Platelets, carotids, and coronaries. Critique on antithrombotic role of antiplatelet agents, exercise, and certain diets

"Antiplatelet" drugs and certain life styles seem to have an "antithrombotic" effect that may help protect against stroke and heart attack. This review of the experience with aspirin, dipyridamole, and sulfinpyrazone offers new interpretations of some of the major clinical trials, suggests guidelines for use of antiplatelet drugs, and integrates novel observations on diet and exercise into the "thromboxane-prostacyclin balance" hypothesis. It is argued that the Canadian stroke study showed that aspirin protects men with transient ischemic attacks from coronary death as well as from stroke, that type II errors may have been made in some clinical trials, that aspirin protects women as well as men, that aspirin benefits patients who have had a heart attack, that the effect of aspirin in angina varies with the type of angina, that the dose of aspirin used may not be critical, that guidelines for use of dipyridamole and sulfinpyrazone are still inconclusive, and that exercise and fish oil supplements may be "antithrombotic."     

Cardiac rehabilitation following coronary artery bypass surgery

Early expectations of coronary revascularization prolonging life and reducing coronary events have been modified by 15 years' experience to mostly initial palliation of ischemic symptoms. Bypass surgery represents only a single therapeutic aspect for coronary atherosclerosis. Technically successful operations often fail miserably without overall risk factor alteration and functional capacity optimization which progressive exercise initiates during the postoperative period. Regular activity program participation improves physical conditioning, raises the symptom-limited exertional level, lessens post surgical musculoskeletal discomfort, and improves morale. Yet exercise alone without comprehensive secondary prevention and risk factor modification will be no more successful at arresting atherosclerosis than any other single measure. Both operative intervention and vigorous exertion are valuable components of coronary artery disease therapy, but must be part of an all-embracing effort. Whether regular exertion combined with overall risk factor modification will prolong life and reduce future cardiac events or beneficially alter the process of atherogenesis remain areas of avid investigation.     

"Warm-up" phenomenon in adult and elderly patients with coronary artery disease: further evidence of the loss of "ischemic preconditioning" in the aging heart

BACKGROUND: A reduction of exercise-induced ischemia in patients with coronary artery disease by means of brief period of exercise followed by resting is called the "warm-up" phenomenon. This phenomenon may represent a clinical counterpart of "ischemic preconditioning." We studied the warm-up phenomenon in both adult and elderly patients with similar angiographic evidence of coronary artery disease, using three exercise tests after excluding the "training effect." METHODS: In order to verify the presence of "training effect," three exercise tests were performed in days 1, 2, and 3 ("training" tests). The third test was used as baseline for a successive test, performed after a recovery period of 10 minutes to reestablish baseline electrocardiographic conditions. A third exercise test was performed 30 minutes later ("warm-up" tests). RESULTS: "Training" tests did not differ in all parameters in both adult and elderly patients. "Warm-up" tests showed that time to onset 1-mm ST depression was significantly higher (p < .001). whereas ST depression and time to recovery was significantly lower in the second and third test in adult but not in elderly patients (p < .001 ). Difference (in seconds) in the time at which 1-mm ST depression occurred on first warm-up exercise compared with the second was inversely correlated with age (p < .001 ). CONCLUSIONS: Previous exercise followed by resting is able to reduce the successive exercise-induced ischemia ("warm-up" phenomenon) in adult but not in elderly patients with coronary artery disease. This is independent of a greater age-related severity of coronary disease and of "training effect." These results confirm the hypothetical age-related reduction of "ischemic preconditioning" in aging heart.     

Coronary artery disease in systemic lupus erythematosus: A review of the literature

CONTEXT: Coronary artery occlusive disease is a common though underappreciated complication of systemic lupus erythematosus (SLE), typically a disease of young women. A case of a premenopausal patient with SLE and an acute myocardial infarction is presented, and the etiology and management of coronary artery disease in SLE reviewed. OBJECTIVES: To review the incidence, risk factors, pathology and treatment of coronary artery disease in systemic lupus erythematosus. DATA SOURCES: MEDLINE search of articles in English-language journals from 1980 to 2000. The index words "systemic lupus erythematosus" and the following co-indexing terms were used: "coronary artery disease," "atherosclerosis," "vasculitis," "anticardiolipin antibodies," "antiphospholipid syndrome." SELECTION SYNTHESIS AND ABSTRACTION: Papers identified were reviewed and abstracted by the authors with a presentation of a summary. RESULTS: The prevalence of coronary artery disease among women with SLE between the ages of 35 and 44 years is at least 50-fold greater than among age-matched control subjects. Of these, coronary atherosclerosis accounts for the vast majority of cases; vasculitis of the coronary arteries and other causes generally believed to be more typical of SLE are comparatively rare. CONCLUSIONS: The evidence suggests that SLE is a significant risk factor for coronary atherosclerosis independent of the classic risk factors of hypertension, tobacco use, and hyperlipidemia.     

