Biomechanical properties of reperfused transmural myocardial infarcts in rabbits during the first week after infarction. Implications for left ventricular rupture.

Left ventricular (LV) rupture potential was studied after transmural myocardial infarction (MI) in rabbits by measuring 1) the tensile strength of infarcted tissue strips, 2) the force required to initiate a tear (tear threshold) in the central infarcted region, and 3) the intracavitary pressure required to rupture the infarcted ventricle. During the first week after MI, infarcts resulting from a permanent coronary occlusion were compared with infarcts reperfused "late" (i.e., 3 hours) after coronary occlusion with a resultant hemorrhagic transmural infarct but no reduction in infarct size. The reperfused hemorrhagic infarcted strips had less tensile strength than strips from permanently occluded infarcts in the initial 24 hours after MI (16 +/- 1 versus 24 +/- 3 g/mm2, p less than 0.05), but the tear threshold and response to increased LV pressure were not influenced by infarct reperfusion at this time. By 3 days after MI, reperfused infarcts had equal tensile strength, had greater resistance to infarct tearing, and could withstand a greater LV distending pressure compared with permanently occluded infarcts. By 5 days after MI, reperfused infarcts maintained a greater tear threshold but had less tensile strength than permanently occluded infarcts, although all infarct values were equivalent or greater than normal LV values. By 7 days after MI, reperfused and permanently occluded infarcts were equally strong by all measurements. Thus, late reperfusion of transmural infarcts increased resistance to infarct tearing and LV rupture above that of nonreperfused permanently occluded infarcts by 3 days after MI and enhanced tissue strength after an initial 24-hour vulnerable period. These findings suggest that late reperfusion may accelerate myocardial healing after MI.     

Opposite effects of amlodipine and enalapril on infarct collagen and remodelling during healing after reperfused myocardial infarction

OBJECTIVES: To compare the effects of the calcium channel blocker amlodipine versus the angiotensin-converting enzyme inhibitor enalapril with or without reperfusion on infarct collagen and remodelling during healing after anterior myocardial infarction (MI). ANIMALS AND METHODS: In vivo left ventricular (LV) remodelling and function (by quantitative echocardiography) and hemodynamics were measured over six weeks in dogs that were randomized 24 h after reperfusion (2 h after anterior MI) or no reperfusion to oral amlodipine (5 mg bid, n=6), enalapril (5 mg bid, n=6), placebo (bid, n=6) or sham surgery (n=6) for six weeks. Ex vivo infarct size, infarct collagen (hydroxyproline), collagen volume fraction and LV topography were measured at six weeks. RESULTS: Compared with placebo controls without reperfusion over six weeks in vivo, enalapril or amlodipine with or without reperfusion produced LV unloading and preserved volumes, shape and function, but enalapril limited LV hypertrophy more than amlodipine. However, compared with no reperfusion, amlodipine preserved infarct wall thickness and shape while enalapril decreased infarct wall thickness and increased the shape index. Ex vivo at six weeks, scar size as a percentage of risk was similar in the MI groups. Importantly, enalapril decreased infarct collagen already lowered by reperfusion, while amlodipine preserved infarct collagen after reperfusion and increased collagen volume fraction in spared myocardium. CONCLUSIONS: Preservation of infarct collagen limits infarct remodelling during healing after reperfused MI and preserves LV shape. Amlodipine and enalapril exert opposite effects on infarct collagen and remodelling after reperfused MI.     

肾脏缺血后处理对兔急性缺血再灌注心肌细胞凋亡和Bcl-2、Bax蛋白表达的影响

目的研究肾脏缺血后处理对兔急性缺血再灌注心肌细胞凋亡的影响,并探讨其保护机制。方法24只新西兰大白兔随机分为3组,每组8只。（1）缺血再灌注组（IR组）：结扎左冠状动脉前降支1h,再灌注6h。（2）肾脏缺血后处理组（RI-Post组）：操作同IR组,在再灌注即刻用动脉血管夹反复夹闭左侧肾动脉（阻断30S,再通30S,重复3次）,再灌注6h。（3）药物干预组（MI组）：结扎左冠状动脉前降支1h,再灌注前10min给予蛋白激酶C抑制剂-GF109203X（O．05mg／kg）耳缘静脉注射持续10min,再灌注即刻行RI-Post组操作,最后心肌再灌注直至6h。实验结束,采用Tunel法检测24只兔梗死区的心肌细胞凋亡,用免疫组化法检测Bax和Bcl-2蛋白在心肌细胞中的表达水平。结果肾脏缺血后处理组与对照组和药物干预组比较,心肌细胞凋亡指数明显减少（P〈0．05）,Bcl-2表达明显增多（P〈0．01）,Bax表达明显减少（P〈0．05）;而药物干预组与对照组相比各检测指标无明显差别（P〉0．05）。结论肾脏缺血后处理可减少急性缺血再灌注后心肌细胞凋亡,并影响Bcl-2、Bax蛋白的表达,从而对缺血心肌产生保护作用,其保护机制可能与激活蛋白激酶C有关。     

