Risk Of Heart Failure With Preserved Ejection Fraction Research Articles

Measurement of myocardial extracellular volume fraction in patients with heart failure with preserved ejection fraction using dual-energy computed tomography.

To measure the myocardial extracellular volume (ECV) in patients with heart failure with preserved ejection fraction (HFpEF) using dual-energy computed tomography with late iodine enhancement (LIE-DECT) and to evaluate the relationship between ECV and risk of HFpEF and cardiac structure and function. A total of 112 consecutive patients with HFpEF and 80 consecutive subjects without heart disease (control group) who underwent LIE-DECT were included. All patients were divided into ischaemic and non-ischaemic groups according to the LIE patterns detected using iodine maps. The ischaemic scar burden was calculated in the ischaemic HFpEF group. Iodine maps and haematocrit were used to measure ECV in the non-ischaemic HFpEF group and remote ECV of the non-scarred myocardium in the ischaemic HFpEF group, respectively. Cardiac structural and functional variables were collected. ECV in patients with non-ischaemic HFpEF (n= 77) and remote ECV in patients with ischaemic HFpEF (n= 35) were significantly higher than those in control subjects (p< 0.001). Multivariate logistic regression analysis revealed that after adjusting for age, sex, body mass index, smoking, and drinking, a higher ECV/remote ECV was still associated with non-ischaemic HFpEF and ischaemic HFpEF (p< 0.001). A positive correlation was established between ECV and cardiac structural and functional variables (p< 0.05) in all participants. Subgroup analysis showed that ECV/remote ECV and ischaemic scar burden positively correlated with heart failure classification in the HFpEF subgroup (p< 0.05). ECV/remote ECV elevation was significantly associated with non-ischaemic and ischaemic HFpEF. Remote ECV and LIE may have synergistic effects in the risk assessment of ischaemic HFpEF. • ECV/remote ECV elevation is associated not only with non-ischaemic HFpEF but also with ischaemic HFpEF. • ECV/remote ECV and ischaemic scar burden are correlated with cardiac structure and function.

A Radiomic MRI based Nomogram for Prediction of Heart Failure with Preserved Ejection Fraction in Systemic Lupus Erythematosus Patients: Insights From a Three-Center Prospective Study.

Myocardial T1 and extracellular volume (ECV) fraction values have important roles in the prognostication of heart failure with preserved ejection fraction (HFpEF). However, the traditional mean quantification of intensity levels is not sufficient. To evaluate a T1 map-based radiomic nomogram as a long-term prognosticator for HFpEF in systemic lupus erythematosus (SLE) patients. Prospective. A total of 115 SLE patients and 50 age- and gender-matched controls. A 3.0T scanner; cine imaging, precontrast and post-contrast T1 mapping and T2 mapping sequences. A radiomic nomogram was developed based on precontrast T1 mapping. Three independent readers assessed and compared the ECV value and the value of the radiomic nomogram for predicting HFpEF in SLE patients. Cox proportional hazard models, Youden index for determining cut-off values for high HFpEF risk vs. low HFpEF risk classification, Kaplan-Meier analysis, intraclass correlation (ICC), and Uno C statistic test. During a median follow-up of 27 (interquartile range, 19-37) months, 31 SLE patients developed HFpEF. Patients with elevated ECV (≥31%) and a higher output (≥42.7) from the radiomic feature "S_33_sum average" of the precontrast T1 map had a significantly higher risk of developing HFpEF than those who had lower ECV (<31%) and an output <42.7. Patients with a higher "S_33_sum average" value on precontrast T1 map had a significantly increased risk for HFpEF (hazard ratio, 1.363, 95% CI, 1.130-1.645), after adjusting for covariates including ECV and LVEF. Finally, "S_33_sum average" from precontrast T1 mapping had modest but significantly incremental prognostic value over the mean ECV value (Uno C statistic comparing models, 0.860 vs. 0.835). The precontrast T1 map-based radiomic nomogram, as a measure of diffuse myocardial fibrosis was associated with HFpEF and provided modest prognostic value for predicting HFpEF in SLE patients. 1 TECHNICAL EFFICACY: Stage 2.

