Incident Heart Failure With Preserved Ejection Fraction Research Articles

Abstract 4122694: The ICAM1 p.K56M Variant and Risk of Heart Failure Among Individuals with Chronic Kidney Disease

Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein that facilitates inflammation through leukocyte adhesion. Approximately 35% of African American individuals carry at least one copy of an ICAM1 missense variant (rs5491; p.K56M), which has been associated with increased risk of heart failure with preserved ejection fraction (HFpEF). Individuals with chronic kidney disease (CKD) are at high risk for HF, but whether the risk of HFpEF conferred by rs5491 extends to individuals with prevalent CKD is unknown. Hypothesis: We hypothesized that in a CKD population, rs5491 is specifically associated with HFpEF, but not HF with reduced ejection fraction (HFrEF). Methods: In the Chronic Renal Insufficiency Cohort (CRIC), participants were enrolled based upon an estimated glomerular filtration rate (eGFR) of 20 to 70 mL/min/1.73m 2 . We estimated associations of rs5491 with incident HF and HF subtypes among African American individuals who were free from HF at baseline in CRIC. Models were adjusted for age, sex, systolic blood pressure, eGFR, body mass index, smoking, diabetes, C-reactive protein, the first 10 principal components of ancestry, and study site. Results: Among 1267 African American participants without HF at baseline (mean age 57±11 years, 51% female, mean eGFR 45±15 mL/min/1.73m 2 ), 464 (37%) had at least one copy of rs5491. During a median follow-up of 10.3 years (IQR: 4.7 – 15.0 years), there were 309 incident overall HF hospitalizations (160 HFpEF, 111 HFrEF, and 38 HF with unknown EF). Each additional rs5491 allele was significantly associated with incident HFpEF (HR 1.35 [95% CI: 1.03-1.76], P=0.029; Figure). The rs5491 variant was not associated with incident overall HF (HR 1.14, 95% CI: 0.93-1.39, P = 0.20) or incident HFrEF (HR 0.76, 95% CI: 0.53-1.10, P=0.15). Conclusion: The ICAM1 p.K56M variant specifically confers increased risk of incident HFpEF among individuals with CKD.

Incident HFpEF and time-dependent changes in markers of LVDD severity in women and men with pre-clinical LVDD

Abstract Background Over time, left ventricular diastolic dysfunction (LVDD) can progress towards heart failure with preserved ejection fraction (HFpEF). Yet, the identification of those at high risk of progression is challenging, and guidance on follow-up or preventive treatment is lacking. Purpose To study the incidence of HFpEF and changes over time in markers of LVDD severity in women and men with pre-clinical LVDD. In addition, we evaluate whether blood pressure and kidney function affect progression of LVDD. Methods We reinvited 146 participants from the HELPFul study (58% women and 42% men) with pre-clinical LVDD after a median follow-up of 4.3 [IQR: 3.9-4.7] years (Figure 1). The follow-up measurements were similar to baseline and encompassed a structured interview, physical examination, blood draw, electrocardiogram and (exercise) echocardiography. We determined HFpEF incidence and report changes over time in cardiovascular risk factors as well as echocardiographic characteristics and biomarkers of LVDD. Additionally, we studied whether changes in blood pressure and kidney function affected LVDD progression using generalized mixed models. LVDD progression was defined as an increase in plasma NT-proBNP levels and HFA-PEFF major functional and morphological abnormalities. All analyses were performed for women and men combined as well as stratified by sex. Results Fifteen (10%) of the 146 participants developed HF of whom 13 had HFpEF (9 women and 4 men) during follow-up. Over time, systolic and diastolic blood pressure levels remained stable while mean kidney function (eGFR) declined from 89±14 to 81±17 mL/min/1.73m2. Median NT-proBNP plasma levels increased from 71 [IQR: 44, 120] to 100 [IQR: 51, 157] pg/mL. The prevalence of major functional abnormalities according to the HFA-PEFF score increased from 84 to 91%, while the prevalence of morphological abnormalities increased from 25% to 39% (Figure 2). A higher systolic blood pressure in women and a higher diastolic blood pressure in men was associated with an increase in NT-proBNP plasma levels over time. Additionally, lower eGFR levels were related to increased NT-proBNP plasma levels over time in both men and women. There was a significant rise in the prevalence of major functional and morphological abnormalities with time, but blood pressure and kidney function did not affect this change over time. Conclusions A small proportion of women and men with preclinical LVDD developed incident HF over a 5-year follow-up period. High blood pressure and reduced kidney function were associated with increased levels of NT-proBNP over time. This highlights the need to further explore cardiorenal protection as a method to prevent HFpEF.Study design and HF outcomesLongitudinal changes in LVDD markers

Diagnosing diastolic dysfunction and heart failure with preserved ejection fraction in patients with atrial fibrillation: a clinical challenge.

