The importance of heart rate in isoprenaline‐induced takotsubo‐like cardiac dysfunction in rats

AIMS: Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine‐induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine‐mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third‐degree atrioventricular block, prevents isoprenaline‐induced TS‐like akinesia in an experimental animal model. METHODS AND RESULTS: We used 142 female Sprague–Dawley rats in two separate protocols. The TS‐like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high‐resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS‐like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter‐quartile range (IQR) 0.0–18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0–0.0, P < 0.001 vs. CONTROL). In the IVAB2 group, 5% had TS‐like dysfunction (P = 0.001). Ejection fraction was higher in both the IVAB1 (92%, IQR 89–95) and IVAB2 groups (93%, IQR 87–96) than in the CONTROL group (78%, IQR 63–87, P < 0.05). In the second protocol, the median degree of akinesia in the CTRL group was 21.9% (IQR 8.9–24.6). In the CHB group, no rat developed akinesia (median 0%; IQR 0.0–0.0, P < 0.001 vs. CONTROL). Ejection fraction was higher in the CHB group (90%, IQR 87–92) than in the CTRL group (51%, IQR 87–92, P < 0.05). CONCLUSIONS: Isoprenaline‐induced TS‐like cardiac dysfunction can be prevented by lowering heart rate. Tachycardia may be an important part of the causal pathway in TS.