Introduction

 It is well known what the unhealthy elements of this lifestyle are: too much food (especially fats and saturated fats) and too little exercise. The result is that the mass of the food consumed overwhelms the body's normal metabolic needs and begins to accumulate throughout the cardiovascular system. Specifically, the system succumbs to a disease process known as atherosclerosis (from the Greek word "athero" for "gruel" and "sclero" for "hard"-- literally, a hardening of the normally soluble "gruel" that flows through the vascular system, delivering nutrients to the body).
 

Defining the Disease State

All of the food mammals ingest is chemically broken down and reorganized as it passes through the gastrointestinal system and into the cardiovascular circulation. This serves 2 purposes: some of the nutrient chemicals are reconfigured to serve as a source of energy for the body's activity, and some are reconfigured to provide building blocks for the body's structure. In this review, we want to concentrate on the second process and what happens when it malfunctions.

 A principal element in the circulation that causes this normally healthy process to malfunction to the point that it becomes a disease state is an excess of plasma cholesterol. Cholesterol is a vital biological molecule that, in excess, accumulates in deposits of atherosclerotic plaque on the walls of the circulatory tree. This, in turn, leads to the blockages and interruptions of the circulation that result in angina, heart attacks, and, ultimately, death.

 Even though this disease process affects so many people, it is not inevitable. With varying degrees of success, it can be both prevented and treated. The best interventions, both as prevention and as therapy, are proper diet and adequate exercise. However, since these principles are not always followed, nor are they necessarily adequate, it is reassuring that several pharmacologic agents have proven effective in combatting the progression of CVD -- including niacin, the fibrates, the bile acid sequestrants, and the "statins" (technical name, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). All of these drugs have been demonstrated to be effective across a range of patients and disease severities, but the most successful and most widely prescribed is the class of drugs known as "statins."

 If we examine the problem of atherosclerosis and its development more closely, we are immediately faced with 2 issues:

• What is cholesterol? Where does it come from? How does it get from our dinner plates into our arteries?
• How and why do statins work

 

A Brief Definition of Terms

 In fact, it was really only in the last 20 years -- especially following the statistically significant mortality results of large clinical trials with the statins in the 1990s -- that assessment of plasma cholesterol levels has become an important measurement in the doctor's office.

 Originally, the name for the problem of elevated cholesterol levels was hypercholesterolemia (or, "too much cholesterol"), and the more general term, to include the other lipid subfractions (ie, triglycerides) in addition to cholesterol, was hyperlipidemia. However, the term dyslipoproteinemia is now considered the most accurate, because it reflects states with multiple lipid abnormalities, such as those characterized by reduced high-density lipoprotein (HDL) but average total plasma cholesterol.

Triglycerides: From Ingestion to Packaging
 

The principal components of the foods we ingest are protein, fat and fatty acids, carbohydrates, and fiber. All of these elements are digested in the stomach and then pass into the intestines, where the nutrient components are absorbed and the remainder is excreted. In this review, we want to concentrate on what happens to the fat and fatty acids. Most dietary fat consists of triglycerides (composed of a glycerol -- a 3-carbon alcohol -- plus 3 long-chain fatty acids of varying length). For an average-sized and normally active individual, a healthy diet should contain about 2000 cal/day, of which 30% may be fat; this represents a daily intake of approximately 66 g of triglycerides and approximately 250 mg of cholesterol. However, the body must take into account the fact that food is not always available and dietary fat content is not always constant. Moreover, the triglycerides the body needs do not come directly from dietary sources, but rather the food consumed must be processed to provide them. Therefore the mammalian gastrointestinal system has evolved mechanisms to ensure a readily available and reliable supply of triglyceride molecules to meet its metabolic demands. After fatty acids are ingested, they pass through the intestines, where they are absorbed into the intestinal cells. Through a series of enzymatic reactions involving apolipoprotein B-48, the fatty acids are turned into a stable emulsion of lymph and triglyceride fat and are packaged into lipoprotein micelles (ie, droplets or globules of fat plus protein) called chylomicrons. These consist of 86% triglyceride fat, 9% phospholipids, 3% cholesterol, and 2% protein. The chylomicrons are then rapidly secreted from the intestinal wall and enter the blood stream, where they are suspended in the plasma.

Panel 1. Triglycerides: From Ingestion to Packaging

When the chylomicrons reach the peripheral circulation, they enter the capillaries of adipose tissue and muscle cells, where they encounter a chemical enzyme called lipoprotein lipase (LPL). This enzyme, in turn, hydrolyzes the triglyceride fat in the chylomicrons and produces a chylomicron remnant, which continues through the circulation until it is taken up into the liver cells.

This process, whereby the ingested fats -- especially the triglycerides -- are "packaged" as lipoproteins for circulation through the cardiovascular system, is entirely healthy and vital for the metabolic processes of the body. A problem occurs when some of the lipoprotein subfractions become elevated, resulting in dyslipoproteinemia.

