Study: Sacubitril/Valsartan Led to Fibrosis Improvements in HFrEF

Inflammation and fibrosis seen in heart failure with reduced ejection fraction (HFrEF) appeared subdued following treatment with angiotensin receptor neprilysin inhibitor sacubitril/valsartan, which the authors of a new study attribute to the natriuretic peptide system being ramped up and activity of the renin-angiotensin-aldosterone system (RAAS) being subdued.

The authors investigated levels of remodeling biomarkers in patients with HFrEF (N = 26), as well as their clinical and echocardiographic parameters, by comparing data from before administration of sacubitril/valsartan to findings seen at the 30- and 60-day marks post-therapy. The biomarkers were procollagen type 1 C-terminal propeptide (PICP), human cartilage glycoprotein-39 (YKL-40), plasma renin activity (PRA), and aldosterone (Aldo). All participants were receiving care at the Heart Failure Unit of Fondazione Cà Granda Ospedale Maggiore Policlinico, in Milan, Italy, between 2019 and 2020.

Findings from the prospective pharmacological, nonprofit, monocentric interventional pilot study were published recently in BioMed Central Cardiovascular Disorders.

“Sacubitril/valsartan is a novel drug combination designed to block the adverse effects of RAAS, to reduce bradykinin potentiation by valsartan, and to inhibit the neprilysin inactivating effect of natriuretic peptides by sacubitril metabolite LBQ657,” the authors wrote. “It has been proven to be superior to conventional angiotensin-converting enzyme inhibition in reducing cardiovascular deaths and HF readmission.”

Following measurements taken at baseline and at the 30- and 60-day marks, decreases in the means (SD) for all 4 biomarkers and in blood pressure, from baseline to the end of the study, were seen:

• Systolic blood pressure (BP) decreased approximately 10%: 113.4 (3.2) mm Hg from 126 (3.0) mm Hg
• Diastolic BP decreased approximately 6%: 71.9 (1.7) mm Hg from 77.5 (2.1) mm Hg
• Left ventricular ejection fraction rose 22.8%: 36.2% (1.0%) from 29.5% (1.0%)
• LV end-systolic volume dropped 12%: 34.0 (10.0) mL/m2 from 38.6 (8.7) mL/m2
• NT-proBNP dropped 53.7%: 1282 (289) ng/L from 2769 (481) ng/L
• PICP level dropped 42.2%: 85.4 (16.8) ng/mL from 147.8 (16.0) ng/mL
• YKL level dropped 46.8%: 101.9 (13.8) ng/mL from 191.8 (25.8) ng/mL
• PRA level dropped 79.2%: 1.55 (0.40) ng/dL from 7.47 (1.78) ng/mL
• Aldo level dropped 76.7%: 5.19 (3.4) ng/mL from 22.3 (5.12) ng/mL

Especially for the biomarkers, maximum benefit from sacubitril/valsartan was seen within 30 days of initiation (P < .001).

Sacubitril/valsartan treatment was begun at a dose of 24/26 mg twice a day. Overall, this dose did not change for 61.5% of patients; however, the dose did increase to 49/51 mg twice a day (the maximum tolerated dose) in 19.2% of patients and to 97/103 mg twice a day (the target dose) in 19.2% of patients.

No adverse events were reported, no patients required hospitalization or had worsening of their HF, and creatinine and electrolyte values remained consistent throughout the study.

Within the study cohort, the mean age was 69.8 (2.3) years, 77% were men, all had New York Heart Association class III disease, 50% had a history of smoking, 62% each had hypertension and hyperlipidemia, and all were on optimal treatment with beta-blockers, mineralcorticoid receptor antagonists, and diuretics before the study protocol initiated treatment with sacubitril/valsartan.

“The major finding of our study was that sacubitril/valsartan treatment in patients with HFrEF was associated with a decrease of circulating markers of fibrosis and inflammation,” the authors wrote. “This effect was already present within 30 days of treatment, persisted during the following 30 days, and was associated with a progressive inhibition of the RAAS.”

Their findings are especially noteworthy because their study is likely the first to find a potential relationship between sacubitril/valsartan treatment and myocardial fibrosis improvement. In turn, these results may add to current knowledge of the mechanism of action of the angiotensin receptor neprilysin inhibitor, particularly because inflammation can worsen HF.

“Our study for the first time documented that sacubitril/valsartan therapy was able to reduce the inflammatory context of HF,” they concluded. “Future studies in larger samples are highly desirable in order to clarify the long-term effect of sacubitril/valsartan on fibrosis in cardiac tissue.”

Reference
Bolla GB, Fedele A, Faggiano A, Sala C, Santangelo G, Carugo S. Effects of sacubitril/valsartan on biomarkers of fibrosis and inflammation in patients with heart failure with reduced ejection fraction. BMC Cardiovasc Disord. Published online May 13, 2022. doi:10.1186/s12872-022-02647-0