Risk Of Heart Failure With Preserved Ejection Fraction Research Articles

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life.

Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions. To identify shared pathways between incident HF and frailty in late life using large-scale proteomics. In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023. Protein aptamers, measured at study V3 and V5. Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty. A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF. In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

Agreement of left atrial pressure with clinical risk scores and echocardiographic features in patients with atrial fibrillation referred for catheter ablation

Abstract Background Heart failure with preserved ejection fraction (HFpEF) frequently coexists with atrial fibrillation (AF). The diagnosis of HFpEF in AF is difficult because some diagnostic criteria for HFpEF may be associated with AF instead of HFpEF per se. Left atrial pressure (LAP) ≥15 mmHg has been used to confirm the diagnosis of HFpEF. Purpose We aimed to 1) determine LAP measurements in patients with AF undergoing catheter ablation; 2) assess the agreement between LAP measurement HFpEF risk scores and 3) determine the association between LAP measurement and clinical and echocardiographic features. Methods Consecutive patients with paroxysmal or persistent AF scheduled for catheter ablation were included. Participants were considered to have HFpEF if the mean LAP was ≥15 mm Hg. The LAP was measured only in sedated patients with spontaneous breathing. Participants had high probability of HFpEF if scored &amp;gt;5points in H2FPEF and/or ≥5 points in HFA-PEFF score. Results Of 107 participants, 29 (27%) had HFpEF according to mean LAP and 32 (30%) had high probability of HFpEF according to HFpEF scores. The highest agreement of HFpEF risk scores relative to elevated LAP was observed for H2FPEF score; among patients with mean LAP ≥15 mm Hg, 38% [n=11/29] of them had also high risk of HFpEF based on H2FPEF score, whereas only 10% [n=3/29] had high risk of HFpEF based on HFA-PEFF score. In multivariable analysis, the independent predictors of HFpEF were left ventricular ejection fraction (LVEF; OR 0.77, 95%CI 0,.64-0.91), intraventricular septum diameter (IVSd; OR 1.75, 95%CI 1.11-2.74), global longitudinal strain (GLS; OR 1.24, 9%CI 1.05-1.48). Conclusions More than one-fourth of patients scheduled for catheter ablation had HFpEF according to elevated LAP. The highest agreement to elevated LAP was observed for the H2FPEF score. Predictors of HFpEF diagnosis were lower LVEF, higher IVSd and GLS.

Risk factors for pregnancy-associated heart failure with preserved ejection fraction and adverse pregnancy outcomes: a cross-sectional study.

Although pregnancy-associated heart failure with preserved ejection fraction (HFpEF) is increasing and contributing to maternal morbidity, little is known about its impact on pregnancy. We examined the risk factors for and adverse pregnancy outcomes of HFpEF in pregnant women. We conducted a cross-sectional analysis of pregnancy-related hospitalizations from 2009 to 2020 using the perinatal database of seven multicenters. Cases of HFpEF were identified using the International Classification of Diseases and echocardiography findings. The patients were categorized into the HFpEF and control groups. Risk factors were evaluated using multivariate logistic regression analysis to generate odds ratios (OR) and 95% confidence intervals (CI). Furthermore, adjusted associations between HFpEF and adverse pregnancy outcomes were determined. Risk scores for the stratification of women at a high risk of HFpEF were calculated using a statistical scoring model. Of the 34,392 women identified, 258 (0.76%) were included in the HFpEF group. In multivariate analysis, HFpEF was significantly associated with old maternal age (OR, 1.04; 95% CI 1.02-1.07), multiple pregnancy (OR, 2.22; 95% CI 1.53-3.23), rheumatic disease (OR, 2.56; 95% CI 1.54-4.26), pregnancy induce hypertension (OR 6.02; 95% CI 3.61-10.05), preeclampsia (OR 24.66; 95% CI 18.61-32.66), eclampsia or superimposed preeclampsia (OR 32.74; 95% CI 21.60-49.64) and transfusion in previous pregnancy (OR 3.89; 95% CI 1.89-8.01). A scoring model to predict HFpEF with those factors achieved an area under the curve of 0.78 at cutoff value of 3. Women with HFpEF also had increased odds ratios of intensive care unit admission during the perinatal period (odds ratio, 5.98; 95% confidence interval, 4.36-8.21) and of postpartum hemorrhage (odds ratio, 5.98; 95% confidence interval, 2.02-3.64). Pregnancy-associated HFpEF is associated with adverse pregnancy outcomes. A scoring model may contribute to screening HFpEF using echocardiography and preparing adverse pregnancy outcomes.

