Heart Failure And Reduced Ejection Fraction Patients Research Articles

ENHANCING FUNCTIONAL CAPACITY AND QUALITY OF LIFE WITH ECCENTRIC CYCLING TRAINING IN HEART FAILURE PATIENTS: A RANDOMIZED CONTROLLED TRIAL

INTRODUCTION Exercise training is recommended for comprehensive management of patients with heart failure and reduced ejection fraction (HFrEF). However, limited exercise capacity prevents many patients from gaining optimal training benefit. Given eccentric cycling is well tolerated in HFrEF, and enables greater power output, we hypothesized that eccentric cycling training would result in superior functional outcomes than concentric cycling training when the interventions were matched for heart rate (HR). METHODS Forty-five participants (9♀, 57±13 y; BMI 27±5 kg/m2) with HFrEF (ejection fraction 33±10%, New York Heart Association class II) were randomized in a 1:1 superiority clinical trial to either eccentric cycling training (ET, n = 25) or concentric cycling training (CT, n = 20). Each intervention involved 2-weeks of familiarization and 12-weeks of training at matched relative intensity (40-80% of HR reserve), twice weekly. Primary outcome was peak oxygen consumption (V̇O2peak), secondary outcomes included 6-minute walk, functional lower extremity strength and health-related quality of life (Minnesota Living with Heart Failure, MLHF). RESULTS Repeated measures ANOVA revealed significant interaction effects for 6-min walk (ET 476±77 to 547±80 m vs CT 485±106 to 516±113 m, P=0.015), 30s sit-to-stand (ET 12±3 to 16±3 repetitions vs CT 13±4 to 14±3 repetitions, P=0.002), and timed up-and-go (ET 7.2±1.2 to 6.2±1.1 s vs CT 7.6±1.5 to 7.3±1.9 s, P=0.019). There were significant time effects for V̇O2peak (ET: 17.7±4.8 to 19.1±5.2 ml/kg/min and CT 17.4±6.0 to 19.8±6.0 ml/kg/min, P<0.001), and MLWHF (ET 31±24 to 23±16 and CT 32±19 to 27±16, P=0.003). CONCLUSION When matched for heart rate to control cardiovascular burden, ET demonstrated superior effect in functional capacity, and similar benefits in aerobic capacity (V̇O2peak) and health-related quality of life, when compared to CT. ET is a novel and efficacious approach for clinical benefit in highly compromised HFrEF patients, who represent a challenge in terms of exercise prescription.

How to Manage Beta-Blockade in Older Heart Failure Patients: A Scoping Review.

Beta blockers (BBs) play a crucial role in enhancing the quality of life and extending the survival of patients with heart failure and reduced ejection fraction (HFrEF). Initiating the therapy at low doses and gradually titrating the dose upwards is recommended to ensure therapeutic efficacy while mitigating potential adverse effects. Vigilant monitoring for signs of drug intolerance is necessary, with dose adjustments as required. The management of older HF patients requires a case-centered approach, taking into account individual comorbidities, functional status, and frailty. Older adults, however, are often underrepresented in randomized clinical trials, leading to some uncertainty in management strategies as patients with HF in clinical practice are older than those enrolled in trials. The present article performs a scoping review of the past 25 years of published literature on BBs in older HF patients, focusing on age, outcomes, and tolerability. Twelve studies (eight randomized-controlled and four observational) encompassing 26,426 patients were reviewed. The results indicate that BBs represent a viable treatment for older HFrEF patients, offering benefits in symptom management, cardiac function, and overall outcomes. Their role in HF with preserved EF, however, remains uncertain. Further research is warranted to refine treatment strategies and address specific aspects in older adults, including proper dosing, therapeutic adherence, and tolerability.

Unraveling the Predictors for Delirium and ICU Stay Duration in Patients with Heart Failure and Reduced Ejection Fraction (HFrEF) Undergoing Coronary Artery Bypass Grafting-A Multicentric Analysis.

Objective: This study assesses predictors for postoperative delirium (POD) and ICU stay durations in HFrEF patients undergoing CABG, focusing on ONCAB versus OPCAB surgical methods. Summary Background Data: In cardiac surgery, especially CABG, POD significantly impacts patient recovery and healthcare resource utilization. With varying incidences based on surgical techniques, this study provides an in-depth analysis of POD in the context of HFrEF patients, a group particularly susceptible to this complication. Methods: A retrospective analysis of 572 patients who underwent isolated CABG surgery with a preoperative ejection fraction under 40% was conducted at four German university hospitals. Patients were categorized into ONCAB and OPCAB groups for comparative analysis. Results: Age and Euro Score II were significant predictors of POD. The ONCAB group showed higher incidences of re-sternotomy (OR: 3.37), ECLS requirement (OR: 2.29), and AKI (OR: 1.49), whereas OPCAB was associated with a lower incidence of delirium. Statistical analysis indicated a significant difference in ICU stay durations between the two groups, influenced by surgical complexity and postoperative complications. Conclusions: This study underscores the importance of surgical technique in determining postoperative outcomes in HFrEF patients undergoing CABG. OPCAB may offer advantages in reducing POD incidence. These findings suggest the need for tailored surgical decisions and comprehensive care strategies to enhance patient recovery and optimize healthcare resources.

