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Objective: To Investigate the association of plasma homocystelne with coronary artery calcification (CAC) in strata based on 10-year risk of coronary heart disease (CHD) in a cohort enriched in persons with hypertension. Participants and Methods: Fasting plasma homocystelne was measured by liquid chromatography electrospray tandem mass spectrometry. Coronary artery calcification was measured noninvasively by electron beam computed tomography and CAC score calculated using the method of Agatston et al. The 10-year CHD risk was calculated based on the Framingham risk score. The association of homocysteine with log-transformed CAC score was assessed in the pooled sample and within each risk stratum by linear regression after adjustment for conventional risk factors. Results: In the 1071 participants studied, homocysteine was associated with CAC quantity (P = .01) after adjustment for CHD risk factors (age, male sex, total and high-density lipoproteln cholesterol, diabetes, history of smoking, body mass Index, and systolic blood pressure), serum creatinine, and statin and hypertension medication use. When the association was assessed in strata based on 10-year CHD risk, homocysteine was significantly (P = .003) associated with CAC quantity in participants at Intermediate 10-year risk of CHD (6%-20%) independent of other risk factors but not in those at lower risk or higher risk. Conclusion: Plasma homocysteine is associated with quantity of CAC Independent of CHD risk factors. When studied in categories of 10-year CHD risk, the association was significant in participants at intermediate risk but not in those at low or high risk. Plasma homocysteine levels may have clinical utility as a marker of CHD risk in such individuals. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between lipoprotein(a) [Lp(a)] levels and the extent of coronary atherosclerosis in a cohort that consisted predominantly of hypertensive patients. Patients and Methods: Patients were ascertained through sibships that contained at least 2 individuals with essential hypertension diagnosed before the age of 60 years. The 10-year coronary heart disease (CHD) risk was estimated on the basis of the Framingham risk equation. Serum Lp(a) was measured by an immunoturbidimetric assay. Coronary artery calcification (CAC) was measured noninvasively by electron beam computed tomography and CAC score calculated using the Agatston score. Results: Patients included 765 non-Hispanic, white individuals (59% women) participating in the Genetic Epidemiology Network of Arteriopathy study. The mean +/- SD age of the patients was 62 +/- 8 years, and 77% had hypertension. The prevalence of detectable CAC was 87% in men and 60% in women. The CAC scores did not differ significantly across quintiles of Lp(a) levels in either men or women. In a multiple regression model that included conventional risk factors, Lp(a) levels were not related to CAC quantity in either sex. No significant interactions were noted between Lp(a) levels and the conventional risk factors in the prediction of CAC quantity. When stratified on the basis of the 10-year CHD risk, 26.5% of the patients were low risk (< 6%), 60.5% were intermediate risk (6%-20%), and 12.9% were high risk (> 20%). Lipoprotein(a) was not associated with CAC quantity within subgroups based on 10-year CHD risk. Conclusion: In this cohort enriched with hypertensive patients, the estimated 10-year CHD risk did not appear to modify the lack of an association between Lp(a) levels and CAC. [ABSTRACT FROM AUTHOR]

Background: Single nucleotide polymorphisms (SNPs) within the 9p21.3 genomic region have been consistently associated with coronary heart disease (CHD), myocardial infarction, and quantity of coronary artery calcification (CAC), a marker of subclinical atherosclerosis. Prior studies have established an association between blood pressure measures and CAC. To examine mechanisms by which the 9p21.3 genomic region may influence CHD risk, we investigated whether SNPs in 9p21.3 modified associations between blood pressure and CAC quantity., Methods: As part of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, 974 participants underwent non-invasive computed tomography (CT) to measure CAC quantity. Linear mixed effects models were used to investigate whether seven SNPs in the 9p21.3 region modified the association between blood pressure levels and CAC quantity. Four SNPs of at least marginal significance in GENOA for a SNP-by-diastolic blood pressure (DBP) interaction were then tested for replication in the Framingham Heart Study's Offspring Cohort (N = 1,140)., Results: We found replicated evidence that one SNP, rs2069416, in CDKN2B-AS1, significantly modified the association between DBP and CAC quantity (combined P = 0.0065; Bonferroni-corrected combined P = 0.0455)., Conclusions: Our results represent a novel finding that the relationship between DBP and CAC is dependent on genetic variation in the 9p21.3 region. Thus, variation in 9p21.3 may not only be an independent genetic risk factor for CHD, but also may modify the association between DBP levels and the extent of subclinical coronary atherosclerosis.

