Temporal trends in cause-specific mortality among individuals with newly diagnosed atrial fibrillation in the Framingham Heart Study.

BACKGROUND: All-cause mortality following atrial fibrillation (AF) has decreased over time. Data regarding temporal trends in causes of death among individuals with AF are scarce. The aim of our study was to analyze temporal trends in cause-specific mortality and predictors for cardiovascular (CVD) and non-CVD deaths among participants with incident AF in the Framingham Heart Study. METHODS: We categorized all newly diagnosed AF cases according to age at AF diagnosis (< 70, 70 to < 80, and ≥ 80 years) and epoch of AF diagnosis (< 1990, 1990-2002, and ≥ 2003). We followed participants until death or the last follow-up. We categorized death causes into CVD, non-CVD, and unknown causes. For each age group, we tested for trends in the cumulative incidence of cause-specific death across epochs. We fit multivariable Fine-Gray models to assess subdistribution hazard ratios (HR) between clinical risk factors at AF diagnosis and cause-specific mortality. RESULTS: We included 2125 newly diagnosed AF cases (mean age 75.5 years, 47.8% women). During a median follow-up of 4.8 years, 1657 individuals with AF died. There was evidence of decreasing CVD mortality among AF cases diagnosed < 70 years and 70 to < 80 years (ptrend < 0.001) but not ≥ 80 years (p = 0.76). Among the cases diagnosed < 70 years, the cumulative incidence of CVD death at 75 years was 67.7% in epoch 1 and 13.9% in epoch 3; among those 70 to < 80 years, the incidence at 85 years was 58.9% in epoch 1 and 18.9% in epoch 3. Advancing age (HR per 1 SD increase 6.33, 95% CI 5.44 to 7.37), prior heart failure (HR 1.49, 95% CI 1.14-1.94), and prior myocardial infarction (HR 1.44, 95% CI 1.15-1.80) were associated with increased rate of CVD death. CONCLUSIONS: In this community-based cohort, CVD mortality among AF cases decreased over time. Most deaths in individuals with AF are no longer CVD-related, regardless of age at AF diagnosis.

Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation.

BACKGROUND: The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. METHODS: We estimated the lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of ≈1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. RESULTS: Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF >55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4-9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3-55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P<0.001). CONCLUSIONS: In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.

Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study.

INTRODUCTION: We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up. METHODS: Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified. RESULTS: Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up. DISCUSSION: Baseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.

Cerebral Microbleeds as Predictors of Mortality: The Framingham Heart Study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMB) represent a common magnetic resonance imaging marker of cerebral small vessel disease, increasingly recognized as a subclinical marker of stroke and dementia risk. CMB detection may reflect the cumulative effect of vascular risk burden and be a marker of higher mortality. We investigated the relation of CMB to risk of death in community dwelling participants free of stroke and dementia. METHODS: We evaluated 1963 Framingham Original and Offspring Cohort participants (mean age 67 years; 54% women) with available brain magnetic resonance imaging and mortality data. Using Cox proportional hazards models, we related CMB to all-cause, cardiovascular, and stroke-related mortality. RESULTS: Participants with CMB (8.9%) had higher prevalence of cardiovascular risk factors and use of preventive medications. During a mean follow-up of 7.2±2.6 years, we observed 296 deaths. In age- and sex-adjusted analysis, CMB were associated with increased all-cause mortality (hazards ratio, 1.39; 95% confidence interval 1.03-1.88), a relation that was no longer significant after adjustment for cardiovascular risk and preventive medication use (hazards ratio, 1.15; 95% confidence interval, 0.82-1.63). CONCLUSIONS: CMBs may represent the deleterious effect of cardiovascular risk factors in the cerebral vasculature. Although their presence was associated with increased all-cause mortality, the effect was no longer present after accounting for vascular risk factors and preventive treatment use. Further studies are required to clarify the role of cardiovascular preventive therapies for prevention of mortality in persons with incidental detection of CMB.

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study.

INTRODUCTION: The identification of novel biomarkers associated with Alzheimer's disease (AD) could provide key biological insights and permit targeted preclinical prevention. We investigated circulating metabolites associated with incident dementia and AD using metabolomics. METHODS: Plasma levels of 217 metabolites were assessed in 2067 dementia-free Framingham Offspring Cohort participants (mean age = 55.9 ± 9.7 years; 52.4% women). We studied their associations with future dementia and AD risk in multivariate Cox models. RESULTS: Ninety-three participants developed incident dementia (mean follow-up = 15.6 ± 5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (hazard ratio [HR] = 1.40; 95% confidence interval [CI] = [1.15-1.70]; P = 8.08 × 10-4). Glutamic acid (HR = 1.38; 95% CI = [1.11-1.72]), taurine (HR = 0.74; 95% CI = [0.60-0.92]), and hypoxanthine (HR = 0.74; 95% CI = [0.60-0.92]) levels also showed suggestive associations with dementia risk. DISCUSSION: We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.