Electrocardiographic predictors of response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction

BackgroundSacubitril/valsartan (SV) is currently recommended as a first-line therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to its significant clinical and prognostic benefit; however, not all patients respond to therapy and predictors of clinical response to SV remain under-studied. AimsTo identify electrocardiographic (ECG) predictors of response to SV therapy in HFrEF patients. MethodsA retrospective analysis of a hospital heart failure registry was undertaken. Consecutive HFrEF patients (New York Heart Association class II–III) on maximal-dose SV were studied. Response to SV was defined as ≥10% relative improvement in left ventricular ejection fraction (LVEF) at 3-months post-maximal-dose therapy. Pre-therapy ECGs were retrospectively analyzed for axes and standard wave and interval durations. Logistic regression was used to estimate odds ratios and 95% confidence intervals for associations between predictors and therapeutic response. Backward stepwise regression was employed to develop a parsimonious model. ResultsP-wave duration (PWD) 100–120 ms, PWD >120 ms, and QTc >460 ms were associated with response to SV on univariate analysis: OR 18.00 (4.45–122.90), 5.00 (1.47–20.42), and 3.10 (1.18–9.22), respectively. The preferred model that included the former two predictors in combination with pre-therapy creatinine, mineralocorticoid receptor antagonist use, and LVEF was highly selective (area under the ROC curve = 0.868). ConclusionsProlongation of both PWD and QTc interval on baseline ECG in HFrEF patients is predictive of therapeutic response to maximal-dose SV therapy and may indicate early cardiac remodeling that is highly amenable to reversal.

Educational status affects prognosis of patients with heart failure with reduced ejection fraction: A post-hoc analysis from the WARCEF trial.

The influence of social determinants of health (SDOH) on the prognosis of Heart Failure and reduced Ejection Fraction (HFrEF) is increasingly reported. We aim to evaluate the contribution of educational status on outcomes in patients with HFrEF. We used data from the WARCEF trial, which randomized HFrEF patients with sinus rhythm to receive Warfarin or Aspirin; educational status of patients enrolled was collected at baseline. We defined three levels of education: low, medium and high level, according to the highest qualification achieved or highest school grade attended. We analysed the impact of the educational status on the risk of the primary composite outcome of all-cause death, ischemic stroke (IS) and intracerebral haemorrhage (ICH); components of the primary outcome were also analysed as secondary outcomes. 2295 patients were included in this analysis; of these, 992 (43.2%) had a low educational level, 947 (41.3%) had a medium education level and the remaining 356 (15.5%) showed a high educational level. Compared to patients with high educational level, those with low educational status showed a high risk of the primary composite outcome (adjusted hazard ratio [aHR]: 1.31, 95% confidence intervals [CI] 1.02-1.69); a non-statistically significant association was observed in those with medium educational level (aHR: 1.20, 95%CI: .93-1.55). Similar results were observed for all-cause death, while no statistically significant differences were observed for IS or ICH. Compared to patients with high educational levels, those with low educational status had worse prognosis. SDOH should be considered in patients with HFrEF. NCT00041938.

The effect of iron deficiency treatment with intravenous ferric carboxymaltose on the arrhythmic burden of patients with HFrEF and cardiac implantable electronic devices

Abstract Background The deleterious effect of iron deficiency (ID) on cardiomyocyte electrochemical stability is well-documented. In patients with heart failure and reduced ejection fraction (HFrEF), ID represents a key comorbidity associated with increased morbidity and mortality. Thus, it has been hypothesized that treating ID may lead to reduced incidence of arrhythmias in HFrEF patients. Purpose To study the effect of intravenous ferric carboxymaltose (IV FCM) treatment on the iron stores, arrhythmic burden, functional capacity and quality of life in HFrEF patients with ID and cardiac implantable electronic devices (CIEDs). Methods Patients with HFrEF, ID and CIEDs scheduled to receive IV FCM as per ESC guidelines were invited to participate. Follow-up lasted 12 months. The primary outcome was related to the amelioration of patients’ iron status. Secondary outcomes relative to arrhythmic burden included (i) the incidence of device-detected ventricular tachycardias (VTs) between the year before recruitment to the study and the follow-up period, (ii) patients’ Lown and Wolf classification as derived from 24hour Holter monitoring. Data related to non-invasive arrhythmic markers such as late potential, microvolt T-wave alternans and deceleration capacity were also available. Results This real-life cohort included 79 patients (84% male). Patients’ median age was 70.8 [IRQ:11.7] years. Median ferritin increased to 150 [125] ng/mL at 12 months (baseline 55 [68] ng/mL, P<0.001). At their final visit, 45 (57%) patients no longer met the ESC criteria for iron deficiency (P<0.001). The CIED-derived incidence of VT episodes decreased significantly after 12 months of IV FCM treatment (0.26±0.83 episodes per patient per year compared to 0.8±2.36, P = 0.048). Patients were also significantly likely to shift to a more favorable Lown and Wolf arrhythmic burden classification (P = 0.01). Patients’ late potential results and microvolt T-wave alternans also improved significantly (P = 0.01 for both tests). Conclusion The results of this real-life cohort analysis suggest significant reduction of the arrhythmic burden in HFrEF and ID after restitution of iron stores. Further studies are needed to further evaluate the impact of these results.

