Sacubitril/Valsartan Reverses Heart Fibrosis Better Than Valsartan Alone in Hypertensive Patients | Research

The takeaway

In a randomized trial of 78 hypertensive patients with enlarged hearts, sacubitril/valsartan reduced cardiac fibrosis twice as much as valsartan alone over 52 weeks, independent of blood pressure effects.

2x greater fibrosis reduction
Sacubitril/valsartan reduced cardiac interstitial volume by 5.2 mL vs. 2.5 mL with valsartan alone (P=0.006), despite identical blood pressure control

What the researchers found

At 52 weeks, sacubitril/valsartan produced a significantly greater absolute reduction in interstitial volume (a measure of cardiac fibrosis) compared to valsartan alone (-5.2 ± 5.4 vs. -2.5 ± 3.1 mL; P = 0.006), despite equivalent 24-hour systolic blood pressure (125 ± 11 vs. 126 ± 11 mmHg; P = 0.762). Secondary endpoints favoring sacubitril/valsartan included reductions in LV mass, left atrial volume, estimated LV filling pressure, NT-proBNP, and high-sensitivity troponin T.

Why it matters

Heart fibrosis — the buildup of scar tissue — is a key driver of heart failure in hypertensive patients, and until recently was considered largely irreversible. This trial provides randomized evidence that sacubitril/valsartan can reverse fibrosis beyond what blood pressure control alone achieves. The mechanism likely involves preserving natriuretic peptides (by inhibiting neprilysin), suggesting that boosting endogenous cardioprotective peptides has direct structural benefits on the heart.

How the study worked

REVERSE-LVH was a phase 2, open-label, randomized trial (NCT03553810). 78 patients with essential hypertension and left ventricular hypertrophy were randomized 1:1 to sacubitril/valsartan or valsartan for 52 weeks. The primary endpoint was change in interstitial volume assessed by cardiovascular magnetic resonance imaging. Secondary endpoints included cardiac volumes, function, mechanics, and circulating biomarkers.

What this study cannot tell us

This was a small (n=78), open-label phase 2 trial without blinding, which introduces potential bias. The study was powered for imaging endpoints, not clinical outcomes like hospitalizations or mortality. The 52-week duration may not capture long-term fibrosis reversal or clinical benefits. The open-label design may have influenced patient behavior and clinician management decisions. Larger confirmatory trials are needed.

How to read the evidence

This is a phase 2 randomized controlled trial published in Nature Communications — moderate-quality evidence. While the randomization and MRI-based endpoints are strengths, the small sample size, open-label design, and lack of clinical outcome data limit the evidence grade.

When this study was published

Published in 2025, this trial addresses a current clinical question about extending sacubitril/valsartan to hypertensive heart disease beyond its established heart failure indication.

The bigger picture

Sacubitril/valsartan (brand name Entresto) is already approved for heart failure, but this trial extends its potential to an earlier disease stage — hypertensive heart disease before overt heart failure develops. The finding that natriuretic peptide augmentation reverses cardiac fibrosis independent of blood pressure has profound implications for preventive cardiology. If confirmed in larger trials, this could shift treatment paradigms toward earlier use of peptide-modulating therapies to prevent the progression from hypertension to heart failure.

Questions still open

Would the fibrosis reduction seen at 52 weeks translate into fewer heart failure events over longer follow-up?
Should sacubitril/valsartan be considered earlier in hypertensive patients before LVH develops?
Is the anti-fibrotic effect primarily mediated through natriuretic peptide preservation, or are other mechanisms involved?

Common questions

How does sacubitril/valsartan protect the heart through peptides?

Sacubitril inhibits neprilysin, an enzyme that breaks down natriuretic peptides — naturally occurring hormones that protect the heart by reducing blood pressure, decreasing fluid retention, and fighting fibrosis (scarring). By preventing their breakdown, sacubitril/valsartan boosts these protective peptide levels. This trial shows that this peptide-boosting mechanism reduces heart fibrosis beyond what blood pressure control alone achieves.

What is cardiac fibrosis and why does it matter?

Cardiac fibrosis is the buildup of scar tissue in the heart muscle, often caused by long-standing high blood pressure. It makes the heart stiffer and less efficient, and is a key step in the progression from hypertension to heart failure. This study shows that fibrosis can be partially reversed with the right treatment — an important finding for preventing heart failure development.

Read the original research

Effects of sacubitril/valsartan on hypertensive heart disease: the REVERSE-LVH randomized phase 2 trial.

Nature communications, 16(1), 6981

View on PubMed ↗Publisher’s paper ↗

Citation

Lee, Vivian; Dalakoti, Mayank; Zheng, Qishi; Toh, Desiree-Faye; Boubertakh, Redha; Bryant, Jennifer A; Aw, Tar-Choon; Lee, Chi-Hang; Richards, A Mark; Butler, Javed; Díez, Javier; Foo, Roger; Cook, Stuart A; Lam, Carolyn Sp; Le, Thu-Thao; Chin, Calvin Wl. (2025). Effects of sacubitril/valsartan on hypertensive heart disease: the REVERSE-LVH randomized phase 2 trial.. Nature communications, 16(1), 6981. https://doi.org/10.1038/s41467-025-62203-0