Heart Failure With Reduced Ejection Fraction Patients Research Articles

Machine learning approach to identify phenotypes in patients with ischaemic heart failure with reduced ejection fraction.

Patients experiencing ischaemic heart failure with reduced ejection fraction (HFrEF) represent a diverse group. We hypothesize that machine learning clustering can help separate distinctive patient phenotypes, paving the way for personalized management. A total of 8591 ischaemic HFrEF patients pooled from the EPHESUS and CAPRICORN trials (64 ± 12 years; 28% women) were included in this analysis. Clusters were identified using both clinical and biological variables. Association between clusters and the composite of (i) heart failure hospitalization or all-cause death, (ii) cardiovascular (CV) hospitalization or all-cause death, and (iii) major adverse CV events was assessed. The derived algorithm was applied in the COMMANDER-HF trial (n = 5022) for external validation. Five clinical distinctive clusters were identified: Cluster 1 (n = 2161) with the older patients, higher prevalence of atrial fibrillation and previous CV events; Cluster 2 (n = 1376) with the higher prevalence of older hypertensive women and smoking habit; Cluster 3 (n = 1157) with the higher prevalence of diabetes and peripheral artery disease; Cluster 4 (n = 2073) with relatively younger patients, mostly men and with the higher left ventricular ejection fraction; Cluster 5 (n = 1824) with the younger patients and lower CV events burden. Cluster membership was efficiently predicted by a random forest algorithm. Clusters were significantly associated with outcomes in derivation and validation datasets, with Cluster 1 having the highest risk, and Cluster 4 the lowest. Mineralocorticoid receptor antagonist benefit on CV hospitalization or all-cause death was magnified in clusters with the lowest risk of events (Clusters 2 and 4). Clustering reveals distinct risk subgroups in the heterogeneous array of ischaemic HFrEF patients. This classification, accessible online, could enhance future outcome predictions for ischaemic HFrEF cases.

Conduction system pacing versus biventricular pacing in heart failure with reduced ejection fraction and electrical dyssynchrony

Biventricular pacing (BiVP) has been the cornerstone of cardiac resynchronization therapy (CRT) in the management of symptomatic heart failure patients with reduced ejection fraction (HFrEF) and electrical dyssynchrony despite guideline-directed medical therapy (GDMT). However, BiVP has some limitations, including technical difficulties and high non-response rates. Conduction system pacing encompassing His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) has recently emerged as a promising alternative to CRT in this group of patients. In this review, we explore the current evidence, guidelines, limitations, gaps in knowledge, and ongoing trials comparing CSP and BiVP for the management of HFrEF with electrical dyssynchrony.

Vascular Endothelial Effects of Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction: Randomized Controlled Trial

BackgroundThe mechanism of how sacubitril/valsartan improves outcomes in heart failure with reduced ejection fraction (HFrEF) is still incompletely understood. ObjectivesThe aim of this trial was to delineate the effects of sacubitril/valsartan on endothelial function, retinal microvascular function, and arterial stiffness in HFrEF. MethodsThis double-blind controlled trial randomized 79 stable HFrEF patients with NYHA class II-IV on guideline-recommended therapy (mean age: 59.4 ± 12 years, left ventricular ejection fraction: 30% ± 7%) to sacubitril/valsartan or valsartan alone for 3 months. The primary endpoint was flow-mediated vasodilation (FMD). Secondary outcomes included flicker-induced dilatation of retinal arterioles and venules (FIDv), retinal arteriovenous ratio, and surrogate markers of arterial stiffness (pulse wave velocity and augmentation index). ResultsThe primary outcome FMD did not significantly differ between sacubitril/valsartan and valsartan alone (FMD 6.6% ± 3.9% vs 6.7% ± 2.8%; ANCOVA coefficient adjusted for baseline values 0.36, 95% CI: −0.78 to 1.51, P = 0.53). The secondary outcomes flicker-induced dilatation of retinal arterioles, arteriovenous ratio, pulse wave velocity, and augmentation index showed no significant differences. FIDv was lower after sacubitril/valsartan versus valsartan alone (FIDv 2.4% ± 1.3% vs 3.1% ± 2.1%; ANCOVA coefficient −0.7, 95% CI: −1.4 to −0.02, P = 0.04). Systolic blood pressure was lower after sacubitril/valsartan versus valsartan alone (ANCOVA coefficient −6.5 mm Hg, 95% CI: −12.7 to −0.3 mm Hg, P = 0.04). There were numerically fewer serious adverse events with sacubitril/valsartan versus valsartan alone. ConclusionsIn this randomized double-blind clinical trial addressing mechanisms, sacubitril/valsartan lowered blood pressure and flicker-induced dilatation of retinal venules in patients with symptomatic HFrEF but did not improve endothelial function, retinal microvascular function, or arterial stiffness compared to valsartan monotherapy. (Differential Vascular and Endocrine Effects of Valsartan/​Sacubitril in Heart Failure With Reduced Ejection Fraction [VASCEND]; NCT03168568)

