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

Jonathan W. Cunningham, Brian L. Claggett, Eileen O'Meara, Margaret F. Prescott, Marc A. Pfeffer, Sanjiv J. Shah, Margaret M. Redfield, Faiez Zannad, Lu May Chiang, Adel R. Rizkala, Victor C. Shi, Martin P. Lefkowitz, Jean Rouleau, John J.V. McMurray, Scott D. Solomon*, Michael R. Zile

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

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)

Original languageEnglish (US)
Pages (from-to)503-514
Number of pages12
JournalJournal of the American College of Cardiology
Volume76
Issue number5
DOIs
StatePublished - Aug 4 2020

Keywords

  • biomarkers
  • fibrosis
  • heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Cunningham, J. W., Claggett, B. L., O'Meara, E., Prescott, M. F., Pfeffer, M. A., Shah, S. J., Redfield, M. M., Zannad, F., Chiang, L. M., Rizkala, A. R., Shi, V. C., Lefkowitz, M. P., Rouleau, J., McMurray, J. J. V., Solomon, S. D., & Zile, M. R. (2020). Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF. Journal of the American College of Cardiology, 76(5), 503-514. https://doi.org/10.1016/j.jacc.2020.05.072