Classification of Lipoproteins

There are 3 major types of lipids that circulate in the plasma: cholesterol and cholesterol esters, phospholipids, and triglycerides. Because lipids are not soluble in water, the principal constituent of blood, they must be packaged in some way in order to be suspended in the plasma. During the initial pass through the gastrointestinal system, they are packaged as chylomicrons, secreted into the circulation, transformed into chylomicron remnants, and then finally delivered to the liver. There they are repackaged as a series of smaller, denser lipoprotein "particles" and are resecreted back into the circulation. Although there is an entire spectrum of these lipoprotein particles, they share most of the same components, the principal difference being their size and density. The figure depicts the major divisions in this spectrum and their principal components: cholesterol (red stars), apolipoprotein B (keys), apolipoprotein A (y shapes), and membrane proteins (blue dots). Each of these lipoprotein particles serves an important step in the body's metabolic process. As they pass through the intestines and

Panel 2.  Classification of Lipoproteins

into the circulation with their contents of fatty acids, they act as little "food trucks," delivering the nutrients in their core to the adipose and muscle tissues. However, some of these particles, when they occur in the wrong amount in the wrong place, can begin to cause problems -- problems so severe that they ultimately lead to CVD, the primary cause of death in the industrialized world.

The difficulty for the physician and for the patient is that most dyslipoproteinemias have few, if any, symptoms and only rarely cause clinical signs evident on physical exam. It is thus important to have a working knowledge of the elements of lipid metabolism in order to ensure proper recognition and management of dyslipoproteinemia.

In the panels that follow, we will discuss how each of these lipoproteins is created and what role it plays. Note that these particle subtypes can be further subdivided. For example, the low-density lipoprotein (LDL) particles can be further subdivided into a range of sizes, from "light, fluffy" LDL particles down to "small, dense" LDL particles, with the smaller particles being more atherogenic (ie, causing atherosclerosis). However, measuring these subfractions of the LDL particles requires sophisticated analytical systems that are generally too expensive and complicated to be used in ordinary medical practice. Therefore, tests that distinguish only the general class of "LDL" particles are considered adequate for the purpose of diagnosis.

In addition, analysis of recent clinical trial data (eg, from the Scandinavian Simvastatin Survival Study, 4S) has shown that assessment of an aggregate of the lipoprotein subfractions other than HDL (ie, very low-density lipoprotein [VLDL] + intermediate-density lipoprotein [IDL] + LDL) is at least as effective, and perhaps more linear, than assessment of LDL alone as a predictor of future CVD events. Thus, in the new US National Cholesterol Education Program (NCEP) guidelines, the "non-HDL" subfraction of cholesterol has become the new target of measurement and treatment. To calculate this parameter, the clinician measures total cholesterol (TC) and then determines the non-HDL level according to the formula:

Structure of a Lipoprotein

As discussed above, the lipoprotein molecules that we ingest are repackaged into particles so that they can be incorporated into a food delivery and fat removal system. As shown in the figure, all of these particles are assembled as lipid "globules," or particles, with a monolayer phospholipid membrane. The important points to remember are that: All cells require cholesterol to maintain the structure of their membranes;   All cellular membranes contain phospholipids, which are necessary for cell-to-cell communication throughout the body; and All cellular membranes contain glycerol, a component of triglycerides.

Panel 3.  Structure of a Lipoprotein

The enlargement of the cell membrane on the right side of the figure shows the components of the monolayer phospholipid membrane:

• Millions of 2-tailed phospholipid molecules, with their "heads" arranged so that they form the outer surface of the membrane of the chylomicron;

 
• A few cholesterol molecules interspersed among the phospholipid molecules that form the particle's membrane;

 
• Membrane-spanning protein "pores"; and

 
• Membrane-spanning apolipoproteins

 
• several apolipoprotein B molecules (Apo B) in the LDL or VLDL particles
• 1 apolipoprotein A molecule (Apo A) in each HDL particle

 All lipoprotein particles are constructed in this manner; the particles differ in their size and density or, in the case of the HDL vs non-HDL, in the apolipoprotein molecule embedded in the surface membrane (Apo A vs Apo B).

 Metabolism of Fatty Acids
 

The human lipid transport system ferries hydrophobic lipid molecules from sites of synthesis to sites of utilization. For example, it transports triglycerides through the digestive system and the liver to peripheral sites of utilization or storage (eg, muscle or adipose tissue), and it transports cholesterol to the liver for bile acid synthesis and for excretion from the body. Not surprisingly, the proteins (or apolipoproteins) that mediate this process are remarkably well conserved through evolution, and the same basic process is observed in most mammals.  As outlined briefly in Panel 1, once the fatty acids are packaged into the chylomicrons and pass out of the intestines and into the circulation, they encounter the enzyme LPL. This enzyme hydrolyzes ("dissolves") some of the fat in the core of the chylomicron, and the depleted globule becomes a chylomicron remnant, which ultimately passes into the liver. The remnant is then taken up into the liver cells and undergoes a series of reactions that repackage the constituent lipids into other lipoprotein particles (as shown in Panel 2) and deliver them back into the circulation.

Panel 4.  Metabolism of Fatty Acids

This process involves 2 important steps: (1) removal of the chylomicron remnants from the circulation, and (2) repackaging of the large chylomicron fragments into smaller, ever more atherogenic particles.