The effect of empagliflozin on ketone bodies in patients with heart failure with reduced ejection fraction (Empire HF)

Abstract Background The thrifty-substrate hypothesis suggests that Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors increase plasma levels of ketone bodies and create a salutary switch in myocardial fuel metabolism. Purpose We investigated the effect of SGLT2 inhibitor on plasma beta-hydroxybutyrate in patients with heart failure and reduced ejection fraction (HFrEF). Method This is a post hoc analysis of the Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction (Empire HF) trial, an investigator-initiated, double-blind, randomized, placebo-controlled trial which enrolled 190 stable HFrEF patients with a left ventricular ejection fraction (LVEF) of ≤40%. Patients were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo. Analyses were performed in patients with complete data using a linear-mixed effect-model with log-transformed beta-hydroxybutyrate, adjusted for baseline beta-hydroxybutyrate value, age, sex, and type 2 diabetes. Results A total of 188 (99%) patients had available data. The groups were well-matched with respect to baseline characteristics. Mean age was 64 (SD, 11) years; LVEF was 29 (SD, 8) %, 13% had type 2 diabetes, New York Heart Association (NYHA) class II was found in 78%. Median plasma levels of beta-hydroxybutyrate were 0.10 (inter quartile range (IQR) 0.05–0.18) mmol/l at baseline, and 0.11(IQR 0.07–0.2) mmol/l at follow-up in the empagliflozin group. In the placebo group, baseline and at follow-up concentrations were 0.10 (0.06–0.17) mmol/l and 0.09 (0.05–0.15) mmol/l, respectively. Empagliflozin increased plasma levels of beta-hydroxybutyrate compared to placebo (adjusted between-groups treatment effect; Ratio of change 1.45 [95%confidence interval (CI); 1.12–1.87], p = 0.005 (Figure 1). The effect of empagliflozin on beta-hydroxybutyrate outcomes was consistent across multiple subgroups analyses including baseline median age, sex, N-terminal-pro B-type natriuretic peptide (NT-proBNP) cut-off 600 pg/mL, treatment with sacubitril–valsartan or beta-blockers, measured glomerular filtration rate (GFR) level, hemoglobin A1c (HbA1c) level, and concomitant type 2 diabetes (all P interaction>0.05). Conclusion In patients with HFrEF, predominantly without diabetes, short-term treatment with empagliflozin increased the levels of beta-hydroxybutyrate. The absolute changes were modest and the exact contribution of ketone bodies to the cardiovascular benefits of SGLT2 inhibitors requires further clarification.Figure 1Table 1

Abstract 14478: Electrocardiographic Predictors of Response to Sacubitril/Valsartan Therapy in Heart Failure With Reduced Ejection Fraction: A Retrospective Cohort Study

Introduction: Sacubitril/valsartan (SV) therapy is currently recommended as first-line therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to its significant clinical and prognostic benefit; however, not all patients respond to therapy and predictors of clinical response to SV remain under-studied. Hypothesis: Certain electrocardiographic (ECG) parameters may predict response to SV therapy in HFrEF patients. Methods: Retrospective analysis of a hospital heart failure registry was undertaken. Consecutive HFrEF patients (NHYA class II - III) on maximal-dose SV were studied. Response to SV was defined as ≥10% relative improvement in left ventricular ejection fraction (LVEF) at 3-months post-therapy. Pre-therapy ECGs were retrospectively analyzed for axes and standard wave and interval durations. Logistic regression was used to estimate odds ratios and 95% confidence intervals for associations between predictors and therapeutic response. For P-wave duration (PWD), the reference level was set to <100ms; for the remaining variables, reference levels were set as: (a) the normal range for ECG variables; (b) absence for bundle branch blocks; and (c) the other category for binary variables. Calibration and discriminative performance of the models were also assessed. Results: In the 102 patients studied, PWD 100 - 120ms, PWD >120ms, and QTc >460ms were independently associated with response to SV therapy: OR 18.00 (4.45 - 122.90), 5.00 (1.47 - 20.42), and 3.10 (1.18 - 9.22) respectively. A multivariate logistic regression model including these predictors, and adjusting for pre-therapy LVEF, was both highly selective (area under the ROC curve = .840) and well-calibrated (Hosmer-Lemeshow p = .973). Conclusions: Prolongation of both PWD and QTc interval on baseline ECG in HFrEF patients is predictive of therapeutic response to maximal-dose SV therapy and may indicate early cardiac remodeling that is highly amenable to reversal.

