AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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. 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

• 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 (Ridker, 1991).

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 (Wallentin, 1997).

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 (Sacks, 1996).

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 (Anderson, 1999). 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 (Gurfinkel, 1997).

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) (Schrott, 1997; Vittinghoff, 2003). 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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Routine blood tests
• • CBC count
  • Chemistry panel
  • Thyroid function tests - To exclude thyroid disorders
• Fasting lipid profile
• • Total cholesterol level
  • LDL-C level
  • HDL cholesterol (HDL-C) level
  • Triglyceride level
• Special tests
• • Specific lipid studies (if necessary)
    • Small, dense LDL-C level
    • Lipoprotein(a) level
    • Apoprotein profile
  • Miscellaneous tests
    • Homocysteine level
    • Inflammatory markers (eg, CRP)
• Tests specific to the presentation of ACS
• • Serum markers
    • Creatine kinase with MB isozymes
    • Troponins (I or T)
    • Lactate dehydrogenase and lactate dehydrogenase isozymes
    • Serum aspartate aminotransferase
  • Inflammatory markers - CRP

Imaging Studies

• Echocardiography
• • Transthoracic echocardiography helps assess left ventricular function, wall motion abnormalities in the setting of ACS or AMI, and mechanical complications of AMI.
  • Transesophageal echocardiography is most often used for assessing possible aortic dissection in the setting of AMI.
  • Stress echocardiography can be used to evaluate hemodynamically significant stenoses in stable patients who are thought to have CAD.
  • Treadmill echocardiography stress testing and dobutamine echocardiography stress testing provide equivalent predictive values.
• Nuclear imaging studies (myocardial perfusion imaging): These studies are also useful in assessing patients for hemodynamically significant coronary artery stenoses.
• • Stress and rest nuclear scintigraphic studies using thallium, sestamibi, or teboroxime are sometimes helpful.
  • Radionuclide stress myocardial perfusion imaging can be used to quantify coronary flow reserve (CFR).
    • Thallium Tl 201 or sestamibi are widely used to quantify CFR. Flow reserve is typically assessed by these techniques during exercise or with pharmacological coronary vasodilators. In contrast to invasive techniques that measure an index of absolute flow reserve (an index related to the quotient of maximal and basal flow), cardiac imaging techniques assess relative CFR (rCFR) by comparing the perfusion of ischemic regions of the left ventricle with presumably normally perfused reference regions.
    • Imaging techniques yield a less quantitative index of flow reserve than catheter-based techniques. In addition, results can be misleading in the setting of diffuse coronary disease when a normal reference region is not available. However, unlike most measures of absolute flow reserve, relative flow reserve is independent of the loading conditions because these affect all regions of the left ventricle equally.
    • Taken together, absolute flow reserve and rCFR provide a more complete description of the severity of physiological stenosis than either method alone.
  • Types of nuclear imaging include a treadmill nuclear stress test, a dipyridamole (Persantine) or adenosine nuclear stress test, and a dobutamine nuclear stress test.
  • MI avid scintigraphy may be indicated.
• Magnetic resonance angiography
• Electron beam CT scanning
• • Electron beam computed tomography (EBCT) scanning is a noninvasive method of evaluating calcium content in the coronary arteries. Healthy coronary arteries lack calcium. As atherosclerotic plaques grow, calcium accumulates because of a perpetuating inflammatory process or the healing and scarring induced by this process. EBCT is currently used as a screening test in asymptomatic patients and as a diagnostic test for obstructive CAD in symptomatic patients, although experts in the field have reached no consensus regarding indications for its use.
  • The American College of Cardiology/American Heart Association Expert Consensus Document (O'Rourke, 2000) indicates the following:
    • EBCT scanning has been demonstrated to have high sensitivity.
    • Overall predictive accuracy is 70%.
    • EBCT has low specificity, ie, a substantial false-positive rate, which raises the index of suspicion for CAD and leads to expensive and unwarranted additional testing to exclude CAD. Consequently, O'Rourke and colleagues do not recommend EBCT scanning to help diagnose obstructive CAD.
  • Whether EBCT scanning is a worthwhile tool for screening of CAD is still unclear. Well-established clinical indicators, such as the Framingham risk score and the National Cholesterol Education Program (NCEP) risk calculator, already accurately predict the likelihood of CAD. Whether EBCT scanning adds to these indicators has yet to be shown. The Multi-Ethnic Study of Atherosclerosis (MESA), sponsored by the US National Institutes of Health, is now assessing prospective evaluation of EBCT scanning in asymptomatic subjects to answer this question (Bild, 2002).
  • EBCT scanning may have niche uses, including (1) determining whether individuals who appear to be at intermediate risk are really at a higher risk (eg, asymptomatic elderly patients who have high calcium scores) and (2) determining a low likelihood of significant CAD if EBCT scanning demonstrates a low or absent calcium score.

