Necrotic Myocardium Research Articles

Surgical Approach to Myocardial Rupture after Acute Myocardial Infarction

Rupture of the ventricular wall is a highly lethal complication of acute myocardial infarction that is diagnosed more frequently with the increased use of two-dimensional echocardiography. External patching techniques were used to treat 4 patients with ventricular rupture, thus avoiding resection of necrotic myocardium. Three of the patients survived. One patient developed a large left ventricular pseudoaneurysm requiring reoperation. The other 2 patients had intact repairs on follow-up echocardiogram obtained after 5 weeks and 3 years, respectively. With prompt recognition and treatment, patient survival and excellent short-term results can be achieved.

Significance of Q-wave regression after anterior wall acute myocardial infarction.

This study was conducted to clarify the significance of abnormal Q-wave regression in anterior wall acute myocardial infarction. A total of 74 patients who presented with a first anterior wall acute myocardial infarction within 6 h of onset were divided into two groups according to the presence (group A, n = 29) or absence (group B, n = 45) of regression of abnormal Q waves. Regression of abnormal Q waves was defined as the disappearance of the Q wave and the reappearance of the r wave > or = 0.1 mV in at least one of leads I, aVL, and V1 to V6. Emergency coronary arteriography revealed that group A had a higher incidence of spontaneous recanalization or good collateral circulation than group B (55% vs 31%, P < 0.05). Peak creatine kinase activity tended to be lower in group A than in group B (2358 +/- 1796 vs 3092 +/- 1946 IU.L-1, P = 0.09). Group A had a greater left ventricular ejection fraction and better regional wall motion at 1 and 6 months after acute myocardial infarction than group B. The degree of improvement of left ventricular ejection fraction and regional wall motion between 1 and 6 months after acute myocardial infarction was significantly greater in group A than in group B. Patients with anterior wall acute myocardial infarction showing Q-wave regression had a trend towards a smaller amount of necrotic myocardium and a significantly larger amount of stunned myocardium.

Validation of intracoronary delivery of metalloporphyrin as an in vivo "histochemical staining" for myocardial infarction with MR imaging.

During the last CMR meeting in Naantali, Finland, we presented how the research in our laboratories in collaboration with the Institut ftir Diagnostikforschung, Berlin, Germany, has dramatically converted metalloporphyrins from being used as tumor-seeking agents to markers of myocardial infarction (MI) (1). This represents a three-episode story. We started with an investigation in primary and secondary liver tumors and found that the observed specific enhancement could be attributed only to nonviable instead of viable tumoral components (2). A subsequent study on several porphyrin agents in induced benign necrosis supported the finding in tumors (3). Eventually, we ended up with a novel application for metalloporphyrinenhanced MRI to visualize acute myocardial infarction (46). Since intravenous injection of metalloporphyrins has already been demonstrated to be effective for accurate identification and localization of irreversible myocardial infarcts in rats (4,5) and dogs (6), the current study was designed to deliver the porphyrin agent into the coronary artery with only 1/10th of the intravenous dose in order to assess (a) whether the necrotic myocardium can be accurately labeled by virtually a single pass of the agent through reperfused coronary artery and (b) whether this technique can be combined with percutaneous transluminal coronary angioplasty (PTCA) to function as an in vivo

Surgical repair of postinfarction ventricular septal defect by infarct exclusion.

Repair of postinfarction ventricular septal defect (VSD) by infarct exclusion has been used for a decade in our unit. It involves securing a glutaraldehyde-preserved bovine pericardial patch to the endocardium of the left ventricle all around the necrotic myocardium to exclude the VSD and the infarct from the left ventricular cavity. Fifty-two patients with postinfarction VSD underwent this type of repair from 1987 to 1996. Thirty-four patients were in shock when undergoing operation; 26 had anterior VSD and 26 had posterior. Ten patients died perioperatively, for surgical mortality of 19%. Three patients developed recurrent VSD; one died and two survived. Preoperative cardiogenic shock and age older than 70 years were associated with an increased operative mortality. Operative survivors were followed up from 6 to 135 months, mean of 65 months. The actuarial survival at 8 years was 59% +/- 6%. Repair of postinfarction VSD by infarct exclusion is a relatively simple operative procedure and seems to have improved the results of surgery in patients with posterior VSD.

Progression of myocardial necrosis during reperfusion of ischemic myocardium.