Thus, one of the first points at which the lipid transport system can malfunction is when removal of the chylomicron remnants from the circulation is overwhelmed. In the normocholesterolemic person, triglyceride levels following a meal (ie, postprandial levels) return to baseline within 8-10 hours. In patients with atherosclerosis, by contrast, the postprandial triglyceride levels are higher and take longer to return to baseline, due to a delayed removal of the chylomicron remnant particles. This illustrates why it is important for a patient with atherosclerosis to maintain a diet low in total and saturated fats, in order to decrease the excess of chylomicron remnants that must be removed from the circulation.

Once the chylomicron remnant is taken up by receptors in the liver, its components are repackaged into a VLDL particle, a process that requires apolipoprotein B100. The VLDL particle is then secreted from the liver back into the circulation. The same LPL that changed chylomicrons into chylomicron remnants now hydrolyzes the triglyceride fats in the core of the VLDL to produce IDL cholesterol.

Recall that the triglyceride molecule consists of glycerol plus 3 fatty acid "tails." To hydrolyze the triglycerides in the core of the VLDL particles, LPL cleaves the fatty acyl residues attached to the glycerol, generating 3 molecules of free fatty acid for each molecule of glycerol. The fatty acids are rapidly taken up by muscle cells for energy utilization (a process requiring insulin) or by adipose cells for storage, and the depleted particle is left as the smaller and denser IDL.

Next, via the interaction of apo E and the LDL receptor in the liver, some of the IDL particles are reabsorbed in the liver, while others are further hydrolyzed by hepatic lipase to produce the still more-compact LDL cholesterol. These LDL particles are then secreted into the circulation to transport their fatty energy molecules throughout the body.

 LDL particles contain mostly cholesterol and apo B100, and normally contain only 4% to 8% of their mass as triglycerides. However, under certain circumstances, especially when triglyceride levels are elevated, LDL particles can be enriched in core cholesterol esters and depleted in triglycerides, making them even smaller and more dense, and hence more atherogenic (as will be discussed below).
 

 Build-up of Plaque in the Arterial Walls
 

After all of the steps outlined above, the vital cholesterol molecules are now packaged as relatively small, dense LDL particles, ready to be circulated throughout the body's vascular system. Again, this is a normal and healthy process. However, at some crucial concentration of LDL particles and viscosity of blood flow, some of the LDL particles begin to "stick" at certain vulnerable points in the arterial wall. At this point, a whole cascade of events follows, with the formerly healthy, smoothly functioning artery now becoming clogged and only sluggishly responsive.  One of the first ultrastructural alterations to occur in the atherosclerotic artery is an accumulation of small LDL lipoprotein particles in the intima (or walls) of the blood vessels. The principal reason for this change is that there is simply too much LDL cholesterol in the circulation -- thus providing another argument for patients, particularly those with atherosclerosis, to consume less fat and saturated fat. When the LDL particles begin to adhere to the vessel wall, they bind via their apolipoprotein "receptors" to the proteoglycans (large

Panel 5.  Build-up of Plaque in Arterial Walls

proteins combined with sugars) in the intima. When examined under high magnification, these lipoprotein particles appear to coalesce into aggregates that "decorate" the walls of the arterial intima. At this point, the problem is compounded, because once the LDL particles bind to the proteoglycans, they begin to exhibit increased susceptibility to oxidative or other chemical modifications, and oxidized LDL particles are particularly chemoattractive to the area of a lesion in the artery wall. Finally, the permeability of the endothelial monolayer increases at sites where these particles have accumulated, causing a predilection for even more accumulation of LDL.

 Thus, once the LDL particles, especially oxidized LDL particles, begin to bind to points in the vessel wall, they lose their ability to flow freely, create a "lesion" on the vessel wall, the problem begins to grow.
 

 Enter the Macrophages
 

As we saw in Panel 5, the first step toward an atherosclerotic artery has occurred: LDL particles, especially the smallest and the oxidized LDL particles, have begun binding to the wall of the artery, creating a "lesion" in the normally smooth arterial wall.  The second morphologically definable event in the initiation of atherosclerosis is the recruitment and accumulation of leukocytes, especially macrophages ("macro" = large; "phage" = to eat), at the site of the lesion.  Normal endothelial cells generally resist adhesive interactions with leukocytes; however, soon after an atherosclerotic lesion forms in the wall of the vessel, leukocytes begin to adhere to the vessel wall and accumulate lipids, becoming lipid-laden macrophages known as "foam cells." In the healthy state, when the system is not overloaded with cholesterol, an elegant control mechanism quenches expression of the LDL receptor as soon as a cell collects enough LDL cholesterol for its metabolic needs. In the pathologic state, however, the LDL receptor is supplanted by molecules known as "scavenger" receptors.

Panel 6.  HDL and the  Reverse Cholesterol Transport System

In contrast to its actions at the LDL receptor, cellular cholesterol sufficiency does not suppress the activity of scavenger receptors. These scavenger receptors preferentially bind to modified (especially oxidized) lipoproteins and mediate increased uptake of oxidized LDL into the macrophages, causing them to rapidly become lipid-laden foam cells under conditions of cholesterol excess.

