Nonlipid Risk Factors Research Articles

Evidence that non-lipid cardiovascular risk factors are associated with high prevalence of coronary artery disease in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia

Background Heterozygous familial hypercholesterolemia (hFH) and familial combined hyperlipidemia (FCH) have been associated with increased risk for coronary artery disease (CAD), but the impact of traditional risk factors to the incidence of CAD in these patients remains unknown. The present study evaluates the contribution of such risk factors to the development of CAD in these two dyslipidemic populations. Methods This cross-sectional study enrolled a total 1306 subjects; 600 individuals with hFH (mean age 41 ± 13 years, 261 males and 339 females), and 706 individuals with FCH (mean age 49 ± 11 years, 463 males and 243 females). Blood samples were collected after 12 hours fasting period, and serum lipids were determined. Multivariate logistic regression models were used to estimate the odds ratios of CAD based on the type of hyperlipidemia, after adjustment for demographic characteristics and risk factors. Results Subjects with FCH were older ( P < 0.001), and they had a significantly increased prevalence of hypertension, diabetes and metabolic syndrome (40 vs. 10%, 13 vs. 2% and 41 vs. 6% respectively, all P < 0.001) compared to the hFH group. Total cholesterol, LDL-cholesterol, and apolipoprotein B levels were higher (all P < 0.001) in hFH subjects. Although in multivariate analysis lipid abnormalities found in hFH were associated with increased risk of CAD ( P < 0.001) compared with lipid abnormalities of FCH, the overall prevalence of CAD was similar between the two groups (16.7 vs. 15.3%, P = NS). Conclusions Despite the high atherogenic potential of altered lipid metabolism found in hFH, the prevalence of CAD is similarly increased in patients with hFH or FCH. This may be related to the clustering of non-lipid cardiovascular risk factors, such as diabetes mellitus, observed in patients with FCH.

Utility of Childhood Non–High-Density Lipoprotein Cholesterol Levels in Predicting Adult Dyslipidemia and Other Cardiovascular Risks: The Bogalusa Heart Study

This study sought to examine the usefulness of non-high-density lipoprotein cholesterol levels in predicting future dyslipidemia and other cardiovascular risk in adulthood. The study sample consisted of a longitudinal cohort of subjects (n = 1163; 30.1% black and 55.4% female) who participated in the Bogalusa Heart Study both as children at 5 to 14 years of age and as adults 27 years later. The childhood level of non-high-density lipoprotein cholesterol, like low-density lipoprotein cholesterol, was the best predictor of the adulthood level; the next best predictor for both variables was the change in BMI from childhood to adulthood. Furthermore, those in the age-, race-, and gender-specific top quartile, compared with those in the bottom quartile, of non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels in childhood were 4.5 and 3.5 times more likely, respectively, to develop adult dyslipidemia, independent of baseline BMI and BMI change after 27 years. Although, at equivalent cutoff points, childhood high-risk versus acceptable-risk status for both lipid measures was associated significantly with increased prevalence of obesity and adverse levels of low-density lipoprotein cholesterol and triglycerides in adulthood, only childhood non-high-density lipoprotein cholesterol high-risk status was associated with increased prevalence of low high-density lipoprotein cholesterol levels, hyperinsulinemia, and hyperglycemia (marginal). Adverse levels of non-high-density lipoprotein cholesterol versus low-density lipoprotein cholesterol in childhood not only equally persist over time and better predict adult dyslipidemia but also are related to nonlipid cardiovascular risk factors in adulthood.

Accumulation of apoE-enriched triglyceride-rich lipoproteins in patients with coronary artery disease

Triglycerides (TGs) are vehicled by multiple particles with different abilities to promote atherosclerosis. Among plasma TG-rich lipoproteins (TRLs), subspecies may or may not contain apolipoprotein E (apoE) molecules: in this study, we evaluated the relative contribution of apoE-rich and apoE-poor TRLs to coronary atherosclerosis. We selected a group of males with premature coronary artery disease (CAD) without any of the classical nonlipid risk factors and/or high plasma lipid levels and evaluated the plasma concentration of TRL subspecies in comparison with healthy controls. Patients with CAD and controls had total cholesterol and TG levels within the normal range (despite slightly, even if significantly, higher TG levels in patients with CAD) and low-density lipoprotein cholesterol levels near optimal values. Nevertheless, patients with CAD had significantly lower high-density lipoprotein cholesterol, smaller low-density lipoprotein peak particle size, and a reduced HDL2b subfraction than controls. In addition, we observed higher concentrations of total TRL in patients with CAD together with a selective increase in apoE-rich particles. All these data were confirmed after correction for TG levels. We also investigated which parameters were associated with the spread of coronary atherosclerosis. Subjects with a single-vessel disease had selectively lower levels of apoE-rich fractions than patients with a multivessel disease. This was confirmed by multivariate analysis. Patients with a premature CAD free of nonlipid conventional risk factors, despite not having elevated lipid levels, show several lipoprotein abnormalities. Besides known atherogenic alterations, the accumulation of apoE-rich TRL subfractions may represent an additive factor that can potentially promote and initiate the atherosclerotic process.

