Background: Heart rate variability ( HRV ) is associated with vascular risk factors for dementia, but whether HRV is associated with specific domains of cognitive performance is unclear. Methods and Results: In the Multi‐Ethnic Study of Atherosclerosis (N=3018; mean age 59.3±9.2 years), we assessed the relationship of 10‐second HRV to scores on tests of global cognitive performance (Cognitive Abilities Screening Instrument), processing speed (Digit Symbol Coding), and working memory (Digit Span). HRV was computed as the SD of normal‐normal intervals (SDNN) and root mean square of successive differences (RMSSD) at Exam 1 (2000–2002) and Exam 5 (2010–2012). Cognitive tests were administered at Exam 5. We report regression coefficients (β [95% CI]) representing cognitive test score change per 2‐fold increase in HRV . After adjustment for age, race/ethnicity, sex, education, apolipoprotein E genotype, and cardiovascular risk factors and incident disease, higher Exam 1 (β=0.37 [0.06, 0.67]) and Exam 5 (β=0.31 [0.04, 0.59]) SDNN were associated with better Cognitive Abilities Screening Instrument performance. Higher Exam 1 (β=0.80 [0.17, 1.43]) and Exam 5 (β=0.63 [0.06, 1.20]) SDNN , and Exam 5 RMSSD (β=0.54 [0.01, 1.08]) were associated with better Digit Symbol Coding performance. Finally, higher Exam 5 SDNN was associated with better Digit Span performance (β=0.17 [0.01, 0.33]). Associations were attenuated after adjustment for resting heart rate. Conclusions: Higher HRV is generally associated with better cognitive performance in this multi‐ethnic cohort of aging adults, and further study of the relationship of autonomic function to cognition is warranted.

Background: This study explored the longitudinal relationship of Lp(a) (lipoprotein[a]) and hypertension to cardiovascular outcomes in a large multiethnic cohort free of baseline cardiovascular disease. Methods: Individuals from the MESA (Multi-Ethnic Study of Atherosclerosis; N=6674) were grouped as follows: group 1: Lp(a) <50 mg/dL and no hypertension; group 2: Lp(a) ≥50 mg/dL and no hypertension; group 3: Lp(a) <50 mg/dL and hypertension; and group 4: Lp(a) ≥50 mg/dL and hypertension. Kaplan-Meier curves and multivariable Cox proportional hazard models were used to assess the relationship of Lp(a) and hypertension with time to cardiovascular disease events. Results: Mean follow-up time was 13.9 (5.0) years and 809 participants experienced a cardiovascular disease event. A statistically significant interaction was found between Log[Lp(a)] and hypertension status ( P =0.091). Compared with the reference group (Lp[a] <50 mg/dL and no hypertension), those with Lp[a] ≥50 mg/dL and no hypertension had no increased risk for cardiovascular disease events (hazard ratio, 1.09 [95% CI, 0.79–1.50]). However, those with Lp(a) <50 mg/dL and hypertension or Lp(a) ≥50 mg/dL and hypertension demonstrated a statistically significant increase in risk compared to the reference group (hazard ratio, 1.66 [95% CI, 1.39–1.98]) and (hazard ratio, 2.07 [95% CI, 1.63–2.62]), respectively. Among those with hypertension, Lp(a) was associated with a significant increase in cardiovascular disease risk (hazard ratio, 1.24 [95% CI, 1.01–1.53]). Conclusions: Although the major contribution to cardiovascular risk was hypertension, elevated Lp(a) significantly modified the association of hypertension with cardiovascular disease. More research is needed to understand mechanistic links among Lp(a), hypertension, and cardiovascular disease.

Vascular risk scores are associated with incident dementia. Information regarding their association with cognitive performance and decline in racially/ethnically diverse cohorts is lacking. In 4 392 Multi-Ethnic Study of Atherosclerosis participants (aged 60.1 ± 9.4 years; 53% women; 41% White, 11% Chinese American, 26% African American, 21% Hispanic), we compared associations of Exam 1 (2000–2002) Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham Stroke Risk Profile (FSRP), and atherosclerotic cardiovascular disease pooled cohort equation (ASCVD-PCE) risk scores with Exam 5 (2010–2012) Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive test performance using multivariable linear regression, and examined racial/ethnic interactions. In 1 838 participants with repeat CASI data at Exam 6 (2016–2018), we related risk scores to odds of a 1-SD decline in CASI performance using multivariable logistic regression. SD increments in each risk score were associated with worse cognitive performance. CAIDE had stronger associations with CASI performance than the FSRP and ASCVD-PCE, but associations of ASCVD-PCE with the DSC and DS were similar to CAIDE (difference in β [95% CI] = −0.57 [−1.48, 0.34] and −0.21 [−0.43, 0.01], respectively). Race/ethnicity modified associations. For example, associations between CAIDE and CASI were greater in African Americans and Hispanics than in Whites (difference in β = 0.69 [0.02, 1.36] and 1.67 [0.95, 2.39], respectively). Risk scores were comparably associated with decline in CASI performance. Antecedent vascular risk scores are associated with cognitive performance and decline in the 4 most common U.S. racial/ethnic groups, but associations differ among risk scores and by race/ethnicity.

