Lipid Management and Cardiovascular Disease



Lipid Management and Cardiovascular Disease


Kathleen A. Berra

Joan M. Fair



Cardiovascular disease (CVD) is the leading cause of death for American women and men and is responsible for 35.2% of all deaths. Approximately one in every five Americans died from CVD in 2005. The death rates vary by gender, age, ethnicity, and socioeconomic status.1 Importantly, the overall death rates from CVD declined by 24.7% from 1994 to 2004 likely as a result of improved risk factor surveillance and management.1 Elevated serum cholesterol and, particularly, elevated low-density lipoprotein (LDL) cholesterol levels are significant modifiable risk factors associated with the development and progression of CVD. More than 106 million Americans have a blood cholesterol higher than the desirable level of 200 mg/dL.1 Furthermore, more than 37 million Americans have a blood cholesterol more than 240 mg/dL, a level at which current treatment guidelines recommend the initiation of dietary or pharmacologic interventions.1, 2, 3 The good news is that, in the United States, age-adjusted prevalence of high LDL cholesterol level in adults dropped from 26.6% in 1984 to 25.3% in 2004. This was associated with an increased awareness of the relationship between high LDL cholesterol and CVD (39.2% vs. 63%) and an increased use of pharmacological therapies to reduce high blood cholesterol (11.7% to 40.8%). The end result has been a decrease in overall death and disability from CVD.1 This information demonstrates that both the incidence of high blood cholesterol and the benefits of treatment are substantial.

There is a large body of evidence, including animal studies,4 observational studies,5 and numerous clinical trials, that consistently point to a relationship between high blood lipids and CVD. A very recent example of this compelling relationship is the INTERHEART Study.6 The INTERHEART study using data from 52 countries, showed that 90% of populationattributable risk is strongly associated with nine easily measured risk factors.6 Two thirds (or 66%) of the population-attributable risks are accounted for by abnormal lipids (using the apo B/apo A-I ratio as a marker for abnormal lipids—a surrogate for LDL measure) and by current smoking. This association holds true for both men and women, across different geographic regions, and ethnic groups.6 Table 36-1 summarizes the results of large randomized lipid-lowering primary and secondary prevention trials.2,7, 8, 9, 10, 11, 12, 13, 14, 15 Meta-analyses of the cholesterol-lowering clinical trials estimated that a 10-mg/dL reduction in total cholesterol results in a 22% reduction in CVD incidence after 2 years of intervention, and a 25% reduction after 5 years.3,16 There is some evidence that cholesterol lowering begun at an early age (e.g., age 40 years) may provide greater risk reduction than if started at a later age (e.g., age 70 years).17 However, recent clinical trials including persons older than 65 years show benefit for CVD risk reduction in older populations.14,18

The Adult Treatment Panel III (ATP III) Guidelines were updated in 2004 in response to these important clinical trials.3 This update highlighted the importance of lipid-lowering therapy in high-risk and moderately high-risk patients to achieve a 30% to 40% reduction in LDL cholesterol level, even if baseline levels were low or “normal” by current guidelines. An LDL goal of <100 mg/dL is now considered a reasonable option for patients designated at high risk. For those considered to be at very high risk an LDL goal of <70 mg/dL is proposed. The LDL goal of <70 mg/dL is suggested on the basis of the known elevated risk for heart attack and stroke in this group. This important ATP III update significantly expands both the numbers of persons needing treatment and redefines LDL treatment goals. Therapeutic Lifestyle Change (TLC) remains the cornerstone of treatment for all adults with elevated risk. TLC includes heart healthy nutrition, weight control, and regular physical activity. Initiation of pharmacologic therapies is based on risk classification.3 See Table 36-2 for LDL goals and cut points for initiation of TLC and pharmacological therapies. Cardiovascular nurses need to understand the pathophysiology of dyslipidemia and should actively participate in the identification and management of lipid disorders.19


BLOOD LIPIDS: STRUCTURE AND FUNCTIONS

The complex relationships between genetic and metabolic mechanisms and the molecular interactions within the cell wall help explain the association between lipid abnormalities and CVD. The major lipid particles, cholesterol and triglycerides, both have important functions in the body. Cholesterol is an essential component of cell membranes, functioning to provide stability while permitting membrane transport; it is a precursor to adrenal steroids, sex hormones, and bile and bile acids. Triglycerides are the major source of energy for the body. Both cholesterol and triglycerides are insoluble molecules and must be transported in the circulation as lipoproteins.

