Incident Heart Failure Events Research Articles

Association of High-Density Lipoprotein Parameters and Risk of HeartFailure: A Multicohort Analysis.

High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease. The authors sought to evaluate the association of HDL particle concentration (HDL-P), HDL particle size (HDL-size), HDL-C, and cholesterol content per particle (HDL-C/HDL-P) with risk of overall heart failure (HF) and subtypes. Participants from the Atherosclerosis Risk In Communities Study, Dallas Heart Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-stage Disease studies without HF history were included. Associations of HDL-P, HDL-size, HDL-C, and HDL-C/HDL-P with risk of overall HF, HF with reduced and preserved ejection fraction were assessed using adjusted Cox models. Among 16,925 participants (53.5% women; 21.8% Black), there were 612 incident HF events (3.6%) (HF with reduced ejection fraction, 309 [50.5%]; HF preserved ejection fraction, 303 [49.5%]) over median follow-up of 11.4 years. In adjusted models, higher HDL-P was significantly associated with lower HF risk (HR of highest vs lowest tertile of HDL-P: 0.76 [95%CI: 0.62-0.93]). Larger HDL-size was significantly associated with higher overall HF risk (HR of largest vs smallest tertile of HDL-size: 1.27 [95%CI: 1.03-1.58]). HF risk associated with HDL-P and HDL-size was similar for HF subtypes. In adjusted analyses, there was no significant association between HDL-C and HF risk. Higher HDL-C/HDL-P was significantly associated with higher overall HF risk (HR of highest vs lowest tertile of HDL-C/HDL-P: 1.29 [95%CI: 1.04-1.60]). Higher HDL-P was associated with a lower risk of HF. In contrast, larger HDL-size was associated with higher risk of HF and there was no significant association observed between HDL-C and HF risk after accounting for cardiovascular risk factors.

Neighborhood Disadvantage and Risk of Heart Failure: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Heart failure (HF) affects >6 million US adults, with recent increases in HF hospitalizations. We aimed to investigate the association between neighborhood disadvantage and incident HF events and potential differences by diabetes status. We included 23 645 participants from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), a prospective cohort of Black and White adults aged ≥45 years living in the continental United States (baseline 2005-2007). Neighborhood disadvantage was assessed using a Z score of 6 census tract variables (2000 US Census) and categorized as quartiles. Incident HF hospitalizations or HF-related deaths through 2017 were adjudicated. Multivariable-adjusted Cox regression was used to examine the association between neighborhood disadvantage and incident HF. Heterogeneity by diabetes was assessed using an interaction term. The mean age was 64.4 years, 39.5% were Black adults, 54.9% females, and 18.8% had diabetes. During a median follow-up of 10.7 years, there were 1125 incident HF events with an incidence rate of 3.3 (quartile 1), 4.7 (quartile 2), 5.2 (quartile 3), and 6.0 (quartile 4) per 1000 person-years. Compared to adults living in the most advantaged neighborhoods (quartile 1), those living in neighborhoods in quartiles 2, 3, and 4 (most disadvantaged) had 1.30 (95% CI, 1.06-1.60), 1.36 (95% CI, 1.11-1.66), and 1.45 (95% CI, 1.18-1.79) times greater hazard of incident HF even after accounting for known confounders. This association did not significantly differ by diabetes status (interaction P=0.59). For adults with diabetes, the adjusted incident HF hazards comparing those in quartile 4 versus quartile 1 was 1.34 (95% CI, 0.92-1.96), and it was 1.50 (95% CI, 1.16-1.94) for adults without diabetes. In this large contemporaneous prospective cohort, neighborhood disadvantage was associated with an increased risk of incident HF events. This increase in HF risk did not differ by diabetes status. Addressing social, economic, and structural factors at the neighborhood level may impact HF prevention.

Life's Essential 8 and heart failure among patients with chronic kidney disease: the Kailuan Cohort Study.

Patients with chronic kidney disease (CKD) are at an increased risk of developing heart failure. The American Heart Association recently released a new metric, Life's Essential 8 (LE8), for health promotion. However, evidence regarding associations between LE8 and heart failure risk among patients with CKD is scarce. A total of 16 190 patients with CKD (mean age 55.9 years), free of cardiovascular disease at recruitment from the Kailuan Study, were included. Cardiovascular health was assessed using the LE8 score. Incident heart failure events were ascertained via linkage of electronic health record data. Cox proportional hazards regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). There were 814 (5.0%) patients in the high LE8 criteria, with 13 180 (81.4%) in the moderate, and 2196 (13.6%) in the low LE8 category, respectively. During a median follow-up of 13.7 years, 724 incident heart failure cases were documented. Compared with the low LE8 category, the HRs (95% CIs) for heart failure were 0.58 (0.48, 0.71) for the moderate LE8 category and 0.32 (0.19, 0.54) for the high LE8 category (P for trend <0.001). In addition, the association was stronger in patients aged ≤65 years compared with their older counterparts (P for interaction = 0.01). Our data showed a strong graded inverse association between the LE8-defined cardiovascular health and the risk of heart failure among patients with CKD. Our findings support the importance of adopting the LE8 among patients with CKD to prevent heart failure.

