Ndumele, Chiadi E.

Background The immune response to infections may become dysregulated and promote myocardial damage contributing to heart failure (HF). We examined the relationship between infection‐related hospitalization (IRH) and HF, HF with preserved ejection fraction, and HF with reduced ejection fraction. Methods and Results We studied 14 468 adults aged 45 to 64 years in the ARIC (Atherosclerosis Risk in Communities) Study who were HF free at visit 1 (1987–1989). IRH was identified using select International Classification of Diseases ( ICD ) codes in hospital discharge records and was treated as a time‐varying exposure. HF incidence was defined as the first occurrence of either a hospitalization that included an ICD, Ninth Revision ( ICD‐9 ) discharge code of 428 (428.0–428.9) among the primary or secondary diagnoses or a death certificate with an ICD‐9 code of 428 or an ICD, Tenth Revision ( ICD‐10 ) code of I50 among any of the listed diagnoses or underlying causes of death. We used multivariable‐adjusted Cox proportional hazards models to assess the association between IRH and incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. Median follow‐up time was 27 years, 55% were women, 26% were Black, mean age at baseline was 54±6 years, 46% had an IRH, and 3565 had incident HF. Hazard ratio (HR) for incident HF events among participants who had an IRH compared with those who did not was 2.35 (95% CI, 2.19–2.52). This relationship was consistent across different types of infections. Additionally, IRH was associated with both HF with reduced ejection fraction and HF with preserved ejection fraction: 1.77 (95% CI, 1.35–2.32) and 2.97 (95% CI, 2.36–3.75), respectively. Conclusions IRH was associated with incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. IRH might represent a modifiable risk factor for HF pathophysiology.

Background The contribution of atrial cardiopathy to dementia risk is uncharacterized. We aimed to evaluate the association of atrial cardiopathy with incident dementia and potential mediation by atrial fibrillation (AF) and stroke. Methods and Results We conducted a prospective cohort analysis of participants in the ARIC (Atherosclerosis Risk in Communities) study attending visit 5 (2011–2013). We used Cox regression to determine the association between atrial cardiopathy and risk of dementia. Structural equation modeling methods were used to determine potential mediation by AF and/or stroke. Atrial cardiopathy was defined if ≥1 of the following at visit 5: P‐wave terminal force >5000 mV·ms in ECG lead V1, NT‐proBNP (N‐terminal pro–brain natriuretic peptide) >250 pg/mL or left atrial volume index ≥34 mL/m 2 by transthoracic echocardiography. We repeated our analysis necessitating ≥2 markers to define atrial cardiopathy. The prevalence of atrial cardiopathy was 34% in the 5078 participants (mean age 75 years, 59% female, 21% Black adults), with 763 participants developing dementia. Atrial cardiopathy was significantly associated with dementia (adjusted HR, 1.35 [95% CI, 1.16–1.58]), with strengthening of the effect estimate when necessitating ≥2 biomarkers (adjusted HR, 1.54 [95% CI, 1.25–1.89]). There was an increased risk of dementia among those with atrial cardiopathy when excluding those with AF (adjusted HR, 1.31 [95% CI, 1.12–1.55]) or stroke (adjusted HR, 1.28 [95% CI, 1.09–1.52]). The proportion of the effect mediated by AF was 4% ( P =0.005), and 9% was mediated by stroke ( P =0.048). Conclusions Atrial cardiopathy was significantly associated with an increased risk of dementia, with only a small percent mediation of the effect by AF or stroke.

Background: Hepatocyte growth factor (HGF) is a cytokine released in response to vascular injury and a novel biomarker of cardiovascular disease (CVD) risk. However, the relationship between ideal cardiovascular health (CVH) and HGF is unknown. We examined whether ideal CVH is associated with lower HGF levels in a multi-ethnic cohort of adults free from clinical CVD at baseline. Methods: We analyzed data from the MESA study of 6,490 men and women aged 45-84 years. The independent variable was the CVH score derived from 7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose). Each metric was scored 0 points (poor), 1 point (intermediate) and 2 points (ideal). The total CVH score ranged from 0-14. An inadequate score was 0-8, average, 9-10 and optimal, 11-14. The number of ideal metrics was also counted. The dependent variable was logarithmically transformed HGF. We examined the association between the CVH score and HGF using linear regression models adjusted for age, sex, race/ethnicity, education, income, health insurance and study site. Results: The mean (SD) age of participants was 62 (10) years. Fifty-three percent were women. Participants with optimal CVH scores had the lowest HGF concentration [Median (IQR): 807 (678-962) pg/mL] compared to those with average [870 (740-1,036)] and inadequate scores [969 (821-1,159)]. A one-unit increment in the CVH score was significantly associated with a 3% lower HGF concentration (Table). Average and optimal CVH scores were also significantly associated with 8% and 12% lower HGF concentrations, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF concentrations. Interactions by age, sex and race/ethnicity were not significant. Conclusion: In this ethnically diverse cohort, optimal CVH was significantly associated with lower HGF levels. Interventions aimed at promoting ideal CVH may reduce vascular injury as indicated by lower serum HGF levels.