Left ventricular (LV) diastolic dysfunction, atrial fibrillation (AF), and heart failure with preserved ejection fraction (HFpEF) share common risk factors and are closely related to one another and to adverse cardiovascular events. Exertional dyspnoea in patients with AF should trigger a comprehensive LV diastolic function evaluation since AF frequently precedes incident HFpEF. An echocardiographic assessment of LV diastolic function in patients with AF is challenging, mainly because of variability in cycle length, the absence of atrial contraction, and the frequent occurrence of left atrial enlargement regardless of LV filling pressures (LVFPs). The algorithm of the 2016 recommendations for the evaluation of LV diastolic function cannot be directly applied in this setting. This review discusses the modalities available for diastolic function assessment and HFpEF diagnosis in patients with AF. Based on currently available data, a reasonable clinical target of diastolic function evaluation in AF would be to reach a binary conclusion: LVFP elevated or not. Recently, a two-step algorithm that combined several echocardiographic parameters plus the inclusion of body mass index has been proposed to differentiate normal from elevated LVFP in patients with AF. The echocardiographic evaluation must be complemented by a thorough clinical evaluation along with natriuretic peptides and cardiac catheterization in selected cases. If a diagnosis of HFpEF cannot be ascertained, a close follow-up for timely identification of diastolic dysfunction markers, along with monitoring and correction of modifiable risk factors, is recommended.

Metabolomic Association and Risk Prediction With Heart Failure in Older Adults.

Older adults have markedly increased risks of heart failure (HF), specifically HF with preserved ejection fraction (HFpEF). Identifying novel biomarkers can help in understanding HF pathogenesis and improve at-risk population identification. This study aimed to identify metabolites associated with incident HF, HFpEF, and HF with reduced ejection fraction and examine risk prediction in older adults. Untargeted metabolomic profiling was performed in Black and White adults from the ARIC study (Atherosclerosis Risk in Communities) visit 5 (n=3719; mean age, 75 years). We applied Cox regressions to identify metabolites associated with incident HF and its subtypes. The metabolite risk score (MRS) was constructed and examined for associations with HF, echocardiographic measures, and HF risk prediction. Independent samples from visit 3 (n=1929; mean age, 58 years) were used for replication. Sixty metabolites (hazard ratios range, 0.79-1.49; false discovery rate, <0.05) were associated with incident HF after adjusting for clinical risk factors, eGFR, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Mannonate, a hydroxy acid, was replicated (hazard ratio, 1.36 [95% CI, 1.19-1.56]) with full adjustments. MRS was associated with an 80% increased risk of HF per SD increment, and the highest MRS quartile had 8.7× the risk of developing HFpEF than the lowest quartile. High MRS was also associated with unfavorable values of cardiac structure and function. Adding MRS over clinical risk factors and NT-proBNP improved 5-year HF risk prediction C statistics from 0.817 to 0.850 (∆C, 0.033 [95% CI, 0.017-0.047]). The association between MRS and incident HF was replicated after accounting for clinical risk factors (P<0.05). Novel metabolites associated with HF risk were identified, elucidating disease pathways, specifically HFpEF. An MRS was associated with HF risk and improved 5-year risk prediction in older adults, which may assist at at-risk population identification.

Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, is associated with incident heart failure (HF). To evaluate the associations of CHIP and key gene-specific CHIP subtypes with incident HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). This population-based cohort study included participants from 2 racially diverse prospective cohort studies with uniform HF subtype adjudication: the Jackson Heart Study (JHS) and Women's Health Initiative (WHI). JHS participants were enrolled during 2000 to 2004 and followed up through 2016. WHI participants were enrolled during 1993 to 1998 and followed up through 2022. Participants who underwent whole-genome sequencing, lacked prevalent HF at baseline, and were followed up for HF adjudication were included. Follow-up occurred over a median (IQR) of 12.0 (11.0-12.0) years in the JHS and 15.3 (9.0-22.0) years in the WHI. Statistical analysis was performed from June to December 2023. Any CHIP and the most common gene-specific CHIP subtypes (DNMT3A and TET2 CHIP). First incident hospitalized HF events were adjudicated from hospital records and classified as HFpEF (left ventricular ejection fraction ≥50%) or HFrEF (ejection fraction <50%). A total of 8090 participants were included; 2927 from the JHS (median [IQR] age, 56 [46-65] years; 1846 [63.1%] female; 2927 [100.0%] Black or African American) and 5163 from the WHI (median [IQR] age, 67 [62-72] years; 5163 [100.0%] female; 29 [0.6%] American Indian or Alaska Native, 37 [0.7%] Asian or Pacific Islander, 1383 [26.8%] Black or African American, 293 [5.7%] Hispanic or Latinx, 3407 [66.0%] non-Hispanic White, and 14 [0.3%] with other race and ethnicity). The multivariable-adjusted hazard ratio (HR) for composite CHIP and HFpEF was 1.28 (95% CI, 0.93-1.76; P = .13), and for CHIP and HFrEF it was 0.79 (95% CI, 0.49-1.25; P = .31). TET2 CHIP was associated with HFpEF in both cohorts (meta-analyzed HR, 2.35 [95% CI, 1.34 to 4.11]; P = .003) independent of cardiovascular risk factors and coronary artery disease. Analyses stratified by C-reactive protein (CRP) in the WHI found an increased risk of incident HFpEF in individuals with CHIP and CRP greater than or equal to 2 mg/L (HR, 1.94 [95% CI, 1.20-3.15]; P = .007), but not in those with CHIP and CRP less than 2 mg/L or those with CRP greater than or equal to 2 mg/L without CHIP, when compared with participants without CHIP and CRP less than 2 mg/L. In this cohort study, TET2 CHIP was an independent risk factor associated with incident HFpEF. This finding may have implications for the prevention and management of HFpEF, including development of targeted therapies.

Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study

BackgroundWhether iron deficiency contributes to incident heart failure (HF) and cardiac dysfunction has important implications given the prevalence of iron deficiency and the availability of several therapeutics for iron repletion. ObjectivesThe aim of this study was to estimate the associations of plasma ferritin level with incident HF overall, HF phenotypes, and cardiac structure and function measures in older adults. MethodsParticipants in the ongoing, longitudinal ARIC (Atherosclerosis Risk In Communities) study who were free of prevalent HF and anemia were studied. The associations of plasma ferritin levels with incident HF overall and heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) were estimated using Cox proportional hazards regression models. Linear regression models estimated the cross-sectional associations of plasma ferritin with echocardiographic measures of cardiac structure and function. ResultsThe cohort included 3,472 individuals with a mean age of 75 ± 5 years (56% women, 14% Black individuals). In fully adjusted models, lower ferritin was associated with higher risk for incident HF overall (HR: 1.20 [95% CI: 1.08-1.34] per 50% lower ferritin level) and higher risk for incident HFpEF (HR: 1.28 [95% CI: 1.09-1.50]). Associations with incident HFrEF were not statistically significant. Lower ferritin levels were associated with higher E/e′ ratio and higher pulmonary artery systolic pressure after adjustment for demographics and HF risk factors but not with measures of left ventricular structure or systolic function. ConclusionsAmong older adults without prevalent HF or anemia, lower plasma ferritin level is associated with a higher risk for incident HF, HFpEF, and higher measures of left ventricular filling pressure.

Longitudinal modeling of cardiac function to identify trajectories with differential risk of heart failure

