Impact of coronary artery calcium on cardiovascular risk categorization and lipid-lowering drug eligibility in asymptomatic hypercholesterolemic men.

BACKGROUND: Application of coronary artery calcium (CAC) for stratifying coronary heart disease (CHD) risk may change the proportion of subjects eligible for risk reduction treatment and decrease cost-effectiveness of primary prevention. We therefore aimed to analyze the impact of CAC on CHD risk categorization. METHODS: We measured CAC with electron beam computed tomography in 500 asymptomatic untreated hypercholesterolemic men and re-calibrated 10-year Framingham CHD risk by adding CAC score information (post CAC test risk) via an algorithm integrating relative risk and expected distribution of CAC in the population tested. Proportions of low (<10%), intermediate (10-20%) and high (>20%) risk categories, and of eligibility for lipid-lowering treatment, were compared between Framingham risk and post CAC test risk. RESULTS: In the overall population, post CAC test risk calculation changed risk categorization defined by Framingham assessment alone, with 10% more low risk and 10% less intermediate risk (p<0.01). Risk reclassifications were bidirectional since 30% of high and 30% of intermediate Framingham risk were downgraded to intermediate and low risk categories respectively, while 11% of low and 14% of intermediate Framingham risk were upgraded to intermediate and high-risk categories respectively. Post CAC test risk did not change the proportion of Framingham-based lipid-lowering treatment eligibility in the overall population but decreased it by 8% in intermediate Framingham risk subgroup (p<0.05). CONCLUSIONS: Addition of CAC to risk prediction resulted rather in downgrading than in upgrading risk and did not change treatment eligibility, except in intermediate risk subjects, less frequently eligible for treatment.

Early thoracic aorta enlargement in asymptomatic individuals at risk for cardiovascular disease: determinant factors and clinical implication.

OBJECTIVES: We analyzed, in above-average risk asymptomatic individuals, the factors determining early thoracic aorta enlargement. METHODS: Ascending aortic diameter (AAD) was measured with noncontrast multidetector computed tomography in 345 participants (mean age 56 years; 78% men) without cardiovascular disease. We analyzed the associations of AAD with risk factors and Framingham risk score (FRS), multidetector computed tomography-assessed coronary artery calcium (CAC), and ultrasound interrogation of plaque presence at five sites (right and left carotid arteries, right and left femoral arteries, and abdominal aorta), the number of diseased sites with presence of plaque being counted from 0 to 5. RESULTS: AAD was positively associated with age (P < 0.001), male sex (P < 0.01), body surface area (BSA; P < 0.001), hypertension (P < 0.001), systolic and diastolic blood pressures in individuals without antihypertensive medication (P < 0.05, P < 0.01), and FRS (P < 0.001). AAD was positively associated with CAC score after adjusting for age, sex, and BSA (P < 0001) or for FRS and BSA (P < 0.001). AAD was higher in the presence of three, four, or five than in the presence of no, one, or two diseased sites with plaque, after adjusting for age, sex, and BSA (P < 0.05) or for FRS and BSA (P < 0.001). When participants were divided into subsets by AAD tertiles and by number of sites with plaque, FRS and CAC score were greatest in individuals with AAD top tertile and 3-5 sites with plaque and lowest in those with AAD bottom tertile and 0-2 sites with plaque (P < 0.001). CONCLUSION: These findings suggest that thoracic ascending aorta dilatation is related to hypertension and represents a part of a generalized atherosclerotic process of the entire vasculature.

The physiological impact of the nonlinearity of arterial elasticity in the ambulatory arterial stiffness index.

The ambulatory arterial stiffness index (AASI) is claimed to be a new estimator for arterial rigidity. It was recently defined as one minus the slope of the linear regression of systolic to diastolic ambulatory pressure during 24 h. Although several reports testify its clinical relevance, the explanation of how this new index is conceptually associated with arterial stiffness remains controversial. In this work we hypothesize that nonlinear arterial elasticity is behind AASI physiological principles. To that end, random number generators were used to emulate arterial cross-sectional area (CSA) during 24 h. Pressure values were calculated using linear and nonlinear elasticity models for rigid and compliant arteries. The AASI was calculated from simulated pressures and also analytically predicted for each model. Additionally, invasive aortic pressure and CSA were continuously measured in a conscious sheep during 24 h to test the nonlinear model. We found that analytical solutions agreed with simulation outcomes; for the nonlinear model, the AASI was higher in rigid arteries with respect to compliant arteries (0.51 versus 0.38) and the linear model systematically predicted AASI = 0. For in vivo pressure measurements, AASI was 0.31. Using the measured pulsatile CSA and an estimation of the elastic constant for the nonlinear model, the AASI was accurately predicted with errors below 5%. We conclude that the AASI is higher in stiffer arteries due to the nonlinear behavior of the arterial wall. With a nonlinear arterial function, the slope of the linear regression of diastolic to systolic pressures during 24 h depends on the product of an elastic constant by the pulsatile CSA. As the elastic constant dominates the product, the reported associations between the AASI and arterial stiffness indices now have a consistent explanation.

