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1.  Predictors of all-cause and cardiovascular disease mortality in type 2 diabetes: Diabetes Heart Study 
Many studies evaluated the best predictors for cardiovascular disease (CVD) events in individuals with type 2 diabetes (T2D), but few studies examined the factors most strongly associated with mortality in T2D. The Diabetes Heart Study (DHS), an intensively phenotyped family-based cohort enriched for T2D, provided an opportunity to address this question.
Associations with mortality were examined in 1022 European Americans affected by T2D from 476 DHS families. All-cause mortality was 31.2 % over an average 9.6 years of follow-up. Cox proportional hazards models with sandwich-based variance estimation were used to evaluate associations between all-cause and CVD mortality and 24 demographic and clinical factors, including coronary artery calcified plaque (CAC), carotid artery intima-media thickness, medications, body mass index, waist hip ratio, lipids, blood pressure, kidney function, QT interval, educational attainment, and glycemic control. Nominally significant factors (p < 0.25) from univariate analyses were included in model selection (backward elimination, forward selection, and stepwise selection). Age and sex were included in all models.
The all-cause mortality model selected from the full DHS sample included age, sex, CAC, urine albumin: creatinine ratio (UACR), insulin use, current smoking, and educational attainment. The CVD mortality model selected from the full sample included age, sex, CAC, UACR, triglycerides, and history of CVD events. Beyond age, the most significant associations for both mortality models were CAC (2.03 × 10−4 ≤ p ≤ 0.001) and UACR (1.99 × 10−8 ≤ p ≤ 2.23 × 10−8). To confirm the validity of the main predictors identified with model selection using the full sample, a two-fold cross-validation approach was used, and similar results were observed.
This analysis highlights important demographic and clinical factors, notably CAC and albuminuria, which predict mortality in the general population of patients with T2D.
Electronic supplementary material
The online version of this article (doi:10.1186/s13098-015-0055-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4490739  PMID: 26146522
Type 2 diabetes; Mortality; Coronary artery calcified plaque; Urine albumin:creatinine ratio
2.  Prediction of mortality using a multi-bed vascular calcification score in the Diabetes Heart Study 
Vascular calcified plaque, a measure of subclinical cardiovascular disease (CVD), is unlikely to be limited to a single vascular bed in patients with multiple risk factors. Consideration of vascular calcified plaque as a global phenomenon may allow for a more accurate assessment of the CVD burden. The aim of this study was to examine the utility of a combined vascular calcified plaque score in the prediction of mortality.
Vascular calcified plaque scores from the coronary, carotid, and abdominal aortic vascular beds and a derived multi-bed score were examined for associations with all-cause and CVD-mortality in 699 European-American type 2 diabetes (T2D) affected individuals from the Diabetes Heart Study. The ability of calcified plaque to improve prediction beyond Framingham risk factors was assessed.
Over 8.4 ± 2.3 years (mean ± standard deviation) of follow-up, 156 (22.3%) participants were deceased, 74 (10.6%) from CVD causes. All calcified plaque scores were significantly associated with all-cause (HR: 1.4-1.8; p < 1x10−5) and CVD-mortality (HR: 1.5-1.9; p < 1×10−4) following adjustment for Framingham risk factors. Associations were strongest for coronary calcified plaque. Improvement in prediction of outcome beyond Framingham risk factors was greatest using coronary calcified plaque for all-cause mortality (AUC: 0.720 to 0.757, p = 0.004) and the multi-bed score for CVD mortality (AUC: 0.731 to 0.767, p = 0.008).
Although coronary calcified plaque and the multi-bed score were the strongest predictors of all-cause mortality and CVD-mortality respectively in this T2D-affected sample, carotid and abdominal aortic calcified plaque scores also significantly improved prediction of outcome beyond traditional risk factors and should not be discounted as risk stratification tools.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0160-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4266952  PMID: 25496604
Vascular calcified plaque; Mortality; Computed tomography; Type 2 diabetes
3.  Analysis of common and coding variants with cardiovascular disease in the diabetes heart study 
Type 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci.
Variants identified in CHARGE were tested for association with CVD phenotypes, including vascular calcification, and conventional CVD risk factors, in the Diabetes Heart Study (DHS) (n = 1208; >80% T2DM affected). This included 36 genotyped or imputed single nucleotide polymorphisms (SNPs) from DHS GWAS data. 28 coding SNPs from 14 top CHARGE genes were also identified from exome sequencing resources and genotyped, along with 209 coding variants from the Illumina HumanExome BeadChip genotype data in the DHS were also tested. Genetic risk scores (GRS) were calculated to evaluate the association of combinations of variants with CVD measures.
