Outcomes In Heart Failure With Preserved Ejection Fraction Research Articles

Heart Failure score and outcomes in patients with preserved ejection fraction after catheter ablation for atrial fibrillation.

Atrial fibrillation (AF) is frequently associated with heart failure with preserved ejection fraction (HFpEF), but the diagnosis and prediction of the outcomes of HFpEF are difficult. Notably, the Heart Failure Association of the European Society of Cardiology proposed the use of the HFA-PEFF score in the diagnosis of HFpEF. This study aimed to assess the prognostic value of the pre- and post-procedural HFA-PEFF scores in patients with preserved ejection fraction (EF) after catheter ablation (CA) for AF. The primary endpoint was a composite of cardiac hospitalization for cardiovascular events and all-cause mortality. The secondary endpoint was AF recurrence. Overall, 354 patients with AF and preserved EF who underwent CA as well as blood tests and transthoracic echocardiography 2weeks before and 6months after CA from January 2018 to December 2019 were retrospectively enrolled in the study. In the 354 participants, univariate analysis showed that the post-procedural HFA-PEFF score was associated with a 3-year risk of the primary endpoint (hazard ratio [HR]=3.73; 95% confidence interval [CI]=2.07-6.73; P<0.001), whereas the pre-procedural HFA-PEFF score was not (HR=1.24, 95% CI=0.82-1.86, P=0.307). Further, the association between the post-procedural HFA-PEFF score and primary endpoint was not modified even after including other relevant variables into the score. Similar to the primary endpoint, the post-procedural HFA-PEFF score was associated with the 3-year risk of AF recurrence (P<0.001). In patients with preserved EF undergoing AF ablation, the HFA-PEFF score at 6months after CA was associated with the primary endpoint and AF recurrence at the 3-year follow-up.

Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.

Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodeling and atrial fibrillation is frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial antiarrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment with the CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with NHE1 inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF.

Estimated pulse wave velocity predicts mortality in patients with heart failure with preserved ejection fraction

ObjectiveEstimated pulse wave velocity (ePWV), a newly established arterial stiffness (AS) parameter, predicts the development of cardiovascular disease (CVD) and death in the general population or in patients with CVD risk factors. However, whether ePWV is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. Our study aimed to evaluate the prognostic value of ePWV on clinical outcomes in HFpEF. Methods and ResultsWe analyzed HFpEF participants from the Americas in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline data (n = 1764). Cox proportional hazard model was used to explore the prognostic value of ePWV on long-term clinical outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalization, and heart failure hospitalization). Each ePWV increase by 1 m/s increased the risk for all-cause death by 16% (HR:1.16; 95% CI:1.10–1.23; P < 0.001) and CVD mortality by 13% (HR:1.13; 95% CI:1.04–1.21; P = 0.002) after adjusting for confounders. Patients were then grouped into 4 quartiles of ePWV. Our study indicated that the highest ePWV quartile (ePWV ≥ 12.806 m/s) was associated with increased risk of all-cause mortality (HR: 1.96; 95% CI: 1.43–2.69; P < 0.001) and CVD mortality (HR: 1.72; 95% CI: 1.16–2.56; P = 0.008) after adjusting for potential confounders. ConclusionThese results suggested ePWV is independently associated with increased all-cause mortality and CVD mortality in HFpEF patients, indicating ePWV is an appropriate predictor of prognosis in patients with HFpEF.

Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial

BackgroundAlthough sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF. ObjectivesThe goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF. MethodsTargeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed. ResultsThe mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro–B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro–B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction. ConclusionsLeveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235)

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction

Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

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.

