C-reactive-protein-associated increase in myocardial infarct size after ischemia/reperfusion

C-Reactive protein (CRP), a marker for acute inflammation, is associated with increased risk of cardiovascular events. The mechanism underlying this association is uncertain. An acute inflammatory response was induced in rabbits by subcutaneous injection of croton oil (CO) 1 to 3 days before 30 min of regional myocardial ischemia/180 min of reperfusion. CO treatment increased plasma CRP from below the limit of detection to 2.5 +/- 0.5 mg/dl and was associated with an increase in infarct size expressed as percentage of risk region [32 +/- 6% vehicle controls (n = 7) to 47 +/- 9% CO-treated rabbits (n = 7; P < 0.05]. After 10 min of ischemia and 180 min reperfusion, no infarct was found in controls; however, an infarct of 7 +/- 1% was found in CO-treated rabbits (P < 0.05; CRP, 2.3 +/- 0.4 mg/dl). The CRP-related increase in infarct size was not observed in croton oil-treated, C6-deficient rabbits (n = 5/group), indicating the involvement of complement. In these rabbits, infarct size was 22 +/- 2% (P < 0.05) despite having plasma CRP of 4.3 +/- 0.4 mg/dl. The CRP-associated increase in infarct size was ameliorated by pretreatment with heparin (n = 7; infarct size 33 +/- 3%; CRP, 2.3 +/- 0.3 mg/dl; P < 0.05) or N-acetylheparin (n = 7; infarct size 23 +/- 4%; CRP, 3.1 +/- 0.5 mg/dl; P < 0.05). These observations may explain why increased serum CRP is associated with an augmented risk for cardiovascular events.     

Postconditioning does not reduce myocardial infarct size in an in vivo regional ischemia rodent model

In our laboratory, postconditioning reliably reduces lethal ventricular arrhythmias in an in vivo rat model but its effect on necrosis in our model is unknown. In the present analysis, we tested a variety of postconditioning regimens in anesthetized rats subjected to 45 minutes of coronary occlusion and 120 minutes of reperfusion or 30 minutes of coronary occlusion and 120 minutes of reperfusion. In all studies, area at risk was determined by the blue dye technique and area of necrosis was assessed with triphenyl tetrazolium chloride staining and computerized planimetry of ventricular slices. Postconditioning regimens included 4 cycles of 10 seconds of reperfusion/10 seconds of reocclusion, 4 cycles of 20 seconds of reperfusion/20 seconds of reocclusion, 8 cycles of 30 seconds of reperfusion/30 seconds of reocclusion, and 20 cycles of 10 seconds of reperfusion/10 seconds of reocclusion. Postconditioning did not reduce myocardial infarct size with any of these regimens.     

Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury

The cardioprotective effectiveness of low-dose pyrroloquinoline quinone (PQQ, 3 mg/kg) was compared with metoprolol, a beta(1)-selective adrenoceptor antagonist. Rats underwent 30 minutes of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Metoprolol and/or PQQ were given at the onset of reperfusion to mimic clinical treatment. Metoprolol and/or PQQ reduced infarct size and protected against ischemia-induced left ventricular dysfunction after 2 hours of reperfusion. Combined therapy augmented left ventricular developed pressure at the end of reperfusion. Metoprolol or PQQ alone enhanced mitochondrial respiratory ratios in ischemic and nonischemic myocardium. Although the PQQ/metoprolol combination therapy increased respiratory ratio values, the effects were small when compared with PQQ alone. Only PQQ decreased lipid peroxidation. Metoprolol and/or PQQ given at the onset of reperfusion reduce infarct size and improve cardiac function. Combination therapy further reduces infarct size. PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage.     