Lipoproteins are complexes of nonpolar lipid cores (triglycerides and cholesterol esters) surrounded by a surface coat of polar lipids (phospholipids and free cholesterol) and specific proteins called apoproteins. Total cholesterol, for example, is composed of 18 different lipid and lipoprotein particles.20 Lipoproteins can be classified according to their density, their migration on an electrophoretic field, or their lipid and apoprotein composition.21

During the 1980s, significant advances were made in determining the function of the apoproteins, the lipid processing enzymes, and lipoprotein receptors. Apoproteins function as more than transport vehicles; they have variant properties that activate enzyme systems or receptor sites to promote the catabolism or removal of lipoproteins from the circulation.22 The functions of nine apoproteins in the lipid metabolic cascade have
been identified: apo A-I, apo A-II, apo B-100, apo B-48, apo C-I, apo C-II, apo C-III, apo E2, apo E3, apo E4, and lipoprotein(a), or Lp(a). In addition, the actions of several lipoprotein-processing enzymes (lipoprotein lipase [LPL], hepatic lipase [HL], lecithin cholesterol acyltransferase, and cholesteryl ester transfer protein [CETP]) and the function of cell receptors, including the LDL and chylomicron remnant receptor, are now established. These advances permit an understanding of lipid metabolism, as well as the abnormalities leading to elevated blood cholesterol.








Table 36-1 ▪ SELECTED, RANDOMIZED, CLINICAL TRIALS USING STATIN THERAPY TO LOWER CHOLESTEROL













































































































































































Trial


Number of Patients


Age (years)


Lipids (mean, mg/dL)


Average Length of Follow-up


Mean Lipid Reduction


Outcomes


Primary Prevention


West of Scotland


6,595 men


45-64


TC: 272


4.9 years


TC: ↓ 20%


Nonfatal MI and



(WOSCOPS)*




LDL: 192



LDL: ↓ 26%


CVD death: ↓ 31%


AFCAPS/TEXCAPS


5,608 men



TC: 221


5.2 years


TC: ↓ 18%


Major coronary events




997 women



LDL: 150



LDL: ↓ 25%


(MI, unstable angina, or sudden cardiac death: ↓ 37%)


Primary and Secondary Prevention


Heart Protection


15,454 men


40-80


TC: 228


5.0 years


LDL ↓ 37 mg/dL


All cause mortality ↓ 13%, major vascular events ↓ 24%
Coronary death rats ↓ 27%, nonfatal/fatal stroke ↓ 25%
Nonfatal MI and coronary death ↓ 27%.



Study


5,082 women


(52% > 65)


LDL: 131‡‡


Prospective Study of


2,804 men


70-82


TC: 150-350


3.2 years


LDL: ↓ 34%


Composite of: coronary death, nonfatal MI, fatal or nonfatal stroke ↓ 24%



Pravastatin in the


3,000 women



Elderly at Risk§


Anglo-Scandinavian


10,350


40-79


LDL: 132


3.3 (stopped early due to benefit)


LDL ↓ 29%


Total cardiovascular events ↓ 21%
Total coronary events ↓ 29%
Total fatal and nonfatal stroke ↓ 7%



Cardiac Outcomes


81% male



Trial-Lipid



Lowering Arm||


Secondary Prevention


Scandinavian


3,617 men


35-70


TC


5.4 years


TC ↓ 28%


CHD deaths: ↓ 42%



Simvastatin


427 women



LDL: 188



LDL: ↓ 38%


Nonfatal MI and CVD death ↓ 37%



Survival Study (4S)


CARE#


4,159


Average 59


LDL: 139


3 years


LDL: ↓ 27%


Major coronary events ↓ 25%
Coronary mortality ↓ 24%
Total mortality ↓ 9%


LIPID**


9,014


31-75


LDL: 150


61 years


LDL: ↓ 25%


Major coronary events ↓ 29%
Coronary mortality ↓ 24%
Total mortality ↓ 23%


Pravastatin or


4,162


≥18


TC: ≤240 mg/dL


24 months


LDL: ↓ 22%


Composite death from any cause, MI, hospitalization from unstable angina, revascularization, or stroke ↓ 16%



Atorvastatin




Mean LDL: 106



Pravastatin



Evaluation and






↓ 51%



Infection—






Atorvastatin



Thrombolysis in MI††


TC, total cholesterol; LDL, low density lipoprotein


* WOSCOPS: Shepherd, J., Cobbe, S. M., Ford, I., et al., for the West of Scotland Coronary Prevention Study Group. (1995). Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New England Journal of Medicine, 333, 1301-1307.

