Introduction The incidence of ventricular arrhythmia is predicted to rise due to obesity and diabetes. Disorders in the peroxisome proliferator-activated receptor-γ co-activators, PGC-1α and PGC-1β, are associated with both conditions. Homozygous knockout PGC-1β(-/-) hearts are chronotropically incompetent, and show abnormal potassium currents and calcium transients. This study examines how these changes lead to arrhythmia.
Methods Monophasic action potentials were recorded from left (LV) and right ventricular (RV) epicardia of wild-type, heterozygous PGC-1β(+/-) and homozygous PGC-1β(-/-) Langendorff-perfused murine hearts, during extrasystolic and incremental pacing. Isoprenaline was added at 1, 10 and 100 nM concentrations, with intervening washout periods preventing desensitisation.
Results Before isoprenaline challenge, the refractory period in both the LV and RV was lower in PGC-1β(-/-) hearts. LV but not RV action potential durations were lower in PGC-1β(+/-) and PGC-1β(-/-) compared to wild-type. Action potential latencies were marginally shorter in PGC-1β(-/-) RV than in the corresponding wild-type, suggesting increased conduction velocity. However, wavelength at refractoriness was similar in all genotypes and both ventricles. Isoprenaline increased occurrences of tachyarrhythmia in a dose-dependent manner in the PGC-1β(-/-). It increased LV but decreased RV action potential duration. Isoprenaline reduced instability generated by action potential duration restitution in the PGC-1β(-/-) but prevented heart rate adaptation.
Conclusion Metabolically compromised PGC-1β(-/-) hearts have decreased action potential duration and refractory period, and are highly sensitive to adrenergic stimulation. These changes permit re-entry, particularly when the myocardium is heterogeneous such as after an infarct, initiating tachyarrhythmia. This may explain the benefits of β-blockers on cardiovascular outcomes in diabetic patients.
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