After correction for multiple comparisons, none of the CHARGE SNPs were associated with vascular calcification (p < 0.0014). Multiple SNPs showed nominal significance with calcification, including rs599839 (PSRC1, p = 0.008), rs646776 (CELSR2, p = 0.01), and rs17398575 (PIK3CG, p = 0.009). Additional COL4A2 and CXCL12 SNPs were nominally associated with all-cause or CVD-cause mortality. Three SNPs were significantly or nominally associated with serum lipids: rs3135506 (Ser19Trp, APOA5) with triglycerides (TG) (p = 5×10−5), LDL (p = 0.00070), and nominally with high density lipoprotein (HDL) (p = 0.0054); rs651821 (5′UTR, APOA5) with increased TGs (p = 0.0008); rs13832449 (splice donor, APOC3) associated with decreased TGs (p = 0.0015). Rs45456595 (CDKN2A, Gly63Arg), rs5128 (APOC3, 3′UTR), and rs72650673 (SH2B3, Glu400Lys) were nominally associated with history of CVD, subclinical CVD, or CVD risk factors (p < 0.010). From the exome chip, rs3750103 (CHN2, His204Arg/His68Arg) with carotid intima-medial thickness (IMT) (p = 3.9×10−5), and rs61937878 (HAL, Val549Met) with infra-renal abdominal aorta CP (AACP) (p = 7.1×10−5). The unweighted GRS containing coronary artery calcified plaque (CAC) SNPs was nominally associated with history of prior CVD (p = 0.033; OR = 1.09). The weighted GRS containing SNPs was associated with CAC and myocardial infarction (MI) was associated with history of MI (p = 0.026; OR = 1.15).
Genetic risk factors for subclinical CVD in the general population (CHARGE) were modestly associated with T2DM-related risk factors and CVD outcomes in the DHS.
PMCID: PMC4021556  PMID: 24725463
Coronary artery calcified plaque; Type 2 diabetes mellitus; Cardiovascular disease; Genetic risk score
4.  Associations between Nonalcoholic Fatty Liver Disease and Subclinical Atherosclerosis in Middle-Aged Adults: The Coronary Artery Risk Development in Young Adults Study 
Atherosclerosis  2014;235(2):599-605.
Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross-sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity.
Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n=2,424). NAFLD was defined as liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score > 0.
Mean participant age was 50.1±3.6 years, (42.7% men, 50.0% black) and BMI was 30.6±7.2 kg/m2. The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p<0.001) and AAC (65.1% vs. 49.9%, p<0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001–1.82) and AAC (OR, 1.74; 95% CI, 1.29–2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74–1.48, AAC OR=1.20; 95% CI, 0.86–1.67). There was no interaction by race or sex.
In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed.
PMCID: PMC4124046  PMID: 24956534
calcium; cardiovascular diseases; epidemiology; imaging; liver; obesity; risk factors
5.  Variation in the Percent of Emphysema-like Lung in a Healthy, Nonsmoking Multiethnic Sample. The MESA Lung Study 
Rationale: Computed tomography (CT)-based lung density is used to quantitate the percentage of emphysema-like lung (hereafter referred to as percent emphysema), but information on its distribution among healthy nonsmokers is limited.
Objectives: We evaluated percent emphysema and total lung volume on CT scans of healthy never-smokers in a multiethnic, population-based study.
Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study investigators acquired full-lung CT scans of 3,137 participants (ages 54–93 yr) between 2010–12. The CT scans were taken at full inspiration following the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) protocol. “Healthy never-smokers” were defined as participants without a history of tobacco smoking or respiratory symptoms and disease. “Percent emphysema” was defined as the percentage of lung voxels below −950 Hounsfield units. “Total lung volume” was defined by the volume of lung voxels.
Measurements and Main Results: Among 854 healthy never-smokers, the median percent emphysema visualized on full-lung scans was 1.1% (interquartile range, 0.5–2.5%). The percent emphysema values were 1.2 percentage points higher among men compared with women and 0.7, 1.2, and 1.2 percentage points lower among African Americans, Hispanics, and Asians compared with whites, respectively (P < 0.001). Percent emphysema was positively related to age and height and inversely related to body mass index. The findings were similar for total lung volume on CT scans and for percent emphysema defined at −910 Hounsfield units and measured on cardiac scans. Reference equations to account for these differences are presented for never, former and current smokers.
