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.

White blood cell count in young adulthood and coronary artery calcification in early middle age: coronary artery risk development in young adults (CARDIA) study.

White blood cell (WBC) count is associated with incident coronary heart disease (CHD). Data are sparse regarding its association in young adults with future coronary artery calcification (CAC). Our study was conducted among coronary artery risk development in young adults (CARDIA) participants (n=3,094). We examined the association between baseline (Y0) WBC counts and CHD risk factors using linear regression models. We further assessed prospective associations between Y0 WBC and inflammatory biomarkers during the follow-up, and the presence of CAC 15 and 20 years later. In total, 272 and 566 subjects had CAC scores>0 at year (Y) 15 and Y20, respectively. Baseline total WBC counts were cross-sectionally associated with SBP, BMI, and smoking, or HDL-cholesterol (p≤0.01) at Y0, and prospectively associated with C-reactive protein at Y7, Y15, and Y20, and fibrinogen at Y5 and Y20 (p<0.01). After adjustment for potential confounding factors, baseline neutrophil count was borderline associated with CAC presence 15 years later (OR=1.18 per unit, 95% CI 1.00-1.44) and total WBC (OR=1.07, 95% CI 0.96-1.19) or eosinophil (OR=1.12, 95%CI 1.00-1.25) was borderline associated with CAC presence at Y20. Baseline total WBC counts in young adults was associated prospectively with CAC presence 20 years later after adjusting for age, sex, and race. Results are attenuated when other risk factors are accounted for. Our results suggest the possible early involvement of WBC, particularly eosinophils, in the early stages of atherosclerosis.

High-sensitivity C-reactive protein as an independent predictor of progressive myocardial functional deterioration: the multiethnic study of atherosclerosis.

BACKGROUND: Systemic inflammation has been linked to the development of heart failure in population studies including Multi-Ethnic Study of Atherosclerosis (MESA), but little evidence exists regarding potential mechanism of this relationship. In this study, we used longitudinal magnetic resonance imaging follow-up analysis to examine whether C-reactive protein (CRP) levels relate to progressive myocardial functional deterioration as a potential mechanism of incident heart failure. METHODS: Regional myocardial functional data from MESA participants who had baseline CRP measurement and also underwent tagged cardiac magnetic resonance imaging both at baseline and at 5-year follow-up were analyzed. Left ventricular midwall and midslice peak circumferential strain (Ecc), of which a more negative value denotes stronger regional myocardial function, was measured. Circumferential strain change was calculated as the difference between baseline and follow-up Ecc. RESULTS: During the follow-up period, participants (n = 785) with elevated CRP experienced a decrease in strain, independent of age, gender, and ethnicity (B = 0.081, ∆Ecc change per 1 mg/L CRP change, 95% CI 0.036-0.126, P < .001, model 1) and, additionally, beyond systolic blood pressure, heart rate, diabetes, smoking status, body mass index, current medication, and glomerular filtration rate (B = 0.099, 0.052-0.145, P < .001, model 2). The relationship remained statistically significant after further adjustment for left ventricular mass, coronary calcium score, and interim clinical coronary events (B = 0.098, 0.049-0.147, P < .001, model 3). CONCLUSION: Higher CRP levels are related to progressive myocardial functional deterioration independent of subclinical atherosclerosis and clinical coronary events in asymptomatic individuals without previous history of heart disease.

Risk factor differences for aortic versus coronary calcified atherosclerosis: the multiethnic study of atherosclerosis.

OBJECTIVE: The goal of this study was to compare and contrast coronary artery calcium (CAC) with abdominal aortic calcium (AAC) in terms of their associations with traditional and novel cardiovascular disease (CVD) risk factors. METHODS AND RESULTS: We measured both AAC and CAC using computed tomography scans in 1974 men and women aged 45 to 84 years from a multiethnic cohort. Traditional and novel CVD risk factors were examined separately in relation to AAC and CAC, using logistic regression for qualitative categorical comparisons and multiple linear regression for quantitative continuous comparisons. AAC was significantly associated with cigarette smoking and dyslipidemia and showed no gender difference. In contrast, CAC showed much weaker associations with smoking and dyslipidemia and a strong male predominance. Age and hypertension were associated similarly and significantly with AAC and CAC. Novel risk factors generally showed no independent association with either calcium measure, although in subset analyses, phosphorus, but not calcium, was related to CAC. The receiver operating characteristic curves for the qualitative results and the r(2) values for the quantitative analyses were both much higher for AAC than for CAC. CONCLUSIONS: AAC showed stronger correlations with most CVD risk factors than did CAC. The predictive value of AAC compared with CAC for incident CVD events remains to be evaluated.

Stochastic tissue window normalization of deep learning on computed tomography.

Tissue window filtering has been widely used in deep learning for computed tomography (CT) image analyses to improve training performance (e.g., soft tissue windows for abdominal CT). However, the effectiveness of tissue window normalization is questionable since the generalizability of the trained model might be further harmed, especially when such models are applied to new cohorts with different CT reconstruction kernels, contrast mechanisms, dynamic variations in the acquisition, and physiological changes. We evaluate the effectiveness of both with and without using soft tissue window normalization on multisite CT cohorts. Moreover, we propose a stochastic tissue window normalization (SWN) method to improve the generalizability of tissue window normalization. Different from the random sampling, the SWN method centers the randomization around the soft tissue window to maintain the specificity for abdominal organs. To evaluate the performance of different strategies, 80 training and 453 validation and testing scans from six datasets are employed to perform multiorgan segmentation using standard 2D U-Net. The six datasets cover the scenarios, where the training and testing scans are from (1) same scanner and same population, (2) same CT contrast but different pathology, and (3) different CT contrast and pathology. The traditional soft tissue window and nonwindowed approaches achieved better performance on (1). The proposed SWN achieved general superior performance on (2) and (3) with statistical analyses, which offers better generalizability for a trained model.

Body Composition and Diabetes Risk in South Asians: Findings From the MASALA and MESA Studies.

OBJECTIVE: South Asians have a higher prevalence of type 2 diabetes compared with other race/ethnic groups. Body composition is associated with the risk for type 2 diabetes. Differences in body composition between South Asians and other race/ethnic groups are one hypothesized mechanism to explain the disproportionate prevalence of type 2 diabetes in this population. RESEARCH DESIGN AND METHODS: This study used data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) and the Multi-Ethnic Study of Atherosclerosis (MESA) cohorts to determine whether body composition mediated the elevated prevalence of impaired fasting glucose and type 2 diabetes in South Asians. Participants (n = 2,615) with complete body composition data were included. Ordinal logistic regression models were calculated to determine the odds for glycemic impairment in South Asians compared with the MESA cohort. RESULTS: In multivariate models, South Asians had a significantly higher prevalence of glycemic impairment and type 2 diabetes compared with all four race/ethnic groups included in the MESA (P < 0.001 for all). In unadjusted and multivariate adjusted models, South Asians had higher odds for impaired fasting glucose and type 2 diabetes compared with all other race/ethnic groups (P < 0.001 for all). The addition of body composition measures did not significantly mitigate this relationship. CONCLUSIONS: We did not identify strong evidence that accounting for body composition explains differences in the risk for type 2 diabetes. Future prospective studies of the MESA and MASALA cohorts are needed to understand how adipose tissue impacts the risk for type 2 diabetes and how to best assess this risk.

Echocardiographic Pulmonary Artery Systolic Pressure in the Coronary Artery Risk Development in Young Adults (CARDIA) Study: Associations With Race and Metabolic Dysregulation.

