Gregory L. Kinney

Low Plasma Adiponectin Levels Predict Progression of Coronary Artery Calcification

Background—Circulating adiponectin levels are lower in men than in women and lower in advanced coronary artery disease, obesity, and type 2 but not type 1 diabetes. However, it is not known whether low adiponectin levels predict development of atherosclerosis independently of other cardiovascular risk factors. Methods and Results—Progression of coronary artery calcification (CAC) over an average of 2.6 years (range, 1.6 to 3.3) was assessed in a cohort of patients with type 1 diabetes and nondiabetic subjects 19 to 59 years of age. In this nested case-control substudy, plasma adiponectin levels were measured in 101 cases with significant CAC progression and in 205 controls. Controls were oversampled on the basis of age, gender, diabetes status, and presence of baseline CAC. In conditional logistic regression adjusted for baseline CAC volume and other significant predictors of CAC progression, adiponectin levels were inversely related to progression of CAC in diabetic (OR, 0.47; 95% CI, 0.24 to 0.94) and nondiabetic (OR, 0.15; 95% CI, 0.05 to 0.40 for a doubling in adiponectin levels) subjects. Adjustment for additional cardiovascular risk factors did not change this association. In conditional logistic regression models by quartiles of plasma adiponectin levels, the probability value for trend was statistically significant for all participants (P<0.001) and nondiabetic participants (P<0.001) and was borderline for type 1 diabetics (P=0.08). Conclusions—Low plasma adiponectin levels are associated with progression of CAC in type 1 diabetic and nondiabetic subjects independently of other cardiovascular risk factors.

Prevalence and Correlates of Depression in Individuals With and Without Type 1 Diabetes

OBJECTIVE Depression is associated with poor glycemic control and complications in people with type 1 diabetes. We assessed the prevalence of depression and antidepressant medication use among adults with and without type 1 diabetes and the association between depression and diabetes complications. RESEARCH DESIGN AND METHODS In 2006–2008, the Coronary Artery Calcification in Type 1 Diabetes Study applied the Beck Depression Inventory II (BDI-II) to 458 participants with type 1 diabetes (47% male, aged 44 ± 9 years, type 1 diabetes duration 29 ± 9 years) and 546 participants without diabetes (nondiabetic group) (51% male, aged 47 ± 9 years). Use of antidepressant medication was self-reported. Depression was defined as a BDI-II score >14 and/or use of antidepressant medication. Occurrence of diabetes complications (retinopathy, blindness, neuropathy, diabetes-related amputation, and kidney or pancreas transplantation) was self-reported. RESULTS Mean BDI-II score, adjusted for age and sex, was significantly higher in participants with type 1 diabetes than in nondiabetic participants (least-squares mean ± SE: 7.4 ± 0.3 vs. 5.0 ± 0.3; P < 0.0001). Type 1 diabetic participants reported using more antidepressant medications (20.7 vs. 12.1%, P = 0.0003). More type 1 diabetic than nondiabetic participants were classified as depressed by BDI-II cut score (17.5 vs. 5.7%, P < 0.0001) or by either BDI-II cut score or antidepressant use (32.1 vs. 16.0%, P < 0.0001). Participants reporting diabetes complications (n = 209) had higher mean BDI-II scores than those without complications (10.7 ± 9.3 vs. 6.4 ± 6.3, P < 0.0001). CONCLUSIONS Compared with nondiabetic participants, adults with type 1 diabetes report more symptoms of depression and more antidepressant medication usage. Depression is highly prevalent in type 1 diabetes and requires further study on assessment and treatment.

Evaluation of Urinary Biomarkers for Coronary Artery Disease, Diabetes, and Diabetic Kidney Disease