Conclusions: Similar to lung function, percent emphysema varies substantially by demographic factors and body size among healthy never-smokers. The presented reference equations will assist in defining abnormal values for percent emphysema and total lung volume on CT scans, although validation is pending.
PMCID: PMC4213995  PMID: 24983825
emphysema; lung volumes; quantitative computed tomography; reference equations
6.  APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes 
Kidney international  2014;87(1):176-181.
Albuminuria and reduced eGFR associate with two apolipoprotein L1 gene (APOL1) variants in non-diabetic African Americans. Whether APOL1 associates with subclinical atherosclerosis and survival remains unclear. To determine this, 717 African American-Diabetes Heart Study participants underwent computed tomography to determine coronary artery, carotid artery, and aorta calcified atherosclerotic plaque mass scores in addition to the urine albumin:creatinine ratio (UACR), eGFR, and C-reactive protein. Associations between mass scores and APOL1 were assessed adjusting for age, gender, African ancestry, BMI, HbA1c, smoking, hypertension, use of statins and ACE inhibitors, albuminuria, and eGFR. Participants were 58.9% female with mean age 56.5 years, eGFR 89.5 ml/min/1.73m2, UACR 169.6 mg/g, coronary artery, carotid artery and aorta calcified plaque mass scores of 610, 171 and 5378, respectively. In fully adjusted models, APOL1 risk variants were significantly associated with lower levels of carotid artery calcified plaque (β −0.42, SE 0.18, dominant model), and marginally lower coronary artery plaque (β −0.36, SE 0.21; dominant model), but not with aorta calcified plaque, C-reactive protein, UACR, or eGFR. After a mean follow-up of 5.0 years, 89 participants died. APOL1 nephropathy risk variants were significantly associated with improved survival (hazard ratio 0.67 for 1 copy; 0.44 for 2 copies). Thus, APOL1 nephropathy variants associate with lower levels of subclinical atherosclerosis and reduced risk of death in African Americans with type 2 diabetes mellitus.
PMCID: PMC4281283  PMID: 25054777
African Americans; apolipoprotein L1 gene (APOL1); atherosclerosis; calcified atherosclerotic plaque; diabetes mellitus; kidney disease
7.  Association of emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study 
Annals of internal medicine  2014;161(12):863-873.
Whereas low lung function is known to predict mortality in the general population, the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) remains uncertain.
To determine whether greater emphysema-like lung on CT is associated with all-cause mortality among persons without airflow obstruction or COPD in the general population.
Prospective cohort study.
Population-based, multiethnic sample from 6 US communities.
2965 participants ages 45-84 years without airflow obstruction on spirometry.
Emphysema-like lung was defined on cardiac CT as the number of lung voxels less than -950 Hounsfield Units, and was adjusted for the number of total imaged lung voxels.
Among 2965 participants, 50.9% of whom never smoked, there were 186 deaths over a median of 6.2 years. Greater emphysema-like lung was independently associated with increased mortality (adjusted hazard ratio [HR]1.14 per one-half of the interquartile range, 95% CI 1.04-1.24, P=0.004), adjusting for potential confounders including cardiovascular risk factors and the forced expiratory volume in one second. Generalized additive models supported a linear association between emphysema-like lung and mortality without evidence for a threshold. The association was of greatest magnitude among smokers, although multiplicative interaction terms did not support effect modification by smoking status.
Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses.
Emphysema-like lung on CT was associated with all-cause mortality among persons without airflow obstruction or COPD in a general population sample, particularly among smokers. Recognition of the independent prognostic significance of emphysema on CT among patients without COPD on spirometry is warranted.
Primary Funding Source
PMCID: PMC4347817  PMID: 25506855
8.  Clinical Characteristics and Outcomes Associated with the Natural History of Early Repolarization in a Young, Biracial Cohort Followed to Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Early repolarization (ER), a common electrocardiographic phenotype, has been associated with increased mortality risk in middle-aged adults. Data are sparse on long-term follow-up and outcomes associated with ER in younger adults.
