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1.  Analysis of common and coding variants with cardiovascular disease in the diabetes heart study 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1475-2840-13-77
PMCID: PMC4021556  PMID: 24725463
Coronary artery calcified plaque; Type 2 diabetes mellitus; Cardiovascular disease; Genetic risk score
2.  Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study 
Atherosclerosis  2013;229(1):155-160.
Objective
A negative relationship between total bilirubin concentration (TBili) and CVD risk has been documented in a series of epidemiological studies. In addition, TBili is thought to be under strong genetic regulation via the UGT1A gene family, suggesting it may be a heritable CVD risk factor. However, few studies directly relate TBili-associated UGT1A variants to CVD severity or outcome. This study replicated the genetic association for TBili in the Diabetes Heart Study (DHS), and examined the relationships of TBili-associated SNPs with measures of subclinical CVD and mortality.
Methods
This investigation included 1220 self-described European American (EA) individuals from the DHS, a family-based study examining risk for macrovascular complications in type 2 diabetes (T2D). Genetic associations with TBili were examined using the Affymetrix Genome-wide Human SNP Array 5.0 and the Illumina Infinium Human Exome beadchip v1.0. Subsequent analyses assessed the relationships of the top TBili-associated SNPs with measures of vascular calcified plaque and mortality.
Results
A genome-wide association study (GWAS) detected 18 SNPs within the UGT1A gene family associated with TBili at p<5×10-8. The top hit was rs887829 (p=8.67×10-20). There was no compelling evidence of association between the top TBili-associated SNPs and vascular calcified plaque (p=0.05-0.88). There was, however, evidence of association with all-cause mortality (p=0.0004-0.06), the top hit being rs2741034.
Conclusion
These findings support a potential role for UGT1A genetic variants in risk for mortality in T2D. Further quantification of the extent of CVD risk conferred by UGT1A gene family variants in a high risk cohort with T2D is still required.
doi:10.1016/j.atherosclerosis.2013.04.008
PMCID: PMC3691283  PMID: 23642732
bilirubin; genetics; cardiovascular disease; vascular calcified plaque
3.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Background
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
Objective
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Design
Cross-sectional population-based study of adults age 45-84 years in the United States
Measurements
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
Results
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
Conclusions
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
doi:10.1136/thoraxjnl-2012-202116
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
4.  Polymorphisms in the Selenoprotein S gene and subclinical cardiovascular disease in the Diabetes Heart Study 
Acta diabetologica  2012;50(3):391-399.
Selenoprotein S (SelS), has previously been associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD). The aim of this study was to examine the role of SELS genetic variants in risk for subclinical CVD and mortality in individuals with type 2 diabetes mellitus (T2DM). The association between 10 polymorphisms tagging SELS and coronary (CAC), carotid (CarCP) and abdominal-aortic calcified plaque (AACP), carotid intima media thickness (IMT) and other known CVD risk factors was examined in 1220 European Americans from the family-based Diabetes Heart Study. The strongest evidence of association for SELS SNPs was observed for CarCP; rs28665122 (5′ region; β=0.329, p=0.044), rs4965814 (intron 5; β=0.329, p=0.036), rs28628459 (3′ region; β=0.331, p=0.039) and rs7178239 (downstream; β=0.375, p=0.016) were all associated. In addition, rs12917258 (intron 5) was associated with CAC (β =−0.230, p=0.032) and rs4965814, rs28628459 and rs9806366 were all associated with self reported history of prior CVD (p=0.020–0.043). These results suggest a potential role for the SELS region in the development subclinical CVD in this sample enriched for T2DM. Further understanding the mechanisms underpinning these relationships may prove important in predicting and managing CVD complications in T2DM.
doi:10.1007/s00592-012-0440-z
PMCID: PMC3597768  PMID: 23161441
genetics; atherosclerosis; calcified plaque; diabetes mellitus
5.  Usefulness of Biventricular Volume as a Predictor of Mortality in Patients with Diabetes Mellitus (From the Diabetes Heart Study) 
The American journal of cardiology  2013;111(8):1152-1158.
