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Ivabradine improved cardiac function, fibrosis and hyperexcitability in rat post-MI SEVERE heart failure
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S1–S23
A novel antiarrhythmic target: M3R/IKM3 Baofeng Yang, Yanjie Lu, Jundong Jiao. Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, China This study was designed to explore the possible role of M3 subtype of acetylcholine muscarinic receptors (M3-mAChR) in cytoprotection of myocardial infarction. Studies were performed in a rat model of myocardial infarction and in isolated myocytes. We found that choline diminished ventricular arrhythmias during ischemia, which was achieved by correcting hemodynamic impairment, and protecting cardiomyocytes from apoptotic death. The beneficial effects of choline were reversed by the M3-selective antagonists but not by the M2selective antagonist. Choline/M3-mAChR activated several survival signaling molecules (antiapoptotic proteins Bcl-2 and ERKs), increased endogenous antioxidant reserve (SOD), and reduced apoptotic mediators (proapoptotic proteins Fas and p38 MAPK) and intracellular Ca2+ overload. In addition, we also found that administration of choline attenuated the ischemia-induced suppression of the association between connexin 43 and M3-mAChR. We concluded that choline reduced ischemic arrhythmias via stimulating the cardiac M3mAChRs which in turn result in alterations of multiple signaling pathways. Keywords: Arrhythmias; Ischemia; Apoptosis doi:10.1016/j.yjmcc.2007.03.036
Effect of ivabradine on structural and electrophysiological remodelling in a rat model of heart failure C. Ceconi, L. Comini, S. Suffredini* , E. Cerbai* , R. Ferrari, M. Bouly° , A. Mugelli* . University of Ferrara, S. Maugeri ⁎ Foundation IRCCS, Italy. University of Florence, S. Maugeri Foundation IRCCS, Italy. °Servier; Italy and France Background: Left ventricular (LV) remodelling plays a major role in the progression toward heart failure (HF) after myocardial infarction (MI). Drugs able to modulate pre- and afterload have a favourable impact on LV remodelling. We hypothesized that heart rate reduction per se, i.e. with ivabradine (IVA), is able to modulate structural and electrophysiological remodelling processes. IVA acts by selectively and specifically blocking the pacemaker current If with no effect on contractility. Methods: IVA was orally given at 10 mg/kg/day for 90 days to Wistar rats 7 days after left descending coronary artery ligation (MI) randomly allocated to IVA or vehicle. End-systolic (ESV) and end-diastolic (EDV) volumes and ejection fraction (EF) were evaluated by echocardiography. Long term IVA effect on transient potassium outward current (Ito) was recorded with the patch-clamp technique in isolated LV myocytes (LVMs) by applying a voltage protocol activation.
S13
Results: At 3 months, IVA significantly reduced heart rate (from 235 ± 4 to 208 ± 5 beats/min, p < 0.05), ESV (from 0.78 ± 0.10 to 0.54 ± 0.08 ml, p < 0.05) and improved EF (from 54.7 ± 2.3 to 62.8 ± 1.7%, p < 0.05) in MI rats. In sham (SH) rats, IVA did not change peak Ito density in LVMs (9.3 ± 1.1 vs. 9.5 ± 1.7 pA/pF). Peak Ito was significantly reduced in LVMs from MI rats (5.1 ± 0.7 pA/pF, p < 0.01 vs. SH) and partially restored by IVA (7.3 ± 0.8 pA/pF, p < 0.05 vs. SH). Conclusions: These data indicate a beneficial effect of ivabradine on electrophysiological and structural remodelling supporting its use in HF treatment. Keywords: Ivabradine; Remodelling; Electrophysiology doi:10.1016/j.yjmcc.2007.03.037
