Longitudinal Associations of Plasma TMAO and Related Metabolites with Cognitive Impairment and Dementia in Older Adults: The Cardiovascular Health Study.

BACKGROUND: Animal studies suggest that gut microbiome metabolites such as trimethylamine N-oxide (TMAO) may influence cognitive function and dementia risk. However potential health effects of TMAO and related metabolites remain unclear. OBJECTIVE: We examined prospective associations of TMAO, γ-butyrobetaine, crotonobetaine, carnitine, choline, and betaine with risk of cognitive impairment and dementia among older adults aged 65 years and older in the Cardiovascular Health Study (CHS). METHODS: TMAO and metabolites were measured in stored plasma specimens collected at baseline. Incident cognitive impairment was assessed using the 100-point Modified Mini-Mental State Examination administered serially up to 7 times. Clinical dementia was identified using neuropsychological tests adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare data. Associations of each metabolite with cognitive outcomes were assessed using Cox proportional hazards models. RESULTS: Over a median of 13 years of follow-up, 529 cases of cognitive impairment, and 522 of dementia were identified. After multivariable adjustment for relevant risk factors, no associations were seen with TMAO, carnitine, choline, or betaine. In contrast, higher crotonobetaine was associated with 20-32% higher risk of cognitive impairment and dementia per interquintile range (IQR), while γ-butyrobetaine was associated with ∼25% lower risk of the same cognitive outcomes per IQR.∥Conclusion:These findings suggest that γ-butyrobetaine, crotonobetaine, two gut microbe and host metabolites, are associated with risk of cognitive impairment and dementia. Our results indicate a need for mechanistic studies evaluating potential effects of these metabolites, and their interconversion on brain health, especially later in life.

Assessment of Plasma Phospholipid Very-Long-Chain Saturated Fatty Acid Levels and Healthy Aging.

Importance: Identifying novel factors that protect against age-related diseases and promote healthy aging is critical to public health. Higher levels of circulating very-long-chain saturated fatty acids (VLSFAs) are integrated biomarkers of diet and metabolism shown to have beneficial associations in cardiovascular disease and total mortality, but whether they are associated with overall healthy aging is unknown. Objective: To examine the association of circulating levels of 3 VLSFAs with unhealthy aging events, including incident chronic disease (cardiovascular disease, cancer, lung disease or severe kidney disease), physical dysfunction, and cognitive decline. Design, Setting, and Participants: This cohort study used 1992 to 2014 data from the Cardiovascular Health Study (CHS). The CHS is a multicenter, population-based study of cardiovascular disease among older adults. Among the 4559 CHS participants with available fatty acid data, 1879 participants who had an age-related event before their first measurement were excluded. Data analysis was performed in 2020. Main Outcomes and Measures: Plasma phospholipid VLSFA levels were measured by thin-layer chromatography followed by gas chromatography. The main outcome was the hazard ratio (HR) of an incident unhealthy aging event associated with serial measures of plasma arachidic acid, behenic acid, and lignoceric acid. Results: Among the 2680 study participants (976 men [36.4%]), the mean (SD) age was 74.7 (4.8) years old at entry. During a median (interquartile range) of 6.4 (2.9-12.9) years of follow-up, 2484 participants experienced an unhealthy event. Compared with the lowest quintile, levels of behenic acid in the highest quintile of the fatty acid distribution were associated with 15% lower risk of an unhealthy event (HR, 0.85; 95% CI, 0.74-0.97; P for trend = .01) after adjustment for demographic characteristics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of lignoceric acid were similarly associated with 16% lower risk of an unhealthy event (HR, 0.84; 95% CI, 0.73-0.95; P for trend = .001). Conclusions and Relevance: These findings suggest that higher levels of circulating behenic acid and lignoceric acid are associated with lower risk of unhealthy aging events. These results highlight the need to explore determinants of circulating VLSFAs for potential novel efforts to promote healthy aging.