Coronary heart disease as a pediatric problem. Prevention through behavior modification

Risk factors for coronary heart disease may be present in early childhood. Primary prevention of coronary atherosclerosis requires early identification and vigorous management of risk factors, and the pediatrician and family physician have a major role in this approach. Alteration of behavior with emphasis on exercise of the endurance type and more rational dietary habits are advocated. The beneficial effects of exercise may occur without alteration of coronary risk factors. Early institution of educational programs and constructive physical activity has the potential to influence favorably cardiovascular health at an early stage.     

Contribution of the risk factor concept to patient care in coronary heart disease

This article deals with the question of whether or not the risk factor concept, a principal aspect of preventive cardiology, has contributed to patient care in coronary heart disease. The risk factors considered are plasma cholesterol, high blood pressure, smoking, diabetes and marked obesity. With the exception of plasma cholesterol and diabetes, all of these factors enhance myocardial oxygen consumption and thus, in the presence of coronary insufficiency, promote myocardial ischemia. Their modification is therefore good general medical practice, even if not related to coronary atherosclerosis. Diabetes needs adequate medical treatment in patients both with and without coronary atherosclerosis.Because of the occasional occurrence of spontaneous regression of coronary atherosclerosis and the morphologic and functional complexity of coronary artery pathology, it has never been and probably never will be demonstrated that lowering plasma cholesterol levels by diet or other means will cause regression of coronary atherosclerosis. It follows that modification or treatment of risk factors is implemented for good medical reasons but does not demonstrably or predictably affect coronary artery disease. It is concluded that the contribution of the risk factor concept to patient care in coronary heart disease has been, and still is, trivial.     

Atherosclerosis and systemic lupus erythematosus

Large increases in mortality related to premature atherosclerosis with coronary artery disease have been reported in patients with systemic lupus erythematosus (SLE). The current pathogenic hypothesis for atherosclerosis involves not only the classic factors identified in the Framingham study, but also includes chronic inflammation, corticosteroid therapy, excess of traditional risk factors, autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized low-density lipoproteins, and to endothelial cells), and cytokine-producing activated T cells. Early risk factor intervention and effective control of inflammation should be incorporated into the management of SLE to protect against atherosclerosis.     

Dipyridamole radionuclide ventriculography: a test with high specificity for severe coronary artery disease

Ventricular dysfunction induced by dipyridamole would be evidence of myocardial ischemia in patients with limited ability to undergo standard exercise testing. Radionuclide ventriculography before and after intravenous dipyridamole infusion was compared with the results of exercise radionuclide ventriculography in a prospective study of 31 patients undergoing coronary angiography. Among these patients, 21 (68%) had significant coronary artery disease (greater than or equal to 50% stenosis), 19 (61%) had severe coronary disease (greater than or equal to 70% stenosis) and 10 (32%) were "normal" (less than 50% stenosis). The left ventricular ejection fraction was calculated, and regional wall motion was scored on a 6 unit scale. In the normal patients, the ejection fraction (+/- SEM) increased 5.6 +/- 2% (units) during exercise and 7.9 +/- 1 units after dipyridamole (both p less than or equal to 0.004 compared with that during rest). However, in patients with coronary artery disease, the ejection fraction failed to increase during exercise or after dipyridamole. In the patients with coronary artery disease, regional wall motion decreased by 4.1 +/- 0.5 units during exercise (p less than 0.003) and by 1.8 units after dipyridamole (p less than 0.02). Receiver operating characteristic analysis demonstrated general comparability between the sensitivity and specificity of exercise and dipyridamole ventriculography, with "optimal" operating points that favored choosing high sensitivity for the former and high specificity for the latter. Specific subsets of patients with severe coronary atherosclerosis were analyzed with use of these criteria. In patients with severe stenosis (greater than or equal to 70%), the sensitivity of dipyridamole ventriculography was 67% compared with 89% for exercise ventriculography. However, at these levels of sensitivity, the specificity of dipyridamole ventriculography was 92% compared with 67% for exercise ventriculography. In this and other subsets of patients, the specificity of dipyridamole ventriculography exceeded that of exercise ventriculography. Thus, it is concluded that dipyridamole radionuclide ventriculography is moderately sensitive and highly specific for detecting severe coronary atherosclerosis. This technique provides a widely applicable, useful alternative to exercise ventriculography in the diagnosis of coronary atherosclerosis in patients who have limited exercise tolerance.     

