% women, 57±11 years) had greater increases of leaflet displacement, thickness, and jet height compared with referents (all p<0.05). Eleven participants with MVP (17%) had ≥ moderate MR (jet height ≥5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) AACs progressed to posterior MVP; 17 (34%) MSDs were reclassified as either posterior MVP (12) or AAC (5). Compared with the 33 MSDs who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and MR jet height (all p<0.05).

Conclusions

NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant MR over a period of 3 to 16 years in a quarter of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression.

Mitral valve prolapse (MVP) is a common disorder afflicting 2–3% of the general population.^{1, 2} It is characterized by fibromyxomatous changes in the mitral leaflet tissue with superior displacement of one or both leaflets into the left atrium (Figure 1A).^{3, 4} The prognosis of MVP has varied widely in the published literature^{1, 5, 6} and is a matter of ongoing debate. In the community-based Framingham Heart Study (FHS), MVP has been described as a benign entity, with a low prevalence of adverse clinical sequelae in a prior cross-sectional evaluation.¹ However, prior tertiary care-based studies^{5, 6} have portrayed MVP as a disease with frequent and serious complications, including stroke, atrial fibrillation, heart failure, and mitral regurgitation (MR) requiring surgery. These discrepancies may be due to inherent selection biases across studies or to the changes in diagnostic criteria for MVP.⁷ Moreover, the benign features of MVP reported previously in the FHS were based on initial cross-sectional observations.¹ Finally, prior studies have analyzed clinical outcomes and progression of MR,^{8, 9} but have not assessed the association of fine structural valvular changes with these outcomes.

Figure 1.

Two-dimensional transthoracic echocardiogram in the parasternal long axis orientation demonstrating A) posterior mitral valve prolapse (MVP), B) abnormal anterior coaptation (AAC), and C) minimal systolic displacement (MSD). All show posterior leaflet bulging (arrows) relative to the anterior leaflet, but only MVP shows diagnostic (> 2 mm) superior leaflet displacement relative to the mitral annulus (dotted line) into the left atrium. Posterior MVP and AAC are similar with regards to an increased coaptation height and an elongated posterior leaflet. MSD shows posteriorly coapting leaflets, as seen in referents. AO, aorta; LV, left ventricle; and RV, right ventricle; Post Dis, posterior displacement.

Previously, non-diagnostic MVP morphologies (NDM) have been described in a familial context.¹⁰ These morphologies include the ‘abnormal anterior coaptation’ form (AAC) and ‘minimal systolic displacement’ (MSD) (Figures 1B and 1C). Both the AAC phenotype and MSD share features of excessive leaflet motion with fully affected individuals, as demonstrated by superior motion towards the left atrium, bulging of the posterior leaflet relative to the anterior (albeit not diagnostic by quantitative assessment) and coaptation asymmetry. In addition, in the AAC morphology, leaflet excess can also manifest itself by anterior motion and a shift of the coaptation point towards the septum and the aortic root similar to posterior MVP (Figure 1C). In genetic studies, we have shown that NDM shared either the complete or a major portion of the haplotype with fully diagnostic MVP.¹⁰ These non-diagnostic forms may, therefore, represent early expression of MVP among those genetically predisposed. NDM have also been observed in the community,¹¹ and have been linked to an increased prevalence of MVP in their offspring. ¹² Nevertheless, their potential progression to diagnostic MVP is unknown.

In the present investigation, we assessed the echocardiographic and clinical features associated with longitudinal progression of MVP and NDM in unselected, systematically screened individuals in the FHS. Our hypotheses are that NDM can evolve into MVP, and that echocardiographic changes in mitral leaflet morphology are associated with both MVP and NDM progression.

METHODS

Participants

Beginning in 1948, 5209 men and women were enrolled into the Original cohort.¹³ A clustered random sampling schema was used to select family members aged 28–62 years living in the same household in the town of Framingham, MA; two-thirds of these households were sampled.¹³ Their offspring, and the offsprings’ spouses, were enrolled into the Offspring cohort (n=5124) starting in 1971, with examination cycles performed at approximately 4 to 8 year intervals and with echocardiograms obtained at examination cycles 2,4,5,6, and 8. The Offspring Examination 5 cohort (1991–1995, N=3799) was reviewed qualitatively with special emphasis placed on participants identified in previous examinations by FHS sonographers as having possible superior mitral valve leaflet displacement.^{1, 11} The 151 individuals identified in this way were paired (1:1) with referents matched for age and sex, drawn from Offspring Examination 5, and without echocardiographic evidence of MVP. Echocardiographic images of six individuals were deemed of inadequate quality for detailed analysis during a recent investigation of clinical and echocardiographic characteristics of NDM at Offspring Examination 5.¹¹ Of the remaining 296 individuals, 261 had available echocardiographic follow-up at either Examination 6 or 8 (between 1996–1998 and 2005–2008, respectively), i.e., approximately 3 to 16 years later. Follow-up at Examination 6 was used only if Examination 8 was not available. Therefore, our final sample consisted of 261 individuals (63 MVP, 10 AAC, 50 MSD, 138 referents without MVP or NDM). Out of 261 subjects, 213 had follow-up at Examination 8 and 48 at Examination 6.

The study protocol was approved by the Institutional Review Board of Boston University Medical Center, and all participants provided written informed consent.

Clinical characteristics

At Examination cycle 5, attendees underwent a routine medical history, targeted physical examination for cardiovascular disease, anthropometry and laboratory assessment of cardiovascular disease (CVD) risk factors. Clinical variables used in the present investigation included: age, sex, body mass index, and the presence of a cardiac systolic murmur (defined as systolic murmur ≥ 3/6 in any location). Additional clinical variables such as history of smoking, systolic/diastolic blood pressure, and hypertension treatment were included in the analysis. Specifically, these variables may be considered potential mitral valve “stressors” that may influence the progression of MR in individuals with MVP. Additionally, these key covariates are also known independent risk factors for other MVP-related outcomes such as atrial fibrillation, heart failure, and stroke. We excluded study participants who had a history of heart failure or myocardial infarction prior to entering our study, as both these conditions may be associated with valvular heart disease (albeit non-primary) and MR.¹⁴ Finally, we examined the future risk of 1) combined CVD - myocardial infarction, angina, stroke, heart failure, atrial fibrillation, fatal events from CVD, and 2) all-cause mortality (death from coronary artery disease, stroke, and “other”) among the four categories of individuals further described below.

Echocardiographic characteristics

All study participants in the Offspring cohort (Examinations 5,6,8) underwent standard two-dimensional transthoracic echocardiography with a commercially available system (Sonos 1000, Hewlett–Packard Medical Products, Andover, MA) with a 2.5-MHz transducer. Images included complete parasternal, apical, and subcostal views and color Doppler assessment of valvular regurgitation. Echocardiographic studies were stored on VHS tape and digitized for subsequent review. All measurements were performed with an off-line cardiac analysis system (Digiview, Houston, TX).

Using current two-dimensional echocardiographic criteria,^{7, 15} MVP was diagnosed as leaflet displacement >2 mm beyond the mitral annulus in a parasternal or apical 3-chamber long-axis view both at baseline Examination 5 and at follow-up Examinations 6 and 8 (Figure 1A). At all three examinations, NDM was defined as ≤2 mm leaflet displacement beyond the annulus in the same echocardiographic views (Figure 1B and 1C).^{10, 11, 16} Among NDM, individuals with AAC did not have diagnostic leaflet displacement beyond the annulus, but showed an anteriorly shifted (>40%) coaptation point (Figure 1B) similar to posterior MVP (Figure 1A). Participants with borderline degrees of mitral valve leaflet displacement but posterior coaptation were designated as having MSD (Figure 1C). We measured changes in annular diameter, leaflet displacement (Figure 1A), thickness, anterior/posterior leaflet projections onto the annulus, and coaptation height (C =P/D as shown in Figure 2). Echocardiograms at Offspring Examination 6 or 8 were examined blinded to Examination 5 diagnosis, clinical history, and physical exam findings. Finally, age- and sex-matched referents lacked evidence of superior leaflet displacement (diagnostic or non-diagnostic) at each of the examinations.