Evaluation and simplified measurement of infarct size by myocardial contrast echocardiography in a rat model of myocardial infarction

To test the feasibility and accuracy of myocardial contrast echocardiography (MCE) for predicting infarct size (IS) in a rat model of myocardial infarction (MI) and to compare a simplified single plane-based measurement of IS with the conventional three plane-based approach. Fifty male SD rats underwent left anterior descending artery ligation and were evaluated by MCE 8 h post MI. IS was calculated by the single and three plane-based approaches, compared to that determined by triphenyltetrazolium chloride (TTC) staining method. Simplified single plane-based MCE approach and TTC method showed similar IS values (38.48 ± 16.80% vs. 35.72 ± 15.33%, P > 0.05) and presented a favorable positive correlation (r = 0.851, P < 0.001). IS values derived from simplified single plane-based approach was also highly significantly correlated with that by the conventional MCE method (r = 0.973, P < 0.001). Bland–Altman plots also displayed satisfactory agreement between them. MCE was validated as a novel technique to quantify infarct area in rats with MI. A single measurement at the mid-papillary muscle level may become a simple, efficient and reliable approach for in vivo IS assessment. Xianghui Chen and Kai Cui are co-first authors.     

Measure for measure-determination of infarct size in murine models of myocardial ischemia and reperfusion: a systematic review

Myocardial ischemia/reperfusion injury (MI/R) is one of the most prominent topics of contemporary research. The frequent failure of potential therapeutic drugs and interventions to transfer to clinical practice demonstrates the limitations in using experimental animal models. Because a variety of transgenic animals are readily available in mice, researchers in recent years have made use of murine models rather than of larger animal models for experimental MI/R. This review focuses on in vivo and ex vivo murine models of MI/R and aims to characterize the source of our mechanistic understanding in mice. A systematic review of the literature demonstrated that there is great diversity among ex vivo (Langendorff) and in vivo models of MI/R.     

The antianginal agent, ranolazine, reduces myocardial infarct size but does not alter anatomic no-reflow or regional myocardial blood flow in ischemia/reperfusion in the rabbit

It has been suggested that ranolazine protects the ischemic/reperfused heart by reducing diastolic wall pressure during ischemia. However, there is limited information regarding the effect of ranolazine on the anatomic zone of no-flow in a model of acute myocardial occlusion/reperfusion. Before coronary artery occlusion (CAO), open-chest anesthetized rabbits were assigned to vehicle or ranolazine. Hearts received 60 minutes of CAO and 3 hours reperfusion. Ischemic risk zone was comparable in the 2 groups. Ranolazine significantly reduced infarct size. There was a non-significant trend for the no-reflow defect to be smaller in the ranolazine group. Regional myocardial blood flow was similar in both groups in the risk zone during ischemia and at 3 hours reperfusion. Heart rates were similar in both groups, whereas mean arterial pressure was reduced in the ranolazine group. While ranolazine was effective in reducing myocardial infarct size, the mechanism by which it did this was independent of improving perfusion during either ischemia or reperfusion, suggesting that ranolazine's effect of reducing infarct size involves alternative mechanisms.     

Reduction of the infarct size by simultaneous administration of L-histidine and diphenhydramine in ischaemic rat brains

Aims

While diphenhydramine is a histamine H₁ receptor antagonist, the agent has been shown to inhibit histamine-N-methyltransferase, a histamine inactivating enzyme in the brain. Since an increase in the brain concentration of histamine ameliorates reperfusion injury after cerebral ischaemia, effects of postischaemic administration of diphenhydramine were evaluated in rats treated with l-histidine, a precursor of histamine.

Methods

The right middle cerebral artery was occluded for 2 h, and the infarct size was determined 24 h after reperfusion of cerebral blood flow. Brain oedema was evaluated by comparing the area of the right hemisphere to that of the left hemisphere.

Results

Focal cerebral ischaemia provoked marked damage in saline-treated control rats, and infarct volumes in the striatum and cerebral cortex were 56 (49-63) mm³ and 110 (72-148) mm³, respectively (means and 95% confidence intervals, n = 6). Administration of l-histidine (1000 mg/kg, intraperitoneal) immediately after reperfusion did not affect the infarct size. Simultaneous administration of diphenhydramine (20 mg/kg, intraperitoneal) with l-histidine reduced the infarct size to 25% and 21% of that in the control group, respectively. The combination therapy completely reduced ischaemia-induced brain oedema.