Impact of implantable cardioverter defibrillators on mortality in heart failure receiving quadruple guideline-directed medical therapy: a propensity score-matched study

BackgroundIn the contemporary management of heart failure with reduced ejection fraction (HFrEF), the recommended quadruple guideline-directed medical therapy (GDMT) consists of angiotensin receptor-neprilysin inhibitor (ARNI), evidence-based beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). This study explored the impact of adding implantable cardioverter-defibrillator (ICD) therapy to this comprehensive regimen in HFrEF patients.MethodsUtilizing deidentified data from the National Electronic Database of the Turkish Ministry of Health, we conducted a nationwide retrospective cohort study on 5450 HFrEF patients receiving quadruple GDMT, including ARNI. Among them, 709 patients underwent additional ICD or cardiac resynchronization therapy defibrillator (CRT-D) implantation. Propensity score matching ensured balanced baseline characteristics between groups. Primary endpoint was determined as all-cause mortality.ResultsIn the matched cohort, all-cause mortality occurred in 108 out of 619 patients (17.4%) in the GDMT group and 101 out of 619 patients (16.3%) in the ICD group, with a hazard ratio (HR) of 0.74 and a 95% confidence interval (CI) ranging from 0.57 to 0.98. The median follow-up time was 1365 days in the matched cohort, 1283 days in the GDMT group. Subgroup analyses consistently demonstrated benefits, particularly among individuals aged 61 years and older (HR: 0.60, 95% CI: 0.42–0.87, p = 0.006), those with sinus rhythm (HR: 0.55, 95% CI: 0.34–0.89, p = 0.013), individuals not using amiodarone (HR: 0.61, 95% CI: 0.42–0.89, p = 0.011), and those with an estimated glomerular filtration rate lower than 61.9 (HR: 0.66, 95% CI: 0.48–0.91, p = 0.011).ConclusionsThis study may offer a glimmer of hope that even after achieving the best current optimal medical therapy, the addition of device therapy could still yield positive outcomes in the management of patients with HFrEF.Graphical

Abstract 4138593: Sex-, Age-and Racial- specific disparities, echocardiographic myocardial mechanics and biomarkers, and 1-year survival among patients with heart failure.

Background: Heart failure with reduced ejection fraction (HFrEF) is a global health burden affecting millions worldwide, particularly among resource constrained communities. Information is limited regarding addative prognostic relations of sex -, age- and racial- differences, myocardial mechanics and biomarkers, in HFrEF. Aim: Assess prognostic implications of sex-, age- and racial- related disparity in HFrEF; and additive prognostic implications of these parameters to other markers including echocardiography (myocardial mechanics). Methodology: The HFrEF patients’ data were prospectively evaluated during the initial assessment and those hospitalized, and subseguently followed for at least 12months. Patients' KCCQ and EQ-5D-5L Questionnaires were assessed during the initial evaluation and follow-up. Sex, age and racial/ethnic disparities, in-hospital management, follow-ups, health status and 1year mortality were assessed. These parameters were further assessed in addition to biomakers and echocardiographic parameters including LV and RV systolic and distolic strain. Multivariable Cox regression models were fitted to investigate additive prognostic differences. Results: The study population consisted mainly of blacks and major factors were hypertension, diabetes, mitral valve disease, and older age (p<0.0001). Of the initial 2642 screened, only 1883 completed the 1year follow-up visit (mean LVEF 38%). Women were likely to have hypertension, atrial fibrillation and diabetes (p<.001). Rheumatic or valvular heart diseases were more commonly identified among younger, black ethnicity, and males patients. No demonstrated sex differences in functional class and biomarkers including NT-proBNP levels. Men demonstrated significant risk for one-year mortality than women, as was black ethnicity and older age. Impaired strain parameters (RV>LV systolic) were independent risk factors for poor survival, more so when added to sex, racial ethnicity, age and biomarkers i.e. the NT-proBNP levels. Conclusion: The prevalence of HFrEF was higher than anticipated. Men, black ethnicity and older age were associated with a high one-year mortality. Impaired strain (RV>LV systolic) parameters were independent risk factors for poor survival, with additive prognostic implications to sex, racial ethnicity, age and traditional biomarkers. These parameters should be assessed routunely to risk stratify HFrEF patients earlier during their disease course.

