Noninvasive Imaging of Atherosclerosis

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CHAPTER 88 Noninvasive Imaging of Atherosclerosis

Jamieson M. Bourque, Christopher M. Kramer

Atherosclerosis is a disease process in which fatty infiltration and inflammation of the wall of medium to large arteries lead to plaque formation and multiple adverse sequelae including rupture, obstruction, and embolism. It is a major source of morbidity and mortality, with 25 million people in the United States demonstrating at least one clinical manifestation of atherosclerosis.¹ It has been the number one cause of death in the United States since 1900 except for 1918, the year of the influenza epidemic.² Atherosclerosis also leads to significant losses in functional capacity and quality of life.

Atherosclerosis should be considered a systemic disease. The primary clinical and research focus has been coronary atherosclerosis; disease in this vascular area affects the most people and is typically the cause of death, even among those with complications of noncoronary vascular disease. It involves almost all arterial beds but most importantly the cerebrovascular, renal, lower extremity, aortic, and mesenteric territories. Although the effects of atherosclerosis vary in each regional circulation, the epidemiology, pathophysiology, presentation, and general treatment strategies are similar and highly linked. The presence of disease and complications in any arterial bed greatly increases the risk of comorbid atherosclerosis and its adverse events in the others.

Noninvasive imaging of the arterial system plays a pivotal role in the diagnosis of atherosclerosis. This disease can often be asymptomatic or with atypical presentation, and the physical examination is imperative but often insufficient. Early diagnosis is of paramount importance as prompt, aggressive therapy significantly reduces atherosclerotic morbidity and mortality.

In this chapter, we focus on noncoronary atherosclerosis, reviewing the epidemiology, pathophysiology, treatment, and noninvasive imaging and other diagnostic strategies available. An understanding of the underlying disease processes and potential therapeutic options is essential to increase the utility and appropriateness of noninvasive evaluation.

ATHEROSCLEROSIS

Definition

Atherosclerosis is a form of arteriosclerosis characterized by the deposition of plaques containing cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries.³ The atheroma is a complex of lipids and fibrous tissue with surrounding hypertrophied smooth muscle and inflammatory cells that leads to progressive vessel luminal narrowing and obstruction of blood flow, directly causing or indirectly mediating the many clinical manifestations of atherosclerotic disease.

Prevalence and Epidemiology

The exact overall prevalence of atherosclerosis is not known because of the numerous arterial beds it encompasses and because it is often silent and found only through screening, which is not universally performed. Moreover, atherosclerotic disease often coexists in multiple vascular systems, making the individual disease prevalence not additive. Atherosclerosis does account for almost three quarters of all deaths from cardiovascular disease.² The majority of these are from coronary atherosclerosis. Although the mortality from coronary heart disease is decreasing, that from noncoronary atherosclerotic disease is increasing, partly owing to the overall aging of the population. Information on the prevalence of noncoronary atherosclerotic disease and the resultant complications is available for the individual arterial systems affected.

Cerebrovascular Atherosclerotic Disease

Cerebrovascular atherosclerosis has the highest impact of noncoronary disease processes. Stroke is the third leading cause of death in the United States, with an annual incidence of 700,000 events. It is associated with high morbidity and mortality, with a 50% 5-year survival and 15% to 30% risk of permanent disability. Sixty percent of new or recurrent strokes are the result of atherothrombotic disease. One third of these are due to carotid atherosclerosis. At the age of 75 years, 53% of women and 63% of men have carotid stenoses of more than 10%.⁴ The presence of carotid bruits approximately doubles the expected stroke risk, but the disease is often in a different cerebral vascular territory and not related to the initial lesion auscultated. Despite the high morbidity and mortality from stroke, individuals with carotid artery disease are more likely to die of cardiovascular causes than of cerebrovascular disease, underscoring the close relationship between noncoronary atherosclerosis and cardiovascular risk.

