Coronary Artery Atherosclerosis

Introduction
Background

Coronary artery atherosclerosis is the principal cause of coronary artery disease (CAD) and is the single largest killer of both men and women in the United States.

Approximately 14 million Americans have CAD. Each year, 1.5 million individuals develop acute myocardial infarction (AMI), the most deadly presentation of CAD, and 500,000 of these individuals die. Survivors of myocardial infarction (MI) continue to have a poor prognosis, and their risk of mortality and morbidity is 1.5-15 times greater than that of the rest of the population. This fact remains true despite a 30% reduction in mortality from CAD over the past 3 decades. Many factors have led to a decrease in mortality and morbidity from AMI, including the introduction of coronary care units, bypass surgery (eg, coronary artery bypass graft), thrombolytic therapy, angioplasty (eg, percutaneous transluminal coronary angioplasty [PTCA]), and a tremendous emphasis on lifestyle modification.

A major recent advance has been a refined understanding of the nature of atherosclerotic plaque and the phenomenon of plaque rupture, which is the proximate cause of acute coronary syndrome (ACS) and AMI. Cardiologists now know that, in many cases (perhaps more than half), the plaque that ruptures and results in the clinical syndromes of ACS and AMI is less than 50% occlusive. These so-called vulnerable plaques, as compared with stable plaques, consist of a large lipid core and thin, fibrous caps and are subjected to greater biomechanical stress, thus leading to rupture that perpetuates thrombosis and ACS.

The treatment of such ruptured plaques has also taken a leap forward with the widespread use of platelet glycoprotein IIb/IIIa inhibitors. Nonetheless, the greatest impact on the CAD epidemic can only be achieved through therapies tailored to prevent the rupture of these vulnerable plaques. Such plaques are far more prevalent than occlusive plaques. Moreover, no compelling data suggest that these plaques should be treated with angioplasty or stent placement. On the other hand, strong evidence from many randomized trials over the past decade supports the efficacy of statin-class drugs for lipid lowering and ACE inhibitors for improving endothelial function, both of which likely lead to plaque stabilization.

This article addresses the pathophysiology, clinical presentation, diagnostic workup, and therapeutic strategies for coronary atherosclerosis.

Pathophysiology

The word atherosclerosis is of Greek origin and literally means focal accumulation of lipid (ie, athere [gruel]) and thickening of arterial intima (ie, sclerosis [hardening]). Coronary artery atherosclerosis or CAD refers to the presence of atherosclerotic changes within the walls of the coronary arteries, which causes impairment or obstruction of normal blood flow with resultant myocardial ischemia. CAD is a progressive disease process that generally begins in childhood and manifests clinically in mid-to-late adulthood. The distribution of lipid and connective tissue in the atherosclerotic lesions determines whether they are stable or at risk of rupture, thrombosis, and clinical sequelae.

Normal coronary artery

The healthy epicardial coronary artery consists of 3 layers, the (1) intima, (2) media, and (3) adventitia. The intima is an inner monolayer of endothelial cells lining the lumen and is bound on the outside by internal elastic lamina, a fenestrated sheet of elastin fibers. The thin subendothelial space in between contains thin elastin and collagen fibers along with a few smooth muscle cells (SMCs).

A healthy endothelial layer is thrombo-resistant because of the production of heparin sulfate and eicosanoids, which inhibit thrombin activation and platelet adhesion, respectively. Endothelial cells also produce relaxation factors (eg, endothelium-derived relaxing factor [EDRF] or nitric oxide) and vasoconstricting factors (endothelin) that affect the resting tone of the underlying media containing several layers of SMCs. The media are bound on the outside by an external elastic lamina that separates them from the adventitia, which consists mainly of fibroblasts, SMCs, and a matrix containing collagen and proteoglycans.