Abstract Background Impairments in left ventricular (LV) systolic and diastolic function are common precursors of clinical heart failure (HF) and underlie HF risk. Little data exist regarding trajectories of cardiac function in mid- to late-life, when HF risk is greatest, and the extent to which such trajectories may differentially relate to risk of HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF). Purpose To (1) identify multidimensional trajectories of cardiac function from mid- to late-life using serial echocardiographic data, (2) apply the resulting models to predict trajectory membership in a separate sample, and (3) determine associations between assigned trajectory and incident HFpEF and HFrEF. Methods We used a Bayesian nonparametric trajectory approach to jointly model longitudinal measures of LV ejection fraction (LVEF) and E/A ratio among 747 participants in two longitudinal cohort studies (the Atherosclerosis Risk in Communities [ARIC] study and Jackson Heart Study [JHS]) who underwent ≥2 echocardiograms in 2000-04 (mean age 65±5 years), 2011-2013 (age 75±5 years), and 2018-19 (age 81±5 years). Using the trajectories inferred from this modeling, we applied Bayes theorem to assign 4,419 ARIC-only participants to their most likely trajectory using single time-point measures of LVEF and E/A ratio acquired in 2011-2013 (age 75±5 years). These assignments were treated as a categorical variable in subsequent analysis. In ARIC-only participants, we used Cox proportional hazards models adjusted for age, sex, obesity, hypertension, diabetes, chronic kidney disease, and coronary heart disease to assess the relationship between assigned trajectory and incident HF. Results In the discovery set (n=747), we identified six trajectories of cardiac function based jointly on longitudinal changes in LVEF and E/A ratio (Figure 1). The pink (prevalence 50%) and light green (17%) trajectories showed increasing LVEF and decreasing E/A ratio with increasing age, while the red trajectory (22%) demonstrated a lack of increase in LVEF. The dark green trajectory (4%) demonstrated progressive LVEF decline, the orange trajectory (2%) steep LVEF decline and rise in E/A ratio, and the blue trajectory (4%) rising E/A ratio despite increasing in LVEF. Analysis of the ARIC-only participants (n=4,419) showed that trajectory membership was differentially associated with risk of incident HFpEF and HFrEF (Figure 2). Compared to the pink trajectory, membership in the orange trajectory was associated with incident HFpEF and HFrEF, the red and the dark green trajectory associated with HFrEF alone, and the blue trajectory with HFpEF alone. Conclusion(s) These results demonstrate the feasibility of identifying trajectories of cardiac function with multidimensional longitudinal data and may have implications for HF risk prediction.

Abstract 12132: The Intercellular Adhesion Molecule-1 Missense Variant rs5491, High-Sensitivity C-reactive Protein, and Heart Failure With Preserved Ejection Fraction Risk

Introduction: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein involved in leukocyte transmigration, thereby promoting inflammation. A missense genetic variant in ICAM1 , rs5491, is common among Black individuals but rare in other race/ethnic groups, and has been associated with increased risk of heart failure with preserved ejection fraction (HFpEF). The pathways by which rs5491 may lead to HFpEF, however, are not known. Hypothesis: We hypothesized that rs5491 is associated with systemic inflammation as measured by high-sensitivity C-reactive protein (hsCRP) and that the association between rs5491 and HFpEF is mediated by higher hsCRP. Methods: Among Black individuals within the Multi-Ethnic Study of Atherosclerosis, we evaluated the association of rs5491 with hsCRP at Exam 1 and performed a formal mediation analysis of hsCRP on the association between rs5491 and incident HFpEF. Results: Among 1558 Black participants (mean age 62±10 y, 47% female), individuals with at least one copy of rs5491 (N=580) had higher hsCRP in unadjusted analysis (2.78 mg/L [IQR: 1.11-6.25] vs 2.25 mg/L [IQR: 0.99-4.82], P=0.009). After covariate adjustment, each additional rs5491 allele was significantly associated with higher hsCRP (β: 0.15, SE: 0.07, P=0.02; Figure ). Each additional rs5491 allele remained significantly associated with incident HFpEF after adjustment for hsCRP in addition to clinical covariates and principal components of ancestry 1-10 (HR 1.86, 95% CI: 1.15-3.01, P=0.01). On mediation analysis, hsCRP did not significantly mediate the association between rs5491 and HFpEF (percent mediated: 0%, 95% CI: 0-31%, P= 0.08). Conclusions: In Black individuals, the ICAM1 missense variant rs5491 is associated with incident HFpEF and systemic inflammation, as measured by hsCRP. The relationship between rs5491 and HFpEF is not mediated by hsCRP, suggesting that other inflammatory pathways may drive HFpEF risk among individuals with this variant.

Abstract 15818: Association of Clonal Hematopoiesis of Indeterminate Potential With Incident Heart Failure With Preserved Ejection Fraction

