Coronary Artery Calcium for Personalized Allocation of Aspirin in Primary Prevention of Cardiovascular Disease in 2019: The MESA Study (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND: Recent American College of Cardiology/American Heart Association Primary Prevention Guidelines recommended considering low-dose aspirin therapy only among adults 40 to 70 years of age who are at higher atherosclerotic cardiovascular disease (ASCVD) risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified. The present study aimed to assess the value of coronary artery calcium (CAC) for guiding aspirin allocation for primary prevention by using 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk. METHODS: The study included 6470 participants from the MESA Study (Multi-Ethnic Study of Atherosclerosis). ASCVD risk was estimated using the pooled cohort equations, and 3 strata were defined: <5%, 5% to 20%, and >20%. All participants underwent CAC scoring at baseline, and CAC scores were stratified as =0, 1 to 99, ≥100, and ≥400. A 12% relative risk reduction in cardiovascular disease events was used for the 5-year number needed to treat (NNT5) calculations, and a 42% relative risk increase in major bleeding events was used for the 5-year number needed to harm (NNH5) estimations. RESULTS: Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the American College of Cardiology/American Heart Association guidelines and using >20% estimated ASCVD risk to define higher risk. Benefit/harm calculations were restricted to aspirin-naive participants <70 years of age not at high risk of bleeding (n=3540). The overall NNT5 with aspirin to prevent 1 cardiovascular disease event was 476 and the NNH5 was 355. The NNT5 was also greater than or similar to the NNH5 among estimated ASCVD risk strata. Conversely, CAC≥100 and CAC≥400 identified subgroups in which NNT5 was lower than NNH5. This was true both overall (for CAC≥100, NNT5=140 versus NNH5=518) and within ASCVD risk strata. Also, CAC=0 identified subgroups in which the NNT5 was much higher than the NNH5 (overall, NNT5=1190 versus NNH5=567). CONCLUSIONS: CAC may be superior to the pooled cohort equations to inform the allocation of aspirin in primary prevention. Implementation of current 2019 American College of Cardiology/American Heart Association guideline recommendations together with the use of CAC for further risk assessment may result in a more personalized, safer allocation of aspirin in primary prevention. Confirmation of these findings in experimental settings is needed.

A Plant-Centered Diet and Markers of Early Chronic Kidney Disease during Young to Middle Adulthood: Findings from the Coronary Artery Risk Development in Young Adults (CARDIA) Cohort.

BACKGROUND: Few studies have evaluated whether plant-centered diets prevent progression of early stage chronic kidney disease (CKD). OBJECTIVES: We examined the association between plant-centered diet quality and early CKD markers. METHODS: We prospectively examined 2869 black and white men and women in the Coronary Artery Risk Development in Young Adults Study free of diagnosed kidney failure in 2005-2006 [examination year 20 (Y20); mean age: 45.3 ± 3.6  y]. CKD marker changes from Y20 to 2015-2016 (Y30) were considered, including estimated glomerular filtration rate (eGFR; serum creatinine), urinary albumin-to-creatinine ratio (ACR), and both. Diet was assessed through interviewer-administered diet histories at Y0, Y7, and Y20, and plant-centered diet quality was quantified with the A Priori Diet Quality Score (APDQS). Linear regression models were used to examine the association of APDQS and subsequent 10-y changes in CKD markers. RESULTS: After adjustment for sociodemographic, behavioral, and diet factors, we found that higher APDQS was related to less adverse changes in CKD markers in the subsequent 10-y period. Compared with the lowest APDQS quintile, the highest quintile was associated with an attenuated increase in lnACR (-0.25 mg/g; 95% CI: -0.37, -0.13 mg/g; P-trend < 0.001), whereas the highest quintile was associated with an attenuated decrease in eGFR (4.45 mL·min-1·1.73 m-2; 95% CI: 2.46, 6.43 mL·min-1·1.73 m-2). There was a 0.50 lower increase in combined CKD markers [ln(ACR) z score - eGFR z score] when comparing the extreme quintiles. Associations remained similar after further adjustment for hypertension, diabetes, and obesity as potential mediating factors. The attenuated worsening CKD marker changes associated with higher APDQS strengthened across increasing initial CKD category; those with the best diet and microalbuminuria in Y10-Y20 returned to high normal albuminuria (all P-interaction < 0.001). CONCLUSIONS: Individuals who consumed plant-centered, high-quality diets were less likely to experience deterioration of kidney function through midlife, especially among participants with initial stage characterized as mild CKD.