Other Tests

• Twelve-lead ECG
• Treadmill ECG stress test
• Holter monitoring for silent ischemia
• Angioscopy

Procedures

• Coronary angiography: Coronary arterial luminography remains the criterion standard for defining significant flow-limiting stenoses that must be revascularized through percutaneous or surgical intervention to improve prognosis. Quantitative coronary angiography (QCA) is used to perform computerized quantitative analysis of the entire coronary tree. It introduces a correction factor for the presence of diffuse disease. QCA has been widely used in many trials of atherosclerotic progression and regression.
• • The role of QCA in regression studies is as follows:
    • The Familial Atherosclerosis Treatment Study (FATS) analyzed 9 angiographic trials of lipid-reducing therapy. Approximately 50% of subjects in the control group exhibited progression, but only 25% of the subjects in the treatment group did so. Regression was observed in 8% of the control group and in 28% of the treatment group. Subjects with mild-to-moderate lesions showed the most benefit (Brown, 1993; Brown, 1995).
    • The reduction in the number of clinical coronary events was much more pronounced (disproportionately greater), although the effect on lesion progression was only modest. For example, in the FATS, only 12% of subjects showed regression. The mean regression in the stenosis was less than 1%; however, this resulted in a 70% reduction in coronary events. ACS is known to develop in nonocclusive ( <50%) plaques in most patients. The luminographic images obtained by coronary arteriograms miss mild-to-moderate vulnerable plaques, which cause most of the acute events.
  • Limitations of coronary arteriography are as follows:
    • Severity of stenosis is generally estimated visually, but estimation is limited by the fact that interobserver variability may range from 30-60%.
    • The presence of diffuse disease also may lead to underestimation of stenoses because the stenosed areas are expressed as a percent of luminal diameter compared with adjacent normal coronary segments, and, in diffuse disease, no such segments exist. This usually occurs in diabetic patients, in whom coronary arteries are traditionally described as small-caliber vessels, when that appearance is actually due to the presence of diffuse symmetrical involvement of the entire vessel, as elucidated by recent IVUS studies.
• Coronary blood flow determinations: Because of the inherent limitations of coronary angiography, attention has been directed to using physiological approaches for determining the severity of coronary stenoses. The 5 methods of measuring human coronary blood flow in the cardiac catheterization laboratory are (1) thermodilution, (2) digital subtraction angiography, (3) electromagnetic flow meters, (4) Doppler velocity probes (for measuring CFR), and (5) pressure wires (for measuring fractional flow reserve [FFR]). Although most current methods measure relative changes in coronary blood flow, useful information about the physiological significance of stenosis, cardiac hypertrophy, and pharmacological interventions can be obtained from these measurements.
• • Doppler velocity probes use a Doppler flow meter, which is based on the principle of the Doppler effect. This is the most widely applied technique for measuring coronary flow in humans. High-frequency sound waves are reflected from moving red blood cells and undergo a shift in sound frequency proportional to the velocity of the blood flow.

    In pulsed-wave Doppler methods, a single piezoelectric crystal can both transmit and receive high-frequency sound waves. These methods have been successfully applied in humans by using miniaturized crystals fixed to the tip of catheters. Technological developments have further miniaturized steerable 12-MHz Doppler guidewires to a diameter of 0.014 inches.

    Flow to a stenosis can therefore be assessed distally and proximally. The Doppler guidewire measures phasic flow velocity patterns and tracks linearly with flow rates in small, straight coronary arteries.

    • Indications for Doppler velocity probe use include determining the severity of intermediate stenosis (40-60%) and for evaluating whether normal blood flow has been restored after PTCA.

      The use of smaller Doppler catheters allows measurement of selective coronary artery flow velocity. By noting the increase in flow velocity following administration of a strong coronary vasodilator, such as papaverine or adenosine, the CFR can be defined. CFR provides an index of the functional significance of coronary lesions that obviates some of the ambiguity of anatomical description.

      The current Doppler probe method has limitations. Limitations include (1) only changes in flow velocity, rather than absolute velocity or volumetric flow, are measurable; (2) the change in flow velocity is directly proportional to changes in volumetric flow only when vessel dimensions are constant at the site of the sample volume; (3) other factors, including left ventricular hypertrophy and myocardial scarring, can also affect CFR; and (4) changes in luminal diameter and arterial cross-sectional area during interventions are not reflected in measurements of flow velocity, thus potentially causing underestimation of the true volume flow.

    • In summary, Doppler wires have a miniaturized Doppler crystal placed at the tip of an angioplasty guidewire, permitting measurement of phasic and mean coronary blood flow velocities. Because this technique does not measure absolute coronary blood flow, several indices of flow velocity have been used for assessing the physiological significance of coronary stenoses. Coronary flow velocity reserve is the ratio of maximum flow velocity to baseline flow velocity.

      Patients with a coronary flow velocity ratio of less than 2 typically have other corroborating evidence of myocardial ischemia and improve symptomatically with revascularization. Conversely, patients with a ratio of more than 2 usually lack other objective evidence of myocardial ischemia and have a favorable outcome with conservative management; therefore, flow velocity measurements can be helpful in the treatment of patients with coronary lesions of intermediate severity. The diastolic-to-systolic velocity ratio has also been used to evaluate stenosis severity. In normal arteries, diastolic flow velocity far exceeds systolic velocity; however, the two are more equal distal to significant stenoses. A ratio of less than 1.7 has been used to define significant coronary lesions.

      During coronary interventions, the Doppler guidewire can be used to judge the adequacy with which stenosis severity has been reduced. Patients with higher CFRs at completion of the procedure have a lower prevalence of abrupt reocclusion and restenosis.