Peripheral Atherosclerotic Disease

Defining peripheral arterial disease (PAD) as a noninvasive ankle-brachial index (ABI) below 0.90, its prevalence in the lower extremities is 2.5% for those younger than 60 years and increases markedly with age to 18.8% for those 70 years of age or older.⁵ Claudication is associated with significant disability and is present in as many as 6% to 7% of the general population 65 years of age and older. The prevalence also varies significantly by risk factor profile. The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) study examined PAD prevalence in the American primary care setting and found that the prevalence was as high as 29% in older Americans or those with significant risk factors (especially tobacco use and diabetes). The disease has high morbidity from both peripheral and cardiovascular events. The annual mortality for those with PAD is 4% to 6% and is as high as 25% for the 1% to 2% of patients with critical limb ischemia.⁵ Individuals with PAD have a 60% to 80% prevalence of significant coronary artery disease (CAD), with a twofold to sixfold increase in cardiovascular death and a 40% increase in the risk of stroke. PAD is often undetected without careful exercise tolerance questioning and judicious screening, going undiagnosed in as many as 55% of affected individuals.

Etiology and Pathophysiology

Insight into the pathogenesis of atherosclerosis is essential so that novel imaging techniques can be used and effective therapies can be devised and implemented. Atherosclerosis development represents much more than simply accumulation of lipid. It stems from a series of complex cellular and molecular processes that are initiated as a result of the many known atherosclerotic risk factors and comorbid conditions that cause the initial stages of atherosclerosis to progress in a predictable fashion. The pathophysiologic process of atherosclerosis remains predominantly uniform across the spectrum of affected arterial beds, although there are some key regional differences.

Atherosclerosis is a disease primarily of the large and medium-sized arteries and is increasingly considered primarily an inflammatory process in response to endothelial injury and lipid oxidation. The primary stages of atherosclerosis are

1 accumulation of inflammatory cells, such as macrophages and smooth muscle cells;

2 accumulation and necrosis of a lipid core; and

3 formation of extracellular matrix, which creates a fibrous cap over the enlarging lipid core and accumulating inflammatory cells.

Positive feedback leads to repeated cycles of this process, and progressive arterial dilation (Glagov phenomenon) and eventually luminal encroachment occur. Severe luminal narrowing can result in myocardial ischemia and symptoms. Alternatively, rupture of the fibrous cap can occur, leading to rapid platelet aggregation, thrombosis, rapid vessel obstruction, and clinical events. Several hypothetical frameworks have been developed to help explain this complex process.

Response to Injury Hypothesis

The primary step in the formation of atherosclerosis is the development of vessel wall endothelial dysfunction, which occurs as a response to injury from risk factors such as elevations and alterations in low-density lipoprotein (LDL), genetic abnormalities, and toxic free radicals stemming from tobacco use.⁷

These adverse processes stimulate the production of cytokines, growth factors, and vasoconstrictive agents. They also lead to inflammatory cell and platelet adhesion, amplified endothelial permeability, smooth muscle cell proliferation, and loss of activity of vasodilatory and fibrinolytic agents such as nitric oxide, causing increased endothelial procoagulancy. Endothelial damage also leads to platelet deposition and resultant monocytic and T-cell infiltration. Cumulatively, these factors lead to increased oxidative stress, which facilitates the next step in the atherosclerotic process.

Oxidation Hypothesis

Oxidation of LDL is required for its uptake by macrophages and accumulation within the vessel wall.⁸ Arterial LDL is progressively oxidized by oxygen free radicals and internalized by macrophages, forming lipoperoxides, a reactive species that triggers further LDL oxidation and plasma membrane destruction. Oxidized LDL is also a potent chemoattractant for macrophages, inducing the expression of vascular cell adhesion molecules and inhibiting macrophage mobility, thereby furthering macrophage and lipid accumulation within the vessel wall. These lipid-laden macrophages are known as foam cells because of their histologic appearance.⁷ As these foam cells accumulate, they undergo apoptosis and necrosis from increased proteolytic activity, forming a necrotic lipid core.

