Epidemiology of Cholesterol and Cardiovascular Disease

Introduction

Humans appear predisposed to atherosclerosis. Evidence of atherosclerosis has been found in mummies from Egypt, Peru, Ancestral Puebloans and Alaskan hunter-gatherers. Cholesterol was implicated in the pathogenesis of atherosclerosis over 150 years ago. In 1920, the structure of cholesterol was elucidated and the relationship between blood cholesterol levels and premature atherosclerosis in Dutch families was found.

During both World Wars, with famine and severe shortages of fat, autopsy studies found low levels of serum cholesterol, reduced burdens of atherosclerosis and lower rates of coronary artery disease (CAD) mortality. Following World War II, numerous animal models of high-fat and high-cholesterol diets demonstrated atherosclerosis initiation and progression and regression of atherosclerosis with low-fat diets.

Circulating cholesterol-containing lipoproteins in plasma were demonstrated to be the source of cholesterol in plaque. Metabolic ward studies by Keys, Hegsted and others quantitated the response of blood cholesterol levels to changes in dietary fat and cholesterol intake. An association between blood cholesterol and the rate of coronary death was found across countries in the Seven Countries and other studies. The seminal Framingham study was launched in 1948 to prospectively study risk factors for atherosclerotic cardiovascular disease (ASCVD).

Autopsies of young soldiers killed in Korea found a high prevalence of coronary atherosclerosis in US soldiers, with virtually no atherosclerosis found in Koreans. Migration studies clearly established that lifestyle, and not genes, was the crucial determinant of serum cholesterol levels and the development of CAD. The Ni-Hon-San study showed that Japanese men in Nippon, Japan and in the US cities of Honolulu and San Francisco had progressively more Westernized diets, higher dietary cholesterol and saturated fat intake from animal fats and higher serum cholesterol levels accompanied by progressively higher risk of CAD.

Through the 1990s, more than 65 cohorts on four continents have reported a clear and consistent relationship between lifetime blood cholesterol levels, the number of other CV risk factors and the subsequent development of CAD and other ASCVD. Countries with habitual diets high in cholesterol and fat, such as northern European countries with high dairy intake, had high rates of CAD. CAD was uncommon in countries with a diet high in vegetables and low in fat and cholesterol, such as the Mediterranean countries and Japan (Figure 4-1). In high-risk populations, the relationship between cholesterol and CAD mortality is curvilinear (Figures 4-1 and 4-2). In lower-risk populations, the association appears more linear (Figure 4-1).

Earlier epidemiologic studies measured total cholesterol. Later studies have found the same robust relationship between low-density lipoprotein cholesterol (LDL-C) levels and ASCVD risk. LDL-C typically makes up 60% to 70% of total serum cholesterol. In most populations studied, an LDL-C ≥100 mg/dL (or total cholesterol ≥150 mg/dL or non–HDL-C ≥130 mg/dL) is atherogenic in both women and men. Newborns have LDL levels of approximately 30 mg/dL and LDL levels of 25-60 mg/dL appear sufficient for normal physiologic processes. Total cholesterol is associated with ASCVD risk at every age in men and women (Figure 4-3). While the relative risk of ASCVD associated with increasing total cholesterol levels is highest in middle age, the absolute risk is highest in older age groups due to the lifetime exposure to even modestly elevated blood cholesterol levels.

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