Porth's Essentials of Pathophysiology, 4e

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Circulatory Function

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be elevated as a result of an increase in any of the lipoproteins. For example, two persons with the same total serum cholesterol of 275 mg/dL may have very different lipid profiles. 11 One person may have a favor- able lipid profile with an HDL of 110 mg/dL, a triglyc- eride level of 175 mg/dL, and an LDL of 130 mg/dL, whereas another person with an HDL of 40 mg/dL, a triglyceride level of 150 mg/dL, and an LDL cholesterol of 205 mg/dL would be at much greater risk for cardio- vascular disease. Management of Hyperlipidemia. A reduction in LDL cholesterol continues to be the primary target for choles- terol-lowering therapy, particularly in people at risk for coronary artery disease (CAD). The major risk factors for CAD, exclusive of LDL cholesterol levels, include cigarette smoking, hypertension, family history of pre- mature CAD in a first-degree relative, age (men ≥ 45 years; women ≥ 55 years), an HDL cholesterol level less than 40 mg/dL, and diabetes mellitus. 6,11,12 Guidelines recommend that persons with none of the major risk factors should have an LDL cholesterol goal of 160 mg/ dL or less; those with two or more of the major risk fac- tors should have an LDL cholesterol goal of less than 130 mg/dL; persons with high-risk factors (i.e., those with CAD, other forms of atherosclerotic disease, or diabetes) should have an LDL cholesterol goal of less than 100 mg/dL; and persons with very–high-risk fac- tors (i.e., acute coronary syndromes or CAD with other risk factors) should have an LDL cholesterol goal of less than 70 mg/dL. 13 It is also recommended that persons with a greater than 20% 10-year risk of experiencing myocardial infarction or coronary death, as determined by the risk assessment tool developed from Framingham Heart Study data, should have an LDL cholesterol goal of less than 100 mg/dL (to calculate a risk score, go to http://hp2010.nhlbihin.net/atpIII/calculator. asp?usertype=prof ) The management of hypercholesterolemia focuses on dietary and therapeutic lifestyle changes; when these are unsuccessful, pharmacologic treatment may be neces- sary. Therapeutic lifestyle changes include an increased emphasis on physical activity, dietary measures to reduce LDL levels, smoking cessation, and weight reduction for people who are overweight. Several dietary elements affect cholesterol and its lipoprotein fractions: (1) excess calorie intake, (2) saturated and trans fats, and (3) cholesterol. 12 Excess calories consistently lower HDL and less consistently elevate LDL. Saturated fats in the diet can strongly influence cholesterol levels. Depending on individual differences, they raise VLDL and LDL levels. Trans fats, which are manufactured from vegetable oils and are used to enhance the taste and extend the shelf life of fast foods, are more atherogenic than satu- rated fats. Dietary cholesterol tends to increase LDL cholesterol. Lipid-lowering drugs work in several ways, includ- ing decreasing cholesterol production, decreasing cho- lesterol absorption from the intestine, and removing cholesterol from the bloodstream. Drugs that act to

directly decrease cholesterol levels also indirectly lower cholesterol levels by stimulating the production of addi- tional LDL receptors. There currently are five major types of medications available for treating hypercho- lesterolemia: 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), bile acid– binding resins, cholesterol absorption inhibitor agents, niacin and its congeners, and the fibrates. 9,12 Inhibitors of HMG-CoA reductase, a key enzyme in the choles- terol biosynthetic pathway, can reduce or block the hepatic synthesis of cholesterol and are the corner- stone of LDL-reducing therapy. Statins also reduce triglyceride levels. The bile acid–binding resins bind and sequester cholesterol-containing bile acids in the intestine. This leads to increased production of LDL receptors by the liver, with resulting increased removal of cholesterol from the blood for synthesis of new bile acids. The cholesterol absorption inhibitor (ezetimibe) interferes with the absorption of cholesterol. Nicotinic acid, a niacin congener, blocks the synthesis and release of VLDL by the liver, thereby lowering not only VLDL levels but also IDL and LDL levels. Nicotinic acid also increases HDL concentrations up to 30%. The fibrates decrease the synthesis of VLDL by the liver and also enhance the clearance of triglycerides from the circulation. Atherosclerosis Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty mate- rials. The term atherosclerosis, which comes from the Greek words atheros (“gruel” or “paste”) and sclerosis (“hardness”), denotes the formation of fibrous plaque in the intimal lining of the large and medium-sized arteries such as the aorta and its branches, the coronary arter- ies, and the cerebral arteries that supply the brain (Fig. 18-6). The disorder, which remains a leading cause of coronary artery disease, stroke, and peripheral artery disease, can begin in the late teens, but usually takes decades to cause symptoms. Some people experience rapidly progressing atherosclerosis during their 30s, others during their 50s or 60s. Epidemiology and Risk Factors Atherosclerosis is a complex disorder. Although its exact cause is unknown, epidemiologic studies have identi- fied predisposing risk factors (Chart 18-1). 1,2,6,11 Some of these are constitutional and cannot be changed, but others are affected by lifestyle and can be modified. The major risk factor, hypercholesterolemia, has both con- stitutional and lifestyle components. Constitutional risk factors such as increasing age, male gender, and family history of premature coronary artery disease cannot be changed. The tendency toward the development of atherosclerosis appears to run in families. Persons who come from families with a strong history of heart disease or stroke due to atherosclerosis are at greater risk for developing atherosclerosis than those with a negative family history. Several genetically