Hypothesis Tests of Indirect Effects for Multiple Mediators.

BackgroundDespite evidence suggesting that early metabolic dysfunction impacts cardiovascular disease risk, current guidelines focus on risk assessments later in life, missing early transitions in metabolic risk that may represent opportunities for averting the development of cardiovascular disease.Methods and ResultsIn 4420 young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we defined a “metabolic” risk score based on components of the Third Report of the Adult Treatment Panel's definition of metabolic syndrome. Using latent class trajectory analysis adjusted for sex, race, and time‐dependent body mass index, we identified 6 distinct metabolic trajectories over time, specified by initial and final risk: low‐stable, low‐worsening, high‐stable, intermediate‐worsening, intermediate‐stable, and high‐worsening. Overall, individuals gained weight over time in CARDIA with statistically but not clinically different body mass index trend over time. Dysglycemia and dyslipidemia over time were highest in initially high or worsening trajectory groups. Divergence in metabolic trajectories occurred in early adulthood (before age 40), with 2 of 3 individuals experiencing an increase in metabolic risk over time. Membership in a higher‐risk trajectory (defined as initially high or worsening over time) was associated with greater prevalence and extent of coronary artery calcification, left ventricular mass, and decreased left ventricular strain at year 25. Importantly, despite similar rise in body mass index across trajectories over 25 years, coronary artery calcification and left ventricular structure and function more closely tracked risk factor trajectories.ConclusionsTransitions in metabolic risk occur early in life. Obesity‐related metabolic dysfunction is related to subclinical cardiovascular phenotypes independent of evolution in body mass index, including coronary artery calcification and myocardial hypertrophy and dysfunction.

The Mediterranean diet has been reported to be inversely associated with incident metabolic syndrome (MetSyn) among older adults; however, this association has not been studied in young African American and white adults. The objective of the present study was to evaluate the association of a modified Mediterranean diet (mMedDiet) score with the 25-year incidence of the MetSyn in 4713 African American and white adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. A diet history questionnaire was used to assess dietary intake at baseline, year 7 and year 20 and a mMedDiet score was created. Cardiovascular risk factors were measured at multiple examinations over 25 years. The MetSyn was defined according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Cox proportional-hazards regression analysis was use to evaluate associations for incident MetSyn across the mMedDiet score categories adjusting for demographic characteristics, lifestyle factors and BMI. Higher mMedDiet scores represented adherence to a dietary pattern rich in fruit, vegetables, whole grains, nuts and fish, but poor in red and processed meat and snack foods. The incidence of MetSyn components (abdominal obesity, elevated TAG concentrations and low HDL-cholesterol concentrations) was lower in those with higher mMedDiet scores than in those with lower scores. Furthermore, the incidence of the MetSyn was lower across the five mMedDiet score categories; the hazard ratios and 95 % CI from category 1 to category 5 were 1·0; 0·94 (0·76, 1·15); 0·84 (0·68, 1·04); 0·73 (0·58, 0·92); and 0·72 (0·54, 0·96), respectively (P trend= 0·005). These findings suggest that the risk of developing the MetSyn is lower when consuming a diet rich in fruit, vegetables, whole grains, nuts and fish.

To examine the prospective association of depressive symptoms with circulating C-reactive protein (CRP) and to determine the direction of that association. Using data from 2,544 healthy participants in the Coronary Artery Risk Development in Young Adults study (ages, 33-45 years; 55% female; 42% black), we examined the prospective association of depressive symptoms, as measured by the Centers for Epidemiologic Studies Depression Scale, with circulating CRP 5 years later. Depressive symptoms in the Coronary Artery Risk Development in Young Adults study Year 15 predicted CRP at Year 20, independent of demographic characteristics, biological and medical risk factors, health behaviors, and Year 15 CRP. This association, however, was conditional on race such that the increase in CRP with increasing depressive symptoms was present in blacks but not whites. In neither blacks nor whites did Year 15 CRP predict Year 20 depressive symptoms. Among black participants, when examined in separate analyses, higher scores on the depressed affect and somatic symptoms subscales of the Centers for Epidemiologic Studies Depression Scale and lower scores on the positive affect subscale were associated with greater Year 20 CRP. The interpersonal problems subscale was unrelated to CRP. When all four subscale scores were entered simultaneously in the same model, black participants' scores on the positive affect and somatic symptoms subscales emerged as independent predictors of Year 20 CRP, whereas the depressed affect and interpersonal problems subscales did not. Depressive symptoms may be linked more closely to inflammation in blacks than in whites.

