Infarct Size In Models Research Articles

Pharmacological efficacy study of the cardio-cerebral stasis transforming medicines on cerebral ischemia and myocardial infarction in rats

The purpose of this study was to investigate the efficacy and mechanisms of cardio-cerebral stasis transforming medicines (CCSTM) against cerebral infarction (CI) and myocardial infarction (MI). CI modeling was conducted using the refined Longa suture-occluded technique, while MI modeling was accomplished through the occlusion of the anterior descending branch of the left coronary artery. We found that compared with the model groups, CCSTM decreased the infarct size in models of CI and MI in a dose-dependent manner. After brain ischemia, CCSTM decreased the level of myeloperoxidase (MPO) and malondialdehyde (MDA), and increased the level of superoxide dismutase (SOD). Besides, CCSTM reduced the concentrations of lactate dehydrogenase (LDH), malondialdehyde MDA, and endothelin (ET) in the plasma of rats injured with MI. Histological examination of brain sections revealed that CCSTM alleviated cerebral damage after ischemia compared with the model group. CCSTM can reduce myocardial and cerebral infarction injury, and the oxidation level after myocardial and cerebral infarction in rats.

Integration of "omics" techniques: Dronedarone affects cardiac remodeling in the infarction border zone.

Dronedarone improves microvascular flow during atrial fibrillation and reduces the infarct size in acute models of myocardial infarction. However, dronedarone might be harmful in patients with recent decompensated heart failure and increases mortality in patients with permanent atrial fibrillation. A pathophysiological explanation for these discrepant data is lacking. This study investigated the effects of dronedarone on gene and protein expression in the infarcted area and border zone in pigs subjected to anterior ischemia/reperfusion myocardial infarction. The ischemia/reperfusion myocardial infarction was induced in 16 pigs. Eight pigs were treated with dronedarone for 28 days after myocardial infarction, the remaining pigs served as control. Microarray-based transcriptome profiling and 2D-DIGE-based proteome analysis were used to assess the effects of dronedarone on left ventricular gene expression in healthy (LV), infarcted (MI), and border zone tissue. Selected targets were validated by RT-qPCR or immunoblot analyses, with special emphasize given to the transcriptome/proteome overlap. Combined "omics" analysis was performed to identify most significant disease and function charts affected by dronedarone and to establish an integrated network. The levels of 879 (BZ) or 7 (MI) transcripts and 51 (LV) or 15 (BZ) proteins were significantly altered by dronedarone, pointing to a substantial efficacy of dronedarone in the border zone. Transcriptome and proteome data indicate that dronedarone influences post-infarction remodeling processes and identify matricellular proteins as major targets of dronedarone in this setting. This finding is fully supported by the disease and function charts as well as by the integrated network established by combined "omics". Dronedarone therapy alters myocardial gene expression after acute myocardial infarction with pronounced effects in the border zone. Dronedarone promotes infarct healing via regulation of periostin and might contribute to the limitation of its expansion as well as cardiac rupture. Thus, there are no experimental hints that dronedarone per se has direct harmful effects after MI in ventricular tissue. Impact statement Dronedarone reduced the infarct size in models of acute myocardial infarction (MI). Here, we show that dronedarone attenuates many of the substantial changes in gene expression that are provoked by acute myocardial infarction (AMI) in pigs. Dronedarone modifies the expression of gene panels related to post-infarction cardiac healing and remodeling processes and, most remarkably, this occurs predominantly in the infarction border-zone and much less so in the vital or infarcted myocardium. Combined "omics" identified matricellular proteins and ECM as major dronedarone-regulated targets and emphasizes their relevance for Disease Charts and Tox Function Charts associated with tissue remodeling and cellular movement. The results demonstrate dronedarone's capability of regulating cardiac repair and remodeling processes specifically in the infarction border zone and identify underlying mechanisms and pathways that might be employed in future therapeutic strategies to improve long-term cardiac tissue function and stability.

Drug development for treatment of cardiac arrhythmias: targeting the gap junctions

reentrant excitation ([12][1]) is likely the most important mechanism for serious life-threatening arrhythmias. Traditionally, a major focus of antiarrhythmic drug development has been to explore the actions of drugs designed to block conduction in reentrant pathways(s). During the latter part of

Reduction in infarct size by ischemic preconditioning persists in a chronic rat model of myocardial ischemia-reperfusion injury.

