Atherogenesis
and Dyslipidemia 
OUTLINE
The Cholesterol -
Atherosclerosis Connection
Lipid
Metabolism
Atherogenesis
Risk Factors
(modifiable and non-modifiable)
Classification
of Dyslipidemias
Secondary
Dyslipidemias
Clinical
Trials
Primary Prevention Secondary Prevention National Cholesterol Education Program
Guidelines
Who to
test Measurement Risk Factors (other than
LDL cholesterol) Treatment Goals
Clinical Management of Hypercholesterolemia
Non-pharmacologic Pharmacologic
Clinical Management of Hypertriglyceridemia
Non-pharmacologic Pharmacologic
Alcohol Concomitant Hypertension
Hormonal Replacement
Therapy in Postmenopausal Women Antioxidants Homocysteine Treatment of Elderly
The Cholesterol - Atherosclerosis
Connection
A large body of evidence supports a direct relationship between LDL cholesterol and the rate of CHD. This includes within-population studies (i.e., Framingham and MRFIT) and between-population studies (i.e., Seven Countries). Familial Hypercholesterolemia, a genetic disorder characterized by high levels of LDL cholesterol, has an exceedingly high rate of premature atherosclerosis. Animals with both spontaneous and diet-induced hypercholesterolemia develop lesions similar to human atherosclerosis.
There are four major subtypes of lipoproteins which vary in size, density, protein and fat content. Chylomicrons and Very Low Density Lipoproteins (VLDL) are the least dense lipoproteins and are comprised primarily of a triglyceride rich core. Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL) are the smallest and most dense lipoproteins and contain a core comprised primarily of cholesterol.
The apoproteins are the protein components of the lipoproteins. In addition to serving as membrane stabilizers, they are also required for synthesis and secretion of certain lipoproteins, serve as cofactors in the activation of enzymes that modify the lipoproteins and interact with specific receptors that remove lipoproteins from the circulation.
While circulating through the peripheral tissues, both the chylomicrons and VLDL are acted upon by the adipose tissue and muscle by the enzyme lipoprotein lipase which removes triglyceride from these particles for storage in fat or energy consumption in muscle. In this manner, the chylomicron is transformed into a cholesterol-rich remnant particle that is removed from the circulation by the liver through the action of a specific remnant receptor. VLDL is likewise transformed into a cholesterol-rich remnant particle which can be removed by the liver or further metabolized to the more cholesterol rich LDL particle by the action of hepatic lipase. A specific LDL receptor is responsible for the uptake of both the VLDL remnants and LDL particles. As VLDL is metabolized by lipoprotein lipase it is left with excess surface coat as its core diminishes in size. In exchange for surface coat, HDL transfers cholesterol esters to VLDL by the action of Cholesterol Ester Transfer Protein (CETP). The exchanged surface coat allows the HDL particle to continue to absorb cholesterol and grow in size while the exchanged cholesterol ester can then be taken up by the liver as the VLDL remnant particles are metabolized. This represents one of the two mechanisms by which HDL can remove cholesterol from tissues. The other mechanism involves direct uptake of the HDL particle by the liver.
Joseph Goldstein and Michael Brown earned a Nobel prize by characterizing the LDL receptor. Individuals with Heterozygous Familial Hyperlipidemia have one LDL gene defective and thus remove LDL at one half the rate of normals, have LDL cholesterol levels twice that of normals and develop premature atherosclerosis. The frequency of this gene in the population is ~ 1/500. Individuals with Homozygous Familial Hypercholesterolemia have no functional LDL receptors, have extremely high LDL levels, i.e., 1000 mg/dl and develop atherosclerosis in their teens. The frequency of this disease is 1/1,000,000.
The first step in atherogenesis is the infiltration and entrapment of Low Density Lipoprotein (LDL) in the blood vessel wall. Ground substances such as the glycoaminoglycans (GAGs) have a high affinity for the apo B-100 of the LDL. Other particles containing apo B-100, i.e., VLDL remnants (IDL) are probably atherogenic as well. Chylomicron remnants which contain the truncated form of apo B, apo B-48 may also become similarly involved.