Associations of Circulating Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 With Long-Term Cardiac Function.

Although VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM-1 and ICAM-1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM-1, ICAM-1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. In MESA (Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM-1 and ICAM-1 at examination 2 (2002-2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010-2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM-1 or ICAM-1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM-1 or ICAM-1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM-1 and ICAM-1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2-30) of the relationship between VCAM-1 and HFpEF and 9% (95% CI, 2-21) of the relationship between VCAM-1 and AF. Higher VCAM-1 and ICAM-1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM-1 and ICAM-1 may promote HFpEF and AF risk through impaired LA reservoir function.

HeartFailure Risk Among African-American Women With an ICAM1 Missense Variant.

A common genetic variant of ICAM1 among African-American individuals (rs5491; p.K56M) is associated with heart failure (HF) hospitalization, but whether this risk is specific to heart failure with preserved ejection fraction (HFpEF) remains unclear. Older women are at high risk for HFpEF, and the relationship between rs5491 and HFpEF across the age spectrum is unknown. This study assessed risk of HF and its subtypes conferred by ICAM1 p.K56M (rs5491). Associations of rs5491 with risk of HF and its subtypes were estimated among African American individuals in WHI (Women's Health Initiative). The study evaluated whether the association between rs5491 and HF hospitalizations was modified by baseline age. Subsequently, African-American women in WHI and MESA (Multi-Ethnic Study of Atherosclerosis) were pooled and analyses were repeated. Among 8,401 women in WHI, the minor allele frequency of rs5491 was 20.7%, and 731 HF hospitalizations occurred over 19.2 years. The rs5491 variant was not associated with HF or its subtypes across WHI. Interaction analyses suggested that age as a continuous variable modified the association of rs5491 with HFpEF hospitalization (interaction P= 0.04). Upon categorizing women into age decades, rs5491 conferred increased risk of HFpEF among women ≥70years (HR per additional rs5491 allele: 1.82 [95%CI: 1.25-2.65]; P = 0.002) but was not associated with HFpEF risk among women<70 years. Pooling African-American women in WHI (n=8,401) and MESA (n=856) demonstrated that the effect modification byage on the association of rs5491 with HFpEF became more significant (interaction P = 0.009), with consistent HFpEF risk effect estimates among women≥70 years. ICAM1 p.K56M (rs5491) is associated with HFpEF among African-American women≥70 years.

Cardiorespiratory Fitness and Risk of Heart Failure with Preserved Ejection Fraction.

Preventive strategies for heart failure (HF) with preserved ejection fraction (HFpEF) include pharmacotherapies and lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and the risk of HFpEF has not been evaluated. Thus, we evaluated the association between CRF and HFpEF incidence. We assessed CRF in US Veterans (624,551 men; mean age 61.2 ± 9.7 years and 43,179 women; mean age 55.0±8.9 years) by a standardized ETT performed between 1999-2020 across US Veterans Affairs Medical Centers. All had no evidence of HF or myocardial infarction prior to completion of the ETT. We assigned participants to one of five age-and-gender-specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT and four categories based on CRF changes in those with two ETT evaluations (n=139,434) ≥1.0 year apart. During the median follow-up of 10.1 years (IQR 6.0-14.3 years), providing 6,879,229 person-years, there were 16,493 HFpEF events with an average annual rate of 2.4 events per 1,000 person-years. The adjusted risk of HFpEF decreased across CRF categories as CRF increased, independent of comorbidities. For fit individuals (≥10.5 METs) the hazard ratio (HR) was 0.48 (95% CI 0.46-0.51) compared with least fit (≤ 4.9 METs; referent). Being unfit carried the highest risk (HR, 2.88; 95% CI, 2.67-3.11) of any other comorbidity. The risk of unfit individuals who became fit was 37% lower (HR 0.63, 95% CI 0.57-0.71), compared to those who remained unfit. Higher CRF levels are independently associated with lower HRpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF. This article is protected by copyright. All rights reserved.