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related expansion of blood cells with somatic mutations, most commonly in DMNT3A , TET2 , and ASXL1 . CHIP is a risk factor for coronary heart disease as well as heart failure (HF). Experimental HF models suggest a role of CHIP pro-inflammatory myeloid cells on cardiac dysfunction via fibrotic remodeling and hypertrophy. However, whether CHIP associates with incident HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF), or both is currently unknown. Hypothesis: We hypothesized that CHIP is more strongly related to HFpEF than HFrEF. Methods: We studied a multiethnic sample of postmenopausal women without prevalent HF from the Women’s Health Initiative (WHI). Whole genome sequencing was performed through the NHLBI TOPMed Program, and CHIP was detected based on 74 pre-specified myeloid driver mutations. Participants were followed through March 2020 with physician adjudication of HFrEF and HFpEF. Cox models tested the association of CHIP with incident HFpEF and HFrEF with adjustment for demographic/clinical risk factors and inverse probability weighting to account for the TOPMed sampling scheme. Results: Among 5,214 women, the mean age was 62 years, and 7.8% had CHIP. Over a median follow-up of 15 years, age-adjusted HFpEF incidence rates were 5.86 (95%CI 5.63-6.10) vs. 3.72 (95%CI 3.68-3.77) per 1,000 person-years among CHIP carriers vs. non-carriers. After multivariable adjustment, CHIP was associated with a 42% increased risk of incident HFpEF (HR 1.42, 95%CI 6-91%; P =0.02). In contrast, there was no evidence of association between CHIP and HFrEF ( Table 1 ). HFpEF was more strongly associated with TET2 CHIP (HR 2.50, 95%CI 1.54-4.06; P &lt;0.001) than with DNMT3A or ASXL1 ( Table 1 ). Conclusions: CHIP, especially TET2 CHIP, is associated with incident HFpEF. This finding has potential precision medicine implications for HFpEF prevention and treatment.

Abstract 16282: Incident Heart Failure With Preserved Ejection Fraction in a Cohort of Patients With Biopsy-Proven Non-Alcoholic Fatty Liver Disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to determine the prevalence, clinical, and echocardiographic (TTE) features of HFpEF in patients with biopsy-proven NAFLD. Methods: We performed a retrospective single-center cohort study of patients with biopsy-proven NAFLD in the Duke NAFLD Biorepository and Clinical Database. Study entry was at the time of liver biopsy and patients were followed until death or 5/1/2023. Clinical and echocardiographic data were abstracted via manual chart review. HFpEF was defined as: at least one TTE characteristic (left atrial volume index ≥ 29 ml/m 2 , septal wall thickness ≥ 1 cm, or evidence of diastolic dysfunction) and signs or symptoms of heart failure (diagnosis of heart failure on problem list, hospitalization for heart failure, elevated NT pro-BNP level, jugular venous distention, use of loop diuretics, pulmonary or peripheral edema, fatigue, or exertional symptoms). Descriptive statistics were evaluated. Results: A total of 742 patients were included in the study. The mean age of the cohort was 50 +/- 12 years, and 83% were White. 95 (13%) had TTE both prior to study entry and during follow up, while 279 patients (38%) had TTE only during follow up. A total of 185 patients met criteria for HFpEF during follow up. After removing patients with TTE evidence of HFpEF prior to study entry, there were 132 cases of incident HFpEF over a mean follow up of 9.1 years, representing 47% of those with TTE after liver biopsy, and 18% of the overall cohort. Considering only TTE criteria, 142 patients had incident HFpEF. During follow up, 12 patients were hospitalized for heart failure. Conclusions: HFpEF is common in patients with NAFLD and a small percentage of patients do not have a chart diagnosis despite meeting echocardiographic criteria, suggesting that HFpEF may be under-recognized. Screening for HFpEF and/or formal care pathways to address early heart failure will be important to prevent morbidity and mortality in this population.

Proteomics and Precise Exercise Phenotypes in Heart Failure With Preserved Ejection Fraction: A Pilot Study.

While exercise impairments are central to symptoms and diagnosis of heart failure with preserved ejection fraction (HFpEF), prior studies of HFpEF biomarkers have mostly focused on resting phenotypes. We combined precise exercise phenotypes with cardiovascular proteomics to identify protein signatures of HFpEF exercise responses and new potential therapeutic targets. We analyzed 277 proteins (Olink) in 151 individuals (N=103 HFpEF, 48 controls; 62±11 years; 56% women) with cardiopulmonary exercise testing with invasive monitoring. Using ridge regression adjusted for age/sex, we defined proteomic signatures of 5 physiological variables involved in HFpEF: peak oxygen uptake, peak cardiac output, pulmonary capillary wedge pressure/cardiac output slope, peak pulmonary vascular resistance, and peak peripheral O2 extraction. Multiprotein signatures of each of the exercise phenotypes captured a significant proportion of variance in respective exercise phenotypes. Interrogating the importance (ridge coefficient magnitude) of specific proteins in each signature highlighted proteins with putative links to HFpEF pathophysiology (eg, inflammatory, profibrotic proteins),and novel proteins linked to distinct physiologies (eg, proteins involved in multiorgan [kidney, liver, muscle, adipose] health) were implicated in impaired O2 extraction. In a separate sample (N=522, 261 HF events), proteomic signatures of peak oxygen uptake and pulmonary capillary wedge pressure/cardiac output slope were associated with incident HFpEF (odds ratios, 0.67 [95% CI, 0.50-0.90] and 1.43 [95% CI, 1.11-1.85], respectively) with adjustment for clinical factors and B-type natriuretic peptides. The cardiovascular proteome is associated with precision exercise phenotypes in HFpEF, suggesting novel mechanistic targets and potential methods for risk stratification to prevent HFpEF early in its pathogenesis.