The occurrence of myocyte necrosis during reperfusion of ischemic myocardium is controversial. This study measured myocardial 2-deoxyglucose uptake, correlated with histology, to determine whether loss of viability occurred during reperfusion of ischemic myocardium. In 12 anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes before 4 hours reperfusion. Myocardial blood flow was measured by microspheres and the tracers 14C-2-deoxyglucose and 18F-2-deoxyglucose were injected intravenously after 5 and 180 minutes of reperfusion, respectively. After 240 minutes, the heart was stained with thioflavin-S (size of no-reflow zone) and triphenyl-tetrazolium chloride (TTC, extent of necrosis). Samples from normal, salvaged, and necrotic myocardium were counted for 14C- and 18F-deoxyglucose and microspheres. With the use of a three-compartment model of 2-deoxyglucose uptake, the rate constant k3 for phosphorylation of 14C- and 18F-2-deoxyglucose was calculated for each sample. Viability was defined as k3> or = 0.125 min(-1) (predictive accuracy 88% versus electron microscopy and 97% versus TTC). Among 58 samples from no-reflow regions, 97% were nonviable after 5 minutes of reperfusion (k3=0.096 +/- 0.027 min[-1]). Among 164 samples from salvaged myocardium, 95% were viable after both 5 and 180 minutes of reperfusion (k3=0.170 +/- 0.056 min[-1] P<.01 versus no-reflow). Among 179 samples from infarcted myocardium, mean k3 after 5 minutes of reperfusion was 0.184 +/- 0.070 min(-1) and 65% of samples were viable, but after 180 minutes of reperfusion mean k3 had decreased to 0.077 +/- 0.032 min(-1) (P<.0001) and 98% of samples were nonviable. A large proportion of samples from infarcted myocardium are viable at the end of the ischemic period but lose viability during the first hours of reperfusion.

Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase.

Peroxynitrite and hydroxyl radical, reactive oxidants produced during reperfusion, are potent triggers of DNA single strand breakage. DNA injury triggers the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), which contributes to cellular energetic depletion. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of myocardial reperfusion injury in a rat model. Occlusion of the left main coronary artery (one hour) followed by reperfusion (one hour) in the anesthetized rat caused severe cardiac necrosis, neutrophil infiltration, and increased plasma creatine phosphokinase activity. There was significant peroxynitrite production during reperfusion, as indicated by a massive increase in nitrotyrosine in the necrotic myocardium. Reperfusion was also associated with a significant loss of myocardial ATP. In vivo administration of the PARS inhibitor 3-aminobenzamide (10 mg/kg i.v.) to rats subjected to myocardial ischemia and reperfusion, reduced myocardial infarct size and blunted the increase in plasma creatine phosphokinase activity and myeloperoxidase activity in infarcted hearts. In addition, 3-aminobenzamide partially preserved the myocardial ATP levels. In vitro, pharmacological inhibition of PARS also ameliorated peroxynitrite-induced cytotoxicity in rat cardiac myocytes and human endothelial cells. 3-aminobenzamide has significant protective effects in myocardial reperfusion injury. We hypothesize that activation of PARS activation plays a role in the pathophysiology of acute myocardial infarction.

The Time Course of Left Ventricular Remodeling After Acute Myocardial Infarction

Myocardial infarction (MI) is a leading cause of heart failure. MI is associated with a 7- to 10-fold greater risk of developing heart failure compared with a normal population. Left ventricular dysfunction and subsequent mortality are highly correlated, with the principal determinants of survival after MI being left ventricular end-diastolic and end-systolic (and particularly the latter) volume. Acute MI results in progressive myocardial cell necrosis and is associated (over the next hours to days) with infarct expansion (thinning and elongation of the necrotic myocardium). The residual normal myocardium also undergoes structural changes, including dilation and hypertrophy (assumed to be a compensatory mechanism in an attempt to maintain stroke volume), a process that occurs over a period of days to months, and one that can lead to progressive left ventricular dysfunction. The development of heart failure after MI results in impaired ventricular function, and consequently potentially adverse neurohumoral activation. These processes of remodeling and neurohumoral activation have taken on increasing importance with the recognition that angiotensin-converting enzyme (ACE) inhibitors could favorably affect the remodeling process and thereby reduce cardiovascular morbidity and mortality when administered in the postinfarction period. 1‐3 The question of how ACE inhibitors prolong survival, however, is not fully answered. The left ventricular structural remodeling following MI is a time-dependent process, but the time course, particularly the early time course, has not been completely elucidated. The time course of remodeling has certain therapeutic implications, including the earliest time at which therapy should be initiated, the latest time at which therapy would have no benefit, and the ultimate duration of therapy. Early experiments in a rat model initiated ACE inhibitor therapy as soon as 2 days after infarction, and demonstrated a benefit in remodeling compared with untreated controls. 4 In subsequent human studies ACE inhibitor therapy was initiated 12 days and then as early as 7 days after infarction, leading up to the Survival and Ventricular Enlargement (SAVE) trial in which therapy was initiated as early as 3 days after infarction. 1,5,6 Questions were already being asked about the risk benefit of earlier ACE inhibitor therapy, but in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS) II trial, enalapril was begun intravenously within the first 24 hours after infarction (followed by oral therapy). 7 CONSENSUS II was terminated prematurely at 6 months when no benefit (and a slight trend toward worsening) was observed in the treated group. However, subsequent studies with oral ACE inhibitor therapy begun within 6 to 24 hours of infarction have demonstrated a benefit in remodeling and morbidity and mortality. 8 ‐11 The disparate results between these 3 trials and CONSENSUS II might be the result of the abrupt hypotensive effects of intravenous enalapril. The zofenopril trial 11 demonstrated that lives were saved within 24 hours of randomization to treatment, which also serves to allay the concern that early treatment could precipitate symptomatic hypotension, a situation that could certainly be problematic in the setting of acute infarction. This further indicates that there should be no unnecessary delay in initiating oral ACE inhibitor therapy follow

