Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: role of myocyte structure and myocardial perfusion.

AIMS: We showed previously that ivabradine (IVA), a selective inhibitor of the cardiac pacemaker I(f) current, achieved protection against ischaemia-induced ventricular fibrillation (VF) in pigs by increasing the VF threshold (VFT). This was correlated to the heart rate reduction (HRR), the limitation of monophasic action potential shortening and the reduction of the hypoxic area. This study investigated myocyte ultrastructure and regional myocardial blood flow (RMBF), potentially involved in these cardioprotective effects of IVA. METHODS AND RESULTS: Myocardial ischaemia was induced in pigs by total 1-min occlusion of the left anterior descending coronary artery following i.v. administration of saline (n=6) or IVA (0.25 mg/kg, n=6). Electrophysiological and haemodynamic parameters, the hypoxic area and the presence of myocyte ultrastructural lesions were evaluated. The RMBF was assessed using positron emission tomography following ischaemia/reperfusion in IVA (0.25 mg/kg, i.v., n=6) or vagal stimulation (n=4) groups. Compared with saline, IVA induced a 32% HRR (p<0.01), a 2.9-fold increase in the VFT (p<0.001) and a reduction of the hypoxic area without any change in left ventricular dP/dt(max). IVA preserved cardiomyocyte morphology, particularly mitochondrial ultrastructure. Compared with baseline, RMBF during reperfusion was increased in the hypoxic area following IVA administration (+218% vs. +97%, p<0.05) or vagal stimulation (+195% vs. +127%, p<0.05). This increase was sharply reduced by atrial pacing in IVA-group. CONCLUSION: IVA exerts a cardioprotection from ischaemia-induced VF by increasing RMBF and preserving cardiomyocyte and mitochondrial ultrastructure, which opens new perspectives regarding potential targets that would be involved in the anti-ischaemic effects of IVA.

Cardiac lesions induced by testosterone: protective effects of dexrazoxane and trimetazidine.

Further to our previous observation of post-mortem cardiac lesions after sudden death in several athletes with a history of anabolic steroid abuse, this study was intended to reproduce these lesions in rabbits administered testosterone oenanthate, a prototypic anabolic steroid abused by athletes, and to provide evidence for the protective effects of trimetazidine and dexrazoxane that are used as antianginal and cardioprotective drugs, respectively. Groups of six rabbits each were administered saline, testosterone, or a combination of testosterone and either trimetazidine or dexrazoxane for 3 months. Histologic cardiac lesions including necrosis, misshapen cell nuclei, interstitial and endocardial fibrosis, lymphocytic infiltrates, and vascular dystrophies were observed in testosterone-treated rabbits. In contrast, no significant lesions were observed in the animals treated with testosterone combined with either trimetazidine or dexrazoxane. This is the first study providing evidence for testosterone cardiotoxicity following sub-chronic exposure in laboratory animals. In addition, these results suggest the protective role of trimetazidine and dexrazoxane.

Heart lesions associated with anabolic steroid abuse: comparison of post-mortem findings in athletes and norethandrolone-induced lesions in rabbits.

Among 15,000 forensic post-mortem examinations performed on the coroner's order over a 24-year period (January 1981-December 2004) in the area of Lyon, France (population: 2,000,000), 2250 cases of unexpected cardiac sudden death were identified retrospectively according to WHO criteria. Of these, 108 occurred during recreational sport and 12 occurred in athletes. In the latter category, a history of anabolic steroid abuse was found in 6 cases, whereas pre-existing ordinary cardiac lesions were observed in the 6 remaining cases. To shed light on the possible role of anabolic steroids in the induction of cardiac lesions, an experimental study was conducted in rabbits that were treated orally with norethandrolone 8mg/kg/day for 60 days, and sacrificed at day 90. The histopathological examination of the heart from treated animals showed coronary thrombosis associated with left ventricle hypertrophy in 3 cases, and lesions analogous to toxic or adrenergic myocarditis in all other treated animals. These findings were very similar to those observed after cardiac sudden death in the 6 athletes with a history of anabolic steroid abuse. In addition, elevated caspase-3 activity in the heart of treated rabbits as compared to controls suggests that apoptosis is involved in the induction of norethandrolone-induced cardiac lesions. These results confirm the cardiotoxic potential of anabolic steroid abuse.

Ivabradine induces an increase in ventricular fibrillation threshold during acute myocardial ischemia: an experimental study.

BACKGROUND: Tachycardia often facilitates ischemic ventricular fibrillation (VF). OBJECTIVE: This study assessed the impact of ivabradine (IVA), a selective inhibitor of the cardiac pacemaker If current, on ventricular fibrillation threshold (VFT) during acute myocardial ischemia. METHODS: The experiments were conducted on a total of 54 domestic pigs. Myocardial ischemia was induced in anesthetized pigs by total 1-minute coronary occlusion at baseline and then on 2 occasions after intravenous administration of saline or 0.5 mg/kg of IVA. VF was triggered by electrical stimuli of increasing intensity at a fixed rate. Heart rate (HR), VFT, monophasic action potential duration, and peak of the time derivative of left ventricular pressure (LV dP/dt max) were monitored on each occasion. The activity of mitochondrial succinodehydrogenase was measured on heart sections. RESULTS: Compared with controls, IVA induced a 31% reduction in HR, a 2.9-fold increase in VFT, and prevented ischemia-induced monophasic action potential duration shortening (+1 +/- 12 vs. -14 +/- 11 milliseconds) without affecting peak LV dP/dt. This beneficial effect on VFT was mainly due to HR reduction and was accompanied by a significant reduction in the hypoxic area (26% +/- 1% vs. 38% +/- 1%, P < 0.0001). CONCLUSION: HR reduction and the decrease in myocardial damage induced by IVA protected against primary ischemic VF without altering myocardial contractility.