Neuropsychological Criteria for Mild Cognitive Impairment and Dementia Risk in the Framingham Heart Study.

OBJECTIVES: To refine mild cognitive impairment (MCI) diagnostic criteria, we examined progression to dementia using two approaches to identifying MCI. METHODS: A total of 1203 Framingham Heart Study participants were classified at baseline as cognitively normal or MCI (overall and four MCI subtypes) via conventional Petersen/Winblad criteria (single cognitive test impaired per domain, >1.5 SD below expectations) or Jak/Bondi criteria (two tests impaired per domain, >1 SD below norms). Cox proportional hazards models were constructed to examine the association between each MCI definition and incident dementia. RESULTS: The Petersen/Winblad criteria classified 34% of participants as having MCI while the Jak/Bondi criteria classified 24% as MCI. Over a mean follow-up of 9.7 years, 58 participants (5%) developed incident dementia. Both MCI criteria were associated with incident dementia [Petersen/Winblad: hazards ratio (HR) = 2.64; p-value=.0002; Jak/Bondi: HR=3.30; p-value <.0001]. When both MCI definitions were included in the same model, only the Jak/Bondi definition remained statistically significantly associated with incident dementia (HR=2.47; p-value=.008). Multi-domain amnestic and single domain non-amnestic MCI subtypes were significantly associated with incident dementia for both diagnostic approaches (all p-values <.01). CONCLUSIONS: The Jak/Bondi MCI criteria had a similar association with dementia as the conventional Petersen/Winblad MCI criteria, despite classifying ~30% fewer participants as having MCI. Further exploration of alternative methods to conventional MCI diagnostic criteria is warranted. (JINS, 2016, 22, 937-943).

Pulse Pressure Is Associated With Early Brain Atrophy and Cognitive Decline: Modifying Effects of APOE-ε4.

We investigated whether midlife pulse pressure is associated with brain atrophy and cognitive decline, and whether the association was modified by apolipoprotein-E ε4 (APOE-ε4) and hypertension. Participants (549 stroke-free and dementia-free Framingham Offspring Cohort Study participants, age range=55.0 to 64.9 y) underwent baseline neuropsychological and magnetic resonance imaging (subset, n=454) evaluations with 5- to 7-year follow-up. Regression analyses investigated associations between baseline pulse pressure (systolic-diastolic pressure) and cognition, total cerebral volume and temporal horn ventricular volume (as an index of smaller hippocampal volume) at follow-up, and longitudinal change in these measures. Interactions with APOE-ε4 and hypertension were assessed. Covariates included age, sex, education, assessment interval, and interim stroke. In the total sample, baseline pulse pressure was associated with worse executive ability, lower total cerebral volume, and greater temporal horn ventricular volume 5 to 7 years later, and longitudinal decline in executive ability and increase in temporal horn ventricular volume. Among APOE-ε4 carriers only, baseline pulse pressure was associated with longitudinal decline in visuospatial organization. Findings indicate arterial stiffening, indexed by pulse pressure, may play a role in early cognitive decline and brain atrophy in mid to late life, particularly among APOE-ε4 carriers.

Population Normative Data for the CERAD Word List and Victoria Stroop Test in Younger- and Middle-Aged Adults: Cross-Sectional Analyses from the Framingham Heart Study.

BACKGROUND/STUDY CONTEXT: To provide baseline normative data on tests of verbal memory and executive function for nondemented younger- and middle-aged adults. METHODS: The Consortium to Establish a Registry for Alzheimer's Disease word list memory task (CERAD-WL) and Victoria Stroop Test (VST) were administered to 3362 Framingham Heart Study (FHS) volunteer participants aged 24-78 years. Analyses of the effects of age, gender, and education were conducted. Normative data on traditional measures and error responses are reported for each test. RESULTS: Traditional measures were significantly associated with both age and education in this cohort. Error responses also evidenced significant age and education effects. CONCLUSION: These data provide a normative comparison for assessment of verbal memory and executive functioning capabilities in younger- and middle-aged adults and may be utilized as a tool for preclinical studies of disease in this population.

Neck Circumference, Brain Imaging Measures, and Neuropsychological Testing Measures.