Figure 2.

Schematic echocardiographic parasternal long-axis measurements performed at Offspring Examinations 5 and at follow-up 6/8. D, annular diameter; A, P, anterior and posterior leaflet projections onto the annulus; C, coaptation height = P/D; LVID, left ventricular internal diameter; AO, aorta; LV, left ventricle. On the left an example of a referent with posterior leaflet coaptation (C = 25–30% of the annulus) and A > P. On the right, an example of abnormal anterior coaptation (AAC) with C > 40% of the annulus and elongated posterior leaflet.

MR severity was quantified by color Doppler as the maximum systolic proximal MR jet height. Previous studies have indicated that proximal jet size basically reflects the size of the vena contracta, a fundamental measure of lesion severity. ^17–20 A jet height of ≤ 2 mm effectively separates trace physiologic backflow from mild MR, while 5 mm or more indicates moderate severity.^{17, 19, 20} All of the above two-dimensional echocardiographic parameters were measured in the parasternal or apical 3-chamber long-axis view at end-systole using an average of three beats. Mitral valve leaflet thickness was measured at end-diastole in the same views as the leading to the trailing edge of the thickest area of the mid-portion of the leaflet, excluding focal areas of thickness and chordae. Patients with other causes of mitral valve disease (rheumatic, functional/ischemic, congenital) or aortic valve disease were excluded from our analysis.

Echocardiographic progression from Examination 5 to Examinations 6/8 was defined as follows: 1) evolution to AAC or MVP from MSD 2) evolution to MVP from AAC, or 3) development of significant MR or need for surgery among subjects with MVP.

Left atrial dimension was calculated by M-mode as the antero-posterior maximal left atrium diameter in systole. Left ventricular internal diameters (Figure 2) were obtained in diastole and systole (LVIDd and LVIDs) by use of a leading-edge technique and averaging of M-mode measurements from at least three cardiac cycles. The fractional shortening percentage was calculated as (LVIDd − LVIDs)/LVIDd x 100.

The intra-observer and inter-observer correlations for mitral leaflet displacement, thickness, and the degree of MR in 20 participants exceeded 0.97 as previously reported.¹ Reproducibility for anterior/posterior leaflet projections and leaflet coaptation height was also very good with correlations exceeding 0.94.¹¹

Statistical methods

Clinical characteristics of Offspring Examination 5 participants with available echocardiographic data at Examination 6 or 8 were compared among the four groups (MVP, MSD, AAC, and referents). ANOVA was used for clinical variables and logistic regression was used for categorical variables. We performed linear regression to estimate changes of echocardiographic variables from Examination 5 to Examinations 6/8 and to compare the four mitral valve categories. We used the Tukey-Kramer test to account for multiple comparisons. Student’s t test (paired) was used to assess differences in echocardiographic measures between Examination 5 and Examinations 6/8 within the referent group. We also used Student’s t test to compare continuous echocardiographic data between MSD or MVP participants that progressed at Examinations 6/8, and those that did not. We adjusted for unequal variances when F test for equal variances gave p<0.1. Since the number with AAC was small (n=10), a statistical comparison between AAC that progressed to MVP and those that did not was not pursued. The relation of jet height change with clinical and echocardiographic variables was explored by stepwise linear regression analysis in the MVP group only. Since 1:1 pairing of cases with referents used in the initial sample (see “Participants” section) was lost due to lack of follow-up for all Examination 5 participants, we used age and sex adjustment in regression analyses to account for matching factors. Finally, we used Cox proportional hazards regression models to examine associations between echocardiographic diagnoses (MVP, MSD, referents) and clinical outcomes (CVD and all-cause mortality) after Examination 5. We did not analyze the AAC subgroup in relation to clinical outcomes due to small numbers. All multivariable models were estimated adjusting for age, sex, body mass index, systolic/diastolic blood pressure and time between examinations.

Analyses were conducted using SAS version V9.3 (Cary, NC). A two-sided p value < 0.05 was the criterion for statistical significance.