Differentiation of myocardial ischemia and necrosis by technetium 99m glucaric acid kinetics

Background. Current clinical approaches may not always be helpful in the early differentiation of necrotic tissue from ischemic viable myocardium in patients with acute myocardial infarction. Tc-99m-glucaric acid is a carbohydrate ligand that may permit differentiation of necrosis from ischemia. However, the myocardial kinetics of Tc-99m-glucaric acid have not been well defined early after myocardial injury. The aim of this study was to evaluate the effect of necrosis in comparison to postischemic injury alone on the kinetics of Tc-99m-glucaric acid with the use of an isolated perfused rat heart model. Methods and Results. Three groups of hearts were studied: group I: control (n = 6); group II: postischemia (15 minutes of no flow with complete reperfusion, n = 6); and group III: necrosis (90 minutes of no flow to induce necrosis with complete reperfusion, n = 6). Tc-99m-glucaric acid (1.3 ± 0.6) mCi/L of buffer) was perfused for 30 minutes to evaluate tracer accumulation. Then tracer-free buffer was perfused for 45 minutes to evaluate clearance. The peak accumulation relative to the control group mean was significantly increased ( p < 0.01) in group III (necrosis) (254% ± 75%) compared with control (100% ± 10%) and compared with postischemia (108% ± 26%). On kinetic data analysis, the monoexponential clearance rate constant (k c) was significantly reduced with necrosis (control: k c = 20.2 ± 14.0 × 10 −4) sec −1; postischemia: k c = 22.3 ± 15.2 × 10 −4 sec −1; and necrosis: k c = 1.2 ± 0.3 × 10 −4 sec −1; p < 0.05). A retention fraction was calculated from the activity after 45 minutes of clearance corrected for the peak activity for each group. The necrotic group had significant myocardial retention in comparison to control and postischemia (control: 12% ± 8%; postischemia: 14% ± 16%); necrosis: 64% ± 10%; p < 0.01). Conclusions. The accumulation and retention of Tc-99m-glucaric acid is markedly increased in the presence of myocardial necrosis in comparison to control and postischemic myocardial injury. In this model, Tc-99m-glucaric acid is capable of defining the presence of necrotic myocardial injury in comparison to postischemic injury alone. This agent may have potential application for the early differentiation of ischemic from necrotic myocardium in acute myocardial infarction.

Avidity of technetium 99m glucarate for the necrotic myocardium: In vivo and in vitro assessment

Background. Similar to other 99mTc-based infarct-avid agents, 99mTc-glucarate localizes in myocardial infarcts. Whether severely ischemic viable myocytes sequester 99mTc-glucarate is uncertain. To assess the infarct specificity, in vitro and in vivo studies were performed. Methods and Results. H9C2 embryonic rat cardiocytes cultured under normoxia (N) or hypoxia (H) for 24 hours in 7.5 μCi 99mTc-glucarate were compared with necrotic cardiocytes. Mean H N ratio (3.0 ± 0.004, mean ± SD) was significantly less than that of the necrotic/N ratio (39.9 ± 6.5, p < 0.01). Reperfused myocardial infarction (MI) in 4 dogs confirmed by 201T1 (0.5 to 1.0 mCi) scintigraphy were imaged serially with simultaneously injected mixture of 99mTc-glucarate and 111In-antimyosin Fab. Infarcts were detected scintigraphically within 4 to 10 minutes with 99mTc-glucarate. 111In-antimyosin required more than 1 hour. Myocardial distribution at 5 hours showed a direct correlation between 99mTc-glucarate and 111In-antimyosin uptake ( r = 0.99, p < 0.0001). Both 99mTc-glucarate ( r = −0.777, p < 0.0001) and 111In-antimyosin ( r = −0.775, p < 0.0001) were inversely related to 201T1 distribution. Conclusions. The near perfect correlation between 99mTc-glucarate and 111In-antimyosin uptake ( r = 0.99) in reperfused canine MI and the insignificant glucarate uptake by viable cardiocytes in vitro attest to the avidity of 99mTc-glucarate for the necrotic myocardium and favor its use as a specific early marker of myocyte necrosis in acute MI.

