Pathophysiology of FMR: an evolving conceptual framework
The long-held view that MR could be distinguishingly classified as primary or secondary according to the underlying pathophysiology is important for decision-making in treatment.18 MR is considered as “primary” (also known as organic) when principally due to a structural or degenerative abnormality of the mitral leaflets, annulus, chordae tendineae and PMs.37 The adverse remodeling of the ventricle is the consequence of valve dysfunction, and patients with primary MR would benefit from MV repair or replacement.37 In contrast, patients with FMR have largely normal mitral leaflets and regurgitation occurs as a consequence of left cardiac chambers remodeling and dysfunction. Regional MI or global LV remodeling and dysfunction (caused by hypertension or dilated cardiomyopathy) may lead to apical and/or lateral PM displacement that results in leaflets tethering and reduced closing forces, annulus dilation and flattening, and loss of leaflet coaptation.38 Occasionally, patients with global LV systolic dysfunction may have left bundle branch block, which can further exacerbate regurgitation due to dyssynchronous PMs contraction.39 Consequently, the management of FMR has largely focused on the restoration of LV structure and function with neurohormonal antagonists and resynchronization devices, and surgical MV intervention is generally reserved as the final option.40
The conceptual outline that is traditionally utilized to characterize MR overlooks the fact that the maintenance of a competent MV requires dynamic and complex interactions among the leaflets and the entire apparatus, which include the annulus, chordae, PMs, and the function and loading condition of segmental or global ventricular muscles that support normal leaflet coaptation.15 Therefore, a restricted focus on static anatomy and the sequence of events over time (original lesions of MV or LV that initiated the disease process) may not provide a sufficient framework for selecting the optimal management, and the distinction between “primary” and “secondary” MR can be blurred in many clinical scenarios: 1) during the decompensated phase of primary MR, LV dilatation and dysfunction could contribute to progressive MR via secondary mechanisms; 2) in the setting of global LV dysfunction without left bundle branch block, some patients with non-ischemic cardiomyopathy have selective delayed activation of one PM (e.g., the anterolateral insertion), and others presenting with PM dysfunction or even rupture due to posteromedial or inferior MI. In these circumstances, asymmetrical tethering or significant prolapse of a single leaflet could lead to severe MR that could be corrected by surgical interventions – a response that can be clinically identical to primary MR, even though the MR is secondary to structural alterations of the LV.15,16,41
Current technological advances have greatly enhanced the ability to characterize the dynamics of MR, allowing quantitative estimation of regurgitant volume (RVol) as well as the EROA.42,43 By interpreting the relationship of EROA and the estimated LV end-diastolic volume (LVEDV) based on the Gorlin hydraulic orifice equation, some investigators have proposed a novel conceptual framework that classifies patients with FMR according to the causal mechanism rather than the severity of the regurgitant lesion and thus identifies patients in whom MR is a direct factor in the disease process among patients with LV dilatation and dysfunction.37-39 For instance, in patients with primary MR or FMR that occurs as a result of regional LV dysfunction/remodeling, severe degrees of MR are usually accompanied by only modest increases in LVEDV, and the magnitude of MR would greatly exceed that predicted by LV volumes (disproportionate MR). In contrast, in patients with FMR that occurs entirely due to global LV dilatation, the severity of MR is proportional to the amount of LV dilatation. This principle may be of great value in selecting optimal treatment since “proportionate” FMR may respond favorably to GDMT aimed at reducing LVEDV (neurohormonal antagonists), while “disproportionate” FMR may benefit selectively from interventions that are directed toward the improvement of leaflet coaptation (cardiac resynchronization therapy or mechanical interventions). Serendipitously, the validity of this novel concept of proportionate and disproportionate MR appears to have been inadvertently tested in 2 recently completed randomized controlled trials (RCTs) of transcatheter mitral valve repair (TMVr) in patients with FMR.15,16,37-39