Proteomic prediction of incident heart failure and its main subtypes.

To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables. In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study. A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study.

Predictive value of protein-bound uremic toxins for heart failure in patients with chronic kidney disease.

This retrospective cohort study aimed to be the first to evaluate the association between plasma protein-bound uremic toxins (PBUTs) concentrations, echocardiographic parameters of heart failure (HF), and incident HF events in patients with chronic kidney disease (CKD) not on dialysis. Retrospective, single-centre, cohort study at the Ghent University Hospital, Belgium. Adults with CKD stages G1-G5, not on dialysis, could be included. Exclusion criteria were ongoing pregnancy, age <18years, active acute infection, active malignancy, history of transplantation, or a cardiovascular event within 3months prior to inclusion. Free and total concentrations of five PBUTs were quantified at baseline: indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), indole-3 acetic acid (IAA), and hippuric acid (HA). Patients were grouped into three echocardiographic categories: normal left ventricular ejection fraction (LVEF) and normal left ventricular end-diastolic pressure (LVEDP), normal LVEF and increased LVEDP, and reduced LVEF, based on available echocardiographic data in a time interval of ±6months around the plasma sample collection. A total of 523 patients were included between January 2011 and January 2014. Echocardiographic data within the predefined timeframe were available for 210 patients (40% of patients). Levels of pCG and pCS were significantly higher in patients with reduced (<50%) versus normal LVEF (P<0.05). After a median follow-up 5.5years, 43 (8.4%) patients reached the composite endpoint of hospitalization or mortality due to HF. Free fractions of IxS, pCS, and pCG showed the strongest association with clinical outcome: free IxS: HR 1.71 (95% CI 1.11-2.63; P=0.015), free pCS: HR 1.82 (95% CI 1.11-3.01; P=0.019), and free pCG: HR 1.67 (95% CI 1.08-2.58; P=0.020), and these results were independent of age, gender, body mass index, diabetes, and systolic blood pressure. In models that were also adjusted for serum creatinine, the free fractions of these PBUTs remained significant. Elevated free concentrations of IxS, pCG, and pCS were independently associated with an increased risk of HF events in non-dialysed CKD patients. Further research is necessary to confirm these findings and investigate the potential impact of PBUT-lowering interventions on HF events in this patient group.

Genetic causal association of adiposity, body fat distribution with incident heart failure in a European cohort: A linear and non-linear Mendelian randomisation analysis

Abstract Background Excess adiposity has been associated with higher risk of heart failure in observational studies. However, these observational studies are prone to residual confounding and the shape and strength of the independent associations of adiposity measures with heart failure is uncertain. Purpose This study aimed to compare the associations of usual and genetically determined general and central adiposity measures on incident heart failure in a European population cohort. Methods The MR analysis was performed in a cohort of 326,300 adults (mean age 55.9 years, 56% women) of European ancestry with complete genetic data and no prior cardiac and vascular disease recruited from UK general population in 2006-2010. Resurvey on a subset of 20,346 participants was conducted in 2012-13. Regression dilution ratios (RDR) of the different adiposity measures were calculated using Pearson’s correlation method to obtain usual levels of each adiposity measure. Participants were followed up by linkage to electronic health records for incident heart failure events. Externally weighted genetic risk scores (GRS) for body mass index (BMI) and waist circumference (WC) adjusted for BMI (WCadjBMI) were constructed using single nucleotide polymorphisms (SNPs) that were genome-wide significant for BMI and WC as reported by the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Associations of usual measured adiposity measures and genetically predicted usual adiposity (76-SNP BMI-GRS [pleiotropic for other adiposity measures], 36-SNP BMI-GRS [non-pleiotropic for other adiposity measures] and 68-SNP WCadjBMI-GRS) with incident HF subtypes were determined using Cox proportional hazards regression models. The shapes of the associations of genetically predicted adiposity with heart failure at different levels of adiposity measures were examined using localized average causal effects within strata of residual adiposity measures after adjustment for GRS and correction for regression dilution. Hazard ratios (HRs) are presented as per equivalent 5 usual BMI units higher adiposity measure. Results Over a median follow-up of 12.8 years, there were 6,570 first-ever incident HF events. A positive non-linear association (J-shape) was observed between genetically predicted BMI and heart failure with while positive log-linear association was observed for genetically predicted WCadjBMI. Consistent with the observational analyses, the hazard ratio per 5 BMI units equivalent higher genetically predicted WCadjBMI were notably stronger (68-SNP WCadjBMI GRS: HR 2.03, 95% CI1.04-3.97) than for genetically predicted BMI (36-SNP GRS-BMI: HR 1.78, 95% CI 1.12-2.81 and 76-SNP GRS-BMI: HR 1.99, 95% CI 1.62-2.45). Conclusion The findings provide evidence for increased heart failure risk at extremes of BMI and also confirm the stronger causal role of central adiposity over general adiposity in heart failure across the whole range of waist circumference.Figure 1Figure 2

