Endogenous circulating testosterone and sex hormone-binding globulin levels and measures of myocardial structure and function: the Framingham Heart Study.

BACKGROUND: The relation between endogenous testosterone concentrations and myocardial mass and function remains incompletely understood. OBJECTIVES: To determine the cross-sectional association between endogenous hormone levels with cardiac magnetic resonance measures of myocardial mass, structure, and function in community-dwelling men across a wide age range. METHODS: A total of 720 men from the Framingham Heart Study Offspring Cohort (age range 37-82, mean = 59.6 years) who underwent cardiac magnetic resonance imaging and had hormone levels measured. Total testosterone (measured using liquid chromatography-tandem mass spectrometry), sex hormone-binding globulin (measured using an immunofluorometric assay), and calculated free testosterone levels were assessed in male participants of the Framingham Heart Study Offspring Cohort at examination 7. Cardiac magnetic resonance imaging was performed between examinations 7 and 8 (2002-2006). RESULTS: Age-adjusted linear regression models showed statistically significant association between total testosterone levels and left ventricular mass (p = 0.009), left ventricular mass index (p = 0.006), cardiac output (p = 0.001), and main pulmonary artery diameter (p = 0.008); the association between total testosterone and these cardiac magnetic resonance measures was weak and was not significant after adjustment for established risk factors-age, body mass index, diabetes, and hypertension. Furthermore, calculated free testosterone level was not significantly associated with any measure of myocardial mass or function. Sex hormone-binding globulin level was significantly associated with left ventricular mass (p = 0.002), left ventricular mass index (p = 0.004), cardiac output (p = 0.003), left ventricular ejection fraction (p = 0.039), and main pulmonary artery diameter (p = 0.042) in age-adjusted models; these associations were also rendered non-significant after adjusting for cardiovascular risk factors. CONCLUSIONS: Neither testosterone nor sex hormone-binding globulin levels in men are associated significantly with myocardial mass and function independent of established cardiovascular risk factors.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study.

INTRODUCTION: Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD. METHODS: Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk. RESULTS: PAI-1 levels (mean ± SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p<0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p<0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p<0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p<0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p=0.037) but not PAI-1 (4.8%, p=0.113). CONCLUSION: PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD.

Reliability of vertebral fracture assessment using multidetector CT lateral scout views: the Framingham Osteoporosis Study.

UNLABELLED: Two radiologists evaluated images of the spine from computed tomography (CT) scans on two occasions to diagnose vertebral fracture in 100 individuals. Agreement was fair to good for mild fractures, and agreement was good to excellent for more severe fractures. CT scout views are useful to assess vertebral fracture. INTRODUCTION: We investigated inter-reader agreement between two radiologists and intra-reader agreement between duplicate readings for each radiologist, in assessment of vertebral fracture using a semi-quantitative method from lateral scout views obtained by CT. METHODS: Participants included 50 women and 50 men (age 50-87 years, mean 70 years) in the Framingham Study. T4-L4 vertebrae were assessed independently by two radiologists on two occasions using a semi-quantitative scale as normal, mild, moderate, or severe fracture. RESULTS: Vertebra-specific prevalence of grade ≥ 1 (mild) fracture ranged from 3% to 5%. We found fair (κ = 56-59%) inter-reader agreement for grade ≥ 1 vertebral fractures and good (κ = 68-72%) inter-reader agreement for grade ≥ 2 fractures. Intra-reader agreement for grade ≥ 1 vertebral fracture was fair (κ = 55%) for one reader and excellent for another reader (κ = 77%), whereas intra-reader agreement for grade ≥ 2 vertebral fracture was excellent for both readers (κ = 76% and 98%). Thoracic vertebrae were more difficult to evaluate than the lumbar region, and agreement was lowest (inter-reader κ = 43%) for fracture at the upper (T4-T9) thoracic levels and highest (inter-reader κ = 76-78%) for the lumbar spine (L1-L4). CONCLUSIONS: Based on a semi-quantitative method to classify vertebral fractures using CT scout views, agreement within and between readers was fair to good, with the greatest source of variation occurring for fractures of mild severity and for the upper thoracic region. Agreement was good to excellent for fractures of at least moderate severity. Lateral CT scout views can be useful in clinical research settings to assess vertebral fracture.

Association between single-slice measurements of visceral and abdominal subcutaneous adipose tissue with volumetric measurements: the Framingham Heart Study.