Apolipoprotein-B, Low-Density Lipoprotein Cholesterol, and the Long-Term Risk of Coronary Heart Disease in Men

We examined whether plasma apolipoprotein-B (apo-B) levels add further information on the risk of coronary heart disease (CHD) after taking into account low-density lipoprotein (LDL) cholesterol concentrations and other traditional risk factors. Among 2,072 CHD-free men from the Québec Cardiovascular Study at entry and followed for 13 years, 230 had a first CHD event (CHD death or nonfatal myocardial infarction). Increased apo-B (tertile 1 vs 3) levels were associated with a significant increased risk of CHD after adjustment for nonlipid and lipid risk factors other than LDL cholesterol levels (relative risk 1.89, 95% confidence interval 1.31 to 2.73). High plasma LDL cholesterol concentrations (tertile 1 vs 3) were also associated with an increased risk of CHD independently of nonlipid and lipid risk factors (relative risk 2.02, 95% confidence interval 1.44 to 2.84). However, apo-B levels modulated to a significant extent the risk of CHD associated with increased concentrations of LDL cholesterol (>/=4.3 mmol/L). For instance, among men with high LDL cholesterol levels, those with an apo-B level <128 mg/dl were not at increased risk for CHD (relative risk 1.53, 95% confidence interval 0.89 to 2.62). In contrast, high levels of apo-B and LDL cholesterol were associated with a significant twofold increased risk of CHD (p <0.001). Receiver-operating curve analysis also indicated that plasma apo-B levels improved the ability to discriminate incident CHD cases among patients with high LDL cholesterol levels compared with a model based on LDL cholesterol levels (p = 0.04). In conclusion, plasma apo-B levels modulated the risk of CHD associated with LDL cholesterol over a 13-year follow-up.

Strategies for Modifying High-Density Lipoprotein Cholesterol: A Role for Nicotinic Acid

Statin-mediated lowering of low-density lipoprotein cholesterol (LDL-C) is regarded as the foundation of lipid-modifying therapy. However, the residual cardiovascular risk for statin-treated patients remains high, indicating the need for therapeutic intervention against other lipid targets as well as non-lipid risk factors. Low levels of high-density lipoprotein cholesterol (HDL-C) are established as a strong independent risk factor for cardiovascular disease. Intervention studies have also demonstrated clinical benefits associated with HDL-C raising. Although lifestyle modification does play an important role in raising HDL-C, most patients with a low HDL-C and at high risk of coronary events also require pharmacological treatment to achieve the target. Of the available treatment options, nicotinic acid is the most potent agent for raising HDL-C (by 26% at clinically recommended doses), while substantially lowering triglycerides and LDL-C. The addition of nicotinic acid to primary statin therapy is a logical approach to dyslipidaemia management, given their complementary mechanism of action, and is supported by recent clinical trials such as the Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER) 2 study. Raising HDL-C will increasingly become an important secondary focus of dyslipidaemia management.

LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham Offspring Study and the Veterans Affairs HDL Intervention Trial

