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Background and ObjectivesPlasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).MethodsEligible CHS participants were free of prevalent stroke and underwent quantification of 1,298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992–1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-SD increase in the log2-transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and noncardioembolic IS and proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.ResultsOf 2,983 eligible participants, the mean age was 74.3 (±4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal probrain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23–1.53,p= 2.08 × 10−08) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16–1.45,p= 4.55 × 10−06) were independently associated with IS risk. These 2 associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident noncardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.DiscussionIn a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and noncardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

BackgroundIn the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.Methods and ResultsIn the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.ConclusionThe CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

COVID-19 inequities have been well-documented. We evaluated whether higher rates of severe COVID-19 in racial and ethnic minority groups were driven by higher infection rates by evaluating if disparities remained when analyses were restricted to people with infection. We conducted a retrospective cohort study of adults insured through Kaiser Permanente (Colorado, Northwest, Washington), follow-up in March–September 2020. Laboratory results and hospitalization diagnosis codes identified individuals with COVID-19. Severe COVID-19 was defined as invasive mechanical ventilation or mortality. Self-reported race and ethnicity, demographics, and medical comorbidities were extracted from health records. Modified Poisson regression estimated adjusted relative risks (aRRs) of severe COVID-19 in full cohort and among individuals with infection. Our cohort included 1,052,774 individuals, representing diverse racial and ethnic minority groups (e.g., 68,887 Asian, 41,243 Black/African American, 93,580 Hispanic or Latino/a individuals). Among 7,399 infections, 442 individuals experienced severe COVID-19. In the full cohort, severe COVID-19 aRRs for Asian, Black/African American, and Hispanic individuals were 2.09 (95% CI: 1.36, 3.21), 2.02 (1.39, 2.93), and 2.09 (1.57, 2.78), respectively, compared to non-Hispanic Whites. In analyses restricted to individuals with COVID-19, all aRRs were near 1, except among Asian Americans (aRR 1.82 [1.23, 2.68]). These results indicate increased incidence of severe COVID-19 among Black/African American and Hispanic individuals is due to higher infection rates, not increased susceptibility to progression. COVID-19 disparities most likely result from social, not biological, factors. Future work should explore reasons for increased severe COVID-19 risk among Asian Americans. Our findings highlight the importance of equity in vaccine distribution. Supplementary Information The online version contains supplementary material available at 10.1007/s40615-021-01205-2.

Background: The effect of physical activity (PA) on incidence of atrial fibrillation (AF) is unclear in African Americans (AA). This study aimed to determine if higher levels of PA are associated with decreased incidence of AF in the Jackson Heart Study (JHS). Methods: Participants of the JHS with PA assessment and without previous AF at baseline were included in the study. PA was categorized based on the American Heart Association physical activity levels. Incident AF was defined as having 12 lead electrocardiogram evidence at a subsequent follow up, or a documented diagnosis code at the time of hospital discharge from 2000 to 2016. Cox proportional hazards models were used to evaluate for the association between baseline PA and incidence of AF. Given significant correlation between PA and baseline cardiovascular disease (CVD), stratified analysis was performed based on CVD status. Results: Of the 4,477 participants followed for a median of 12.5 years, 398 developed AF (7.13 cases per 1,000 person-years). Ideal and intermediate PA were associated with a reduced risk of incident AF compared with poor PA (unadjusted HRs with 95% CIs 0.47 [0.34 - 0.64] and 0.72 [0.58 - 0.90], respectively) (Table). After adjustment for traditional cardiovascular risk factors, the associations attenuated and became no longer significant (0.73 [0.53 - 1.00] and 1.00 [0.80 - 1.25], respectively). In stratified analysis based on baseline CVD status, in participants without baseline CVD, ideal PA was significantly associated with a reduced risk of AF while intermediate PA was not (0.68 [0.47 - 0.98] and 1.00 [0.78-1.29], respectively). In participants with baseline CVD, ideal PA or intermediate PA was not associated with incident AF. Conclusion: Ideal PA was associated with a reduced risk of AF in participants without baseline CVD in this AA community cohort. Our findings show intertwined relationship among PA, CVD, and incident AF. Physical activity could be a possible therapeutic target to reduce AF incidence in the AA general population without CVD.