Associations between baseline heart rate and blood pressure and time to events in HFrEF patients: data from the QUALIFY international registry.

A high resting heart rate (RHR) and low systolic blood pressure (SBP) are a risk factor and a risk indicator, respectively, for poor heart failure (HF) outcomes. This analysis evaluates the associations between baseline RHR and SBP with outcomes and treatment patterns in HF patients with reduced ejection fraction (HFrEF) in the QUALIFY international registry. Between September 2013 and December 2014, 7317 HFrEF patients with a previous HF hospitalization within 1-15 months were enrolled in the QUALIFY registry (Quality of Adherence to Guideline Recommendations for Life-Saving Treatment in Heart Failure Survey). Complete follow-up data were available for 5138 patients. The relationships between RHR and SBP and outcomes were assessed using a Cox proportional hazards model and were analyzed according to baseline values as high RHR (H-RHR) ≥ 75 vs. low RHR (L-RHR) < 75 bpm) and high SBP (H-SBP): ≥ 110 vs. low SBP (L-SBP): <110 mmHg and analyzed according to each of the following 4 phenotypes: (H-RHR/L-SBP, L-RHR/L-SBP, H-RHR/H-SBP and L-RHR/H-SBP (reference group). Compared to the reference group, H-RHR/L-SBP was associated with the worst outcomes for the combined primary endpoint of CV death and HF hospitalization (HR 1.83, CI 1.51-2.21, p<0.001), CV death (HR 2.7, CI 1.69-4.33, p <0.001), and HF hospitalization (HR 1.62, CI 1.30-2.01, p<0.001). Low-risk patients with L-RHR/H-SBP achieved more frequently >=50% of target doses of ACEIs and BBs than the other groups. However, 48% and 46% of low-risk patients were not well treated with ACEIs and BBs, respectively (<=50% of target dose or no treatment). In patients with HFrEF and recent hospitalisation, elevated RHR and lower SBP identify patients at increased risk for CV endpoints. While SBP and RHR are often recognized as barriers that deter physicians from treating with high doses of recommended drugs, they are not the only reason leaving many patients suboptimally treated. This article is protected by copyright. All rights reserved.

Upgrade of right ventricular pacing to cardiac resynchronization therapy in heart failure: a randomized trial.

De novo implanted cardiac resynchronization therapy with defibrillator (CRT-D) reduces the risk of morbidity and mortality in patients with left bundle branch block, heart failure and reduced ejection fraction (HFrEF). However, among HFrEF patients with right ventricular pacing (RVP), the efficacy of CRT-D upgrade is uncertain. In this multicentre, randomized, controlled trial, 360 symptomatic (New York Heart Association Classes II-IVa) HFrEF patients with a pacemaker or implantable cardioverter defibrillator (ICD), high RVP burden ≥ 20%, and a wide paced QRS complex duration ≥ 150 ms were randomly assigned to receive CRT-D upgrade (n = 215) or ICD (n = 145) in a 3:2 ratio. The primary outcome was the composite of all-cause mortality, heart failure hospitalization, or <15% reduction of left ventricular end-systolic volume assessed at 12 months. Secondary outcomes included all-cause mortality or heart failure hospitalization. Over a median follow-up of 12.4 months, the primary outcome occurred in 58/179 (32.4%) in the CRT-D arm vs. 101/128 (78.9%) in the ICD arm (odds ratio 0.11; 95% confidence interval 0.06-0.19; P < .001). All-cause mortality or heart failure hospitalization occurred in 22/215 (10%) in the CRT-D arm vs. 46/145 (32%) in the ICD arm (hazard ratio 0.27; 95% confidence interval 0.16-0.47; P < .001). The incidence of procedure- or device-related complications was similar between the two arms [CRT-D group 25/211 (12.3%) vs. ICD group 11/142 (7.8%)]. In pacemaker or ICD patients with significant RVP burden and reduced ejection fraction, upgrade to CRT-D compared with ICD therapy reduced the combined risk of all-cause mortality, heart failure hospitalization, or absence of reverse remodelling.

Incidence of atrial and ventricular arrhythmias in obese patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan.