Extracellular Matrix Formation and the Fibrous Cap

Progressive inflammation leads to activation of the infiltrating T lymphocytes and macrophages. These then secrete a variety of cytokines, chemokines, lytic enzymes, and growth factors that stimulate the formation of an extracellular matrix. Continued development of this matrix induces the creation of a fibrous cap over the proliferating smooth muscle cells and necrotic lipid core.

Progression to Clinical Significance

During the initial stages of atherosclerosis, the blood vessel dilates to maintain lumen size, a process known as the Glagov phenomenon (Fig. 88-1). However, the repeated cycles of inflammation, smooth muscle cell and fibrous tissue proliferation, and expansion of the lipid core eventually overwhelm the compensatory response, leading to progressive luminal obstruction. Decreased luminal blood flow from the increasing vessel blockage will eventually lead to insufficient supply to meet oxygen demand, and ischemia will ensue.

FIGURE 88-1 Glagov phenomenon. The artery on the left has early atherosclerotic findings, including a small lipid core. As the atherosclerosis progresses, the lipid core enlarges, but the artery dilates eccentrically to maintain the original lumen size. Eventually, the lesion progression is sufficient to overload the compensatory dilation, and lumen encroachment occurs (not shown).

More rapid vessel occlusion can also occur, leading to ischemia and potentially infarction, depending on the vascular bed. The activated T lymphocytes present can secrete matrix metalloproteinases and other lytic molecules that can degrade the fibrous cap, leading to cap rupture and the uncovering of the prothrombotic elements underneath. This exposure, along with other procoagulant factors released by activated inflammatory cells, can induce platelet aggregation and ultimately thrombosis and rapid vessel occlusion (Fig. 88-2).

FIGURE 88-2 Atherosclerotic lesion progression. This illustration shows an advanced atherosclerotic plaque with uptake of oxidized LDL by macrophages, which become foam cells. Reactive oxygen species induce necrosis and apoptosis, leading to a necrotic core. Inflammatory cells promote cytokine and growth factor release that stimulates fibrous cap formation.

(Modified from Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115.)

Risk Factors

The risk factors for atherosclerosis are similar across the multiple arterial beds affected, regardless of the end-organ perfused. They fall into two categories: those that are modifiable and those beyond our control. Modifiable risk factors can be further broken down into those that are predominantly a result of lifestyle indiscretions and those that are primarily manifestations of clinical disease that can be treated (Table 88-1).

TABLE 88-1 Risk Factors for the Development of Atherosclerosis

Modifiable Risk Factors

Lifestyle indiscretions

Obesity

Tobacco use

Physical inactivity

Clinical comorbid conditions

Lipid abnormalities*

Elevated low-density lipoprotein or total cholesterol level

Low high-density lipoprotein level

Elevated triglyceride levels

Diabetes mellitus

Metabolic syndrome, insulin resistance

Hypertension (both systolic and diastolic are independently associated)

Risk Factors (Not Modifiable)

Advanced age

Male gender

Race^†

Genetic predisposition (positive family history)

Prothrombotic and proinflammatory comorbid conditions (such as systemic lupus erythematosus, rheumatoid arthritis)

New/Under Investigation

Increased lipoprotein(a)

High-sensitivity C-reactive protein elevation

Homocysteine elevation

Increased fibrinogen

* Each of these lipid abnormalities provides independent incremental risk.

† The black population has a higher rate of atherosclerosis than the white population does.

Risk Factors (Not Modifiable)

Increasing age is the most powerful risk factor for noncoronary atherosclerotic vascular disease (AVD). The atherosclerotic process occurs in a stepwise fashion over time, and those with advanced age are more likely to have a higher burden and greater complexity of disease. Data from the Framingham study show that 7% to 9% of individuals 75 years of age or older have carotid stenoses of 50% or more. In contrast, less than 1% had that degree of obstruction at 50 years of age.⁴

Gender also plays a significant role in the prevalence of atherosclerosis. However, with the increasing number of female smokers and disproportionate prevalence and rate of increase in obesity, these gender differences are narrowing.² Race also has a significant impact on the likelihood of atherosclerotic disease. For instance, black populations have a 38% higher incidence than do white populations of ischemic stroke and stroke mortality adjusted for risk factors.⁴