To examine whether vasomotor symptoms (VMS) and migraine headaches, hypothesized to be vasoactive conditions, are associated with greater risk for cardiovascular disease (CVD) events including strokes. We performed a secondary data analysis of a subset of women (n = 1,954) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based cohort, which began data collection at 18 to 30 y of age. We examined whether migraine headaches and VMS trajectories (characterized as minimal, increasing, and persistent) at CARDIA year 15 examination were associated with higher risk of CVD events and stroke (both ischemic and hemorrhagic) using Cox proportional hazards regression models and adjustment for traditional CVD risk factors (age, cigarette use, and levels of systolic and diastolic blood pressure, fasting glucose, high- and low-density cholesterol, and triglycerides) and reproductive factors. Among women with minimal VMS (n = 835), increasing VMS (n = 521), and persistent VMS (n = 598), there were 81 incident CVD events including 42 strokes. Women with histories of migraine and persistent VMS had greater risk of CVD (hazard ratio [HR], 2.25; 95% CI, 1.15-4.38) after adjustment for age, race, estrogen use, oophorectomy, and hysterectomy compared with women without migraine histories and with minimal/increasing VMS. After adjustment for CVD risk factors, these associations were attenuated (HR, 1.51; 95% CI, 0.73-3.10). Similarly, women with histories of migraine and persistent VMS had greater risk of stroke (HR, 3.15; 95% CI, 1.35-7.34), but these associations were attenuated after adjustment for CVD risk factors (HR, 1.70; 95% CI, 0.66-4.38). Migraines and persistent VMS jointly associate with greater risk for CVD and stroke, although risk is attenuated with adjustment for traditional CVD risk factors.

Introduction We examined the prospective association between diet quality and circulating soluble intercellular adhesion molecule 1 (sICAM-1) and p-selectin, higher values of both of which indicate endothelial dysfunction, a stage in the development of atherosclerosis. We hypothesized that higher diet quality relates inversely with these biomarkers of endothelial dysfunction. Methods We studied 2,569 black and white men and women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, aged 18-30 at year 0 (1985-86). Diet was assessed at years 0 and 7; sICAM-1 and p-selectin were assayed at year 15. Principal component analysis yielded a diet pattern score rich in refined grain, butter and red meat (meat diet), higher scores reflecting poorer diet quality, and one rich in plant foods (fruit and vegetable (FV) diet), higher scores reflecting better diet quality. Linear regression models predicted sICAM-1 and p-selectin from the diet pattern scores, adjusting for sex, race, study center, age, total energy, smoking status, educational attainment and physical activity and in a separate model additionally adjusted for BMI (all regressors average of year 0 and 7). Results Concentrations of sICAM-1 and p-selectin (year 15 mean and standard deviation (SD)) were 153.4±44.1 ng/mL and 36.7±11.3 ng/mL, respectively. Both diet pattern scores were associated with sICAM-1 ( table ), most strongly the meat diet. The mean sICAM-1 was 17.3 ng/mL lower in the lowest than the highest meat diet quintile, amounting to an effect size of 39% of an SD for sICAM-1 (17.3/44.1 ng/mL). P-selectin was positively associated with the meat diet , but was not significantly associated with the FV diet. Associations were little affected by adjustment for BMI. Conclusion The association of higher diet quality with biomarkers of endothelial dysfunction should be considered as a possible pathway through which diet may affect the development of cardiovascular disease. Estimated mean biomarkers of endothelial dysfunction, sICAM-1 and P-selectin by quintile of 3 diet pattern scores. The CARDIA Study, 1985-86 to 2005-06 Quintile of Dietary Pattern Consumption 1 2 3 4 5 p-trend sICAM-1 (153.4±44.1 ng/mL) Meat diet N 536 576 577 504 376 Model 1 b (se) 0 3.5 (2.5) 10.2 (2.9) 17.5 (3.6) 17.3 (5.3) 0.001 Model 2 b (se) 0 3.0 (2.5) 8.4 (2.8) 15.4 (3.5) 16.5 (5.2) 0.0023 FV diet N 427 506 530 565 541 Model 1 b (se) 0 −1.8 (2.7) −3.1 (2.9) −5.8 (3.0) −8.4 (3.3) 0.011 Model 2 b (se) 0 −1.5 (2.7) −3.0 (2.8) −5.6 (2.9) −8.2 (3.3) 0.0066 P-selectin (36.7±11.3 ng/mL) Meat diet N 538 584 581 515 388 Model 1 b (se) 0 0.6 (0.7) 1.8 (0.8) 3.1 (0.9) 5.6 (1.4) 0.0018 Model 2 b (se) 0 0.5 (0.7) 1.6 (0.8) 2.9 (0.9) 5.6 (1.4) 0.0026 FV diet N 433 516 535 567 555 Model 1 b (se) 0 0.5 (0.7) 0.5 (0.8) −0.1 (0.8) −0.7 (0.9) 0.144 Model 2 b (se) 0 0.5 (0.7) 0.5 (0.8) 0.0 (0.8) −0.6 (0.9) 0.1321 Each row represents a separate regression model. Model 1 adjusted for race, sex, center, age, education, energy intake and physical activity, model 2 additionally adjusted for BMI. Each cell provides for a given quintile of the particular diet pattern score the number at risk (N) or the regression coefficient and standard error (b (se)) comparing mean sICAM-1 or p-selectin to its value in the lowest diet pattern score quintile.

