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
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
127 0091-7370/99/0300-0127 $01.75 © Institute for Clinical Science, Inc.
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
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
High Risk for Pancreatitis
200 - 239
L D L -C
1 3 0 -1 5 9
H D L -C Triglyceride TC/HDL»
>60 <200 < 5 .0
<35 >400 > 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 .
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
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
<110 1 1 0 -1 2 9
2.85 2 .8 5 -3 .3 4
<170 1 7 0 -1 9 9
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)
Therapy D iet Drug
Ideal G oal
(C H D Risk factor3) < 2 risk factors
> 2 risk factors
aRisk factors in Table I. Low HDL «.s.«.
M o d if ie d L D L
Lipoprotein particles are a heterogeneous mixture of lipoproteins. They differ from each other in size, density, lipid content and apolipoprotein composition as well as in function.17 D epending on the analytical methods used, H D L and LD L each can be resolved into a num ber of subfractions. The two major classes for H D L are H D L 2 and H D L 3.18 T he larger, lighter H D L 2, but not H D L 3, particles are decidedly associated with the extent and pro gression of C H D . H D L particles can also be separated into subfractions according to their apolipoprotein composition. H D L with apo AI only is the so-called LpAI particle, and H D L co n taining b o th AI and A ll is know n as L pA L A II. LpA I may re p re se n t th e a n ti atherogenic fraction o f H D L .19 Quantification of LpAI and LpALII allows for a m ore accu rate prediction of C H D risk. L D L also exists in subspecies that vary in size and density.20,21 The smaller dense L D L particles are more atherogenic because they have lower L D L -receptor binding capacity, but they have increased ability to bind to pro teoglycans on the arterial wall and greater oxi dative susceptibility. As well as separation of L D L into subfractions by particle diam eter, L D L subclasses pattern separated on 2 to 14 p ercent gradient polyacrylamide gel can be identified as phenotypes A and B. Phenotype A is characterized by a predom inance of large L D L particles, type B by a preponderance of smaller and denser L D L particles. Individuals with type B pattern are at higher risk for C H D . L D L particles are also known to be m odi fied through oxidation and glycation.22,23,24 These modified LD Ls are readily taken up by scavenger receptors. This process is not subject to feedback control and can result in accumulation of LD L in macrophage and e n d o th e lia l cells, m aking m od ified L D L highly atherogenic. L i p o p r o t e i n (a) [L p (a)]
Lipoprotein (a) [Lp(a)] is a cholesterol-rich plasma lipoprotein. Its structure is similar to
that of LDL, but with an additional apolipoprotein (a) link to apo B through a disulfide bond. Elevated Lp(a) is related to prem ature cardiovascular disease and stroke.25-26 W hen the plasma concentration o f Lp(a) is above 30 mg/dL, the risk for C H D increases two-fold. W hen both L D L and Lp(a) are elevated, the risk is extended five-fold. The similarity in structure of Lp(a) to plas minogen and L D L may be the mechanism for atherosclerosis and thrombosis. In thrombosis, Lp(a) inhibits fibrinolysis by com peting with plasminogen for fibrin binding; it also impedes the activation of plasminogen by tissue specific plasminogen activator (t-PA). Lp(a) can carry cholestero l in to m acro p h ag e an d sm ooth muscle cells, which plays a role in foam cell formation. Lp(a) is an independent risk factor for C H D and can work synergistically with other factors to increase the risk. There is no meaningful way to treat elevated Lp(a) levels. Standard therapy, including diet, ch o lestero l synthesis in h ib ito rs, bile acid sequestrates and probucol, have no effect. Nia cin, neomycin and bezafibrate may have some beneficial result. Screening for Lp(a) concen tration is recom m ended for patients with coro nary disease or individuals with a family history of C H D , as well as patients with infarction or with elevated LD L, low H D L and renal or coagulation dysfunction. Patients w ith high Lp(a) should undergo aggressive therapy to eliminate other treatable risk factors and thus minimize overall C H D risk.
A p o lip o p ro te in
E ( a p o E) P o l y m o r p h i s m
Apo E functions as receptor-binding ligand to m ediate the interaction o f lipoproteins with the receptors and initiate th eir up-taking by the cell surface L D L receptor or receptorrelated proteins. Consequently, apo E plays a critical role in transporting triglycerides and cholesterol and in lipoprotein metabolism.27,28,29 The apo E gene is highly polymorphic. The three most comm on alleles are e2, e3 and e4. The combination of these alleles form ed six genotypes, which coded for six com m on p h e
notypes: E2/2, E3/3, E4/4 and E2/3, E3/4, E 2/E 4.30 The th ree isoforms have different receptor-binding qualities and different bio logical properties. Com pared to apo E3, apo E4 has a higher and apo E 2 lower (less than 2 percent) binding ability. Apo E3 is the most com mon isoform in the general population and is identified as the wild type. ApoE polymorphism affects the efficiency o f dietary cholesterol absorption. In individu als with apo E4/3 and E4/4, the increase in plasma LD L-C concentrations is greater when dietary cholesterol intake rises. The effect of dietary fat intake on the increase of L D L cho lesterol follows the order in term s of pheno types with apo E4/3, 4/4 > 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-
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 .
wu TABLE VI Normal Reference Range for Plasma Homocysteine (Fasting)
N ew born
Adult M ale
Adult Fem ale
1 5 -2 0
2 5 -2 7
Plasma Hey (|o.M)
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 <9 versus ^ 1 5 (xmol/L.37,38 The normal range (table VI) is commonly set at 5 to 15 mol/L. Since plasma Hey is a graded risk factor, the risk for vascular diseases increases progressively with plasma Hey con centration. Ideally, th e plasm a level of Hey should be below 10 |i,mol/L. F ib r i n o g e n
Elevated plasma concentration of fibrinogen is linked to cardiovascular disease.39 Excessive concentration of plasm a fibrinogen has a pow erful, independent effect on the onset and pro gression of ischemic heart disease, stroke and low er e x tre m ity a rte ria l d isease. It also increases the risk o f reocclusion after grafting and angioplasty. A high co n c e n tra tio n o f fibrinogen broadens th e risk for thrombosis through a variety of mechanisms, including formation of atherom a, increase o f blood vis cosity and platelet aggregation and formation of fibrin and clots. R eferen ces 1. The expert panel, report of the national cholesterol education program expert panel on detection, evalu ation, and treatm ent of high cholesterol in adults. Arch Intern Med 1988;148:36-69. 2. The expert panel, summary of the 2nd report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high cholesterol in adults (adult Treatment Panel II). JAMA 1993;269:3015-3023. 3. Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Ann Intern Med 1992;152:56-64.
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