Heart Failure And Preserved Ejection Fraction Patients 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 0.02-0.98; p = 0.048), 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 [Correction added on 29 April 2024, after first online publication: In the preceding sentence, "95% CI 0.02 - 0.09" has been corrected to "95% CI 0.02 - 0.98; p = 0.048" in this version.]. 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.

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

Does the Measurement of Ejection Fraction Still Make Sense in the HFpEF Framework? What Recent Trials Suggest.

Left ventricular ejection fraction (LVEF) is universally accepted as a cardiac systolic function index and it provides intuitive interpretation of cardiac performance. Over the last two decades, it has erroneously become the leading feature used by clinicians to characterize the left ventricular function in heart failure (HF). Notably, LVEF sets the basis for structural and functional HF phenotype classification in current guidelines. However, its diagnostic and prognostic role in patients with preserved or mildly reduced contractile function is less clear. This is related to several concerns due to intrinsic technical, methodological and hemodynamic limitations entailed in LVEF measurement that do not describe the chamber's real contractile performance as expressed by pressure volume loop relationship. In patients with HF and preserved ejection fraction (HFpEF), it does not reflect the effective systolic function because it is prone to preload and afterload variability and it does not account for both longitudinal and torsional contraction. Moreover, a repetitive measurement could be assessed over time to better identify HF progression related to natural evolution of disease and to the treatment response. Current gaps may partially explain the causes of negative or neutral effects of traditional medical agents observed in HFpEF. Nevertheless, recent pooled analysis has evidenced the positive effects of new therapies across the LVEF range, suggesting a potential role irrespective of functional status. Additionally, a more detailed analysis of randomized trials suggests that patients with higher LVEF show a risk reduction strictly related to overall cardiovascular (CV) events; on the other hand, patients experiencing lower LVEF values have a decrease in HF-related events. The current paper reports the main limitations and shortcomings in LVEF assessment, with specific focus on patients affected by HFpEF, and it suggests alternative measurements better reflecting the real hemodynamic status. Future investigations may elucidate whether the development of non-invasive stroke volume and longitudinal function measurements could be extensively applied in clinical trials for better phenotyping and screening of HFpEF patients.

Renin-angiotensin system inhibitor exerts prognostic effects in HFpEF patients with low baseline chloride level

BackgroundFew interventions have shown improved prognosis in patients with heart failure and preserved ejection fraction (HFpEF). Serum chloride levels, which are affected by serum renin secretion, are associated with the prognosis of HFpEF patients. However, the relationship between serum chloride levels and the effects of renin-angiotensin system inhibitors (RASi) in HFpEF patients remains unclear. We investigated whether the prognostic benefit of RASi depends on baseline serum chloride levels in HFpEF patients. MethodsThis observational study included 506 hospitalized patients with HFpEF (ejection fraction ≥50%) who were discharged. They were divided into two categories based on serum chloride levels at admission (cutoff level: 101 mEq/L) according to previous reports. In each chloride category, all-cause mortality, the primary endpoint, was compared between patients who received RASi and those who did not. ResultsPatients who received RASi had a significantly lower mortality rate after discharge than those who did not, but only in the lower chloride category (log-rank, P = 0.001). Multivariable Cox regression analysis confirmed the effect of risk reduction by RASi on all-cause mortality in the lower chloride category (adjusted hazard ratio: 0.31, 95% confidence interval: 0.11–0.84). The prognostic advantages of RASi were evident in the lower chloride category, but not in the higher chloride category, at admission (P for interaction = 0.027). ConclusionRASi administration was associated with an improved prognosis only in HFpEF patients with a low baseline serum chloride level. Clinicians should consider RASi administration if patients' serum chloride levels are low, to improve the long-term prognosis of HFpEF patients.

Abstract 15835: Deep Learning Based Personalized Treatment Recommender System for HFpEF Patients in the TOPCAT Americas Population

Introduction: The NHLBI supported TOPCAT trial (NCT00094302) investigated whether treatment with spironolactone (SPL) reduces hospitalization due to heart failure (hHF) in 3,445 adults with prior heart failure and preserved ejection fraction (HFpEF). We reused publicly available patient-level data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses with deep learning (DL) on the American TOPCAT cohort to generate treatment recommendations for HFpEF. Methods: Clinical phenogroups based on baseline characteristics of the American TOPCAT cohort (n = 1,053) were created using KPrototypes, suited for mixed data clustering. Treatment outcomes were assessed for hHF by DeepSurv, a DL generalization of Cox proportional hazards model, and Random Survival Forest (RSF), a tree-based survival analysis model. Comparison of survival probabilities from both models was used to create a recommender system used to guide treatments. Results: Cluster 1 was composed of younger patients with high cardiometabolic risk compared with Cluster 2. Diabetic patients (type 1 and type 2) comprised 93.2% of patients in cluster 1 and 10.1% of patients in Cluster 2. Among both clusters, DeepSurv and RSF trained well based on calculated C-indices, with DeepSurv often outperforming the RSF model (C-index = 0.797 vs. 0.698). Both approaches corroborated with each other and recommended the SPL treatment for the majority of patients in Cluster 1 (Figure 1). The models also recommended the SPL treatment for the majority of patients in cluster 2, although DeepSurv was less confident in this suggestion than RSF (Figure 1). Conclusions: This preliminary analysis shows the potential effectiveness of tailoring SPL as a treatment for HFpEF. The efficacy of deep learning models shows how advanced techniques can be used to promote precision medicine. Further analyses will be done to establish guided treatment efficacy in DL-generated subgroups of HFpEF patients.

Abstract 13669: Ascending Aortic Augmentation Pressure Does Not Decrease During Exercise in HFpEF: Implications for SV Reserve Impairment

Aortic augmentation pressure (aAP; difference between first [aP1] and second [aP2] peaks of the aortic pressure waveform) decreases during exercise in young healthy individuals, lowering mid-late systolic afterload, an important determinant of cardiac work and stroke volume (SV). In patients with heart failure and preserved ejection fraction (HFpEF), SV responses to exercise (i.e. SV reserve) are often abnormal (≤ 50%). A lack of fall in aAP during exercise in HFpEF could contribute to impairments in SV reserve. Therefore, we studied 15 HFpEF patients (age, 71 ± 6 years; 10 women; BMI 39.2 ± 6.2 kg/m 2 ) in the seated upright position. During rest and six-minutes of cycling at 20 Watts, we recorded beat-by-beat radial arterial blood pressure and estimated ascending aortic blood pressure waveforms in real-time via a generalized inverse transfer function (SphygmoCor). SV was calculated from cardiac output (Qc, acetylene rebreathe) and heart rate (ECG), with total peripheral resistance (TPR) calculated as the quotient of radial MAP and Qc. HR (Rest: 75 ± 14 vs 20W: 93 ± 12 bpm, P &lt; 0.0001), SV (Rest: 61 ± 17 vs 20W: 84 ± 19 ml, P = 0.0003) and Qc (Rest: 4.5 ± 1.0 vs 20W: 7.7 ± 1.6 L/min, P &lt; 0.0001) increased from rest to 20 Watts, whilst TPR decreased (Rest: 21.3 ± 4.4 vs 20W: 14.0 ± 3.8 mmHg/L/min, P &lt; 0.0001); SV reserve was 43 ± 33 %. Aortic diastolic pressure did not change (Rest: 70 ± 12 vs 20W: 76 ± 15 mmHg, P = 0.0976), whereas aP1 (Rest: 112 ± 18 vs 20W: 130 ± 20 ml, P = 0.0002) and aP2 (Rest: 123 ± 26 vs 20W: 142 ± 25 ml, P = 0.0021) increased during exercise (Figure). Notably, aAP was not different between rest and exercise (Rest: 11 ± 11 vs 20W12 ± 11 mmHg, P = 0.4969). Therefore, the contribution of aAP to mid-late systolic afterload is unchanged during exercise in HFpEF, unlike in young healthy adults. Unchanged aAP may be a mechanism of high mid-late systolic afterload during exercise in HFpEF, which could contribute to impairments in SV reserve related to reduced ventricular contractile reserve.

Neuregulin-1β, Biomarkers of Inflammation and Myocardial Fibrosis in Heart Failure Patients