PTC1 and PTC2: New Indices of Blood Pressure Waveforms and Cardiovascular Disease.

Systolic and diastolic blood pressures provide information about cardiovascular disease (CVD) but are only extremes of the pressure waveform during the cardiac cycle. We developed summaries of the pressure decay, called PTC1 and PTC2, that are related to arterial compliance and to an existing proprietary summary that has been shown to predict CVD. We derived the summaries from a Windkessel model (consisting of a decaying exponential plus a dampened cosine, with an intercept so they are independent of calibration with blood pressure, unlike the proprietary measures), and we estimated them using nonlinear least squares with standard, free software. Among 6,228 adults from the Multi-Ethnic Study of Atherosclerosis, initially free of CVD in 2000-2002, mean PTC2 was 94 (standard deviation, 46) milliseconds. During median 15-year follow-up, there were 911 CVD events (including 609 incidents of coronary heart disease and 270 strokes). One-standard-deviation higher PTC2 was associated with 17% (95% confidence interval: 10, 24) lower CVD risk, after adjustment for traditional risk factors. Results were similar for PTC1. PTC1 and PTC2 are relatively straightforward to compute and add information beyond traditional risk factors for prediction of CVD. Our work enables others to replicate and extend our results with waveforms from any suitable device.

A prospective controlled study of metabolic and physiologic effects of kidney donation suggests that donors retain stable kidney function over the first nine years.

While there have been numerous studies of living kidney donors, most have been retrospective without suitable controls and have yielded conflicting results. To clarify this we studied 205 living donor candidates and 203 controls having no medical conditions precluding donation. Before and at six months, one, two, three, six, and nine years after donation we measured iohexol glomerular filtration rate, clinic blood pressure, urine protein excretion and metabolic parameters reported to be affected by kidney function. We measured 24 hour ambulatory blood pressure at three, six, and nine years and at six and nine years blood pressure after treadmill exercise, carotid-femoral pulse wave velocity and arterial elasticity. Between six months and nine years, the mean (95% confidence interval) change in glomerular filtration rate was significantly different among 133 donors 0·02 (-0·16-0·20) mL/min/1·73m2/year versus -1·26 (-1·52--1·00) mL/min/1·73m2/year in 113 healthy controls. Blood pressure, urine protein, urine albumin, glucose, hemoglobin A1c, insulin, and lipoproteins were not different in controls versus donors; but parathyroid hormone, homocysteine and uric acid remained higher at nine years. At six and nine years carotid-femoral pulse wave velocity was not different, but the mean small artery elasticity was significantly lower in 141 donors 6·1 mL/mmHg x100, versus 113 controls 7·1 mL/mmHg x100, and 6·1 mL/mmHg x100 in 137 donors versus 7·6 mL/mmHg x100 in 112 controls at six and nine years, respectively [significant adjusted difference of 1·1 mL/mmHg x100]. Thus, donors remain healthy with stable kidney function for the first nine years, but differences in metabolic and vascular parameters could be harbingers of adverse outcomes requiring future interventions.

Association of C2, a derivative of the radial artery pressure waveform, with new onset of type 2 diabetes mellitus: the MESA study.

BACKGROUND: Although microvascular dysfunction is known to result from diabetes, it might also lead to diabetes. Lower values of C2, a derivative of the radial artery pressure waveform, indicate microvascular dysfunction and predict hypertension and cardiovascular disease (CVD). We studied the association of C2 with incident diabetes in subjects free of overt CVD. METHODS: Among multi-ethnic participants (n = 5214), aged 45-84 years with no diabetes, C2 was derived from the radial artery pressure waveform. Incident diabetes (N = 651) was diagnosed as new fasting glucose ≥ 126 mg/dL or antidiabetic medicine over ~ 10 years. The relative incidence density (RID) for incident diabetes per standard deviation (SD) of C2 was studied during ~ 10 years follow-up using four levels of adjustment. RESULTS: Mean C2 at baseline was 4.58 ± 2.85 mL/mmHg × 100. The RID for incident diabetes per SD of C2 was 0.90 (95% CI 0.82-0.99, P = 0.03). After adjustment for demographics plus body size, the corresponding RID was 0.81 (95% CI 0.73-0.89, P < 0.0001); body mass index (BMI) was the dominant covariate here. After adjustment for demographics plus cardiovascular risk factors, the RID was 0.98 (95% CI 0.89, 1.07, P = 0.63). After adjustment for all the parameters in the previous models, the RID was 0.87 (95% CI 0.78, 0.96, P = 0.006). CONCLUSIONS: In a multi-ethnic sample free of overt CVD and diabetes at baseline, C2 predicted incident diabetes after adjustment for demographics, BMI and CVD risk factors. Differences in arterial blood pressure wave morphology may indicate a long-term risk trajectory for diabetes, independently of body size and the classical risk factors.

