Author + information
- Received April 20, 2020
- Revision received May 28, 2020
- Accepted May 28, 2020
- Published online July 27, 2020.
- Jonathan W. Cunningham, MDa,
- Brian L. Claggett, PhDa,
- Eileen O’Meara, MDb,
- Margaret F. Prescott, PhDc,
- Marc A. Pfeffer, MD, PhDa,
- Sanjiv J. Shah, MDd,
- Margaret M. Redfield, MDe,
- Faiez Zannad, MD, PhDf,
- Lu-May Chiang, PhDc,
- Adel R. Rizkala, PharmDc,
- Victor C. Shi, MDc,
- Martin P. Lefkowitz, MDc,
- Jean Rouleau, MDb,
- John J.V. McMurray, MDg,
- Scott D. Solomon, MDa,∗ (, )@scottdsolomon and
- Michael R. Zile, MDh,i,∗∗ ()
- aCardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- bMontreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
- cNovartis, East Hanover, New Jersey
- dNorthwestern University Feinberg School of Medicine, Chicago, Illinois
- eMayo Clinic, Rochester, Minnesota
- fCentre d'Investigations Cliniques-Plurithématique 1433, and Institut National de la Santé et de la Recherche Médicale U1116, Centre Hospitalier Regional Universitaire, French Clinical Research Infrastructure Network, Investigation Network Initiative Cardiovascular and Renal Clinical Trialists, Nancy, France
- gBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- hRalph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina
- iDivision of Cardiology, Medical University of South Carolina, Charleston, South Carolina
- ↵∗Address for correspondence:
Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
- ↵∗∗Dr. Michael R. Zile, Division of Cardiology, Medical University of South Carolina, Thurmond/Gazes Building, Room 323, 30 Courtenay Drive, Charleston, South Carolina 29425.
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)
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.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received April 20, 2020.
- Revision received May 28, 2020.
- Accepted May 28, 2020.
- 2020 The Authors