OBJECTIVE: Volumetric visceral abdominal adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) as measured by computed tomography (CT) are associated with metabolic risk factors. We sought to identify the correlations of VAT and SAT between area-based measures at different anatomic locations with volumetric measurements to identify the optimal anatomic site, and to relate measurements at this site with metabolic risk factors. METHODS: We measured SAT and VAT volumes across the total imaging volume, whereas we measured SAT and VAT area at seven predefined anatomic landmarks in 200 participants from the Framingham Heart Study (mean age 54 years, 50% women) who underwent abdominal multi-detector CT. Correlation coefficients were used to assess the association between area measurements and volumes as well as metabolic risk factors stratified by gender. RESULTS: Area-based measurements of SAT and VAT obtained at all anatomic landmarks were strongly associated with SAT and VAT volumes (all r>0.93, P<0.0001 and r>0.87, P<0.0001, for women and men; respectively). Consistently, area-based measurements of SAT and VAT obtained at L(3/4) were most strongly associated with volumetric measured VAT and SAT independent of age (both r=0.99 in men, r=0.96 for SAT and r=0.99 for VAT in women, all P-value <0.0001) and were similarly correlated with risk factors compared with SAT and VAT volumes (all P<0.05 for fasting plasma glucose, triglycerides, high-density lipoprotein, systolic blood pressure). CONCLUSION: Among area-based measurements of SAT and VAT, those obtained at the level of L(3/4) were strongly associated with SAT and VAT volumes and cardio-metabolic risk factors in both men and women.

The application of computerized tomography (CT) to the dental ageing of children and adolescents.

INTRODUCTION: Following a mass disaster, the aim of the Disaster Victim Identification process is to establish the identity of the victims. The ageing screening process on victims in Victoria may now be complemented with the use of computerized tomography (CT), where previously any dental ageing analysis was performed using conventional radiographs. The aim of this study was to assess the accuracy of age estimation using the dental ageing method proposed by Moorrees, Fanning and Hunt (MFH) using CT images. Intra- and inter-rater variability between two raters, one experienced and one inexperienced, was also assessed. MATERIALS AND METHODS: The two raters were blinded to the ages of 96 deceased Australian children aged up to 15 years. Using three-dimensional (3D) shaded surface displays (SSD) and reformatted CT images, the age was first estimated based on prior experience alone, followed at a later date by the age estimation utilizing the MFH method. These estimates were then compared to the known chronological age. The results were statistically analyzed in a one-sample t-test, using the mean log-ratio of the estimated age to the chronological age. RESULTS: Our findings show that the experienced rater was more accurate in age estimation than the less experienced when using prior experience (p<0.0001). The use of reformatted CT images to perform an ageing estimate using the MFH method was found to systematically underestimate the chronological age by 10% by both raters (p=0.784). There was no significant difference between the two raters. Intra-rater reliability was high (p=0.135). CONCLUSIONS: CT can provide accurate estimates of dental ages. Prior experience with dental ageing and/or CT improves the accuracy. However, with the use of validated ageing charts, inexperienced raters can also achieve accurate age estimates using CT images.

Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue.

BACKGROUND: Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue. METHODS: Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n=100) who underwent multidetector CT of the thorax (ECG triggering, 2.5 mm slice thickness) and the abdomen (helical CT acquisition, 2.5 mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between -195 and -45 HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined. RESULTS: The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97 and 0.97; 0.99 and 0.98, respectively). Similarly, the relative intra- and inter-observer difference was small for both AAT (-1.85+/-1.28% and 7.85+/-6.08%; respectively) and TAT (3.56+/-0.83% and -4.56+/-0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r=0.65 and 0.77, P<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r=0.39 and 0.42, P<0.0001 and P=0.009), waist circumference (r=0.49 and 0.57, P<0.0001 for both) and body mass index (r=0.47 and 0.58, P<0.0001 for both). CONCLUSION: Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors and clinical outcomes.

Genetic and non-genetic correlates of vitamins K and D.