Reperfusion alters the relation between blood flow and the remaining myocardial infarction

This study evaluated whether or not reperfusion of ischemic myocardium 2 hours after occlusion alters the basic relation between myocardial blood flow and infarction occurring during permanent occlusion. Awake mongrel dogs chronically instrumented with proximal circumflex coronary occluders were subjected to permanent occlusion (group A, n = 10) or occlusion followed by reperfusion 2 hours later (group B, n = 11). Myocardial blood flow was quantified with radioactive microsphere injections before, 6 hours after occlusion (group A), immediately before release, and 4 hours after reperfusion (group B). Three days later, the dogs were killed, and the heart was sectioned systematically into approximately 80 1-2-g circumferential and transmural samples for radioactive counting and histologic infarct quantification. Epimyocardial and endomyocardial samples from the permanent occlusion group (A) and the reperfused group (B) were separated by infarct range and related to regional myocardial blood flow measurements. In groups A and B, regional myocardial blood flow in endomyocardial and epimyocardial layers were inversely related to the extent of infarction. For given degrees of infarction, myocardial blood flow was significantly higher (greater than twofold) in the reperfused group. Myocardial samples with extensive infarction (51-75%) showed only mild (20-30%) reductions in blood flow when compared with nonischemic regions in the reperfused group. Thus, although early reperfusion may salvage ischemic myocardium, these studies showed that reperfusion causes a new relation between blood flow to the ischemic region and eventual histologic infarct size. When myocardial blood flow is used as an index of myocardial salvage after reperfusion, the basic relation obtained from permanent occlusion studies substantially overestimates the extent of myocardial salvage and underestimates the degree of remaining infarction.     

Use of computerized tomography to assess myocardial infarct size and ventricular function in dogs during acute coronary occlusion and reperfusion

Prospectively ECG-gated and nongated computed tomography (CT) can be used to assess global and regional left ventricular (LV) function and to measure myocardial infarct (MI) size. In the current study, CT was used to assess the effects of coronary occlusion and reperfusion in 16 dogs. Ten dogs were subjected to permanent occlusion of the proximal left anterior descending coronary artery and 6 dogs were reperfused after a 2-hour period of total coronary occlusion. Gated scans were used to quantitate the extent of wall thickening in the ischemic zone and to assess changes in mid-LV cross-sectional chamber area at end-diastole and end-systole. Nongated scans were used to estimate the size of the initial perfusion defect during contrast injection shortly after coronary occlusion and the size of the MI as indicated by delayed enhancement of the infarct 10 to 30 minutes after cessation of contrast administration. Neither group showed significant changes in end-diastolic chamber area during acute occlusion or 3 days later. Both groups showed a significant deterioration in percent change in chamber area both early after coronary occlusion and 3 days later; however, in the permanent occlusion group, percent wall thickening in the ischemic zone decreased from 46.2 +/- 16.5% (mean +/- standard deviation) to 1.6 +/- 9.0% during acute occlusion (p less than 0.01) and thickening remained depressed 3 days later (2.4 +/- 10.1%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Granulocyte-colony stimulating factor administration after myocardial infarction in a porcine ischemia-reperfusion model: functional and pathological effects of dose timing.