Objective We tested the hypothesis that concentrations of LpA-I and/or LpA-I:A-II HDL subclasses are significantly associated with CHD prevalence and recurrent cardiovascular events. Methods LpA-I levels were determined by differential electroimmunoassay in male participants with ( n = 169) and without CHD ( n = 850) from the Framingham Offspring Study (FOS) and in male participants with CHD from the placebo arm of the Veterans Affairs HDL Intervention Trial (VA-HIT) ( n = 741). Data were analyzed cross-sectionally (FOS) and prospectively (VA-HIT) and were adjusted for established lipid and non-lipid CHD risk factors. Results We observed slightly but significantly higher LpA-I levels in CHD cases compared to all or to HDL-C-matched controls and slightly but significantly higher LpA-I:A-II levels in CHD cases compared to HDL-C-matched controls it the FOS. Neither LpA-I nor LpA-I:A-II levels were significantly different between groups with and without recurrent cardiovascular events in the VA-HIT. No significant differences were observed in LpA-I and LpA-I:A-II levels in low HDL-C (≤40mg/dl) subjects with CHD (VA-HIT, n = 711) and without CHD (FOS, n = 373). Plasma LpA-I concentration had a positive correlation with the large LpA-I HDL particle (α-1) but no correlation with the small LpA-I HDL particle (preβ-1). LpA-I:A-II concentration had a positive correlation with the large (α-2) and an inverse correlation with the small (α-3) LpA-I:A-II HDL particles. Conclusion Our data do not support the hypothesis that CHD prevalence (FOS) or recurrence of cardiovascular events (VA-HIT) are associated with significant reductions in the concentrations of LpA-I and/or LpA-I:A-II HDL subclasses.

Apolipoprotein E Genotype and Incident Ischemic Stroke

A relationship between the apolipoprotein E (apoE) genotype and ischemic stroke has been inconsistently reported. We explored this relation in the Atherosclerosis Risk in Communities Study (ARIC). The ARIC cohort involves 15 792 men and women, aged 45 to 64 years at baseline and sampled from 4 U.S. communities. Between 1987 and 2001, 498 incident ischemic strokes occurred. After stratifying by race and sex and adjusting for other nonlipid risk factors, there was no significant relation between the apoE genotype and incident stroke, except in black women (hazard ratio for epsilon2 genotype relative to epsilon3/epsilon3=0.53; 95% CI, 0.28 to 0.99). For the most part, in this middle-aged sample, apoE was not a risk factor for incident ischemic stroke.

Hepatic and Cardiovascular Consequences of Familial Hypobetalipoproteinemia

Individuals with familial hypobetalipoproteinemia (FHBL) have been reported to be prone to fatty liver disease (FLD). Conversely, the profound reduction of low-density lipoprotein (LDL) cholesterol in this disorder might decrease cardiovascular risk. In the present study, we assessed hepatic steatosis as well as noninvasive surrogate markers for cardiovascular disease (CVD) in subjects with FHBL and in matched controls. Hepatic steatosis was assessed by abdominal ultrasonography. Carotid intima-media thickness (IMT) and distal common carotid arterial wall stiffness as surrogate markers for CVD risk were measured using high-resolution B-mode ultrasonography. Whereas transaminase levels were only modestly elevated, both prevalence (54% versus 29%; P=0.01) and severity of steatosis were significantly higher in FHBL individuals compared with controls. Despite similar IMT measurements, arterial stiffness was significantly lower in FHBL (P=0.04) compared with controls. Additionally, the increase in arterial stiffness as seen in the presence of traditional risk factors was attenuated, suggesting that very low levels of apoB-containing lipoproteins can negate the adverse effects of other risk factors on the vasculature. FHBL is characterized by an increased prevalence and severity of fatty liver disease. The observed decreased level of arterial wall stiffness, most pronounced in the presence of nonlipid risk factors, is indicative of cardiovascular protection in these subjects.

The Predictive Value of Lipid Markers in Vascular Disease

Lipid markers are well established predictors of vascular disease. The most frequently measured lipid variables are total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides. In this review we consider the predictive value of these variables and other more specialised related tests. We also discuss the effect of lipid altering drugs on these markers. The interaction of other vascular risk factors and the lipid effects of non-lipid altering drugs (e.g. blood pressure lowering agents) are also briefly described. Similarly, we discuss the effects of lipid lowering drugs on non-lipid vascular risk factors. Finally, we briefly consider the effect of altering the lipid profile on surrogate markers and events associated with atherosclerosis.

Apolipoprotein E and progression of chronic kidney disease.

