Symptomatic Heart Failure With Reduced Ejection Fraction Research Articles

Evaluating haemodynamic changes: vericiguat in patients with heart failure with reduced ejection fraction.

Vericiguat has been used to treat patients with heart failure with reduced ejection fraction (HFrEF) who demonstrated worsening heart failure despite treatment with other guideline-directed medical therapies. The haemodynamic effects of vericiguat remain unclear. This study enrolled 12 patients (median age, 63 [quartiles 53.5, 70] years; 16.7%(N=2) women) with symptomatic HFrEF (New York Heart Association functional class II-IV) who demonstrated worsening heart failure despite treatment with the four foundational guideline-recommended therapies between March and December 2022, with follow-ups completed in June 2023. A balloon-tipped pulmonary artery thermodilution catheter was placed in the right internal jugular vein to perform right heart catheterisation (RHC) on day 1. Haemodynamic data were acquired before and after vericiguat intake (2.5mg) on days 2 and 3. The data on days 2 and 3 were averaged. RHC was repeated on day 105 (37, 168). Oral intake of vericiguat 2.5mg decreased mean pulmonary artery pressure (19.3 [14.3, 26.8] mmHg) and pulmonary artery wedge pressure (PAWP) (11 [7.5, 15] mmHg) before the intake to mean pulmonary artery pressure (17.5 [12.5, 24] mmHg) and PAWP (9.3 [6.8, 14] mmHg) at 30min after (both P<0.05). Reduction in PAWP was also found from 14.5 [9.5, 19.5] mmHg on day 1 to 9.5 [6.5, 12.5] mmHg on day 105 (37, 168) (P<0.05), when vericiguat was titrated to 2.5mg 25% (N=3), 5mg 50% (N=6), and 10mg 25% (N=3). The consistent reduction in PAWP underscores the well-tolerated nature of vericiguat and its potential to enhance cardiac performance in patients with HFrEF.

Use of sacubitril/valsartan in patients with heart failure in primary care in Germany: the AURORA-HF noninterventional study.

Sacubitril/valsartan (Sac/Val) is the first angiotensin receptor-neprilysin inhibitor indicated for symptomatic chronic heart failure (HF) with reduced ejection fraction (HFrEF). Given most patients with HF in Germany are managed by general practitioners, AURORA-HF investigated the baseline characteristics and 1‑year follow-up of patients starting Sac/Val in primary care in Germany. This was aprospective, multicenter, observational study, with all treatment decisions independent of participation. The only inclusion criteria were adults (age ≥ 18years) with symptomatic HFrEF. The study comprised four groups, depending on therapy on entry: initiation of (1)Sac/Val or (2)other HF therapy; and no change in HF regimen that (3)included or (4)did not include Sac/Val. Baseline data were captured for all groups; 1‑year follow-up was recorded in groups1 and2. Of 1278 patients in the baseline analyses, 513 (40.1%) had newly started Sac/Val (449 [87.5%] completing the 1‑year follow-up), 265 (20.7%) had newly started other HF regimens (245, 92.5%) with 1‑year follow-up, while 249 with Sac/Val (19.5%) and 251 without Sac/Val (19.6%) patients had unchanged therapies. Patients treated with Sac/Val had ahigher New York Heart Association (NYHA) class at baseline and more often aleft ventricular ejection fraction (LVEF) < 35%. The only baseline parameter significantly correlating with Sac/Val discontinuation during the 1‑year follow-up was diabetes mellitus (odds ratio: 2.44; 95% confidence interval: 1.14-5.24). In the Sac/Val group,30.7% of patients were in NYHA classI/II on study entry, improving to 51.0% at 1‑year follow-up. In the no Sac/Val group, the corresponding rates of NYHA I and II classes were 49.8% and 58.2%, respectively. The overall adverse event profile of Sac/Val was good, with only 6.0% patients experiencing serious adverse events leading to permanent discontinuation. In patients with symptomatic HFrEF treated in primary care, the group in whom Sac/Val was initiated was characterized by ahigher NYHA class and lower LVEF compared to patients in whom Sac/Val was not initiated. Sac/Val was well tolerated, with ahigh proportion completing 1year of therapy.