Abstract 4135905: The Impact of Emergent Atrial Fibrillation in Patients With Newly Diagnosed Heart Failure and Differences in Risk Among Preserved vs. Reduced Ejection Fraction

Background: Atrial fibrillation (AF) and heart failure (HF) are associated with an increased risk of adverse events, with their diagnoses often coexisting. The impact of AF in HF needs additional study, with further delineation among HF type. Therefore, this study sought to determine the degree of AF burden among newly diagnosed HF patients and whether differences in risk exist between heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) patients. Methods: Patients with new-onset HF between 2000-2019 were studied. To be included, patients had to have 1-year of follow-up, an ejection fraction (EF) measurement within 30 days of HF diagnosis, and no history of cancer. EF was used to define HFrEF (EF <40%) and HFpEF (EF > 40%). Multivariable Cox hazard regression was used to evaluate the risk of death and HF hospitalization at 1- and 3-years. Results: A total of 21,925 patients were studied with HFrEF (n=7931 [36.2%]) and HFpEF (n=13,994 [63.8%]). HFpEF patients were older (74 vs. 65 years) and more often female (53.7% vs. 33.1%). Prevalent AF was 40.5% (n=8879), being more common in HFpEF compared to HFrEF (65.2% vs. 34.8%). Among AF patients, HFpEF patients were also older (76 vs. 72 years) and more often female (52.7% vs. 30.8%) compared to HFrEF. The presence of AF was associated with an increased risk of HFpEF (OR=1.11, p=0.001). Prevalent AF was associated with an increased risk of death and follow-up HF hospitalization (Table). Death at 1-year and 3-years were similar between the HF groups (Table). However, the risk of HF hospitalization was greater among HFrEF patients (Table). Similar associations persisted when AF patients were propensity matched (Table). Conclusions: Among a newly diagnosed HF population, AF was common (40%) and was associated with an increased risk of HFpEF, death, and HF hospitalization. These results provide a rationale for aggressive management of HF and AF patients and the need for a randomized clinical trial to determine optimal therapy by ablation and 4-pillar HF therapy.

Abstract 4135273: Frailty increases the risk of in-hospital mortality and post-procedural complications in patients undergoing Cardiac Implantable Electronic Devices placement

Background: Heart failure with reduced ejection fraction (HFrEF) often necessitates the use of cardiac implantable electronic devices (CIED) such as cardiac resynchronization therapy defibrillators (CRT-D) or implantable cardioverter-defibrillators (ICD). These devices are proven to reduce mortality, prevent hospitalizations, and improve symptoms and quality of life. Frailty, characterized by an age-associated decline in physiological reserve, significantly impacts outcomes in these patients. This study uses the Hospital Frailty Risk Score (HFRS) to assess the effect of frailty on mortality and post-procedural complications in HFrEF patients undergoing CIED implantation. Hypothesis: Frail patients with HFrEF have worse in-hospital outcomes after CIED placement Methods: We conducted a retrospective cohort study using the 2020 National Inpatient Sample database from the Healthcare Utilization Project. Our population included patients aged 18 years or older with HFrEF who underwent CRT-D or ICD placement, identified using ICD-10 procedure codes. The primary risk factor was frailty, classified by an HFRS score of ≥5 (frail) or <5 (not frail). The primary outcome was in-hospital mortality, and the secondary outcome was the composite of post-procedural complications. Multivariate regression analysis was used to estimate the odds ratio. Results: Out of 24,809 patients who underwent ICD or CRT-D placement, 48.8% were frail. Non-Frail patients had lower mean age compared to Frail patients (66.2 vs 67.3 years old, p=0.003). In-hospital mortality was 1.1%, and 7% experienced post-procedural complications. In-hospital mortality was higher in frail patients compared to non-frail patients (2% vs 0.3%, p<0.001). In the multivariate analysis, frail patients had higher odds of in-hospital mortality compared to the non-frail group subset (OR=5.97; 95% CI: 2.77-12.88, p<0.001). Additionally, frailty was associated with higher odds of post-procedural complications (OR=1.28; 95% CI: 1.01-1.63, p<0.001), increased length of stay (5 vs 11.6 days, p<0.001), and total hospital charges (215,668 vs 324,474 , p<0.001). Conclusion: Frailty significantly increases the risk of in-hospital mortality and post-procedural complications in HFrEF patients. This highlights the importance of considering frailty as part of a pre-procedural risk stratification assessment and tailoring management strategies to improve outcomes for these high-risk patients.

Abstract 4132149: Elevated Levels of Plasma Mitochondrial DNA Damage-Associated Molecular Patterns (DAMPS) in Humans and Dogs with Heart Failure and Reduced Ejection Fraction

