Mitral Valve Remodeling in Response to Atrial and Ventricular Changes: Mechanisms and Clinical Implications for Functional Mitral Regurgitation

Mitral regurgitation (MR) is a frequent and heterogeneous disease associated with significant morbidity and mortality. Normal mitral valve closure requires a complex interplay between left ventricular shape and dynamics, papillary muscles, mitral annulus, and both mitral leaflets. Anomalies of the left ventricle or the left atrium can therefore cause functional mitral regurgitation (FMR), which can be improved by related therapeutic interventions. However, heart failure therapies (revascularization, resynchronization, and pharmacological treatment) are incomplete treatments for FMR, which remains frequent. Another key component in FMR is the valve itself, as the leaflets undergo significant changes in the process. Those changes can be beneficial and prevent FMR, or detrimental and contribute to valve dysfunction. Mitral valve remodeling starts with biological changes occurring at the cellular level and is ultimately reflected macroscopically by leaflet enlargement and/or thickening. This remodeling also modifies the biomechanical properties of the valve, critical for adequate coaptation. Some conditions result in adequate valve enlargement, which remains proportional with the annulus and ventricular sizes, preventing FMR despite significant myocardial disease. Other conditions, ischemic heart disease in particular, are associated with maladaptive valve changes with excessive thickening and fibrotic remodeling. This adverse evolution is associated with the presence of transforming growth factor beta in the leaflets, which can be influenced pharmacologically. Clinical observational studies and experimental works are suggesting potential therapeutic targets to prevent FMR by influencing the valve biology. While those interventions still require clinical validation, they could represent an entirely new strategy for this common and morbid disease.