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Update on Risk Factors for Atherosclerosis: The Role of Inflammation and Apolipoprotein E

Posted on: Friday, 25 February 2005, 03:00 CST

Over 1 million adults will have a new or recurrent myocardial infarction this year. Traditional risk factor assessment predicts less than one-half of all future cardiovascular events, and many patients develop atherosclerosis in the absence of these factors. Alternative risk factors, including genotype and the inflammatory response, are presented, along with intervention considerations for the medical-surgical nurse.

Mortality and morbidity from coronary heart disease (CHD) remain high in spite of traditional diagnostic and intervention methods aimed at identifying persons at risk. Although the death rate from CHD is on the decline, approximately 1.2 million Americans will have a new or recurrent coronary attack (MI, angina pectoris, or both) this year, and approximately 42% of these individuals will die in a given year (American Heart Association [AHA], 2003). Of those who survive, an estimated 67% do not make a full recovery and are at a 1.5% to 15% higher risk than the general population for the occurrence of illness, further hard coronary events such as MI, and death (AHA, 2003).

The excessive death and disability rates from CHD occur despite a broad national campaign aimed at identifying persons at risk. Conventional risk factor assessment and modification strategies (for example, smoking cessation, lower cholesterol diet, exercise, weight loss, pharmacological management) have been aimed primarily at preventing atherosclerosis, which accounts for nearly 75% of all cardiovascular deaths (AHA, 2003). However, the predictive value of this assessment is poor because conventional risk factors predict less than 50% of future cardiovascular events; many patients develop atherosclerosis in the absence of these factors (Kullo, Gau, & Tajik, 2000; Valabhji & Elkeles, 2002). Furthermore, conventional risk factors may exhibit differing effects in various ethnic groups; for example, Chinese and Japanese have low coronary artery disease rates despite high smoking rates (Kullo et al., 2000). Development of atherosclerosis in the absence of conventional risk factors, differing effects of risk factors based on ethnicity, and the pervasive nature of atherosclerosis after lifestyle changes and medication use suggest that other risk factors may play a pivotal role in the development of atherosclerosis (Kullo et al., 2000; Ross, 1999).

Atherosclerosis is no longer considered a slowly degenerative dis ease that is treated primarily with surgery. Neither is it believed to be the sole result of the accumulation of large amounts of lipids in the arterial wall (Kullo et al., 2000; Ross, 1999). Recent molecular advances suggest the role of cellular, molecular, and genetic influences leading to atherosclerosis in a chronic inflammatory process, typical of other inflammatory conditions such as rheumatoid arthritis and pulmonary fibrosis (Kullo et al, 2000; Pentikainen, Oorni, Ala-Korpela, & Kovanen, 2000; Ross, 1999; Weissberg, 2000). Cholesterol and low-density lipoproteins continue to make a major contribution to the development of atherosclerosis in this inflammatory hypothesis (Pentikainen et al., 2000). The purpose of this article is to review hyperlipidemia in atherosclerosis, the effect of the apolipoprotein E genotype on hyperlipidemia, the inflammatory hypothesis of atherosclerosis, and possible interventions.

Hyperlipidemia

Hyperlipidemia is defined as an elevation in triglycerides and cholesterol (Durstine, Moore, & Thompson, 2003). Because lipids are not soluble in aqueous solutions, triglycerides and cholesterol must combine in the serum with proteins, called apolipoproteins, to form a stable and usable particle. In other words, lipids are hydrophobic and need a mechanism to get from their point of origin to their point of use. Four different lipoprotein (lipid + apolipoprotein) classes exist (see Table 1). These include chylomicrons, derived from intestinal absorption of dietary triglycerides; very low density lipoprotein (VLDL), made in the liver and primarily responsible for transporting endogenous triglycerides; low-density lipoprotein (LDL), the final stage of VLDL catabolism and the primary cholesterol carrier; and high-density lipoprotein (HDL), which is involved in the reverse transport of cholesterol (Durstine et al., 2003; Tulenko & Sumner, 2002). Two subfractions of LDL also exist: intermediate-density lipoprotein (IDL) and lipoprotein(a). While the chylomicrons, VLDL, and LDL are involved in transporting lipids from the intestine or liver to peripheral tissues, HDL is responsible for carrying cholesterol from the peripheral tissues to the liver.

