Craig Johnson

Predictive Value of Brachial Flow-Mediated Dilation for Incident Cardiovascular Events in a Population-Based Study The Multi-Ethnic Study of Atherosclerosis

Background— Although brachial artery flow-mediated dilation (FMD) predicts recurrent cardiovascular events, its predictive value for incident cardiovascular disease (CVD) events in adults free of CVD is not well established. We assessed the predictive value of FMD for incident CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods and Results— Brachial artery FMD was measured in a nested case-cohort sample of 3026 of 6814 subjects (mean±SD age, 61.2±9.9 years) in MESA, a population-based cohort study of adults free of clinical CVD at baseline recruited at 6 clinic sites in the United States. The sample included 50.2% female, 34.3% white, 19.7% Chinese, 20.8% black, and 25.1% Hispanic subjects. Probability-weighted Cox proportional hazards analysis was used to examine the association between FMD and 5 years of adjudicated incident CVD events, including incident myocardial infarction, definite angina, coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or other revascularization), stroke, resuscitated cardiac arrest, and CVD death. Mean (SD) FMD of the cohort was 4.4% (2.8). In probability-weighted Cox models, FMD/unit SD was significantly associated with incident cardiovascular events in the univariate model (adjusted for age and sex) (hazard ratio, 0.79; 95% confidence interval, 0.65 to 0.97; P=0.01), after adjustment for the Framingham Risk Score (FRS) (hazard ratio, 0.80; 95% confidence interval, 0.62 to 0.97; P=0.025), and in the multivariable model (hazard ratio, 0.84; 95% confidence interval, 0.71 to 0.99; P=0.04) after adjustment for age, sex, diabetes mellitus, cigarette smoking status, systolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, heart rate, statin use, and blood pressure medication use. The c statistic (area under the curve) values of FMD, FRS, and FRS+FMD were 0.65, 0.74, and 0.74, respectively. Compared with the FRS alone, the addition of FMD to the FRS net correctly reclassifies 52% of subjects with no incident CVD event but net incorrectly reclassifies 23% of subjects with an incident CVD event, an overall net correct reclassification of 29% (P<0.001). Conclusions— Brachial FMD is a predictor of incident cardiovascular events in population-based adults. Even though the addition of FMD to the FRS did not improve discrimination of subjects at risk of CVD events in receiver operating characteristic analysis, it improved the classification of subjects as low, intermediate, and high CVD risk compared with the FRS.

Sex hormones are associated with right ventricular structure and function: The MESA-right ventricle study

RATIONALE Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown. OBJECTIVES We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease. METHODS Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression. MEASUREMENTS AND MAIN RESULTS Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], -0.87; 95% CI, -1.67 to -0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women. CONCLUSIONS Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.

Age-related variations in the methylome associated with gene expression in human monocytes and t cells

Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age- and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55–94 years). None of the age-eMS detected in 227 T cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers, and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may play in the aging process.

A simplified lesion classification for predicting success and complications of coronary angioplasty

In 1988, the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures presented a classification of coronary lesions utilizing 26 lesion features to predict the success and complications of balloon angioplasty. Using data from the Registry of the Society for Cardiac Angiography and Interventions (SCAI) we evaluated the ability of this classification to predict success and complications. Lesion success, death in hospital, emergency cardiac bypass surgery, and major adverse events were evaluated in 41,071 patients who underwent single-vessel angioplasty from January 1993 to June 1996. Logistic models using the ACC/AHA lesion classification, vessel patency, or both, were compared. A new classification based on the interaction of the ACC/AHA classification plus lesion patency was compared with the existing ACC/AHA classification. Vessel patency, added to the ACC/AHA classification, improved prediction of lesion success (p </=0.0001). Class A and patent B lesions had similar success and complication rates, so a simplified classification (SCAI) using only 7 lesion characteristics could be created. This system (I: non-C patent, II: C patent, III: non-C occluded, and IV: C occluded) improved prediction of lesion success compared with the ACC/AHA classification (Bayesian Information Criterion statistic: ACC/AHA 16539, SCAI 15956; and area under the receiver- operating characteristics curve 0.659, 0.693, respectively). The SCAI classification was preferred for predicting major complications and in-hospital death and was similar to the ACC/AHA classification for predicting emergency bypass surgery.

Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis

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

Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry.

Adult height is a classic polygenic trait of high heritability (h 2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10−12 and 2p14-rs4315565, P = 1.2×10−8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10−4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.

Association between sleep apnea, snoring, incident cardiovascular events and all-cause mortality in an adult population: MESA

BACKGROUND We assessed the association between sleep apnea, snoring, incident cardiovascular (CV) events and all-cause mortality in the Multi Ethnic Study of Atherosclerosis (MESA) cohort. METHODS Out of 5338 respondents to a sleep questionnaire administered during the second MESA exam period, 208 had physician diagnosed sleep apnea (PDSA), 1452 were habitual snorers (HS) and 3678 were neither a habitual snorer nor had PDSA (normal participants). Cox proportional hazard analysis was used to assess the associations adjusting for age, gender, race/ethnicity, smoking, diabetes mellitus, total cholesterol, HDL, triglycerides, BMI, current alcohol use, benzodiazepine use, BP medications and statin use. RESULTS Over a 7.5 year average follow-up period, 310 adjudicated CV events including MI, stroke, angina, resuscitated cardiac arrest, stroke death and CVD death and 189 deaths occurred. Compared to HS, PDSA was associated with higher incident CV rates in both univariate and multivariable models [hazard ratio (95%); 1.89 (1.22-2.93), p = 0.004 and 1.91 (1.20-3.04), p = 0.007, respectively]. PDSA was also associated with a higher death rates compared with HS [hazard ratio (95%); 2.13 (1.25-3.63), p = 0.006 and 2.70 (1.52-4.79), p = 0.007, respectively]. Compared with normal participants, PDSA had higher incident CV event rates in both univariate and multivariable models [hazard ratio (95%); 2.23 [1.39-3.60], p = 0.001 and 2.16 [1.30-3.58], p = 0.003, respectively]. Similarly, PDSA had a higher death rate compared with normal participants in both the univariate and multivariable models [hazard ratio (95% CI); 2.44 (1.36-4.37), p = 0.003 and 2.71 (1.45-5.08), p =0 .002, respectively]. Habitual snorers had similar incident CV event rates and death rates in both univariate and multivariable models compared with normal participants. CONCLUSION PDSA but not habitual snoring was associated with high incident CV events and all-cause mortality in a multi-ethnic population based study of adults free of clinical CV disease at baseline.

Relation of cardiovascular risk factors to right ventricular structure and function as determined by magnetic resonance imaging (results from the multi-ethnic study of atherosclerosis).

The effect of cardiovascular risk factors on the left ventricle is well known but their effect on right ventricle has not been studied using advanced imaging techniques. The purpose of the present study was to determine the relation between the cardiovascular risk factors and right ventricular (RV) structure and function and its interaction with the left ventricle. Cardiac magnetic resonance images from 4,204 participants free of clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis were analyzed. Multivariate linear regression models were used to study the cross-sectional association between individual RV parameters and risk factors. All RV parameters, except for ejection fraction, decreased with age (p <0.0001). The RV mass was positively associated with systolic blood pressure (+0.4 g, p <0.0001) and high-density lipoprotein cholesterol (+0.2 g, p <0.0001). It was inversely related with diastolic blood pressure (-0.3 g, p <0.0001) and total cholesterol (-0.2 g, p <0.01). The RV end-diastolic volume was positively associated with systolic blood pressure (+1.6 ml, p <0.01) and high-density lipoprotein cholesterol (+1.8 ml, p <0.0001). It was inversely related with diastolic blood pressure (-2.2 ml, p <0.01), total cholesterol (-1.4 ml, p <0.0001), current smoking (-2.7 ml, p <0.05), and diabetes mellitus (-3.1 ml, p <0.01). The RV ejection fraction was positively associated with systolic blood pressure (+1.0%, p <0.0001), high-density lipoprotein cholesterol (+0.4%, p <0.0001) and inversely with diastolic blood pressure (-0.7%, p <0.0001). In conclusion, the mass and volumes of the right ventricle decrease with age. Cardiovascular risk factors, especially blood pressure and high-density lipoprotein cholesterol, are associated with subclinical changes in the RV mass and volume.