Stress hyperglycemia ratio as a prognostic indicator for long-term adverse outcomes in heart failure with preserved ejection fraction

BackgroundRecent studies highlighted that stress hyperglycemia ratio (SHR) is a potential predictor for future risk in heart failure (HF) patients. However, its implications specifically in HF with preserved ejection fraction (HFpEF) are not yet fully elucidated. We aimed to investigate the association between SHR and long-term clinical outcomes in HFpEF patients.MethodsHFpEF patients enrolled between 2015 and 2023, were followed (mean 41 months) for a composite outcome of all-cause, cardiovascular mortality, and HF rehospitalization. SHR was established as the ratio of acute-chronic glycemia from admission blood glucose and glycated hemoglobin. The optimal cut-off for SHR to predict outcomes based on event prediction was determined through ROC analysis, and the cutoff was identified at 0.99. The effect of SHR on adverse risk was examined through the Cox hazards and Kaplan-Meier survival methods. A Pearson correlation analysis was conducted to assess the relationship between SHR and the severity of HF, as indicated by N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Furthermore, the incremental prognostic value of SHR was further assessed by the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI).ResultsAmong the 400 enrolled patients, 190 individuals (47.5%) encountered composite events over the 41-month follow-up period. SHR was significantly elevated in patients with events compared with those without (p < 0.001). All patients were stratified into high SHR (n = 124) and low SHR (n = 276) groups based on the SHR cutoff. The high SHR group had a significantly higher incidence of adverse events than the low SHR group (log-rank; p < 0.001). Additional analysis indicated a poorer prognosis in patients with low left ventricular EF (LVEF) levels (50 < LVEF < 60) and high SHR (SHR > 0.99) in comparison to the other groups (log-rank p < 0.001). In adjusted analysis, after accounting for age, sex, diabetes, and NT-proBNP, elevated SHR remained independently predictive of adverse outcomes (adjusted HR: 2.34, 95% CI 1.49–3.67; p < 0.001). Furthermore, adding SHR to a model with MAGGIC score provided an incremental improvement in predicting adverse events. Additionally, SHR displayed a slight correlation with NT-proBNP.ConclusionElevated SHR was independently associated with an increased risk for composite events of all-cause, cardiovascular mortality, and HF readmission than those with lower SHR. SHR is a valuable tool for predicting and stratifying long-term adverse risks among HFpEF patients.

Phenotypic differences in Obese Patients with Heart Failure with Preserved Ejection Fraction (HFpEF) - A Mini Review

The incidence of heart failure with preserved ejection fraction (HFpEF) continues to rise, and obesity continues to be a predominant comorbid condition affecting patients with HFpEF. Recent research sheds light on the important pathophysiologic role that obesity plays in the development of HFpEF, with many areas of opportunity existing for future developments in understanding the etiology and management of the disease. Crucial in these pathophysiologic developments are studies that clearly characterize the obesity phenotype in HFpEF and compare it to presentations of HFpEF in patients without obesity. This paper reviews the existing literature on the obesity phenotype within HFpEF and discusses some of the prevailing ideas behind the pathophysiologic interplay between the conditions, as well as the existing treatments demonstrating improved outcomes in HFpEF.

Anemia and 1-year outcomes in hospitalized patients with heart failure with preserved ejection fraction: Findings from the China Cardiovascular Association Database-Heart Failure Center Registry

