Author + information
- Thomas E. Sharp III, BAa,
- Hajime Kubo, PhDa,
- Remus M. Berretta, BSa,
- Timothy Starosta, BSb,
- Markus Wallner, MD, PhDa,
- Giana J. Schena, BSa,
- Alexander R. Hobby, BSa,
- Daohai Yu, PhDc,
- Danielle M. Trappanese, PhDa,
- Jon C. George, MDa,d,
- Jeffery D. Molkentin, PhDe and
- Steven R. Houser, PhDa,∗ ()
- aCardiovascular Research Center, Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- bDepartment Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- cDepartment of Clinical Sciences, Temple Clinical Research Institute, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
- dDepartment of Cardiology, Temple University Hospital, Philadelphia, Pennsylvania
- eDepartment of Pediatrics and Howard Hughes Medical Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- ↵∗Address for correspondence:
Dr. Steven R. Houser, Temple University, Lewis Katz School of Medicine, 3500 North Broad Street, Medical Education Research Building 10th Floor, Philadelphia, Pennsylvania 19140.
• Acute protein kinase A α (PKCα) inhibition with ruboxistaurin reduces heart size post-myocardial infarction.
• Acute PKCα inhibition with ruboxistaurin increases contractility post-myocardial infarction.
• PKCα phosphorylation at Thr638 is positively correlated to increases in left ventricular volumes and reduced ejection fraction, indicative of disease progression.
Inotropic support is often required to stabilize the hemodynamics of patients with acute decompensated heart failure; while efficacious, it has a history of leading to lethal arrhythmias and/or exacerbating contractile and energetic insufficiencies. Novel therapeutics that can improve contractility independent of beta-adrenergic and protein kinase A-regulated signaling, should be therapeutically beneficial. This study demonstrates that acute protein kinase C-α/β inhibition, with ruboxistaurin at 3 months’ post-myocardial infarction, significantly increases contractility and reduces the end-diastolic/end-systolic volumes, documenting beneficial remodeling. These data suggest that ruboxistaurin represents a potential novel therapeutic for heart failure patients, as a moderate inotrope or therapeutic, which leads to beneficial ventricular remodeling.
- acute myocardial infarction
- heart failure with reduced ejection fraction
- invasive hemodynamics
- PKCα/β inhibitor
- positive inotropy
This work was supported by the National Institutes of Health, NHLBI – Project Program Grant (5P01HL108806-04) (to Drs. Molkentin and Houser). Mr. Sharp received pre-doctoral fellowship funding from the American Heart Association (14PRE20450006). Eli Lilly & Company provided the drug (ruboxistaurin) to Dr. Molkentin for this current study. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All 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 16, 2017.
- Revision received May 10, 2017.
- Accepted June 20, 2017.