Cause Of Coronary Heart Disease Research Articles

Intercellular adhesion molecule 1 gene K469E polymorphism is associated with coronary heart disease risk: a meta-analysis involving 12 studies

Coronary atherosclerosis is a leading cause of coronary heart disease (CHD). Atherosclerotic lesion is a complex polygenic disease in which gene-environment interactions play a critical role in disease onset and progression. The ICAM1 gene-E469K polymorphism has been reported to be associated with CHD, but results were conflicting. A systematic review and meta-analysis of the published studies were performed to gain a clearer understanding of this association. The PubMed, Embase, and CNKI databases were searched for case-control studies published up to August 2011. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Twelve eligible studies, comprising 2,157 cases and 1,952 controls, were included in the meta-analysis. The pooled result showed that the ICAM1 gene-E469K polymorphism was significantly associated with an increased risk of CHD (OR=1.496, 95% CI=1.363-1.642, for the allele K vs. allele E; OR=1.919, 95% CI=11.635-2.253, for the K allele carriers vs. EE). Subgroup analysis supported the results in the Asian populations and in the Caucasian populations. This meta-analysis suggests that the ICAM1 gene K469E polymorphism is associated with CHD risk and the K allele is a more significant risk factor for developing CHD among Asian and Caucasians populations.

Pleiotropic Effects of Glucagon-like Peptide-1 (GLP-1)-Based Therapies on Vascular Complications in Diabetes

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathies, which could account for disabilities and high mortality rates in patients with diabetes. Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family. L cells in the small intestine secrete GLP-1 in response to food intake. GLP-1 not only enhances glucose-evoked insulin release from pancreatic β-cells, but also suppresses glucagon secretion from pancreatic α-cells. In addition, GLP-1 slows gastric emptying. Therefore, enhancement of GLP-1 secretion is a potential therapeutic target for the treatment of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) is a responsible enzyme that mainly degrades GLP-1, and the half-life of circulating GLP-1 is very short. Recently, DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists have been developed and clinically used for the treatment of type 2 diabetes as a GLP-1-based medicine. GLP-1R is shown to exist in extra-pancreatic tissues such as vessels, kidney and heart, and could mediate the diverse biological actions of GLP-1 in a variety of tissues. So, in this paper, we review the pleiotropic effects of GLP-1-based therapies and its clinical utility in vascular complications in diabetes.

Atherosclerosis in young Brazilians suffering violent deaths: a pathological study

BackgroundAtherosclerosis is the leading cause of coronary heart disease and ischemic stroke, which can cause sudden death in adulthood. In general, the clinical manifestations of cardiovascular diseases are caused by atherosclerosis, which is a process that starts during middle age. More recent studies indicate that the atherosclerotic process begins during childhood.MethodsTo evaluate the extent of atherosclerotic disease in young Brazilians, we conducted a study of the pathological alterations in the major arteries of victims of violent death. Samples of the right carotid artery, left coronary artery, and thoracic aorta of young victims of violent death were analyzed and graded in accordance with the histological atherosclerotic lesion types proposed by the American Heart Association. Samples were collected from 100 individuals who had died from external causes, aged from 12 to 33 years.ResultsThe majority of cases (83%) were male, and 66% of deaths were homicides caused by firearms. The median age was 20.0 years and mean body mass index was 20.9 kg/m2. Of the right carotid artery specimens, 3% were normal, 55% had type I, 40% had type II, 1% had type III, and 1% had type IV atherosclerotic lesions. Of the left coronary artery specimens, 5% were normal, 48% had type I, 41% had type II, 3% had type III, and 3% had type IV lesions. Of the thoracic aorta specimens, none were normal, 13% had type I, 64% had type II, 22% had type III, and 1% had type IV lesions. Overall, 97.34% of arteries examined had some degree of atherosclerosis. The most common histological type was type II (foam cells). No thoracic aorta specimens were normal, and the coronary artery specimens had the most atherosclerosis.ConclusionsOur results show a high prevalence of atherosclerotic lesions among young people in Brazil. Intervention should be undertaken to decrease the rate of sudden cardiac death in the adult population.

