Established Risk Factors For Atherosclerosis Research Articles

Biochemical Endothelial Markers and Cardiovascular Remodeling in Refractory Arterial Hypertension

Background. Hypertension is the most important and well established risk factor for atherosclerosis. The vascular and cardiac remodeling present in refractory hypertensive patients are related to endothelial dysfunction, a key factor in early atherogenesis and cardiovascular disease. However the mechanistic relationship among biochemical endothelial function markers, cardiovascular remodeling, and refractory hypertension is unknown. Methods. We evaluated the left ventricular mass and function, carotid thickness, and plasma nitrate/nitrite (NO2/NO3), cyclic 3′‐5′‐guanosine monophosphate (cGMP), and thromboxane B2 (TXB2) levels in refractory hypertensive (RH; n = 20) and healthy (CONTROL; n = 20) subjects 22–65 years old. Carotid thickness, left ventricular mass index (LVMI), and left ventricular fraction ejection (LVFE) were estimated by duplex scan ultrasound. Nitrates/nitrites were assayed using the Griess reaction, and plasma cGMP and thromboxane B2 were determined by enzymatic immunoassay (EIA). Results. Left ventricular mass index was higher in the RH group (138 ± 20 vs. 108 ± 17 g/m2, p < 0.001) but there was no significant difference in the ejection fraction (67 ± 5% vs. 69 ± 4%). Pulse pressure (61 ± 9 mmHg vs. 46 ± 10 mmHg) and carotid thickness (1.59 ± 0.22 mm vs. 1.04 ± 0.14 mm) were significantly higher (p < 0.001) in RH patients whereas NO2/NO3, cGMP, and thromboxane B2 plasma concentrations were similar in both groups. Conclusion. There was no association between cardiovascular remodeling and the particular biochemical markers of endothelial function we assessed in refractory hypertensive patients.

Non-traditional risk factors for atherosclerosis.

During the last 10 years, several "non-traditional" risk markers for atherosclerosis have been identified. Among them, new markers of lipoprotein metabolism (i.e. lipoprotein [a]), endothelial dysfunction (i.e. homocysteine), hemostasis (i.e. fibrinogen) and inflammation (i.e. C-reactive protein) have been linked to an excessive risk of cardiovascular disease. These factors should help the clinician to better identify individuals at risk of premature atherosclerotic disease and/or improve the predictive value of established risk factors for atherosclerosis. Finally, these factors are expected to improve the knowledge in the pathophysiology of cardiovascular diseases, and perhaps to impact future therapeutic decisions. In this review article, we will analyze the markers in which there are at least some evidence to support their acceptance as "non-traditional risk factors" for atherosclerotic disease.

Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.

Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 microg/min) and sodium nitroprusside (20 microg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (DeltaCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P=0.03). Angiographic severity of CAD was also lower in these subjects (P=0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (DeltaCVR during acetylcholine = -46+/-3% versus -36+/-3%, respectively, P=0.02), whereas DeltaCVR with sodium nitroprusside was similar in both groups (-55+/-2% versus -53+/-2%, P=0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis (P=0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.

