Epidemiology is generally limited to observation and analysis of events that occur spontaneously.

KEY TERMS

Atherosclerosis

Cancer

Cardiovascular disease

Cholesterol

Diabetes

Hypertension

Mutation

National Institutes of Health (NIH)

Sensitivity

The early successes of public health against infectious diseases led to a change in the major causes of illness and death beginning in the 1920s. Chronic degenerative diseases, especially heart disease and cancer, are now the leading causes of death in the United States. While they are primarily diseases of old age—when everyone must die of something—they also strike people in their prime, robbing them of productive years of life. Cancer is the leading cause of death among Americans aged 45 to 65, and cardiovascular disease runs a close second. Cardiovascular disease kills the most people overall. Other significant diseases of current public health concern include diabetes, arthritis, and Alzheimer’s disease, which may not be as deadly in the short run but have severe impacts on the quality of life. It is the mission of public health to prevent such premature death and disability.

Prevention of disease usually requires some understanding of the cause, a requirement that is generally much more difficult to fulfill for chronic diseases than for infectious ones. There is no single pathogen that causes cancer or heart disease, nor is there one for arthritis, diabetes, or Alzheimer’s disease. In most cases, chronic diseases have multiple causes, making it more difficult for scientists to recognize significant risk factors and establish preventive measures. Moreover, these diseases tend to develop over long periods of time, further complicating the task of pinning down causes. In some cases, however, the gradual onset provides the advantage of early detection, permitting secondary prevention—interventions early in the disease process that can mitigate its impact.

As chronic degenerative diseases became a growing problem during the 20th century, scientists began to focus on efforts to understand their causes. The growth of the National Institutes of Health (NIH), which sponsors most biomedical research in the United States, has reflected the growth of concern about these diseases. In its early days as a one-room Laboratory of Hygiene that opened in 1887, the NIH conducted research primarily on infectious diseases. Congress created the National Cancer Institute in 1937 and the Heart Institute—now called the National Heart, Lung, and Blood Institute (NHLBI)—in 1948. Currently there are 27 different institutes and centers, each of them focused on a different organ or problem, mostly chronic diseases. One institute, for example, is concerned with arthritis, one with diabetes, and one with neurological disorders and stroke.

Research into the causes of chronic disease, like research into the causes of infectious disease, relies on epidemiologic methods and laboratory research, which usually includes studies of animals as models, or stand-ins for human patients. The importance of research on animal models to the understanding of human disease cannot be overemphasized. Epidemiology is generally limited to observation and analysis of events that occur spontaneously. Ethical concerns severely limit the experiments that can be done on humans. In experiments on laboratory animals, scientists can carefully control the conditions so that cause-and-effect relationships can be clearly proven. Mice and rats are the most commonly used laboratory animals; as mammals, they share the majority of biochemical and physiological processes with humans. Because of their short life spans, the effects of various exposures and interventions can be studied over the lifetime of the animals. However, mammals can differ in unpredictable ways in their susceptibility to infectious or toxic agents. Different experimental animals have proven useful for studying different diseases, and extrapolation of results from any particular mammal to humans is not always valid.

The identification of an animal model can significantly improve progress toward understanding a disease. It is not always easy to find an experimental animal that is susceptible to the disease one wishes to study. For instance, there is no good animal model for AIDS, a fact that has hampered progress in developing drug therapies or vaccines. Asian macaque monkeys, which can be made sick by simian immunodeficiency virus, a relative of human immunodeficiency virus (HIV), are the closest substitute. Only chimpanzees can be infected with HIV, and chimps are no longer used for research for ethical reasons and cost.1 Animals also differ in how they metabolize some chemicals; a dose of dioxin that would kill a guinea pig has no effect on a mouse or rat, and it is difficult from this evidence to predict the chemical’s toxicity to humans.

Scientists have been increasingly successful in devising methods of growing cells and tissues in laboratory glassware for studying biomedical processes. Such laboratory cultures are commonly used to investigate the cancer-causing potential of various chemicals. Much of the research on HIV has been done using cultured human cells, and a great deal has been learned. However, such experiments provide oversimplified conditions that may lead to invalid conclusions about the complex interactions that occur in intact animals. In the case of HIV, for example, a number of drugs that appeared to inactivate the virus in test tube experiments have proved to be ineffective in human patients.

Cardiovascular Disease

Cardiovascular disease encompasses two of the three leading causes of death in the United States: heart disease and stroke. Risk for dying from cardiovascular disease increases with age, is higher in men than in women, and is higher in blacks than in whites.

The causes of cardiovascular disease have been relatively well established through epidemiologic studies, including the Framingham Study, which identified high blood cholesterol, high blood pressure, and smoking as major risk factors. Animal experiments and examination of the bodies of people who have died of the disease have also contributed to an understanding of how it develops. Knowledge about cardiovascular disease has been facilitated by its prevalence in the United States and the fact that it follows a similar progression in many of its victims. The important role of blood components in determining individual risk was readily established because blood is easy to study; it can be drawn from patients and experimental subjects without major discomfort or ethical objections.