Background: Identification of novel biomarkers of cerebral small vessel disease is critical to elucidate pathophysiology and guide therapeutic development for prevention. We evaluated plasma proteomic associations of clinically asymptomatic, covert brain infarction (cBI) and white matter hyperintensity (WMH) burden on cranial magnetic resonance imaging (MRI) in the population-based Cardiovascular Health Study (CHS). Methods: Eligible CHS participants underwent one or two cranial MRI scans (~5 years apart) and aptamer-based SOMAScan platform measurement of up to 7288 plasma proteins concurrent with the initial MRI. cBI was defined by MRI signal characteristics and size ≥ 3 mm, and WMH burden was graded (WMG) 0 (least) to 9 (most severe). The relationship between 1-standard deviation increase in each log 2 -normalized plasma protein fluorescence was modeled separately with incident cBI and WMG worsening (≥1 grade increase) using multivariable relative risk regression, adjusting for demographics, estimated glomerular filtration rate (eGFR), and stroke risk factors. In secondary analyses, multivariable linear regression evaluated the cross-sectional relationship between each plasma protein with number of cBI and WMG on initial MRI. Bonferroni correction, based on the number of principal components that explained 99% of the protein fluorescence variance in CHS participants, accounted for multiple comparisons (p-5 (0.05/2377)). Results: For eligible participants (n=2615), mean age was 74.4 ± 4.9 years, 61.7% were women, and 16.4% were Black. After adjustment for demographics, eGFR, and stroke risk factors, multiple circulating proteins were associated with cBI and WMG (Table). Conclusion: Multiple plasma proteins - implicated in systemic inflammation, fatty acid metabolism, neuronal adhesion/migration, and cellular cytoskeletal integrity/remodeling - were independently associated with cBI and WMG in a cohort of older adults.

Objective Hormone therapy (HT) is used by menopausal women to treat vasomotor symptoms. Venous thromboembolism (VTE) is an important risk of HT use, and more knowledge on the comparative safety of different estrogenic compounds is useful for women who use HT for these symptoms. The objective was to compare the risk of VTE among users of oral conjugated equine estrogen (CEE), oral estradiol (E2), and transdermal E2, in a cohort of women veterans. Methods This retrospective cohort study included all women veterans aged 40 to 89 years, using CEE or E2, without prior VTE, between 2003 and 2011. All incident VTE events were adjudicated. Time-to-event analyses using a time-varying HT exposure evaluated the relative VTE risk between estrogen subtypes, with adjustment for age, race, and body mass index, with stratification for prevalent versus incident use of HT. Results Among 51,571 users of HT (74.5% CEE, 12.6% oral, and 12.9% transdermal E2 at cohort entry), with a mean age of 54.0 years, the incidence of VTE was 1.9/1,000 person-years. Compared with CEE use, in the multivariable regression model, there was no difference in the risk of incident VTE associated with oral E2 use (hazard ratio 0.96, 95% CI 0.64-1.46) or with transdermal E2 use (hazard ratio 0.95, 95% CI 0.60-1.49). Results were unchanged when restricting to incident users of HT. Conclusions Among women veterans, the risk of VTE was similar in users of oral CEE, oral E2, and transdermal E2. These findings do not confirm the previously observed greater safety of transdermal and oral E2 over CEE.

Acute pancreatitis is a serious gastrointestinal disease that is an important target for drug safety surveillance. Little is known about the accuracy of ICD-10 codes for acute pancreatitis in the United States, or their performance in specific clinical settings. We conducted a validation study to assess the accuracy of acute pancreatitis ICD-10 diagnosis codes in inpatient, emergency department (ED), and outpatient settings.We reviewed electronic medical records for encounters with acute pancreatitis diagnosis codes in an integrated healthcare system from October 2015 to December 2019. Trained abstractors and physician adjudicators determined whether events met criteria for acute pancreatitis.Out of 1,844 eligible events, we randomly sampled 300 for review. Across all clinical settings, 182 events met validation criteria for an overall positive predictive value (PPV) of 61% (95% confidence intervals [CI] = 55, 66). The PPV was 87% (95% CI = 79, 92%) for inpatient codes, but only 45% for ED (95% CI = 35, 54%) and outpatient (95% CI = 34, 55%) codes. ED and outpatient encounters accounted for 43% of validated events. Acute pancreatitis codes from any encounter type with lipase3 times the upper limit of normal had a PPV of 92% (95% CI = 86, 95%) and identified 85% of validated events (95% CI = 79, 89%), while codes with lipase3 times the upper limit of normal had a PPV of only 22% (95% CI = 16, 30%).These results suggest that ICD-10 codes accurately identified acute pancreatitis in the inpatient setting, but not in the ED and outpatient settings. Laboratory data substantially improved algorithm performance.