BACKGROUND: The determinants of pulmonary artery systolic pressure (PASP) are not fully understood. It is unknown whether racial differences in PASP exist or if other population characteristics are associated with pulmonary pressure in humans. We examined echocardiographically estimated PASP in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a middle-aged, biracial community-based cohort. METHODS AND RESULTS: At the CARDIA year-25 examination, 3469 participants underwent echocardiography, including measurement of tricuspid regurgitant jet velocity to estimate PASP. Clinical features, laboratory values, pulmonary function tests, and measurement of adipose depot volume were analyzed for association with PASP. PASP was estimated in 1311 individuals (61% female, 51% white). Older age, higher blood pressure, and higher body mass index were associated with higher PASP. Black race was associated with higher PASP after adjustment for demographics and left and right ventricular function (ß 0.94, 95% CI 0.24-1.64; P=0.009), but this association was no longer significant after further adjustment for lung volume (ß 0.42, 95% CI -0.68 to 0.96; P=0.74). Insulin resistance, inflammation (C-reactive protein and interleukin-6), and visceral adipose volume were independently associated with higher PASP after adjustment for relevant covariates. PASP rose with worsening diastolic function (ratio of early transmitral Doppler velocity to average mitral annular tissue Doppler velocity [E/e'] and left atrial volume index). CONCLUSIONS: In a large biracial cohort of middle-aged adults, we identified associations among black race, insulin resistance, and diastolic dysfunction with higher echocardiographically estimated PASP. Further studies are needed to examine racial differences in PASP and whether insulin resistance directly contributes to pulmonary vascular disease in humans.

Is alcohol consumption associated with calcified atherosclerotic plaque in the coronary arteries and aorta?

BACKGROUND: The goal was to investigate the relation of alcohol consumption to the presence of calcified atherosclerotic plaque in the coronary arteries (CAC) and aorta. Previous results have been conflicting, showing increases, decreases, or no effect of alcohol on risk of calcified plaque. METHODS: We evaluated the relation of alcohol intake to presence of CAC and calcified plaque in the aorta among 3166 white and African American subjects from the NHLBI Family Heart Study who underwent cardiac computed tomography scans. RESULTS: With adjustments for age, race, study center, body mass index, hyperglycemia/diabetes, hypertension, and smoking, odds ratios (and 95% CI) for CAC scores >100 in nondrinkers and consumers of 1 to 3, 4 to 7, 8 to 14, and >14 drinks per week were 1.0, 0.8 (0.4, 1.3), 1.1 (0.6, 1.9), 0.9 (0.5, 1.5), and 1.5 (0.9, 2.5), respectively, for men and 1.0, 0.9 (0.5, 1.6), 1.3 (0.8, 2.3), 1.3 (0.7, 2.2), and 2.1 (0.8, 5.9) for women. Sensitivity analyses with other cut-points for calcification gave similar results. Analyses of alcohol and aortic calcification showed similar, nonsignificant associations. CONCLUSIONS: Despite its frequently demonstrated beneficial effects on coronary artery disease risk, alcohol consumption in this study was not associated with calcified atherosclerotic plaque in the coronary arteries or in the aorta. This suggests that its effects on cardiovascular risk may occur through mechanisms other than those associated with the development of calcified plaque.

Association of a 62 Variants Type 2 Diabetes Genetic Risk Score With Markers of Subclinical Atherosclerosis: A Transethnic, Multicenter Study.

BACKGROUND: Type 2 diabetes mellitus (T2D) and cardiovascular disease share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes mellitus. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA. METHODS AND RESULTS: In a cross-sectional analysis, including ≤9210 European Americans, 3773 African Americans, 1446 Hispanic Americans, and 773 Chinese Americans without known cardiovascular disease and enrolled in the Framingham Heart Study, Coronary Artery Risk Development in Young Adults, Multi-Ethnic Study of Atherosclerosis, and Genetic Epidemiology Network of Arteriopathy studies, we tested a 62 T2D-loci genetic risk score for association with measures of SCA, including coronary artery or abdominal aortic calcium score, common and internal carotid artery intima-media thickness, and ankle-brachial index. We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors-adjusted model (significance, P<0.01=0.05/5, number of traits analyzed). An inverse association with coronary artery calcium score in Multi-Ethnic Study of Atherosclerosis Europeans (fully-adjusted P=0.004) and with common carotid artery intima-media thickness in the Framingham Heart Study (P=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with ß-cell and insulin resistance genetic risk sub-scores in the Framingham Heart Study and in the Coronary Artery Risk Development in Young Adults. CONCLUSIONS: SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and cardiovascular disease risk loci.