AFCAPS/TEXCAPS: Downs, J. R., Clearfield, M., Weis, S., et al., for the AFCAPS/TexCAPS Research Group. (1998). Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA, 279, 1615-1622.

HPS: Heart Protection Study Collaborative Group. (2002). Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: A randomised placebo-controlled trial. Lancet, 360, 7Y22.

§ Shepherd, J., Blauw, G. J., Murphy, M. B., et al., PROSPER study group. (2002). Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. PROspective Study of Pravastatin in the Elderly at Risk. Lancet, 360, 1623-1630.

|| Sever, P. S., Dahlof, B., Poulter, N. R., et al., ASCOT investigators. (2003). Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial. Lancet, 361, 1149-1158.

4S: Scandinavian Simvastatin Survival Study Group. (1994). Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet, 344, 1383-1389.

# CARE: Sacks, F. M., Pfeffer, M. A., Moye, L. A., et al., for the Cholesterol and Recurrent Events Trial Investigators. (1996). The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. New England Journal of Medicine, 335, 1001-1009.

** LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. (1998). Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. New England Journal of Medicine, 339, 1349-1357.

†† Cannon, C. P., Braunwald, E., McCabe, C. H., et al., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. (2004). Intensive versus moderate lipid lowering with statins after acute coronary syndromes. New England Journal of Medicine, 350, 1495-1504.

‡‡ Serum lipids were determined by direct LDL measurement method as baseline samples were nonfasting. If calculated by Friedewald (as in other trials) LDL would be ˜15% higher.










Table 36-2 ▪ GUIDELINES FOR INITIATION OF TLC AND/OR PHARMACOTHERAPIES—MODIFICATIONS BASED ON THE UPDATE TO ATP III3























































Risk Category


LDL-C Goal


Initiate TLC


Consider Drug Therapy


1.


High Risk* CHD or CHD Risk


<100 mg/dL


≥100 mg/dL


≥100 mg/dL



Equivalents (10-year risk <20%)


optional goal <70 mg/dL



<100 mg/dL: consider drug options


2.


Moderately High Risk


<130 mg/dL


≥130 mg/dL


≥130 mg/dL



10-year risk 10%-20%




100-129 mg/dL: consider drug options


3.


Moderate Risk


<130 mg/dL


≥130 mg/dL


≥160 mg/dL



10-year risk <10%


4.


Lower Risk


<160 mg/dL


≥160 mg/dL


≥190 mg/dL



0-1 risk factor




160-189 mg/dL: LDL lowering drug optional


* Risk factors include cigarette smoking, hypertension (BP > 140/90 mm Hg or on antihypertensive medication), low HDL-C (<40 mg/dL), family history of premature heart disease (CHD in first-degree male relative < 55 years of age, or in a female relative > 65 years of age), and age (men ≥ 45 years of age and women ≥ 55 years of age).

CHD includes history of MI, unstable angina, stable angina, coronary artery procedures (stenting, angioplasty, bypass surgery, or evidence of clinically significant myocardial ischemia.

CHD Risk Equivalents include manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease (transient ischemic attach or stroke or carotid origin or > 50% obstruction in carotid artery), diabetes, and 2+ risk factors with 10-year risk for hard CHD > 20%.



LIPID METABOLISM AND TRANSPORT

The gut and liver are responsible for the production of the six principal lipoproteins. Exogenous lipoproteins are formed in the mucosa of the small intestine after digestion of dietary fats. During the digestive process, hydrolyzed products of ingested fats enter epithelial cells of the small intestine, where they are converted into triglycerides and cholesterol esters. These products are then aggregated into the lipoprotein complexes known as chylomicrons. Chylomicrons pass into small lymph vessels and reach the circulatory system through the thoracic duct. In the peripheral capillaries, chylomicrons are hydrolyzed by the enzyme LPL, located on the capillary endothelium. Free fatty acids and glycerol then enter adipose tissue cells. A cholesterol-rich chylomicron remnant (a second lipoprotein complex) is released into the circulation when lipolysis is nearly complete. Chylomicron remnants are cleared rapidly by the liver (Fig. 36-1).23,24

