Author + information
- Received March 17, 2020
- Revision received July 13, 2020
- Accepted July 13, 2020
- Published online September 28, 2020.
- Dominique Croteau, MS∗,
- Fuzhong Qin, MD, PhD∗,
- Jordan M. Chambers, PhD,
- Ethan Kallick, MS,
- Ivan Luptak, MD, PhD,
- Marcello Panagia, MD, PhD,
- David R. Pimentel, MD,
- Deborah A. Siwik, PhD and
- Wilson S. Colucci, MD∗ ()
- Cardiovascular Medicine Section and Myocardial Biology Unit, Boston University School of Medicine, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Wilson S. Colucci, Cardiovascular Medicine Section, Boston University Medical Center, 72 East Concord Street, Boston, Massachusetts 02118.
• MHD associated with obesity, diabetes, and/or metabolic syndrome is an important precursor of HFpEF.
• Mice fed a HFHS diet develop MHD with myocardial hypertrophy, fibrosis, diastolic dysfunction, and impaired energetics.
• Mice on HFHS diet were treated with matched doses of VAL or sac SAC/VAL for 16 weeks.
• Only SAC/VAL prevented diastolic dysfunction and fibrosis, and to a lesser extent oxidative stress, whereas VAL and SAC/VAL had similar effects on hypertrophy and energetics.
• Neprilysin inhibition exerts beneficial effects on MHD that are complimentary to VAL, suggesting that SAC/VAL has promise to prevent the development of HFpEF in patients with or at risk for MHD.
Mice with obesity and metabolic heart disease (MHD) due to a high-fat, high-sucrose diet were treated with placebo, a clinically relevant dose of sacubitril (SAC)/valsartan (VAL), or an equivalent dose of VAL for 4 months. There were striking differences between SAC/VAL and VAL with regard to: 1) diastolic dysfunction; 2) interstitial fibrosis; and to a lesser degree; 3) oxidative stress—all of which were more favorably affected by SAC/VAL. SAC/VAL and VAL similarly attenuated myocardial hypertrophy and improved myocardial energetics. In mice with obesity-related MHD, neprilysin inhibition exerts favorable effects on diastolic function.
↵∗ Ms. Croteau and Dr. Qin contributed equally to this work and are joint first authors.
Supported by funds from a Novartis investigator-initiated trial (SAC/VAL696BUSNC22T) to Dr. Colucci; National Institutes of Health grants HL-064750 (Dr. Colucci) and K08 HL123744 (Dr. Panagia); and an American Heart Association Fellow-to-Faculty Award 15FTF25890062 (Dr. Luptak). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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: Basic to Translational Science author instructions page.
- Received March 17, 2020.
- Revision received July 13, 2020.
- Accepted July 13, 2020.
- 2020 The Authors