Ⅱ型糖尿病大鼠心梗后非梗死区心室重构的研究

目的:对比观察糖尿病(DM)大鼠心肌梗死(MI)后非梗死区域心肌肥大、增殖分化和细胞凋亡的改变,探讨DM对MI后心室重构的影响。方法:将实验大鼠分为正常对照组、糖尿病对照组、MI对照组及糖尿病MI组,从各组大鼠的左心室梗死周边取材,采用免疫组化染色法检测转化生长因子-β1(TGF-β1)、增殖细胞核抗原(PCNA),用末端脱氧核苷酸转移酶介导的dUTP末端缺口标记法(TUNEL)检测凋亡细胞,并进行对比分析。结果:DM大鼠MI后非梗死区域存在着明显的心肌肥大、增殖分化和细胞凋亡。试验表明,糖尿病MI组大鼠梗死区周边凋亡细胞及PCNA、TGF-β1的阳性率均明显高于DM对照组及MI对照组(P0.01)。DM对照组大鼠梗死区周边凋亡细胞的比例明显高于MI对照组(P0.01)。结论:DM可增强TGF-β1和PCNA的表达及增加细胞凋亡,三者可能为DM大鼠MI后高心律失常及高死亡率的病理生理基础。     

High cardiac angiotensin-II-forming activity in infarcted and non-infarcted human myocardium

The aims of this study were to compare human cardiac angiotensin-II-forming activity (AIIFA) between the intact area of control autopsy hearts without cardiac disease (n = 10) and the infarcted or non-infarcted area of autopsy hearts with myocardial infarction (MI, n = 7) and to determine responsible angiotensin-II-forming enzymes. Cardiac total and chymase-dependent AIIFAs were significantly higher in the infarcted and non-infarcted myocardium than those in non-MI heart, while angiotensin-converting enzyme-dependent AIIFA increased only in the infarcted myocardium. The density of chymase antibody-positive mast cells in the non-infarcted area of MI heart correlated positively with total or chymase-dependent AIIFA. Augmented AIIFA was also detected in the left atrium of post-MI hearts. Our results indicated that cardiac angiotensin II formation could be activated in the infarcted as well as in non-infarcted myocardium of the post-MI human heart.     

Effects of candesartan and cilazapril on rats with myocardial infarction assessed by echocardiography

The purpose of this study was to compare the angiotensin II type 1 receptor antagonist candesartan cilexitil (candesartan) and the angiotensin-converting enzyme inhibitor cilazapril on cardiac function, assessed by Doppler echocardiography and cardiac gene expression associated with cardiac remodeling, in rats with myocardial infarction. Candesartan or cilazapril was administered after myocardial infarction. At 1 and 4 weeks after myocardial infarction, cardiac function and mRNA expression in noninfarcted myocardium were analyzed. Candesartan and cilazapril equally prevented increases in hypertrophy in noninfarcted myocardium, left ventricular dilatation, and ejection fraction at 4 weeks. The E-wave/A-wave velocity ratio and the rate of E-wave deceleration, measures of diastolic function, increased to 9.2+/-0.6 and 26.3+/-2. 6 m/s2 at 1 week after myocardial infarction. Candesartan and cilazapril, administered at a dose of 1 mg/kg per day, prevented increases in E-wave/A-wave velocity ratio and E-wave deceleration at 1 and 4 weeks. Candesartan and cilazapril significantly suppressed increased mRNA expression of beta-myosin heavy chain, alpha-skeletal actin, and atrial natriuretic peptide in noninfarcted ventricle at 1 and 4 weeks and expression of collagen I and III at 4 weeks to a similar extent. When given at a dose of 10 mg/kg per day, both candesartan and cilazapril prevented cardiac dysfunction and gene expression to the same extent as when given at 1 mg/kg per day. In conclusion, Doppler echocardiography showed that candesartan and cilazapril equally improved systolic and diastolic function and that ventricular remodeling accompanied modulation of cardiac gene expression.     