Objective: Matrix gla protein (MGP) inhibits arterial and cartilaginous calcification. A threonine to alanine (Thr83Ala) polymorphism (codon 83) in MGP is associated with myocardial infarction and femoral artery calcification. We examined the association of the MGP Thr83Ala polymorphism with quantity and progression of coronary artery calcification (CAC), a noninvasive measure of subclinical coronary atherosclerosis., Methods and Results: In 605 participants of the Epidemiology of Coronary Artery Calcification Study, generalized linear mixed models were fit to determine the association of MGP Thr83Ala with CAC quantity and progression. There was a significant additive relation between MGP Thr83Ala and CAC progression (P=0.001). In the fully adjusted model, every 1 Ala83 allele increase was associated with an estimated 1.9% (95% confidence interval, 0.7%-3.0%) per year since baseline larger increase in CAC quantity. A proxy single nucleotide polymorphism for MGP Thr83Ala (rs6488724) was similarly associated with CAC progression in an independent cohort from the Genetic Epidemiology Network of Arteriopathy (GENOA) study., Conclusions: Increased risk of myocardial infarction associated with MGP ThrAla83 genotype observed elsewhere may be related to faster progression of subclinical coronary atherosclerosis. MGP genotype could be a potential candidate for identifying individuals at increased risk of atherosclerotic disease who would benefit from aggressive primary prevention strategies.

Background: Short stature is associated with increased risk of coronary heart disease (CHD); although the mechanisms for this relationship are unknown, shared genetic factors have been proposed. Subclinical atherosclerosis, measured by coronary artery calcification (CAC), is associated with CHD events and represents part of the biological continuum to overt CHD. Many molecular mechanisms of CAC development are shared with bone growth. Thus, we examined whether there was evidence of shared genes (pleiotropy) between adult stature and CAC., Methods: 877 Asymptomatic white adults (46% men) from 625 families in a community-based sample had computed tomography measures of CAC. Pleiotropy between height and CAC was determined using maximum-likelihood estimation implemented in SOLAR., Results: Adult height was significantly and inversely associated with CAC score (P = 0.01). After adjusting for age, sex and CHD risk factors, the estimated genetic correlation between height and CAC score was -0.37 and was significantly different than 0 (P = 0.001) and -1 (P < 0.001). The environmental correlation between height and CAC score was 0.60 and was significantly different than 0 (P = 0.024)., Conclusions: Further studies of shared genetic factors between height and CAC may provide important insight into the complex genetic architecture of CHD, in part through increased understanding of the molecular pathways underlying the process of both normal growth and disease development. Bivariate genetic linkage analysis may provide a powerful mechanism for identifying specific genomic regions associated with both height and CAC., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels., Methods: To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals., Results: From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-C levels (P < 10(-68)). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample (P < 10(-36)). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10(-6) in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69-7.21) of having detectable CAC, and a 9.28-fold higher odds (2.93-29.35) of having extensive CAC (CAC score ≥400)., Conclusion: The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.

Objective: The etiology of breast arterial calcification (BAC) is not well understood. We examined reproductive history and cardiovascular disease (CVD) risk factor associations with the presence of detectable BAC in asymptomatic postmenopausal women., Methods: Reproductive history and CVD risk factors were obtained in 240 asymptomatic postmenopausal women from a community-based research study who had a screening mammogram within 2 years of their participation in the study. The mammograms were reviewed for the presence of detectable BAC. Age-adjusted logistic regression models were fit to assess the association between each risk factor and the presence of BAC. Multiple variable logistic regression models were used to identify the most parsimonious model for the presence of BAC., Results: The prevalence of BAC increased with increased age (p < 0.0001). The most parsimonious logistic regression model for BAC presence included age at time of examination, increased parity (p = 0.01), earlier age at first birth (p = 0.002), weight, and an age-by-weight interaction term (p = 0.004). Older women with a smaller body size had a higher probability of having BAC than women of the same age with a larger body size., Conclusions: The presence or absence of BAC at mammography may provide an assessment of a postmenopausal woman's lifetime estrogen exposure and indicate women who could be at risk for hormonally related conditions.