Abstract 18395: Urinary Metals as Novel Risk Factors for Incident Heart Failure and Subtypes in Indigenous Communities in the US: Evidence From the Strong Heart Study

Introduction: Chronic exposure to metals is an independent risk factor for CVD, yet the role of metal exposure on heart failure (HF) and HF subtypes remains understudied. Indigenous communities in the US suffer a high burden of CVD and have been historically exposed to moderate and high levels of environmental metals. In this study we evaluate the prospective association between urinary metal levels and incident HF and HF subtypes in the Strong Heart Study, the largest US cohort of American Indian adults. Hypothesis: We hypothesize that urinary metals are prospectively associated with increased HF risk, and the associations will be different for ejection fraction (EF) &lt;50% and EF &gt;50%. Methods: A total of 2,706 participants (mean (SD) age 56.4(8.1) years, 58% female) with urinary metals available at baseline (1989-1991) were included. Incident HF events were ascertained through 2019 by a physician panel, including classification of HF subtypes (EF50% and EF&lt;50%). Progressively adjusted Cox proportional hazards models were used to identify the risk of incident HF and HF subtypes by an interquartile range (IQR) change in urine metals (Table 1). Results: A total of 444 participants developed HF (90 EF &gt;50%, 127 EF&lt;50%, 227 unclassified). Baseline levels of all metals were higher among participants who developed HF. In fully adjusted models (Model 2), higher levels of urinary cadmium, molybdenum and zinc were significantly associated with HF risk. The associations varied by HF subtype. While no significant associations were identified for those EF≥50%, higher levels of urinary tungsten, molybdenum, and zinc were significantly associated with HF EF&lt;50% risk. Conclusions: We identified an association between baseline urine levels of several essential and non-essential metals and incident HF risk in the Strong Heart Study, with strongest associations for those with EF&lt;50%. These findings can help identify novel modifiable risk factors of HF and inform prevention strategies.

Abstract 14327: Association Between Alcohol Intake and Incidence of Heart Failure With and Without Reduced Ejection Fraction Among Participants of the VA Million Veteran Program

Introduction: Little is known about the relation of total alcohol intake and beverage types on risk of heart failure (HF). This study aims to examine the relation between amount of alcohol consumed and type of alcohol with risk for HF including subtypes [heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction] in a large cohort of US Veterans. Methods: The study cohort included 329,543 Million Veteran Program participants who completed a baseline and lifestyle survey. Subjects with prevalent HF at baseline and incomplete alcohol information were excluded. Moderate alcohol intake was defined as consuming 12-24 g/day for men and 12g/day for women. We used ICD-9-10 codes and EF to define HFpEF and HFrEF. The associations between alcohol intake, beverage preference, and incidence of HFpEF and HFrEF were assessed using Cox proportional hazard model (CPHM) adjusted for age, sex, race, body mass index, cigarette smoking, education, exercise, diet, baseline prevalence of high cholesterol, hypertension, diabetes mellitus, statin use and atrial fibrillation. Results: Mean age was 65 years and 91.4% were men. With mean follow-up of 4.5 years, we observed 20,694 incident HF events (6078 HFrEF and 4531 HFpEF). The CPHM showed J shaped relationship between alcohol consumption and HF risk. Compared to never drinkers, adjusted HRs (95% CI) for HF were 0.89 (0.85, 0.95), 0.85 (0.79,0.91), 0.80 (0.74, 0.86), 0.80 (0.72, 0.88), 0.93 (0.84, 1.04) and 1.03(0.95, 1.12) for categories of current drinkers of ≤6 g/d, &gt;6-12 g/d, &gt;12-24g/d, &gt;24-36g/d, &gt;36-48 g/d and heavy drinking (&gt; 48 g/d)/alcohol use disorder, respectively. We found a similar association pattern between alcohol intake and risk of HFpEF and HFrEF (Fig). There was no difference in alcohol preference and HF risk among light and moderate drinkers. Conclusion: Light to moderate alcohol consumption is associated with a lower risk of heart failure irrespective of subtypes.