Angiotensin blockade inhibits increased JNKs, AP-1 and NF- kappa B DNA-binding activities in myocardial infarcted rats

Inhibition of the renin-angiotensin system has been shown to prevent left ventricular remodeling after myocardial infarction. However, the effect of angiotensin on the signal transduction pathway of left ventricular remodeling after myocardial infarction is as yet unknown. The purpose of this study was to measure myocardial MAPKs and AP-1, NF- kappa B, and Sp-1 DNA-binding activities after myocardial infarction. Moreover, we evaluated the effects of angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) on signal transduction pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. Temocapril (ACE inhibitor) (3 and 30 mg/kg/day) and candesartan cilexitil (ARB) (1 and 10 mg/kg/day) were orally administered once a day. After ligation of the left descending coronary artery, JNKs (p46JNK and p55JNK) increased to 2.0- (P<0.01) and 2.8-fold (P<0.01) at 7 days, respectively. ERKs (p44ERK and p42ERK) and p38 activities did not increase significantly. AP-1 and NF- kappa B binding activities increased at 5 days, reached their peak 2.2- and 2.0-fold at 7 days. Sp-1 did not change. ACE inhibitor and ARB inhibited JNKs, NF- kappa B and AP-1 activities. Increased JNKs, AP-1, NF- kappa B, and Sp-1 DNA-binding activities were suppressed by both drugs in the infarcted region. Doppler-echocardiography showed that ACE inhibitor and ARB prevented the dilatation of left ventricular cavity at 14 days and improved diastolic filling pattern. JNKs, AP-1 and NF- kappa B activation in myocardial infarcted rats could be responsible for left ventricular remodeling after myocardial infarction and angiotensin may be related to the activation of these signals.     

Studies on pathophysiological significance of sympathetic activity in myocardial infarction.

In an attempt to elucidate the pathophysiological significance of the sympathetic hyperactivity in the acute stage of myocardial infarction, the author observed changes in the urinary excretion of CA, the CA content in the myocardium and the hemodynamics in both clinical and experimental myocardial infarction, and the following were found: 1) In clinical myocardial infarction, the urinary excretion of CA was markedly increased immediately after an attack, and the assay of myocardial specimens form the autopsied patients of acute myocardial infarction revealed that the CA content in the non-infarcted area was lower than that in the infarcted area. 2) In the experiments on rabbits with ligated coronary artery, the increase in cardiac contractility and rise in blood pressure in response to CA was supressed after the ligation of coronary artery. In the early stage of experimental myocardial infarction, the decrease of myocardial CA content in the non-infarcted area was, as in autopsied patients, predominant over the decrease of that in the infarcted area. In the chronic stage (more than one week after the coronary ligation), the CA content in the infarcted area showed further decrease, but in the non-infarcted area it was recovered to the level in the control animals. The uptake of exogenous NA into the non-infarcted area decreased in the acute stage, and in the infarcted area it showed marked decreased in the chronic stage. The urinary excretion of CA was increased in the acute stage of myocardial infarction. 3) The administration of betamethasone suppressed the decrease in the CA content in the myocardium following the ligation of coronary artery. Based on these findings, the author came to a postulation that the sympathetic hyperactivity which is suggested by increased urinary excretion of CA and decreased CA content in the myocardium results from the reasonable biophylactic reaction so as to supplement the cardiac hypofunction derived from myocardial infarction.     

A novel activation process of protein kinase C in the remote, non-ischemic area of an infarcted heart is mediated by angiotensin-AT1 receptors

BACKGROUND: Translocation and activation of protein kinase C (PKC) has been shown to occur in the ischemic heart. It is, however, controversial if this activation process occurs also in the non-ischemic, remote area of an infarcted heart early after infarction. Furthermore, the mechanisms contributing to the translocation process induced by acute myocardial ischemia in both areas are not fully elucidated. METHODS: Regional myocardial infarction was induced by left anterior descending coronary artery (LAD-) ligation in situ for 2.5 min in rats or in pigs. To evaluate the influence of angiotensin and bradykinin signaling, ramiprilat, candesartan, or the bradykinin-receptor antagonist HOE 140 was given. In biopsies from the ischemic and the non-ischemic remote area, PKC activity and intracellular isozyme distribution were determined. RESULTS: Translocation and activation of PKC could be demonstrated for the first time in the myocardium remote from the infarcted area. This activation was conserved both in pigs and in rats. All major cardiac isozymes of PKC were involved. Whereas bradykinin-receptor blockade had no effect, both angiotensin-converting enzyme inhibition (ACEI) and angiotensin receptor could effectively block this activation process of PKC. CONCLUSION: In the area remote from a myocardial infarction, the activation of PKC could be detected for the first time as early as 2.5 min after LAD ligation. This newly characterized activation in the non-infarcted area can be prevented by ACEI via an angiotensin-AT1-receptor-dependent mechanism. It is supposed that this newly characterized activation process of PKC plays an important role in the signal transduction in the remote myocardium in acute myocardial infarction as a trigger for the late development of hypertrophy and heart failure.     

