Review of Risk Factors for Cardiovascular Diseases*

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ANNALS O F CLIN IC AL AND LABORATORY SC IEN CE, Vol. 29, No. 2 Copyright © 1999, Institute for Clinical Science, Inc.

R eview o f Risk Factors for Cardiovascular D iseases* LILY L. WU, Ph.D. Departments o f Pathology and Internal Medicine, University o f Utah Health Science Center, Salt Lake City, UT 84132

ABSTRACT Traditional risk factors for coronary heart disease (C H D ) include only the patient’s age and family history and w hether there is evidence o f hypertension, elevated LDL, low H D L , diabetes or history of smoking. In recent years, considerable progress has b e e n m ad e in id en tify in g a new g e n era tio n o f risk factors, including Lp(a), triglycerides, subfractions of H D L and LDL, modified LDL, apo E pheno/ genotype, homocysteine and fibrinogen. At th e same time, studies have broadened our knowledge of traditional markers. These advances have enabled physicians to make a b etter assessment of patient risk for C H D and to prescribe more appro­ priate treatm ent.

Introduction Coronary heart disease (CH D ) is a multifac­ torial disease. Many risk factors have been identified in the p ast.1,2,3 These are listed in table I. R ecent years have witnessed a signifi­ cant im provem ent in our understanding of these traditional risk factors. Additionally, a new generation o f biochem ical markers for C H D risk has been categorized. These devel­ opm ents have led to b e tte r assessm ent of patient risk and m ore accurate treatm ent for patients. This paper will endeavor to provide up-to-date information relating to traditional and newly-classified biochemical markers. C h olesterol

and

L ip o p r o t e i n s

Hypercholesterolem ia is a well-established risk factor for C H D .4 It has been suggested,

* Send reprint requests to: Lily L. Wu, Ph.D., ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108.

however, that any complete risk assessment of C H D should include other related m easure­ ments: triglycerides, high density lipoprotein (H D L) and the ratio of total cholesterol over H D L , particularly for individuals w ith low total cholesterol.4 Cholesterol and lipoprotein levels recom m ended for adults and children by the National Cholesterol Education Program (N CEP) are shown in tables II and III. L o w - D e n s it y L i p o p r o t e i n ( L D L )

Clinical studies have indicated that individu­ als w ith elev ated low -density lip o p ro te in (LDL) are at greater risk for CHD . M ost myo­ cardial infarctions (MI) occur in patients with 40 to 50 percent stenosis, rather than advanced occlusion. Studies have disclosed the im por­ tance o f stabilizing rupture-prone atheroscle­ rotic plaques. Recent clinical trials have dem ­ o n strated th a t aggressively low ering L D L cholesterol (LDL-C) could stabilize, reduce or even reverse the progression o f atherosclerotic

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w u

Low

TABLE I Major Conventional Coronary Heart Disease Risk Factors M ajor Risk Factor Age

Description Male > 45 yr. Female > 55 yr., or postmenopause without estrogen replacement

Family history of ECHD

Ml in male 1° relatives at age >55 Ml in fem ale 1° relatives at age > 65

Hypertension

Blood pressure > 140/90 mmHg or on antihypertensive medication

Low HDL < 35 mg/dl Diabetes mellitus Cigarette smoking High HDL

> 60 mg/dl (subtract one risk factor)

H i g h - D e n s i t y L i p o p r o t e i n ( H D L ) 8 ,9 ,1 0

T he prim e purpose o f high-density lipo­ protein (H D L) is to mobilize cholesterol from th e perip h ery and deliver to the liver for removal from blood circulation by catabolic mechanism. H D L concentration, therefore, is inversely correlated with risk for C H D .11,12 H D L can also protect L D L from oxidation damage. Each 1 percent increase in H D L cho­ lesterol has been associated with a 2 to 4 per­ cent decrease in C H D risk. H D L concentra­ tio n > 6 0 m g /d L ca n b e c o n s id e r e d a protective factor for C H D . Low H D L often is evidence of high levels o f other atherogenic lipoproteins and frequently accompanies other risk factors, such as insulin resistance, diabetes and elevated high blood pressure. This m ulti­ plicity of relationships may explain why low levels of H D L would predict C H D and would u n d e rs c o re th e im p o rta n c e o f m e a s u r­ ing HD L. H ig h T r ig ly c e r id e

ECHD = Early coronary disease. Ml = Myocardial infraction.

