Coronary Artery Disease Risk Assessment Research Articles

Genetic risk for coronary artery disease in individuals with or without type 2 diabetes

Given that a substantial proportion of individuals with coronary artery disease (CAD) also have type 2 diabetes, it is important to identify genes that confer susceptibility to CAD independently in subjects with type 2 diabetes and in those without this condition. A large-scale association study was performed to identify genes that confer susceptibility to CAD in either the absence or presence of type 2 diabetes. The study population comprised 5207 unrelated Japanese individuals, including 3085 subjects with CAD and 2122 controls. Among all subjects, 1704 individuals had type 2 diabetes and 3503 individuals did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer–probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, hypercholesterolemia, and hyperuricemia revealed that the following polymorphisms were significantly ( P<0.005) associated with CAD: the 1019C → T of the connexin 37 gene for men with type 2 diabetes; the 2445G → A in the fatty acid-binding protein 2 gene for women with this condition; the −863C→ A in the tumor necrosis factor-α gene, the −219G → T in the apolipoprotein E gene, the 1019C → T in the connexin 37 gene for men without type 2 diabetes; and the −482C → T in the apolipoprotein C-III gene for women without this condition. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for CAD in the absence or presence of type 2 diabetes.

Atherosclerosis imaging and calcified plaque: coronary artery disease risk assessment

Over the last decade, there has been increased recognition that atherosclerosis imaging adds greatly to the ability to identify patients at high risk for cardiac events. Technologies such as electron beam computed tomography and carotid intimal media thickness have contributed significantly to our understanding of the prevalence of preclinical atherosclerosis and its consequences. Guidelines and policy toward these modalities have shifted, with increased recognition of the importance among experts in cardiology, lipidology, and preventive medicine. Because most adverse events related to atherosclerosis occur in individuals at an intermediate risk, data suggest that it will be most cost-effective to concentrate screening efforts on this group of patients. This article reviews the current understanding of the value of coronary artery calcium screening in asymptomatic and symptomatic patients. The validity of measuring coronary artery calcium with new multislice computed tomography scanners is also reviewed. Accurate measurement of subclinical coronary atherosclerosis should significantly improve the accuracy of global cardiovascular risk prediction and allow for tracking of atherosclerosis burden as well as better prediction of future cardiovascular events.

Genetic evaluation for coronary artery disease.

There is substantial evidence that genetic factors contribute to coronary artery disease (CAD). Currently, family history collection and interpretation is the best method for identifying individuals with genetic susceptibility to CAD. Family history reflects not only genetic susceptibility, but also interactions between genetic, environmental, cultural, and behavioral factors. Stratification of familial risk into different risk categories (e.g., average, moderate, or high) is possible by considering the number of relatives affected with CAD and their degree of relationship, the ages of CAD onset, the occurrence of associated conditions, and the gender of affected relatives. Familial risk stratification should improve standard CAD risk assessment methods and treatment guidelines (e.g., Framingham CAD risk prediction score and Adult Treatment Panel III guidelines). Individuals with an increased familial risk for CAD should be targeted for aggressive risk factor modification. Individuals with a high familial risk might also benefit from early detection strategies and biochemical and DNA-based testing, which can further refine risk for CAD. In addition, individuals with the highest familial risk might have mendelian disorders associated with a large magnitude of risk for premature CAD. In these cases, referral for genetic evaluation should be considered, including pedigree analysis, risk assessment, genetic counseling and education, discussion of available genetic tests, and recommendations for risk-appropriate screening and preventive interventions. Research is needed to assess the feasibility, clinical validity, clinical utility, and ethical, legal, and social issues of an approach that uses familial risk stratification and genetic evaluation to enhance CAD prevention efforts.

Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk

The objective of the present study was to examine concordance/discordance among 4 atherogenic indexes of cardiovascular risk: plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, non–high-density lipoprotein (non-HDL) cholesterol, and apolipoprotein B-100 (apoB). Analyses were conducted in a cohort of 2,103 men without coronary artery disease (CAD) at the onset of the Quebec Cardiovascular Study. Although there were strong and highly significant correlations among the 4 risk indexes (0.78 < r < 0.97), only 50% of all subjects had concordant apoB and LDL cholesterol levels (i.e., values that fell into the same quintile of the population distribution). Moreover, concordance/discordance was not the same throughout the range of both variables; it was greater at the extremes of their respective distributions (65%), but significantly less in the midpoints (<40%). ApoB appeared to be more concordant with non-HDL cholesterol than with LDL cholesterol, although >1/3 of all subjects had discordant levels. Kappa analysis confirmed that there was only fair agreement between apoB and total or LDL cholesterol (0.38 and 0.36, respectively) and only moderate agreement between non-HDL cholesterol and apoB (0.47). Finally, a significant proportion of subjects (528 of 2,103) who had disproportionately higher apoB levels than would have been predicted based on their LDL cholesterol concentrations was more obese and manifested several features of the metabolic syndrome. They also had a significantly increased cardiovascular risk. In summary, plasma apoB and the various cholesterol indexes are complementary rather than competitive indexes of atherosclerotic risk and provide further evidence as to why measurement of apoB should be part of a standard lipoprotein assessment of CAD risk.

Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy.

Formation of nitric oxide-derived oxidants may serve as a mechanism linking inflammation to development of atherosclerosis. Nitrotyrosine, a specific marker for protein modification by nitric oxide-derived oxidants, is enriched in human atherosclerotic lesions and low-density lipoprotein (LDL) recovered from human atheroma. To determine whether systemic levels of nitrotyrosine are associated with the prevalence of coronary artery disease (CAD) and are modulated by hydroxymethylglutaryl coenzyme-A reductase inhibitor (statin) therapy. A case-control and interventional study at 2 urban tertiary-care referral centers; recruitment for each was from June 1, 2001, until January 1, 2002. For the case-control study, 100 case-patients with established CAD and 108 patients with no clinically evident CAD were recruited consecutively. In the interventional study, participants aged 21 years or older with hypercholesterolemia (LDL cholesterol > or =130 mg/dL [> or =3.5 mmol/L]) underwent nutrition and exercise counseling. Those whose levels did not decrease with 6 to 8 weeks were enrolled in the study (n = 35). For 12 weeks, they received 10 mg/d of oral atorvastatin therapy. In the case-control study, the association between systemic levels of protein-bound nitrotyrosine, CAD risk, and presence of CAD. In the interventional study, the change in nitrotyrosine, lipoprotein, and C-reactive protein (CRP) levels. Nitrotyrosine levels were significantly higher among patients with CAD (median 9.1 micromol/mol [interquartile range, 4.8-13.8 micromol/mol] tyrosine vs 5.2 micromol/mol [interquartile range, 2.2-8.4 micromol/mol]; P<.001). Patients in the upper quartile of nitrotyrosine (29%; P<.001) had a higher odds of CAD compared with those in the lowest quartile (unadjusted odds ratio, 6.1; 95% confidence interval, 2.6-14.0; P<.001). In multivariate models adjusting for Framingham Global Risk Score and CRP, upper quartiles of nitrotyrosine remained associated with CAD (odds ratio, 4.4; 95% confidence interval, 1.8-10.6; P<.001). Statin therapy reduced nitrotyrosine levels significantly (25%; P<.02) with a magnitude similar to reductions in total cholesterol levels (25%; P<.001) and LDL particle number (29%; P<.001) yet were independent of alterations in lipoproteins and inflammatory markers like CRP. The findings from this preliminary study indicate that nitrotyrosine levels are associated with the presence of CAD and appear to be modulated by statin therapy. These results suggest a potential role for nitric oxide-derived oxidants as inflammatory mediators in CAD and may have implications for atherosclerosis risk assessment and monitoring of anti-inflammatory actions of statins.

Lipid profiles associated with antiretroviral drug choices.

