Chronic Sympathetic Hyperactivity Triggers Electrophysiological Remodeling and Disrupts Excitation-Contraction Coupling in Heart

Author(s)

Joca, Humberto C. ^{[1, 2]} ; Santos-Miranda, Artur ^{[1, 3]} ; Joviano-Santos, V, Julliane ; Maia-Joca, Rebeca P. M. ^[1] ; Brum, Patricia C. ^[4] ; Williams, George S. B. ^[2] ; Cruz, Jader S. ^[1]

Affiliation

^[1] Univ Fed Minas Gerais, Inst Biol Sci, Dept Biochem & Immunol, Belo Horizonte, MG - Brazil

^[2] Univ Maryland, Sch Med, Ctr Biomed Engn & Technol, Baltimore, MD 21201 - USA

^[3] V, Univ Fed Sao Paulo, Dept Biophys, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1 MAY 14 2020.
• Web of Science Citations: 1

Abstract

The sympathetic nervous system is essential for maintenance of cardiac function via activation of post-junctional adrenergic receptors. Prolonged adrenergic receptor activation, however, has deleterious long-term effects leading to hypertrophy and the development of heart failure. Here we investigate the effect of chronic adrenergic receptors activation on excitation-contraction coupling (ECC) in ventricular cardiomyocytes from a previously characterized mouse model of chronic sympathetic hyperactivity, which are genetically deficient in the adrenoceptor alpha 2A and alpha 2C genes (ARDKO). When compared to wild-type (WT) cardiomyocytes, ARDKO displayed reduced fractional shortening (similar to 33%) and slower relaxation (similar to 20%). Furthermore, ARDKO cells exhibited several electrophysiological changes such as action potential (AP) prolongation (similar to 50%), reduced L-type calcium channel (LCC) current (similar to 33%), reduced outward potassium (K+) currents (similar to 30%), and increased sodium/calcium exchanger (NCX) activity (similar to 52%). Consistent with reduced contractility and calcium (Ca2+) currents, the cytosolic Ca2+ ({[}Ca2+](i)) transient from ARDKO animals was smaller and decayed slower. Importantly, no changes were observed in membrane resting potential, AP amplitude, or the inward K+ current. Finally, we modified our existing cardiac ECC computational model to account for changes in the ARDKO heart. Simulations suggest that cellular changes in the ARDKO heart resulted in variable and dyssynchronous Ca2+-induced Ca2+ release therefore altering {[}Ca2+](i) transient dynamics and reducing force generation. In conclusion, chronic sympathetic hyperactivity impairs ECC by changing the density of several ionic currents (and thus AP repolarization) causing altered Ca2+ dynamics and contractile activity. This demonstrates the important role of ECC remodeling in the cardiac dysfunction secondary to chronic sympathetic activity. (AU)

• FAPESP's process: 18/20777-3 - Genetic variants of the Nav 1.5 sodium channel and its therapeutic implications.
• Grantee: Julliane Vasconcelos Joviano dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/22830-9 - Involvement of the Ca2+/ Calmodulin/CAMKII signaling axis in the electrical and contractile dysfunctions of the heart in the chronic phase of Chagas Disease
• Grantee: Artur Santos Miranda
• Support Opportunities: Scholarships in Brazil - Post-Doctoral