Abstract 16789: Modeling the Optimal Strategy of Natriuretic Peptide Testing for Heart Failure Prevention in Diabetes: A Pooled Cohort Analysis

Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with heart failure (HF) risk and measurement is recommended in diabetes. Incorporation of NT-proBNP with WATCH-DM, a HF risk score validated in diabetes, improved HF risk prediction in low-risk individuals (score &lt;13). Whether WATCH-DM can improve the yield of NT-proBNP testing and inform allocation of SGLT2 inhibitors is unknown. Methods: Adults with diabetes and free of HF at baseline from ARIC, CHS, CRIC, DHS, FOS, and MESA cohorts were included. Participants without cardiovascular disease (CVD) were stratified into high- vs. low-risk categories based on 4 approaches: 1) WATCH-DM (score ≥ vs. &lt;13); 2) NT-proBNP (≥ vs. &lt;125 pg/mL); 3) WATCH-DM plus NT-proBNP (both high vs. not); 4) WATCH-DM-based NT-proBNP (if score &lt;13, measure NT-proBNP) (either high vs. not). Five-year cumulative incidence rates of HF, number needed to treat (NNT 5 ) and number needed to screen (NNS 5 ) were estimated based on pooled treatment effects of SGLT2 inhibitors. Results: The study included 6,410 participants (47.5% women, 35.1% Black, 20.5% with CVD) with 428 (6.7%) incident HF events over 5-year follow-up. The 5-year risk of HF was 12.3% among participants with CVD and comparable to those without CVD identified as high-risk based on all 4 approaches ( Figure ). Among participants without CVD, WATCH-DM-based NT-proBNP identified 46% of participants as high-risk and accounted for 80% of HF events. The NNT 5 with an SGLT2 inhibitor to prevent 1 HF event in participants with CVD was 25 and similar to the primary prevention population identified as high-risk ( Figure ). The NNS 5 was lowest in the WATCH-DM-based NT-proBNP strategy ( Figure ). Conclusions: Selective NT-proBNP assessment based on a validated clinical risk score for HF improved the yield of testing and may represent an efficient approach to risk stratification and allocation of therapies among individuals with diabetes.

Abstract 12911: Life’s Essential 8 and Heart Failure: The Million Veteran Program

Background: Heart failure (HF) incidence has increased over past decades and is associated with poor quality of life, increased comorbidities, and high treatment costs. Prevention for HF warrant a major public health priority. Aim: To quantify the association of Life’s Essential 8 (LE8) score with HF. Methods: LE8 score (0-800) was developed based on the AHA guidelines among 348,311 Veterans who enrolled in the VA Million Veteran Program (MVP) (2011-2021) and free of HF at baseline. Cox proportional hazard models were used to calculate the hazard ratios (HR) with their 95% confidence intervals (CI) for first incident HF event, and HF subtypes (HF with reduced ejection fracture (HFrEF) and HF with preserved EF (HFpEF)) across categories of LE8 score. The population attributable fraction (PAF) was calculated to estimate the proportional reduction in HF events that would occur if LE8 was changed to the ideal level. Results: A total of 31,397 HF events were recorded over 1.8 million person-years of follow-up. LE8 score was negatively associated with incidence of HF, HFrEF and HRpEF, even after extensive adjustment for potential confounders ( Figure 1A ). The multivariate-adjusted HR for HF was 0.76 (95% CI: 0.73-0.78), 0.63 (0.61-0.65), 0.52 (0.50-0.54), 0.41 (0.39-0.43), 0.34 (0.32-0.36), 0.28 (0.27-0.30), and 0.23 (0.21-0.25), respectively, among Veterans whose LE8 score was 350-, 400-, 450-, 500-, 550-, 600- and ≥650, respectively, as compared to those with LE8 score &lt;350. The PAF for HF was 7.1%, 10.3%, 15.1%, 15.8%, 17.1%, 17.5% 18.4%, and 49.1% for not ideal sleep, diet, lipid, activity, BMI, smoking, glucose/HbA1c, and blood pressure, respectively, with an estimated joint PAF of 83.2% for total HF, 79.5% for HFrEF and 90.1% for HFpEF for not ideal of any LE8 ( Figure 1B ). Conclusion: Greater adherence to a healthy LE8 lifestyle could be a key component in prevention of HF among Veterans. Assuming everyone follows a lifestyle meet ideal LE8, majority of HF cases will be prevented.

