Mitral Valve Prolapse Progression Research Articles

Biology of mitral valve prolapse: from general mechanisms to advanced molecular patterns-a narrative review.

Mitral valve prolapse (MVP) represents the most frequent cause of primary mitral regurgitation. For several years, biological mechanisms underlying this condition attracted the attention of investigators, trying to identify the pathways responsible for such a peculiar condition. In the last ten years, cardiovascular research has moved from general biological mechanisms to altered molecular pathways activation. Overexpression of TGF-β signaling, for instance, was shown to play a key role in MVP, while angiotensin-II receptor blockade was found to limit MVP progression by acting on the same signaling pathway. Concerning extracellular matrix organization, the increased valvular interstitial cells density and dysregulated production of catalytic enzymes (matrix metalloproteinases above all) altering the homeostasis between collagen, elastin and proteoglycan components, have been shown to possibly provide a mechanistic basis contributing to the myxomatous MVP phenotype. Moreover, it has been observed that high levels of osteoprotegerin may contribute to the pathogenesis of MVP by increasing collagen deposition in degenerated mitral leaflets. Although MVP is believed to represent the result of multiple genetic pathways alterations, it is important to distinguish between syndromic and non-syndromic conditions. In the first case, such as in Marfan syndrome, the role of specific genes has been clearly identified, while in the latter a progressively increasing number of genetic loci have been thoroughly investigated. Moreover, genomics is gaining more interest as potential disease-causing genes and loci possibly associated with MVP progression and severity have been identified. Animal models could be of help in better understanding the molecular basis of MVP, possibly providing sufficient information to tackle specific mechanisms aimed at slowing down MVP progression, therefore developing non-surgical therapies impacting on the natural history of this condition. Although continuous progress has been made in this field, further translational studies are advocated to improve our knowledge of biological mechanisms underlying MVP development and progression.

Circulating transforming growth factor-beta1 and progression of the mitral valve prolapse: fifteen-year follow-up

Abstract Introduction Transforming growth factor-β1 (TGF-β1) is a crucial regulatory cytokine that contributes to the development of the mitral valve and regulates extracellular matrix protein synthesis in syndromic and non-syndromic mitral valve prolapse (MVP). Our aim was to evaluate the effect of elevated circulating TGF-β level on the progression of the valve myxomatosis and leaflets billowing at long-term follow-up. Methods 78 asymptomatic young subjects (mean age 19.7±1.6, 72% male) with MVP were consecutively enrolled in our observational, prospective, single-center study. MVP was diagnosed by billowing one or both mitral leaflets >2 mm above the mitral annulus in the long-axis parasternal view. Concentration of TGF-β1 in serum was determined by enzyme-linked immunosorbent assay using a test system Human Platinum ELISA. Results During 1170 person-years of follow-up (median 14.5 years), no deaths or MVP-related events occurred. Posterior leaflet's thickening (from 3.9±1.4 mm to 4.4±1.7 mm (D=+0.5 mm), p<0.01) and increase of the billowing (progression in maximal prolapse depth from 3.5±2.4 mm to 4.8±2.8 mm (D=+1.3 mm), p<0.001) leads to the mitral regurgitation (MR) progression (vena contracta: 2.3±0.4 mm vs. 3.5±0.4 mm (D=+1.2 mm), p<0.0001) over 15 years of follow-up. TGF-β1 serum level was increased (15.2±12.3 ng/ml) and strongly correlated with the thickening of the posterior leaflet (r=0.72; p≤0.0001). In multivariate Cox analysis the TGF-β1 level was the independent predictor of the posterior leaflet's thickening (2.07; 95% CI: 1.34 – 3.29; p=0.001) and progression of the billowing (2.89; 95% CI: 1.61 – 4.37; p=0.0001). TGF-β1 >7.0 ng/ml was a strong predictor (area under ROC curve = 0.84 (95% CI, 0.7–0.9); sensitivity 82%, specificity 95%) for progression of MVP (maximal prolapse depth increase: D +1.9±1.2 mm (TGF-β1 >7.0 ng/ml) vs. 0.7±0.6 mm (TGF-β1 <7.0 ng/ml), p<0.0001) and MR (vena contracta increase: D +1.1±0.5 mm (TGF-β1 >7.0 ng/ml) vs. 0.5±0.4 mm (TGF-β1 <7.0 ng/ml), p<0.0001). Conclusions Despite the overall benign prognosis, we found the obvious echocardiographic progression of the valve myxomatosis and leaflets billowing at long-term follow-up in young person. Elevated above 7.0 ng/ml TGF-β1 serum level might serve as a prognostic biomarker and identifies patients with increased risk of the mitral valve prolapse progression. Funding Acknowledgement Type of funding sources: None.

Evolution of Mitral Valve Prolapse: Insights From the Framingham Heart Study.

Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation 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); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 57±11 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P<0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height ≥5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P<0.05). NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression.

Mitral valve prolapse syndrome and MASS phenotype: Stability of aortic dilatation but progression of mitral valve prolapse

BackgroundMitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS. MethodsThis retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38±17years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42±15years with mean follow-up of 66±49months. ResultsAt baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P<.001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P<.001). In contrast, the incidence of endocarditis (P=.292), heart failure (P=.644), and mitral valve surgery (P=.140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P=.013), moderate MVR (P=.019) and flail MV leaflet (P=.017) as independent predictors of mitral valve surgery. ConclusionsThe study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse.