Problematic eating behaviors and attitudes predict long-term incident metabolic syndrome and diabetes: The Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: Problematic relationship to eating and food (PREF) captures a broad range of unhealthy eating behaviors. We previously reported that higher BMI is associated with PREF and graded by the number of PREF endorsed. In this study, we prospectively examined the association between PREF and metabolic syndrome and diabetes. METHOD: Eight PREF behaviors were assessed and summed to form the PREF score in 3800 black and white adults (age 27-41 years) in the Coronary Artery Risk Development in Young Adults Study. Diagnoses of incident metabolic syndrome and diabetes were made through 15 years of follow-up. Logistic regression estimated the association with metabolic syndrome. Proportional hazards regression estimated the association with diabetes. RESULTS: The odds ratio of metabolic syndrome was 1.25 per PREF point through 5 years of follow-up (95% CI: 1.17-1.34) and 1.17 per point from 5 to 10 years of follow-up (95% CI: 1.08-1.27). Hazard of diabetes was 1.20 per PREF point through 15 years of follow-up (95% CI: 1.12-1.28). Both associations attenuated after adjustment for BMI. DISCUSSION: Among participants with PREF, higher scores associate with metabolic syndrome and diabetes, with partial attenuation after adjustment for BMI. Early identification of PREF in middle-aged adults may reduce the burden of metabolic health outcomes.

Questionnaire-based problematic relationship to eating and food is associated with 25 year body mass index trajectories during midlife: The Coronary Artery Risk Development In Young Adults (CARDIA) Study.

OBJECTIVE: Problematic eating behaviors and attitudes are of public health concern. Questionnaire-based assessment of these behaviors is important for large-scale research on eating behaviors. The questionnaire on eating and weight patterns-revised (QEWP-R) measures potential problematic behaviors and attitudes toward food (including anxieties, compensatory actions, overeating and loss of control, dieting, and shape concerns) that in aggregate may indicate diagnosable eating disorders. An important question regards the prevalence of these issues and their longitudinal associations with body mass index (BMI) in generally healthy middle aged adults. METHOD: Based on eight constructs measured on QEWP-R, we created a new problematic relationship to eating and food (PREF) scale by assigning a point for each construct endorsed. Analyses were conducted in 3,892 black and white men and women participating in the community-based Coronary Artery Risk Development in Young Adults (CARDIA) Study. The QEWP-R was administered in CARDIA year 10, when participants were aged 27-41 years. We used linear regression to model the relationship of individual constructs and the PREF scale to BMI over CARDIA follow-up. RESULTS: Fifty-five percent of participants had 1-5 points and 4% had 6-8 points on the PREF scale. Each separate construct was positively associated with BMI, except concern about weight and shape. Adjusting for age, race, sex, education, and study center, mean BMI at CARDIA year 10, the time of PREF assessment, was approximately 1.0-2.5 kg/m2 higher per PREF category. CONCLUSION: In middle age, problematic behaviors and attitudes toward food were common and associated with higher BMI.

Electrocardiographic abnormalities and mortality in aging survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study.

BACKGROUND: Electrocardiography (ECG), predictive of adverse outcomes in the general population, has not been studied in cancer survivors. We evaluated the prevalence of ECG abnormalities and associations with mortality among childhood cancer survivors. METHODS: Major and minor abnormalities were coded per the Minnesota Classification system for participants in the St Jude Lifetime Cohort Study (n = 2,715) and community controls (n = 268). Odds ratios (ORs) and 95% CIs were calculated using multivariable logistic regression; and hazard ratios, using Cox proportional hazards regression. RESULTS: Survivors were a median age of 31.3 (range 18.4-63.8) years at evaluation and 7.4 (range 0-24.8) years at diagnosis. Prior therapies included cardiac-directed radiation (29.5%), anthracycline (57.9%), and alkylating (60%) chemotherapies. The prevalence of minor ECG abnormalities was similar among survivors and controls (65.2% vs 67.5%, P = .6). Major ECG abnormalities were identified in 10.7% of survivors and 4.9% of controls (P < .001). Among survivors, the most common major abnormalities were isolated ST/T wave abnormalities (7.2%), evidence of myocardial infarction (3.7%), and left ventricular hypertrophy with strain pattern (2.8%). Anthracyclines ≥300 mg/m2 (OR 1.7 95% CI 1.1-2.5) and cardiac radiation (OR 2.1 95% CI 1.5-2.9 [1-1,999 cGy], 2.6 95% CI 1.6-3.9 [2,000-2,999 cGy], 10.5 95% CI 6.5-16.9 [≥3,000 cGy]) were associated with major abnormalities. Thirteen participants had a cardiac-related death. Major abnormalities were predictive of all-cause mortality (hazard ratio 4.0 95% CI 2.1-7.8). CONCLUSIONS: Major ECG abnormalities are common among childhood cancer survivors, associated with increasing doses of anthracyclines and cardiac radiation, and predictive of both cardiac and all-cause mortality.

Collagen Turnover Markers in Relation to Future Cardiovascular and Noncardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Sustained remodeling of extracellular matrix can compromise organs and tissues. Procollagen type III N-terminal propeptide (PIIINP) and collagen type I carboxy-terminal telopeptide (ICTP) reflect collagen synthesis and degradation. We studied their predictive value for future death and disease. METHODS: A total of 3068 men and women in the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease (CVD) and in generally good health had a baseline blood sample taken for ICTP and PIIINP. Median follow-up was 13.0 years. Among 4 primary outcomes, CVD events (n = 697) were adjudicated, death (n = 571) was by death certificate, and chronic inflammatory-related severe hospitalization and death (ChrIRD, n = 726) and total cancer (n = 327) were classified using International Classification of Diseases codes. We used Poisson regression to study baseline ICTP and PIIINP relative to these outcomes. RESULTS: Mean (SD) PIIINP was 5.47 (1.95) µg/L and ICTP was 3.37 (1.70) µg/L. PIIINP and ICTP were highly correlated with each other and with estimated glomerular filtration rate (eGFR). Adjustment for age and eGFR attenuated relative risks, remaining 20%-30% per SD of both PIIINP and ICTP in prediction for total death and ChrIRD, and of PIIINP for cancer, with little additional attenuation by adjusting for risk factors and inflammatory biomarkers. CVD outcome was generally unrelated to PIIINP but became marginally inversely related to ICTP in the most adjusted model. CONCLUSIONS: The collagen biomarkers PIIINP and ICTP, in part through pathophysiologically parallel associations with renal function, predicted ChrIRD and total death. Moreover, PIIINP predicted future cancer. These collagen markers may help differentiate healthy from unhealthy aging.

Invited Commentary: Hypertension and Arterial Stiffness--Origins Remain a Dilemma.

In this issue of the Journal, Chen et al. (Am J Epidemiol. 2016;183(7):599-608) present repeated measures of aorto-femoral pulse wave velocity, capacitive compliance (C1), and oscillatory compliance (C2) in the Bogalusa Heart Study, with the purpose of addressing which comes first: blood pressure elevation or arterial stiffening. After an average follow-up period of 7 years (2000-2010), the authors found that blood pressure at a mean age of 36 years predicted change in arterial stiffening by a mean age of 43 years, but not the reverse. Essential hypertension results from a mosaic of pathological mechanisms. It has been theorized that biological pathways involving increased sympathetic tone, insulin resistance, renin-angiotensin-aldosterone activation, and inflammation lead to hyperkinetic circulation, volume overload, and vascular remodeling. The resultant accelerated vascular aging may be assessed by determining the degree of arterial stiffness. The findings of Chen et al. add important empirical information to the literature but do not solve the dilemma regarding the origins of essential hypertension, partly because there are many techniques for estimating the many aspects of arterial stiffness which are not fully understood. Mathematical features of estimates might not be uniform across the age range. There is a need for tracking blood pressure and different aspects of arterial stiffness from childhood onward, with an aim of preventing hypertension in adult life.