Circulating microparticles may influence early carotid artery remodeling.

OBJECTIVES: To test associations of circulating microparticles with large artery remodeling before atherosclerosis is detectable. METHODS: In 232 untreated symptom-free individuals, we measured microparticles of various cellular origins (platelet, endothelial and leukocyte) by specific anti-GPIb (glycoprotein Ib), anti-cluster of differentiation (CD) 105 and anti-CD11a antibodies, and common carotid artery intima-media thickness (IMT), internal and external diameters by ultrasound. RESULTS: Except for CD105 microparticles with IMT to lumen ratio (IMT/D, P < 0.05), microparticles correlated with no carotid dimensions. Significant interactions existed between each microparticle type and IMT on internal and external diameters (GPIb, P < 0.01; CD105 and CD11a microparticles P < 0.001) consisting of lower trend in increased diameter with increasing IMT in individuals with high than in those with low microparticle level (according to the median) of each origin. As a result, individuals within the third IMT tertile had lower internal diameter in the presence of high than in the presence of low level of GPIb, CD105 or CD11a microparticles (P = 0.001, <0.05 or 0.01, respectively), and lower external diameter in the presence of high than in the presence of low level of GPIb and CD11a microparticles (P = 0.001 and 0.01). Also, individuals within third IMT tertile exhibited positive correlations of IMT with CD105 and CD11a microparticles (P < 0.05), negative correlations of internal diameter with GPIb (P < 0.05), CD105 (P < 0.05) and CD11a microparticles (P < 0.01) and of external diameter with GPIb and CD11a microparticles (P < 0.05), and positive correlations of IMT/D with CD105 and CD11a microparticles (P < 0.001). CONCLUSION: Increased levels of leukocyte and endothelial-derived microparticles are associated with carotid inward remodeling in individuals with the greatest IMT before atherosclerosis is detectable.

The value of carotid intima-media thickness for predicting cardiovascular risk.

We reviewed prospective epidemiological data in the general population, mostly middle-aged to older persons, to determine the association of carotid intima-media thickness (CIMT) (assessed by B-mode ultrasonography) with cardiovascular risk. Reported risks were expressed as absolute (event risk per persons-years in subjects with a high CIMT) and relative (hazard ratio of high vs low CIMT). They were hardly comparable as the result of differences between the analyzed studies, including the site and procedure of CIMT measurement, the report of adjusted or unadjusted models, and the arbitrary cutoff point to evaluate the CIMTAEs ability to predict risk. Despite these heterogeneities, the following four main conclusions emerged: (1) CIMT was an independent but relatively modest (as judged by absolute risk) predictor of coronary heart disease (CHD); (2) CIMT was an independent predictor for stroke, slightly better than for CHD as judged by the relative risks of both events; (3) CIMT added little to the CHD prediction by risk factors, as judged by c statistic and receiver operating characteristic curve analysis (however, appropriate data for stroke on this important issue were lacking); and (4) the CHD prediction by CIMT was inferior to that by ultrasonography-assessed carotid plaque because plaque may be more representative of atherosclerosis than CIMT.

Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation.

BACKGROUND: Postulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years. METHODOLOGY/PRINCIPAL FINDINGS: 5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)--the 5-HT/MAO catabolite--in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0.01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0.00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0.001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0.0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity. CONCLUSIONS/SIGNIFICANCE: This is one of the first reports that smoking induces an epigenetic modification. A better understanding of the epigenome may help to further elucidate the physiopathology and the development of new therapeutic approaches to tobacco addiction. The results could have a larger impact than cardiovascular damage, considering that MAO-dependent 5-HT catabolism is also involved in addiction, predisposition to cancer, behaviour and mental health.

Exercise tolerance test for predicting coronary heart disease in asymptomatic individuals: A review.

