Rosamond, Wayne D.

Introduction: Deep neural networks are increasingly used to generate diagnostic algorithms in cardiovascular medicine. A biomarker of cardiovascular aging, derived from a deep-learning algorithm applied to digitized 12-lead electrocardiograms (ECGs), has recently been introduced. This biomarker, delta age (δ-age), is defined as the difference between predicted ECG age and chronological age. Hypthesis: We hypothesized that δ-age will improve the prediction of incident fatal and non-fatal myocardial infarction (MI) and stroke on top of what contemporary CVD prediction tools would do. Methods: In this cohort study, we included 7,111 men and women from the Norwegian Tromsø Study conducted in 2015-16, with follow-up through 2021 for incident fatal and non-fatal myocardial infarction (MI) and hemorrhagic or cerebral stroke. We used Cox proportional hazards regression models to assess the independent effect of δ-age on MI and stroke. Discrimination was evaluated using Harrell’s concordance statistic (C-index) and the net reclassification improvement (NRI). Results: During a median follow-up of 5.9 years, we observed 155 incident cases of MI, 141 cases stroke and 290 cases with either MI or stroke. δ-age was observed with a mean of 0 and standard deviation of 6.2 years. In men and women combined, hazard ratios (HRs) per standard deviation increase in δ-age, after adjustment for traditional risk factors, were 1.24 (95% confidence interval (CI) 1.09, 1.41) for the combined outcome, 1.26 (1.06, 1.49) for MI and 1.25 (1.03, 1.50) for stroke. In men, the corresponding HRs were 1.27 (1.09, 1.49), 1.46 (1.18, 1.79) and 1.02 (0.80, 1.31), respectively, and in women, 1.20 (0.97, 1.49), 0.87 (0.64, 1.20) and 1.58 (1.19, 2.11), respectively. The C-index increased modestly when δ-age was added to a model with traditional risk factors. The 95% CI for the C-index increase excluded zero for the combined outcome overall, and for MI in men and for stroke in women. The NRI was 26.0% (13.3%, 38.1%) for the combined outcome, 17.5% (0.6%, 33.5%) for MI and 37.2% (20.1%, 53.0%) for stroke. Conclusions: Incorporating δ-age into primary prevention risk prediction models significantly improved performance beyond traditional cardiovascular risk factors for the combined outcome and separately for MI and stroke.

Introduction: Incident intracerebral hemorrhage (ICH) is an uncommon medical event that can lead to devastating outcomes, including death. Small vessel disease (SVD), as measured by cerebral microbleeds (CMBs) and white matter hyperintensities (WMH), has been associated with risk factors and might be a predictor of incident ICH. CMBs result from irregularities in brain vessel structure due to chronic hypertension and cerebral amyloid angiopathy. These microhemorrhages are a possible risk factor for ICH. Methods: A cohort of ARIC (Atherosclerosis Risk in Communities) participants underwent 3T MRI at visit 5 (2011-2013). CMBs were assessed using a T2* gradient echo. CMBs are homogenous hypointense lesions ≤10 mm in diameter. WMH volumes were derived from FLAIR images using an automated program to measure the volumetric burden of leukoaraiosis. During 10 years of follow-up, incident ICH was noted in 7 (0.4%) out of 1,656 participants were dichotomized based on the presence of CMB and the median of WMH volume. Results: ARIC subjects (n=1656, mean age=76±5 years; 40% men; 26% African American race) underwent MRI. CMBs were present in 385 (23.25%) patients out of 1656. ICH occurred in 0.16% and 1.30% of patients without CMBs and with CMBs, respectively. Kaplan Meier (KM) survival analysis between CMBs and ICH was significant (logrank p=0.002). Cox Regression yielded a significant crude hazards ratio (HR 8.7, 95% CI 1.7-44.7, p=0.010). Adjustment for age, gender, race, and hypertension was also significant (HR 9.9, 95% CI 1.9-52.0, p=0.07). KM survival analysis between WMH median (11.68 cm 3 ) and ICH was significant (logrank p=0.006). Figure 1 displays the KM curves of those with and without CMBs and the incidence of ICH as well as those below and above WMH median and incidence of ICH. Conclusion: CMBs and WMH detected by MRI appear to be an important predictor for the occurrence of incident ICH. Further research is needed to observe if MRI could be used to screen subjects at high-risk for elevated risk of incident ICH.

