Early subcellular Ca²⁺ remodelling and increased propensity for Ca²⁺ alternans in left atrial myocytes from hypertensive rats

Hypertension is a major risk factor for atrial fibrillation. We hypothesized that arterial hypertension would alter atrial myocyte calcium (Ca²⁺) handling and that these alterations would serve to trigger atrial tachyarrhythmias.

Left atria or left atrial (LA) myocytes were isolated from spontaneously hypertensive rats (SHR) or normotensive Wistar-Kyoto (WKY) controls. Early after the onset of hypertension, at 3 months of age, there were no differences in Ca²⁺ transients (CaTs) or expression and phosphorylation of Ca²⁺ handling proteins between SHR and WKY. At 7 months of age, when left ventricular (LV) hypertrophy had progressed and markers of fibrosis were increased in left atrium, CaTs (at 1 Hz stimulation) were still unchanged. Subcellular alterations in Ca²⁺ handling were observed, however, in SHR atrial myocytes including (i) reduced expression of the α1C subunit of and reduced Ca²⁺ influx through L-type Ca²⁺ channels, (ii) reduced expression of ryanodine receptors with increased phosphorylation at Ser2808, (iii) decreased activity of the Na⁺/Ca²⁺ exchanger (at unaltered intracellular Na⁺ concentration), and (iv) increased SR Ca²⁺ load with reduced fractional release. These changes were associated with an increased propensity of SHR atrial myocytes to develop frequency-dependent, arrhythmogenic Ca²⁺ alternans.

In SHR, hypertension induces early subcellular LA myocyte Ca²⁺ remodelling during compensated LV hypertrophy. In basal conditions, atrial myocyte CaTs are not changed. At increased stimulation frequency, however, SHR atrial myocytes become more prone to arrhythmogenic Ca²⁺ alternans, suggesting a link between hypertension, atrial Ca²⁺ homeostasis, and development of atrial tachyarrhythmias.