Sex-influenced association of nonalcoholic fatty liver disease with coronary heart disease.

OBJECTIVE: This study investigated whether nonalcoholic fatty liver disease (NAFLD) predicts prevalent coronary heart disease (CHD). METHODS: Epidemiologic studies have used various definitions for NAFLD. Here, we considered both liver fat burden measured by CT (FL) and the non-specific measure of hepatic inflammation -alanine aminotransferase (ALT). The association of FL and ALT with CHD (self report of coronary bypass, myocardial infarction, or percutaneous transluminal coronary angioplasty) was investigated in 2756 European-American participants of the Family Heart Study. RESULTS: FL (p = 0.0084) and ALT (≥40 U/L, p = 0.014) were each individually associated with prevalent CHD. However, when accounting for traditional metabolic risk factors in a multivariate model FL had no predictive value for CHD in either men or women; whereas ALT was a significant predictor of CHD in men, and the association strengthened among non-diabetic men. In non-diabetic women, neither FL nor ALT was associated with CHD. CONCLUSIONS: ALT (≥40 U/L) was a predictor of prevalent CHD in men but not in women, while CT measured FL was not significant in either sex. The failure to account for traditional risk factors, heterogeneity by sex, and varying definitions of NAFLD may account for some of the conflicting evidence in the literature regarding the association between NAFLD and coronary disease.

The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to hepatic inflammation to cirrhosis. We sought to identify common genetic variants contributing to NAFLD, using CT measured fatty liver (FL), and alanine aminotransferase levels (ALT), as a biochemical marker of hepatic inflammation. METHODS: We employed a correlated meta-analysis (CMA) to test whether combining FL and ALT genomewide association (GWA) results, using ∼2.5 million imputed SNPs, could enhance ability to detect variants influencing both traits. RESULTS: Variants of the ERLIN1-CHUK-CWF19L1 gene cluster were associated with concomitant variation of FL and ALT. Nine variants (rs2862954, rs1408579, rs10883451, rs11597086, rs11591741, rs17729876, rs17668255, rs17668357, rs12784396) displayed genomewide significant associations at loci concomitantly influencing FL and ALT (2.47 × 10(-9) ≤ CMA-p ≤ 4.29 × 10(-10)) as compared with the suggestive significance of marginal tests (4.11 × 10(-5) ≤ GWA-p ≤ 2.34 × 10(-6)). For example, the missense variant in ERLIN1-rs2862954 was genomewide significant (CMA-p = 4.88 × 10(-10)) for the combination of FL and ALT, while the respective univariate associations were suggestive (FL:p = 5.74 × 10(-6), ALT:p = 3.71 × 10(-6)). Further we investigated whether the concomitant associations were driven mainly by ALT levels. When we adjusted FL by ALT, the correlated associations diminished but did not vanish (CMA-p ≤ 3.3 × 10(-7)). Our findings suggest ERLIN1-CHUK-CWF19L1 variants are associated with early stage of FL accumulation (measured by CT) to hepatic inflammation (ALT levels), and the association enhances when accounting for the correlations between their scans. CONCLUSIONS: CMA approach enhanced the ability to identify novel variants of the ERLIN1-CHUK-CWF19L1 influencing both simple steatosis and hepatic steatosis with inflammation, which suggest that this gene cluster may regulate the susceptibility of NAFLD in a wide spectrum of disease.

Relationship between baseline coronary calcium score and demonstration of coronary artery stenoses during follow-up MESA (Multi-Ethnic Study of Atherosclerosis).