Table 1.

Plasma Lipoproteins

Figure 1.

Lipid Metabolism

Lipid Metabolism

Lipid metabolism occurs via two pathways: exogenous and endogenous (Guyton & Hall, 2000; LaCharity, 1998; Lu, Lee, & Patel, 2001; Kamboh, 2004) (see Figure 1). The exogenous pathway begins with the intake of dietary fat, specifically saturated fat and cholesterol (Guyton & Hall, 2000). Dietary fat is taken up by cells in the intestine, and triglyceriderich chylomicrons are formed (Tulenko & Sumner, 2002). HDL and the chylomicron exchange triglyceride (to HDL) and cholesterol-ester (to chylomicron), causing the chylomicron to shrink and the HDL to increase in mass. Eventually the chylomicron remnant is taken up by the liver, where it binds to a lipoprotein lipase through the action of apolipoprotein E (apoE) (Kamboh, 2004; Tulenko & Sumner, 2002). In endogenous lipid metabolism, the chylomicron remnants give the liver free fatty acids which are quickly made into triglyceride (Tulenko & Sumner, 2002). From this triglyceride, the liver makes VLDL, consisting of a rich triglyceride core and an outer surface made of free cholesterol, phospholipids, apolipoprotein B-IOO (apoB-100), and apo-E (Guyton & Hall, 2000; Tulenko & Sumner, 2002). Lipoprotein lipase, located in the walls of the capillaries, hydrolyzes the triglycerides in the circulating VLDL into glycerol and fatty acids. HDL absorbs the surface particles from the VLDL remnants; the hydrolyzecl remnant with a higher density of lipoprotein forms an IDL (Guyton & Hall, 2000; Tulenko & Sumner, 2002). These IDLs are either attracted back to the liver cells or remain in the blood and undergo further triglyceride hydrolysis induced by the lipoprotein lipase via apo-E (Guyton & Hall, 2000; Tulenko & Sumner, 2002). This further hydrolysis increases the density of the lipoprotein even more, and the cholesterol and phospholipids reach their greatest content levels in these newly derived LDLs. According to Guyton and Hall (2000) and Kamboh (2004), the center of LDL comprises almost entirely fat-soluble esterified cholesterol while the outer membrane is made of phospholipids and nonesterified cholesterol. Approximately 60% to 70% of the body's cholesterol is retained in LDL (LaCharity, 1998).

The LDLs remain soluble in plasma because they generate a negative electric charge. Additionally, a large apoB-100 molecule is located at one pole of the LDL and acts as a recognition site for LDL receptors on almost all cells of the body (Pentikainen et al., 2000). When this apoB-100 attaches to the LDL receptors, the entire lipoprotein is transported inside the cell, where it is digested, and cholesterol and phospholipids are released for cellular structural purposes (Guyton & Hall, 2000; LaCharity, 1998; Pentikainen et al., 2000) (see Figure 2). When the choiesterol concentration inside the cell reaches capacity, the cell makes fewer LDL receptors, thus reducing the amount of LDL transported into the cell (Guyton & Hall, 2000). Any excess LDL not taken in by the cells (intracellular) is removed by the lymphatic system to prevent extracellular accumulation of LDL (Pentikainen et al,, 2000). The liver, sensitive to both the LDL concentrations and the LDLs that returned earlier in the catabolic process, ceases making endogenous cholesterol.

Figure 2.

Entry of LDL into the Cell

Accumulation in the Arterial Intima

LDL receptors clear more than two-thirds of circulating LDL from the blood (LaCharity, 1998). If, however, a defect occurs in the LDL receptors, LDL metabolism is blocked and elevated serum plasma LDL occurs. This LDL may be taken up by blood vessels throughout the body, including the coronary arteries (Guyton & Hall, 2000; Tulenko & Sumner, 2002). This defect is especially evident among families with hypercholesterolemia, who have elevated levels of LDL throughout life. Although individuals are usually heterozygous for this trait (inherit one normal allele and one disease allele from parents), they can be homozygous (inherited a copy of the allele from both parents); clinical symptoms appear between infancy and 30 years of age in a rapidly progressing atherosclerotic process (Kamboh, 2004; Tulenko & Sumner, 2002).