In the liver, the endogenous lipoprotein cascade begins with the production of very-low-density lipoproteins (VLDLs). Triglycerides are resynthesized from chylomicrons and packaged with specific apoproteins, apo B-100, apo C-I, apo C-II, and apo E, to form VLDL. Once VLDL is released into the circulation, intermediate-density lipoproteins (IDLs) and VLDL remnants are formed from VLDL lipolysis. This process takes place in the capillary endothelium and is mediated by LPL, the same enzyme responsible for the hydrolysis of chylomicrons. Apo C-II also acts as a cofactor in these processes.25

LDL receptors in the liver recognize and bind with apo E on the IDL particle and remove approximately half of the IDL from the circulation. The remainder is converted by HL into smaller cholesterol-rich lipoproteins known as LDL. Apo B-100 is the remaining protein left on the surface coat of LDL particles. The LDL receptors on cells of the liver and other organs that require cholesterol for structural and metabolic functions bind with apo B-100 and facilitate the removal of LDL from the blood. Figure 36-2 illustrates the endogenous pathway. The LDL particle is the major cholesterol-carrying lipoprotein in the blood and, consequently, the most atherogenic lipoprotein.21 Under normal conditions, more than 93% of the cholesterol in the body is located in the cells, and only 7% circulates in the blood. Two thirds of the blood cholesterol is carried by LDL. Increased cellular uptake of cholesterol through the LDL receptor pathway suppresses the cell’s own synthesis of cholesterol by inhibiting the hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase enzyme. This enzyme determines the rate of cholesterol synthesis. As cellular cholesterol levels increase, the activity of the LDL receptor is downregulated, and synthesis of new LDL receptors is inhibited.26 These feedback control mechanisms serve as the rationale for determining the treatment of elevated blood cholesterol.

Several metabolic and genetic disorders can be related to elevated LDL cholesterol levels. Habitually high dietary intakes of saturated fats and cholesterol beyond that needed for cell functions result in blood levels of LDL beyond normal and result in
inhibited LDL receptor activity. High LDL levels also can result from a decrease in clearance of LDL because of a deficiency in LDL receptors. This deficiency may be caused by genetic abnormalities in the structure of the receptor binding sites (where apolipoproteins bind) or by a decrease in LDL receptors on the surface of cells. In addition, genetic mutation in apoproteins, particularly apo E and apo B-100, can result in decreased cholesterol clearance. The metabolic consequence is an increased blood level of this atherogenic lipoprotein and the synthesis of cholesterol within cells, a process normally suppressed by LDL uptake.






Figure 36-1 The exogenous metabolism of lipoproteins and the transport of chylomicrons to the tissues and chylomicron remnants to the liver.






Figure 36-2 The endogenous lipid transport system originates in the liver. LDLs provide essential cholesterol to the tissue cells.


REVERSE CHOLESTEROL TRANSPORT

Studies have consistently observed a protective effect of high-density lipoprotein (HDL). For example, high levels of HDL have been associated with a reduced risk of CVD.8,27 It has been suggested that the protective effect of HDL is greater than the atherogenic effect of LDL cholesterol. For men in the Framingham Heart Study, a 50% reduction in coronary risk was found with every 10-mg/dL increment in HDL.28 Studies have indicated that increased apo A-I levels may also be inversely related to CVD.29 Clinical trial data demonstrated that pharmacological increases of HDL cholesterol significantly decreased coronary and stroke events among patients with CVD.30

At present, the synthesis and metabolism of HDL is not fully elucidated. Over the last decade, research directed at identifying therapeutics to raise HDL levels has led to an increased understanding of the complex mechanisms involved in HDL synthesis and its role in reverse cholesterol transport (the transport of cholesterol from the tissues to the liver resulting in biliary excretion of cholesterol).31

