ROLE OF SODIUM/CALCIUM EXCHANGER IN CARDIAC ALTERNANS DEVELOPMENT IN SHR HEARTS

TORRES JB; DI MARZIO GD; MARIANGELO JIE; MUNDIÑA - WEILENMANN C; SAID M

Mendoza

Congreso; Congreso anual de la International Society for Heart Research Latinamerican Section; 2023

International Society for Heart Research (ISHR) Lat Section y Federación Argentina de Cardiología

Introduction. Cardiac alternans is a clinical condition observed in patients with different cardiac diseases and is thought to be a precursor to life-threatening arrhythmias. At cellular level, alternans describe the cyclic, beat-to-beat oscillations of action potential duration, amplitude of contraction or amplitude of the cytosolic calcium (Ca) transient at a constant heart rate. Experimental evidencesuggests that cardiac alternans are ultimately caused by disturbances of intracellular Ca handling. In general, factors that favor cytosolic Ca removal during excitation-contraction-coupling, rescue from alternans, whereas those that cause Ca impairment promote them. The sodium-calcium exchanger (NCX), is the primary mechanism which extrudes Ca from the cell. However, NCX could also contribute to Ca entry (reverse mode) depending on the membrane potential and ionic concentrations. We have demonstrated that the hypertrophied myocardium of spontaneously hipertensive rats (SHR) is prone to cardiac alternans. Myocytes from this strain have increased intracellular sodium (Na) and Ca concentrations, which could influence the activity of NCX. Objectives. We investigated how pharmacological inhibition of the reverse mode of NCX affects the occurrence of pacing-induced mechanical alternans in SHR hearts. Material & Methods. Alternans was elicited by increasing stimulation frequency from 4 Hz (basal) to 8.5 Hz in 6 months SHR hearts, perfused in the absence or presence of 5 μM KBR, a reverse mode of NCX inhibitor. Results KBR treatment reduced the frequency threshold for the appearance of mechanical alternans with respect to untreated hearts (6.8 ± 0.5 vs. 8.0 ± 0.3 Hz, respectively, n = 5-8). At 8.5 Hz, the magnitude of alternans, quantified as alternans ratio (AR), was significantly higher in the presence of KBR (AR: 0.53 ± 0.09 vs 0.11 ± 0.03 without the inhibitor, p< 0.05, n = 3- 5). Cardiac function, evaluated by left ventricular developed pressure, decreased as heart rate increased and this negative force-frequency relationship was more pronounced in the presence of KBR (42.06 ± 6.1 mmHg vs 80.04 ± 6.30 mmHg without treatment, p< 0.05, n = 3-6). Conclusion. The present results support a prominent role played by NCX in modulating the hypertrophied myocardium alternans in SHR. These findings point to NCX as a potential target for preventing cardiac alternans, substrate for lethal arrhythmias.