Author + information
- Received September 28, 2018
- Revision received November 8, 2018
- Accepted November 13, 2018
- Published online February 18, 2019.
- Michael R. Zile, MDa,∗ (, )@MUSChealth,
- Eileen O'Meara, MDb,
- Brian Claggett, PhDc,
- Margaret F. Prescott, PhDd,
- Scott D. Solomon, MDc,
- Karl Swedberg, MDe,
- Milton Packer, MDf,
- John J.V. McMurray, MDg,
- Victor Shi, MDd,
- Martin Lefkowitz, MDd and
- Jean Rouleau, MDb
- aMedical University of South Carolina and Department of Veterans Affairs Medical Center, Charleston, South Carolina
- bMontreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada
- cBrigham and Women's Hospital, Boston, Massachusetts
- dNovartis Pharmaceuticals Corporation, East Hanover, New Jersey
- eUniversity of Gothenburg, Gothenburg, Sweden
- fBaylor University Medical Center, Dallas, Texas
- gUniversity of Glasgow, Glasgow, United Kingdom
- ↵∗Address for correspondence:
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 is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of sacubitril/valsartan, we hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by sacubitril/valsartan in comparison to enalapril.
Objectives The purpose of this study was to examine the effects of sacubitril/valsartan on biomarkers of ECM homeostasis and the association between the rate of primary composite outcome (cardiovascular death or HF hospitalization) and these biomarkers.
Methods Biomarkers at baseline (n = 2,067) and both baseline and 8 months after randomization (n = 1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP), and N-terminal propeptide of collagen III (PIIINP). The effects of sacubitril/valsartan on biomarkers were compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to primary outcome.
Results At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9, PINP, and PIIINP had decreased more in the sacubitril/valsartan than enalapril group. At baseline, higher values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes.
Conclusions Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection fraction, sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have important prognostic value. These findings suggest that sacubitril/valsartan may reduce profibrotic signaling, which may contribute to the improved outcomes. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255)
Dr. Zile has performed research sponsored by Novartis; and has received consulting fees from Novartis for participating in Executive Steering Committee activities for clinical studies. Dr. O’Meara has been performing research sponsored by Novartis, Bayer, AstraZeneca, Merck, Servier, and Amgen; and has received personal and/or institutional consulting and conference fees from Novartis, Pfizer, Servier, AstraZeneca, and Bayer. Drs. Prescott, Lefkowitz, and Shi are employees of Novartis Pharmaceuticals Corporation. Dr. Prescott owns Novartis stock granted as part of his salary. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has served as a consultant for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, and Cardiac Dimensions. Drs. Solomon, Swedberg, Packer, McMurray, and Rouleau have participated in Executive Steering Committee activities for clinical studies sponsored by Novartis. Dr. Packer has served as a consultant for Akcea, Amgen, AstraZeneca, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Novo Nordisk, Relypsa, Sanofi, and Synthetic Biologics. Dr. McMurray’s employer, Glasgow University, has been paid by Novartis for his time spent as Executive Committee member and then co-principal investigator of ATMOSPHERE, co-principal investigator of the PARADIGM-HF and PARAGON-HF trials, and Executive/Steering Committee member for PARADISE-MI and PERSPECTIVE trials (with sacubitril/valsartan), and meetings/presentations related to these trials, aliskiren, and sacubitril/valsartan; his travel and accommodation for some of these meetings has also been paid by Novartis (these payments were made through a consultancy with Glasgow University, and Dr. McMurray has not received personal payments in relation to these trials/drugs). Dr. Rouleau has served as a consultant to Novartis and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received September 28, 2018.
- Revision received November 8, 2018.
- Accepted November 13, 2018.
- 2019 American College of Cardiology Foundation
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