Normal left ventricular myocardial thickness for middle aged and older subjects with SSFP cardiac MR: The Multi-Ethnic Study of Atherosclerosis

Background— Increased left ventricular myocardial thickness (LVMT) is a feature of several cardiac diseases. The purpose of this study was to establish standard reference values of normal LVMT with cardiac magnetic resonance and to assess variation with image acquisition plane, demographics, and left ventricular function. Methods and Results— End-diastolic LVMT was measured on cardiac magnetic resonance steady-state free precession cine long and short axis images in 300 consecutive participants free of cardiac disease (169 women; 65.6±8.5 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Mean LVMT on short axis images at the mid-cavity level was 5.3±0.9 mm and 6.3±1.1 mm for women and men, respectively. The average of the maximum LVMT at the mid-cavity for women/men was 7/9 mm (long axis) and 7/8 mm (short axis). Mean LVMT was positively associated with weight (0.02 mm/kg; P=0.01) and body surface area (1.1 mm/m2; P<0.001). No relationship was found between mean LVMT and age or height. Greater mean LVMT was associated with lower left ventricular end-diastolic volume (0.01 mm/mL; P<0.01), a lower left ventricular end-systolic volume (−0.01 mm/mL; P=0.01), and lower left ventricular stroke volume (−0.01 mm/mL; P<0.05). LVMT measured on long axis images at the basal and mid-cavity level were slightly greater (by 6% and 10%, respectively) than measurements obtained on short axis images; apical LVMT values on long axis images were 20% less than those on short axis images. Conclusions— Normal values for wall thickness are provided for middle-aged and older subjects. Normal LVMT is lower for women than men. Observed values vary depending on the imaging plane for measurement.

Normal left ventricular myocardial thickness for middle-aged and older subjects with steady-state free precession cardiac magnetic resonance: the multi-ethnic study of atherosclerosis.

Background— Increased left ventricular myocardial thickness (LVMT) is a feature of several cardiac diseases. The purpose of this study was to establish standard reference values of normal LVMT with cardiac magnetic resonance and to assess variation with image acquisition plane, demographics, and left ventricular function. Methods and Results— End-diastolic LVMT was measured on cardiac magnetic resonance steady-state free precession cine long and short axis images in 300 consecutive participants free of cardiac disease (169 women; 65.6±8.5 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Mean LVMT on short axis images at the mid-cavity level was 5.3±0.9 mm and 6.3±1.1 mm for women and men, respectively. The average of the maximum LVMT at the mid-cavity for women/men was 7/9 mm (long axis) and 7/8 mm (short axis). Mean LVMT was positively associated with weight (0.02 mm/kg; P=0.01) and body surface area (1.1 mm/m2; P<0.001). No relationship was found between mean LVMT and age or height. Greater mean LVMT was associated with lower left ventricular end-diastolic volume (0.01 mm/mL; P<0.01), a lower left ventricular end-systolic volume (−0.01 mm/mL; P=0.01), and lower left ventricular stroke volume (−0.01 mm/mL; P<0.05). LVMT measured on long axis images at the basal and mid-cavity level were slightly greater (by 6% and 10%, respectively) than measurements obtained on short axis images; apical LVMT values on long axis images were 20% less than those on short axis images. Conclusions— Normal values for wall thickness are provided for middle-aged and older subjects. Normal LVMT is lower for women than men. Observed values vary depending on the imaging plane for measurement.