Introduction: Hepatocyte Growth Factor (HGF) is a mesenchymal cytokine linked to incident heart failure (HF), with recent data from our group showing a strong and independent association with HF with preserved ejection fraction (HFpEF). Cardiac MRI (cMRI) allows for precise analysis of morphologic changes in left ventricular (LV) structure. Increasing LV mass and concentric remodeling (defined by an increasing mass:volume ratio) are imaging markers of HFpEF risk. Whether HGF is associated with adverse LV remodeling over time is unknown. Hypothesis: Higher HGF will be associated with increasing LV mass, decreasing LV volume and increasing mass:volume ratio over 10 yrs. Methods: We studied 4762 participants of the MESA cohort, free of cardiovascular disease (CVD) and HF at baseline, who completed both HGF measurement and cMRI at baseline. Participants with LV EF<50% were excluded. Of these, 2855 completed a 2 nd cMRI at 10 yrs. We examined the cross-sectional and longitudinal associations of HGF and LV parameters using multivariable-adjusted linear mixed effect models. Results: The mean (SD) for age was 61 (10) yrs. Median (IQR) for HGF level was 888 pg/mL (745-1066); 53% women. At baseline, the 3 rd HGF tertile, compared to the 1 st , was associated with greater mass:volume ratio [relative difference 1.66 (0.43, 2.89)] and lower LV end diastolic volume [-1.87 mL (-3.45, -0.28)], after adjustment for CVD risk factors and NT- proBNP (model 2) [Table] . In longitudinal analysis, the 3 rd HGF tertile was also associated with increasing mass:volume ratio [difference in 10-yr change: 4.79 (2.73, 6.85)] and decreasing LV end diastolic volume [-4.97 (-7.10, -2.85)]. Conclusions: In a community cohort, higher HGF levels were independently associated with a concentric LV remodeling pattern of increasing mass:volume ratio and decreasing LV end diastolic volume over 10 yrs. This association may suggest an intermediate phenotype explaining the association of HGF with HFpEF risk.

Background Atrial fibrillation (AF) is a risk factor for cognitive decline, possibly from silent brain infarction. Left atrial changes in structure or function (atrial cardiopathy) can lead to AF but may impact cognition independently. It is unknown if AF or atrial cardiopathy also acts on Alzheimer disease–specific mechanisms, such as deposition of β‐amyloid. Methods and Results A total of 316 dementia‐free participants from the ARIC (Atherosclerosis Risk in Communities) study underwent florbetapir positron emission tomography, electrocardiography, and 2‐dimensional echocardiography. Atrial cardiopathy was defined as ≥1: (1) left atrial volume index >34 mL/m 2 ; (2) P‐wave terminal force >5000 µV×ms; and (3) serum NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) >250 pg/mL. Cross‐sectional associations between global cortical β‐amyloid (>1.2 standardized uptake value ratio) and adjudicated history of AF and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Participants (mean age, 76 years) were 56% women and 42% Black individuals. Odds of elevated florbetapir standardized uptake value ratio were significantly increased among those with atrial cardiopathy (odds ratio, 1.81; 95% CI, 1.02–3.22) and doubled for those with enlarged left atrial volume index after adjustment for demographics/risk factors (95% CI, 1.04–4.61). There was no association between P‐wave terminal force or NT‐proBNP and elevated florbetapir standardized uptake value ratio, nor between AF and elevated standardized uptake value ratio. Conclusions Among healthy, nondemented community‐dwelling older individuals, we report an association between atrial cardiopathy, left atrial volume index, and elevated brain amyloid, by positron emission tomography, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede or occur simultaneously with amyloid deposition.

Background: Atrial fibrillation (AF) is a risk factor for cognitive decline, perhaps due to silent cerebral infarction, but it is unknown if it also acts on Alzheimer’s Disease (AD)-specific mechanisms, such as deposition of β-amyloid (Aβ). Left atrial changes in structure or function, or atrial cardiopathy, can lead to AF but may cause infarcts independently, and thus might also impact cognition. We hypothesize that Aβ is associated with AF and atrial cardiopathy, independent of AF, when defined similarly to an ongoing clinical trial (ARCADIA). Methods: 321 participants without dementia from the Atherosclerosis Risk in Communities study underwent florbetapir (FBP) PET, electrocardiogram and 2D echocardiography. Atrial cardiopathy was defined as ≥1 of: 1) left atrial volume index (LAVI) >34 ml/m2; 2) P-wave terminal force >5000 uV x ms and 3) serum NT proBNP>250 pg/mL. Cross-sectional associations between global cortical Aβ (>1.2 standardized uptake value ratio (SUVR)) and adjudicated history of atrial fibrillation and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Results: Participants, with mean age 76 y, were 56% female and 42% black. Odds of elevated FBP SUVR was increased for those with atrial cardiopathy (Model 3) and nearly doubled among those with enlarged LAVI that remained significant after sequential adjustment, including AF (Table). There was no significant association between either P-wave terminal force or NT proBNP and elevated FBP SUVR (Table), nor between elevated SUVR and AF. Conclusions: In this cross-sectional analysis of a cohort of healthy, nondemented community-dwelling older individuals, we report a significant association between atrial cardiopathy as well as LAVI and elevated amyloid, by PET, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede, or occur simultaneously with amyloid deposition.