Mice With Cardiac Overexpression of Peroxisome Proliferator–Activated Receptor γ Have Impaired Repolarization and Spontaneous Fatal Ventricular Arrhythmias

Abstract

Background Diabetes and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation and altered cardiac electrical properties, manifested by prolongation of the QRS duration and QT interval. It is difficult to distinguish the contribution of cardiomyocyte lipid accumulation versus the contribution of global metabolic defects to the increased incidence of sudden death and electrical abnormalities. Methods and Results In order to study the effects of metabolic abnormalities on arrhythmias without the complex systemic effects of diabetes and obesity, we studied cardiac-specific transgenic mice expressing PPARγ1 via the cardiac α-myosin heavy-chain promoter. The PPARγ-transgenic mice develop abnormal accumulation of intracellular lipids and die as young adults, prior to a significant reduction in systolic function. Using implantable ECG telemeters, we found that these mice have prolongation of the QRS and QT intervals, and spontaneous ventricular arrhythmias, including polymorphic ventricular tachycardia and ventricular fibrillation. Isolated cardiomyocytes demonstrated prolonged action potential duration caused by reduced expression and function of the potassium channels responsible for repolarization. Short-term exposure to pioglitazone, a PPARγ agonist, had no effect on mortality or rhythm in WT mice, but further exacerbated the arrhythmic phenotype and increased the mortality in the PPARγ TG mice. Conclusions Our findings support an important link between PPARγ activation, cardiomyocyte lipid accumulation, ion channel remodeling and increased cardiac mortality.

Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity

“…RSG is well known to have detrimental effects on the heart and has been linked to increased risk of fatal cardiac arrhythmia [8, 38]. This may be partially associated with a reduction in cardiac expression of the voltage-dependent K + channel proteins (KCNA2 and KCNA5) and the gap junction protein CX43.…”

“…Molecular compounds have been designed to target PPARγ, such as the clinically available Rosiglitazone (RSG) and Pioglitazone [6] for oral treatment of type 2 Diabetes. However, in addition to attenuating inflammation and promoting insulin sensitivity, these compounds are often associated with severe side effects including weight gain, edema, bone fracture, and congestive heart failure, which have severely limited their clinical application [7, 8]. …”

Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity

“…We recently showed that pharmacologic and genetic activation of cardiac PPARγ in mice treated with lipopolysaccharide (LPS) corrected cardiac dysfunction, further supporting the beneficial effects of increased PPARγ activity [54]. However, ectopic expression of ACSL1 or PPARγ in the heart eventually results in cardiac hypertrophy, myofibrillar disorganization, interstitial fibrosis, and left-ventricular dysfunction [32, 55, 56], indicating that prolonged overexpression of these proteins has negative consequences. Similarly, although treatment with some PPAR agonists alleviates lipid-induced toxicity by increasing uptake of circulating lipids by adipose tissue [57], more robust activation of PPARγ can cause cardiac hypertrophy [58].…”

Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure

“…Heart failure was documented by reduced FS and increased heart expression of BNP. Although not specifically studied in these mice, cardiac lipotoxicity in a previous mouse model led to sudden death from ventricular fibrillation (38). Dgat1 Ϫ/Ϫ mice do not have heart dysfunction (6).…”