BACKGROUND: Acute MI results in cardiomyocyte death, left ventricular (LV) dysfunction and adverse remodeling. The use of growth factors may prevent this. The aim of this study was to assess early and delayed administration of granulocyte colony-stimulating factor (G-CSF) in a porcine model of myocardial infarction (MI) and reperfusion. METHODS: MI was induced by balloon occlusion followed by reperfusion. There were 3 groups: Control (n = 11), Early (n = 17), and Delayed treatment (n = 8). The Early group received G-CSF 10 microg/kg/d every other day for 20 days beginning immediately. The Delayed group received G-CSF 10 microg/kg/d daily for 10 days beginning on day 5. Magnetic resonance imaging was performed on days 5 and 56. LV end-diastolic volumes (EDV), end-systolic volumes, ejection fraction, expansion index, sphericity index, thinning ratio, and infarct mass were calculated. Histology was analyzed at 56 days. RESULTS: At 56 days the change in EDV was 53% less in the Early (p = 0.005) and 24% greater in the Delayed (p = NS) group versus Control. The Delayed group also showed a 60% increase in normalized infarct mass (p = 0.055) and an 88% increase in expansion index (p = 0.003). Both groups had significantly less capillary density in the infarct border zone. The Delayed also had decreased arteriolar density in the mid scar. CONCLUSIONS: Early treatment with G-CSF after MI decreases ventricular dilatation, while delayed treatment has a deleterious effect on LV remodeling. This may be related to changes in myocardial vascularity. The effects of G-CSF therapy and its dose timing help to elucidate the results of recent human trials.     

Implicación de la isoforma antiangiogénica VEGF-A165b en la angiogénesis y la función sistólica tras un infarto de miocardio reperfundido

Introduction and objectivesAngiogenesis helps to reestablish microcirculation after myocardial infarction (MI). In this study, we aimed to further understand the role of the antiangiogenic isoform vascular endothelial growth factor (VEGF)-A₁₆₅b after MI and to explore its potential as a coadjuvant therapy to coronary reperfusion.MethodsTwo mice MI models were formed: a) permanent coronary ligation (nonreperfused MI); b) transient 45-minute coronary occlusion followed by reperfusion (reperfused MI); in both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. We determined serum and myocardial VEGF-A₁₆₅b levels. In both experimental MI models, we assessed the functional and structural role of VEGF-A₁₆₅b blockade. In a cohort of 104 ST-segment elevation MI patients, circulating VEGF-A₁₆₅b levels were correlated with cardiovascular magnetic resonance-derived left ventricular ejection fraction at 6 months and with the occurrence of adverse events (death, heart failure, and/or reinfarction).ResultsIn both models, circulating and myocardial VEGF-A₁₆₅b levels were increased 21 days after MI induction. Serum VEGF-A₁₆₅b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A₁₆₅b blockade increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in nonreperfused, MI experiments. In patients, higher VEGF-A₁₆₅b levels correlated with depressed ejection fraction and worse outcomes.ConclusionsIn experimental and clinical studies, higher serum VEGF-A₁₆₅b levels are associated with worse systolic function. Their blockade enhances neoangiogenesis, reduces infarct size, and increases ejection fraction in reperfused, but not in nonreperfused, MI experiments. Therefore, VEGF-A₁₆₅b neutralization represents a potential coadjuvant therapy to coronary reperfusion.     

Relation of circulating interleukin-6 to left ventricular remodeling in patients with reperfused anterior myocardial infarction

BACKGROUND: During the remodeling process after myocardial infarction (MI), the expression of proinflammatory cytokines is enhanced in the myocardium. However, only a few clinical studies have been conducted on cytokine involvement in left ventricular (LV) remodeling after MI. HYPOTHESIS: Circulating proinflammatory cytokines may be involved in LV remodeling in patients with reperfused MI. METHODS: We studied 25 patients with acute anterior MI who had undergone coronary reperfusion therapy, and 10 normal control subjects with no cardiac disease. In all patients, LV ejection fraction, end-diastolic volume index (EDVI), and end-systolic volume index (ESVI) were determined using left ventriculography at the acute phase and 6 months after onset. The delta EDVI and delta ESVI were calculated as the value of LV volume reduction, suggesting LV reverse remodeling. Serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were measured using enzyme-linked immunosorbent assay. RESULTS: Serum levels of IL-6 and TNF-alpha at the acute phase were significantly higher in patients with MI than in control subjects (both p < 0.05). The IL-6 levels correlated well negatively with delta EDVI (r = 0.779, p = 0.039), whereas no correlation was found for TNF-alpha. According to multivariate analysis, IL-6 at the acute phase was a significant independent predictor for LV remodeling after reperfused MI (p = 0.007). CONCLUSIONS: Circulating IL-6 levels correlated closely with LV geometric changes during the remodeling process in patients with reperfused MI. Our study addresses the usefulness of another marker for LV remodeling after MI.     