A prediction model for estimating NT-proBNP in a general Japanese population: the Toon Health Study.

As part of the Toon Health Study, which is an ongoing population-based cohort study, we aimed to develop a prediction model for N-terminal pro-brain natriuretic peptide (NT-proBNP) in a general Japanese population. We sought to explore the influence of various demographic and clinical factors on NT-proBNP levels and assess the model's performance. In addition, our objectives included internal validation and investigation of the diagnostic potential of the observed-to-predicted NT-proBNP ratio (OPR) at baseline for predicting the risk of heart failure with preserved ejection fraction (HFpEF). In this prospective cohort study, participants were recruited from Toon City, Japan, as part of the larger Toon Health Study, focusing on cardiovascular risk factors. We measured the NT-proBNP levels and used linear regression with penalization (ridge regression) to develop the model. The model incorporated 10 prespecified predictors (age, gender, body mass index, diastolic blood pressure, heart rate, haemoglobin, albumin, total cholesterol, haemoglobin A1c, and estimated glomerular filtration rate) and underwent assessment using R2 and root mean squared error (RMSE). Internal validation was conducted through bootstrapping. In a post hoc analysis, we explored the OPR's diagnostic potential using 5year follow-up data (n=636) to predict the elevation of NT-proBNP>125pg/mL at the 5year follow-up as the risk of HFpEF. A total of 2505 participants (age: 60.4±12.9years, men: 35%) were enrolled in this study. There was a linear relationship between the observed and predicted values of NT-proBNP in which the logarithm of observed NT-proBNP was <6, which corresponds to 403pg/mL in NT-proBNP. The prediction model demonstrated satisfactory performance (R2 : 0.291, RMSE: 0.688), with age identified as a dominant predictor. The stability of the model was underscored by the internal validation. The OPR at baseline predicted NT-proBNP>125pg/mL at the 5year follow-up with an area under the curve of 0.793. This study introduces the first prediction model for NT-proBNP in a general Japanese population. Although the model has acceptable performance, ongoing refinement is essential. Our transparent approach to model development, alongside a web-based interactive tool, lays the groundwork for further improvements and external validation. The OPR holds potential for predicting the future risk of HFpEF. This research contributes to understanding the nuanced influence of patient backgrounds on levels of NT-proBNP in asymptomatic individuals within the context of a broader population-based cohort study.

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.

Heart failure with preserved ejection fraction risk is associated with prevalence and severity of obstructive sleep apnea.