Once entrapped in the vessel wall, LDL undergoes modification through oxidation, derivatization or glycosylation. Initially, when minimally modified, endothelial cells react by secreting a chemotactic substance which attracts monocytes to the area. Monocytes then migrate through the vessel wall, transform into macrophages which then begin digesting the LDL particles as they becomes more oxidized.
The macrophage lacks the ability to autoregulate the uptake of modified LDL. Modified LDL is cytotoxic and inhibits further migration of the macrophage out of the vessel. Eventually the cytoplasm of the cell is packed with lipid. When a slide preparation is made through an area with nests of these cells, as in a fatty streak, the lipid is removed leaving a foamy like appearance.
Fatty Streaks are smooth raised plaques located beneath the endothelium. They represent the initial phase of atherosclerosis. They occur early in life and are present in teen-agers. They are composed primarily of foam cells (lipid laden macrophages) and may regress, remain dormant or progress to a more complicated atherosclerotic lesion.
The fibrous plaque represents the second phase. As the fatty streak progresses, smooth muscle cells (not normally present in the subendothelial space) migrate from the media to the subendothelial space where they proliferate and produce connective tissue to form a fibrous cap. The final lesion to develop is the complicated lesion which can manifest calcification, hemorrhage, ulceration and thrombosis.
The major modifiable risk factors for the development of atherosclerosis are: Diabetes mellitus, hypertension, cigarette smoking, hypercholesterolemia, obesity and physical inactivity. Elevated levels of the amino acid homocysteine are generating increasing interest since levels can be modified by vitamin supplementation. The major non-modifiable risk factors are age, male > 45 or female > 55 and a family history of premature CAD. This is defined as a first degree male relative developing atherosclerosis before the age of 55 or a first degree female relative developing atherosclerosis before the age of 65.
Classification of Dyslipidemias
The Phenotypic Classification of the Hyperlipoproteinemias based upon serum electrophoresis are: Types I, IIA, IIB, III, IV and V.
Type I Hyperlipidemia is characterized by severe elevations of chylomicrons with resultant elevations of triglycerides in the thousands. This condition results from either a congenital deficiency of lipoprotein lipase or apo C-II, the apolipoprotein required to activate lipoprotein lipase. Eruptive xanthomas and pancreatitis represent the clinical manifestations of the disorder.
Type IIA Hyperlipidemia is characterized by elevation of only LDL cholesterol. Genetic conditions which can cause this are Familial Hypercholesterolemia, Polygenic Hypercholesterolemia, Familial Combined Hyperlipidemia and Familial Defective Apolipoprotein B-100. These individuals are at high risk for developing premature coronary heart disease.
Familial Hypercholesterolemia is caused by a defective LDL receptor gene. In the heterozygous form 50% of the LDL receptors are defective and cholesterol levels are approximately twice that of normals. In the homozygous form, no functioning LDL receptors are present and cholesterol levels are extremely high on the order of 1000 mg/dl. The incidences of the two forms are ~1/500 and 1/1,000,000.
Type IIB Hyperlipidemia is characterized by elevation of both LDL cholesterol and triglycerides. Familial Combined Hyperlipidemia is the most common genetic cause of this disorder where both VLDL and LDL are elevated. This disorder effects approximately 1-2% of the American population. Approximately 10% of patients with myocardial infarction before the age of 60 come from families with this disease.
Type III Hyperlipidemia
develops due to a defect in VLDL remnant clearance. Also known as
Familial Dysbetalipoproteinemia, these individuals have
difficulty removing triglyceride rich VLDL remnant particles and
consequently have elevations of cholesterol and triglycerides
that are equivalent. Tuberous and planar xanthomas are common.
Premature coronary heart disease is frequent.
Type IV Hyperlipidemia is characterized by Hypertriglyceridemia. Individuals with Type IV Hyperlipidemia have triglyceride levels generally between 250 and 500 mg/dl. Causes are multiple-genetic, other diseases such as Diabetes or Nephrosis, medications, i.e., BCP's and in some cases dietary factors particularly high sugar and alcohol intake.
Type V Hyperlipidemia have elevated levels of chylomicrons and VLDL. Defective lipolysis and an overproduction of VLDL are responsible. Triglyceride levels can be in the thousands. Eruptive Xanthomas and pancreatitis can occur. Causes can be genetic or secondary to diabetes mellitus, obesity or alcohol consumption.