"Silent" myocardial ischemia during and after exercise testing in patients with coronary artery disease

Although many patients with coronary artery disease (CAD) have a positive exercise test without pain, the frequency and significance of this "silent" ischemia is unclear. Therefore, we studied 122 consecutive clinically stable patients with angiographically defined CAD (greater than 75 per cent luminal stenosis) and a positive exercise test. Seventy-eight patients had pain or anginal equivalent during or after a positive exercise test; 44 did not, including 32 (26 per cent) with no symptoms at all. Patients were evaluated as to age, sex, prior myocardial infarction, congestive failure, hypertension, diabetes mellitus, and digoxin or propranolol therapy--in addition to anginal symptoms before, during, or after the exercise itself. Extent of CAD, presence of collaterals, and left ventricular ejection fraction were also determined. All exercise tests were evaluated for evidence of ST-T abnormalities or prior infarction on the control ECG as well as peak heart rate during exercise and post-exercise degree of ST segment depression. There were no significant differences between patients with and without exercise-induced pain in regard to any of the clinical and angiographic features noted above, demonstrating that "silent" myocardial ischemia during or after exercise testing is not uncommon and is not readily attributable to any obvious clinical or catheterization findings. Further studies are necessary to determine if patients with evidence of "silent" myocardial ischemia are especially prone to sudden death.     

Coronary artery spasm and its relationship to exercise in patients without severe coronary obstructive disease

Coronary artery spasm is reported to occur with exercise. In patients without severe coronary atherosclerosis, the evidence for exercise-induced coronary artery spasm is limited. Three patients with positive exercise tests but no severe coronary atherosclerosis are presented. Coronary artery spasm was provoked and verified by angiography in all three, but coronary angiography during exercise failed to demonstrate spasm. The literature is reviewed and the value of a routine protocol for evaluation is discussed.     

Levels of serum sex hormones and risk factors for coronary heart disease in exercise-trained men

On the basis of previous findings, it has been hypothesized that hyperestrogenemia may be the major predisposing factor for coronary heart disease and that an elevation in the estradiol-to-testosterone ratio, or a closely related hormonal alteration, may cause the expression of risk factors for coronary heart disease. The present study was carried out to investigate whether exercise training, which has been reported to reduce risk factors for coronary heart disease, affects the serum sex hormone levels. The serum sex hormone levels, established risk factors for coronary heart disease, and physical fitness were measured in 10 men who had undergone at least six months of intensive exercise training and in 10 sedentary men of similar age. Despite evidence for a strikingly higher level of physical fitness and a lower level of risk factors in the trained group, no significant difference in mean serum estradiol level was found. Nor did three subjects from the sedentary group show a decrease in estradiol level after three to four months of exercise training. The mean estradiol-to-testosterone ratio, however, was significantly lower in the trained group and might account for the lower level of risk factors in that group. If the hypothesis is correct, exercise training may decrease established risk factors for coronary heart disease without decreasing the risk of coronary heart disease.     

Homocysteine levels in patients with risk factors for atherosclerosis

BACKGROUND: Abundant epidemiological evidence has demonstrated that the presence of mild to moderate hyperhomocysteinemia is an independent risk factor for atherosclerosis in the coronary, cerebral, and peripheral vasculature, and for vascular disease, including coronary disease. It has been demonstrated that plasma total homocysteine level is a strong predictor of mortality in patients with angiographically confirmed coronary artery disease. HYPOTHESIS: The study was undertaken to determine the extent of homocysteine levels in patients without documented coronary artery disease, but with at least one risk factor for atherosclerosis. METHODS: Fasting blood samples were collected prospectively from 160 consecutive patients (50 women and 110 men, mean age 65+/-7 years) who had at least one risk factor for atherosclerosis, but had no documented coronary artery disease. Homocysteine levels were measured by an immunoassay method. RESULTS: Of the patients studied, 78 (48.75%) with at least one risk factor for atherosclerosis had high homocysteine levels; 62 patients had mild hyperhomocysteinemia (15-30 micromol/l); and 16 patients had moderate hyperhomocysteinemia (30-100 micromol/l). CONCLUSIONS: Our data suggest that hyperhomocysteinemia is highly prevalent in patients with risk factors for atherosclerosis. Homocysteine level (an independent convertible risk factor to atherosclerosis) should be measured routinely in patients with risk factors for atherosclerosis and treated appropriately.     