To compare clinical outcomes among patients with heart failure and reduced ejection fraction (HFrEF) according to body mass index (BMI) after initiating treatment with an angiotensin-receptor neprilysin inhibitor (ARNI). We gathered data from 2016 to 2020 at the University Medical Center Mannheim; 208 consecutive patients were divided into two groups according to BMI (< 30 kg/m2 ; n = 116, ≥ 30 kg/m2 ; n = 92). Clinical outcomes, including mortality rate, all-cause hospitalizations and congestion, were systematically analysed. At the 12-month follow-up, the mortality rate was similar in both groups (7.9% in BMI < 30 kg/m2 vs. 5.6% in BMI ≥ 30 kg/m2 ; P = .76). All-cause hospitalization before ARNI treatment was comparable in both groups (63.8% in BMI < 30 kg/m2 vs. 57.6% in BMI ≥ 30 kg/m2 ; P = .69). After ARNI treatment, the hospitalization rate was also comparable in both groups at the 12-month follow-up (52.2% in BMI < 30 kg/m2 vs. 53.7% in BMI ≥ 30 kg/m2 ; P = .73). Obese patients experienced more congestion compared with non-obese patients at follow-up, without statistical significance (6.8% in BMI < 30 kg/m2 vs. 15.5% in BMI ≥ 30 kg/m2 ; P = .11). Median left ventricular ejection fraction (LVEF) improved in both groups, but significantly more in non-obese compared with obese patients at the 12-month follow-up (from 26% [3%-45%] [min.-max.] vs. 29% [10%-45%] [min.-max.] [P = .56] to 35.5% [15%-59%] [min.-max.] vs. 30% [13%-50%] [min.-max.] [P = .03], respectively). The incidence of atrial fibrillation (AF), non-sustained (ns) and sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) was less in non-obese than in obese patients after initiation of sacubitril/valsartan at the 12-month follow-up (AF: 43.5% vs. 53.7%; P = .20; nsVT: 9.8% vs. 28.4%; P = .01; VT: 14.1% vs. 17.9%; P = .52; VF: 7.6% vs. 13.4%; P = .23). The incidence of congestion in obese patients was higher compared with non-obese patients. LVEF improved significantly more in non-obese compared with obese HFrEF patients. Furthermore, AF and the ventricular tachyarrhythmia rate were revealed more in obesity compared with those without obesity at the 12-month follow-up.

Iron deficiency in Taiwanese patients with heart failure and reduced ejection fraction.

Iron deficiency (ID) is a common co-morbidity among patients with heart failure and reduced ejection fraction (HFrEF), and is associated with poorer outcomes independent of anemia. This study aimed to evaluate the prevalence and prognostic significance of ID in Taiwanese patients with HFrEF. We included HFrEF patients from two multicenter cohorts at different periods. The multivariate Cox regression analysis was applied to assess the risk of outcomes associated with ID, accounting for the varying risk of death. Of the 3,612 patients with HFrEF registered from 2013-2018, 665 (18.4%) had available baseline iron profile measurements. Of these, 290 (43.6%) were iron deficient; 20.2% had ID+/anemia+, 23.4% ID+/anemia-, 21.5% ID-/anemia+, and 34.9% ID-/anemia-. Regardless of anemia status, patients with coexisting ID had a higher risk than those without ID [all-cause mortality: 14.3 vs. 9.5 per 100 patient-years, adjusted hazard ratio (HR) 1.33, 95% confidence interval (CI) 0.96-1.85, p=0.091; cardiovascular mortality: 10.5 per 100 patient-years vs 6.1, adjusted HR 1.54 (95% CI 1.03-2.30, p= 0.037); cardiovascular mortality or first unplanned hospitalization for HF: 36.7 vs 19.7 per 100 patient-years, adjusted HR 1.57 (95% CI 1.22-2.01, p<0.001)]. Among patients eligible for treatment in the IRONMAN trial design (43.9%), parenteral iron therapy was estimated to reduce heart failure hospitalizations and cardiovascular deaths by 13.7 per 100 patient-years. Iron profiles were tested in less than one-fifth of the Taiwanese HFrEF cohort. ID was present in 43.6% of tested patients and was independently associated with poor prognosis in these patients.

Clinical characteristics of heart failure with reduced ejection fraction patients with rare pathogenic variants in dilated cardiomyopathy-associated genes: A subgroup analysis of the PARADIGM-HF trial.

To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj ] = 4 × 10-3 ), leaner (27.8 kg/m2 vs. 29.4 kg/m2 ; padj = 3.2 × 10-3 ), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10-3 ), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10-4 ). Deleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology.