To assess atrial fibrillation risk factors in people with HIV, we identified incident atrial fibrillation in a large clinical cohort of people receiving care. Compared with 970 controls without atrial fibrillation, the 97 with adjudicated incident atrial fibrillation were older, less likely Hispanic, and had more coronary disease, heart failure, and chronic obstructive pulmonary disease. In multivariable analysis, nonuse of antiretroviral therapy and prescription of antiretroviral regimens with multiple core agents were associated with increased atrial fibrillation risk.

The Life's Simple 7 (LS7) metric consists of 7 modifiable health behaviors and measures that are known health factors for cardiovascular wellness. Relatively little is known about the association of LS7 score with cardiac arrhythmias. In the setting of the Multi-Ethnic Study of Atherosclerosis, we studied the LS7 score (range 0 to 14), assessed at the 2010 to 2102 study visit, in relation to cardiac arrhythmias assessed by Zio Patch ambulatory electrocardiographic monitoring in 2016 to 2018. In participants free of clinically recognized cardiovascular disease and atrial fibrillation, we used logistic and linear regression to examine the association of total LS7 score with atrial fibrillation, supraventricular ectopy, and ventricular ectopy. In 1,329 participants in the analysis, the mean (SD) age was 67 (8) years and 48% were men. A more favorable total LS7 score was associated with fewer premature ventricular contractions (PVCs) per hour (ratio of geometric means for optimal [11 to 14] versus inadequate [0 to 7] score 0.52 [95% confidence interval 0.34 to 0.81]). After adjustment for sociodemographic characteristics, the association was attenuated (0.66 [0.43 to 1.01]). =Among the LS7 components, a more favorable body mass index was associated with less ventricular ectopy. We did not detect associations of total LS7 score with atrial arrhythmias. In conclusion, in this longitudinal study of older participants free of clinically recognized cardiovascular disease, there was little evidence of association of the LS7 cardiovascular health score with subclinical cardiac arrhythmias. However, there was a suggestion that a more favorable LS7 score was associated with fewer PVCs and specifically, that a more favorable body mass index was associated with fewer PVCs.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Marijuana use among all age groups has been increasing, including among older adults aged ≥65 years. There is a lack of epidemiologic data examining arrhythmia risk among users of marijuana. We evaluated cross-sectional associations between current and past marijuana smoking and arrhythmias among 1485 participants from the Multiethnic Study of Atherosclerosis who underwent extended ambulatory electrocardiographic monitoring with the Zio Patch XT. Outcomes included premature atrial contractions, runs of supraventricular tachycardia, premature ventricular contractions, and runs of nonsustained ventricular tachycardia (NSVT). Compared with never users, participants reporting current use of marijuana (n = 40, 3%) had more supraventricular tachycardia/day (adjusted geometric mean ratio [GMR] 1.42, 95% confidence interval [CI] 0.87 to 2.32), more premature atrial contractions/hour (GMR 1.22, 95% CI 0.72, 2.13), and more NSVT/day (GMR 1.28, 95% CI 0.95 to 1.73); although, CIs overlapped 1. Additionally, more frequent marijuana use was associated with more runs of NSVT/day (GMR 1.56, 95% CI 1.13, 2.17). In conclusion, our results suggest that current marijuana use may be associated with a greater burden of arrhythmias. There is a need for additional research, mainly using a prospective design, to clarify if marijuana use causes atrial and ventricular arrhythmias or other cardiovascular complications among older adults.