Background: The American Heart Association recently published an updated algorithm for quantifying cardiovascular health (CVH)—the Life’s Essential 8 score. We quantified US levels of CVH using the new score. Methods: We included individuals ages 2 through 79 years (not pregnant or institutionalized) who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys in 2013 through 2018. For all participants, we calculated the overall CVH score (range, 0 [lowest] to 100 [highest]), as well as the score for each component of diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, using published American Heart Association definitions. Sample weights and design were incorporated in calculating prevalence estimates and standard errors using standard survey procedures. CVH scores were assessed across strata of age, sex, race and ethnicity, family income, and depression. Results: There were 23 409 participants, representing 201 728 000 adults and 74 435 000 children. The overall mean CVH score was 64.7 (95% CI, 63.9–65.6) among adults using all 8 metrics and 65.5 (95% CI, 64.4–66.6) for the 3 metrics available (diet, physical activity, and body mass index) among children and adolescents ages 2 through 19 years. For adults, there were significant differences in mean overall CVH scores by sex (women, 67.0; men, 62.5), age (range of mean values, 62.2–68.7), and racial and ethnic group (range, 59.7–68.5). Mean scores were lowest for diet, physical activity, and body mass index metrics. There were large differences in mean scores across demographic groups for diet (range, 23.8–47.7), nicotine exposure (range, 63.1–85.0), blood glucose (range, 65.7–88.1), and blood pressure (range, 49.5–84.0). In children, diet scores were low (mean 40.6) and were progressively lower in higher age groups (from 61.1 at ages 2 through 5 to 28.5 at ages 12 through 19); large differences were also noted in mean physical activity (range, 63.1–88.3) and body mass index (range, 74.4–89.4) scores by sociodemographic group. Conclusions: The new Life’s Essential 8 score helps identify large group and individual differences in CVH. Overall CVH in the US population remains well below optimal levels and there are both broad and targeted opportunities to monitor, preserve, and improve CVH across the life course in individuals and the population.

Introduction: Understanding the role of risk factors associated with accelerated cognitive decline has important public health relevance for the aging US population. To test hypotheses that mid-life cardiovascular (CV) risk factors increase risk of dementia in old age, the Atherosclerosis Risk in Communities (ARIC) cohort was evaluated for dementia in 2011-2013. Anticipating challenges of complete dementia ascertainment in an elderly population, supplementary data sources were collected to aid analysis accounting for potentially informative attrition. Methods: ARIC enrolled 15,792 participants 45-64 years old at baseline (1987-1989) from four US communities and collected baseline CV exposure data. A complete neurocognitive battery including informant interview was completed 2011-2013, yielding an algorithmic diagnosis of dementia, mild cognitive impairment (MCI) or normal cognition. Cognitively impaired and a random sample of cognitively normal were selected for further clinical evaluation. Syndromic diagnoses (dementia/MCI/normal) and etiologic diagnoses were made by a panel of experts using standardized criteria. Standardized protocols, timely reports of reviewer reliability, ongoing training of reviewers and a web-based data management system were developed to ensure reliability, consistency and efficiency of data collection and review. Living participants not attending the visit were asked to complete the Telephone Interview for Cognitive Status (TICS). Based on dementia discharge codes and death codes identified during cohort surveillance, interviewer impression of hearing loss or cognitive impairment or need for a proxy during semi-annual calls, or random sampling, participants refusing the TICS are eligible for proxy dementia interview. Medicare claims are being examined to identify missed dementia discharge codes. Results: Of 11,017 participants alive as of 2011, 6495 (59%) completed the neurocognitive battery; 2937 of these (45%) were selected for, and completed, additional clinical assessments and classification by committee (algorithmic or reviewer diagnosis: dementia 5%, MCI 21%). Of the 4522 participants who did not undergo the neurocognitive battery, 1463 (32%) completed the TICS (dementia 7%), while 1627 of the remaining participants were eligible for proxy calls (903 completed to date, dementia 58%). Conclusions: Participants who were not examined were more likely to be cognitively impaired, highlighting the importance of collecting supplementary data to support analyses of midlife CV risk factors accounting for informative attrition. Collection of exam data in an elderly cohort is difficult and requires a multi-pronged approach, especially for an outcome highly correlated with attrition. The strategy described here could be applied in other settings.

