Heart Failure With Reduced Ejection Fraction Patients Research Articles

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.

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.

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.

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.

Impact of various iron deficiency definitions on mortality risk in chronic heart failure across the spectrum of left ventricular ejection fraction spectrum

Abstract Introduction Iron deficiency (ID) is prevalent in chronic heart failure (HF) but lacks a consensus definition. Purpose This study evaluates the prevalence of ID and its association with all-cause mortality and first hospitalization for HF, using current European Society of Cardiology (ESC) guidelines, transferrin saturation (TSAT) &amp;lt;20%, ferritin &amp;lt;100 ng/ml, and serum iron ≤13 μmol/L as ID criteria. Methods and Results Of 8587 new-onset HF patients registered in the Danish Heart Failure Registry from April 2003 to July 2021, we found varying ID prevalence (35.4% to 67%) based on different definitions. In heart failure with reduced ejection fraction (HFrEF) patients, irrespective of anemia, ID defined by TSAT &amp;lt;20% and serum iron ≤13 μmol/L was associated with all-cause mortality (non-anemic, HR: 1.42, 95% CI:1.22-1.64 and HR: 1.25, 95% CI: 1.1-1.43; anemic, HR: 1.22, 95% CI: 1.1-1.35 and HR: 1.26, 95% CI: 1.12-1.41, respectively) and first HF hospitalization (non-anemic, HR:1.41, 95% CI:1.23-1.62, HR: 1.33, 95% CI: 1.18-1.51; anemic, HR:1.27, 95% CI:1.12-1.45 and HR: 1.26, 95% CI:1.09-1.45, respectively). ID per ESC guidelines was only associated to mortality in non-anemic HFrEF (HR: 1.24, 95% CI:1.09-1.42) and first HF hospitalization in HFrEF, irrespective of anemia (non- anemic, HR:1.24, 95% CI:1.09-1.42; anemic, HR:1.35, 95% CI:1.2-1.52). No association was observed between the various definitions and outcomes in patients with heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction. Conclusion ID, when defined by TSAT &amp;lt;20% or serum iron ≤13 μmol/L, is associated with increased mortality and first hospitalization in HFrEF patients, regardless of anemia. Conversely, ID as per ESC guidelines is associated with mortality in non-anemic HFrEF patients and first hospitalization in HFrEF, irrespective of anemia status.Figure 1:Forest plot mortalityFigure 2:Forest plot hospitalization

Machine learning identification of risk factors for ischaemic stroke in patients with heart failure with reduced ejection fraction but without atrial fibrillation: A report from WARCEF trial

Abstract Background The prediction of ischaemic stroke in patients with heart failure with reduced ejection fraction (HFrEF) but without atrial fibrillation (AF) remains challenging and risk stratification based clinical factors alone has limited discrimination. Our aim was to evaluate the performance of machine learning (ML) to identify risk factors for ischaemic stroke in such HFrEF patients. Methods We performed a post-hoc analysis of the WARCEF trial, only including patients without prior history of AF, and censoring those who developed incident AF during follow-up. We evaluated the performance of 9 ML models to identify risk factors for incident stroke, using metrics including area under the curve (AUC), precision, specificity, and decision curve analysis. The importance of each feature in constructing the model was quantified using SHapley Additive exPlanations (SHAP) values. Results We included 2,213 patients with HFrEF but without AF (mean age 59±12 years; 79% male). Of these, 74 (3.3%) had an ischaemic stroke during mean follow-up of 3.5±1.8 years. Out of the 29 patient-demographics variables, 12 were selected for the ML training. All ML models demonstrated high AUC values, outperforming the CHA2DS2-VASc score (Figure 1). The logistic regression model exhibited a slight deviation from this trend. The XGBoost model achieved an AUC of 0.86 (95% confidence interval [CI]: 0.72-0.99), while the Random Forest model showed an AUC of 0.85 (95% CI: 0.74-0.96). Similarly, the Support Vector Machine and Light Gradient Boosting Machine models recorded AUCs of 0.85 (95% CI: 0.72-0.97) and 0.83 (95% CI: 0.70-0.96), respectively. Each of these models attained precision and specificity scores of 1.0, indicating high performance. These models consistently provided significant net clinical benefits. Key risk factors for stroke identified across these models were creatinine clearance and blood urea nitrogen. The use of warfarin appears to be protective. Conclusions Machine-learning models can identify risk factors for ischaemic stroke in patients with HFrEF but without AF. Worsening renal failure was predictive of an incident stroke, while warfarin use was protective against stroke (Figure 2).Figure 1Figure 2