BackgroundDNA methylation-based GrimAge acceleration (GrimAA) is associated with a wide range of age-related health outcomes including cardiovascular disease. Since DNA methylation is modifiable by external and behavioral exposures, it is important to identify which of these exposures may have the strongest contributions to differences in GrimAA, to help guide potential intervention strategies. Here, we assessed the relative contributions of lifestyle- and health-related components, as well as their collective association, to GrimAA.ResultsWe included 744 participants (391 men and 353 women) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with blood DNA methylation information at CARDIA Exam Year (Y) 20 (2005–2006, mean age 45.9 years). Six cumulative exposures by Y20 were included in the analysis: total packs of cigarettes, total alcohol consumption, education years, healthy diet score, sleep hours, and physical activity. We used quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods to assess the relative contribution of each exposure to a single overall association with GrimAA. We also assessed the collective association of the six components combined with GrimAA. Smoking showed the greatest positive contribution to GrimAA, accounting for 83.5% of overall positive associations of the six exposures with GrimAA (QGC weight = 0.835). The posterior inclusion probability (PIP) of smoking also achieved the highest score of 1.0 from BKMR analysis. Healthy diet and education years showed inverse contributions to GrimAA. We observed a U-shaped pattern in the contribution of alcohol consumption to GrimAA. While smoking was the greatest contributor across sex and race subgroups, the relative contributions of other components varied by subgroups.ConclusionsSmoking, alcohol consumption, and education showed the highest contributions to GrimAA in our study. Higher amounts of smoking and alcohol consumption were likely to contribute to greater GrimAA, whereas achieved education was likely to contribute to lower GrimAA. Identifying pertinent lifestyle- and health-related exposures in a context of collective components can provide direction for intervention strategies and suggests which components should be the primary focus for promoting younger GrimAA.

Association of nut consumption with CVD risk factors in young to middle-aged adults: The Coronary Artery Risk Development in Young Adults (CARDIA) study

Endothelial dysfunction is a form of subclinical cardiovascular disease that may be involved in preterm birth and small-for-gestational-age deliveries. However, concentrations of biomarkers of endothelial dysfunction before pregnancy have rarely been measured. We hypothesized that higher levels of biomarkers of endothelial dysfunction (cellular adhesion molecules and selectins) would be associated with odds of preterm birth and/or small-for-gestational-age deliveries. We included 235 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were nulliparous at Y7, reported ≥1 live birth through Y25, and had ≥1 biomarker measured at Y7. We tested for associations between individual biomarkers and an averaged z-score representing total endothelial dysfunction with preterm birth and/or small-for-gestational-age deliveries using Poisson regression, adjusted for demographic and clinical characteristics at the exam immediately preceding index birth. At Y7, total evidence of endothelial dysfunction was similar in women who did (n = 59) and did not have (n = 176) preterm birth and/or small-for-gestational-age deliveries. There was no association between biomarkers of endothelial dysfunction (either individual biomarker or total score) with odds of preterm birth and/or small-for-gestational-age deliveries after adjustment: IRR = 1.01, 95% CI: 0.74, 1.39, p = 0.93 for total endothelial biomarker score. Associations were not modified by race. We conclude that biomarkers of endothelial dysfunction in nulliparous women, measured ~3 years before pregnancy, did not identify women at risk for preterm birth and/or small-for-gestational-age deliveries. This suggests that the maternal endothelial dysfunction that is believed to contribute to these birth outcomes may not be detectable before pregnancy.