Comparing Arterial Function Parameters for the Prediction of Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA).

Arterial dysfunction has been linked to decline in cardiac function and increased risk of cardiovascular disease events. We calculated the value of arterial function, measured at baseline (2000-2002), in predicting time to first coronary heart disease (CHD) event (median follow-up, 10.2 years) among participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Measures included the following: C1 and C2, derived from diastolic pulse contour analysis from the radial artery blood pressure waveform obtained by tonometry (n = 6,336); carotid distensibility and Young's elastic modulus at the carotid artery, derived from carotid artery ultrasonography (n = 6,531 and 6,528); and aortic distensibility, measured using cardiac magnetic resonance imaging (n = 3,677). After adjustment, the hazard ratio for a CHD event per standard-deviation increment in arterial function was 0.97 (95% confidence interval (CI): 0.86, 1.10) for C1, 0.73 (95% CI: 0.63, 0.86) for C2, 0.98 (95% CI: 0.86, 1.11) for carotid distensibility, 0.99 (95% CI: 0.90, 1.09) for Young's modulus, and 0.90 (95% CI: 0.74, 1.10) for aortic distensibility. We examined the area under the receiver operating characteristic curve for the model with full adjustment plus the addition of each measure individually. C2 provided additional discrimination for the prediction of CHD (area under the curve = 0.736 vs. 0.743; P = 0.04). Lower C2 was associated with a higher risk of future CHD events.

Comparison of the Predictive Value of GlycA and Other Biomarkers of Inflammation for Total Death, Incident Cardiovascular Events, Noncardiovascular and Noncancer Inflammatory-Related Events, and Total Cancer Events.

BACKGROUND: GlycA is a biomarker that reflects integrated concentrations and glycosylation states of several acute-phase proteins. We studied the association of GlycA and inflammatory biomarkers with future death and disease. METHODS: A total of 6523 men and women in the Multi-Ethnic Study of Atherosclerosis who were free of overt cardiovascular disease (CVD) and in generally good health had a baseline blood sample taken. We assayed high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer. A spectral deconvolution algorithm was used to quantify GlycA signal amplitudes from automated nuclear magnetic resonance (NMR) LipoProfile® test spectra. Median follow-up was 12.1 years. Among 4 primary outcomes, CVD events were adjudicated, death was by death certificate, and chronic inflammatory-related severe hospitalization and death (ChrIRD) and total cancer were classified using International Classification of Diseases (ICD) codes. We used Poisson regression to study baseline GlycA, hsCRP, IL-6, and d-dimer in relation to total death, CVD, ChrIRD, and total cancer. RESULTS: Relative risk per SD of GlycA, IL-6, and d-dimer for total death (n = 915); for total CVD (n = 922); and for ChrIRD (n = 1324) ranged from 1.05 to 1.20, independently of covariates. In contrast, prediction from hsCRP was statistically explained by adjustment for other inflammatory variables. Only GlycA was predictive for total cancer (n = 663). Women had 7% higher values of all inflammatory biomarkers than men and had a significantly lower GlycA prediction coefficient than men in predicting total cancer. CONCLUSIONS: The composite biomarker GlycA derived from NMR is associated with risk for total death, CVD, ChrIRD, and total cancer after adjustment for hsCRP, IL-6, and d-dimer. IL-6 and d-dimer contribute information independently of GlycA.

Pulsatile Load Components, Resistive Load and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Left ventricular (LV) afterload is composed of systemic vascular resistance (SVR) and components of pulsatile load, including total arterial compliance (TAC), and reflection magnitude (RM). RM, which affects the LV systolic loading sequence, has been shown to strongly predict HF. Effective arterial elastance (Ea) is a commonly used parameter initially proposed to be a lumped index of resistive and pulsatile afterload. We sought to assess how various LV afterload parameters predict heart failure (HF) risk and whether RM predicts HF independently from subclinical atherosclerosis. METHODS: We studied 4345 MESA participants who underwent radial arterial tonometry and cardiac output (CO) measurements with the use of cardiac MRI. RM was computed as the ratio of the backward (Pb) to forward (Pf) waves. TAC was approximated as the ratio of stroke volume (SV) to central pulse pressure. SVR was computed as mean pressure/CO. Ea was computed as central end-systolic pressure/SV. RESULTS: During 10.3 years of follow-up, 91 definite HF events occurred. SVR (P = .74), TAC (P = .81), and Ea (P = .81) were not predictive of HF risk. RM was associated with increased HF risk, even after adjustment for other parameters of arterial load, various confounders, and markers of subclinical atherosclerosis (standardized hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.18-1.88; P = .001). Pb was also associated with an increased risk of HF after adjustment for Pf (standardized HR 1.43, 95% CI 1.17-1.75; P = .001). CONCLUSIONS: RM is an important independent predictor of HF risk, whereas TAC, SVR, and Ea are not. Our findings support the importance of the systolic LV loading sequence on HF risk, independently from subclinical atherosclerosis.