SGLT2 inhibitors are associated with development of heart failure with improved ejection fraction

Abstract Background Heart failure (HF) with improved ejection fraction (EF), termed HFimpEF, has been proposed as a new HF classification associated with better clinical outcomes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce cardiovascular death and hospitalization for HF irrespective of diabetes. Purpose Analyze the effect of SGLT2 inhibitors on the development of HFimpEF. Methods Consecutive HF with reduced EF (HFrEF) patients with follow-up echocardiogram at around 12 months were enrolled from 2017 to 2022. Patients were classified into HFimpEF (follow-up EF &amp;gt; 40% and ≥ 10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. A 1:2 propensity score matched analysis was performed. Results Of all the HFrEF patients in the cohort, 46.6% of patients developed HFimpEF. We matched 93 and 186 patients treated with or without SGLT2 inhibitors according to propensity score. In the matched cohort, treatment with SGLT2 inhibitors was associated with nearly a doubled likelihood of the development of HFimpEF (OR: 1.978 [95% CI 1.184~3.346]). Subgroup analysis revealed this association was only present in HF patients with an ischemic etiology (OR: 3.427 [95% CI 1.614~7.573], P for interaction=0.022). There was no significant interaction term between SGLT2 inhibitors and the presence of diabetes for the development of HFimpEF. Conclusions This study reveals that treatment with SGLT2 inhibitors is associated with increased likelihood of HFimpEF, especially in those with an ischemic etiology.

The development and long-term maintenance of heart failure with improved ejection fraction after a heart failure hospitalization: how are mortality rates affected?

Abstract Background According to the current ESC HF Guidelines (GLs), the implementation of the guideline-directed medical therapy (GDMT) is of strategic importance in heart failure (HF) with reduced ejection fraction (HFrEF). In the effect of the successful implementation of the modern GDMT, significant improvement in terms of the left ventricular ejection fraction (LVEF) might be expected in HFrEF. Hence, a new HF category, the improved ejection fraction (HFimpEF), was introduced in the current ESC HF GLs, which has come to the spotlight in the recent years. However, its course and long-term prognosis are still not clearly understood. Aim To assess the development and long-term maintenance of the HFimpEF category among a consecutive patient cohort requiring hospitalization due to HFrEF, evaluate its effect on prognosis, and examine the independent predictors of its development. Patients and methods A retrospective analysis was carried in a real-world cohort of 270 HFrEF patients (male: 77%, age: 61[49-68]years, coronary artery disease: 47%, diabetes: 30%, hypertension: 60%, atrial fibrillation: 35%, LVEF: 25[20-30]%, eGFR at admission: 59[45-73]mL/min/1.73m², NT-proBNP at admission: 4733[2368-9711]pg/mL, SBP: 120[107-135]mmHg) hospitalized for HF in 2019-2023 at two tertiary cardiac centers. At admission the complex modern GDMT of HFrEF had been already introduced (RASi[ACEi/ARB/ARNI]: 61%, βB: 63%, MRA: 47%, SGLT2i: 6%) in the minority of the cohort. The improvement to the HFimpEF category was examined after the therapy optimization (OMT). All-cause mortality (ACM) rates were evaluated with Kaplan-Meier method and the predictors of the development to HFimpEF category were assessed with logistic regression analysis. Results In the total cohort at discharge, a high proportion of patients received RASis (94%), βBs (90%), MRAs (97%), and SGLT2is (35%). 79 patients (29%) evolved to the HFimpEF category after OMT. During the median 810 [456-1161] days of follow-up (FU), HFimpEF patients had lower, but unquestionably still increased mortality rates (29% vs. 10%, p=0.001; non-HFimpEF vs. HFimpEF patients). At two years of the FU period, based on the available echocardiographies, 98 % of the patients remained in the HFimpEF category. After performing a multivariate logistic regression analysis, the severity of the LV systolic dysfunction (LVSD) and the „de novo" diagnosis of HFrEF proved to be independent predictors of the development of the HFimpEF category. Conclusions In the effect of the implementation of GDMT, a significant proportion (29%) of our multimorbid, hospitalized HFrEF patient cohort improved to the HFimpEF category. The predictors of its development were the severity of the LVSD and "de novo" HFrEF diagnosis. During the FU period, most of the HFimpEF patients remained in this category. However, their persistently elevated mortality rates raise the awareness of the importance of the conscious application and maintenance of GDMT.