Drug Eluting Coronary Artery Stents

Atherosclerosis is the primary cause of coronary heart disease, which is characterized by a narrowing (stenosis) of the arteries that supply blood to tissues of the heart. Over the past decade, the use of "Bare metallic stents" during Percutaneous Transluminal Coronary Angioplasty (PTCA) has become a common practice for treating the coronary arterial stenosis. However, the restenosis is common problem in patients receiving stents. Recently, Drug-Eluting Stents (DES) with synthetic polymer coatings which act as drug reservoirs and elute drugs over a period of several weeks or months have emerged to tackle restenosis. The polymer coatings on these stents contain various drugs like immunosuppressive drugs, anti-neoplastic drugs, anti-inflammatory drugs, migration inhibitor drugs and enhanced healing drugs that inhibit thrombus formation, inflammation or cellular proliferation which in turn prevent restenosis. Different methods like dip coating, dip spin coating, ultrasonic spray coating and ink-jet coating help to coat stent uniformly. Drug from the stent can be released by diffusion, dissolution or ion exchange mechanism. There are some disadvantages of the polymer coated stents and hence they are being superseded by completely bioabsorbable stents. Such stents are heading for clinical trials and may hit the market soon. This review gives a glimpse over DES and the future prospects of DES.

Atherosclerosis: pathogenesis and increased occurrence in individuals with HIV and Mycobacterium tuberculosis infection

Atherosclerosis is a leading cause of coronary heart disease and stroke. Since 1981, more than 980,000 cases of AIDS have been reported in the United States. According to the Centers for Disease Control, more than 1 million Americans may be infected with HIV. By killing or damaging CD4+ T cells of the body’s immune system, HIV progressively destroys the body’s ability to fight infections. People diagnosed with AIDS often suffer from life-threatening diseases caused by opportunistic infections such as tuberculosis. HIV-infected individuals have increased risks for atherosclerosis. This review summarizes the effects of oxidized low density lipoproteins in impairing macrophage functions in individuals with atherosclerosis (with and without HIV infection) thereby enhancing the susceptibility to Mycobacterium tuberculosis infection.

Imaging of coronary atherosclerosis: intravascular ultrasound

Atherosclerosis is the main cause of coronary heart disease, which is today the leading cause of death worldwide and will continue to be the first in the world in 2030. In the formation of atherosclerotic coronary lesions, a critical primary step is the accumulation and oxidation of low-density lipoprotein (LDL) particles. Oxidized-LDL favours leucocyte recruitment and their activation, as well as cell death. This leads to generation of complex atherosclerotic plaques. These plaques have a high content of necrotic core, a thin inflamed fibrous cap (intense accumulation of macrophages) and scarce presence of smooth muscle cells (i.e. thin-capped fibroatheroma). At early stages of the formation of the atheroma, the remodelling of the vessel wall usually prevents plaque from encroaching on the lumen, thereby masking the presence of atheroma on angiography. In contrast, greyscale intravascular ultrasound can fully assess the extension of the disease axially and longitudinally. This intravascular imaging technique has played a vital role in advancing our understanding of the pathophysiology of coronary artery disease, and in the development of novel cardiovascular drugs and device therapies. This intravascular imaging technology and its clinical and research applications are discussed in more detail below.

Smooth Muscle Cell Pathophysiology and Advanced Glycation End Products (AGEs)

Accelerated atherosclerosis is the leading cause of coronary heart disease and stroke, which could account for high mortality rates in patients with diabetes. Although several hyperglycemia-elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of cardiovascular disease (CVD) in diabetes, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the phenomenon 'metabolic memory' and 'legacy effect', that is, vascular stresses during the diabetic exposure have persisted after glucose normalization. Further, there is a growing body of evidence that a receptor for AGEs (RAGE) is involved in signal transduction of AGEs in a variety of cells. In this paper, we review the role of the AGE-RAGE system in accelerated atherosclerosis, especially focusing on smooth muscle cell pathophysiology, and also discuss the possibility that the AGE/RAGE axis could be a potential therapeutic target for prevention of CVD in patients with diabetes.