Background: Ischemic Stroke (IS) is associated with an increased risk of dementia, but the relative contribution of IS severity or recurrence to cognition is not known. We aimed to determine the risk of dementia after incident IS and how it varies by stroke severity and recurrence in the Atherosclerosis Risk in Communities (ARIC) study. Methods: 15,405 ARIC participants free of stroke and dementia at baseline (1987-9) were followed for IS and dementia through 2019. Incident and recurrent IS were classified by expert review of hospital records, with stroke severity by the National Institutes of Health Stroke Scale (NIHSS) classified as NIHSS≤5, 6-10, 11-15, ≥16. Dementia cases were adjudicated through expert review of in-person evaluations, informant interviews, phone assessments, hospitalization code or death certificates. Poisson regression models with robust error variance were used to estimate dementia incidence in participants with and without IS, and associations between time-dependent IS incidence (excluding dementia in the first year after stroke), frequency and severity, and dementia were studied with Cox proportional hazards models, adjusting for demographics, APOE ε4 and vascular risk factors . Results: 1151 IS (970 incident) and 2807 dementia cases were identified. NIHSS was available for 877 IS (76%). Adjusted incidence rates (95% CI) of dementia per 100 person-years were 0.45 (0.42-0.49) in participants without IS vs. 1.33 (1.15-1.55) in those with IS. Compared to no IS, risk of dementia (adjusted HR, 95% CI) increased with IS number and severity from 1.71 (1.47-1.99) for participants with one IS to 6.68 (3.58-12.46) for those with ≥3 events, and from 1.64 (1.36-1.98) for NIHSS≤5 to 4.43 (1.84-10.68) for NIHSS≥16 ( Table ). Conclusion: Risk of dementia is significantly increased after stroke, independent of vascular risk factors. These data suggest a dose-response relationship between number of stroke events and stroke severity, and risk of dementia.

More than 40 years after the 1978 Bethesda Conference on the Declining Mortality from Coronary Heart Disease provided the scientific community with a blueprint for systematic analysis to understand declining rates of coronary heart disease, there are indications the decline has ended or even reversed despite advances in our knowledge about the condition and treatment. Recent data show a more complex situation, with mortality rates for overall cardiovascular disease, including coronary heart disease and stroke, decelerating, whereas those for heart failure are increasing. To mark the 40th anniversary of the Bethesda Conference, the National Heart, Lung, and Blood Institute and the American Heart Association cosponsored the “Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40” symposium. The objective was to examine the immediate and long-term outcomes of the 1978 conference and understand the current environment. Symposium themes included trends and future projections in cardiovascular disease (in the United States and internationally), the evolving obesity and diabetes epidemics, and harnessing emerging and innovative opportunities to preserve and promote cardiovascular health and prevent cardiovascular disease. In addition, participant-led discussion explored the challenges and barriers in promoting cardiovascular health across the lifespan and established a potential framework for observational research and interventions that would begin in early childhood (or ideally in utero). This report summarizes the relevant research, policy, and practice opportunities discussed at the symposium.

Background Prior studies have demonstrated a link between the metabolic syndrome and increased risk of cardiovascular mortality. Whether the metabolic syndrome is associated with sudden cardiac death is uncertain. Methods and Results We characterized the relationship between sudden cardiac death and metabolic syndrome status among participants of the ARIC (Atherosclerosis Risk in Communities) Study (1987–2012) free of prevalent coronary heart disease or heart failure. Among 13 168 participants, 357 (2.7%) sudden cardiac deaths occurred during a median follow‐up of 23.6 years. Participants with the metabolic syndrome (n=4444) had a higher cumulative incidence of sudden cardiac death than those without it (n=8724) (4.1% versus 2.3%, P <0.001). After adjustment for participant demographics and clinical factors other than components of the metabolic syndrome, the metabolic syndrome was independently associated with sudden cardiac death (hazard ratio, 1.70, 95% confidence interval, 1.37–2.12, P <0.001). This relationship was not modified by sex (interaction P =0.10) or race (interaction P =0.62) and was mediated by the metabolic syndrome criteria components. The risk of sudden cardiac death varied according to the number of metabolic syndrome components (hazard ratio 1.31 per additional component of the metabolic syndrome, 95% confidence interval, 1.19–1.44, P <0.001). Of the 5 components, elevated blood pressure, impaired fasting glucose, and low high‐density lipoprotein were independently associated with sudden cardiac death. Conclusions We observed that the metabolic syndrome was associated with a significantly increased risk of sudden cardiac death irrespective of sex or race. The risk of sudden cardiac death was proportional to the number of metabolic syndrome components.

We examined the association of variation in the type 2 diabetes risk-conferringTCF7L2gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean (BMI<25 kg/m2) individuals homozygous for theTallele of theTCF7L2rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97;P=.01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of theTCF7L2rs7903146 T allele with CHD risk.