OBJECTIVE LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Introduction: Atrial fibrillation (AF) increases stroke risk and is associated with accelerated cognitive decline. Information is mixed about the relationship of AF and other supraventricular (SV) arrhythmias with brain changes on magnetic resonance imaging (MRI). Hypothesis: Prevalent AF and SV ectopy are associated with reduced gray matter (GM) volume and subclinical vascular brain injury. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), participants completed Zio Patch monitoring and brain MRI. Prevalent AF was estimated from ambulatory monitoring, hospital surveillance, Medicare claims, and MESA electrocardiogram (ECG). For secondary analyses, AF was categorized into continuous - AF during 100% of monitoring - and intermittent - prevalent AF with Results: In MESA, 967 participants without a history of stroke or transient ischemic attack (TIA) completed >24 hours of ECG monitoring (median, 14.0 days) and completed brain MRI a median 17 months later. Mean (standard deviation) age was 72 (8) years; 53% were women. A total of 116 participants had prevalent AF, of whom 20 had continuous AF. Compared with no AF, prevalent AF was associated with lower WM FA (-0.22 standard deviations, 95% CI: -0.39, -0.04) and higher prevalence of CMBs (prevalence ratio: 1.46, 95% CI: 1.18, 1.80). In secondary analyses, compared with no AF, continuous but not intermittent AF was associated with lower GM volume (-18.6 mL, 95% CI: -31.4, -5.8). Rates of premature atrial contractions and runs of SV tachycardia were not significantly associated with brain MRI measures. Conclusions: In a multi-ethnic sample free of a history of stroke or TIA, prevalent AF was associated with lower WM FA, a measure of WM injury, and presence of CMBs. These results highlight the importance of AF prevention for brain health. Further analysis of subclinical infarcts is needed in this sample, and study in other settings is needed to confirm whether greater AF burden is associated with reduced GM volume.

Introduction: Abnormalities in left atrial (LA) function can be identified before the development of overt LA structural changes. Little is known about the relationship between LA mechanics and the risk of subclinical atrial and ventricular arrhythmias. Methods: 1,441 participants of the Multi-Ethnic Study of Atherosclerosis completed speckle-tracking echocardiography and Zio Patch monitoring from 2016-2018 (mean age 73 years, 52% female); participants in atrial fibrillation (AF) during echocardiography or cardiac monitoring were excluded. Absolute values of LA reservoir, booster pump, and conduit strain were measured. We evaluated associations of LA strain measures with atrial arrhythmias (presence of monitor-detected AF, AF burden, frequency of premature atrial contractions [PACs], frequency of supraventricular tachycardia [SVT] runs) and with ventricular arrhythmias (frequency of premature ventricular contractions, presence of non-sustained ventricular tachycardia [NSVT], frequency of NSVT runs). Primary analyses adjusted for demographic variables, blood pressure, smoking, diabetes, and clinical cardiovascular disease (4%). Results: Cardiac monitoring (median 14 days) detected AF in 3%. Each standard deviation (5.4%) lower (worse) LA reservoir strain was associated with a 64% higher risk of monitor-detected AF (95% CI 16-137%), 33% higher PAC frequency (95% CI 22-46%), and 15% higher SVT frequency (95% CI 7-24%). Adjustment for kidney function, NT-proBNP, LA volume, and LV ejection fraction and global longitudinal strain had little impact on associations. Findings were similar for LA booster pump strain and null for LA conduit strain (Figure). Associations of LA reservoir and booster pump strain with ventricular arrhythmias were completely attenuated after adjustment for LV function. Conclusions: In a multi-ethnic community-based cohort, abnormal LA mechanics may be an important risk factor for subclinical atrial arrhythmias.

SummaryMendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P−8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14×10−65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015–2019 in 2 integrated health-care institutions in the Northwest United States. We used one site’s manually reviewed gold-standard outcomes data for model development and the other’s for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.

