Question:

Diabetic cardiomyopathy is a pathology associated with diastolic ventricular dysfunction. However, it is not known if hyperglycemia is impacting the atrial remodeling at a structural and functional level. We tested the hypothesis that calcium (Ca) homeostasis is altered in atrial tissue in early stages of diabetes. We characterized the Ca handling mechanisms in atrial myocytes from type 2 diabetic rats, 1 month after the onset of hyperglycemia.

Methodology:

Zucker Diabetic Fatty rats (ZDF, fa/fa) and control Lean (fa/+) rats were sacrificed at 12-14 weeks for atrial myocytes isolation. Epifluorescence (Fura-2/AM) and confocal microscopy (Fluo-4/AM) were used to quantify [Ca²⁺] transients (CaTs) at the global and subcellular level in 1 Hz electrically stimulated atrial myocytes. SR Ca load and SR Ca leak were evaluated with 10 mM Caffeine and 1 mM Tetracaine (Tet) application, respectively. MagFluo-4/AM staining was used for the morphometric evaluation of atrial myocytes.

Results:

Blood glucose levels were significantly elevated in ZDF rats. Morphometric analysis indicated similar size of the atrial myocytes in ZDF vs Lean, suggesting no structural changes at this age. In isolated atrial myocytes, global CaTs had increased diastolic (0.80±0.07, n=10 ZDF vs 0.61±0.03, n=7 Lean, P=0.053) and systolic (1.18±0.13, n=10 ZDF vs 0.79±0.02, n=7 Lean, P<0.05) Fura-2 ratios. Subcellular analysis of CaTs showed a trend (P=0.1) toward higher amplitude at the central cytoplasm and a better propagation of Ca towards the center of the atrial myocytes (P<0.05) in ZDF vs Lean rats. There was no difference in subsarcolemmal and nucleoplasmic CaTs between the two groups of rats. SR Ca load was not significantly different at this age (δF/F0: 5.4±0.5, n=9 ZDF vs 7.3±1.8, n=11 Lean, P=0.37) while Tet-sensitive SR Ca leak normalized to SR Ca content tended to be higher (P=0.067) in ZDF than Lean controls (4.6±0.1%, n=5 vs 2.5±0.5%, n=6), in line with the increased diastolic Ca levels. The incidence of spontaneous Ca release events during the resting state was low and not different between groups.

Conclusions:

In summary, atrial myocytes from rats with early type 2 diabetes are not different in size, but they display changes in cytoplasmic CaTs with increased diastolic and systolic Ca and increased SR Ca leak. At this stage, there is no evidence of an increased propensity for arrhythmogenic events due to hyperglycemia.