HDL particles are composed of proteins ˜50%, phospholipids ˜30% and cholesterol ˜25%, triglycerides ˜5%, and assorted lipoprotein-processing enzymes.31 The intestine and liver are responsible for synthesizing the precursors of HDL and its major lipoprotein, apo A-I to form incomplete (or nascent) lipidpoor HDL precursors. These precursors acquire excess cholesterol through a variety of mechanisms outlined below. One early step is the cholesterol efflux from macrophages mediated by the membrane protein, adenosine triphosphate binding cassette transporter A-1 (ABCA1), one of a family of proteins that transport molecules across cell membranes.32 It is proposed that ABCA1 allows binding with apo A-I in nascent HDL to form more mature HDL particles.33 Other steps include the action of the enzyme, lecithin cholesterol acyltransferase, which converts free cholesterol in the tissues into an HDL cholesteryl ester core.34,35 Apo A-I has been shown to activate lecithin cholesterol acyltransferase and may influence the activity of the CETP. CETP facilitates the exchange of cholesterol esters for the triglycerides in apo B lipoproteins including LDL and VLDL.36 Apo C-II is a cofactor for LPL. In the presence of circulating triglycerides, apo C-II moves from HDL to the triglyceride particle, activating LPL and promoting the catabolism of VLDL.37 This mechanism, in part, explains the clinical observation of an inverse association between high triglycerides and low HDL levels. A third apoprotein, apo E, is thought to facilitate direct transfer of cholesterol esters to hepatocyte receptors.37 Cholesterol esters are then excreted in bile or bile acids.38

Although the protective effect of HDL has been linked to its role in the reverse transport of cholesterol, it is clear that other factors, particularly genetic factors, determine coenzyme, apoprotein, and receptor activity. In fact, it is estimated that 50% to 70% of the variation in HDL is genetically determined influencing the receptor and enzyme activity involved in the catabolism of HDL.39 Deletions or mutations of the apo A-I gene results in very reduced HDL levels (e.g., A-I Milano) and may be associated with increased atherosclerosis. One important recent discovery was that of the ABCA1 genetic defect manifested in Tangiers disease as a disorder with extremely low HDL levels and with accelerated cholesterol tissue deposition.32,40

Recent studies have found that plasma HDL levels are regulated by a class of enzymes including LPL, HL, and endothelial lipase (EL).41 LPL is synthesized by adipose and skeletal muscle cells and acts primarily on the hydrolysis of triglycerides. HL is synthesized in the liver cells and acts on triglyceride and phospholipid catabolism. EL is synthesized in endothelial cells and appears to regulate HDL levels by preventing the transfer of triglycerides and remnant particles to HDL. Evidence includes genetically modified animal models that over express EL show a marked decrease in HDL levels42 and human studies observing genetic variants in the EL gene in persons with high HDL levels.39

While we have gained a greater understanding of the role of HDL in reverse cholesterol transport, studies also suggest that HDL may have both pro- and anti-inflammatory properties and in the face of inflammatory states, HDL may be altered to become proinflammatory.43,44 This may explain the finding that atherosclerosis (as an inflammatory disease) is observed even in persons with normal to high HDL levels. Studies have also suggested that HDL may act as an antioxidant, by preventing the oxidation of LDL, thus rendering it less atherogenic,45,46 or by attenuating the expression of other enzymes and molecules that alter endothelial dilation and chemotactic properties.47

At present, there are two major subclasses of HDL based on density and apoprotein composition. HDL3 is richer in apo A-II than HDL2, which has a higher concentration of apo A-I.29
Production of apo A-I is higher in women than in men and is increased by exercise training, alcohol consumption, and estrogen administration.21 Premenopausal women have more than three times the concentration of HDL2 than do men. Studies have also suggested that HDL may act as an antioxidant, preventing the oxidation of LDL.45,46


LDL VARIANTS


LDL Particle Size

Mounting evidence suggests that the size of the LDL particle plays an important role in its atherogenicity. Particle size is determined by flotation rates after ultracentrifugation procedures. LDL can be separated into a small dense LDL particle (phenotype B) and a larger less dense LDL particle (phenotype A).48 Clinical trial evidence suggests that people with a predominance of small dense LDL particles have a higher incidence of CVD and more accelerated progression of coronary lesions.49 The exact mechanism of the negative influence of the small dense LDL particle is not completely understood. One possible explanation is that the smaller denser particles have a greater ability to penetrate the endothelial space and participate fully in the subendothelial atherosclerotic process. Small LDL particles also appear to be more susceptible to oxidation than larger LDL particles.50 In addition, the small dense LDL particle is most commonly found in conjunction with a constellation of other factors, including hypertriglyceridemia, low HDL cholesterol, and insulin resistance.51

Research also suggests that it is possible to increase (alter) the size of the LDL particle to the larger (phenotype A) size by reducing triglycerides and normalizing insulin sensitivity. In addition, lipid-lowering drugs such as bile acid-binding resins, niacin, and the fibrates are reported to alter particle size favorably.48