In symptom-free subjects, exercise tolerance testing (ETT) has a doubtful utility for detecting latent coronary heart disease (CHD) because of frequent false positives, but it may be valuable for predicting future CHD. To clarify the latter question, we calculated CHD incidence associated with presence or absence of ETT-induced abnormalities of ST-segment depression, exercise capacity, and heart rate using published prospective ETT studies in primary prevention populations. Based on 5-23 years of follow-up, yearly incidence of fatal and non-fatal CHD ranged from 0.9 to 5.8% in the presence of ST-segment depression and from 1.2 to 1.7% in the presence of impaired maximal heart rate, and pooling of all data provided a linear positive relationship between pre- and post-test CHD incidence. Yearly incidence of CHD death was 0.8% in the presence of ST-segment depression, 0.2-0.3% in the presence of impaired heart rate recovery, and 0.5% in the presence of low exercise capacity. Absence of ST-segment depression was associated with <1.5% yearly incidence of fatal and non-fatal CHD events, except for one study and <0.2% yearly incidence of CHD or CVD death in all populations analyzed. Lastly ETT-induced ST-segment depression conveys a CHD risk superior to that associated with ETT-induced heart rate and exercise capacity abnormalities. This may be due to difference in pretest CHD incidences in ETT studies.

Comparative associations of adiposity measures with cardiometabolic risk burden in asymptomatic subjects.

BACKGROUND: Obesity increases the risk of cardiovascular diseases and diabetes. OBJECTIVE: To determine which measure of adiposity, body mass index (BMI), waist circumference (WC) or body fat mass (BFM) is the most predictive of the coronary heart disease (CHD) risk and of the presence of the metabolic syndrome. METHODS: A cross-sectional study of 649 consecutive men and women aged 22-79 years, in primary prevention. RESULTS: BMI, WC and BFM were strongly associated with conventional cardiometabolic risk factors. For a 1-S.D. increase in BMI, WC and BFM, the odds ratios (95% CIs) of having the metabolic syndrome after adjustment for age, gender, and drug treatments were as follows: BMI, 3.40 (2.68-4.37); WC, 4.79 (3.61-6.53); and BFM, 3.19 (2.49-4.16). WC annihilated the association of BMI and BFM with the metabolic syndrome when measures of adiposity were introduced two by two. For CHD risk, the odds ratios (95% CIs) were as follows: 1.62 (1.16-2.24), 1.72 (1.22-2.42), and 1.92 (1.40-2.62) respectively. BFM annihilated the associations of BMI and WC with CHD risk when measures of adiposity were introduced two by two. CONCLUSIONS: WC shows the best association with the metabolic syndrome, while BFM shows the best association with high CHD risk. BMI shows weaker relationships with the metabolic syndrome, and high CHD risk. Our findings suggest that BFM can be used as a complementary measure to identify CHD risk in adult subjects.

Relationship of circulating biomarkers of inflammation and hemostasis with preclinical atherosclerotic burden in nonsmoking hypercholesterolemic men.

BACKGROUND: Relations of mediators of inflammation and hemostasis with preclinical atherosclerosis have been poorly analyzed. The aim of this study was to test potential associations of these blood markers with indicators of cardiovascular risk and atherosclerotic burden in asymptomatic, nonsmoking, hypercholesterolemic men. METHODS: A total of 87 men underwent cardiovascular risk assessment by means of 10-year Framingham risk calculation (median 9%) and atherosclerotic burden evaluation by means of ultrasonographic measurement of common carotid intima-media thickness and assessment of atherosclerotic plaques at three arterial sites (three-site plaques). RESULTS: Of the markers C-reactive protein, tumor necrosis factor-alpha, interleukin-10, factor VIIc, fibrinogen, plasminogen activator inhibitor-activator, soluble intercellular adhesion molecule-1, soluble P-selectin (sP-selectin), and von Willebrand factor, only sP-selectin was positively and independently associated with high Framingham risk score (>9%) (71.7 +/- 3.6 ng/mL, n = 33 v 59.6 +/- 2.8, n = 54; mean +/- SEM; P < .05) and with three-site plaques (75.4 +/- 5.7 ng/mL, n = 14 v 62.0 +/- 2.5, n = 73; P < .05). After adjustment for all of the above markers and for cardiovascular risk factors, odd ratios of having high Framingham risk and three-site plaques were 3.38 (1.43 to 10.21) and 5.23 (1.74 to 23.52) respectively, per 1-standard deviation increase in sP-selectin. CONCLUSIONS: These results confirm that among several hemostasis and inflammation mediators, only sP-selectin blood level was associated with preclinical atherosclerosis. It might confer to sP-selectin measurement a clinical usefulness for detecting and managing high cardiovascular risk in primary prevention.

Influence of hypertension on early carotid artery remodeling.

