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Allograft vasculopathy (AV) causes intimal thickening with progressive luminal obstruction, endothelial dysfunction, and abnormal vasomotion. Subendocardial vacuolization indicating ongoing ischemia was observed at autopsy in transplanted hearts with severe AV. Whether myocyte vacuolization can be observed with lesser degrees of AV in cardia transplant patients has not been reported. Thirty-nine cardiac transplant patients without flow-limiting disease in large epicardial arteries underwent invasive assessment of AV. Eight to 10 segments of the left anterior descending artery were analyzed by intracoronary ultrasound, and an average intimal index was calculated. Endothelial response to acetylcholine was assessed with serial quantitative angiography. Endomyocardial biopsies taken 5 to 7 days prior to the invasive studies were histopathologically reviewed for the presence of small intramyocardial arteries and myocyte vacuolization. Myocyte vacuolization was evident in biopsies from 20 patients (51%). Intramyocardial arteries were observed in 30 cases (76%); 14 had abnormal arteries. All patients had some degree of intimal thickening by intracoronary ultrasound, and 7 (17 %) had severely abnormal average intimal index (>0.2). Endothelial dysfunction was present in 23 patients (58%). Vacuolization failed to show an association with abnormal small artery histology or large epicardial artery ultrasound disease. However, a significant association between vacuolization and endothelial dysfunction was observed (p = 0.05). Myocyte vacuolization, possibly indicating ischemic injury, is common in biopsies from cardiac transplant patients and is associated with abnormal acetylcholine response in large epicardial arteries. We speculate that myocyte vacuolization may be caused at least in part by impaired coronary flow associated with endothelial dysfunction.

Purpose: To review prospective epidemiologic studies and randomized trials regarding the role of antioxidant vitamins (vitamins E and C and beta-carotene) in the prevention of cardiovascular disease, with emphasis on differences in results obtained by these two types of studies., Data Sources: Computerized and manual searches of the literature on antioxidant vitamins and cardiovascular disease., Study Selection: Prospective epidemiologic studies and randomized trials that included 100 or more participants and provided quantified estimates of antioxidant vitamin intake., Data Synthesis: Comparisons of relative risk reductions (RRR) across observational studies and randomized trials, including assessment of dose-response relations., Results: All three large epidemiologic cohort studies of vitamin E noted that high-level vitamin E intake or supplementation was associated with a significant reduction in cardiovascular disease (RRR range, 31% to 65%), as measured by various fatal and nonfatal cardiovascular end points. To obtain these reductions, vitamin E supplementation must last at least 2 years. Less consistent reductions were seen in studies of beta-carotene (RRR range, -2% to 46%) and vitamin C (RRR range, -25% to 51%). Considerable biases in observational studies, such as different health behaviors of persons using antioxidants, may account for the observed benefit. By contrast, none of the completed randomized trials showed any clear reduction in cardiovascular disease with vitamin E, vitamin C, or beta-carotene supplementation. The trials were not specifically designed to assess cardiovascular disease, did not provide data on nonfatal cardiovascular end points, may have had insufficient treatment durations, and used suboptimal vitamin E doses. The completed trials were of adequate size to indicate that the true therapeutic benefit of vitamin E and other antioxidants in reducing fatal cardiovascular disease (a survival benefit as long as 5 years) is probably more modest than the epidemiologic data suggest., Conclusion: The epidemiologic data suggest that antioxidant vitamins reduce cardiovascular disease, with the clearest effect for vitamin E; however, completed randomized trials do not support this finding. Much of this controversy should be resolved by the ongoing large-scale and long-term randomized trials designed specifically to evaluate effects on cardiovascular disease.

This review summarizes the evidence from five of the larger randomized controlled trials evaluating the effects of angiotensin converting enzyme inhibitors started in the early phase of myocardial infarction on subsequent mortality and major morbidity. Altogether, information on about 98,000 patients is available from these trials. In four studies, trial treatment was started within 24 h, and in one study within 36 h, of the onset of symptoms of acute myocardial infarction, and mortality was assessed after a few weeks or months of treatment. When taken together, these trials show that angiotensin converting enzyme inhibitors produce a significant 7% relative risk reduction in mortality (P < 0.006), which corresponds to an absolute difference of about five fewer deaths per 1,000 patients treated. The benefits may be greater in higher-risk patients (e.g. those with previous myocardial infarction, heart failure or large infarcts). These results demonstrate that for a wide range of patients without clear contraindications, angiotensin converting enzyme inhibitors started early in acute myocardial infarction prevent further deaths in the first few weeks when added to standard therapy (aspirin, thrombolytic therapy and beta-blockers). The early benefits seen with ACE inhibitors seems to persist for at least the first year. The clinical implications of these results are discussed.