BACKGROUND: Perivascular fat may have direct effects on local vascularity. Neck fat is associated with carotid intimal thickness, a predictor of brain aging outcomes. This study investigated whether neck circumference, an estimation of neck fat, has unique associations with brain aging outcomes. METHODS: The study sample (n = 2082, 53.5% women, mean age 60.9 years) was derived from Framingham Heart Study participants with brain magnetic resonance imaging (MRI) and neuropsychological (NP) test measures. Multivariable-adjusted regressions examined cross-sectional associations of neck circumference with brain MRI and NP test measures. Models were also constructed with waist circumference and body mass index (BMI) as exposures. RESULTS: A 1 standard deviation (2.8 cm [women]; 2.9 cm [men]) increment in neck circumference was associated with lower total cerebral brain volume (ß = -.22, P = .0006) and lower frontal brain volume (ß = -.55, P < .0001). However, a similar association was observed for both waist circumference and BMI. There were no associations between neck circumference and NP test measures after full covariate adjustment. CONCLUSIONS: There were no unique associations between neck circumference and brain MRI or NP measures. Consistent with prior observations, all adiposity measures showed associations with more adverse brain MRI and NP measures, suggesting a global association of generalized adiposity.

Associations of Circulating Growth Differentiation Factor-15 and ST2 Concentrations With Subclinical Vascular Brain Injury and Incident Stroke.

BACKGROUND AND PURPOSE: Growth differentiation factor-15 (GDF-15) and soluble (s)ST2 are markers of cardiac and vascular stress. We investigated the associations between circulating concentrations of these biomarkers and incident stroke and subclinical vascular brain injury in a sample from the Framingham Offspring cohort. METHODS: We followed 3374 stroke- and dementia-free individuals (mean age, 59.0±9.7 years; 53% women) attending the Framingham Offspring sixth examination cycle 11.8±3.0 years for incident stroke. A subsample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing ≈4.0±1.7 years after the sixth examination. RESULTS: After adjustment for traditional cardiovascular risk factors, B-type natriuretic peptide, high-sensitivity C-reactive protein, and urine albumin levels, higher stress biomarker levels were associated cross-sectionally with lower brain volumes (ß coefficients for intracranial volume comparing fourth [Q4] versus first biomarker [Q1] quartiles: -0.71% for GDF-15; P=0.002 and 0.47% for sST2; P=0.02) and worse performance on the visual reproduction test (ß coefficients for Q4 versus Q1: -0.62 for GDF-15; P=0.009 and -0.40 for sST2; P=0.04). Higher GDF-15 concentrations were also associated with greater log-transformed white-matter hyperintensity volumes (ß for Q4 versus Q1=0.19; P=0.01). Prospectively, a total of 203 (6%) individuals developed incident stroke/transient ischemic attack during follow-up. After multivariable adjustment, sST2 remained significantly associated with stroke/transient ischemic attack, hazard ratio for Q4 versus Q1 of 1.76, 95% confidence interval of 1.06 to 2.92, and P=0.03. CONCLUSIONS: Circulating GDF-15 and sST2 are associated with subclinical brain injury and cognitive impairment. Higher sST2 concentrations are also associated with incident stroke, suggesting potential links between cardiac stress biomarkers and brain injury.

Long-term exposure to fine particulate matter, residential proximity to major roads and measures of brain structure.

BACKGROUND AND PURPOSE: Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging. METHODS: Framingham Offspring Study participants who attended the seventh examination were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter [PM2.5] and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age), and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends. RESULTS: A 2-µg/m(3) increase in PM2.5 was associated with -0.32% (95% confidence interval, -0.59 to -0.05) smaller total cerebral brain volume and 1.46 (95% confidence interval, 1.10 to 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95% confidence interval, 0.01 to 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter. CONCLUSIONS: Exposure to elevated levels of PM2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia- and stroke-free persons.

Mid-life Cardiovascular Risk Impacts Memory Function: The Framingham Offspring Study.

INTRODUCTION: This study incorporates unique error response analyses with traditional measures of memory to examine the association between mid-life cardiovascular risk factors and later-life memory function. METHODS: The Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was assessed in 1755 Framingham Offspring participants (54% women, mean age=54±9 y) from 1991 to 1995. Memory tests including Logical Memory and Visual Reproductions were administered from 2005 to 2008. Linear and logistic regression examined the association between FSRP and memory measures. Interaction between the presence of the ApoE4 allele and each FSRP component on the memory measures was also assessed. RESULTS: FSRP and the individual components of age, sex, and smoking were related to lower standard scores of memory. The new error response analyses reinforced the standard analyses and also identified new relationships. Participants with diabetes were found to make more errors on Logical Memory, and those with a history of smoking were found to make more errors on Visual Reproductions. Lastly, ApoE4 smokers experienced significant verbal memory loss, whereas ApoE4 smokers did not. CONCLUSIONS: Middle-aged healthy adults with cardiovascular risk factors including diabetes, history of smoking, and ApoE4 positivity were found to have greater later-life memory impairments.