In this review we will discuss the recent finding that different drug classes/antiretroviral therapy regimens may differ importantly with respect to their effect on the plasma lipid profile. On the basis of this we will illustrate how such differences, together with knowledge of the presence of other classic coronary artery disease risk factors, open the door for individualized treatment based on criteria in addition to the HIV-1 viral load and CD4 cell count. A large proportion of patients using protease inhibitor-based therapy develop insulin resistance and elevated plasma concentrations of LDL-cholesterol, total cholesterol and triglycerides, which has raised the concern that HIV-infected patients treated with antiretroviral therapy may be at an increased risk of developing premature coronary artery disease. Recent findings suggest that the use of non-nucleoside reverse transcriptase inhibitor-based therapy, in particular nevirapine, results in an elevation in HDL-cholesterol, which may be associated with a decreased incidence of coronary artery disease. It is becoming increasingly important to carry out an adequate coronary artery disease risk assessment in each patient both before and approximately annually after the initiation of antiretroviral therapy. In patients with an already considerable risk of coronary artery disease based on traditional risk factors, particularly when it is expected to be difficult to modify these, starting with either a triple nucleoside reverse transcriptase inhibitor or a non-nucleoside reverse transcriptase inhibitor-based regimen may be the preferred option, given the propensity of such regimens to have either no effect or potentially even beneficial effects on the lipoprotein profile.

Short peptide receptor mimics for atherosclerosis risk assessment of LDL

Short peptides sequences were selected that showed binding selectivity towards healthy or oxidised (unhealthy) low density lipoprotein (LDL), respectively. These were investigated for application in atherosclerosis risk monitoring. Comparison was also made with the LDL receptor ligand repeat peptide (LR5). The peptides were immobilised on a gold surface plasmon resonance surface and LDL binding detected as a shift in the resonance. 3.7×10 7 (±5.6×10 6) LDL/mm 2/μg/ml solution LDL were bound on GlySerAspGlu–OH and 6.8×10 7 (±9.2×10 6) LDL/mm 2/μg/ml on GlyCystineSerAspGlu, compared with ∼10 8 LDL/mm 2/μg/ml on LR5. In this first group, binding of LDL decreased with oxidation level and a good correlation was found between LDL binding and residual amino groups on the apoprotein of the LDL following oxidation, or the change in relative electrophoretic mobility (REM) of LDL. The decrease in binding was 1.1×10 7 LDL particles/mm 2 per% oxidation for GlySerAspGlu–OH, 1.8×10 7 LDL particles/mm 2 per% oxidation for GlyCystineSerAspGlu and 2.4×10 7 LDL particles/mm 2 per% oxidation for LR5. A second group of three peptides were also selected showing increased binding with LDL oxidation: GlyCystineCysCys (1.5×10 7 LDL/mm 2 per μg/ml), GlyLysLysCys–SH (10 7 LDL/mm 2 per μg/ml) and GlyLysLys–OH (5.6×10 7 LDL/mm 2 per μg/ml). The latter gave a linear increase in LDL binding with oxidation level (1.2×10 7 LDL particles/mm 2 per% oxidation). LDL concentration is around 2–3 mg/ml in plasma compared with the low detection levels with this method (1–10 μg/ml), allowing a strategy to be developed requiring the minimum sample volume and diluting with physiological buffer prior to assay. By using a comparative reading between LDL adsorption on surfaces from the first and second group of peptides (e.g. GlyCystineSerAspGlu and GlyLysLys–OH, respectively), LDL oxidation could be determined without knowledge of LDL concentration. Higher binding was seen on GlyCystineSerAspGlu than GlyLysLys–OH below 30% LDL oxidation, whereas above 30% oxidation the binding on the latter surface was greater. Simple correlation of this form could provide good tests for atherosclerosis risk.

Distribution and correlates of non-high-density lipoprotein cholesterol in children: the Bogalusa Heart Study.

Serum non-high-density lipoprotein (HDL) cholesterol (total cholesterol minus HDL cholesterol) is considered a better screening tool than low-density lipoprotein (LDL) cholesterol for the assessment of coronary artery disease (CAD) risk in adults because it includes all classes of atherogenic lipoproteins. Although population frequency distribution and clinically useful cutpoints for this variable in adults have been reported recently, such information is lacking in children. Therefore, this study sought to provide population-based data on the distribution and correlates of non-HDL cholesterol in biracial (black-white) children. The study sample consisted of 2843 5- to 17-year-olds (57% white, 50% female) who participated in a cross-sectional screening of cardiovascular risk factors as part of the Bogalusa Heart Study. Non-HDL cholesterol levels were similar in black and white children, and higher in girls than in boys, especially among the younger (5-11 years) age group. Age was inversely related to both non-HDL cholesterol and LDL cholesterol. Body fatness as measured by body mass index and waist circumference was positively associated with non-HDL cholesterol. The magnitude of correlation with triglycerides was relatively higher for non-HDL cholesterol versus LDL cholesterol. Non-HDL cholesterol showed an inverse relation to HDL cholesterol. In a multivariate analysis, body mass index, age, gender, waist circumference, and cigarette smoking accounted for 7.7% of the variance in non-HDL cholesterol. Non-HDL cholesterol levels equivalent to currently recommended LDL cutpoints (110, 130, 160, and 190 mg/dL) for CAD risk assessment were 123, 144, 176, and 207 mg/dL. Population-based data on non-HDL cholesterol are now available for children, which may help improve the CAD risk assessment and intervention.

High-density lipoprotein cholesterol and the role of statins.

Low levels of high-density lipoprotein cholesterol (HDL-C) are currently considered to be a major risk factor for the development of coronary artery disease (CAD). Deficiencies in the HDL metabolic pathway promote atherosclerosis and contribute to CAD. Low HDL-C levels are included in the Framingham 10-year risk assessment for CAD although they are not yet targeted for therapy. Recent clinical trials have shown benefits from raising HDL-C, particularly in patients with lower baseline levels. The statin class of drugs, used primarily to lower the level of low-density lipoprotein-cholesterol, may be able to raise the HDL-C level as well. Statins could potentially affect HDL-C by different modes of action, most importantly by altering reverse cholesterol transport. Among the currently available statins, simvastatin has demonstrated the most consistent ability to raise HDL-C level, but further large-scale studies at an early stage will be needed to prove the antiatherogenic effects of this class of drugs.

Activity and concentration of lipoprotein lipase in post-heparin plasma and the extent of coronary artery disease

Numerous studies have found polymorphisms in the lipoprotein lipase (LPL) gene to be associated with the risk of coronary artery disease (CAD), implicating LPL in the development of atherothrombotic disease. It remains controversial, however, whether LPL acts in a pro- or anti-atherogenic fashion. We quantitated activity and concentration of LPL in post-heparin plasma from 194 male patients undergoing coronary angiography. HDL cholesterol was significantly associated with LPL activity quartiles (1.09±0.26 the highest vs. 0.96±0.25 mmol/l the lowest quartile, P<0.01). There was also a trend towards higher total (5.61±1.33 vs. 5.16±1.44 mmol/l, P=0.059) and LDL cholesterol (3.92±1.39 vs. 3.46±1.06 mmol/l, P=0.09) with higher LPL activity. In contrast, measures of CAD extent showed no differences between LPL quartiles ( P>0.30 for prior myocardial infarction, number of diseased vessels, Gensini and extent scores). Additionally, there was no difference in LPL activity (CAD: n=158, 168±70 nmol/ml/min, no CAD: n=36, 180±89 nmol/ml/min, P=0.47) or concentration (280±121 ng/ml and 288±111 ng/ml, P=0.72) between patients with and without CAD. Our data show that, in spite of an association with lipoprotein parameters, LPL in post-heparin plasma is unrelated to the presence or the extent of CAD. Therefore, lipoprotein lipase determination in plasma does not appear to be a useful marker in the assessment of CAD risk.

Genetic predisposition to coronary artery disease.