Background: Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with increased inflammatory response that contributes to progressive worsening of the HF state. Potential endogenous triggers of this process include damage-associated molecular patterns (DAMPs). DAMPs originate from within cells following tissue stress or injury and activate pattern recognition receptors of the immune system, triggering an inflammatory response. Mitochondria are the major cell organelles that release DAMPs into the circulation. Chronic HF is associated with multi-organ mitochondrial dysfunction and cell injury and death. Purpose: The present study sought to quantify differences in mitochondrial DNA (mtDNA) DAMPs in the setting of HFrEF in humans and dogs compared to normal humans and dogs. Methods: Plasma samples were obtained from 9 HFrEF patients with left ventricular ejection fraction (LVEF) ≤35% and 9 age-matched healthy subjects, and from 6 dogs with coronary microembolization-induced HF (LVEF ≤35%) and 6 normal dogs. DNA fragments were isolated from 1 ml of plasma using a commercially available kit. Quantitative PCR and specifically designed primers were used to measure the amount of DNA in plasma from COX1 (cytochrome c oxidase subunit 1), ND1 (NADH dehydrogenase subunit 1) and ND6 (NADH dehydrogenase subunit 6) using an Applied Biosystems 7500 Fast-PCR unit. The relative abundances of plasma mtDNA DAMPs were expressed as threshold cycles (C T ). Results: Compared to normal human subjects, mtDNA DAMPs levels of COX1 , ND1 and ND6 in plasma of HFrEF patients was 4-fold, 9-fold and 8-fold greater, respectively. Similarly, compared to normal dogs, mtDNA DAMPs levels of COX1 , ND1 and ND6 in plasma of HFrEF dogs was increased 48-fold, 12-fold and 4-fold, respectively. Conclusions: These findings indicate a marked increase of mtDNA DAMPs in plasma of humans and dogs with HFrEF. The increase of mtDNA DAMPs is consistent with the elevated systemic inflammatory state of HFrEF. The results underscore mitochondrial abnormalities as integral players in the progressive worsening of HFrEF.

Abstract 4124531: Digital Health Intervention to Enhance Optimization of Heart Failure Care: From Reciprocal Innovation using Human-Centered Design to Pilot Study

Introduction: Guideline-directed medical therapy (GDMT) for Heart Failure with reduced ejection fraction (HFrEF) reduces adverse events by 70%, but is underutilized. The Human Centered Design (HCD) methodology can be useful to build a strategy to optimize GDMT centered on patients’ demands and perspectives. We aimed to reciprocally innovate a telephone-based digital health intervention (DHI) from a Brazilian trial to an app co-developed for a US trial and iterate it again to the Brazilian context using HCD. We will evaluate the app’s usability and utility to facilitate HF GDMT optimization, considering barriers of the Brazilian public health system users, such as low literacy and socioeconomic status. Methods: Mixed methods study. Steps were carried out according to HCD method: (1) empathizing and identifying challenges, (2) suggesting solutions, (3) prototype development, (4) ranking features for feasibility and utility (5) engineering work and (6) prototype testing. In stages 1-3, semi-structured interviews were held with 10 HF patients and 2 health professionals. Steps 4 and 5 were done by the research team. In stage 6, we conducted a pilot study with 10 HFrEF patients, with at least one GDMT drug with an optimization gap. The primary outcome was the app’s usability assessed by an engagement score, and the app’s utility at 4 weeks. Secondary outcomes included change in self-care score using the European Self-Care Behavior Scale. After step 6, new interviews were carried out to capture the user experience and identify new iterations. Interviews were recorded and transcribed for content analysis. Results: The average engagement score was 80% (SD 16) and the app’s utility score was 82% (SD 8). The average self-care score increased by 32% (SD 25) at the end of the pilot. The main challenges were lack of knowledge about HF and self-care. Technical difficulties and lack of trust in the app to handle health data were mentioned. In the pilot, patients reported the app was easy to use and contributed to self-care and understanding of HF. Among the DHI components, teleconsultation was best evaluated, followed by the educational videos. The greatest challenge was connecting the blood pressure cuff and scale via Bluetooth. Conclusion: The app was well accepted and considered useful by patients. User contributions were fundamental to create tools that facilitate engagement and utility. The final product will be evaluated in a randomized, multicenter, clinical trial.

Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction

Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment. Methods: Potent siRNAs against a hepatic target with cardioprotective potential were designed in silico. Candidate siRNAs were screened in vitro in HEK293 cells and in vivo in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment. Results: ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice. Conclusions: High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.

Upgrading Right Ventricular Pacing to Cardiac Resynchronization in HFrEF Patients Improves Symptoms and Functional Outcomes.