Ischemic preconditioning (PC) has been consistently observed to reduce infarct size in models of regional myocardial ischemia. However, it is also known to render the heart resistant to injury for only a finite period of time (< 2 h). Myocardial adenosine is widely believed to be one of the mediators of PC and may produce myoprotection in part through an anti-neutrophil effect during the early reperfusion period. When infarct size is assessed following a relatively short period of reperfusion (< 3 h) PC hearts may appear protected although reperfusion injury in the myocardium may be ongoing. Thus, infarct expansion may occur as the effects of PC fade. To substantiate that PC produces a sustained reduction in myocardial necrosis, 27 male Sprague-Dawley rats were anesthetized with pentobarbital and instrumented for regional coronary occlusion (30 min) and reperfusion (7 days). Animals were randomized to a control group (n = 16) or PC (n = 11), which consisted of 2 cycles of 5 min of ischemia and 5 min of reperfusion immediately prior to coronary occlusion. Successful reperfusion was confirmed visually and the occluding suture was left in the chest during recovery. Seven days later, staining for risk area was made by the injection of Evans blue dye while the occluder was in place and necrosis was detected with triphenyltetrazolium chloride staining. Planimetry was performed by a blinded investigator who found the risk area to be 27.2 +/- 1.6 and 33.6 +/- 1.7% of the left ventricle (p = NS) in PC and controls, respectively. All hemodynamic measurements were comparable between groups at all times during ischemia and reperfusion. PC reduced infarct size from 43.3 +/- 2.0% of area at risk to 20.6 +/- -2.1%, a 48% reduction (p < 0.01), and eliminated transmural necrosis which was common in the control group. From these studies we conclude that ischemic PC results in a permanent reduction in infarct size rather than a transient reduction in infarct size in the context of a gradually evolving infarction due to reperfusion injury.

Attenuation of myocardial ischemia-reperfusion injury with nitric oxide replacement therapy

The coronary vascular endothelium produces nitric oxide (NO) during the conversion of L-arginine to L-citrulline. Although NO is a potent vasodilator, at lower concentrations, it also has antineutrophil actions that reduce the inflammatorylike components of ischemia-reperfusion injury. The endothelium is damaged in the early minutes after reperfusion, ie, before neutrophils accumulate and before myocardial necrosis fully develops, and this suggests that endothelial injury is a springboard event in the postischemic inflammatory cascade. Studies of coronary artery occlusion and reperfusion suggest that early damage to the coronary endothelium impairs NO production, which, in turn, abrogates the endogenous antineutrophil effects of NO. However, this impaired endogenous NO-related cardioprotection can be restored either by providing specifically at the onset of reperfusion the precursor to NO (L-arginine) or by providing agents that donate NO. In studies, L-arginine or NO donors reduce infarct size in models of coronary occlusion and reperfusion. The mechanism or mechanisms of this cardioprotection involve preservation of endothelial function and inhibition of neutrophil accumulation in ischemic-reperfused tissue. The cardioprotective potential of NO offers a new therapeutic approach to the reduction of ischemia-reperfusion injury after coronary artery occlusion.

The role of thromboxane A2 in reperfusion injury.

Thromboxane A2 (TXA2) receptor antagonists can limit infarct size in models of coronary occlusion and reperfusion, but it was unknown if these compounds can mitigate reperfusion injury. Anesthetized open chest dogs were subjected to left circumflex coronary (LCX) occlusion for 90 min. Two minutes before reperfusion, the dogs were given iv saline (0.9% NaCl) or the TXA2 antagonist SQ 29,548 (0.2 mg/kg + 0.2 mg/kg/hr). Reperfusion was instituted for 5 hr at which time infarct size was determined. Regional myocardial blood flow was determined before, during, and after occlusion. SQ 29,548 treatment resulted in a significant reduction in infarct size (57 +/- 7 and 34 +/- 8% of the left ventricular area at risk infarcted in the saline and SQ 29,548 groups, respectively). No differences in collateral flow during occlusion were observed between groups, but SQ 29,548 treatment resulted in a significantly higher subendocardial reperfusion flow (54 +/- 10 and 93 +/- 14 ml/min/100g for the saline and SQ 29,548 groups, respectively). Thus, TXA2 seems to play a role in exacerbating reperfusion injury and TXA2 receptor blockade may have potential as a mode of therapy for ischemia-reperfusion damage.

Effects of calcium antagonists on infarcting myocardium

Numerous studies have been conducted over the past 10 years on the effects of calcium antagonists on regional myocardial ischemia and infarct size. Verapamil, for example, reduced the degree of adenosine triphosphate degradation during 15 minutes of coronary occlusion followed by reperfusion in an anesthetized canine preparation. It also preserved the ultrastructural appearance of mitochondria in myocardium subjected to 1 hour of ischemia. Using an 8-hour permanent coronary artery occlusion model in which risk zone was assessed with radioactive microspheres and infarct size determined by tetrazolium staining, verapamil, administered 1 hour after occlusion, resulted in a modest decrease in infarct size. In a reperfusion model in which anesthetized dogs were subjected to 3 hours of coronary artery occlusion followed by 3 hours of reperfusion, verapamil decreased infarct size when it was administered during the period of ischemia, but failed to decrease infarct size when administered only during the reperfusion phase, i.e., after 3 hours of ischemia. Although verapamil is known to have negative inotropic effects, the newer calcium antagonist agent nisoldipine is less negatively inotropic, and might therefore be preferable in the situation of compromised hemodynamics. In a 6-hour permanent coronary artery occlusion model, nisoldipine decreased infarct size without decreasing left ventricular contractility. Most published reports support the concept that calcium antagonists decrease infarct size in models of experimental infarction. Of 4 major clinical studies, only 1 has shown that calcium antagonists are capable of reducing infarct size in man. However, in most of these studies, drug therapy commenced relatively late—4 or more hours after symptoms. In order for these drugs to demonstrate beneficial effects, the risk zone may have to be small and the degree of collateral flow adequate, the drug may have to be given very early or even before coronary occlusion (in a prophylactic fashion) and administration of the drug may have to be coupled to early coronary reperfusion.