Oxidized LDL

Ongoing research in lipid metabolism is investigating the issue of oxidation. Molecular biologists have established that modified or oxidized LDL is taken up more rapidly in vitro by monocytes and macrophages than is native LDL.52 It has also been shown that Lp(a) is a primary carrier of oxidized LDL and account for the relationship between elevated Lp(a) and atherosclerosis.53

Oxidized LDL has been found to be cytotoxic, and it is postulated that this facilitates endothelial injury, leading to the development of fatty streaks and atherosclerotic lesions. Oxidative inhibitors can block the modification of LDL to an oxidized form. Studies are ongoing in this area but a clear understanding of oxidized lipids and CVD remains elusive.54


The Role of Lp(a)

Genetic researchers investigating variant LDL particles uncovered a lipoprotein, Lp(a), that is similar to LDL with each particle linked to a molecule of the atherogenic apo B-100 in a 1:1 ratio.55 The attached protein, apolipoprotein(a) (apo[a]) is unique and is similar in DNA sequence to plasminogen, a substance that breaks up blood clots Recent prospective studies and meta-analysis have found elevated levels of Lp(a) are independent predictors of CVD. Lp(a) has also been detected in atherosclerotic plaques.56 Lp(a) levels vary inversely to the size of the apo(a) protein. Those who are Black and South Asian have higher Lp(a) levels compared with those who are Caucasian or from other Asian populations.57 Epidemiology studies suggest that Lp(a) levels above 25 to 30 mg/dL constitute CVD risk, further, it is estimated that 37% of those at high risk of CVD have elevated levels of Lp(a).55 Currently only one therapeutic agent, niacin, lowers Lp(a) levels. A more complete understanding of the mechanisms by which Lp(a) influences atherosclerosis and the effect of apo(a) size is needed. Like Lp(a), there are a number of emerging lipid risk factors that may further explain the relationship of dyslipidemia to coronary heart disease (CHD) (Table 36-3).


Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)

The search for biomarkers that identify those at risk for CVD has led to interest in Lp-PLA2, an enzyme that hydrolyzes lipids and preferentially oxidized LDL thereby triggering inflammatory processes.58 It is known that Lp-PLA2 is produced by macrophages (prominent in the inflammatory atherosclerotic process) and mainly carried in circulation bound to LDL cholesterol. Clinical trial studies have observed a positive but inconsistent association between elevated Lp-PLA2 and risk of CVD and stroke.58 A cut-point of 235 ng/mL or more (greater than the 50th percentile from population studies) has been suggested as a level indicative of risk for CVD.59


CHOLESTEROL AND ENDOTHELIAL FUNCTION

Serum cholesterol levels and diets high in saturated fat have been associated with impairments in endothelial functioning. The endothelium acts to regulate vascular tone, platelet adhesion, thrombosis, and growth factors.60 Studies have demonstrated that elevated cholesterol results in a reduced vasodilation response. Furthermore, when cholesterol is lowered, vasodilation responses improve.61

Elevated cholesterol also increases platelet aggregation and monocyte adhesion, factors that lead to thrombus formation and plaque rupture.62 Continuing research suggests that the lipids influence a variety of endothelial responses that appear to contribute to the atherosclerotic process.


DYSLIPIDEMIC DISORDERS

Although the metabolic processes related to blood lipids are complex and influenced by both genetic and environmental factors, the management of dyslipidemia has been well characterized. National recommendations have been developed on the basis of the scientific evidence and taking into account the need for both primary and secondary prevention of CVD.2,3 In general, lipid disorders can be characterized by the specific lipid abnormalities observed (see Table 36-3).


HYPERCHOLESTEROLEMIA

Hypercholesterolemia is the most common dyslipidemia and, in most people, decreased LDL clearance is responsible for the
observed abnormality. A high intake of dietary cholesterol and saturated fatty acids downregulates LDL receptor activity and receptor synthesis, resulting in decreased LDL clearance.63








Table 36-3 ▪ LIPID ABNORMALITIES AND ASSOCIATED MECHANISMS


















































































Lipid Abnormality


Mechanisms


Elevated total cholesterol


High dietary intake of saturated fat and cholesterol



LDL receptor deficiency and other enzyme/receptor abnormalities.


Elevated LDL-cholesterol


LDL receptor deficiency



Apoprotein B-100 genetic defect, other enzyme/receptor abnormalities.