Conclusion

Because histamine H₁ action does not influence ischaemic brain damage, elevation of the central histamine concentration by blockade of histamine-N-methyltransferase may be a likely mechanism responsible for the alleviation.     

Reduction in myocardial infarct size: prevention of heart cell death.

The course of myocardial necrosis, the clinical syndrome, and methods of treatment are presented. Heart cell death may be prevented by maintaining the balance between myocardial oxygen and energy supply and consumption. New technics of improving this balance by reducing myocardial energy demand, altering metabolism, increasing myocardial substrate supply, and protecting cellular integrity are discussed.     

多普勒组织成像技术对缺血心肌再灌注前后室壁运动的定量研究

目的　利用多普勒组织成像技术 (DTI)观察正常人及冠心病患者心肌运动的特点 ,并了解缺血心肌再灌注前后心肌运动改变情况。方法　 16例健康人及 18例冠心病患者均行DTI检测 ,冠心病患者再灌注后再行DTI ,比较手术前后DTI变化情况。结果　冠心病患者和健康人相比 ,收缩期峰值速度 (VS)明显降低 (室间隔心尖段除外 ) ,舒张早期峰值速度 (VE)也明显减低 (间壁心尖段及下壁心尖段除外 )。再灌注前后比较 ,运动恢复节段VS、VE 均明显提高。结论　DTI能定量分析缺血心肌再灌注前后室壁运动变化情况。     

定量组织速度显像技术评价犬心肌缺血再灌注局部心室壁运动

目的　探讨定量多普勒组织速度显像 (QTVI)评价犬急性心肌缺血再灌注局部心室壁运动异常的可行性 ,为QTVI应用于临床判断心肌缺血部位及再灌注后存活心肌的评估提供实验依据。方法　应用QTVI观察 7条犬冠状动脉结扎前基础状态、结扎后不同时间点及再灌注后的局部室壁每一节段的收缩期峰值流速(Vs)、舒张早期峰值流速 (Ve)。且术后心肌标本经 1%氯代三苯基四氮唑溶液染色及透射电镜超微结构观察以证实心肌细胞有无坏死。结果　结扎犬冠状动脉 5min、10min组局部心肌各节段Vs、Ve较基础状态明显降低(均P <0 .0 5 )。结扎 3 0min后局部心肌收缩速度Vs有一定程度恢复 ,Ve恢复时间晚于Vs。血流再灌注后基本呈恢复趋势 ,但仍低于基础状态。结论　QTVI技术可定量评价缺血再灌注后局部室壁运动异常 ,对临床诊断急性心肌缺血和帮助治疗决策有一定的应用价值。     

心肌缺血预适应对急性心肌梗死面积及近期预后的影响

目的 :观察急性心肌梗死前心绞痛发作与梗死范围及近期预后的关系。方法 :选择 178例急性心肌梗死患者 ,根据梗死前 72h以上有无心绞痛 ,分为A组 (有心绞痛 ) 76例 ,B组 (无心绞痛 ) 10 2例。对两组的梗死面积、并发症和病死率进行统计分析。结果 :A组梗死面积小 (两组间有显著差异 ,P <0 0 5 ) ,住院期间严重心律失常、心力衰竭、心原性休克发生率及病死率均低于B组 (两组间有显著差异 ,P <0 0 5 )。结论 :急性心肌梗死前有心绞痛发作对心肌有明显的保护作用     

Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function

Purpose

Bioactive NO carriers in circulating blood formed during NO inhalation selectively distribute blood flow to areas in need, and may thus improve collateral perfusion to the area-at-risk in acute myocardial infarction (AMI). Here, we tested the hypothesis that NO inhalation during the ischemic phase of AMI may improve left ventricular function and reduce infarct size in rats.