While heart failure with preserved ejection fraction (HFpEF) is associated with the presence of obstructive sleep apnea (OSA), few studies have examined the association between scoring systems used to predict HFpEF risk, such as the H2FPEF and HFA-PEFF scores, and OSA prevalence and severity. We performed chart review on all patients who underwent both an echocardiogram and sleep study at the University of Pennsylvania between July 1, 2020, and June 30, 2022. There were 277 patients in the final cohort after excluding patients with relevant comorbidities. Associations between echocardiographic parameters and OSA severity, as well as between H2FPEF score and OSA severity, were examined using linear tests of trend. The association between H2FPEF score and prevalent OSA was examined with logistic regression. OSA severity was associated with echocardiographic markers, including left atrial volume index (P = .03) and left ventricular relative thickness (P = .008). Patients with high H2FPEF risk scores had over 17-fold higher odds of prevalent OSA compared with those with low-risk scores (17.7; 95% CI 4.3, 120.7; P < .001). Higher H2FPEF scores were strongly correlated with OSA severity (P < .001). After controlling for body mass index, H2FPEF scores were not associated with prevalence or severity of OSA. In an ambulatory population referred for sleep study and echocardiogram, markers of diastolic dysfunction were associated with OSA severity. OSA prevalence and severity were associated with increased H2FPEF scores, although these associations were largely explained by obesity. Clinicians should have low thresholds for referring patients with OSA for cardiac workup and patients with HFpEF for sleep study. Connolly JE, Genuardi MV, Mora JI, Prenner SB. Heart failure with preserved ejection fraction risk is associated with prevalence and severity of obstructive sleep apnea. J Clin Sleep Med. 2024;20(3):381-387.

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 18068: Isometric Handgrip Exercise Myocardial Perfusion Reserve Correlates With Coronary Microvascular Dysfunction and Abnormal Left Ventricular Strain: A Report From the Women’s Ischemia Syndrome Evaluation Pre-Heart Failure With Preserved Ejection Fraction Study

Background: Impaired coronary artery response to isometric handgrip exercise (IHE) has previously been demonstrated to reflect endothelial dysfunction, an important contributor to ischemia with no obstructive coronary arteries (INOCA) and coronary microvascular dysfunction (CMD). Stress perfusion cardiac magnetic resonance (CMR) imaging is typically performed with pharmacologic stress using myocardial perfusion reserve index (MPRI) as a measure of CMD. IHE-MPRI has not been comprehensively studied in patients with INOCA, who are at risk for heart failure with preserved ejection fraction (HFpEF). Hypothesis: IHE-MPRI is related to CMD measured by pharm-MPRI and left ventricular (LV) structural and functional abnormalities in INOCA patients at risk for HFpEF. Methods: Participants with INOCA underwent comprehensive CMR with first-pass perfusion with adenosine or regadenoson, rest, and IHE. MPRI was adjusted to rest rate-pressure product (RPP). Lack of a satisfactory IHE response (defined as increase in heart rate≥10 bpm or systolic blood pressure ≥10 mmHg) was excluded. CMR measures of LV structure, function, MPRI, T1 and T2 mapping were analyzed using commercial software, blinded to clinical data. Pearson correlations were performed. Results: Of the participants (n=44) with IHE-MPRI, mean age was 55±11 years, body mass index 27±7 kg/m 2 , and 98% female, 31% hypertension, 12.5% diabetes, 19% hyperlipidemia. IHE-MPRI adjusted for rest RPP significantly correlated positively with pharm-MPRI and inversely with time to peak strain, diastolic strain measures and myocardial T2 ( Figure ). IHE-MPRI was not related to resting or IHE heart rate, systolic strain, LV mass, volumes, mass-volume ratio, native T1 or extracellular volume. Conclusion: IHE-MPRI relates to CMD and LV strain among patients with INOCA. Measurement of IHE-MPRI may improve understanding of CMD and LV structural and functional abnormalities that may contribute to development of HFpEF.

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 14625: Association of Eicosanoid Metabolites With Cardiac Structure and Function

Introduction: Eicosanoids are bioactive lipids that govern the upstream initiation of pro- and anti-inflammatory activity. They may serve as important pathways by which obesity and cardiometabolic disease lead to the development of heart failure with preserved ejection fraction (HFpEF). Objective: We sought to examine the association of plasma circulating eicosanoid metabolites with subclinical cardiac remodeling as ascertained by cardiac magnetic resonance imaging (CMR) as important determinants of HFpEF risk. Methods: We studied 3880 MESA study participants (mean age 63±10 years, 53% women) who underwent plasma metabolite profiling using a mass spectrometry-based platform and CMR. We used multivariable linear regression to examine the association of eicosanoid metabolites with left ventricular mass index (LVMI, primary outcome), LV end-diastolic volume index (LVEDV), and left atrial volume (LAV). Results: Of 811 eicosanoids, 158 were associated with LVMI (Figure; FDR q &lt;0.05 for all). Specifically, derivatives of eicosadienoic acid (15 oxoEDE), linoleic acid (9,10 diHOME), and arachidonic acid (12(R) HETE) were negatively associated with LVMI and prostaglandin 19R-hydroxy-PGE1 was positively associated with LVMI. Of 158 metabolites, 65 were are also associated with LVEDV including derivatives of linoleic acid (13(S) HOTrE), oxylipin 11-HETE and 15 oxoEDE. Of 158 metabolites, Adrenic acid is also associated with LAV. Conclusions: We found that specific eicosanoids including 15 oxoEDE, 9,10 diHOME, and 12(R) HETE were associated with LVMI, an important measure of subclinical cardiac remodeling and precursor to HFpEF. As causal drivers of HFpEF are poorly characterized, a better understanding of pro- and anti-inflammatory eicosanoid pathways that contribute to cardiac remodeling may have important implications for the prevention of HFpEF.

Abstract 14853: Effects of Yearlong High Intensity Aerobic Exercise on Reducing Left Atrial Epicardial Adipose Tissue

Background: Left atrial epicardial adipose tissue (LA EAT) is often elevated in patients with heart failure and has been linked to abnormal atrial function and increased risk for atrial fibrillation. Whether LA EAT is potentially modifiable is unknown. We tested the hypothesis that one year of high intensity interval training (HIIT) would reduce LA EAT area and in turn be associated with improved atrial function in an obese cohort at risk for developing heart failure with preserved ejection fraction (HFpEF). Methods: Middle-aged obese adults (n = 80, age 40-55 yrs) enriched for increased HFpEF risk (N-terminal pro-B-type natriuretic peptide &amp;gt;40 pg/mL or high-sensitivity cardiac troponin T &amp;gt;0.6 pg/mL; visceral fat &amp;gt;2kg) were randomized to one year of HIIT or attention control. Outcome variables included LA EAT area and LA strain. LA EAT area was quantified through tracings of anterior, posterior, and lateral EAT depots in long axis views on cardiac MRI. LA strain was measured with MRI feature tracking as reservoir strain during left ventricular (LV) systole, conduit strain during early LV diastole, and contractile strain during late LV diastole. Results: Fifty-three participants completed the study. There was no difference in LA EAT area after one year in either the HIIT group (n = 26) or controls (n = 27); difference in mean = -0.17 cm 2 , 95% CI = -0.93 to 0.59, p = 0.66. However, amongst all participants, reduction in LA EAT was associated with improvement in LA reservoir strain (r = -0.50, 95% CI = -0.68 to -0.26, p &amp;lt; 0.001) and LA conduit strain (r = 0.51, 95% CI = 0.27 to 0.68, p &amp;lt; 0.001) but not LA contractile strain (r = 0.15, 95% CI = -0.13 to 0.40, p = 0.298). Conclusions: One year of HIIT did not reduce LA EAT in at-risk obese patients. However, regardless of assignment, decreased LA EAT was associated with improved LA reservoir and conduit strain, suggesting efforts to reduce LA EAT may improve LA function in at-risk obese patients.