Atherosclerosis - Theories of genesis

The encrustation theory

This theory, proposed by Rokitansky in 1851, suggested that atherosclerosis begins in the intima with deposition of thrombus and its subsequent organization by the infiltration of fibroblasts and secondary lipid deposition.

The lipid theory

In 1856, Virchow proposed that atherosclerosis starts with lipid transudation into the arterial wall and its interaction with cellular and extracellular elements, causing "intimal proliferation."

The response-to-endothelial injury theory

Ross proposed this more unifying theory. Termed the response-to-injury hypothesis, it postulates that atherosclerosis begins with endothelial injury, making the endothelium susceptible to the accumulation of lipids and the deposition of thrombus.

The currently accepted response-to-vascular injury theory

Over the past decade, Fuster and colleagues have proposed that vascular injury starts the atherosclerotic process.1 The effect of such vascular injury can be classified as follows:
Type I - Vascular injury involving functional changes in the endothelium with minimal structural changes, (ie, increased lipoprotein permeability and white blood cell adhesion)
Type II - Vascular injury involving endothelial disruption with minimal thrombosis
Type III - Vascular injury involving damage to media, which may stimulate severe thrombosis, resulting in unstable coronary syndromes

According to the response-to-vascular injury theory, injury to the endothelium by local disturbances of blood flow at angulated or branch points, along with systemic risk factors (eg, hyperglycemia, dyslipidemia, cigarette smoking, possibly infection) perpetuates a series of events that culminate in the development of atherosclerotic plaque.

Role of endothelium

Endothelium is the monolayered inner lining of the vascular system. It covers almost 700 m2 and weighs 1.5 kg.

Functions of endothelium
Providing a nonthrombogenic surface: This is achieved by producing prostaglandin derivatives such as prostacyclin, a potent vasodilator and inhibitor of platelet aggregation, and by its surface covering of heparan sulfate.
Secreting the most potent vasodilator, EDRF, a thiolated form of nitric oxide: EDRF formation by endothelium is critical in maintaining a balance between vasoconstriction and vasodilation in the process of arterial homeostasis.
Secreting agents effective in lysing fibrin clots: These agents include plasminogen and procoagulant materials such as von Willebrand factor and type 1 plasminogen activator inhibitor.
Secreting various cytokines and adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1
Secreting a number of vasoactive agents, such as endothelin, angiotensin II (A-II), serotonin, and platelet-derived growth factor, which may be important in vasoconstriction

Endothelium, through the above mechanisms, regulates the following:
Vascular tone
Platelet activation
Monocyte adhesion and inflammation
Thrombus generation
Lipid metabolism
Cellular growth and vascular remodeling

Endothelial damage occurs in many clinical settings and can be demonstrated in individuals with dyslipidemia, hypertension, diabetes, advanced age, nicotine exposure, and products of infective organisms (ie, Chlamydia pneumoniae). Experimental studies have shown that endothelial damage may be reversed if the underlying cause is attenuated. Endothelial damage may cause changes that are localized or generalized and transient or persistent, as follows:
Increased permeability to lipoproteins
Decreased nitric oxide production
Increased leukocyte migration and adhesion
Prothrombotic dominance
Vascular growth stimulation
Vasoactive substance release

Endothelial dysfunction is the initial step that allows diffusion of lipids and inflammatory cells (ie, monocytes, T lymphocytes) into the endothelial and subendothelial spaces. Secretion of cytokines and growth factors promotes intimal migration; SMC proliferation; and accumulation of collagen matrix, monocytes, and other white blood cells, forming an atheroma. More advanced atheromas, even though nonocclusive, may rupture, thus leading to thrombosis and the development of ACS and MI.

Multiple studies have demonstrated that risk-factor modification through therapeutic lifestyle change (TLC), reduction of low-density lipoprotein cholesterol (LDL-C) levels, and smoking cessation rapidly improves endothelial function.