Impaired artery elasticity predicts cardiovascular morbidity and mortality- A longitudinal study in the Vara-Skövde Cohort.

It is still debated whether arterial elasticity provides prognostic information for cardiovascular risk beyond blood pressure measurements in a healthy population. To investigate the association between arterial elasticity obtained by radial artery pulse wave analysis and risk for cardiovascular diseases (CVD) in men and women. In 2002-2005, 2362 individuals (men=1186, 50.2%) not taking antihypertensive medication were included. C2 (small artery elasticity) was measured using the HDI/Pulse Wave CR2000. Data on acute myocardial infarction or stroke, fatal or non-fatal, was obtained between 2002-2019. Cox- regression was used to investigate associations between C2 and future CVD, adjusting for confounding factors such as age, sex, systolic blood pressure, heart rate, HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LDL- cholesterol, CRP (C-Reactive Protein), alcohol consumption, smoking and physical activity. At baseline, the mean age of 46 ± 10.6 years and over the follow-up period, we observed 108 events 70 events in men [event rate: 5.9%], 38 in women [event rate: 3.2%]. In the fully adjusted model, and for each quartile decrease in C2, there was a significant increase in the risk for incident CVD by 36%. (HR = 1.36, 95% CI: 1.01-1.82, p = 0.041). The results were accentuated for all men (HR = 1.74, 95% CI: 1.21-2.50, p = 0.003) and women over the age of 50 years (HR = 1.70, 95% CI: 0.69-4.20). We showed a strong and independent association between C2 and CVD in men. In women after menopause, similar tendencies and effect sizes were observed.

Sleep Irregularity and Subclinical Markers of Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis.

Background Sleep irregularity has been linked to incident cardiovascular disease. Less is known about associations of sleep regularity with atherosclerosis. We examined cross-sectional associations of actigraphy-assessed sleep duration and sleep timing regularity with subclinical atherosclerosis in the community-based MESA (Multi-Ethnic Study of Atherosclerosis). Methods and Results MESA Sleep Ancillary Study participants (N=2032; mean age, 68.6±9.2 years; 37.9% White) completed 7-day wrist actigraphy. Participants underwent assessments of coronary artery calcium, carotid plaque presence, carotid intima-media thickness, and the ankle-brachial index. Sleep regularity was quantified by the 7-day with-in person SD of sleep duration and sleep onset timing. Relative risk regression models were used to calculate prevalence ratios and 95% CIs. Models are adjusted for demographics, cardiovascular disease risk factors, and other objectively assessed sleep characteristics including obstructive sleep apnea, sleep duration, and sleep fragmentation. After adjustment, compared with participants with more regular sleep durations (SD ≤60 minutes), participants with greater sleep duration irregularity (SD >120 minutes) were more likely to have high coronary artery calcium burden (>300; prevalence ratio, 1.33 [95% CI, 1.03-1.71]) and abnormal ankle-brachial index (<0.9; prevalence ratio, 1.75 [95% CI, 1.03-2.95]). Compared with participants with more regular sleep timing (SD ≤30 minutes), participants with irregular sleep timing (SD >90 minutes) were more likely to have high coronary artery calcium burden (prevalence ratio, 1.39 [95% CI, 1.07-1.82]). Associations persisted after adjustment for cardiovascular disease risk factors and average sleep duration, obstructive sleep apnea, and sleep fragmentation. Conclusions Sleep irregularity, particularly sleep duration irregularity, was associated with several measures of subclinical atherosclerosis. Sleep regularity may be a modifiable target for reducing atherosclerosis risk. Future investigation into cardiovascular risk reduction interventions targeting sleep irregularity may be warranted.