Methods

Following left anterior descending coronary artery (LAD) occlusion, rats received 50?ppm NO for 2?h of ischemia, during subsequent 3?h of reperfusion, or for 5?h of ischemia and reperfusion. Effects of inhaled NO were compared to those of intravenous nitrite as a putative carrier formed during NO inhalation. Downstream signaling via soluble guanylate cyclase was tested by inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).

Results

NO inhalation during myocardial ischemia increased left ventricular systolic pressure, contractility, relaxation, and cardiac output, and reduced myocardial infarction size and area-at-risk as compared to untreated controls. NO inhalation during the reperfusion phase caused a comparable protective effect. Combined inhalation during ischemia and reperfusion did not further improve left ventricular hemodynamics, but had an additive protective effect on the myocardial area-at-risk. NO inhalation increased circulating nitrite levels, and mimicking of this effect by intravenous nitrite infusion achieved similar protection as NO inhalation during myocardial ischemia, while ODQ blocked the protective NO effect.

Conclusions

Inhalation of NO during myocardial ischemia improves left ventricular function and reduces infarct size by mechanisms that increase levels of circulating nitrite and involve soluble guanylate cyclase. NO inhalation may represent a promising early intervention in AMI.     

Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs

The antiarrhythmic and cardioprotective effect of increasing gap junction intercellular communication during ischemia/reperfusion injury has not been studied. The antiarrhythmic peptide rotigaptide (previously ZP123), which maintains gap junction intercellular communication, was tested in dogs subjected to a 60-min coronary artery occlusion and 4 h of reperfusion. Rotigaptide was administered i.v. 10 min before reperfusion as a bolus + i.v. infusion at doses of 1 ng/kg bolus + 10 ng/kg/h infusion (n = 6), 10 ng/kg bolus + 100 ng/kg/h infusion (n = 5), 100 ng/kg bolus + 1000 ng/kg/h infusion (n = 8), 1000 ng/kg bolus + 10 mug/kg/h infusion (n = 6), and vehicle control (n = 5). Premature ventricular complexes (PVCs) were quantified during reperfusion. A series of four or more consecutive PVCs was defined as ventricular tachycardia (VT). The total incidence of VT was reduced significantly with the two highest doses of rotigaptide (20.3 +/- 10.9 and 4.3 +/- 4.1 events; p < 0.05) compared with controls (48.7 +/- 6.0). Total PVCs were reduced significantly from 25.1 +/- 4.2% in control animals to 11.0 +/- 4.4 and 1.7 +/- 1.3% after the two highest doses of rotigaptide. Infarct size, expressed as a percentage of the left ventricle, was reduced significantly from 13.2 +/- 1.9 in controls to 7.1 +/- 1.0 (p < 0.05) at the highest dose of rotigaptide. Ultrastructural evaluation revealed no differences in myocardial injury in the infarct area, area at risk, border zone, or normal zone in vehicle and rotigaptide-treated animals. However, rotigaptide did increase the presence of gap junctions in the area at risk (p = 0.022, Fisher's exact test). Rotigaptide had no effect on heart rate, blood pressure, heart rate-corrected QT interval, or left ventricular end-diastolic pressure. In conclusion, these results demonstrate that rotigaptide is a potent antiarrhythmic compound with cardioprotective effects and desirable safety.     