Flow-Mediated Dilation in Lower-Extremity Vein Grafts

Autogenous vein bypasses manifest a substantial late stenosis and occlusion rate due, at least in part, to the hostile conditions of the arterial milieu. The present study was undertaken to evaluate flow-mediated dilation (FMD)-a putative measure of endothelial health and, potentially, long-term function-in chronically implanted vein grafts performed for critical lower-extremity ischemia. Eleven patients, four men, seven women (mean age: 64 ±14 years; range: 30 to 81 years), with saphenous vein bypasses performed for critical lower-extremity ischemia a mean of 346 ±457 days previously (range: 47 to 1640 days), had their grafts studied in the resting state, following 5 minutes' tourniquet application to produce hyperemia, and following administration of nitroglycerin. Baseline and maximal postischemic brachial artery and vein graft diameters were determined ultrasonographically. An Atherosclerosis Risk Score (ARS) was calculated by assigning one point for each of six established risk factors for atherosclerosis (smoking, diabetes, hypertension, hypercholesterolemia, male gender, and age &gt;60 years). Vein graft flow and diameter increased significantly with hyperemia (20% ±23%; p=0.04, and 3% ±3%; p=0.01 by paired t-test, respectively). Mean ARS was 3.6 ±1.2 (range: 2 to 5). FMD in vein grafts correlated inversely with ARS (r=-0.66, p=0.03). Seven of the 11 vein grafts demonstrated FMD &gt;1% of baseline diameter. No differences were observed between the seven patients with “reacting” grafts and four with “non-reacting” grafts except in the mean ARS (2.9 ±0.9 vs. 4.3 ±0.5, respectively, p=0.05) and in the frequency of diabetes (33% vs. 100%; p=0.05). Chronically implanted saphenous vein grafts performed for limb-threatening ischemia exhibit FMD. FMD in vein grafts appears to be influenced adversely by concurrent atherosclerotic risk factors, and is reduced compared to FMD reported in other vessels.

Homocyst(e)ine and atherosclerosis in patients on chronic hemodialysis.

Hyperhomocyst(e)inemia is an established risk factor for atherosclerosis. We performed this study to identify the correlating variables and risk factors for atherosclerosis, as measured by the atherosclerotic score (AS), and to determine the relative risk for cardiovascular disease in relation to plasma homocyst(e)ine levels in patients on chronic hemodialysis. We evaluated and measured 61 patients on chronic hemodialysis for clinical and biochemical parameters including atherosclerotic score (AS) and plasma homocyst(e)ine. We divided patients into high and low groups, first, by the mean AS, and second, by the median value of plasma total homocyst(e)ine levels. Then we compared the variables between the two groups. Out of the 61 patients, the median plasma total homocyst(e)ine level was 24.4 micromol/L (mean+/-SD, 27.7+/-17.4; range, 9.8-127.4 micromol/L), and the median AS was 5 (mean+/-SD, 6.2+/-2.8; range, 3-13) out of a possible 20 points. AS was significantly correlated with plasma total homocyst(e)ine levels (r=0.37) and age (r=0.67). Through multivariate analysis, plasma total homocyst(e)ine level and age were determined as significant risk factors for the high-AS group (p<0.05). However, plasma total homocyst(e)ine level did not correlate with age (p>0.05). Eighteen of the 61 patients, presented with cardiovascular disease until the present study, had an AS>6. Cardiovascular disease was found more often in the high-homocyst(e)ine group (>24.4 micromol/L) than in the low-homocyst(e)ine group (odds ratio, 9.3; 95% confidence interval, 2.3-37.4). Regardless of age, hyperhomocyst(e)inemia (especially homocyst(e)ine levels >24.4 micromol/L) is a risk factor that can be modified for the development of cardiovascular disease in patients on chronic hemodialysis.

The Frequency of a Common Mutation of the Methionine Synthase Gene in the Australian Population and its Relation to Smoking and Coronary Artery Disease

Modest elevations in levels of circulating homocysteine are common in patients with vascular disease. Methionine synthase is a vitamin B12-dependent enzyme catalysing the re-methylation of homocysteine to methionine; reduced methionine synthase activity results in elevated level of homocysteine. A case-control study. We explored the frequency and distribution of a 2756A-->G (D919G) mutation of the methionine synthase gene, detected by polymerase chain reaction genotyping, in 745 Australian Caucasian patients aged < or = 65 years (550 men and 195 women) with and without angiographically documented coronary artery disease (CAD). The frequency distributions of AA, AG and GG genotypes were 61.9%, 33.8% and 4.3%, respectively, and were in Hardy-Weinberg equilibrium. There was no correlation between the methionine synthase mutation and CAD from simple chi2 comparison. However, the interactive term of life-time smoking dose with methionine synthase genotypes was predictive of both the number of significantly diseased vessels (> or =50% luminal obstruction; chi2 = 12.518, P=0.0019), and the presence or absence of significant CAD (chi2=7.045, P=0.027). A stepwise logistic regression analysis showed that smokers who were also GG homozygotes had more severe CAD compared with smokers of other genotypes. The methionine synthase genotypes were not associated with any of the other established CAD risk factors assessed in our study. We conclude that the methionine synthase 2756A-->G mutation is common, with homozygosity occurring in approximately 4% of white Australians, and that it has an interactive effect with life-time smoking dose to increase the severity of CAD. Smokers who are also GG homozygotes have additionally elevated CAD risk.