(TG) a n d

L ip o p ro te in R e m n a n ts

plaques.6 Lowering LD L-C is also considered effective in diminishing th e risk o f C H D m or­ bidity and mortality.7 Table IV outlines criteria and goals for treatm ent recom m ended for low­ ering LDL.

M ultiple analyses o f epidemiological data often disclosed that elevated triglyceride (TG) concentrations are not an independent risk factor for C H D . However, recent studies have suggested an independent association betw een TG and C H D .13’14,15,16 It is well known that triglyceride increases as H D L decreases. It is

TABLE II Lipid Abnormalities

Desirable

Borderline

High Risk

High Risk for Pancreatitis

Cholesterol

240

L D L -C

< 130

1 3 0 -1 5 9

>160

-

H D L -C Triglyceride TC/HDL»

>60 6.0

-

2 0 0 -4 0 0 5.0 - 6 . 0

-

> 1000 —

All in mg/dL except the TC /D H L. aNot yet recommended by ATP 1993, but it does provide substantial information about C H D .

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R E V IE W O F RISK F A C T O R S F O R CA RD IO V A SC U LA R D ISE A S E S

TABLE III

L ip o p r o t e i n S u b c l a s s e s

National Cholesterol Education Program Classification for Children and Adolescents L D L -C (mg/DL) (mmoL/L) Desirable Borderline High risk

TC

200

now considered im portant clinically if high tri­ glyceride concentrations are detected during the fasting state. Elevated TG is associated with over-production of very low-density lipo­ protein (VLDL), im paired chylomicron and V LD L catabolism . T he im proper catabolic products o f chylomicron and VLDL—the socalled rem nants— are very atherogenic. They tend to bind to arterial endothelium and to the deendothelialized areas, w here locally present lip opro tein lipase will in itiate triglyceride hydrolysis and reduce the size of adhering par­ ticles. These then are allowed to en ter the deeper structures of the arterial wall, resulting in atherosclerosis. Increased serum triglycer­ ides can also effect changes in the size and com position o f H D L and L D L particles. Elevated serum triglyceride levels are strongly associated with small dense, and more athero­ genic, L D L particles. TABLE IV National Cholesterol Education Program Low -Density-Lipoprotein Cholesterol Decision Values (mg/dL)

Patient’s Condition

Therapy D iet Drug

Ideal G oal

(C H D Risk factor3) < 2 risk factors

>160

> 190

2 risk factors

>130

> 160

100

> 130

apo E3/3 > apo E3/2. The response to drug treatm ent in the apo E phenotype is significantly different. Patients carrying E 4 have a lower response than those with the apo E2 phenotype.31 The composition of lipoprotein particles is influenced by the apo E phenotype. Apo E4 individuals are m ost likely to have smaller dense atherogenic L D L particles and are at greater risk for C H D . Apo E2 has a protective effect on C H D and is associated with longevity. Apo E2/2 is useful for confirming type III hyperlipidem ia (familial dysbetalipoproteinem ia).32 Type III hyperlipidemia is character­ ized by elevated plasma cholesterol and tri­ g ly cerid e levels an d by th e p re se n c e o f significant amounts of abnormal chylomicron and V LD L rem nants, which are collectively known as (3-VLDL. 3 -VLDL can be up-taken into peritoneal macrophages or smooth muscle through receptors. These P-VLDL receptors are not down-regulated by intracellular choles­ terol concentration. Thus, the massive choles­ terol accumulation can lead to foam cell for­ m ation and eventually to atherosclerosis. Apo E2 has a m uch lower affinity for receptors than is the case in E 3 or E4. Consequendy, individuals who are homozygous for the E2 allele (phenotype E2/2) are prone to a buildup of lipoprotein rem nant particles in their blood circulation. About 5 percent of E2 homozy­ gotes will evidence large quantities of rem nant particles as a result of the presence of an addi­ tional lipid-increasing factor w hich causes

R E V IE W O F RISK FA CT O RS F O R C A R D IO V A SC U LA R D ISE A S E S

elevated lipoprotein-exceeded apo E2/2 han­ dling ability. These factors can be excessive dietary cholesterol and/or fat intake, obesity, d iab etes or a g en e tic tra it such as L D L receptor m utation in familial hypercholesterolnem ia, th e re b y b rin g in g a b o u t type III hyperlipidemia. Diagnosis o f type III hyperli­ poproteinem ia is im portant. It is associated with accelerated atherosclerosis of both the c o ro n ary an d p e rip h e ra l a rte rie s , w hich responds extremely well to dietary and fibrateclass drag therapy.33 H o m o c y s t e in e

