Factors contributing to the risk of cardiovascular disease reflected by plasma adiponectin: data from the coronary risk factors for atherosclerosis in women (CORA) study

Objective

An inverse association of adiponectin with coronary heart disease (CHD) has been reported, but the results are inconsistent. We used data from the CORA study to investigate into plasma concentrations of adiponectin and factors that may mediate the link to incident CHD.

Design

The CORA study is a population-based case-control study on 200 women with incident CHD and 255 age-matched controls.

Results

Plasma concentrations of adiponectin were significantly lower in women with CHD (p < 0.0001), and in women with BMI ≥25 kg/m² (p < 0.02), even more so with central obesity (WHR ≥0.85), prevalent diabetes or insulin resistance (HOMA-IR ≥3.8), or low HDL-cholesterol (<50 mg/dl), and in smokers (each p < 0.0001). Adiponectin also correlated with intake of fruit and vegetables, meat and sausage and alcohol as dietary markers of cardiovascular risk. Strikingly, the trend towards lower adiponectin concentrations with increasing BMI or waist circumference was less marked than the difference of adiponectin between CHD cases and controls. In a logistic regression model the odds ratio of adiponectin of 0.943 per 1 μg/ml (CI 0.919-0.968, p < 0.0001) for risk of CHD was progressively reduced by elevated WHR, obesity-related risk factors, smoking, and dietary parameters.

Conclusions

Plasma adiponectin indicates protection from CHD in women that is attenuated by combined effects of central obesity and dependent risk factors, parameters of nutrition and smoking. Thus, the impact of adiponectin goes beyond its relation to central adiposity, but may also reflect independent effects of lifestyle.     

Prognostic significance of elevated lipoprotein(a) in coronary artery revascularization patients

Background

Although lipoprotein(a) [Lp(a)] has been considered a cardiovascular risk factor for many years, there is a paucity of data in regard to the potential risk of elevated Lp(a) in symptomatic patients with CAD. Therefore, we sought to evaluate whether elevated Lp(a) is associated with worse outcome in symptomatic patients with coronary artery disease (CAD), and to clarify the prognostic value of Lp(a) in the era of coronary artery revascularization.

Methods

6252 consecutive subjects (59.2% male, mean age 61.2 ± 11.2 years) suspected of having CAD underwent coronary angiography. Laboratory values for lipid parameters including Lp(a) were obtained on the day of coronary angiography. Baseline risk factors, coronary angiographic findings, length of follow-up, and major adverse cardiovascular events (MACE), including cardiac death and non-fatal myocardial infarction were recorded.

Results

Over a mean follow-up period of 3.1 ± 2.2 years, there were 100 MACE (56 cardiac deaths and 44 non-fatal myocardial infarctions), with an event rate of 1.6%. In multivariate Cox regression analysis, elevated Lp(a) was a significant predictor of MACE [hazard ratio 1.773 (95% confidence interval 1.194–2.634, p = 0.005)], and the addition of this factor to the model significantly increased the global х² value over traditional risk factors and CAD (from 79.1 to 88.7, p = 0.003).

Conclusions

Elevated Lp(a) is an independent prognostic risk factor for cardiovascular events, and moreover, has incremental prognostic value in symptomatic patients with coronary artery revascularization.     

The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes

Aims/hypothesis Individuals with type 1 diabetes have an increased incidence of coronary artery disease (CAD) and a higher risk of cardiovascular death compared with individuals of the same age in the general population. While chronic hyperglycaemia and insulin resistance partially explain excess CAD, little is known about the potential genetic determinants of accelerated coronary atherosclerosis in type 1 diabetes. The aim of the present study was to evaluate the association of apolipoprotein A-IV (APOA4) polymorphisms with coronary artery calcification (CAC) progression, a marker of subclinical atherosclerosis.Subjects and methods Two previously well-studied functional APOA4 polymorphisms resulting in the substitution of the amino acid Thr for Ser at codon 347 and Gln for His at codon 360 were genotyped in 634 subjects with type 1 diabetes and 739 non-diabetic control subjects, the participants of the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) study.Results The His360 allele was associated with a significantly higher risk of CAC progression among patients with type 1 diabetes (33.7 vs 21.2%, p=0.014), but not in the control subjects (14.1 vs 11.1%, p=0.42). Logistic regression analysis confirmed that the presence of the APOA4 His360 allele predicts an increased risk of progression of coronary atherosclerosis in adults with type 1 diabetes of long duration (odds ratio = 3.3, p=0.003 after adjustment for covariates associated with CAD risk).Conclusions/interpretation This is the first report suggesting an association between the APOA4 Gln360His polymorphism and risk of CAC progression in subjects with type 1 diabetes. Additional studies are needed to explore potential interactions between APOA4 genotypes and metabolic/oxidative stress components of the diabetic milieu leading to rapid progression of atherosclerosis. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Association of computed tomography-derived left atrial size with major cardiovascular events in the general population: The Heinz Nixdorf Recall Study

Background

Echocardiography based data suggests that left atrial (LA) size is associated with cardiovascular morbidity and mortality. Once non-contrast cardiac CT is performed for prevention purposes, information on the LA is readily available. We aimed to determine whether LA area from non-contrast cardiac CT is associated with incident major cardiovascular (CV) events, independent of CV risk factors and coronary artery calcium (CAC), based on a general population cohort.

