Christina L. Wassel

Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events

IMPORTANCE Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD. OBJECTIVE To determine the independent associations of CAC volume and CAC density with incident CVD events. DESIGN, SETTING, AND PARTICIPANTS Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010. MAIN OUTCOMES AND MEASURES Incident coronary heart disease (CHD) and all CVD events RESULTS During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02. CONCLUSIONS AND RELEVANCE CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.

Fetuin-A and Incident Diabetes Mellitus in Older Persons

CONTEXT Fetuin-A is a hepatic secretory protein that binds the insulin receptor and inhibits insulin action in vitro. In prior cross-sectional studies in humans, higher fetuin-A levels were associated with insulin resistance. However, the longitudinal association of fetuin-A with incident type 2 diabetes mellitus is unknown. OBJECTIVE To determine whether fetuin-A levels are associated with incident diabetes in older persons. DESIGN, SETTING, AND PARTICIPANTS Observational study among 3075 well-functioning persons aged 70 to 79 years. In this case-cohort study, we retrospectively measured fetuin-A levels in baseline serum among 406 randomly selected participants without prevalent diabetes, and all participants who developed incident diabetes mellitus during a 6-year follow-up (to August 31, 2005). MAIN OUTCOME MEASURE Incident diabetes mellitus. RESULTS Incident diabetes developed in 135 participants (10.1 cases/1000 person-years). Participants with fetuin-A levels within the highest tertile (> 0.97 g/L) had an increased risk of incident diabetes (13.3 cases/1000 person-years) compared with participants in the lowest tertile (< or = 0.76 g/L) (6.5 cases/1000 person-years) in models adjusted for age, sex, race, waist circumference, body weight, physical activity, blood pressure level, fasting glucose level, high-density lipoprotein cholesterol concentration, triglyceride concentration, and C-reactive protein level (adjusted hazard ratio, 2.41; 95% confidence interval, 1.28-4.53; P = .007). The association was not affected by adipocytokine levels but was moderately attenuated by adjustment for visceral adiposity (adjusted hazard ratio of highest vs lowest tertile 1.72; 95% confidence interval, 0.98-3.05; P = .06). CONCLUSION Among well-functioning older persons, serum fetuin-A is associated with incident diabetes, independent of other markers of insulin resistance.

Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease

Diabetic kidney disease is the leading cause of ESRD, but few biomarkers of diabetic kidney disease are available. This study used gas chromatography-mass spectrometry to quantify 94 urine metabolites in screening and validation cohorts of patients with diabetes mellitus (DM) and CKD(DM+CKD), in patients with DM without CKD (DM-CKD), and in healthy controls. Compared with levels in healthy controls, 13 metabolites were significantly reduced in the DM+CKD cohorts (P≤0.001), and 12 of the 13 remained significant when compared with the DM-CKD cohort. Many of the differentially expressed metabolites were water-soluble organic anions. Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduced levels of urinary organic acids, and human kidney tissue from patients with diabetic nephropathy demonstrated lower gene expression of OAT1 and OAT3. Analysis of bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism and suggested global suppression of mitochondrial activity in diabetic kidney disease. Supporting this analysis, human diabetic kidney sections expressed less mitochondrial protein, urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1α (a master regulator of mitochondrial biogenesis). We conclude that urine metabolomics is a reliable source for biomarkers of diabetic complications, and our data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.

Fibroblast growth factor-23 and early decrements in kidney function: the Heart and Soul Study.

BACKGROUND Fibroblast growth factor-23 (FGF-23) is associated with mortality in dialysis patients, and concentrations are elevated in moderate chronic kidney disease (CKD). The threshold of CKD or albuminuria at which FGF-23 begins to change is unknown. METHODS In 792 outpatients with stable cardiovascular disease (CVD) and normal kidney function to moderate CKD, we evaluate the associations of estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) with plasma FGF-23 concentrations. RESULTS Compared to participants with eGFR >or=90 ml/min/1.73 m(2), mean FGF-23 concentrations were 7.8 RU/ml higher (4.3-11.5, P = 0.01) in those with eGFR 60-89 ml/min/1.73 m(2) in models adjusted for age, sex, race, ACR, blood pressure, diabetes and body mass index. More advanced decrements in eGFR were associated with much higher FGF-23 concentrations. In spline analysis, the slope of change in FGF-23 concentration was evident at eGFR <90 ml/min/1.73 m(2). Compared to participants with ACR <30 mg/g, mean FGF-23 concentrations were 18.4 RU/ml higher (9.3-29.2, P < 0.001) in those with ACR 30-299 mg/g in models adjusted for identical covariates plus eGFR and much higher in individuals with ACR >or=300 mg/g. Spline analysis demonstrated a linear relationship of ACR with FGF-23, independent of eGFR, even among persons with ACR <30 mg/g. CONCLUSION Modest decrements in eGFR or elevations in albuminuria are each independently associated with higher FGF-23 concentrations in outpatients with stable CVD.