Abstract Background Little evidence exists regarding the association of anemia and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). Purpose To determine the associations of anemia and clinical outcomes in HFpEF. Methods Data were from 575 China Cardiovascular Association Database-HF Center certified secondary and tertiary hospitals across overall 31 provinces of mainland China. Between January 2017 and December 2021, 48,992 HFpEF patients with an left ejection fraction (LVEF) ≥50% and hemoglobin (Hb) data were included. According to the World Health Organization criterion (Hb &amp;lt;12g/dL for women and &amp;lt;13 g/dL for men), participants were categorized into two groups (with and without anemia). The primary outcome was a composite of hospitalization for HF and cardiovascular (CV) death, and the secondary outcomes were all-cause hospitalization and all-cause death. Results Among the overall patients, 50.0% were men, the mean age was 72.2 years, and 48.1% (n = 23,570) had anemia. Compared with individuals without anemia, participants with anemia were older and more symptomatic, more likely to have New York Heart Association class III/IV, and had greater comorbid burden. At 1-year’s follow-up, anemia was independently associated with an increased risk of primary outcome (hazard ratio [HR]: 1.08, 95% CI: 1.03-1.12), all-cause death (HR: 1.30, 9%% CI: 1.21-1.38), and all-cause hospitalization (HR: 1.06, 95% CI: 1.02-1.10). There was a trend toward increased risk of primary and secondary outcome with increasing severity of anemia (all P-trends were &amp;lt;0.05). The results were consistent in all the subgroups analyses (sex, age (≥75 and &amp;lt;75 years old), NYHA class (Ⅰ/Ⅱ and Ⅲ/Ⅳ), eGFR (≥60 and &amp;lt;60 ml/min/1.73m2)). The restricted cubic spline showed significant nonlinear relationships between primary outcome and hemoglobin as continuous variable, with a risk nadir around 13-15g/dL. Conclusion Anemia was common in Chinese HFpEF patients and was an independent risk factor for adverse clinical outcomes at 1 year’s follow-up. Further studies are needed to evaluate whether ameliorating anemia can improve outcome in HFpEF patients.Graphic Abstract

Abstract 14466: Study Protocol: Heart Camp Connect - Promoting Adherence to Exercise in Adults With Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) remains a challenge in cardiovascular care. A chief complaint in adults with HFpEF is fatigue, and regular exercise training is the only treatment shown to routinely improve this symptom. Adherence to exercise recommendations is difficult. We significantly improved 12-month adherence to exercise in adults with persistent HF using an in-person coaching intervention. Secondary analysis of our HFpEF subgroup showed promising long-term exercise adherence. These findings support our recently funded trial to test an intervention delivered in-person vs. virtually to achieve long-term exercise adherence in adults with HFpEF. Aims: We will: 1) Evaluate effects of in-person vs. virtual coaching and enhanced usual care on 12- and 18-month exercise adherence, 2) Determine the optimal minutes of moderate-intensity exercise that yields clinically meaningful change in patient-reported outcomes, 3) Evaluate interventional mechanisms and interim clinical events as mediators of adherence behaviors, and (4) Examine the cost of intervention delivery. Approach: This multi-site, 3-group randomized controlled trial will recruit 300 adults with stable HFpEF to compare an in-person coaching intervention to a virtual coaching, and both to enhanced usual care (UC). After a run-in period, all participants receive a medical fitness center membership (in-person or virtual) for 18 months and are randomized following a 2-2-1 strategy to in-person coaching and exercise (n=120), virtual coaching and exercise (n=120) or UC virtual exercise only (n=60). The primary outcome is adherence to ≥120 minutes of exercise/week measured using a heart rate monitor at 12 months, with a sustainability endpoint at 18 months. Secondary outcomes include health status, physical function and activity, HFpEF symptoms, and inflammatory biomarkers. Data are collected at baseline, 6, 12, and 18 months. Conclusions: Our findings will guide selection of the most efficacious and cost-effective delivery approaches to promote exercise adherence. Identifying active interventional mechanisms and the dose of exercise needed to elicit a response will help to achieve a clinically meaningful change in patient-reported outcomes in HFpEF.

Abstract 18410: Correlation Between Body Mass Index and NT-proBNP Levels in Heart Failure With Preserved Ejection Fraction: Implications for Clinical Outcomes