Ivabradine improved cardiac function, fibrosis and hyperexcitability in rat post-MI SEVERE heart failure Paul Milliez, Janelise Samuel, Claude Delcayre. INSERM U689, Paris The selective sinus node If current inhibitor Ivabradine (Iva) reduces heart rate (HR) without negative inotropic effect. We investigated in a rat model of post-MI severe heart failure, the effects of a chronic Iva administration on LV function, structure and electrical remodelling. Methods: MI was induced by coronary artery ligation in adult rats, echocardiography and Holter ECG were performed 2 months after MI i.e. before randomization (n = 12/group) into MI and MI+Iva (10 mg/kg/d) groups, and 3 months (m) later. Results: 2m-post MI, all rats displayed severe decreased LVEF, and increased LVEDP compared to sham-operated (28% ± 3 vs. 66% ± 5 and 32 ± 2 vs. 10 ± 1 mm Hg, respectively; P < 0.05). In 5m-post-MI, LVEF and LVEDP were stabilized with Iva (31 ± 1% and 24 ± 2 mm Hg), while they were worsened in MI groups (21 ± 3% and 38 ± 2 mm Hg). Blood pressure, body and heart weights were similar in MI and MI+ Iva. Iva reduced HR (RR : 201 ± 5 vs. 179 ± 3 ms in MI; P < 0.05) and ventricular premature beats (514 ± 152 vs. 4717 ± 1363/day for MI; p < 0.05), and improved HR variability (SDRR: 5 ± 1.5 vs. 3.9±0.6 for MI; p < 0.05). There were no effects of Iva on duration (ms) of PR (45 ± 3 vs. 44 ± 3), QRS (51 ± 3 vs. 46 ± 3) and QT (106 ± 7 vs. 99 ± 6, for MI and MI+ Iva, respectively). The increased ventricular collagen in MI (4.0 ± 0.1 vs. 0.8 ± 0.2% in sham; P < 0.05) was markedly reduced in MI+Iva (1.8 ± 0.1%, p < 0.0001 vs. MI). Conclusion: In rat post-MI heart failure Iva not only improved LV function and remodelling but markedly reduced ventricular excitability and HR without harmful effects on conduction. Such effects of Iva on cardiac remodelling open new perspectives for the treatment of severe heart failure. Keywords: Heart rate; Myocardial infarction; Cardiac doi:10.1016/j.yjmcc.2007.03.038
A novel antiarrhythmic target: M3R/IKM3 Baofeng Yang, Yanjie Lu, Jundong Jiao. Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, China This study was designed to explore the possible role of M3 subtype of acetylcholine muscarinic receptors (M3-mAChR) in cytoprotection of myocardial infarction. Studies were performed in a rat model of myocardial infarction and in isolated myocytes. We found that choline diminished ventricular arrhythmias during ischemia, which was achieved by correcting hemodynamic impairment, and protecting cardiomyocytes from apoptotic death. The beneficial effects of choline were reversed by the M3-selective antagonists but not by the M2selective antagonist. Choline/M3-mAChR activated several survival signaling molecules (antiapoptotic proteins Bcl-2 and ERKs), increased endogenous antioxidant reserve (SOD), and reduced apoptotic mediators (proapoptotic proteins Fas and p38 MAPK) and intracellular Ca2+ overload. In addition, we also found that administration of choline attenuated the ischemia-induced suppression of the association between connexin 43 and M3-mAChR. We concluded that choline reduced ischemic arrhythmias via stimulating the cardiac M3mAChRs which in turn result in alterations of multiple signaling pathways. Keywords: Arrhythmias; Ischemia; Apoptosis doi:10.1016/j.yjmcc.2007.03.036
Effect of ivabradine on structural and electrophysiological remodelling in a rat model of heart failure C. Ceconi, L. Comini, S. Suffredini* , E. Cerbai* , R. Ferrari, M. Bouly° , A. Mugelli* . University of Ferrara, S. Maugeri ⁎ Foundation IRCCS, Italy. University of Florence, S. Maugeri Foundation IRCCS, Italy. °Servier; Italy and France Background: Left ventricular (LV) remodelling plays a major role in the progression toward heart failure (HF) after myocardial infarction (MI). Drugs able to modulate pre- and afterload have a favourable impact on LV remodelling. We hypothesized that heart rate reduction per se, i.e. with ivabradine (IVA), is able to modulate structural and electrophysiological remodelling processes. IVA acts by selectively and specifically blocking the pacemaker current If with no effect on contractility. Methods: IVA was orally given at 10 mg/kg/day for 90 days to Wistar rats 7 days after left descending coronary artery ligation (MI) randomly allocated to IVA or vehicle. End-systolic (ESV) and end-diastolic (EDV) volumes and ejection fraction (EF) were evaluated by echocardiography. Long term IVA effect on transient potassium outward current (Ito) was recorded with the patch-clamp technique in isolated LV myocytes (LVMs) by applying a voltage protocol activation.
