Background - Type 2 diabetes (DM2) is one of the most common chronic disorders worldwide and is an important cause of cardiovascular disease. Studies investigating the risk of atrial and ventricular arrhythmias in diabetic patients taking different oral diabetes medications are sparse. Methods - We used IBM MarketScan® Medicare Supplemental Database to examine the risk of arrhythmias for patients on different oral diabetes medications by propensity score matching. Results - We found that patients on metformin monotherapy had significantly reduced risk of atrial arrhythmias, including atrial fibrillation, compared to monotherapy with DPP4 or TZD medications. Patients on metformin monotherapy had significantly reduced risk of atrial arrhythmias, ventricular arrhythmias, and bradycardia compared to monotherapy with sulfonylureas. Combination therapy with sulfonylureas and metformin had an increased risk of atrial arrhythmias compared to some other combinations. Conclusions - Different oral diabetes medications have significantly different long-term risk of arrhythmia. Specifically, metformin is associated with reduced risk of atrial fibrillation and ventricular arrhythmias compared to sulfonylureas.

The epidemics of obesity and diabetes mellitus are associated with an increased incidence of both atrial fibrillation (AF), the most common sustained arrhythmia in adults, and sudden cardiac death (SCD). Obesity and DM are known to have adverse effects on cardiac structure and function. The pathologic mechanisms are thought to involve cardiac tissue remodeling, metabolic dysregulation, inflammation, and oxidative stress. Clinical data suggest that left atrial size, epicardial fat pad thickness, and other modifiable risk factors such as hypertension, glycemic control, and obstructive sleep apnea may mediate the association with AF. Data from human atrial tissue biopsies demonstrate alterations in atrial lipid content and evidence of mitochondrial dysfunction. With respect to ventricular arrhythmias, abnormalities such as long QT syndrome, frequent premature ventricular contractions, and left ventricular hypertrophy with diastolic dysfunction are commonly observed in obese and diabetic humans. The increased risk of SCD in this population may also be related to excessive cardiac lipid deposition and insulin resistance. While nutritional interventions have had limited success, perhaps due to poor long-term compliance, weight loss and improved cardiorespiratory fitness may reduce the frequency and severity of AF.

Background: Obesity and diets high in saturated fat increase the risk of arrhythmias and sudden cardiac death. However, the molecular mechanisms are not well understood. We hypothesized that an increase in dietary saturated fat could lead to abnormalities of calcium homeostasis and heart rhythm by a NOX2 (NADPH oxidase 2)-dependent mechanism. Methods: We investigated this hypothesis by feeding mice high-fat diets. In vivo heart rhythm telemetry, optical mapping, and isolated cardiac myocyte imaging were used to quantify arrhythmias, repolarization, calcium transients, and intracellular calcium sparks. Results: We found that saturated fat activates NOX (NADPH oxidase), whereas polyunsaturated fat does not. The high saturated fat diet increased repolarization heterogeneity and ventricular tachycardia inducibility in perfused hearts. Pharmacological inhibition or genetic deletion of NOX2 prevented arrhythmogenic abnormalities in vivo during high statured fat diet and resulted in less inducible ventricular tachycardia. High saturated fat diet activates CaMK (Ca 2+ /calmodulin-dependent protein kinase) in the heart, which contributes to abnormal calcium handling, promoting arrhythmia. Conclusions: We conclude that NOX2 deletion or pharmacological inhibition prevents the arrhythmogenic effects of a high saturated fat diet, in part mediated by activation of CaMK. This work reveals a molecular mechanism linking cardiac metabolism to arrhythmia and suggests that NOX2 inhibitors could be a novel therapy for heart rhythm abnormalities caused by cardiac lipid overload.

Sepsis-induced cardiomyopathy (SIC) is associated with increased patient mortality. At present, there are no specific therapies for SIC. Previous studies have reported increased reactive oxygen species (ROS) and mitochondrial dysfunction during SIC. However, a unifying mechanism remains to be defined. We hypothesized that PKCδ is required for abnormal calcium handling and cardiac mitochondrial dysfunction during sepsis and that genetic deletion of PKCδ would be protective. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) surgery decreased the ejection fraction of wild-type (WT) mice but not PKCδ knockout (KO) mice. Similarly, WT cardiomyocytes exposed to lipopolysaccharide (LPS) demonstrated decreases in contractility and calcium transient amplitude that were not observed in PKCδ KO cardiomyocytes. LPS treatment decreased sarcoplasmic reticulum calcium stores in WT cardiomyocytes, which correlated with increased ryanodine receptor-2 oxidation in WT hearts but not PKCδ KO hearts after sepsis. LPS exposure increased mitochondrial ROS and decreased mitochondrial inner membrane potential in WT cardiomyocytes. This corresponded to morphologic changes consistent with mitochondrial dysfunction such as decreased overall size and cristae disorganization. Increased cellular ROS and changes in mitochondrial morphology were not observed in PKCδ KO cardiomyocytes. These data show that PKCδ is required in the pathophysiology of SIC by generating ROS and promoting mitochondrial dysfunction. Thus, PKCδ is a potential target for cardiac protection during sepsis. NEW & NOTEWORTHY Sepsis is often complicated by cardiac dysfunction, which is associated with a high mortality rate. Our work shows that the protein PKCδ is required for decreased cardiac contractility during sepsis. Mice with deletion of PKCδ are protected from cardiac dysfunction after sepsis. PKCδ causes mitochondrial dysfunction in cardiac myocytes, and reducing mitochondrial oxidative stress improves contractility in wild-type cardiomyocytes. Thus, PKCδ is a potential target for cardiac protection during sepsis.

There is a high prevalence of diabetes in lung transplant patients. Earlier endocrine participation in lung transplant services is likely to lower diabetes-related morbidity and mortality further.