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Sharp TE, Kubo H, Berretta RM, et al. Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction. JACC Basic Transl Sci. 2017;2(6):669-683doi: 10.1016/j.jacbts.2017.06.007.
Sharp, T. E., Kubo, H., Berretta, R. M., Starosta, T., Wallner, M., Schena, G. J., Hobby, A. R., Yu, D., Trappanese, D. M., George, J. C., Molkentin, J. D., & Houser, S. R. (2017). Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction. JACC. Basic to translational science, 2(6), 669-683. https://doi.org/10.1016/j.jacbts.2017.06.007
Sharp, Thomas E, et al. "Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction." JACC. Basic to translational science vol. 2,6 (2017): 669-683. doi: https://doi.org/10.1016/j.jacbts.2017.06.007
Sharp TE, Kubo H, Berretta RM, Starosta T, Wallner M, Schena GJ, Hobby AR, Yu D, Trappanese DM, George JC, Molkentin JD, Houser SR. Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction. JACC Basic Transl Sci. 2017 Dec 25;2(6):669-683. doi: 10.1016/j.jacbts.2017.06.007. eCollection 2017 Dec. PMID: 30062182; PMCID: PMC6058945.
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JACC Basic Transl Sci. 2017 Dec 25;2(6):669-683. doi: 10.1016/j.jacbts.2017.06.007. eCollection 2017 Dec.

Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction.

JACC. Basic to translational science

Thomas E Sharp, Hajime Kubo, Remus M Berretta, Timothy Starosta, Markus Wallner, Giana J Schena, Alexander R Hobby, Daohai Yu, Danielle M Trappanese, Jon C George, Jeffery D Molkentin, Steven R Houser

Affiliations

  1. Cardiovascular Research Center, Department of Physiology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania.
  2. Department Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  3. Department of Clinical Sciences, Temple Clinical Research Institute, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania.
  4. Department of Cardiology, Temple University Hospital, Philadelphia, Pennsylvania.
  5. Department of Pediatrics and Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

PMID: 30062182 PMCID: PMC6058945 DOI: 10.1016/j.jacbts.2017.06.007

Abstract

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.

Keywords: ADHF, acute decompensated heart failure; DIG, digitalis; DOB, dobutamine; ECG, electrocardiogram; EDPVR, end-diastolic pressure-volume relationship; EDV, end-diastolic volume; ESPVR, end-systolic pressure-volume relationship; ESV, end-systolic volume; Ees, elastance end-systole; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; IR, ischemia–reperfusion; LAD, left anterior descending coronary artery; LV, left ventricle/ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVVPed10, left ventricular end-diastolic volume at a pressure of 10 mm Hg; LVVPes80, left ventricular end- systolic volume at a pressure of 80 mm Hg; MI, myocardial infarction; PKA, protein kinase A; PKC, protein kinase C; PKCα/β inhibitor; PLN, phospholamban; PRSW, pre-load recruitable stroke work; RBX, ruboxistaurin; acute myocardial infarction; heart failure with reduced ejection fraction; invasive hemodynamics; positive inotropy

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