Significance of Negative U Waves in the Precordial Leads During Anterior Wall Acute Myocardial Infarction

This study was conducted to clarify the clinical significance of negative U waves in the precordial leads during anterior wall acute myocardial infarction (AMI). In all, 141 patients with first anterior wall AMI (≤6 hours) were classified into 2 groups according to the presence (group A, n = 31) or absence (group B, n = 110) of negative U waves in the precordial leads on the admission electrocardiogram (ECG). The number of leads showing ST elevation ≥1 mm on the admission ECG was smaller in group A than in group B (5.2 ± 1.3 vs 6.2 ± 1.7, p <0.01). Emergent coronary arteriography revealed that group A had a higher incidence of good collateral circulation than group B (39% vs 19%, p <0.05). Peak creatine kinase activity was lower in group A than in group B (1,708 ± 1,271 vs 2,735 ± 1,865 IU/L, p <0.01). The number of abnormal Q waves on the predischarge ECG was smaller in group A (2.0 ± 1.5 vs 3.4 ± 2.0, p <0.01). Group A had a greater left ventricular ejection fraction and better regional wall motion in the anterobasal, anterolateral, and apical regions in the chronic phase than group B. In conclusion, patients with anterior wall AMI having negative U waves in the precordial leads on admission had a relatively smaller mass of necrotic myocardium than those without the waves. Therefore, negative U waves during anterior wall AMI may be a useful marker for identifying patients with smaller infarction partly due to better collateral circulation.To clarify the clinical significance of negative U waves in the precordial leads during anterior wall acute myocardial infarction (AMI), 141 patients with first anterior wall AMI were retrospectively studied. Results indicate that patients with anterior wall AMI having negative U waves in the precordial leads on admission had a relatively smaller mass of necrotic myocardium than those without the waves.

Effect of Endothelin Antagonists on Myocardial Infarct Size after Coronary Artery Occlusion and Reperfusion in Rat

Background:Although experimental and clinical evidences suggest that endothelin-1(ET-1 may play a pathophysiological role in ischemic heart disease, it is still controversial whether ET-1 produced during myocardial ischemia and reperfusion affects the extent of necrotic myocardium. This study was performed to investigate the role of ET-1 and the effect of ET antagonists in infarct size determination. Methods:Male Wistar rats(260-400g were anesthetized with pentobarbital(i.p. 50mg/kg and ventilation was assisted via tracheostomy tube. The heart was exposed by midline incision and the left anterior descending coronary artery was ligated with 6-0 silk suture. The ligature was released after 1 hour and reperfusion was performed for 2 hours. In the first set of experiment, FR139317(ET-A antagonist was given as bolus i.v.(3mg/kg 10 minutes before reperfusion, followed by continuous infusion(total 24mg/kg throughout reperfusion. In the other protocol, bosentan(ET-A/ET-B antagonist;10mg/kg was given 10 minutes before coronary occlusion as i.v. bolus. At the end of reperfusion, the heart was excised and stained with Evans blue dye(1% w/v and triphenyltetrazolium chloride(TTC;1% to distinguish infarct region(not stained by TTC and Evans blue, ischemic but viable myocardium(stained brick-red by TTC but not stained by Evans blue and nonischemic myocardium(dyed by Evans blue. These three regions of myocardium were separated and weighed for analysis. Infarct size(in percent was expressed as the ratio of infarct region to ischemic myocardium(i.e. infarct region plus ischemic but viable myocardium. Results:In the first protocol, infarct region was 57.0±3.8% of the ischemic myocardium in control(n=9 and 58.9±4.9% in FR139317 group(n=7; The difference was not significant statistically. Likewise, ET-A/ET-B antagonist bosentan given before coronary occlusion did not reduce infarct size significantly;the ratio was 74.2±3.2% in control(n=7 and 69.5±2.0% in bosentan group(n=7.