BACKGROUND In this study we sought to validate urinary biomarkers for diabetes and two common complications, coronary artery disease (CAD) and diabetic nephropathy (DN). METHODS A CAD score calculated by summing the product of a classification coefficient and signal amplitude of 15 urinary polypeptides was previously developed. Five sequences of biomarkers in the panel were identified as fragments of collagen alpha-1(I) and alpha-1(III). Prospectively collected urine samples available for analysis from 19 out of 20 individuals with CAD (15 with type 1 diabetes [T1D] and four without diabetes) and age-, sex-, and diabetes-matched controls enrolled in the Coronary Artery Calcification in Type 1 Diabetes study were analyzed for the CAD score using capillary electrophoresis and electrospray ionization mass spectrometry. Two panels of biomarkers that were previously defined to distinguish diabetes status were analyzed to determine their relationship to T1D. Three biomarker panels developed to distinguish DN (DNS) and two biomarker panels developed to distinguish renal disease (RDS) were examined to determine their relationship with renal function. RESULTS The CAD score was associated with CAD (odds ratio with 95% confidence interval, 2.2 [1.3-5.2]; P = 0.0016) and remained significant when adjusted individually for age, albumin excretion rate (AER), blood pressure, waist circumference, intraabdominal fat, glycosylated hemoglobin, and lipids. DNS and RDS were significantly correlated with AER, cystatin C, and serum creatinine. The biomarker panels for diabetes were both significantly associated with T1D status (P < 0.05 for both). CONCLUSIONS We validated a urinary proteome pattern associated with CAD and urinary proteome patterns associated with T1D and DN.

Coronary artery and thoracic calcium on noncontrast thoracic CT scans: Comparison of ungated and gated examinations in patients from the COPD Gene cohort

OBJECTIVE Coronary artery calcification (CAC) and thoracic aortic calcification, (TAC) are frequently detected on ungated multidetector computed tomography (MDCT) performed for lung evaluations. We sought to evaluate concordance of CAC and TAC scores on ungated (thoracic) and electrocardiogaphically (ECG)-gated (cardiac) MDCT scans. METHODS Fifty patients, enrolled in the Genetic Epidemiology of COPD study (COPDGene), were recruited to undergo gated CAC scans with 64-detector row CT, in addition to the ungated thoracic studies already being obtained as part of their study evaluation. Coronary and thoracic calcium were measured similarly (Agatston score, requiring 3 contiguous voxels of >130 Hounsfield units) with low-dose ungated studies and ECG-gated MDCT performed at the same scanning session. Intertechnique scoring variability and concordance were calculated. RESULTS Correlations between gated and ungated CAC and TAC were excellent (r = 0.96). The relative differences (median variability) measured by ECG-gated versus ungated MDCT were relatively high for CAC (44%) but not for TAC (8%). Prevalence of depicted CAC (n = 33; 66%) and TAC (n = 21; 42%) were coincident between ECG-gated and ungated MDCT, respectively (intertechnique concordance, 100%). Bland-Altman plots for CAC showed mean differences of 354 (confidence interval, 169-538) and 16.1 (confidence interval, -89 to 121). CONCLUSION Low-dose ungated MDCT is reliable for prediction of the presence of CAC and assessment of Agatston score. Concordance between methods and between TAC and CAC is high. This technique should allow for atherosclerotic disease risk stratification among patients undergoing ungated lung CT evaluation without requiring additional scanning. Measurement of TAC is almost as accurate from gated CT, and CAC scores are highly concordant.

Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease.

RATIONALE The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Serum Cystatin C Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals With Type 1 Diabetes

OBJECTIVE—Renal function is an important determinant of coronary atherosclerosis, and serum cystatin C is a novel accurate measure of glomerular filtration rate (GFR) and a predictor of cardiovascular events and mortality. We hypothesized that in individuals with type 1 diabetes, cystatin C would 1) predict progression of subclinical coronary atherosclerosis (SCA) and 2) be a stronger predictor of SCA than serum creatinine, GFR (estimated by the Cockcroft-Gault [GFRCG] and Modification of Diet in Renal Disease [GFRMDRD] formulas), and albumin excretion rate. RESEARCH DESIGN AND METHODS—Coronary artery calcification was measured twice, using Imatron C-150 Ultrafast CT, over a 2.5 ± 0.4-year interval in 509 adults with type 1 diabetes (42% male, age 36 ± 9 years, duration 23 ± 9 years). SCA progression (n = 131) was defined as a >2.5 increase in square root calcium volume score or development of clinical coronary artery disease. Predictors of SCA progression were examined in a model selected by stepwise logistic regression and an a priori–determined model. Next, each measure of renal function was inserted into the stepwise model, one at a time, and Akaike information criterion was used to compare the fit of the competing models. RESULTS—The stepwise model included cystatin C (odds ratio 1.44, 95% CI 1.00–2.18, P = 0.048), age, baseline coronary artery calcification, sex, diabetes duration, systolic blood pressure, and HDL. The stepwise model had a better fit than any of the competing models with serum creatinine, GFRCG, GFRMDRD, or albumin excretion rate replacing cystatin C. CONCLUSIONS—In individuals with type 1 diabetes, cystatin C modestly predicts SCA.