Walnut consumption and cardiac phenotypes: The Coronary Artery Risk Development in Young Adults (CARDIA) study

Background: Added sugar (AS) and AS-rich foods and beverages have shown unfavorable associations with overall and cardiovascular health; however, their associations with epigenetic age has not been studied. Aim: To examine the associations of AS intake and AS-rich carbohydrate (CHO) food score with the pace of epigenetic aging in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Methods: There were 850 adults included in this cross-sectional study using data from Year 20 (2005-06). Trained interviewers administered a diet history, and foods were coded using Nutrition Data System for Research (NDSR), which outputs nutrients, including AS, and food groups. An AS-rich CHO food score was created including refined grain breads and rolls, quick breads, sweet bakery products, ready-to-eat cereals, candy, sugar products, and sugar-sweetened beverages. Year 20 epigenetic age measures were calculated from DNA methylation data, generating acceleration measures GrimAge acceleration (GrimAA) and PhenoAge acceleration (PhenoAA). Multivariable linear regression evaluated the associations of GrimAA and PhenoAA across quartiles of AS and AS-rich CHO food score, adjusted for demographic characteristics and lifestyle factors (see footnotes in table). Results: Participants who consumed more AS completed fewer years of education, were less likely to be current drinkers or smokers, and more likely to be ever smokers. They had lower intakes of total CHO, protein, total fat, and saturated fat, and fewer servings of vegetables, red and processed meat, eggs, and diet beverages. Consuming more AS was positively associated with PhenoAA (p trend =0.029), but not GrimAA (p trend =0.85). The AS-rich CHO food score was also positively associated with PhenoAA (p trend <0.001), but not GrimAA (p trend =0.14). Conclusions: Consuming greater amounts of AS and AS-rich CHO foods and beverages were associated with an increased risk for accelerated epigenetic aging.

Social relationships and their biological correlates: Coronary Artery Risk Development in Young Adults (CARDIA) study

Hemostatic factors play an important role in the complications of ischemic heart and vessel disease. Dietary fats such as n-3 fatty acids have been shown to possibly influence hemostatic factors. However, most studies reporting an inverse association between cardiovascular disease and fish and n-3 fatty acid consumption used supplemental doses of fish oil or intakes exceeding the typical amount consumed by the US population. This report examined the associations of usual intakes of fish, linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid with fibrinogen, factor VII, factor VIII, and von Willebrand factor in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The analyses reported here included 1672 black and white men and women aged 24 to 42 years in 1992 to 1993. After adjustment for age, body mass index, diabetes, number of cigarettes smoked per day, race, and energy and alcohol consumption, no significant associations were observed between those who consumed no fish versus those who consumed the highest level of dietary fish with respect to fibrinogen, factor VIII, or von Willebrand factor for any race-sex group. Comparisons of tertile 1 versus tertile 3 for dietary linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid were also not significantly associated with fibrinogen, factor VII, factor VIII, or von Willebrand factor for any race-sex group. These data suggest that customary intakes of fish and n-3 fatty acids in populations that generally do not consume large amounts of these food items are not associated with these hemostatic factors.