Myocardial kinetics of technetium-99m teboroxime in the presence of postischemic injury, necrosis and low flow reperfusion

This study evaluated technetium-99m (Tc-99m) teboroxime kinetics in postischemic and partially necrotic myocardium with complete and low flow reperfusion using an isolated perfused rat heart model. Technetium-99m teboroxime has been proposed for use in the early diagnosis of reperfusion after thrombolysis on the basis of models of myocardial necrosis with complete reperfusion. Clinically, however, reperfusion is frequently incomplete, resulting in a mixture of necrotic, ischemic and postischemic tissue. Hearts were classified into five groups: group 1 (n = 8, control); group 2 (n = 7, 30 min of no flow with complete reperfusion); group 3 (n = 12, 60 min of no flow to induce partial necrosis, followed by complete reperfusion); group 4 (n = 8, continuous low flow without flow interruption); and group 5 (n = 9, 60 min of no flow with low flow reperfusion). Buffer containing Tc-99m teboroxime was perfused for 15 min, followed by tracerfree buffer for 35 min, to evaluate uptake and clearance, respectively. Uptake slopes for groups 1 to 5 were (mean +/- SD) 3.0 +/- 0.7, 2.6 +/- 0.8, 2.1 +/- 0.5, 0.8 +/- 0.2 and 0.8 +/- 0.3, respectively (p < or = 0.0005 for groups 1, 2 and 3 vs. groups 4 and 5, and p = 0.003 for group 3 vs. groups 1 and 2). Clearance curves from groups 1 to 3 were best fit by a biexponential function (p < 0.001); those from groups 4 and 5 were monoexponential. In groups 1, 2 and 3, the initial clearance rate constants (ki) (0.9 +/- 0.5 x 10(-3); 1.0 +/- 0.2 x 10(-3); 1.1 +/- 0.5 x 10(-3) s-1, respectively) and the monoexponential rate constants (Kmono) (2.0 +/- 0.3 x 10(-4); 2.2 +/- 0.4 x 10(-4); 2.1 +/- 0.2 x 10(-4) s-1, respectively) were significantly greater than those in groups 4 and 5 (0.9 +/- 0.5 x 10(-4); 1.2 +/- 0.3 x 10(-4) s-1, respectively, p < or = 0.005). The uptake and initial clearance kinetics of Tc-99m teboroxime depend mainly on myocardial flow in this model. The presence of partial necrosis and postischemic injury has little effect on the initial clearance but leads to some reduction in uptake at normal flow rates. Evaluation of Tc-99m teboroxime kinetics may permit early noninvasive detection of inadequate reperfusion in acute myocardial infarction.

Myocardial inflammatory infiltrate in human chronic chagasic cardiomyopathy: Immunohistochemical findings

Chagas' disease is the most common form of chronic myocarditis in the world. It is characterized by a progressive chronic myocarditis that leads to cardiomegaly, arrhythmias, cardiac failure, and thromboembolic phenomena. This communication reports studies on the immunohistochemistry of chronic infiltrates in 30 endomyocardial biopsies and in contracting and specialized myocardium of autopsies of four patients suffering from Chagas' cardiomyopathy. Expression of the following antigens was studied: common leucocyte antigen (CLA-CD45R), L-26(CD20), CD68, kappa and lambda light chains and T-UCLH-1 (CD45RO), and MB-1. Streptavidin-peroxidase and streptavidin-alkaline phosphatase with biotinylated anti-mouse IgG were used as detection systems. Double immunostaining for the simultaneous demonstration of T lymphocytes (CD45R0) and macrophages was performed using both immunoenzymatic techniques consecutively. Expression of CD31 was detected for the demonstration of endothelial cells. In endomyocardial biopsies, tissue forms of trypanosomes were not found. The percentage of fibrous tissue was 24.1% ± 12.8% (range 8.2%–49%). Eosinophils were scarce (1/high-power field), but associated with necrotic areas of the myocardium. Mast cells were scarce or absent. They were always situated in fibrotic areas. The most remarkable finding was the presence of infiltrates consisting of macrophages and CLA-positive mononuclear cells. Twenty-six and one-half percent of them were T lymphocytes, and 10.5% were B lymphocytes. Lymphocytic infiltration was particularly associated with necrotic and degenerative myocardial lesions. Thirty percent of the infiltrate was composed of macrophages (positive CD68 cells). The remaining infiltrate was composed of mononuclear cells resembling macrophages and CLA-negative mononuclear cells. Contacts between CD68-positive cells and T lymphocytes were frequently found. CD31 antibodies clearly pointed out normal endothelial cells, in either normal or damaged vessels. No isolated cells positive for these antibodies were found within the mononuclear infiltrate. In autopsied hearts, myocardial lesions consisted of a chronic inflammatory process with fibrotic scars and extensive mononuclear infiltrates. No amastigote nests were found. A statistically significant difference ( p < 0.05) was obtained when the percentage of fibrosis was compared in the specialized and contracting myocardiums (51.6% ± 18% vs. 43.4 % ± 8%). Eosinophils were scarce in infiltrates, reaching 5%, and they were associated with necrotic myocardium. Mast cells also were scarce or absent in specialized and in contracting myocardium. Almost all the lymphocytic population was T lymphocytes. Such infiltrates were more prominent in the working myocardium (39%) and in the specialized cells of the left branch of the His bundle than in the atrioventricular node and in the right Hisian branch (34.4%). The 31% of mononuclear cells were CD68 positive, thus corresponding to macrophages. Contacts among T lymphocytes and macrophages were frequently observed. Although much that is concerned with Chagas' cardiomyopathy is controversial, these may be the major ingredients for its pathogenesis: the parasite or a part of it, lymphocytes and macrophages, and fibrosis. Then a multifactorial or “combined theory” may be suggested to explain the sequence of events that lead to the chronic stage of the disease.

Sympathetic reinnervation after acute myocardial infarction

Myocardial infarction produces sympathetic denervation of the necrotic myocardium and noninfarcted myocardium apical to the injury. Proof of sympathetic reinnervation after myocardial infarction has, however, remained elusive. In this study, we investigated whether cardiac sympathetic reinnervation occurs in men recovering from myocardial infarction. I-123 metaiodobenzylguanidine (MIBG), I-123 paraphenylpentadecanoic acid, and Tc-99m sestamibi scintigraphic imaging were conducted in 13 men 3 and 12 months after a first myocardial infarction to determine the extent of denervated myocardium, the size of the infarct, and the size of the myocardium with reduced perfusion, respectively. A defect was determined as regional uptake of ≤ 30% of the maximal myocardial activity. The size of the MIBG defect was not significantly different between 3 and 12 months after infarction (17 ± 8% and 18 ± 8% of left ventricular mass, respectively). There was also no significant change in the extent of viable but denervated myocardium at 3 and 12 months (average 9 ± 6% and 10 ± 5%, respectively). MIBG activity of the infarct zone (expressed as a percentage of MIBG activity of the myocardium with normal perfusion) did not change (17 ± 13% and 20 ± 16%), whereas MIBG activity of the periinfarct zone increased during follow-up (32 ± 11% and 41 ± 14%, p < 0.01). This was associated with an increase in periinfarct I-123 paraphenylpentadecanoic acid activity (40 ± 11% and 48 ± 9%, p < 0.05), but not Tc-99m sestamibi activity (48 ± 10% and 48 ± 11%). In conclusion, we did not observe sympathetic reinnervation in the infarct zone between 3 and 12 months after myocardial infarction. However, MIBG activity of the periinfarct zone increased, suggesting partial reinnervation, and this was associated with a recovery of myocardial metabolic activity of the periinfarct zone.

Paramagnetic metalloporphyrins: infarct avid contrast agents for diagnosis of acute myocardial infarction by MRI.

In previous experiments in tumors we demonstrated that metalloporphyrins are particularly avid for nonviable tumor components. This study was performed to find out whether these agents can be used as MRI contrast agents for the visualization of acute myocardial infarction (MI). A total of 44 rats, 6 normal controls and 38 with occlusive MI (2-24 h old), were used. Gadolinium mesoporphyrin (Gd-MP) or manganese tetraphenylporphyrin (Mn-TPP) was intravenously injected at doses of 0.1, 0.05, and 0.01 mmol/kg. Three to 24 h after injection, axial and coronal T1-weighted (TR/TE 300/15 ms) spin-echo MR images were obtained before and after killing the animals and correlated with triphenyl tetrazolium chloride (TTC) histochemical preparations. The Gd-MP content in infarcted and noninfarcted myocardium was measured using inductively coupled plasma atomic emission spectroscopy (ICP-AES). MRI without contrast media could not discern the MI. However, 3-24 h after injection of either Gd-MP or Mn-TPP, the infarcted area was positively stained on MR images. This area matched well with the negatively TTC-stained area on the heart slices (r = 0.97). The contrast ratios between the infarcted necrotic myocardium and the noninfarcted regions varied from 150 to 300% depending on the type of agents and doses used. Neither false-positive nor false-negative findings were encountered. The metalloporphyrin concentration was more than 10 times higher in the infarcted than in the noninfarcted heart. Metalloporphyrins appear to be promising MRI contrast agents for detection and quantification of necrosis in MI. These preclinical results may open new perspectives in cardiac imaging.

A late increase in free radical activity post myocardial infarction.

Free radicals (FR) are a highly reactive chemical species which have been implicated in the pathogenesis of reperfusion injury. Experimental models of reperfusion injury have demonstrated that FR scavengers improve myocardial salvage and thus it has been postulated that they may be of benefit in acute myocardial infarct (MI) patients treated with thrombolysis. Previous studies of FR activity post MI have focused on the immediate post reperfusion period; the present study investigates FR activity in post MI patients over a longer time span. Free radicals have a very short half-life and in clinical studies their activity is usually assessed indirectly by measuring either the level of FR reaction products such as malondialdehyde (MDA) or FR scavengers such as plasma thiols (PSH). In the presence of increased FR activity MDA levels increase and PSH levels decrease. Twenty-two acute MI patients had blood samples taken on admission, day 7 and day 21 post MI for measurement of MDA and PSH levels. On day 7 post MI a significant increase in MDA was detected P = 0.0001 (Sign test) (median change +2.1 mumol.l) and a significant decrease was detected in PSH P = 0.04 (Sign test) (median change, -38 mumol.l-1). No significant differences were detected between admission and day 21 levels of MDA and PSH. This study demonstrates the presence of enhanced FR activity at a later time point than has previously been recognised. White blood cells utilise FRs during phagocytosis and the late rise in FR activity detected in this study may reflect white blood cell removal of necrotic myocardium.

Absence of lethal reperfusion injury after 3 hours of reperfusion. A study in a single-canine-heart model of ischemia-reperfusion.

Whether reperfusion can cause necrosis of previously viable myocytes (lethal reperfusion injury) remains controversial. Numerous studies examined the ability of various agents to prevent or limit reperfusion injury, but the results were contradictory. In a single-canine-heart model of ischemia-reperfusion, we previously demonstrated that 5 minutes of reperfusion does not increase the transmural extent of necrosis. Since the 5-minute period of reperfusion is considered by some to be too short for the full manifestation of reperfusion injury, we reexamined the issue of lethal reperfusion injury using a modification of the single-heart model of ischemia-reperfusion that allowed extending the reperfusion period to 3 hours. In anesthetized, open-chest dogs, the distal half of the left anterior descending coronary artery (LAD) segment between the last diagonal branch and the apex was perfused via a shunt from the left carotid artery. The shunt was closed for periods of 90 to 180 minutes, depending on the ECG severity of ischemia, and reperfused for 3 hours. While the distal region was perfused from the carotid artery, the LAD was occluded proximal to the last diagonal branch for the same period of time as the distal region had been earlier. The time of occlusion was chosen such that the end of the occlusion period coincided with the end of the experiment. Thus, both regions of the LAD territory were subjected to identical periods of ischemia, but only the distal region was reperfused. At the end of the experiment, the boundary between the proximal (nonreperfused) and distal (reperfused) area was delineated by blue dye, and the heart was arrested, cut into slices 1 cm thick parallel to the LAD, and placed in triphenyltetrazolium chloride. The epicardial edges of necrosis in the reperfused and the nonreperfused regions were examined for any shift that might suggest a difference in the transmurality of necrosis. The areas of necrotic and viable myocardium were measured by planimetry within 1 cm on either side of the boundary. In all 14 dogs, the epicardial edges of necrosis ran as a single line across the boundary, and no shift was present. There was also no difference in the transmurality of necrosis between the reperfused and nonreperfused regions (64.9 +/- 20.7% versus 66.1 +/- 17.0% of left ventricular wall thickness, respectively, P = .32 by paired t test). In a single-canine-heart model of ischemia-reperfusion, there was no evidence of lethal reperfusion injury after 3 hours of reperfusion.

Mechanism of impaired myocardial function during progressive coronary stenosis in conscious pigs. Hibernation versus stunning?