Fibrinolysis and risk factors of atherosclerotic disease, with special emphasis on diabetes mellitus.

This paper reviews and discusses the evidence supporting the involvement of defective fibrinolysis in the pathogenesis of atherosclerosis, with emphasis on diabetes mellitus. According to the literature, defective fibrinolysis has been observed in association with virtually every major "risk factor" for coronary heart disease, including diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hypertension, obesity, cigarette smoking and lack of physical exercise. The interrelationships between disturbances in carbohydrate and fat metabolism and fibrinolysis are considered. Attention is drawn to the need for increased clinical attention to the potential role of defective fibrinolysis in atherogenesis, and periodic assessments of the fibrinolytic status are suggested as a promising approach toward early recognition of atherosclerotic tendency and risk. The judicious use of physiologic, dietary and pharmacologic means to correct defective fibrinolysis prophylactically and for the treatment of some forms of atherosclerosis is advocated.     

Sudden death during exercise

Although death during exercise is rare, vigorous physical activity is associated with increased risk for fatality, particularly in individuals with overt cardiac disease or a high coronary risk profile. The mechanism of death is usually a lethal ventricular arrhythmia, but this may vary depending on the underlying cardiac condition. Cardiac disease is present in the great majority of individuals who die during exercise. In young persons, hypertrophic cardiomyopathy and congenital coronary anomalies are most frequent, whereas older victims usually have coronary artery atherosclerosis. Cardiac disease is typically unrecognized before the fatal event in young individuals; in the older group, most have overt coronary disease or identifiable risk factors. Screening asymptomatic subjects to identify increased cardiac risk during exercise is problematical in terms of logistics, expense and accuracy. However, careful evaluation, including exercise testing, is mandatory before a program of increased physical activity is initiated in cardiac patients. For other individuals, firm guidelines are lacking, and the extent of the evaluation must be determined on an individual basis.     

Alcohol versus exercise for coronary protection

Both alcohol and exercise have been said to protect against coronary heart disease. The epidemiologic data suggest exercise, per se, does, but alcohol, per se, does not protect against coronary heart disease. Recent longitudinal data suggest teetotalers, especially those who have never smoked, have the lowest coronary heart disease mortality of all. Other cross-sectional and longitudinal studies that suggest light drinkers have the lowest coronary heart disease mortality may be biased because: (1) the teetotalers include some ex-drinkers who may have quit drinking because of coronary heart disease; and (2) the light drinkers include some who drink very rarely, and/or drink very small amounts, and/or have a lower risk of coronary heart disease independent of alcohol because they are more health-conscious in general. The metabolic data also suggest exercise, but not alcohol, protects against coronary heart disease. Exercise increases the level of high-density lipoprotein 2, which correlates well with coronary heart disease risk; alcohol in moderation seems to increase the level of high-density lipoprotein 3, which correlates poorly with coronary heart disease risk and may merely reflect hepatic enzyme induction. Exercise and alcohol influence blood pressure, body weight, and glucose tolerance in opposite directions; in each instance, the influence of exercise is beneficial, that of alcohol detrimental, to the prevention of coronary heart disease. There seems to be no reason to use alcohol for coronary protection.     

Exercise as a coronary protective factor

Exercise has multiple beneficial actions, both in normal subjects and in patients with coronary artery disease, which can be cardioprotective. Apart from reducing known risk factors and protecting against their deleterious effects, exercise also reduces the risk of coronary artery disease by increasing cardiovascular fitness. The exact contribution of each of these mechanisms in reducing coronary artery disease morbidity and mortality is unclear. Although fitness may be desirable, much of the cardioprotection can be achieved through increased leisure time and recreational physical activity. The risk-benefit ratio is very much in favor of moderate intensity exercise. Even in the absence of a controlled trial, the available evidence suggests that efforts to encourage physical activity are justified.     