Individuals with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. This study examined the relationship between BiVV and risk for mortality in European Americans with type 2 DM from the Diabetes Heart Study. BiVV was calculated from 771 non-contrast computed tomography scans performed to image coronary artery calcified plaque (CAC). Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional hazards regression was performed to determine risk for mortality (all-cause and CVD-mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years (mean ± SD) of follow-up, 23% of the sample were deceased. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, CAC, history of hypertension and prior myocardial infarction (p<0.0001–0.012). BiVV was significantly associated with all-cause (HR: 2.45; CI: 1.06–5.67; p=0.036) and CVD-mortality (HR: 4.36; CI: 1.36–14.03; p=0.014) in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p=0.04) and 0.74 to 0.77 (p=0.02) for all-cause and CVD-mortality on inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contra-indicated, BiVV from computed tomography may be considered as a tool for stratification of high-risk individuals, such as those with type 2 DM.
doi:10.1016/j.amjcard.2012.12.044
PMCID: PMC3618594  PMID: 23351459
cardiovascular disease; heart size; diabetes; risk-prediction
6.  Coronary Calcium Score Predicts Cardiovascular Mortality in Diabetes 
Diabetes Care  2013;36(4):972-977.
OBJECTIVE
In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors.
RESEARCH DESIGN AND METHODS
A total of 1,123 T2DM participants, ages 34–86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%.
RESULTS
Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0–9 as the reference group were, CAC 10–99: 2.93 (0.74–19.55); CAC 100–299: 3.17 (0.70–22.22); CAC 300–999: 4.41(1.15–29.00); and CAC ≥1,000: 11.23 (3.24–71.00). AUC (95% CI) without CAC was 0.70 (0.67–0.73), AUC with CAC was 0.75 (0.72–0.78), and NRI was 0.13 (0.07–0.19).
CONCLUSIONS
In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.
doi:10.2337/dc12-1548
PMCID: PMC3609509  PMID: 23230101
8.  Admixture Mapping of Coronary Artery Calcified Plaque in African Americans with Type 2 Diabetes 
Background
The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping (AM) may be informative for identifying genetic variants associated with subclinical cardiovascular disease (CVD).
Methods and Results
AM of CAC was performed in 1,040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study (AA-DHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Family Heart Study (FamHS) using the Illumina custom ancestry informative marker (AIM) panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each AIM, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each AIM using these probabilities and CAC, accounting for global ancestry, age, gender and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, LOD=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0) and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, while markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1,350 AAs without diabetes and 2,497 diabetic European Americans from MESA and the Diabetes Heart Study.
Conclusions
Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical CVD.
doi:10.1161/CIRCGENETICS.112.964114
PMCID: PMC3578054  PMID: 23233742
ancestry; cardiovascular disease risk factors; type 2 diabetes; admixture mapping
9.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
doi:10.1161/HYPERTENSIONAHA.111.00272
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
10.  Patient-controlled sharing of medical imaging data across unaffiliated healthcare organizations 
Background
Current image sharing is carried out by manual transportation of CDs by patients or organization-coordinated sharing networks. The former places a significant burden on patients and providers. The latter faces challenges to patient privacy.
Objective
To allow healthcare providers efficient access to medical imaging data acquired at other unaffiliated healthcare facilities while ensuring strong protection of patient privacy and minimizing burden on patients, providers, and the information technology infrastructure.
Methods
An image sharing framework is described that involves patients as an integral part of, and with full control of, the image sharing process. Central to this framework is the Patient Controlled Access-key REgistry (PCARE) which manages the access keys issued by image source facilities. When digitally signed by patients, the access keys are used by any requesting facility to retrieve the associated imaging data from the source facility. A centralized patient portal, called a PCARE patient control portal, allows patients to manage all the access keys in PCARE.
Results
A prototype of the PCARE framework has been developed by extending open-source technology. The results for feasibility, performance, and user assessments are encouraging and demonstrate the benefits of patient-controlled image sharing.
Discussion
The PCARE framework is effective in many important clinical cases of image sharing and can be used to integrate organization-coordinated sharing networks. The same framework can also be used to realize a longitudinal virtual electronic health record.
Conclusion
The PCARE framework allows prior imaging data to be shared among unaffiliated healthcare facilities while protecting patient privacy with minimal burden on patients, providers, and infrastructure. A prototype has been implemented to demonstrate the feasibility and benefits of this approach.
doi:10.1136/amiajnl-2012-001146
PMCID: PMC3555338  PMID: 22886546
Medical image; health information exchange; image sharing; diagnostic imaging; electronic health records; pcareportal
11.  Circulating soluble ICAM-1 and subclinical atherosclerosis: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Clinical chemistry  2011;58(2):10.1373/clinchem.2011.168559.