Epidemiology and Pathophysiology of Mitral Valve Prolapse

Mitral valve (MV) prolapse (MVP) is a common disorder, afflicting 2% to 3% of the general population.1,2 It is characterized by typical fibromyxomatous changes in the mitral leaflet tissue with superior displacement of 1 or both leaflets into the left atrium.3,4 With a prevalence of 2% to 3%, MVP is expected to affect ≈7.8 million individuals in the United States and >176 million people worldwide. MVP can be associated with significant mitral regurgitation (MR), bacterial endocarditis, congestive heart failure, and even sudden death.5–7 MVP is a clinical entity that is not fully understood, despite being known for more than a century. A “midsystolic click” was first described in 1887 by Cuffer and Barbillon.8 In 1963, Barlow and Pocock9 demonstrated the presence of MR by angiography in patients with the “click-murmur” syndrome. Criley et al10 subsequently coined the term MVP. MVP may be familial or sporadic. Despite being the most common cause of isolated MR requiring surgical repair,11 little is known about the genetic mechanisms underlying the pathogenesis and progression of MVP. Studies on the heritable features of MVP have been limited by the analysis of relatively small pedigrees and by self-referral and selection biases, including a preponderance of data from hospital-based cohorts.12,13 Nonetheless, the majority of data favor an autosomal-dominant pattern of inheritance in a large proportion of individuals with MVP.12,13 Despite the variability in clinical features, familial MVP might be considered a prevalent mendelian cardiac abnormality in humans. Although filamin-A has been identified as causing an X-linked form of MVP,14 the causative genes for the more common form of autosomal-dominant MVP have yet to be defined. In this review, we summarize our current knowledge of the diagnosis, epidemiology, prognosis, …

Modulation of Transforming Growth Factor-β Signaling and Extracellular Matrix Production in Myxomatous Mitral Valves by Angiotensin II Receptor Blockers

Little is known about the pathophysiology of myxomatous degeneration of the mitral valve, the pathological hallmark of mitral valve prolapse, associated with symptomatic mitral regurgitation, heart failure, and death. Excess transforming growth factor (TGF)-β signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF-β signaling is dysregulated in clinical specimens of sporadic mitral valve prolapse compared with explanted nondiseased mitral valves and we tested the effects of angiotensin II receptor blockers on TGF-β signaling in cultured human mitral valve cells. Operative specimens, cultured valve tissues, and cultured valvular interstitial cells were obtained from patients with mitral valve prolapse undergoing mitral valve repair or from organ donors without mitral valve disease. Increased extracellular matrix in diseased valve tissue correlated with an upregulation of TGF-β expression and signaling as evidenced by SMAD2/3 phosphorylation. Both TGF-β ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF-β increased basal extracellular matrix production, whereas serological neutralization of TGF-β inhibited disease-driven extracellular matrix overproduction. TGF-β-induced extracellular matrix production in cultured valvular interstitial cells was dependent on SMAD2/3 and p38 signaling and was inhibited by angiotensin II receptor blockers. TGF-β has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF-β signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients.

Natural History of Mitral Valve Prolapse in Military Aircrew

Objective: Mitral valve prolapse (MVP) is a common cardiac abnormality whose natural history differs among various patient populations. High-performance flight is associated with exposure to varying acceleration forces and strenuous isometric physical activity. The effect of the military flying environment on the natural history and progression of MVP is poorly defined. Methods: We evaluated a cohort which included all military aviators in the Israeli Air Force diagnosed with MVP. Medical records and echocardiographic studies of participants were reviewed for the development of clinical or echocardiographic complications. Results: The study population was comprised of 24 aviators, 14 of whom were high-performance aviators. Average follow-up was 23.5 years (total 563 person-years). Four aviators suffered from MVP-related complications including 2 cases of flail valve due to chordae rupture and 1 case each of newly diagnosed atrial fibrillation and infective endocarditis. Progression of asymptomatic mitral regurgitation was identified in 11 aviators. Conclusions: Military aviators with MVP may be prone to serious medical complications. A detrimental effect of high-performance flight on patients with MVP is suggested.

The progression of mitral valve prolapse: A follow-up investigation in the Framingham heart study Lisa A. Freed, Emelia J. Benjamin, Daniel Levy, Martin G. Larson, Jane C. Evans, Deborah L. Fuller, Birgitta Lehman, Robert A. Levine. Massachusetts General Hospital, Boston, MA, NHLBI's Framingham Heart Study, Framingham, MA

The progression of mitral valve prolapse: A follow-up investigation in the Framingham heart study Lisa A. Freed, Emelia J. Benjamin, Daniel Levy, Martin G. Larson, Jane C. Evans, Deborah L. Fuller, Birgitta Lehman, Robert A. Levine. Massachusetts General Hospital, Boston, MA, NHLBI's Framingham Heart Study, Framingham, MA

Long-Term Site-Related Differences in the Progression and Regression of the Idiopathic Mitral Valve Prolapse Syndrome

The natural history of uncomplicated mitral valve prolapse (MVP) is not clearly understood. To determine the site-related differences in regression and progression of MVP, 112 patients with idiopathic MVP were enrolled in this echocardiographic follow-up study. Cardiovascular complications, including dysarrhythmias (n = 3, 2.7%), overt congestive heart failure (n = 4, 3.6%), progression of mitral regurgitation over one grade (n = 28, 25.0%), newly confirmed chordal rupture (n = 1, 0.9%), and surgical repair (n = 2, 1.8%), were observed in these patients during a follow-up period of 1–13 years (mean, 4.0 ± 2.8 years). Multivariate analysis and Kaplan-Meier analysis revealed that posterior leaflet prolapse and significant mitral regurgitation (grade ≥2) were considerable risks for cardiovascular complications. Regression of MVP was seen in 17 (18.7%) of the anterior prolapse patients; however, new prolapse was observed in 40 (35.7%) patients, mainly in posterior prolapse patients. These results suggest that site-related differences exist in uncomplicated MVP prognosis and that MVP in the posterior leaflet has a poor outcome compared to that in the anterior leaflet.