OBJECTIVES: The MESA (Multi-Ethnic Study of Atherosclerosis) is a population-based study of 6,814 men and women. We sought to analyze the relationship between the extent of coronary artery calcium (CAC) at baseline and the severity of coronary stenoses in clinically indicated coronary angiography studies during follow-up. BACKGROUND: CAC is an established predictor of major cardiovascular events. Yet, the relationship between CAC and the distribution and severity of coronary artery stenoses has not been widely explored. METHODS: All MESA participants underwent noncontrast enhanced cardiac computed tomography during enrollment to determine baseline CAC. We analyzed 175 consecutive angiography reports from participants who underwent coronary catheterization for clinical indications during a median follow-up period of 18 months. The relationship between baseline CAC and the severity of coronary stenosis detected in coronary angiographies was determined. RESULTS: Baseline Agatston score was 0 in only 7 of 175 (4%) MESA participants who underwent invasive angiography during follow-up. When coronary arteries were studied separately, 13% to 18% of coronary arteries with >or=75% stenosis had 0 calcium mass scores at baseline. There was close association between baseline calcium mass score and the severity of stenosis in each of the coronary arteries (test for trend, p < 0.001). For example, mean calcium mass scores for <50%, 50% to 74%, and >or=75% stenosis in the left anterior descending coronary artery were 105.1 mg, 157.2 mg, and 302.2 mg, respectively (p < 0.001). Finally, there was a direct relationship between the total Agatston Score at baseline and the number of diseased vessels (test for trend, p < 0.001). CONCLUSIONS: The majority of patients with clinically indicated coronary angiography during follow-up had detectable coronary calcification at baseline. Although there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenoses had no calcification at baseline.

Relationship of thoracic aortic calcium to coronary calcium and its progression (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

Thoracic aortic calcium (TAC) has been associated with a higher prevalence of coronary arterial calcium (CAC). The purpose of this study was to assess the relations between TAC and incident CAC and CAC progression in a cohort from the Multi-Ethnic Study of Atherosclerosis (MESA). MESA is a prospective cohort study of 6,814 participants free of clinical cardiovascular disease at entry who underwent noncontrast cardiac computed tomographic scanning at baseline examination and at a 2-year follow-up assessment. The independent associations between TAC and incident CAC in those without CAC at baseline and between TAC and CAC progression in those with CAC at baseline were investigated. The final study population consisted of 5,755 subjects (84%; mean age 62 +/- 10 years, 48% men) who had follow-up CAC scores an average of 2.4 years later. Incident CAC was significantly higher in those with TAC compared with those without TAC at baseline (11 per 100 patient-years vs 6 per 100 patient-years). Similarly, TAC was associated with a higher CAC change (p <0.0001) in those with some CAC at baseline. In analysis adjusted for demographics and follow-up duration, TAC was associated with incident CAC (relative risk 1.72, p <0.0001) as well as with a greater CAC change (first quartile: relative risk 2.89, 95% confidence interval -3.16 to 8.95; fourth quartile: relative risk 24.21, 95% confidence interval 18.25 to 30.18). In conclusion, TAC is associated with the incidence and progression of CAC. The detection of TAC may improve risk stratification efforts. Future clinical outcomes studies are needed to support such an approach.

A submersible autonomous sensor for spectrophotometric pH measurements of natural waters.

An autonomous sensor for long-term in situ measurements of the pH of natural waters is described. The system is based upon spectrophotometric measurements of a mixture of sample and sulfonephthalein indicator. A simple plumbing design, using a small, low-power solenoid pump and valve, avoids the need for quantitative addition of indicator. A approximately 50-microL slug of indicator is pulled into the sample stream by the pump, and subsequent pumping and mixing results in a section of indicator and sample where absorbance measurements can be made. The design also permits direct determination of the indicator pH perturbation. Absorbances are recorded at three wavelengths (439, 579, and 735 nm) using a custom-built 1.7-cm path length fiber-optic flow cell. Solution blanks are obtained by periodically flushing the cell with sample. Field tests were performed in a local river over an 8-day period. The in situ accuracy, based on comparison with laboratory spectrophotometric pH measurements, was -0.003 pH unit (n = 16), similar to the measurement precision. No drift was observed during the 8-day period. The absorbance ratio used to calculate pH, in combination with a simple and robust optical design, imparts an inherent stability not achievable with conventional potentiometric methods, making the design feasible for long-term autonomous pH measurements.