Delayed ventricular conduction alters ventricular repolarization in patients with heart failure: an electrocardiographic imaging study

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Personal grant from the Dutch Heart Foundation. Background In the normal human heart, the polarity of the T-wave is concordant with the QRS complex. This phenomenon is often explained by longer repolarization of earlier activated regions. Patients with delayed ventricular conduction often have discordant T-waves, but the link to regional repolarization is unknown. Aim To compare epicardial repolarization-activation (RT-AT) relations in patients with heart failure and reduced ejection fraction (HFrEF) with those having a structural normal heart. Methods 14 patients with HFrEF and delayed ventricular conduction and 11 patients no history of structural heart disease and a normal surface ECG (nQRS) were analyzed using electrocardiographic imaging (ECGI). HFrEF patients were subcategorized as left bundle branch block (LBBB, n=6) or non-specified intraventricular conduction disturbance (IVCD, n=8). Noninvasive ECGI was used to assess epicardial activation (ATs) and repolarization times (RTs). RT-AT relationships were evaluated for 24 epicardial segments using linear regression analysis. Interventricular repolarization dispersion (inter-RTD) was defined as the difference between average left-ventricular (LV) and right-ventricular RT, while total epicardial repolarization dispersion (total-RTD) was defined as the standard deviation of all epicardial RTs. The maximum of the local RT gradients (RTG) was defined as their 95th percentile. RT parameters were described as median±IQR and Kruskal Wallis tests were used to evaluate the differences between the groups. Results An HFrEF patient’s representative 24-segment AT and RT bullseyes with a positive RT-AT relation (~depolarize last, repolarize last) is provided in Figure1A. A positive RT-AT slope was present in the majority of HFrEF patients (1.14±0.17 for LBBB and 1.16±0.55 for IVCD), whereas the nQRS group (-0.25±2.16) demonstrated an overall slightly negative slope with high variability (Figure 1B and 1C). Individual (thin lines) and group-averaged (thick lines) RT-AT slopes normalized for the earliest AT and earliest RT (in case of a positive RT-AT slope) or latest RT (in case of a negative slope) are visualized in Figure 1C. Both inter-RTD (41±25 for LBBB, 32±13 ms for IVCD, and 8±20 ms for nQRS) as well as total-RTD (34±9for LBBB, 34±12 ms for IVCD, and 24±8 ms for nQRS) was significantly higher in the LBBB and IVCD group compared to the nQRS group, whereas RTG did not differ between the groups (Figure 1B). RT-AT slopes, inter-RTD, total-RTD, and RTG did not significant differ between the LBBB and IVCD subgroup. Conclusion This ECGI study shows that in patients with HFrEF, later activated regions also have a later completion of repolarization, regardless of conduction delay, whereas a variable RT-AT relation is present in subjects with structural normal hearts. HFrEF additionally initiates a higher degree of interventricular and total repolarization dispersion.

Effect of Intravenous Iron Replacement on Recurrent Heart Failure Hospitalizations and Cardiovascular Mortality in Patients with Heart Failure and Iron Deficiency: A Bayesian Meta-Analysis.

Iron deficiency is common in patients with heart failure and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron-deficient HFrEF patients using consistent subgroup definitions across trials. Individual participant data was used from the FAIR-HF (n=459), CONFIRM-HF (n=304) and AFFIRM-AHF (n=1,108) trials. This data was re-analyzed following as closely as possible the approach taken in the analyses of IRONMAN (n=1,137), for which study level data was used. Definitions of outcomes and subgroups from the FAIR-HF, CONFIRM-HF and AFFIRM-AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin-Wei-Yang-Ying model, and the data were pooled using Bayesian random effect meta-analysis. Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR: 0.73, 95% credible interval (CI) [0.48-0.99]; between-trial heterogeneity tau=0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR]: 1.49 , 95% CI [0.95-2.37], age < vs ≥69.4 years (RRR= 0.68 [0.40-1.15]), ischemic vs non-ischemic etiology of HF (RRR=0.73 [0.42-1.33]), transferrin saturation < vs ≥20% (RRR=0.75 [0.40-1.34]), estimated glomerular filtration rate (≤ vs >60 mL/min/1.73m2 (RRR=0.97 [0.56-1.68]), haemoglobin < vs ≥ 11.8 (RRR=0.95 [0.53-1.60]), ferritin < vs ≥35 μg/L (RRR=1.26 [0.72-2.48]) and New York Heart Association Class II vs III/IV (RRR=0.91 [0.54-1.56]). Treatment of iron-deficient HFrEF patients with intravenous iron - namely with ferric carboxymaltose or ferric derisomaltose - results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present. This article is protected by copyright. All rights reserved.

PO-01-181 DELAYED VENTRICULAR CONDUCTION ALTERS VENTRICULAR REPOLARIZATION IN PATIENTS WITH HEART FAILURE: AN ELECTROCARDIOGRAPHIC IMAGING STUDY

