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C H A P T E R 144

ATHEROTHROMBOSIS

Roy L. Silverstein

Morbidity and mortality from atherosclerosis, the pathologic process pathophysiologic mechanisms that govern plaque formation, plaque
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underlying acute myocardial infarction, sudden death, stroke, and progression, and acute arterial thrombosis. Translation of this knowl-
limb loss, represent an enormous burden on society and health care edge into diagnostic, preventive, and therapeutic strategies has been
systems. Even though death rates from heart attack and stroke have impressive, but there is still a need for improvement. This chapter
dropped precipitously over the past 60 years (72% and 78%, respec- will summarize the current prevailing models of atherogenesis and
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tively, from 1950 to 2008) , cardiovascular diseases are still the atherothrombosis, highlighting some key knowledge gaps and poten-
number one cause of death in the United States, accounting for more tial new therapeutic targets.
than 30% of all deaths—approximately 2200 per day (or one every
40 seconds). Unfortunately as the developing world adopts a more
“Western” lifestyle (i.e., one marked by a high-fat, calorie-rich diet, LIPOPROTEIN HOMEOSTASIS AND THE
and limited physical activity), these statistics are becoming the norm “CHOLESTEROL HYPOTHESIS”
worldwide. The annual financial burden of cardiovascular disease in
the United States in 2010 was estimated by the American Heart Human epidemiologic and clinical trial data and animal model
Association (AHA) to be $445 billion, including $172 billion due to studies show unequivocally that elevated levels of plasma lipids,
lost productivity. These costs are predicted to triple over the ensuing especially LDL cholesterol, are essential for plaque development.
20 years; analyses of population survey data predict an increase in Atherosclerotic lesions can be induced in “atheroresistant” animals,
cardiovascular disease prevalence from 36.9% to 40.5%. It is interest- including mice and rabbits, by manipulating their diets and/or
ing to note that as treatment of the acute complications of athero- genomes to cause hypercholesterolemia. The development of mouse
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sclerosis improves, the burden of chronic complications, particularly genetic models nearly 25 years ago has provided great mechanistic
heart failure, is expected to increase by as much as 25% over the next insights into the underlying pathobiology of plaque formation. In
20 years. 1 humans, raising LDL cholesterol levels increases the risk for athero-
Much of our knowledge of the epidemiology of cardiovascular sclerosis proportionally and lowering levels either by lifestyle change
disease comes from large-scale, long-term population studies, the or pharmacologic intervention reduces risk proportionally. In general,
most important being the Framingham Heart Study sponsored by lowering LDL cholesterol levels by 10% reduces risk for cardiovascu-
the National Heart, Lung, and Blood Institute (NHLBI). This lar events by 25% and cardiovascular death by 10%.
ongoing prospective study began in 1948 with a cohort of ≈5200 Normally cholesterol levels are tightly controlled in response to
men and women between the ages of 30 and 62 years in Framingham diet and cellular needs by a complex transcriptional pathway medi-
(MA, USA), and has since added two subsequent generations and ated by sterol response element-binding protein 2 (SREBP2). At low
several other cohorts. Through this study and others elsewhere in the levels of cellular cholesterol, SREBP2 is activated and binds to specific
United States and Europe major risk factors for cardiovascular disease DNA sequences in target genes known as sterol response elements to
have been identified, including cigarette smoking, low-density lipo- activate their transcription. Two key target genes are HMGCR and
protein (LDL) cholesterol, systolic blood pressure, male sex, meno- LDLR, which encode 3-hydroxy-3-methylglutaryl coenzyme A
pause, physical inactivity, body mass index, high-sensitivity C-reactive (HMGCoA) reductase (the rate-limiting enzyme in cholesterol bio-
protein (hsCRP), and coronary artery calcification scores determined synthesis) and the LDL receptor, respectively, thereby increasing both
by radiographic imaging. Additionally, high-density lipoprotein cholesterol production and cellular LDL uptake. At high levels of
(HDL) was identified as a protective factor. Based on these data, risk cellular cholesterol, SREBP2 is inactive, cholesterol biosynthesis is
scores have been developed to guide physicians and patients, and turned off, and LDL receptor expression is downregulated. As shown
public health campaigns developed targeting hypertension, elevated in Fig. 144.2, statins decrease cellular cholesterol biosynthesis by
cholesterol, and lifestyle modifications. These measures have clearly inhibiting HMGCoA reductase and thereby induce an increase in
contributed to the reductions in cardiovascular mortality just noted, LDL receptor expression, driving down plasma LDL cholesterol
although they cannot account for the entire decrement. Racial and levels.
ethnic disparities are well described in cardiovascular risk, with blacks Multiple randomized clinical trials have demonstrated efficacy of
having higher rates than all other groups. statin class drugs in reducing risk for cardiovascular events in high-
risk individuals. Initial studies focused on secondary prevention in
patients with a history of a previous atherosclerotic event, but later
PATHOBIOLOGY trials demonstrated efficacy as part of a primary prevention strategy
in subjects with elevated LDL cholesterol or in subjects with normal
Atherosclerosis is caused by the progressive formation of arterial LDL cholesterol in the setting of other risk factors, such as diabetes,
plaques, which are characterized by accumulation of lipids, in par- hypertension, or elevated plasma levels of hsCRP. The latter studies,
ticular cholesterol and its derivatives, and inflammatory cells in the along with those showing benefit of lowering LDL cholesterol to
tunica intima of large- and medium-sized arteries (Fig. 144.1). levels well below “normal” (e.g., to 70 mg/dL in high-risk individu-
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Although occlusion of blood flow by plaque encroachment into the als), are consistent with the concept that “normal” levels of LDL
lumen can occur and cause ischemia of downstream tissues, most of cholesterol, as defined by population means in the Western world,
the severe clinical events associated with atherosclerosis derive from are not reflective of a true normal biology.
acute or subacute thrombosis at a site of an unstable, inflamed, or Genetic studies of rare individuals with extremely low LDL cho-
ruptured plaque, or at a site of recent mechanical or pharmacologic lesterol levels identified a null mutation in a gene known as PCSK9
intervention, a process termed atherothrombosis. The past 45 years that encodes a serine protease enzyme involved in downregulating
have seen a remarkable increase in our understanding of the basic LDL receptor expression. Individuals with this mutation seem to be

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