Abstract 12360: Association of Coagulation Factor XI Levels With Cardiac Function and Cardiovascular Events: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Coagulation Factor XI (FXI) inhibitors are a promising and novel class of anticoagulants, but a recent animal study showed that FXI has an anti-fibrotic role that ameliorated diastolic dysfunction and heart failure (HF). Whether FXI levels are associated with cardiac function and cardiovascular (CV) events in humans is unknown. Hypothesis: We hypothesize that lower FXI levels are associated with worse cardiac function and higher risk of CV events (HF and atrial fibrillation [AF]). Methods: We included 4,471 participants (mean age 75 years, 57% female, 17% Black) who attended ARIC Visit 5 (2011-2013) with plasma FXI measured by Somalogic and cardiac function measured by echocardiography. HF and AF events were ascertained through 2019. Linear regression was used to assess the association between FXI and cardiac function measures. Logistic regression and Cox proportional hazard model were used to examine the association of FXI levels with prevalent and incident HF and AF, respectively. Result: At baseline, there were 665 and 419 participants with prevalent HF and AF; over a median follow-up of 7 years, there were 643 and 415 incident HF and AF events. Among cardiac function measures, we found significant associations between FXI level and E/A ratio, left atrial (LA) volume index, LA reservoir strain, and LA contractile strain, but not E/e’ ratio, LA conduit strain, left ventricular (LV) ejection fraction or LV global longitudinal strain (Table). Lower FXI levels was associated with a higher odds of prevalent AF but not prevalent HF (Table). No significant associations were found between FXI levels and incident HF or AF. Conclusion: Lower FXI levels are associated with worse diastolic function, LA function and size, and prevalent AF, but not LV systolic function, prevalent HF, or incident HF or AF. More research is needed to assess unwanted effects of FXI inhibition on cardiac function and risk of CV events.

Abstract 16482: Proteomic Measures Associated With Leisure-Time Physical Activity and Heart Failure Risk in Late-Life - The Atherosclerosis Risk in Communities Study

Introduction: Leisure-time physical activity (LTPA) is associated with lower heart failure (HF) risk. However, the underlying molecular mechanisms by which LTPA impacts HF risk is unclear. Methods: We evaluated participants at Atherosclerosis Risk in Communities study visits 3 (1993-95) and 5 (2011-13) with plasma proteomics data (Somascan v4) and without HF or stroke. LTPA was assessed by the Baecke questionnaire as metabolic equivalent (MET)-minutes/week. We performed cross-sectional associations of 4,955 proteins with LTPA at visit 3 and then at visit 5 LTPA using multivariable quantile regression models at Bonferroni-corrected significance (p&lt;1e-5, p&lt;0.0004, respectively). We related these proteins to incident HF after visit 3 and then visit 5 using multivariable Cox regression models at Bonferroni-corrected significance (p&lt;0.00086, p&lt;0.003, respectively). Results: Thirty-nine proteins were associated with LTPA at visit 3 (n=10,402; age 60±6 yrs, 54% women; mean 688.6 MET-minutes/week, 773 incident HF events) and visit 5 (n=4,135; 75±5 yrs, 58% women; mean 834.8 MET-minutes/week, 362 events), of which 5 proteins were also associated with incident HF at both visits. Higher levels of THBS2, GABARAP, and BAGE2 were associated with lower LTPA and higher HF risk while higher levels of ART3 associated with higher LTPA and lower risk of incident HF (Figure). PTK7 demonstrated discordant associations with LTPA and HF risk. Levels of THBS2, GABARAP, BAGE2, and ART3 accounted for a significant proportion of the LTPA-HF association (p&lt;0.05). Conclusion: Large-scale proteomics can identify novel biomarkers potentially linking LTPA to HF risk. Further study is needed of THBS2, GABARAP, BAGE2, and ART3, which may link the association of LTPA on HF.

Abstract 16389: Inflammatory Chronic Kidney Disease is Associated With Incident Heart Failure: A Pooled Cohort Analysis

Introduction: High sensitivity C-reactive protein (hsCRP), a biomarker of inflammation, can risk stratify patients for cardiovascular disease including heart failure (HF). It is not well established if inflammation increases the risk of HF in patients with chronic kidney disease (CKD) and if hsCRP can be utilized to risk stratify patients with CKD for their risk of incident HF. Aims: We assessed the role of hsCRP in risk stratifying patients with CKD for incident HF. Methods: We studied participants of 3 major epidemiologic cohorts: Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. High inflammation was classified as hsCRP &gt;3 mg/L and CKD was classified as estimated glomerular filtration rate &lt;60 mL/min/1.73m2. Participants were stratified into 3 groups: neither CKD nor high inflammation, CKD without high inflammation, or CKD with high inflammation. Cox hazards models adjusted for age, sex, race, body mass index, smoking, alcohol use, diabetes, hypertension, and coronary disease were utilized for analysis. Results: 8,692 participants with 460 incident HF events followed over a median 8.32 years were included in our analysis. Participants with CKD without high inflammation (HR = 1.45; 95% CI 1.14 to 1.85) and CKD with high inflammation (2.05; 1.61 to 2.61) were associated with an increased risk of incident HF compared with participants without CKD or high inflammation (referent, Figure). Furthermore, participants with CKD and a hsCRP &gt;3 mg/L had an increased risk of incident HF (1.41; 1.06 to 1.88) compared with participants with CKD but hsCRP ≤3 mg/L (referent). Conclusions: Patients with CKD and high levels of inflammation carry a 2-fold increased risk of incident HF. In patients with CKD, hsCRP levels &gt;3mg/L may be useful to risk stratify patients with increased risk of developing HF.

