Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity

• Type of Material: Article
• Authors: Joshua D. Lovelock, University of Illinois at Chicago; Michelle M. Monasky, University of Illinois at Chicago; Euy-Myoung Jeong, University of Illinois at Chicago; Harvey A. Lardin, University of Illinois at Chicago; Hong Liu, University of Illinois at Chicago; Bindiya G. Patel, University of Illinois at Chicago; Domenico M. Taglieri, University of Illinois at Chicago; Lianzhi Gu, University of Illinois at Chicago; Praveen Kumar, University of Illinois at Chicago; Narayan Pokhrel, University of Illinois at Chicago; Dewan Zeng, Gilead; Luiz Belardinelli, Gilead; Dan Sorescu, Emory University; R. John Solaro, University of Illinois at Chicago; Samuel C. Dudley, University of Illinois at Chicago
• Language: English
• Date: 2012-03-16
• Publisher: Lippincott Williams and Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCRESAHA.111.258251
• Title of Journal or Parent Work: Circulation Research
• Volume: 110
• Issue: 6
• Start Page: 841
• End Page: U114
• Grant/Funding Information: Sources of Funding SCD: R01 HL085558, R01 HL073753, P01 HL058000, and a Veterans Affairs MERIT grant.; RJS: RO1 HL022231, RO1 HL064035, PO1 HL062426; JDL, MM: T32 HL007692.; DS: R01 HL090851, ARRA supplement R01HL090851-02S1.
• Keywords: Cardiac & Cardiovascular Systems; CONTRACTILE DYSFUNCTION; diastole; RAT VENTRICULAR MYOCYTES; BINDING-PROTEIN-C; Science & Technology; Life Sciences & Biomedicine; Hematology; oxidative stress; Cardiovascular System & Cardiology; ranolazine; myofilaments; PRESERVED EJECTION FRACTION; LATE SODIUM CURRENT; HYDROGEN-PEROXIDE; ANGINA-PECTORIS; Peripheral Vascular Disease; FORCE DECLINE; SKELETAL TROPONIN-I; HEART-FAILURE

Abstract

Rationale: Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I Na), reducing the net cytosolic Ca 2+ efflux. Objective: Oxidative stress in the DOCA-salt model may increase late I Na, resulting in diastolic dysfunction amenable to treatment with ranolazine. Methods and Results: Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E′:sham, 31.9±2.8, sham+ranolazine, 30.2±1.9, DOCA-salt, 41.8±2.6, and DOCA-salt+ranolazine, 31.9±2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16±0.01 versus sham+ranolazine, 0.18±0.01 versus DOCA-salt, 0.23±0.2 versus DOCA-salt+ranolazine, 0.17±0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18±0.02, DOCA-salt+ranolazine, 0.13±0.01, sham, 0.11±0.01, sham+ranolazine, 0.09±0.02 seconds; P=0.0004). Neither late I Na nor the Ca 2+ transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca 2+ with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca 2+ response and cross-bridge kinetics. Conclusions: Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.