It has been known for decades that atherosclerosis—hardening of the arteries—is part of the development of cardiovascular disease. Pathologists performing autopsies on people who died of heart attacks found, within the inner-wall lining of the deceased’s arteries, a buildup of plaque composed of fat and cholesterol, blood cells, and clotting materials. The formation of plaque begins at an early age in the United States. Fatty streaks, the first stage in the development of plaque, have been found on autopsy in half the children aged 10 to 14 who died of accidental causes.2 A classic study, published in 1955, examined the arteries of American soldiers killed in the Korean War and found that 77 percent of the men, whose average age was 22, showed some signs of atherosclerosis.3 More recent studies have confirmed these findings and have shown that plaque was more likely to be found in adolescents and young adults with risk factors such as smoking, hypertension, obesity, and high levels of low-density lipoprotein cholesterol.4

Animal studies showed that diet plays a role in the formation of plaque. Rabbits fed milk, meat, and eggs instead of their normal vegetarian diet were found to develop atherosclerotic plaque very similar to that found in humans.5 It was easy to deduce that the American diet was responsible for the high rate of cardiovascular disease in the United States.

Experiments on rats, rabbits, and monkeys have clarified the process by which high cholesterol and fat in the blood interact with other risk factors such as smoking, high blood pressure, and diabetes to form plaque in the arteries. These factors cause chronic injury of the artery’s inner wall, which the body attempts to repair, leading to a “healing” process that runs wild, becoming a disease in itself. The higher the levels of cholesterol and other fats in the blood, the more they are incorporated into the scab-like buildup, and the faster the plaque forms. A heart attack or stroke results when the plaque ruptures, releasing clots that may block an artery in the heart or brain, cutting off the blood supply.6

Recent evidence suggests that atherosclerosis may also have an infectious component caused by bacteria that are often found in plaque.7 The blood cells in plaque are characteristic of an immune response, and a number of chemicals in the blood suggest that atherosclerosis is an inflammatory condition like arthritis. These findings may lead to new approaches to prevention, diagnosis, and treatment of atherosclerosis.

With the major risk factors for cardiovascular disease well established, much of the recent epidemiologic and biomedical research has focused on trying to understand what determines the relative presence or absence of these risk factors. A great deal has been learned about the various lipids (fats) in the blood, each of which plays a role in the individual’s risk of cardiovascular disease, and how their concentrations may be increased or decreased. Factors that affect blood pressure have also been extensively studied. Diabetes, which has its own research institute at NIH, greatly increases the risk of cardiovascular disease (see later in the chapter for a discussion of the biomedical basis of diabetes). All of these risk factors are determined in part by genetics, but they can be significantly modified by individual behavior and are thus susceptible to public health intervention.

High blood cholesterol is a well-known risk factor for atherosclerosis and heart disease. Cholesterol levels of 200 mg/dL (milligrams per deciliter of blood) or below are considered desirable: Persons with that level of cholesterol have less than one-half the heart attack risk of those with levels above 240 mg/dL.8 Most of the cholesterol in the blood is bound up with protein in various forms, and some forms are more harmful than others. For example, if a high percentage of a person’s cholesterol is in the form of high-density lipoprotein (HDL), sometimes called “good cholesterol,” the person’s risk of heart disease is much lower than that of someone with a high percentage of cholesterol in the form of low-density lipoprotein (LDL), “bad cholesterol.” Many current studies try to identify factors that affect not only total cholesterol, but also the relative concentrations of HDL and LDL.

Although previous expert advice was that people limit their consumption of eggs and other cholesterol-containing foods, recent evidence suggests that cholesterol-containing foods are not the source of cholesterol in the blood. The greater concern is saturated fat and trans fat, as well as a deficiency of fruit and vegetables.9 In humans, as in rabbits, vegetarians have lower cholesterol levels than meat eaters. Vigorous exercise lowers total cholesterol and increases HDL. Moderate consumption of alcoholic beverages has a similar effect, although heavy drinking damages the heart. Other dietary substances such as fish, olive oil, and oat bran also appear to have favorable effects on blood lipids. Smoking lowers HDL levels. Genes play an important role in the HDL–LDL balance. Some people can eat lots of fat with very little effect on their blood cholesterol, while others must work much harder to maintain favorable levels.

In the past decades, the use of cholesterol-lowering drugs called statins has increased dramatically. The number of Americans who took the drugs grew from about 11 million in 1999 to almost 41 million in 2011.10,11 Epidemiologic studies have clearly shown that statins can prevent heart attacks, even in people with cholesterol levels previously considered normal and, for the most part, they appear to be safe for long-term use. However, from a public health perspective, the trend toward prescribing drugs for healthy people to take for the rest of their lives is troubling. Moreover, some statins can be expensive. As a spokesman for the American Heart Association is quoted as saying, “If you’re going to increase my health insurance because my next door neighbor has borderline high cholesterol, and if he’s sitting around and watching TV and eating and getting fat, do you want me to pay for that?”11

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