Role of LDL - Oxidative stress

The most atherogenic type of lipid is the low-density lipoprotein (LDL) component of total serum cholesterol. The endothelium's ability to modify lipoproteins may be particularly important in atherogenesis. LDLs appear to be modified by a process of low-level oxidation when bound to the LDL receptor, internalized, and transported through the endothelium. LDLs initially accrue in the subendothelial space and stimulate vascular cells to produce cytokines for recruiting monocytes, which causes further LDL oxidation. Extensively oxidized LDL (oxLDL) is picked up by the scavenger receptors on macrophages, which absorb the LDL and turn into foam cells. oxLDL is exceedingly atherogenic and is responsible for the following:
Promoting cholesterol accumulation in macrophages, which then become foam cells: All macrophages are derived from circulating monocytes. When the monocyte enters a tissue, it appears to take on characteristics peculiar to the host tissue. In most inflammatory sites, the macrophage acts as a scavenger cell to remove foreign substances by phagocytosis and intracellular hydrolysis. As a scavenger cell, the macrophage attempts to remove injurious materials (eg, oxLDL) via scavenger receptors and can oxidize LDL by such means as lipoxygenase enzymes (eg, 15-lipoxygenase) forming the foam cells.
Enhancing endothelial production of leukocyte adhesion molecules, ie, cytokines and growth factors that regulate SMC proliferation, collagen degradation, and thrombosis (eg, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1)
Inhibiting nitric oxide synthase activity and increasing reactive oxygen species generation (eg, superoxide, hydrogen peroxide), thus reducing endothelium-dependent vasodilation
Altering the SMC response to A-II stimulation and increasing vascular A-II concentrations: The SMCs that proliferate in the intima to form advanced atheromas are originally derived from the media. The theory that accumulation of SMCs in the intima represents the sine qua non of the lesions of advanced atherosclerosis is now widely accepted.

Substantial evidence suggests that oxLDL is the prominent component of atheromas. Antibodies against oxLDL react with atherosclerotic plaques, and plasma levels of immunoreactive altered LDL are greater in persons with AMI than in controls. Oxidative stress has therefore been recognized as the most significant contributor to atherosclerosis by causing LDL oxidation and increasing nitric oxide breakdown.

Histopathology of atherosclerotic lesions

Classification according to Stary system2 :
Stary I lesion: The endothelium also expresses surface adhesion molecules E selectin and P selectin, attracting more polymorphonuclear cells and monocytes in the subendothelial space.
Stary II lesion: Macrophages begin to take up large amounts of LDL (fatty streak).
Stary III lesion: As the process continues, macrophages eventually become foam cells.
Stary IV lesion: Lipid exudes into the extracellular space and begins to coalesce to form the lipid core.
Stary V lesion: SMCs and fibroblasts move in, forming fibroatheromas with soft inner lipid cores and outer fibrous caps.
Stary VI lesion: Rupture of the fibrous cap with resultant thrombosis causes ACS.
Stary VII and VIII lesions: As lesions stabilize, they become fibrocalcific (Stary VII lesion) and, ultimately, fibrotic with extensive collagen content (Stary VIII lesion).

Atherosclerotic plaque may require 10-15 years for full development. Further growth is determined by the local activity of regulatory substances (ie, interleukin (IL)–1, IL-6, transforming growth factor-beta) and by thrombin, leukotriene, prostaglandin, fibrin, and fibrinogen.

Although a logical conclusion is that the most severely stenotic lesions are the ones at the greatest risk of sudden occlusion, this is not the case. As previously described, ACS has been shown to more often develop because of rupture and thrombosis of mild (<60%) coronary stenoses. This occurs because of the relatively higher lipid content of the lipid core, the thinner fibrous cap, and the increased leukocyte activity at the shoulder regions of the plaque. These characteristics make such plaques, called the vulnerable plaques, much more prone to rupture.