New possibilities in pharmacotherapy for the heart failure with reduced ejection fraction treatment in patients with recent deterioration

Heart failure with reduced ejection fraction (HFrEF) is a public health issue, because some patients, despite using standard treatment, still develop worsening heart failure. The risk of adverse outcomes is especially high in patients who require readmission or emergency care on an outpatient basis. They need a new type of treatment. Vericiguat is the first oral soluble guanylate cyclase stimulator approved for the treatment of adults with symptomatic HFrEF. This article summarizes the main results of the use of this drug. The effectiveness and tolerability of vericiguat, the dependence of its action on the initial state of patients (the presence of coronary heart disease, atrial fibrillation, renal failure, the level of N-terminal pro b-type natriuretic peptide (NT-proBNP) and the duration of the period after hospitalization) are considered. It is reported that the use of the drug reduces the risk of hospitalization for worsening HF and death from cardiovascular diseases in all patients with HFrEF, regardless of the considered baseline parameters, but does not significantly affect the patients’ quality of life of. These results may be useful in determining the place of vericiguat in the management of a growing population of patients with chronic HFrEF who have experienced recent deterioration despite receiving standard therapy.

Tricuspid Regurgitation and Clinical Outcomes in Heart Failure With Reduced Ejection Fraction

BackgroundTricuspid regurgitation (TR) is common and is associated with poor outcomes in patients with heart failure (HF). However, data with adjudicated events from fully characterized patients with heart failure with reduced ejection fraction (HFrEF) are lacking. ObjectivesThis study sought to explore the association between mild or moderate/severe TR and clinical outcomes of patients with HFrEF. MethodsGALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a double-blind, placebo-controlled randomized trial comparing omecamtiv mecarbil vs placebo in patients with symptomatic HFrEF. ResultsAmong the 8,232 patients analyzed in the GALACTIC-HF trial, 8,180 (99%) had data regarding baseline TR (none: n = 6,476 [79%], mild: n = 919 [11%], and moderate/severe: n = 785 [10%]). The primary composite outcome of a first HF event or cardiovascular death occurred in 2,368 (36.6%) patients with no TR, 353 (38.4%) patients with mild TR, and 389 (49.6%) patients with moderate/severe TR. Moderate/severe TR was independently associated with a higher relative risk of the primary composite outcome compared with either no TR (adjusted HR: 1.12 [95% CI: 1.01-1.26]; P = 0.046) or no/mild TR (adjusted HR: 1.14 [95% CI: 1.02-1.27]; P = 0.025) driven predominantly by HF events. The association between moderate/severe TR and clinical outcomes was more pronounced in outpatients with worse renal function, higher left ventricular ejection fraction, and lower N-terminal pro–B-type natriuretic peptide and bilirubin levels. The beneficial treatment effect of omecamtiv mecarbil vs placebo on clinical outcomes was not modified by TR. ConclusionsIn symptomatic patients with HFrEF, baseline moderate/severe TR was independently associated with cardiovascular death or HF events driven predominantly by HF events. The beneficial treatment effect of omecamtiv mecarbil on the primary outcome was not modified by TR.

Patient Perspectives on Digital Interventions to Manage Heart Failure Medications: The VITAL-HF Pilot.

Use of guideline-directed medical therapy (GDMT) for treatment of heart failure with reduced ejection fraction (HFrEF) remains unacceptably low. The purpose of this study was to determine whether a digital health tool can augment GDMT for patients with HFrEF. Participants ≥ 18 years old with symptomatic HFrEF (left ventricular ejection fraction ≤ 40%) and with access to a mobile phone with internet were included. Participants were given a blood pressure cuff, instructed in its use, and given regular symptom surveys via cell-phone web-link. Data were transmitted to the Story Health web-based platform, and automated alerts were triggered based on pre-specified vital sign and laboratory data. Health coaches assisted patients with medication education, pharmacy access, and lab access through text messages and phone calls. GDMT titration plans were individually created in the digital platform by local clinicians based on entry vitals and labs. Twelve participants enrolled and completed the study. The median age and LVEF were 52.5 years (IQR, 46.5-63.5) and 25% (IQR, 22.5-35.5), respectively. There were 10 GDMT initiations, 52 up-titrations, and 13 down-titrations. Five participants engaged in focus-group interviews following study completion to understand first-hand perspectives regarding the use of digital tools to manage GDMT. Participants expressed comfort knowing that there were clinicians regularly reviewing their data. This alleviated concerns of uncertainty in daily living, led to an increased feeling of security, and empowered patients to understand decision-making regarding GDMT. Frequent medication changes, and the associated financial impact, were common concerns. Remote titration of GDMT for HFrEF is feasible and appears to be a patient-centered approach to care.