Aims: Elevated small dense LDL cholesterol (sd-LDL-C) increases atherosclerotic cardiovascular disease (CVD) risk. Although coronary artery calcification (CAC) is widely used for predicting CVD events, few studies have examined the relationship between sd-LDL-C and CAC. Methods and results: This study included 4672 individuals with directly measured baseline sd-LDL-C and CAC from the Multi-Ethnic Study of Atherosclerosis [mean (standard deviation) age: 61.9 (10.4) years; 52.5% women; 47.3% with baseline CAC (mean score >0)]. We used multi-variable general linear models and restricted cubic splines with the goodness of fit testing to evaluate the association of sd-LDL-C with the presence of CAC. Odds ratios [OR (95% confidence interval)] were adjusted for demographics and cardiovascular risk factors, including estimated total LDL-C. Higher quartiles of sd-LDL-C were associated with the presence of CAC, even after accounting for total LDL-C. Compared with the lowest quartile of sd-LDL-C, participants in Quartiles 2, 3, and 4 had higher odds for the presence of baseline CAC [Quartile 2 OR: 1.24 (1.00, 1.53); Quartile 3 OR: 1.51 (1.19, 1.93); and Quartile 4 OR 1.59 (1.17, 2.16)]. Splines suggested a quadratic curvilinear relationship of continuous sd-LDL-C with CAC after adjustment for demographics and CVD risk factors (quadratic vs. first-order sd-LDL-C terms likelihood ratio test: P = 0.015), but not after accounting for total LDL-C (quadratic vs. first-order terms: P = 0.156). Conclusion: In a large, multi-ethnic sample without known CVD, higher sd-LDL-C was associated with the presence of CAC, above and beyond total LDL-C. Whether selective direct measurement of sd-LDL-C is indicated to refine cardiovascular risk assessment in primary prevention warrants further investigation.

Context: Higher visit-to-visit glucose variability (GV) is associated with dysglycemia and type 2 diabetes (T2D), key risk factors for cognitive decline. Objective: Evaluate the association of GV with cognitive performance and decline in racially/ethnically diverse older populations with and without T2D. Methods: We calculated the standard deviation of glucose (SDG), average real variability (ARV), and variability independent of the mean (VIM) among 4367 Multi-Ethnic Study of Atherosclerosis participants over 6 clinical examinations. Participants completed a cognitive assessment at the fifth examination, and a subset completed a second assessment 6 years later. We used multivariable linear regression to estimate the association of intraindividual GV with cognitive test scores after adjustments for cardiovascular risk factors and mean glucose level over the study period. Results: Two-fold increments in the VIM and SDG were associated with worse Cognitive Abilities Screening Instrument (CASI) performance, while two-fold increments in VIM and ARV were associated with worse Digit Symbol Coding test score. GV measures were not associated with change in CASI performance among 1834 participants with repeat CASI data 6 years later. However, among 229 participants with incident T2D, the SDG and VIM were associated with decline in CASI (−1.7 [95% CI: −3.1, −0.3] and −2.1 [−3.7, −0.5] points, respectively). In contrast, single-timepoint glucose and HbA1c were not associated with CASI decline among participants with or without incident T2D. Conclusion: Higher visit-to-visit GV over 16 to 18 years is associated with worse cognitive performance in the general population, and with modest global cognitive decline in participants with T2D.

Atherogenic dyslipidemia (AD), characterized by low high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides (TG), is associated with increased cardiovascular disease (CVD) risk. This study evaluates the association between AD and CVD in hypertension treated to systolic blood pressure(SBP) targets of <120 mmHg (intensive) or < 140 mmHg (standard). We included 9361 participants from the Systolic Blood Pressure Intervention Trial (SPRINT). Based on baseline lipid profiles, low HDL-C was defined as <40 mg/dL in men or < 50 mg/dL in women, and high TG as ≥150 mg/dL. Participants were classified into four lipid categories according to these cutoffs. AD was defined as the combination of low HDL-C and high TG. We used multivariable Cox regression to evaluate the association between lipid categories and the primary SPRINT outcome, a composite of major CVD events. Over a median 3.8-year follow-up, 726 primary outcome events occurred. AD was present in 9.5 % of cases (n = 104), while 7.4 % (n = 434) occurred in those with normal HDL-C and TG. Compared to the reference group (normal HDL-C with normal TG), hazard ratios (HRs) for CVD events were 1.07 (95 % CI: 0.85-1.35) for high TG alone, 1.20 (95 % CI: 0.95-1.52) for low HDL-C alone, and 1.41 (95 % CI: 1.12-1.77) for AD. Similarly, HRs for the primary outcome associated with AD were 1.38 (95 % CI: 1.02-1.87) and 1.44 (95 % CI: 1.01-2.05) in the standard and intensive SBP-lowering arms, respectively. Among SPRINT participants, AD was associated with a higher CVD risk. Early detection of AD in hypertensive patients, even without diabetes, may prompt greater therapeutic effort to reduce long-term CVD risk.