Introduction: N-terminal pro B type natriuretic peptide (NT-proBNP) is associated with increased cardiovascular events in heart failure with preserved ejection fraction (HFpEF). Adiposity is inversely correlated with NT-proBNP. It remains unclear whether obese HFpEF patients exhibit disproportionate outcomes with lower NT-proBNP. Hypothesis: We aimed to study the relationship between NT-proBNP and BMI in the Johns Hopkins University (JHU) HFpEF cohort to identify patient characteristics with increased NT-proBNP in obese HFpEF patients, adjusting for the inverse relation between NT-proBNP and BMI. Methods: We identified 338 individuals from June 2013 to November 2022. Univariate linear regression was performed between NT-proBNP and BMI. The cohort was split based on the median BMI and studentized residuals from NT-proBNP-BMI relationship (low BMI high BNP [Group 1] high BMI high BNP [Group 2] low BMI low BNP [Group 3] high BMI low BNP [Group 4]). Kruskal-Wallis test or Chi-square test was used to compare groups. Results: The median BMI of the cohort was 37kg/m 2 , and with every 1kg/m 2 increase in the BMI, the cut-off for elevated NT-proBNP reduced by 4 pg/ml. High BMI HFpEF patients were younger, predominantly female, and on diuretics (p&lt;0.05 for all), independent of their NT-proBNP levels. Group 4 patients performed better on the 6-minute walk test (240±136 m), had better renal function (eGFR: 68.7±27.3), and less left ventricular (LV) hypertrophy and only mild diastolic dysfunction on echocardiography. Surprisingly, Group 2 resembled Group 1 despite having 70% reduced median NT-proBNP (1898[1047,4409] vs 574[207,1322], p&lt;0.0001). Both “high BNP” groups exhibited lower event free survival for all -cause mortality(p=0.0001) and HF-hospitalization(p&lt;0.05). Conclusions: NT-proBNP is predictive of clinical outcomes in HFpEF even in the presence of obesity. BMI adjusted NT-proBNP may be useful in the diagnosis and prognosis of HFpEF.

Abstract 13828: Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARADIGM-HF Proteomic Sub-Study

Introduction: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Goal: To identify serum proteins associated with risk for HF hospitalization (HFH) and cardiovascular (CV) death in patients with HFpEF, including proteins with differential associations with clinical outcomes in HFpEF compared to HFrEF. Methods: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF in the PARAGON-HF trial using a modified aptamer proteomic assay. Baseline protein concentrations significantly associated with total HFH and CV death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared to 2515 patients with HFrEF from the PARADIGM-HF and ATMOSPHERE trials. Results: We identified 288 proteins to be robustly associated with the risk of HFH and CV death (335 events over an average of 2.7 years of follow-up) in a HFpEF trial population. Proteins most strongly related to HFpEF outcomes included B2M, TIMP1, SERPINA4, and SVEP1 ( Figure ). Protein-outcome associations in patients with HFpEF did not markedly differ compared to HFrEF. Just 3 proteins (APOE, RTF1, and VWF) were differentially associated with outcomes between the HF subtypes (FDR &lt;0.05). A proteomic risk score derived in HFpEF patients was not superior to a previous proteomic score derived in HFrEF nor to clinical risk factors, NT-proBNP, or high-sensitivity cardiac troponin. Conclusions: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis. SVEP1, a cell adhesion protein recently identified as a HFrEF prognosis biomarker, also strongly predicted risk in HFpEF. Our results demonstrate substantial similarities in serum proteomic risk markers across the EF spectrum.

Abstract 17602: Cardiac Structure and Function and Renal Outcomes in Patients With Heart Failure With Preserved Ejection Fraction: Insights From the PARAGON-HF Trial