Emulsified isoflurane protects rat heart in situ after regional ischemia and reperfusion

Volatile anesthetic postconditioning reduces myocardial infarct size against ischemia/reperfusion (I/R) injury. We tested the hypothesis that emulsified isoflurane (EIso) administrated after ischemia exerts cardioprotection in a rat model of myocardial I/R. Male SD rats underwent 30‐min coronary occlusion followed by 3‐h reperfusion except for sham rats. All vehicles were administrated intravenously at reperfusion onset for 30 min. In the first study, 56 rats were given saline (CON), 30% intralipid (IL) and 1, 2, 4, 8 or 16 mL/kg EIso for infarct size measurement. In a second study, 32 rats were randomized to four groups and administrated saline in sham (sham) and control (CON) groups, 30% intralipid in IL group and 2 mL/kg emulsified isoflurane in EIso group. Cardiomyocytic enzyme activity was determined. Myocardial mitochondria and cytosol were isolated to determine mitochondrial energy metabolism, cytochrome c release, mitochondrial membrane potential (ΔΨm) and opening of the mitochondrial permeability transition pore (mPTP). Morphologic changes in mitochondria were observed by transmission electron microscopy. Compared with CON and IL, 2, 4 and 8 mL/kg EIso limited infarct size (P < 0.01). Serum levels of cardiac enzyme leakage were reduced in EIso‐treated hearts compared with CON (P < 0.01 or P < 0.05). EIso preserved the ultrastructure of mitochondria, protected against mPTP opening, decreased cytochrome c release and preserved ATP production and ΔΨ_m. In conclusion, EIso is effective in reducing infarct size and in preserving mitochondrial function after ischemia and reperfusion injury.     

斑点追踪成像技术评价梗死心肌和缺血心肌对左心室局部收缩功能的影响

目的应用超声斑点追踪成像(STI)技术分析梗死心肌及缺血心肌节段心肌纵向、径向及周向的收缩期峰值应变及应变率,评价其对左心室局部心肌收缩功能的影响。方法 35例心肌梗死患者(梗死组)、25例心肌缺血患者(缺血组)和25例正常体检者(正常组),接受超声检查,采集左心室长轴观、心尖四腔观,心尖二腔观及左心室短轴观(二尖瓣环水平、乳头肌水平和心尖水平)二维灰阶图像,按左心室18节段划分法,分析各个切面观心肌节段的纵向、径向和周向收缩期峰值应变及应变率。结果心肌缺血组纵向收缩期峰值应变及应变率低于正常组(P<0.05),而径向收缩期峰值应变、应变率和周向收缩期峰值应变、应变率低于正常节段,但差异无统计学意义(P>0.05);心肌梗死组径向、周向、纵向应变及应变率均显著低于正常组节段(P<0.01),也较缺血组节段低(P<0.05)。结论超声斑点追踪成像技术能准确评价梗死心肌和缺血心肌局部运动异常,纵向应变及应变率反映心肌缺血较其他指标敏感。     

左旋精氨酸对急性心肌缺血/再灌注损伤大鼠内皮素-1的影响

目的 探讨内皮素-1(ET-1)在大鼠心肌缺血/再灌注(I/R)损伤过程中的变化规律及左旋精氨酸(L-Arg)的影响.方法 采用结扎冠状动脉前降支0.5h复制Wistar大鼠心肌I/R损伤模型.110只大鼠按随机数字表法分为假手术组(C)、缺血0.5h组(I)、缺血0.5h+再灌注0.5h组(R0.5)、缺血0.5h+再灌注1h组(R1)、缺血0.5h+再灌注2h组(R2)、L-Arg+假手术组(L+C)、L-Arg+缺血0.5h组(L+I)、L-Arg+缺血0.5h+再灌注0.5h组(L+R0.5)、L-Arg+缺血0.5h+再灌注1h组(L+R1)、L-Arg+缺血0.5h+再灌注2h组(L+R2).用酶联免疫吸附法测定各组大鼠血清肌酸激酶(CK)、乳酸脱氢酶(LDH)活性;用放射免疫法测量血清ET-1水平;用逆转录-聚合酶链反应(RT-PCR)、蛋白质免疫印迹法(Western blotting)检测各组心肌组织中ET-1 mRNA和蛋白表达.结果 Ⅰ组和R组血清CK、LDH、ET-1均较C组明显升高,且R组较Ⅰ组升高明显.R组ET-1 mRNA和蛋白表达均较C组明显升高,以R2组最为显著(ET-1mRNA:0.775±0.029比0.310±0.076;ET-1蛋白:0.773±0.055比0.340±0.099,均P＜0.05);而静脉给予L-Arg预处理可明显降低ET-1 mRNA和蛋白表达(ET-1 mRNA:0.340±0.049比0.775±0.029;ET-1蛋白:0.390±0.094比0.773±0.055,均P＜0.05).结论 在心肌I/R损伤的某些阶段可试用L-Arg进行干预,降低ET-1的表达.     

