Pathological Remodeling of Mitral Valve Leaflets from Unphysiologic Leaflet Mechanics after Undersized Mitral Annuloplasty to Repair Ischemic Mitral Regurgitation

Abstract

Background Undersized ring annuloplasty is a commonly used surgical repair for ischemic mitral regurgitation, in which annular downsizing corrects regurgitation, but alters valve geometry and elevates tissue stresses. In this study, we investigated if unphysiological leaflet kinematics after annuloplasty might cause pathogenic biological remodeling of the mitral valve leaflets, and if preserving physiologic leaflet kinematics with a better technique can moderate such adverse remodeling. Methods and Results Twenty‐nine swine were induced with ischemic mitral regurgitation, and survivors were assigned to groups: 7 underwent annuloplasty, 12 underwent annuloplasty with papillary‐muscle approximation, 6 underwent papillary‐muscle approximation, and 3 were sham controls. Pre‐and post‐surgery leaflet kinematics were measured, and valve tissue was explanted after 3 months to assess biological changes. Anterior leaflet excursion was unchanged across groups, but persistent tethering was observed with annuloplasty. Posterior leaflet was vertically immobile after annuloplasty, better mobile with the combined approach, and substantially ( P =0.0028) mobile after papillary‐muscle approximation. Procollagen‐1 was higher in leaflets from annuloplasty compared with the other groups. Heat shock protein‐47 and lysyl oxidase were higher in groups receiving annuloplasty compared with sham. α‐ SMA was elevated in leaflets from animals receiving an annuloplasty, indicating activation of quiescent valve interstitial cells, paralleled by elevated transforming growth factor‐β expression. Conclusions This is the first study to demonstrate that surgical valve repairs that impose unphysiological leaflet mechanics have a deleterious, pathological impact on valve biology. Surgeons may need to consider restoring physiologic leaflet stresses as well as valve competence, while also exploring pharmacological methods to inhibit the abnormal signaling cascades.

The secret life of the mitral valve

“…In a swine experimental model of moderate IMR, pathogenic biological changes in the MV leaflets were demonstrated within a short period of 3 months. Collagen levels were elevated in these stressed leaflets and the profibrotic changes in the valve paralleled increase in TGF‐β 47 . Surgical repair with restrictive mitral annuloplasty alone frequently do not restore physiological leaflet configuration and, if mechanical strains remains elevated, pathogenic changes in valve leaflets can be induced.…”

The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

“…We hope that we have taken a first step toward similar studies that may support pharmacological support of TR surgery and/or intervention. Interestingly, recent work has demonstrated that not only disease, but also surgical repair may initiate mitral valve tissue (mal)adaptation (54). It is possible that the tricuspid valve, similarly, may (mal)adapt to repair.…”

Mitral valve leaflet response to ischemic mitral regurgitation: From gene expression to tissue remodeling

“…27 Altered mechanical loads following undersized ring annuloplasty and/or papillary muscle approximation also show differences in several genes related to ECM remodeling. 28 This feedback interaction between VICs and their micro-mechanical environment and the way this scales to the levels of the tissue and organ (valve and ventricle) warrants further investigation, especially in the context of IMR.…”

“…Although recent reports have continued to shed light on the MV remodeling processes post-MI, either unaltered 23,29,30 or in the context of various interventions 25,28,31 , fundamental questions regarding MV remodeling in IMR remain. In particular, detailed analyses of the functional physiological behaviors of the post-MI MV necessary for informing advanced computational simulations of patient-specific surgical procedures remain lacking.…”

“…In particular, detailed analyses of the functional physiological behaviors of the post-MI MV necessary for informing advanced computational simulations of patient-specific surgical procedures remain lacking. At the underlying sub-cellular response level, individual genes/proteins (e.g., 29,31 ) or gene panels related to a single process 28 have been investigated, but there has not been a transcriptomics study that investigates all genes/processes that change in response to IMR in vivo. Transcriptomics provides an unbiased approach for investigating the importance of individual genes/processes in the context of global gene expression, potentially uncovering novel genes that would otherwise be overlooked by deciding which genes should be investigated a priori.…”