Abstract 16954: Sex Differences in Cardiac and Vascular Function With Healthy Aging: Implications for Greater Risk of HFpEF in Women

Introduction: Mechanisms mediating the disproportionate risk for heart failure with preserved ejection fraction (HFpEF) in women are poorly understood. Impaired stroke volume (SV) reserve, increased afterload, arterial and left ventricular (LV) stiffness contribute to exercise intolerance in HFpEF. It is unknown whether subclinical changes in these measures predispose women to HFpEF; therefore, we compared resting and exercise cardiovascular structure and function across age in healthy men and women. Methods: We studied 192 sedentary normotensive, non-obese adults (53% female; age: 58 ± 13 [20-90] years) at rest, during sub- and maximal exercise. We measured systolic blood pressure (SBP; electrosphygmomanometry) and aortic stiffness (carotid-femoral pulse wave velocity; aPWV). Myocardial stiffness was assessed as the slope of individual pressure-volume (right heart catheterization-echocardiography) curves generated by graded LV loading and unloading. SV was calculated from cardiac output (Q˙c; C 2 H 2 rebreathe)/heart rate to assess afterload (Ea; SBP/SV) and SV reserve (% change from rest) during exercise. Data were compared via two-way ANOVA (age*sex). Results: There was no significant age*sex interaction for aPWV, SV reserve, resting or maximal SBP, or myocardial stiffness; however, there was a main effect for sex with higher myocardial stiffness in women (Figure). aPWV and SV reserve were not different between sexes (p=0.349, p=0.940). Maximal exercise SBP was lower in women, but a similar proportion of each sex had an exaggerated maximal exercise SBP (Men: &gt;210; Women: &gt;190 mmHg; 28% vs 35%, χ 2 =0.290). Peak exercise afterload was higher in women (Figure) due to lower SV. Conclusions: Increased risk for HFpEF in women may be driven in part by greater myocardial stiffness throughout the aging process. Sex related abnormalities in afterload were most prominent with exercise in women, which may predispose to LV hypertrophy and increased stiffness.

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 16161: Effects of Year Long Aerobic Exercise on Left Atrial Size in Patients With Left Ventricular Hypertrophy

Introduction: Habitual aerobic exercise is associated with left atrial (LA) enlargement and risk of atrial fibrillation. This risk may be accentuated in patients with increased left ventricular (LV) stiffness due to high LA pressure during exercise. We tested the hypothesis that 1 year long endurance exercise would increase LA size to a greater extent in patients with left ventricular hypertrophy (LVH) at risk for heart failure with preserved ejection fraction (HFpEF) than previously published age appropriate controls. Methods: Middle-aged adults (age 45-64 yrs) with LVH (n=53) enriched for increased HFpEF risk (N-terminal pro-B-type natriuretic peptide &gt;40 pg/mL or high-sensitivity cardiac troponin T &gt;0.6 pg/mL) and healthy subjects (n=58) were randomized to one year of high intensity aerobic exercise or yoga control. LA and LV volumes were measured using 3D echo. Results: Of 111 participants, 83 had complete data available (LVH cohort: 18 exercisers, 10 yoga; healthy cohort: 29 exercisers, 26 yoga). Baseline LA size was larger in LVH vs healthy subjects (42 ± 12 vs 35 ± 9 mL; p=0.005). There was a nominal increase in LA size in LVH exercisers compared to LVH yoga (8 ± 9 vs 4 ± 7 mL; p=0.29) which was proportional to LV size (LA/LV ratio 0.05 ± 0.07 vs 0.06 ± 0.1; p=0.81). Healthy subject exercisers increased LA size compared to healthy yoga controls (4 ± 5 vs 0 ± 6 mL; p=0.02) with no increase in LA/LV ratio (-0.02 ± 0.08 vs -0.03 ± 0.08; p=0.62). Among exercising subjects only, increase in LA size was larger in LVH compared to healthy subjects after year long aerobic training (p=0.04) with greater increase LA/LV ratio (p&lt;0.001). Conclusions: One year of aerobic training resulted in higher LA size in patients with at-risk LVH compared to healthy subjects. The increase in LA size was greater than changes in LV size suggesting chronic aerobic training may preferentially affect LA remodeling.