Diastolic Dysfunction With Preserved Ejection Fraction After the Fontan Procedure.

BackgroundHeart failure phenotyping in single‐ventricle Fontan patients is challenging, particularly in patients with normal ejection fraction (EF). The objective of this study was to identify Fontan patients with abnormal diastolic function, who are high risk for heart failure with preserved ejection fraction (HFpEF), and characterize their cardiac mechanics, exercise function, and functional health status.Methods and ResultsData were obtained from the Pediatric Heart Network Fontan Cross‐sectional Study database. EF was considered abnormal if <50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e’/end‐diastolic volume) was >90th percentile (≥0.26 mL‐1). Patients were divided into: controls=normal EF and diastolic function; systolic dysfunction (SD) = abnormal EF with normal diastolic function; diastolic dysfunction (DD) = normal EF with abnormal diastolic pressure:volume quotient. Exercise function was quantified as percent predicted peak VO2. Physical Functioning Summary Score (FSS) was reported from the Child Health Questionnaire. A total of 239 patients were included, 177 (74%) control, 36 (15%) SD, and 26 (11%) DD. Median age was 12.2 (5.4) years. Arterial elastance, a measure of arterial stiffness, was higher in DD (3.6±1.1 mm Hg/mL) compared with controls (2.5±0.8 mm Hg/mL), P<0.01. DD patients had lower predicted peak VO2 compared with controls (52% [20] versus 67% [23], P<0.01). Physical FSS was lower in DD (45±13) and SD (44±13) compared with controls (50±7), P<0.01.ConclusionsFontan patients with abnormal diastolic function and normal EF have decreased exercise tolerance, decreased functional health status, and elevated arterial stiffness. Identification of patients at high risk for HFpEF is feasible and should be considered when evaluating Fontan patients.

Optimal management of blood glucose, blood pressure and atrial fibrillation to reduce the risk of heart failure with preserved ejection fraction.

Type 2 diabetes mellitus (T2DM), hypertension and atrial fibrillation (AF) are risk factors for heart failure with preserved ejection fraction (HFpEF). To examine the effects of the simultaneous control of all three conditions on new-onset HFpEF in this population. This prospective cohort study enrolled 552 patients with T2DM, hypertension and AF, but without clinical signs or symptoms of heart failure. The participants were followed up for 5 years to examine the effects of glycaemic control (haemoglobin A1c: <7.0%, 7.0%-8.0% and >8.0%), blood pressure (BP) control (systolic BP: <120, 120-140 and >140 mmHg) or rhythm versus rate control for AF on new-onset HFpEF. With a follow up of 5 years, the new-onset HFpEF occurred in 62 of 552 enrolled participants. Among the different control level for diabetes, hypertension and AF, the intensive blood glucose (BG) control, poor BP control and rate control of AF had the highest risk of new-onset HFpEF, and the conservative BG control, intensive BP control and rhythm control of AF had the lowest risk of new-onset HFpEF. Multivariable Cox regression analysis showed that both poor BP control (hazard ratio (HR): 1.421, 95% confidence interval (CI): 1.013-1.992, P = 0.042) and rate control of AF (HR: 1.362, 95% CI: 1.006-1.821, P = 0.033) were independently associated with the development of new-onset HFpEF. This study demonstrated that, besides intensive BP control, conservative BG control and rhythm control of AF were crucial factors to delay the progression of HFpEF among patients with T2DM, hypertension and AF.

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.