In the BUDAPEST (Biventricular Upgrade on left ventricular reverse remodeling and clinical outcomes in patients with left ventricular Dysfunction and intermittent or permanent APical/SepTal right ventricular pacing)-CRT Upgrade randomized trial, the authors have demonstrated improved mortality and morbidity after cardiac resynchronization therapy (CRT) upgrade in patients with heart failure with reduced ejection fraction (HFrEF) with high right ventricular (RV) pacing burden. This substudy sought to examine the impact of CRT upgrade on symptoms, functional outcome, and exercise capacity. In the BUDAPEST-CRT Upgrade trial, 360 HFrEF patients with pacemaker or implantable cardioverter-defibrillator (ICD) and≥20% RV pacing burden were randomly assigned (3:2) to cardiac resynchronization therapy with defibrillator (CRT-D) upgrade (n=215) or ICD (n=145). The prespecified tertiary endpoints were changes in quality of life (QoL) (EQ-5D-3L), NYHA functional class, 6-minute walk test, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Up to 12months, NYHA functional class improved in the CRT-D upgrade arm compared with ICD only (adjusted OR: 0.50 [95%CI: 0.32-0.80]; P = 0.003). A remarkable decrease was observed in NT-proBNP levels in the CRT-D arm (adjusted difference-1,257 pg/mL [95%CI:-2,287 to-228]; P = 0.017). The progression of age-related worsening of QoL was moderated by CRT-D upgrade (EQ-5D-3L difference by each year: 0.015 [95%CI: 0.005-0.025]; Pinteraction=0.003). However, exercise tolerance (6-minute walk test) remained unchanged in both groups. HFrEF patients with pacemaker/ICD and≥20% RV pacing burden receiving CRT upgrade showed a substantial improvement in NYHA functional class and decrease in natriuretic peptide levels, as compared with ICD alone. Moreover, CRT-D upgrade could moderate the progression of worsening of QoL attributed to ageing in this vulnerable, elderly patient population. (Biventricular Upgrade on left ventricular reverse remodeling and clinical outcomes in patients with left ventricular Dysfunction and intermittent or permanent APical/SepTal right ventricular pacing [BUDAPEST]-CRT Upgrade trial).

Impact of Obstructive Sleep Apnea in Patients with Acute Heart Failure: A Nationwide Cohort Study

Background/Objectives: Heart failure presents a significant public health challenge, affecting millions in the US, with projections of increasing prevalence and economic burdens. Obstructive sleep apnea (OSA) is highly prevalent among HF patients. This study analyzes the impact of OSA on the outcomes in patients admitted with acute decompensated heart failure. Methods: We conducted a retrospective cohort study using the National Inpatient Sample database (NIS) 2020, focusing on patients admitted with acute heart failure. Patient outcomes were compared between those with and without a secondary diagnosis of OSA, identified via validated ICD-10 codes. Subgroup analysis was conducted between heart failure patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Results: Among 65,649 patients with acute heart failure, 4595 (7%) patients were found to have OSA. The patients with OSA were more likely to be male, older in age and had a higher burden of comorbidities. No significant differences were observed in mortality between heart failure patients with and without OSA. In HFrEF patients, OSA was associated with longer hospital stays (6.45 days vs. 5.79 days, p < 0.001), higher rates of acute kidney injury (AKI) (adjusted odds ratio 1.28, 95% CI: 1.07–1.54, p = 0.007), and atrial fibrillation (adjusted odds ratio 1.35, 95% CI: 1.13–1.61, p = 0.001). In HFpEF patients, an association between OSA and AF was observed (adjusted odds ratio 1.20, 95% CI: 1.01–1.42, p = 0.03). Conclusions: OSA is associated with poor in-hospital outcomes in patients admitted with acute heart failure. HFrEF subgroup is especially vulnerable, with OSA leading to a significant increase in healthcare utilization and complication rates in these patients. This nationwide study underscores the importance of timely identification and treatment of OSA in heart failure to alleviate healthcare burdens and improve patient outcomes.

Heart Rate Variability and Heart Failure with Reduced Ejection Fraction: A Systematic Review of Literature.

Autonomic impairment is a hallmark of heart failure with reduced ejection fraction (HFrEF). While there have been studies on general values for each index of heart rate variability (HRV) analysis in HFrEF, a systematic review comprehensively examining representative values in HFrEF is lacking. We searched PubMed, Embase, and Cochrane databases to extract studies reporting representative values of HRV metrics in HFrEF. A total of 470 HFrEF patients from 6 studies were included in the review. In general, time and frequency domains were abnormally lower in HFrEF, portending a worse prognosis. In HFrEF, the mean or median value of the standard deviation of NN interval, root mean square successive difference, pNN50, and low-frequency power/high-frequency power were 40 to 121 msec, 19 to 62 msec, 1.3 to 14%, and 1.00 to 1.73, respectively. In this systematic review, most HRV metrics were found to be calculated from 24- hour Holter recordings and were lower in HFrEF patients with poor prognosis.