Association of Cardiovascular Health Score With Early- and Later-Onset Diabetes and With Subsequent Vascular Complications of Diabetes.

BACKGROUND Little attention has been paid to how well the American Heart Association's cardiovascular health (CVH) score predicts early-onset diabetes in young adults. We investigated the association of CVH score with early- and later-onset diabetes and with subsequent complications of diabetes. METHODS AND RESULTS Our sample included 4547 Black and White adults in the CARDIA (Coronary Artery Risk Development in Young Adults) study without diabetes at baseline (1985-1986; aged 18-30 years) with complete data on the CVH score at baseline, including smoking, body mass index, physical activity, diet quality, total cholesterol, blood pressure, and fasting blood glucose. Incident diabetes was determined based on fasting glucose, 2-hour postload glucose, hemoglobin A1c, or self-reported medication use throughout 8 visits for 30 years. Multinomial logistic regression was used to assess the association between CVH score and diabetes onset at age <40 years (early onset) versus age ≥40 years (later onset). Secondary analyses assessed the association between CVH score and risk of complications (coronary artery calcium, clinical cardiovascular disease, kidney function markers, diabetic retinopathy, and diabetic neuropathy) among a subsample with diabetes. We identified 116 early- and 502 later-onset incident diabetes cases. Each 1-point higher CVH score was associated with lower odds of developing early-onset (odds ratio [OR], 0.64 [95% CI, 0.58-0.71]) and later-onset diabetes (OR, 0.78 [95% CI, 0.74-0.83]). Lower estimates of diabetic complications were observed per 1-point higher CVH score: 19% for coronary artery calcification≥100, 18% for cardiovascular disease, and 14% for diabetic neuropathy. CONCLUSIONS Higher CVH score in young adulthood was associated with lower early- and later-onset diabetes as well as diabetic complications.

Nontraditional Risk Factors for Progression Through Chronic Kidney Disease Risk Categories: The Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: There may be nontraditional pathways of chronic kidney disease (CKD) progression that are complementary to classical pathways. Therefore, we aimed to examine nontraditional risk factors for incident CKD and its progression. METHODS: We used the generally healthy population (n = 4382) starting at age 27-41 years in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which is an observational longitudinal study. Nontraditional risk factors included forced vital capacity, inflammation, serum urate, and serum carotenoids. CKD risk category was classified using the estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) measured in 1995-1996 and repeated every 5 years for 20 years: No CKD, low risk, moderate risk, high risk, and very high risk. RESULTS: At baseline, 84.8% had no CKD (eGFR ≥60 mL/min/1.73 m2 and UACR <10 mg/g), 10.3% were in the low risk (eGFR ≥60 and UACR 10-29), and 4.9% had CKD (eGFR <60 and/or UACR ≥ 30). Nontraditional risk factors were significantly associated with the progression of CKD to higher categories. Hazard ratios per standard deviation of the predictor for incident CKD and its progression from the No CKD and low and moderate risk into CKD were inverse for forced vital capacity and serum carotenoids and positive for serum urate, GlycA, and C-reactive protein, the first 3 even after adjustment for conventional risk factors. CONCLUSION: Several nontraditional markers were significantly associated with an increased risk of progression to higher CKD categories in generally healthy young to middle-aged adults.

Racial Differences and Contributory Cardiovascular and Non-Cardiovascular Risk Factors Towards Chronic Kidney Disease Progression.

Background: The prevalence of advanced chronic kidney disease (CKD) is higher in Black than in White Americans. We evaluated CKD progression in Black and White participants and the contribution of biological risk factors. We included the study of lung function (measured by forced vital capacity [FVC]), which is part of the emerging notion of interorgan cross-talk with the kidneys to racial differences in CKD progression. Methods: This longitudinal study included 2175 Black and 2207 White adult Coronary Artery Risk Development in Young Adults (CARDIA) participants. Estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were measured at study year 10 (age 27-41y) and every five years for 20 years. The outcome was CKD progression through no CKD, low, moderate, high, or very high-risk categories based on eGFR and UACR in combination. The association between race and CKD progression as well as the contribution of risk factors to racial differences were assessed in multivariable-adjusted Cox models. Results: Black participants had higher CKD transition probabilities than White participants and more prevalent risk factors during the 20-year period studied. Hazard ratios for CKD transition for Black (vs White participants) were 1.38 from No CKD into ≥ low risk, 2.25 from ≤ low risk into ≥ moderate risk, and 4.49 from ≤ moderate risk into ≥ high risk. Racial differences in CKD progression from No CKD into ≥ low risk were primarily explained by FVC (54.8%), hypertension (30.9%), and obesity (20.8%). In contrast, racial differences were less explained in more severe transitions. Conclusion: Black participants had a higher risk of CKD progression, and this discrepancy may be partly explained by FVC and conventional risk factors.

