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 - Funding Information:
PARAGON-HF was sponsored by Novartis. Dr. Cunningham has received a National Heart, Lung, and Blood Institute T32 postdoctoral training grant (T32HL094301). Dr. Claggett has received consulting fees from AOBiome, Biogen, Boehringer Ingelheim, Corvia, Gilead, and MyoKardia. Dr. O'Meara has received HSFC grant for the Bio-AIMI-HF study; has participated in clinical trials and steering committees for Amgen and American Regent; and has received honoraria for clinical trials, speaking, and consulting for her or her institution from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Pfizer. Drs. Prescott, Chiang, Rizkala, Shi, and Lefkowitz are employees of Novartis. Dr. Pfeffer has received consulting fees from AstraZeneca, DalCor, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz, MyoKardia, Servier, Takeda, and Corvidia. Dr. Shah has received grants from the National Institutes of Health (R01 HL140731, R01 HL120728, R01 HL107577, and R01 HL149423), American Heart Association, Actelion, AstraZeneca, Corvia, and Novartis; and has received consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiora, Eisai, Ionis, Ironwood, Merck, Novartis, Pfizer, Sanofi, and United Therapeutics. Dr. Redfield has served as an unpaid consultant for Novartis. Dr. Zannad has received personal fees from Janssen, Novartis, Bayer, Boston Scientific, Amgen, CVRx, Boehringer Ingelheim, AstraZeneca, Vifor Fresenius, Cardior Pharmaceuticals, Cerno Pharmaceuticals, Applied Therapeutics, and Merck; and has received other payments from CVCT and Cardiorenal. Dr. Rouleau has received personal fees from Novartis and AstraZeneca. Dr. McMurray has consulted for Bayer, Cardiorentis, Amgen, Theracos, AbbVie, DalCor, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Vifor Fresenius, KRUK, and Novartis; all payments were made through a consultancy with Glasgow University and were not personal payments. Dr. Solomon has received grants and personal fees from Novartis, Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, MyoKardia, Theracos, and Cytokinetics; has received grants from Celladon, Bellerophon, Ionis, Lone Star Heart, Mesoblast, Eidos, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, and Sanofi Pasteur; and has received personal fees from Akros, Corvia, Ironwood, Merck, Roche, Takeda, Quantum Genomics, AOBiome, Janssen, Cardiac Dimensions, Tenaya, and Daiichi-Sankyo. Dr. Zile has received a grant from Novartis; and has received consulting fees from Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and MyoKardia V Wave.
Funding Information:
PARAGON-HF was sponsored by Novartis. Dr. Cunningham has received a National Heart, Lung, and Blood Institute T32 postdoctoral training grant (T32HL094301). Dr. Claggett has received consulting fees from AOBiome, Biogen, Boehringer Ingelheim, Corvia, Gilead, and MyoKardia. Dr. O’Meara has received HSFC grant for the Bio-AIMI-HF study; has participated in clinical trials and steering committees for Amgen and American Regent; and has received honoraria for clinical trials, speaking, and consulting for her or her institution from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Pfizer. Drs. Prescott, Chiang, Rizkala, Shi, and Lefkowitz are employees of Novartis. Dr. Pfeffer has received consulting fees from AstraZeneca, DalCor, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz, MyoKardia, Servier, Takeda, and Corvidia. Dr. Shah has received grants from the National Institutes of Health (R01 HL140731, R01 HL120728, R01 HL107577, and R01 HL149423), American Heart Association, Actelion, AstraZeneca, Corvia, and Novartis; and has received consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiora, Eisai, Ionis, Ironwood, Merck, Novartis, Pfizer, Sanofi, and United Therapeutics. Dr. Redfield has served as an unpaid consultant for Novartis. Dr. Zannad has received personal fees from Janssen, Novartis, Bayer, Boston Scientific, Amgen, CVRx, Boehringer Ingelheim, AstraZeneca, Vifor Fresenius, Cardior Pharmaceuticals, Cerno Pharmaceuticals, Applied Therapeutics, and Merck; and has received other payments from CVCT and Cardiorenal. Dr. Rouleau has received personal fees from Novartis and AstraZeneca. Dr. McMurray has consulted for Bayer, Cardiorentis, Amgen, Theracos, AbbVie, DalCor, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Vifor Fresenius, KRUK, and Novartis; all payments were made through a consultancy with Glasgow University and were not personal payments. Dr. Solomon has received grants and personal fees from Novartis, Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, MyoKardia, Theracos, and Cytokinetics; has received grants from Celladon, Bellerophon, Ionis, Lone Star Heart, Mesoblast, Eidos, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, and Sanofi Pasteur; and has received personal fees from Akros, Corvia, Ironwood, Merck, Roche, Takeda, Quantum Genomics, AOBiome, Janssen, Cardiac Dimensions, Tenaya, and Daiichi-Sankyo. Dr. Zile has received a grant from Novartis; and has received consulting fees from Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and MyoKardia V Wave.
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 -