The result is the precursor lesion, known as the "fatty streak," which consists mainly of accumulations of lipid-engorged leukocytes (principally macrophages) and which appears on the interior wall of the blood vessel almost like a "pimple." As these lesions, or fatty streaks, evolve into atherosclerotic plaque, it is the extracellular matrix that makes up much of the volume, although plaques often also develop areas of calcification as they evolve. Indeed, the presence of calcifications is one of the ways that plaque can be visualized with current imaging techniques.
 

 The Atherosclerotic Vessel
 

Once plaque is established, this section of this vessel has become atherosclerotic. For a long time, it was thought that CVD occurred when one of these plaques formed and grew until it obstructed flow through the blood vessels, interrupting flow of blood to the heart (or the brain) and resulting in ischemia (ie, "no flow"), which the patient experienced as angina, then a heart attack (or stroke), and ultimately, if not treated in time, ischemic death. This picture is wrong for 3 reasons:  First, advanced imaging techniques have shown that the vessel "remodels" and the wall of the vessel bulges outward, so that the lumen size remains relatively unchanged (often making the presence of plaque difficult to visualize on simple angiography). Only after the plaque burden exceeds the capacity of the artery to remodel outward does encroachment on the arterial lumen begin.  As these plaques encroach on the luminal space, they are called "stenoses." Eventually, the stenoses may grow to a size at which they impede blood flow through the artery; lesions that produce stenoses > 60% of the lumen size can cause flow limitations under conditions of increased demand.

Panel 7.  The Atherosclerotic Vessel

 Second, however, the problem is not that the plaque grows until it completely obstructs the vessel. Rather, the problem is that the plaque becomes unstable, bursts, and empties a cocktail of thrombogenic substances that grow into the blockage that leads to ischemia.

 Finally, atherosclerosis is not a discrete area of plaque at a single area of the arterial tree, but a diffuse disease process that creates the "fatty streaks," or atherosclerotic lesions, over wide areas throughout the vasculature.

 The initiation and evolution of the atherosclerotic plaque generally takes place over many years, during which the affected person often has no symptoms. This is why, once the patient becomes symptomatic (generally experiencing angina), the disease is already established, and strong and effective therapeutic measures are required.

 The Maturation of HDL
 

As we saw in Panel 2, evolution of the non-HDL family of lipoprotein particles that culminates in oxidized LDL and atherosclerotic plaque does not account for all of the elements in the metabolism of cholesterol.  All of the non-HDL particles discussed thus far (ie, VLDL, IDL, and LDL) share the same components, including the apolipoprotein that mediates their principal binding activity, Apo B. However, the same basic chemical components can also be assembled into a very dense arrangement with a different membrane-spanning apolipoprotein molecule, Apo A. These smallest particles, known as HDL cholesterol, are created by a process that is conceptually the reverse of the VLDL -> IDL -> LDL sequence.  Like the non-HDL particles, nascent HDL particles are assembled in the liver and intestine and are then secreted into the circulation as particles consisting almost entirely of phospholipids and Apo A1. Because these nascent HDL particles contain little or no cholesterol (ie, they have no central lipophilic core), they appear flat, or discoid. The nascent HDL particle is thus primed to remove cholesterol that it encounters in peripheral cells as it travels through the circulation.

Panel 8.  The Maturation of HDL

 As these nascent HDL particles move through the circulation, Apo A1 in the HDL membrane binds with phospholipids from non-HDL particle membranes and with phospholipids that are shed from those membranes when the core triglyceride-rich lipoproteins are spilled out during hydrolyzation by LPL. Next, a free fatty acid from lecithin is transferred to the unesterified cholesterol that has been absorbed into the nascent HDL particle by the action of lecithin-cholesterol acyl transferase (LCAT) and its activating cofactor, Apo A1. This free cholesterol is then esterified (ie, combined with an alcohol and depleted of water) by plasma LCAT and, because cholesterol esters are hydrophobic, they move to the core of the lipoprotein, causing the HDL particle to assume its mature spherical configuration.
 

 HDL and the Reverse Cholesterol Transport System

As discussed above, as the nascent HDL moves through the body, it removes unesterified (free) cholesterol from peripheral cells, such as macrophages, through the transfer of cholesterol across the cell membrane by the ABC1 transporter protein. The mature, spherical HDL particle, which contains these cholesterol esters in its core, then returns to the liver and is selectively taken up by the liver through the interaction of HDL with the hepatic HDL receptor. This process is known as "reverse cholesterol transport."  About 50% of the cholesterol esters in mature HDL particles will be delivered to the liver through the HDL receptor. The other 50% are transferred by cholesterol ester transfer protein from HDL to the Apo B-containing lipoproteins VLDL, IDL, and LDL, and the "forward" transport of cholesterol recommences.

Panel 9.  HDL and the  Reverse Cholesterol Transport System

 The Big Picture

Thus, if we now look at the entire sequence, we can see what happens to the food on our plate, especially to the food rich in fats or saturated fats. Once it is ingested, the chemical components are packaged and distributed throughout the body for our metabolic needs; if taken in excess of these needs, they are stored as body fat and atherosclerotic plaque in our arteries.  Now we need to look more closely at the "black box" where most of these transformations take place -- the liver. How do the fatty foods that we consume and that enter the body as fatty globules known as chylomicrons become the various forms of cholesterol that ultimately, in excess, can become the underlying cause of death? In short, how are the fatty acids in our food transformed in the liver into the cholesterol in our circulation?