Abstract 11702: Sex Differences in Diabetic Cardiomyopathy: Greater Reduction in Myocardial Perfusion Reserve in Women Than Men Driven by Increased Resting Perfusion

Introduction: Type 2 diabetes (T2D) confers a higher relative risk of heart failure in women than men. Women also have a greater prevalence of heart failure with preserved ejection fraction (HFpEF), linked to microvascular dysfunction. We hypothesize that sex-specific differences are present in the pathophysiological alterations of myocardial structure, function, and perfusion associated with T2D. Methods: Cross-sectional case-control study. Participants underwent comprehensive cardiac phenotyping with echocardiography and cardiac magnetic resonance with adenosine stress/rest perfusion. Global myocardial perfusion was derived as a mean of three short axis slices. Image analysis was performed by two observers blinded to all participant information. Statistical analysis was performed with independent-sample T-tests or Mann-Whitney test. Results: Individuals with T2D (n=287, 41% female) were compared with age-matched controls (n=87, 41% female). Women with T2D were more obese than men (body mass index 35.7±7.2 vs 32.4±5.3 kg/m 2 , p&lt;0.05). Both women and men with T2D had increased left ventricular (LV) concentric remodelling (greater LV mass/volume ratio), impaired diastolic (higher E/e’) and systolic (lower global longitudinal strain) function compared to controls. LV mass index was significantly increased in women only. Comparing T2D and controls, stress perfusion was not significantly different in both sexes whereas resting perfusion was increased in women (1.4±0.6 vs 1.0±0.4 ml/min/g, p&lt;0.05) but not in men. Consequently, women with T2D have a lower myocardial perfusion reserve than men (2.6±0.9 vs 3.1±0.9, p&lt;0.001). Conclusions: In asymptomatic people with T2D, women have increased LV mass index and lower myocardial perfusion reserve than men, driven primarily by increased resting perfusion. These findings support the growing evidence that microvascular dysfunction partly explains the greater risk of HFpEF in women with T2D.

Right ventricular longitudinal systolic strain as a predictor of new onset heart failure with preserved ejection fraction in hypertensive patients

Abstract Purpose Accurate assessment of right ventricular (RV) systolic function is important, as it is an established prognostic marker in cardiac diseases. Speckle-tracking echocardiography is a sensitive tool for detection of subclinical left ventricular impairment in essential hypertension. We associated RV function using longitudinal peak systolic strain (GLS) in patients with essential hypertension with the risk of future development of heart failure with preserved ejection fraction (HFpEF). Methods We performed a retrospective observational study that included 452 patients with essential hypertension (266 males, aged 63±18 years) and 175 normotensives (100 males, aged 66±15 years). Standard echocardiography was performed at the initial visit. 2D speckle tracking echocardiography with evaluation of longitudinal strain in each segment of the RV (basal: RVLS-B; mid: RVLS-M, apical: RVLS-A) and global RV free-wall strain (RVLS-G) were also performed. We studied the cases of new onset HFpEF in hypertensive patients. Results The median follow up was 85 months (22–122). RVLS-G, RVLS-B and RVLS-M were significantly impaired in hypertensives compared to controls (RVLS-G: −16.1±9.7 vs −20.0±5.1, RVLS-B: −11.7±3.7 vs −20.6±3.3, RVLS-M: −16.3±5.4 vs −20.7±4.9, p&amp;lt;0.05 for all). No significant difference was detected for the RVLS-A (−20.1±3.8 for hypertensives vs −21.31±6.5 for controls, p=NS). Thirty two hypertensive patients developed HFpEF (7%). A cut-off RVLS-G worse than −17% was significantly associated with new onset HFpEF (p&amp;lt;0.001) in those patients. A multivariate Cox regression analysis showed that RVLS-G had independent significant prognostic value for the risk of HFpEF (HR: 10.5, 95% confidence interval (CI): 7.3–25.4). Conclusions Essential hypertension leads to a decrease of RVLS which is strong predictor of a new onset HFpEF. Future studies are needed to assess the significance of these findings and the effects of treatment. Funding Acknowledgement Type of funding sources: None.