Ferric carboxymaltose reduces the burden of arrhythmic events in heart failure with reduced ejection fraction: the role of the non-invasive arrhythmic biomarkers

BackgroundTreating iron deficiency (ID) with ferric carboxymaltose (FCM) in patients with heart failure with reduced ejection fraction (HFrEF) enhances morbidity, quality of life (QoL), and exercise capacity. MethodsThis single center, prospective follow-up study aims to assess FCM's impact on arrhythmic events and non-invasive markers in HFrEF patients with cardiac implantable electronic devices (CIEDs) and ID. Symptomatic HFrEF patients with ID and CIEDs scheduled for IV FCM were followed for 12-months. Arrhythmic activity was evaluated from CIEDs and non-invasive markers from Holter recordings pre- and post-FCM. Ventricular tachycardia/ventricular fibrillation (VT/VF) episodes, non-sustained VT (nsVT), late potentials (LPs), Microvolt T-wave alternans (MTWA), heart rate variability, turbulence (HRT) QTc, and premature ventricular contractions (PVCs, number and Lown and Wolf classification) were assessed. Left ventricular EF (LVEF), global longitudinal strain (LV GLS), QoL (KCCQ, EQ-5D-5L), six-minute walking distance (6MWD), peak oxygen consumption, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels were also recorded. ResultsNinety-six patients in optimal medical treatment participated (median age 71.9 [12.3] years, 83% male). Post-FCM treatment, VT/VF (P=0.043) and nsVT (P<0.001) frequency decreased significantly. The Lown and Wolf classification improved (P=0.002) and predicted VT/VF episodes better than other markers (AUC 0.737, P=.001). MTWA, LPs and HRT improved statistically significantly post-FCM. Hospitalization rates and NT-proBNP levels decreased, while LVEF, LV GLS, 6MWD, QoL and peak VO2 improved statistically significantly (P<0.001). ConclusionsOur study provides real-world evidence that IV FCM led to statistically significant reduction in ventricular arrhythmic episodes, as well as an improvement in non-invasive arrhythmic markers.

The Distribution of Left Ventricular Ejection Fraction, Characteristics, and Clinical Outcomes of Patients with Newly Diagnosed Heart Failure in Taiwan.

Data regarding the distribution of left ventricular ejection fraction among patients with newly diagnosed heart failure (HF) and the outcomes of patients with heart failure with preserved ejection fraction (HFpEF) in Taiwan are limited. Patients with newly diagnosed HF were identified from a multi-institutional database between 2016 and 2020. Outcomes were compared between patients with HFpEF and heart failure with reduced ejection fraction (HFrEF) after propensity score matching (PSM). Of 7,736 newly diagnosed HF patients, 4,393 (56.8%) had HFpEF and 1,977 (25.6%) had HFrEF. The HFpEF group was older (71.5 vs. 64.2 years) and more likely to be female (48.9% vs. 31.1%). Comorbidities were more common in the HFpEF patients. Median follow-up was 2.1 years. Prior to PSM, the HFpEF patients had higher all-cause mortality risk [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.11-1.33] but lower cardiovascular (CV) death risk (HR 0.84, 95% CI 0.72-0.97) compared to those with HFrEF. The HFpEF group had a trend of higher overall hospitalization risk (HR 1.06, 95% CI 0.99-1.14), but lower HF hospitalization risk (HR 0.61, 95% CI 0.55- 0.67). After PSM, all-cause mortality and overall hospitalization were comparable. The HFpEF group had lower rates of CV death (HR 0.82, 95% CI 0.68-1.0) and HF hospitalization (HR 0.60, 95% CI 0.53-0.69) compared to the HFrEF group. Among patients with newly diagnosed HF, HFpEF is the predominant phenotype, characterized by older age, higher female prevalence, and increased comorbidities. After adjusting for these factors, all-cause death and hospitalization risks became similar between the HFpEF and HFrEF patients. The HFpEF patients had lower risks of CV death and HF hospitalization.

Temporal trends in sudden cardiac death after acute decompensation in HFrEF patients: a 13-year Japanese multicentre registry study

Abstract Background The implementation of guideline-based medical therapy (GBMT) for heart failure with reduced ejection fraction (HFrEF) has significantly contributed to reducing mortality risks. Yet, detailed analyses on temporal trends of sudden cardiac death (SCD) among these patients, especially post-discharge following acute decompensation, remain scarce. Purpose This study aimed to explore changes in the incidence of SCD over the last 13 years in patients with HFrEF discharged after acute decompensation treatment, and to identify clinical factors associated with SCD risk. Methods We analyzed 2,604 consecutive HFrEF (left ventricular ejection fraction [LVEF] ≤40%) patients enrolled in a Japanese multicentre acute heart failure (HF) registry from 2009 to 2021. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient or death due to documented or presumed cardiac arrhythmia without a clear non-cardiovascular cause. The determination of death cause (SCD, pump failure death, or other) was made by a central adjudicating committee. The Fine and Gray method was employed to analyze factors associated with SCD. The variables submitted to the model included age (≥70 years), gender, LVEF (&amp;lt;30%), ischaemic aetiology and prescription of GBMT (use of renin-angiotensin system inhibitors, β-blockers and mineralocorticoid receptor antagonist) at discharge. Results The mean age of studied patients was 70.9±14.2 years, and 70.0% were male. During the 1-year follow-up period, 262 deaths (10.1%) occurred, including 51 SCDs (2.0%). Older age was associated with an increased risk of SCD (adjusted hazard ratio [HR] 2.81, 95% confidence interval [CI] 1.40-5.64, P=0.004). Further, patients with an ischaemic aetiology had a higher risk of SCD (HR 1.84, 95% CI 1.06-3.22, P=0.032). During the study period, mean age remained constant (71.0 years to 70.7 years, P for trend =0.884). The proportion of ischaemic aetiology also remained constant (from 37.2% to 38.2%, P for trend =0.972). Overall, there were significant decreases in the incidence of all cause death and SCD (from 13.7% to 8.4%, P for trend =0.002; and from 3.5% to 1.0%, P for trend &amp;lt;0.001; Figure A). Notably, there was an increase in the prescription rate of three classes of GBMT at discharge (from 30.9% to 45.6%, P for trend &amp;lt;0.001; Figure B), and the rate of implantable cardioverter-defibrillator (ICD) use in eligible patients (New York Heart Association functional class II-III with LVEF ≤35%) remained constant (from 9.6% to 11.6%, P for trend =0.157; Figure B). Conclusions With the increasing use of GBMT, the incidence of SCD decreased in real-world patients with HFrEF registered in a Japanese acute HF registry over the past decade.

