Effects of rare and common blood pressure gene variants on essential hypertension: results from the Family Blood Pressure Program, CLUE, and Atherosclerosis Risk in Communities studies.

RATIONALE: Hypertension affects ≈30% of adults in industrialized countries and is the major risk factor for cardiovascular disease. OBJECTIVE: We sought to study the genetic effect of coding and conserved noncoding variants in syndromic hypertension genes on systolic blood pressure (BP) and diastolic BP to assess their overall impact on essential hypertension. METHODS AND RESULTS: We resequenced 11 genes (AGT, CYP11B1, CYP17A1, HSD11B2, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1, and WNK4) in 560 European American (EA) and African American ancestry GenNet participants with extreme systolic BP. We investigated genetic associations of 2535 variants with BP in 19997 EAs and in 6069 African Americans in 3 types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9747 EA and 3207 African American Atherosclerosis Risk in Communities subjects. Finally, we genotyped 37 missense and common noncoding variants in 6591 EAs and in 6521 individuals (3659 EA/2862 African American) from the CLUE and Family Blood Pressure Program studies, respectively. None of the variants individually reached significant false-discovery rates ≤0.05 for systolic BP and diastolic BP. However, on pooling all coding and noncoding variants, we identified at least 5 loci (AGT, CYP11B1, NR3C2, SCNN1G, and WNK1) with higher association at evolutionary conserved sites. CONCLUSIONS: Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units), and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.

Loneliness and its predictors among older adults prior to and during the COVID-19 pandemic: cross-sectional and longitudinal survey findings from participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort in the USA.

OBJECTIVES: We aimed to ascertain the prevalence of perceived loneliness among older adults following the onset of the COVID-19 pandemic and to examine factors contributing to the perception of loneliness. DESIGN: Cross-sectional and longitudinal data from the Atherosclerosis Risk in Communities (ARIC) Study cohort. SETTING: The ARIC Study cohort, a prospective cohort that recruited (1987-1989) participants from four distinct communities in the USA. PARTICIPANTS: 2984 ARIC cohort members. PRIMARY AND SECONDARY OUTCOMES: Perceived loneliness assessed using the University of California at Los Angeles (UCLA) UCLA three-item Loneliness Scale telephone interviews conducted May-October 2020 and prior to March 2020. RESULTS: Of the total 5037 participants alive in 2020, 2984 (56.2%) responded to the UCLA three-item questionnaire (mean age 82.6 (SD 4.6) years, 586 (19.6%) black participants, 1081 (36.2%) men), of which 66 (2.2%) reported having had a COVID-19 infection during the observation period. The proportion of participants reporting feeling lonely was 56.3% (n=1680). Among participants with repeat measures of loneliness (n=516), 35.2% (n=182) reported feeling more lonely following pandemic onset. Self-rated health and emotional resilience were strongly associated with self-perceived loneliness. The burden of COVID-19 infections, concern about the pandemic and decreased self-reported physical activity were greater among black as compared with white participants and among those with an educational attainment of less than high school as compared with high school or more. CONCLUSION: Findings from this study document the increase in perceived loneliness among older adults during the COVID-19 pandemic in the USA.

Association of white matter microstructural integrity with cognition and dementia.

Late-life measures of white matter (WM) microstructural integrity may predict cognitive status, cognitive decline, and incident mild cognitive impairment (MCI) or dementia. We considered participants of the Atherosclerosis Risk in Communities study who underwent cognitive assessment and neuroimaging in 2011-2013 and were followed through 2016-2017 (n = 1775 for analyses of prevalent MCI and dementia, baseline cognitive performance, and longitudinal cognitive change and n = 889 for analyses of incident MCI, dementia, or death). Cross-sectionally, both overall WM fractional anisotropy and overall WM mean diffusivity were strongly associated with baseline cognitive performance and risk of prevalent MCI or dementia. Longitudinally, greater overall WM mean diffusivity was associated with accelerated cognitive decline, as well as incident MCI, incident dementia, and mortality, but WM fractional anisotropy was not robustly associated with cognitive change or incident cognitive impairment. Both cross-sectional and longitudinal associations were attenuated after additionally adjusting for likely downstream pathologic changes. Increased WM mean diffusivity may provide an early indication of dementia pathogenesis.

Biomarkers and degree of atherosclerosis are independently associated with incident atherosclerotic cardiovascular disease in a primary prevention cohort: The ARIC study.

BACKGROUND AND AIMS: Biomarkers and atherosclerosis imaging have been studied individually for association with incident cardiovascular disease (CVD); however, limited data exist on whether the biomarkers are associated with events with a similar magnitude in the presence of atherosclerosis. In this study, we assessed whether the presence of atherosclerosis as measured by carotid intima media thickness (cIMT) affects the association between biomarkers known to be associated with coronary heart disease (CHD) and incident cardiovascular disease (CVD) in a primary prevention cohort. METHODS: 8127 participants from the ARIC study (4th visit, 1996-1998) were stratified as having minimal, mild, or substantial atherosclerosis by cIMT. Levels of C-reactive protein, lipoprotein-associated phospholipase A2, cardiac troponin T, N-terminal pro-brain natriuretic peptide, lipoprotein(a), cystatin C, and urine albumin to creatinine ratio were measured in each participant. Hazard ratios were used to determine the relationship between the biomarkers and incident CHD, stroke, and CVD in each category of atherosclerosis. RESULTS: While each of the biomarkers was significantly associated with risk of events overall, we found no significant differences noted in the strength of association of biomarkers with CHD, stroke, and CVD when analyzed by degree of atherosclerosis. CONCLUSIONS: These findings suggest that the level of atherosclerosis does not significantly influence the association between biomarkers and CVD.

Pre-morbid body mass index and mortality after incident heart failure: the ARIC Study.

BACKGROUND: Although obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding. OBJECTIVES: This study sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF. METHODS: In the ARIC (Atherosclerosis Risk In Communities) study, we used body mass index (BMI) measured ≥6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) compared with normal BMI (18.5 to <25 kg/m(2)) with mortality after incident HF. RESULTS: Among 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 ± 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being pre-morbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared with normal BMI. The protective effect of overweight and obesity was consistent across subgroups on the basis of a history of cancer, smoking, and diabetes. CONCLUSIONS: Our results, for the first time, demonstrate that patients who were overweight or obese before HF development have lower mortality after HF diagnosis compared with normal BMI patients. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients.

Rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects.

OBJECTIVE: Statins, among the most commonly prescribed medications, are associated with a wide range of musculoskeletal side effects. These include a progressive autoimmune myopathy with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies that requires immunosuppression. However, it remains unknown whether these antibodies are found in statin users with and without self-limited musculoskeletal side effects; this limits their diagnostic utility. The current work assessed the prevalence of anti-HMGCR antibodies in these groups of statin users. METHODS: We determined the prevalence of anti-HMGCR antibodies in 1,966 participants (including 763 current statin users) in a substudy of the community-based Atherosclerosis Risk in Communities (ARIC) Study and 98 French Canadian subjects with familial hypercholesterolemia, including 51 with documented statin intolerance. RESULTS: No participant in the ARIC substudy, including those with past or current statin exposure at the time of sample collection, had anti-HMGCR antibodies. Similarly, none of 51 patients with self-limited statin intolerance or 47 statin-tolerant patients receiving maximal statin therapy were anti-HMGCR positive. CONCLUSION: The majority of patients with and without statin exposure, including those with self-limited statin intolerance, do not develop anti-HMGCR antibodies. Therefore, anti-HMGCR antibodies are highly specific for those with an autoimmune myopathy.