Evaluate whether smoking exposure and depressive symptoms accumulated over 25 years are synergistically associated with subclinical heart disease, measured by coronary artery calcification (CAC). Participants (baseline: 54.5% women; 51.5% Black; age range = 18-30 years) were followed prospectively from 1985 to 2010 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Smoking status was queried yearly from Year 0 to Year 25 to compute packyears of smoking exposure. Depressive symptoms were measured on the Center for Epidemiologic Studies Depression (CES-D) scale every 5 years to compute cumulative scores from Year 5 to Year 25. A three-level multinomial logistic regression was used to evaluate the association between cumulative smoking, cumulative depressive symptoms, and their interaction with moderate-risk CAC (score 1-99) and higher-risk CAC (score ≥100) compared with no CAC (score = 0) at Year 25. Models were adjusted for sociodemographic, clinical, and behavioral covariates. Among 3,189 adults, the cumulative Smoking × Depressive Symptoms interaction was not significant for moderate-risk CAC (p = .057), but was significant for higher-risk CAC (p = .001). For adults with a 30-packyear smoking history, average CES-D scores 2, 10, and 16 were, respectively, associated with odds ratios (95% confidence intervals) 3.40 (2.36-4.90), 4.82 (3.03-7.66), and 6.25 (3.31-11.83) for higher-risk CAC (all ps < .05). Cumulative smoking exposure and cumulative depressive symptoms have a synergistic association with subclinical heart disease, where higher lifetime smoking exposure and depressive symptoms are associated with greater odds of CAC. (PsycINFO Database Record

PURPOSE: Physical activity (PA) is vital for healthy aging, playing a key role in preserving cardiovascular health, mobility, and mitigating chronic disease risk. Yet, engagement in PA, especially higher intensity exercise, often declines with aging. Despite its importance, patterns of decline across diverse populations are not well understood. This study aims to examine changes in PA from early adulthood to midlife, examining trends by activity type across domains and intensity category. METHODS: Data are from 5,114 (n = 5,115; n = 1 withdrew) Coronary Artery Risk Development in Young Adults (CARDIA) participants [58% female, 55% Black, aged 24.8 ± 3.7 years (baseline; 1985-86)] who attended at least one exam across exams 1-10 (average: 7.4 exams attended). Participation in PA within 13 category prompts was measured by the CARDIA Physical Activity History (PAH) questionnaire at each exam. Participant data were grouped based on ages (5-year age increments from <25 to ≥65 years). Across each PA category, participants reporting no participation over the past 12 months were determined as non-participants in the respective PA category. Findings are presented as heat maps. RESULTS: Leisure-time walking is the most commonly reported activity type, maintaining high participation rates (>75%) into midlife (Figure). Similarly, home-based activities show consistent engagement, with less decline compared to other types of activities. In contrast, participation in higher-intensity activities such as jogging/running, swimming, and racket sports, as well as structured group activities and vigorous sports, declines with age. CONCLUSIONS: Leisure-time walking remains a prevalent and stable form of PA as individuals age, while higher intensity activities and structured group exercises decline with age. Emphasizing walking in interventions, which demonstrated sustained high engagement, may offer an effective strategy for promoting PA supporting healthy aging. Supported by: The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts 75N92023D00002, 75N92023D00003, 75N92023D00004, 75N92023D00005, and 75N92023D00006 from the National Heart, Lung, and Blood Institute (NHLBI).

Incarceration is associated with increased cardiovascular disease mortality, but prospective studies exploring mechanisms of this association are lacking. We examined the independent association of prior incarceration with incident hypertension, diabetes, and dyslipidemia using the Coronary Artery Risk Development in Young Adults (CARDIA) study-a cohort of young adults aged 18 to 30 years at enrollment in 1985-1986, balanced by sex, race (black and white), and education (high school education or less). We also examined the association of incarceration with left ventricular hypertrophy on echocardiography and with barriers to health care access. Of 4350 participants, 288 (7%) reported previous incarceration. Incident hypertension in young adulthood was more common among former inmates than in those without incarceration history (12% vs 7%; odds ratio, 1.7 [95% confidence interval {CI}, 1.2-2.6]), and this association persisted after adjustment for smoking, alcohol and illicit drug use, and family income (adjusted odds ratio [AOR], 1.6 [95% CI, 1.0-2.6]). Incarceration was significantly associated with incident hypertension in those groups with the highest prevalence of prior incarceration, ie, black men (AOR, 1.9 [95% CI, 1.1-3.5]) and less-educated participants (AOR, 4.0 [95% CI, 1.0-17.3]). Former inmates were more likely to have left ventricular hypertrophy (AOR, 2.7, [95% CI, 0.9-7.9]) and to report no regular source for medical care (AOR, 2.5, [95% CI, 1.3-4.8]). Cholesterol levels and diabetes rates did not differ by history of incarceration. Incarceration is associated with future hypertension and left ventricular hypertrophy among young adults. Identification and treatment of hypertension may be important in reducing cardiovascular disease risk among formerly incarcerated individuals.