Understanding the genetic basis of coronary artery disease (CAD) can improve management and prevention. Family and twin studies, animal models and gene association studies support a genetic basis for CAD. Genes contribute to CAD development and progression, and response to risk factor modification and lifestyle choices. Family history is the best indicator of a predisposition to CAD and further refinement is possible with biochemical and DNA testing. Many inherited cardiovascular risk factors can be modified, such as LDL cholesterol, homocysteine and lipoprotein(a). Early detection of CAD might lead to earlier intervention for genetically susceptible individuals. However, data are lacking regarding the efficacy of this approach in preventing clinical events. Despite this lack of evidence, knowledge of genetic CAD susceptibility has value in providing risk information and guiding decision making. Further research that investigates outcomes regarding genetic risk assessment for CAD is necessary.

Noninvasive procedures for subclinical atherosclerosis risk assessment

Noninvasive procedures for subclinical atherosclerosis risk assessment

Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease.

Remnant lipoproteins are atherogenic, but assays of remnants have not been available in routine clinical laboratories because of the lack of practical and validated methods. A simple and reliable method for such an assay, using an immunochemical approach, has recently been developed. This study prospectively examined whether remnant lipoprotein levels in fasting serum, measured by our method, may have prognostic value in patients with coronary artery disease (CAD). Remnant lipoprotein levels in fasting serum were measured in 135 patients with CAD by an immunoaffinity mixed gel containing anti-apolipoprotein (apo) A-1 and anti-apoB-100 monoclonal antibodies. Patients were followed up for </=36 months until occurrence of 1 of the following clinical coronary events: recurrent or refractory angina pectoris requiring coronary revascularization, nonfatal myocardial infarction, or cardiac death. Kaplan-Meier analysis demonstrated a significantly higher probability of developing coronary events in patients with the highest tertile of remnant levels (>5.1 mg cholesterol/dL; 75th percentile of distribution of remnant levels) than in those with the lowest tertile of remnant levels (</=3.3 mg cholesterol/dL; 50th percentile of the distribution). Higher levels of remnants were a significant and independent predictor of developing coronary events in multivariate Cox hazard analysis including the following covariates: extent of coronary artery stenosis, age, sex, smoking, hypertension, diabetes mellitus, hypercholesterolemia, low HDL cholesterol, and hypertriglyceridemia. Higher levels of remnant lipoproteins in fasting serum predict future coronary events in patients with CAD independently of other risk factors. Thus, measurement of fasting remnant levels, assessed by the current immunoseparation method, may be helpful in assessment of CAD risk.

PREOPERATIVE CARDIAC EVALUATION OF WOMEN FOR NONCARDIAC SURGERY

Cardiac risk assessment is a crucial aspect of perioperative evaluation because it is estimated that 1 million people, regardless of gender, will have perioperative cardiac complications at a cost of 20 billion dollars. Unfortunately, establishment of optimal guidelines for selected patient subgroups, particularly women, are lacking. More prospective studies are needed to help evaluate the most cost-effective, yet accurate way to noninvasively assess the presence of coronary artery disease in women.

Euphenic Prevention of Coronary Artery Disease

The purpose of this feasibility study was to incorporate the primary prevention of coronary artery disease (CAD) into periconception care. The first task was the preconceptional screening for CAD. The family and case histories and risk status of prospective mothers and fathers were obtained. Serum total cholesterol was measured in 3,530 female and 3,127 male participants. The mean serum nonfasting cholesterol was 192 ± 40 mg/dl in women and 204 ± 49 mg/dl in men. The levels of total cholesterol exceeded the upper limit of desirable total cholesterol (200 mg/dl) in 37% of women and in 49% of men. Only 7% of women and 5% of men had previous knowledge about their high total cholesterol. The second task was risk assessment for CAD in prospective parents and their planned baby and the identification of couples at high risk. The third step was the education of couples at high risk: how to reduce risk factors and how to enhance protective factors. Three months later, the short-term follow-up study indicated a 49 mg/dl (18%) and 43 mg/dl (16%) (range 250 to 300) reduction in total cholesterol in female and male participants, respectively, mainly due to an education program including change in diet, cessation of smoking, and so forth. The long-term follow-up will include both parents and children 3 years after the birth. Periconception care is appropriate for both a general and selective approach to population screening for total cholesterol and for primary prevention of CAD.