RESULTS

Baseline clinical characteristics of our study sample are summarized in Table 1. Age, sex, blood pressure, treatment for hypertension, and history of smoking were similar in all mitral valve groups (p>0.05 for all comparisons). Individuals with MVP had a higher prevalence of a precordial systolic murmur compared to the other three categories (p<0.05). Baseline echocardiographic characteristics of MVP phenotypes in Offspring Examination 5 have been previously published.¹¹ The mean length of echocardiographic follow-up was similar for all echocardiographic categories (11, 10, 12, 12 years for MVP, AAC, MSD, and referents, respectively).

Table 1.

Baseline clinical characteristics of Offspring Examination 5 participants with available Echo 6 or 8 follow-up.

	MVP (n=63)	AAC (n=10)	MSD (n=50)	Referents (n=138)
Demographics and Lifestyle
Age (years)	57±11	59±7	57±10	55±10
Women, n (%)	33 (52)	6 (60)	35 (70)	87 (63)
History of smoking, n (%)	8 (13)	1 (10)	5 (10)	30 (22)
Clinical
Body mass index (kg/m2)	24.5±2.9	24.9±3.4	24.6±3.3	26.2±4.8
Systolic blood pressure (mm Hg)	122±17	125±18	124±14	123±19
Diastolic blood pressure (mm Hg)	72±10	74±4	74±7	73±0
Treatment for hypertension, n (%)	6 (10)	1 (10)	8 (16)	30 (22)
Systolic murmur, n (%)	8 (13)*	0 (0)	0 (0)	1 (0.7)

MVP = mitral valve prolapse; AAC = abnormal anterior coaptation; MSD = minimal superior systolic displacement of the mitral leaflets. Values are expressed as mean ± SD (%),

^*p<0.05 for comparison among all four groups.

Tukey-Kramer adjusted p values.

Baseline characteristics of Offspring Examination 5 participants with (N = 261) and without (N = 35) available Echo 6/8 follow-up are shown in Supplemental Table 1. Except for a higher proportion of subjects treated for hypertension among the participants without follow-up, there were no significant differences between the two groups with regards to age, gender, history of smoking, body mass index, systolic/diastolic blood pressure, or presence of a systolic murmur on auscultation. In addition, there was a similar proportion of participants with MVP, MSD, AAC, and referents in the two groups (Fisher’s exact p value = 0.39).

Echocardiographic progression

At follow-up, 8/10 (80%) AACs progressed to posterior MVP, 17/50 (34%) MSDs were reclassified as either MVP (n = 12; 4 bileaflet, 1 anterior, and 7 posterior prolapse) or as AAC (n = 5). The MVP group had predominantly posterior leaflet involvement (28/63 or 44%). Eleven participants with MVP (17%) had ≥ moderate MR with 2/11 having flail leaflet and jet height >7 mm at follow-up. All 11 individuals had an average jet height of 3 mm or mild MR at baseline. Additionally, five of the 63 participants with MVP (8%) underwent mitral valve repair at follow-up.

Differences in progression of echocardiographic variables from Examination 5 to Examinations 6/8 are shown in Table 2. MVP, AAC, and MSD all had greater changes of either anterior or posterior thickness compared to referents (all p < 0.05). MVP and AAC shared a greater increase in posterior displacement and MR jet height compared to referents (with greater posterior displacement change in AAC compared with MVP and MSD). MSD was similar to referents with regards to most mitral valve measures except for anterior leaflet thickness and anterior displacement (the latter changes likely secondary to the evolution into bileaflet or anterior MVP). Changes in leaflet projections onto the annulus and coaptation height were similar among MVP, AAC, MSD, and referents. Progression of left ventricular chamber parameters (Table 2) was also comparable in the four categories. As opposed to the 33 MSDs that did not progress, the 17 that did progress had significantly greater leaflet displacement, thickness, coaptation height, and MR jet height (Table 3), all p<0.05. The 16/63 MVP participants who progressed to either significant MR or underwent mitral valve surgery did not have significantly different changes in valvular measures compared to the individuals with MVP who did not progress (< moderate MR), although valvular determinants of jet height change could be identified in a separate analysis (see below). AACs who progressed to posterior MVP had on average mild MR (jet height = 2.3 ± 1.4 mm) and coaptation height = 56 ± 4% at follow-up. Finally, among 138 referents, 8 evolved into MSD, 2 into MVP, and 2 into AAC at follow-up. Consequently, when changes of echocardiographic measures were assessed within the referent group only, there was a significant increase in posterior displacement, posterior projection onto the annulus, coaptation height, and left atrial diameter from Examination 5 to Examinations 6/8.