Inter-arm systolic blood pressure difference: non-persistence and association with incident cardiovascular disease in the Multi-ethnic Study of Atherosclerosis.

We investigated inter-arm systolic blood pressure (sIAD) difference, reproducibility, and incident cardiovascular disease (CVD). We hypothesized that higher sIAD values have low prevalence and nonpersistence over years, but that CVD risk is higher starting from the time of first high absolute sIAD. In Multi-Ethnic Study of Atherosclerosis participants (n = 6725, 53% female, 45-84 years old), Doppler systolic blood pressure (SBP) measurements were made in both arms (10-minute interval) thrice over 9.5 years. Proportional hazards for CVD (coronary heart disease, heart failure, stroke, peripheral arterial disease (PAD)) over 16.4 years were tested according to time-varying absolute inter-arm difference with covariates: (1) age, gender, race, and clinic; (2) model 1 plus height, heart rate, BP, antihypertensives, BMI, smoking status, lipids, lipid lowering medication, and diabetes. High sIAD was not persistent across exams. Maximum absolute sIAD ≥ 15 mmHg was found at least once in 815 persons. Maximum absolute sIAD had a graded relationship with incident stroke or PAD: 6.2% events; model 2 hazard ratio per 10 mmHg 1.34 (95% CI, 1.15-1.56) and this risk was approximately doubled for maximum absolute sIAD ≥ 15 mmHg vs 0-4 mmHg. Total CVD risk (18.4% events) was increased only for maximum absolute sIAD ≥25 mmHg. Associations with incident CVD did not differ for higher SBP in left vs right arm. A higher maximum absolute sIAD at any exam was associated with greater risk for stroke and PAD especially for values ≥ 15 mmHg, and ≥25 mmHg for other CVD. Measuring SBP between arms may help identify individuals at risk for CVD.

The association between arterial compliance, as assessed by PTC1 and PTC2 from radial artery waveforms, and age, sex, and race/ethnicity.

BACKGROUND: There is limited literature on differences in arterial compliance, as assessed from arterial pressure waveforms, with age, sex, and race/ethnicity. PTC1 and PTC2 are indices of arterial compliance, which are derived from a Windkessel model of the waveform, relatively easy to obtain, and associated with cardiovascular disease. METHOD: PTC1 and PTC2 were computed from radial artery waveforms from participants of the Multi-Ethnic Study of Atherosclerosis at baseline and again 10 years later. We evaluated the association of PTC1, PTC2, and 10-year change in PTC1 and PTC2 with age, sex, and race/ethnicity. RESULTS: Among 6245 participants in 2000-2002 (mean ±â€ŠSD of age was 62 ±â€Š10 years; 52% female; 38% White, 12% Chinese, 27% Black, and 23% Hispanic/Latino), means ±â€ŠSDs for PTC1 and PTC2 were 394 ±â€Š334 and 94 ±â€Š46 ms. After adjustment for cardiovascular disease risk factors, mean PTC2 was 1.1 ms (95% confidence interval: 1.0, 1.2) lower (arterial stiffness was greater) per year older age, was 22 ms (19, 24) lower for females, and varied by race/ethnicity ( P  < 0.001; e.g., 5 ms lower for Blacks compared with Whites), although the differences were smaller at older ages ( P  < 0.001 for age-sex, P  < 0.001 for age-race/ethnicity interactions). Among 3701 participants with repeat measurements in 2010-2012, arteries had stiffened (mean ±â€ŠSD 10-year decrease in PTC2: 13 ±â€Š46 ms) consistent with cross-sectional age-trend and tended to stiffen less for females and Blacks consistent with cross-sectional age-interactions. CONCLUSION: Differences in arterial compliance by age, sex, and race/ethnicity lend support to identify and act on societal factors that may drive health disparities.