Chronic Kidney Disease, Heart Failure, and Adverse Cardiac Remodeling in Older Adults: The ARIC Study

BackgroundThe associations of kidney dysfunction and damage with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), as well as adverse cardiac remodeling, in late-life remain incompletely understood. ObjectivesThe authors sought to define the associations between kidney dysfunction and damage and incident HFrEF and HFpEF and cardiac structure and function in late-life. MethodsThis study included 5,170 adults initially free of a heart failure (HF) diagnosis who had estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) measured at visit 5 (2011-2013) of the ARIC (Atherosclerosis Risk In Communities) study. Multivariable Cox proportional hazards models were used to estimate the associations of eGFR and UACR with incident HF, HFrEF, and HFpEF through 2019. Multivariable linear regression models were used to investigate the associations of eGFR and UACR at visit 5 with changes in cardiac structure and function between visits 5 and 7 in 2,313 participants with available echocardiograms. ResultsThe mean age of participants was 76 ± 5 years, and 2,225 (43%) were men. The mean eGFR and median UACR were 66 ± 18 mL/min/1.73 m2 and 11 mg/g (25th, 75th percentile: 6, 22 mg/g), respectively. In fully adjusted models, both lower eGFR and higher UACR were associated with greater risk of any HF, HFrEF, and HFpEF. Lower eGFR was associated with larger increases in left ventricular end-diastolic volume index and worsening of diastolic measures. UACR did not associate with changes in cardiac structure or function. ConclusionsMild to moderate kidney dysfunction and damage associate with incident HF and adverse cardiac remodeling in late-life.

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.

The Association of Protein Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct clinical entities, yet there is scant evidence for associations of proteomic signatures with future development of HFpEF versus HFrEF. We evaluated the association of 71 protein biomarkers with incident HFpEF versus HFrEF (left ventricular ejection fraction ≥ versus <50%) among Framingham Heart Study participants using multivariable Cox models. Among 7038 participants (mean age 49 years; 54% women), 5 biomarkers were associated with increased risk of incident HFpEF (false discovery rate q<0.05): NT-proBNP (N-terminal pro-B-type natriuretic peptide; hazard ratio [HR], 2.13; 95% CI, 1.52-2.99; P<0.001), growth differentiation factor-15 (HR, 1.67; 95% CI, 1.32-2.12; P<0.001), adrenomedullin (HR, 1.58; 95% CI, 1.23-2.04; P<0.001), uncarboxylated matrix Gla protein (HR, 1.55; 95% CI 1.23-1.95; P<0.001), and C-reactive protein (HR, 1.46; 95% CI, 1.17-1.83; P=0.001). Fourteen biomarkers were associated with incident HFrEF (multivariable P<0.001, q<0.05 for all). Of these, 3 biomarkers were associated with both HF subtypes (NT-proBNP, growth differentiation factor-15, and C-reactive protein). When compared directly, myeloperoxidase, resistin, and paraoxanase-1 were more strongly associated with HFrEF than HFpEF. We identified 5 protein biomarkers of new-onset HFpEF representing pathways of inflammation, cardiac stress, and vascular stiffness, which partly overlapped with HFrEF. We found 14 biomarkers associated with new-onset HFrEF, with some distinct associations including myeloperoxidase, resistin, and paraoxanase-1. Taken together, these findings provide insights into similarities and differences in the development of HF subtypes. URL: https://clinicaltrials.gov/ct2/show/NCT00005121; Unique identifier: NCT0005121.

Coronary Artery Disease and Heart Failure With Preserved Ejection Fraction: The ARIC Study.