Table 2.

Echocardiographic features of progression by valve phenotype.

Change in	MVP (n=63)	AAC (n=10)	MSD (n=50)	Referents (n=138)
Anterior thickness (mm)	0.2±0.1*	0.5±0.2*	0.2±0.1*	−0.03±0.04
Posterior thickness (mm)	− 0.004±0.1	0.4±0.2*	0.1±0.1	−0.1±0.04
Anterior displacement (mm)	0.3±0.1	0.3±0.2	0.5±0.1*	0.1±0.1
Posterior displacement (mm)	0.8±0.1*	1.9±0.2*†	0.2±0.1†‡	0.1±0.1
Anterior projection (mm)	−1.7±0.5	−1.9±1.2	−1.8±0.5	−0.2±0.3
Posterior projection (mm)	2.3±0.3	1.6±0.8	1.8±0.4	2.0±0.2
Annular diameter (mm)	0.5±0.4	0.8±1.0	0.08±0.5	1.6±0.3
Coaptation height (%)	6.7±1.0	5.6±2.5	5.3±1.1	5.2±0.7
Jet height (mm)	0.6±0.2*	1.0±0.4*	0.3±0.2	−0.2±0.1
LA diameter (mm)	0.1±0.1	0.4±0.1	0.2±0.1	0.2±0.04
LV end-diastolic diameter (mm)	0.1±0.1	0.001±0.2	0.1±0.1	0.03±0.04
LV end-systolic diameter (mm)	0.1±0.1	−0.1±0.2	0.1±0.1	0.01±0.04
LV fractional shortening (%)	0.3±1.0	1.1±2.8	−1.8±1.1	0.2±0.7

MVP = mitral valve prolapse; AAC = abnormal anterior coaptation; MSD = minimal systolic displacement; LA = left atrium; ant-post = antero-posterior; LV = Left ventricular. Values expressed as least squares mean ± SE.

^{*,†,and ‡}p<0.05 compared with referents, MVP, and AAC, respectively. Otherwise, p > 0.05.

Tukey-Kramer adjusted p values.

Table 3.

Echocardiographic features of MSD progression.

Change in	MSD progressed N= 17	MSD not progressed N = 33	P value
Anterior thickness (mm)	0.5±0.6	0.04±0.4	0.002
Posterior thickness (mm)	0.6±0.8	−0.2±0.4	0.0005
Anterior displacement (mm)	0.9±1.2	0.3±0.5	0.05
Posterior displacement (mm)	0.8±0.8	−0.1±0.5	0.0002
Anterior projection (mm)	−5.7±6.5	0.4±3.1	0.002
Posterior projection (mm)	5.4±3.1	−0.2±1.6	<0.0001
Annular diameter (mm)	−0.04±3.7	0.1±3.2	0.85
Coaptation height (%)	17±10	−0.9±5.7	<0.0001
Jet height (mm)	1.0±0.9	−0.03±1.0	0.002

MSD = minimal systolic displacement. Values expressed as means ± SE.

Correlates of mitral regurgitation progression in MVP

When we examined the association between jet height change and progression of valvular or left ventricular dimensions (LVIDs and LVIDd) among MVP participants in an exploratory analysis, only changes in leaflet displacement (anterior/posterior) and LVIDs remained statistically significant (p=0.03, 0.04, and 0.01, respectively; model adjusted R²=0.31) in the final stepwise regression model (Figures 3A–C). After removing flail leaflet from the analysis, none of the valvular or left ventricular measures contributed significantly to MR progression (all p>0.05).

Figure 3.