Introduction: Chronic kidney disease is common and associated with a worse prognosis in patients with heart failure (HF). However, the association of cardiac structure and function with renal outcomes in patients with HF with preserved ejection fraction (HFpEF) is not known. Goal: Identify cardiac structural and functional correlates of renal outcomes in HFpEF. Methods: Patients enrolled in the echocardiographic sub-study of the PARAGON-HF trial were included. The endpoint of interest was a composite renal endpoint: a ≥50% decline in estimated glomerular filtration rate (eGFR) relative to baseline, development of end-stage renal disease, or death attributable to renal causes. Multivariable Cox proportional hazards models were used to identify measures of cardiac structural and functional parameters associated with the composite renal endpoint, adjusting for baseline eGFR, systolic blood pressure, NT-proBNP, treatment arm (sacubitril-valsartan or valsartan) and diabetes. Results: In 1,097 patients (53% women, mean age 74±8 years), over a median follow-up of 2.9 years (IQR 2.6-3.4 years) there were 28 composite renal events (0.9 per 100 patient-years). After multivariable adjustment, higher left ventricular (LV) posterior wall thickness and mass index, right ventricular (RV) end-diastolic and end-systolic areas as well as impaired RV function (lower fractional area change and lower absolute RV free wall longitudinal strain), but not LV systolic function (LVEF and global longitudinal strain) were each associated with a significantly higher risk for the composite renal endpoint ( Figure ). Conclusions: In the PARAGON-HF echocardiographic sub-study, evidence of cardiac biventricular remodeling and deterioration of RV function were associated with an increased risk of renal events. These results underscore the close relationship between the heart and kidneys in patients with HF even when LVEF is preserved.

Pathophysiologic and prognostic importance of cardiac power output reserve in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by multiple cardiac reserve limitations during exercise. Cardiac power output (CPO) is an index of global cardiac performance and can be estimated non-invasively by echocardiography. We hypothesized that CPO reserve during exercise would be associated with impaired cardiovascular reserve, exercise intolerance, and adverse outcomes in HFpEF. Exercise stress echocardiography was performed in 425 dyspnoeic patients [217 HFpEF and 208 non-heart failure (HF) controls] to estimate CPO at rest and during exercise. We classified patients with HFpEF based on the median value of changes in CPO from rest to peak exercise (ΔCPO >0.49 W/100 g). Patients with HFpEF and a lower CPO reserve had poorer biventricular systolic function, impaired chronotropic response during exercise, and worse aerobic capacity than controls and those with a higher CPO reserve. During a median follow-up of 358 days, a composite outcome of all-cause mortality or HF events occurred in 30 patients. Patients with a lower CPO reserve had four-fold and nearly 10-fold increased risks of the outcomes compared with those with a higher CPO reserve and controls, respectively [hazard ratio (HR) 4.05, 95% confidence interval (CI) 1.16-10.1, P = 0.003 and HR 9.61, 95% CI 3.58-25.8, P < 0.0001]. We further found that a lower CPO reserve had an incremental prognostic value over the H2FPEF score and exercise duration. In contrast, resting CPO did not predict clinical outcomes in patients with HFpEF. A lower CPO reserve was associated with biventricular systolic dysfunction, chronotropic incompetence, exercise intolerance, and adverse outcomes in patients with HFpEF.

Left Atrial Myopathy in Heart Failure With Preserved Ejection Fraction.

The left atrium (LA) plays an important role in facilitating left ventricular (LV) filling by acting as a reservoir, passive conduit, and active booster pump, as well as a regulator of blood volume through A-type natriuretic peptide secretion in response to stimulation by mechanical stretch of the cavity. LA myopathy has emerged as one of the most important non-LV contributors to disease progression in heart failure with preserved ejection fraction (HFpEF). LA dysfunction is common in HFpEF and is associated with more severe pulmonary vascular disease and right ventricular dysfunction, and increases the risk of incident atrial fibrillation or atrial functional mitral regurgitation, leading to limitations in cardiac output reserve and reduced exercise capacity. LA deformation assessed by 2-dimensional speckle-tracking echocardiography is useful for estimating abnormal hemodynamics or exercise capacity, discriminating HFpEF from non-cardiac dyspnea and is an independent predictor of adverse outcome in HFpEF. Thus, interventions directly targeting LA myopathy may improve outcomes in HFpEF with LA myopathy. This review provides information regarding the physiology of the LA in patients with HFpEF and discusses the importance of evaluation of LA function, management issues, and future directions through ongoing trials of medical interventions.

Endotrophin, a fibroblast matrikine, may be a driver of fibroblast activation in fibro-inflammatory diseases.