Heart failure with preserved ejection fraction as amodel disease for the cardio-pulmonary-renal syndrome : Importance of visceral fat expansion as central pathomechanism

Heart failure with preserved ejection fraction (HFpEF) is aheterogeneous syndrome with diverse underlying etiologies and pathophysiological factors. Obesity and type2 diabetes mellitus (T2DM), diseases which frequently coexist, induce acluster of metabolic and nonmetabolic signaling derangements, which promote induction of inflammation, fibrosis and myocyte stiffness, all representing hallmarks of HFpEF. In contrast to other HFpEF risk factors, obesity and T2DM are often associated with the formation of an enlarged visceral adipose tissue (VAT), which is a highly active endocrine organ that can sustainably exacerbate inflammation and fibrotic remodeling of myocardial, renal, and vascular tissues via various paracrine and vasocrine signals. An abnormally large epicardial adipose tissue (EAT) thus not only causes a mechanical constriction of the diastolic filling procedure of the heart but is also associated with an increased release of proinflammatory adipokines that trigger atrial fibrillation and impaired left ventricular contraction parameters. Obese patients with HFpEF therefore belong to aunique HFpEF phenotype with aparticularly poor prognosis that could benefit from an EAT-oriented phenotype-specific intervention. In addition to statins and antidiabetic drugs such as metformin, glucagon-like peptide‑1 (GLP-1) receptor agonists and sodium-glucose transporter2(SGLT-2) inhibitors could also play an important role.

Epicardial Fat Expansion in Diabetic and Obese Patients With Heart Failure and Preserved Ejection Fraction-A Specific HFpEF Phenotype.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with diverse etiologies and pathophysiological factors. Obesity and type 2 diabetes mellitus (T2DM), conditions that coexist frequently, induce a cluster of metabolic and non-metabolic signaling derangements which are in favor to induce inflammation, fibrosis, myocyte stiffness, all hallmarks of HFpEF. In contrast to other HFpEF risk factors, obesity and T2DM are often associated with the generation of enlarged epicardial adipose tissue (EAT). EAT acts as an endocrine tissue that may exacerbate myocardial inflammation and fibrosis via various paracrine and vasocrine signals. In addition, an abnormally large EAT poses mechanical stress on the heart via pericardial restrain. HFpEF patients with enlarged EAT may belong to a unique phenotype that can benefit from specific EAT-targeted interventions, including life-style modifications and pharmacologically via statins and fat modifying anti-diabetics drugs; like metformin, sodium-glucose cotransporter 2 inhibitors, or glucagon-like peptide-1 receptor agonists, respectively.

Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defined. Under the definition of HFpEF there is a wide spectrum of different myocardial structural alterations. Myocardial hypertrophy and fibrosis, coronary microvascular dysfunction, oxidative stress and inflammation are only some of the main pathological detectable processes. Furthermore, there is a lack of effective pharmacological targets to improve HFpEF patients’ outcomes and risk factors control is the primary and unique approach to treat those patients. Myocardial tissue characterization, through invasive and non-invasive techniques, such as endomyocardial biopsy and cardiac magnetic resonance respectively, may represent the starting point to understand the genetic, molecular and pathophysiological mechanisms underlying this complex syndrome. The correlation between histopathological findings and imaging aspects may be the future challenge for the earlier and large-scale HFpEF diagnosis, in order to plan a specific and effective treatment able to modify the disease’s natural course.

Associations between menopause, cardiac remodeling, and diastolic function: the CARDIA study.

Heart failure with preserved ejection fraction (HFpEF) affects more women than men. Menopause may influence HFpEF development in women. We assessed cross-sectional and longitudinal associations between menopause and echocardiographic measures of left ventricular (LV) function and cardiac remodeling. We studied 1,723 women with available echo data from at least two of: year 5 (Y5) (1990-1991), Y25 (2010-2011), or Y30 (2015-2016) in the Coronary Artery Risk Development in Young Adults study. Cardiac structure and function were measured using 2D and Doppler echocardiography. Cross-sectional associations between menopausal status and repeated echo measures at Y25 and Y30 were analyzed using linear mixed models. Two-segmented models were used to compare longitudinal changes in echocardiographic measures in the premenopausal period to changes in the postmenopausal period. Mean ± SD age (years) at enrollment was 27 ± 3 in those with menopause by Y25, 25 ± 3 in those with menopause between Y25 and Y30, and 21 ± 3 in those premenopausal at Y30. There were no significant differences in race, body mass index, systolic blood pressure, or diabetes between the groups. Postmenopausal women had higher early diastolic mitral inflow (E) to annular (e') velocity ratio than premenopausal after adjusting for demographics and risk factors (P < 0.05). Menopause was associated with relative increases in the rates of change in LV mass and left atrial volume, even after adjustment. Change in E/e' ratio was similar before and after menopause. Menopause is associated cross-sectionally with worse diastolic function and longitudinally with adverse LV and left atrial remodeling. This may contribute to the increased HFpEF risk in postmenopausal women.

