Author + information
- Received May 27, 2019
- Revision received July 15, 2019
- Accepted July 16, 2019
- Published online December 23, 2019.
- Bo Bai, PhDa,b,
- Wulin Yang, PhDc,d,
- Yanyun Fu, PhDa,
- Hannah Lee Foon, SWA, PhDe,
- Wan Ting Tay, MAppStatf,
- Kangmin Yang, PhDb,
- Cuiting Luo, BSb,
- Jayantha Gunaratne, PhDe,
- Philip Lee, PhDa,
- Michael R. Zile, MDg,h,
- Aimin Xu, PhDb,i,
- Calvin W.L. Chin, MD, PhDf,
- Carolyn S.P. Lam, MD, PhDf,∗∗∗ (, )
- Weiping Han, PhDa,∗∗ ( and )
- Yu Wang, PhDb,∗ ()
- aSingapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore
- bState Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- cAnhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- dHefei Cancer Hospital, Chinese Academy of Sciences, Hefei, China
- eTranslational Biomedical Proteomics, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
- fNational Heart Centre Singapore and Duke-National University of Singapore, Singapore
- gDivision of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- hRalph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina
- iDepartment of Medicine, The University of Hong Kong, Hong Kong, China
- ↵∗Address for correspondence:
Dr. Yu Wang, Department of Pharmacology and Pharmacy, The University of Hong Kong, Sassoon Road 21, Hong Kong, China.
- ↵∗∗Dr. Weiping Han, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, 11 Biopolis Way, Singapore.
- ↵∗∗∗Dr. Carolyn S.P. Lam, National Heart Centre Singapore and Duke-National University of Singapore, 5 Hospital Drive, Singapore.
• The lean diabetic SKO mouse represents a novel and validated murine model of HFpEF.
• The SKO HFpEF mouse model recapitulates the cardiac structure and function abnormalities in lean diabetic HFpEF patients in Asia.
• Altered cellular titin phosphorylation and increased extracellular interstitial fibrosis associated with neutrophil extracellular traps contribute to the left ventricular stiffness.
• Metabolic disturbances arising from insulin resistance and diabetes in the absence of hypertension or obesity may lead to HFpEF.
The lean diabetic patients with heart failure with preserved ejection fraction (HFpEF) in Asia suffer from adverse clinical outcomes and poor life quality. The suitable animal models are urgently needed for mechanistic study and therapeutic innovations. Our study reports that lipodystrophic mice with seipin depletion are lean, diabetic, and recapitulate major manifestations of clinical HFpEF, thereby clarifying that lean diabetes per se may produce HFpEF characteristics. We further demonstrate that increased cardiac titin phosphorylation and reactive interstitial fibrosis associated with neutrophil extracellular traps lead to left ventricular stiffness and suggest that both pathways may be potential therapeutic targets in Asian HFpEF patients.
This work is support by the Agency for Science, Technology and Research Biomedical Research Council, Bayer and the Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT) Biomedical Research Council program (SPF2014/001, SPF2013/002, SPF2014/003, SPF2014/004, SPF2014/005); Research Grant Council grants (17121714) and Collaborative Research Funds (C7055-14G) of Hong Kong; the U.S. National Institutes of Health grants (1R01HL123478-01A1, NIH-NHLBI); and the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) study is further supported by grants from Boston Scientific Investigator Sponsored Research Program, National Medical Research Council Singapore (R-172-003-219-511), and Bayer. Dr. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, WebMD Global LLC, Radcliffe Group Ltd and Corpus;and participated on behalf of the ASIAN-HF investigators. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Membership of ASIAN-HF authors is provided in the Supplemental Appendix.
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 May 27, 2019.
- Revision received July 15, 2019.
- Accepted July 16, 2019.
- 2019 The Authors