Abstract 12847: The Heart Bus: A Mobile Patient-Centered Approach to Improve Early Diagnosis of Heart Failure in the Community

Introduction: Heart failure with preserved ejection fraction (HFpEF) is associated with poor quality of life and considerable morbidity and mortality risk. Early diagnosis is expected to improve clinical outcomes, but requires imaging and laboratory analyses with frequent hospital visits. We developed a mobile care unit, the Heart Bus, to improve early diagnosis of HF. Methods: The Heart Bus was a 70 m 2 trailer with examination rooms, cardiac ultrasound, exercise testing equipment, a clinical laboratory, and 4 staff. During 2020-2022, the Heart Bus team reached out to the population in local newspapers, via HF patient digital platforms, and visited locations in the West Coast of Sweden. Eligible participants had suspected signs or symptoms of HF. Participants underwent echocardiography and tests for cardiopulmonary exercise, vascular function, adenosine-stress coronary flow reserve, and routine biochemistry and haematology. Molecular and physiological deep phenotyping were also performed in the Heart Bus to facilitate future patient stratification and precision medicine (data to be presented Nov 2023). Results: Of 218 participants screened over 18 months (12/month), 200 were included. Most participants actively reached out to take part. Twenty three participants (11.5%) had HFrEF, 54 (27.0%) had HFmrEF, and 62 (31.0%) had HFpEF; 70 (35.0%) had a previous HF diagnosis. Of the remaining patients, 60 (30.0%) had intermediate risk of HFpEF. The phenotypes of the EF-stratified HF subgroups were similar. However, participants in the HFpEF cohort had more women ( p &lt; 0.001), lower lung volume ( p &lt; 0.01), higher pulse wave velocity ( p &lt; 0.01) and poorer kidney function ( p &lt; 0.05) than those with HFrEF. Conclusions: The Heart Bus mobile clinic identified large numbers of patients with HF and may represent a cost-effective way to early HF diagnosis also for underserved communities, those located remotely, or have other thresholds for admittance to HF clinics.

Abstract 14281: Association of Sleep Apnea Prevalence and Severity With H 2 FPEF Score and Echocardiographic Markers of Heart Failure With Preserved Ejection Fraction

Background: While heart failure with preserved ejection fraction (HFpEF) is highly associated with the presence of sleep apnea, few studies have examined the association between diagnostic scoring systems used to predict HFpEF risk, such as the H 2 FPEF score, and OSA prevalence and severity. Methods: We performed a retrospective chart review on all patients (N = 434) who underwent both an echocardiogram and a sleep study at the University of Pennsylvania between July 1, 2020, and June 30, 2022. Associations between echocardiographic parameters and OSA severity, as well as between H 2 FPEF score and OSA severity, were examined using linear tests of trend. The association between H 2 FPEF score categorization and odds of prevalent OSA was examined with logistic regression. Results: OSA severity was associated with echocardiographic markers of diastolic dysfunction including greater LV mass index (p = 0.04), left atrial volume index (p = 0.03), and LV relative thickness (p = 0.008). Patients with intermediate H 2 FPEF risk scores had 4.3 times greater odds of prevalent OSA compared with those patients with low risk H 2 FPEF scores (95% CI 2.2, 8.7, p &lt; 0.001). Patients with high H2FPEF risk scores had over 17-fold higher odds of prevalent OSA compared to those with low-risk scores (17.7, 95% CI 4.3, 120.7, p &lt; 0.001) (Figure 1). Increasing risk of HFpEF according to H 2 FPEF categorization was strongly correlated with OSA severity as measured by apnea-hypopnea index (p &lt; 0.001) and oxygen desaturation index (p = 0.002). Conclusions: In an ambulatory population referred for both sleep study and echocardiogram, markers of diastolic dysfunction were associated with OSA severity. OSA prevalence and severity were strongly associated with increased H 2 FPEF scores. Clinicians should have a low threshold for referring OSA patients with dyspnea for cardiac workup, as well as a low threshold for referring HFpEF patients for sleep study.