Mid-adulthood risk factor profiles for CKD.

Early identification of CKD risk factors may allow risk factor modification and prevention of CKD progression. We investigated the hypothesis that risk factors are present ≥30 years before the diagnosis of CKD in a case-control study using data from the Framingham Offspring Study. Patients with incident CKD (eGFR≤60 ml/min per 1.73 m2) at examination cycles 6, 7, and 8 were age- and sex-matched 1:2 to patients without CKD at baseline (examination 5). CKD risk factors were measured at each examination cycle. Logistic regression models, adjusted for age, sex, and time period, were constructed to compare risk factor profiles at each time point between cases and controls. During follow-up, 441 new cases of CKD were identified and matched to 882 controls (mean age 69.2 years, 52.4% women). Those who ultimately developed CKD were more likely to have hypertension (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.23 to 2.51), obesity (OR, 1.71; 95% CI, 1.14 to 2.59), and higher triglyceride levels (OR, 1.43; 95% CI, 1.12 to 1.83) 30 years before CKD diagnosis, and were more likely to have hypertension (OR, 1.38; 95% CI, 1.07 to 1.79), higher triglyceride levels (OR, 1.35; 95% CI, 1.11 to 1.64), lower HDLc (OR, 0.89; 95% CI, 0.81 to 0.97), and diabetes (OR, 2.90; 95% CI, 1.59 to 5.29) 20 years before CKD diagnosis. These findings demonstrate that risk factors for CKD are identifiable ≥30 years before diagnosis and suggest the importance of early risk factor identification in patients at risk for CKD.

Gender and incidence of dementia in the Framingham Heart Study from mid-adult life.

BACKGROUND: Gender-specific risks for dementia and Alzheimer's disease (AD) starting in midlife remain largely unknown. METHODS: Prospectively ascertained dementia/AD and cause-specific mortality in Framingham Heart Study (FHS) participants was used to generate 10- to 50-year risk estimates of dementia/AD on the basis of the Kaplan-Meier method (cumulative incidence) or accounting for competing risk of death (lifetime risk [LTR]). RESULTS: Overall, 777 cases of incident dementia (601 AD) occurred in 7901 participants (4333 women) over 136,266 person-years. Whereas cumulative incidences were similar in women and men, LTRs were higher in women older than 85 years of age. LTR of dementia/AD at age 45 was 1 in 5 in women and 1 in 10 in men. Cardiovascular mortality was higher in men with rate ratios decreasing from approximately 6 at 45 to 54 years of age to less than 2 after age 65. CONCLUSION: Selective survival of men with a healthier cardiovascular risk profile and hence lower propensity to dementia might partly explain the higher LTR of dementia/AD in women.

Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB. METHODS: We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [APOE]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed). RESULTS: CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (P<0.0001) and was higher in men (P<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (P<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (P<0.05). Statin use increased risk of lobar and mixed location CMB (P<0.05). The latter association was not affected by adjustment for cholesterol levels or concomitant medication use. CONCLUSIONS: We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.

Midlife cardiovascular risk impacts executive function: Framingham offspring study.

INTRODUCTION: Novel error scores and traditional indices of executive function (EF) were related to cardiovascular risk factors measured 10 to 15 years earlier. METHODS: From 1991 to 1995, the Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was ascertained in 1755 Framingham Offspring participants (54% women, mean age=54±9 y). Participants were administered EF tests, which included: FAS and Animals Fluency tests, Trail Making Test B (TrB), and Digit Span-Backwards (DS-B), from 2005 to 2009. Linear and logistic regression were used to relate the FSRP and its components to both error responses and traditional scores. RESULTS: Consistent with previous findings, the FSRP and the individual components, diabetes and sex, were associated with several traditional measures of EF. Of interest were relationships between the FSRP score and TrB Total Errors (P=0.04), DS-B% Total Errors (P=0.02) and DS-B Capacity Score (P=0.03), and prevalent CVD related to making FAS Perseverations in the 75th percentile (P=0.03). By comparison, FSRP and CVD were not related to the traditional DS-B or FAS scores. In addition, age was associated with higher Animals % Total Errors and % Perseverations among ApoE4+ individuals and with higher TrB Total Errors among ApoE4- individuals. CONCLUSIONS: For those middle-aged and healthy, including those who are ApoE4+, cardiovascular risk factors are related to impairments in EF as ascertained by novel errors and traditional measures.