BACKGROUND Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS We conducted a case–control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal ( RESULTS The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10−8) and in the race-combined analysis (P = 1.5 × 10−9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6–0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

Objective To compare incident dementia risk among patients who initiated treatment with metformin or sulfonylurea in Veterans Health Affairs (VHA) patients with replication in Kaiser Permanente Washington (KPW) patients to determine whether first-choice antidiabetic medications are associated with reduced risk of dementia. Patients and Methods Cohorts contained 75,187 VHA patients and 10,866 KPW patients, 50 years and older, who initiated monotherapy with metformin or sulfonylurea. Patients were free of dementia diagnoses and any diabetes treatment for 2 years before cohort entry. Variables were extracted from electronic health data from VHA (1999-2015) and KPW (1996-2015), which included diagnosis codes, pharmacy data, laboratory values, and demographic characteristics. Propensity scores and inverse probability of treatment weighting controlled for confounding. Results Veterans Health Affairs patients were 60.8±6.8 years of age on average, and KPW patients were 63.1±9.5 years of age. In the VHA sample, 72,769 (96.8%) were male; and in the KPW sample, 5480 (50.4%). After adjusting for confounding, metformin initiation was associated with a significantly (P=.02) lower risk of dementia in VHA (hazard ratio, 0.9; 95% CI, 0.9-1.0), with a similar point estimate in KPW (hazard ratio, 0.9; 95% CI, 0.7-1.1). Metformin was not associated with dementia risk in patients 75 years and older. Conclusion Existing epidemiological studies of metformin and incident dementia have been inconsistent. Using a similar study design in 2 patient populations that differed in clinical and demographic characteristics, our results provide robust evidence that metformin use is associated with a modestly lower risk of incident dementia.

Sex- and race-based differences in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are poorly understood. Clinical decisions are often informed by absolute-as opposed to relative-risk, but absolute risk of incident heart failure (HF) associated with NT-proBNP concentration across these important demographic categories is unclear.To determine whether physiologic determinants of NT-proBNP concentrations account for sex and race differences, and to more uniformly predict HF risk using NT-proBNP in these demographic subgroups.In the longitudinal Atherosclerosis Risk in Communities epidemiologic prospective community-based cohort study, the association of NT-proBNP concentration with relative and absolute risk of HF by sex- and race-based categories was assessed at study visit 2 (1990-1992) and study visit 5 (2011-2013) using Cox and Poisson regression. These data were analyzed from June 2018 to October 2021. The contribution of clinical, anthropometric, echocardiographic, and laboratory parameters to sex- and race-based differences in NT-proBNP concentration was assessed at visit 5 using linear regression. Participants included were free of HF in midlife (visit 2; a total of 12 750 participants) and late life (visit 5; a total of 5191 participants).NT-proBNP concentration.Incident HF or death.Among the 5191 HF-free participants at visit 5, the mean (SD) age was 76.0 (5.2) years, 2104 (41%) were male, 1043 (20%) were Black, and the median (IQR) NT-proBNP concentration was 124 (64-239) pg/. In both midlife and late life, NT-proBNP concentration was lowest in Black men (median [IQR] concentration: visit 2, 30 [14-67] pg/mL; visit 5, 74 [34-153] pg/mL) and highest in White women (median [IQR] concentration: visit 2, 70 [42-111] pg/mL; visit, 5, 154 [82-268] pg/mL). Sex and race differences in NT-proBNP concentration persisted after accounting for age, income, education, area deprivation index, cardiovascular diseases, left ventricular structure (LV), LV function, LV wall stress, weight and fat mass, and estimated glomerular filtration rate. Substantial differences in the absolute risk of incident HF or death existed across the sex- and race-based categories at any NT-proBNP concentration (eg, 7-fold [rate ratio, 6.7; 95% CI, 4.6-9.9] and 3-fold [rate ratio, 2.7; 95% CI, 1.7-4.1] difference at visit 2 and visit 5, respectively, at guideline-recommended thresholds) with higher risk consistently observed among Black men and lower risk in White women. Results were replicated in a cohort of participants from the Cardiovascular Health Study.In this study, sex- and race-based differences in NT-proBNP persisted after accounting for known physiologic determinants. Absolute risk associated with a given value of NT-proBNP varied substantially by sex and race. Consideration of NT-proBNP values in the context of sex and race allows for more uniform prediction of absolute risk across important demographic subgroups.