Apolipoprotein E (APOE) genetic variation has been implicated in diabetic nephropathy with the epsilon2 allele increasing and the epsilon4 allele decreasing risk. APOE allelic associations with chronic kidney disease beyond diabetic nephropathy are unknown, with no studies reported in high-risk African American populations. To quantify the risk of chronic kidney disease progression associated with APOE in a population-based study including white, African American, diabetic, and nondiabetic individuals. Prospective follow-up (through January 1, 2003) of Atherosclerosis Risk in Communities (ARIC) study participants, including 3859 African American and 10,661 white adults aged 45 to 64 years without severe renal dysfunction at baseline in 1987-1989, sampled from 4 US communities. Incident chronic kidney disease progression, defined as hospitalization or death with kidney disease or increase in serum creatinine level of 0.4 mg/dL (35 micromol/L) or more above baseline, examined by APOE genotypes and alleles. During median follow-up of 14 years, chronic kidney disease progression developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall; 8.8 in African Americans and 4.4 in whites). Adjusting for major chronic kidney disease risk factors, epsilon2 moderately increased and epsilon4 decreased risk of disease progression (likelihood ratio test, P = .03). Further adjustment for low- and high-density lipoprotein cholesterol and triglycerides did not attenuate relative risks (RRs) (epsilon2: 1.08 [95% CI, 0.93-1.25] and epsilon4: 0.85 [95% CI, 0.75-0.95] compared with epsilon3; likelihood ratio test, P = .008). Epsilon4 decreased risk of end-stage renal disease (RR, 0.60 [95% CI, 0.43-0.84]). Epsilon2 was associated with a decline in renal function (RR, 1.25 [95% CI, 1.02-1.53]), though not with events, such as hospitalizations or end-stage renal disease. Risks were similar stratified by race, sex, diabetes, and hypertension (all P values for interaction >.05). Excess risk of chronic kidney disease in African Americans was not explained by APOE alleles. APOE variation predicts chronic kidney disease progression, independent of diabetes, race, lipid, and nonlipid risk factors. Our study suggests that nonlipid-mediated pathways, such as cellular mechanisms of kidney remodeling, may be involved in the association of APOE alleles and progression of chronic kidney disease.

Components of the Metabolic Syndrome and Risk for First-Ever Acute Ischemic Nonembolic Stroke in Elderly Subjects

Metabolic syndrome (MetSyn) represents a constellation of lipid and nonlipid risk factors for cardiovascular disease and is a recognized target for increased behavioral therapy. The association between acute ischemic/nonembolic stroke and the MetSyn in elderly individuals was assessed in a population-based case-control study in the prefecture of Ioannina, Greece. A total of 163 patients aged older than 70 years admitted with first-ever-in-a-lifetime acute ischemic/nonembolic stroke and 166 controls were included. The prevalence of MetSyn (defined according to NCEP/ATP III criteria) was high in stroke patients (46.0% versus 15.7%, P<0.001). Compared with controls as a group (with and without MetSyn), stroke patients with the MetSyn showed higher concentrations of triglycerides, lipoprotein(a), uric acid, and fibrinogen, and lower high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I levels. In logistic regression analysis, crude and adjusted odd ratios (ORs) for MetSyn were 5.33 (95% confidence interval [CI], 2.91 to 9.79; P<0.0001) and 2.59 (95% CI, 1.24 to 5.42; P=0.012), respectively. The analysis of interaction between MetSyn and its individual components revealed significant associations with abdominal obesity (adjusted OR, 2.74; 95% CI, 1.15 to 6.50; P=0.02), hypertension (OR, 2.03; 95% CI, 0.91 to 4.49; P=0.08), high fasting glucose levels (OR, 2.95; 95% CI, 1.19 to 7.35; P=0.02), high triglyceride (OR, 5.55; 95% CI, 2.71 to 11.37; P<0.0001]), and low HDL cholesterol (OR, 5.42; 95% CI, 2.85 to 10.30; P<0.0001). Notably, in stroke patients with the MetSyn the inverse relationship between HDL cholesterol levels and ischemic stroke was negated (OR, 1.04; 95% CI, 1.02 to 1.05; P<0.0001). MetSyn is associated with an increased risk for acute ischemic/nonembolic stroke in elderly subjects with significant contributions from its individual components. In the presence of MetSyn, HDL cholesterol loses its protective role against ischemic stroke.

Are Remnant-Like Particles Independent Predictors of Coronary Heart Disease Incidence?