Post-prandial acyl ghrelin infusion in heart failure patients increases gastric emptying rate

Abstract Background Acyl ghrelin (ghrelin) increases cardiac output (CO) and contractility in patients with heart failure with reduced ejection fraction (HFrEF). In healthy humans, ghrelin increases gastric emptying rate (GER) and hunger, a potential add-on benefit for HFrEF patients suffering from cachexia with symptoms of delayed gastric emptying and loss of appetite. Aim Determine if post-prandial ghrelin infusion increases GER and hunger in HFrEF patients; compare to CO. Methods This study was a component of a double-blind placebo-controlled trial of acyl ghrelin vs. placebo in HFrEF. Patients (n=29) arrived fasted and received a 500 kcal breakfast and 1.5 g paracetamol. They next received placebo (vehicle, n=15) or ghrelin infusion (0.1 µg/kg/min, n=14) for 120 min. Blood was tapped for plasma at 0, 30, 60, 120 and 150 min into the meal. Plasma concentration of paracetamol was measured to assess GER of a liquid bolus. Hunger scores and CO were recorded. Mann-Whitney rank sum test was used for statistics. Results Paracetamol peaked at 30 min in 8 of 14 (57%) in the ghrelin treatment group versus 1 of 15 (7%) in the placebo group (P=0.004, Fig 1). Remaining patients peaked at later time points. There were no anomalous peaks at 0 min baseline or 2880 min (2 days). The ghrelin treatment group data was segregated into rapid (peak at 30 min, n=8) and slow (peak &amp;gt;30 min, n=6) GER subgroups. The rapid subgroup had a ghrelin treatment effect on CO (one-way repeat measures) (P&amp;lt;0.001, Fig 2). Baseline (t=0) CO for the rapid GER subgroup was 4.06 ±1.41 L/min (median ±SD) and 3.95 ±0.62 L/min for the slow GER subgroup (P=0.31). Data points shown are median ± SEM, each patient normalized to own baseline (100%); * P&amp;lt;0.05, ** P&amp;lt;0.01, *** P&amp;lt;0.001, pairwise comparison to baseline. Hunger gradually increased. The greatest increase in hunger was at 150 min, at which time median fold increase in hunger relative baseline was 1.6 (placebo), 1.7 (ghrelin, slow GER) and 2.3 (ghrelin, rapid GER). These hunger differences between groups did not reach significance. However, this trend was consistent with ghrelin induction of hunger, especially in those with potent GER and CO responses. Conclusions Ghrelin increases GER, and potentially hunger, in HFrEF patients in addition to increasing CO. Some HFrEF patients may benefit from this add-on effect.Fig 1.Time of paracetamol peak.Fig 2.Cardiac output.

Electrical heart failure treatment in the Goldilocks zone: cardiac contractility modulation proves equally effective for heart failure control in HFrEF patients with mid-range QRS durations