In the normal human heart, the polarity of the T-wave is concordant with the QRS complex. This phenomenon is explained by longer repolarization of earlier activated regions. Patients with delayed ventricular conduction have discordant T-waves, but the link to regional repolarization is unknown. To compare epicardial repolarization-activation (RT-AT) relations in patients with heart failure and reduced ejection fraction (HFrEF) with those having a structural normal heart. 14 patients with HFrEF and delayed ventricular conduction and 11 patients no history of structural heart disease and a normal surface ECG (nQRS) were analyzed using ECG imaging (ECGI). HFrEF patients were categorized as left bundle branch block (LBBB, n=6) or non-specified intraventricular conduction disturbance (IVCD, n=8). ECGI was used to assess epicardial activation (ATs) and repolarization times (RTs). RT-AT relationships were evaluated for 24 segments using linear regression analysis. Interventricular repolarization dispersion (inter-RTD) was defined as the difference between average left-ventricular (LV) and right-ventricular RT, while total epicardial repolarization dispersion (total-RTD) was defined as the standard deviation of all epicardial RTs. The maximum of the local RT gradients (RTG) was defined as their 95th percentile. Kruskal Wallis tests were used to evaluate the differences between the groups. An HFrEF patient’s representative AT and RT bullseyes with a positive RT-AT relation (∼depolarize last, repolarize last) is provided in Figure1A. A positive RT-AT slope was present in the majority of HFrEF patients (1.14±0.17 for LBBB and 1.16±0.55 for IVCD), whereas the nQRS group (-0.25±2.16) demonstrated an overall slightly negative slope with high variability (Figure 1B and 1C). Individual (thin lines) and group-averaged (thick lines) RT-AT normalized slopes are visualized in Figure 1C. Both inter-RTD as well as total-RTD was significantly higher in the LBBB and IVCD group compared to the nQRS group, whereas RTG did not differ between the groups (Figure 1B). None of the RT parameters significantly differed between the LBBB and IVCD subgroup. This ECGI study shows that in patients with HFrEF, later activated regions also have a later completion of repolarization, regardless of conduction delay, whereas a variable RT-AT relation is present in subjects with structural normal hearts. HFrEF additionally initiates a higher degree of interventricular and total repolarization dispersion.

Atrial natriuretic peptide stimulates autophagy/mitophagy and improves mitochondrial function in chronic heart failure

Mitochondrial dysfunction, causing increased reactive oxygen species (ROS) production, is a molecular feature of heart failure (HF). A defective antioxidant response and mitophagic flux were reported in circulating leucocytes of patients with chronic HF and reduced ejection fraction (HFrEF). Atrial natriuretic peptide (ANP) exerts many cardiac beneficial effects, including the ability to protect cardiomyocytes by promoting autophagy. We tested the impact of ANP on autophagy/mitophagy, altered mitochondrial structure and function and increased oxidative stress in HFrEF patients by both ex vivo and in vivo approaches. The ex vivo study included thirteen HFrEF patients whose peripheral blood mononuclear cells (PBMCs) were isolated and treated with αANP (10–11 M) for 4 h. The in vivo study included six HFrEF patients who received sacubitril/valsartan for two months. PBMCs were characterized before and after treatment. Both approaches analyzed mitochondrial structure and functionality. We found that levels of αANP increased upon sacubitril/valsartan, whereas levels of NT-proBNP decreased. Both the ex vivo direct exposure to αANP and the higher αANP level upon in vivo treatment with sacubitril/valsartan caused: (i) improvement of mitochondrial membrane potential; (ii) stimulation of the autophagic process; (iii) significant reduction of mitochondrial mass—index of mitophagy stimulation—and upregulation of mitophagy-related genes; (iv) reduction of mitochondrial damage with increased inner mitochondrial membrane (IMM)/outer mitochondrial membrane (OMM) index and reduced ROS generation. Herein we demonstrate that αANP stimulates both autophagy and mitophagy responses, counteracts mitochondrial dysfunction, and damages ultimately reducing mitochondrial oxidative stress generation in PBMCs from chronic HF patients. These properties were confirmed upon sacubitril/valsartan administration, a pivotal drug in HFrEF treatment.

Hyponatremia in Stable Patients with Advanced Heart Failure: Association to Hemodynamics and Outcome

Introduction: Hyponatremia is associated with worse outcomes in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). However, it is unclear whether the worse prognosis is driven by hemodynamic derangement and how this potentially could be associated with hyponatremia. Methods: The study included 502 patients with HFrEF evaluated for advanced HF therapies, who underwent a right heart catheterization (RHC). Hyponatremia was defined as p-Na ≤136 mmol/L. The risk of all-cause mortality and a composite endpoint including mortality, left ventricular assist device (LVAD) implantation, implantation of total artificial heart (TAH), or heart transplantation (HTx) was evaluated using Cox regression analyses and Kaplan-Meier models. Results: Included patients were predominantly men 79% and had a median age of 54 years (IQR: 43–62). A third (165) of the patients had hyponatremia. In both univariate and multivariate regression analyses, p-Na was associated with increased central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (mPAP) but not with cardiac index. Hyponatremia was significantly associated with the combined endpoint (HR: 1.36 [95% CI, 1.07–1.74]; p = 0.01), but not all-cause mortality in adjusted Cox models. Conclusion: In stable HFrEF patients evaluated for advanced HF therapies, lower p-Na was associated with more deranged invasive hemodynamic measurements. Hyponatremia remained significantly associated with the combined endpoint but not all-cause mortality in adjusted Cox models. The study suggests that the increased mortality associated with hyponatremia in HFrEF patients could partly be driven by hemodynamic derangement.

