Enhanced Ca ²⁺ Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular Myocytes

Abstract

Background-Ventricular arrhythmias are a major cause of sudden death in patients with heart failure and hypertrophy.The dog with chronic complete atrioventricular block (CAVB) has biventricular hypertrophy and ventricular arrhythmias and is a useful model to study underlying cellular mechanisms. We investigated whether changes in Ca 2ϩ homeostasis are part of the contractile adaptation to CAVB and might contribute to arrhythmogenesis. Methods and Results-In enzymatically isolated myocytes, cell shortening, Ca 2ϩ release from the sarcoplasmic reticulum (SR), and SR Ca 2ϩ content were enhanced at low stimulation frequencies. Ca 2ϩ influx through L-type Ca 2ϩ channels was unchanged, but Ca 2ϩ influx via the Na/Ca exchanger was increased and contributed to Ca 2ϩ loading of the SR. Inward Na/Ca exchange currents were also larger. Changes in Ca 2ϩ fluxes were less pronounced in the right versus left ventricle. Conclusions-Enhanced Na/Ca exchange activity may improve contractile adaptation to CAVB but at the same time facilitate arrhythmias by (1) increasing the propensity to Ca 2ϩ overload, (2) providing more inward current leading to (nonhomogeneous) action potential prolongation, and (3)

9–Anthracene carboxylic acid is more suitable than DIDS for characterization of calcium-activated chloride current during canine ventricular action potential

“…Moreover, the UV illumination used for intracellular calcium concentration measurements could degrade DIDS (Sipido et al 1993). The increase of calcium transients with high rate of stimulation is similar to what was presented by Sipido et al (2000). Moreover, the increase of calciumactivated chloride current was also demonstrated, even in the absence of any inhibitor (Sipido et al 1993).…”

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na + /Ca 2+ Exchanger in a Murine Model

“…2,3 However, others have suggested that DADs and EADs share a common mechanism that may be NCX dependent. 4 To date, the role of chronically altered NCX expression in the generation of arrhythmia has been limited to models with increased NCX expression 5 and to animal models of heart failure or hypertrophy 1,[6][7][8][9][10] in which NCX is known to be overexpressed. Yet, in heart failure, a multitude of proarrhythmic alterations other than the upregulation of NCX has been identified, 11 most importantly a reduction of K + currents 12,13 which promote a prolongation of AP duration and the occurrence of arrhythmia.…”

Dofetilide as Activator of Na/Ca Exchange: New Perspectives on an ‘Old’ Drug

“…Upregulation of NCX is one of the mechanisms in heart failure that reduces the SR content and thus contractility [21,22]. Upregulation of NCX is also seen as one of the major mechanisms contributing to the increased susceptibility to arrhythmias in heart failure [23,24].…”

“…I Kr blockers like dofetilide cause QT prolongation and enhance the susceptibility to triggered arrhythmias, one of the known risks. A higher NCX activity may further increase the likelihood of afterdepolarizations triggering ventricular arrhythmias [23,24]. Increasing Ca influx via reverse mode NCX promotes Ca overload and spontaneous Ca release.…”