Development and validation of a brief dementia screening indicator for primary care.

BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives. METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening. RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78). CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.

Bidirectional Association Between Atrial Fibrillation and Myocardial Infarction, and Relation to Mortality in the Framingham Heart Study.

BACKGROUND: Individuals with both atrial fibrillation (AF) and myocardial infarction (MI) have higher mortality compared with individuals with only 1 condition. Whether mortality differs according to the temporal order of AF and MI is unclear. METHODS AND RESULTS: We included participants from the FHS (Framingham Heart Study) from 1960 and onwards. We assessed the hazard ratio (HR) of new-onset AF and MI, and mortality according to MI and AF status (prevalent and interim) using multivariable-adjusted Cox proportional hazards models. Interim diseases were modeled as time-varying variables. For the analysis of new-onset AF, 10 923 participants (55% women; mean±SD age, 54±8 years) were included. For new-onset MI, 10 804 participants (55% women; mean±SD age, 54±8 years) were included. Compared with no MI, the hazard of new-onset AF was higher in participants with prevalent (HR, 1.60 [95% CI, 1.32-1.94]) and interim MI (HR, 3.96 [95% CI, 3.18-4.91]). Both ST-segment-elevation MI and non-ST-segment-elevation MI were associated with new-onset AF. Interim AF, not prevalent AF, was associated with higher hazard rate of new-onset MI (HR, 2.21 [95% CI, 1.67-2.92]). Interim AF was associated with both ST-segment-elevation MI and non-ST-segment-elevation MI. Mortality was significantly greater among participants with AF and MI compared with participants with 1 of the 2, regardless of temporal order. CONCLUSIONS: We report a bidirectional association between AF and MI, which was observed for both non-ST-segment-elevation MI and ST-segment-elevation MI. Participants with both AF and MI had considerably higher mortality compared with participants with only 1 of the 2 conditions, regardless of order.

Incidence and prognostic significance of newly-diagnosed atrial fibrillation among older U.S. veterans hospitalized with COVID-19.

Most prior studies on the prognostic significance of newly-diagnosed atrial fibrillation (AF) in COVID-19 did not differentiate newly-diagnosed AF from pre-existing AF. To determine the association between newly-diagnosed AF and in-hospital and 30-day mortality among regular users of Veterans Health Administration using data linked to Medicare. We identified Veterans aged ≥ 65 years who were hospitalized for ≥ 24 h with COVID-19 from 06/01/2020 to 1/31/2022 and had ≥ 2 primary care visits within 24 months prior to the index hospitalization. We performed multivariable logistic regression analyses to estimate adjusted risks, risk differences (RD), and odds ratios (OR) for the association between newly-diagnosed AF and the mortality outcomes adjusting for patient demographics, baseline comorbidities, and presence of acute organ dysfunction on admission. Of 23,299 patients in the study cohort, 5.3% had newly-diagnosed AF, and 29.2% had pre-existing AF. In newly-diagnosed AF adjusted in-hospital and 30-day mortality were 16.5% and 22.7%, respectively. Newly-diagnosed AF was associated with increased mortality compared to pre-existing AF (in-hospital: OR 2.02, 95% confidence interval [CI] 1.72-2.37; RD 7.58%, 95% CI 5.54-9.62) (30-day: OR 1.86; 95% CI 1.60-2.16; RD 9.04%, 95% CI 6.61-11.5) or no AF (in-hospital: OR 2.24, 95% CI 1.93-2.60; RD 8.40%, 95% CI 6.44-10.4) (30-day: 2.07, 95% CI 1.80-2.37; RD 10.2%, 95% CI 7.89-12.6). There was a smaller association between pre-existing AF and the mortality outcomes. Newly-diagnosed AF is an important prognostic marker for patients hospitalized with COVID-19. Whether prevention or treatment of AF improves clinical outcomes in these patients remains unknown.

Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham Study.

BACKGROUND AND PURPOSE: Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample. METHODS: In 3440 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests. RESULTS: During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2-Q4, 1.47; 95% confidence interval, 1.09-2.00; P=0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04-1.40; P=0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (ß±SE=-0.05±0.02; P=0.025), and better visual memory (ß±SE=0.18±0.07; P=0.005). CONCLUSIONS: Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.