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THE LIVING HEART IN THE 21ST CENTURY

Prometheus Books

Chapter One

The New Biology

One of the most frequent causes of heart disease is atherosclerosis. Atherosclerosis is a lifelong process that leads to the thickening and hardening of artery walls. It is the underlying cause of nearly three-fourths of all cardiovascular deaths. Atherosclerotic plaques, also called lesions, can develop in the coronary arteries that surround the heart muscle and provide it with blood (see figure 1.1). These plaques reduce the flow of blood and oxygen to the heart, which can cause the chest pain or discomfort of angina. In more severe cases of coronary heart disease, the plaques entirely block the flow of blood to the heart, or they rupture, producing large blood clots that can then cut off the heart's blood supply. In both instances, the result is a heart attack, or what doctors call a myocardial infarction.

Heart attacks are a very common form of heart disease. According to the American Heart Association, one heart attack occurs approximately every twenty-five seconds in the United States. Every minute, a person dies from one. In one year, approximately 785,000 Americans will have a first attack, while about 470,000 will have a repeat attack. Many of these events can be prevented by implementing healthy lifestyle changes and by controlling risk factors for atherosclerotic vascular disease.

A heart attack is just one of the events that can occur due to atherosclerosis. Atherosclerosis can also develop in any of the major arteries and in the aorta, the large vessel that carries blood away from the heart (see figures 1.2a, 1.2b, and 1.2c). Plaques gradually constrict these arteries, and they can rupture, leading to subsequent clot formation. Clots that become lodged in the carotid arteries in the neck or the cerebral arteries in the brain can block blood flow to the brain, causing a stroke or transient ischemic attack (TIA). In addition, plaques can reduce the flow of blood and oxygen to surrounding tissues, which may eventually die. Atherosclerosis that develops in the femoral arteries of the leg or in the brachial arteries of the arms, called peripheral artery disease (PAD), can cause pain, decreased function, and in severe cases, gangrene leading to amputation. Atherosclerosis of the renal arteries in the kidney can cause high blood pressure and eventual kidney failure. Finally, the consequences of atherosclerosis can lead to arrhythmias (disorders of heart rate or rhythm), heart failure, and other conditions affecting the heart.

Understanding how coronary heart disease (CHD) and atherosclerosis develop is the first step in prevention. Many people in the twenty-first-century United States have high-fat, sedentary lifestyles that greatly increase the risk of developing atherosclerosis. However, atherosclerosis is not just a modern disease. Evidence of atherosclerosis has been found in Egyptian mummies dating from the third millennium BCE and in Peruvian remains from the first millennium BCE. The difference is that now, in the twenty-first century, we understand how and why atherosclerosis develops, as well as key strategies for prevention. This chapter highlights the major concepts about atherosclerosis that have emerged after more than a century of scientific research and due to recent advances in molecular biology. The story begins with cholesterol.

WHY CHOLESTEROL?

In 1904, a German pathologist named Felix Marchand first proposed the term "atherosclerosis" to describe a process that nineteenth-century physicians were aware of but did not yet understand. Marchand chose this name because of the appearance of the arteries he examined: "athero" is the Greek root for "gruel" or "porridge," while "sclerosis" is the root for "hardening." His choice emphasized the resemblance between the fatty atherosclerotic plaques found within hardened arteries and porridge. At the time, physicians did not know what material these soft, pulpy deposits consisted of, or what effect they might have on the body.

In 1913, scientists got their first real clue when a Russian scientist named Nikolai Anichkov fed rabbits cholesterol purified from egg yolks and was able to produce the same gruel-like deposits found in human arteries. Anichkov also determined that the amount of cholesterol fed to the rabbits was related to the size and number of plaques that developed. Scientists did not fully recognize the significance of his findings until decades later. Now, however, it is clear that cholesterol is a major component of atherosclerotic lesions and that high levels of cholesterol in the blood, or plasma, can cause atherosclerosis and its many complications.

In the middle of the twentieth century, researchers studying large populations discovered a relationship between saturated fat consumption, total cholesterol levels, and heart disease. In the 1950s, the Seven Countries Study found that high consumption of saturated fat in countries such as the United States and Finland led to increased blood cholesterol levels and to much higher rates of heart disease, as compared to countries with low saturated fat consumption, such as Japan, Greece, and Italy. In the 1960s, the Ni-Hon-San study examined men of Japanese descent who were living in Japan, Honolulu, and San Francisco. It showed that cholesterol levels and heart disease all increased as diets became more Westernized and consumption of saturated fat increased. Japanese men living in San Francisco were found to have more heart attacks than those living in Honolulu and more than those living in Japan. Both the Seven Countries Study and the Ni-Hon-San study show that different populations can vary greatly in terms of their cholesterol levels and that these differences are mostly due to diet and lifestyle, not genetics. Other population studies, including the Framingham Heart Study, which began in 1948 in Massachusetts, have further verified the relationship between elevated blood cholesterol and coronary heart disease. In general, these trials have established that each 1 percent increase in total blood cholesterol leads to an approximate 2 percent increase in risk for coronary heart disease events.

