By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco, Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: Among patients who presented with heart failure with reduced ejection fraction and severe functional mitral regurgitation, mitral regurgitation improved in 38% of patients with medical management. Improvement in mitral regurgitation was associated with increased survival.

SOURCE: Nasser R, Van Assche L, Vorlat A, et al. Evolution of functional mitral regurgitation and prognosis in medically managed heart failure patients with reduced ejection fraction. JACC Heart Fail 2017;5:652-659.

In heart failure with reduced ejection fraction (HFrEF), functional mitral regurgitation (FMR) develops because of left ventricular (LV) dilation and dysfunction. The resulting tethering of the structurally normal mitral leaflets causes failure to coapt. Development of FMR is associated with worse prognosis. Medical therapy for HFrEF, including ACE inhibitors and beta-blockers, improves outcomes and is associated with improvements in LV remodeling. Whether medical management of HFrEF can reduce the severity of FMR and improve prognosis has not been well studied. Nasser et al studied 163 patients with HFrEF treated at an academic medical center in Belgium. About half the patients had ischemic cardiomyopathy. MR severity was assessed by echocardiography at baseline and follow-up. All patients were treated with maximally tolerated doses of standard medical therapy for HFrEF (ACE inhibitors, beta-blockers, and aldosterone antagonists). Median follow-up was 50 months. Improvement in FMR was defined as a reduction from severe to nonsevere MR, and worsening MR was defined as an increase from nonsevere to severe MR. The primary endpoint was a composite of all-cause death, heart transplant, or hospitalization for HF or arrhythmia.

At baseline, 31% of patients demonstrated severe FMR. Patients with severe FMR were older and exhibited larger LV volumes and lower EF. During the study period, 38% of patients with severe FMR improved to nonsevere FMR, while 18% of those with nonsevere FMR at baseline progressed to severe FMR. Patients with sustained severe FMR or those who progressed to severe FMR received a significantly worse prognosis compared to those who improved or remained nonsevere (P < 0.0001). In multivariate models, the presence of severe FMR at follow-up was the single strongest predictor of both the primary endpoint and mortality (odds ratio, 2.5). On the other hand, severity of FMR at baseline was not associated with worse prognosis.

Patients with severe FMR at follow-up exhibited more LV enlargement and were more likely to demonstrate a restrictive LV filling pattern compared to those with nonsevere FMR. The authors concluded that severe FMR can be treated successfully with medical therapy in nearly 40% of patients, with associated improvements in LV remodeling and prognosis.

COMMENTARY

In multiple studies of HFrEF, FMR is associated with an increased risk of adverse outcomes, including death. The negative effect of FMR often is attributed to progressive LV remodeling because of the increased volume overload caused by MR. This creates a vicious cycle whereby the worsening LV remodeling leads to increased FMR and more LV volume overload. There is growing interest in repair of FMR, whether surgically or percutaneously. However, current medical therapy for HFrEF can improve LV remodeling and theoretically reduce the severity of FMR. Understanding the effect of medical therapy on FMR and identifying which patients will improve with medical therapy alone is crucial for appropriate patient selection for surgical or percutaneous treatment of FMR. Nasser et al showed that in a subset of patients with HFrEF and severe FMR, the degree of MR can improve with aggressive medical therapy for heart failure. Patients in whom FMR improves are less likely to show increasing LV volumes. Perhaps most importantly, patients in whom FMR improved during the study period showed significantly better survival and lower rates of the composite endpoint compared to those in whom FMR remained severe. These findings suggest an initial course of aggressive medical therapy may be indicated for most, if not all, patients with HFrEF and FMR before considering invasive valve repair.

The authors highlighted the importance of targeting volume status to prevent the progression of FMR. Patients with improvement in FMR severity during the study period were more likely to show improvement in the LV filling pattern, reflecting improvement in volume status. In the study population, diuretics were up-titrated aggressively as needed to keep patients euvolemic, and extensive education regarding dietary sodium and fluid restriction was provided. Although this association does not prove more aggressive, diuretic use can improve FMR. Given the proposed pathophysiology of FMR, it would make sense that reducing LV volume overload would help improve FMR severity.

This was a relatively small, single-center study. Only 50 patients presented with severe FMR at baseline, so, ideally, the findings should be replicated in a larger cohort to confirm the observed rate of improvement, and, hopefully, identify clinical predictors of FMR improvement. The study by Nasser et al provides helpful insight into the clinical course of patients with HFrEF and FMR who are managed medically. However, many important questions remained unanswered. First, how can clinicians identify those patients with FMR who will improve with medical therapy alone? Second, how should clinicians manage those patients who will not improve with medical therapy alone, or those in whom severe FMR persists despite maximally tolerated therapy? Percutaneous mitral valve repair has gained significant interest in recent years, but its utility in FMR is unproven. The creators of the Cardiovascular Outcomes Assessment of the Mitra-Clip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial randomized patients with severe FMR to MitraClip vs. medical therapy. The results are expected in late 2018. Until then, clinicians should use maximally tolerated medical therapy for HFrEF, including use of diuretics and salt restriction, to optimize each patient’s volume status.