  • rCFR is calculated as follows: ([rCFR] = CFR target/CFR reference). rCFR involves Doppler coronary flow measurements of target and reference vessel CFR with a Doppler-tipped guidewire. Compared with patients who have negative stress imaging study findings, patients who have positive stress study findings showed more angiographically severe stenoses (74% +/- 13% vs 44% +/- 24%; P = .0005) with lower target CFRs (1.68 +/- 0.55 vs 2.46 +/- 0.74; P = .002) and lower rCFRs (0.72 +/- 0.22 vs 1 +/- 0.26; P <.003) (El-Shafei, 2001).
    • Based on cut points (CFR >1.9; rCFR >0.75), compared with CFR, rCFR had similar agreement (kappa 0.54 vs 0.5), sensitivity (63% vs 71%), specificity (88% vs 83%), and positive predictive value (83% vs 81%) with myocardial perfusion tomography.
    • Although rCFR, as with CFR, correlates with stress myocardial perfusion imaging results, rCFR did not have significant incremental prognostic value over CFR alone for myocardial perfusion imaging. However, rCFR does provide additional information regarding the status of the microcirculation in patients with CAD and complements the CFR for lesion assessment.
  • With regard to FFR, the measurement of pressure gradients across coronary stenoses was originally advocated to assess the results of coronary angioplasty. Owing to the large profile of catheters used, this technique was never widely applied. However, new technology using 0.018-inch guidewires to assess pressure gradients across stenoses has been introduced.
    • Myocardial FFR has been used as an index of functional severity of coronary artery stenosis.

      Pressure gradients are determined by measuring the ratio of the mean pressure distal to a coronary stenosis compared with that proximal to the stenosis. The proximal stenosis is measured through the tip of the guiding catheter, and the distal pressure is measured through the tip of the guidewire. Maximal vasodilation is induced by intracoronary administration of either adenosine or papaverine.

      FFR is calculated from the ratio of the mean pressure distal to a coronary stenosis to the mean aortic pressure during maximal hyperemia. If the FFR is less than 0.75, sensitivity is at least 80% and specificity is at least 85% for an abnormal exercise test result.

      Pressure wire measurement has been less well validated than Doppler flow reserve measurement; however, early studies indicate improved clinical utility owing to the ease of use and the reproducibility of results.

    • In summary, myocardial FFR is a recently developed index of the functional severity of coronary stenoses that is calculated only from simultaneous pressure measurements proximally and distally to a stenosis obtained with a pressure monitoring guidewire.

      FFR represents the fraction of the normal maximal coronary flow that can be achieved in an artery in which flow is restricted by a coronary stenosis. The concept of FFR is founded in the previously noted observation that myocardial perfusion is entirely pressure dependent during maximal hyperemia.

      Maximal blood flow in the presence of a stenosis is therefore determined by the driving pressure distal (Pd) to the stenosis, whereas the theoretical normal maximal blood flow is determined by the pressure proximal (Pp) to the stenosis. FFR is calculated during maximal hyperemia (obtained with adenosine or papaverine) as FFR = Pd/Pp. FFR less than 0.75 is typically associated with other objective evidence of myocardial ischemia.

      Measurement of FFR in patients with coronary stenoses of moderate severity has been shown to be a useful index of the functional severity of the stenoses and the need for coronary revascularization. Measurement of FFR can also guide the adequacy of reducing coronary stenosis severity with balloon angioplasty or stenting.

• Intravascular ultrasound
• • IVUS demonstrates the luminal dimensions and, more importantly, the tissue composition of the vascular wall in tomographic subsegments that can be summated to create a 3-dimensional picture showing arterial remodeling and the diffuseness of atherosclerosis with clarity unobtainable by angiography (luminography).
  • IVUS delineates vascular remodeling—both positive (Glagov phenomenon) and negative. Positive remodeling shows adaptive outward expansion of the external elastic membrane to accommodate growing plaques. Negative remodeling exhibits discrete areas of vascular luminal encroachment by the ingrowing plaques.
  • In a 2000 IVUS study of 85 subjects, Schoenhagen and colleagues demonstrated that positive remodeling is more commonly associated with unstable angina, whereas negative remodeling is associated with stable angina.
  • The apparently paradoxical findings of angiographic studies suggesting that AMI most often occurs in less than 50% of stenosed arterial segments, and those of autopsy studies showing AMI to be associated with large plaques, are reconciled by IVUS findings. IVUS shows the responsible lesions to be large plaques that have positively remodeled, thus causing minimal luminal encroachment and exhibiting echolucency suggesting a lipid-rich pool in the plaque center.
  • The ability of IVUS to identify positively remodeled plaques and the presence of diffuse disease in some ways makes it better than angiography, the less-than-perfect criterion standard. IVUS can much more clearly demonstrate the presence or absence of fibrosis, calcium, and ulceration, as well as eccentricity of the plaques.
  • Ostial lesions can also be better defined by IVUS.
• Stenosis severity and clinical events
• • The severity of stenoses and their propensity to cause MI, unstable angina, or sudden coronary death are poorly correlated.
  • Pathologic and angiographic studies have revealed that MIs and unstable angina are most often caused by rupture of atherosclerotic plaques with formation of a superimposed occlusive thrombus.
  • Most atherosclerotic lesions responsible for these serious events are mild stenoses of inconsequential hemodynamic significance and are characterized by an abundance of lipid, numerous inflammatory cells, and a thin, fragile fibrous cap.
  • These observations suggest that although measurements of CFR may be useful in the assessment of the severity of stenoses and in the identification of lesions responsible for effort angina, they are not likely to identify the more dangerous plaques responsible for unstable angina, AMI, and sudden ischemic death.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

The treatment goals for patients with coronary artery atherosclerosis are to relieve symptoms and to prevent future cardiac events such as unstable angina, AMI, and death.