The impaired tolerance of the recently infarcted rat heart to cardioplegic arrest: the protective effect of orotic acid

After myocardial infarction, a reduced mass of non-infarcted myocardium remains to maintain cardiac output. This acutely stressed, non-infarcted myocardium exhibits many metabolic disturbances, and undergoes a process of acute hypertrophy. These stress-induced disturbances may reduce the tolerance of the heart to the global ischaemia of cardioplegic arrest and may explain the increased mortality and morbidity associated with cardiac surgery in patients with recent myocardial infarction. We postulated that orotic acid, a pyrimidine precursor which augments the rate of protein synthesis during hypertrophy, might improve the response of the recently infarcted heart to cardioplegic arrest. Myocardial infarction was induced in rats by coronary ligation, and after 2 days or 3 days the hearts were excised and perfused on the working heart apparatus. After measurement of work capacity, the hearts underwent 1 hour of hypothermic cardioplegic arrest. Post-arrest function was then measured and expressed as a percentage of the pre-arrest value. A group of sham-operated, non-infarcted hearts served as controls. There were two distinct findings: (1) when subjected to hypothermic cardioplegic arrest 2 days after myocardial infarction, hearts recovered only 49% of pre-arrest function, compared with 80% recovery in non-infarcted controls (P less than 0.001). Three days after infarction, recovery had improved to 68% (P less than 0.01 vs. 2 days, P less than 0.05 vs. non-infarcted). (2) Treatment with oral orotic acid following infarction augmented recovery from cardioplegic arrest to 83%, 2 days after infarction (P less than 0.001 vs. untreated) and to 87%, 3 days after infarction (P less than 0.01 vs. untreated).(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased expression of Na+/H+ exchanger isoform 1 (NHE1) in non-infarcted myocardium after acute myocardial infarction

Although cardiac NHE1 is activated during myocardial ischemia and reperfusion injury, little is known about changes in expression in non-infarcted myocardium after acute myocardial infarction (AMI). The purpose of this study was to examine left ventricular function and region dependent NHE1 expression after myocardial infarction. Therefore, we produced two AMI models in rats, a small infarction model which was continuously ligated at the branches of the left coronary artery, and an extensive infarction model continuously ligated at the root of the artery. We examined NHE1 mRNA expression using RNase protection assay and protein levels using Western blot analysis in non-infarcted myocardium during the 24 hour period after AMI. The level of NHE1 mRNA and protein expression in the whole heart including the infarcted myocardium did not change after a small infarction. On the other hand, in the case of an extensive infarction, the levels of NHE1 mRNA and protein expression decreased significantly by 21.5% (P<0.05) and by 22.0% (P<0.05), respectively, in non-infarcted myocardium. Left ventricular systolic pressure (LVSP) decreased significantly by 13% and 38% with the branch and root ligation, respectively. However, left ventricular end-diastolic pressure (LVEDP) only increased with the root ligation. These results indicate that NHE1 expression decreased in response to extensive myocardial infarction only in non-infarcted myocardium. The present study may be important in furthering the understanding of NHE1 in myocardial infarction and suggests that decreased expression of NHE1 in non-infarcted myocardium may decrease the extent of cardiac cell injury.     