Hyperhomocysteinemia and Venous Thrombosis: A Meta-analysis

Hyperhomocysteinemia is an established risk factor for atherosclerosis and vascular disease. Until the early nineties the relationship with venous thrombosis was controversial. At this moment ten case-control studies on venous thrombosis are published. We performed a metaanalysis of these reports. We performed a MEDLINE-search from 1984 through June 1997 on the keywords "homocysteine" or "hyperhomocysteinemia" and "venous thrombosis", which yielded ten eligible case-control studies. We found a pooled estimate of the odds ratio of 2.5 (95% CI 1.8-3.5) for a fasting plasma homocysteine concentration above the 95th percentile or mean plus two standard deviations calculated from the distribution of the respective control groups. For the post-methionine increase in homocysteine concentration we found a pooled estimate of 2.6 (95% CI 1.6-4.4). These data from case-control studies support hyperhomocysteinemia as a risk factor for venous thrombosis. Further research should focus on the pathophysiology of this relationship and on the clinical effects of reducing homocysteine levels by vitamin supplementation.

Psychological stress and the progression of carotid artery disease.

We examined the relation between cardiovascular reactivity (the response of the cardiovascular system to psychological stress) and the severity and progression of carotid atherosclerosis. Using duplex ultrasonography, we measured the change in the area of all detectable plaques in the extracranial carotid arteries during 2 years. Cardiovascular reactivity was assessed by measuring changes in hemodynamics during a frustrating cognitive task (the Stroop Color Word Interference Task). Established risk factors for atherosclerosis were measured by interviewing patients, a physical examination, and blood assays for 351 subjects with a wide range of types of atherosclerotic disease. Atherosclerotic plaques were present in the carotid arteries of 273 (78%) subjects. In a forward stepwise multiple regression analysis, it was found that greater age (beta = 0.46), a history of hypertension (beta = 0.20), use of lipid level-lowering agents (beta = 0.18), a longer history of smoking (beta = 0.13), a larger cholesterol:high-density lipoprotein ratio (beta = 0.13), a smaller change in heart rate during the task (beta = -0.12), and a higher resting systolic blood pressure (SBP; beta = 0.11) were associated significantly with a greater plaque area (R2 = 0.35). In 136 untreated subjects who were followed up for 2 years, a greater change in SBP during the task (beta = 0.28), a higher total cholesterol: high-density lipoprotein ratio (beta = 0.23), a shorter resting preejection period (beta = -0.19), and a lower body mass index (beta = -0.17) were significant predictors of the change in atherosclerosis, after controlling for age and initial plaque area in a stepwise multiple regression analysis (R2 = 0.24). These results support the hypothesis that hemodynamic responses under conditions of mental stress may influence the progression of atherosclerosis.

LDL‐apheresis significantly reduces urinary apo(a) excretion

Increased plasma Lp(a) is an established risk factor for atherosclerosis. We recently described the presence of apo(a) fragments in urine and the significant correlation between urinary apo(a) concentrations and plasma Lp(a). Here we investigated urinary apo(a) in patients suffering from familial hypercholesterolaemia (FH), treated with LDL apheresis. Before treatment, plasma Lp(a) levels and urinary apo(a) normalized to creatinine were > 2-fold increased in FH patients (P < 0.0001) as compared to controls. LDL-apheresis led to a reduction of plasma Lp(a) by 75% and a concomitant immediate reduction of urinary apo(a) by 45%. We conclude that a steady state condition for urinary apo(a) is rapidly achieved via LDL-apheresis.