Methods and Results
We prospectively examined 5,039 participants (mean age 25 years at baseline, 40% black) from the CARDIA cohort over 23 years. Twelve-lead electrocardiograms were recorded and analyzed at Years 0, 7 and 20 and coded as definite or probable ER using a standardized algorithm. Cox regression was used, and models were adjusted for important baseline and clinical covariates. Kaplan-Meier curves were created for presence of ER and total mortality and cardiovascular (CV) mortality. Participants with ER were more likely to be black, male, smoke, have higher systolic blood pressure, lower heart rate, and BMI, and also higher exercise duration, and longer PR, QRS and QT intervals. ER was associated with total mortality (HR1.77, 1.38–2.28, p<0.01), and CV mortality (HR 1.59, 1.01–2.50, p=0.04) in unadjusted analyses, but adjustment for age, sex, and race attenuated associations almost completely. Sex-race stratified analyses showed no significant associations between ER and outcome for any of the subgroups except blacks.
The presence of ER at any time point over 23 years of follow-up was not associated with adverse outcomes. Black race and male sex confound the unadjusted association of ER and outcomes, with no race-sex interactions noted. Further studies are necessary to understand the factors associated with heightened risk of death in those who maintain ER into and beyond middle age.
PMCID: PMC4136505  PMID: 24759868
ECG; ECG criteria; outcome; mortality; early repolarization
9.  Association of egg consumption and calcified atherosclerotic plaque in the coronary arteries: the NHLBI Family Heart Study 
e-SPEN journal  2014;9(3):e131-e135.
Background and Aims
Eggs are a ubiquitous and important source of dietary cholesterol and nutrients, yet their relationship to coronary heart disease (CHD) remains unclear. While some data have suggested a positive association between egg consumption and CHD, especially among diabetic subjects, limited data exist on the influence of egg consumption on subclinical disease. Thus, we sought to examine whether egg consumption is associated with calcified atherosclerotic plaques in the coronary arteries.
In a cross-sectional design, we studied 1848 participants of the NHLBI Family Heart Study without known CHD. Egg consumption was assessed by a semi-quantitative food frequency questionnaire and coronary-artery calcium (CAC) was measured by cardiac CT. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC.
Mean age was 56.5 years and 41% were male. Median consumption of eggs was 1/week. There was no association between frequency of egg consumption and prevalent CAC. Odds ratios (95% CI) for CAC were 1.0 (reference), 0.95 (0.66-1.38), 0.94 (0.63-1.40), and 0.90 (0.57-1.42) for egg consumption of almost never, 1-3 times per month, once per week, and 2+ times per week, respectively (p for trend 0.66), adjusting for age, sex, BMI, smoking, alcohol, physical activity, income, field center, total calories, and bacon.
Additional control for hypertension and diabetes mellitus, or restricting the analysis to subjects with diabetes mellitus or fasting glucose >126 mg/dL did not alter the findings.
These data do not provide evidence for an association between egg consumption and prevalent CAC in adult men and women.
PMCID: PMC4309282  PMID: 25642410
egg; diet; epidemiology; subclinical disease; coronary calcium; atherosclerosis
10.  The Interaction of Age with Lipoproteins as Predictors of Aortic Valve Calcification in the Multi-Ethnic Study of Atherosclerosis 
Archives of internal medicine  2008;168(11):1200-1207.
Previous epidemiologic studies have shown that low-density lipoprotein is an independent risk factor for prevalent aortic valve calcification (AVC); however, to our knowledge, the interactions between plasma lipoprotein concentrations and age on the relative risks (RRs) for AVC prevalence and severity have not been examined in a large, racially and ethnically diverse cohort.
Using stepwise RR regression, the relationships of baseline fasting lipid levels and lipoprotein levels to baseline prevalence and severity of AVC were determined in 5801 non–statin-using participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
In age-stratified, adjusted analyses, the low-density lipoprotein–associated RRs (95%confidence intervals) for prevalent AVC were higher for younger compared with older participants (age 45-54 years, 1.69 [1.19-2.39]; age 55-64 years, 1.48 [1.24-1.76]; age 65-74 years, 1.09 [0.95-1.25]; and age 75-84 years, 1.16 [0.99-1.36]; P interaction=.04]. There was a similar, significant interaction of age with total cholesterol–associated RR for prevalent AVC (P interaction=.04). In contrast, total- to high-density lipoprotein cholesterol ratio RRs were similar across all age strata (P interaction=.68). At multivariate analyses, no lipoprotein parameter was associated with AVC severity.
In this racially and ethnically diverse, preclinical cohort, low-density lipoprotein was a risk factor for AVC only in participants younger than 65 years, whereas the total cholesterol/high-density lipoprotein cholesterol ratio was associated with a modest increased risk of AVC across all ages. These findings may have important implications for the efficacy of and targets for dyslipidemia therapies in calcific aortic valve disease.