Role of the alarmin S100A9 in the pathogenesis of heart failure with preserved ejection fraction

Abstract Background A systemic low-grade inflammation induced by comorbidities is recognized to underlie heart failure (HF) with preserved ejection fraction (HFpEF)-specific remodelling. Recent evidence states that the innate immunity member S100A9, which is mainly present as the heterodimer S100A8/9, is an important contributor of sterile inflammation in the comorbidities of HFpEF, with adipose tissue being an important source. Though, its specific involvement in HFpEF has not been explored so far. Purpose The present study aimed to unravel the role of S100A9 in the pathogenesis of HFpEF via the two-hit HFpEF mouse model, S100A8/9 stimulation on murine left ventricle (LV) and C4 fibroblasts (Fb) and gene expression analysis of endomyocardial biopsy (EMB)-derived Fb from HFpEF and HF with reduced ejection fraction (HFrEF) patients. Methods Wild type (WT) C57BL/6JN or S100A9 knock-out (ko) mice were exposed to a high-fat diet (HFD) and L-NAME (1 g/L in drinking water) over 15 weeks. Controls received standard diet. LV function was characterized via conductance catheter measurements. At the day of sacrifice, the LV, spleen, blood, and adipose tissue were collected for subsequent analyses. In vitro, murine LV-derived Fb and C4 Fb were stimulated with the heterodimer S100A8/9. EMB-Fb from HFpEF and HFrEF patients were screened for S100A9 and downstream components of the NLRP3 inflammasome. Results WT HFD+L-NAME mice exhibited a preserved EF, combined with a reduced LV relaxation (dP/dtmin; p&amp;lt;0.01), elevated LV relaxation time (Tau; p&amp;lt;0.05), and impaired LV contractility (dP/dtmax; p&amp;lt;0.05), in parallel to a low-grade systemic inflammation evident by increased C-reactive protein levels. S100A9+, CD68+ and Ly6G+ cells, and CD68+ and Ly6G+ cells expressing S100A9 were increased in the LV, spleen and adipose tissue of WT HFD+L-NAME mice compared to WT mice on chow diet. Changes in LV function were less pronounced in S100A9ko HFD+L-NAME mice, which were characterized by lower systemic C-reactive protein levels, and lower presence of CD68+ and Ly6G+ cells in the LV, spleen and adipose tissue versus WT HFD+L-NAME mice, in the absence of S100A9. Moreover, S100A9ko HFD+L-NAME exhibited lower expression of pro-inflammatory and fibrosis-related genes versus WT HFD+L-NAME mice. Stimulation of murine LV-Fb and C4 Fb with S100A8/A9 increased the mRNA expression of the pro-inflammatory chemokines chemokine (C-C motif) ligand (CCL) 2 and CCL7, and the % of NLRP3-, ASC-, caspase 1-, and IL-1ß-expressing cells, respectively. Finally, mRNA expression of S100A9 and components of the NLRP3 inflammasome was higher in EMB-Fb of HFpEF versus HFrEF patients. Conclusion These data support that adipose tissue is an extra-cardiac source of S100A9 contributing to systemic low-grade inflammation. S100A8/9 in the heart can boost the inflammatory potential of cardiac fibroblasts, further supporting the pro-inflammatory role of S100A9 in the pathogenesis of HFpEF development.

Quality of life in patients with heart failure and improved ejection fraction: one-year follow-up with ARNI and SGLT2i