Potential of quantity of coronary artery calcification to identify new risk factors for asymptomatic atherosclerosis.

The goals of this study of adults asymptomatic for coronary artery disease (CAD) were to examine the relations between established CAD risk factors and quantity of coronary artery calcification (CAC) in three arterial locations using generalized linear mixed models and to estimate the variability in quantity of CAC explained by established CAD risk factors and the variability due to noise or artifact in the measure. The community-based sample included 740 asymptomatic adults (378 women) aged 20-59 years without hypertension or diabetes. Participants were recruited from Rochester, Minnesota, between 1990 and 1994. Quantity of CAC in three arterial locations was detected noninvasively by electron beam computed tomography. Sex, arterial location, age, body size, blood pressure, lipid metabolism, and smoking were significantly (p < 0.05) associated with quantity of CAC. Age was more strongly associated with quantity of CAC in the left than in the right coronary or circumflex arterial locations (p < 0.005). In each sex, risk factors together explained less than 40% of the variability in quantity of CAC. Noise or artifact in the measure accounted for only a small proportion of unexplained variability. Future studies of new risk factors for artery-specific quantity of CAC and its progression could provide additional etiologic insights into the atherosclerotic process.

Thickening of the Carotid Wall

Background and Purpose We investigated the relationships between prevalent coronary heart disease (CHD), clinically manifest atherosclerotic disease (ASD), and major established risk factors for atherosclerosis and intima-media thickness (IMT) in the common carotid arteries (CCA) and internal carotid arteries (ICA) separately and in combination in older adults. We wished to determine whether a noninvasive measurement can serve as an indicator of clinically manifest atherosclerotic disease and to determine which of the two variables, CCA IMT or ICA IMT, is a better correlate. Methods IMT of the CCA and ICA was measured with duplex ultrasound in 5117 of 5201 individuals enrolled in the Cardiovascular Health Study, a study of the risk factors and the natural history of cardiovascular disease in adults aged 65 years or more. Histories of CHD, peripheral arterial disease, and cerebrovascular disease were obtained during baseline examination. Risk factors included cholesterol levels, cigarette smoking, elevated blood pressure, diabetes, age, and sex. Relationships between risk factors and IMT were studied by multiple regression analysis and canonical variate analysis. Prediction of prevalent CHD and ASD by IMT measurements in CCAs and ICAs were made by logistic regression, adjusting for age and sex. Results IMT measurements of the CCAs and ICAs were greater in persons with CHD and ASD than those without, even after controlling for sex ( P &lt;.001). IMT measurements in the ICA were greater than those in the CCA. Risk factors for ASD accounted for 17% and 18% of the variability in IMT in the CCA and ICA, respectively. These same risk factors accounted for 25% of the variability of a composite measurement consisting of the sum of the ICA IMT and CCA IMT. The ability to predict CHD and ASD was greater for ICA IMT (odds ratio [confidence interval]: 1.36 [1.31 to 1.41] and 1.35 [1.25 to 1.44], respectively) than for CCA IMT (1.09 [1.05 to 1.13] and 1.17 [1.09 to 1.25]). Conclusions Whereas CCA IMT is associated with major risk factors for atherosclerosis and existing CHD and ASD in older adults, this association is not as strong as that for ICA IMT. The combination of these measures relates more strongly to existing CHD and ASD and cerebrovascular disease risk factors than either taken alone.