Background: The use of oral calcium supplementation among the elderly for prevention and treatment of osteoporosis and osteopenia is increasing. The incidence of aortic valve disease and coronary artery disease also is increasing. No study thus far has been done to demonstrate whether this affects the progression of calcification in both the valves and vasculature. We sought to determine whether ingestion of oral calcium supplementation has an effect on aortic valve calcification (AVC) and coronary artery calcification (CAC)., Methods: We performed an independent assessment of AVC, CAC, and calcium supplementation among patients enrolled in the Epidemiology of Coronary Artery Calcification study who were >60 years of age and had baseline and 4-year follow-up AVC data. In this population-based study of Olmsted County (Minnesota) residents, AVC and CAC scores were determined prospectively by electron beam computed tomography. We evaluated baseline demographic data and analyzed whether those patients using calcium supplementation had a higher rate of progression of both AVC and CAC., Results: We identified 257 patients (mean age, 67.8+/-5.2 years), 144 of whom were women. Twenty-five patients (all women) reported using calcium supplements. Analysis of the 144 women (25 taking calcium supplementation) showed there was no difference in the progression of AVC (mean difference in baseline and follow-up AVC score; no supplement versus supplement, 30+/-9 vs 39+/-28; P=.73) or CAC (mean difference in baseline and follow-up CAC score; no supplement vs supplement, 47+/-15 vs 112+/-22; P=.154). There were no significant differences between the 2 groups with regard to baseline AVC, serum calcium, renal function, diabetes, hypertension, cholesterol, or body mass index., Conclusion: In this community-based observational study with a 4-year follow-up, no significant increased progression of AVC or CAC was found in women taking oral calcium supplementation. Larger prospective, randomized studies are needed to confirm these findings.

Background: Hypertension during pregnancy (HDP) increases the risk of future coronary heart disease (CHD), but it is unknown whether this association is mediated by renal injury. Reduced renal function is both a complication of HDP and a risk factor for CHD., Methods: Logistic regression models were fit to examine the association between a history of HDP and the presence and extent of coronary artery calcification (CAC), a measure of subclinical coronary artery atherosclerosis, in 498 women from the Epidemiology of Coronary Artery Calcification Study (mean age 63.3 +/- 9.3 years)., Results: Fifty-two (10.4%) women reported a history of HDP. After adjusting for age at time of study participation, HDP was associated with increased serum creatinine later in life (p = 0.014). HDP was positively associated with the presence of CAC after adjusting for age at time of study participation (OR = 2.7, 95% CI 1.4-5.4). This association was slightly attenuated with adjustment for body size and blood pressure (OR = 2.4, 95% CI 1.2-4.9) but was not further attenuated with adjustment for serum creatinine and urinary albumin/creatinine ratio (OR = 2.6, 95% CI 1.3-5.3). Results were similar for CAC extent., Conclusions: HDP may increase a woman's risk of future CHD beyond traditional risk factors and renal function. Women with a history of HDP should be monitored for potential increased risk of CHD as they age.

Background: Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis., Methods and Results: CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity (p = 0.03) and CIMT (p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: -77.8% to -9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: -20.1% to -8.1%) in CIMT., Conclusions: Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process.

Coronary artery calcification (CAC) and common carotid artery intima-media thickness (CIMT) are measures of subclinical vascular disease. This 2000-2006 study aimed to characterize the associations among coronary artery disease risk factors, CAC quantity, and CIMT and to estimate shared genetic and environmental contributions to both CAC and CIMT among 478 asymptomatic Amish adults in Lancaster County, Pennsylvania. Heritability for CAC quantity and CIMT, adjusted for age and sex, was 0.42 (P = 0.0001) and 0.29 (P = 0.003), respectively. CAC quantity and CIMT were modestly correlated (adjusted r = 0.14, P = 0.003) but showed little evidence of shared genetic or environmental factors. However, significant genetic correlations were found for CAC quantity and total cholesterol (0.44 (standard error, 0.19); P = 0.03), for CAC quantity and low density lipoprotein cholesterol (0.55 (standard error, 0.17); P = 0.005), and for CIMT and waist circumference (0.58 (standard error, 0.25); P = 0.046), suggesting shared genes for these risk factors and measures of subclinical disease. Results suggest that some of the same genes influence variation in CAC and low density lipoprotein cholesterol, whereas a different set of genes influences variation in CIMT and waist circumference.

As part of the Genetic Epidemiology Network of Arteriopathy study, hypertensive non-Hispanic White sibships were screened using 471 single nucleotide polymorphisms (SNPs) to identify genes influencing coronary artery calcification (CAC) measured by computed tomography. Individuals with detectable CAC and CAC quantity > or =70th age- and sex-specific percentile were classified as having a high CAC burden and compared to individuals with CAC quantity <70th percentile. Two sibs from each sibship were randomly chosen and divided into two data sets, each with 360 unrelated individuals. Within each data set, we applied two machine learning algorithms, Random Forests and RuleFit, to identify the best predictors of having high CAC burden among 17 risk factors and 471 SNPs. Using five-fold cross-validation, both methods had approximately 70% sensitivity and approximately 60% specificity. Prediction accuracies were significantly different from random predictions (P-value<0.001) based on 1,000 permutation tests. Predictability of using 287 tagSNPs was as good as using all 471 SNPs. For Random Forests, among the top 50 predictors, the same eight tagSNPs and 15 risk factors were found in both data sets while eight tagSNPs and 12 risk factors were found in both data sets for RuleFit. Replicable effects of two tagSNPs (in genes GPR35 and NOS3) and 12 risk factors (age, body mass index, sex, serum glucose, high-density lipoprotein cholesterol, systolic blood pressure, cholesterol, homocysteine, triglycerides, fibrinogen, Lp(a) and low-density lipoprotein particle size) were identified by both methods. This study illustrates how machine learning methods can be used in sibships to identify important, replicable predictors of subclinical coronary atherosclerosis.