Neuregulin-1 β (NRG-1) is an emerging biomarker of heart failure (HF). The mechanisms of its action in HF patients are yet to be investigated. Cardioprotective and anti-inflammatory effects of NRG-1 have been reported. Aim . To assess NRG-1 levels in HF patients and investigate the association between NRG-1 and biomarkers of inflammation and myocardial fibrosis. Material and Methods. NRG-1, biomarkers of inflammation and fibrosis (hsCRP, IL-6, sVCAM-1, MMP-9, Galectin-3, ST2, TGF- β ) were assessed in 47 patients with HF and preserved ejection fraction (HFpEF); 39 patients with HF and reduced ejection (HFrEF) and 40 healthy participants. The associations between NRG-1 and biomarkers of inflammation and fibrosis, as well as the composite outcomes of cardiovascular death and HF hospitalisations were assessed. Results. Median NRG-1 levels in HFpEF were 0.969 (0.348; 1.932) ng/ml, in HFrEF – 0.63 (0.348; 1.932), in healthy participants 0.379 (0.195; 0.861) ng/ml, and was significantly higher in HFpEF compared to healthy volunteers (р=0.004). There was no difference in NRG-1 concentration between HFpEF and HFrEF. In HF patients, all biomarkers of inflammation and fibrosis were higher than in controls. ST2, IL-6 and TGF- β were significantly higher in HFrEF compared to HFpEF patients, while hsCRP, sVCAM-1, MMP-9, and Galectin-3 levels were comparable. In HFpEF, NRG-1 was associated with hsCRP (r s =0.378, p=0.023) and IL-6 (r s =0.378, p=0.014). Median follow-up time in patients with HFpEF and in patients was 312 (236; 388) days, in HFrEF – 147 (98; 237) days. In HFpEF, 2 patients died and 19 were hospitalized due to HF. In HFrEF, 10 deaths and 19 hospitalizations were registered. Kaplan-Mayer analysis showed that HFpEF patients with increased NRG-1 and IL-6 had higher levels of HF hospitalisation (log rank test, р=0.046 and р=0.012, respectively). In a multivariable cox proportional hazard model, the association between the NRG-1 and outcomes remained significant after adjustment for age, gender and NTproBNP but diminished when hsCRP and IL-6 were included in the model. Conclusion. NGR-1 level significantly higher in HFpEF compared to healthy participants, and comparable with NRG-1 concentrations in HFrEF. In HFpEF, NRG-1 was associated with biomarkers of inflammation and fibrosis. The prognostic value of NRG-1 in HF requires further investigations.

Changes in left atrial function in patients undergoing cardioversion for atrial fibrillation: relevance of left atrial strain in heart failure

BackgroundLeft atrial (LA) reservoir strain provides prognostic information in patients with and without heart failure (HF), but might be altered by atrial fibrillation (AF). The aim of the current study was to investigate changes of LA deformation in patients undergoing cardioversion (CV) for first-time diagnosis of AF.Methods and resultsWe performed 3D-echocardiography and strain analysis before CV (Baseline), after 25 ± 10 days (FU-1) and after 190 ± 20 days (FU-2). LA volumes, reservoir, conduit and active function were measured. In total, 51 patients were included of whom 35 were in SR at FU-1 (12 HF and preserved ejection fraction (HFpEF)), while 16 had ongoing recurrence of AF (9 HFpEF). LA maximum volume was unaffected by cardioversion (Baseline vs. FU-2: 41 ± 11 vs 40 ± 10 ml/m2; p = 0.85). Restored SR led to a significant increase in LA reservoir strain (Baseline vs FU-1: 12.9 ± 6.8 vs 24.6 ± 9.4, p < 0.0001), mediated by restored LA active strain (SR group Baseline vs. FU-1: 0 ± 0 vs. 12.3 ± 5.3%, p < 0.0001), while LA conduit strain remained unchanged (Baseline vs. FU-1: 12.9 ± 6.8 vs 13.1 ± 6.2, p = 0.78). Age-controlled LA active strain remained the only significant predictor of LA reservoir strain on multivariable analysis (β 1.2, CI 1.04–1.4, p < 0.0001). HFpEF patients exhibited a significant increase in LA active (8.2 ± 4.3 vs 12.2 ± 6.6%, p = 0.004) and reservoir strain (18.3 ± 5.7 vs. 22.8 ± 8.8, p = 0.04) between FU-1 and FU-2, associated with improved LV filling (r = 0.77, p = 0.005).ConclusionReestablished SR improves LA reservoir strain by restoring LA active strain. Despite prolonged atrial stunning following CV, preserved SR might be of hemodynamic and prognostic benefit in HFpEF.Graphical abstract

Influence of baseline parameters on one-year physical, mental, and health-related quality of life in patients with heart failure and preserved ejection fraction.

AimsTo identify baseline parameters longitudinally influencing overall health‐related quality of life (HRQoL), physical function and mental health 1 year later in patients with chronic heart failure and preserved ejection fraction (HFpEF).Methods and resultsWe performed post hoc analyses of the randomized aldosterone in diastolic heart failure (Aldo‐DHF) trial, including 422 patients with HFpEF and NYHA class II or III. Overall HRQoL, measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), physical functioning and mental health, both measured by the Short Form 36 Health Survey (SF‐36), after 12 months were predicted in correlation analyses and multivariate regression analyses with continuous values and worst versus three better HRQoL quartiles as dependent variables. The mean age of the study population was 66.8 ± 7.6 years, 52.4% were female, and 86.0% had NYHA class II. All HRQoL variables at 1 year were predicted by their respective baseline values (all P < 0.001), which were also the best variables to predict lowest versus higher HRQoL quartiles (all P < 0.001). For overall HRQoL, six‐minute‐walking‐distance (P = 0.009), Borg‐score (P = 0.001), coronary heart disease (P = 0.036) and SF‐36 role‐emotional (P = 0.005) independently predicted one‐year‐outcome, while depression diagnosis (P = 0.044), self‐reported health status (P = 0.023) and PHQ depression (P = 0.001) were only significant predictors when excluding MLHFQ total score at baseline. In logistic regression analyses, only SF‐36 role‐emotional (P = 0.016) independently predicted overall HRQoL group status at follow up. For physical functioning, Borg‐score (P ≤ 0.001), 6 min walking distance (P = 0.005), coronary heart disease (P = 0.009), and SF‐36 vitality (P = 0.001) were significant independent predictors, also when excluding baseline physical functioning. Low SF‐36 vitality (P = 0.021) and presence of coronary heart disease (P = 0.027) independently predicted a patient's membership in the lowest quartile 1 year later. For mental health, SF‐36 physical functioning (P = 0.025) and HADS anxiety (P = 0.046) were independent predictors, while self‐rated fatigue and poor performance (P = 0.033) and SF‐36 vitality (P = 0.008) only served as significant predictors when excluding mental health at baseline. HADS anxiety (P = 0.009) also served as independent predictor of a patient's group status after 1 year.ConclusionOverall HRQoL, physical functioning, and mental health of HFpEF patients 1 year later are mainly influenced by their respective baseline values. Other self‐rated baseline parameters also showed independent effects while objective severity measures had limited predictive value.

Poorer Exercise Accommodation of Regional Systolic Myocardial Motion after Spironolactone Treatment in Heart Failure Patients with Preserved Ejection Fraction and Ventricular Dyssynchrony.

Patients with heart failure and preserved ejection fraction (HFpEF) are known to have reduced systolic myocardial velocity (Sm) with impaired accommodation to exercise. We tested the impact of an aldosterone antagonist on Sm at rest and post-exercise. Forty-nine HFpEF patients (65 ± 11 years, 24 male) with HF signs/symptoms, mitral E/Ea (annular early diastolic velocity) > 8, and left ventricular (LV) EF > 50% were randomized to spironolactone (25 mg/day, 25 patients) or the Control. At baseline and 6 months, we analyzed Sm of basal LV segments at rest and after a 6 min treadmill exercise. At 6 months, post-exercise mean Sm in the spironolactone group became greater than that in the Control (9.2 ± 1.6 vs. 8.3 ± 1.0 cm/s, p = 0.021), mainly due to the increment of post-exercise % increase of lateral Sm (44 ± 30 vs. 30 ± 19% at baseline, p = 0.045). Further analyses showed the presence of systolic dyssynchrony (standard deviation of electromechanical delay of 6-basal LV segments > 35 ms) was independently associated with a poorer response to spironolactone, defined as a post-exercise % increase of lateral Sm < 50% (OR = 2.7, 95% CI = 1.8–4.2) and the increment of Ea < 1.5 cm/s (OR = 1.5, 95% CI = 1.1–2.3). Spironolactone could improve exercise accommodation of regional systolic myocardial velocity for HFpEF patients. However, its benefits could be decreased in those with ventricular dyssynchrony. This suggested possible therapeutic impacts from underlying heterogeneity within HFpEF patients.

Delayed repolarization and ventricular tachycardia in patients with heart failure and preserved ejection fraction.

Sudden death is the most common mode of mortality in patients with heart failure and preserved ejection fraction (HFpEF). Ventricular arrhythmias (VA) have been suspected as the etiology but the supporting evidence in patients with HFpEF is scarce. We sought to investigate VA prevalence, and to determine if VA are associated with prolonged repolarization, in patients with HFpEF. In a retrospective case-control study design, Cedars-Sinai patients who underwent prolonged ambulatory electrocardiographic monitoring (Zio Patch) between 2016 and 2018 were screened for a clinical diagnosis of HFpEF. Patients with normal diastolic and systolic function who underwent Zio Patch monitoring were also reviewed as controls. Multivariable logistic regression was used to compare the prevalence of rhythm disturbances in patients with and without HFpEF. Ventricular tachycardia (VT) was more prevalent in patients with HFpEF (37% vs. 16% in controls, p = 0.001). Most episodes were non-sustained except for one case of sustained VT in a patient with HFpEF. Covariate-adjusted logistic regression including HFpEF diagnosis, age, sex, body mass index, and the presence of comorbidities revealed that only HFpEF was associated with increased risk of VT (relative risk 2.86, p = 0.023). Subgroup-analyses revealed an association between increased QTc interval and risk of VT (460 ± 38 ms in HFpEF patients with VT vs. 445 ± 28 ms in HFpEF patients without VT, p = 0.03). Non-sustained VT was more prevalent in patients with HFpEF compared to patients without HFpEF, and QTc interval prolongation was associated with VT in HFpEF.

Abstract 17311: Ventricular Arrhythmias and Fibrosis in Patients With Heart Failure and Preserved Ejection Fraction

Introduction: Sudden death due to ventricular arrhythmias (VA) is one of the main causes of mortality in patients with heart failure and preserved ejection fraction (HFpEF). Ventricular fibrosis in HFpEF has been suspected as a substrate of VA, but the degree of fibrosis has not been well characterized. Hypothesis: HFpEF patients with increased degree of fibrosis will manifest more VA. Methods: Cedars-Sinai medical records were probed using Deep 6 artificial intelligence data extraction software to identify patients with HFpEF who underwent cardiac magnetic resonance imaging (MRI). MRI of identified patients were reviewed to measure extra-cellular volume (ECV) and degree of fibrosis. Ambulatory ECG monitoring (Ziopatch) of those patients were also reviewed to study the prevalence of arrhythmias. Results: A total of 12 HFpEF patients who underwent cardiac MRI were identified. Patients were elderly (mean age 70.3 ± 7.1), predominantly female (83%), and overweight (mean BMI 32 ± 9). Comorbidities included hypertension (83%), dyslipidemia (75%), and coronary artery disease (67%). Mean left ventricular ejection fraction by echocardiogram was 63 ± 8.7%. QTc as measured on ECG was not significantly prolonged (432 ± 15 ms). ECV was normal in those patients for whom it was available (24.2 ± 3.1, n = 9) with 3/12 patients (25%) demonstrating ventricular fibrosis by MRI (average burden of 9.6 ± 5.9%). Ziopatch was obtained in 8/12 patients (including all 3 patients with fibrosis) and non-sustained ventricular tachycardia (NSVT) was identified in 5/8 (62.5%). One patient with NSVT and without fibrosis on MRI also had a sustained VA recorded. In those patients who had Ziopatch monitoring, there was no association between presence of fibrosis and NSVT (X2 = 0.035, p = 0.85). Conclusions: Ventricular fibrosis was present in 25% of HFpEF patients in this study and NSVT was observed in 62.5% of those patients with HFpEF who had Ziopatch monitoring. The presence of fibrosis by Cardiac MRI was not associated with NSVT in this study; however, the size of the cohort precludes broadly generalizable conclusions about this association. Further investigation is required to better understand the relationship between ventricular fibrosis by MRI and VA in patients with HFpEF.

Abstract 16091: Cardiac Mechanical Determinants of Exercise Function in Differing Fontan Heart Failure Phenotypes

Introduction: The objective of this study was to investigate the association of contractility, afterload, and diastolic dysfunction to exercise function between patients with heart failure and preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). Hypothesis: Cardiac mechanical determinants of exercise would be different in HFrEF versus HFpEF Methods: Core-lab echocardiograms were obtained from the publically-available Pediatric Heart Network Fontan Cross-sectional Study database. Ejection fraction was considered abnormal if &lt; 50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e’/end-diastolic volume) was &gt; 10 th percentile. Patients were divided into three groups: 1 = normal EF and normal diastolic function, 2 = decreased EF with normal diastolic function (HFrEF), 3 = normal EF with abnormal diastolic function (HFpEF). End-systolic elastance (Ees), a measure of contractility, and arterial elastance (Ea), a measure of afterload, were calculated. Results: 238 patients were included. Differences between groups are reported in the Table. In group 1, there were no significant correlations between exercise and echocardiographic measures. In patients with HFrEF, Ea was correlated with percent predicted max O 2 pulse (ppO 2 P-max) (r = -0.40, p = 0.03). In patients with HFpEF, lateral E:e’/EDV was correlated with ppO 2 P-max (r = -0.57, p = 0.02). No measures correlated with percent predicted peak VO 2 in either group. Conclusions: As Fontan patients progress to heart failure, stroke volume during exercise is limited by afterload in patients with HFrEF. Alternatively, stroke volume is limited by diastolic dysfunction in HFpEF patients. These measures of cardiac mechanics may be useful in identifying the mechanisms that drive exercise dysfunction in Fontan patients of varying heart failure phenotypes.

Abstract 13104: The Concomitant Inflammation Affect the Ratio of N-terminal Pro B-type Natriuretic Peptide to B-type Natriuretic Peptide in Patients With Heart Failure and Preserved Ejection Fraction

Backgrounds: Although B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP ) are interrelated parameters in assessment heart failure severity and prognosis, the ratio of NT-proBNP to BNP (NT-proBNP/BNP) are affected by various clinical factors, such as renal function. However, little is known about the influence of inflammation on NT-proBNP/BNP in patients with heart failure and preserved ejection fraction (HFpEF). Methods and Results: Patients data were extracted from PURSUIT-HFpEF registry, which is a multicenter prospective observational study including patients hospitalized for acute heart failure with left ventricular ejection fraction of &gt;50%. Of 871 patients, data of BNP and NT-proBNP was available in 654 patients. The median baseline concentration of BNP was 474 pg/ml (299-720), NT-proBNP was 3310 pg/ml (1740-6840), and NT-proBNP/BNP was 7.6 (5.0-11.8). In multivariable linear regression analyses, older age [odds ratio (OR); 1.05, 95% confidence interval (CI); 1.02-1.09, p=0.001], higher creatinine [OR; 2.63, 95% CI; 1.66-4.16, p&lt;0.001], and higher C-reactive protein (CRP) [OR; 1.17, 95% CI; 1.06-1.28, p&lt;0.001] were significantly associated with a higher NT-proBNP/BNP (&gt;median value of 7.6). However, other factors expected to affect NT-proBNP/BNP, such as atrial fibrillation and body mass index, were not associated with a higher NT-proBNP/BNP in this study. Patients in the highest CRP quartile had significantly higher NT-proBNP/BNP than those with other quartiles. Conclusion: In HFpEF patients, concomitant inflammation was associated with high NT-proBNP/BNP, which indicated that we need a careful interpretation on these two natriuretic peptides of patients with HFpEF and inflammatory status, such as infection.

Abstract 16140: Fontan Patients With Heart Failure and Preserved Ejection Fraction Have Similar Afterload but More Favorable Ventricular-arterial Coupling Than Fontan Patients With Reduced Ejection Fraction

Introduction: The cardiac mechanics that contribute to the development of heterogenous heart failure phenotypes in Fontan patients have not been investigated. The objective of this study was to investigate the differences in contractility, afterload, and ventriculo-arterial (VA) coupling between patients with heart failure and preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). Methods: Core-lab echocardiograms were obtained from the publically-available Pediatric Heart Network Fontan Cross-sectional Study database. Ejection fraction was considered abnormal if &lt; 50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e’/end-diastolic volume) was &gt; 10 th percentile. Patients were divided into three groups: 1 = normal EF and normal diastolic function, 2 = decreased EF with normal diastolic function, 3 = normal EF with abnormal diastolic function. End-systolic elastance (Ees), a measure of contractility, and arterial elastance (Ea), a measure of afterload, were calculated. VA coupling was defined as Ea/Ees. Results: 238 patients (61% left, 39% right ventricular dominant) were included. Differences between groups are reported in the Table. Conclusion: Both Fontan patients with HFpEF and HFrEF display increased afterload compared to their non-heart failure counterparts. However, HFpEF patients displayed a hypercontractile state to maintain a VA coupling ratio comparable to the non-heart failure group. These measures of cardiac mechanics may be useful in identifying the mechanisms that drive Fontan patients toward HFpEF versus HFrEF phenotypes.

What Type of Patients Did PARAGON-HF Select? Insights from a Real-World Prospective Cohort of Patients with Heart Failure and Preserved Ejection Fraction.

The PARAGON-HF clinical trial suggested that sacubitril/valsartan may become a treatment option for particular subgroups of patients with heart failure and preserved ejection fraction (HFpEF). However, the proportion of real-world HFpEF patients who are theoretically superimposable with the PARAGON-HF population is yet unknown. The present study was performed to define the proportion of real-world PARAGON-HF-like patients and to describe their clinical characteristics and long-term prognosis in comparison with those who would not meet PARAGON-HF criteria. We systematically applied PARAGON-HF inclusion and exclusion criteria to a total of 427 HFpEF patients who have been participating in a prospective national registry between December 2010 and December 2019. In total, only 170 (39.8%) registry patients were theoretically eligible for PARAGON-HF. Patients not meeting inclusion criteria (41.0%) were less impaired with respect to exercise capacity (median 6-min walk distance: 385 m (IQR: 300–450) versus 323 m (IQR: 240–383); p < 0.001) had lower pulmonary pressures (mean pulmonary artery pressure (mPAP): 31.2 mmHg, standard deviation (SD): ±10.2 versus 32.8 mmHg, SD: ±9.7; p < 0.001) and better outcomes (log-rank: p < 0.001) as compared to the PARAGON-like cohort. However, patients theoretically excluded from the trial (19.2%) were those with most advanced heart failure symptoms (median 6-min walk test: 252 m (IQR: 165–387); p < 0.001), highest pulmonary pressures (mPAP: 38.2 mmHg, SD: ±12.4; p < 0.001) and worst outcome (log-rank: p = 0.037). We demonstrate here that < 40% of real-world HFpEF patients meet eligibility criteria for PARAGON-HF. We conclude that despite reasons for optimism after PARAGON-HF, a large proportion of HFpEF patients will remain without meaningful treatment options.

Atrial fibrillation burden and risk of new development through artificial intelligence analysis of an electrocardiogram in hospitalized patients with heart failure and preserved ejection fraction

Abstract Background Analysis of a 12-lead electrocardiogram (ECG) in sinus rhythm by artificial intelligence (AI) has demonstrated to identify the risk of underlying paroxysmal atrial fibrillation (AF) with reasonable accuracy in the overall population. Purpose This study investigates whether AI based ECG analysis can predict new AF development in patients with heart failure and preserved ejection fraction (HFpEF) without previous AF history, as well as predict AF burden in patients with AF history. Methods This retrospective cohort study includes 424 patients with HFpEF, consecutively admitted to receive treatment with intravenous diuretics for congestion. A previously validated AI algorithm that provides an AF risk score based on ECG analysis was applied in all subjects. Patients were stratified according to AF history: (1) no history; (2) paroxysmal AF; (3) persistent AF; or (4) permanent AF. In patients without AF history, the impact of AI-predicted AF risk on new AF development was assessed. In patients with previous AF episodes, the relationship between AI-predicted AF risk and AF burden as well as underlying echocardiography substrate was evaluated. Results Eighty-three patients had paroxysmal AF (19.5%), 48 persistent AF (11%), and 121 permanent AF (28.5%). AF patients were older, with lower body mass index and higher heart rate. Lower systolic blood pressure, larger left atrial volume index (LAVI), worse diastolic function, more tricuspid valve regurgitation, and more need for pacing were observed with increasing AF severity. In 172 patients without AF history followed for 979±875 days, 61 developed AF (35%) after a median time of 2,118 days. AI-predicted AF risk was associated with new-onset AF after adjustments for age, gender, systolic blood pressure, body mass index and LAVI [HR (95% CI) = 1.15 (1.04–1.28); P-value=0.007; figure]. Only 5/61 patients who developed AF during follow-up (8.2%) were anticoagulated at baseline. In patients with previous AF, the AI-predicted risk score increased significantly with AF burden (46±25% in paroxysmal AF, 59±22% in persistent AF, and 69±17% in permanent AF; P-value&amp;lt;0.001). The score was weakly but significantly correlated with LAVI (Pearson's r=0.27; P-value&amp;lt;0.001) and right ventricular systolic pressure (Pearson's r=0.30; P-value&amp;lt;0.001). When stratifying patients according to AI-predicted AF risk (0–25% versus 26–50% versus 51–75% versus 76–100%), there was a progressively longer time since onset of the first AF episode [29 months (4–77 months) versus 9 months (0–62 months) versus 38 months (2–88 months) versus 54 months (3–112 months), respectively; P-value=0.046]. Conclusions An AI-predicted AF risk score based on ECG analysis was associated with AF burden in HFpEF patients and did independently predict new-onset AF in those without previous history. Time to new onset of atrial fibrillation Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Belgian American Educational Foundation (B.A.E.F.); Special Research Fund (BOF) of Hasselt University (Hasselt, Belgium)

