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Leukotriene B4 is elevated in diabetes and promotes ventricular arrhythmogenesis in guinea pig
Andrea Corbin1,2, Kelly A Aromolaran1, Ademuyiwa S Aromolaran1,2,3,4
1Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, Utah, USA.
Insights
Diabetes elevates leukotriene B4 (LTB4), increasing sudden cardiac death risk. LTB4 causes arrhythmias and prolongs the QT interval, but LTB4 receptor inhibition may offer therapeutic benefits for diabetic patients.
Area of Science:
- Cardiovascular Research
- Molecular Medicine
- Diabetes Complications
Background:
- Diabetes Mellitus (DM) significantly increases the risk of sudden cardiac death (SCD), primarily due to ventricular arrhythmias.
- The underlying molecular mechanisms linking DM to cardiac arrhythmias are not fully understood.
- Leukotriene B4 (LTB4), a pro-inflammatory mediator, is elevated in DM and implicated in cardiac dysfunction.
Purpose of the Study:
- To investigate the role of elevated Leukotriene B4 (LTB4) in diabetes-associated cardiac arrhythmias.
- To elucidate the cellular and electrophysiological effects of LTB4 in the diabetic heart.
- To assess the potential therapeutic benefit of inhibiting LTB4 signaling in DM.
Main Methods:
- Electrophysiology, immunofluorescence, and confocal microscopy were used to study LTB4 effects in guinea pig hearts and ventricular myocytes.
- LTB4 levels and its effects on arrhythmogenesis and ion channel function (hERG1/IKr) were assessed in mouse models of DM and in cell cultures.
- QT interval prolongation was measured in guinea pigs following LTB4 challenge, with and without LTB4 receptor (LTB4R) inhibition.
Main Results:
- LTB4 was found to be elevated in multiple mouse models of diabetes.
- LTB4 induced significant cellular arrhythmogenesis, including spontaneous beats and early afterdepolarizations (EADs).
- LTB4 severely depressed hERG1/IKr current density and prolonged the QT interval in vivo, effects reversible by LTB4R inhibition.
Conclusions:
- Elevated LTB4 contributes to cardiac arrhythmias and electrophysiological abnormalities in diabetes.
- LTB4-induced hERG1/IKr dysfunction and QT prolongation represent key proarrhythmic mechanisms in DM.
- Inhibition of the LTB4 receptor (LTB4R) may represent a novel therapeutic strategy for preventing SCD in diabetic patients.
Abstract:
Diabetes (DM) patients have an increased risk (~50%) for sudden cardiac death (SCD), mostly as a result of ventricular arrhythmias. The molecular mechanisms involved remain partially defined. The potent proinflammatory lipid mediator leukotriene (LT) B4, is pathologically elevated in DM compared to nondiabetic patients, resulting in increased LTB4 accumulation in heart, leading to an increased risk for life-threatening proarrhythmic signatures. We used electrophysiology, immunofluorescence, and confocal microscopy approaches to evaluate LTB4 cellular effects in guinea pig heart and ventricular myocytes. We have observed that LTB4 is increased in multiple mouse models (C57BL/6 J/Lepob/ob and PANIC-ATTAC) of DM, promotes profound cellular arrhythmogenesis (spontaneous beats and early after depolarizations, EADs), and severely depresses the rapidly activating delayed rectifier K current (hERG1/IKr) density in HEK293 cells and guinea pig ventricular myocytes. We have further found that guinea pigs challenged with LTB4 displayed a significantly prolonged QT interval, and that this can be prevented with LTB4R inhibition, suggesting that preventing such LTB4R effects may be therapeutically beneficial in DM. Our data suggests that a further elucidation of LTB4 vulnerable substrates, and how this leads to ventricular arrhythmias, is likely to lead to continued improvements in management options, and the development of new therapies for prevention of SCD in DM patients.
