Leptin decreases heart rate associated with increased ventricular repolarization via its receptor

Abstract

Leptin has been proposed to modulate cardiac electrical properties via ␤-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated. We identified the protein expression of leptin receptors at cell surface of sinus node, atrial, and ventricular myocytes isolated from rat heart. Leptin at low doses (0.1-30 g/kg) decreased resting heart rate; at high doses (150 -300 g/kg), leptin induced a biphasic effect (decrease and then increase) on heart rate. In the presence of high-dose propranolol (30 mg/kg), high-dose leptin only reduced heart rate and sometimes caused sinus pauses and ventricular tachycardia. The leptin-induced inhibition of resting heart rate was fully reversed by leptin antagonist. Leptin also increased heart rate-corrected QT interval (QTc), and leptin antagonist did not. In isolated ventricular myocytes, leptin (0.03-0.3 g/ml) reversibly increased the action potential duration. These results supported our hypothesis that in addition to indirect pathway via sympathetic tone, leptin can directly decrease heart rate and increase QT interval via its receptor independent of ␤-adrenergic receptor stimulation. During inhibition of ␤-adrenergic receptor activity, high concentration of leptin in myocardium can cause deep bradycardia, prolonged QT interval, and ventricular arrhythmias.leptin; leptin receptor; resting heart rate; QT interval NEW & NOTEWORTHYLeptin is believed to increase heart rate via adrenergic receptor stimulation. We found evidence that leptin can exert local direct inhibition of heart rate and prolongation of QTc interval via its receptor. The findings offer better understanding of higher incidence of prolonged QT and sudden cardiac death in obesity.LEPTIN IS A 16-KDA ADIPOKINE released from adipocytes acting via its receptor. Detection of adipocytes in obese human heart (21, 30) and leptin receptors in human cardiac ventricles (19) has suggested that leptin can have autocrine and paracrine effects on cardiac functions.Leptin has been demonstrated to play an important role in cardiac contractility (19, 37), development of hypertrophy (12,19,37,39), and apoptosis (20). However, studies of leptin on cardiac electrical properties are rare and limited to indirect effects via adrenergic receptor stimulation. It has been widely accepted that leptin increases the heart rate through increasing sympathetic activity (5, 9, 10). Leptin-mediated increase in sympathetic activity can explain obese subjects with higher heart rate to meet the increased metabolic demands (25), but it cannot explain why many of them exhibit unchanged or decreased resting heart rate (2, 7).In heart failure patients, fatty infiltration of cardiomyocytes has been demonstrated. The percentage of fat in myocardium is positively correlat...

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