BackgroundWhether coronary artery disease (CAD) is a significant risk factor for heart failure (HF) with preserved ejection fraction (HFpEF) is unclear.Methods and ResultsAmong 9902 participants in the ARIC (Atherosclerosis Risk in Communities) study, we assessed the association of incident CAD with subsequent incident HFpEF (left ventricular ejection fraction [≥50%]) and HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction <50%) using survival models with time‐updated variables. We also assessed the extent to which echocardiographic correlates of prevalent CAD account for the relationship between CAD and incident HFpEF. Over 13‐year follow‐up, incident CAD developed in 892 participants and 178 subsequently developed HF (86 HFrEF, 71 HFpEF). Incident HFrEF and HFpEF risk were both greatest early after the CAD event. At >1 year post‐CAD event, adjusted incidence of HFrEF and HFpEF were similar (7.2 [95% CI, 5.2–10.0] and 6.7 [4.8–9.2] per 1000 person‐years, respectively) and CAD remained predictive of both (HFrEF: hazard ratio, 2.76 [95% CI, 1.99–3.84]; HFpEF: 1.85 [1.35–2.54]) after adjusting for demographics and common comorbidities. Among 4779 HF‐free participants at Visit 5 (2011–2013), the 490 with prevalent CAD had lower left ventricular ejection fraction and higher left ventricular mass index, E/e’, and left atrial volume index (all P<0.01). The association of prevalent CAD with incident HFpEF post‐Visit 5 was not significant after adjusting for echocardiographic measures, with the greatest attenuation observed for left ventricular diastolic function.ConclusionsCAD is a significant risk factor for incident HFpEF after adjustment for demographics and common comorbidities. This relationship is partially accounted for by echocardiographic alterations, particularly left ventricular diastolic function.

Vitamin D Levels in Black Americans and the Association With Left Ventricular Remodeling and Incident Heart Failure With Preserved Ejectin Fraction: The Jackson Heart Study

BackgroundIn observational studies, a lower serum vitamin D3 concentration has been associated with an increased risk of cardiovascular disease. However, the associations between serum vitamin D3 levels and left ventricular (LV) structure and heart failure with preserved ejection fraction (HFpEF) have not been well-characterized among Black Americans. The prevalence of vitamin D3 deficiency is higher among Black Americans than in other race/ethnicity groups. We hypothesized that serum vitamin D3 levels are associated with LV concentric remodeling and incident HFpEF in Black Americans. Methods and ResultsAmong 5306 Black Americans in the Jackson Heart Study cohort, we investigated the relationships between serum vitamin D3 levels and LV structure and function, evaluated with echocardiography, and incident HF hospitalization, categorized as either HF with reduced EF (HFrEF; an EF of <50%) or HFpEF (an EF of ≥50%). After adjustment for possible confounding factors, lower vitamin D3 levels were associated with greater relative wall thickness (β for 1 standard deviation [SD] increase –0.003, 95% confidence interval –0.005 to –0.000). Over a median follow-up period of 11 years (range 10.2–11.0 years), 340 participants developed incident HF (7.88 cases per 1000 person-years), including 146 (43%) HFrEF and 194 (57%) HFpEF cases. After adjustment, higher serum vitamin D3 levels were associated with decreased hazard for HF overall (hazard ratio for 1 SD increase 0.88, 95% confidence interval 0.78–0.99) driven by a significant association with HFpEF (hazard ratio for 1 SD increase 0.84, 95% confidence interval 0.71–0.99). ConclusionsIn this community-based Black American cohort, lower serum vitamin D3 levels were associated with LV concentric remodeling and an increased hazard for HF, mainly HFpEF. Further investigation is required to examine whether supplementation with vitamin D3 can prevent LV concentric remodeling and incident HFpEF in Black Americans.

NT-pro B-type natriuretic peptide, early menopause, and incident heart failure in postmenopausal women of the ARIC study.

N-Terminal pro B-type Natriuretic Peptide (NT-proBNP), a biomarker of heart failure (HF) has been associated with early menopause. We evaluated the modifying role of early menopause on the association of NT-proBNP with incident HF, and separately for HF subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). We included 4,352 postmenopausal women including 1,174 with early menopause, ages 63.5 ± 5.5 years, without prevalent HF at the Atherosclerosis Risk in Communities study Visit 4. Binary log-transformation was performed for NT-proBNP. Cox proportional hazards models were used to examine the association of NT-proBNP with incident HF, and separately for incident HFpEF and incident HFrEF, testing for effect modification by early menopause and adjusting for HF risk factors. We observed 881 HF events over a mean follow-up of 16.5 years. The interaction terms of NT-proBNP and early menopause were not significant for incident HF (Pinteraction 0.95) and incident HFpEF (Pinteraction 0.17) but were significant for incident HFrEF (Pinteraction 0.03). The adjusted hazard ratios resulting from each doubling of NT-proBNP levels amongst women with and without early menopause were 1.33 (1.20-1.47) and 1.34 (1.24-1.44), respectively, for incident HF; 1.57 (1.34-1.86) and 1.38 (1.24-1.54), respectively, for incident HFpEF; and 1.68 (1.42-1.99) and 1.36 (1.22-1.52), respectively, for incident HFrEF. The association of NT-proBNP with incident HFpEF is similar irrespective of early menopause status. However, the association of NT-proBNP with incident HFrEF is greater among women with early menopause when compared to those without early menopause.