Methods

Subjects aged 45–75 years without prevalent CV disease from the population-based Heinz Nixdorf Recall Study were enrolled between 2000 and 2003. LA area at the level of the mitral valve was quantified from non-contrast cardiac CT. Major CV events (coronary event, stroke, CV death) were assessed during follow-up. The association of LA with events was assessed using Cox regression analysis.

Results

Overall, 3958 subjects (59.2 ± 7.7 years, 53% female) were included. Mean LA area was 17.64 ± 4.22 cm² (range: 7.16–44.13 cm²). During 8.0 ± 1.5 years of follow-up, 221 major CV events occurred. In univariate analysis, increase of LA size by 1 standard deviation was associated with nearly 50% excess events (HR (95%CI): 1.48 (1.32–1.65)), which remained significant after adjustment for CV risk factors (HR (95%CI): 1.25 (1.09–1.43)) and when additionally adjusting for CAC (HR (95%CI): 1.22 (1.07–1.40)). Associations for LA size were similar for each endpoint and again independent of risk factors and CAC (coronary event: HR (95%CI): 1.21 (1.01–1.45); stroke: 1.31 (1.05–1.63); CV death: 1.33 (1.03–1.71)).

Conclusion

LA size is associated with incident major CV events independent of risk factors and CAC-score. Once cardiac CT imaging is performed, assessment of LA size may complement information of this imaging modality.     

Gender differences in alcohol metabolism: Relationship to liver volume and effect of adjusting for body mass

Background & Aims: Alcoholic liver disease purportedly develops more readily in women than in men. Some studies have demonstrated faster rates of alcohol elimination in women. This study examined whether gender differences in alcohol metabolism are related to differences in liver volume and/or differences in lean body mass. Methods: Ten men and 10 women had alcohol elimination rates determined by clamping of the breath alcohol concentration at 50 mg/dL by means of a constant rate of intravenous infusion of 6% ethanol. Liver volume was determined by computed tomography. Results: Mean alcohol elimination rate and mean computed liver volume were not significantly different in men and women. Lean body mass was 42% greater in men than in women. Consequently, the calculated alcohol elimination rate and liver volume per kilogram of lean body mass were 33% and 38% higher in women than in men, respectively. When the alcohol elimination rate was calculated per unit liver volume, no gender-related difference was found. Conclusions: Women have greater clearance of ethanol per unit lean body mass, confirming previous oral alcohol administration studies. Women have approximately the same liver volume as men, explaining the equivalent alcohol elimination rates seen when men and women are compared on the basis of liver size.GASTROENTEROLOGY 1998;115:1552-1557     

Qualitative score of systemic arteriosclerosis by vascular ultrasonography as a predictor of coronary artery disease in type 2 diabetes

Objective

Patients with type 2 diabetes mellitus (T2DM) are at risk of polyvascular comorbidities and poor prognosis. Non-invasive techniques for early prediction of coronary artery disease (CAD) are desirable to prevent cardiovascular events in these patients. The aim of the present study was to investigate the association between CAD and systemic arteriosclerosis by qualitative vascular ultrasonography.

Methods

The study subjects were 102 consecutive outpatients with T2DM [males/females = 60/42, age: mean ± SD 67 ± 9 (range, 40–85) years] evaluated by vascular ultrasonography for arteriosclerosis in the abdominal aorta, carotid, renal, and common iliac arteries. The total number of detected arteriosclerotic vascular lesions in the four arteries was determined. CAD was diagnosed by two cardiologists using either stress electrocardiography, myocardial scintigraphy, multi-detector row computed tomography or coronary angiography.

Results

Multiple arteriosclerotic vascular lesions (>1) were detected in 64 (63%) patients. The total systemic vascular score was significantly higher in patients with CAD than those without (average score 2.7 versus 1.0, p < 0.0001). None of the CAD patients had a total score of 0. Age- and sex-adjusted multiple logistic regression analysis identified total score of ≥2 as the only predictor of CAD (p < 0.001). The sensitivity, specificity, positive and negative predictive values for total systemic vascular score in the prediction of CAD were 98%, 77%, 83%, and 97%, respectively, which were better than those for carotid mean and maximum intima-media thickness.

Conclusion

Non-invasive qualitative evaluation of systemic arteriosclerosis by the total systemic vascular score is potentially useful for the early prediction of CAD in T2DM patients.     

The degree of hair graying as an independent risk marker for coronary artery disease,a CT coronary angiography study

Background

Cardiovascular disease is a leading cause of death worldwide. Aging is an unavoidable coronary risk factor and is associated with dermatological signs that could be a marker for increased coronary risk. We tested the hypothesis that hair graying as a visible marker of aging is associated with risk of coronary artery disease (CAD) independent of chronological age.

Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis

The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, −629C/A, Taq1B, and −2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p < 0.001) and activity (13.1% and 9.4%, respectively; p < 0.01) and lower HDL-C (5.6% and 6.0%, respectively; p < 0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p = 0.006 and p = 0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p = 0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the −629A, Taq1B B2, and −2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p < 0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p < 0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p < 0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.     

Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL

Background

Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave proproteins into mature end products. Previously, MBTPS1 and PCSK9 have been shown to regulate cholesterol metabolism and LDL receptor recycling, whereas FURIN and PCSK5 have been suggested to inactivate lipases and regulate inflammation in atherosclerosis. Here, we systematically analyzed the expression of PCSKs and their targets in advanced atherosclerotic plaques.

Methods and results

Microarray and quantitative real-time PCR experiments showed that FURIN (42.86 median fold, p = 2.1e−8), but no other PCSK, is universally overexpressed in the plaques of different vascular regions. The mRNA expression screen of PCSK target proteins in plaques identified many known factors, but it also identified the significant upregulation of the previously overlooked furin-processed B cell activating cytokines APRIL (TNFSF13, 2.52 median fold, p = 3.0e−5) and BAFF (TNFSF13B, 2.97 median fold, p = 7.6e−6). The dysregulation of FURIN did not associate with its htSNPs or the previously reported regulatory SNP (−229, rs4932178) in the promoter. Immunohistochemistry experiments showed the upregulation of FURIN in the plaque lymphocytes and macrophages where it was co-expressed with BAFF/TNFSF13B and APRIL/TNFSF13.

Conclusions

Our data unequivocally show that FURIN is the primary PCSK that is dysregulated in the immune cells of advanced human atherosclerotic plaques, which implies a role for this enzyme in plaque pathology. Therefore, drugs that inhibit FURIN in arteries may modulate the course of this disease.     

Antioxidant vitamins and the risk of carotid atherosclerosis : The perth carotid ultrasound disease assessment study (CUDAS)

OBJECTIVES

This study examined whether dietary intake or plasma levels of antioxidant vitamins were independently associated with common carotid artery intima-media (wall) thickness (IMT) or focal plaque, or both, in a large, randomly selected community population.

BACKGROUND

Oxidation of low-density lipoprotein (LDL) cholesterol is thought to be important in early atherogenesis. Antioxidant micronutrients may therefore protect against lipid peroxidation and atherosclerotic vascular disease.

METHODS

We studied 1,111 subjects (558 men and 553 women; age 52 ± 13 years [mean ± SD], range 27 to 77). We measured dietary vitamin intake and fasting plasma levels of vitamins A, C and E, lycopene and alpha- and beta-carotene and performed bilateral carotid artery B-mode ultrasound imaging.

RESULTS

After adjustment for age and conventional risk factors, there was a progressive decrease in mean IMT, with increasing quartiles of dietary vitamin E intake in men (p = 0.02) and a nonsignificant trend in women (p = 0.10). Dietary vitamin E levels accounted for 1% of the variance in measured IMT in men. For plasma antioxidant vitamins, there was an inverse association between carotid artery mean IMT and plasma lycopene in women (p = 0.047), but not in men. None of the other dietary or plasma antioxidant vitamins, nor antioxidant vitamin supplements, were associated with carotid artery IMT or focal carotid artery plaque.

CONCLUSIONS

This study provides limited support for the hypothesis that increased dietary intake of vitamin E and increased plasma lycopene may decrease the risk of atherosclerosis. No benefit was demonstrated for supplemental antioxidant vitamin use.     

Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: possible role of reactive oxygen species

OBJECTIVES

This study was designed to examine the effect of antioxidant supplementation on the endothelial function and insulin sensitivity in patients with coronary spastic angina (CSA).

BACKGROUND

Insulin resistance may play a key role in coronary heart disease, and there is a possible link between acetylcholine-induced coronary vasoconstriction and hyperinsulinemia in patients with CSA. Endothelial dysfunction is present in the systemic arteries in CSA patients, and reactive oxygen species may cause inactivation of nitric oxide in these patients.

METHODS

We measured flow-mediated dilation of the brachial artery using ultrasound technique in 22 patients with CSA and 20 control subjects. We also evaluated glucose tolerance using a 75-g oral glucose tolerance test and insulin sensitivity using steady-state plasma glucose (SSPG) methods in the same patients.

RESULTS

The incidence of impaired glucose tolerance was higher in the CSA group than in the control group. Vitamin C infusion augmented flow-mediated dilation and decreased SSPG levels in the CSA group (from 3.27 ± 0.77% to 7.00 ± 0.59% [p < 0.001 by analysis of variance (ANOVA)] and from 177.3 ± 13.3 to 143.1 ± 14.9 mg/dl [p = 0.047 by ANOVA], respectively) but not in the control group (from 6.47 ± 0.66% to 6.80 ± 0.60% and from 119.8 ± 11.7 mg/dl to 118.1 ± 11.3 mg/dl, respectively). The steady-state plasma insulin levels were not affected by vitamin C infusion in either group.

CONCLUSIONS

Vitamin C improves both endothelial function and insulin sensitivity in patients with CSA. Thus, reactive oxygen species and/or decreased nitric oxide bioactivity may play an important role in the genesis of both endothelial dysfunction and insulin resistance in patients with CSA.