Myocardial enzyme depletion in infarcted human hearts: infarct size and equivalent tissue mass

Myocardial activities of several enzymes were measured in infarcted and non-infarcted areas of heart sections obtained from eight patients who died after acute myocardial infarction. Similar data were obtained from four patients with cardiovascular disorders who died from causes other than myocardial infarction and from six patients without previously known heart disease. It was found that both non-infarcted and infarcted tissue samples contained considerably altered enzyme activities. This finding explains the low correlations between enzymatic and histological estimates of infarct size previously reported. However, when the residual myocardial activities of different enzymes were compared with each other, a close correlation was found between creatine kinase, alpha-hydroxybutyrate dehydrogenase, and aspartate aminotransferase. It appears that the pathological changes in the myocardial activities of these enzymes may be explained by the phenomenon of diluted myocardium. This indicates that myocardial injury, as estimated from plasma enzyme activities, may still be expressed meaningfully in gram equivalents of healthy myocardium.     

重组人生长激素对心肌梗死大鼠心功能及心肌炎性因子表达的影响

目的 观察重组人生长激素(rhGH)对大鼠急性心肌梗死后心功能及心肌炎性因子表达的影响. 方法 结扎大鼠左冠状动脉前降支建立心肌梗死模型,将术后24 h存活的大鼠随机分为对照组和rhGH组,另设假手术组.rhGH组给予rhGH 2 mg.kg-1.d-1皮下注射,对照组和假手术组给予等体积的生理盐水皮下注射,4周后观察rhGH对大鼠心功能及心肌细胞肿瘤坏死因子-α(TNF-α)、白介素-1p(IL-1p)、白介素-6(IL-6)、白介素-10(IL-10)mRNA表达的影响. 结果 与假手术组比较,对照组心肌组织中促炎性细胞因子TNF-α、IL-1β、IL-β和IL-10 mRNA表达(假手术组分别为0.10±0.02、0.08±0.01、0.18±0.01和0.14±0.05;梗死区分别为0.77±0.15、0.93±0.17、1.10±0.14和0.73±0.11;非梗死区分别为0.88±0.14、0.95±0.17、1.18±0.11和0.83±0.16)明显升高.与对照组比较,rhGH组心肌组织中TNF-α、IL-1β、IL-6 mRNA表达(梗死区分别为0.35±0.10、0.36±0.10、0.43±0.11;非梗死区分别为0.51±0.10、0.42±0.11、0.51±0.12)明显下降,IL-10 mRNA表达(梗死区为1.18±0.18;非梗死区为1.21±0.22)升高,P＜0.05.心脏超声显示rhGH组左室功能明显改善. 结论 早期rhGH治疗改善了心肌梗死大鼠心肌炎性因子表达和心脏功能.rhGH有效改善心功能与其降低心肌细胞促炎细胞因子和升高抗炎因子的作用有关.     

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca²⁺ transport protein, such as sarcoplasmic reticulum Ca²⁺(SR-Ca²⁺)-ATPase, Na⁺-Ca²⁺ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca ²⁺ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ration of E wave to A wave velocity. Expression of myocardial α-skeletal actin, β-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca²⁺-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na⁺-Ca²⁺ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling. Received: 9 August 1999, Returned for revision: 16 September 1999, Revision received: 5 January 2000, Accepted: 26 January 2000     

Cellular repopulation of myocardial infarction in patients with sex-mismatched heart transplantation.

AIMS: Recent studies have suggested that human extracardiac progenitor cells are capable of differentiating into cardiomyocytes. In animal studies, myocardial infarction attracted bone marrow stem cells and enhanced their differentiation into cardiomyocytes. Based on these findings, we hypothesised that myocardial infarction stimulates the invasion of progenitor cells and their differentiation into endothelial and cardiac cells in the human heart. METHODS AND RESULTS: We compared autopsy samples from male control patients who had received a female donor heart with samples from such patients who developed myocardial infarction after transplantation. Fluorescence in situ hybridisation (FISH) for detection of the Y-chromosome was combined with immunofluorescence staining for CD45 and CD68 to distinguish host-derived inflammatory cells. Additionally, we used a 3D-confocal imaging technique to indisputably assign Y-chromosome-positive nuclei to their cytoplasm. In patients with myocardial infarction after heart transplantation (n=5), host-derived non-inflammatory progenitor and endothelial cells were significantly increased compared to non-infarcted patients (n=9). Yet, by using this novel multi-step approach, only 0.02% of all cells were estimated to be male cardiomyocytes and their increase in infarcted regions to 0.07% was not significant. CONCLUSION: Myocardial infarction enhances the invasion of extracardiac progenitor cells and their regeneration of endothelial cells. However, a significant differentiation into cardiomyocytes as a physiological mechanism of postischaemic regeneration does not occur in transplanted patients.     

Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheep

Cardiac remodeling following myocardial infarction (MI) is a maladaptive process, fundamental to the progression of ischemic heart failure. The extent of remodeling is influenced by mechanical stress, inflammatory response and activation of matrix metalloproteinases (MMPs). This study examined regional association between these parameters in response to acute MI. Coronary ligation was performed in ten sheep. Sonomicrometer transducers measured segmental length in the infarcted, border and non-infarcted region. Regional tissue samples obtained 3 h post MI from six sheep were analysed using RT-PCR, gelatin zymography and Western blot. Six sham-operated sheep served as controls. Region-specific dilation and reduced contraction was associated with corresponding alterations in matrix molecules.IL-6 and MMP-9 mRNA were increased in the infarcted and border regions compared to controls.MMP-2 and TIMP-1 mRNA increased in non–infarcted myocardium and both correlated positively with segmental shortening. IL-6 mRNA levels, in contrast, were negatively associated with segmental shortening. In summary, inflammatory cytokines and MMPs are altered early after MI in a region-specific manner, and these changes correspond to acute regional myocardial dysfunction. Therapies for LV remodeling from the time of reperfusion may benefit from further understanding this portfolio of acute alterations.     

Left ventricular dilatation following myocardial infarction: clinical course and potential for therapy

The enlarged heart has long been recognized as an important sign of systolic dysfunction of many different etiologies. Regardless of etiology, cardiac enlargement is associated with decreased survival. Cardiac enlargement after acute myocardial infarction (AMI) may be a progressive process. Early after AMI, the process of infarct expansion, or thinning and stretching of the infarct region leads to early volume enlargement detectable within 3 days of the infarct. During the next 2 weeks, volume enlargement takes place which includes lengthening of both the infarcted and the non-infarcted regions. Finally, additional left ventricular enlargement occurs during the next year after the infarction. Both experimental and clinical studies have demonstrated that such progressive LV enlargement may be halted by angiotensin converting enzyme inhibition with captopril. A large scale randomized trial is currently under way to determine whether captopril improves survival after infarction (Survival and Ventricular Enlargement, SAVE).     

PCI术后AMI患者非梗死区冠脉血流储备的变化及其对左室功能的影响

目的 观察和分析急性心肌梗死（AMI）患者PCI术后非梗死区冠脉血流储备（CFR）的变化及其对左室功能的影响。方法 22名AMI患者PCI术后1周行二维超声心动图和多巴酚丁胺负荷实时心肌声学造影（MCE）检查,测量左室功能和梗死区、非梗死区CFR,比较非梗死区CFR与梗死区及正常对照组CFR;根据非梗死区CFR值将患者分为两组,比较两组远期左室功能的变化。结果 非梗死区CFR值与正常对照组相比明显下降,非梗死区CFR与左室舒张末期容积呈负相关。结论 AMI后非梗死区心肌同样存在微循环功能障碍,非梗死区CFR值能预测AMI后远期左室功能。     

Influence of frequency of atrial contraction on coronary blood flow and ventricular performance in the conscious dog with myocardial infarction.

The effects of alterations in the frequency of contraction on coronary blood flow and ventricular performance were studied in 12 conscious, unsedated dogs with established myocardial infarction. Total and regional coronary blood flow was measured using radioactive microspheres. The peak increase in flow to the right ventricle was 71% to the infarcted area of the left ventricle was 72% to the non-infarcted area of the left ventricle was 90% and to the ventricular septum was 104%. Despite the generalized increases in regional myocardial blood flow, flow tended to decrease to the subendocardial portion of the infarcted area of the left ventricle. The peak increases in coronary flow and the reduction in flow to the subendocardial portion of the infarcted area occurred at a heart rate of approximately 200/min provided by atrial pacing. Myocardial contractility, as evidenced by peak increases of 16% in maximum LV dP/dt and 12% in dP/dtP, was only enhanced with abrupt incremental changes in heart rate and not with continuous atrial pacing over 15-min periods. Despite the generalized increases in coronary perfusion coronary sinus oxygen content decreased with a widening of the coronary arteriovenous oxygen difference indicating increased myocardial oxygen usage. Thus increasing frequency of contraction in myocardial infarction results in a slight initial but not sustained inotropic effect, a moderate and generalized increase in regional myocardial blood flow, increased myocardial oxygen consumption, and the potential for subendocardial extension of the area of myocardial damage within the infarcted area.     