Extracellular matrix proteins harbor signaling domains that once released from the parent molecule can trigger cellular responses. One of these molecules is endotrophin, a type VI collagen derived fragment, whose circulatory levels have been associated to an increased risk of adverse outcome in heart failure with preserved ejection fraction (HFpEF). Here we show that the stimulation of human cardiac fibroblasts by endotrophin upregulates the synthesis of type I collagen, the main interstitial collagen that accumulates in the myocardium during fibrogenesis. These data provide a possible mechanistic explanation for the relation between circulating endotrophin levels and risk of outcome in HFpEF.

Renal tubular damage and clinical outcome in heart failure with preserved ejection fraction and chronic kidney disease.

Despite advances in heart failure (HF) treatment, HF with preserved ejection fraction (HFpEF) remains a health problem with a high mortality rate. HFpEF is composed of diverse phenogroups, of which patients with concomitant renal impairment have worse outcomes. Renal tubular damage (RTD) is associated with the development of HF and chronic kidney disease (CKD). However, the impact of RTD on HF progression in patients with HFpEF and CKD remains unclear. The aim of the present study was to examine whether RTD could predict HF-related events in patients with HFpEF and CKD. We measured RTD markers, such as urinary β2 -microglobulin to creatinine ratio (UBCR) and N-acetyl-β-d-glucosamidase (NAG) level, in 319 consecutive patients with HFpEF and CKD who were hospitalized for acute HF (49% females, mean age 76±12). Based on previous reports, high UBCR and high NAG levels were defined as UBCR ≥300μg/gCr and NAG >14.2U/gCr, respectively. There were 91 HF-related events, defined as HF hospitalizations or HF deaths, during the median follow-up period of 5.2years. The prevalence of high UBCR increased with advancing New York Heart Association functional class and albuminuria. Kaplan-Meier analysis demonstrated that patients with high UBCR had more HF-related events than those with normal or low UBCR. Multivariate Cox proportional hazards regression analyses demonstrated that high UBCR, but not high NAG level, was an independent predictor of HF-related events after adjusting for confounding risk factors in patients with HFpEF and CKD (hazard ratio, 2.60; 95% confidence interval, 1.52-4.72; P=0.0009). UBCR significantly improved the C-statistic, with a significant net reclassification index and integrated discrimination improvement (0.738 vs. 0.684; P=0.0244). RTD, as assessed by a high UBCR, was associated with the severity and clinical outcomes of HFpEF and CKD, indicating that it could be a feasible marker for HF progression.

Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF

BackgroundSystemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). ObjectivesThis study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species–producing enzyme, myeloperoxidase, affects these biomarkers. MethodsUsing supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database. ResultsTNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients. ConclusionsBiomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.

Prognostic value of myocardial flow reserve in patients with heart failure with preserved ejection fraction

