Myocardial impulse propagation is impaired in right ventricular tissue of Zucker Diabetic Fatty (ZDF) rats

Abstract

BackgroundDiabetes increases the risk of cardiovascular complications including arrhythmias, but the underlying mechanisms remain to be established. Decreased conduction velocity (CV), which is an independent risk factor for re-entry arrhythmias, is present in models with streptozotocin (STZ) induced type 1 diabetes. Whether CV is also disturbed in models of type 2 diabetes is currently unknown.MethodsWe used Zucker Diabetic Fatty (ZDF) rats, as a model of type 2 diabetes, and their lean controls Zucker Diabetic Lean (ZDL) rats to investigate CV and its response to the anti-arrhythmic peptide analogue AAP10. Gap junction remodeling was examined by immunofluorescence and western blotting. Cardiac histomorphometry was examined by Masson`s Trichrome staining and intracellular lipid accumulation was analyzed by Bodipy staining.ResultsCV was significantly slower in ZDF rats (56±1.9 cm/s) compared to non-diabetic controls (ZDL, 66±1.6 cm/s), but AAP10 did not affect CV in either group. The total amount of Connexin43 (C×43) was identical between ZDF and ZDL rats, but the amount of lateralized C×43 was significantly increased in ZDF rats (42±12 %) compared to ZDL rats (30±8%), p<0.04. Judged by electrophoretic mobility, C×43 phosphorylation was unchanged between ZDF and ZDL rats. Also, no differences in cardiomyocyte size or histomorphometry including fibrosis were observed between groups, but the volume of intracellular lipid droplets was 4.2 times higher in ZDF compared to ZDL rats (p<0.01).ConclusionCV is reduced in type 2 diabetic ZDF rats. The CV disturbance may be partly explained by increased lateralization of C×43, but other factors are likely also involved. Our data indicates that lipotoxicity potentially may play a role in development of conduction disturbances and arrhythmias in type 2 diabetes.

Roles of impaired intracellular calcium cycling in arrhythmogenicity of diabetic mouse model

“…Although limited data showed slow CV in db/db mice, reduced cardiac conduction reserve has been reported previously in streptozocin‐induced type 1 diabetic rats and Zucker diabetic fatty type 2 diabetic rats . In accordance with these reports, our mapping data showed slower CV at all PCLs in db/db mice hearts compared with the control ones (Figure ).…”

“…Propagation of the action potentials through the working myocardium depends on I Na activation followed by gap junction conduction. The conduction disturbance in the diabetic rats has been explained by increased lateralization of connexin‐43, which is associated with nonfunctional gap junctions . Meantime, calmodulin/CaMKII has been proposed not only directly regulating connexin‐43 gating properties but also indirectly modifying their expression and subcellular localization in the intercalated disc .…”

“…reported that CaMKIIδc overexpression may shift the voltage dependence of Na + channel availability to more negative membrane potentials, enhance intermediate inactivation, and slow recovery from inactivation, resulting in a loss of I Na function . Other factors, such as lipotoxicity, could decrease I Na and thereby slow CV in type 2 diabetes hearts, provoking arrhythmogenesis.…”

Acute intramyocardial lipid accumulation in rats does not slow cardiac conduction per se

“…We have investigated the type 2 Zucker diabetic fatty (ZDF) rat (Olsen et al. ), and the prediabetic fructose‐fat fed rat (Axelsen et al. ) which both show a decreased cardiac conduction velocity ex vivo.…”

“…In ZDF rats, the conduction slowing was not explained by either changes in connexin 43 expression, cell size, or fibrosis (Olsen et al. ), factors that are closely associated with conduction slowing. As for the ZDF rats, we also investigated connexin 43 expression and localization, as well as levels of fibrosis and cell size in the fructose‐fat fed rats.…”