OBJECTIVE: To assess the genetic and nongenetic correlates of circulating measures of vitamins K and D status in a community-based sample of men and women. SUBJECTS/METHODS: A cross-sectional study of 1762 participants of the Framingham Offspring Study (919 women; mean age 59 years). Vitamin K status was measured as plasma phylloquinone and serum percent undercarboxylated osteocalcin (ucOC), and vitamin D was measured using plasma 25-hydroxyvitamin D (25(OH)D). Associations between vitamin K status and vitamin D status with biologically plausible nongenetic factors were assessed using stepwise regression. Heritability and linkage were determined using Sequential Oligogenic Linkage Analysis Routines (SOLAR). RESULTS: Nongenetic factors accounted for 20.1 and 12.3% of the variability in plasma phylloquinone in men and women respectively, with triglycerides and phylloquinone intake being the primary correlates. In men 12.2% and in women 14.6% of the variability in %ucOC was explained by nongenetic factors in our models. Heritability estimates for these vitamin K status biomarkers were nonsignificant. Season, vitamin D intake, high-density lipoprotein (HDL) cholesterol and waist circumference explained 24.7% (men) and 24.2% (women) of the variability in plasma 25(OH)D. Of the three vitamins examined, only 25(OH)D was significantly heritable (heritability estimate=28.8%, P<0.01), but linkage analysis of 25(OH)D did not achieve genome-wide significance. CONCLUSIONS: Variability in biomarkers of vitamin K status was attributed to nongenetic factors, whereas plasma 25(OH)D was found to be significantly heritable. Further studies are warranted to investigate genetic loci influencing vitamin D status.

Comparison of anthropometric, area- and volume-based assessment of abdominal subcutaneous and visceral adipose tissue volumes using multi-detector computed tomography.

PURPOSE: Cross-sectional imaging may enable accurate localization and quantification of subcutaneous and visceral adipose tissue. The reproducibility of multi-detector computed tomography (MDCT)-based volumetric quantification of abdominal adipose tissue and the ability to depict age- and gender-related characteristics of adipose tissue deposition have not been reported. METHODS: We evaluated a random subset of 100 Caucasian subjects (age range: 37-83 years; 49% women) of the Framingham Heart Study offspring cohort who underwent MDCT scanning. Two readers measured subcutaneous and visceral adipose tissue volumes (SAV and VAV; cm(3)) and areas (SAA and VAA; cm(2)) as well as abdominal sagital diameter (SD) and waist circumference (WC). RESULTS: Inter-reader reproducibility was excellent (relative difference: -0.34+/-0.52% for SAV and 0.59+/-0.93% for VAV, intra-class correlation (ICC)=0.99 each). The mean SAA/VAA ratio was significantly different from the mean SAV/VAV ratio (2.0+/-1.2 vs 1.7+/-0.9; P<0.001). The ratio of SAV/VAV was only weakly inversely associated with SD (ICC=-0.32, P=0.01) and not significantly associated with WC (ICC=-0.14, P=0.14) or body mass index (ICC=-0.17, P=0.09). The mean SAV/VAV ratio was significantly different between participants <60 vs >60 years (1.9+/-1.0 vs 1.5+/-0.7; P<0.001) and between men and women (1.2+/-0.5 vs 2.2+/-0.9; P<0.001). CONCLUSION: This study demonstrates that MDCT-based volumetric quantification of abdominal adipose tissue is highly reproducible. In addition, our results suggest that volumetric measurements can depict age- and gender-related differences of visceral and subcutaneous abdominal adipose tissue deposition. Further research is warranted to assess whether volumetric measurements may substantially improve the predictive value of obesity measures for insulin resistance, type 2 diabetes mellitus and other diseases.

Abdominal aortic calcification and exostoses at the hand and lumbar spine: the Framingham Study.

Bony proliferation (exostoses) and vascular calcification are common in elderly men and women, but it is unclear whether they have a common etiology. Lateral lumbar and hand radiographs were obtained (1967-1970) in 777 men and 1,241 women (mean age 59, range 47-80 years) from the Framingham Heart Study. Each group of hand exostoses, specifically apiostoses (tufting), enthesophytes, and osteophytes, was graded on a scale of 0-3 (absent to severe) and summed across phalanges of digits 2-5. Anterior lumbar osteophytes were assessed in intervertebral spaces T12-L5 and abdominal aortic calcification (AAC) at lumbar segments L1-L4. Information on age, sex, body mass index, smoking, alcohol consumption, physical activity, systolic blood pressure, total cholesterol level, diabetes, and estrogen replacement therapy in women was obtained at the time of radiography and adjusted for in multivariate analyses. We used multivariable logistic regression models to assess the relationship between AAC (dependent variable) and exostoses for each sex. Multivariable adjusted logistic regression revealed a significant association between increased anterior lumbar osteophytes and prevalent AAC in men [odds ratio (OR) = 1.20, 95% confidence interval (CI) 1.1-1.3 per unit increase in osteophytes] and in women (OR = 1.25, 95% CI 1.1-1.4). There also was an inverse association between enthesophytes and AAC in women only (OR = 0.82, 95% CI 0.73-0.92). Apiostoses were weakly associated with AAC in men only. Hand osteophytes were not associated with AAC. In conclusion, in this cross-sectional study, anterior lumbar osteophytes and AAC occurred in the same individuals after adjustment for age and other covariates. In general, hand exostoses were not associated with aortic calcification.

Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction.

BACKGROUND: Recent advances in high-throughput genomics technology have expanded our ability to catalogue allelic variants in large sets of candidate genes related to premature coronary artery disease. METHODS AND RESULTS: A total of 398 families were identified in 15 participating medical centers; they fulfilled the criteria of myocardial infarction, revascularization, or a significant coronary artery lesion diagnosed before 45 years in men or 50 years in women. A total of 62 vascular biology genes and 72 single-nucleotide polymorphisms were assessed. Previously undescribed variants in 3 related members of the thrombospondin protein family were prominent among a small set of single-nucleotide polymorphisms that showed a statistical association with premature coronary artery disease. A missense variant of thrombospondin 4 (A387P) showed the strongest association, with an adjusted odds ratio for myocardial infarction of 1.89 (P=0.002 adjusted for covariates) for individuals carrying the P allele. A variant in the 3' untranslated region of thrombospondin-2 (change of thymidine to guanine) seemed to have a protective effect against myocardial in individuals homozygous for the variant (adjusted odds ratio of 0.31; P=0.0018). A missense variant in thrombospondin-1 (N700S) was associated with an adjusted odds ratio for coronary artery disease of 11.90 (P=0.041) in homozygous individuals, who also had the lowest level of thrombospondin-1 by plasma assay (P=0.0019). CONCLUSIONS: This large-scale genetic study has identified the potential of multiple novel variants in the thrombospondin gene family to be associated with familial premature myocardial infarction. Notwithstanding multiple caveats, thrombospondins specifically and high-throughput genomic technology in general deserve further study in familial ischemic heart disease.

Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study.

Vascular calcification and osteoporosis are common age-related processes that are prominently displayed on routine lateral lumbar spine radiographs as dense calcium mineral deposits of the aorta that lie adjacent to osteopenic vertebrae. Using a population-based cohort of older men and women, we tested the hypothesis that the progression of vascular calcification of the abdominal aorta should be greatest in those individuals with the greatest amount of bone loss. From the original population-based Framingham Heart Study cohort, 364 women and 190 men had lateral lumbar spine and hand radiographs performed between 1966 and 1970 and repeated between 1992 and 1993. The lateral lumbar films were read for the presence of aortic calcification using a semiquantitative method, and the hand films were read for second metacarpal relative cortical area (MCA). Using multivariate regression techniques, the 25-year progression of the abdominal aortic calcification index was examined in relation to the change in the MCA, while adjusting for recognized risk factors for atherosclerotic cardiovascular disease. During the 25 years of follow-up, the MCA decreased by 22.4% in women (from 79.6 +/- 7.8 (SD) to 61.8 +/- 10.3) and by 13.3% in men (from 80.6 +/- 6.9 to 69.9 +/- 8.3). The aortic calcification score increased over eightfold in women (from 1.2 +/- 2.7 (SD) to 9.9 +/- 6.7) and sixfold in men (from 1.6 +/- 2.8 to 9.6 +/- 6.3). There was a significant association between percent change in MCA and change in aortic calcification index (P = 0.01) in women after controlling for all potential confounders. No association was observed in men (P = 0.50), including the 50% of men with the greatest bone loss. This is the first longitudinal study to show that women with the greatest magnitude of bone loss also demonstrate the most severe progression of abdominal aortic calcification, suggesting that the two processes may be related.

Genetic factors contribute to the variance in frequency domain measures of heart rate variability.

Power spectral analysis of heart rate variability (HRV) provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HRV only partially explain its variability in the population. The purpose of this study was to estimate the contribution of genetic factors to the variance in HRV measures and assess the heritability of HRV. Subjects who underwent Holter recordings at a routine examination were eligible, excluding subjects with congestive heart failure, coronary artery disease, diabetes mellitus and those taking cardioactive medications. We analyzed the low-frequency power (LF), high-frequency power (HF), LF/HF ratio, very low-frequency power (VLF) and total power (TP). Heritability analysis was done by studying correlations between siblings (n = 682, in 291 sibships, 517 pairs) and between spouse pairs (n = 206 pairs). Adjustments were made for sex, age, systolic and diastolic blood pressure, heart rate, coffee and alcohol intake. SAS procedure MIXED was used to estimate and test significance of correlation within sibling pairs and within spouse pairs. Results from separate models were combined to estimate the components of variance of each phenotype, i.e. variance attributable to measured covariates, additive genetic effects (heritability) and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21-0.26) compared to spouses (0.01-0.19). The measured covariates in general accounted for 13-40% of the total phenotypic variance, whereas genes accounted for 13-23% of the variation among HRV measures. Genetic factors contribute towards a substantial proportion of the variance in heart rate and HRV. Recognition of the genetic determinants of HRV may provide additional insight into the pathophysiology of the autonomic nervous system and offer clues toward its modulation.