“A delicate diplomatic situation”: tobacco industry efforts to gain control of the Framingham Study

BackgroundThe Framingham Heart Study (henceforth Framingham) is among the gold standards for epidemiological research. Being a prospective cohort study of 5,000+ men and women, it provided early findings about the causes of coronary heart disease (CHD), following a cohort over the course of 24 years. After US government funding ended, the tobacco industry funded Council for Tobacco Research (CTR) provided continued funding for analyses related to smoking. ObjectiveThis study sought to understand the tobacco industry's motivation and activities in funding Framingham. Study Design and SettingWe analyzed previously undisclosed tobacco industry documents, conducting iterative searches of the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu/), and assembled a historical case study. ResultsCTR funded Framingham to obtain full access to Framingham data. CTR planned for long-time industry consultant Carl Seltzer to reanalyze them to suggest that tobacco-related morbidity and mortality primarily resulted from “constitutional” factors, such as age or ethnicity. Once data were obtained, CTR terminated funding for the Framingham principal investigator, who disagreed with Seltzer. Seltzer's critical analyses of subsequently published work by the Framingham team created confusion about the association between CHD and cigarette smoking. ConclusionResearchers accepting tobacco industry funding risk losing control of data, analysis, and publication.

Commentary: Broken hearts and minds--depression and incident heart disease and stroke

Of several possible ‘psychosocial’ causes of coronary heart disease (CHD), depression probably has the strongest candidature. Since both CHD and cerebrovascular disease (CBVD) share similar pathophysiological roots, it might be expected that if depression caused increased risk of heart attack it would also cause increased risk of stroke. Evidence supporting this latter proposition is both less extensive and less convincing. The public health importance of these issues is considerable, given the contribution of CHD and CBVD to health in general and health inequality in particular and considering the disproportionate experience of depression amongst the disadvantaged. Much of the current cardiovascular disease primary prevention effort is based on population screening with risk stratification and risk reduction treatment for those exceeding a risk threshold. Risk stratification plays less of a role in secondary prevention where risk reduction treatment is generally assumed to be beneficial. Non-causal risk markers may have a role in stratification but are unlikely to lead to effective risk reduction treatment. These points are worth remembering when considering the relevance of epidemiological evidence to clinical practice. New evidence of possible practical relevance is provided by the paper by Hermann Nabi and colleagues in the current issue of the IJE. In the Health and Social Support (HeSSup) study, around 24 000 men and women aged 20–54 years were recruited from the Finnish general population in 1998. They completed a questionnaire that included the Beck Depression Inventory along with health and demographic information. Over the next 7 years they were followed up through linkage to hospital and mortality registers. Baseline questionnaire data were also augmented through linkage to prescription records. HeSSup exemplifies the way that routine administrative data can be used to add value to epidemiological studies. Markers of depression (scores of 10 or above on the Beck inventory or prescriptions for antidepressant medication) at recruitment showed typical associations with increased risk of incident fatal and non-fatal CHD events including an apparent dose–response relation with increasing symptom severity. In general, these associations were not apparent in relation to incident CBVD. HeSSup has several strengths; it was large enough to consider both CHD and CBVD outcomes in the same population; it used a standard instrument to measure exposure to depression and backed this up with antidepressant prescription data; outcomes were ascertained from clinical registries and were thus much less likely to be biased in comparison to endpoints based on symptom self-reports. These strengths should be considered alongside weaknesses common to many observational studies. Depression was only measured at baseline and use of anti-depressant prescriptions as an index of depression, though methodologically ingenious, is problematic. Taking treatment as a measure of disease severity in this context is generally questionable as it ignores the possibility that effective treatment may ameliorate the influence of the risk factor; further, irrespective of their effect on depression, anti-depressant drugs may directly influence cardiovascular disease risk. Alongside these issues of exposure measurement, available covariate information limited the ability to consider questions of confounding and mediation. In addition, the original response rate of HeSSup was relatively low, and older, more socially disadvantaged respondents were under-represented. These factors may have implications for external validity. As the HeSSup investigators argue, prior evidence for a causal influence of depression on CBVD is inconclusive. If anything, HeSSup makes this evidence more conclusively negative. Longer follow-up in older populations alongside better measurement of exposure to depression may provide a different picture but, until it does, there appears no basis to add depression Published by Oxford University Press on behalf of the International Epidemiological Association

Sympathetic Nervous Activation in Essential Hypertension

nappropriate and excessive activation of the sympathetic nervous system has been invoked as a cause of coronary heart disease. This pathophysiological linkage can take 2 forms. The most direct and explicit is when acute sympathetic nervous activation triggers adverse cardiac events (myocar- dial infarction, atrial fibrillation, ventricular arrhythmias, and Takotsubo cardiomyopathy have all been documented) dur- ing acute severe mental stress. 1 Systematic evidence has been gathered at times of disasters, including war, missile attacks on civilians, and earthquakes, that strongly supports this proposition. The recently published and already celebrated analysis of coronary heart disease clinical presentations in German nationals in Munich during the 2006 Federation Internationale de Football Association World Cup provides a telling example in demonstrating a dose-response relationship of the level of acute mental stress (judged from the closeness of the contest and the particular relevance of the result to Germany), and presumably sympathetic nervous activation, to cardiac events.2 The case is no less strong that chronic sympathetic activa- tion is similarly adverse. In patients with heart failure, the cardiac sympathetic outflow is preferentially and often very highly activated. The level of this stimulation of the cardiac sympathetic outflow is directly related to reduced survival. 3 -Adrenergic blocking drugs break this link. Similarly, in patients with end-stage renal disease, the very high level of sympathetic activity, which is equal to that present in heart failure, almost certainly contributes directly to cardiovascular mortality.4 A similar claim has been made for depressive illness that the sympathetic activation present in the heart 5 underlies the increased cardiovascular mortality that exists, but here the case is less certain. In patients with essential hypertension, sympathetic acti- vation is also common, present in perhaps 50% of patients. 6 Recent evidence with endovascular radiofrequency ablation of the renal sympathetic nerves in patients with drug-resistant hypertension suggests that this activation of the sympathetic nervous system sustains the blood pressure elevation. 6 Per-

VEGF and IL-4 gene variability and its association with the risk of coronary heart disease in north Indian population

Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that has been shown to play a significant role in neovascularization during inflammation in atherosclerotic plaques, formation of collateral vessels to an area of ischemic myocardium and neovascularization at the edges of a myocardial infarction during its repair. Interleukin-4 (IL-4) has important role in immune cell chemotaxis, formation of endothelial cell adhesion molecules and has numerous anti-inflammatory effects which prevent the complications of atherosclerosis, the primary cause of coronary heart disease (CHD). In this study, we have analyzed the effect of 1154 A/G polymorphism of VEGF and 70 bp VNTR polymorphism of intron 3 in IL-4 genes in coronary heart disease (CHD) patients (n = 300) and their age matched controls (n = 300). To analyze polymorphic alleles, ARMS-PCR and RFLP techniques were used. Multiple logistic regression analysis was carried out with statistical software. GG genotype was associated with a decreased risk of development of CHD (OR 0.22, 95% CI 0.12-0.38, P < 0.001). However, A allele showed an increased risk whereas G allele decreased the risk of CHD with diabetes mellitus, hypertension, chronic mental stress and positive familial history of myocardial infarction (MI)/CHD. GG genotype was found to have protective effect with alcohol intake (OR 0.34, 95% CI 0.14-0.82, P < 0.01) and central obesity (OR 0.15, 95% CI 0.04-0.56, P < 0.001). GG genotype of VEGF has also shown significant association with IL-4 (P2P2 and P1P2) genotypes.

Patients' Perspectives on Cardiac Rehabilitation, Lifestyle Change and Taking Medicines: Implications for Service Development

Cardiac rehabilitation programmes offer eligible coronary heart disease patients information on lifestyle modification and medicines. Our aim was to understand patients' perspectives on these topics. In-depth qualitative interviews were conducted and audiotaped with 15 patients approximately three months after hospital discharge, after they had completed a hospital-based cardiac rehabilitation programme. Repeat interviews with ten patients explored whether their perspectives had changed when interviewed again approximately nine months later. Patients tended to talk about the exercise component of cardiac rehabilitation and only talk about the information provision component when prompted, which suggested they viewed the programme as being primarily about exercise. They seemed to have little subsequent contact with health services, except routine six-monthly check-ups for their coronary heart disease. Unmet information needs were common, especially about medicines. Nevertheless, all patients reported continuing to take cardiac medicines, but tended to only maintain changes to aspects of lifestyle perceived as causes of coronary heart disease, rather than viewing lifestyle recommendations as standards to achieve. Ensuring that individual patients' information needs about medicines and lifestyle are adequately met remains a key focus for cardiac rehabilitation development. Key aspects include individualizing information and actively seeking and responding to patients' needs during and after cardiac rehabilitation.

The polypill in the primary prevention of cardiovascular disease

Coronary heart disease (CHD) and stroke are the most common causes of death worldwide. The polypill, a multi-component tablet or capsule designed to reduce several cardiovascular causal risk factors simultaneously, has the potential to reduce the incidence of heart attacks and stroke by about 80%, the precise reduction depending on the formulation of the polypill and adherence to preventive treatment. The full public health impact can only be realized if the polypill is used to prevent first cardiovascular disease events, because most heart attacks and strokes are first events. A simple and effective method of selecting who should be offered the polypill is needed. Even though serum cholesterol and blood pressure are important causes of CHD and stroke and lowering them has a large preventive effect (a 1.8 mmol/L reduction in LDL cholesterol reduces the incidence of CHD events by about 60% and a 10 mmHg reduction in diastolic blood pressure also reduces the incidence of stroke by about 60%), they are poor screening tests. They add little to age in discriminating between individuals who will and will not have a CHD event or stroke. Including them in a risk assessment algorithm needlessly complicates the screening process and tends to medicalize the preventive strategy. Age alone is effective and a simpler means of selecting people for preventive treatment using the polypill.

A historical perspective on the discovery of statins

Cholesterol is essential for the functioning of all human organs, but it is nevertheless the cause of coronary heart disease. Over the course of nearly a century of investigation, scientists have developed several lines of evidence that establish the causal connection between blood cholesterol, atherosclerosis, and coronary heart disease. Building on that knowledge, scientists and the pharmaceutical industry have successfully developed a remarkably effective class of drugs—the statins—that lower cholesterol levels in blood and reduce the frequency of heart attacks.

Childhood obesity: time to shrink a parent

An observer from another planet might well be confused by the dramatic increase in obesity, and our responses to it, over the past 30 years,1 soaring above the WHO criteria for a nutritional epidemic2 overtaking smoking as the leading cause of Coronary Heart Disease (CHD),3 and committing most of the current generations to chronic ill health and disability. Our interplanetary observer could see how a protracted process of excess fat accumulation leads to multiple organ-specific pathologies, and to vast attributable health-care expenditure. Hence, it is a disease alright, the consequence of gene–environment interactions and long established as ICD-9: 278. It is not to be trivialized as an expression of personal greed and an idle life. Obesity is also observably socially defined, emerging on an epidemic scale, perhaps as an unplanned product of an unregulated free market.4

A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.

Pigment epithelium-derived factor (PEDF) as a therapeutic target in cardiovascular disease

In this review we discuss the role of pigment epithelium-derived factor (PEDF) as a possible new target molecule to therapeutically influence cardiovascular disease. PEDF is a multifunctional, pleiotropic protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic and neuroprotective properties. First identified in retinal pigment epithelium cells, it is expressed in various tissues throughout the body such as the eye, liver and adipose tissue. Recently PEDF has also been characterized in the heart. PEDF has been suggested to have a protective role in atherosclerosis, the main cause of coronary heart disease, myocardial infarction and heart failure due to its anti-inflammatory, antioxidant and antithrombotic effects in the vessel wall and platelets. Additionally PEDF has strong antiangiogenic effects by inducing apoptosis in endothelial cells and by regulating the expression of other angiogenic factors. Therefore blocking of PEDF locally for example in ischemic tissue in the heart might favour angiogenesis, induce neovascularization and lead to increased perfusion of the injured tissue. On the other hand, local overexpression of PEDF restricted to atherosclerotic lesions might block angiogenesis, inflammation and thrombosis at these sites and thus counteract destabilization and rupture of the lesion otherwise caused by inflammatory activation and excessive angiogenesis and inhibit subsequent thrombus formation.

Commentary: Making risk factors more cost-effective predictors of disease

This commentary will apply Michael Marmot’s 1 call for theories that make more accurate predictions to risk factors, which provide the etiological model for most chronic diseases. The use of risk factor research in health care will be compared with that in the life insurance industry, which developed the concept. Two proposals will be made to improve the predictive accuracy and cost-effectiveness of risk factors in health care. Marmot uses theories of the causes of coronary heart disease to examine models of causation in epidemiology and public health. He shows that science does not proceed in a straightforward inductive chain from facts to causal hypotheses and theories. Nor can hypotheses be refuted by simply producing facts that contradict them. Consequently, he suggests that a useful theory is one that produces relationships which accurately predict health outcomes. Accurate predictions, however, should not be the only objective of health care models, especially since predictions tend to be less accurate in chronic diseases than in most infectious diseases. A problem of equal urgency is cost-effectiveness. Too much health research fails to incorporate cost-effectiveness in its design or analyses and consequently too much health care produces only a small amount of benefit for the societal expenditures involved. Cost-effectiveness is a key issue because of the steep increases in health care expenditures that have afflicted all advanced countries. In the USA, health care expenditures have reached one-sixth of the gross domestic product and are climbing steadily. Individual states spend up to one-quarter of their budgets on medical care for the poor. Increased public and private expenditures for health care have reduced the standard of living in many ways, including less spending for education, social welfare, income security, the environment, infrastructure and public safety.

Diet and lifestyle influences on risk of coronary heart disease

Coronary heart disease (CHD) stems from the interplay between genetic and environmental factors. However, modifiable environmental factors, especially diet and lifestyle, are largely responsible for increased risk of CHD at population levels. Although cigarette smoking, obesity, and physical inactivity are well-established causes of CHD, the role of specific dietary factors has not been clearly defined until more recently. Cumulative evidence indicates that types of fats and carbohydrates are more important than total amounts in determining risk of CHD. Epidemiologic and clinical trial data strongly support that dietary patterns rich in fruits, vegetables, whole grains, and nuts can reduce risk of CHD. Diet and lifestyle modification, combined with pharmacologic treatment of hypertension and high lipid levels (if necessary), could prevent the vast majority of CHD events.

Pathophysiology of Coronary Heart Disease and Biological Mechanisms for the Cardioprotective Effects of Regular Aerobic Exercise

Atherosclerosis, the underlying cause of coronary heart disease (CHD), is a chronic inflammatory condition involving the subendothelial layer of coronary as well as other large-and medium-sized arteries. This disease process is initiated early in life by multiple risk factors. Endothelial dysfunction and lipid infiltration are fundamental for the initiation and progression of the atherosclerotic process. After many asymptomatic decades, acute coronary syndromes are generally triggered by a coronary occlusion, caused by a thrombosis initiated by disruption of a vulnerable lipid-laden plaque with a thin, noncalcified fibrosis cap. Epidemiology studies over the past 50 years have consistently observed an inverse association between CHD and regular physical activity and/or cardiorespiratory fitness. Supporting evidence of causative relationships has been provided by exercise training studies demonstrating multiple, plausible, cardioprotective, biological mechanisms. These pleotropic effects may be classified as (1) direct antiatherosclerotic effects and indirect effects via reduction of other risk factors, (2) anti-ischemic effects by decreasing myocardial oxygen demands and increasing its vascular supply and by decreasing the severity of ischemic injuries by direct conditioning effects on cardiomyocytes, (3) antiarrhythmic effects by improving electrical stability of the heart, and (4) antithrombotic (and prothrombolytic) effects, reducing risk of a coronary thrombotic occlusion. It is concluded based on an impressive body of evidence that regular aerobic exercise attenuates the risk of CHD at all stages of the atherothrombotic process.