Sodium-Glucose Cotransporter 2 Inhibitors First Strategy Improve Decongestion in Patients with Symptomatic Heart Failure and Reduced Ejection Fraction When Compared to Angiotensin Receptor Neprilysin Inhibitor First Strategy.

Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician's choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49-100] days vs. 112 [86-138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319-2507] pg/mL vs. 570 [206-1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.

Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction-the SCIENCE trial.

The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue-derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF). The study was a European multicentre, double-blind, placebo-controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II-III, left ventricular ejection fraction (LVEF) <45%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6-month follow-up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug-related severe adverse events or difference in cardiac-related adverse events during a 3-year follow-up period. There were no significant differences between groups during follow-up in LVESV (0.3 ± 5.0ml, p=0.945), nor in secondary endpoints of left ventricular end-diastolic volume (-2.0 ± 6.0ml, p=0.736) and LVEF (-1.6 ± 1.0%, p=0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-min walk test, NT-proBNP, C-reactive protein or quality of life the first year in any groups. The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre-defined endpoints and induce restoration of cardiac function or clinical symptoms.

Abstract 13640: Sex Differences in Heart Failure With Reduced Ejection Fraction in the GALACTIC-HF Trial

Introduction: Women with heart failure with reduced ejection fraction (HFrEF) are undertreated with guideline recommended therapy and experience worse quality of life compared with men. Low enrollment of women in HFrEF outcomes trials has limited inferences about drug efficacy in women. We investigated sex-differences in baseline characteristics, clinical outcomes, and response to omecamtiv mecarbil in the GALACTIC-HF trial. Methods: The GALACTIC-HF trial randomized patients with symptomatic HFrEF with EF of 35% or less to omecamtiv mecarbil or placebo. Baseline characteristics for male and female participants were compared using parametric or non-parametric tests. Risk of the primary endpoint, heart failure event or cardiovascular death, was compared between sexes using Kaplan-Meier curves and Cox regression adjusted for 13 relevant clinical covariates. Treatment effect heterogeneity was evaluated by the sex*treatment interaction term. Results: Of the 8,232 patients enrolled, 1749 (21.2%) were women. Women had lower total Kansas City Cardiomyopathy score (59.1 vs 65.8, P&lt;0.001) and were less likely to be treated with ARNI (17.5% vs 20.0%, P=0.02), SGLT2 inhibitor (1.5% vs 2.9% P=0.001), ICD (24.5% vs 33.7%, P&lt;0.001) or CRT (11.5% vs 14.7%, P&lt;0.001). Compared to men, women had lower rates of the primary end point (hazard ratio [HR] 0.89 95% CI 0.81-0.97, p=0.01), which persisted after covariate adjustment (HR 0.85 [95% CI 0.77-0.92], p=0.001). Sex did not significantly modify treatment effect of omecamtiv mecarbil on the primary endpoint (p-interaction = 0.37). Women had higher rates of any reported adverse event but lower risk of serious adverse event leading to treatment discontinuation. Conclusions: Women with HFrEF had worse quality of life, were less likely to be treated with guideline-based therapies and had 15% lower risk of HF event or cardiovascular death compared with men. The effect of omecamtiv mecarbil did not significantly differ by sex.

New heart failure guidelines offer a changing landscape

New heart failure guidelines offer a changing landscape

Current and future use of neuromodulation in heart failure.

Autonomic imbalance is a common finding in heart failure (HF) with reduced ejection fraction (HFrEF). Addressing different targets within the autonomic nervous systems has been evaluated in patients with HF, including renal sympathetic denervation, vagal nerve stimulation, and baroreceptor activation therapy (BAT). Although all are pathophysiologically plausible and promising, only BAT shows sufficient evidence for implementation into clinical practice in randomized controlled trials. Baroreceptor activation therapy can be used in patients with symptomatic HFrEF despite optimal guideline-directed medication and device therapy. This article reviews the current and future use of neuromodulation in HF and provides an overview on current guideline recommendations and clinical practice.