Background: Comparison of atherosclerosis and its risk factors among diverse populations may provide insights into the pathogenesis of the disease. We investigated differences in traditional coronary artery disease (CAD) risk factors and presence and quantity of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis, between two diverse non-Hispanic white populations living in the US., Methods and Results: Members of the Old Order Amish (OOA), a unique culture with a physically active rural lifestyle who rarely use prescription medications, were compared to another non-Hispanic white population with a more typical US lifestyle, Epidemiology of Coronary Artery Calcification (ECAC), Study participants from Rochester, Minnesota. Although age- and sex-adjusted presence and quantity of CAC in those with detectable CAC were similar between study groups, there were significant differences in the distribution of many traditional CAD risk factors. OOA had significantly less abdominal adiposity and history of cigarette smoking but a less advantageous lipid profile than ECAC participants. Importantly, after adjusting for CAD risk factors, presence of CAC and quantity of CAC among those with detectable CAC were significantly higher among OOA than ECAC participants., Conclusions: Identification of factors contributing to differences in subclinical disease across groups could increase our understanding of mechanisms for coronary atherosclerosis.

Background: On the basis of the Framingham risk algorithm, overestimation of clinical events has been reported in some European populations. Electron-beam computed tomography-derived quantification of coronary artery calcification (CAC) allows for non-invasive assessment of coronary atherosclerosis in the general population and may thus add important in vivo information on the path from risk factor exposure to formation of clinical events. The current study was undertaken to compare the relationship between risk factors and subclinical coronary atherosclerosis between non-Hispanic white cohorts in Germany and US-America, the hypothesis being that subclinical coronary atherosclerosis might be less prevalent in Europe at the same level of classical risk factor exposure., Methods: The Heinz Nixdorf Recall (HNR) study, conducted in the German Ruhr area and the Epidemiology of Coronary Calcification (ECAC) study, conducted in Olmsted County, Minnesota, both recruited large unselected cohorts, men and women aged 45-74 years, from the general population. All subjects with no history of coronary artery disease (CAD) or stroke were included (n=3120 in HNR, n=703 in ECAC). Coronary risk factors were assessed by personal and computer-assisted interviews and direct laboratory measurements. Cardiovascular medication use (antihypertensive, lipid-lowering, and anti-diabetic) was noted. CAC scores were determined using the Agatston method in an identical fashion in both studies., Results: Adverse levels of risk factors were more prevalent, and the Framingham risk score was higher (10.6+/-7.6 versus 9.3+/-7.1, p<0.001) in HNR than ECAC, respectively. There was no difference in body mass index (BMI). CAC scores were greater in HNR than in ECAC (mean values, 155.7+/-423.0 versus 107.2+/-280.0; median values, 11.9 versus 2.4; p<0.001, respectively). When subjects were matched on CAD risk factors, presence and quantity of CAC were similar in the 2 cohorts. Risk factors significantly associated with CAC score in both studies included: age, male sex, current and former smoking, systolic blood pressure, and non-HDL-cholesterol. Inferences were similar after excluding subjects using lipid- or blood pressure-lowering medications. Using the same risk factor variables for modelling, the predicted CAC scores were comparable in both cohorts., Conclusions: In the higher-risk German cohort, presence and quantity of CAC were greater than in the lower-risk US-American cohort. Risk factor associations with CAC were very similar in both unselected populations. We could not demonstrate a relative increase in subclinical coronary atherosclerosis in the US-American cohort. It appears possible to compare CAC as a measure of subclinical coronary artery disease in different populations on different continents, and accordingly, scanning guidelines might be translated across these populations.

Vascular calcification and osteoporosis are common age-related processes that are influenced by both genetic and nongenetic factors. Whether common genes underlie these processes is not known. We measured coronary artery calcification (CAC), aortic calcification (AC), and bone mineral density (BMD) in 682 men and women from large Old-Order Amish families. We assessed the heritabilities of these traits and then evaluated, using variance decomposition procedures, whether variation in the traits was influenced by a common set of genes (i.e., pleiotropy). Significant heritabilities were detected for BMD of the femoral neck and spine (0.65, 0.63) and CAC and AC (0.43, 0.42). Mean BMD did not differ significantly across quartiles of either CAC or AC in either sex. In neither the total group nor any single subgroup (men, women, postmenopausal women) did any of the genetic or environmental correlations between BMD and vascular calcification achieve statistical significance. However, subjects with a history of cardiovascular disease (CVD) events had significantly lower BMD at the femoral neck compared to subjects who reported no prior history of CVD (age-, sex-, body mass index-, and family structure-adjusted P = 0.003). We detected no evidence for shared genes affecting the joint distribution of bone and vascular calcification. However, our results do reveal a lower BMD in subjects with a prior history of CVD in the Old-Order Amish.

Background: Aortic valve calcification (AVC) is considered degenerative. Recent data suggested links to atherosclerosis or coronary disease (CAD)., Methods and Results: AVC and coronary artery calcifications (CAC) were prospectively assessed by Electron-Beam-Computed-Tomography in 262 population-based research participants > or = 60 years. AVC was frequent (27%) with aging (P<0.01) and in men (P<0.05). AVC was associated with diabetes, hypertension, higher body-mass-index, and serum glucose (all P<0.05). AVC was a marker of higher prevalence (P<0.01) and severity of CAD (CAC score: 441+/-802 versus 265+/-566, P<0.05) independently of age. After follow-up of 3.8+/-0.9 years, AVC score increased (94+/-271 versus 54+/-173, P<0.01, +11+/-32 U/year), faster with higher baseline AVC score (P<0.01). Compared with participants remaining free of AVC, de novo acquisition of AVC was associated with higher LDL-cholesterol (141+/-31 versus 121+/-27 mg/dL, P<0.05) and faster CAC progression (+78+/-87 versus +28+/-47 U/year, P<0.05). In multivariate analysis, LDL-cholesterol independently determined AVC acquisition while higher baseline AVC scores determined faster progression of existing AVC., Conclusion: In the population, AVC is frequent with aging and atherosclerotic risk factors. AVC is a marker of subclinical CAD. AVC is progressive, appearing de novo with progressive atherosclerosis whereas established AVC progresses independently of atherosclerotic risk factors and faster with increasing initial AVC loads.

In the present study, we investigated whether measures of brachial artery reactivity were associated with the presence and extent of subclinical coronary atherosclerosis in asymptomatic adults. Electron beam computed tomography was employed to assess the presence and quantity of CAC (coronary artery calcium) in 441 participants (mean age, 61 years; 49% men) without prior history of CHD (coronary heart disease) or stroke, and CAC score was calculated using the method described by Agatston and co-workers [(1990) J. Am. Coll. Cardiol. 15, 827-832] High-resolution ultrasound was employed to measure BAD (brachial artery diameter), FMD (flow-mediated dilatation) and NMD (nitroglycerine-mediated dilatation). CAC score and FMD were log-transformed after adding 1 to reduce skewness. Multivariable logistic and linear regression models based on generalized estimating equations were used to assess whether BAD, FMD and NMD were each independently associated with the presence and quantity of CAC after adjustment for CHD risk factors and use of statin and hypertension medication. CAC was detectable in 64% of participants. After adjustment for age and sex, FMD was not correlated (r=-0.06; P=0.27), BAD was positively correlated (r=0.16; P=0.004) and NMD was inversely correlated in a borderline significant manner (r=-0.10; P=0.084) with log(CAC+1). In multivariable logistic regression analyses, FMD was not associated, whereas higher BAD (P=0.021) and lower NMD (P=0.030) were independently associated with the presence of CAC. In multivariable linear regression analyses, higher BAD (P=0.004) and lower NMD (P=0.016), but not FMD, were independently associated with log(CAC+1). We conclude that greater diameter of the brachial artery and lower vasodilator response to nitroglycerine, but not FMD, are associated with subclinical coronary atherosclerosis.