Influence of embryonic cardiomyocyte transplantation on the progression of heart failure in a rat model of extensive myocardial infarction.

Cell transplantation has been proposed as a future therapy for various myocardial diseases. It is unknown, however, whether the encouraging results obtained in animal models of ischemia and reperfusion, cryoinjury or cardiomyopathy can be reproduced in the setting of permanent coronary artery occlusion and extensive myocardial infarction (MI). Embryonic cardiac cells were isolated and cultured for 3 days to confirm viability, morphology and to label cells with BrdU or the reporter gene LacZ. Seven days after extensive MI, rats were randomized to cell (1.5x10(6)) transplantation (n=11) or culture medium injection (n=16) into the myocardial scar. Echocardiography study was performed before and 53+/-3 days after implantation to assess left ventricular (LV) remodeling and function. During follow-up, there was no mortality among cell-treated rats v 4 of 16 control rats (P=0.12). X-gal staining, BrdU and alpha -SMA immunohistochemistry identified the engrafted cells 1 week, 4 weeks and 8 weeks after transplantation, respectively. Antibodies against alpha -SMA, connexin-43, fast and slow myosin heavy chain revealed grafts in various stages of differentiation in 10 of 11 cell-treated hearts. Many of them, however, kept their embryonic phenotype and were isolated from the host myocardium by scar tissue. Serial echocardiography studies revealed that cell transplantation prevented scar thinning, LV dilatation and dysfunction while control animals developed scar thinning, significant LV dilatation accompanied by progressive deterioration in LV contractility. Transplantation of embryonic cardiomyocytes after extensive MI in a rat model attenuate LV dilatation, infarct thinning, and myocardial dysfunction. Still, many grafts remain isolated and do not differentiate into an adult phenotype, even when studied 2 months after grafting.     

Influence of reperfusion therapy on left ventricular remodeling after acute myocardial infarction

To determine the relation between reperfusion therapy and left ventricular function and remodeling after acute myocardial infarction (AMI), 75 consecutive patients with anterior AMI were studied. The patients were divided into four groups according to the reperfusion outcome and time to reperfusion from onset of MI: 12 patients with spontaneous reperfusion, 18 patients with early (less than 4th) successful reperfusion, 16 patients with late (greater than or equal to 4th) successful reperfusion and 29 patients with unsuccessful reperfusion. The right oblique left ventriculograms (LVG), which was performed early (n = 19) and late after infarction (n = 75) were analyzed to assess left ventricular (LV) volume and global and regional LV function. At the late examination, spontaneous early and late reperfused patients showed smaller LV volume (endo diastolic and endo-systolic volume index) than unsuccessfully reperfused patients LV volume was similar in both early and late reperfused patients. Spontaneous and early reperfused patients showed higher LV ejection fraction (EF) and better regional wall motion (RWM) than unsuccessfully reperfused patients. Both EF and RWM was similar in late and unsuccessfully reperfused patients at the late examination. Endo-diastolic and endo-systolic volume index increased significantly with time in patients with unsuccessful reperfusion (n = 10), as compared with the index found in the early examination. In patients with late reperfusion (n = 5), end-diastolic volume index increased with time, but end-systolic volume index was unchanged. RMW improved in patients with early reperfusion (n = 4), but was unchanged in patients with late and unsuccessful reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Late coronary artery reperfusion has additive beneficial effects on infarct expansion when combined with early angiotensin converting enzyme inhibitor therapy post myocardial infarction