Genetics also plays a significant role in the development of atherosclerosis. This is evident from studies of common carotid artery wall thickness and abdominal calcification, in which familial factors contribute 64% to 92% and 50% of the variation, respectively. Genetically increased risk does not follow a mendelian pattern but is rather the result of changes in multiple genes that have varying effects on the cardiovascular system. The majority of isolated risk-associated genes to date modulate other known cardiovascular risk factors rather than the atherosclerotic process itself. Genes that work independently of known comorbid conditions are the subject of intense ongoing research.

Known genes that promote lipid abnormalities include apolipoprotein E (APOE) and cholesteryl ester transfer protein (CETP). Mutations in the LDL receptor gene are particularly damaging, leading to familial hypercholesterolemia in its homozygous form and significant lipid abnormalities even when heterozygous, which occurs in approximately 1 in 500 persons.⁸ Contributors to the inflammatory process include peroxisome proliferator–activated receptor γ, vascular cell adhesion molecule, and tumor necrosis factor α.⁹ Significant research is necessary to identify new genes and to determine the full impact of known genetic abnormalities, their response to environmental conditions, and the subsequent therapeutic implications.

Proinflammatory conditions such as systemic lupus erythematosus and rheumatoid arthritis have up to a 50-fold increase in the risk of AVD, with the largest differences appreciated in younger patients. The proposed mediators of this increased risk include immune complex deposition; increased fibrinogen, von Willebrand factor, and other procoagulants; higher lipoprotein levels from glucocorticoid therapy; and direct vascular injury with endothelial cell progenitor cell depletion. Rarely, vasculitis is the inciting factor. Systemic lupus erythematosus specifically can cause dyslipidemia through lipoprotein lipase autoantibodies and increased oxidized LDL uptake through anti–β₂-glycoprotein 1 autoantibodies.

Modifiable Risk Factors

Many of the known modifiable risk factors have well-established interactions with the pathophysiologic processes of noncoronary atherosclerosis. For example, hypertension causes increased levels of angiotensin II, which stimulates smooth muscle growth and lipoxygenase activity, a contributor to LDL oxidation and inflammation. Lipoxygenase also increases free radical production and subsequently reduces nitric oxide formation. Homocysteine decreases nitric oxide availability in addition to its direct toxicity to the endothelium and its prothrombotic effects.⁷

Tobacco use and diabetes mellitus appear to confer the greatest risk of noncoronary AVD (Fig. 88-3).⁹ Tobacco use doubles the risk of ischemic stroke. Smoking also increases the risk of PAD by twofold to sixfold, and more than 80% of those with PAD have smoked or continue to do so. This effect occurs in a dose-dependent manner.⁵ In the Edinburgh Artery Study, the odds ratio (OR) for PAD with tobacco use (OR, 1.8-5.6) was approximately twofold to threefold higher than for CAD (OR, 1.1-1.6).

FIGURE 88-3 Relative risk of peripheral arterial disease by risk factor. Tobacco use and diabetes confer the greatest risk of peripheral arterial disease.

The proposed pathophysiologic mechanisms for the increased risk of disease in PAD versus CAD are (1) increased endothelial dysfunction (measured through von Willebrand and tissue plasminogen activator antigens), (2) reduced circulating antioxidants, (3) increased plasma fibrinogen levels, and (4) altered lipoprotein profiles. The Edinburgh Artery Study specifically addressed the differential odds ratios by measuring risk factors and analyzing the prevalence of these two conditions in 1592 subjects both with and without a history of tobacco use.¹⁰ This study confirmed increased levels of von Willebrand and tissue plasminogen activator antigens (markers of endothelial disruption), reduced antioxidant levels, and increased fibrinogen levels. However, correction for these variables decreased the PAD odds ratio to only 2.7 from 3.9, with little change in the CAD odds ratio. Although the differential effect of tobacco use was partly mitigated by adjusting for these potential contributors, it is clear that other unknown mechanisms still predominate.¹⁰