PMCID: PMC4441013  PMID: 18541828
11.  Baseline Subclinical Atherosclerosis Burden and Distribution are Associated with the Frequency and Mode of Future Coronary Revascularization: Multi-Ethnic Study of Atherosclerosis (MESA) 
JACC. Cardiovascular imaging  2014;7(5):476-486.
We sought to evaluate the impact of coronary artery calcium (CAC) burden and regional distribution on the need for and type of future coronary revascularization (percutaneous [PCI] vs. surgical [CABG]) among asymptomatic individuals.
The need for coronary revascularization and the chosen mode of revascularization are thought to be a function of disease burden and anatomic distribution. The association between the baseline burden and regional distribution of CAC and the risk and type of future coronary revascularization remains unknown.
6,540 MESA participants (individuals aged 45-84 years, free of known baseline cardiovascular disease) with vessel-specific CAC measurement were followed for median 8.5 (7.7 – 8.6) years. Annualized rates and multivariable adjusted hazard ratios for revascularization and revascularization type were analyzed according to CAC score category, number of vessels with CAC (0-4, including the left main), and by involvement of individual coronary arteries.
A total of 265 revascularizations (4.2%) occurred during follow-up, and 206 (78% of total) were preceded by adjudicated symptoms. Revascularization was uncommon when CAC=0 (0.6%), with graded increase over both rising CAC burden and increasingly diffuse CAC distribution. The revascularization rate per 1,000 person-years for CAC 1-100, 101-400, and >400 was 4.9, 11.7 and 25.4; for 1, 2, 3, and 4 vessels with CAC the rates were 3.0, 8.0, 16.1, and 24.8. In multivariable models adjusting for CAC score, number of vessels with CAC remained predictive of mode of revascularization. Independent predictors of CABG vs. PCI included 3 or 4 vessel CAC, higher CAC burden, and involvement of the left main. Risk for CABG was extremely low with <3 vessel baseline CAC. Results were similar when considering only symptom-driven revascularizations.
In this multi-ethnic cohort of asymptomatic individuals, baseline CAC was highly predictive of future coronary revascularization procedures, with measures of CAC burden and distribution each independently predicting need for PCI vs. CABG over 8.5 year follow-up.
PMCID: PMC4024837  PMID: 24831208
cardiac CT; coronary artery calcium; coronary artery disease; revacularization
12.  Heart Rate–Corrected QT Interval Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Diabetes Heart Study 
Diabetes Care  2014;37(5):1454-1461.
Heart rate–corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.
We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.
At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03–1.36]) and 29% increased risk for CVD mortality (1.29 [1.05–1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95–3.15]; CVD mortality 2.86 [1.35–6.08]).
Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.
PMCID: PMC4182905  PMID: 24574343
13.  Patient-Centered Imaging: Shared Decision Making for Cardiac Imaging Procedures with Exposure to Ionizing Radiation 
To identify key components of a radiation accountability framework fostering patient-centered imaging and shared decision-making in cardiac imaging.
An NIH-NHLBI/NCI-sponsored symposium was held in November 2012 to address these issues.
Symposium participants, working in three tracks, identified key components of a framework to target critical radiation safety issues for the patient, the laboratory, and the larger population of patients with known or suspected cardiovascular disease.
Use of ionizing radiation during an imaging procedure should be disclosed to all patients by the ordering provider at the time of ordering, and reinforced by the performing provider team. An imaging protocol with effective dose ≤3mSv is considered very low risk, not warranting extensive discussion or written consent. However, a protocol effective dose <20mSv was proposed as a level requiring particular attention in terms of shared decision-making and either formal discussion or written informed consent.
Laboratory reporting of radiation dosimetry is a critical component of creating a quality laboratory fostering a patient-centered environment with transparent procedural methodology. Efforts should be directed to avoiding testing involving radiation, in patients with inappropriate indications. Standardized reporting and diagnostic reference levels for computed tomography and nuclear cardiology are important for the goal of public reporting of laboratory radiation dose levels in conjunction with diagnostic performance.
The development of cardiac imaging technologies revolutionized cardiology practice by allowing routine, noninvasive assessment of myocardial perfusion and anatomy. It is now incumbent upon the imaging community to create an accountability framework to safely drive appropriate imaging utilization.
PMCID: PMC3994983  PMID: 24530677
Radiation Safety; Appropriate Use; Image Quality; Imaging
14.  Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study 
Diabetes Care  2014;37(4):1157-1164.
Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard.
Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models.
The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22–1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02–0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10–1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08–1.65]; P = 0.008), CAC (β 0.29 [0.08–0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05–1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08–1.96]; P = 0.01).
These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.
PMCID: PMC4178326  PMID: 24574349
15.  Relationships Between Calcified Atherosclerotic Plaque and Bone Mineral Density in African Americans With Type 2 Diabetes 
Inverse relationships have been reported between bone mineral density (BMD) and calcified atherosclerotic plaque (CP). This suggests these processes may be related. We examined relationships between BMD and CP in 753 African Americans with type 2 diabetes from 664 families, accounting for the effects of modifiable cardiovascular disease (CVD) risk factors. Association analyses were performed using generalized estimating equations (GEEs) to assess cross-sectional relationships between computed tomography–determined measures of thoracic and lumbar vertebral volumetric BMD (vBMD) and CP in the coronary and carotid arteries and infrarenal aorta. Significant inverse associations were seen between thoracic and lumbar vBMD and CP in all three vascular beds in unadjusted analyses. A fully adjusted model accounting for age, sex, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, C-reactive protein, hemoglobin A1c, smoking, and hormone-replacement therapy revealed significant inverse associations between thoracic vBMD and CP in coronary and carotid arteries and aorta, whereas lumbar vBMD was associated with CP in coronary artery and aorta. Inverse associations exist between vertebral BMD and calcified atherosclerotic plaque in African-American men and women with type 2 diabetes. This relationship was independent of conventional CVD risk factors and supports the hypothesis that bone metabolism and atherosclerotic plaque mineralization are related processes.
PMCID: PMC4341826  PMID: 21437982
16.  Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study 
Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema.
Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
PMCID: PMC3977717  PMID: 24383474
emphysema; computed tomography; multiethnic; cohort study; genetic association
17.  Adipose Tissue Density, a Novel Biomarker Predicting Mortality Risk in Older Adults 
Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics.
VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4–13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.
Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36–2.80; Health ABC) and 1.88 (1.31–2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35–2.28; Health ABC) and 1.56 (1.15–2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12–2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21–2.07), and AGES-Reykjavik, 1.43 (1.07–1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.
VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
PMCID: PMC3859360  PMID: 23707956
Obesity; Aging; Leptin; Adiponectin.
18.  Adult Height and Prevalence of Coronary Artery Calcium: The NHLBI Family Heart Study 
Adult height has been hypothesized to be inversely associated with coronary heart disease but studies have produced conflicting results. We sought to examine the relationship between adult height and the prevalence of coronary artery calcium (CAC), a direct measure of subclinical atherosclerosis and surrogate marker of CHD.
Method and Results
We evaluated the relationship between adult height and CAC in 2,703 participants from the NHLBI Family Heart Study who underwent cardiac computed tomography. We used generalized estimating equations to calculate the prevalence odds ratios for the presence of CAC (CAC>0) across sex-specific quartiles of height. The mean age of the sample was 54.8 years and 60.2% were female. There was an inverse association between adult height and CAC. After adjusting for age, race, field center, waist circumference, smoking, alcohol, physical activity, systolic blood pressure, antihypertensive medications, diabetes, diabetic medications, LDL cholesterol, HDL cholesterol, lipid-lowering medications, and income, individuals in the tallest quartile had 30% lower odds of having prevalent CAC. The odds ratios (95% CI) for the presence of CAC across consecutive sex-specific quartiles of height were 1.0 (reference), 1.15 (0.86–1.53), 0.95(0.73–1.22), and 0.70 (0.53–0.93), p for trend <0.01. There was no evidence of effect modification for the relationship between adult height and CAC by age or socioeconomic status.
The results of our study suggest an inverse, independent association between adult height and CAC.
PMCID: PMC3970195  PMID: 24336983
risk factor; imaging; epidemiology
19.  Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study 
Atherosclerosis  2009;209(1):283-289.
Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors.
To test population-level associations between atherosclerosis types and bone integrity.
Main Outcome Measures
Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity.
Design, Setting and Participants
A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005.
904 post-menopausal female (62.4 years; 62% non-white; 12% ABI<1; 17% CCA-IMT>1mm; 33% ICA-IMT>1mm) and 929 male (61.4 years; 58% non-white; 6% ABI<1; 25% CCA-IMT>1mm; 40% ICA-IMT>1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results.
Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes.