Remnant-like particles have been proposed as a new risk factor for coronary heart disease (CHD). This is the first long-term prospective investigation of the relationship between remnant-like particles and a cardiovascular disease outcome in healthy men. A cohort of 1156 Japanese-American men aged 60 to 82 from the Honolulu Heart Program was followed for 17 years. During that period 164 incident cases of CHD were identified. In multivariate Cox regression analyses, baseline remnant-like particle cholesterol (RLP-C) and triglyceride (RLP-TG) levels were significantly related to CHD incidence independently of nonlipid cardiovascular risk factors and of total cholesterol or high-density and low-density lipoprotein cholesterol levels. Total triglyceride levels were an independent predictor of CHD incidence. However, in models including RLP and triglyceride level simultaneously, neither variable was significant when adjusted for the other. This finding can be attributed to the strong correlation between RLP-C and RLP-TG levels and total triglycerides. When individuals with normal triglyceride levels (n=894) were separated from those with elevated triglycerides (n=260), the association between RLPs and CHD relative risk was only significant for the group with elevated triglyceride levels. RLP levels predicted CHD incidence independently of nonlipid risk factors and of total cholesterol or high-density and low-density lipoprotein cholesterol levels. However, RLP levels did not provide additional information about CHD incidence over and above total triglyceride levels. Therefore, this study does not support the need for testing of remnants in men if measures of fasting triglycerides are available.

Inflammatory markers and long-term risk of ischemic heart disease in men: A 13-year follow-up of the Quebec Cardiovascular Study

We tested the hypothesis that elevated plasma interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen concentrations are independent risk factors and interact in increasing the long-term risk of ischemic heart disease (IHD) in men. A total of 1982 IHD-free men from the Quebec Cardiovascular Study were followed over a period of 13 years during which 210 first fatal IHD events and non-fatal myocardial infarctions were recorded. Increased CRP levels (4th versus 1st quartile) were not associated with an increased risk of IHD after adjustment for non-lipid risk factors (age, body mass index, systolic blood pressure, diabetes, smoking and medication use at baseline), lipid risk factors (LDL and HDL cholesterol and triglyceride levels) and for IL-6 and fibrinogen (RR = 0.70, 95% CI = 0.43–1.13). High plasma IL-6 levels (4th versus 1st quartile) were associated with a 70% greater risk of IHD independent of confounding risk factors and of the other 2 inflammatory markers (RR = 1.71, 95% CI = 1.07–2.75). The relationship between high fibrinogen levels (4th versus 1st quartile) and IHD risk was borderline significant in multivariate analyses (RR = 1.53, 95% CI = 0.97–2.43). An inflammation score based on plasma IL-6 and fibrinogen levels improved the IHD risk predictive value of a multivariate model of traditional risk factors ( p = 0.03). Including plasma CRP levels into the inflammatory score provided no additional predictive value. In conclusion, elevated plasma IL-6 concentrations are more strongly related to IHD risk than CRP and fibrinogen. An inflammation score based on high plasma IL-6 and fibrinogen levels used in combination with traditional risk factors may improve our ability to adequately identify high risk individuals.

Non-high density lipoprotein cholesterol is the best discriminator of myocardial infarction in young individuals

Background: Several studies have shown that non-high density lipoprotein (HDL) cholesterol is a strong and independent predictor of cardiovascular events. We investigated whether non-HDL cholesterol can discriminate young individuals with myocardial infarction (MI) from age- and sex-matched controls. Methods: We conducted a case–control study which included 100 consecutive patients who had survived their first MI before the age of 36 years and 100 age- and sex-matched healthy controls without a history of cardiovascular disease. Cardiovascular risk factors were reported and fasting lipids and apolipoproteins were measured. Results: Patients with premature MI had significantly higher levels of total cholesterol, low density lipoprotein cholesterol, triglycerides, apolipoprotein B, lipoprotein (a) and non-HDL cholesterol and significantly lower levels of HDL cholesterol and apolipoprotein A. Multivariate logistic regression analysis showed that for every 10 mg/dl increase in non-HDL cholesterol levels, the odds of having a MI were increased by 34% after controlling for age, sex, body mass index, presence of hypertension, diabetes and smoking habits. Moreover, participants in the highest tertile of non-HDL cholesterol levels had 28-fold higher odds for having a MI (95% confidence interval, 7.5–104.1), compared to those in the lowest tertile. Finally, discriminant analysis showed that non-HDL cholesterol ( λ-Wilks = 0.68) was the strongest discriminator for MI among all studied risk factors while smoking ( λ-Wilks = 0.80) was the strongest discriminator for MI among the non-lipid risk factors. Conclusions: Our study suggests that among conventional lipid and non-lipid risk factors non-HDL cholesterol is the best discriminator to predict the presence of MI in individuals under the age of 36 years.