Panel 10.  The Big Picture

 Understanding the Synthesis of Cholesterol
 

What is cholesterol? Chemically, cholesterol is a "pearly, fat-like steroid alcohol," meaning that the cholesterol molecule contains only carbon, hydrogen, and oxygen atoms. This would mean it is similar to a sugar -- but it is assembled as an alcohol -- except that it is hydrophobic, and thus acts more like an oil.  This sounds exotic, but cholesterol is nevertheless a very important molecule, because it is found in animal fats and oils, in bile, blood, brain tissue, milk, the yolk of egg, and the myelin sheaths of nerve fibers, as well as in the liver, kidneys, and adrenal glands. In fact, cholesterol is a constituent of all living animal cells. As might be expected for such an important molecule, cellular cholesterol content is closely controlled by several mechanisms. Recall from Panel 4 that circulating plasma cholesterol levels correlate more with saturated fat intake than with dietary cholesterol -- meaning that the cholesterol that causes the atherosclerotic complications in the vasculature does not enter the body as cholesterol; rather, it is actually synthesized by the body -- in the liver -- from other chemicals.

Panel 11.  Understanding the Synthesis of Cholesterol

So what is the recipe for the synthesis of cholesterol? We need to know this if we are going to understand how statins work to correct the problem of too much cholesterol.

 We have seen that dietary fat is packaged by the intestines as chylomicrons--containing the triglycerides, lipoproteins, and other components--which are, in turn, secreted into the circulation to eventually enter the liver as chylomicron remnants. These are the primary elements of food that are delivered to the liver. However, the fats in these chylomicron remnants are only a small part of the range of blood-borne bioactive chemicals that ultimately pass through the liver. Most of the molecules that the body processes as food are composed of complicated arrangements of a few basic atoms, usually hydrogen (H), carbon (C), and oxygen (O). The increasingly intricate arrangements of these atoms form distinct classes of molecules as they are metabolized through a series of chemical reactions. The general order of these reactions is to begin with a carbohydrate, progress to an alcohol, and finally to an aldehyde.

 Starting from these few atoms and this cholesterol pathway, the liver cells eventually produce mevalonic acid, or mevalonate. Mevalonate is a precursor of 3 types of molecules: coenzyme Q (which is a group of related quinones occurring in the lipid fraction of mitochondria and serving, along with the cytochromes, as an intermediate in electron transport, similar in structure and function to vitamin K1); squalene (an intermediate in cholesterol synthesis in all animals examined); and cholesterol.

Between the simpler molecules and mevalonate is a chemical known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). For HMG CoA to become mevalonate, it needs a catalyst, called HMG CoA reductase. It follows that if the activity of this catalyst can be inhibited, then the amount of mevalonate will be controlled, and ultimately the amount of cholesterol that is produced will be controlled. (In fact, HMG CoA reductase is the "rate-limiting enzyme" in the HMG CoA-to-mevalonate reaction, because it is impossible to construct more mevalonate molecules than there are HMG CoA reductase molecules to catalyze the reaction.)

 Putting HMG CoA Reductase Inhibitors Into Action
 

As discussed above, most of the cholesterol that courses through the circulation does not enter the system directly from dietary sources. Rather, it is synthesized in the smooth endoplasmic reticulum by means of a series of chemical reactions that at one point are catalyzed by HMG CoA reductase. As we saw in Panel 11, the first way to block cholesterol synthesis is by interrupting the conversion of HMG CoA to mevalonate (so that mevalonate cannot generate cholesterol). In order for HMG CoA to become mevalonate, the reaction must be catalyzed by the enzyme HMG CoA reductase. If this enzyme is blocked, mevalonate cannot be generated and cholesterol cannot be synthesized.  This is the principal mechanism of action of the most popular and most effective of the "cholesterol-blocking" medicines, the HMG CoA reductase inhibitors, which are collectively known as "statins." There is a whole family of statins (see Panel 14) that, because of variations in their molecular structures, produce their therapeutic effects in slightly different ways.

Panel 12.  Putting HMG CoA Reductase Inhibitors Into Action

 However, there are 3 other ways, besides blocking the HMG CoA reductase enzyme, that cholesterol can be removed from the circulation:

• Receptor-mediated endocytosis of LDL, whereby the liver cells, or hepatocytes, attach cholesterol via LDL receptors on their membranes and remove it from circulation;

 
• Selective uptake of free cholesterol from inside the LDL particles; and

 
• Cholesterol efflux from plasma membrane to cholesterol acceptor particles (predominantly HDL)

Finally, in addition to induction of the LDL receptors, another control mechanism is to inhibit the synthesis of VLDL (a precursor of LDL, as seen in Panel 2) and apolipoprotein B (a constituent of all non-HDL particles, as seen in Panel 2).

 Improving the Plasma Lipid Profile

In Panels 1-12, we saw how the food on our plates becomes the cholesterol that is so important for the body's cellular structures, as well as how, in excess, cholesterol can become an underlying cause of cardiovascular disease. We also saw that it is not the cholesterol molecule per se that concerns us, but rather the way that it is "packaged" into lipoprotein particles for transport throughout the cardiovascular system.  As we have seen, cholesterol does not enter the body directly from the food we consume, nor is there a one-to-one relationship between dietary cholesterol intake and plasma cholesterol levels. Rather, most of the cholesterol in circulation is the result of hepatic activity that packages and repackages dietary fat into lipoprotein particles for transport to the muscles and fat storage depots of the body. This process involves a complex chemical reaction that at one point requires a catalyst, HMG CoA reductase, to complete the synthesis of cholesterol. If the activity of this enzyme is inhibited, then the metabolism of lipids, and hence the plasma levels of cholesterol, are reduced.

Panel 13.  Improving the Plasma Lipid Profile

 As discussed, there is a whole spectrum of these lipoprotein particles that share basically identical components and structures but that differ crucially in their size and density. Because the most readily available biological analyses sort these subfractions according to these 2 parameters, plasma cholesterol is categorized on a scale from "low density lipoprotein" (LDL) to "high density lipoprotein" (HDL), and out of the spectrum of lipoprotein particles, these are the 2 most important medically.

 We should also recall that not all lipoprotein particles have deleterious effects: the smallest, densest particles, HDL, actually serve to remove cholesterol from deposits in the circulatory system and return it to the liver for further processing, a process termed "reverse cholesterol transport."

 The other important difference among the lipoprotein particles concerns which apolipoprotein is embedded in the particle's membrane: the HDL particle's membrane contains Apo A, whereas non-HDL particle membranes contain several Apo B molecules. These membrane apolipoproteins mediate where and when the particles bind and exchange their contents with the tissues of the body as they carry out their roles in the fat and cholesterol transport system.

 All of these lipoprotein subfractions are important in the maintenance of cardiovascular health. However, when they occur in the wrong concentration in the wrong part of the system, the particles are no longer processed through healthy metabolic pathways, and the vasculature succumbs to the disease state of atherosclerosis.

 Targeting Plasma Cholesterol Levels. In 1985, the National Heart, Lung, and Blood Institute (NHLBI), a division of the US National Institutes of Health (NIH), created the National Cholesterol Education Program (NCEP). The purpose of the NCEP is to educate healthcare professionals and the public about the benefits of lowering high blood cholesterol. Over the years, the NCEP has published a series of protocols discussing and detailing the plasma cholesterol levels that should be the targets for healthy individuals. The most recent protocol, known as the third Adult Treatment Panel (ATP III), was released earlier this year.

 Ultimately, it is the extremes of the lipoprotein spectrum -- LDL particles with Apo B and HDL particles with Apo A -- that travel through our circulation and can be measured in the doctor's office, and so it is these lipoprotein subfractions that the patient must monitor. The target plasma cholesterol levels defined by the ATP III are shown in Table 1.
 

Table 1. ATP III Classification of LDL, Total, and HDL Cholesterol

 

LDL Cholesterol (mg/dL)
< 100	Optimal
100 - 129	Near optimal/above optimal
130 - 159	Borderline high
160 - 189	High
> 190	Very high
HDL Cholesterol (mg/dL)
< 40	Low
> 60	High
Total Cholesterol (mg/dL)
< 200	Desirable
200 - 239	Borderline high
> 240	High

 Body weight is a function of body size: a large person will logically have a greater body weight than a small person. However, the mathematical ratio of body size to body weight, or body mass index (BMI), is relatively constant. To determine BMI, a person's weight in kilograms is divided by height in meters, squared, or

For example, for a person 6 feet tall who weighs 210 pounds, the BMI can be calculated as:
 
 

The spectrum of BMI values are then categorized in Table 2.
 
 

Table 2. Categorization of Body Mass Index (BMI)

 

	BMI
Healthy body weight	20 - 25
Overweight	> 25
Mild obesity	27 - 30
Moderate obesity	> 30 </= 35
Morbid obesity	> 35 </= 50

 Making Lifestyle Changes. Controlling food intake is only one of the parameters in controlling body weight, however. It is true that mass consumed tends to end as mass in the body -- unless that mass is converted to energy. If we recall Einstein's famous physical formula:

then this should remind us that if the chemical components of food are "burned" to fuel the activity of the muscles, they cannot be accumulated as fat. Therefore, the other way to avoid the unhealthy status of overweight is by consuming the food calories in the muscles as fuel, instead of sending those calories to the body's fat depots for storage.

Even in the absence of overconsumption, a sedentary lifestyle will store food calories in fat depots instead of burning them, and a "healthy" level of activity does not require a rigorous exercise regimen. Twenty minutes of activity as mild as walking fairly briskly will be sufficient to appropriately apportion the food contents of a proper diet to fuel vs storage.

Finally, smoking is a known risk factor for CVD. It is beyond the scope of this review to discuss the ways that inhalation of carcinogens damages the endothelium, and the harmful effects of smoking are independent of the effects of excess cholesterol. Nevertheless, along with proper diet and adequate exercise, smoking cessation is an imperative to avoid CVD.