Soluble (Pro)Renin Receptor Levels Are Regulated by Plasma Renin Activity and Correlated with Edema in Mice and Humans with HFrEF

Symptomatic heart failure with reduced ejection fraction (HFrEF) is characterized by edema and chronic pathological activation of the classical renin–angiotensin–aldosterone system (RAAS). The soluble (pro)renin receptor (s(P)RR) is released into circulation by proteolytic cleavage of tissue expressed (P)RR and is a candidate biomarker of RAAS activation. However, previous studies linked elevated levels of s(P)RR in patients with HFrEF to renal dysfunction. Utilizing prospectively enrolled patients with comparable rEF, we show that increased plasma levels of s(P)RR are associated with symptomatic HF (characterized by edema), independent of chronic renal dysfunction. We also found that s(P)RR levels were positively correlated with patient plasma renin activity (PRA). Normotensive mice with dilated cardiomyopathy (DCM) and HFrEF, without renal dysfunction, showed plasma s(P)RR and PRA patterns similar to human HFrEF patients. Plasma s(P)RR levels positively correlated with PRA and systemic edema, but not with EF, resembling findings in patients with HFrEF without chronic kidney dysfunction. In female DCM mice with elevated PRA levels and plasma s(P)RR levels, a randomized, blinded trial comparing the direct renin inhibitor, aliskiren vs. vehicle control, showed that direct renin inhibition normalized PRA, lowered s(P)RR, and prevented symptomatic HFrEF. Considered in light of previous findings, these data suggest that, in HFrEF, in the absence of renal dysfunction, elevation of plasma s(P)RR levels is caused by increased PRA and associated with the development of systemic edema.

The effect of intravenous ferric carboxymaltose on right ventricular function - insights from the IRON-CRT trial.

Ferric carboxymaltose (FCM) improves left ventricular function in heart failure with reduced ejection fraction (HFrEF). Yet, the effect of FCM on right ventricular (RV) function remains insufficiently elucidated. This is a pre-defined analysis of the IRON-CRT trial in which symptomatic HFrEF patients with iron deficiency and reduced left ventricular ejection fraction (LVEF) despite optimal medical therapy and cardiac resynchronization therapy (CRT) underwent 1:1 randomization to FCM or placebo in a double-blind fashion. RV function was measured as the change from baseline to 3-month follow-up in RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE) and pulsed Doppler peak velocity at the RV lateral annulus (RV S'), systolic pulmonary artery pressure (SPAP) and its coupling to the right ventricle (TAPSE/SPAP ratio). The RV contractile reserve was measured as the change in TAPSE during incremental pacing at 70, 90 and 110 bpm. A total of 75 patients underwent randomization and received FCM (n=37) or placebo (n=38). At baseline 72.5% had RV dysfunction and 70% had RV dilatation. At 3-month follow-up, patients receiving FCM had a significant improvement in RV FAC (+4.1% [+1.4% - +6.9%] vs. -2.2% [-4.9% - +0.6%] in the placebo group, p=0.002) and TAPSE (+0.98 mm [+0.28 mm - +1.62 mm] vs. -0.19 mm [-0.85 mm - +0.48 mm] in the placebo group, p=0.020), but not RV S'. Patients receiving FCM had a numerically lower SPAP (p=0.073) and significant improvement in TAPSE/SPAP ratio (+0.097 [+0.048 - +0.146] vs. +0.002 [-0.046 - +0.051] in the placebo group, p=0.008). At baseline both groups had diminished RV contractile reserve during incremental pacing, which was attenuated at 3-month follow-up in the FCM group (p=0.004). Patients manifesting more RV function improvement were more likely to exhibit higher degrees of LVEF improvement (p < 0.05 for all). Treatment with FCM in HFrEF patients results in an improvement in RV function and structure and improves the RV contractile reserve.

Developments in Exercise Capacity Assessment in Heart Failure Clinical Trials and the Rationale for the Design of METEORIC-HF.

Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity. Current guideline-directed medical therapy has indirect effects on cardiac performance with minimal impact on measured functional capacity. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases cardiac contractility and in a phase 3 cardiovascular outcomes study significantly reduced the primary composite end point of time to first heart failure event or cardiovascular death in patients with HFrEF. The objective of the METEORIC-HF trial (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure) is to assess the effect of omecamtiv mecarbil versus placebo on multiple components of functional capacity in HFrEF. The primary end point is to test the effect of omecamtiv mecarbil compared with placebo on peak oxygen uptake as measured by cardiopulmonary exercise testing after 20 weeks of treatment. METEORIC-HF will provide state-of-the-art assessment of functional capacity by measuring ventilatory efficiency, circulatory power, ventilatory anaerobic threshold, oxygen uptake recovery kinetics, daily activity, and quality-of-life assessment. Thus, the METEORIC-HF trial will evaluate the potential impact of increased myocardial contractility with omecamtiv mecarbil on multiple important measures of functional capacity in ambulatory patients with symptomatic HFrEF. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03759392.

Efficacy and Safety of Angiotensin Receptor Neprilysin Inhibitor versus Angiotensin Converting Enzyme Inhibitor in Heart Failure with Reduced Ejection Fraction- A Prospective Observational Study from a Major Tertiary Care Hospital, Assam, India

Introduction: Angiotensin Receptor Neprilysin Inhibitor (ARNI) has shown to reduce morbidity and mortality in comparison to Angiotensin Converting Enzyme Inhibitors (ACEI) inpatients of Heart Failure with Reduced Ejection Fraction (HFrEF). However, the use of ARNI in real-world practice is limited and has not been studied in North Eastern Indian population. Aim: To compare the efficacy and safety of ARNI with ACEI in the management of symptomatic chronic HFrEF in North Eastern Indian population. Materials and Methods: The prospective observational study was conducted in the Department of Cardiology at Gauhati Medical College, Guwahati, Assam, India, from April 2019 to October 2020. The study included patients with diagnosis of chronic HFrEF &lt;40%, on ACEI therapy and who had atleast one hospitalisation for Acute Decompensated Heart Failure (ADHF) in the last 6 months. A total of 63 patients were included in this study. Three patients were lost on follow-up. Out of the 60 patients who were included in the final analysis, 30 patients each were included in two groups i.e, ARNI group and ACEI group. As perdiscretion of the treating physician, the patients were started on ARNI 50 mg twice daily which consist of Sacubitril/Valsartan (24/26 mg), along with other anti-heart failure medications, and they were compared with the patients who continued on ACEI. Uptitration was considered with the aim to double the dose till the target dose was achieved at every 2-4 weeks at the treating physician’s discretion The endpoints included the rate of repeat HF hospitalisation, mortality, renal outcomes and quality of life. All statistical analyses were performed using Statistical Package for Social Sciences (SPSS, IBM) software version 20.0. Results: The demographics and clinical characteristics were comparable between the groups. The dose of ARNI was uptitrated to a maximum of 100 mg twice daily in 11 patients. ARNI significantly reduced HF hospitalisation (36.7% vs. 66.7%; p-value=0.039) and mortality (10% vs. 20%, p-value=0.038) compared to patients with ACEI. There was a significant improvement in the KCCQ score in the ARNI group as compared to the ACEI group (p-value=0.001). Treatment with ARNI was also associated with a significant improvement in the New York Heart Association (NYHA) functional class, serum creatinine, and estimated Glomerular Filtration Rate (eGFR) and a significant reduction in N-Terminal pro B-type Natriuretic Peptide (NT-proBNP) level. Conclusion: In patients with symptomatic HFrEF, shifting to ARNI from background therapy on ACE inhibitors in comparison with continuation of ACE inhibitors appeared to be safe and superior in reducing the risk of death and of hospitalisation, when initiated on outpatient basis. ARNI could not be uptitrated in two-third of patients, yet substantial benefits are evident even at low doses in comparison to ACE inhibitor ramipril.