Interestingly, the arterial intima does not contain lymphatic vessels that carry away the LDL as do other extrahepatic tissues in the body (Pentikainen et al., 2000). The LDL must be transported across the intimai layer through an elastic layer to the medial layer of the artery. Passage of LDL particles to the media is therefore slowed, and a steady accumulation in the intima results in a ten-fold higher concentration of LDL in the intimai fluid over that of the interstitial fluid of other tissues. The higher LDL concentration in the intima causes down-regulation of LDL receptors and blo\cks the exit of LDL into cells, resulting in accumulation in the arteries (Pentikainen et al., 2000). LDL cholesterol is the primary component of plaques in atherosclerosis (Tulenko & Sumner, 2002).

Apolipoprotein E

Five main types of apolipoproteins (A, B, C, D, E) exist in human plasma and some have subgroupings (for example, A-I, A-II, A-III, AIV), resulting in approximately 12 different apolipoproteins (Eichner et al., 2002). Apolipoproteins provide structural integrity to circulating serum lipoproteins, and act as co-factors in enzymatic reactions and ligands (binding sources) for lipoprotein receptors. Without apoE, lipoprotein remnants (chylomicron, VLDL) are not taken to the liver for metabolism, resulting in hypercholesterolemia and atherosclerosis (Ross, 1999). Specifically, apo-E is a prominent player in lipid metabolism and the transport of cholesterol in human tissues, and is critical in the formation of VLDL and chylomicrons (Eichner et al., 2002; Fullerton et al., 2000; Lahoz et al, 2001).

Table 2.

Types of Apolipoprotein E Alleles and their Functions

Structure of ApoE

ApoE is a 299-amino acid plasma glycoprotein synthesized by the liver and locally in the brain, and by other tissues such as steroidogenic organs, skin and macrophages, and the nervous system (Smith, 2000). It is responsible for the variability in individual total and low-density lipoprotein serum cholesterol (LDL-C) (Smith, 2000). Single nucleotide substitutions within codons 112 and 158 result in three common alleles for the apoE locus (ε2, ε3, ε4) which code for three isoforms (E2, E3, and E4, respectively) (Smith, 2000). The isoforms are metabolically distinct, differing in their affinity for lipoprotein particles and the extent to which they bind both apoE and low-density lipoprotein receptors (Fullerton et al., 2000). Six potential genotypes (E2/2, E2/3, E2/4, E3/3, E3/4, E4/4) may arise from these isoforms because one allele is inherited from each parent (Smith, 2000). The ε3 allele is the most common form (>60%), while the ε2 is the least common allele across populations (Eichner et al., 2002; Fullerton et al., 2000). Certain populations report a higher 4 allele frequency, including African-American, Finnish, and Swedish populations, while several Asian populations have a lower 4 allele frequency. A higher 4 allele frequency is associated with increased risk of CAD (Smith, 2000).

Molecular and Functional Differences

Population studies indicate that variation in the apoE gene locus affects the level of total LDL and LDL-C in the general population (Lahoz et al., 2001). The various apoE protein products that are derived from the three alleles differ in their receptor binding ability, catabolic rates, and plasma concentration of apoE (Chen et al., 2003) (see Table 2). The ε2 allele is associated with increased circulating apoE and, therefore, up-regulation of LDL receptor activity and delayed clearance of chylomicron remnants by the liver (Fullerton et al., 2000). This results in decreased circulating cholesterol. Compared to persons with the "normal" 3 allele, persons with the egr;2 allele have lower cholesterol levels (Davignon, Cohn, Mabile, & Bernier, 1999). A study by Chen et al. (2003) comparing total and LDL-C levels in women found that ε2 as compared to egr;3 individuals had a lower total cholesterol (14 mg/dL on average) and lower LDL-C (17.02 mg/dL on average). The egr;4 allele, however, is associated with decreased levels of circulating apoE, down-regulation of LDL receptor activity, and enhanced uptake of chylomicron remnants, resulting in higher serum cholesterol levels (Chen et al., 2003; Fullerton et al., 2000). Having the ε4 allele is reported to increase total serum cholesterol by an average of 5 to 8 mg/dL and LDL-C by 7 mg/dL (Chen et al., 2003). Additionally, persons with either the ε2 or ε4 allele have increased triglyceride levels over subjects with the ε3 allele (Fullerton et al., 2000). Thus, although the ε2 allele may have some protective effect against coronary heart disease based on circulating cholesterol levels, some studies indicate that the ε2 allele is also associated with an increased risk for CHD (Lahoz et al., 2001). However, the ε4 allele has been implicated as the major apoE variant associated with increased CHD risk.