Objectives: We sought to determine whether abnormalities in small intramyocardial vessels could be detected on routine cardiac transplant biopsy specimens and whether these features correlate with intimal thickening by intracoronary ultrasound and endothelial dysfunction in large epicardial vessels., Background: Variability in clinical presentation of allograft vasculopathy suggests differential involvement of large and small vessels. Intracoronary ultrasound and endothelial function studies detect large-vessel abnormalities but may not reflect changes in small intramyocardial arteries. The latter could be detected in routine cardiac biopsy specimens by histologic and immunohistochemical studies., Methods: Thirty-nine cardiac transplant recipients underwent intracoronary ultrasound and acetylcholine studies 5 to 7 days after endomyocardial biopsy. Biopsy tissue was evaluated for coronary artery endothelial plumping and intimal thickening and increased immunostaining for fibronectin, tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility. Large-vessel disease was assessed by calculating an average intimal index from intracoronary ultrasound of the left anterior descending coronary artery. Endothelial function was determined by quantitative coronary analysis after acetylcholine challenge., Results: Coronary arteries were found in the biopsy tissue of 30 (76%) of the 39 patients who formed the study group. Fourteen of 30 patients had abnormal histologic findings. Immunohistochemical analysis for fibronectin, possible in 20 of 30 patients, was positive in 14 (70%) of 20 and correlated with abnormal histologic findings (p = 0.01). Immunostaining was positive for tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility in 12 (40%) and 13 (43%) of 30 patients, respectively. All patients had intimal thickening by intracoronary ultrasound, but intimal index did not correlate significantly with small-artery disease by histologic or immunohistochemical analysis. Large-vessel endothelial dysfunction in 13 patients (43%) did not correlate with either abnormal ultrasound findings or small-vessel disease., Conclusions: Intramyocardial arteries are readily observed in biopsy specimens from cardiac transplant recipients and provide useful information about allograft vasculopathy. Lack of correlation between intramyocardial and epicardial vessel disease suggests discordant progression of allograft vasculopathy.

Objective: Collagen is lysed early during ischemia-reperfusion, but whether this is due to ischemia or reperfusion injury is not known. The effect of oxygen free radicals and free radical scavengers on left ventricular hemodynamics, myocardial morphology and collagen content were studied in an isolated, Langendorff-perfused rat heart model of regional ischemia-reperfusion., Methods: All hearts received left anterior descending coronary artery ischemia for 20 mins. Group 1 had ischemia only; group 2 had ischemia followed by reperfusion with oxygenated Krebs-Henseleit buffer for 20 mins; group 3 had oxygen free radicals generated by hypoxanthine and xanthine oxidase during reperfusion; group 4 had free radical scavengers with superoxide dismutase plus catalase; group 5 had both oxygen free radicals and free radical scavengers during reperfusion., Results: Left ventricular developed pressure decreased significantly in group 3 during ischemia followed by reperfusion (58 +/- 3.1 mmHg versus 42 +/- 2.4 mmHg, P = 0.004), but did not change significantly in any of the other groups. Necrosis score on pathology was highest in group 3; this score also was higher than that in group 5 with free radical scavengers added (3.0 +/- 0.3 versus 2.0 +/- 0.4, P = 0.07) and higher than that of group 2 with reperfusion with buffer only (3.0 +/- 0.3 versus 1.4 +/- 0.5, P < 0.05). Collagen content decreased significantly compared with control in group 3 only with ischemia followed by reperfusion with the addition of oxygen free radicals (18.4 +/- 1.5 versus 11.9 +/- 1.7 g/mg protein, P < 0.05). The addition of free radical scavengers in group 5 mainly attenuated the collagen loss. Scanning electron microscopy revealed profound structural changes of the extracellular collagen matrix in numerous regions of 'stunning' independent of tissue necrosis., Conclusions: We conclude that: first, oxygen free radicals trigger significant collagen damage and left ventricular dysfunction during reperfusion; second, these changes extend beyond the ischemic damage alone; and third, free radical scavengers can effectively limit oxygen free radical-induced collagen loss and left ventricular dysfunction.