Simple bivariate scatter plots demonstrating the correlation between change in mitral regurgitation jet height and A) change in anterior leaflet displacement, B) posterior leaflet displacement, and C) left ventricular end-systolic internal diameter (LVIDs) from Offspring Examination 5 to 6/8. Anterior displacement = 0 in panel A denotes participants with posterior leaflet involvement only. Shaded area represents 95% confidence intervals, dotted lines denote 95% prediction limits.

Clinical outcomes

For our analysis of clinical outcomes, follow-up was available in 285 Offspring Examination 5 participants (77 MVP, 57 MSD, 151 referents). During 5668 person-years of follow-up (mean 19 ± 4 years), 62 deaths occurred. After adjusting for covariates (age, sex, body mass index, systolic and diastolic blood pressure), mortality was higher among participants with MVP (23/77 or 30%) than in referents (25/151 or 17%), but the adjusted hazard ratio [HR] was borderline statistically significant (HR 1.67, 95% confidence interval [CI] 0.93 – 2.9, p = 0.08). Of the 23 individuals with MVP who died, the cause of death was coronary artery disease in one, cerebral vascular accident in one, and “other” causes (non-cardiovascular) in 21. Mortality among participants with MSD and referents was similar (14/57 or 25% versus 25/151 or 17%; HR, 1.24, 95% CI 0.64 – 2.44, p = 0.53).

We analyzed incident CVD among 265 participants Offspring Examination 5 participants (73 MVP, 54 MSD, 138 referents) after excluding 20 individuals with prevalent CVD. During 4887 person-years of follow-up (mean 18 ± 5 years), there were 65 new CVD events. After adjusting for covariates, individuals with MVP had a greater hazard for CVD events compared with referents. This hazard was borderline significant (21/73 or 29% in MVP versus 31/138 or 22% in referents, HR = 1.70, 95% CI 0.95 – 3.03, p = 0.07). Specifically, 12 participants with MVP developed atrial fibrillation, four had a myocardial infarction, three were diagnosed with congestive heart failure, and two had a stroke. Individuals with MSD did not differ from referents with regards to incident CVD (13/54 or 24% versus 31/138 or 22%; HR = 1.15, 95% CI 0.59 – 2.24, p = 0.68).

Compared to Offspring Examination 5 participants with Echo 6/8 follow-up, the number of deaths was higher among subjects without echocardiographic follow-up (15/35 or 43% versus 49/261 or 19%, p = 0.001), but the prevalence of incident CVD was similar (5/35 or 18% versus 61/261 or 25%, P = 0.42).

DISCUSSION

Our group has previously described non-diagnostic MVP morphologies among gene carriers in large pedigrees,¹⁰ and in the community-based FHS sample.¹¹ In the current investigation, we demonstrate that NDM may evolve to fully diagnostic MVP over a period of 3 to 16 years, confirming the clinical significance of mild MVP expression in the community. Recent valvular guidelines²¹ highlight the importance of mitral valve disease progression (stages A to D), and the shift to earlier intervention, prior to symptoms and left ventricular remodeling (stage C1). In this context, individuals with NDM may be considered stage A or “at risk” for developing progressive primary MR. When NDM are considered separately, AAC and NDM appear to have potentially different prognostic implications. At baseline,¹¹ AAC is “geometrically congruent” with posterior MVP, as AAC and MVP share an anteriorly shifted coaptation point and posterior leaflet asymmetry. We found that AAC progressed to posterior MVP in 80% of cases, with significant changes of posterior displacement and jet height in both categories when compared to referents. The degree of MR on follow-up was overall mild, but not trivial in participants with AAC. On the other hand, we observed that MSD is overall a “milder” non-diagnostic morphology. First, MSD is more similar to referents with regards to baseline echocardiographic measurements, i.e., a posteriorly displaced coaptation point in a prior study.¹¹ Second, in genetic studies, we have shown that MSD shared only a portion of the haplotype with fully diagnostic MVP (versus the complete haplotype in AAC).¹⁰ In the current investigation, a smaller proportion of individuals with MSD progressed to diagnostic MVP (24% versus 80% in AAC). In addition, the MSD category was similar to the referent group with regards to changes in most mitral valve measures and clinical outcomes.