Platelet glycoprotein IIIa Pl(a) polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study.

BACKGROUND: Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl(A) genotype in modulating platelet aggregability. Methods and Results-- Glycoprotein IIIa Pl(A) genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the Pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl(A2)-positive genotype (P>0.90). CONCLUSION: Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding Pl(A) genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.

Genetic and environmental contributions to platelet aggregation: the Framingham heart study.

BACKGROUND: Platelet aggregation plays an important role in arterial thrombosis in coronary heart disease, stroke, and peripheral arterial disease. However, the contribution of genetic versus environmental influences on interindividual variation in platelet aggregability is poorly characterized. METHODS AND RESULTS: We studied the heritability of platelet aggregation responses in 2413 participants in the Framingham Heart Study. The threshold concentrations of epinephrine and ADP required to produce biphasic platelet aggregation and collagen lag time were determined. Mixed-model linear regression was used to calculate correlation coefficients within sibships and within spouse pairs. Variance and covariance component methods were used to estimate the proportion of platelet aggregation attributable to measured covariates versus additive genetic effects. After accounting for environmental covariates, the adjusted sibling correlations for epinephrine, ADP, and collagen lag time were 0.24, 0.22, and 0.31, respectively (P=0.0001 for each). In contrast, adjusted correlations for spouse-pairs were -0.01, 0.05, and -0.02, respectively (all P>0.30). The estimated heritabilities were 0.48, 0.44, and 0.62, respectively. Measured covariates accounted for only 4% to 7% of the overall variance in platelet aggregation, and heritable factors accounted for 20% to 30%. The platelet glycoprotein IIIa Pl(A2) polymorphism and the fibrinogen Hind III beta-148 polymorphism contributed <1% to the overall variance. CONCLUSIONS: In our large, population-based sample, heritable factors play a major role in determining platelet aggregation, and measured covariates play a lesser role. Future studies are warranted to identify the key genetic variants that regulate platelet function and to lay the groundwork for rational pharmacogenetic approaches.

Applicability of cholesterol-lowering primary prevention trials to a general population: the framingham heart study.

BACKGROUND: Four large trials have shown cholesterol-reduction therapy to be effective for primary prevention of coronary heart disease (CHD). METHODS: To determine the generalizability of these trials to a community-based sample, we compared the total cholesterol and high-density lipoprotein cholesterol (HDL-C) distributions of patients in the 4 trials with those of Framingham Heart Study subjects. Lipid profiles that have not been studied were identified. Twelve-year rates of incident CHD were compared between subjects who met eligibility criteria and those who did not. RESULTS: The Framingham sample included 2498 men and 2870 women aged 30 to 74 years. Among Framingham men, 23.4% to 42.0% met eligibility criteria for each of the 4 trials based on their lipid levels; 60.2% met eligibility criteria for at least 1 trial. For the 1 trial that included women, 20.2% of Framingham women met eligibility criteria. In general, subjects with desirable total cholesterol levels and lower HDL-C levels and subjects with average total cholesterol levels and average to higher HDL-C levels have not been included in these trials. Among subjects who developed incident CHD during follow-up, 25.1% of men and 66.2% of women would not have been eligible for any trial. Most ineligible subjects who developed CHD had isolated hypertriglyceridemia (>2.25 mmol/L [>200 mg/dL]). CONCLUSIONS: In our sample, 40% of men and 80% of women had lipid profiles that have not been studied in large trials to date. We observed a large number of CHD events in "ineligible" subjects in whom hypertriglyceridemia was common. Further studies are needed to define the role of lipid-lowering therapy vs other strategies for primary prevention in the general population.

Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality.