The major goal of this study was to determine whether impaired myocardial contractile function during the development of progressive coronary artery stenosis induced by ameroid constriction in conscious pigs reflected myocardial "hibernation" or "stunning." Minipigs were instrumented with a coronary ameroid constrictor and hydraulic occluder, regional wall thickness crystals, a left ventricular (LV) pressure gauge, and aortic and left atrial catheters. In the seven pigs in which it was measured, systolic wall thickening (WT) distal to the ameroid fell by a maximum of 56 +/- 6% at 20 +/- 3 days after ameroid implantation and then began to recover. At 1 day after ameroid implantation, brief complete coronary artery occlusion (CAO) resulted in wall thinning distal to the ameroid (-113 +/- 4%) and transmural decreases in myocardial blood flow in endocardial (from 0.82 +/- 0.08 to 0.02 +/- 0.01 mL/min per gram) and epicardial (from 0.73 +/- 0.13 to 0.03 +/- 0.02 mL/min per gram) layers. At 20 +/- 3 days, baseline myocardial blood flow was not altered either in endocardial (0.92 +/- 0.10 mL/min per gram) or epicardial (0.85 +/- 0.12 mL/min per gram) layers, whereas brief complete coronary artery occlusion still reduced WT (-83 +/- 12%) and myocardial blood flow in endocardial (to 0.21 +/- 0.03 mL/min per gram) and epicardial (to 0.43 +/- 0.12 mL/min per gram) layers, indicating that the coronary artery was not totally occluded. Pathology in four pigs demonstrated no gross necrotic myocardium shortly after this time point. Transient reductions in WT distal to the ameroid were observed during progressive coronary artery stenosis in response to spontaneous increases in activity. Beat-by-beat analysis of these episodes revealed that acute reductions in WT followed increases in LV dP/dt and heart rate and exhibited delayed recovery. These data suggest that the reduced function during ameroid-induced coronary stenosis reflected cumulative myocardial stunning rather than a primary deficit in coronary blood flow or "hibernating myocardium."

Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo.

Neutrophil adhesion and direct cytotoxicity for cardiac myocytes require chemotactic stimulation and are dependent upon CD18-ICAM-1 binding. To characterize the potential role of IL-8 in this interaction, canine IL-8 cDNA was cloned and the mature recombinant protein expressed in Escherichia coli BL21 cells. Recombinant canine IL-8 markedly increased adhesion of neutrophils to isolated canine cardiac myocytes. This adhesion resulted in direct cytotoxicity for cardiac myocytes. Both processes were specifically blocked by antibodies directed against CD18 and IL-8. In vivo, after 1 h of coronary occlusion, IL-8 mRNA was markedly and consistently induced in reperfused segments of myocardium. IL-8 mRNA was not induced in control (normally perfused) myocardial segments. Minimal amounts of IL-8 mRNA were detected after 3 or 4 h of ischemia without reperfusion. Highest levels of induction were evident in the most ischemic myocardial segments. IL-8 mRNA peaked in the first 3 h of reperfusion and persisted at high levels beyond 24 h. IL-8 staining was present in the inflammatory infiltrate near the border between necrotic and viable myocardium, as well as in small veins in the same area. These findings provide the first direct evidence for regulation of IL-8 in ischemic and reperfused canine myocardium and support the hypothesis that IL-8 participates in neutrophil-mediated myocardial injury.

Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction: Role of magnetic resonance imaging

Nineteen patients (16 men and 3 women, mean age 51 years) with previous anterior myocardial infarction and severe stenosis (≥90%) of the left anterior descending coronary artery were studied by magnetic resonance imaging (MRI) without and with contrast media to verify the capability of MRI in identifying viable myocardium in areas of severe systolic dysfunction. In corresponding left ventricular segments, a comparison was made between regional signal intensities (SI) determined on MRI images before and 4, 8, 12, and 30 minutes after administration of paramagnetic contrast media (gadolinium diethylenetriaminepentaacetic acid, 0.4 mmol/kg intravenously) and metabolic parameters determined by iodine 123 phenylpentadecanoic acid (IPPA) scintigraphy. The SI and the time of maximum postcontrast enhancement were analyzed by dividing the left ventricle into 11 segments. Each segment was classified as normal (group 1, n = 116), hibernating (group 2, n = 50), or necrotic (group 3, n = 43) on the basis of the IPPA washout rate (>30%, 10% to 30%, and <10%, respectively). Regional SI demonstrated significant differences in absolute values at 12 minutes (group 3: 1.62 ± 0.58 vs group 1: 1.32 ± 0.52, p < 0.01, and vs group 2: 1.34 ± 0.48, p < 0.05) and at 30 minutes (group 3: 1.71 ± 0.47 vs group 1: 1.21 ± 0.55, p < 0.01, and vs group 2: 1.49 ± 0.57, p < 0.05) and in temporal distribution. These results suggest that MRI has a potential role in differentiating viable from necrotic myocardium in patients with chronic severe systolic dysfunction.