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