Cardiac Contractility Modulation for Advanced Heart Failure

Heart failure with reduced ejection fraction (HFrEF) is a major health burden affecting over 13 million people worldwide. Despite emergence of novel pharmacotherapies, it remains a condition with high mortality and morbidity. Currently, guidelines recommend cardiac resynchronization therapy (CRT) for the treatment of medically refractory HFrEF associated with widened QRS on ECG. However, clinical benefits of CRT do not extend to the majority of HFrEF patients who have no significant intraventricular conduction delay. In addition, even in those who fulfilled the stringent criteria for CRT implantation, two-thirds do not respond to therapy. Cardiac contractility modulation (CCM) is a device-based therapy that involves administration of non-excitatory electrical impulses to the right ventricular septum during the absolute refractory period. Studies have shown that these electrical impulses increase cytosolic calcium and regulates local gene expression, resulting in an improved functional capacity and reduces hospitalization in those with symptomatic HFrEF. In this presentation, we summarize the pathophysiological mechanisms, clinical data, potentials and limitations of CCM. Heart failure with reduced ejection fraction (HFrEF) is a major health burden affecting over 13 million people worldwide. Despite emergence of novel pharmacotherapies, it remains a condition with high mortality and morbidity. Currently, guidelines recommend cardiac resynchronization therapy (CRT) for the treatment of medically refractory HFrEF associated with widened QRS on ECG. However, clinical benefits of CRT do not extend to the majority of HFrEF patients who have no significant intraventricular conduction delay. In addition, even in those who fulfilled the stringent criteria for CRT implantation, two-thirds do not respond to therapy. Cardiac contractility modulation (CCM) is a device-based therapy that involves administration of non-excitatory electrical impulses to the right ventricular septum during the absolute refractory period. Studies have shown that these electrical impulses increase cytosolic calcium and regulates local gene expression, resulting in an improved functional capacity and reduces hospitalization in those with symptomatic HFrEF. In this presentation, we summarize the pathophysiological mechanisms, clinical data, potentials and limitations of CCM.

Benefits of Angiotensin Receptor-Neprilysin Inhibitor in Heart Failure with Reduced Ejection Fraction: A Longitudinal Study

Introduction: Combination of Angiotensin Receptor and Neprilysin Inhibitors (ARNI) has become the mainstay drug in treatment of Heart Failure (HF) with reduced Ejection Fraction (HFrEF). However, there are very few studies to evaluate the extent and spectrum of benefit of ARNI therapy in Indian HFrEF patients. Aim: To observe the benefits of sacubitril/valsartan (ARNI) therapy on left ventricle function, parameters of cardiac remodelling, N terminal pro Brain-natriuretic peptide (NT-proBNP), rate of rehospitalisation for HF and detailed subgroup analysis in symptomatic HFrEF patients who are already receiving optimal medical therapy. Materials and Methods: This longitudinal study was conducted at Cardiology Department of Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India, from September 2018 to August 2020. Total 200 patients of HFrEF with previous echocardiographic records of past 6 months, who did not show any further improvement in left ventricle dysfunction or cardiac dimensions were included in the study. Patients were started on ARNI initially from 100 mg/day and up titrated to 400 mg/day. At each follow-up (6 weeks, 4 months, 6 months, 9 months and 1 year) clinical examination, New York Heart Association (NYHA) functional class, 2D Echocardiography and NT-ProBNP were done. Echocardiographic parameters of Cardiac Reverse Remodelling (CRR) i.e., Left Ventricular Ejection Fraction (LVEF), Left Ventricular End Diastolic Diameter (LVEDD), Left Ventricle End-Systolic Diameter (LVESD) were recorded at each follow-up. All categorical variables were shown in the form of frequency, mean with standard deviation and percentage. Intergroup comparison between different time periods was done by one-way Analysis of Variance (ANOVA) and paired t-test. A p-value &lt;0.05 was considered statistically significant. Results: Mean age of study population was 58.61±11.95 years, of whom 104 (59.77%) were males, and 70 (40.22%) were females. Mean LVEF increased from 30.42% at baseline to 45.98%, after 1 year (p-value &lt;0.05). There was reduction in mean LVEDD of 4.5 mm (p&lt;0.05) and LVESD of 3.86 mm (p-value &lt;0.05) at 1 year. These benefits of CRR were observed in all the subgroups of study population (including diabetics, hypertensive, tobacco users, age, gender). Reduction in NT-ProBNP from 1097.65±769.7 pg/mL at baseline to 127.28 pg/mL after 1 year with mean reduction of 970.37±731.33 pg/mL (p-value &lt;0.05). Rate of rehospitalisation for HF was 13.2% (N=23). A positive although weak correlation was seen between change in NT-ProBNP level and change in LVEF, LVEDD, LVESD as per spearman’s rank correlation coefficient. Conclusion: ARNI was well tolerated in this Indian population as 72% achieved maximum dose of 400 mg. There was significant improvement in LV systolic function and cardiac dimensions and benefits extended to different subgroups of HFrEF patients along with positive although weak correlation between fall in NT-ProBNP level and improvement in LV function and cardiac dimensions over and above optimal medical therapy.