Diabetes mellitus is the other of the two most significant modifiable risk factors, increasing the risk of PAD by 2- to 4-fold and ischemic stroke by 1.8- to 6-fold.⁵^,¹¹ The risks of critical limb ischemia and major amputation are also higher with diabetes. The pathophysiologic mechanism underlying this increased risk is multifactorial. Increased levels of C-reactive protein promote apoptosis and stimulate procoagulant tissue factors, leukocyte adhesion molecules, and inhibitors of fibrinolysis. The hyperglycemia, insulin resistance, and fatty acid production associated with diabetes reduce the bioavailability of nitric oxide, decreasing vasodilation and allowing increased smooth muscle cell proliferation and platelet activation. Finally, diabetes increases procoagulant tissue factor and fibrinogen production, leading to a hypercoagulable state.¹² Unlike tobacco use, diabetes does not appear to increase the risk of noncoronary AVD disproportionately to the risk of CAD.

Unlike with coronary vascular disease, the lipid abnormality most strongly associated with noncoronary AVD is the combination of high triglyceride and low high-density lipoprotein (HDL) levels, which are also highly linked with diabetes. These lipid abnormalities are closely involved in the noncoronary atherosclerotic process along with increased LDL. Triglyceride-rich lipoproteins stimulate smooth muscle cell proliferation and extracellular matrix deposition. Low levels of HDL increase atherosclerotic risk through a relative decrease in its beneficial processes, including reverse cholesterol transport for its excretion, endothelial protection, and anti-inflammatory effects.⁸

The metabolic syndrome includes these cholesterol derangements as well as abdominal obesity, hypertension, and insulin resistance. This risk factor complex leads to a low-grade inflammatory state with increased levels of C-reactive protein, tumor necrosis factor α, and fibrinogen. Although LDL levels may remain within normal ranges, the particles are smaller and more dense, which renders them prone to detrimental oxidation. Moreover, each component of the metabolic syndrome independently increases atherosclerotic risk. Adipose tissue worsens insulin sensitivity and causes a system-wide proinflammatory state. Persistent hyperglycemia from insulin resistance and the high coprevalence of diabetes mellitus lead to advanced glycation end-products that trigger additional arterial inflammation.

Both physical inactivity and obesity have been shown to increase C-reactive protein levels and to cause endothelial dysfunction. They also worsen many other disease states that independently increase the risk of disease. Decreased exercise promotes the formation of proatherogenic cytokines. All of these changes lead to an increased risk of noncoronary AVD.

Novel Risk Factors

Greater understanding of the most common risk factors associated with noncoronary AVD have led to the development of risk scores for stroke and claudication based on the Framingham data. However, novel contributors of risk, especially those estimating inflammation, such as high-sensitivity C-reactive protein, lipoprotein(a), and homocysteine, are challenging these existing paradigms.⁹ Lipoprotein(a), for instance, self-aggregates and increases inflammation by impairing fibrinolysis through regulation of fibrinogen activator inhibitor 1 and by inducing smooth muscle cell proliferation.

These novel factors may have additional predictive value only in patients with premature or rapidly progressive disease. Moreover, treatment of these comorbid conditions, such as vitamin supplementation for elevated homocysteine levels, does not necessarily decrease subsequent risk.

There is some variation in risk factors based on the anatomic localization of disease. For instance, in aortic disease, tobacco use continues to play a significant role (partly because of elastin degradation). It and male sex confer the highest risk for AAAs, whereas those of Asian descent rarely develop this disorder. A family history of AAA is especially important. In PAD, however, diabetes plays a larger role, especially for the female gender. PAD appears to have a higher incidence in African-American and Hispanic subgroups. Other than these examples, few data are available on gender- and ethnicity-based risk differences.⁹

Condition	Clinical Symptoms and Review of Systems
Cerebrovascular disease	Altered mental status Headaches Vision changes (diplopia, blurred vision, visual field defects) Dysphagia Word-finding or speech articulation difficulties Peripheral motor and sensory deficits