Abstract P120: Neighborhood Factors Influence Cardiovascular Outcomes for Depressed and Non-Depressed Individuals With Heart Failure With Reduced Ejection Fraction

Introduction: Neighborhood-level measures including Area Deprivation Index (ADI) and walkability are associated with increased cardiovascular disease (CVD) morbidity, higher utilization of health services, and mortality. We sought to understand the impact of these neighborhood-level factors on hospital readmissions and mortality among recently hospitalized depressed and non-depressed individuals with heart failure and reduced ejection fraction (HFrEF) who enrolled in the NHLBI-funded Hopeful Heart Trial of “blended” collaborative care for HFrEF and co-morbid depression. . Hypothesis: We hypothesized worse ADI and Walk Scores will be associated with increased 12-month incidence of all-cause or cardiac-specific hospital readmission and mortality. Methods: From 3/14-10/17, Hopeful Heart enrolled 756 hospitalized HFrEF patients (EF&lt;45%) and NYHA class II-IV symptoms including 629 depressed (screen-positive on 2-item Patient Health Questionnaire (PHQ-2) for depression prior to discharge and scored ≥10 on the PHQ-9 administered via telephone two weeks post-discharge) and 127 non-depressed HFrEF patients (PHQ-2 negative and PHQ-9 &lt;5). We determined participants’ ADI score (0-100 scale, higher scores indicating greater deprivation) and Walk Score (0-100 scale, higher meaning more walkable) using home addresses at the time of hospital discharge. We categorized participants into top quartile (Q4) ADI and Walk score groups versus all other quartiles combined (Q1-Q3), and then compared these two groups using unadjusted, nonparametric Kaplan-Meier analyses with log-rank tests for differences in 12-month mortality and unadjusted chi-square tests for differences in 12-month incidence of readmission. Results: Of the 756 HFrEF participants (44% female; 73% white; EF: 28.3±9.1% mean; ADI: mean 66.7±23.5; Walk Score: mean 33.4±25.9), the mean PHQ-9 score for both ADI and Walk Score Q4 groups was similar to the Q1-3 groups. Participants in the Q4 group for ADI had a higher incidence of readmission that those in Q1-Q3 (81% -144 out of 178 - versus 70% - 400 out of 572, p=0.004), while those in the Q4 group for Walk Score were readmitted at a similar level to those in Q1-Q3. Those individuals in the top quartile for ADI and Walk Score showed no differences in cardiovascular (CV) mortality (14% incidence, 24 out of 171, for ADI; 14% total incidence, 25 out of 175 for Walk Score) or all-cause mortality (23% total incidence, 171 out of 750, for ADI; 23% total incidence, 175 out of 756 for Walk Score) compared with all other quartiles. Conclusions: Worse ADI but not Walk Score is predictive of higher risk of 12-month hospital readmission, and neither measure is predictive of 12-month CV or all-cause mortality. Further studies are needed to elaborate how area deprivation and other neighborhood factors affect outcomes for individuals with heart failure and design interventions to address these disparities.

Effectiveness and Safety of Sacubitril/Valsartan in Patients with Chronic Kidney Disease-A Real-World Experience.

data regarding the effectiveness and safety of sacubitril/valsartan in heart failure and reduced ejection fraction (HFrEF) patients with chronic kidney disease (CKD) are scarse. to evaluate the effectiveness and safety of sacubitril/valsartan in HFrEF and CKD in a real-world population. we included consecutive ambulatory HFrEF patients that initiated sacubitril/valsartan between February 2017 and October 2020, stratified by CKD (KDIGO stage 5 excluded). the incidence rate per 100 patient-years and the annualized length of stay (LOS) of acute decompensated HF hospitalizations (HFH). all-cause mortality, NYHA improvement, and titration of sacubitril/valsartan. We included 179 patients, 77 with CKD, those being older (72 ± 10 vs. 65 ± 12 years, p < 0.001), had higher NT-proBNP (4623 ± 5266 vs. 1901 ± 1835 pg/mL, p < 0.001), and high anaemia incidence (p < 0.001). After 19 ± 11 months, a significant reduction in HFH adjusted incidence rate (57.5% decrease in CKD vs. 74.6%, p = 0.261) was observed, with 5 days there was a reduction in annualized LOS in both groups (p = 0.319). NYHA improved similarly in both groups (p = 0.670). CKD patients presented non-significant higher all-cause mortality (HR = 2.405, 95%CI: [0.841; 6.879], p = 0.102). Both groups had similar sacubitril/valsartan maximum dose achievement and drug withdrawal. sacubitril/valsartan was effective on reducing HFH and LOS without affecting all-cause mortality in a CKD real-world population.