Background: Individually, late coronary artery reperfusion and early angiotensin converting enzyme (ACE) inhibitor therapy prevent infarct expansion post myocardial infarction (MI). Objectives: To examine the effect of late reperfusion on infarct expansion when added to early ACE inhibitor therapy post MI. Methods: Rats were randomized into two groups: Reperfusion group: rats underwent coronary artery occlusion followed by reperfusion 2 hours after MI, a time too late to reduce infarct size. A control group: rats underwent permanent coronary artery occlusion followed by a sham operation 2 hours after MI. All rats received enalapril (2.0 ± 0.2 mg/kg) daily in drinking water, started immediately after the second operation. Rats were sacrificed 2 weeks after coronary occlusion. Hearts were arrested and fixed at a constant pressure, then sectioned and photographed for morphometric analysis. Results: Infarct size was similar in the reperfusion and control groups (23 ± 2 vs 26 ± 2%, p = NS). Septal thickness was also similar in both groups (1.8 ± 0.1 vs 1.8 ± 0.1 mm, p = NS). There was a trend towards thicker infarcts in the reperfusion group compared to the control group (0.84 ± 0.06 vs 0.72 ± 0.05 mm, p = 0.1). Compared to early ACE inhibition alone, late reperfusion combined with early ACE inhibition limited infarct expansion (expansion index, 1.13 ± 0.12 vs 1.44 ± 0.14, p < 0.05), prevented left ventricular (LV) dilation (LV volume, 0.30 ± 0.02 vs 0.39 ± 0.03 ml, p < 0.01) and prevented LV hypertrophy (LV weight, 0.71 ± 0.18 vs 0.77 ± 0.20 gm, p < 0.05). Conclusions: Late coronary artery reperfusion prevents infarct expansion, LV dilation and hypertrophy even when added to early ACE inhibitor therapy post MI. This suggests that late reperfusion may be beneficial in patients with acute MI treated with early ACE inhibitor therapy.     

Long-term prognosis of late spontaneous reperfusion after failed thrombolysis for acute myocardial infarction

BACKGROUND: Early reperfusion improves left ventricular (LV) function and survival after acute myocardial infarction (MI). Thrombolytic therapy achieves early patency of the infarct artery in about two-thirds of patients. In nearly half of the remaining patients, in whom early reperfusion was not achieved with thrombolytic therapy, the infarct artery might reopen by the time of predischarge angiography. However, the impact of such late spontaneous reperfusion after failed thrombolytic therapy on LV function and long-term survival remained unclear. HYPOTHESIS: This study was undertaken to assess implication of late spontaneous reperfusion after failed thrombolytic therapy on LV function and long-term survival after acute MI. METHODS: The study consisted of 198 patients with anterior acute MI who underwent thrombolytic therapy and predischarge angiography: 160 patients with infarct artery patent early and late after therapy (persistent patency), 17 patients with infarct artery occluded early after therapy but patent at predischarge angiography (late spontaneous reperfusion), and 21 patients with infarct artery occluded early and late after therapy (persistent occlusion). RESULTS: Persistent patency was associated with enhanced improvement in LV ejection fraction (7.7 +/- 11.8%) compared with late spontaneous reperfusion (0.0 +/- 9.6%, p = 0.03) and persistent occlusion (-1.4 +/- 9.7%, p = 0.003). Persistent patency was associated with better long-term survival than with late spontaneous reperfusion (p < 0.001) and persistent occlusion (p < 0.001). Multivariate analysis comparing persistent patency and late spontaneous reperfusion showed that early reperfusion was an independent predictor of long-term survival. CONCLUSION: Late spontaneous reperfusion after failed thrombolytic therapy was associated with poor LV function and long-term survival, emphasizing the importance of early reperfusion.     

Echocardiographically detected dyskinesis, myocardial infarct size, and coronary risk region relationships in reperfused canine myocardium

After permanent coronary artery occlusion, the extent of two-dimensional echocardiographically detected dyskinesis correlates well with infarct size. Reperfusion after coronary artery occlusion decreases infarct size; however, contractile function of myocardium salvaged in this way may remain depressed for several weeks. The purpose of this study was to explore the relationship between echocardiographically detected dyskinesis and infarct size in reperfused myocardium. We hypothesized that after transient coronary artery occlusion, the relationship between dyskinesis and infarct size would be altered because of the prolonged depression of contractile function after reperfusion so that dyskinesis would not predict infarct size. We also wanted to explore two related questions: (1) Does inotropic stimulation of reperfused myocardium result in improved systolic function in segments that are dysfunctional but not necrotic? (2) Does the relationship between infarct size and coronary risk region, which is linear in myocardium subjected to permanent coronary occlusion, remain linear in myocardium subjected to a sequence of occlusion and reperfusion? Thirty-seven sedated dogs with preplaced circumflex occluders underwent 1 or 2 hr of coronary artery occlusion, then 2 or 10 days of reperfusion. The percentage of the left ventricle that was dyskinetic was estimated from short-axis two-dimensional echocardiograms at the chordal and papillary muscle level obtained at control, after 1 or 2 hr of occlusion, after 20 min of reperfusion, and after 2 or 10 days of reperfusion. At 2 or 10 days of reperfusion, echocardiograms were also obtained during infusion of dobutamine. Area at risk was determined from postmortem barium-gelatin angiography and infarct size was determined at pathologic examination. We found a significant linear correlation between infarct size and risk region size in reperfused myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered response of reperfused myocardium to repeated coronary occlusion in dogs

It is hypothesized that myocardium subjected to a 5 minute period of coronary occlusion and a 30 minute period of reperfusion has latent abnormalities that become overt when the reperfused myocardium is "challenged" by a subsequent coronary occlusion. This hypothesis is clinically relevant because reperfused myocardium is frequently subjected to recurrent ischemia, as in patients with unstable angina, vasospastic angina or recurrent thrombosis after initial coronary occlusion and thrombolysis. In 19 open chest dogs, the response of regional myocardial function to brief coronary occlusions was studied. Systolic wall thickening and diastolic thinning were measured using a specially developed miniature 5 MHz echocardiographic transducer fixed to the epicardium by suction. All 19 dogs underwent an initial "challenge" coronary occlusion (30 seconds). Thereafter, the control group (n = 8) underwent no intervention for 30 minutes, while the intervention group (n = 11) underwent 5 minutes of coronary occlusion followed by 30 minutes of reperfusion. All dogs were then subjected to a second "challenge" coronary occlusion (30 seconds). In the control group, responses to the second challenge occlusion were the same as to the first occlusion. In the intervention group, regional and global systolic function and myocardial perfusion after the 5 minute coronary occlusion intervention returned to baseline levels, but the response to the second challenge coronary occlusion was significantly different in the intervention group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-Dependent Reduction of Myocardial Infarct Mass in Rabbits by the NHE-1 Inhibitor Cariporide (HOE 642)

The aim of this study was to investigate the dose-dependent effect of pretreatment with the selective sodium-hydrogen exchange NHE-subtype 1 inhibitor cariporide on myocardial infarct mass in a rabbit model of coronary ligation and reperfusion. Furthermore, in a second part of the study, we tested the effect of cariporide in the rabbits when given prior to reperfusion.

Rabbits (n=49) were randomized in 7 groups: saline vehicle, cariporide: 0.01, 0.03, 0.1 and 0.3 mg/kg, and subjected to a 30 min occlusion of a branch of the left coronary artery followed by 2 h reperfusion. Cariporide was given as a bolus intravenously 10 min before occlusion or 5 min before reperfusion. After reperfusion, myocardial infarct mass was determined by triphenyl tetrazolium chloride staining and expressed as a percent of area at risk.

Cariporide given intravenously 10 min before occlusion in doses of 0.01, 0.03, 0.1, 0.3 mg/kg, led to a dose-dependent reduction in infarct mass from 58 ± 6% in controls to 48 ± 4% (-17 %, NS), 36 ± 5% (-38 %, p<0.05), 26 ± 6% (-55 %, p<0.05), 11 ± 4% (-81 %, p<0.05) respectively, whereas area at risk did not differ in between the groups. The effect of the lowest dose of 0.01 mg/kg did not reach significance. Plasma levels at different doses of cariporide were correlated to the respective infarct mass.

After coronary occlusion left ventricular end-diastolic pressure (LVEDP) significantly increased throughout occlusion and reperfusion. Cariporide in the doses of 0.3, 0.1 and 0.03 mg/kg normalized LVEDP when measured after 2 h reperfusion. In controls hemodynamic parameters such as mean arterial blood pressure (MAP), heart rate (HR), left ventricular pressure (LVP) and LV dP/dt_max, were not significantly changed by ischemia/reperfusion with the exception of MAP, LVP and LV dP/dt_max, which were significantly decreased after 120 min reperfusion. Cariporide at doses of 0.1, 0.03 and 0.01 mg/kg did not significantly influence these parameters, whereas the highest dose of 0.3 mg/kg prevented the decrease of MAP and LVP.

Cariporide (0.3 mg/kg i.v.) administered 5 min before reperfusion significantly reduced infarct mass by 31 %. Under these conditions the increase of LVEDP after coronary occlusion was not influenced by cariporide. As in the pretreatment experiments, the decrease of MAP and LVP was prevented when measured 2 h after reperfusion.