Treating dyslipidemia in high-risk patients: case reviews and discussion.

The inclusion of coronary heart disease (CHD) risk equivalents in the highest CHD risk category, in addition to the lowest low-density lipoprotein cholesterol (LDL-C) targets, has dramatically increased the number of persons eligible for highly effective risk reduction and lipid-lowering treatment. Two such high-risk groups are persons with diabetes and those with metabolic syndrome. These patients typically have a number of lipid and nonlipid risk factors that require aggressive intervention. In patients with diabetes, treatment with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors ("statins") to lower LDL-C levels and improve other lipid measures has been shown to produce protective benefits at least equal to those observed in nondiabetic patients. Although metabolic syndrome is not yet recognized as a CHD risk equivalent and use of Framingham risk scoring may not place some patients with the syndrome in the highest risk category, there is accumulating evidence that these patients are at very elevated risk and should be treated aggressively. Particular problems in risk assessment arise in immigrant groups such as South Asians, in whom traditional risk assessment may be inaccurate. In this article, Dr Deedwania examines the clinical evidence regarding cardiovascular risk associated with diabetes and metabolic syndrome and discusses current therapeutic options. Two case reports are presented, followed by roundtable discussions among the contributors to this Special Report.

A prospective study of the APOA1 XmnI and APOC3 SstI polymorphisms in the APOA1/ C3/ A4 gene cluster and risk of incident myocardial infarction in men

Background : Apolipoproteins AI/CIII/AIV play important roles in the metabolism of triglycerides (TG) and high-density lipoprotein (HDL) cholesterol. However, whether genetic variations in the APOA1/ C3/ A4 gene cluster are associated with the risk of myocardial infarction (MI) remains uncertain and prospective data are sparse. Methods: In a prospective nested case-control study of 385 incident cases of MI and 373 age- and smoking-matched controls from the Physicians’ Health Study, we examined the relationship between 2 common single nucleotide polymorphisms (APOA1 XmnI and APOC3 SstI ) in the APOA1/ C3/ A4 gene cluster and haplotypes defined by these SNPs and risk of incident MI. Results: No significant differences in allele or genotype frequency for the APOA1 XmnI and APOC3 SstI polymorphisms were detected between cases and controls. After adjusting for non-lipid coronary risk factors, the relative risks for incident MI were 1.00 (95% CI 0.68–1.47) for men carrying the X2 allele compared with those homozygous for the X1 allele in the APOA1 XmnI site and 1.07 (95% CI 0.69–1.64) for men carrying the S2 versus those homozygous for the S1 allele in the APOC3 SstI site. Moreover, we did not observe any effect modification by HDL or TG levels for the associations of these APOA1 and APOC3 genotypes with MI risk. There were significant differences in TG levels among men carrying different haplotypes ( P = 0.01) and men carrying the X1-S2 haplotype had higher levels of TG than those carrying the X2-S1 haplotype (202 mg/dl versus 157 mg/dl, P = 0.03); however, haplotype frequencies defined by these two polymorphisms did not differ significantly between cases and controls. Conclusion: In this prospective study of apparently healthy middle-aged US men, carriers of the X1-S2 haplotype in the APOA1 XmnI and APOC3 SstI variants across the APOA1/ C3/ A4 gene cluster had higher TG levels, but there was no evidence for significant associations between these two common variants or haplotypes defined by them and risk of incident MI in this cohort.

Tissue plasminogen activator antigen and D-dimer as markers for atherothrombotic risk among healthy postmenopausal women.