Mechanisms of the effects of risk factors

The presence of risk factors accelerates the rate of development of atherosclerosis. Smoking increases platelet activity and catecholamine levels, alters prostaglandins, and decreases high-density lipoprotein (HDL) levels. Hypertension causes endothelial dysfunction and increases collagen, elastin, and endothelial permeability and platelet and monocyte accumulation. Diabetes causes endothelial dysfunction, decreases endothelial thrombo-resistance, and increases platelet activity, thus accelerating atherosclerosis.

Plaque growth and vascular remodeling

As endothelial injury and inflammation progress, fibroatheromas grow and form the plaque. As the plaque grows, 2 types of remodeling occur, (1) positive remodeling and (2) negative remodeling.

Positive remodeling

Positive remodeling is an outward compensatory remodeling (the Glagov phenomenon) in which the arterial wall bulges outward and the lumen remains uncompromised. Such plaques grow further, although they usually do not cause angina because they do not become hemodynamically significant for a long time. In fact, the plaque does not begin to encroach on the lumen until it occupies 40% of the cross-sectional area. The encroachment must be 70% or greater to cause flow limitation. Such positively remodeled lesions thus form the bulk of the vulnerable plaques, grow for years, and are more prone to result in plaque rupture and ACS than stable angina, as documented by intravascular ultrasound (IVUS) studies.

Negative remodeling

Many fewer lesions exhibit almost no compensatory vascular dilation, and the atheroma steadily grows inward, causing gradual luminal narrowing. Many of the plaques with initial positive remodeling eventually progress to the negative remodeling stage, causing narrowing of the vascular lumen. Such plaques usually lead to the development of stable angina. They are also vulnerable to plaque rupture and thrombosis.

Plaque rupture - The main event causing acute presentations

Eruption of the vulnerable plaque

Tight coronary atheromas rarely cause ACS and MI. In fact, most of the atheromas that cause ACS are less than 50% occlusive as demonstrated by coronary arteriography. Atheromas (plaques) with smaller obstruction experience greater wall tension, which changes in direct proportion to their radii.

Most plaque ruptures occur because of disruption of the fibrous cap, which allows contact between the highly thrombogenic lipid core and the blood. These modestly obstructive plaques, which have a greater burden of soft lipid core and thinner fibrous caps with chemoactive cellular infiltration near the shoulder region, are called vulnerable plaques. The amount of collagen in the fibrous cap depends on the balance between synthesis and destruction of intercellular matrix and inflammatory cell activation.

T cells that accumulate at sites of plaque rupture and thrombosis produce the cytokine interferon gamma, which inhibits collagen synthesis. Already formed collagen is degraded by macrophages that produce proteolytic enzymes and by matrix metalloproteinases (MMPs), particularly MMP-1, MMP-13, MMP-3, and MMP-9. The MMPs are induced by macrophage- and SMC-derived cytokines such as IL-1, tumor necrosis factor (TNF), and CD154 or TNF-alpha. Authorities postulate that lipid lowering stabilizes the vulnerable plaques by modulating the activity of the macrophage-derived MMPs.

Inflammatory markers in atherosclerosis

In recent years, the role of inflammatory cells and signaling in the development, rupture, and thrombosis of an atheromatous plaque has been extensively studied. Infection or inflammation, which may be local or distant, generates potent proinflammatory cytokines (eg, IL-1B, TNF-alpha) that stimulate production of adhesion molecules, procoagulants, and messenger cytokine, ie, IL-6. IL-6 induces hepatic production of acute phase reactants such as C-reactive protein (CRP) and serum amyloid-A.