S13
Results: At 3 months, IVA significantly reduced heart rate (from 235 ± 4 to 208 ± 5 beats/min, p < 0.05), ESV (from 0.78 ± 0.10 to 0.54 ± 0.08 ml, p < 0.05) and improved EF (from 54.7 ± 2.3 to 62.8 ± 1.7%, p < 0.05) in MI rats. In sham (SH) rats, IVA did not change peak Ito density in LVMs (9.3 ± 1.1 vs. 9.5 ± 1.7 pA/pF). Peak Ito was significantly reduced in LVMs from MI rats (5.1 ± 0.7 pA/pF, p < 0.01 vs. SH) and partially restored by IVA (7.3 ± 0.8 pA/pF, p < 0.05 vs. SH). Conclusions: These data indicate a beneficial effect of ivabradine on electrophysiological and structural remodelling supporting its use in HF treatment. Keywords: Ivabradine; Remodelling; Electrophysiology doi:10.1016/j.yjmcc.2007.03.037
Ivabradine improved cardiac function, fibrosis and hyperexcitability in rat post-MI SEVERE heart failure Paul Milliez, Janelise Samuel, Claude Delcayre. INSERM U689, Paris The selective sinus node If current inhibitor Ivabradine (Iva) reduces heart rate (HR) without negative inotropic effect. We investigated in a rat model of post-MI severe heart failure, the effects of a chronic Iva administration on LV function, structure and electrical remodelling. Methods: MI was induced by coronary artery ligation in adult rats, echocardiography and Holter ECG were performed 2 months after MI i.e. before randomization (n = 12/group) into MI and MI+Iva (10 mg/kg/d) groups, and 3 months (m) later. Results: 2m-post MI, all rats displayed severe decreased LVEF, and increased LVEDP compared to sham-operated (28% ± 3 vs. 66% ± 5 and 32 ± 2 vs. 10 ± 1 mm Hg, respectively; P < 0.05). In 5m-post-MI, LVEF and LVEDP were stabilized with Iva (31 ± 1% and 24 ± 2 mm Hg), while they were worsened in MI groups (21 ± 3% and 38 ± 2 mm Hg). Blood pressure, body and heart weights were similar in MI and MI+ Iva. Iva reduced HR (RR : 201 ± 5 vs. 179 ± 3 ms in MI; P < 0.05) and ventricular premature beats (514 ± 152 vs. 4717 ± 1363/day for MI; p < 0.05), and improved HR variability (SDRR: 5 ± 1.5 vs. 3.9±0.6 for MI; p < 0.05). There were no effects of Iva on duration (ms) of PR (45 ± 3 vs. 44 ± 3), QRS (51 ± 3 vs. 46 ± 3) and QT (106 ± 7 vs. 99 ± 6, for MI and MI+ Iva, respectively). The increased ventricular collagen in MI (4.0 ± 0.1 vs. 0.8 ± 0.2% in sham; P < 0.05) was markedly reduced in MI+Iva (1.8 ± 0.1%, p < 0.0001 vs. MI). Conclusion: In rat post-MI heart failure Iva not only improved LV function and remodelling but markedly reduced ventricular excitability and HR without harmful effects on conduction. Such effects of Iva on cardiac remodelling open new perspectives for the treatment of severe heart failure. Keywords: Heart rate; Myocardial infarction; Cardiac doi:10.1016/j.yjmcc.2007.03.038