Medical facilities in the neighborhood and incidence of sudden cardiac arrest.

BACKGROUND: Medical establishments in the neighborhood, such as pharmacies and primary care clinics, may play a role in improving access to preventive care and treatment and could explain previously reported neighborhood variations in sudden cardiac arrest (SCA) incidence and survival. METHODS: The Cardiac Arrest Blood Study Repository is a population-based repository of data from adult cardiac arrest patients and population-based controls residing in King County, Washington. We examined the association between the availability of medical facilities near home with SCA risk, using adult (age 18-80) Seattle residents experiencing cardiac arrest (n = 446) and matched controls (n = 208) without a history of heart disease. We also analyzed the association of major medical centers near the event location with emergency medical service (EMS) response time and survival among adult cases (age 18+) presenting with ventricular fibrillation from throughout King County (n = 1537). The number of medical facilities per census tract was determined by geocoding business locations from the National Establishment Time-Series longitudinal database 1990-2010. RESULTS: More pharmacies in the home census tract was unexpectedly associated with higher odds of SCA (OR:1.28, 95% CI: 1.03, 1.59), and similar associations were observed for other medical facility types. The presence of a major medical center in the event census tract was associated with a faster EMS response time (-53 s, 95% CI: -84, -22), but not with short-term survival. CONCLUSIONS: We did not observe a protective association between medical facilities in the home census tract and SCA risk, orbetween major medical centers in the event census tract and survival.

In the Wrong Place with the Wrong SNP: The Association Between Stressful Neighborhoods and Cardiac Arrest Within Beta-2-adrenergic Receptor Variants.

BACKGROUND: Sudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest. METHODS: The Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing. RESULTS: Fewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]). CONCLUSIONS: Findings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway.

Ethnic differences in sudden cardiac arrest resuscitation.

OBJECTIVE: Ethnic differences in sudden cardiac arrest resuscitation have not been fully explored and studies have yielded inconsistent results. We examined the association of ethnicity with factors affecting sudden cardiac arrest outcomes. METHODS: Retrospective cohort study of 3551 white, 440 black and 297 Asian sudden cardiac arrest cases in Seattle and King County, Washington, USA. RESULTS: Compared with whites, blacks and Asians were younger, had lower socioeconomic status and were more likely to have diabetes, hypertension and end-stage renal disease (all p<0.001). Blacks and Asians were less likely to have a witnessed arrest (whites 57.6%, blacks 52.1%, Asians 46.1%, p<0.001) or receive bystander cardiopulmonary resuscitation (whites 50.9%, blacks 41.4%, Asians 47.1%, p=0.001), but had shorter average emergency medical services response time (mean in minutes: whites 5.18, blacks 4.75, Asians 4.85, p<0.001). Compared with whites, blacks were more likely to be found in pulseless electrical activity (blacks 20.9% vs whites 16.6%, p<0.001), and Asians were more likely to be found in asystole (Asians 41.1% vs whites 30.0%, p<0.001). One of the strongest predictors of resuscitation outcomes was initial cardiac rhythm with 25% of ventricular fibrillation, 4% of patients with pulseless electrical activity and 1% of patients with asystole surviving to hospital discharge (adjusted OR of resuscitation in pulseless electrical activity compared with ventricular fibrillation: 0.30, 95% CI 0.24 to 0.34, p<0.001, adjusted OR of resuscitation in asystole relative to ventricular fibrillation 0.21, 95% CI 0.17 to 0.26, p<0.001). Survival to hospital discharge was similar across all three ethnicities. CONCLUSIONS: While there were differences in some prognostic characteristics between blacks, whites and Asians, we did not detect a significant difference in survival following sudden cardiac arrest between the three ethnic groups. There was, however, an ethnic difference in presenting rhythm, with pulseless electrical activity more prevalent in blacks and asystole more prevalent in Asians.