ε4 allele

The exact risk associated with having the ε4 allele has not been determined. The ε4 allele has been associated with elevated LDL-C, coronary heart disease, and myocardial infarction (KoIovou, Daskalova, & Mikhailidis, 2003; Lahoz et al., 2001). In a study comparing apoE genotype to cardiovascular (CV) disease among offspring of the Framingham study, the estimated odds of developing CV disease were greater for men and women with the ε4 allele over those with the ε3 allele (viewed as the "norm," without significant disease association) (Lahoz et al., 2001). Other studies have supported these findings (Eichner et al., 2002; Kolovou et al., 2003). Another study found that the ε4 allele was a significant risk predictor of coronary and aortic atherosclerosis on autopsy among middle-aged men (<53 years of age) (Ilveskoski et al., 1999). The ε4 allele was also significantly associated with decreased longevity (p<0.05) in male twins who were studied in relation to their parent's longevity quintiles (Reed, Carmelli, Robinson, Rinehart, & Williams, 2003).

The effect of apoE genotype/phenotype on plasma lipoprotein levels decreases with age, thus offsetting the hyperlipidemic effect of the ε4 allele in older individuals (Smith, 2000). These findings were also noted in a study of older women over 65 years of age (Vogt, Cauley, & Kuller, 1997). In this study, women with the ε4 allele had a doubling of the relative risk for death from CV and cancer. Yet, no significant increase in mortality was found among women with the ε4 allele (E4/3, E4/4 genotypes) over women with the E3/3 genotype (ε3 allele). This finding suggested that women with the 4 allele who survived to age 70 or beyond had a similar life expectancy to women with the E3/3 genotype. However, Davignon et al. (1999) suggested that the ε4 allele increases the risk for a silent MI in the older adult population.

Although there are many apolipoproteins involved in lipid metabolism, apolipoprotein E plays a prominent role in total and LDL- C cholesterol levels. Allelic variation in the apoE gene, especially the ε4 allele, is a significant predictor of CV disease among men and women, particularly in middle age. ApoE affects the amount of lipids available in the artery for plaque formation.

Inflammatory Hypothesis of Atherosclerosis

Plaque formation. The presence of cholesterol in the arterial intima is the most relevant feature of atherosclerosis (Pentikainen et al., 2000). Atherosclerosis begins as early as infancy with the formation of a "fatty streak" (Ross, 1999). LDL, with its high concentration of cholesterol, is transported into the arterial intima, and begins the inflammatory process. To trigger inflammation, the LDL must be acted upon, or modified, and this typically occurs through oxidation (Pentikainen et al., 2000; Ross, 1999). This modified LDL and the by-products released by it are pro- inflammatory and attract monocyte-derived macrophages (Pentikainen et al., 2000). The macrophages ingest the modified LDL particles and are converted into "foam cells" which anchor to the endothelium and form the fatty streak (Pentikainen et al., 2000; Ross, 1999; Weissberg, 2000). Branches, bifurcations, and curves in the arteries are natural sites for this anchorage (Ross, 1999). Eventually, through a complex process of cellular factors including nitrous oxide, prostacyclin, angiotensin II, proteolytic enzymes, cytokines, and growth factors, more monocytes and T cells, platelets, and vascular smooth muscle cells are attracted. An acellular core of cholesterol esters surrounded by a fibrous cap is formed (Ross, 1999; Weissberg, 2000). Advanced lesions contain calcium hydroxyapatite and new blood vessels (Weissberg, 2000).