Clinical trajectory of patients with a worsening heart failure event and reduced ventricular ejection fraction

Recent data suggest that patients with heart failure with reduced ejection fraction (HFrEF) and worsening heart failure (WHF) have potential for greater benefit from newer HF therapies. We investigated characteristics and outcomes of patients with HFrEF and WHF by severity of left ventricular dysfunction. We identified patients with chronic symptomatic HFrEF (left ventricular ejection fraction [LVEF] ≤35%) and evidence of WHF (emergency department visit or hospitalization for acute HF within 12 months of index echocardiogram) treated at Duke University between 1/2009 and 12/2018. Patients were stratified by LVEF≤25% or 26% to35%. Cox models were used to estimate cause-specific hazard ratios and 5-year event incidence of death and hospitalization across the range of LVEF. Of 2823 patients with HFrEF and WHF, 1620 (57.4%) had an LVEF≤25% and 1203 (42.6%) had an LVEF 26% to35%. Compared to patients with LVEF 26% to35%, those with LVEF≤25% were younger and more commonly men with a lower cardiovascular comorbidity burden. Patients with LVEF≤25% were less commonly on beta blockers (85.9% vs 90.5%) but more commonly treated with mineralocorticoid receptor antagonists (49.3% vs 41.1%) and implantable defibrillators (41.3% vs 28.2%). Patients with LVEF≤25% had significantly higher hazards for death (HR 1.24 [95% CI 1.11 - 1.38]), all-cause hospitalization (HR 1.21 [95% CI 1.10 - 1.33]), and HF hospitalization (HR 1.25 [95% CI 1.1 - 1.38]) through 5-years. More than half of patients with chronic HFrEF and WHF have severe LV dysfunction. Important differences in comorbidities, HF therapies, and outcomes exist between those with LVEF≤25% and those with LVEF 26% to35%.

Abstract 8895: Design of Phase IV, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Trial Evaluating Sodium Zirconium Cyclosilicate for the Management of Hyperkalemia in Patients With Symptomatic Heart Failure With Reduced Ejection Fraction (REALIZE-K Trial)

Introduction: International guideline-recommended therapies for heart failure (HF) with reduced ejection fraction (HFrEF), including mineralocorticoid receptor antagonists (MRA), are underutilized, in part due to concerns of hyperkalemia (HK) especially among those at high risk. The REALIZE-K trial aims to evaluate the efficacy and safety of sodium zirconium cyclosilicate (SZC), a selective potassium (K + ) binder, to enable MRA use in patients with HFrEF at high risk for HK. Methods: REALIZE-K is a prospective, double-blind, placebo (PBO)-controlled randomized withdrawal trial enrolling symptomatic HFrEF (NYHA class II-IV and LVEF ≤40%) patients on guideline-directed medical therapy (but not full-dose MRA) with either HK (serum K + 5.1-5.9 mmol/L) or high risk for HK during MRA titration. All eligible patients enter a 1-month open-label run-in phase, during which patients with hyperkalemia receive SZC to correct HK; all patients undergo protocol-mandated titration of spironolactone (SPL) as tolerated to a target of 50 mg QD with supplemental SZC to maintain normokalemia (serum K + 3.5-5.0 mmol/L; Figure ). All patients tolerating ≥25 mg QD of SPL will be randomly assigned to continued SPL+SZC or SPL+PBO during an 8-month double-blind withdrawal phase. Serial K + monitoring will guide protocol-directed dosing of SZC/PBO and SPL during the randomized period. The primary study endpoint is the occurrence at 8 months of normokalemia on SPL ≥25 mg QD without the need for rescue therapy for severe HK in the SZC vs PBO group. Secondary endpoints include individual components of the primary endpoint and health status assessed by Kansas City Cardiomyopathy Questionnaire Total Symptom Score. Exploratory endpoints include time to first occurrence of the composite of CV death or worsening HF, and change in mean urine albumin-creatinine ratio. Conclusions: REALIZE-K will evaluate the efficacy and safety of SZC, enabling MRA therapy for HFrEF patients at high risk for HK.

