Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs

BackgroundArrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.MethodsMI was induced in 7 male and 7 female pigs (Norwegian landrace, 35–40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90 min, before observation for 1 h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70 min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60 min of ischemia, and 5 and 60 min of reperfusion. ECG and invasive blood pressure were monitored throughout.ResultsThe protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5 min of reperfusion compared to baseline, but not at 60 min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion.ConclusionMyocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias

Datasheet1_Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs.docx

BackgroundArrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.MethodsMI was induced in 7 male and 7 female pigs (Norwegian landrace, 35–40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90 min, before observation for 1 h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70 min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60 min of ischemia, and 5 and 60 min of reperfusion. ECG and invasive blood pressure were monitored throughout.ResultsThe protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5 min of reperfusion compared to baseline, but not at 60 min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion.ConclusionMyocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias.</p

Exercise training stabilizes RyR2-dependent Ca2+ release in post-infarction heart failure

Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca 2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca 2+ release in rats with post-myocardial infarction HF. Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO 2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca 2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding. Results: ET increased VO 2max in HF-ET rats to 127% of HF-SED ( P &amp;lt; 0.05). This coincided with attenuated spontaneous SR Ca 2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca 2+ transient amplitude and slowed Ca 2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca 2+ homeostasis and major proteins involved in the regulation of SR Ca 2+ release and reuptake could not explain the attenuated spontaneous SR Ca 2+ release or reduced Ca 2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta 1 -adrenoceptor density and beta 1 :beta 2 -adrenoceptor ratio in HF-ET. Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca 2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca 2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway