Heart Failure And Preserved Ejection Fraction Research Articles

N-terminal pro-B-type natriuretic peptide post-discharge monitoring in the management of patients with heart failure and preserved ejection fraction-a randomized trial: The NICE study.

There is a lack of specific studies assessing the impact of natriuretic peptide monitoring in the post-discharge management of patients with heart failure (HF) and preserved ejection fraction (HFpEF), throughout the vulnerable phase following acute HF hospitalization. The NICE study aims to assess the clinical benefit of incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) into the post-discharge management of HFpEF patients. Individuals admitted with HFpEF (left ventricular ejection fraction >50%) were included in a multicentre randomized controlled study employing an open-label design with event blinding (NCT02807168). Upon discharge, 157 patients were randomly allocated to either NT-proBNP monitoring (n = 79) or no access to NT-proBNP (control group, n = 78) during pre-scheduled visits at 2, 4 and 12 weeks. Clinical endpoints were evaluated at 6 months. The primary endpoint of HF rehospitalizations occurred in 12.1% patients, without significant differences observed between the NT-proBNP monitoring group (12.8%) and the control group (11.4%) (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.47-2.81, p = 0.760). Regarding secondary endpoints, the NT-proBNP monitoring group demonstrated a significantly lower risk of death (1.3% vs. 10.1%; HR 0.12, 95% CI 0.02-0.09), whereas non-HF hospitalizations (12.8% vs. 19.0%, p = 0.171) and any adverse clinical event (26.9% vs. 36.7%, p = 0.17) did not reach statistical significance. Awareness of NT-proBNP levels were associated with higher doses of diuretics and renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers) in the NT-proBNP monitoring group. Post-discharge monitoring of NT-proBNP in HFpEF patients did not exhibit an association with reduced rates of HF hospitalization in this study. Nonetheless, it appears to enhance global clinical management by optimizing medical therapies and contributing to improved overall survival.

Effects of sacubitril/valsartan according to polypharmacy status in PARAGON-HF.

Patients with heart failure (HF) and preserved ejection fraction (HFpEF) have a particularly high prevalence of comorbidities, often necessitating treatment with many medications. The aim of this study was to evaluate the association between polypharmacy status and outcomes in PARAGON-HF. In this post hoc analysis, baseline medication status was available in 4793 of 4796 patients included in the primary analysis of PARAGON-HF. The effects of sacubitril/valsartan, compared with valsartan, were assessed according to the number of medications at baseline: 683 non-polypharmacy (<5 medications); 2750 polypharmacy (5-9 medications), and 1360 hyper-polypharmacy (≥10 medications). The primary outcome was total HF hospitalizations and cardiovascular deaths. Patients with hyper-polypharmacy were older, had more severe limitations due to HF (worse New York Heart Association class and Kansas City Cardiomyopathy Questionnaire scores), and had greater comorbidity. The non-adjusted risk of the primary outcome was significantly higher in patients taking more medications, and similar trends were seen for HF hospitalization and cardiovascular and all-cause death. The effect of sacubitril/valsartan versus valsartan on the primary outcome from the lowest to highest polypharmacy category was (as a rate ratio): 1.19 (0.76-1.85), 0.94 (0.77-1.15), and 0.77 (0.61-0.96) (pinteraction = 0.16). Treatment-related adverse events were more common in patients in the higher polypharmacy categories but not more common with sacubitril/valsartan, versus valsartan, in any polypharmacy category. Polypharmacy is very common in patients with HFpEF, and those with polypharmacy have worse clinical status and a higher rate of non-fatal and fatal outcomes. The benefit of sacubitril/valsartan was not diminished in patients taking a larger number of medications at baseline.

Assessment of the cardiac output at rest and during exercise stress using real-time cardiovascular magnetic resonance imaging in HFpEF-patients

This methodological study aimed to validate the cardiac output (CO) measured by exercise-stress real-time phase-contrast cardiovascular magnetic resonance imaging (CMR) in patients with heart failure and preserved ejection fraction (HFpEF). 68 patients with dyspnea on exertion (NYHA ≥ II) and echocardiographic signs of diastolic dysfunction underwent rest and exercise stress right heart catheterization (RHC) and CMR within 24 h. Patients were diagnosed as overt HFpEF (pulmonary capillary wedge pressure (PCWP) ≥ 15mmHg at rest), masked HFpEF (PCWP ≥ 25mmHg during exercise stress but < 15mmHg at rest) and non-cardiac dyspnea. CO was calculated using RHC as the reference standard, and in CMR by the volumetric stroke volume, conventional phase-contrast and rest and stress real-time phase-contrast imaging. At rest, the CMR based CO showed good agreement with RHC with an ICC of 0.772 for conventional phase-contrast, and 0.872 for real-time phase-contrast measurements. During exercise stress, the agreement of real-time CMR and RHC was good with an ICC of 0.805. Real-time measurements underestimated the CO at rest (Bias:0.71 L/min) and during exercise stress (Bias:1.4 L/min). Patients with overt HFpEF had a significantly lower cardiac index compared to patients with masked HFpEF and with non-cardiac dyspnea during exercise stress, but not at rest. Real-time phase-contrast CO can be assessed with good agreement with the invasive reference standard at rest and during exercise stress. While moderate underestimation of the CO needs to be considered with non-invasive testing, the CO using real-time CMR provides useful clinical information and could help to avoid unnecessary invasive procedures in HFpEF patients.

Ablation for atrial fibrillation improves the outcomes in patients with heart failure with preserved ejection fraction: a single-center cohort study

Abstract Introduction Patients with heart failure and preserved ejection fraction (HFpEF) are frequently associated with atrial fibrillation (AF), and such clinical condition has worse clinical status than those with sinus rhythm. Whether the use of a strategy to maintain sinus rhythm in patients with HFpEF would affect outcomes remains uncertain. Purpose To investigate whether the strategy of AF ablation to maintain sinus rhythm compared to no ablation is associated with improvement of all-cause death and rehospitalization for worsening heart failure in patients with AF and HFpEF. Methods In this retrospective cohort study, a total of 1034 patients with HFpEF and AF (69 [63, 76] years, 478 [46.2%] female) were analyzed, 392 patients who received first-time AF ablation were assigned to the ablation group, and the remaining 642 patients with merely medical therapy were assigned to the no ablation group. The primary end point was a composite of all-cause mortality or rehospitalization for worsening heart failure and was assessed by the Kaplan-Meier method and Cox proportional hazard model. Baseline differences were adjusted by multivariable-adjustment analysis, propensity score-matched analysis, and inverse probability of treatment weighting analysis. Atrial tachycardia/AF recurrence was assessed in a multivariable-adjusted Fine &amp; Gray model, with death treated as a competing risk factor. Results After a median follow-up period of 39 months, the cumulative incidence of the primary end point was significantly lower in the ablation group compared to the no ablation group after multivariable adjustment in the overall cohort (adjusted hazard ratio [HR], 0.65 [95% CI, 0.45-0.94], P = 0.02; incidence rate difference [IRD], -0.39 [95% CI, -0.54 to -0.25]). Analyses for secondary outcomes revealed that clinical benefit produced by AF ablation was mainly driven by rehospitalization for worsening heart failure (adjusted HR, 0.65 [95% CI, 0.44-0.96], P = 0.03) with an estimated IRD of -0.31 (95% CI, -0.45 to -0.18). Results were consistent in the propensity score-matched analysis and inverse probability of treatment weighting analysis. In addition, patients in the ablation group had a 34% relative decrease in the atrial tachycardia/AF recurrence (adjusted HR, 0.66 [95% CI, 0.55-0.81], P &amp;lt; 0.001) relative to no ablation group in the multivariate-adjusted Fine &amp; Gray model. Patients who received AF ablation and maintained sinus rhythm during the follow-up period had a lower risk of the primary end point (P &amp;lt; 0.001 by log-rank test). Conclusion(s) Among HFpEF and AF patients, the strategy of AF ablation to maintain sinus rhythm led to a lower risk of the composite of death from any cause or hospitalization for worsening heart failure.Figure 1.Kaplan–Meier curvesTable 1.Incidence rate and hazard ratio

Right ventricular uncoupling in heart failure with preserved ejection fraction: a simple parameter to predict long-term mortality?

Abstract Introduction Several prognostic models have been developed for risk stratification of mortality in patients with acute heart failure (AHF). eRecent evidence suggests that the right ventricular (RV)-pulmonary artery (PA) uncoupling is associated with poor outcomes in heart failure. Patients with heart failure and preserved ejection fraction (HFpEF) are a heterogeneous population with a wide range of clinical outcomes. However, the prognostic utility of RV-PA uncoupling for predicting long-term mortality in these patients remains elusive. Objective To assess the prognostic value of right ventricle-pulmonary artery coupling for long-term mortality in hospitalized patients with HFpEF. Methods Retrospective analysis of a consecutive, prospective, single-center cohort. Adult patients hospitalized between 2015 and 2020 with a primary diagnosis of AHF and left ventricular ejection fraction (LVEF) &amp;gt;40% were included. The primary endpoint was long-term all-cause mortality. Ventricular uncoupling was assessed as the ratio of tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) estimated from an echocardiogram performed within 3 months of the index hospitalization. Univariable Cox proportional hazards regression models were used to calculate hazard ratios (HR), and multivariable Cox regression was performed with previously analyzed covariates: age, sex, atrial fibrillation, renal dysfunction and E/e'. Results Of 465 patients with HFpEF, 361 (77%) PASP and TAPSE could be estimated simultaneously. During a mean follow-up of 20.9 months, the primary outcome event occurred in 100 patients (27.7%). The optimal cut-off for the primary endpoint was TAPSE/PASP=0.38. Univariable Cox regression showed that RV-PA uncoupling was associated with the primary endpoint of long-term mortality (hazard ratio [HR] 1.96 [95% CI, 1.32-2.92], P=0.001). Kaplan-Meier analysis showed that patients with a ratio &amp;lt;0.38 were at high risk of all-cause mortality (Figure 1). Multivariable analysis also showed that RV-PA uncoupling was significantly associated with long term mortality independent of age, sex, atrial fibrillation, renal dysfunction and E/e' (HR 2.21 [95% CI, 1.26-3.81], P=0.005). Conclusions In patients hospitalized for AHF with preserved ejection fraction, RV-PA uncoupling as determined by the TAPSE/PASP ratio was independently associated with long-term all-cause mortality. TAPSE/PASP was associated with mortality independently of age, sex, renal function, atrial fibrillation and diastolic dysfunction. This simple echocardiographic parameter may identify a population at higher risk for events during follow-up.Kaplan-Meier for all-cause mortality

Abstract 16270: Pulse Pressure Amplification Contributes to the Exaggerated Peripheral Blood Pressure Response to Exercise in Patients With HFpEF

Background: Patients with suspected heart failure and preserved ejection fraction (HFpEF) undergo invasive (right heart catheterization) cardiopulmonary exercise testing (iCPET) to confirm diagnosis. During iCPET peripheral arterial blood pressure (BP) is measured using a brachial cuff or radial arterial catheter. Notably, peripheral BP is typically higher than central BP and this difference is assessed by measuring pulse pressure amplification (PPA; peripheral - central PP; PP = systolic BP [SBP] - diastolic BP). The effect of PPA on the assessment of (exaggerated) exercise BP in HFpEF is unknown. Methods: 20 patients with HFpEF (75% Female; age: 69±7 years, BMI: 38±7 kg/m 2 ) were studied at rest and during submaximal and maximal cycling exercise. We measured radial BP (arterial catheterization) and derived ascending aortic BP using a transfer function applied to radial arterial waveforms (SphygmoCor). Pulse pressure amplification was assessed as radial-aortic pulse pressure. Data were compared with one-way and two-way (Site*Exercise Stage) ANOVA. Results: The increase in radial PP with exercise was greater than aortic PP (Site*Stage P&lt;0.001; Figure A); thus, PPA increased with exercise (ANOVA, P =0.001; Figure B). The increase in PPA was due to a greater increase in radial compared to aortic SBP (Site*Stage P=0.002; Figure C). The change in diastolic pressure was not different between sites (Figure D). Increases in PPA accounted for ~30% of the increase in radial SBP. The incidence of exaggerated exercise SBP (Male: &gt;210 mmHg; Female: &gt;190 mmHg) was higher in the radial artery compared to aorta (95 vs 40 %, χ2&lt;0.001). Conclusion: Peak exercise SBP was ~50 mmHg greater in the radial artery compared to aorta. The marked overestimation of central BP during exercise when measuring peripheral BP leads to misguided interpretation of BP responses to exercise, the magnitude of afterload and has implications for the assessment of ventricular-arterial coupling.

Abstract 13242: Annual Body Weight Change and Subsequent Prognosis in Heart Failure With Preserved Ejection Fraction: Insights From the PURSUIT-HFpEF Registry

Introduction: Maintaining optimal body weight is important in heart failure management. Weight gain (WG) may signal excessive caloric intake and fluid retention, whereas weight loss (WL) would imply cachexia. Both conditions could affect the prognosis of heart failure with reduced ejection fraction. However, the significance of WG and WL in patients with heart failure and preserved ejection fraction (HFpEF) has not been well established. Methods: An analysis was performed from a prospective multicenter observational registry for HFpEF (PURSUIT-HFpEF Registry) conducted in the Osaka region of Japan. Of 1231 patients who enrolled in the registry, we enrolled 662 patients (age, 82±9 years; females, 54.1%; body mass index, 22.3±4.3kg/m 2 ; atrial fibrillation, 38.3%) whose weight at discharge and one year later were both available. WG and WL were defined as a gain or loss of ≥5% weight between baseline and 1 year, respectively. Other patients who did not demonstrate a significant change in weight were categorized as having a stable weight (SW). All-cause mortality was the primary endpoint. Results: During 1-year, the median body weight slightly increased from 52.1 (interquartile range [IQR]: 45.1-61.9) to 53.0 kg (IQR 45.0-63.0) kg (p &lt;0.001), with a median change of 0.6 kg (IQR: -1.8-2.8). A total of 182 (27%), 125 (19%), and 355 (54%) patients experienced WG, WL, and SW, respectively. During a follow-up of 603 days (IQR: 329-982), 149 patients died. The mortality rate was highest in patients experiencing WL, followed by those experiencing WG and SW (30.2% vs. 21.5% vs. 18.0%, respectively; log-rank p = 0.006). After adjusting for potential confounders, Cox regression analysis revealed that WL, not WG, was independently associated with higher mortality (hazard ratio 2.44 [95% CI 1.51-3.95], p &lt;0.001). Conclusions: Significant number of patients with HFpEF experienced WG and WL within a year. Patients who experienced WL had a higher risk of mortality compared to those who experienced WG and SW. These results highlight the importance of monitoring body weight changes in the management of HFpEF.

Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial

In the STEP-HFpEF trial, semaglutide improved symptoms, physical limitations and exercise function and reduced body weight in patients with obesity phenotype of heart failure and preserved ejection fraction (HFpEF). This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I–III (body mass index (BMI) 30.0–34.9 kg m−2, 35.0–39.9 kg m−2 and ≥40 kg m−2) and according to body weight reduction with semaglutide after 52 weeks. Semaglutide consistently improved all outcomes across obesity categories (P value for treatment effects × BMI interactions = not significant for all). In semaglutide-treated patients, improvements in KCCQ-CSS, 6MWD and CRP were greater with larger body weight reduction (for example, 6.4-point (95% confidence interval (CI): 4.1, 8.8) and 14.4-m (95% CI: 5.5, 23.3) improvements in KCCQ-CSS and 6MWD for each 10% body weight reduction). In participants with obesity phenotype of HFpEF, semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories. In semaglutide-treated patients, the magnitude of benefit was directly related to the extent of weight loss. Collectively, these data support semaglutide-mediated weight loss as a key treatment strategy in patients with obesity phenotype of HFpEF. ClinicalTrials.gov identifier: NCT04788511.

Abstract P3157: MicroRNA-16 Exerts Anti-fibrotic Effects Via Suppression Of Tgfbr3 In Rats With Heart Failure And Preserved Ejection Fraction

Background: Cardiosphere-derived cells (CDCs) reverse diastolic dysfunction by attenuating ventricular fibrosis in rats with heart failure and preserved ejection fraction (HFpEF). MicroRNAs packaged in exosomes secreted from CDCs (CDCexo), are discovered to mediate the beneficial effects of CDCs. Hypothesis: The anti-fibrotic effects of CDCs are mediated by microRNAs contained in CDCexo. Methods: Dahl salt-sensitive rats were fed either a high-salt diet to induce HFpEF, or a normal-salt diet to serve as controls. Echocardiogram-verified HFpEF rats were randomized to receive human CDCexo (n=37) vs. vehicle (n=47) via tail vein weekly for 4 weeks. Control rats (n=16) served as the normal phenotype. RNA sequencing of CDCexo was performed to search for candidate microRNAs. Single-cell RNA sequencing was performed in isolated ventricular cells to investigate the mechanisms of CDCexo. Five most abundant microRNAs were selected and injected via tail vein to HFpEF rats. MicroRNA-injected HFpEF rat hearts underwent single-cell RNA sequencing to investigate its mechanisms. Results: HFpEF rats injected with CDCexo demonstrated improved diastolic function compared to HFpEF rats injected with vehicle (E/E’ ratio 12.1±2.6 vs. 18.7±4.6 in vehicle, p&lt;0.0001). Masson’s trichrome staining revealed reduced ventricular fibrosis in CDCexo rats (3.5±1.4 vs. 5.4±1.4 % in vehicle rats, p=0.016). Negative regulation of transforming growth factor beta (TGF-β) receptor signaling pathway (p=0.002) was identified in isolated cardiac fibroblasts after CDCexo injection. MicroRNA-16 was revealed as the most abundant microRNA in CDCexo, and intravenous delivery of microRNA-16 recapitulated the beneficial responses (improvement of diastolic function and attenuation of ventricular fibrosis) of CDCexo in rats with HFpEF. Single-cell RNA sequencing of microRNA-16-injected HFpEF hearts confirmed down-regulation of TGF-β receptor activity (p=0.018) in cardiac fibroblasts via suppression of Tgfbr3. Conclusion: CDCexo improved diastolic function by suppressing ventricular fibrosis in rats with HFpEF. MicroRNA-16, the most abundant microRNA in CDCexo, recapitulated the beneficial responses of CDCexo in HFpEF rats, via suppression of Tgfbr3 in cardiac fibroblasts.

Left-to-right ventricular volume ratio and outcome in heart failure with preserved ejection fraction.

Age-specific and gender-specific reference values for left ventricular (LV) and right ventricle volumes are available. The prognostic implications of the ratio between these volumes in heart failure and preserved ejection fraction (HFpEF) have never been evaluated. We examined all HFpEF outpatients undergoing a cardiac magnetic resonance from 2011 to 2021. The left-to-right ventricular volume ratio (LRVR) was defined as the ratio between the LV and right ventricle end-diastolic volume indexes (LVEDVi/RVEDVi). Among 159 patients [median age 58 years (interquartile range 49-69), 64% men, LV ejection fraction 60% (54-70%)] the median LRVR was 1.21 (1.07-1.40). Over 3.5 years (1.5-5.0), 23 patients (15%) experienced all-cause death or heart failure hospitalization, and 22 (14%) cardiovascular death or heart failure hospitalization. The risk of all-cause death or heart failure hospitalization increased with an LRVR less than 1.0 or at least 1.4. An LRVR less than 1.0 was associated with a higher risk of all-cause death or heart failure hospitalization [hazard ratio 5.95, 95% confidence interval (CI) 1.67-21.28; P = 0.006] and cardiovascular death or heart failure hospitalization (hazard ratio 5.68, 95% CI 1.58-20.35; P = 0.008) as compared with LRVR 1.0-1.3. Furthermore, an LRVR at least 1.4 was associated with a higher risk of all-cause death or heart failure hospitalization (hazard ratio 4.10, 95% CI 1.58-10.61; P = 0.004) and cardiovascular death or heart failure hospitalization (hazard ratio 3.71, 95% CI 1.41-9.79; P = 0.008) as compared with LRVR 1.0-1.3. These results were confirmed in patients without dilation of either ventricle. LRVR values less than 1.0 or at least 1.4 are associated with worse outcomes in HFpEF. LRVR may become a valuable tool for risk prediction in HFpEF.

Efficacy of SGLT2-inhibitors across different definitions of heart failure with preserved ejection fraction.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been evaluated in phase 3 randomized-controlled trials (RCTs) that enrolled individuals with heart failure and preserved ejection fraction (HFpEF) based on detailed clinical, biochemical, and echocardiographic criteria (hereafter HF-RCTs), and in cardiovascular outcomes trials (CVOTs) in diabetic patients, in which the diagnosis of HFpEF relied on medical history. We performed a study-level meta-analysis of the efficacy of SGLT2i across different definitions of HFpEF. Three HF-RCTs (EMPEROR-Preserved, DELIVER, and SOLOIST-WHF) and four CVOTs (EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS-CV, and SCORED) were included, for a total of 14 034 patients. SGLT2i reduced the risk of cardiovascular death or heart failure hospitalization (HFH) in all RCTs pooled together [risk ratio 0.75, 95% confidence interval (95% CI) 0.63-0.89, NNT 19], in HF-RCTs (risk ratio 0.71, 95% CI 0.52-0.97, NNT 13), and in CVOTs (risk ratio 0.78, 95% CI 0.60-0.99, NNT 26). SGLT2i also decreased the risk of HFH in all RCTs (risk ratio 0.81, 95% CI 0.73-0.90, NNT 45), in HF-RCTs (risk ratio 0.81, 95% CI 0.72-0.93, NNT 37), and in CVOTs (risk ratio 0.78, 95% CI 0.61-0.99, NNT 46). By contrast, SGLT2i were not superior to placebo for cardiovascular death or all-cause death in all RCTs, HF-RCTs, or CVOTs. Results were comparable after excluding one RCT at a time. Meta-regression analysis confirmed that the type of RCT (HF-RCT vs. CVOT) did not influence the SGLT2i effect. In RCTs, SGLT2i improved the outcomes of patients with HFpEF regardless of how the latter was diagnosed.

Hypoxaemia in patients with heart failure and preserved ejection fraction.

It is widely held that heart failure (HF) does not cause exertional hypoxaemia, based upon studies in HF with reduced ejection fraction, but this may not apply to patients with HF and preserved ejection fraction (HFpEF). Here, we characterize the prevalence, pathophysiology, and clinical implications of exertional arterial hypoxaemia in HFpEF. Patients with HFpEF (n = 539) and no coexisting lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxaemia (oxyhaemoglobin saturation <94%) was observed in 136 patients (25%). As compared to those without hypoxaemia (n = 403), patients with hypoxaemia were older and more obese. Patients with HFpEF and hypoxaemia had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar-arterial oxygen difference, increased dead space fraction, and greater physiologic shunt compared to those without hypoxaemia. These differences were replicated in a sensitivity analysis where patients with spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and pulmonary capillary pressures were related to lower arterial oxygen tension (PaO2 ), especially during exercise. Body mass index (BMI) was not correlated with the arterial PaO2 , and hypoxaemia was associated with increased risk for death over 2.8 (interquartile range 0.7-5.5) years of follow-up, even after adjusting for age, sex, and BMI (hazard ratio 2.00, 95% confidence interval 1.01-3.96; p = 0.046). Between 10% and 25% of patients with HFpEF display arterial desaturation during exercise that is not ascribable to lung disease. Exertional hypoxaemia is associated with more severe haemodynamic abnormalities and increased mortality. Further study is required to better understand the mechanisms and treatment of gas exchange abnormalities in HFpEF.

NOCTURNAL HYPERTENSION IS ASSOCIATED WITH HEART FAILURE RE-HOSPITALIZATION IN PATIENTS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION

Objective: Nocturnal hypertension is reported as a risk factor for cardiovascular disease. This study was to explore the potential association between nocturnal hypertension and heart failure (HF) rehospitalization in patients with HF and preserved ejection fraction(HFpEF). Design and method: Totally, 538 patients with HFpEF were consequently recruited in this study and followed up until they were readmitted for HF or the end of this study. Cox regression analysis was used to reveal the potential association between nighttime blood pressure (BP) levels, nocturnal hypertension and nocturnal BP patterns and HF rehospitalization. Kaplan-Meier curve was used to assess the cumulative events free rate between groups. Results: The mean age of the study population was 77.14±8.68 years, and 41.2% was men. After a median follow up duration of 10.93 (4.19, 21.13) months, 176 (32.7%) patients with HFpEF were readmitted for HF. Cox analyse had revealed that nighttime systolic blood pressure (BP) level (Hazards ratio(HR):1.018, 95% confidence interval(CI): 1.008-1.028, p = 0.001), nightime diastolic BP level (HR:1.024, 95%CI:1.007-1.042, p = 0.007), nocturnal hypertension (HR:1.688, 95%CI:1.229-2.317, p = 0.001) were associated with HF rehospitalizaiton. Kaplan-Meier analysis had demonstrated that patients with nocturnal hypertension had significantly lower events free rate (Log rank test, p&lt;0.001). Furthermore, patients with a riser pattern had a higher risk of HF rehospitalization (HR:1.828, 95%CI:1.055-3.166, p = 0.031) and lower events free rate (Log rank test, p = 0.003) than those with a dipper pattern. Conclusions: Nighttime BP levels, nocturnal hypertension and a riser pattern are independently associated with HF rehospitalization in patients with HFpEF. Well controlled nighttime BP levels should be emphasized and considered in patients with HFpEF.

Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction

The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved ejection fraction (HFpEF). To assess the safety and efficacy of empagliflozin in combination with background diuretic therapy and the association of empagliflozin with the need for conventional diuretics. This was a post hoc analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved). EMPEROR-Preserved was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from March 2017 to April 2021. Patients with class II to IV heart failure and left ventricular ejection fraction greater than 40% were included. Of 5988 patients enrolled, 5815 (97.1%) had baseline data on diuretic use and were included in this analysis, which was conducted from November 2021 to August 2022. Participants in EMPEROR-Preserved were randomized to empagliflozin or placebo. In this analysis, participants were divided into 4 subgroups: no diuretics and furosemide-equivalent diuretic dose of less than 40 mg, 40 mg, and greater than 40 mg at baseline. The main outcomes of interest were first hospitalization for heart failure (HHF) or cardiovascular death (CV death) and its components. Association of empagliflozin vs placebo with outcomes by baseline diuretic status (no diuretic vs any dose) and dose (no diuretic, <40 mg, 40 mg, and > 40mg) was assessed. Association of empagliflozin use with changes in diuretic therapy was also studied. Among 5815 patients (mean [SD] age, 71.9 [9.4] years; 2594 [44.6%] female) with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking less than 40 mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking greater than 40 mg. In the placebo arm, patients with higher diuretic doses had worse outcomes. Empagliflozin decreased the risk of HHF or CV death, regardless of background diuretic status (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93] for the diuretic group vs HR, 0.72; 95% CI, 0.48-1.06 for the nondiuretic group; P for interaction = .58). Similarly, diuretic status was not associated with changes in improvements in first HHF, total HHF, rate of decline in estimated glomerular filtration rate, and Kansas City Cardiomyopathy Questionnaire 23 clinical summary score with empagliflozin. Findings were consistent when patients were categorized by diuretic dose. Empagliflozin was associated with a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65-0.84) and an increased likelihood of de-escalation (HR, 1.15; 95% CI, 1.02-1.30). Empagliflozin was associated with an increased risk of volume depletion in patients taking diuretics (HR, 1.34; 95% CI, 1.13-1.59). In this study, treatment with empagliflozin was similar regardless of diuretic use or dose. Empagliflozin use was associated with decreased conventional diuretic dosing. ClinicalTrials.gov Identifier: NCT03057951.

PO-455617-5 ANTI-ARRHYTHMIC EFFECTS OF BIOINSPIRED MODIFIED Y RNA IN RATS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION

Exosomes secreted from cardiosphere-derived cells (CDCs) attenuate ventricular arrhythmias and prolong survival of rats with heart failure and preserved ejection fraction (HFpEF). Y RNA fragments were abundant in exosomes secreted from CDCs, and they mediate the anti-inflammatory and anti-fibrotic effects of CDCs. We tested the hypothesis that bioinspired modified Y RNA decrease ventricular arrhythmias in rats with HFpEF by reversing electrical remodeling. Dahl salt-sensitive (DSS) rats (n=19) were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF. Echocardiogram was performed at 14 weeks of age to confirm the development of diastolic dysfunction (increased E/E’ ratio). Symptomatic rats with diastolic dysfunction were diagnosed with HFpEF. TY1 (Therapeutic Y RNA1, a modified Y RNA in transfection reagent) was injected via the tail vein (twice weekly for 4 weeks) to rats with HFpEF (n=7). Vehicle (phosphate-buffered saline in transfection reagent) and scramble (in transfection reagent) were also injected via the tail vein as placebo (n=8 and 4, respectively). Echocardiogram and programmed electrical stimulation (PES) were performed after 4 weeks of TY1 vs. vehicle or scramble injections. Electrocardiogram was performed to measure QTc intervals as a marker for adverse electrical remodeling. Ventricular arrhythmias were induced in 80% of vehicle-injected and 100% of scramble-injected HFpEF rats by PES, as compared to only 33% of TY1-injected HFpEF rats (p=0.036). The duration of ventricular arrhythmias was significantly lower in TY1-injected HFpEF rats as compared to vehicle-injected and scramble-injected HFpEF rats (4 [IQR 0-5] beats in TY1 vs. 30 [IQR 8-54] beats in vehicle, p=0.034; vs. 21 [16-48] beats in scramble; p=0.031). QTc interval was reduced in TY1-injected HFpEF rats as compared to vehicle or scramble-injected HFpEF rats (QTc interval 238±16 ms in TY1 vs. 271±24 ms in vehicle, p=0.034; vs. 280±7 ms in scramble, p=0.017). Survival was prolonged in TY1-injected HFpEF rats as compared to vehicle or scramble-injected HFpEF rats, although statistically insignificant due to a low number of rats (86% in TY1 vs. 63% in vehicle or 75% in scramble). TY1, a modified Y RNA, reduced ventricular arrhythmias in rats with HFpEF by reversing adverse electrical remodeling of HFpEF (as manifested by a shortened QTc interval). Given these encouraging data, TY1 merits further investigation as a novel therapeutic candidate for ventricular arrhythmias.

PO-02-209 ANTI-ARRHYTHMIC EFFECTS OF BIOINSPIRED MODIFIED Y RNA IN RATS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION

Exosomes secreted from cardiosphere-derived cells (CDCs) attenuate ventricular arrhythmias and prolong survival of rats with heart failure and preserved ejection fraction (HFpEF). Y RNA fragments were abundant in exosomes secreted from CDCs, and they mediate the anti-inflammatory and anti-fibrotic effects of CDCs. We tested the hypothesis that bioinspired modified Y RNA decrease ventricular arrhythmias in rats with HFpEF by reversing electrical remodeling. Dahl salt-sensitive (DSS) rats (n=19) were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF. Echocardiogram was performed at 14 weeks of age to confirm the development of diastolic dysfunction (increased E/E’ ratio). Symptomatic rats with diastolic dysfunction were diagnosed with HFpEF. TY1 (Therapeutic Y RNA1, a modified Y RNA in transfection reagent) was injected via the tail vein (twice weekly for 4 weeks) to rats with HFpEF (n=7). Vehicle (phosphate-buffered saline in transfection reagent) and scramble (in transfection reagent) were also injected via the tail vein as placebo (n=8 and 4, respectively). Echocardiogram and programmed electrical stimulation (PES) were performed after 4 weeks of TY1 vs. vehicle or scramble injections. Electrocardiogram was performed to measure QTc intervals as a marker for adverse electrical remodeling. Ventricular arrhythmias were induced in 80% of vehicle-injected and 100% of scramble-injected HFpEF rats by PES, as compared to only 33% of TY1-injected HFpEF rats (p=0.036). The duration of ventricular arrhythmias was significantly lower in TY1-injected HFpEF rats as compared to vehicle-injected and scramble-injected HFpEF rats (4 [IQR 0-5] beats in TY1 vs. 30 [IQR 8-54] beats in vehicle, p=0.034; vs. 21 [16-48] beats in scramble; p=0.031). QTc interval was reduced in TY1-injected HFpEF rats as compared to vehicle or scramble-injected HFpEF rats (QTc interval 238±16 ms in TY1 vs. 271±24 ms in vehicle, p=0.034; vs. 280±7 ms in scramble, p=0.017). Survival was prolonged in TY1-injected HFpEF rats as compared to vehicle or scramble-injected HFpEF rats, although statistically insignificant due to a low number of rats (86% in TY1 vs. 63% in vehicle or 75% in scramble). TY1, a modified Y RNA, reduced ventricular arrhythmias in rats with HFpEF by reversing adverse electrical remodeling of HFpEF (as manifested by a shortened QTc interval). Given these encouraging data, TY1 merits further investigation as a novel therapeutic candidate for ventricular arrhythmias.

P218 WILD TYPE TRANSTHYRETIN CARDIAC AMYLOIDOSIS (WTATTR) AND HEART FAILURE WITH REDUCED EJECTION FRACTION (HFREF): CAN ANGIOTENSIN RECEPTOR/NEPRILYSIN INHIBITORS (ARNI) BE A THERAPEUTIC OPTION?

Abstract Background wtATTR is associated with high mortality rate, median survival from diagnosis is 43 months and mortality reaches 50% at 4 years. Most patients (pts) present with heart failure and preserved ejection fraction (HFpEF), fewer with HFrEF. Tafamidis is the only modifying–disease agent available in Italy and therapeutic strategy is based on diuretic titration. Beta blockers and therapies for neurohormonal antagonism have raised concerns about their efficacy and safety. The role of ARNI has not been explored. We report our experience of the use of ARNI in pts with wtATTR not eligible to Tafamidis due to advanced NYHA classes. Cases 4 male pts (median age 81 y.o.) received diagnosis of wtATTR between 2018 and 2019 when Tafamidis was not available. Median left ventricular ejection fraction (mLVEF) at the time was 51%. 2 years later they presented with acute HFrEF (Tab1–T0), NYHA classes III–IV with median systolic blood pressure 105 mmHg. Average N–terminal pro natriuretic peptide (NTproBNP) levels were 13888pg/ml and median estimated glomerular filtration rate (eGFR) was 36 mil/min/1,72m2. mLVEF was 23%. Once congestion was relieved pts started Sacubitril/Valsartan (S/V) with titration of dose. At 6 months follow–up (FU) (Tab1–T1) pts were downgraded to NYHA class II and no symptomatic hypotension was reported. Average NTproBNP levels were reduced to 7.800pg/l, only mild worsening of renal function was reported (median eGFR 31mil/minx1.73m2). Absolute increase of mLVEF (46%) was shown on echocardiography. At 12 months FU (Tab 1–T2) pts were clinically stable in NYHA class II, NTproBNP median values had mildly increased to 9700pg/ml and average eGRF was stable (30mil/minx1.73m2). Echocardiogram highlighted minimal reduction of mLVEF compared to previous result (41%). During FU only 1 of the pts required hospitalization for intravenous diuretic therapy and S/V was temporarily suspended. Conclusion The efficacy of S/V in HFrEF is well known. Our brief study proves that ARNI can be tolerated in frail pts affected by wtATTR with no other therapeutic options, guaranteeing a long hospitalization–free period with improvement in quality of life. The result may be purely due to the natriuretic effect of ARNI in patients so strictly reliant on volemic state. More complicated effects may be mediated by neprilisin on amyloid protein; further studies are warranted to establish the role of ARNI in wtATTR.

Ventricular stiffening and chamber contracture in heart failure with higher ejection fraction.

Ancillary analyses from clinical trials have suggested reduced efficacy for neurohormonal antagonists among patients with heart failure and preserved ejection fraction (HFpEF) and higher ranges of ejection fraction (EF). A total of 621 patients with HFpEF were grouped into those with low-normal left ventricular EF (LVEF) (HFpEF<65% , n = 319, 50% ≤ LVEF <65%) or HFpEF≥65% (n = 302, LVEF ≥65%), and compared with 149 age-matched controls undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing. A sensitivity analysis was performed in a second non-invasive community-based cohort of patients with HFpEF (n = 244) and healthy controls without cardiovascular disease (n = 617). Patients with HFpEF≥65% had smaller left ventricular (LV) end-diastolic volume than HFpEF<65% , but LV systolic function assessed by preload recruitable stroke work and stroke work/end-diastolic volume was similarly impaired. Patients with HFpEF≥65% displayed an end-diastolic pressure-volume relationship (EDPVR) that was shifted leftward, with increased LV diastolic stiffness constant β, in both invasive and community-based cohorts. Cardiac filling pressures and pulmonary artery pressures at rest and during exercise were similarly abnormal in all EF subgroups. While patients HFpEF≥57% displayed leftward shifted EDPVR, those with HFpEF<57% had a rightward shifted EDPVR more typical of heart failure with reduced EF. Most pathophysiologic differences in patients with HFpEF and higher EF are related to smaller heart size, increased LV diastolic stiffness, and leftward shift in the EDPVR. These findings may help to explain the absence of efficacy for neurohormonal antagonists in this group and raise a new hypothesis, that interventions to stimulate eccentric LV remodelling and enhance diastolic capacitance may be beneficial for patients with HFpEF and EF in the higher range.

Health status across major subgroups of patients with heart failure and preserved ejection fraction.

There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anaemia, and atrial fibrillation/flutter. In the EMPEROR-Preserved trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12, 32 and 52 weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5- and 10-point increase and 5-point decrease in KCCQ score from baseline to week 12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anaemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ-CSS score improved during follow-up; patients with atrial fibrillation/flutter at enrollment (p trend = 0.014) and CKD (p trend < 0.001) had less improvement. A 5-point increase in KCCQ-CSS at week 12 was associated with lower risk of cardiovascular death or heart failure hospitalization (5%), cardiovascular death (8%), and first heart failure hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ-CSS, -TSS and -OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (p trend = 0.153, 0.08 and 0.078, respectively). Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients.

Functional outcome after cardiac rehabilitation and its association with survival in heart failure across the spectrum of ejection fraction

BackgroundThere is limited evidence regarding the effects of cardiac rehabilitation (CR) in patients with heart failure and preserved ejection fraction (HFpEF). MethodsWe studied 1784 patients admitted to inpatient CR. The patients were grouped into HFpEF (EF≥0.50), HF with mildly reduced EF (HFmrEF; EF 41–49), and HF with reduced EF (HFrEF; EF≤0.40). A standardized 6-min walking test was performed at admission and discharge. Measures of functional outcome were: (1) absolute increase in 6-min walking distance (6MWD) from admission to discharge >50 m and (2) increase in 6MWD to ≥300 among the patients who walked <300 m at admission. ResultsAfter adjustment, the patients with HFpEF or HFmrEF were as likely as those with HFrEF to achieve an increase in 6MWD >50 m (odds ratio 0.95 [95%CI 0.71-1.24; p=0.648] and 1.04 [95%CI 0.77-1.41; p=0.769], respectively) or an increase in 6MWD to ≥300 m (odds ratio 0.79 [95%CI 0.51-1.23; p=0.299] and 0.65 [95%CI 0.38-1.12; p=0.118], respectively). The adjusted hazard ratio of 5-year mortality for patients who achieved an increase in 6MWD >50 m was 0.60 (95%CI 0.51-0.71; p<0.001) and that for patients who achieved an increase in 6MWD at discharge to ≥300 m 0.61 (95%CI 0.48-0.79; p<0.001). In each EF group, both outcomes remained independently associated with improved survival. ConclusionsOur data suggest that patients with HFpEF or HFmrEF are as likely as those with HFrEF to benefit from CR in terms of functional improvement. Functional improvement was independently associated with improved long-term survival, regardless of EF.