Background: We examined the associations of serum uric acid (UA) with indices of coronary heart disease (CHD) risk, including the 10-year probability of CHD (10y-CHDr), metabolic syndrome (MS), inflammation (C-reactive protein [CRP] and fibrinogen), and the presence and quantity of coronary artery calcium (CAC)., Methods: Subjects (n = 1107, mean age 58 years, 59% women) belonged to sibships with > or =2 individuals with hypertension diagnosed before age 60 years. UA was measured by a colorimetric method, CAC by electron beam computed tomography, and CAC score calculated using the method of Agatston. The correlation of UA with 10y-CHDr, MS components, log CRP, and fibrinogen was assessed after adjustment for age and gender. Multivariable regression was used to assess whether UA was associated with CAC presence and quantity after (1) adjustment for age and gender, and (2) additional adjustment for CHD risk factors., Results: Most subjects (71%) had hypertension and 14% had diabetes. Mean (+/- SD) UA level was 5.97 +/- 1.6 mg/dL, and CAC was detectable in 63% of patients. After adjustment for age and gender, UA was significantly correlated with 10y-CHDr, number of MS components, log CRP, and fibrinogen. UA was associated with CAC presence and quantity after adjustment for age and gender but not after further adjustment for systolic blood pressure (BP), diabetes, total and HDL-cholesterol, smoking, and body mass index (BMI)., Conclusions: Serum UA was significantly correlated with several indices of CHD risk. UA was associated with presence and quantity of CAC, but not independently of conventional risk factors.

Background: Coronary artery calcification (CAC) is an important indicator of future coronary artery disease events. Since elevated blood pressure (BP) is an important predictor of CAC, genetic polymorphisms in the renin-angiotensin system and their interaction may play a role in explaining CAC quantity variation., Material/methods: As part of the Epidemiology of Coronary Artery Calcification Study, 166 asymptomatic women and 166 asymptomatic men were genotyped for the insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene and the -6 promoter polymorphism of the angiotensinogen (AGT) gene. We used a novel method to detect gene-gene interaction and compared it to the standard two-way analysis of variance (ANOVA) method., Results: Based on a two-way ANOVA model, there was no evidence for epistasis for either systolic BP or CAC in either men or women. However, using a novel method, we found evidence of significant gene-gene interaction in systolic BP in men and gene-gene interaction in both systolic BP levels and CAC quantity in women., Conclusions: Our study demonstrates that new methods of assessing epistasis maybe important in understanding the complex genetics of systolic blood pressure as well as subclinical coronary atherosclerosis.

We measured 381 genomewide markers and performed genetic linkage analyses in search of loci influencing coronary artery calcification (CAC), a measure of atherosclerosis determined by electron beam computed tomography, in 948 non-Hispanic white siblings (mean age [+/-standard deviation] = 59.6 +/- 9.9 years; 73.7% hypertensive). Measured risk factors for atherosclerosis included body mass index, pulse pressure, and high-density lipoprotein (HDL)-cholesterol. After adjustment for sex and age, the logarithm transformed measure of CAC was heritable (0.40 +/- 0.08, P < 0.0001) and genetically correlated with body mass index (0.28, P < 0.001), pulse pressure (0.36, P < 0.001), and HDL-cholesterol (-0.19, P < 0.001). Univariate linkage analysis demonstrated evidence of linkage for CAC, defined by maximum LOD scores (MLS) >or= 1.30, on chromosomes 1p, 4p, 5q, 7p, 13q, and 14q. Bivariate linkage analyses of CAC with each risk factor provided evidence of two regions with pleiotropic effects on CAC and HDL-cholesterol on chromosomes 4p16 (MLS=3.03, P = 0.00084) and 9q12 (MLS = 3.21, P = 0.00056), and of a region with pleiotropic effects on CAC and body mass index on chromosome 17p11 (MLS = 3.04, P = 0.00082). Inasmuch as the chromosome 9 and 17 regions were not detected in the univariate linkage analysis for CAC, multivariate linkage analyses of CAC and genetically correlated risk factors may help localize genes for coronary atherosclerosis.

We investigated the relationship of aortic pulse wave velocity (aPWV), a measure of central arterial stiffness, with the presence and quantity of coronary artery calcium (CAC) in a community-based sample of adults without prior history of heart attack or stroke (n=401, mean age 59.8 years, 53% men). ECG-gated waveforms of the right carotid and right femoral artery were obtained by applanation tonometry, and aPWV was calculated using established methods. CAC was measured noninvasively by electron beam computed tomography, and CAC score was calculated. aPWV was significantly correlated with log(CAC +1; r=0.41; P<0.0001) and pulse pressure (r=0.47; P<0.0001). Multivariable logistic and linear regression models were used to identify independent predictors of the presence and quantity of CAC, respectively. In multivariable logistic regression analyses, aPWV was associated with the presence of CAC (P=0.011) after adjustment for age, male sex, total cholesterol, high-density lipoprotein cholesterol, diabetes, history of smoking, systolic blood pressure, body mass index, and use of hypertension and statin medications. In multivariable linear regression analyses, aPWV was significantly associated with log(CAC +1) after adjustment for the covariates enumerated above (P<0.0001). aPWV remained significantly associated with both the presence and quantity of CAC even after the additional adjustment for diastolic blood pressure. We conclude that aPWV is related to subclinical coronary atherosclerosis independent of conventional risk factors (including indices of blood pressure) and may be a biomarker of cardiovascular risk in asymptomatic individuals.