Hom ocysteine (Hey) is a thiol-containing amino acid. In plasma, 70 to 80 percent of Hey is present in protein-bound form, primarily bound to albumin. T he rem ainder exists as dimers of homocysteine (homocystine), mixed disulfides and only trace am ount as free thiol (homocysteine). Currently, all forms are col­ lectively called to tal plasm a hom ocysteine (tHcy). M ore than a dozen enzymes and cofac­ tors have a role in the complex processes to m aintain th e hom eostasis o f hom ocysteine. D eficien cy o r d y sfu n ctio n o f any o f th e enzymes or cofactors (such as vitamins B6 or B12 or folate) involved in the Hey metabolism may raise levels o f homocysteine in the blood circulation. Elevated homocysteine is an inde­ p en d en t risk factor for atherosclerosis and thrombosis.34,35,36 Elevated tH cy also acts synergistically with other risk factors, such as high LDL-C, Lp(a) and fibrinogen. Extrem ely high levels o f tH cy may be attributed to a major gene effect. Plasma tH cy levels are also influ­ enced by polygenic and environm ental factors. tH cy levels are im pacted by age, by a history of smoking and by many drugs. These factors are listed in table V. Homocysteinuria is a rare form o f inborn errors of metabolism (1:200,000 to 500,000). The most com m on form results from defi­ ciency of cysthionine-p-synthase. O thers may involve m ethylenetetrahydrofolate reductase or methyltransferase. T he major gene defect causes the enzyme to lose m ore than 90 p e r­ cent o f its activity. Hom ocysteinuria is charac-

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TABLE V Factors Causing Elevated Plasma Homocysteine Enzyme defects-genetic factors Cystathionine p synthase 5 , 1 0-M ethylene tetrahydrofolate reductase Methionine synthase Cobalamin (B 12) metabolism disorder Vitamin deficiencies B 12, B 6 and folate Diseases Renal and liver failure Acute lymphoblastic leukemia Drugs Methotrexate, nitrous oxide, metformin, phenytoin antagonists, anticonvulsants, 6-azaurdine Age and gender

terized by extrem e elevation of plasma hom o­ cysteine (50 to 500 |xmol/L). Patients with homocysteinuria are at high risk at an early age for pulm onary embolism, stroke, myocardial infarction, arterial occlusion or venous throm ­ boembolism. Thirty percent of homocystein­ uria individuals experience a throm boem bolic event by age 30, and their mortality rate is 20 percent before age 20. M oderately elevated plasma Hey is present in 5 to 7 percent of the general population and 20 to 40 p erce n t of cardiovascular disease patients. Recent clinical studies indicate that m oderately elevated plasma Hey (15 to 50 (xmol/L) is an independent predictor for ath­ erosclerosis and thromboembolism. It is linked w ith cerebral, peripheral and cardiovascular diseases. Patients with homocysteinemia are also at risk for deep vein thrombosis and p re­ m ature occlusive vascular disease. Individuals w ith homocysteinemia and coagulating factor defects such as Factor-V (Leiden) m utation may experience thrombosis at a very young age. Nygard recently dem onstrated a strong, graded connection betw een the plasma Hey level and overall mortality in patients diag­ nosed with angiographically-confirmed C H D .

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wu TABLE VI Normal Reference Range for Plasma Homocysteine (Fasting)

Age Group

N ew born

Adole­ scents

Adult M ale

Adult Fem ale

Elderly

Centena~ riants

1 5 -2 0

2 5 -2 7

Plasma Hey (|o.M)

3 -6

5 -8

6 -1 5

3 -1 2

Hey = Homocysteine.

In this group, the four-year mortality was 3.8 percent, versus 24 percent if their plasma Hey level had been
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Review of Risk Factors for Cardiovascular Diseases*

ANNALS O F CLIN IC AL AND LABORATORY SC IEN CE, Vol. 29, No. 2 Copyright © 1999, Institute for Clinical Science, Inc. R eview o f Risk Factors for Ca...

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