Background
Soluble intercellular adhesion molecule-1 (sICAM-1) is associated with endothelial dysfunction and clinical cardiovascular disease. We investigated the relationship of subclinical atherosclerosis with sICAM-1 concentration.
Methods
sICAM-1 concentration was assayed at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) Study (black and white men and women, average age 40 years). We assessed progression of coronary artery calcification through year 20 (CAC, n=2378), and both carotid artery stenosis (n=2432) and intima media thickness at year 20 (IMT, n = 2240).
Results
Median sICAM-1 was 145.9 ng/ml. Among a subgroup with advanced atherosclerotic plaque (either CAC or stenosis), IMT was 0.010 (95% confidence interval (CI) 0.003–0.017 mm) higher per standard deviation of sICAM-1 (44 ng/ml) in a model adjusted for age, race, sex, clinic, smoking, exercise, body size, education, blood pressure, antihypertensive medication, plasma lipids, and cholesterol lowering medication. With the same adjustment, the odds ratios (OR) for the presence of year 20 carotid artery stenosis per SD of sICAM-1 was 1.12 (CI 1.01–1.25, p<0.04), while for occurrence of CAC progression the OR was 1.16 (CI 1.04–1.31, p<0.01). The associations with CAC and carotid stenosis were strongest in the top 20th of the sICAM-1 distribution.
Conclusion
sICAM-1 concentration may be an early biomarker that indicates changes in the artery wall that accompany atherosclerosis, as well as the presence of advanced plaque in the coronary and carotid arteries. This finding holds in people with low total burden of atherosclerosis, decades prior to the development of clinical CVD.
doi:10.1373/clinchem.2011.168559
PMCID: PMC3867124  PMID: 22179741
12.  Prognosis of Individuals with Asymptomatic Left Ventricular Systolic Dysfunction in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation  2012;126(23):2713-2719.
Background
Limited data exist on the prevalence, associations and prognosis of individuals with asymptomatic left ventricular systolic dysfunction (ALVSD), especially in populations without prior clinical cardiovascular disease (CVD).
Methods and Results
Kaplan-Meier and Cox proportional hazard analyses were used to assess the association between ALVSD, defined as left ventricular ejection fraction less than 50%, and adjudicated incident congestive heart failure (CHF), all-cause mortality, and CVD events.
Out of 5004 participants, 112 participants had CHF, 321 had a CVD event, and 278 died after 9 years of follow-up. The overall prevalence of ALVSD was 1.7%, with a higher prevalence in African Americans (2.6%). ALVSD had worse cardiovascular risk profile and was also associated with increased risk in unadjusted and adjusted models for incident CHF [HR (95%): 12.0(7.04 – 20.3), p<0.0001 and 8.69(4.89 – 15.45), p<0.001 respectively], CVD [HR (95%):3.32(1.98 -5.58), p<0.001 and 2.21(1.30 – 3.73), p=0.003 respectively] and all-cause mortality [HR(95%):3.47(2.03 – 5.94), p<0.0001 and 2.00(1.13-3.54), p=0.017 respectively]. A 10% decrement in LVEF at baseline was associated with increase in risk in unadjusted and adjusted models for clinical CHF [HR (95%CI): 2.17(1.82 -2.63), p<0.0001 and 2.13(1.73 - 2.51), p<0.001 respectively] and all-cause mortality [HR (95%CI): 1.22(1.05 – 1.41), p=0.009 and 1.17(1.00 – 1.36), p=0.047 respectively]. Among the subset of participants with ALVSD, LVMI was particularly informative about risk for incident CHF (c- index = 0.74).
Conclusions
ALVSD is uncommon in individuals without prior clinical CVD, but is associated with high risk for CHF, CVD, and all-cause mortality. LVMI had good discrimination for incident CHF in MESA participants with ALVSD.
doi:10.1161/CIRCULATIONAHA.112.112201
PMCID: PMC3533250  PMID: 23124035
heart failure; death; cardiovascular diseases; magnetic resonance imaging; population
13.  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 MR (CMR) and to assess variation with image acquisition plane, demographics and LV function.
Methods and Results
End-diastolic LVMT was measured on CMR 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±0.9mm and 6.3±1.1mm for women and men, respectively. The average of the maximum LVMT at the mid-cavity for women/men were 7mm/9mm (long axis) and 7mm/8mm (short axis). Mean LVMT was positively associated with weight (0.02mm/kg, p=0.01) and body-surface-area (1.1mm/m2, p<0.001). No relationship was found between mean LVMT and age or height. Greater mean LVMT was associated with lower LV end-diastolic volume (0.01mm/ml, p<0.01), a lower LV end-systolic volume (−0.01mm/ml, p=0.01) and lower LV stroke volume (−0.01mm/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.