OBJECTIVE: We aimed to analyze the influence of hypertension on early large artery remodeling. METHODS AND RESULTS: Carotid intima-media thickness (IMT) and diameter were measured ultrasonographically in 394 normotensive subjects and 327 untreated and 528 treated hypertensive patients. IMT and diameter were increased in hypertensive groups, treated or untreated, compared with the normotensive group (P<0.001). Positive association existed between diameter and IMT in the overall study population (P<0.001), and this association interacted with the category of clinical groups (P<0.01). The slope of the diameter-IMT relationship was different between normotensive, untreated hypertensive, and treated hypertensive groups (P<0.01), with higher value in the treated hypertensive group than in untreated hypertensive and normotensive groups (P<0.05, P<0.01). Adjustment for blood pressure, lipid-lowering therapy, or multiple covariates (age, sex, systolic and diastolic blood pressures, body mass index, lipid-lowering therapy, smoking, and previous cardiovascular disease) did not abolish the diameter-IMT slope difference between clinical groups (P<0.01). CONCLUSIONS: The sensitivity of carotid artery enlargement in response to increase in wall thickness was unchanged in untreated hypertension but altered by antihypertensive therapy compared with the normotensive condition.

Determinants of progression of coronary artery calcifications in asymptomatic men at high cardiovascular risk.

Extended coronary artery calcifications (CAC) are predictive for cardiovascular complications but little is known about factors likely to influence CAC deposit. An analysis was undertaken to assess the cardiovascular risk factors that are capable of predicting CAC change over time. A retrospective analysis of CAC change was carried out in 55 asymptomatic men who underwent sequential electron beam computed tomographic measurement of CAC score a mean of 3.3 years apart. To ensure maximal accuracy in CAC change analysis, patients were included who had an initial CAC score of 10 or greater and with difference between both scores of 20% or greater of the initial score. The annual change rate in CAC score was calculated by dividing the change in CAC score by the interval between scores. Subjects' risk factors were analyzed and included body mass index, blood pressure, blood lipids and glucose, plasma lipoprotein(a) and fibrinogen, smoking status, and family history of coronary heart disease. The annual change rate in CAC score correlated positively with lipoprotein(a) (r = 0.42, p<0.01) and with initial CAC score (r = 0.46, p<0.001) and these associations persisted in multivariate analysis (p = 0.01, p = 0.001 respectively, R2 = 0.31). In contrast, no association existed between annual CAC change and baseline values and follow-up changes of other risk factors. The association of lipoprotein(a) with CAC progression in symptom-free patients with preexisting coronary calcifications provides new insights into the progression of coronary artery disease and may be useful for planning therapy and follow-up.

Intima-media thickness: a new tool for diagnosis and treatment of cardiovascular risk.

Increased intima-media thickness (IMT) is a non-invasive marker of early arterial wall alteration, which is easily assessed in the carotid artery by B-mode ultrasound, and more and more widely used in clinical research. Methods of IMT measurement can be categorized by two approaches: (i) measurement at multiple extracranial carotid sites in near and far walls and (ii) computerized measurement restricted to the far wall of the distal common carotid artery. Because IMT reflects global cardiovascular risk, its normal value might be better defined in terms of increased risk rather than in terms of statistical distribution within a healthy population. The available epidemiological data indicate that increased IMT (at or above 1 mm) represents a risk of myocardial infarction and/or cerebrovascular disease. Close relationships have been shown between: (i) most traditional cardiovascular risk factors; (ii) certain emerging risk factors such as lipoproteins, psychosocial status, plasma viscosity, or hyperhomocysteinemia; and (iii) various cardiovascular or organ damages such as white matter lesion of the brain, left ventricular hypertrophy, microalbuminuria or decreased ankle to brachial systolic pressure index. Thus, IMT gives a comprehensive picture of the alterations caused by multiple risk factors over time on arterial walls. Prospective primary and secondary prevention studies have also shown that increased IMT is a powerful predictor of coronary and cerebrovascular complications (risk ratio from 2 to 6) with a higher predictive value when IMT is measured at multiple extracranial carotid sites than solely in the distal common carotid artery. Therapeutic double-blind trials have shown that lipid-lowering drugs, such as resin and overall statines, and to a lesser extent antihypertensive drugs, such as calcium antagonists, may have a beneficial effect on IMT progression in asymptomatic or in coronary patients. However, methodological standardization of IMT measurement still needs to be implemented before routine measurement of IMT can be proposed in clinical practice as a diagnostic tool for stratifying cardiovascular risk in primary prevention and for aggressive treatment decision. It can be anticipated however, that the presence of increased carotid IMT in one individual with intermediate cardiovascular risk would lead to his classification into the high-risk category and thus influence the aggressiveness of risk factor modifications.