Increased VO2 peak after a structured exercise-training program is associated with reduced levels of cardiac myosin binding protein C in patients with symptomatic chronic heart failure

Abstract Background Cardiac myosin-binding protein C (cMyC), a cardiac contractile protein, is a novel biomarker of myocardial injury, rising earlier and disappearing faster than cardiac troponins. It is a promising biomarker for use in triage of patients with chest pain presenting in the emergency department. It also has prognostic significance in patients with heart failure. However, the effects of systematic exercise training on plasma levels of cMyC has previously not been evaluated. Purpose The aim of this study was to assess the effect of a 12-week exercise training program on changes in plasma levels of cMyC in patients with chronic symptomatic heart failure with reduced ejection fraction (HFrEF). The changes in plasma levels of cMyC in an intervention group, performing structured exercise programs, were compared to those in a control group, instructed to perform regular recommended exercise (RRE) according to current guidelines. Methods This was a post hoc analysis of the SMARTEX-HF trial in 215 patients with symptomatic HF with Left Ventricular Ejection Fraction (LVEF) &amp;lt;35% and NYHA II-III. The patients were randomly assigned to High Intensity Interval Training (HIIT, n=77), Moderate Continuous Training (MCT, n=65) or RRE, (n=73) for 12 weeks. HIIT and MCT groups constituted the intervention group (IG). Measurements and clinical data were acquired before and after the 12-week intervention. Statistical analysis We divided the patients in two groups with Δ VO2Peak above and below the median of the sample. The absolute changes of cMyC were then compared between the two groups. Mann-Whitney U test was used to compare continuous variables between the groups. Chi-squared test and Fisher exact test were used to compare categorical variables, as appropriate. A two-tailed p&amp;lt;0.05 was considered significant. Results There were no differences in changes of cMyC plasma levels, measured at baseline and after the intervention, between patients in the IG and RRE-group (p=0.580). When dividing the entire study population according to Δ VO2Peak higher or lower than median value 0.48 ml/kg/min, we found a statistically significant greater reduction of cMyC values after 12 weeks of exercise training for those with higher than median Delta VO2Peak values compared to those with lower values (p=0.012). This finding was even stronger for the percentage change in cMyC levels (p=0.004 between groups). Conclusion In patients with symptomatic chronic HFrEF performing a structured 12-week exercise training program, a greater increase in Δ VO2Peak is significantly associated with a reduction in cMyC, suggesting cMyC may provide a dynamic measure of cardiorespiratory state. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Central Norwegian Health authority,Norwegian University of Science and Technology Baseline characteristicsBoxplot cMyC vs peak VO2

Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a global cause of morbidity and mortality with over 60 million estimated cases worldwide. The burden of HF care is expected to increase with an ageing population as evidenced by the fact that 80% of HF-related hospitalizations occur in those aged above 65. Given the significant morbidity and mortality associated with HFrEF, there is a need for new prognostic therapies that have an impact on morbidity and mortality. In February of 2021, the National institute for Health and Care Excellence (NICE) released new guidance on the utility of Dapagliflozin for the management of heart failure with reduced ejection fraction (HFrEF). NICE advocated that dapagliflozin is a viable treatment option in symptomatic HFrEF patients on optimal medical management. The current list price of dapagliflozin is around £36.59 per 28-tablet pack with an estimated annual cost of £476.98 equating to £6939 per quality-adjusted life year. The guidance was mainly based on evidence produced from the 2019 DAPA-HF trial. This demonstrated that in HFrEF population, the use of dapagliflozin led to a significant reduction in worsening HF events, cardiovascular, and all-cause death. In this article, we summarize the evidence base for sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.