Sealing the Leak: A Drug Finds Its Sweet Spot in HFpEF

Key Takeaway: In a randomized trial of 84 patients with heart failure with preserved ejection fraction (HFpEF) and mitral valve regurgitation, treatment with sacubitril/valsartan (Entresto) was shown to significantly improve how the heart and lungs handle the stress of exercise—the very issue that makes the condition so debilitating. The drug also increased exercise capacity, lowered a key blood marker of cardiac strain, and provided a meaningful improvement in quality of life over a six-month follow-up.

A Stubborn Condition Meets a Targeted Response

Picture a patient: they can walk to the mailbox but return breathless. It’s not that their heart is weak in the conventional sense; rather, it’s stiff, overstretched, and leaking blood backward through a valve that’s supposed to close tightly. They’ve been told their heart’s pumping power is “preserved,” meaning their ejection fraction looks normal on an echocardiogram, yet they feel anything but normal. For the millions living with this frustrating form of heart failure, effective treatments are often few and far between, leaving physicians with little to offer. Now, a new clinical trial reveals that a well-known medication may offer real, measurable relief—but specifically in those whose disease is complicated by a leaky mitral valve.

What Did Researchers Aim to Test?

Heart failure with preserved ejection fraction accounts for about half of all heart failure cases worldwide, and its prevalence is rising as populations age^[2]. Unlike the more familiar form of heart failure where the heart muscle is too weak to pump effectively, HFpEF involves a heart that contracts normally but is stiff, fails to relax properly, and generates dangerously high pressures during filling, especially during physical activity. A significant subset of these patients develops a condition called atrial functional mitral regurgitation (AFMR): the left atrium becomes so stretched over time that the mitral valve, the gateway between the left upper and lower chambers, can no longer close properly. With every beat, blood leaks backward, worsening congestion and shortness of breath.

Sacubitril/valsartan, marketed as Entresto, combines a neprilysin inhibitor with an angiotensin receptor blocker. It was originally developed for heart failure with reduced ejection fraction, where it showed landmark survival benefits^[3]. Its role in HFpEF, however, has been more controversial. The large-scale PARAGON-HF trial showed a trend toward benefit that narrowly missed statistical significance for the overall HFpEF population^[4]. This left clinicians with a question: Could the drug have a powerful effect in the right subgroup?

To answer that, researchers designed a randomized controlled trial involving 84 individuals with confirmed HFpEF and AFMR. Participants were assigned to receive either sacubitril/valsartan or standard guideline-directed therapy and were followed for six months. The primary endpoint was a sophisticated exercise measurement: pulmonary artery pressure relative to cardiac output during exertion—that is, how much pressure builds up in the lung circulation for each unit of blood the heart pumps during exercise.

What the Study Revealed

The results were striking. Patients treated with sacubitril/valsartan showed a significant improvement in the primary endpoint—pulmonary pressure relative to cardiac output on exercise—compared to the control group at six months^[1]. This is not a subjective measure; it reflects a fundamental improvement in the hemodynamic abnormality that underlies symptoms in these patients.

Beyond the primary endpoint, the drug group achieved significantly better results in peak oxygen consumption (peak VO2, p=0.002), the gold-standard measure of aerobic fitness and functional capacity. Quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), also improved significantly (p=0.002). Levels of NT-proBNP, a blood protein released when the heart is under strain, fell in the treatment group. Left atrial volume decreased, and the dynamic worsening of mitral regurgitation that typically occurs during exercise was blunted.

Why This Treatment Works: The Mechanism of Action

To understand why sacubitril/valsartan appears so effective in this subgroup, it helps to follow the vicious cycle it interrupts. In HFpEF with AFMR, the stiffened left ventricle creates high filling pressures. Over months and years, these pressures are transmitted backward to the left atrium, stretching the chamber. As the atrium enlarges, so does the mitral valve annulus—the fibrous ring supporting the leaflets. The leaflets can no longer meet in the middle, and the valve begins to fail^[5]. During exercise, when the heart rate increases and more blood returns to the heart, this leak worsens dramatically, flooding the lungs with back-pressured blood and leading to the profound shortness of breath patients describe.

Sacubitril inhibits neprilysin, an enzyme that breaks down the body’s own natriuretic peptides—hormones that reduce blood volume, relax blood vessels, and counter the fibrosis and remodeling that stiffen the heart^[6]. By allowing these protective peptides to accumulate, sacubitril promotes sodium excretion, lowers blood volume, and reduces the filling pressures that stretch the atrium. Meanwhile, valsartan blocks the renin-angiotensin system, counteracting vasoconstriction and further reducing the afterload the heart must pump against. Together, these two agents shrink the atrial volume, tighten the mitral annulus, and lower the pressure gradient that drives blood backward, especially during the hemodynamic stress of exercise.

The reduction in left atrial volume observed in this study is a particularly encouraging sign. Atrial remodeling is both a consequence and a driver of AFMR, and reversing it suggests the drug is addressing the architecture of the disease, not just the symptoms.

Important Limitations

As compelling as these findings are, context is crucial. This was a relatively small study—84 patients—and while the results reached statistical significance across multiple endpoints, larger trials will be needed to confirm the magnitude of the benefit and assess long-term outcomes like hospitalization and mortality. The study lasted six months, which is sufficient to detect hemodynamic and functional changes but shorter than what is needed to evaluate the durability of the effect. Patient selection was also carefully controlled; real-world populations are more heterogeneous, and not every HFpEF patient with mitral regurgitation may fit the profile studied here.

What These Results Mean for Patients

For people living with HFpEF who also have a leaky mitral valve—and who struggle with breathlessness during even the most modest activities—this study offers something rare: objective evidence that a specific medication can improve the core hemodynamic problem driving their symptoms. The findings suggest that the sweet spot for sacubitril/valsartan may not be across the broad, heterogeneous HFpEF population, but in a well-defined subgroup where the drug’s mechanism of action aligns precisely with the disease pathology. If you have both diagnoses and have not yet tried Entresto, this study provides a strong, evidence-based reason to discuss it with your cardiologist. The improvements in exercise capacity, lung pressures, and quality of life reported here are the kinds of outcomes that translate directly to a better daily life—climbing the stairs without pausing, walking the dog without worry, and reclaiming the physical activities that give life meaning.

Scientific Sources

1. Dhont S, et al. Angiotensin Receptor Neprilysin Inhibitor in Heart Failure With Preserved Ejection Fraction and Secondary Mitral Regurgitation: The PRAISE-MR Randomized Trial. Circulation. 2026;153(25):1973-1983. PubMed: https://pubmed.ncbi.nlm.nih.gov/42104906/
2. Dunlay SM, et al. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2017. PMID: 28492288
3. McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014. PMID: 25176015
4. Solomon SD, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019. PMID: 31475794
5. Deferm S, et al. Atrial functional mitral regurgitation: JACC review topic of the week. J Am Coll Cardiol. 2019. PMID: 31097168
6. Hubers L, et al. Combined angiotensin receptor antagonism and neprilysin inhibition. Circulation. 2016. PMID: 26976916