Antibiotic trials for coronary heart disease

The possibility has been raised in recent years that infection might contribute as an inflammatory stimulus to chronic "noninfectious" degenerative diseases. Within the past decade, serious attention has been given to the possibility of bacterial vectors as causal factors of atherosclerosis. To date, the greatest amount of information has related to the intracellular organism Chlamydia pneumoniae. This interest has been stimulated by the frequent finding of bacterial antigens and, occasionally, recoverable organisms, within human atherosclerotic plaque. Indirect evidence for and against the benefit of anti-Chlamydia antibiotic agents comes from epidemiologic studies. Given the potential for confounding in observational studies, prospective, randomized intervention trials are required. These antibiotic trials have generated enthusiastic expectations for proving (or disproving) the infectious-disease hypothesis of atherosclerosis and establishing new therapies. However, these expectations have been tempered by important limitations and uncertainties. Negative outcomes can be explained not only by an incorrect hypothesis but also by inadequate study size or design or by an ineffective antibiotic regimen. In contrast, if studies are positive, the hypothesis still is not entirely proved, because a nonspecific anti-inflammatory effect or an anti-infective action against other organisms might be operative. The clinical trial data to date have not provided adequate support for the clinical use of antibiotics in primary or secondary prevention of coronary heart disease. New and innovative experimental approaches, in addition to traditionally designed antibiotic trials, should be welcome in our attempts to gain adequate insight into the role of infection in atherosclerosis and its therapy.     

Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus

Fatty acid-binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.     

Comparison of coronary calcium and stress myocardial perfusion imaging in apparently healthy siblings of individuals with premature coronary artery disease

Detection of subclinical coronary atherosclerosis is possible using exercise myocardial perfusion imaging for inducible ischemia or multidetector computed tomography for coronary artery calcium (CAC), which is used to detect subclinical coronary atherosclerosis. The extent to which these screening tests converge in an asymptomatic population that is at increased risk for coronary artery disease remains unknown. We compared the concordance of findings in 260 asymptomatic middle-age siblings of hospitalized index patients <60 years of age with documented coronary artery disease. All subjects underwent maximal exercise testing with postexercise and delayed attenuation-corrected thallium single-photon emission computed tomography and multidetector computed tomography for CAC. An abnormal exercise single-photon emission computed tomographic (SPECT) result occurred in >50% of subjects with a CAC score >100, but also in 12% with no CAC, 9% with CAC scores of 1 to 10, and 20% with CAC scores of 11 to 100. In subjects with an abnormal exercise SPECT result, 59% had CAC scores < or =100. Overall, there was only a modest agreement between an abnormal exercise SPECT result and high CAC scores. In conclusion, although moderate or severe CAC is often associated with inducible ischemia, the absence of CAC or the presence of only mild CAC by no means precludes inducible myocardial ischemia. These screening tests may reflect different aspects or stages of coronary disease in an asymptomatic middle-age population.     

Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease

Homocysteine is a graded risk factor for the incidence of stroke and for the degree of carotid atherosclerosis. Homocysteine is also a graded risk factor for the incidence of myocardial infarction but we do not know its precise relations to the severity of atherosclerosis in coronary patients. Seventy five symptomatic coronary patients were recruited for the study. Fifty of these patients had coronary artery disease only and were compared in a case-control manner to 50 healthy controls matched for age and sex. The 25 other coronary patients had also symptoms in another atherosclerotic territory (cerebral, peripheral or both) and were also compared to 25 matched controls. Mean plasma homocysteine level was significantly higher in coronary patients than in controls (11.7±0.7μmol l⁻¹, n=50 versus 9.9±0.5μmol l⁻¹, n=50, p<0.05). Homocysteine in patients with symptomatic atherosclerosis in two or three arterial sites was 15.7±1.5μmol l⁻¹ which differed significantly from matched controls and from patients with coronary artery disease only (p=0.01). The extent of coronary atherosclerosis evaluated by an angiographic coronary score correlated weakly to plasma homocysteine levels (r=0.25, p<0.05). The patients with both hypertension and high levels of homocysteine (>11.3μmol l⁻¹, median value) had more severe coronary atherosclerosis (coronary score of 16.3±2.3 versus 11.9±0.9, p<0.05) and more diffuse atherosclerosis (number of atherosclerotic territories of 1.5±0.2 versus 1.2±0.7, p=0.08) than the coronary patients without this association. There were no other high risk association when considering the other classical risk factors.

Thus, the highest levels of homocysteine were present in patients with coronary disease and another symptomatic localisation of atherosclerosis. A small gradient in the extent of coronary atherosclerosis was found with increasing levels of homocysteine. The presence of both hypertension and hyperhomocysteinemia was associated with more severe coronary atherosclerosis.