Physical Activity, Subclinical Myocardial Injury, and Risk of Heart Failure Subtypes in Black Adults

ObjectivesThis study sought to evaluate the independent associations and interactions between high-sensitivity cardiac troponin I (hs-cTnI) and physical activity (PA) with risk of heart failure (HF) subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). BackgroundBlack adults are at high risk for developing HF. Physical inactivity and subclinical myocardial injury, as assessed by hs-cTnI concentration, are independent risk factors for HF. MethodsBlack adults from the Jackson Heart Study without prevalent HF who had hs-cTnI concentration and self-reported PA assessed at baseline were included. Adjusted Cox models were used to evaluate the independent and joint associations and interaction between hs-cTnI concentrations and PA with risk of HFpEF and HFrEF. ResultsAmong 3,959 participants, 25.1% had subclinical myocardial injury (hs-cTnI ≥4 and ≥6 ng/l in women and men, respectively), and 48.2% were inactive (moderate-to-vigorous PA = 0 min/week). Over 12.0 years of follow-up, 163 and 150 participants had an incident HFpEF and HFrEF event, respectively. In adjusted analysis, higher hs-cTnI concentration (per 1-U log increase) was associated with higher risk of HFpEF (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.25 to 1.72]) and HFrEF (HR: 1.57; 95% CI: 1.35 to 1.83]). In contrast, higher PA (per 1-U log increase) was associated with a lower risk of HFpEF (HR: 0.93; 95% CI: 0.88 to 0.99]) but not HFrEF. There was a significant interaction between hs-cTnI and PA for risk of HFpEF (p interaction = 0.04) such that inactive participants with subclinical myocardial injury were at higher risk of HFpEF but active participants were not. ConclusionsAmong Black adults with subclinical myocardial injury, higher levels of PA were associated with attenuated risk of HFpEF.

Abstract MP34: The Association Between Periodontal Disease And Incident Heart Failure: The Atherosclerosis Risk In Communities Study

Introduction: Periodontal disease, resulting from inflammatory host-response to dysbiotic subgingival microbiota, has been associated with incident hypertension, heart attack, stroke and diabetes. Limited data exist investigating the prospective relationship between periodontal disease and incident heart failure (HF) and HF subtypes. We hypothesize that periodontal disease is associated with increased risk for heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Methods: We studied 6,707 participants enrolled in the Atherosclerosis Risk in Communities Study who received a full-mouth clinical periodontal examination at visit 4 (1996-1998) and had longitudinal follow-up starting in 2005. Participants were classified as being periodontally healthy, having periodontal disease (based on the Periodontal Profile Classification (PPC)), or being edentulous. Hospitalization records were reviewed, and HF events were adjudicated and classified as HFpEF, HFrEF or HF of unknown ejection fraction (HFunknownEF) from 2005-2018. We used multivariable-adjusted Cox proportional hazards models to assess the association between periodontal disease or edentulism and incident HF. Results: Among participants 58% had periodontitis and 19% were edentulous. During a median follow-up time of 13 years, 1,178 cases of incident HF occurred (350 HFpEF, 319 HFrEF and 509 HFunknownEF). Periodontal disease and being edentulous were both associated with increased risk for both HFpEF and HFrEF (Table). Conclusion: Periodontal disease measured in mid-life was associated with both incident HFpEF and HFrEF. Adverse microbial exposures underlying periodontal disease might represent a modifiable risk factor for inflammation-induced heart failure pathophysiology.

