Ivabradine is as effective as metoprolol in the prevention of ventricular arrhythmias in acute non-reperfused myocardial infarction in the rat

Figures

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  Figure 1. Heart rate profile and arrhythmic mortality within 6 h of myocardial infarction induction or sham operation in rats (A) Average heart rate after induction of myocardial infarction (MI) or sham operation (Sham) in saline, ivabradine (Iva) or metoprolol (Meto)-treated rats; (B) Kaplan–Meier presentation of arrhythmic mortality. Data are means ± SEM. *p < 0.05 versus respective saline group. For group sizes see Table 1. Figure created using SigmaPlot v.14.0 (https://systatsoftware.com/products/sigmaplot/).

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  Figure 2. Ventricular arrhythmias within 6 h of myocardial infarction induction or sham operation in rats (A) Incidence, (B) total duration of ventricular tachycardia/ventricular fibrillation (VT/VF) and (C) ventricular premature beat (VPB) count in three periods after MI/sham surgery: 0–1, 2–3 and 4–6 h. Panels A and B do not include data for sham, since only two VT episodes occurred in all sham groups throughout the experiment (in Sham + Iva and Sham + Meto groups). (D) Overall arrhythmia score and (E) percentage of animals free from VT/VF. Horizontal bars represent median, the bottom and the top of the boxes represent the upper and the lower quartile, he whiskers represent 10th and 90th percentile, while the solid circles represent the individual data points. The horizontal lines show statistical significance, p < 0.05. For group sizes see Table 1. (F)–(K) are sample ECG recordings demonstrating various ventricular arrhythmias in the post-myocardial infarction rats; horizontal axis indicates time in seconds. (F) A single early VPB, occurring before the completion of cardiac repolarization. (G) A pair of late VPB, occurring after the completion of cardiac repolarization. (H) An…

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  Figure 3. ECG parameters within 6 h of myocardial infarction induction or sham operation in rats (A) QRS duration, (B) QT duration, (C) corrected QT duration calculated using modified Bazett’s formula normalized to rat RR interval, (D) QT/QRS ratio, an index of cardiac electrophysiological balance, reflecting the wave length, (E) Tpeak-end, interval from peak T wave to its end, reflecting duration of intramural dispersion of repolarization. (F) sample 2-lead ECG recordings from saline-, ivabradine and metoprolol-treated sham operated and MI rats, taken 6 h after sham operation/MI induction. (G) Evolution of MI in ECG recordings: baseline, 1 h, 3 h and 6 h after induction of MI. Data are means ± SEM. *p < 0.05 versus respective saline group; # p < 0.05 versus untreated MI. For group sizes see Table 1. Figure created using SigmaPlot v.14.0 (https://systatsoftware.com/products/sigmaplot/).

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  Figure 4. Epicardial monophasic action potentials (MAPs) recorded 6 h after myocardial infarction induction or sham operation in rats, separately in remote healthy left ventricular tissue (Remote) and infarct borderzone (Border) (A) MAP duration at 90% of action potential repolarization. (B) MAP amplitude. (C) MAP upstroke velocity. The solid circles represent the individual data points. (D) Sample MAPs from a sham operated animal, MI, MI + Iva and MI + Meto. Black line indicates MAP from remote LV tissue, blue one from infarct borderzone. The horizontal lines show statistical significance, p < 0.05. For group sizes see Table 1.

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  Figure 5. Ca2+ handling parameters in myocardial infarction or sham operated rats treated with saline, ivabradine or metoprolol (A) Amplitude of Ca2+ transients, (B) Ca2+ transient decay, (C) SR Ca2+ content, (D) sarcoplasmic Ca2+-ATPase (SERCA) activity, (E) sodium-calcium exchanger (NCX) activity, (F) amplitude of Ca2+ transient/SR Ca2+ content (T/C) ratio, (G) sample recording of electrically invoked Ca2+ transients. Mean ± SEM from (n = 42–118) cardiomyocytes isolated from at least 5 rats in each group. The horizontal lines show statistical significance, p < 0.05. a.u., arbitrary units. Figure created using SigmaPlot v.14.0 (https://systatsoftware.com/products/sigmaplot/).

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  Figure 6. Time course and magnitude of heart rate reduction following administration of ivabradine and metoprolol as intravenous bolus or oral gavage. *p < 0.05 versus respective saline group. Each group n = 5 animals. Figure created using SigmaPlot v.14.0 (https://systatsoftware.com/products/sigmaplot/).