Effect of Cigarette Smoking and Nicotine on Plasma Endothelin-1 Levels

Although cigarette smoking is an established risk factor for atherosclerosis, the true mediator of vessel diseases associated with smoking is not known. Because endothelin-1 (ET-1) exhibits potent vasoconstrictor activity, it may act as a mediator in this condition. We determined venous ET-1 and nicotine levels in 12 smokers (age 21-24 years, 2-52 pack-years) before and 10 min, 4 h, and 8 h after the beginning of smoking. To distinguish an isolated effect of nicotine, 11 nonsmokers (age 24-50 years) were investigated while they were wearing a transdermal nicotine delivery system (TNDS). ET-1 was measured by RIA and nicotine by HPLC. Baseline ET-1 plasma levels before the exposure to either smoking or nicotine administration were comparable in smokers (1.07 +/- 0.3 pg/ml) and in nonsmokers (1.04 +/- 0.3 pg/ml). Smokers had borderline significantly higher ET-1 plasma levels within 10 min after the onset of smoking (1.3 +/- 0.3 pg/ml vs. 1.08 +/- 0.3 pg/ml; p = 0.055) but not after 4 and 8 h. Nonsmokers exposed to TNDS did not exhibit any significant plasma ET-1 changes. We conclude that the increase in plasma ET-1 after cigarette smoking is of borderline significance and is a transitory phenomenon restricted to the first 10 min after the onset of smoking. Although nicotine itself seems to be an unlikely mediator, other smoke components, such as CO or tar, may be responsible for the increase in plasma ET-1 in smokers. The absence of an ET-1 increase after transcutaneous nicotine application underscores the safety of TNDS in smoking withdrawal therapy.

Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group.

This article describes the prevalence of extracranial carotid atherosclerosis assessed by ultrasonography, its association with risk factors, and its relation to symptomatic coronary disease and stroke in men and women aged > or = 65 years. Maximum percent stenosis, maximum common carotid artery wall thickness, and maximum internal carotid artery wall thickness were assessed using duplex ultrasound in 5,201 men and women aged > or = 65 years in the Cardiovascular Health Study, a study of the risk factors and natural history of cardiovascular disease in the elderly. Existing coronary disease and stroke were assessed by physical examination and participant history. Detectable carotid stenosis was present in 75% of men and 62% of women, although the prevalence of > or = 50% stenosis was low, 7% in men and 5% in women. Maximum stenosis and maximum wall thickness measurements increased with age and were uniformly greater at all ages in men than in women (p < 0.00001). Established risk factors for atherosclerosis (hypertension, smoking, diabetes) and indications of vascular disease (left ventricular hypertrophy, major electrocardiographic abnormality, bruits, and history of heart disease or stroke) related to all three carotid artery measures in the elderly. Of the three ultrasound measures, the best correlate for a history of coronary disease was maximum internal carotid artery wall thickness. For stroke the best correlate was common carotid artery wall thickness. Multiple logistic regression models of prevalent coronary heart disease and stroke that included the ultrasound findings indicated, after adjustment for age and sex, that maximum internal wall thickness and maximum common carotid wall thickness were significant correlates of both. Maximum stenosis did not add significantly to the correlation. In the elderly the incidence of carotid atherosclerosis was high, although the frequency of severe disease was low. The prevalence and severity of carotid atherosclerosis continued to increase with age even in the late decades of life, and more disease was found in men than in women at all ages. Known risk factors for atherosclerosis continued to relate to carotid abnormalities in the later decades of life, both in symptomatic and asymptomatic subjects.

Systemic hypertension alters vasomotor function in experimental vein grafts

Hypertension is an established risk factor for atherosclerosis, a disease that is important in the pathophysiology of vein graft failure. Hypertension can also alter arterial vasoreactivity. The vasomotor function and histologic characteristics of autogenous vein grafts in hypertensive rabbits were assessed in this study. Hypertension was induced in 13 male New Zealand white rabbits by use of the Goldblatt one clip two kidney method. The right carotid artery was divided and bypassed with the reversed right external jugular vein 7 days later in these animals and in 13 normotensive controls. Blood pressure and renal function were assessed serially, and all the grafts were harvested after 28 days. Three grafts in each group were examined by light microscopy. The responses of the remaining grafts to norepinephrine, histamine, serotonin, and angiotensin II were determined in vitro under isometric tension. Endothelium-dependent relaxation to acetylcholine and calcium ionophore (A23187) was assessed in precontracted grafts. The mean arterial pressure was significantly increased after the Goldblatt procedure was performed. Intimal hyperplasia was observed in both groups, but the grafts in the hypertensive groups showed increased adventitial and medial fibrosis and a reduced number of vasa vasora. The grafts in the hypertensive rabbits were hypersensitive to all agonists as indicated by a significant reduction in their median effective dose values, and their maximal responses to all agonists were also significantly reduced. No graft relaxed in response to acetylcholine, and whereas precontracted grafts in normotensive rabbits had a maximal relaxation of 24% ± 6% of precontraction with A23187, this was absent in the grafts in the hypertensive rabbits. The results suggest that angiotensin-induced hypertension may adversely affect vein graft patency by inducing hypersensitivity to physiologically important agonists and reducing the effect of receptor-independent endothelium-derived relaxation on vasomotor tone.