Abstract 17003: Associations of SGLT2 Inhibitor-Related Plasma Proteins With Incident Heart Failure: The Atherosclerosis Risk in Communities Study

Introduction: The mechanisms by which SGLT2 inhibitors reduce heart failure (HF) hospitalization is unclear. Data from EMPEROR-Reduced and two pilot clinical trials identified 288 plasma proteins modifiable by SGLT2 inhibitors. Methods: Among participants in the community-based ARIC study who were free of HF and had aptamer-based proteomic measurements (SomaLogic, Boulder, CO) at Visit 2 (mid-life, n=10,983; 1991-1993) and Visit 5 (late-life, n=4,321; 2011-2013), we studied the association of these 288 SGLT2 inhibitor-related proteins with incident HF after Visit 2 (1149 incident HF events) and Visit 5 (453 events) using multivariable Cox proportional hazards regression models, cardiometabolic traits using multivariable linear regression and Mendelian randomization to assess for potential causal effects. Results: The mean age was at 57±6 at Visit 2 and 76±5 at Visit 5 and 55% were women. Of 288 plasma proteins reported to be modulated by SGLT2 inhibition, 39 associated with incident HF after both Visit 2 and Visit 5: 24 with HFpEF [LVEF&gt;50%], 2 with HFrEF, and 8 with both ( Figure ). These proteins also associated with plasma glucose levels, hematocrit and urine albumin-to-creatinine ratio and were enriched with immune signaling pathways and the fatty acid binding pathway. Two sample Mendelian randomization suggested causal effects of higher IGFBP1, lower CHRDL1 and higher B2M on higher incident HF risk (P&lt;0.05). Conclusions: Proteins impacted by SGLT2 inhibition and associated with risk of HF suggest glucose metabolism, erythropoiesis and kidney damage as potential contributors to the effect of SGLT2 inhibitors on HF outcomes.

Abstract 15965: Electrocardiogram-Based Artificial Intelligence Predicts Incident Heart Failure

Introduction: Heart failure (HF) is a major cause of cardiovascular morbidity. Efficient and accurate prediction of incident heart failure episodes may enable preventive efforts. Methods: Using raw 12-lead ECG waveforms, we developed a convolutional neural network to predict HF admissions (Electrocardiogram to Heart Failure, “ECG2HF”). ECG2HF was developed in 91,573 individuals in Massachusetts General Hospital (MGH), and validated in three independent test sets: MGH, Brigham and Women’s Hospital (BWH), and the UK Biobank, among individuals without a prior HF episode. HF events were identified using a validated natural language processing model (MGH and BWH), and inpatient diagnosis codes (UK Biobank). Discrimination was quantified using time-dependent average precision (AP) and area under the receiver operating characteristic curve (AUROC). Among individuals with available data, we compared ECG2HF to the Pooled Cohort Equations for Heart Failure (PCE-HF). Results: The test sets comprised MGH (15,695 individuals, age 55±17, 51% women), BWH (52,124 individuals, age 55±17, 59% women), and UK Biobank (42,135 individuals, age 65±8, 52% women). ECG2HF consistently discriminated incident HF events (MGH 10-year AP: 0.17 [95% CI 0.15-0.20], 10-year AUROC 0.88 [0.86-0.89]; BWH: 0.15 [0.14-0.17], 0.87 [0.85-0.88]; UK Biobank 3-year AP 0.036 [0.024-0.057], 3-year AUROC 0.73 [0.68-0.77]). ECG2HF risk consistently stratified longitudinal HF incidence. Compared to PCE-HF, discrimination using ECG2HF was favorable in MGH/BWH (improvement in AP 0.07 [-0.11-0.14], improvement in AUROC 0.13 [0.088-0.18]), and UK Biobank (improvement in AP 0.016 [0.0060-0.033], improvement in AUROC -0.0093 [-0.062-0.044]). Conclusions: Artificial intelligence-enabled analysis of the 12-lead ECG may facilitate identification of individuals at risk for HF to enable early treatment to reduce HF-related morbidity.