Aim: To summarize the risk factors associated with coronary heart disease and strokes and to evaluate measures used in the prevention and treatment of these diseases., Method: A review of the results of randomly allocated clinical trials of treatment for both primary and secondary prevention of coronary heart disease and strokes., Results: Reductions in elevated blood pressure and cholesterol and cessation of cigarette smoking have clearly been shown to reduce the incidence of coronary heart disease. A reduction in blood pressure has also been shown to reduce the risk of strokes. In addition to other classical risk factors, such as abnormal serum lipids, diabetes and a genetic predisposition, recent studies have shown that elevated levels of fibrinogen and other clotting factors, elevated levels of renin and decreased levels of anti-oxidant vitamins such as E, C and beta-carotene can predict coronary heart disease and strokes. Thrombolytic therapy, aspirin and beta-blockers have been shown to reduce mortality in patients with myocardial infarction, and the latter two agents reduce mortality, re-infarction and strokes with long-term use. Treatment with intravenous magnesium and nitrates has shown promise but larger trials are required to confirm the results. Both aspirin and heparin have proven value in reducing the incidence of myocardial infarction and death in unstable angina. Following an acute myocardial infarction, long-term therapy with aspirin, beta-blockers, lipid-lowering agents and oral anticoagulants has been shown to reduce mortality and re-infarction. In patients with large infarcts associated with a low ejection fraction or heart failure, the use of angiotensin converting enzyme (ACE) inhibitors reduces mortality, hospitalization for heart failure and re-infarction. The use of diuretics to lower blood pressure reduces strokes. In contrast, calcium antagonists do not appear to consistently reduce mortality or prevent vascular events when used for primary or secondary prevention of either myocardial infarction or strokes., Conclusions: Myocardial infarction and strokes can be prevented by refraining from smoking and maintaining appropriate blood pressure levels and a favourable balance of lipids. Following a myocardial infarction, further drug treatment should include aspirin, thrombolytic therapy (in acute myocardial infarction), beta-blockers, ACE inhibitors (in patients with a low ejection fraction) and perhaps anticoagulants.

High resolution (125-microns lateral, 55-microns axial) images of 16 muscular (femoral) and 15 elastic (common carotid) human arteries were made in vitro with use of a prototype 45-MHz intravascular imaging system. Four distinct regions of scattering, excluding plaque, were identified in the ultrasound images corresponding histologically to the adventitia, media, thickened intima and elastic laminae, both internal and external. Arterial samples imaged under pressure and in a collapsed state underwent dimensional changes but exhibited similar levels of backscatter amplitude. All the elastic arteries displayed a prominent echogenic media, whereas all the muscular arteries displayed an echolucent media. Scattering from the internal elastic lamina in muscular arteries provided an excellent landmark for defining the location and extent of intimal thickening or plaque. In elastic arteries the internal elastic lamina could not be distinguished from the echogenic media; consequently, the boundary between the media and intimal layer was indistinct. Differences in the relative concentration and organization of collagen and elastin were found to provide a consistent explanation for the differences in scattering that were observed between individual layers within an artery as well as between muscular and elastic arteries.

If reciprocal electrocardiographic changes during acute myocardial infarction (AMI) are a result of ischemia of the wall opposite the AMI, a stress test is expected to induce similar changes in the corresponding electrocardiographic leads. Right atrial pacing was used as a myocardial stress method in 137 consecutive patients recovering from a transmural AMI, and the appearance of pacing-provoked ischemia before hospital discharge was correlated to the presence of absence of ST depression in the opposite wall during the initial 48 hours. Of the 137 patients, 83 (61%) had reciprocal changes; they were more common in inferior (87%) than in anterior (37%) AMI (p less than 0.01). Of 54 patients without reciprocal changes, only 5 (9%) had ST depression during predischarge pacing; however, of the 83 patients with reciprocal changes, 41 had pacing-induced ischemia (p less than 0.01) and 42 did not, indicating that in half of this group the reciprocal changes represent ischemia of the opposite wall. In the other half of the group, without ST depression during pacing, these changes may be a "mirror image" phenomenon. Follow-up showed that angina pectoris, positive treadmill test response 6 months later, or recurrent AMI all consequences of impaired myocardial blood supply, were significantly more frequent in patients with reciprocal changes. This group could be further separated according to the results of right atrial pacing, because angina pectoris or recurrent AMI were infrequent among those with reciprocal changes and negative pacing responses, but was frequent among those with reciprocal changes and positive pacing responses.(ABSTRACT TRUNCATED AT 250 WORDS)