C-reactive protein

CRP appears to provide prognostic information for CAD. In the Physicians' Health Study, men with CRP levels in the highest quartile had a 3-times greater risk of MI. Use of aspirin resulted in a significant (55.7%) reduction in the risk of MI in men in the highest CRP quartile, suggesting that the aspirin-related reduction in the risk of first MI was clearly related to the level of CRP.3

The Fragmin and/or Early Revascularization During Instability in Coronary Artery (FRISC)-II study, which included 900 subjects followed for 4 years, showed that subjects with baseline CRP levels of more than 10 mg/L had significantly worse outcomes than those with lower levels.4

CRP can also help predict treatment efficacy, as demonstrated in the Cholesterol and Recurrent Events (CARE) trial of pravastatin treatment in post-MI patients. CRP levels tended to increase over time in the placebo group, whereas levels remained lower in the treatment group at 5 years. Additionally, the efficacy of statin therapy was greater in subjects with higher levels of CRP.5

The role of infection

Traditional risk factors, such as dyslipidemia, tobacco abuse, hypertension, and diabetes, often do not account for atherosclerosis in many patients. Certain nontraditional risk factors, including hyperhomocystinemia, are sometimes blamed. However, accumulating evidence suggests that atherosclerosis is an inflammatory disease; therefore, a great deal of attention has recently been focused on the possibility that infectious agents play a role in the etiology of CAD. Certain infectious agents have been implicated based on their isolation from the atheromatous plaques or on the presence of positive serology findings for organisms such as C pneumoniae, Helicobacter pylori, herpes simplex virus, and cytomegalovirus.

Even though prospective studies have fallen short of providing definitive evidence, C pneumoniae appears to exhibit the strongest association. C pneumoniae has been isolated from autopsy and arthrectomy specimens and in both early and well-developed lesions. When studied by means of immunologic cytochemistry and tissue staining, the association has been found in 70-100% of cases. Possible mechanisms by which infectious agents exert their effect may include (1) local effects on the endothelium, SMCs, or macrophages or (2) systemic effects by generating cytokines, stimulating monocytes, and promoting hypercoagulability.

Some of the completed studies have shown variable results. In the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infarction with Chlamydia (ACADEMIC) trial, markers of inflammation improved at 6 months in the subjects with positive serologic evidence of chlamydial infection, but no difference in clinical events was observed.6 In another trial, the Randomization Trial of Roxithromycin in Non–Q-Wave Coronary Syndromes (ROXIS), a reduction in CRP level was observed at 1 month and was associated with a significant decrease in triple clinical endpoint. The effect, however, dissipated by 3-6 months.7

Several multicenter trials have evaluated the effect of antibiotic therapy on recurrent cardiac events when used as secondary prevention. The London study, Argentinian study, ACADEMIC trial, Azithromycin in Acute Coronary Syndrome (AZACS) study, and the South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA) trial all returned negative results in terms of any significant benefit from antibiotic therapy. However, these trials were not powered to detect the difference in the rate of composite events to begin with, while 3 of the recently presented trials were powered to detect such a difference.

First of these, the Weekly Intervention with Zithromax (Azithromycin) Against Atherosclerosis-Related Disorders (WIZARD) trial, enrolled 7700 subjects with a prior history of MI and positive C pneumoniae antibody findings and treated them with azithromycin. The follow-up period averaged 2.5 years. No significant difference in the rate of composite events (ie, death, MI, revascularization) was found.

The second trial, the results of which were presented at the 2004 European Society of Cardiology meeting held in Munich, Germany (sponsored by the US National Heart, Lung, and Blood Institute [NHLBI]), called the Azithromycin Coronary Events (ACES) study, randomized 4000 subjects with a history of stable CAD with 1- to 4-year follow-up to azithromycin at 600 mg once per week for 1 year versus placebo. The occurrence rate of composite events (ie, death, MI, revascularization) was 22.3% in the azithromycin cohort and 22.4% in the placebo cohort. The difference was not significant.

A new antibiotic, gatifloxacin, was tested in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial, which enrolled 4162 subjects with ACS. The results of the lipid arm of the PROVE-IT trial already indicated more aggressive LDL-C lowering in high-risk patients with CAD. The results of the antibiotic portion of the trial were presented at the 2004 European Society of Cardiology meeting in Munich, Germany. Again, the rates of composite events for the gatifloxacin and placebo groups were 23.7% and 25.1%, respectively, and the difference was not statistically significant.

