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

• Published in: Cardiovascular research Vol. 106; no. 1; pp. 87 - 97
• Main Authors: Pluteanu, Florentina, Heß, Johannes, Plackic, Jelena, Nikonova, Yulia, Preisenberger, Judit, Bukowska, Alicja, Schotten, Ulrich, Rinne, Andreas, Kienitz, Marie-Cecile, Schäfer, Martin K-H, Weihe, Eberhard, Goette, Andreas, Kockskämper, Jens
• Format: Journal Article
• Language: English
• Published: England 01-04-2015
• Subjects: Animals; Arrhythmias, Cardiac - epidemiology; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Atrial Remodeling - physiology; Calcium - metabolism; Calcium Channels, L-Type - metabolism; Disease Models, Animal; Heart Atria - metabolism; Heart Atria - pathology; Hypertension - metabolism; Hypertension - pathology; Male; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Patch-Clamp Techniques; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Risk Factors; Sarcoplasmic Reticulum - metabolism; Sodium - metabolism; Sodium-Calcium Exchanger - metabolism; Tachycardia - epidemiology; Tachycardia - metabolism; Tachycardia - physiopathology; Hypertension; Atrium; Alternans; Calcium
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvv045

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.