Conclusion
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.
doi:10.1161/CIRCIMAGING.112.973560
PMCID: PMC3412148  PMID: 22705587
magnetic resonance imaging; myocardial thickness; normal values
14.  Tongue Adiposity and Strength in Healthy Older Adults 
The Laryngoscope  2012;122(7):1600-1604.
Objectives/Hypothesis
To identify treatable risk factors for aspiration in older adults—particularly those associated with sarcopenia – we examined tongue composition. We hypothesized that 1) isometric and swallowing posterior tongue strength would positively correlate with posterior tongue adiposity, and 2) healthy older adults who aspirate would have greater tongue adiposity than healthy older adults who did not aspirate.
Study Design
Prospective
Methods
Participants were 40 healthy adults, comprised of 20 aspirators (Mean age = 78 years) and 20 non-aspirators (Mean age = 81 years), as identified via flexible endoscopic evaluation of swallowing. Measures of maximal isometric posterior tongue strength and posterior swallowing tongue strength were acquired via tongue manometry. An index of posterior tongue adiposity was acquired via computed tomography for a 1 cm region of interest.
Result(s)
Posterior tongue adiposity was correlated with posterior tongue isometric (r = .32, p = 0.05) but not swallowing pressures (p > 0.05) as examined with separate partial correlation analyses. Tongue adiposity did not significantly differ as a function of age, gender, or aspiration status (p > 0.05).
Conclusion(s)
Lower posterior isometric tongue strength was associated with greater posterior tongue adiposity. However, aspiration in healthy older adults was not affected by posterior tongue adiposity. This finding offers insight into the roles of tongue composition and strength in healthy older adults.
doi:10.1002/lary.23290
PMCID: PMC3474535  PMID: 22522371
Tongue; Adiposity; Fat; Swallowing; Older Adults; Computed Tomography
15.  Impact of HDL genetic risk scores on coronary artery calcified plaque and mortality in individuals with type 2 diabetes from the Diabetes Heart Study 
Background
Patients with type 2 diabetes (T2D) are at elevated risk for cardiovascular disease (CVD) events and mortality. Recent studies have assessed the impact of genetic variants affecting high-density lipoprotein cholesterol (HDL) concentrations on CVD risk in the general population. This study examined the utility of HDL-associated single nucleotide polymorphisms (SNPs) for CVD risk prediction in European Americans with T2D enrolled in the Diabetes Heart Study (DHS).
Methods
Genetic risk scores (GRS) of HDL-associated SNPs were constructed and evaluated for potential associations with mortality and with coronary artery calcified atherosclerotic plaque (CAC), a measure of subclinical CVD strongly associated with CVD events and mortality. Two sets of SNPs were used to construct GRS; while all SNPs were selected primarily for their impacts on HDL, one set of SNPs had pleiotropic effects on other lipid parameters, while the other set lacked effects on low-density lipoprotein cholesterol (LDL) or triglyceride concentrations.
Results
The GRS were specifically associated with HDL concentrations (4.90 × 10-7 < p < 0.02) in models adjusted for age, sex, and body mass index (BMI), but were not associated with LDL or triglycerides. Cox proportional hazards regression analysis suggested the HDL-associated GRS had no impact on risk of CVD-mortality (0.48 < p < 0.99) in models adjusted for other known CVD risk factors. However, associations between several of the GRS and CAC were observed (3.85 × 10-4 < p < 0.03) in models adjusted for other known CVD risk factors.
Conclusions
The GRS analyzed in this study provide a tool for assessment of HDL-associated SNPs and their impact on CVD risk in T2D. The observed associations between several of the GRS and CAC suggest a potential role for HDL-associated SNPs on subclinical CVD risk in patients with T2D.
doi:10.1186/1475-2840-12-95
PMCID: PMC3695806  PMID: 23799899
High-density lipoprotein cholesterol; Type 2 diabetes; Coronary artery calcified plaque; Mortality; Genetic risk score
16.  Aortic Valve Calcium Independently Predicts Coronary and Cardiovascular Events in a Primary Prevention Population 
Jacc. Cardiovascular Imaging  2012;5(6):619-625.
Objective
This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
Background
Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial and it is unknown if this association extends to younger individuals.