The results show that pretreatment with the NHE-subtype 1 inhibitor cariporide is cardioprotective by reducing infarct mass in rabbits in a dose-dependent manner, While the cardioprotective effect of pretreatment could be demonstrated over a broad range of doses, the efficacy of the compound when given only on reperfusion was significant but more limited.     

Vascular remodeling during healing after myocardial infarction in the dog model: effects of reperfusion, amlodipine and enalapril

OBJECTIVES: We sought to determine whether reperfusion and the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor enalapril, during healing over six weeks after myocardial infarction (MI), limit structural vascular remodeling in the noninfarct zone (NIZ). BACKGROUND: The effect of reperfusion and amlodipine or enalapril on structural vascular remodeling during healing of MI has not been determined. METHODS: We randomly assigned 54 dogs to reperfused or nonreperfused MI, followed by twice-daily doses of oral placebo, amlodipine (5 mg) or enalapril (5 mg) for six weeks and three days off treatment, or to three matching sham groups. We measured in vivo hemodynamic data and left ventricular (LV) function and remodeling (by echocardiography) over the six weeks, as well as ex vivo structural vascular, ventricular and collagen remodeling in the hearts after six weeks. RESULTS: Compared with placebo and sham groups, both amlodipine and enalapril with or without reperfusion produced LV unloading and limited structural LV remodeling and dysfunction over six weeks in vivo, and also decreased the NIZ resistance vessel media/lumen area ratio at six weeks ex vivo. In addition, amlodipine, but not enalapril, preserved infarct scar collagen and increased the border zone collagen volume fraction and perivascular fibrosis, as well as NIZ resistance vessel media thickness. Enalapril, but not amlodipine, decreased transforming growth factor-beta in the border zone and NIZ. CONCLUSIONS: The results indicate that therapy with amlodipine and enalapril during healing after reperfused MI limits structural vascular remodeling in the NIZ, probably by different mechanisms.     

Patient Self-Management of Oral Anticoagulant Therapy: An International Update

While glucose-insulin-potassium (GIK) has been suggested to be cardioprotective, few studies have assessed its effect on anatomic myocardial infarct size in an ischemia-reperfusion protocol. Anesthetized rabbits were subjected to a 30-minute coronary artery occlusion followed by 4 hours of reperfusion. Rabbits were pretreated with a GIK infusion lasting 90 minutes or placebo. GIK infusion markedly increased serum glucose levels by over twofold, but the area of necrosis expressed as the area at risk was not reduced by GIK infusion (25%) versus control (20%). In a rabbit infarct model of ischemia/reperfusion, GIK failed to reduce myocardial infarct size.     

Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia

OBJECTIVES: The goal of this study was to assess whether selectin blockade reduces myocardial platelet deposition and platelet-mediated injury after transient ischemia. BACKGROUND: Selectins participate in platelet adhesion to reperfused endothelium. METHODS: Thiopental-anesthetized, open-chest pigs were subjected to mechanical injury of the left anterior descending coronary artery followed by a 48-min occlusion and 2 (n = 20) or 4 (n = 16) h of reperfusion. Fifteen minutes before occlusion, animals were blindly allocated to receive a continuous intravenous infusion of the selectin blocker fucoidan (30 microg/kg/min, plus a 1-mg/kg bolus in the latter group) or saline. In isolated rat hearts infused with thrombin-activated platelets, the effects of fucoidan (30 microg/ml) administered during reperfusion after 40 min of global ischemia were also analyzed. RESULTS: Fucoidan did not prevent the development of cyclic reductions in coronary flow, but reduced the content of (99m)Tc-labeled platelets in reperfused myocardium after 2 h of reperfusion (23.4 +/- 3.3 vs. 42.1 +/- 8.3 x 10(6) platelets/g in treated and untreated animals, p = 0.03) and attenuated the impairment in the coronary flow reserve and reduced infarct size after 4 h (53 +/- 2% vs. 73 +/- 5% of the ischemic region, respectively, p = 0.003). Treated animals showed a trend toward less neutrophil infiltration early after reperfusion, but not after 4 h. In isolated hearts, fucoidan improved functional recovery and reduced coronary resistance and lactate dehydrogenase release, lacking any beneficial effects if given in the absence of platelets. CONCLUSIONS: The results suggest that selectin-dependent adhesion is a prominent mechanism of platelet deposition in reperfused cardiac microvessels and highlight its potential as a therapeutic target in patients with acute myocardial infarction.     

