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.
Highlights
Atrial fibrillation (AF) is the most common sustained arrhythmia, represents a major risk factor for stroke and is associated with high morbidity and mortality[1]
Animal models have shown that hypertension and elevated afterload cause structural and cellular remodeling of the atria that establishes a substrate for re-entrant arrhythmias[3,4,5,6,7]
From confocal volume images the cell volume (Fig 1B), surface area (Fig 1C), volume/area ratio (Fig 1D), width (Fig 1E), depth (Fig 1F) and width/ depth ratio (Fig 1G) were calculated. These data show that left atrial (LA) myocytes from aortic banding (AoB) rats developed marked hypertrophy in comparison with cells from sham-operated animals (Sham) controls
Summary
Atrial fibrillation (AF) is the most common sustained arrhythmia, represents a major risk factor for stroke and is associated with high morbidity and mortality[1]. The AF-associated remodeling of Ca2+ handling is consistent with an increased susceptibility to triggered activity in atria from AF patients[8, 12]. Propagating Ca2+-induced Ca2+ release, which is known to be arrhythmogenic in ventricular myocytes[16], depends on the microscopic cellular architecture[17, 18] and might be altered during hypertension-induced cellular remodeling. We have examined this possibility by analyzing cell geometry, ryanodine receptor labeling and the spread of Ca2+ signals across cells from sham-operated and elevated afterload (aortic-banded) animals[4]
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