Risk Of Heart Failure With Preserved Ejection Fraction Research Articles

Heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and has a prevalence that is expected to rise with the growing ageing population. HFpEF is associated with significant morbidity and mortality. Specific HFpEF risk factors include age, diabetes, hypertension, obesity and atrial fibrillation. Haemodynamic contributions to HFpEF include changes in left ventricular structure, diastolic and systolic dysfunction, left atrial myopathy, pulmonary hypertension, right ventricular dysfunction, chronotropic incompetence, and vascular dysfunction. Inflammation, fibrosis, impaired nitric oxide signalling, sarcomere dysfunction, and mitochondrial and metabolic defects contribute to the cellular and molecular changes observed in HFpEF. HFpEF impacts multiple organ systems beyond the heart, including the skeletal muscle, peripheral vasculature, lungs, kidneys and brain. The diagnosis of HFpEF can bemade in individuals with signs and symptoms of heart failure with abnormality in natriuretic peptide levels or evidence of cardiopulmonary congestion, facilitated by the use of HFpEF risk scores and additional imaging and testing with the exclusion of HFpEF mimics. Management includes initiation of guideline-directed medical therapy and management of comorbidities. Given the significant impact of HFpEF on quality of life, future research efforts should include a particular focus on how patients can live better with this disease.

Vitamin B-6 Prevents Heart Failure with Preserved Ejection Fraction Through Downstream of Kinase 3 in a Mouse Model

BackgroundThere is an urgent need to develop an efficient therapeutic strategy for heart failure with preserved ejection fraction (HFpEF), which is mediated by phenotypic changes in cardiac macrophages. We previously reported that vitamin B-6 inhibits macrophage-mediated inflammasome activation. ObjectivesWe sought to examine whether the prophylactic use of vitamin B-6 prevents HFpEF. MethodsHFpEF model was elicited by a combination of high-fat diet and Nω-nitro-l-arginine methyl ester supplement in mice. Cardiac function was assessed using conventional echocardiography and Doppler imaging. Immunohistochemistry and immunoblotting were used to detect changes in the macrophage phenotype and myocardial remodeling-related molecules. ResultsCo-administration of vitamin B-6 with HFpEF mice mitigated HFpEF phenotypes, including diastolic dysfunction, cardiac macrophage phenotypic shifts, fibrosis, and hypertrophy. Echocardiographic improvements were observed, with the E/E' ratio decreasing from 42.0 to 21.6 and the E/A ratio improving from 2.13 to 1.17. The exercise capacity also increased from 295.3 to 657.7 min. However, these beneficial effects were negated in downstream of kinase (DOK) 3-deficient mice. Mechanistically, vitamin B-6 increased DOK3 protein concentrations and inhibited macrophage phenotypic changes, which were abrogated by an AMP-activated protein kinase inhibitor. ConclusionsVitamin B-6 increases DOK3 signaling to lower risk of HFpEF by inhibiting phenotypic changes in cardiac macrophages.

Immune cell profiling of the ICAM1 p.K56M heart failure with preserved ejection fraction risk variant.

Intercellular adhesion molecule-1 (ICAM-1) facilitates inflammation via leucocyte recruitment and has been implicated in heart failure with preserved ejection fraction (HFpEF). Approximately 35% of African American individuals carry a copy of an ICAM1 missense variant (rs5491; p.K56M), which is associated with an increased risk of HFpEF. The pathways by which rs5491 increases HFpEF risk are not well defined. We evaluated the circulating immune cell profile of rs5491. Among African American individuals in the Multi-Ethnic Study of Atherosclerosis, we evaluated the associations of rs5491 with 29 circulating peripheral blood mononuclear cell subsets. The top immune cells were then related to echocardiographic measures of structure and function. Among 502 individuals with immune cell profiling (mean age 63years, 51% female), 191 individuals (38%) had at least one copy of rs5491. Each additional rs5491 allele was significantly associated with higher proportions of Tc17 CD8+ cytotoxic T cells (β=1.34, SE=0.45, P=9.5×10-5) and Tc2 CD8+ cytotoxic T cells (β=1.19, SE=0.44, P=0.00012). There were no other associations noted between rs5491 and the remaining immune cells. A higher proportion of Tc17 cells was significantly associated with a higher left ventricular ejection fraction, E/e' average and right ventricular systolic pressure (RVSP), while a higher proportion of Tc2 cells was significantly associated with a higher RVSP. The ICAM1 p.K56M variant (rs5491) carries a distinct and inflammatory T-cell subset profile. These cytotoxic T cells are in turn associated with alterations in cardiac function and adverse haemodynamics later in life, thus providing insight into pathways by which rs5491 may increase the risk of HFpEF.

An evidence-based screening tool for heart failure with preserved ejection fraction: the HFpEF-ABA score.

Heart failure with preserved ejection fraction (HFpEF) is under-recognized in clinical practice. Although a previously developed risk score, termed H2FPEF, can be used to estimate HFpEF probability, this score requires imaging data, which is often unavailable. Here we sought to develop an HFpEF screening model that is based exclusively on clinical variables and that can guide the need for echocardiography and further testing. In a derivation cohort (n = 414, 249 women), a clinical model using age, body mass index and history of atrial fibrillation (termed the HFpEF-ABA score) showed good discrimination (area under the curve (AUC) = 0.839 (95% confidence interval (CI) = 0.800-0.877), P < 0.0001). The performance of the model was validated in an international, multicenter cohort (n = 736, 443 women; AUC = 0.813 (95% CI = 0.779-0.847), P < 0.0001) and further validated in two additional cohorts: a cohort including patients with unexplained dyspnea (n = 228, 136 women; AUC = 0.840 (95% CI = 0.782-0.900), P < 0.0001) and a cohort for which HF hospitalization was used instead of hemodynamics to establish an HFpEF diagnosis (n = 456, 272 women; AUC = 0.929 (95% CI = 0.909-0.948), P < 0.0001). Model-based probabilities were also associated with increased risk of HF hospitalization or death among patients from the Mayo Clinic (n = 790) and a US national cohort across the Veteran Affairs health system (n = 3076, 110 women). Using the HFpEF-ABA score, rapid and efficient screening for risk of undiagnosed HFpEF can be performed in patients with dyspnea using only age, body mass index and history of atrial fibrillation.

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.

Heart Failure Risk Among African-American Women With an ICAM1 Missense Variant

BackgroundA 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. ObjectivesThis study assessed risk of HF and its subtypes conferred by ICAM1 p.K56M (rs5491). MethodsAssociations 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. ResultsAmong 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 ≥70 years (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 by age on the association of rs5491 with HFpEF became more significant (interaction P = 0.009), with consistent HFpEF risk effect estimates among women ≥70 years. ConclusionsICAM1 p.K56M (rs5491) is associated with HFpEF among African-American women ≥70 years.

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.

Cardiorespiratory fitness and risk of heart failure with preserved ejection fraction.

Preventive strategies for heart failure 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 and 2020 across US Veterans Affairs Medical Centers. All had no evidence of heart failure 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 a median follow-up of 10.1 years (interquartile range 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 1000 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% confidence interval [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 HFpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF.

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 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 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 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.