Amount of leisure-time physical activity and risk of nonfatal myocardial infarction.

PURPOSE: To investigate the shape of the relation between amount of leisure-time physical activity (LTPA) and myocardial infarction (MI) risk. METHODS: Data were from a case-control study in a Washington State health maintenance organization, 1986 to 2002. Participants had no prior cardiovascular disease and good self-reported health before selection. Telephone interviews asked 697 nonfatal MI cases and 3,397 control subjects about 26 types of LTPA. Models adjusted for age, sex, year, treated hypertension, family history of heart disease, smoking, alcohol, aspirin, race, retirement, income, and education. RESULTS: Some LTPA was reported by 90% of control subjects and 84% of cases. Compared with no LTPA, participation in LTPA was associated with lower risk of MI (adjusted odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.52, 0.86). Among active participants, LTPA time was associated with risk of MI (OR = 0.66 for high versus low quartile, 95% CI: 0.51, 0.86). Risk of MI decreased with increasing total or nonstrenuous LTPA time up to the median, beyond which we could not detect an association between LTPA time and MI risk. CONCLUSIONS: Time engaged in LTPA, even nonstrenuous LTPA, was associated with lower risk of MI, and the shape of this relationship was nonlinear.

Incidence of out-of-hospital cardiac arrest.

Estimates of the incidence of out-of-hospital primary cardiac arrest (CA) have typically relied solely upon emergency medical service or death certificate records and have not investigated incidence in clinical subgroups. Overall and temporal patterns of CA incidence were investigated in clinically defined groups using systematic methods to ascertain CA. Estimates of incidence were derived from a population-based case-control study in a large health plan from 1986 to 1994. Subjects were enrollees aged 50 to 79 years who had had CA (n = 1,275). A stratified random sample of enrollees who had not had CA was used to estimate the population at risk with various clinical characteristics (n = 2,323). Poisson's regression was used to estimate incidence overall and for 3-year time periods (1986 to 1988, 1989 to 1991, and 1992 to 1994). The overall CA incidence was 1.89/1,000 subject-years and varied up to 30-fold across clinical subgroups. For example, incidence was 5.98/1,000 subject-years in subjects with any clinically recognized heart disease compared with 0.82/1,000 subject-years in subjects without heart disease. In subgroups with heart disease, incidence was 13.69/1,000 subject-years in subjects with prior myocardial infarction and 21.87/1,000 subject-years in subjects with heart failure. Risk decreased by 20% from the initial to the final time period, with a greater decrease observed in those with (25%) compared with those without (12%) clinical heart disease. Thus, CA incidence varied considerably across clinical groups. The results provide insights regarding absolute and population-attributable risk in clinically defined subgroups, information that may aid strategies aimed at reducing mortality from CA.

Inhaled beta-2 adrenergic receptor agonists and primary cardiac arrest.

PURPOSE: We sought to investigate if short-acting, inhaled beta2-adrenergic receptor agonists were associated with higher risk of primary cardiac arrest in patients with asthma or chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: We conducted a population-based study involving 454 patients enrolled in a health maintenance organization, aged 40 to 79 years, who had asthma or COPD and who experienced primary cardiac arrest during 1980 to 1994. We randomly selected 586 controls from strata of enrollees, defined by age, sex, calendar year, and prior heart disease. Medication use was assessed from computerized pharmacy data, and risk factors from medical record review. RESULTS: Use of inhaled beta-agonists was associated with a twofold increased risk of primary cardiac arrest (odds ratio [OR] = 1.9; 95% confidence interval [CI]: 1.1 to 3.3) among patients with asthma, but not among those with COPD (OR = 1.3; 95% CI: 0.6 to 2.7), after adjustment for risk factors. This association was observed only with use of two or more canisters of metered-dose, inhaled beta-agonists for 3 months, and when inhaled steroids were not used. CONCLUSION: These results support current guidelines recommending inhaled steroids as first-line asthma therapy.