Our investigation demonstrates that MVP progresses to significant MR alone or requiring surgery in a quarter of unselected FHS participants with MVP over a period of 3 to 16 years. Therefore, with regards to MR progression, MVP may no longer be considered a benign clinical entity as previously reported in cross-sectional studies.¹ Similarly to other community-based investigations,²¹ a subgroup of MVP cases with worse prognosis can be identified in the FHS, highlighting the clinical heterogeneity of this valvulopathy. Mortality at 20 years was higher (albeit borderline statistically significant due to the small sample size) among FHS participants with MVP than in referents. Our findings are particularly relevant, as our study population is unselected and free of referral-bias, whereas other community-based studies^{8, 22} are characterized by a mixed spectrum of community-dwelling and referred patients.

Compared to other longitudinal investigations^23,24 our data are novel as we describe the echocardiographic changes associated with MR progression in MVP and over a longer follow-up period (>10 years). A prior study²² highlighted that over a follow-up of only 1.5 years, MR volume increased by more than 8 mL in 51% of 74 individuals with MVP. The progression of the valvular lesion (particularly a new flail leaflet), and an increase in the mitral annular diameter were the two independent predictors of an increase in the mitral regurgitant volume;²² other valvular parameters (such as leaflet thickness, displacement, or coaptation height) were not examined in that report. In the present investigation, since flail represents the end of the MVP progression spectrum, we included participants with flail (n=2) when assessing MR correlates within the MVP group. In the current analysis, greater leaflet displacement and LVIDs were the most important valvular parameters associated with MR progression. These findings support the recognized role of leaflet coaptation asymmetry in the mechanism of MR and the importance of LVIDs as a marker of MR progression. Anteriorly shifted coaptation point, a novel echocardiographic feature associated with increased posterior leaflet length in posterior MVP in both echocardiographic and surgical studies,^{10, 25} was not a significant determinant of MR progression in the present investigation. This discrepancy could be secondary to the co-existence of posterior with isolated anterior or bileaflet (anterior > posterior) MVP. In both categories, a long, redundant anterior leaflet shifts the coaptation point posteriorly, likely obscuring the contribution of posterior MVP with an anteriorly shifted coaptation point.¹¹

Whereas differences in increases of leaflet displacement and thickness could be detected within each of the four mitral valve categories evaluated, changes in anterior/posterior projections onto the annulus and coaptation height were similar among the four groups. These valve measurements may differ within the same MVP and NDM category, as coaptation height is > 40% in posterior MVP and AAC, but 25–30% and similar to referents in anterior MVP and MSD.¹¹ Therefore, these measurements may have a wide within-group scatter, hence reducing inter-group differences.

Moreover, there was no significant change in left atrial or left ventricular cavity dimensions or systolic function over time within the four groups, confirming that changes in MR are likely secondary to progression of valvular parameters in these individuals, and not to dilated left ventricular chambers or systolic dysfunction. In addition, as the mean follow-up length was similar for MVP, NDM, and referents, greater echocardiographic progression in MVP and NDM cannot be justified by a longer follow-up period compared to participants without MVP or NDM.

Finally, a small, but nontrivial proportion of referents progressed to NDM and MVP. This observation is consistent with the notion that MVP may have an age-dependent expression and can manifest later in life.¹⁶

Strengths and Limitations

The strengths of our investigation include the unique availability of longitudinal clinical and echocardiographic data, a well characterized phenotype for using a contemporary definition,⁷ and the ability to systematically evaluate NDM. In addition, all echocardiographic measurements at Examinations 6/8 were performed blinded to MVP or NDM diagnosis at Examination 5. Moreover, risk factors potentially contributing to MVP progression (blood pressure, age, sex, body mass index) were systematically and routinely ascertained. Finally, our sample was community-based and our participants were unselected, reducing the likelihood of selection bias characteristic of tertiary-care based investigations.

Our study has several limitations. First, our analyses were limited to a modest-sized sample of white individuals of European ancestry, so our results may not be generalizable to other ethnicities. In addition, we describe intermediate range follow-up over 3 to 16 years in a small number of individuals within the four different mitral valve categories. Presently, we cannot describe the lifetime risk of death or CVD in MVP, and we have limited power to describe clinical outcomes. Second, the sample size for the AAC group was very small; hence, some of the statistically non-significant comparisons (between AAC and the other categories) may have been related to limited power to discern differences. Third, given the strong hereditary component of MVP, parental MVP may represent an important factor influencing MVP progression. This was not evaluated in our investigation because of a lack of data on MVP status in the original Framingham Heart Study cohort (parents of Offspring cohort participants); current diagnostic criteria for MVP were not implemented at the time of acquisition of echocardiographic data for the Original cohort. In addition, two-dimensional echocardiographic studies were obtained for Original cohort attendees at examination cycle 20, at which time most participants were older than 75 years and many had died. Fourth, three-dimensional echocardiography has significantly improved assessment of MV anatomy in MVP.^{26, 27} As our investigation was based on two-dimensional transthoracic imaging, the role of three-dimensional echocardiography in detection and quantification of NDM remains unclear. Moreover, the use of less sophisticated echocardiographic equipment in older Examinations, and image acquisition by different sonographers over time are inevitable in a longitudinal cohort study design, and may have potentially affected the validity of our results. Fifth, MR quantification was based on a linear dimension (JH), which cannot distinguish MR isolated to mid-late systole from holosystolic, volumetrically significant MR.^{28, 29} Finally, no systematic assessment of Marfan syndrome (another genetic condition associated with MVP) was conducted during the clinical examinations at the Heart Study.

Clinical and Research Implications

NDM may progress to fully diagnostic MVP and, as previously demonstrated, parental NDM is associated with a two-fold increased risk of developing MVP in the offspring.¹² Taken together, these findings are consistent with the concept that NDM are true early MVP phenotypes rather than subtle echocardiographic findings. Recognizing early forms of MVP may be important because the condition often manifests clinically in the fifth or sixth decade of life as a severe cardiac event. A murine model of Marfan syndrome with aortic dilatation and in vitro studies of non-syndromic MVP^{30, 31} have demonstrated that angiotensin II receptor blockade can reduce clinical disease progression by regulation of TGF-beta. Similarly, it is conceivable that earlier targeted intervention in genetically susceptible individuals may potentially prevent the progression of MVP, although this premise remains to be tested. Further studies are needed to assess whether NDM, and specifically AAC (more similar to posterior MVP than MSD) should be reported in routine echocardiographic studies or be re-evaluated in follow-up echocardiograms outside the familial setting.

Moreover, a quarter of community MVP cases progress to significant MR or need for valve surgery. This observation highlights the need to identify the genetic determinants (either susceptibility or modifier genes) and the environmental factors associated with the variability of MVP progression. In our investigation, we have identified valvular determinants of progression, an important finding for risk stratification and follow-up recommendations.

CONCLUSIONS

NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant MR or need for valve surgery over 3 to 16 years in a quarter of unselected individuals in the community, suggesting that the natural history of MVP-related MR may not be as benign as previously reported. Changes in mitral leaflet morphology are associated with both MVP and NDM progression. The clinical and genetic factors associated with MVP progression require further study.

Clinical Perspectives.

Mitral valve prolapse (MVP) remains the most important cause of primary mitral regurgitation requiring surgery. Non-diagnostic MVP morphologies have been described in the familial context, and may represent early expression of MVP in those genetically predisposed. Longitudinal studies of MVP progression among unselected individuals in the community, including those with non-diagnostic MVP morphologies, are lacking. We demonstrate that non-diagnostic MVP morphologies may evolve into MVP, highlighting the clinical significance of mild MVP expression in the community. In addition, we demonstrate that a quarter of MVP cases in the Framingham Heart Study progresses to significant MR or need for valve surgery over 3 to16 years, suggesting that the natural history of MVP-related MR may not be as benign as previously depicted in cross-sectional studies. Overall, our observations highlight the need to identify the genetic determinants and the environmental factors associated with the variability of MVP progression.