Remote postconditioning

Objectives A series of brief coronary artery reperfusions and reocclusions applied during the early minutes of coronary artery reflow (“postconditioning”) attenuates reperfusion injury. However, it is not known whether brief ischemia–reperfusion applied to a distant organ at the onset of myocardial reperfusion (i.e. “remote postconditioning”, remote PostC) reduces infarct size in the reperfused myocardium. In an in vivo anesthetized rat model of myocardial infarction induced by coronary artery occlusion and reperfusion, this study tested the hypothesis that remote postC induced by a single 5 minute episode of renal artery (RA) occlusion and reperfusion applied immediately before the onset of coronary artery reperfusion protects the myocardium from reperfusion injury by mechanisms involving endogenous adenosine receptor activation. Methods All rats were subjected to a total of 30 minutes of left coronary artery occlusion (LCAO) and 3 hours of reperfusion. The rats were randomized to one of six groups: 1) Control: LCAO and reperfusion only with no other intervention; 2) Remote PostC: after 24 minutes of LCAO the RA was occluded for 5 minutes and released 1 min before coronary artery reperfusion; 3) Permanent RA occlusion: the RA was permanently occluded after 24 minutes LCAO continuing to the end of reperfusion; 4) Delayed Remote PostC: after 26 minutes LCAO the RA was occluded for 5 minutes, and its release was delayed until 1 min after coronary artery reperfusion; 5) CON + SPT: rats with LCAO and reperfusion received 10 mg/kg IV of the non–selective adenosine receptor antagonist 8–sulfophenyl theophylline [SPT] administered 5 minutes before coronary artery reperfusion; and 6) Remote PostC + SPT: after 24 minutes of LCAO the RA was occluded for 5 minutes and released 1 minute before coronary artery reperfusion in the presence of 10 mg/kg SPT given 5 min before coronary artery reperfusion. Results Myocardial infarct size (percentage necrosis/area at risk, mean ± SEM) was reduced by 50% in Remote PostC (25 ± 4%) compared to Control (49 ± 4%, p = 0.003), consistent with a reduction in plasma CK activity (44 ± 5 vs. 67 ± 6 U/ml, p = 0.023). In contrast, permanent RA occlusion before LCAO and reperfusion failed to reduce myocardial infarct size (47 ± 5%) vs Control. Delaying the release of the RA occlusion (delayed Remote PostC) abrogated the myocardial infarct reduction observed with Remote PostC (48 ± 6%). SPT alone had no effect on infarct size (47 ± 4% in CON + SPT vs. 49 ± 4% in CON); however, Remote PostC+SPT abrogated the myocardial infarct size reduction in Remote PostC (50 ± 3% in Remote PostC + SPT vs. 25 ± 4% in Remote PostC). Conclusions Remote renal postconditioning applied immediately before the onset of coronary artery reperfusion provides potent myocardial infarct size reduction likely exerted during the first minutes of coronary artery reperfusion. This inter–organ remote postconditioning phenomenon is likely mediated in part by release of adenosine by the ischemic–reperfused kidney and subsequent activation of adenosine receptors.     

冠状动脉内给予乙酰半胱氨酸对缺血再灌注心肌梗死面积的影响

目的:观察冠状动脉内给予小剂量N-乙酰半胱氨酸(NAC)对家兔心肌缺血再灌注(I/R)后心肌梗死面积的影响。方法:36只家兔随机分为假手术组(S组,12只)、(I/R组,12只)和NAC治疗组(NAC组,12只)。NAC组在结扎前降支1h后恢复血流灌注,然后用无损伤血管钳夹闭主动脉和肺动脉10s,同时于心尖部注入200g/L的NAC溶液0.5ml,S组和I/R组给予0.5ml0.9%氯化钠溶液。再灌注3h后从颈动脉采血,测定血清肌酸磷酸激酶(CK)、乳酸脱氢酶(LDH)的含量和谷胱甘肽过氧化物酶(GPH-Px)活性。蛋白印迹法检测缺血区心肌组织中I-κB的表达,并分别用双重染色测定心肌梗死面积。结果:与I/R组比较,NAC组CK和LDH明显降低(P<0.01),而GPH-Px活性则明显增高(P<0.01),缺血区心肌组织中I-κB的表达明显减少,心肌梗死面积也显著减少(P<0.01)。结论:冠状动脉内给予小剂量NAC能明显减少心肌I/R后的心肌梗死面积。