HDL apolipoprotein A-I and HDL apolipoprotein A-II concentrations in male company employees in Westphalia aged 40 years and older.

The major structural components of high density lipoproteins were determined in the sera of 638 male employees aged 40 years and older. It was demonstrated that the HDL apolipoprotein A-I/HDL cholesterol ratio as well as the HDL apolipoprotein A-II/HDL cholesterol ratio are similarly correlated to a cumulative score of established risk factors for atherosclerosis. Most important, however, is the finding that the correlation of these ratios to the risk factor rating of atherosclerosis is found in subgroups with normal or elevated HDL cholesterol values. Furthermore, it is shown that the relative content of apolipoproteins A-I and A-II in individual HDL is partly dependent on the plasma concentration of HDL cholesterol and triglycerides. It is concluded that HDL composition may have an additional predictive significance for the development of atherosclerosis.

LIVER-FUNCTION TESTS DURING INTAKE OF CONTRACEPTIVE TABLETS IN PRE-MENOPAUSAL WOMEN.

<h3>Objectives</h3> Pentraxins are a superfamily of multifunctional conserved proteins, some of which are components of the humoral arm of innate immunity and behave as functional ancestors of antibodies. They are divided into short (C reactive protein) and long pentraxins (pentraxin 3; PTX3). We investigated the diagnostic values of systematic arterial and coronary sinus (PTX3) in developing prediction models for estimating pretest probability of coronary artery disease (CAD) among an intermediate-risk population of patients with chronic stable angina. <h3>Design</h3> Cross-sectional analysis. <h3>Setting</h3> Referral cardiology hospital. <h3>Participants</h3> Patients with chronic stable angina, without evidence of previous CAD if they were referred for angiography. <h3>Main outcome measures</h3> All participants underwent diagnostic angiography. Prevalence rate ratio (PRR) of angiographically-determined coronary artery stenosis was separately examined in association with coronary sinus and femoral artery PTX3 concentrations using a general linear model. Duke treadmill score (DTS) was derived from the results of treadmill exercise cardiac stress testing. PTX3 data were collected in 100 patients with DTS-determined intermediate-risk chronic stable angina (aged 56.1 (1.1) years, 51 female). <h3>Results</h3> Both coronary sinus (PRR: 2.33, 95% CIs 1.64 to 3.31) and femoral artery PTX3 (PRR: 2.09, 95% CIs 1.46 to 2.97) independently predicted the prevalence rate of coronary artery involved with stenosis independent of the established CAD risk factors. Femoral artery PTX3 was highly correlated with coronary sinus PTX3 (β=0.8, 95% CIs 0.66 to 0.94; p value&lt;0.001). When we added femoral artery PTX3 to the predictive models incorporating traditional CAD risk factors, net reclassification improvement indices were 40% (cutpoint-free) and 15% (cutpoint-based). In the presence of PTX3, high-density lipoprotein cholesterol (HDL-C) was no longer protective against CAD. <h3>Conclusions</h3> Gathering information on systemic arterial PTX3 may help more accurately reclassify DTS-determined patients with intermediate-risk chronic stable angina into more appropriate risk categories. PTX3 possibly, at least in part, mediates the protective effect on CAD of HDL-C.