Abstract 368: Mechanisms of Arrhythmogenic Substrates in Lipotoxic Heart

Obesity is associated with dangerous pathologies including insulin resistance, hyperglycemia, and diabetes all of which are present as independent risks to developing fatal arrhythmias, which lead to sudden cardiac death. Cardiac lipotoxicity is a common mechanism that links these pathologies to cardiac dysfunction. The molecular mechanisms of cardiac lipotoxicity in obese heart are unknown. We investigated the effects of high-fat diet (HFD)-induced lipotoxicity on atrial electrical remodeling. Electrophysiology and rapid atrial pacing (RAP) were used to evaluate the effects of cardiac lipotoxicity in obese guinea pig hearts that show no signs of hyperglycemia or inflammation. HFD atria were associated with increased voltage-dependent potassium (I K ) and decreased L-type calcium current (I Ca,L ) densities, spontaneous beats, and increased vulnerability to atrial tachycardia with pacing. Further we see a marked reduction in I Kur and increased I K1 phenotype only after RAP. Human cardiac computer simulation studies underscore the translational relevance, as results were identical to data in lipotoxic guinea pig model. The data are the first to show that I K and I Ca,L underlie initiation of atrial arrhythmogenesis, while IK ur and IK 1 may act to sustain the arrhythmia. RNA sequencing assay in lipotoxic myocytes further revealed upregulation of PI3K and/or downregulation of AMPK as prime candidates for modulation of atrial ionic currents. The data provide a unique mechanism-based insight for targeted treatment options in patients.

Cardiomyocyte-specific ACSL1 Deficiency Prevents Cardiac Lipotoxicity and Alleviates Heart Dysfunction in the ob/ob Model of Obesity

Cardiac lipotoxicity is associated with structural remodeling and functional changes that are features of obesity-related cardiomyopathy. Both high fat diet and the ob/ob mutation lead to increased fatty acid (FA) uptake, elevated triacylglycerol (TAG) content, hypertrophy, and systolic and diastolic dysfunction in murine hearts. Cardiomyocyte-specific long-chain acyl-CoA synthetase 1 (ACSL1) deficiency (Acsl1H-/-) results in a 90% reduction in FA activation, suggesting that Acsl1 ablation might alleviate obesity-associated myocardial dysfunction. Double knockout ob-Acsl1H-/- and ob-Acsl1flox/flox control mice were treated with tamoxifen at 20 weeks of age; heart function, TAG content, and relevant gene expression were assessed immediately before and 2 and 5 weeks after treatment. Heart weights initially increased in lean and obese Acsl1H-/- mice, but normalized in ob-Acsl1H-/- mice by 5 weeks. Ventricular TAG content was decreased by 51% and 61% in ob-Acsl1H-/- mice 2 and 5 weeks after Acsl1 knockout induction, respectively. Moreover, ACSL1 knockout resulted in increased survival of ob/ob mice, suggesting that lack of ACSL1 protected obese hearts subjected to stress. Our results indicate that partial knockdown of cardiac ACSL1 is sufficient to reverse cardiac TAG accumulation and to ameliorate heart dysfunction even in the context of established obesity-related cardiomyopathy.

Silencing the Very Low-density Lipoprotein Receptor (VLDLR) Prevents Obesity Associated with Excess Lipid Deposition (P21-040-19)

Objectives Obesity is associated with an insulin resistant state, characterized by abnormalities in lipid metabolism, a leading cause of morbidity and mortality in cardiovascular diseases (CVD). Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of apolipoprotein E triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity associated lipotoxicity is not well understood. Methods In the current study, lean WT, VLDLR-deficient (VLDLR−/−), genetically obese leptin-deficient (Lepob/ob), and leptin–VLDLR double-null (Lepob/ob/VLDLR−/−) mice were used to determine the impact of VLDLR deficiency on obesity-induced cardiac lipotoxicity. Results The results showed that insulin sensitivity and glucose uptake were reduced in the hearts of Lepob/ob mice, and at the same time, VLDLR expression was upregulated and associated with increased VLDL uptake resulting in excess lipid deposition. These changes were accompanied by upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in Lepob/ob mice reduced VLDL uptake and prevented excess lipid deposition. Moreover, VLDLR deficiency reduced superoxide overproduction and normalized glucose uptake. In isolated cardiomyocytes, VLDLR deficiency prevented VLDL-mediated induction of NOx activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. An important observation showed that Lepob/ob/VLDLR−/− mice compared to Lepob/ob mice, had significantly improved heart performance and energetic reserves. Conclusions These findings suggest that that when VLDLR is silenced (deficiency), lipid deposition is also reduced, preventing cardiac lipotoxicity in obesity. In addition, the effects may be linked to the role of VLDLR on VLDL uptake, which triggers a cascade of events leading to insulin resistance and superoxide overproduction. Funding Sources Institutional Support. Howard University, Washington DC 20059 Hackensack University Medical Center, NJ 07601