BACKGROUND: The impact of abdominal arterial calcific deposits on the prediction of cardiovascular disease (CVD) over a long follow-up interval deserves greater scrutiny. METHODS AND RESULTS: Lateral lumbar radiographs were studied as a predictor of incident coronary heart disease (CHD), CVD, and CVD mortality in 1049 men and 1466 women (mean age, 61 years) who were followed from 1967 to 1989. Anterior and posterior wall calcific deposits in the aorta at the level of the first through fourth lumbar vertebrae were graded according to increasing severity using a previously validated rating scale for abdominal aortic calcium (AAC) that ranges from 0 to 24 points. There were 454 cases of CHD, 709 cases of CVD, and 365 CVD deaths. Proportional hazards logistic regression was used to test for associations between AAC and later events after adjustment for age, cigarette use, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy, body mass index, cholesterol, and HDL cholesterol. In comparisons with the lowest AAC tertile, the multivariate age-adjusted relative risks (RR) for CVD were increased in tertile 2 (men: RR, 1.33; 95% confidence interval [CI], 1.02 to 1.74; women: RR, 1.25; 95% CI, 0.95 to 1.65) and tertile 3 (men: RR, 1.68; 95% CI, 1.25 to 2.27; women: RR, 1.78; 95% CI, 1.33 to 2.38). Similar results were obtained with CHD and CVD mortality. CONCLUSIONS: AAC deposits, detected by lateral lumbar radiograms, are a marker of subclinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality.

Scan reproducibility of magnetic resonance imaging assessment of aortic atherosclerosis burden.

Subclinical atherosclerosis precedes the onset of clinical disease by many years. Noninvasive magnetic resonance imaging (MRI) offers the opportunity to visualize and quantify atherosclerotic plaque. However, the reproducibility of MRI measurements of abdominal and thoracic aortic atherosclerosis has not been reported. Electrocardiogram-gated, T2-weighted, turbo spin echo MRI of the descending thoracic and abdominal aorta was performed on 16 subjects, comprising 10 subjects with multivessel coronary artery disease (CAD) and 6 subjects without angiographic CAD. Three identical MRIs were performed on each subject, with subject repositioning between the second and third scans. Aortic anatomic and plaque measurements were performed in a blinded fashion. Fourteen subjects (88%) had MRI evidence of atherosclerotic plaque on at least one image. Slice plaque burden, plaque area, and plaque perimeter were greater in the CAD group (52% vs. 9%, p = 0.002; 264 vs. 18 mm2, p = 0.009; 159 vs. 15 mm, p = 0.006, respectively). Measurements of total aortic lumen area, lumen circumference, plaque area, and plaque perimeter correlated highly among the three scans (all r = 0.96, all p < 0.001). Measurements of slice-specific aortic lumen area and lumen circumference also correlated highly (all r = 0.98, all p < 0.001). Correlations of slice-specific plaque area and plaque perimeter were significant (all p < 0.001) but less robust (r = 0.62-0.85). These data demonstrate that MRI is a reproducible technique for assessing aortic anatomy and total aortic atherosclerosis, but increased slice density should be considered if serial evaluation of slice-specific data is desired.

Impact of high-normal blood pressure on the risk of cardiovascular disease.

BACKGROUND: Information is limited regarding the absolute and relative risk of cardiovascular disease in persons with high-normal blood pressure (systolic pressure of 130 to 139 mm Hg, diastolic pressure of 85 to 89 mm Hg, or both). METHODS: We investigated the association between blood-pressure category at base line and the incidence of cardiovascular disease on follow-up among 6859 participants in the Framingham Heart Study who were initially free of hypertension and cardiovascular disease. RESULTS: A stepwise increase in cardiovascular event rates was noted in persons with higher baseline blood-pressure categories. The 10-year cumulative incidence of cardiovascular disease in subjects 35 to 64 years of age who had high-normal blood pressure was 4 percent (95 percent confidence interval, 2 to 5 percent) for women and 8 percent (95 percent confidence interval, 6 to 10 percent) for men; in older subjects (those 65 to 90 years old), the incidence was 18 percent (95 percent confidence interval, 12 to 23 percent) for women and 25 percent (95 percent confidence interval, 17 to 34 percent) for men. As compared with optimal blood pressure, high-normal blood pressure was associated with a risk-factor-adjusted hazard ratio for cardiovascular disease of 2.5 (95 percent confidence interval, 1.6 to 4.1) in women and 1.6 (95 percent confidence interval, 1.1 to 2.2) in men. CONCLUSIONS: High-normal blood pressure is associated with an increased risk of cardiovascular disease. Our findings emphasize the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease.