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

J Am Coll Cardiol. 2020 Aug 4;76(5):503-514. doi: 10.1016/j.jacc.2020.05.072.

Abstract

Background: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.

Objectives: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).

Methods: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.

Results: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.

Conclusions: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Keywords: biomarkers; fibrosis; heart failure.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aminobutyrates / pharmacology*
  • Angiotensin Receptor Antagonists / pharmacology
  • Biomarkers / metabolism
  • Biphenyl Compounds
  • Drug Combinations
  • Extracellular Matrix / metabolism*
  • Female
  • Heart Failure / blood
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Humans
  • Male
  • Neprilysin
  • Prospective Studies
  • Stroke Volume / drug effects
  • Stroke Volume / physiology*
  • Tetrazoles / pharmacology*
  • Valsartan
  • Ventricular Function, Left / drug effects
  • Ventricular Function, Left / physiology*

Substances

  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Biomarkers
  • Biphenyl Compounds
  • Drug Combinations
  • Tetrazoles
  • Valsartan
  • Neprilysin
  • sacubitril and valsartan sodium hydrate drug combination

Associated data

  • ClinicalTrials.gov/NCT01920711