Secondary and possibly reversible forms of dyslipidemias include: Diabetes mellitus, hypothyroidism, nephrotic syndrome, obstructive liver disease and certain pharmacologic agents. Agents which can raise LDL or lower HDL levels include: progestins, anabolic steroids, corticosteroids and certain antihypertensive agents such as beta-blockers and diuretics. Beta-blockers without intrinsic sympathomimetic activity (ISA) tend to decrease HDL and raise triglycerides. Thiazide and loop diuretics can cause a modest and sometimes transient rise in LDL (5-10mg/dl). Birth control pills can cause hypertriglyceridemia in some women.
The two most recent primary prevention trials, the Lipid Research Clinics (LRC) Coronary Primary Prevention Trial and The Helsinki Heart Study significantly reduced the incidence of CAD. The LRC trial used the drug Cholestyramine and the Helsinki study used the drug Gemfibrozil. Since these trials the more powerful HMG CoA Reductase inhibitors are now available making therapy more tolerable and effective.
Regression of atherosclerotic lesions is seen in patients undergoing aggressive cholesterol lowering. The first major secondary prevention trial to demonstrate this was the Cholesterol Lowering Atherosclerosis Study (CLAS) using the drugs colestipol and niacin. This was followed by the Familial Atherosclerosis Treatment Study using niacin/colestipol and lovastatin/colestipol. Since then, several other trials have confirmed the findings that not only can aggressive cholesterol lowering angiographically cause lesions to regress, but can also dramatically reduce the occurrence of clinical events. Of note, regression occurs primarily in patients whose LDL cholesterol has been reduced to less than 100 mg/dl. Most important, the Scandinavian Simvastatin Survival Study (4S trial) has recently shown that cholesterol lowering with medication when applied to patients with atherosclerosis not only decreases coronary events, but can prolong survival as well.
National
Cholesterol Education Program Guidelines
All adults 20 years of age and older should have their total cholesterol as well as HDL-cholesterol measured every five years. Measurements need not be taken in the fasting state since total cholesterol and HDL will not be affected. Triglycerides may be elevated with a non-fasting blood test.
Coronary
Heart Disease Risk Factors Other than LDL Choleterol
Age
Male: >
45 years
Female: > 55 years or
premature menopause without estrogen
replacement.
Family
history of premature coronary heart disease: definite
myocardial infarction
or sudden death before age 55 in father or
other male first
degree relative, or before age 65 in mother or other
female first degree
relative.
Current
cigarette smoking
Hypertension
(> 140/90 mmHg or on antihypertensive meds)
Low
HDL cholesterol (< 35 mg/dl)
Diabetes
mellitus
High HDL cholesterol
(> 60 mg/dl) Treatment
Goals:
Patients without evidence of
atherosclerotic disease and fewer than two other risk
factors, should have LDL
levels less
than 160 mg/dl.
Patients without evidence of
atherosclerotic disease and with two or more other risk
factors, should have LDL
levels less
than 130 mg/dl.
Patients with evidence of
atherosclerotic disease
should have LDL levels less than 100 mg/dl.
Clinical Management of
Hypercholesterolemia
The American public currently consumes about 40% of total calories as fat. The goal of the Step I and Step II NCEP diet is to reduce total fat consumption to less than 30% of the total calories consumed. The goal of the Step I diet is to reduce total cholesterol to less than 300 mg/day, but in the Step II diet to less than 200 mg/day.
Weight loss, exercise and smoking cessation are critical elements as well. Overall reduction in fat intake will facilitate weight loss since fat is calorically dense (over twice as many calories per gram as protein or carbohydrates). Exercise, besides promoting weight loss, has been shown to independently increase longevity. Smoking has been shown to lower HDL levels and to raise homocysteine levels.
In patients without two or more risk factors drug therapy should be considered if the LDL remains above 190 mg/dl and dietary therapy for at least six months duration has failed. In patients without evidence of atherosclerotic disease and with two or more risk factors drug therapy should be considered if the LDL cholesterol remains greater than 160 mg/dl . Patients with atherosclerotic disease should be considered candidates for drug therapy if the LDL is greater than 100 mg/dl.