• Relief of symptoms
• • Typically, patients with CAD are first seen after they present with a cardiac event. The main focus of their treatment is treating the index event. The past 4 decades have witnessed tremendous progress in the areas of acute cardiac care, coronary care unit expansion, thrombolytic usage, and percutaneous intervention.
  • The use of adjunctive therapy in the form of glycoprotein IIb/IIIa inhibitors has failed to show additional mortality benefit in large trials such as the Global Use of Strategies To Open Occluded Coronary Arteries in Acute Myocardial Infarction-V (GUSTO-V) trial and the Assessment of the Safety and Efficacy of New Thrombolytic Regimens-3 (ASSENT-3) trial.
• Prevention of future cardiac events
• • Findings from the World Health Organization's Monitor Trends in Cardiovascular Diseases (MONICA) project involving 21 countries showed a 4% fall in CAD death rates. Improvement in the case fatality rate accounted for only one third of the decline. However, two thirds of the decline resulted from a reduction in the number of events. These findings strongly suggest that the largest impact on decreasing the global burden of atherosclerosis will come from prevention of events.
  • Fortunately, the natural history of CAD is characterized by early onset and a long dormant phase. This provides an excellent opportunity to intervene in order to reduce the number and severity of cardiovascular events. The goals of therapy should include arresting CAD or even reversing its progression. High-risk subgroups, in particular, can be targeted for early intervention. Grover and colleagues have shown statin therapy in diabetic patients without CAD to be as cost-effective as statin therapy in nondiabetic patients with CAD.
  • Pharmacotherapeutic strategies that affect the risk factor profile, such as the administration of statins for LDL reduction or the administration of agents that alter the atherosclerotic plaque, are of paramount importance in this regard.
  • • The current understanding of CAD suggests that luminal stenosis is not the only cause of acute coronary events; instead, a perpetual inflammatory process leads to plaque formation and its growth with glagovian remodeling with a thin, fibrous cap that ruptures, thus extruding the thrombogenic lipid pool and causing thrombotic luminal occlusion and MI.
    • Large, multicenter randomized trials of various pharmacologic modalities have recently achieved great success in the treatment of patients with coronary artery atherosclerosis.
• Statins: The introduction of statins has prompted significant advances in the management of CAD. Over the past decade, several large-scale trials of cholesterol-reducing agents, particularly statins, have unequivocally proven the lipid hypothesis and provided substantial evidence of the advantages of lipid management in various subgroups of patients.
• • Mechanism of therapeutic effect
  • • Statins decrease the number of cardiovascular events by retarding the progression of atherosclerosis, stopping new lesion development, stabilizing the existing plaques, and reducing subintimal inflammation.
    • Previous studies examined the effect of statins on CAD progression. A review of 9 angiographic regression studies indicates that while angiographic changes caused by insignificant plaque reduction were small, the associated clinical responses appeared significantly greater.
    • In 1997, Thompson performed a meta-analysis of these trials and suggested a lower goal for LDL levels than the one currently recommended by the Adult Treatment Panel III (ATP-III) guidelines. Generally, a 45% reduction in the LDL level is needed to almost fully stop the progression of atherosclerosis. Apparently, a greater effect is observed on newer or minimal lesions than on older plaques, as was shown by the Pravastatin Limitation of Atherosclerosis in Coronary Arteries (PLAC)-1 study and the Multicenter Anti-Atheroma Study (MAAS). B-mode ultrasound was used in 4 trials for assessment of the antiatherosclerotic effect of statins. All of the trials showed a consistent benefit on plaque reduction in peripheral arteries.
    • In the past decade, large controlled clinical trials have shown benefit in the primary and secondary prevention of CAD in subjects with elevated serum cholesterol levels. The efficacy of statins has recently been extended to include primary prevention of CAD in patients with average cholesterol levels.
    • Apart from lowering LDL levels, statins have been shown in vitro to influence several other components of the atherosclerotic process. For example, statins cause (1) decreased cholesterol esterification, LDL oxidation, and macrophage uptake of oxLDL (a putative stimulus that initiates endothelial cell adhesion); (2) reduced SMC proliferation and/or migration; (3) decreased monocyte-endothelial cell adhesion; (4) reduction in the expression of adhesion molecules; (5) a lessening of tissue factor expression and an increase in endothelial nitric oxide synthetase III level; (6) reduced vascular A-II levels; and (7) anti-inflammatory effects (decrease in CRP).
  • Clinical studies
  • • The meta-analysis of 5 major statin trials totaling more than 30,000 subjects provides indisputable evidence of the effectiveness of statins in a variety of patient subgroups over a 5- to 6-year follow-up period.
    • These studies include the West of Scotland Coronary Prevention Study (WOSCOPS) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) for primary prevention and the Scandinavian Simvastatin Survival Study (4S), CARE, and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trials for secondary prevention. On average, statin therapy produced a 20% reduction in total cholesterol levels, a 28% reduction in LDL levels, and a 13% reduction in triglyceride levels, along with a 5% rise in HDL levels.
    • Overall, the number of coronary events and coronary deaths was reduced by 31% and 29%, respectively. The total mortality rate was decreased by 21% (P <.001), and cardiovascular mortality was decreased by 27% (P <.001). Rate reductions of cardiovascular events were similar between males and females and in persons older than 65 years and those younger than 65 years.
    • Most of the post-MI studies with statins did not begin administration of the drug for 3-6 months after the MI. Ironically, statins affect endothelial function and could be of benefit if begun early. An analysis of the GUSTO and Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) studies showed that patients who were on lipid-lowering treatment at the time of hospital discharge had a 33% lower mortality rate at 6 months compared with those who were not. A Swedish registry exhibited a similar reduction in 1-year mortality rates in patients who were started on antilipid treatment in the hospital.
    • A prospective study, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL), recently evaluated the benefits of starting 80 mg of atorvastatin within 24-96 hours of admission for ACS. Such early introduction of statin therapy caused a 16% decrease in the incidence of nonfatal MI, cardiac arrest, or recurrent ischemic symptoms over a 16-week follow-up period. The mortality rate was not reduced, but the trial was not designed to investigate this endpoint. Additionally, 2 studies (Aggrastat to Zocor [A to Z], PROVE IT) are assessing the effects of statin use in persons with ACS.
  • Management guidelines
  • • The NCEP ATP III guidelines suggest a goal LDL-C level of less than 130 mg/dL for everyone and less than 100 mg/dL for patients with known CAD. Whether more aggressive LDL lowering would provide additional benefit is unclear.
    • A target LDL-C level of 100 mg/dL (rather than 130 mg/dL) was shown to be more beneficial by the Post-Coronary Artery Bypass Graft Trial (PCABGT) involving 1350 subjects. Sequential reduction of LDL levels in a subgroup analysis of the 4S study exhibited further event reduction with each quartile of lipid lowering. A newer trial, the Treating to New Targets (TNT) trial, is underway and is comparing LDL reduction to less than 100 mg/dL with reduction to less than 75 mg/dL with atorvastatin in approximately 10,000 subjects with CAD.
    • Two other end-point trials in progress include the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) and the Incremental Decrease in Endpoints through Aggressive Lipid-Lowering (IDEAL) study.
  • Significance of treating low HDL levels and high triglyceride levels
  • • This lipid pattern is frequently encountered in diabetic patients. Most of these patients fit into the category of dysmetabolic syndrome.
    • Two of the trials currently in progress include Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Lipids in Diabetes Study (LDS). These studies are assessing the benefits of fibrates—alone or in combination with statins—to raise HDL levels and to reduce triglyceride levels.
  • Safety
  • • Despite the withdrawal of cerivastatin (Baycol) from the market because of serious adverse effects, all other statins currently available on the market are very safe and effective.
    • Statins are well tolerated. The percentage of patients experiencing adverse effects approaches that of patients on placebo. Liver function should be monitored, and musculoskeletal syndromes should be sought.
  • Recent trials of most significant impact
  • • The lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) examined the benefits of cholesterol lowering in the primary prevention of CAD in hypertensive patients who are not conventionally deemed dyslipidemic. The study was stopped prematurely because of a significant 36% reduction in the primary endpoints (ie, nonfatal MI, fatal CHD). In hypertensive patients who achieved good blood pressure control, LDL-C lowering produced clinically significant additional reductions in risk for both CAD and stroke.
    • This is in contrast to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the only other large study performed mainly in hypertensive patients, in which a modest differential in triglycerides and LDL-C levels was obtained between the 2 treatment groups, but a significant benefit was not observed.
    • Most observational studies fail to show cholesterol as a major risk factor for stroke. However, stroke incidence is reduced with LDL-C lowering in most statin trials, mostly in subgroup or retrospective analysis. In the ASCOT-LLA, a 27% stroke reduction was observed in subjects with good blood pressure control and average LDL-C levels.
    • Stroke reduction was also demonstrated for individuals older than 70 years. Previously, the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) trial showed a reduction in CAD events—but not stroke—in elderly patients older than 70 years. The reduction in both CAD and stroke occurred within the first year, suggesting that statin therapy, in addition to antihypertensive therapy, should be initiated early in hypertensive patients. The benefits were consistent across all baseline lipid levels in patients with average LDL-C levels. This study is consistent with the recent PROSPER trial and Heart Protection Study (HPS), which suggest that statin therapy should be initiated based on overall risk status, not simply on baseline lipid levels.
    • Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) was recently published (Colhoun, 2004). The trial addressed the issue that even though type 2 diabetes is associated with an enhanced risk of cardiovascular disease, the role of lipid-lowering therapy with statins for primary prevention in this setting is unclear. CARDS examined the effectiveness of atorvastatin at 10 mg/d in such patients who did not have high levels of baseline LDL-C. The 2838 subjects were aged 40-75 years and were being treated in 132 centers in the United Kingdom and Ireland. They were randomized to placebo (n = 1410) or atorvastatin at 10 mg/d (n = 1428).

      Study entrants had no documented previous history of cardiovascular disease, but they had at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The trial was terminated 2 years earlier than expected, with median follow up of 3.9 years, because the prespecified early stopping rule for efficacy had been met. While127 patients allocated to placebo (2.46 per 100 person-years at risk) had at least one major cardiovascular event, only 83 subjects allocated to atorvastatin had such events (1.54 per 100 person-years at risk; rate reduction of 37% with 95% confidence interval [CI] of -52 to -17; P = .001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years.

      Overall, acute coronary events were reduced by 36% (-55 to -9), coronary revascularizations were reduced by 31% (-59 to 16), and strokes were reduced by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, P = .59), which was not significant. No excess adverse events were noted in the atorvastatin group. Thus, atorvastatin at 10 mg/d is considered effective and helps decrease the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high baseline LDL-C levels.

    • The lipid-lowering arm of the ALLHAT examined the effects of lipid-lowering therapy on all-cause mortality and coronary heart disease endpoints in patients with moderate hypercholesterolemia, who were older than 55 years, had mild-to-moderate hypertension plus at least 1 additional risk factor, and had fasting LDL-C levels of 120-189 mg/dL (or 100-129 mg/dL if known CHD). Subjects were randomized to receive pravastatin at 40 mg/d (n = 5170) or usual care (n = 5185) and were followed for up to 8 years. At year 4, pravastatin reduced LDL-C levels by 28%, versus 11% with usual care. However, neither all-cause mortality nor CHD event rates differed significantly between groups.

      While pravastatin failed to significantly reduce all-cause mortality or CHD compared with usual care in this population (older subjects with well-controlled hypertension and moderately elevated LDL-C), the authors speculated that this may be due to smaller differences in total cholesterol and LDL-C levels between the pravastatin and usual care groups compared with previous statin trials. Overall, 9 large long-term statin trials have supported the safety and efficacy of this treatment in the prevention and treatment of CHD.

    • The HPS cholesterol-lowering with simvastatin in 5963 subjects with diabetes randomized (1) 5963 adults aged 40-80 years from the United Kingdom known to have diabetes and (2) an additional 14,573 with occlusive arterial disease (but no diagnosed diabetes) to receive simvastatin at 40 mg/d or matching placebo. Both among the participants who presented with diabetes and among those who did not, highly significant reductions of approximately 25% occurred in the first event rate for major coronary events, for strokes, and for revascularizations.

      For the first occurrence of any of these major vascular events among participants with diabetes, a definite 22% (95% CI, 13-30; P <.0001) reduction in the event rate occurred, which was similar to that among the other high-risk individuals studied. Additionally, highly significant reductions of 33% (95% CI, 17-46; P = .0003) occurred among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry. Finally, a reduction of 27% (95% CI, 12-40; P = .0007) occurred among the 2426 diabetic participants whose pretreatment LDL-C concentration was below 116 mg/dL.

      Thus, this study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes, even if they do not already have manifestations of coronary disease or high cholesterol concentrations. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent 45 people per 1000 from having at least one major vascular event. Statin therapy should, therefore, be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol levels.

    • The PROSPER trial was designed to examine the efficacy and safety of statins in elderly men and women with, or at high risk of developing, cardiovascular disease and stroke. A group of 5804 men (n = 2804) and women (n = 3000) aged 70-82 years with a history of, or risk factors for, vascular disease were randomized to pravastatin (40 mg/d, n = 2891) or placebo (n = 2913). Baseline cholesterol concentrations ranged from 4-9 mmol/L, and the follow-up period was 3.2 years. The primary endpoint was a composite of coronary death, nonfatal MI, and fatal or nonfatal stroke.

      Pravastatin lowered LDL-C concentrations by 34% and reduced the incidence of the primary endpoint to 408 events, compared with 473 on placebo (hazard ratio 0.85; 95% CI, 0.74-0.97; P = .014). Coronary heart disease death and nonfatal MI risk was also reduced (hazard ratio, 0.81; 95% CI, 0.69-0.94; P = .006). Stroke risk was unaffected (hazard ratio 1.03; 95% CI, 0.81-1.31; P = .8), but the hazard ratio for transient ischemic attack was 0.75 (95% CI, 0.55-1; P = .051). Mortality from coronary disease fell by 24% (P = .043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. The authors concluded that pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. The PROSPER trial, therefore, extends to elderly individuals the treatment strategy currently used in middle-aged people.

    • The PROVE-IT (Thrombolysis in Myocardial Infarction [TIMI] 22) trial examined whether statins are effective in reducing events in patients with ACS and whether intensive LDL-C lowering to an average of 65 mg/dL achieves a greater reduction in clinical events than standard LDL-C lowering to an average of 95 mg/dL. The results demonstrated that in patients recently hospitalized for an ACS, intensive LDL-C lowering (median LDL-C level of 62 mg/dL) using high-dose statins (atorvastatin, 80 mg/d) compared with moderate lipid-lowering therapy (median LDL-C level of 95 mg/dL) using moderate-dose statins (pravastatin, 40 mg/d) reduced the risk of all-cause mortality or major cardiac events by an additional 16% (P = .005). These benefits emerged within 30 days post-ACS, with continued benefit observed throughout the 2.5 years of follow-up. Additionally, the benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups.
    • The Aggressive Lipid Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial enrolled 2442 subjects (1:1 randomization) with a history of CHD, defined as AMI more than 3 months before screening, PTCA more than 6 months before screening, and coronary artery bypass graft or unstable angina more than 3 months before screening to atorvastatin (n = 1217) therapy versus usual care (n = 1225) and followed them for 52 months. The atorvastatin dose was initiated at 10 mg and titrated up to 80 mg or until an LDL level of less than 80 mg/dL was achieved. Usual care was defined as the lipid treatment program prescribed by the patient's primary physician and could include diet, weight loss, physical activity, behavior modification, and antihyperlipidemic medication (including atorvastatin). The composite endpoint included cardiac death, nonfatal MI, resuscitated cardiac arrest, revascularization, or unstable angina requiring hospitalization.

      The baseline LDL level was reduced from 147 mg/dL to 95 mg/dL (56% reduction) in the atorvastatin group and to 111 mg/dL (36% reduction) in the usual care group. The primary endpoint (composite of cardiac death, nonfatal MI, resuscitated cardiac arrest, revascularization, or unstable angina) was reduced by 17% in the atorvastatin group compared with the usual care group. Atorvastatin therapy was associated with a 47% decrease in nonfatal MI versus usual care. The mean dose of atorvastatin in the study was 40.5 mg/d. Intensive lipid lowering with atorvastatin was well tolerated (ie, no myopathy or rhabdomyolysis, and <1.3% rate of aspartate aminotransferase or alanine aminotransferase increase above 3 times normal). These results clearly show the important cardiovascular benefits of intensively lowering cholesterol with atorvastatin and the additional benefits in patients at high risk for recurrent coronary events than it provides for patients already receiving usual care.

    • The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, a double-blinded, randomized multicenter trial, used IVUS to measure progression of atherosclerosis in 654 subjects randomized to receive a moderate lipid-lowering regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg of atorvastatin. The baseline LDL-C level of 150.2 mg/dL was reduced to 110 mg/dL in the pravastatin group and to 79 mg/dL in the atorvastatin group (P <.001). CRP was also measured, and it decreased 5.2% with pravastatin and 36.4% with atorvastatin (P <.001). The percentage change in atheroma volume measured by IVUS showed a significantly lower progression rate in the atorvastatin (intensive) group (P = .02).

      Overall, while progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; P = .001) compared with baseline, progression did not occur in the atorvastatin group (-0.4%; P = .98). The study concluded that for patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin significantly reduces the progression of coronary atherosclerosis compared with pravastatin. These differences may be related to the greater reduction in atherogenic lipoproteins and CRP in the patients treated with atorvastatin.

      The Z phase of the A to Z trial studied an early intensive versus a delayed conservative simvastatin strategy in patients with ACS. Phase Z of the A to Z trial randomized patients with ACS to receive 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) or placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232). Among the subjects in the placebo plus simvastatin group, the median LDL-C level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the subjects in the simvastatin only group, the median LDL-C level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin.

      A total of 343 subjects (16.7%) in the placebo plus simvastatin group experienced the primary endpoint, compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (P = .14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) subjects in the 2 groups (P = .05). While no difference was evident during the first 4 months between the groups for the primary endpoint (P = .89), from 4 months through the end of the study, the primary endpoint was significantly reduced in the simvastatin only group (P = .02). Myopathy (creatine kinase level >10 times the upper limit of normal and associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin at 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P = .02).

      This trial did not achieve the prespecified endpoint. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

• Recent data and the ATP-III update
• ATP-III of the NCEP 2004 updated guidelines: The ATP III issued an update to its evidence-based guidelines for cholesterol management, initially published in 2001. Five major trials since 2001 addressed some new issues that were not previously examined. TLCs remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of an LDL-C level of less than 100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C levels. The major recommendations for modifications to footnote the ATP III treatment algorithm include the following:
• • In high-risk persons, the recommended LDL-C goal is less than 100 mg/dL, but, when risk is very high, an LDL-C goal of less than 70 mg/dL is a therapeutic option, and a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option even applies to patients at very high risk who have a baseline LDL-C level of less than 100 mg/dL.
  • Furthermore, when a high-risk patient has a high triglyceride level or low HDL-C level, a strategy of combining a fibrate or nicotinic acid with an LDL-lowering drug should be considered.
  • For moderately high-risk persons (>2 risk factors and 10-y risk of 10-20%), the recommended LDL-C goal is less than 130 mg/dL, but an LDL-C goal of less than 100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option can also be extended to moderately high-risk persons with a baseline LDL-C level of 100-129 mg/dL.
  • When LDL-lowering drug therapy is used in high-risk or moderately high-risk persons, the intensity of therapy should be sufficient to achieve at least a 30-40% reduction in LDL-C levels.
  • In addition, persons at high risk or moderately high risk who have lifestyle-related risk factors, such as obesity, physical inactivity, elevated triglyceride level, low HDL-C level, or metabolic syndrome, are candidates for TLC to modify these risk factors, regardless of LDL-C level.
  • Finally, for persons in lower-risk subsets, recent clinical trials do not modify the goals and cut points of lipid treatment.
• Veterans Affairs HDL Intervention Trial
• • Recent additional follow-up and analysis of the Veterans Affairs HDL Intervention Trial (VA-HIT) indicate that treatment with gemfibrozil versus placebo resulted in a 32% reduction in major cardiovascular events (P <.004) and a 41% reduction in CHD deaths (P = .02) in 769 male subjects with diabetes mellitus and CHD with HDL-C levels of less than 40mg/dL and LDL-C levels of less than 140 mg/dL.
  • Interestingly, among 1733 nondiabetic men, increased plasma fasting insulin levels and insulin resistance, as assessed by the homeostasis model assessment for insulin resistance (HOMA-IR), ie, fasting insulin [µU/mL] X fasting glucose [mmol/L]/22.5), were predictive of increased major cardiovascular events and of greater benefit from gemfibrozil treatment (Rubins, 2002; Robins, 2003).
  • Somewhat inexplicable was the finding that despite higher plasma triglyceride and lower HDL-C levels in insulin-resistant subjects, these measurements were associated with greater treatment benefit only in those subjects classified as not having insulin resistance by HOMA-IR. One unanswered question is whether body mass index or waist circumference, which strongly correlated with fasting insulin in nondiabetic subjects, could also be used to predict those with greater or lesser CHD risk reduction with gemfibrozil therapy.
  • This is the first trial to demonstrate the cardiovascular benefit of treating diabetic and insulin-resistant subjects with low HDL-C levels. Interestingly, the insulin resistance was more predictive of CHD event rate and benefit from gemfibrozil than were HDL-C or triglyceride levels. Because no significant reduction in LDL-C was realized with gemfibrozil therapy, one possibility is that additional CHD benefit would be accrued by adding statins, which have been shown in subgroup analyses of several trials to benefit CHD risk in diabetic patients and in nondiabetic patients with low HDL-C levels.
  • One caveat is that because of the relatively higher risk of myopathy with combined gemfibrozil-statin treatment and findings that indicate much less risk with statins and fenofibrate, the latter is currently the preferred choice for combined treatment.
• ACE inhibitors: The efficacy of ACE inhibitors on CAD has been examined in blood pressure reduction studies and in studies of subjects with high-risk factors for CAD.
• Mechanism of therapeutic effect
• • ACE inhibitors are effective blood pressure–reducing agents. They also affect the heart and vasculature through direct and other mechanisms.
  • ACE inhibitors were not shown to affect the plaque in a randomized angiographic regression trial, the Quinapril Ischemic Event Trial (QUIET) of 463 subjects with CAD. B-mode ultrasound studies investigating plaque regression have also provided confusing results at best. Although the second Prevention of Atherosclerosis with Ramipril Trial (PART 2) showed no reduction in intimal-medial thickness (IMT) at 4-year follow-up in 617 subjects randomized to placebo or ramipril (5-10 mg/d), the Study to Evaluate Carotid Ultrasound Changes with Ramipril and Vitamin E (SECURE) showed a reduction in carotid IMT proportional to the dose of ramipril (2.5-10 mg/d) in 750 subjects over a 4.5-year follow-up period.
  • ACE inhibitors probably affect endothelial function, as well as those of A-II and kinin, to elicit the clinical effects observed in the clinical trials. Tissue binding is variable among the ACE inhibitors, with the highest affinity shown by quinapril, benazepril, and ramipril. In the Trial on Reversing Endothelial Dysfunction (TREND) study, which included 105 subjects with CAD (but without CHF or left ventricular dysfunction), the group receiving quinapril at 40 mg/d showed significantly improved response (P = .002) to acetylcholine. ACE inhibitors also increase nitric oxide levels by increasing its release through a kinin-mediated pathway and through reduction of its breakdown.
  • ACE inhibitors also decrease the plasma levels of type 1 plasminogen activator inhibitor, increase the release of tissue-type plasminogen activator, and favorably affect the fibrinolytic balance, an effect not observed with the angiotensin receptor-blocking agents.
• Clinical studies
• • In terms of blood pressure reduction, even though a greater stroke incidence was observed with higher baseline blood pressure in the treatment group in the Captopril Prevention Project (CAPPP), a pooled analysis of 16,161 patients from blood-pressure control trials evaluating ACE inhibitors showed no difference in the outcome risk.
  • A possible direct effect of ACE inhibitors on atherosclerosis, independent of blood pressure reduction, was suggested by the Heart Outcomes Prevention Evaluation (HOPE) study, which included 9297 subjects with history of CAD, stroke, peripheral vascular disease, or diabetes, along with one other CAD risk factor (eg, hypertension, hypercholesterolemia, hypoalphalipoproteinemia, tobacco abuse, microalbuminuria). Subjects were randomized to placebo or ramipril (10 mg/d). At 5-year follow-up, the cardiac death rate was reduced by 25%, nonfatal MI by 20%, need for bypass surgery/PTCA by 16%, and all-cause mortality by 16%. The effects were unrelated to the blood pressure–lowering effect.
  • Two new studies to evaluate similar endpoints are underway. They include the Prevention of Events with ACE Inhibitors (PEACE) study and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study.
• Antiplatelet agents (eg, aspirin, clopidogrel): These agents help reduce the number of acute coronary events. Convincing data are now available from the following studies:
• Antiplatelet Trialists' Collaboration
• Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial
• Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial
• Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (PCI-CURE) trial
• Calcium channel blockers: These agents play a significant role in the treatment of angina or ischemia in symptomatic patients with CAD and are included in the American College of Cardiology/American Heart Association guidelines for stable angina management. Other indications for calcium channel blocker (CCB) therapy include hypertension and use along with diuretics in isolated systolic hypertension.
• Mechanism of therapeutic effect
• • CCBs—both dihydropyridines (eg, nifedipine) and nondihydropyridines (eg, verapamil, diltiazem), as well as the newer agents (eg, amlodipine)—have been shown to reduce atherosclerosis in animal models. This effect appears to be independent of the blood pressure–lowering effect and of the calcium channel blocking properties.
  • Amlodipine has antioxidant effects and normalizes the levels of oxLDL in primates given atherogenic meals. It also augments nitric oxide release. CCBs also inhibit monocyte adhesion, retard growth factor release, decrease SMC proliferation and migration, reduce platelet aggregability, and block cholesterol uptake by macrophages.
• Clinical studies
• • Hypertension trials using CCBs have shown similar benefits to beta-blockers and diuretics. The Nordic Diltiazem (NORDIL) study compared diltiazem with beta-blockers and diuretics in 10,881