TY - JOUR
T1 - Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF
AU - Cunningham, Jonathan W.
AU - Claggett, Brian L.
AU - O'Meara, Eileen
AU - Prescott, Margaret F.
AU - Pfeffer, Marc A.
AU - Shah, Sanjiv J.
AU - Redfield, Margaret M.
AU - Zannad, Faiez
AU - Chiang, Lu May
AU - Rizkala, Adel R.
AU - Shi, Victor C.
AU - Lefkowitz, Martin P.
AU - Rouleau, Jean
AU - McMurray, John J.V.
AU - Solomon, Scott D.
AU - Zile, Michael R.
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2020/8/4
Y1 - 2020/8/4
N2 - 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.
AB - 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.
KW - biomarkers
KW - fibrosis
KW - heart failure
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UR - http://www.scopus.com/inward/citedby.url?scp=85088109581&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2020.05.072
DO - 10.1016/j.jacc.2020.05.072
M3 - Article
C2 - 32731928
AN - SCOPUS:85088109581
SN - 0735-1097
VL - 76
SP - 503
EP - 514
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 5
ER -