Reduction of ischemia--reperfusion induced myocardial infarct size in rats by caffeic acid phenethyl ester (CAPE)

Myocardial ischemia--reperfusion (MI/R) represents a clinically relevant problem associated with thrombolysis, angioplasty, and coronary bypass surgery. MI/R injury is known to occur on restoration of coronary flow after a period of myocardial ischemia. Injury of myocardium caused by I/R includes cardiac contractile dysfunction, arrhythmias, as well as irreversible myocyte damage. Prevention of myocardial death in acute coronary syndromes is the immediate goal of therapy. The main factor concerned with the experimental generation of reperfusion damage is oxygen-derived free radicals. This MI/R injury has been shown to be salvaged by supplementing antioxidants to diseased hearts. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has antioxidant and anti-inflammatory properties, and may function in cardiac protection against I/R-induced damage. To test this hypothesis, we randomly assigned 14 male Wistar rats for necrosis experiments. To produce myocardial necrosis, the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion in anesthetized rats. CAPE (50 microM kg-1) was given intravenously 10 min before occlusion and continued during ischemia by infusion pump. The volume of infarct and the risk zone was determined by planimentry of each tracing and multiplying by the slice thickness. Infarct was normalized by expressing it as a percentage of the area at risk. Compared to control group, CAPE administration statistically reduced the myocardial infarct size/area of risk zone (50 +/- 4% and 32 +/- 6%, respectively) and the myocardial infarct size (23 +/- 3% and 9 +/- 4%, respectively) in rat model of ischemia-reperfusion. In conclusion, this result shows that CAPE is important in reducing I/R-induced myocardial damage.     

Brain natriuretic peptide limits myocardial infarct size dependent of nitric oxide synthase in rats

BACKGROUND: Brain natriuretic peptide (BNP) has recently been shown to have a cardioprotective effect in animal models of myocardial ischemia-reperfusion (I-R) injury. We hypothesized that exogenous BNP limits myocardial infarction on nitric oxide synthase pathway. METHODS: A rat model of myocardial I-R injury was established by ligating the left descending coronary artery for 30 min and then reperfusing for 2 h. BNP was injected with different dose 5 min after the ligation and lasting for 145 min. The myocardial infarct size and the area at risk of ischemia were measured by staining with triphenyltetrazolium chloride (TTC) and Evans blue dye. To examine the role of nitric oxide synthase (NOS), expression of eNOS in the left ventricle was analyzed by western blotting. Nomega-nitro-L-arginine methyl ester (L-NAME; 30 ug/kg), or S-methylisothiourea (SMT; 3 ug/kg) was administrated before I-R with or without BNP. RESULTS: The control infarct-to-risk ratio was 45.1+/-1.72% (means+/-SE). BNP infused 5 min after ischemia limited infarct size in a dosage-dependent manner, with maximal protection observed at 0.01 ug/(kg min) (infarct-to-risk: 24.7+/-1.69%, P<0.01 vs. control), associated with a 10-fold increase of myocardial endothelial nitric oxide synthase above the control value. Protection afforded by BNP was abolished by L-NAME but not by SMT, suggesting the involvement of putative endothelial but not inducible nitric oxide synthase activation. CONCLUSIONS: We conclude that natriuretic peptide/NOS/NO signaling may constitute an important injury-limiting mechanism in myocardium.