Computed Tomographic Measures of Pulmonary Vascular Morphology in Smokers and Their Clinical Implications

RATIONALE Angiographic investigation suggests that pulmonary vascular remodeling in smokers is characterized by distal pruning of the blood vessels. OBJECTIVES Using volumetric computed tomography scans of the chest we sought to quantitatively evaluate this process and assess its clinical associations. METHODS Pulmonary vessels were automatically identified, segmented, and measured. Total blood vessel volume (TBV) and the aggregate vessel volume for vessels less than 5 mm(2) (BV5) were calculated for all lobes. The lobe-specific BV5 measures were normalized to the TBV of that lobe and the nonvascular tissue volume (BV5/T(issue)V) to calculate lobe-specific BV5/TBV and BV5/T(issue)V ratios. Densitometric measures of emphysema were obtained using a Hounsfield unit threshold of -950 (%LAA-950). Measures of chronic obstructive pulmonary disease severity included single breath measures of diffusing capacity of carbon monoxide, oxygen saturation, the 6-minute-walk distance, St Georges Respiratory Questionnaire total score (SGRQ), and the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index. MEASUREMENTS AND MAIN RESULTS The %LAA-950 was inversely related to all calculated vascular ratios. In multivariate models including age, sex, and %LAA-950, lobe-specific measurements of BV5/TBV were directly related to resting oxygen saturation and inversely associated with both the SGRQ and BODE scores. In similar multivariate adjustment lobe-specific BV5/T(issue)V ratios were inversely related to resting oxygen saturation, diffusing capacity of carbon monoxide, 6-minute-walk distance, and directly related to the SGRQ and BODE. CONCLUSIONS Smoking-related chronic obstructive pulmonary disease is characterized by distal pruning of the small blood vessels (<5 mm(2)) and loss of tissue in excess of the vasculature. The magnitude of these changes predicts the clinical severity of disease.

Association Between Interstitial Lung Abnormalities and All-Cause Mortality

IMPORTANCE Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated. OBJECTIVE To investigate whether interstitial lung abnormalities are associated with increased mortality. DESIGN, SETTING, AND POPULATION Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006). EXPOSURES Interstitial lung abnormality status as determined by chest CT evaluation. MAIN OUTCOMES AND MEASURES All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. RESULTS Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. CONCLUSIONS AND RELEVANCE In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

Measurement of abdominal fat by CT compared to waist circumference and BMI in explaining the presence of coronary calcium

OBJECTIVE: To evaluate the association between standard and computed tomography (CT)-based measures of obesity and subclinical atherosclerosis, defined as coronary artery calcium (CAC) by Electron Beam Computed Tomography (EBCT).DESIGN: Cross-sectional, observational study of anthropometric and CT obesity measures and presence of CAC.SUBJECTS: Participants were 383 men and 379 women, aged 20–58 y and asymptomatic for coronary artery disease (CAD).MEASUREMENTS: Intra-abdominal fat (IAF) and subcutaneous fat (SQF) were measured at the level of lumbar 2–3 and 4–5 spaces, using EBCT. Body mass index (BMI) was calculated from height and weight, and minimum waist circumference and maximum hip circumference were measured. CAC was measured by EBCT.RESULTS: In both men and women, BMI, waist circumference, IAF, and SQF were significantly related to CAC. However, BMI or waist circumference explained variation in the presence of CAC as well as IAF or SQF, univariately and after adjustment for additional cardiovascular risk factors.CONCLUSION: CT-based obesity exposure measures are not superior to BMI or waist circumference in association studies of subclinical CAD.

Serum Uric Acid Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals without Renal Disease

OBJECTIVE To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. RESEARCH DESIGN AND METHODS CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0 ± 0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate. RESULTS In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07–1.58], P = 0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome. CONCLUSIONS Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease.