The heart failure drug sacubitril/valsartan significantly lowered pulmonary pressures, reduced right ventricular hypertrophy, and improved heart function in a rat model of pulmonary hypertension — outperforming valsartan alone.
RV pressure dropped from 62 to 46 mmHgSacubitril/valsartan reduced right ventricular systolic pressure by 26% in rats with pulmonary hypertension after six weeks of treatment
What the researchers found
In rats with SU5416/hypoxia-induced pulmonary hypertension, six weeks of sacubitril/valsartan treatment significantly reduced right ventricular systolic pressure (62±4 vs 46±5 mmHg), right ventricular hypertrophy (RV/LV+S ratio: 0.74±0.06 vs 0.46±0.06), and myocardial collagen content (8.2±0.3 vs 6.4±0.4 µg/50 µg protein) compared to placebo.
Right ventricular contractility also improved (31.2±1.8 vs 43.1±3.6 mm/s). Valsartan alone did not achieve these improvements. The combination treatment increased lung levels of ANP, BNP, and cGMP while decreasing plasma endothelin-1, and reduced pulmonary vascular wall thickness — indicating benefits to both the heart and the lung vasculature.
Why it matters
Pulmonary hypertension remains difficult to treat, and the right ventricle's response to it is a major driver of patient outcomes. Sacubitril/valsartan (marketed as Entresto) is already widely used for left-sided heart failure. This study suggests it could potentially be repurposed for pulmonary hypertension by leveraging its unique dual mechanism — blocking angiotensin while simultaneously preserving natriuretic peptides that naturally dilate lung blood vessels.
How the study worked
Pulmonary hypertension was induced in Sprague-Dawley rats using the SU5416/hypoxia model. Animals were divided into four groups: normoxic controls (n=18), PH with placebo (n=34), PH with sacubitril/valsartan (n=24), and PH with valsartan alone (n=16). Treatment lasted six weeks. Outcomes included right ventricular pressure, hypertrophy index, collagen content, contractility, pulmonary vascular wall thickness, natriuretic peptide levels, and PKC isozyme expression.
What this study cannot tell us
This is an animal study using a specific rat model (SU5416/hypoxia) that mimics some but not all features of human pulmonary arterial hypertension. The six-week treatment duration may not capture long-term effects. Group sizes were unequal (16–34 per group). Results in rats may not translate directly to humans due to differences in drug metabolism, hemodynamics, and disease complexity. The study did not assess survival outcomes.
How to read the evidence
This is a well-designed preclinical animal study with appropriate controls (including valsartan-only comparison), but results are from rats and cannot be directly extrapolated to human patients. Evidence strength is low to moderate for clinical applicability.
When this study was published
Published in 2019 in Circulation: Heart Failure, a top cardiovascular journal. The findings remain relevant as clinical interest in sacubitril/valsartan for pulmonary hypertension continues to grow.
The bigger picture
This study connects two major peptide systems — natriuretic peptides (ANP/BNP) and the renin-angiotensin system — in the context of pulmonary hypertension. By showing that preserving natriuretic peptides through neprilysin inhibition adds benefit beyond angiotensin blockade alone, it supports the growing view that targeting peptide degradation pathways is a viable therapeutic strategy. Clinical trials testing sacubitril/valsartan in human pulmonary hypertension are an important next step.
Questions still open
- Would sacubitril/valsartan show similar benefits in human patients with pulmonary arterial hypertension?
- Does the neprilysin inhibition component (sacubitril) account for most of the benefit over valsartan alone, or is synergy required?
- Could sacubitril/valsartan be combined with existing pulmonary hypertension therapies for additive benefit?
Common questions
What is sacubitril/valsartan and how does it work?
Why was valsartan alone not effective but the combination was?
Read the original research
Treatment of Pulmonary Hypertension With Angiotensin II Receptor Blocker and Neprilysin Inhibitor Sacubitril/Valsartan.
Circulation. Heart failure, 12(11), e005819
Citation
Clements, Richard T; Vang, Alexander; Fernandez-Nicolas, Ana; Kue, Nouaying R; Mancini, Thomas J; Morrison, Alan R; Mallem, Krishna; McCullough, Danielle J; Choudhary, Gaurav. (2019). Treatment of Pulmonary Hypertension With Angiotensin II Receptor Blocker and Neprilysin Inhibitor Sacubitril/Valsartan.. Circulation. Heart failure, 12(11), e005819. https://doi.org/10.1161/CIRCHEARTFAILURE.119.005819