Outcomes of plaque formation. Lesion ruptures can and do take place in small plaques, and they are often undetectable. Through mechanical forces or inflammatory processes, the fibrous cap of the lesion is destroyed and the contents are exposed to the circulation once again, leading to platelet accumulation, fibrin deposition, thrombus formation, and increased size. Arteries can remodel themselves to a point and accommodate lesion growth, making most atherosclerotic plaque lesions clinically silent. However, in an advanced plaque, two scenarios other than silence can occur. If the lesion remains stable (thick fibrous cap covers the lipid core) and becomes large enough, blood flow is occluded and nutrients and oxygen fail to get through the vessel. This results in tissue ischemia and stable angina. Stable lesions are usually detectable on diagnostic imaging because of their size, encroachment into the artery wall, and higher calcium content. Alternatively, less- advanced lesions may rupture and produce unstable angina or MI. Many of the ruptured lesions leading to MI have 50% or less stenosis associated with them, explaining why MI occurs frequently in persons with no symptoms (Weissberg, 2000). These lesions are not necessarily detectable by diagnostic imaging methods such as angiography because the artery wall remodels itself.

Diagnostic Measurements

Bloodwork. An expert panel from the National Heart, Lung, and Blood Institute (NHLBI) released its final report on detection, treatment, and evaluation of high blood cholesterol in adults (ATP- III guidelines) in 2002. According to these guidelines (NHLBI, 2002), measurement of LDL, total, and HDL cholesterol should be performed after a 9 to 12-hour fast. Optimal levels include an LDL level less \than 100 mg/dL, total cholesterol less than 200 mg/dL, and HDL greater than or equal to 60 mg/dL (see Table 1).

Currently, it is possible to determine the apoE genotype, but this is not done on a population basis. It may be feasible eventually to determine an individual's genotype as it relates to the protein products involved in the inflammatory process and lipid metabolism. When this technology becomes available, tailored interventions designed specifically for each individual may be possible. Finally, based on the inflammatory process, measurement of inflammatory markers such as C-reactive protein should be considered (Weissberg, 2000).

Pedigree analysis. A detailed family pedigree should be developed to determine genetic risk within the individual's family. Currently, until genetic testing for cardiovascular disease is feasible in the general population, a comprehensive family history remains the clinician's best tool for assessing risk of inherited disease. Spahis (2002) provides an overview of constructing a family pedigree. In addition to gathering information about early death from heart disease as suggested by the ATP-III guidelines, risk factors such as aortic stenosis, peripheral vascular disease, hyperlipidemia, familial hypercholesterolemia, diabetes, and hypertension should be considered. Pedigrees should be discussed with adults with children so parents understand the future risk of the children and the benefits of early lifestyle modifications. In addition to the family history, a detailed medical history should be performed for each individual, including environmental factors such as smoking, diet, and exercise.

Table 3.

Major Interventions to Decrease Risk of Atherosclerosis

Imaging. Soft plaques do not always appear on imaging studies such as angiography. Coronary angiography assesses the lumen diameter to identify the presence of plaque and therefore has poor sensitivity in picking up soft plaques or plaques in areas where the lumen has remodeled (Grobbee &Bots, 2003; Weissberg, 2000). However, angiography is useful for more advanced lesions and is used often in clinically evident disease. Other forms of imaging such as ultrasonography, electron beam computed tomography, multi-slice computed tomography, magnetic resonance imaging, and positron emission tomography scanning have positive features and limitations. According to one review, B-mode ultrasonography provides the best method for tracking early changes in atherosclerotic disease (Grobbee & Bots, 2003). Bmocle ultrasonography is sensitive in distinguishing between plaques with high lipid content and those that are more stable, fibrous, and calcified.