Hypertriglyceridemia: Risks and perspectives

The evidence linking hypertriglyceridemia and coronary artery disease (CAD) is reviewed. A positive correlation between plasma triglyceride level and CAD incidence has been demonstrated in most prospective studies on univariate analysis. However, the significance is weakened on multivariate analysis, in particular when level of highdensity lipoprotein (HDL) cholesterol is taken into account, perhaps because of the close metabolic interrelation between the triglyceride-rich lipoproteins and HDL particles. Recent analyses of clinical data have shown that the combination of elevations of low-density lipoprotein cholesterol and triglyceride and low levels of HDL cholesterol confers particularly high risk for CAD. The U.S. National Institutes of Health Consensus Development Conference on Triglyceride, High Density Lipoprotein, and Coronary Heart Disease in February 1992 made recommendations to integrate more fully HDL cholesterol and triglyceride levels into the assessment and treatment of dyslipidemia and CAD risk. Treatment of hypertriglyceridemia should focus on diet and weight control, exercise, and smoking cessation, as well as control of other major risk factors for CAD, notably hypercholesterolemia and hypertension.

The MspI restriction fragment length polymorphism 3′ to the apolipoprotein A-II gene: relationships with lipids, apolipoproteins, and premature coronary artery disease

In previous studies, a restriction fragment length polymorphism (RFLP) has been identified using MspI restriction endonuclease in the 3′ region of the apo A-II gene. The rare variant site for this MspI ( M2) has been reported to be associated with higher levels of HDL cholesterol and apo A-II. We have studied the frequency and lipid associations of this RFLP in a population of 168 coronary artery disease (CAD) male and female patients, who had more than 50% narrowing of one or more arteries prior to age 60 years, as well as 255 aged-matched males and females from the Framingham Offspring Study. We also studied 31 kindreds in which the proband had premature CAD. The frequency of the M2 allele was higher in CAD cases (0.20) than in the controls (0.13) ( P < 0.05). In general, those subjects carrying the M2 allele had lower HDL cholesterol and apo A-I plasma levels; however, this difference was only significant ( P < 0.02 and 0.002, respectively) in females with CAD. No cosegregation of the M2 allele with hypoalphalipoproteinemia was found in 31 kindreds studied. However, in both generations there was a trend for those subjects carrying the M2 allele to have lower HDL cholesterol levels than those carrying the M1 allele. Sequence analysis of the apo A-II gene of subjects homozygous for either the M1 ( n = 1) or the M2 allele ( n = 2) revealed that this RFLP is due to a T→C single base mutation 528 by 3′ to the apo A-II gene. In the subjects homozygous for the M2 allele no other mutations were found within the coding region of the apo A-II gene that could result in changes in the primary sequence of the protein. These data indicate that the MspI RFLP 3′ to the apo A-II gene is somewhat more frequent in the CAD group. However, there was no significant association between this RFLP and any of the parameters examined. In conclusion, this DNA marker lacks the specificity to be clinically useful for CAD risk assessment in the population studied.

Relation of arteriographically defined coronary artery disease to serum lipoprotein particles mapped with monoclonal antibodies.

