31 Jan Cancer Drug May Improve Complicated Form of Heart Failure
MedicalResearch.com Interview with:
Steven R. Houser, PhD, FAHA
Senior Associate Dean, Research
Vera J. Goodfriend Endowed Chair, Cardiovascular Research
Chair and Professor, Physiology
Director, Cardiovascular Research Center (CVRC)
Deborah M Eaton
Doctorate Student / Research Assistant
MedicalResearch.com: What is the background for this study?
Response: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately 50% of cases of HF and to date clinical trials with HFpEF patients have failed to produce positive outcomes. Part of this is likely due to the lack of HFpEF animal models for preclinical testing. Our lab addressed this gap in knowledge by developing an animal model that mimics critical features of the human HFpEF phenotype. We performed an in-depth cardiopulmonary characterization highlighting that the model has characteristics of human disease. We then tested the effects of a pan-HDAC inhibitor, vorinostat/SAHA, in collaboration with Dr. Timothy McKinsey, who is an expert in HDAC inhibitors and recently published work1 that laid the foundation for this study.
MedicalResearch.com: What are the main findings?
Response: In our model of HFpEF, treatment with pan-HDAC inhibition had a profound impact including:
- anti-hypertrophic effects: left ventricle hypertrophy was reduced in animals with pressure overload (similar to hypertension) and established left ventricle hypertrophy was partially reversed.
- improved isovolumic relaxation, decreased left ventricular filling pressures and left atrial size
- Decreased pulmonary arterial pressure, improved lung compliance and function, and preserved lung structure
- Switch in skeletal muscle fiber composition with a significant increase in the percentage of type 1 muscle fibers. Type 1 fibers have a higher oxidative capacity compared to type 2 fibers and are known to be reduced in patients with HFpEF
- Myofibril relaxation is an HDAC-dependent mechanism for diastolic dysfunction and is restored with SAHA treatment
We also performed in vitro studies and found that HDAC inhibition directly modified mitochondrial function, which suggests that modulation of mitochondria function via HDAC inhibition can explain certain aspects of our in vivo results. The changes we observed in mitochondria function and metabolism correlated with associated post-translational modifications, which were assessed via acetylation proteomics. These changes help restore the energy supply needed to fuel the failing heart.
MedicalResearch.com: What should readers take away from your report?
Response: HFpEF is a complex syndrome with no proven therapies, but we have developed a large animal model that recapitulates key features of the cardiopulmonary HFpEF phenotype and tested a potential new therapy with very positive results. Pan-HDAC inhibition greatly improved the cardiopulmonary phenotype and also mediated improvements in mitochondrial function.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The drug we tested is a pan-HDAC inhibitor which means it has a very broad range of targets. We are looking into testing more specific HDAC inhibitors to see if narrowing the range of targets is beneficial in the HFpEF phenotype.
We have no disclosures.
- Jeong MY, Lin YH, Wennersten SA, Demos-Davies KM, Cavasin MA, Mahaffey JH, Monzani V, Saripalli C, Mascagni P, Reece TB, Ambardekar AV, Granzier HL, Dinarello CA and McKinsey TA. Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci Transl Med. 2018;10.
2. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction
BY MARKUS WALLNER, DEBORAH M. EATON, REMUS M. BERRETTA, LAURA LIESINGER, MATTHIAS SCHITTMAYER, JUERGEN GINDLHUBER, JICHUAN WU, MARK Y. JEONG, YING H. LIN, GIULIA BORGHETTI, SANDY T. BAKER, HUAQING ZHAO, JESSICA PFLEGER, SANDRA BLASS, PETER P. RAINER, DIRK VON LEWINSKI, HEIKO BUGGER, SADIA MOHSIN, WOLFGANG F. GRAIER, ANDREAS ZIRLIK, TIMOTHY A. MCKINSEY, RUTH BIRNER-GRUENBERGER, MARLA R. WOLFSON, STEVEN R. HOUSER
SCIENCE TRANSLATIONAL MEDICINE08 JAN 2020
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