 Pharmacologic Intervention. These are the fundamental principles for avoiding CVD: diet, exercise, and smoking cessation. However, as acknowledged in the Introduction, these principles are not always followed, nor are they necessarily adequate. Therefore, if the target cholesterol levels and BMI ratios listed in the tables above cannot be attained, the individual should obtain medical counseling, which will probably suggest the addition of medical therapy to a regimen of better diet and exercise.

 The figure lists the various interventions and the effects that they have on the 2 most important cholesterol subfractions, LDL and HDL. There are several classes of pharmacologic agents that have proven effective as therapy. All of these drugs modify plasma cholesterol and triglyceride concentrations in the healthy direction, with the exception of bile acid sequestrants, which appear to have no effect on plasma triglyceride levels or may even have a negative effect by elevating them. The differences among these agents are primarily in the degree to which they change the plasma lipid levels, their contraindications, and their side-effect profiles.

 Bile acid sequestrants lower LDL moderately (15% to 30%) and raise HDL very little (3% to 5%). They are absolutely contraindicated in cases of dysbetalipoproteinemia (high levels of Apo B, usually an inherited disorder) or for extremely high triglyceride levels (> 400 mg/dL; should be used with caution when triglycerides > 200 mg/dL). The side effects include gastrointestinal problems such as constipation; they may also decrease the absorption of other drugs.

 Nicotinic acid lowers LDL slightly (5% to 25%), raises HDL nicely (15% to 35%), and lowers triglycerides significantly (20% to 50%). It cannot be used in cases of chronic liver disease or severe gout. Side effects include an unpleasant degree of facial flushing, induction of hyperglycemia or hyperuricemia (gout), some degree of hepatotoxicity, and upper gastrointestinal distress.

 Fibric acids slightly lower LDL (5% to 20%), slightly raise HDL (10% to 20%), and significantly lower triglycerides (20% to 50%). They cannot be used in cases of severe renal or hepatic disease. Side effects include dyspepsia, gallstones, and myopathy.

 Finally, there is the most successful class of lipid-lowering agents, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins."

 HMG CoA Reductase Inhibitors
 

Numerous large clinical trials have established that an excess of plasma cholesterol, when uncontrolled, will lead to a series of insults to the circulatory system that results in cardiovascular disease and ultimately, if untreated, death. Conversely, control of plasma cholesterol levels to within the ranges established by several published guidelines has been shown to significantly decrease the morbidity and mortality of CVD.  All of the current guidelines are based on a series of large, well-controlled clinical trials testing lipid control agents, for the most part statins, against the absence of trial drug. The first of the lipid-lowering trials were the Scandinavian Simvastatin Survival Study (4S), with simvastatin, and the Cholesterol and Recurrent Events (CARE) trial, with pravastatin. The primary finding of both these trials was that lowering LDL cholesterol in patients at risk for CVD to within the range advocated by subsequent guidelines (see Table 1 in Panel 13) will significantly decrease the number of deaths from coronary artery disease. Subsequently, both the West of Scotland Coronary Prevention Study (WOSCOPS) and the Air Force/Texas Coronary Atherosclerosis Prevention Study

Panel 14. HMG CoA Reductase Inhibitors

(AFCAPS/TexCAPS) found that using a statin to lower plasma cholesterol levels produced a significant reduction in coronary events, even in subjects without clinically evident CVD.

 Further clinical trials have refined the definition of a "healthy" lipid profile. Post hoc analysis of the 4S results found that patients with the "lipid triad" (high LDL, low HDL, high triglycerides) had a worse prognosis than patients with isolated elevated LDL. The Post Coronary Artery Bypass Graft (Post-CABG) trial found that lowering LDL to an aggressive target (< 100 mg/dL) resulted in significantly fewer clinical events than lowering to a more modest target (to 132-136 mg/dL). (On the other hand, subsequent analysis of the CARE and the WOSCOPS results has suggested that there is diminishing benefit in lowering LDL to levels below 100 mg/dL.) And the AFCAPS/TexCAPS study found that of all the lipid parameters assessed, low levels of the HDL apolipoprotein, Apo A-1, was the most consistent predictor of risk of future events.

 Therefore, good medical practice dictates that all people should maintain plasma levels of the various lipoprotein subfractions (LDL, HDL, Apo B, Apo A-1, triglycerides) within the limits set by the NCEP guidelines, as referred to above. When a lifestyle that includes a properly balanced and apportioned diet, plus adequate physical activity, does not succeed in achieving these target levels, then therapeutic intervention with a lipid-modifying pharmacologic agent should be considered. As discussed, the ideal anti-atherosclerotic agent would do 3 things:

• lower LDL

 
• lower triglycerides

 
• raise HDL

 Statins have 2 principal deleterious side effects: increased liver enzymes (statins are absolutely contraindicated in patients with active or chronic liver disease) and myopathy. The true incidence of the latter side effect is still unknown at this time, but the occurrence of rhabdomyolysis (characterized by muscle weakness or pain and elevation of muscle creatine kinase enzyme levels) has been identified as a cause of death in a small number of patients taking one of the statins, cerivastatin, which has resulted in the withdrawal of this drug from the market worldwide (as indicated in the figure).