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction.

Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.

Depressive Symptoms, Cardiac Structure and Function, and Risk of Incident Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction in Late Life.

BackgroundDepressive symptoms are associated with heightened risk of heart failure (HF), but their association with cardiac function and with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) in late life is unclear. We aimed to determine the prevalence of depression in HFpEF and in HFrEF in late life, and the association of depressive symptoms with cardiac function and incident HFpEF and HFrEF.Methods and ResultsWe studied 6025 participants (age, 75.3±5.1 years; 59% women; 20% Black race) in the ARIC (Atherosclerosis Risk in Communities) study at visit 5 who underwent echocardiography and completed the Center for Epidemiologic Studies Depression Scale questionnaire. Among HF‐free participants (n=5086), associations of Center for Epidemiologic Studies Depression Scale score with echocardiography and incident adjudicated HFpEF and HFrEF were assessed using multivariable linear and Cox proportional hazards regression. Prevalent HFpEF, but not HFrEF, was associated with a higher prevalence of depression compared with HF‐free participants (P<0.001 and P=0.59, respectively). Among HF‐free participants, Center for Epidemiologic Studies Depression Scale score was not associated with cardiac structure and function after adjusting for demographics and comorbidities (all P>0.05). Over 5.5‐year follow‐up, higher Center for Epidemiologic Studies Depression Scale score was associated with heightened risk of incident HFpEF (hazard ratio [HR] [95% CI], 1.06 [1.04–1.12]; P=0.02), but not HFrEF (HR [95% CI], 1.02 [0.96–1.08]; P=0.54), independent of echocardiographic measures, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), troponin, and hs‐CRP (high‐sensitivity C‐reactive protein) (HR [95% CI], 1.06 [1.00–1.12]; P=0.04).ConclusionsWorse depressive symptoms predict incident HFpEF in late life, independent of common comorbidities, cardiac structure and function, and prognostic biomarkers. Further studies are necessary to understand the mechanisms linking depression to risk of HFpEF.

Abstract 13754: Association of Cumulative Excess Adiposity With Heart Failure With Preserved and Reduced Ejection Fraction: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Prior studies suggest that obesity, measured at a single time point, has a stronger association with heart failure with preserved ejection fraction (HFpEF) than heart failure with reduced ejection fraction (HFrEF). Longstanding obesity is associated with both diastolic and systolic dysfunction, but there is scarce data on the association of cumulative adiposity with risks for HFpEF and HFrEF. Hypothesis: Higher cumulative adiposity is associated with increased risk for both HFpEF and HFrEF. Methods: We performed a prospective analysis of 8,895 individuals (mean age 63, 57% women, 19% Black adults) without HF or coronary heart disease (CHD) who attended ARIC Visit 4 (1996-99). We calculated cumulative excess body-mass index (BMI) years from age 25 to Visit 4 by centering the BMI variable at 25 kg/m2 at each of the first 4 ARIC visits and at age 25 (self-reported), and multiplying the average BMI by the number of years from age 25 to Visit 4. Cumulative excess BMI years were categorized into quartiles. The outcomes were cases of incident HFpEF (EF ≥50%) and HFrEF (EF &lt;50%) during the period of HF adjudication in ARIC (1/1/2005-12/31/2019); we excluded those with HF prior to 2005. We used Cox models to calculate incidence rates and estimate hazard ratios (HRs) for the associations of cumulative excess BMI years with incident HFpEF and HFrEF, adjusting for covariates including incident CHD. Results: There were 554 HFpEF and 482 HFrEF events over 14 years of follow-up. Higher quartiles of cumulative excess BMI years were associated with greater incidence of HFpEF and HFrEF (Table). Compared to the lowest quartile, the highest quartile of cumulative excess BMI years was associated with greater risk for HFpEF (HR: 1.57, 95% CI 1.22-2.03) and HFrEF (1.50, 95% CI 1.13-1.99). Conclusions: Excess cumulative weight is associated with similarly increased risks of HFpEF and HFrEF, indicating the importance of obesity prevention for reducing the risks for different subtypes of HF.