High dietary intake of saturated fat and cholesterol


Elevated triglycerides


Deficiency in LPL



Obesity, physical inactivity, insulin resistance, glucose intolerance



Excessive alcohol intake


Low HDL


Apoprotein A-I deficiency, other enzyme/receptor abnormalities



Reduced VLDL clearance



Cigarette smoking, physical inactivity



Insulin resistance



Elevated triglycerides



Overweight and obesity



Very high carbohydrate (CHO) intake (>60% total calories) Certain drugs (β-blockers, anabolic steroids, progestational agents)


Increased lipoprotein remnants (VLDL is a surrogate marker for Lipoprotein remnants when triglyceride (Tg) is >200 mg/dL)


Defective apolipoprotein E Seen in familial combined hyperlipidemia


Level is genetically determined


Lp(a)


Lipoprotein phospholipase A2 (LpPLA2)


An enzyme that hydrolyzes cholesterol and initiates inflammatory processes


Small LDL particles


Particle Size is determined by level of Triglycerides; LDL particle is denser and more atherogenic at higher levels of TG


HDL Subspecies


Low levels of HDL 2 and 3 increases CVD risk? Genetically determined versus lifestyle and other lipid levels


Apolipoprotein B


A potential marker for all atherogenic lipoprotein


Apolipoprotein A-I


Increased CVD risk when apo A-I is low


Combined dyslipidemias small, dense


Defects in VLDL and LDL receptor activities coexisting with environmental influences such as obesity, physical inactivity, diet high in saturated fat, and cigarette smoking


LDL, high triglycerides, low HDL elevated


LDL and triglycerides


National Cholesterol Education Program (2001).



Familial (Severe) Hypercholesterolemia

Severe hypercholesterolemia is caused most commonly by a genetic disorder and is known as familial hypercholesterolemia (FH). There are two types of FH, heterozygous and homozygous. Plasma LDL cholesterol normally binds to cell membrane receptors and is taken into the cell for several biologic functions. In heterozygous FH, there is one normal gene and one abnormal gene for the LDL receptor.

Because only half the normal number of LDL receptors are synthesized, LDL is removed from the blood at two thirds the normal rate.26 The result is a two- to three-fold increase in blood LDL levels. One person in 500 is thought to have this genetic disorder, which eventually results in an increased risk for myocardial infarction (MI).2,64 The homozygous form of FH develops when two abnormal genes are inherited. The one in one million persons who have this disorder have LDL levels six times normal and may have an MI as early as age 5 to 15 years.2,26,48,64 In addition, a genetic defect related to apo B-100 results in marked elevations in LDL cholesterol.


Hypertriglyceridemia

The relationship between triglycerides and CVD is not entirely clear. Elevated serum triglyceride levels have been associated with CVD. However, the strength of the association is diminished when other CVD risks are accounted for, leading some to suggest that elevated triglycerides are a marker for other atherogenic factors.65 Chylomicrons and VLDL are lipoprotein carriers of triglyceride and, whereas chylomicrons are not considered to be atherogenic, the remnants of VLDL catabolism are smaller particles that are richer in cholesterol esters.65 These remnant particles, or IDL, are considered more atherogenic.66

Elevated triglycerides are frequently observed in people who also have low HDL levels and small dense LDL particles. This combination of lipid abnormalities is considered an atherogenic phenotype.65 In addition, elevated triglycerides (and its associated small dense LDL particle size and low HDL cholesterol level) commonly exists with insulin resistance (with or without glucose intolerance), hypertension, obesity (particularly abdominal obesity pattern), and prothrombotic and proinflammatory states. This combination of risk factors is commonly called the metabolic syndrome and is linked to increased CVD risk.2,3 See Table 36-4 for a summary of the metabolic syndrome characteristics. These associations suggest that elevated triglyceride levels may be a marker for other CVD risk factors. Diabetes also results in increased plasma triglyceride levels because of increased
VLDL. LDL cholesterol is more glycated in patients with diabetes compared with nondiabetic subjects. Glycated LDL particles have increased oxidative susceptibility.65 HDL is often low in patients with diabetes as a result of increased HL triglyceride activity. Additionally, hyperglycemia is associated with significantly increased mortality in patients with acute coronary syndrome. The Heart Protection Study (HPS) further confirmed the importance of lipid management in persons with type 2 diabetes. HPS included 5,963 persons with diabetes (ages 40 to 80 years). Those subjects receiving simvastatin 40 mg/day had significant reductions of 25% for major coronary events including stroke and revascularization.12

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