Abstract Introduction A baseline Heart Failure (HF) with reduced Ejection fraction (HFrEF) &amp;lt;=40% that improved for &amp;gt;=10 points and a second measured left ventricle ejection fraction (LVEF) &amp;gt;40%, can be considered as HF with improved ejection fraction (HFimpEF). The novel therapy for HFrEF and HFimpEF are sacubitril/valsartan (ARNI- angiotensin receptor/neprilysin inhibitor) and Sodium-glucose cotransporter-2 inhibitors (SGLT2i). Purpose Our study aimed to evaluate ARNI and SGLT2i therapy on the health status of HFrEF patients, as well as the prognostic impact of HFimpEF in terms of quality of life and outcomes (mortality and rehospitalization due to HF) during a one-year follow-up. Methods In this prospective study, we included 376 hospitalized HFrEF patients, in whom ARNI and SGLT2i were initiated into regular therapy. A 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) was performed at discharge and after one year. The primary prognostic endpoints were all-cause mortality and HF rehospitalization. Results Initially, about two-thirds of the study population were men (71%), mean age of 61.0±11.5 years, mean LVEF 27.5±5.2 % and mean KCCQ overall summary (KCCQ-OS) score of 48.5±12.5, while quality of life KCCQ-QoL 37.4±10.2. After one year LVEF was increased by 35.6±7.1 %. The total number of 143 patients (38%) met the criteria for HFimpEF, with the improvement of mean LVEF (45.2±8.6 %., p&amp;lt;0.001). Overall, HFimpEF patients experienced an average 5.3 ± 18.6-point improvement in the KCCQ-OS compared with 2.5 ± 17.4 points for non-HFimpEF group (differences in mean changes of 2.9 [95% CI: 1.4 to 4.7). This is largely due to improvements in the domain of KCCQ-QoL (5.8 ± 29.7 points vs. 2.9 ± 22.2 points, respectively). During one year of follow-up, combined SGLT2i + ARNI therapy was represented statistically significantly more in HFimpEF compared to the non-HFimpEF group (86% vs. 34%, p&amp;lt;0.0005), where 45% took only one medicine and 21% none. The HFimpEF group had a significantly better outcome in terms of all-cause mortality (2.8% vs. 18.9%, p&amp;lt;0.005) and HF rehospitalization (3.5% vs. 40%, p&amp;lt;0.0001). The one-year KCCQ-12 was independently associated with outcomes; the hazard ratio for the integrated endpoints (mortality and HF rehospitalization) was 1.08 (95% CI: 1.05–1.11, p = 0.005). Conclusions In routine clinical practice, initiation of the ARNI and SGLT2i therapy was associated with significant improvements in the health status of HFrEF patients, but also change to HFimpEF. The one-year quality of life in patients with heart failure and improved ejection fraction was superior to baseline and compared to the non-HFimpEF group. HFimpEF was associated with a better outcome. All HF patients should undergo KCCQ-12 because it is an independent predictor of outcome.

Baroreflex activation therapy in heart failure patients with reduced ejection fraction: a long-term follow up

Abstract Introduction Heart failure with reduced ejection fraction (HFrEF) is a major public health concern with substantial morbidity and mortality. Overactivation of the sympathetic nervous system is a key pathophysiological process driving heart failure progression. Baroreceptor activation therapy (BAT) targets this autonomic imbalance and is a promising treatment strategy for patients with HFrEF. Current short-term studies indicate that BAT provides symptomatic relief, improvement in left ventricular function and cardiac biomarkers. However, data regarding the long-term effect of BAT on HFrEF are scarce. Purpose This study aims to assess long-term outcome in HFrEF patients who underwent BAT. Methods Patients with HFrEF who received BAT between 2014-2023 were followed until latest available follow-up. Symptom burden, echocardiography and laboratory testing were assessed before BAT implantation and in subsequent follow ups. Results 23 patients (mean age 66±10 years, 83% men) with HFrEF were included in the study. Etiology of heart failure was ischemic in 70%. The majority of patients (96%) suffered from NYHA III with a mean left ventricular ejection fraction (LVEF) of 23±8% and NTproBNP of 2463±2922pg/ml. Complication occurred in one patient during BAT implantation (4%). Mean follow-up was 3±2 (max. 7.5) years. BAT reduced NYHA classification in 12 patients (52%) after 1 year, of which 1 patient remained in ameliorated NYHA for 7.5 years. Evolution of NYHA functional class over time is shown in Figure 1. Echocardiographic evaluation revealed significant improvement in LVEF of 9±9% after 1 year (p&amp;lt;0.001) and by 11±9% after 2 years (p=0.005). In long-term a trend towards improved LVEF could be observed (Figure 2). In addition, BAT mildly reduced NTproBNP in the first 2 years (after 1 year non-significantly by -396±1006pg/ml and significantly after 2 years by -566±651pg/ml (p=0.039)). Seven patients reaching recommended replacement time underwent device exchange. Four patients deceased during observation time. Conclusion BAT resulted in a substantial reduction in NYHA classification, improvement in LVEF, and a delayed reduction in NTproBNP levels. These findings highlight the long-term efficacy and potential benefits of BAT as a therapeutic intervention for patients with HFrEF.Sankey plot of NYHA class over timeAlteration of LVEF over time