All the above trials used different patient populations and types and doses of antibiotics, but antibiotic therapy does not appear to have a significant role in secondary prevention. However, the role of inflammation in the pathogenesis of coronary atherosclerosis; its assessment via measurement of the CRP level or other molecules; and therapy with statins, ACE inhibitors, and, possibly, yet-to-be-discovered agents, remain very active areas of research with a strong possibility of significant improvement in therapy.

Frequency
United States

Atherosclerotic coronary heart disease caused 466,101 deaths in the United States in 1997, accounting for 20% of all deaths. An American experiences a coronary event approximately every 29 seconds, with 1 person dying nearly every minute. Approximately 14 million people alive today have coronary disease (6.5 million males and 7.5 million females). Roughly 1.5 million Americans have a new or recurrent AMI each year, and 40% of these individuals die from it. However, from 1987-1997, the death rate from coronary heart disease declined 24.9%.
International

The international incidence of ACS and AMI, especially in developed countries, is similar to that observed in the United States. Despite consumption of rich foods, inhabitants of France and the Mediterranean region appear to have a lower incidence of CAD. This phenomenon (sometimes called the French paradox) is partly explained by greater use of alcohol, with its possible HDL-raising benefit, and by consumption of the so-called Mediterranean diet, which includes predominant use of monounsaturated fatty acids, such as olive oil or canola oil, which are less atherogenic. Eskimos have been found to have a lower prevalence of CAD as a result of consuming fish oils containing omega-3 fatty acids.
Mortality/Morbidity

In the United States, approximately 14 million persons experience CAD and its various complications. Congestive heart failure (CHF) that develops because of ischemic cardiomyopathy in hypertensive MI survivors has become the most common discharge diagnosis for medical patients in American hospitals.

Annually, approximately 1.5 million Americans have an AMI, a third of whom die.
The survivors of MI have a poor prognosis, carrying a 1.5- to 15-fold higher risk of mortality and morbidity than the rest of the population.
For example, historically within 1 year of MI, 25% of men and 38% of women die. These rates may overstate the 1-year mortality rate today, given advances in the treatment of CHF and sudden cardiac death. Among survivors, 18% of men and 34% of women have a second MI within 6 years, 7% of men and 6% of women die suddenly, 22% of men and 46% of women are disabled with CHF, and 8% of men and 11% of women have a stroke.
Race

The incidence, prevalence, and manifestations of CAD vary significantly with race, as does the response to therapy.

African Americans appear to have higher morbidity and mortality rates, even when corrected for educational and socioeconomic status. The risk-factor burden experienced by African Americans differs from that of whites. The prevalence of hypertension, obesity, dysmetabolic syndrome, and lack of physical activity are much higher, whereas the prevalence of hypercholesterolemia is lower. African Americans with AMI present later than average, are less often subjected to invasive strategies, and experience greater overall mortality. Similar statistics can also be cited for presentation and treatment of patients with stable CAD.
Asian Indians exhibit a 2- to 3-fold higher prevalence of CAD than whites in the United States. They have greater prevalences of hypoalphalipoproteinemia, high lipoprotein(a) levels, and diabetes.
People in Mediterranean areas have a lower prevalence of CAD.

Sex

Men traditionally have a higher prevalence of CAD. Women, however, follow men by 10 years, especially after menopause. Nevertheless, the value of estrogen supplementation has been discredited by the Heart and Estrogen/Progestin Replacement Study (HERS).8,9 The presence of diabetes eliminates the protection associated with female sex.