PMCID: PMC4254856  PMID: 19819456
20.  Longitudinal association between serum urate and subclinical atherosclerosis: the Coronary Artery Risk Development in Young Adults (CARDIA) study 
Journal of internal medicine  2013;274(6):10.1111/joim.12120.
The aim of the present study was to determine whether serum urate (sUA) concentration is positively associated with subclinical atherosclerosis, independent of body mass index (BMI), among generally healthy adults.
Design and setting
The CARDIA study followed 5115 black and white individuals aged 18–30 years in 1985–1986 (year 0). Subclinical atherosclerosis comprised coronary artery calcified plaque (CAC; years 15, 20 and 25) and maximum common carotid intima–media thickness (IMT; year 20). sUA (years 0, 10, 15 and 20) was modelled as gender-specific quartiles that were pooled. Discrete-time hazard regressions and generalized linear regressions were used for analyses.
Mean sUA concentration was lower in women than in men, and increased with age. Adjusting for demographic and lifestyle factors, the highest versus lowest quartile of sUA at year 0 was associated with a 44% [95% confidence interval (CI) 20%, 73%] greater risk of CAC progression from year 15 to 25 (Ptrend < 0.001), which was attenuated by adjustment for BMI at year 0 (Ptrend = 0.45). A stronger association was found between sUA at year 15 and CAC progression at year 20 or 25 (hazard ratio 2.07, 95% CI 1.66, 2.58 for the highest versus lowest sUA quartile Ptrend < 0.001), which was attenuated but remained significant with additional adjustment for BMI at year 15 (Ptrend = 0.01). A greater increment in sUA concentration from year 0 to year 15, independent of change in BMI, was related to a higher risk of CAC progression (Ptrend < 0.001). Similar associations were found between sUA and IMT, but only in men.
sUA may be an early biomarker for subclinical atherosclerosis in young adults; starting in early middle age, sUA predicts subclinical atherosclerosis independently of BMI.
PMCID: PMC3825786  PMID: 23952533
calcified plaque; intima–media thickness; subclinical atherosclerosis; urate; uric acid
21.  Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle Age 
JAMA  2013;310(3):280-288.
Younger individuals are experiencing a greater cumulative exposure to excess adiposity over their lifetime. However, few studies have determined the consequences of long-term obesity.
To examine whether the duration of overall and abdominal obesity was associated with the presence and 10-year progression of coronary artery calcification (CAC), a subclinical predictor of coronary heart disease.
Prospective study of 3275 white and black adults aged 18 to 30 years at baseline in 1985–1986 who did not initially have overall obesity (body mass index [BMI] ≥30) or abdominal obesity (men: waist circumference [WC] >102 cm; women: >88 cm) in the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants completed computed tomography scanning for the presence of CAC during the 15-, 20-, or 25-year follow-up examinations. Duration of overall and abdominal obesity was calculated using repeat measurements of BMI and WC, respectively, performed 2, 5, 7, 10, 15, 20, and 25 years after baseline.
Presence of CAC was measured by computed tomography at the year 15 (2000–2001), year 20 (2005–2006), or year 25 (2010–2011) follow-up examinations. Ten-year progression of CAC (2000–2001 to 2010–2011) was defined as incident CAC in 2010–2011 or an increase in CAC score of 20 Agatston units or greater.
During follow-up, 40.4% and 41.0% developed overall and abdominal obesity, respectively. Rates of CAC per 1000 person-years were higher for those who experienced more than 20 years vs 0 years of overall obesity (16.0 vs 11.0, respectively) and abdominal obesity (16.7 vs 11.0). Approximately 25.2% and 27.7% of those with more than 20 years of overall and abdominal obesity, respectively, experienced progression of CAC vs 20.2% and 19.5% of those with 0 years. After adjustment for BMI or WC and potential confounders, the hazard ratios for CAC for each additional year of overall or abdominal obesity were 1.02 (95% CI, 1.01–1.03) and 1.03 (95% CI, 1.02–1.05), respectively. The adjusted odds ratios for CAC progression were 1.04 (95% CI, 1.01–1.06) and 1.04 (95% CI, 1.01–1.07), respectively. Associations were attenuated but largely persisted following additional adjustment for potential intermediate metabolic factors during follow-up.
Longer duration of overall and abdominal obesity was associated with subclinical coronary heart disease and its progression through midlife independent of the degree of adiposity. Preventing or at least delaying the onset of obesity in young adulthood may lower the risk of developing atherosclerosis through middle age.
