Mechanisms of electrical remodeling in lipotoxic guinea pig heart

Objectives To develop an adult guinea pig model of lipotoxicity and explore the underlying mechanisms associated with changes in the expression of the delayed rectifier potassium current ( I K ). Background Lipotoxicity may represent a common link among metabolic disorders and a higher vulnerability to arrhythmias. Methods Whole-cell patch clamp, and palmitic acid (PA, a potent inducer of lipotoxicity), were used to assess mechanisms of short-term (∼50 days) high-fat diet (HFD) feeding on atrial electrophysiology in guinea pig hearts and myocytes. Results HFD fed guinea pigs were significantly heavier, displayed hypertriglyceridemia and hypercholesterolemia; but no signs of hyperglycemia or inflammation compared to low-fat diet fed controls. Increasing cardiac PA levels, resulted in shortened atrial action potential duration, and increased I K density. Inhibition of phosphoinositide 3-kinase (PI3K) prevented increases in I K due to PA. Acute (≥1hr) exposure of atrial myocytes to exogenous PA (1 mM) increased the density of the rapid delayed rectifier potassium current I Kr , while it was decreased with the unsaturated oleic acid (OA, 1 mM). Serine-threonine protein phosphatase-2 (PP2A) inhibition with cantharidin reversed the effect of OA on I Kr . Conclusion Our data provide evidence of a novel lipotoxic guinea pig model with signs of vulnerability to arrhythmias. Inhibition of PA/PI3K/ I K and/or activation of the OA/PP2A/ I Kr pathways may be therapeutically beneficial for lipotoxic arrhythmias.