This study was designed to investigate the relation of a molecular analysis of apolipoprotein B (apoB)-containing atherogenic lipoprotein particles to coronary artery disease (CAD) in middle-aged men. Two groups of men were studied. The first consisted of 97 patients with angiographically documented CAD (greater than 50% stenosis of at least one coronary artery). The second group consisted of 145 subjects without symptomatic CAD, who served as controls. In both groups, measurements were obtained for total cholesterol level, triglyceride level, cholesterol contents in apoB- and nonapoB-containing particles (LpB, LpnonB), total apoB and apolipoprotein AI (apoAI levels), lipoprotein particles recognized by monoclonal antibodies anti-apoB (LpBL3, LpBL5, LpBL7) and anti-apoAI (LpAI-2GII). Taking into account age, body mass index, hypertension, diabetes, smoking habits, and drug consumption, the analysis showed that the mean levels of cholesterol were identical in both groups but differed when cholesterol content in LpB and LpnonB subfractions were assessed, thus reflecting an increase in the low density fraction and a decrease in the high density fraction, respectively. This was confirmed by an increase in total apoB and a decrease in total apoAI. Measurements of LpBL3, LpBL5, LpBL7, and LpAI-2GII particles also discriminated between the two groups. After adjustment for cholesterol content in LpnonB particles, a difference in total apoB was no longer significant between groups, whereas LpBL3, LpBL5, and LpBL7 levels remained significantly higher in CAD patients. The measurement of separate concentrations of apoB in different particles may permit a more-accurate assessment of CAD risk than measurements of total apoB levels.

Restriction fragment length polymorphisms of the apolipoprotein A-I, C-III, A-IV gene locus Relationships with lipids, apolipoproteins, and premature coronary artery disease

Data from various laboratories have indicated associations of various alleles determined by RFLPs within or adjacent to several apolipoprotein genes with abnormalities in plasma lipids and/or premature coronary artery disease (CAD). In order to assess such relationships we have examined allele frequencies of 8 different RFLPs within or adjacent to the apo A-I, C-III and A-IV gene complex on the long arm of chromosome 11 ( MspI, 5′ to the apo A-I gene; MspI, within the apo A-1 gene; PstI, 3′ to the apo A-I gene; SstI, 3′ to the apo C-III gene; PvuII, within the apo C-III gene; PvuII, 5′ to the apo C-III gene; XbaI, within the apo A-IV gene; and XbaI, 3′ to the apo A-IV gene) in 202 patients with CAD (50% narrowing of one or more coronary arteries) prior to age 60 and 145 normal controls. None of the allele frequencies of these RFLPs were significantly different in cases as compared to controls. With regard to associations with plasma lipids and apolipoprotein levels, the rare allele determined by the absence of the PstI site was associated with elevated triglyceride levels ( P < 0.05) in cases, but not in controls. In contrast, the rare MspI allele 5′ to the apo A-I gene was associated with elevated triglyceride levels ( P < 0.05) in controls but not in cases. In both cases and controls, subjects with the uncommon SstI allele had triglyceride levels that were 9 and 38% higher than in those without this allele. These differences were significant ( P < 0.05) only in controls. Our data indicate that the rare allele determined by the SstI site within this gene complex deserves further study in order to understand its association with elevated triglycerides in Caucasian populations. However, at the present time all these DNA markers lack sufficient specificity to be clinically useful for CAD risk assessment.

Cholesterol esterification rates in very low density lipoprotein- and low density lipoprotein-depleted plasma. Relation to high density lipoprotein subspecies, sex, hyperlipidemia, and coronary artery disease.

The fractional rate of cholesterol esterification in very low density lipoprotein- and low density lipoprotein-depleted plasma (FERHDL) was studied in normolipidemic subjects and in individuals with hyperlipidemia and proven coronary artery disease (CAD). The FERHDL was significantly higher than the FER in whole plasma and was significantly higher in normal men than in normal women. In addition, men and women with primary hyperlipidemia had significantly higher FERHDL values relative to their sex-matched controls. The most significant increases in FERHDL values, however, were observed in individuals with CAD. In all patient groups, FERHDL was positively correlated with plasma triglyceride concentration. In addition, FERHDL was negatively related to plasma high density lipoprotein (HDL) cholesterol concentration in all groups except in men with CAD and in normolipidemic women. The gradient gel electrophoretic pattern of HDL from individuals with either low or high FERHDL values indicated an inverse relation between this activity and the relative amount of HDL2b particles. FERHDL likely reflects the metabolic properties of the heterogeneous population of HDL particles in the plasma and may be a function of the relative content of larger and smaller HDL particles. It appears to be a sensitive and reliable functional measure of the particle size distribution in the HDL pool and one of potential clinical value in the assessment of risk for CAD.