Evaluation of phosphodiesterase 9A as a novel biomarker in heart failure with preserved ejection fraction.

AimsMurine models implicate phosphodiesterase 9A (PDE9A) as a nitric oxide‐independent regulator of cyclic guanosine monophosphate and promising novel therapeutic target in heart failure (HF) with preserved ejection fraction (HFpEF). This study describes PDE9A expression in endomyocardial biopsies (EMBs) and peripheral blood mononuclear cells (PBMNCs) from patients with different HF phenotypes.Methods and resultsEndomyocardial biopsies and PBMNCs were obtained from patients with HFpEF (n = 24), HF with reduced ejection fraction (n = 22), and inflammatory cardiomyopathy (n = 24) and patients without HF (n = 7). PDE9A expression was increased in EMBs and PBMNCs from patients with HFpEF as compared with other HF phenotypes or subjects without HF. Endomyocardial PDE9A expression in HFpEF correlated with the inflammatory cell count in EMBs, but not with cardiac fibrosis or left ventricular diastolic wall stress. PDE9A expression in PBMNCs was increased in HFpEF patients with higher high‐sensitivity C‐reactive protein levels and in response to pro‐inflammatory stimulation. As a validation cohort, 719 patients with HFpEF and 1106 subjects without HF were identified from the LIFE‐Heart study. PDE9A expression in PBMNCs was obtained from array data and displayed an age‐dependent distribution. PDE9A levels were elevated and conferred increased risk for HFpEF in middle‐aged subjects, but not in elderly HFpEF patients. Following age adjustment, lower PDE9A expression in PBMNCs was associated with worse survival in patients with HFpEF (log‐rank test P‐value <0.001).ConclusionExpression profiling indicates an up‐regulation of endomyocardial PDE9A in different HF phenotypes with the most robust increase in EMBs and PBMNCs from patients with HFpEF. An exclusive risk effect of PDE9A expression on HFpEF in middle‐aged patients and an unexpected association with survival calls for further studies to better characterize the role of PDE9A as a treatment target.

Risk Prediction in Patients With Heart Failure With Preserved Ejection Fraction Using Gene Expression Data and Machine Learning.

Heart failure with preserved ejection fraction (HFpEF) has become a major health issue because of its high mortality, high heterogeneity, and poor prognosis. Using genomic data to classify patients into different risk groups is a promising method to facilitate the identification of high-risk groups for further precision treatment. Here, we applied six machine learning models, namely kernel partial least squares with the genetic algorithm (GA-KPLS), the least absolute shrinkage and selection operator (LASSO), random forest, ridge regression, support vector machine, and the conventional logistic regression model, to predict HFpEF risk and to identify subgroups at high risk of death based on gene expression data. The model performance was evaluated using various criteria. Our analysis was focused on 149 HFpEF patients from the Framingham Heart Study cohort who were classified into good-outcome and poor-outcome groups based on their 3-year survival outcome. The results showed that the GA-KPLS model exhibited the best performance in predicting patient risk. We further identified 116 differentially expressed genes (DEGs) between the two groups, thus providing novel therapeutic targets for HFpEF. Additionally, the DEGs were enriched in Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways related to HFpEF. The GA-KPLS-based HFpEF model is a powerful method for risk stratification of 3-year mortality in HFpEF patients.

The diagnostic and prognostic value of galectin-3 in patients at risk for heart failure with preserved ejection fraction: results from the DIAST-CHF study.