Association of Metabolic Dysfunction-Associated Fatty Liver Disease With Risk of HF and AF

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is a novel concept of hepatic disease. Although the prevalences of heart failure (HF) and atrial fibrillation (AF) are increasing worldwide, limited data have assessed the extent to which MAFLD is associated with incident HF and AF. ObjectivesThe authors sought to examine the association of MAFLD with incident HF and AF. MethodsAnalyses were conducted using a nationwide epidemiologic database including 3,279,918 individuals (median age 45 years; 57.6% men). Metabolic dysfunction was defined as 1 or more of the following: overweight (body mass index ≥23 kg/m2), metabolic syndrome, or diabetes mellitus. FLD was defined as fatty liver index of >30. MAFLD was defined as the coexistence of metabolic dysfunction and FLD. We categorized study participants into 4 groups: non-FLD/nonmetabolic dysfunction (n = 1,709,116), metabolic dysfunction (n = 584,483), FLD (n = 89,497), and MAFLD (n = 896,822). The primary outcomes were HF and AF. ResultsOver a mean follow-up period of 1,160 ± 905 days, 62,746 incident HF events and 15,408 incident AF events were recorded. Compared with the non-FLD/non–metabolic dysfunction group, HRs for HF and AF, respectively, were 1.20 (95% CI: 1.18-1.23) and 1.13 (95% CI: 1.08-1.19) for metabolic dysfunction, 1.24 (95% CI: 1.19-1.30) and 1.13 (95% CI: 1.04-1.23) for FLD, and 1.73 (95% CI: 1.69-1.76) and 1.51 (95% CI: 1.46-1.57) for MAFLD. MAFLD was also associated with a higher risk of developing myocardial infarction, angina pectoris, and stroke. A risk of developing cardiovascular events differed between MAFLD subtypes (Wald test P < 0.001). ConclusionsMAFLD was associated with a greater risk of developing HF and AF, suggesting the clinical importance of this novel hepatic disease concept.

Allostatic load and incident heart failure in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study

BackgroundAllostatic load (AL) is the physiologic “wear and tear” on the body from stress. Yet, despite stress being implicated in the development heart failure (HF), it is unknown whether AL is associated with incident HF events.MethodsWe examined 16,765 participants without HF at baseline from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. The main exposure was AL score quartile. AL was determined according to 11 physiologic parameters, whereby each parameter was assigned points (0–3) based on quartiles within the sample, and points were summed to create a total AL score ranging from 0–33. The outcome was incident HF event. We examined the association between AL quartile (Q1-Q4) and incident HF events using Cox proportional hazards models, adjusted for demographics, socioeconomic factors, and lifestyle.ResultsThe mean age was 64 ± 9.6 years, 61.5% were women, and 38.7% were Black participants. Over a median follow up of 11.4 years, we observed 750 incident HF events (635 HF hospitalizations and 115 HF deaths). Compared to the lowest AL quartile (Q1), the fully adjusted hazards of an incident HF event increased in a graded fashion: Q2 HR 1.49 95% CI 1.12–1.98; Q3 HR 2.47 95% CI 1.89–3.23; Q4 HR 4.28 95% CI 3.28–5.59. The HRs for incident HF event in the fully adjusted model that also adjusted for CAD were attenuated, but remained significant and increased in a similar, graded fashion by AL quartile. There was a significant age interaction (p-for-interaction < 0.001), whereby the associations were observed across each age stratum, but the HRs were highest among those aged < 65 years.ConclusionAL was associated with incident HF events, suggesting that AL could be an important risk factor and potential target for future interventions to prevent HF.

Electrocardiographic markers of atrial cardiomyopathy and risk of heart failure in the multi-ethnic study of atherosclerosis (MESA) cohort.