PMCID: PMC4226407  PMID: 23860986
22.  Subclinical Atherosclerotic Calcification and Cognitive Functioning in Middle-Aged Adults: The CARDIA Study 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.08.038.
Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults.
This cross-sectional study included 2,510 black and white adults (age: 43–55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010–11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory).
A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p<0.05).
In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging.
PMCID: PMC3828555  PMID: 24125414
atherosclerosis; heart disease; calcium score; cognition; subclinical disease; risk factors
23.  Obstructive Sleep Apnea and Progression of Coronary Artery Calcium: The Multi‐Ethnic Study of Atherosclerosis Study 
Obstructive sleep apnea (OSA) is a common condition associated with cardiovascular disease. Its potential effect on progression of subclinical atherosclerosis is not well understood. We tested the hypothesis that self‐reported OSA is associated with progression of coronary artery calcium (CAC). We also evaluated whether traditional cardiovascular risk factors accounted for the association.
Methods and Results
In the Multi‐Ethnic Study of Atherosclerosis (MESA) prospective cohort, we studied 2603 participants who at baseline (2002–2004) completed a sleep questionnaire and underwent coronary computed tomography (CT) and, then 8 years later (2010–2011), a repeat coronary CT. Participants were categorized by symptoms of habitual snoring or reported physician diagnosis of OSA. At baseline, 102 (3.9%) reported diagnosed OSA; 666 (25.6%) reported diagnosed habitual snoring; and 1835 (70.5%) reported neither habitual snoring nor OSA (“normal”). At baseline, CAC prevalence was highest among those with OSA but similar for those with and without habitual snoring. During 8 years of follow‐up, greater progression of CAC was observed among those with OSA versus normal (mean increase of 204.2 versus 135.5 Agatston units; P=0.01), after accounting for demographics, behaviors, and body habitus. Modest attenuation was observed after adjustment for cardiovascular risk factors (188.7 versus 138.8; P=0.06). CAC progression among habitual snorers was similar to that observed in the normal group.
OSA was associated with CAC score progression after adjustment for demographics, behaviors, and body mass index. However, the association was not significant after accounting for cardiovascular risk factors, which may mediate the association between OSA and CAC.
PMCID: PMC4323795  PMID: 25261530
coronary artery calcium; obstructive sleep apnea; snoring; subclinical atherosclerosis risk factor
24.  The influence of subclinical cardiovascular disease and related risk factors on cognition in type 2 diabetes mellitus: The DHS-Mind study 
We hypothesized that measures of coronary artery calcified plaque (CAC) collected at baseline from the Diabetes Heart Study (DHS) would explain associations between cognition and diabetes collected at follow-up approximately 7 years later. The DHS is a sibling study of cardiovascular disease (CVD) in a cohort with a high prevalence of type 2 diabetes (~80%). Associations between baseline CAC and cognitive performance were tested using generalized estimating equations and mixed effects models to adjust for familial relationships. Diabetes status was associated (p<0.05) with poorer performance on tests of verbal memory, processing speed, and semantic fluency adjusting for age, sex, education, and hypertension status. As hypothesized, including CAC in the statistical model attenuated this association. Additionally, CAC and fasting glucose predicted performance in tasks not associated with diabetes status in this study (Stroop Task, Phonemic Fluency). These results confirm work attributing the heterogeneity of cognitive outcomes in type 2 diabetes to subclinical risk factors that combine to affect different aspects of brain function. Importantly, these results imply that risk factor intervention should begin before comorbidities, particularly CVD, become clinically apparent.
PMCID: PMC3770734  PMID: 23659774
type 2 diabetes; cardiovascular disease; atherosclerosis; cognition
25.  Characterization of European-ancestry NAFLD-Associated Variants in Individuals of African and Hispanic Descent 
Hepatology (Baltimore, Md.)  2013;58(3):966-975.
Nonalcoholic Fatty Liver Disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European-ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African and/or Hispanic Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African-American (n=3124) and one Hispanic-American (n=849) cohorts. All analyses controlled for variation in age, age2, gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African-American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9kg/m2, respectively. Hepatic steatosis was 0.20–0.34 heritable in African-and Hispanic-American families (p<0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1.
We show for the first time that multiple genetic variants are associated with hepatic steatosis across ancestries and explain a substantial proportion of the genetic predisposition in African and Hispanic Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.
PMCID: PMC3782998  PMID: 23564467
liver steatosis; single nucleotide polymorphisms; obesity; meta-analysis; genetic variance

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