Even in women, the most common cause of death is CAD, which accounts for more deaths than those related to breast and uterine diseases combined.
Women with AMI present later than average, are less often subjected to invasive strategies, and experience greater overall mortality. Similar statistics can also be cited for the presentation and treatment of patients with stable CAD.
Age

Age is the strongest risk factor for the development of CAD. Elderly persons still experience higher mortality and morbidity rates from CAD. Complication rates of multiple therapeutic interventions tend to be higher; however, the magnitude of benefit from the same interventions is greater because these patients form the high-risk subgroup.
Clinical
History

Coronary artery atherosclerosis manifests in a broad spectrum of presentations. Most individuals remain asymptomatic. The condition is a progressive disease process that generally begins in childhood and manifests clinically in mid-to-late adulthood.

The spectrum of presentation includes symptoms and signs consistent with the following conditions:
Asymptomatic state (subclinical phase)
Stable angina pectoris
Unstable angina (ie, ACS)
Acute MI
Chronic ischemic cardiomyopathy
Congestive heart failure
Sudden cardiac arrest
History may include the following:
Chest pain
Shortness of breath
Weakness, tiredness, reduced exertional capacity
Dizziness, palpitations
Leg swelling, weight gain
Symptoms related to risk factors

Physical

Physical examination may reveal the following findings in various combinations:

Pulse volume, rate, and regularity: Tachycardia is common in persons with ACS and AMI. Heart rate irregularity may signal the presence of atrial fibrillation or frequent supraventricular or ventricular ectopic beats. Ventricular tachycardia is the most common cause of death for persons with AMI.
High or low blood pressure: Hypotension often reflects hemodynamic compromise and is a predictor of poor outcome in the setting of AMI.
Diaphoresis: This is a common finding.
Tachypnea: Patients often have rapid breathing.
Shock
Syncope
Leg edema
Congestive heart failure: Signs and symptoms of CHF may indicate cardiogenic shock or a mechanical complication of AMI such as ischemic mitral valve regurgitation.
Heart sounds and gallop: An S4 gallop is a common early finding. The presence of an S3 is an indication of reduced left ventricular function.
Heart murmurs: These, particularly those of mitral regurgitation and ventricular septal defect, may be found after the initial presentation; their presence indicates a grave prognosis. The murmur of aortic insufficiency may signal the presence of aortic dissection as a primary etiology, with or without the complication of AMI.
Pulmonary congestion, rales
Stigmata of risk factors: Patients may develop xanthelasmas, livedo reticularis, or both.
Body habitus: Central obesity is often seen.
Diagonal ear crease, short stature, baldness, thoracic hairiness
Findings consistent with previous CAD: These patients may have scarring from coronary artery bypass graft or similar surgeries.

Causes

To varying degrees, coronary artery atherosclerosis results from the interplay of multiple risk factors, as follows:

Family history of premature CAD
Hypercholesterolemia (high LDL syndrome)
Hypertension
Cigarette smoking
Diabetes mellitus
Hypoalphalipoproteinemia
Dysmetabolic syndrome
Obesity
Physical inactivity
Nontraditional risk factors
Hyperhomocystinemia
High lipoprotein(a) levels
High iron levels
Syndromes of accelerated atherosclerosis - Graft atherosclerosis, CAD after cardiac transplantation
Restenosis
Infection
C pneumoniae
H pylori
Herpes simplex virus

Of note, algorithms for predicting the risk of cardiovascular disease have generally been developed for a follow-up period of 10 years or less. Because clustering of risk factors at younger ages and increasing life expectancy suggest the need for longer-term risk prediction, In a 2009 study, Pencina and colleagues constructed an algorithm for predicting 30-year risk of coronary death, myocardial infarction, or stroke—“hard” CVD events.10

Prospective 30-year follow-up of 4,506 participants of the Framingham Offspring cohort showed that standard risk factors (male sex, systolic blood pressure, antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking, and diabetes mellitus), measured at baseline, were significantly related to the incidence of hard cardiovascular disease and remained significant when updated regularly on follow-up. Body mass index was associated positively with 30-year risk of hard CVD only in models that did not update risk factors.

http://emedicine.medscape.com/article/153647-overview