Background: Emerging data suggest that C-reactive protein (CRP), a marker of inflammation, is associated with functional properties of arteries. We investigated the relationship of CRP to measures of arterial wave reflection and stiffness (aortic augmentation index [AIX], carotid-femoral pulse wave velocity [PWV], and pulse pressure) in asymptomatic individuals from the community., Methods: Subjects (n = 214) had a mean age of 59 years and 53% were men. CRP was measured by a high-sensitivity assay and values were log-transformed to reduce skewness. Radial artery waveforms were obtained by applanation tonometry, a validated transfer function was used to derive an ascending aortic pressure waveform, and AIX calculated. PWV was calculated from electrocardiogram-gated waveforms of the right carotid and right femoral artery obtained by applanation tonometry., Results: Log CRP was correlated with AIX (r = 0.24, P = .0005), PWV (r = 0.25, P = .0002), and pulse pressure (r = 0.29, P < or = .0001). In separate backward elimination multiple regression analyses, log CRP was significantly associated with AIX (P = .038) and pulse pressure (P = .036), and marginally significantly associated with PWV (P = .054), after adjustment for heart rate, height, and coronary heart disease (CHD) risk factors (age, sex, body mass index, mean arterial pressure, total cholesterol, HDL cholesterol, diabetes, hypertension, and history of smoking)., Conclusions: These results suggest that CRP, a marker of systemic inflammation, is related to measures of arterial wave reflection and stiffness in asymptomatic subjects from the community. Further studies are needed to understand the mechanisms underlying this association and the implications for assessment and management of CHD risk.

Coronary artery disease (CAD) is the leading cause of death in adults after successful kidney transplantation. Children who have undergone successful kidney transplantation are entering young adulthood; however, the prevalence and extent of CAD in this population is unknown. We conducted a pilot study in young adults with stable allograft function, who received kidney transplants as children to measure coronary artery calcification (CAC), a marker of coronary artery atherosclerosis and CAD. We evaluated 19 young adults after successful pediatric kidney transplantation for known CAD risk factors; these patients underwent noninvasive imaging with electron-beam computed tomography (EBCT) for measurement of CAC. Prevalence and quantity of CAC were then compared to asymptomatic individuals from the community. All patients had multiple risk factors for CAD. Mean age at evaluation was 32 years (range: 21-48 years). CAC is uncommon in individuals in the community in this age range; however, nearly half of our patients had CAC detected with the quantity of CAC comparable to asymptomatic individuals from the community 10-40 years older. These data suggest young adults who received pediatric kidney transplants are at increased risk for developing early CAC and need close monitoring to detect early CAD so as to prevent premature cardiac morbidity and mortality.

Metabolic syndrome was associated with the presence and quantity of coronary artery calcium, a marker of subclinical coronary atherosclerosis, in 1,129 asymptomatic adults, ages 20 to 79 years, from a community-based study. The association was independent of 10-year risk of coronary heart disease based on the Framingham risk score.

Background: Lipoprotein(a) (Lp(a)) is a potential risk factor for coronary artery disease (CAD). The relationship between serum Lp(a) and coronary artery calcification (CAC), a measure of subclinical coronary artery atherosclerosis, has not been extensively explored., Material/methods: Electron beam computed tomography was performed on 616 asymptomatic, white individuals (285 men) from a community-based study. Mean age was 57.2 years. Serum Lp(a) levels were measured by an immunoturbidimetric assay. Tobit regression was used to determine the sex-specific association of Lp(a) levels with presence and quantity of CAC., Results: In women, Lp(a) was a significant predictor (P=0.0426) of presence and quantity of CAC after adjustment for age, hypertension status, waist circumference, presence of high low-density lipoprotein cholesterol (LDL-C), and history of smoking. In men, after adjusting for age, hypertension status, body mass index, presence of high LDL-C, and history of smoking, a positive interaction between Lp(a) and history of smoking (P=0.0387) was significantly associated with presence and quantity of CAC., Conclusions: Sex-specific relationships between Lp(a) and CAC provide evidence supporting sex-specific risk factor profiling for CAD. In women, Lp(a) alone may be an independent risk factor for coronary atherosclerosis, while in men, Lp(a) may confer higher risk conditional on the presence and level of other risk factors. The role of Lp(a) in the prediction and pathogenesis of subclinical coronary atherosclerosis needs to be further elucidated.

Background: Dyslipidemia in hypertensive sibships may be characterized by atherogenic small low-density lipoprotein (LDL) particles. Whether LDL particle size is associated with the extent of coronary atherosclerosis in hypertensive sibships is unknown., Methods: Subjects (n = 792, mean age 62 years, 60% women) were ascertained through sibships containing at least two individuals with essential hypertension diagnosed before age 60 years. The LDL particle size was measured by polyacrylamide gel electrophoresis. Coronary artery calcium (CAC) was measured noninvasively by electron beam computed tomography, and CAC score was calculated using the method of Agatston et al. Sex-specific multiple regression models were used to assess independent predictors of LDL particle size and the association of LDL particle size with CAC., Results: In all, 76% of women and 77% of men were hypertensive. In each sex, independent predictors of smaller LDL particle size were total cholesterol, triglycerides, and lower HDL cholesterol. In women, greater age was an additional predictor of smaller LDL particle size. After adjustment for age and statin use, LDL particle size was significantly associated with the amount of CAC in women but not in men. After further adjustment for HDL cholesterol, triglycerides, diabetes, smoking, and hypertension, LDL particle size was not independently associated with CAC in either sex., Conclusions: After adjustment for age and statin use, LDL particle size was found to be significantly related to CAC quantity in women but not in men belonging to hypertensive sibships. In women, LDL particle size may mediate some of the atherogenic effects of low-HDL cholesterol-high-triglyceride dyslipidemia, but does not appear to be independently associated with the extent of coronary atherosclerosis in either sex., (Copyright 2004 American Journal of Hypertension, Ltd.)

Polycystic ovary syndrome (PCOS), a common endocrine disorder of reproductive-aged women, is associated with multiple risk factors for coronary heart disease (CHD), such as diabetes mellitus, dyslipidemia, visceral obesity, and hypertension. However, premature coronary atherosclerosis has not been demonstrated in PCOS women. Electron beam computed tomography (EBCT) noninvasively measures coronary artery calcium (CAC), a marker for coronary atherosclerosis. We measured CAC by EBCT in 30- to 45-yr-old premenopausal PCOS women and compared the results to CAC in 1) recruited normal ovulatory volunteers matched for age and weight to the PCOS cohort, and 2) community-dwelling women of similar age in an extant coronary calcium database. Healthy, community-dwelling, ovulatory controls (n = 71) were matched by age and body mass index (BMI) to PCOS women (n = 36). Women with diabetes or known CHD were excluded. Subjects underwent EBCT scanning, oral glucose tolerance testing, and CHD risk factor assessment. PCOS women had significantly higher levels of serum total and low density lipoprotein cholesterol and testosterone levels than matched controls. PCOS and control women were obese and had a greater mean BMI than community-dwelling women (33 kg/m(2) for PCOS vs. 31 kg/m(2) for control; P < 0.001). CAC was more prevalent in PCOS women (39%) than in matched controls (21%; odds ratio, 2.4; P = 0.05) or community-dwelling women (9.9%; odds ratio, 5.9; P < 0.001). BMI, waist circumference, and total and low density lipoprotein cholesterol levels predicted CAC prevalence after adjustment for BMI. CAC is more prevalent in PCOS women than in obese or nonobese women of similar age. PCOS women are at increased risk for atherosclerosis and should be targeted for primary prevention of CHD.

Objective: To study the role of the coronary microcirculation in response to different-sized microemboli, we measured changes in intramyocardial microvascular blood volume (Bv), perfusion (F) and transit time (TT) and also microvascular patterns of injury., Methods: Bv, F and TT were quantitated in 24 pigs at baseline and again 2 min after repeat injections of 10- or 100-microm microspheres at rest or during intracoronary adenosine infusion. The association of Bv and TT was assessed in the microsphere pigs and in nine control pigs. Microvascular injury was studied on gross-pathologic and histologic samples., Results: At rest, initial injection of 10-microm microspheres led to increases in Bv and F, but progressively decreased with additional injections. In contrast, even small numbers of 100-microm microspheres always led to decreases in Bv and F. Injection of microspheres during adenosine-induced vasodilation always resulted in decreases in peak Bv and F irrespective of their diameters, but microvascular TTs remained unaltered. In control pigs, however, TTs were inversely related to adenosine-induced changes in Bv. Histologically, 100-microm microspheres resulted in patchy distribution of microcirculatory plugging, while 10-microm microspheres induced contiguous hemorrhagic myocardial injury., Conclusion: Microsphere-induced changes in intramyocardial Bv and F and the associated pattern of myocardial injury are related to the size of embolized microvessels and the initial perfusion state. Microvascular functional volume reserve mechanisms appear to play a key role accompanying flow- and TT-preservation.