Introduction: Chronic kidney disease (CKD) patients are at high risk for atrial fibrillation (AF) and ventricular arrhythmias. Arrhythmias are often asymptomatic and not detected clinically, so the true prevalence among CKD patients is unknown. Extended ambulatory cardiac monitoring is a sensitive and unbiased method for detecting arrhythmias. Hypothesis: We assessed the hypothesis that impaired kidney function is associated with atrial and ventricular arrhythmias as measured by extended ambulatory cardiac monitoring. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), kidney function was assessed at the 2016-2018 study visit: estimated glomerular filtration rate (eGFR) using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation and urinary albumin-creatinine ratio (UACR). UACR was log 2 transformed for analysis. At the same visit, extended ambulatory cardiac monitoring was conducted for up to two 14-day periods per participant using the Zio Patch XT (iRhythm Technologies, Inc., San Francisco, CA). Device information was consolidated for participants with 2 devices, and 7 arrhythmia outcomes were studied: presence of monitor-detected AF (>30 seconds), presence of subclinical AF (in those with no history of clinically detected AF), frequency of premature atrial contractions, frequency of runs of ≥ 4 beats of supraventricular tachycardia (SVT), frequency of premature ventricular contractions, presence of runs of ≥ 4 beats of ventricular tachycardia (VT), and frequency of runs of VT. Continuous outcome variables were natural log transformed. Analyses used logistic regression for binary outcomes and linear regression for continuous outcomes, adjusted for demographic and clinical risk factors. Results: A total of 1459 participants had eGFR measures and 1369 had UACR measures; 178 had a history of clinically detected AF. Mean (standard deviation (SD)) age was 74 (8) years; with 52% women. Median (interquartile range) kidney function measures were eGFR 77 (62, 88) ml/min/1.73 m 2 and UACR 6 (3, 18) mg/g, and total monitoring duration was 14 (14, 26) days. AF was detected in 7%, all but one participant had supraventricular ectopy, and 99% had ventricular ectopy. A doubling of UACR was associated with increased odds of monitor-detected AF (odds ratio 1.18; 95% confidence interval (CI): 1.06-1.32) while eGFR was not significantly associated. Neither eGFR nor UACR was associated with subclinical AF or with ventricular arrhythmias. The analysis of eGFR and frequency of runs of SVT yielded results opposite of the expected direction: a 10 ml/min/1.73 m 2 greater eGFR was associated with a 7% greater frequency of SVT (95% CI: 1%-12%). Conclusion: In summary, in a large population of older individuals across a wide range of kidney function, we found little evidence that impaired kidney function was associated with increased monitor-detected arrhythmias.

Purpose: High blood pressure (BP) is a well-known risk factor for atrial fibrillation (AF), but a single BP measurement may provide limited information about AF risk in older adults. We evaluated whether longitudinal measures of BP were associated with subclinical arrhythmias after adjustment for more conventional BP measures such as a single cross-sectional BP value. Methods: This study included 1,256 Multi-Ethnic Study of Atherosclerosis (MESA) and 1,948 Atherosclerosis Risk in Communities study (ARIC) participants who underwent extended ambulatory electrocardiographic monitoring and who were free of clinically-detected cardiovascular disease, including AF. Using BP measurements from six exams (2000-2018 in MESA, 1987-2017 in ARIC), we examined cross-sectional BP at the most recent exam, individual long-term mean BP from exams 1-5, BP trend during exams 1-5, and visit-to-visit variability during exams 1-5 in systolic BP (SBP) and pulse pressure (PP) for each participant. Logistic regression models were used to examine BP exposures in relation to subclinical AF and linear regression models were used to examine BP exposures in relation to frequency of supraventricular ectopy. Models adjusted for participant demographics, height, weight, diabetes, antihypertensive medication use and cross-sectional BP. Results from each study were combined with inverse variance-weighted meta-analysis. Results: At Exam 6, the mean age was 73 years in MESA and 79 years in ARIC, and 4% had subclinical AF. A 10 mmHg higher cross-sectional SBP and a 10 mmHg higher cross-sectional PP were associated with less AF (odds ratio [OR] SBP 0.86, 95% confidence interval [CI] 0.76, 0.96 and OR PP 0.73, 95% CI 0.63, 0.84). In contrast, a 4 mmHg higher visit-to-visit variability in SBP was associated with a greater prevalence of subclinical AF (OR 1.20, 95% CI 1.02, 1.38) and with a greater frequency of premature atrial contractions/hour (8%, 95% CI 1%, 15%). For PP as well, a 4 mmHg higher visit-to-visit variability was associated with a greater prevalence of AF (OR 1.18, 95% CI 1.00-1.37). In addition, a 10 mmHg higher long-term mean PP was associated with a greater prevalence of subclinical AF (OR 1.36, 95% CI 1.08-1.70). Conclusion: Our results indicate that information on BP assessed longitudinally for several years, especially visit-to-visit BP variability, is associated with a greater prevalence of subclinical atrial arrhythmias, while cross-sectional BP values alone were not associated with a greater prevalence of subclinical atrial arrhythmias. Prior longitudinal BP assessment, rather than current BP, may be more helpful in identifying older adults who are at higher risk of atrial arrhythmias.