Calcified Atherosclerosis in Different Vascular Beds and the Risk of Mortality

Objective— The goal of this study was to determine differences in risks for total and cause-specific mortality related to calcified atherosclerosis in different vascular beds. Methods and Results— A total of 4544 patients underwent computed tomography scans that were interrogated for calcium in different vascular beds. Mortality assessment was conducted by death certificate adjudication. At baseline, the mean age was 56.8 years, and 43% were female. After an average of 7.8 years, there were 163 deaths. With full adjustment, the presence of calcium in the thoracic aorta (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2–3.5), carotids (HR, 1.60; CI, 1.1–2.5), and iliac (HR, 1.67; CI, 1.0–2.9) arteries were associated with total mortality, whereas the presence of coronary calcium was associated with cardiovascular disease (CVD) mortality (HR, 3.4; CI, 0.8–10.9). For severity of calcium burden, a 1-SD increment in the iliac arteries was the strongest predictor for all types of mortality. C-statistics were not significantly larger when noncoronary vascular beds were added to models with CVD risk factors or CVD risk factors plus coronary artery calcium. Conclusion— The associations between calcified atherosclerosis and mortality differ by vascular bed, suggesting that the location and severity of calcification in different vascular beds provide unique information for mortality.

Prevalence and Correlates of Diabetes in South Asian Indians in the United States: Findings From the Metabolic Syndrome and Atherosclerosis in South Asians Living in America Study and the Multi-Ethnic Study of Atherosclerosis

BACKGROUND Individuals from South Asia have high diabetes prevalence despite low body weight. We compared the prevalence of diabetes among South Asian Indians with other U.S. ethnic groups and explored correlates of diabetes. METHODS This was a cross-sectional study of 150 South Asian Indians (ages 45-79) in California, using similar methods to the Multi-Ethnic Study of Atherosclerosis (MESA). Type 2 diabetes was classified by fasting plasma glucose (FPG) >or=126 mg/dL, 2-h postchallenge glucose >or=200 mg/dL, or use of hypoglycemic medication. RESULTS A total of 29% of Asian Indians had diabetes, 37% had prediabetes, and 34% had normal glucose tolerance. After full adjustment for covariates, Indians still had significantly higher odds of diabetes compared to whites and Latinos, but not significantly different from African Americans and Chinese Americans in MESA: Indians [odds ratio (OR), 1.0], whites [OR, 0.29; 95% confidence interval (CI), 0.17-0.49], Latinos (OR, 0.59; CI, 0.34-1.00) African Americans (OR, 0.77; CI 0.45-1.32), Chinese Americans (OR, 0.78, CI, 0.45-1.32). Variables associated with prediabetes or diabetes among Indians included hypertension, fatty liver, visceral adiposity, microalbuminuria, carotid intima media thickness, and stronger traditional Indian beliefs. CONCLUSIONS Indian immigrants may be more likely to have diabetes than other U.S. ethnic groups, and cultural factors may play a role, suggesting that this is a promising area of research.

Equations to Estimate Creatinine Excretion Rate: The CKD Epidemiology Collaboration

BACKGROUND AND OBJECTIVES Creatinine excretion rate (CER) indicates timed urine collection accuracy. Although equations to estimate CER exist, their bias and precision are untested and none simultaneously include age, sex, race, and weight. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Participants (n = 2466) from three kidney disease trials were randomly allocated into equation development (2/3) and internal validation (1/3) data sets. CER served as the dependent variable in linear regression to develop new equations. Their stability was assessed within the internal validation data set. Among 987 individuals from three additional studies the equations were externally validated and compared with existing equations. RESULTS Mean age was 46 years, 42% were women, and 9% were black. Age, sex, race, weight, and serum phosphorus improved model fit. Two equations were developed, with or without serum phosphorus. In external validation, the new equations showed little bias (mean difference [measured - estimated CER] -0.7% [95% confidence interval -2.5% to 1.0%] and 0.3% [95% confidence interval -2.6% to 3.1%], respectively) and moderate precision (estimated CER within 30% of measured CER among 79% [76% to 81%] and 81% [77% to 85%], respectively). Corresponding numbers within 15% were 51% [48% to 54%] and 54% [50% to 59%]). Compared with existing equations, the new equations had similar accuracy but showed less bias in individuals with high measured CER. CONCLUSIONS CER can be estimated with commonly available variables with little bias and moderate precision, which may facilitate assessment of accuracy of timed urine collections.

