Physicians' Academy for Cardiovascular Education

ARNI favorably changes biomarkers of ECM homeostasis in HFpEF

Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF

Literature - Cunningham JW, Claggett BL, O’Meara E, et al. - J Am Coll Cardiol 2020;76:503–14

Introduction and methods

It has been suggested that changes in myocardial extracellular matrix (ECM) homeostasis occur during development of heart failure (HF) in patients with HFrEF and HFpEF. Changes in synthesis, processing, degradation and turnover of proteins such as collagen may result in structural remodeling [1]. These changes can be determined by measuring circulating biomarkers [2-6], including propeptides of collagen (N-terminal propeptide of collagen I [PINP] and N-terminal propeptide of collagen III [PIIINP]), soluble ST2 (sST2) which enhances activation of fibroblasts (collagen-producing myocardial cells), collagen I telopeptides (CITPs) which are released during collagen turnover and degradation, and tissue inhibitor of matrix metalloproteinase (TIMP-1) which inhibits degradation of collagen.

In HFrEF patients, sacubitril/valsartan favorably altered circulating biomarkers [7] and thereby likely inhibits fibrosis. It is unknown whether this is also true for HFpEF patients.

Data from the PARAGON-HF [8] were used to investigate whether 1) circulating biomarkers that reflect determinants of ECM homeostasis are abnormal in HFpEF patients; 2) baseline levels of these biomarkers and changes from baseline predict HF events; and 3) treatment with sacubitril/valsartan compared to valsartan alone favorably changed levels of these biomarkers.

PARAGON-HF was a multicenter, double-blind clinical trial and enrolled patients with chronic HFpEF who were randomized to sacubitril/valsartan or valsartan alone. The primary endpoint, a composite of total (first and recurrent) hospitalizations for HF and CV death, just missed significance in the PARAGON-HF trial.

For this biomarker substudy, data of the five biomarkers sST2, PINP, PIIINP, CITP, TIMP-1 were evaluated. Biomarkers were measured at baseline (n=1135), 16 weeks (n=1113) and 48 weeks (n=1016) after randomization.

Main results


In a subanalysis of the PARAGON-HF trial, higher levels of TIMP-1 were associated with risk of the primary endpoint. Treatment with sacubitril/valsartan resulted in favorable changes in some biomarkers (TIMP-1 and sST2) and changes in TIMP-1 were associated with risk of the primary endpoint. These results suggest that changes in biomarkers reflecting ECM homeostasis may lead to myocardial fibrosis and contribute to HFpEF pathogenesis and prognosis. Sacubitril/valsartan may result in beneficial outcomes by reducing fibrosis in HFpEF patients.


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