Interventions

Perhaps the best hope for asymptomatic persons at risk for atherosclerosis is a multi-faceted approach based on individual genetic and environmental conditions (see Table 3). The extent to which the apoE alleles affect lipid levels and contribute to atherosclerosis varies based on age, gender, genotype, and environmental factors such as diet and smoking (Lahoz et al., 2001). Based on the 10-year risk profile established for adults through the ATP-III guidelines, lifestyle modifications in the form of diet, exercise, and weight management are recommended, accompanied by pharmacologie intervention if LDL-C levels warrant it (NHLBI, 2002). Chapter V of the NHLBI final report provides excellent guidelines for adopting a healthy lifestyle and reducing the risk of cardiovascular disease.

Diet. Because diets high in saturated fats and cholesterol are known to contribute to the development of atherosclerosis, dietary intervention is usually the first step toward lowering plasma lipid levels (Pentikainen et al., 2000; Valabhji & Elkeles, 2002). Reductions in LDL-C and in the ratio of HDL cholesterol to total cholesterol by either diet or drug have been associated with successful reduction in coronary artery disease and its progression (Rosenson, 2004). Interestingly, persons with the apoE ε4 allele are especially sensitive to dietary fat and cholesterol. LDL- C levels, which are high among persons with the ε4 allele, can be increased by saturated fatty acids and Irans fatty acids (Kromhout, Menotti, Kesteloot, & Sans, 2002). Additionally, persons exhibiting the ε4 allele have an increased response to dietary intervention in some studies over those with either the ε2 or ε3 allele (Ordovas & Mooser, 2002). A lowfat diet suppresses the untoward effects of having the apoE 84 allele (Reed et al., 2003).

Exercise. A regular exercise routine can lower triglycride levels, raise HDL levels, and increase metabolism of lipoproteins. Indirectly, exercise is beneficial by aiding weight loss and reducing adiposity. In addition to a low-fat diet, the American College of Sports Medicine recommends exercising 5 days per week, once per day (Durstine et al., 2003). Walking is often a recommended form of exercise because sports equipment and facilities are not necessary and the associated injury risk is minimal. Strength training is also often recommended, to include one set of 10 to 12 repetitions in the major muscle groups.

Medications. Medications are begun generally when lifestyle intervention has been ineffective in lowering LDL cholesterol levels (NHLBI, 2002). Recommended pharmacologic interventions include HMG- CoA reductase inhibitors (statins), bile acid sequestrants, nicotinic acid, and fibric acids (Reed et al., 2003). HMG-CoA reductase inhibitors (statins) provide improvements across the lipid profile, work to decrease LDL-C by 20% to 60%, and have demonstrated a 20% to 40% decrease in the risk of major coronary events (Durstine et al., 2003; Grobbee & Bots, 2003). These medications slow plaque progression and can reverse early atherosclerotic lesions. Currently, six statins are available in the United States: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), rosuvastatin calcium (Crestor), and simvastatin (Zocor). The most noticeable side effect of these medications is muscle discomfort (Durstine et al., 2003). Individuals exhibiting the ε4 allele have increased response to dietary intervention. Individuals with the 2 allele appear to be more responsive to statin therapy over those with other apoE alleles (Ordovas & Mooser, 2002).

Bile acid sequestrants (cholestyramine [Questran], colestipol [Colestid], colesevelam [WelChol]) inhibit the intestinal reabsorption of bile, thus increasing the amount excreted in the stool (Durstine et al., 2003). Hepatic LDL receptor activity is increased so more LDLC can be used for bile acid production, reducing plasma LDL-C levels. Side effects include constipation, bloating, flatulence, and in some cases, interference with absorption of fat-soluble vitamins and some medications (Durstine et al., 2003).

Nicotinic acid (niacin) inhibits VLDL synthesis in the liver and thus decreases LDL, total cholesterol, and triglycerides (Miller, 2003). Niacin is the most useful agent for increasing low HDL-C levels and also works to decrease LDL-C levels. Side effects of niacin are reversible hepatitis, stimulation of gout and peptic ulcers, glucose intolerance, flushing, and lowered blood pressure (Durstine et al., 2003).