The association of electrocardiographic (ECG) markers of atrial cardiomyopathy with heart failure (HF) and its subtypes is unclear. This analysis included 6,754 participants free of clinical cardiovascular disease (CVD), including atrial fibrillation (AF), from the Multi-Ethnic Study of Atherosclerosis. Five ECG markers of atrial cardiomyopathy (P-wave terminal force in V1 [PTFV1], deep-terminal negativity in V1 [DTNV1], P-wave duration [PWD], P-wave axis [PWA], advanced intra-atrial block [aIAB]) were derived from digitally recorded electrocardiograms. Incident HF events through 2018 were centrally adjudicated. An ejection fraction (EF) of 50% at the time of HF was used to classify HF as HF with reduced EF (HFrEF), HF with preserved EF (HFpEF), or unclassified HF. Cox proportional hazard models were used to examine the associations of markers of atrial cardiomyopathy with HF. The Lunn-McNeil method was used to compare the associations in HFrEF vs. HFpEF. 413 HF events occurred over a median follow-up of 16 years. In adjusted models, abnormal PTFV1 (HR (95%CI): 1.56(1.15-2.13), abnormal PWA (HR (95%CI):1.60(1.16-2.22), aIAB (HR (95%CI):2.62(1.47-4.69), DTNPV1 (HR (95%CI): 2.99(1.63-7.33), and abnormal PWD (HR (95%CI): 1.33(1.02-1.73), were associated with increased HF risk. These associations persisted after further adjustments for intercurrent AF events. No significant differences in the strength of association of each ECG predictor with HFrEF and HFpEF were noted. Atrial cardiomyopathy defined by ECG markers is associated with HF, with no differences in the strength of association between HFrEF and HFpEF. Markers of atrial Cardiomyopathy may help identify individuals at risk of developing HF.

Trends in Incidence of Chronic Heart Failure in Patients With Rheumatoid Arthritis: A Population-Based Study Validating Different Heart Failure Definitions.

To assess trends in the incidence of heart failure (HF) in patients with incident rheumatoid arthritis (RA) from 1980 to 2009 and to compare different HF definitions in RA. The study population comprised Olmsted County, Minnesota residents with incident RA (age ≥ 18 yrs, 1987 American College of Rheumatology criteria met in 1980-2009). All subjects were followed until death, migration, or April 30, 2019. Incident HF events were defined as follows: (1) meeting the Framingham criteria for HF, (2) diagnosis of HF (outpatient or inpatient) by a physician, or (3) International Classification of Diseases, 9th revision (ICD-9), or ICD, 10th revision (ICD-10), codes for HF. Patients with HF prior to the RA incidence/index date were excluded. Cox proportional hazards models were used to compare incident HF events by decade, adjusting for age, sex, and cardiovascular risk factors. HF definitions 2 and 3 were compared to the Framingham criteria. The study included 905 patients with RA (mean age 55.9 years; 68.6% female; median follow-up 13.4 years). The 10-year cumulative incidence of HF events by any chart-reviewed method in the RA cohort in the 1980s was 11.66% (95% CI 7.86-17.29), in the 1990s it was 12.64% (95% CI 9.31-17.17), and in the 2000s it was 7.67% (95% CI 5.36-10.97). The incidence of HF did not change across the decades of RA incidence using any of the HF definitions. Physician diagnosis of HF and ICD-9/10 code-based definitions of HF performed well compared to the Framingham criteria, showing moderate to high sensitivity and specificity. The incidence of HF in patients with incident RA in the 2000s vs the 1980s was not statistically significantly different. Physician diagnosis of HF and ICD-9/10 codes for HF performed well against the Framingham criteria.

Abstract P174: The Association Between Infection-Related Hospitalization and Incident Heart Failure: The Atherosclerosis Risk in Communities Study

Introduction: Infections are associated with worse clinical outcomes among patients with heart failure (HF). However, little is known about the influence of infection-related hospitalizations on development of incident HF and its subtype. Hypothesis: We hypothesize that those with an infection-related hospitalization (hereafter ‘infection’) compared to those without infection, will experience an increased rate of incident HF events (any HF, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)). Methods: We examined 14,398 participants enrolled in the Atherosclerosis Risk in Communities Study who were HF free at visit 1 (1987-1989). Hospitalized infections and HF were identified via participant self-report and active surveillance of hospitalizations. Among the hospitalized, infection was further defined using ICD-9/10 codes in the first five positions of hospital records. A subset of HF events was further classified as HFpEF or HFrEF via chart abstraction and adjudication by centrally trained and certified physicians. Infection was treated as a time-varying exposure and the co-occurrence of infection and HF in the same hospital visit were excluded. Multivariable-adjusted Cox proportional hazards models assessed the association between infection and incident HF, HFrEF, and HFpEF. Results: The overall baseline sample was 54% (7,835 of 14,398) female, 26% (3,688 of 14,398) Black and had a mean(SD) age of 54(5.8). Mean(SD) time to infection was 16.1(8.7) years, and 2.3(7.5) years from infection to incident HF. Average follow-up among the full sample was 23.0(8.5). Overall, 46% (6,603 of 14,398) had an infection and 3,561 developed any HF. Among participants with subtype adjudication, 470 had HFpEF and 450 had HFrEF. Infection-related hospitalization was associated with an increased risk for both HFpEF and HFrEF (Table). Conclusion: Infection-related hospitalization was associated with both incident HFpEF and HFrEF. A stronger effect is seen among those with HFpEF.