Abstract
Ventricular arrhythmias and sudden cardiac death (SCD) occur most frequently in the setting of coronary artery disease, cardiomyopathy and heart failure but are also increasingly observed in persons suffering from diabetes mellitus and obesity. The incidence of these metabolic disorders is rising in Western countries, but adequate prevention and treatment of arrhythmias and SCD in affected patients is limited because of our incomplete knowledge of the underlying disease mechanisms. Here, an overview is presented of the prevalence of electrophysiological disturbances, ventricular arrhythmias, and SCD in the clinical setting of diabetes and obesity. Experimental studies are reviewed, which have identified disease pathways and associated modulatory factors, in addition to pro-arrhythmic mechanisms. Key processes are discussed, including mitochondrial dysfunction, oxidative stress, cardiac structural derangements, abnormal cardiac conduction, ion channel dysfunction, prolonged repolarization, and dysregulation of intracellular sodium and calcium homeostasis. In addition, the recently identified pro-arrhythmic effects of dysregulated branched chain amino acid metabolism, a common feature in patients with metabolic disorders, are addressed. Finally, current management options are discussed in addition to the potential development of novel preventive and therapeutic strategies based on recent insight gained from translational studies.
Highlights
N RESUME Les arythmies ventriculaires et la mort cardiaque subite surviennent le plus souvent dans le contexte d’une coronaropathie, d’une cardiomyopathie et d’une insuffisance cardiaque, mais elles sont de plus en plus observees chez des personnes atteintes de diabète et d’obesite
It is associated with an increased risk of cardiovascular mortality, malignant ventricular arrhythmias, and sudden cardiac death (SCD);[8,46] the latter may in part be explained by its association with QT-prolongation.[46]
We identified a line of mutagenized mice presenting with sudden death (Fig. 3), in which mice were systematically found dead in their cages at young age without any preceding symptoms or significant findings in the postmortem pathology that could explain the occurrence of sudden death.[49]
Summary
Since 1980, the number of adults with diabetes mellitus (DM) has nearly quadrupled to a prevalence of approximately 8% to 9% and is expected to increase further.[7]. Short-term variability of the QT interval has been proposed as a sensitive indicator of repolarization instability and a more reliable predictor of ventricular arrhythmias and SCD and was shown to be increased in individuals with impaired glucose tolerance.[20]. Studies have shown that being obese or overweight is associated with significant QTc-prolongation and enhanced QT dispersion,[28,29] which is already observed at an early age in obese children.[30] Additional risk factors such as hypertension, diabetes, and heart failure often co-exist in the obese patient, potentially contributing to arrhythmia and risk of SCD. It remains incompletely clear whether the observed repolarization changes in obese patients are solely the consequence of these comorbidities or whether they are () a direct consequence of obesity itself. Animal studies have confirmed the increased arrhythmia susceptibility and repolarization changes in the setting of obesity.[31,32]
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