HMG CoA Reductase inhibitors and bile acid sequestrants are good combination therapy in patients with resistant hypercholesterolemia. By having different mechanisms of action these compounds work synergistically and are the preferred agents for combination therapy. Alternatively, niacin alone or in combination with a bile acid sequestrant or HMG CoA Reductase inhibitor can be used. It remains controversial whether slow release niacin is more hepatotoxic than regular crystalline niacin. Remember, when using either reductase inhibitors or niacin, liver function tests must be checked initially for the first several months and then again with any increase in dose.
More recently, attention on more natural methods of cholesterol lowering are coming into vogue. Dietary soluble fiber enhancement, with commercial dietary supplementation is proving to be a very effective all natural approach to cholesterol lowering. In a recent trial examining the effects of dietary soluble fiber supplementation, total serum cholesterol and LDL cholesterol fell on average by (-14.9%) and (-17.9%) respectively, while HDL cholesterol increased (+30.1%). Serum triglycerides decreased (-30.7%) and the cardiovascular risk ratio (LDL/HDL) fell by (-36%). Total cholesterol reduction was seen as low as (-45%) with LDL decreasing as low as (-59%) and HDL increasing as high as (+48%). Soluble fiber supplementation is a safe, effective, all natural approach to cholesterol lowering and can be used as first line therapy or in conjunction with Reductase inhibitors replacing the bile acid sequestrants.
Clinical Management of
Hypertriglyceridemia
As in hypercholesterolemia, the non-pharmacologic management is much the same with the exception of a few caveats. Patients with hypertriglyceridemia are extremely sensitive to weight loss, generally much more so than patients with hypercholesterolemia. Diet and exercise are, therefore, important. Also simple sugars and alcohol should be avoided. Diabetes should be controlled and some drugs like birth control pills or beta blockers may need to be discontinued.
Patients with fasting triglycerides greater than 500 mg/dl and who have failed non-pharmacologic therapy should be treated with drug therapy. These patients often have post-prandial triglycerides in excess of 1000 mg/dl putting them at risk for developing pancreatitis. They should be aggressively treated.
Niacin and gemfibrozil are the preferred agents for the treatment of hypertriglyceridemia. Both compounds also have the favorable effect of raising HDL.
Alcohol
Although alcohol does cause a rise in HDL cholesterol, it is not certain that this effect affords any protection against atherosclerosis. Because of the well known adverse effects, it is not recommended for the prevention of coronary heart disease.
Hypertension
Beta blockers raise triglycerides and lower HDL levels. Lipids levels should be monitored and lipid lowering therapy instituted when needed.
Hormonal
Replacement Therapy
Data suggests that the incidence of CHD is dramatically reduced by post-menopausal hormonal replacement therapy (HRT). This is especially true in women who have had hysterectomies and who, therefore, do not need to have a concomitant progestin added.
Antioxidants
Antioxidant therapy may be useful in preventing atherosclerosis. By inhibiting the oxidation of LDL, chemotactic factors are not secreted thus preventing the migration of monocytes to the vessel wall and subsequent inflammatory reaction. Vitamin E and possibly C may be useful in this regard. Beta Carotene should be avoided as it has recently been shown that it does not bestow protection and actually may increase the risk of cancer in cigarette smokers.
Homocysteine
High plasma levels of the amino acid homocysteine have been found to be an independent risk factor for the development of coronary heart disease. Homocysteine levels can be reduced by the ingestion of folic acid, vitamin B6 and vitamin B12. Although there are no prospective randomized trials demonstrating that homocysteine modification using vitamin supplementation reduces heart disease, this therapy may be of value in high risk patients.
Elderly
Because the elderly are especially vulnerable to the side effects of drugs and have survived for years without them, a conservative approach should be taken. Additionally, one must remember that it takes several years before seeing a favorable effect of lipid lowering therapy in primary prevention. One still should strongly consider cholesterol lowering drugs in elderly patients with known atherosclerosis.
For more information
or questions e-mail: 
Murphy@cvmg.com
Franklin L. Murphy, M.D.,
FACC, FACP
Clinical Professor of Medicine
UCLA School of Medicine
414 North Camden Drive, Suite 1100
Beverly Hills, California 90210
Office (310) 278-3400