Background High blood pressure (BP) is a well‐known risk factor for atrial fibrillation (AF), but a single BP measurement may provide limited information about AF risk in older adults. Methods and Results This study included 1256 MESA (Multi‐Ethnic Study of Atherosclerosis) and 1948 ARIC (Atherosclerosis Risk in Communities) study participants who underwent extended ambulatory electrocardiographic monitoring and who were free of clinically detected cardiovascular disease, including AF. Using BP measurements from 6 examinations (2000–2018 in MESA and 1987–2017 in ARIC study), we calculated individual long‐term mean, trend, and detrended visit‐to‐visit variability in systolic BP and pulse pressure for each participant. Outcomes, assessed at examination 6, included subclinical AF and supraventricular ectopy. Results from each study were combined with inverse variance‐weighted meta‐analysis. At examination 6, the mean age was 73 years in MESA and 79 years in ARIC study, and 4% had subclinical AF. Higher visit‐to‐visit detrended variability in systolic BP was associated with a greater prevalence of subclinical AF (odds ratio [OR], 1.20; 95% CI, 1.02–1.38) and with more premature atrial contractions/hour (geometric mean ratio, 1.08; 95% CI, 1.01–1.15). For pulse pressure as well, higher visit‐to‐visit detrended variability was associated with a greater prevalence of AF (OR, 1.18; 95% CI, 1.00–1.37). In addition, higher long‐term mean pulse pressure was associated with a greater prevalence of subclinical AF (OR, 1.36; 95% CI, 1.08–1.70). Conclusions Antecedent visit‐to‐visit variability in systolic BP and pulse pressure, but not current BP, is associated with a higher prevalence of subclinical atrial arrhythmias. Prior longitudinal BP assessment, rather than current BP, may be more helpful in identifying older adults who are at higher risk of atrial arrhythmias.

BACKGROUND Anaphylaxis is a life-threatening allergic reaction that is difficult to identify accurately with administrative data. We conducted a population-based validation study to assess the accuracy of ICD-10 diagnosis codes for anaphylaxis in outpatient, emergency department, and inpatient settings. METHODS In an integrated healthcare system in Washington State, we obtained medical records from healthcare encounters with anaphylaxis diagnosis codes (potential events) from October 2015 to December 2018. To capture events missed by anaphylaxis diagnosis codes, we also obtained records on a sample of serious allergic and drug reactions. Two physicians determined whether potential events met established clinical criteria for anaphylaxis (validated events). RESULTS Out of 239 potential events with anaphylaxis diagnosis codes, the overall positive predictive value (PPV) for validated events was 64% (95% CI = 58 to 70). The PPV decreased with increasing age. Common precipitants for anaphylaxis were food (39%), medications (35%), and insect bite or sting (12%). The sensitivity of emergency department and inpatient anaphylaxis diagnosis codes for all validated events was 58% (95% CI = 51 to 65), but sensitivity increased to 95% (95% CI = 74 to 99) when outpatient diagnosis codes were included. Using information from all validated events and sampling weights, the incidence rate for anaphylaxis was 3.6 events per 10,000 person-years (95% CI = 3.1 to 4.0). CONCLUSIONS In this population-based setting, ICD-10 diagnosis codes for anaphylaxis from emergency department and inpatient settings had moderate PPV and sensitivity for validated events. These findings have implications for epidemiologic studies that seek to estimate risks of anaphylaxis using electronic health data.