 Nevertheless, the efficacy of HMG CoA reductase inhibition has been so clearly established that the current guidelines unambiguously recommend the addition of an agent in the statin "class" for control of hypercholesterolemia in all cases except where clearly contraindicated. As long as physicians are aware of the signs and symptoms of untoward reactions, statins should continue to be viewed as extremely effective and well tolerated in the majority of patients.

There remains the question whether any statin is functionally the same as any other -- in other words, whether the beneficial effects shown in the large clinical trials by some of the early statins can be generalized to the other statins as a "class" effect. The class effect of statins is associated with their primary mode of action, enzyme inhibition, as assessed by their measured effects on LDL (or non-HDL) and HDL cholesterol as well as on triglyceride levels and (in more sophisticated analyses) on Apo B levels. The differences among the statins at this time therefore are principally in the degree to which they affect enzyme levels. The complete safety profile and other effects -- for example, the amount of atherosclerosis regression (as opposed to just LDL lowering) -- have yet to be reported across the class of statins.

In light of the new NHLBI treatment goals, the principal treatment goal for patients with elevated cholesterol levels should be to reduce LDL levels to within the ranges specified in the ATP III guidelines as quickly as possible, with as few dose adjustments as necessary. The desirability of avoiding dose titrations is especially important, since there is often a reluctance on the part of clinicians to up-titrate statin doses for fear of increased side effects. However, since currently available information does not suggest significant differences among the statins in terms of safety and side-effect parameters, the need to effectively lower LDL at the starting dose is emphasized.

 Panel 14 details the relative efficacies of the statins currently marketed in the United States for lowering the principal unhealthy subfraction, LDL cholesterol. The newer statin formulations (atorvastatin, currently marketed; rosuvastatin, expecting approval in mid 2002) appear to be the most effective on a per dosage basis in lowering LDL cholesterol. However, recall that the goal is to reduce the total non-HDL cholesterol burden in the circulatory system. This can be achieved both by lowering plasma LDL cholesterol levels directly, and also indirectly, by raising HDL levels in order to maximize the "reverse cholesterol transport." The newest of these statins, rosuvastatin, appears to be mildly effective for raising HDL across the full range of doses (10 to 80 mg), whereas the currently most effective statin, atorvastatin, appears to raise HDL levels less at increasing doses.

Conclusion

 Thus, it is clear that humanity faces a potential healthcare catastrophe. Avoiding this bleak future will require alterations in individual behavior (to include proper diet and weight control, adequate activity and exercise levels, and avoidance of all forms of the tobacco habit), a dedication of public policy toward aiding and promoting these individual goals, and continued education of the medical profession and development of lipid-lowering drugs to ameliorate the problem when behavior and public policy fall short of their imperatives. Clearly the "statins," as a class, are a successful contribution to this task, but there is still much to be done.

Stopping Statins Can Be Deadly
For Certain Patients, Discontinuing Drugs Can Mean Increased Risk of Heart Attack, Death
By: Jennifer Warner

WebMD Medical News

March 4, 2002 -- Stopping cholesterol-lowering statin drug therapy in people with heart disease can dramatically increase their risk of death. A new study found patients who discontinued using the drugs when they were hospitalized for chest pain were three times as likely to have a heart attack or die than those who kept taking their medication.

Researchers say the study adds evidence that statins may do more than just lower cholesterol, and that the drugs may protect the heart in other important ways. For example, recent research has shown that statins can reduce harmful inflammation in the arteries that can lead to blood clots.

But this study, published today in Circulation: Journal of the American Heart Association, also supports the idea that statins increase the release of  protective nitric oxide in the inner walls of the heart. Animal research has shown that when the statins are suddenly withdrawn, a rebound effect occurs, and the nitric oxide levels drop below normal -- increasing the risk of heart attack or other cardiac events.

                        A human study to test this rebound effect would be unethical, but
                        researchers were able to show a similar withdrawal effect in humans by
                        looking at medical records of patients who'd been enrolled in an international
                        heart disease trial.

                        Of the 465 patients who had been taking a statin drug for six months when
                        admitted to the hospital for chest pains, 379 continued taking the drug, and
                        86 stopped. After 30 days, researchers looked at the number of patients
                        who died or suffered a heart attack.

                        People who were kept on their statin medication had half the risk of death or
                        a nonfatal heart attack than those who had never taken a statin drug. Those
                        who stopped using statins after hospitalization had nearly three times the
                        risk compared with those who continued using their medication.

                        "The increase in deaths and acute heart attacks was only explained by the
                        statin withdrawal," says study author Christian W. Hamm, MD, of the
                        Kerckhoff Heart Center in Bad Nauheim, Germany in a news release.

                        In addition, significantly more patients who had stopped statin therapy
                        required additional procedures to restore blood flow within one week after
                        hospitalization.

                        Hamm says there is no particular medical rule suggesting that hospitalized
                        patients should discontinue statin drugs, so the physicians must have either
                        assumed the statins were no longer beneficial or just forgot to continue the
                        patients on the therapy.

                        "The message to physicians is: Don't stop statins," says Hamm.

                        Three statin drugs accounted for about 95% of those prescribed in the study
                        and included Zocor, Mevacor, and Pravachol.
 
 

                        Medically Reviewed
                        By Charlotte Grayson
http://my.webmd.com/content/article/1756.50193