Urinary Creatinine Excretion Rate and Mortality in Persons With Coronary Artery Disease The Heart and Soul Study

Background— In persons with coronary artery disease, low body mass index is associated with greater mortality; however, it is uncertain whether low muscle mass is a risk factor for mortality in this setting. Methods and Results— In this study, 903 individuals with coronary artery disease provided 24-hour urine collections. We measured urine creatinine and volume and calculated creatinine excretion rate, a marker of muscle mass. Cox proportional-hazards models evaluated the association of creatinine excretion rate with mortality risk. Over a median follow-up of 6.0 years, 232 participants (26%) died. Compared with the highest sex-specific creatinine excretion rate tertile, the lowest tertile (<1068 mg/d in men, <766 mg/d in women) was associated with >2-fold risk of mortality (hazard ratio, 2.30; 95% confidence interval, 1.51 to 3.51) in models adjusted for age, sex, race, cystatin C–based estimated glomerular filtration rate, body mass index, traditional cardiovascular disease risk factors, and C-reactive protein levels. The association was essentially unaltered with further adjustment for physical fitness, left ventricular mass, left ventricular ejection fraction, or fasting insulin and glucose levels. Conclusions— Lower creatinine excretion rate is strongly associated with mortality in outpatients with coronary artery disease, independently of conventional measures of body composition, kidney function, and traditional coronary artery disease risk factors. Future studies should determine whether low creatinine excretion rate may be a modifiable risk factor for mortality among persons with coronary artery disease, potentially through resistive exercise training or nutrition interventions.

Genetic Ancestry Is Associated With Subclinical Cardiovascular Disease in African-Americans and Hispanics From the Multi-Ethnic Study of Atherosclerosis

Background— Differences in cardiovascular disease (CVD) burden exist among racial/ethnic groups in the United States, with African-Americans having the highest prevalence. Subclinical CVD measures have also been shown to differ by race or ethnicity. In the United States, there has been a significant intermixing among racial/ethnic groups creating admixed populations. Very little research exists on the relationship of genetic ancestry and subclinical CVD measures. Methods and Results— These associations were investigated in 712 black and 705 Hispanic participants from the Multi-Ethnic Study of Atherosclerosis candidate gene substudy. Individual ancestry was estimated from 199 genetic markers using STRUCTURE. Associations of ancestry and coronary artery calcium (CAC) and common and internal carotid intima media thickness were evaluated using log-binomial and linear regression models. Splines indicated linear associations of ancestry with subclinical CVD measures in African-Americans but presence of threshold effects in Hispanics. Among African-Americans, each SD increase in European ancestry was associated with an 8% (95% CI, 1.02 to 1.15; P=0.01) higher CAC prevalence. Each SD increase in European ancestry was also associated with a 2% (95% CI −3.4% to −0.5%, P=0.008) lower common carotid intima media thickness in African-Americans. Among Hispanics, the highest tertile of European ancestry was associated with a 34% higher CAC prevalence (P=0.02) when compared with the lowest tertile. Conclusions— The linear association of ancestry and subclinical CVD suggests that genetic effects may be important in determining CAC and carotid intima media thickness among African-Americans. Our results also suggest that CAC and common carotid intima media thickness may be important phenotypes for further study with admixture mapping.

Blood Pressure and Vascular Calcification

The aim of this study was to determine the associations between the presence and extent of calcified atherosclerosis in multiple vascular beds and systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, isolated systolic hypertension, and hypertension. A total of 9510 patients (42.5% women) underwent electron beam computed tomography scanning as part of a routine health maintenance screening. At the same visit, blood pressure was measured with the participant in the seated position using a mercury sphygmomanometer. Mean age was 58±11.4 years, and body mass index was 27.1±4.5. The prevalences of any calcification in the carotids, coronaries, subclavians, thoracic aorta, abdominal aorta, and iliacs were 31.9%, 57.2%, 31.7%, 37.0%, 54.3%, and 48.8%, respectively. In separate multivariable logistic models containing traditional cardiovascular disease risk factors, pulse pressure and systolic blood pressure were significantly associated with the presence of calcification in all of the vascular beds except the iliacs and subclavians, respectively, with pulse pressure having stronger magnitudes of the associations for most of the vascular beds. Age-stratified analyses indicated that these associations were stronger in those >60 years of age compared with subjects <60 years of age, and sex-stratified analyses demonstrated that men had a greater association compared with women. Also, the magnitudes of the associations for isolated systolic hypertension were, in general, larger than those for hypertension. Pulse pressure and isolated systolic hypertension are robust and important correlates for calcified atherosclerosis in different vascular beds. Isolated systolic hypertension may be clinically relevant in diagnosing or preventing calcified atherosclerosis.