Methods
We performed a prospective analysis of 6,685 participants in the Multi-Ethnic Study of Atherosclerosis. All subjects, aged 45-84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium (CAC) scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and non-fatal strokes, resuscitated cardiac arrest and cardiovascular death, while a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers and subclinical coronary atherosclerosis.
Results
Over a median follow up of 5.8 [IQR 5.6, 5.9] years, adjusting for demographics and cardiovascular risk factors, subjects with AVC (n=894, 13.4%) had higher risks of cardiovascular (HR, 1.50; 95% CI, 1.10-2.03) and coronary (HR, 1.72; 95% CI, 1.19-2.49) events compared to those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for CAC substantially attenuated both cardiovascular (HR, 1.32; 95% CI: 0.98-1.78) and coronary (HR, 1.41; 95% CI, 0.98-2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR, 2.51; 95% CI, 1.22-5.21).
Conclusions
In this multiethnic MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation.
doi:10.1016/j.jcmg.2011.12.023
PMCID: PMC3376353  PMID: 22698532
17.  Prediction of Cardiac Events in Patients with Reduced Left Ventricular Ejection Fraction Using Dobutamine Cardiovascular Magnetic Resonance Assessment of Wall Motion Score Index 
Objectives
To assess the utility of dobutamine cardiovascular magnetic resonance (DCMR) results for predicting cardiac events in individuals with reduced left ventricular ejection fraction (LVEF).
Background
It is unknown whether DCMR results identify a poor cardiac prognosis when the resting LVEF is moderately to severely reduced.
Methods
Two-hundred consecutive patients aged 30 to 88 (average 64) years with a LVEF ≤55% that were poorly suited for stress echocardiography, underwent DCMR in which LV wall motion score index (WMSI), defined as the average wall motion of the number of segments scored, was assessed at rest, during low dose, and after peak intravenous infusion of dobutamine/atropine. All participants were followed for an average of 5 years after DCMR to ascertain the post testing occurrence of cardiac death, myocardial infarction (MI), and unstable angina or congestive heart failure warranting hospitalization.
Results
After accounting for risk factors associated with coronary arteriosclerosis and MI, a stress induced increase in WMSI during DCMR was associated with future cardiac events (p< 0.001). After accounting for resting LVEF, a DCMR stress induced change in WMSI added significantly to predicting future cardiac events (p=0.003), but this predictive value was confined primarily to those with a LVEF >40%.
Conclusions
In individuals with mild to moderate reductions in LVEF (40% to 55%), dobutamine induced increases in WMSI forecast MI and cardiac death to a greater extent than an assessment of resting LVEF. In those with a LVEF < 40%, a dobutamine induced increase in WMSI does not predict MI and cardiac death beyond the assessment of resting LVEF.
doi:10.1016/j.jacc.2008.04.025
PMCID: PMC3666037  PMID: 18634983
magnetic resonance imaging; cardiac prognosis; myocardial ischemia; dobutamine stress imaging
18.  Relationship between genetic variants in myocardial sodium and potassium channel genes and QT interval duration in diabetics: the Diabetes Heart Study 
Background
Genetic variants in myocardial sodium and potassium channel genes are associated with prolonged QT interval and increased risk of sudden death. It is unclear whether these genetic variants remain relevant in subjects with underlying conditions such as diabetes that are associated with prolonged QT interval.
Methods
We tested single nucleotide polymorphisms (SNPs) in five candidate genes for association with QT interval in a family-based study of subjects with type 2 diabetes mellitus (T2DM). Thirty-six previously reported SNPs were genotyped in KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 in 901 European Americans from 366 families. The heart rate-corrected (QTc) durations were determined using the Marquette 12SL program. Associations between the QTc interval and the genotypes were evaluated using SOLAR adjusting for age, gender, T2DM status, and body mass index.
Results
Within KCNQ1 there was weak evidence for association between the minor allele of IVS12+14T>C and increased QTc (p=0.02). The minor allele of rs2236609 in KCNE1 trended toward significance with longer QTc (p=0.06), while the minor allele of rs1805123 in HERG trended toward significance with shorter QTc (p=0.07). However, no statistically significant associations were observed between the remaining SNPs and QTc variation.
Conclusions
We found weak evidence of association between three previously-reported SNPs and QTc interval duration. While it appears as though genetic variants in previously identified candidate genes may be associated with QT duration in subjects with diabetes, the clinical implications of these associations in diabetic subjects at high risk for sudden death remains to be determined.
doi:10.1111/j.1542-474X.2008.00276.x
PMCID: PMC3650725  PMID: 19149796
QT interval; diabetes; association study; genetics; ion channels
19.  Metabolic Syndrome, Diabetes, and Incidence and Progression of Coronary Calcium: The Multiethnic Study of Atherosclerosis (MESA) 
Jacc. Cardiovascular Imaging  2012;5(4):358-366.
Objectives
The purpose of the study was to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM), compared to those with neither condition.
Background
MetS and DM are associated with subclinical atherosclerosis as evidenced by coronary artery calcium (CAC).
Methods
The Multiethnic Study of Atherosclerosis included 6,814 African-American, Asian, Caucasian, and Hispanic adults aged 45–84 free of cardiovascular disease at baseline. 5,662 subjects (51% female, mean age 61.0 ± 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac CT scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%), compared to neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years.
Results
Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals) for incident CAC were 1.7 (1.4–2.0), 1.9 (1.4–2.4), and 1.8 (1.4–2.2) (all p<0.01) and absolute differences in mean progression (volume score) were 7.8 (4.0–11.6; p<0.01), 11.6 (2.7–20.5; p<0.05), and 22.6 (17.2–27.9; p<0.01) for those with MetS without DM, DM without MetS, and both DM and MetS, respectively. Similar findings were seen in analysis using Agatston calcium score. In addition, progression predicted CHD events in those with MetS without DM (adjusted hazard ratio 4.1, 95% CI=2.0–8.5, p<0.01) and DM (4.9 [1.3–18.4], p<0.05) among those in highest tertile of CAC increase vs. no increase).
Conclusions
Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared to individuals without these conditions, with progression also predicting CHD events in those with MetS and DM.
doi:10.1016/j.jcmg.2011.12.015
PMCID: PMC3327555  PMID: 22498324
atherosclerosis; diabetes; risk factors; calcification
20.  Genetic analysis of haptoglobin polymorphisms with cardiovascular disease and type 2 diabetes in the diabetes heart study 
Background
Haptoglobin (HP) is an acute phase protein that binds to freely circulating hemoglobin. HP exists as two distinct forms, HP1 and HP2. The longer HP2 form has been associated with cardiovascular (CVD) events and mortality in individuals with type 2 diabetes (T2DM).
Methods
This study examined the association of HP genotypes with subclinical CVD, T2DM risk, and associated risk factors in a T2DM-enriched sample. Haptoglobin genotypes were determined in 1208 European Americans (EA) from 473 Diabetes Heart Study (DHS) families via PCR. Three promoter SNPs (rs5467, rs5470, and rs5471) were also genotyped.
Results
Analyses revealed association between HP2-2 duplication and increased carotid intima-media thickness (IMT; p = 0.001). No association between HP and measures of calcified arterial plaque were observed, but the HP polymorphism was associated with triglyceride concentrations (p = 0.005) and CVD mortality (p = 0.04). We found that the HP2-2 genotype was associated with increased T2DM risk with an odds ratio (OR) of 1.49 (95% CI 1.18-1.86, p = 6.59x10-4). Promoter SNPs were not associated with any traits.
Conclusions
This study suggests association between the HP duplication and IMT, triglycerides, CVD mortality, and T2DM in an EA population enriched for T2DM. Lack of association with atherosclerotic calcified plaque likely reflect differences in the pathogenesis of these CVD phenotypes. HP variation may contribute to the heritable risk for CVD complications in T2DM.
doi:10.1186/1475-2840-12-31
PMCID: PMC3576297  PMID: 23399657
Haptoglobin; Genetic polymorphism; Cardiovascular disease; Type 2 diabetes
21.  Relationships between serum MCP-1 and subclinical kidney disease: African American-Diabetes Heart Study 
BMC Nephrology  2012;13:148.
Background
Monocyte chemoattractant protein-1 (MCP-1) plays important roles in kidney disease susceptibility and atherogenesis in experimental models. Relationships between serum MCP-1 concentration and early nephropathy and subclinical cardiovascular disease (CVD) were assessed in African Americans (AAs) with type 2 diabetes (T2D).
Methods
Serum MCP-1 concentration, urine albumin:creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and atherosclerotic calcified plaque (CP) in the coronary and carotid arteries and infrarenal aorta were measured in 479 unrelated AAs with T2D. Generalized linear models were fitted to test for associations between MCP-1 and urine ACR, eGFR, and CP.
Results
Participants were 57% female, with mean ± SD (median) age 55.6±9.5 (55.0) years, diabetes duration 10.3±8.2 (8.0) years, urine ACR 149.7±566.7 (14.0) mg/g, CKD-EPI eGFR 92.4±23.3 (92.0) ml/min/1.73m2, MCP-1 262.9±239.1 (224.4) pg/ml, coronary artery CP 280.1±633.8 (13.5), carotid artery CP 47.1±132.9 (0), and aorta CP 1616.0±2864.0 (319.0). Adjusting for age, sex, smoking, HbA1c, BMI, and LDL, serum MCP-1 was positively associated with albuminuria (parameter estimate 0.0021, P=0.04) and negatively associated with eGFR (parameter estimate −0.0003, P=0.001). MCP-1 remained associated with eGFR after adjustment for urine ACR. MCP-1 levels did not correlate with the extent of CP in any vascular bed, HbA1c or diabetes duration, but were positively associated with BMI. No interaction between BMI and MCP-1 was detected on nephropathy outcomes.
Conclusions
Serum MCP-1 levels are associated with eGFR and albuminuria in AAs with T2D. MCP-1 was not associated with subclinical CVD in this population. Inflammation appears to play important roles in development and/or progression of kidney disease in AAs.
doi:10.1186/1471-2369-13-148
PMCID: PMC3534523  PMID: 23151275
African Americans; Albuminuria; Atherosclerotic calcified plaque; Diabetes; GFR; MCP-1
22.  ASSOCIATION OF PNPLA3 SNP RS738409 WITH LIVER DENSITY IN AFRICAN AMERICANS WITH TYPE 2 DIABETES MELLITUS 
Diabetes & metabolism  2011;37(5):452-455.
Aim
Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in patients with obesity and type 2 diabetes mellitus (T2DM), and has been associated with the single nucleotide polymorphism (SNP) rs738409 in the PNPLA3 gene. This association remains to be investigated in African Americans with T2DM, a group at lower risk for hepatic steatosis relative to European Americans with T2DM.
Methods
We examined 422 African Americans with T2DM (40.3% male; age: 56.4 ± 9.6 years; BMI: 35.2 ± 8.2 kg/m2), all with measures of liver density reflecting hepatic fat content on abdominal computed tomography, and blood glucose and lipid profiles. Associations between rs738409 and phenotypes of interest were determined using SOLAR, assuming an additive model of inheritance with covariates age, sex, BMI and use of lipid-lowering medications.
Results
Mean ± SD liver density was 55.4 ± 10.2 Hounsfield Units. SNP rs738409 in PNPLA3 was significantly associated with liver density (P=0.0075) and hepatic steatosis (P=0.0350), but not with blood glucose, HbA1c, total cholesterol, triglycerides, high-density or low-density lipoprotein levels or liver function tests (P=0.15–0.96).
Conclusion
These findings provide evidence that the PNPLA3 SNP rs738409 contributes to risk for increased liver fat content in African Americans with T2DM, an effect that appears to be independent from serum lipids. Although African Americans are less susceptible to fatty liver than European Americans, PNPLA3 appears to be a risk locus for hepatic steatosis in diabetic African Americans.
doi:10.1016/j.diabet.2011.05.001
PMCID: PMC3215942  PMID: 21665509
type 2 diabetes; genetics; fatty liver disease; African American
23.  Pericardial Fat is Associated with Carotid Stiffness in the Multi-Ethnic Study of Atherosclerosis 
Background and Aims
Arterial stiffness is a prominent feature of vascular aging and a risk factor for cardiovascular disease (CVD). Fat around the heart and blood vessels (i.e. pericardial fat, Pfat) may contribute to arterial stiffness via a local paracrine effect of adipose tissue on the surrounding vasculature. Thus, we determined the association between Pfat and carotid stiffness in 5,770 participants (mean age 62 yrs, 53% female, 25% African American, 24% Hispanic, and 13% Chinese) from the Multi-Ethnic Study of Atherosclerosis.
Methods and Results
Pfat was measured by computed tomography, and ultrasonography of the common carotid artery was used to calculate the distensibility coefficient (DC) and young’s modulus (YM). Lower DC and higher YM values indicate stiffer arteries. Pfat quartile was highly associated with demographic, behavioral, anthropometric, hemodynamic, metabolic, and disease variables in both men and women. After adjusting for height, clinical site, CVD risk factors, and medications, a 1-standard deviation (41.91 cm3) increment in Pfat was associated with a 0.00007±0.00002 1/mmHg lower DC (p=0.0002) in men and a 48.1±15.1 mmHg/mm higher YM in women (p=0.002). Additional adjustment for C-reactive protein, coronary artery calcification, and carotid intima-media thickness had only modest effects. More importantly, adjusting for body mass index and waist circumference did not significantly change the overall results.
Conclusion
Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.
doi:10.1016/j.numecd.2009.10.010
PMCID: PMC2929306  PMID: 20153618
pericardial fat; arterial stiffness; distensibility; carotid artery
24.  Coronary Calcium Score and Prediction of All-Cause Mortality in Diabetes  
Diabetes Care  2011;34(5):1219-1224.
OBJECTIVE
In diabetes, it remains unclear whether the coronary artery calcium (CAC) score provides additional information about total mortality risk beyond traditional risk factors.
RESEARCH DESIGN AND METHODS
A total of 1,051 participants, aged 34–86 years, in the Diabetes Heart Study (DHS) were followed for 7.4 years. Subjects were separated into five groups using baseline computed tomography scans and CAC scores (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed adjusting for age, sex, race, smoking, and LDL cholesterol to examine the association between CAC and all-cause mortality. Areas under the curve with and without CAC were compared. Natural splines using continuous measures of CAC were fitted to estimate the relationship between observed CAC and mortality risk.
RESULTS
A total of 17% (178 of 1,051) of participants died during the follow-up. In multivariate analysis, the odds ratios (95% CIs) for all-cause mortality, using CAC 0–9 as the reference group, were CAC 10–99: 1.40 (0.57–3.74); CAC 100–299: 2.87 (1.17–7.77); CAC 300–999: 3.04 (1.32–7.90); and CAC ≥1,000: 6.71 (3.09–16.87). The area under the curve without CAC was 0.68 (95% CI 0.66–0.70), and the area under the curve with CAC was 0.72 (0.70–0.74) (P = 0.0001). Using splines, the estimated risk (95% CI) of mortality for a CAC of 0 was 6.7% (4.6–9.7), and the risk increased nearly linearly, plateauing at CAC ≥1,000 (20.0% [15.7–25.2]).
CONCLUSIONS
In diabetes, CAC was shown to be an independent predictor of mortality. Participants with CAC (0–9) were at lower risk (0.9% annual mortality). The risk of mortality increased with increasing levels of CAC, plateauing at approximately CAC ≥1,000 (2.7% annual mortality). More research is warranted to determine the potential utility of CAC scans in diabetes.
doi:10.2337/dc11-0008
PMCID: PMC3114476  PMID: 21398528
25.  Genetic Mapping of Vascular Calcified Plaque Loci on Chromosome 16p in European Americans from the Diabetes Heart Study 
Annals of human genetics  2011;75(2):222-235.
SUMMARY
A carotid artery calcified plaque (CarCP) linkage peak on chromosome 16p (LOD 4.39 at 8.4cM) in European American (EA) families with type 2 diabetes mellitus (T2DM) from the Diabetes Heart Study (DHS) has been refined by fine-mapping and candidate genes and SNPs evaluated for association with subclinical CVD. Fine-mapping was based on 104 SNPs in 937 subjects from 315 families, including 45 SNPs in six candidate genes (CACNA1H, SEPX1, ABCA3, IL32, SOCS1, and KIAA0350). Linkage and association analyses using variance components analysis (SOLAR; adjusting for age, gender, BMI, and T2DM status) refined the original CarCP linkage into two distinct linkage regions (LOD scores: 3.89 at 6.9cM and 4.86 at 16.0cM). Evidence of linkage for coronary calcified plaque (LOD: 2.27 at 19cM) and a vascular calcification principle component (LOD: 3.71 at 16.0cM) was also observed. The strongest evidence for association with CarCP was observed with SNPs in the A2BP1 gene region (rs4337300 p=0.005) with modest evidence of association with SNPs in CACNA1H (p=0.010–0.033). Bayesian Quantitative Trait Nucleotide analysis identified a SNP, rs1358489, with either a functional effect on CarCP or in linkage disequilibrium with a functional SNP. This study refined the 16p region contributing to vascular calcification. Although the causal variants remain to be identified the results are consistent with a linkage peak which is due to multiple common variants, though rare variants cannot be excluded.
doi:10.1111/j.1469-1809.2010.00632.x
PMCID: PMC3074504  PMID: 21309755
type 2 diabetes; subclinical cardiovascular disease; fine mapping

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