Clinical Pharmacology and Therapeutics

CHAPTER 27
PREVENTION OF ATHEROMA:
LOWERING PLASMA CHOLESTEROL
AND OTHER APPROACHES
● Introduction 177
● Pathophysiology 177
● Prevention of atheroma 179
● Drugs used to treat dyslipidaemia 180
INTRODUCTION
Atheroma is the most common cause of ischaemic heart disease,
stroke and peripheral vascular disease. Since these are
the major causes of morbidity and mortality among adults in
industrialized societies, its prevention is of great importance.
An important practical distinction is made between preventive
measures in healthy people (called ‘primary prevention’)
and measures in people who have survived a stroke or a heart
attack, or who are symptomatic, e.g. from angina or claudication
(called ‘secondary prevention’). The absolute risk per unit
time is greatest in those with clinical evidence of established
disease, so secondary prevention is especially worthwhile
(and cost-effective, since the number needed to treat to prevent
a further event is lower than with primary prevention).
Primary prevention inevitably involves larger populations
who are at relatively low absolute risk per unit time, so interventions
must be inexpensive and have a low risk of adverse
effects.
A family history of myocardial infarction confers an
increased risk of ischaemic heart disease and genetic factors are
important in the development of atheroma. Epidemiological
observations, including the rapid change in incidence of coronary
disease in Japanese migrants from Japan (low risk) to
Hawaii (intermediate risk) to the west coast of the USA (high
risk), and the recent substantial decline in coronary risk in the
USA population, indicate that environmental factors are also of
paramount importance in the pathogenesis of atheroma.
PATHOPHYSIOLOGY
Atheromatous plaques are focal lesions of large- and mediumsized
arteries (Figure 27.1). They start as fatty streaks in the
intima and progress to proliferative fibro-fatty growths that
can protrude into the vascular lumen and limit blood flow.
Figure 27.1: A coronary artery dissected open longitudinally, with
a severe stenosis (arrowed) caused by an atheromatous plaque.
These plaques are rich in both extracellular and intracellular
cholesterol. During their development, they do not initially
give rise to symptoms, but as they progress they may cause
angina pectoris, intermittent claudication or other symptoms
depending on their anatomical location. They may rupture or
ulcerate, in which event the subintima acts as a focus for
thrombosis: platelet-fibrin thrombi propagate and can occlude
the artery, causing myocardial infarction or stroke.
Epidemiological observations (e.g. the Framingham study)
have shown that there is a strong positive relationship between
the concentration of circulating cholesterol, specifically of
the low-density lipoprotein (LDL) fraction, and the risk of
atheroma. This relationship is non-linear and depends strongly
on the presence or absence of other risk factors, including male
sex, arterial hypertension, cigarette smoking, diabetes mellitus,
and left ventricular hypertrophy (Figure 27.2).
Figure 27.3 summarizes metabolic pathways involved in
lipid transport. Approximately two-thirds of cholesterol circulating
in the blood is synthesized in the liver. Hepatocytes synthesize
cholesterol and bile acids from acetate, and secrete them