Aim. To study the prognostic value of myocardial blood flow (MBF) and myocardial flow reserve (MFR) parameters in patients with heart failure with preserved ejection fraction (HFpEF) and non-obstructive coronary artery disease (CAD) in risk stratification of HFpEF progression during a 12-month follow-up.Materials and methods. The study included 58 patients with non-obstructive CAD and HFpEF (LVEF 62 [58; 66]%). Dynamic CZT-SRECT was used to evaluate MFR and MBF at rest (rest-MBF) and stress (stress-MBF). NT-proBNP levels were determined by the enzyme immunoassay. Diastolic dysfunction parameters were measured using 2D transthoracic echocardiography. Left ventricular systolic global longitudinal strain (GLS) was assessed using 2D speckle tracking.Results. After a 12-month follow-up, the patients were retrospectively divided into 2 groups: group 1 (n = 11) included patients with an unfavorable course of HFpEF, group 2 (n = 47) encompassed patients with a favorable course of the disease. In group 1, the level of NT-proBNP was 3.8 times higher than in group 2 (284.5 [183.42; 716.73] and 1,071.4 [272.4; 2,168.1] pg / ml, respectively). MFR values in group 1 were lower by 45.4%(p &lt; 0.001) than in group 2 (1.19 [0.86; 1.55] vs. 2.18 [1.7; 2.55], respectively). In group 1, rest-MBF levels were higher by 23.6% (p = 0.046) and stress-MBF was lower by 28.2% (p = 0.046) than in group 2. The multivariate regression analysis revealed that NT-proBNP levels (odds ratio (OR) 3.23; p = 0.008), GLS (OR 2.27; p = 0.012), and MFR (OR 8.09; p &lt; 0.001) were independent predictors of adverse outcomes in HFpEF. Based on the ROC analysis, MFR levels ≤ 1.62 (AUC = 0.827; p &lt; 0.001), GLS ≤–18 (AUC = 0.756; p = 0.002), and NT-proBNP≥ 760.5 pg / ml (AUC = 0.708; p = 0.040) may be considered as markers of adverse outcomes. However, the combined determination of NT-proBNP and MFR had a greater significance (AUC 0.935; p &lt; 0.001) in risk stratification compared with the monomarker model, while the addition of GLS did not increase the significance of the analysis.Conclusion. Levels of NT-proBNP, GLS, and MFR may be used as non-invasive markers of an adverse course of HFpEF in patients with non-obstructive CAD, while the combined determination of NT-proBNP and MBF increases the prognostic value of the analysis.

Epicardial adipose tissue density is a better predictor of cardiometabolic risk in HFpEF patients: a prospective cohort study

BackgroundEpicardial adipose tissue (EAT) accumulation is associated with multiple cardiometabolic risk factors and prognosis of heart failure with preserved ejection fraction (HFpEF). The correlation between EAT density and cardiometabolic risk and the effect of EAT density on clinical outcome in HFpEF remain unclear. We evaluated the relationship between EAT density and cardiometabolic risk factors, also the prognostic value of EAT density in patients with HFpEF.MethodsWe included 154 HFpEF patients who underwent noncontrast cardiac computed tomography (CT) and all patients received follow-up. EAT density and volume were quantified semi-automatically. The associations of EAT density and volume with cardiometabolic risk factors, metabolic syndrome and the prognostic impact of EAT density were analyzed.ResultsLower EAT density was associated with adverse changes in cardiometabolic risk factors. Each 1 HU increase in fat density, BMI was 0.14 kg/m2 lower (95% CI 0.08–0.21), waist circumference was 0.34 cm lower (95% CI 0.12–0.55), non-HDL-cholesterol was 0.02 mmol/L lower (95% CI 0–0.04), triglyceride was 0.03 mmol/L lower (95% CI 0.01–0.04), fasting plasma glucose was 0.05 mmol/L lower (95% CI 0.02–0.08), TyG index was 0.03 lower (95% CI 0.02–0.04), Log2(TG/HDL-C) was 0.03 lower (95% CI 0.02–0.05), METS-IR was 0.36 lower (95% CI 0.23–0.49), MetS Z-score was 0.04 lower (95% CI 0.02–0.06), and Log2(CACS + 1) was 0.09 lower (95% CI 0.02–0.15). After adjusting for BMI and EAT volume, the associations of non-HDL-cholesterol, triglyceride, fasting plasma glucose, insulin resistance indexes, MetS Z-score, and CACS with fat density remained significant. The area under the curve (AUC) for the presence and severity of metabolic syndrome was greater in EAT density than volume (AUC: 0.731 vs 0.694, 0.735 vs 0.662, respectively). Over a median follow-up of 16 months, the cumulative incidence of heart failure readmission and composite endpoint increased with lower level of EAT density (both p < 0.05).ConclusionsEAT density was an independent impact factor of cardiometabolic risk in HFpEF. EAT density might have better predictive value than EAT volume for metabolic syndrome and it might have prognostic value in patients with HFpEF.