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Mitral valve disease—morphology and mechanisms

Key Points

  • Mitral valve disease is a major cause of heart failure and mortality

  • Even in adult life, the mitral valve is a dynamic structure and therapeutically accessible

  • Genetic analysis has revealed that regulation of growth signalling and cell migration pathways could potentially be modified to limit progression from developmental defects to clinically evident valve degeneration, such as mitral valve prolapse

  • Mitral valve enlargement is an important determinant of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy and might be stimulated by valvular–ventricular interactions

  • Mitral valve plasticity allows adaptation to ventricular remodelling, but adverse processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with worse prognosis

  • Understanding these concepts can create new opportunities to reduce the clinical progression of mitral valve disease through early detection and biological modification

Abstract

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

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Figure 1: Models of mitral valve disease.
Figure 2: Mitral valve structure.
Figure 3: Morphological features of normal and myxomatous mitral valves.
Figure 4: Cell lineages that contribute to valve formation.
Figure 5: Mitral valve growth and development.
Figure 6: Echocardiographic diagnosis of mitral valve prolapse.
Figure 7: Anatomy of mitral valve prolapse.
Figure 8: Mechanisms of mitral valve prolapse.
Figure 9: Proposed mechanism of mitral valve disease in Marfan syndrome.
Figure 10: Mitral valve enlargement in SAM.
Figure 11: 3D echocardiography showing increase in systolic anterior motion and LVOTO with increased mitral leaflet area.
Figure 12: Mechanism of ischaemic mitral regurgitation.
Figure 13: HE and Masson staining in the normal (left) and stretched (right) MV demonstrating increased leaflet thickness and spongiosa matrix after 2 months of stretching in a sheep model.
Figure 14: Evidence for reactivated EMT owing to leaflet stretch.

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Acknowledgements

All the authors are part of the Leducq Transatlantic Network, which brings together clinical and basic scientists from multiple centres to identify mechanisms of both inherited and acquired mitral valve disease, with the aim of discovering therapies to modify the natural history favourably. The authors acknowledge support of grant 07CVD04 of the Leducq Foundation, Paris, France for the Leducq Mitral Transatlantic Network of Excellence, and Leducq Foundation Career Development Awards 10CDA01 to D.P.J. and 11CDA04 to M. Padala. Additional support came from the French Society of Cardiology, Paris, France (MVP France and REMY Registry: A.A.H., X.P.J.), the French National Research Agency, Paris, France (A.A.H., E.M.), the French Ministry of Health, Paris, France (A.A.H.; Clinical Research Hospital Program, J.-J.S., T.L.T., H.L.M., V.P.), the National Institutes of Health, Bethesda, MD, R01 HL72265 (R.A.L.), R01 HL109506 (R.A.L., E.A., J.B.), R01 HL114805 (E.A.), K24 HL67434 (R.A.L.), K23 HL116652 (F.N.D.), R01 HL127692 (S.A.S., D.P.M., R.A.L.), R01 HL033756 (R.R.M., R.A.N.), NIGMS P30 GM103342 (R.R.M., R.A.N.), P20 RR21949 (R.R.M., R.A.N.), AHA 11SDG5270006 (R.A.N.), the Doris Duke Charitable Trust, New York, NY (S.A.S., R.A.L.), the Ellison Foundation, Boston, MA (R.A.L.), the American Society of Echocardiography, Raleigh, NC, (J.P.D.-B.), the Austrian Health Ministry Erwin-Schrödinger Fund, Vienna (J.P.D.-B.), the Spanish Society of Cardiology, Barcelona (PROMESA: L.F.-F., J.S.), the Eurostars CARDIOMARK Project E!6490, European Union, Brussels, (J.-J.S.), the INSERM-DGOS and Nantes University Translational Research Programs (J.-J.S., C.D., T.L.T.), Fondation GenaVie, Nantes, France (T.L.T.), the French Foundation of Cardiology, Paris, France (T.L.T.), the Danish Heart Foundation, Copenhagen (M.O.J.), the Fondation de la Recherche Medicale, Paris, France (M. Pucéat), the Fonds de Recherche du Québec-Santé, Montreal, Quebec, Canada (J. Beaudoin), and the Quebec Office of the Heart and Stroke Foundation, Montreal, Quebec, Canada (J. Beaudoin).

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R.A.L., A.A.H., and D.P.J. are joint first authors. M.P. and J.P.D.-B. are joint second authors. All authors researched data for the article, made substantial contribution to discussion of the content, and wrote, reviewed, and edited the manuscript before submission.

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Levine, R., Hagége, A., Judge, D. et al. Mitral valve disease—morphology and mechanisms. Nat Rev Cardiol 12, 689–710 (2015). https://doi.org/10.1038/nrcardio.2015.161

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