Author + information
- Received October 23, 2018
- Revision received November 20, 2018
- Accepted December 10, 2018
- Published online March 11, 2019.
- Carmen C. Sucharov, PhDa,∗ (, )@CUAnschutz,
- Stephanie J. Nakano, MDb,
- Dobromir Slavov, PhDa,
- Jessica A. Schwisow, BSa,
- Erin Rodriguez, BSa,
- Karin Nunley, MSa,
- Allen Medway, MDa,
- Natalie Stafford, MPHa,
- Penny Nelson, MSa,
- Timothy A. McKinsey, PhDa,c,
- Matthew Movsesian, MDd,e,f,
- Wayne Minobe, BSa,
- Ian A. Carroll, PhDg,
- Matthew R.G. Taylor, MD, PhDa and
- Michael R. Bristow, MD, PhDa,g
- aDivision of Cardiology and Cardiovascular Institute, University of Colorado Denver, Aurora, Colorado
- bDepartment of Pediatrics, University of Colorado Denver, Children's Hospital Colorado, Aurora, Colorado
- cUniversity of Colorado Anschutz Medical Campus Consortium for Fibrosis Research & Translation, Aurora, Colorado
- dCardiology Section, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah
- eDepartment of Internal Medicine (Cardiovascular Medicine), University of Utah School of Medicine, Salt Lake City, Utah
- fDepartment of Pharmacology & Toxicology, University of Utah School of Medicine, Salt Lake City, Utah
- gARCA Biopharma, Westminster, Colorado
- ↵∗Address for correspondence:
Dr. Carmen C. Sucharov, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue P-15, Room 8003, Campus Box B-139, PO Box 6511, Aurora, Colorado 80045.
Background The phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit.
Objectives The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF.
Methods PDE3A promoter studies were performed in a cloned luciferase construct. In human left ventricular (LV) preparations, mRNA expression was measured by reverse transcription polymerase chain reaction, and PDE3 enzyme activity by cAMP-hydrolysis.
Results The authors identified a 29-nucleotide (nt) insertion (INS)/deletion (DEL) polymorphism in the human PDE3A gene promoter beginning 2,214 nt upstream from the PDE3A1 translation start site. Transcription factor ATF3 binds to the INS and represses cAMP-dependent promoter activity. In explanted failing LVs that were homozygous for PDE3A DEL and had been treated with PDE3i pre-cardiac transplantation, PDE3A1 mRNA abundance and microsomal PDE3 enzyme activity were increased by 1.7-fold to 1.8-fold (p < 0.05) compared with DEL homozygotes not receiving PDE3i. The basis for the selective up-regulation in PDE3A gene expression in DEL homozygotes treated with PDE3i was a cAMP response element enhancer 61 nt downstream from the INS, which was repressed by INS. The DEL homozygous genotype frequency was also enriched in patients with HF.
Conclusions A 29-nt INS/DEL polymorphism in the PDE3A promoter regulates cAMP-induced PDE3A gene expression in patients treated with PDE3i. This molecular mechanism may explain response heterogeneity to this drug class, and may inform a pharmacogenetic strategy for a more effective use of PDE3i in HF.
This work was supported by Leducq Foundation Transatlantic Networks of Excellence grant FLQ-06 CVD 02 to Drs. Bristow and Movsesian; National Institutes of Health (NIH) grant 2R01 HL48013 to Dr. Bristow; NIH grant R21 HL097123 and American Heart Association (AHA) grants 11IRG5070006 and 13GRNT16950045 to Dr. Sucharov; NIH grant T32 HL007822 and American Academy of Pediatric fellowship grant to Dr. Nakano; NIH (HL116848 and HL127240) and American Heart Association (16SFRN31400013) grants to Dr. McKinsey; the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (Merit Review grants CARA-029-09F and CARA-027-12S to Dr. Movsesian), and an American Heart Association (grant-in-aid to Dr. Movsesian); and ARCA Biopharma. Intellectual property relevant to this work has been licensed by the University of Colorado to ARCA Biopharma. Dr. Carroll is an employee of ARCA Biopharma. Dr. Taylor has been a consultant for Rocket Pharma, Protalix Pharma, Genzyme/Sanofi Pharma, Pfizer Pharma, Valerion Pharma, Allomek Pharma, Array Biopharma, and ARCA Biopharma. Dr. Bristow is an officer, director, and equity holder in ARCA Biopharma. 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 October 23, 2018.
- Revision received November 20, 2018.
- Accepted December 10, 2018.
- 2019 American College of Cardiology Foundation
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