WHAT IS CHOLESTEROL?

Cholesterol belongs to a group of naturally occurring molecules called lipids. The term "lipid" is often used to refer to fats, but lipids are actually a class of molecules, including fats, oils, waxes, and sterols, that can be dissolved in other fats, oils, and lipids but not in water (they are "lipophilic"). A major function of lipids is energy storage, which is how we commonly think of fats and oils. Other functions of lipids include maintaining the structure of cell membranes and regulating a wide variety of cellular activities, especially those that involve molecular signaling.

Cholesterol is a simple lipid. (Because of its chemical structure, it is also classified as an alcohol and as a form of steroid called a sterol.) Fatty acids, which are derived from animal and vegetable fats and oils, are another type of simple lipid. Omega fatty acids, for example, are most commonly found in fish. Trans fatty acids are a kind of processed plant oil sometimes used in commercial food preparation. Complex lipids include triglycerides, cholesteryl esters, and phospholipids. Triglycerides store energy in the body and are the primary components of vegetable oils and animal fats. Most fat in the human body and in food is in the form of triglycerides. Cholesteryl ester is a molecule of cholesterol that has undergone a chemical process called esterification that makes it easier to transport in the blood. Most of the cholesterol in the bloodstream exists in the form of cholesteryl esters. Phospholipids are an important component of cell membranes and of lipoproteins, which are specialized macromolecules (very large molecules) that transport cholesterol in the blood.

Too much cholesterol in the blood can lead to atherosclerosis, plaque formation, and heart disease, but cholesterol is essential to all animal life and is naturally synthesized by all animals. It plays a number of roles in the human body (see table 1.1). Most importantly, cholesterol is a major component of cell membranes and helps to maintain membrane fluidity. It is needed to form bile acids, which aid in the digestion and absorption of fat in the intestines. In addition, it is the main precursor for vitamin D and for the steroid hormones, including progesterone, estrogen, and testosterone. Cholesterol also plays roles in the conduction of nerve impulses and in cell signaling processes. Without cholesterol, the body would not be able to function on many different levels. Not surprisingly, a highly complex system has evolved to regulate the amount of cholesterol that is present at any given time in the bloodstream and available for transport to different parts of the body.

Cholesterol is carried in the blood mostly in the form of cholesteryl ester by lipoproteins, which are composed of both lipids and proteins. Lipoproteins contain some free cholesterol, but their major lipid components are cholesteryl esters, triglycerides, and phospholipids in varying concentrations. Lipoproteins are classified according to density in five major categories: high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and chylomicrons (see figure 1.3). When doctors measure your cholesterol levels, they are determining the relative quantities of various lipoproteins and their components present in the blood at that moment. You may already be aware of HDL cholesterol (HDL- C), the "good" cholesterol, and LDL cholesterol (LDL-C), the "bad" cholesterol. (The "C" refers to the amount of cholesterol carried by HDL and LDL lipoproteins.) In order to understand what makes these types of cholesterol "good" or "bad," we need to go into a little more biological detail.

BASICS OF LIPID METABOLISM

The body synthesizes its own cholesterol, and in addition, cholesterol is acquired through the diet. When you consume a meal, the small intestines absorb only some of the cholesterol contained in the food, and the rest is excreted as waste. There is a wide variation among individuals in how much cholesterol tends to be absorbed by the intestines. These variations are probably determined in large part by genetics. Depending on how much cholesterol is absorbed from dietary sources, the body increases or decreases the amount of cholesterol it synthesizes so that cholesterol levels in the blood remain relatively constant.

Following a meal, the cholesterol that is absorbed into intestinal cells is packaged, along with triglycerides, as chylomicrons, which are extremely large lipoproteins not associated with atherosclerosis or heart disease. (Patients are asked to fast before having their cholesterol tested because the triglycerides present in chylomicrons following a meal can affect the accuracy of the measurements.) Chylomicrons are then transported through the lymphatic circulation (a subset of the circulatory system that helps maintain fluid balance) from the intestines and introduced into the bloodstream via the thoracic duct (a part of the lymphatic system located in the chest). The blood then circulates chylomicrons to tissues in various parts of the body where they are broken down to smaller particles known as chylomicron remnants. As they are broken down, chylomicrons release free fatty acids, which are either used by muscles immediately for energy or are converted to triglycerides to be stored as fat. The chylomicron remnants return to the liver with their remaining loads of cholesterol, most of which is then excreted by the intestines as waste. Unlike chylomicrons themselves, chylomicron remnants can contribute to the formation of atherosclerotic plaques, and a delay in digesting and removing them from the body is associated with an increased risk of coronary heart disease.