Plasma markers of fibrinolytic function are associated with incident coronary events among several, but not all, prospective epidemiologic investigations of healthy individuals. Few studies have evaluated this relationship in women. In addition, although menopausal hormone therapy (HT) may alter markers of fibrinolytic function, the relevance of this effect for coronary risk assessment has not been studied. In a prospective, nested case-control study among 75 343 postmenopausal women without prior cardiovascular disease or cancer, we evaluated the relationships of elevated tissue plasminogen activator (tPA) antigen and D-dimer with subsequent first coronary heart disease events over a median period of 2.9 years. Baseline levels of both biomarkers were higher among 304 cases compared with 304 controls matched on age, smoking status, ethnicity, and length of follow-up; median values were 9.0 versus 7.4 ng/mL (P<0.001) for tPA antigen and 27.6 versus 23.4 ng/mL (P=0.001) for D-dimer. In matched-pairs analyses, the odds ratio in the highest versus lowest quartile of tPA antigen was 3.5 (95% CI, 2.1 to 5.8; P trend <0.001) and for D-dimer was 2.0 (95% CI, 1.2 to 3.2; P trend=0.005). After adjustment for lipid and nonlipid risk factors, including C-reactive protein, tPA antigen remained a significant predictor. Multivariable-adjusted associations for D-dimer, although attenuated, largely remained statistically significant. When stratified by HT, the relationship between tPA antigen and incident coronary heart disease was similar among nonusers, estrogen-only users, and current users of any HT. Elevated tPA antigen and, to a lesser extent, D-dimer are independently associated with incident coronary events among postmenopausal women. In analyses stratified by HT, tPA antigen remained a consistent marker of increased coronary risk.

New risk factors for atherosclerosis and patient risk assessment.

Advances in our understanding of the ways in which the traditional cardiovascular risk factors, including standard lipid (eg, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) and nonlipid (eg, hypertension) risk factors, interact to initiate atherosclerosis and promote the development of cardiovascular disease have enhanced our ability to assess risk in the individual patient. In addition, the ongoing identification and understanding of so-called novel risk factors may further improve our ability to predict future risk when these are included along with the classic risk factors in assessing the global risk profile. This review briefly summarizes the evidence that some newer risk factors, including impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and high-sensitivity C-reactive protein, contribute to an increased risk of coronary and cardiovascular diseases.

M.580 Antioxidant vitamins (A, E and C) in the risk profile of cardiovascular disease in dyslipidemic patients

The aim of this study was to determine whether apolipoproteins (apo) B and A-I measured in childhood and adolescence predict atherosclerosis in adulthood.Exposure to dyslipidemia in childhood predicts the development of atherosclerosis. Apolipoproteins B and A-I might be good markers of atherogenic dyslipidemia, but there is a paucity of information concerning their importance in childhood.Apolipoproteins B and A-I, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, blood pressure, obesity, insulin, C-reactive protein, and smoking were assessed in 1980 and 2001 among 879 subjects in the Cardiovascular Risk in Young Finns Study (ages 3 to 18 years at baseline). Carotid artery intima-media thickness (IMT) and brachial artery flow-mediated dilation (FMD) were measured in 2001 at the age of 24 to 39 years.In subjects ages 12 to 18 years at baseline, apoB and apoB/apoA-I ratio were directly (p < 0.001) related and apoA-I was inversely (p = 0.01) related with adulthood IMT. In subjects ages 3 to 18 years at baseline, apoB (p = 0.02) and the apoB/apoA-I ratio (p < 0.001) were inversely related and apoA-I (p = 0.003) was directly related to adulthood FMD. These relations were not altered when the effects of nonlipid risk factors and adulthood apolipoproteins were taken into account. The apoB/apoA-I ratio measured in adolescence was superior to LDL/HDL ratio (c-values, 0.623 vs. 0.569, p = 0.03) in predicting increased IMT in adulthood (IMT ≥90th percentile and/or carotid plaque).Apolipoproteins B and A-I measured in children and adolescents reflect a lipoprotein profile predisposing to the development of subclinical atherosclerosis in adulthood. These markers might have value in pediatric lipid risk assessment.

Managing dyslipidaemia ? multiple patients and multiple approaches: metabolic syndrome, familial hypercholesterolaemia and hypertension

High risk of coronary heart disease (CHD) events is present in a number of patient populations in addition to those with pre-existing CHD, other atherosclerotic disease or diabetes. Patients with the metabolic syndrome are at increased CHD risk and require attention to low-density lipoprotein cholesterol (LDL-C) lowering in addition to management of hypertriglyceridaemia, low high-density lipoprotein cholesterol and non-lipid risk factors. Patients with hypertension in addition to other cardiovascular risk factors are at increased risk of CHD and have recently been shown to derive marked benefit from statin treatment. Patients with heterozygous familial hypercholesterolaemia, characterised by dramatically raised LDL-C and high risk for early CHD, require large reductions in LDL-C to meet recommended target levels, and newer statins possess the LDL-C-lowering efficacy to bring many of these patients to such goals. Identification of high-risk patients and prompt institution of appropriate management strategies can serve to reduce the overall burden of cardiovascular disease.