Cellular Hypertrophy and Increased Susceptibility to Spontaneous Calcium-Release of Rat Left Atrial Myocytes Due to Elevated Afterload

Abstract

Atrial remodeling due to elevated arterial pressure predisposes the heart to atrial fibrillation (AF). Although abnormal sarcoplasmic reticulum (SR) function has been associated with AF, there is little information on the effects of elevated afterload on atrial Ca2+-handling. We investigated the effects of ascending aortic banding (AoB) on Ca2+-handling in rat isolated atrial myocytes in comparison to age-matched sham-operated animals (Sham). Myocytes were either labelled for ryanodine receptor (RyR) or loaded with fluo-3-AM and imaged by confocal microscopy. AoB myocytes were hypertrophied in comparison to Sham controls (P<0.0001). RyR labeling was localized to the z-lines and to the cell edge. There were no differences between AoB and Sham in the intensity or pattern of RyR-staining. In both AoB and Sham, electrical stimulation evoked robust SR Ca2+-release at the cell edge whereas Ca2+ transients at the cell center were much smaller. Western blotting showed a decreased L-type Ca channel expression but no significant changes in RyR or RyR phosphorylation or in expression of Na+/Ca2+ exchanger, SR Ca2+ ATPase or phospholamban. Mathematical modeling indicated that [Ca2+]i transients at the cell center were accounted for by simple centripetal diffusion of Ca2+ released at the cell edge. In contrast, caffeine (10 mM) induced Ca2+ release was uniform across the cell. The caffeine-induced transient was smaller in AoB than in Sham, suggesting a reduced SR Ca2+-load in hypertrophied cells. There were no significant differences between AoB and Sham cells in the rate of Ca2+ extrusion during recovery of electrically-stimulated or caffeine-induced transients. The incidence and frequency of spontaneous Ca2+-transients following rapid-pacing (4 Hz) was greater in AoB than in Sham myocytes. In conclusion, elevated afterload causes cellular hypertrophy and remodeling of atrial SR Ca2+-release.

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

“…Moreover, the increase in current density produced by inhibition of serine/threonine protein phosphatase activity with calyculin A provides evidence of phosphorylation-dependent basal regulation of I CaL in both groups of cells. In these respects, the data resemble those reported by Dinanian et al in human atrial myocytes from patients with heart failure (19) and by Boixel et al in a model of coronary artery ligation-induced heart failure in rats similar to that used in the present study (4) and contrast with studies of chronic hypertension and pressure overload in rats that show a reduction in atrial ␣ 1c subunit protein expression (38,51). However, contrary to the mechanism proposed by Boixel et al (4), the insensitivity of basal I CaL to H-89 and PKI in the present study demonstrated that protein kinase A did not contribute to the constitutive regulation of atrial I CaL .…”

“…Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained (10,13,22,29,30,32,34,48). In addition to atrial enlargement, fibrosis and conduction abnormalities that establish a substrate for reentry, cellular remodeling involving cellular hypertrophy, changes in membrane structure, and abnormal expression and function of ion channels and transporters are also likely to contribute to the genesis of AF (4,10,13,15,16,18,22,26,29,30,32,34,35,38,48,51).…”

“…Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained (10,13,22,29,30,32,34,48). In addition to atrial enlargement, fibrosis and conduction abnormalities that establish a substrate for reentry, cellular remodeling involving cellular hypertrophy, changes in membrane structure, and abnormal expression and function of ion channels and transporters are also likely to contribute to the genesis of AF (4,10,13,15,16,18,22,26,29,30,32,34,35,38,48,51).Atrial L-type Ca 2ϩ current (I CaL ) is reduced in heart disease, both in animal models (4,13,29,38) and in myocytes from human dilated atria (19,33). The loss of I CaL has been suggested to have a number of sequelae that contribute to the genesis of AF, including 1) changes in action potential configuration and the rate dependence of refractoriness, 2) abnormalities in Ca 2ϩ handling and the triggering of episodes of AF, and 3) hypocontractility and dilatation of the atria (15,29,33,35,42).…”

Aging Modulates the Substrate and Triggers Remodeling in Atrial Fibrillation

“…19 In a rat model hypertrophic LA myocytes had a high arrhythmogenic potential with greater incidence and frequency of spontaneous Ca 2+ -transients. 20 Connexin Modification Gap junctions are composed of narrow membrane channels that permit small molecules to diffuse intercellularly. In rat ventricular cardiomyocytes, gap junctions provide low-resistance electrical coupling between adjacent cardiac myocytes.…”

The Effect of Various Cardiac Rehabilitation Programs on Cardiac Dimensions of Post-CABG Patients

“…Third, a stretch of cardiac myocytes causes the activation of ion channels that induce increased Ca 2+ influx, which may in turn activate downstream pathways and serve as an intracellular signal of hypertrophy and gene regulation (31). In addition, stretch of cardiac myocytes increases the concentration of Ang II and ET-1 in the conditioning medium and stimulates protein synthesis and gene expression associated with mitogen-activated protein Kinase activity (32).…”