Along with the intestines, the liver is a key organ that maintains a balance of cholesterol within the blood. In addition to clearing the dietary cholesterol that is delivered by chylomicron remnants, the liver synthesizes the cholesterol needed to maintain the body's normal functioning. It can also take the cholesterol it produces out of the circulation. The entire process is one of continual synthesis, removal, and excretion.

The first step in the body's synthesis of cholesterol is the production of very low-density lipoprotein (VLDL) by the liver. VLDL has a high content of triglycerides, and it circulates in the blood in order to transport energy to various tissues throughout the body. VLDL can also be converted to intermediate- density lipoprotein (IDL), which is then converted to LDL. As VLDL is converted to IDL and then to LDL, it becomes increasingly enriched in cholesterol (in the form of cholesteryl esters) and depleted of triglycerides, resulting in progressively smaller and denser lipoprotein particles. LDL is the primary carrier of cholesterol in the blood, and LDL-C has deservedly gained a reputation as the "bad" cholesterol. VLDL, IDL, and LDL all promote atherosclerosis because they contain a protein called apolipoprotein B (apo B). Chylomicrons contain a different form of apo B, about one-half the size of that found in the other lipoproteins. LDL is the most important and the most commonly measured of the lipoproteins containing apo B. Scientists believe that primarily LDL and modified forms of LDL penetrate the walls of arteries, which is a key step in the formation of atherosclerotic plaques. If levels of LDL-C in the blood become too high, atherosclerosis starts to develop.

HOW DOES ATHEROSCLEROSIS DEVELOP?

When arteries are healthy, they have strong, flexible walls and a smooth inner lining. Atherosclerosis is a disease of the intima, or the innermost layer, of the arterial wall. Arteries have three layers: a thick, flexible outer wall called the adventitia; a middle, elastic layer called the media, which contains smooth muscle cells and is capable of constriction and relaxation; and the intima (see figure 1.4). The intima consists of a thin layer of endothelial cells, called the endothelium, that are directly exposed to blood flow through the lumen, or the inner space of the artery. A thin, internal elastic membrane separates the intima and the media. The vasa vasorum are a network of small blood vessels that supply large vessels.

In the past, it was believed that atherosclerotic plaques developed progressively, with excess cholesterol in the blood gradually accumulating and leading to bigger and bigger plaques. Contemporary research now indicates that atherosclerosis may be considered a type of inflammatory disease involving many different steps. The disease develops depending on the balance between LDL cholesterol, which is deposited into atherosclerotic plaques, and HDL, the "good" cholesterol responsible for transporting lipid back out of the plaque.

Scientists have long debated what the initiating step in the atherosclerotic process might be. What occurs in the arterial wall that causes cholesterol to accumulate and plaques to form in the first place? Generally, lipoproteins such as LDL flow in and out of the arterial wall, but in atherosclerosis, something occurs that makes their behavior different from normal. For the past few decades, scientists have believed that atherosclerosis begins as a "response to injury." According to this theory, LDL particles penetrate the endothelium, causing damage to the surface of the arterial wall. This initial injury triggers a dysfunctional and inflammatory response within the vessel wall, which then starts the atherosclerotic process. The effects of cigarette smoking, high blood pressure, and diabetes can also damage the endothelium and accelerate the atherosclerotic process.

This view has since been modified to further explain why some lipoproteins cause damage to the arterial wall, while others do not. In 1995, researchers proposed a "response to retention" theory. They hypothesized that the first step in the atherosclerotic process occurs when LDL particles penetrate the endothelium and then become trapped in the arterial wall. Apo B particles in LDL are believed to bind to molecules called proteoglycans, which normally provide structural support within the arterial wall. LDL is then "retained" within the intima, where it can subsequently injure the endothelium and cause dysfunction. Although VLDL and IDL also contain apo B, LDL particles are smaller and may be more likely to penetrate the endothelium and bind to proteoglycans than larger lipoproteins.

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Excerpted from THE LIVING HEART IN THE 21ST CENTURY by MICHAEL E. DEBAKEY ANTONIO M. GOTTO JR. Copyright © 2012 by Michael E. DeBakey, MD, and Antonio M. Gotto Jr. . Excerpted by permission of Prometheus Books. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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