Echoventriculography in acute myocardial infarction. II: Monitoring of left ventricular performance.

In acute myocardial infarction the overall left ventricular pump function and the regional performance of the infarcted and non-infarcted myocardial segments were studied serially by echocardiographic techniques in 24 patients during the first week of their illness. Left ventricular cavity sizes were acutely increased in 62 per cent of the patients (P less than 0-005). The end-systolic diameter in anterior infarcts increased to the greatest extent, +44 per cent, the end-diastolic diameter by +27 per cent, giving a volume of 246+/-25 ml. In the anterior myocardial infarcts all the function parameters deteriorated more than in the posteroinferior ones. Ejection fraction was subnormal (P less than 0-005) in every patient, and mean circumferential fibre shortening (Vcf) was slowed by about 30 per cent (P less than 0-005). Regionally, contraction of the infarcted area of the ventricle was asynergic in every instance, and its function was almost totally lost (P less than 0-001). Systolic paradoxical motion was a constant and stable finding in the anterior infarctions but not so in the posterior ones. While this asynergic systolic contraction may distort echocardiographic measurement of the end-systolic left vlic phase. The serial deviations from normal in the amplitude or velocity of the uninvolved segments were small, but in the case of clearly enlarged end-diastolic volumes these figures in fact indicate supernormal, compensating function. Both overall and regional performance were worst within the first 3 days of infarction, improving thereafter. The patient with a fatal course showed, instead, progressive deterioration. This noninvasive left ventriculogram by ultrasound gives valuable insight into overall pump function and ventricular volumes, little studied so far in acute infarction, and it may serially quantify the segmental function of both the infarcted and uninvolved regions.     

Increased apoptosis in remote non-infarcted myocardium in multivessel coronary disease

BACKGROUND: Multivessel coronary disease after myocardial infarction is a major risk factor for unfavorable cardiac remodeling and death due to pump failure, but underlying pathophysiologic mechanisms are still uncompletely established. Post-infarction myocardial apoptosis has been recently implicated as a cause of ongoing cell loss leading to cardiac failure. Our aim was to assess the role of post-infarction myocardial apoptosis and pro-apoptotic factor expression in the non-infarcted remote myocardium of subjects with multivessel coronary disease. METHODS: Twenty-one males dying after recent myocardial infarction with permanent occlusion of the infarct-related artery were selected at autopsy. Apoptosis was assessed at viable myocardial regions remote from infarction by co-staining for in situ end-labeling of DNA fragmentation and cleaved caspase-3. Expression of pro-apoptotic factor bax and hypoxia-induced factor-1alpha was evaluated by immunohistochemistry. RESULTS: Subjects with multivessel disease (N=11) showed a significantly two-fold higher myocardial apoptosis in comparison to subjects with single vessel disease (N=10) (0.9% vs. 0.5%, p=0.013). Similarly, myocardial bax expression was increased in patients with multivessel disease (3.0% vs. 1.4%, p=0.029). Stratification for the number of diseased coronary vessels confirmed the association between extent of coronary disease and apoptotic rates (p=0.022). Even in subjects dying over 30 days after infarction multivessel disease remained predictive of enhanced myocardiocyte apoptosis at remote regions (p=0.033). CONCLUSIONS: Post-infarction myocardial apoptosis and bax expression in remote left ventricular regions are significantly increased in male patients with multivessel coronary disease in comparison to those with isolated infarct-related artery occlusion. These findings suggest that apoptotic cell loss in the viable non-infarcted myocardium, possibly due ongoing ischemia, may play a relevant role in the unfavorable clinical course typical of multivessel disease after myocardial infarction.