A novel SGLT-2 score to identify HFpEF patients who may benefit from SGLT-2 inhibitors

Abstract Background Established heart failure (HF) treatments have shown no effects in HF and preserved ejection fraction (HFpEF). Subgroup analyses of the HFpEF populations suggest that certain patients benefit from HF treatments. This underlines the importance of individualized therapy regimens in HFpEF. Sodium-glucose transporter 2 (SGLT-2) inhibitors are emerging as a promising treatment of HF. The mechanisms leading to improved outcomes include 1) treatment of diabetes, 2) osmodiuresis preventing volume overload, 3) enhancement of the cardio protective Angiotensin (Ang) 1–7 pathway, instead of Ang II. We aimed to characterize patients by factors which are modified by SGLT-2 inhibitors to identify individuals who may benefit from these drugs. Methods HFpEF patients were included in a single center registry. Baseline evaluation included assessment of HbA1c, fluid status measured by body composition monitor and plasma angiotensin concentration. A “SGLT-2 score” with a maximum of 3 points was calculated using the following parameters: 1) HbA1c &amp;gt;6.5%, 2) overhydration, defined as a fluid overload of &amp;gt;1,5L and 3) plasma renin activity (PRA) levels above the median as a parameter of over-all RAS activity. Primary outcome was defined as all-cause death or HF hospitalization. All parameters used in the “SGLT-2 score” were independently predictive for the chosen endpoint. Kaplan Meier analyses was used to show the association between the score and outcomes. Results 90 patients were included in this registry. Median HbA1c was 6.0%, median fluid status was 1.2L and the median Ang II levels in the “high PRA-group” were 5.35.1 pmol/L. After a mean follow up time of 44.0±38.7 months, 60 patients (66.6%) reached the endpoint. Kaplan Meier analysis showed an association between SGLT-2 score and outcome (p=0.003). Conclusion Patients with HbA1c &amp;gt;6.5%, overhydration and high RAS activity have poor outcomes. We propose the future use of this score to identify a subgroup of HFpEF patients who may benefit from SGLT-2 inhibitors. Kaplan Meier analysis Funding Acknowledgement Type of funding source: None

Sacubitril/valsartan and circulating neprilysin hypothesis in patients with HFpEF

Abstract Background Neprilysin serum levels (sNEP) exhibited significant prognostic value in patients with heart failure (HF). In the PARADIGM-HF study benefit of sacubitril/valsartan was observed in patients with reduced ejection fraction (HFrEF), while in the PARAGON-HF benefit was only observed in the subgroup of patients with LVEF &amp;lt;57%. Objective To assess the prognostic value of sNEP in ambulatory patients with HF and preserved ejection fraction (HFpEF) and LVEF &amp;gt;57% (group 1), in comparison with patients with LVEF ≤57% (group 2). Methods Consecutive patients with HF attended at the Unit from May 2006 to February 2016 were considered for the study. The primary end-point was the composite of cardiovascular death or HF hospitalization. All-cause death, cardiovascular death, HF hospitalization and the composite of all-cause death or HF hospitalization were secondary end-points. Competing risk methods (R package by Bob Gray for SPSS) were used when required. Results sNEP was measured in 1428 patients (age 67.7±12.7, 70.3% men, LVEF 35.8% ±14, 48.9% from ischemic etiology), 144 of which had a LVEF &amp;gt;57% (age 70.1±15, 43.8% men, 53.5% from hypertensive or valvular etiologies). sNEP levels did not significantly differ between the two groups of patients (p=0.31). During a mean follow-up of 6±3.9 years, 856 deaths were recorded (459 from cardiovascular causes) and 523 patients suffered at least one HF hospitalization. The primary end-point occurred in 941 patients (in 111 of the 144 patients with LVEF &amp;gt;57%). Table 1 shows sNEP age- and sex-adjusted hazard ratios for the primary and secondary end-points. Conclusions sNEP prognostic value in patients with HFpEF and LVEF &amp;gt;57% outperforms that observed in patients with lower LVEF. These data support the personalized use of sNEP in identifying HFpEF patients that may benefit from treatment with sacubitril/valsartan. Funding Acknowledgement Type of funding source: None