Ischemia-Mediated Dysfunction in Subpapillary Myocardium as a Marker of Functional Mitral Regurgitation

Abstract

Objectives: The goal of this study was to test whether ischemia-mediated contractile dysfunction underlying the mitral valve affects functional mitral regurgitation (FMR) and the prognostic impact of FMR.

Background: FMR results from left ventricular (LV) remodeling, which can stem from myocardial tissue alterations. Stress cardiac magnetic resonance can assess ischemia and infarction in the left ventricle and papillary muscles; relative impact on FMR is uncertain.

Methods: Vasodilator stress cardiac magnetic resonance was performed in patients with known or suspected coronary artery disease at 7 sites. Images were centrally analyzed for MR etiology/severity, mitral apparatus remodeling, and papillary ischemia.

Results: A total of 8,631 patients (mean age 60.0 ± 14.1 years; 55% male) were studied. FMR was present in 27%, among whom 16% (n = 372) had advanced (moderate or severe) FMR. Patients with ischemia localized to subpapillary regions were more likely to have advanced FMR (p = 0.003); those with ischemia localized to other areas were not (p = 0.17). Ischemic/dysfunctional subpapillary myocardium (odds ratio: 1.24/10% subpapillary myocardium; confidence interval: 1.17 to 1.31; p < 0.001) was associated with advanced FMR controlling for infarction. Among a subgroup with (n = 372) and without (n = 744) advanced FMR matched (1:2) on infarct size/distribution, patients with advanced FMR had increased adverse mitral apparatus remodeling, paralleled by greater ischemic/dysfunctional subpapillary myocardium (p < 0.001). Although posteromedial papillary ischemia was more common with advanced FMR (p = 0.006), subpapillary ischemia with dysfunction remained associated (p < 0.001), adjusting for posteromedial papillary ischemia (p = 0.074). During follow-up (median 5.1 years), 1,473 deaths occurred in the overall cohort; advanced FMR conferred increased mortality risk (hazard ratio: 1.52; 95% confidence interval: 1.25 to 1.86; p < 0.001) controlling for left ventricular ejection fraction, infarction, and ischemia.

Conclusions: Ischemic and dysfunctional subpapillary myocardium provides a substrate for FMR, which predicts mortality independent of key mechanistic substrates.

Keywords: cardiac magnetic resonance; ischemia; mitral regurgitation.

Figure 1.. Study Design

Schematic of multicenter image/data acquisition, de-identification, and centralized core lab analysis. All sites employed a similar stress CMR protocol. Ancillary clinical data were collected using a standardized reporting system, as were global LV chamber size/function, regional contractility, infarction, and ischemia. Mortality was obtained via the SSDI. Data were de-identified prior to core lab analyses, including assessment of MR etiology and severity in all patients, and papillary muscle ischemia and mitral apparatus geometric indices among a nested case-control cohort of patients with and without advanced FMR (bottom left: yellow arrow denotes papillary muscle ischemia, middle: yellow lines denote annular diameter and tenting height, fill denotes tenting area, right: yellow line denotes inter-papillary muscle distance).

Figure 2.. Mitral Apparatus Partitions.

2A. Bullseye plot (17-segment model) illustrating LV wall myocardium subtended within the mitral apparatus, which was defined as segments adjacent to the anterolateral and posteromedial papillary muscles (blue denotes sub-papillary regions [basal-mid anterior/anterolateral, inferior/inferolateral walls]). 2B. Converged bullseye plots depicting associations of FMR with LV wall ischemia (left) and infarction (right) localized to sub-papillary regions (blue) or regions anatomically distant from the papillary muscles (grey): Patients with ischemia or infarction isolated to sub-papillary regions were more likely to have advanced FMR (both p<0.01), whereas those with ischemia or infarction isolated to other regions were not (p=NS).

Figure 3.. Representative Examples

Examples of LV sub-papillary ischemia in patients with and without advanced FMR, illustrating hypothesized modulatory impact of contractile dysfunction. 3A. Advanced FMR: Stress CMR-evidenced ischemia involving the LV inferior, inferoseptal, and inferolateral walls (top left [arrow denotes perfusion defect]), which were viable on LGE-CMR (top right). Note impaired contractile function in ischemic territories as discerned by cine-CMR (middle left: short axis, middle right: 2-chamber orientation [arrow denotes dysfunctional region]). Quantitative analysis demonstrated advanced FMR (regurgitant fraction 33%, volume 31ml) [bottom left: phase contrast CMR, bottom right: differential LV/aortic stroke volume). 3B. No FMR: Stress CMR-evidenced ischemia involving LV inferior wall and inferoseptum (top left), which were viable on LGE-CMR (top right). Cine-CMR demonstrated preserved contractility in ischemic territories (middle left: short axis, middle right 2-chamber orientation). Quantitative analysis demonstrated equivalent LV-aortic stroke volume, consistent with absence of MR.

Figure 4.. Mortality in Relation to FMR Severity

Kaplan-Meier survival curves depicting all-cause mortality among groups stratified based on FMR severity. Mortality increased in relation to FMR severity (p<0.001), including when patients with mild FMR were compared to those with no FMR as well as among patients with advanced FMR in relation to all other groups.

Central Illustration:. Sub-Papillary Ischemia is Associated with Functional Mitral Regurgitation

Multicenter data from the SCMR registry demonstrated stress CMR evidenced LV ischemia underlying the mitral valve to be a key determinant of FMR. Extent of ischemic and dysfunctional LV myocardium in sub-papillary segments remained associated with FMR when controlling for LV infarction in corresponding territories or papillary muscle ischemia. During follow-up, mortality risk increased in proportion to severity of FMR: FMR severity remained associated with increased mortality even after adjustment for conventional prognostic indices and determinants of FMR (LV ischemia, infarction, dysfunction).