Long-Term Endurance Exercise Training Alters Repolarization in a New Rabbit Athlete's Heart Model.

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete's heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro. Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro. APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit "athlete's heart" to life-threatening arrhythmias.

Long-term endurance training-induced cardiac adaptation in new rabbit and dog animal models of the human athlete's heart.

Sudden cardiac death in athletes is rare and most often unexpectable. For a better understanding of cardiac remodeling, this study presents the effects of chronic vigorous exercise on cardiac structure and electrophysiology in new rabbit and dog athlete's heart models. Rabbits and dogs were randomized into sedentary ('Sed'), exercised (subjected to 16 weeks chronic treadmill exercise ('Ex') groups, and a testosterone-treated ('Dop') group in dogs. Echocardiography and electrocardiogram were performed. Proarrhythmic sensitivity and autonomic responses were tested in conscious dogs. 'Ex' animals exhibited left ventricular enlargement with bradycardia (mean RR in 'Ex' vs. 'Sed' rabbits: 335 ± 15 vs. 288 ±19 ms, p ≤ 0.05, and in 'Dop' vs. 'Ex' vs. 'Sed' dogs: 718 ± 6 vs. 638 ± 38 vs. 599 ± 49 ms) accompanied by an increase of heart rate variability in both species (e.g. SD RR in 'Ex' vs. 'Sed' rabbits: 3.4 ± 0.9 vs. 1.4 ± 0.1 ms, p ≤ 0.05, and in 'Dop' vs. 'Ex' vs. 'Sed' dogs: 156 ± 59 vs. 163 ± 44 vs. 111 ± 49 ms) indicating an increased vagal tone. A lower response to parasympatholytic agent atropine and more pronounced QTc interval lengthening after dofetilide challenge were found in 'Ex' and 'Dop' dogs compared to the 'Sed' group. No morphological and functional changes were found after chronic steroid treatment in dogs. The structural-functional findings share more similarities with human athlete's heart. Slight repolarization sensitivity in the exercised dogs may indicate an increased risk of arrhythmias in athletes under different circumstances. These animal models might be useful for the further investigations of the cardiovascular effects of competitive training.

New in vitro model for proarrhythmia safety screening: IKs inhibition potentiates the QTc prolonging effect of IKr inhibitors in isolated guinea pig hearts.

INTRODUCTION: Preclinical in vivo QT measurement as a proarrhythmia essay is expensive and not reliable enough. The aim of the present study was to develop a sensitive, cost-effective, Langendorff perfused guinea pig heart model for proarrhythmia safety screening. METHODS: Low concentrations of dofetilide and cisapride (inhibitors of the rapid delayed rectifier potassium current, IKr) were tested alone and co-perfused with HMR-1556 (inhibitor of the slow delayed rectifier potassium current, IKs) in Langendorff perfused guinea pig hearts. The electrocardiographic rate corrected QT (QTc) interval, the Tpeak-Tend interval and the beat-to-beat variability and instability (BVI) of the QT interval were determined in sinus rhythm. RESULTS: Dofetilide and HMR-1556 alone or co-perfused, prolonged the QTc interval by 20±2%, 10±1% and 55±10%, respectively. Similarly, cisapride and HMR-1556 alone or co-perfused, prolonged the QTc interval by 11±3%, 11±4% and 38±6%, respectively. Catecholamine-induced fast heart rate abolished the QTc prolonging effects of the IKr inhibitors, but augmented the QTc prolongation during IKs inhibition. None of the drug perfusions increased significantly the Tpeak-Tend interval and the sinus BVI of the QT interval. DISCUSSION: IKs inhibition increased the QTc prolonging effect of IKr inhibitors in a super-additive (synergistic) manner, and the QTc interval was superior to other proarrhythmia biomarkers measured in sinus rhythm in isolated guinea pig hearts. The effect of catecholamines on the QTc facilitated differentiation between IKr and IKs inhibitors. Thus, QTc measurement in Langendorff perfused guinea pig hearts with pharmacologically attenuated repolarization reserve and periodic catecholamine perfusion seems to be suitable for preclinical proarrhythmia screening.

Ventricular cycle length irregularity affects the correlation between ventricular rate and coronary flow in isolated, Langendorff perfused guinea pig hearts.

INTRODUCTION: Heart rate affects coronary flow, but the mechanism is complex. The relationship between rhythm and flow is unclear, especially in experimental settings used for determining drug actions. The present study examined whether ventricular irregularity influences coronary flow independently of heart rate. METHODS: Guinea pig hearts were perfused (Langendorff mode) at constant pressure. Hypokalemic Krebs solution facilitated spontaneous development of arrhythmias. The ECG, left ventricular and perfusion pressures were recorded, and the coronary flow was measured. Beat-to-beat ventricular cycle length variability was quantified. Hearts were retrospectively allocated to arbitrary 'Low' or 'High' RR variability groups. RESULTS: A positive linear correlation was found between mean ventricular rate and coronary flow. The slope of the regression line was significantly greater in the 'High' versus 'Low' RR variability group, with greater coronary flow values in the 'High' RR variability group in the physiological heart rate range. During regular rhythm, left ventricular pressure exceeded perfusion pressure and prevented coronary perfusion at peak systole. However, ventricular irregularity significantly increased the number of beats in which left ventricular pressure remained below perfusion pressure, facilitating coronary perfusion. DISCUSSION: In isolated hearts, cycle length irregularity increases the slope of the positive linear correlation between mean ventricular rate and coronary flow via producing beats in which left ventricular pressure remains below perfusion pressure. This means that changes in rhythm have the capacity to influence coronary flow independently of heart rate in isolated hearts perfused at constant pressure, which should be noted in drug studies on arrhythmias performed in Langendorff hearts.