AimsGalectin‐3 (Gal‐3) predicts long‐term outcome among patients with heart failure (HF) with preserved ejection fraction (HFpEF). The ability of Gal‐3 to diagnose and predict incident HFpEF in a cohort at risk for HFpEF is of particular interest. We aimed to determine the association between Gal‐3 and clinical manifestations of HFpEF, the relationship between Gal‐3 and all‐cause mortality, or the composite of cardiovascular hospitalization and death.Methods and resultsThe observational Diast‐CHF study included patients aged 50 to 85 years with ≥1 risk factor for HF (e.g. hypertension, diabetes mellitus, and atherosclerotic disease) or previously suspected HF. Patients were followed for 10 years. The association between Gal‐3, evidence of diastolic dysfunction, and Framingham criteria for HF was examined. All deaths and hospitalizations were adjudicated as cardiovascular or non‐cardiovascular. The analysis population was composed of 1386 subjects (67 years old, 50.9% female). The area under the receiver operating characteristic curve to diagnose HFpEF was 0.71. At a cut‐off value of 13.57 ng/mL, sensitivity was 0.61 and specificity was 0.73 for Gal‐3, and the diagnostic power to detect HFpEF was superior to N‐terminal pro‐brain natriuretic peptide (area under the receiver operating characteristic curve 0.59, P > 0.001). Baseline Gal‐3 was associated with risk factors for HF (P < 0.001). Higher levels of Gal‐3 predicted incident HFpEF (P < 0.05), adjusted all‐cause mortality (P < 0.001), and the adjusted composite of cardiovascular hospitalization and death (P < 0.001), both independent from N‐terminal pro‐brain natriuretic peptide.ConclusionsGal‐3 differentiated patients with HFpEF from an overall cohort of well‐characterized patients with risk factors for HFpEF. Independent of other factors, baseline Gal‐3 levels were associated with a higher risk for incident HFpEF, mortality, or the composite of cardiovascular hospitalization and death over 10 year follow‐up. In conjunction with clinical parameters, Gal‐3 adds a statistically significant value for the diagnosis of HFpEF within this study, yet the clinical relevance remains debatable.

Association of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life

BackgroundIndependent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied. MethodsWe pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF. ResultsA total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF. ConclusionsMidlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

Abstract 13300: Hepatocyte Growth Factor and 10-year Change in Left Ventricular Structure: The Multi-Ethnic Study of Atherosclerosis

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

Abstract 15067: Association of Baseline and Longitudinal Changes in Body Composition Measures With Risk of Heart Failure and Myocardial Infarction in Type 2 Diabetes Mellitus - Findings From the Look Ahead Trial

Introduction: Intentional weight loss is associated with lower risk of heart failure (HF) and atherosclerotic cardiovascular disease among patients with type 2 diabetes mellitus (T2DM). However, the contribution of changes in body composition measures [lean mass (LM), fat mass (FM), waist circumference (WC)] to the risk of HF and myocardial infarction (MI) is not well-known. Methods: Adults with T2DM who had overweight or obesity enrolled in the Look AHEAD (Action for Health in Diabetes) trial without prevalent HF were included. LM and FM were predicted using validated equations and compared with DXA measurements. Adjusted Cox models were used to evaluate the associations of baseline and longitudinal changes in LM, FM, and WC over 1- (Y0 to Y1) and 4-year (Y0 to Y4) follow-up with risk of overall HF, HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF) and MI. Results: Among 5,103 participants, there were 257 incident HF events over 12.4 years of follow-up. Predicted and measured LM and FM were highly correlated (R 2 =0.87-0.92). LM and FM decreased with greater declines in the intensive lifestyle intervention arm (Figure 1A). In adjusted analyses, baseline measures of body composition were not significantly associated with risk of HF. Decline in FM, but not LM, over 1- and 4-year follow-up was significantly associated with lower risk of HF (Figure 1B). A significant association was observed between decline in WC and risk of overall HF and HFpEF but not HFrEF. Among adults without a history of CVD, changes in body composition were not associated with risk of MI. Conclusions: In adults with T2DM who had overweight or obesity, a lifestyle intervention is associated with significant loss of FM and LM. Decline in FM and WC, but not LM, were each significantly associated with lower risk of HF but not MI. Furthermore, decline in WC was significantly associated with lower risk of HFpEF but not HFrEF.