Fibric acid derivatives (gemfibrozil [Lopid], fenofibrate [Tricor], clofibrate [Abitrate]) are used to decrease triglyceride levels. These drugs have few side effects but should not be used in conjunction with statins because rhabdomyolysis (acute disease characterized by skeletal muscle destruction) can occur (Durstine et al., 2003). These drugs inhibit VLDL secretion, increase lipoprotein lipase activity, and decrease triglyceride levels up to 50%. However, they have little effect on LDL levels (Tulenko & Sumner, 2002).

Finally, other medications are helpful in decreasing untoward events associated with atherosclerosis such as MI. These include anti-inflammatory medications such as aspirin and antioxidants such as vitamin E. Other medications such as beta blockers, thiazide diuretics, and oral contraceptives increase lipid panel components (Durstine et al., 2003). For example, beta blockers, such as metoprolol (Lopressor), atenolol (Tenormin), and propanolol (Inderal) increase plasma triglycerides and decrease HDL (Fogari et al., 1999; Malmqvist, Kahan, Isaksson, & Ostergren, 2001). Oral contraceptives containing ethinylestradiol and levonorgestrel (Leios, Stediril) increased triglyceride levels significantly, increased total cholesterol and LDL slightly, and decreased HDL levels as shown among 90 healthy women after 6 months of treatment (Scharnagl et al., 2004). Finally, the effect of thiazides, such as hydrochlorothiazide (Hydrodiuril, Esiclrix, Micro-zide), on plasma lipid levels appears to be dose related; higher doses increase cholesterol levels, while lower doses have minimal effects (Ott, LaCroix, Ichikawa, Scholes, & Barlow, 2003).

Other lifestyle modifications. Alcohol, tobacco, and body mass index also interact with apoE and increase the risk of CHD (Kromhout et al., 2002; Ribalta, Vallve, Girona, & Masana, 2003). Smoking provides the strongest link with development of CHD followed by diet (Kromhout et al., 2002). Giving up cigarettes, drinking in moderation, and losing weight through diet and exercise are important lifestyle modifications necessary for lowering the risk of atherosclerosis and CHD.

Conclusion

Traditional risk factor assessment and interventions based on this assessment continues to be the primary methods of treatment for individuals at risk for cardiovascular disease. Despite recent declines in CHD resulting from these interventions, rates of atherosclerosis and MI remain high. Other risk factors, including genotype and the inflammatory response, must be considered as well.

ApoE genotyping is already available, although not on a widespread basis. This may be due in part to the fact that the \risk of having a particular apoE genotype and developing CHD is not yet well established. While it cannot be used to diagnose individuals, the information from research on individuals with differing apoE alleles provides the practitioner with valuable information. If a patient is not responding well to a low-fat diet, he or she may have a genotype that would benefit more from statin therapy. Conversely, the patient who maintains high lipid levels despite statin therapy may have the genotype that doesn't respond well to this type of therapy and should be counseled on maintaining a strict low-fat diet.

In the future, when genotyping is more widespread for apoE and the other genes involved in lipid metabolism and the inflammatory process, treatment can be tailored to the unique profile of each person. Until then, traditional risk factor assessment must continue because it is working to reduce CHD. Also, greater efforts must be made at the adult and pediatric levels to encourage a healthy lifestyle, including exercise, weight management, and a healthy diet beginning in childhood. Finally, the knowledge generated at the laboratory bench must be considered when making practice decisions.

Definitions of Genetic Terms

Allele: One of the variant forms of a gene at a specific location on a chromosome.

Genotype: The genetic identity of the individual that does not show in outward characteristics.

Gene locus: Specific point on a chromosome where a gene is located.

Pedigree: Visual representation of family history using symbols for individual family members connected by lines to show relationship and transmission of inherited traits through multiple generations.

Phenotype: The observable traits or characteristics of an organism such as brown hair, blue eyes, or high cholesterol.

Source: National Human Genome Research Institute (2004)

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Susan M. Foley, PhD, RN, is a Research Assistant Professor, School of Nursing, and a Student in the Graduate School of Public Health Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.

Copyright Anthony J. Jannetti, Inc. Feb 2005

Source: Medsurg Nursing

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