Abstract Background Current guidelines recommend a four pillar therapy for heart failure with reduced ejection fraction (HFrEF). A subgroup of patients, namely those with a QRS duration (QRSd) ≥150 ms, may also qualify for cardiac resynchronization therapy. However, a 30% CRT non-responder rate persists, with patients with narrower QRSd (i.e., QRSd &amp;lt;150 ms) and non-left bundle branch block receiving less benefit. At present, cardiac contractility modulation (CCM) has only been established in patients with QRSd &amp;lt;120 ms. Given these limitations, new options for additional device therapy are urgently sought for those patients who face drug-refractory HFrEF and with intermediate QRSd of 120-149 ms. Purpose Primarily to evaluate the impact of CCM on HF-related hospitalizations and secondarily on left ventricular EF (LVEF) as well as quality of life (by Minnesota Living with Heart Failure Questionnaire (MLWHF) score and New York Heart Association (NYHA) class) in a real-world population of HFrEF patients with QRSd 120-149 ms, compared to QRSd &amp;lt;120 ms. Methods CCM-REG enrolled 503 HF patients receiving CCM with a follow-up of up to 2 yrs. HF-related hospitalization rates were available for 1 yr pre-implant. Safety was assessed by comparison of actual versus MAGGIC score predicted mortality. Results 455 patients were studied for these analyses. Among 111 subjects with QRSd 120-149 ms (mean QRSd 130±8 ms, age 68±10 yrs, 20% female, LVEF 29±9%, 82% NYHA class III), CCM diminished HF-related hospitalization rate by 72% (pre- vs. post-implant 0.90 vs. 0.25 events/per patient-yr over 2 yrs; p&amp;lt;0.001; Figure). LVEF improved by 7±8% (p=0.01 vs. baseline), MLWHFQ score by 10±23 pts (p=0.01 vs. baseline), and NYHA class by 0.5±0.7 classes (&amp;lt;0.001 vs. baseline). The effect size was similar to that in the QRSd &amp;lt;120 ms patients. Mortality within first year was 19% in QRSd 120-149 ms patients and thus not significantly different from the MAGGIC score prediction. Conclusions CCM significantly improved HF control in symptomatic HFrEF patients with moderately prolonged QRSd 120-149 ms. The effect was similar to patients with QRSd &amp;lt;120ms.Reduction in hospitalization rates

The role of fibrosis and inflammation for response and outcome prediction in candidates to cardiac resynchronization therapy: is response the right answer?

Abstract Background Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Purpose Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Methods 86 consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. An echocardiographic reduction of LV end-systolic volume ≥15% was used to define a patient as responder to CRT. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Results 44% of patients experienced the primary outcome. the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 38.5 ng/ml, AUC: 0.63, p=0.03, (OR 7.13 [1.12;45.41], p=0.03), together with TAPSE&amp;gt;17.5 mm (OR 10.86 [3.15;37.44], p&amp;lt;0.001) significantly correlated with the structural response to CRT in several prediction models. Baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p&amp;lt;0.001, HR 8.33 (1.88–33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p&amp;lt;0.001, HR 333 (250–1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood (Table). At Kaplan-Meyer curve patients with both high baseline sST2 and Gal-3 had the lowest survival probability (Figure). Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08–1.22), p &amp;lt; 0.001; HR: 0.84 (0.74–0.91), p = 0.04; HR: 1.26 (1.10–1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. Conclusion In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

Independent risk factors of ejection fraction deterioration post discharge in hospitalized heart failure patients with mildly reduced ejection fraction

Abstract Background The identification of independent risk factors for left ventricular ejection fraction (LVEF) deterioration is of clinical importance in patients diagnosed heart failure with mildly reduced ejection fraction (HFmrEF). This study aimed to determine the independent risk factors of LVEF deterioration post discharge among hospitalized HFmrEF patients. Methods This retrospective study analyzed data from 807 HFmrEF patients admitted to our hospital between January 2015 and August 2020. LVEF values were assessed by echocardiography between 6 months and 1 year after discharge. Patients were followed up to a mean of 33 months. The primary endpoint was disease progression expressed as heart failure with reduced ejection fraction (HFrEF) between 6 months and 1 year post discharge. The secondary endpoint was all-cause death. Multivariate logistic regression analysis was conducted to identify independent risk factors associated with LVEF deterioration. Results There were 225 patients progressed to HFrEF between 6 months and 1 year post discharge. All-cause death was significantly higher in HFrEF patients (43%) compared to patients with stable LVEF (unchanged or improved, 24%, P&amp;lt;0.001). Multivariate logistic regression analysis showed that the independent risk factors associated with worsening LVEF in patients with HFmrEF were: female (OR=1.71, 95% CI 1.14 to 2.57, P=0.009), higher NT-proBNP (≥2312 pg/ml, OR=1.71, 95% CI 1.14 to 2.57, P=0.010), higher uric acid (≥318 µmol/L, OR=11.63, 95% CI 7.89 to 17.15, P&amp;lt;0.001), and larger end-diastolic left ventricular dimension (OR=1.05, 95% CI 1.02 to 1.08, P&amp;lt;0.001). Conclusion Results of this study might help risk stratification to identify hospitalized HFmrEF patients with increased risk of progression to HFrEF post discharge. Patients with above clinical features should undergo more intensively monitoring and enhance care adherence to HF guideline medications. Future studies are needed to validate if tailored guideline adherence management strategies for post-discharged HFmrEF patients based on personalized risk stratification could mitigate LVEF progression and improve survival of these patients.