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Aims Methods Conclusion In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy.The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all‐cause death. As an event‐driven trial, at least 1080 primary events are expected, but follow‐up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo.VICTOR is the first large event‐driven HFrEF trial performed in the contemporary era of quadruple foundational guideline‐directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF. [ABSTRACT FROM AUTHOR]

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Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro–B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions We investigated the prevalence, clinical characteristics, and prognosis of patients with heart failure (HF) with improved ejection fraction (HFimpEF).We used data from BIOSTAT‐CHF including patients with a left ventricular ejection fraction (LVEF) ≤40% at baseline who had LVEF re‐assessed at 9 months. HFimpEF was defined as a LVEF >40% and a LVEF ≥10% increase from baseline at 9 months. We validated findings in the ASIAN‐HF registry. The primary outcome was a composite of time to HF rehospitalization or all‐cause mortality. In BIOSTAT‐CHF, about 20% of patients developed HFimpEF, that was associated with a lower primary event rate of all‐cause mortality (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.28–0.97, p = 0.040) and the composite endpoint (HR 0.46, 95% CI 0.30–0.70, p < 0.001) compared with patients who remained in persistent HF with reduced ejection fraction (HFrEF). The findings were similar in the ASIAN‐HF (HR 0.40, 95% CI 0.18–0.89, p = 0.024, and HR 0.29, 95% CI 0.17–0.48, p < 0.001). Five independently common predictors for HFimpEF in both BIOSTAT‐CHF and ASIAN‐HF were female sex, absence of ischaemic heart disease, higher LVEF, smaller left ventricular end‐diastolic and end‐systolic diameter at baseline. A predictive model combining only five predictors (absence of ischaemic heart disease and left bundle branch block, smaller left ventricular end‐systolic and left atrial diameter, and higher platelet count) for HFimpEF in the BIOSTAT‐CHF achieved an area under the curve of 0.772 and 0.688 in the ASIAN‐HF (due to missing left atrial diameter and platelet count).Approximately 20–30% of patients with HFrEF improved to HFimpEF within 1 year with better clinical outcomes. In addition, the predictive model with clinical predictors could more accurately predict HFimpEF in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) with improved ejection fraction (EF, HFimpEF) is a distinct HF subtype, characterized by left ventricular (LV) reverse remodeling and myocardial functional recovery. Multiple cardiometabolic factors are implicated in this process. Epicardial adipose tissue (EAT), emerging as an endocrine and paracrine organ, contributes to the onset and progression of HF. However, the relation between EAT and the incidence of HFimpEF is still unclear. Methods: A total of 203 hospitalized HF patients with reduced EF (HFrEF, LVEF ≤ 40%) who underwent coronary CT angiography (CCTA) during index hospitalization were consecutively enrolled between November 2011 and December 2022. Routine follow-up and repeat echocardiograms were performed. The incidence of HFimpEF was defined as (1) an absolute LVEF improvement ≥ 10% and (2) a second LVEF > 40% (at least 3 months apart). EAT volume and density were semiautomatically quantified on non-enhanced series of CCTA scans. Results: During a median follow-up of 8.6 (4.9 ~ 13.3) months, 104 (51.2%) patients developed HFimpEF. Compared with HFrEF patients, HFimpEF patients had lower EAT volume (115.36 [IQR 87.08 ~ 154.78] mL vs. 169.67 [IQR 137.22 ~ 218.89] mL, P < 0.001) and higher EAT density (-74.92 ± 6.84 HU vs. -78.76 ± 6.28 HU, P < 0.001). Multivariate analysis showed lower EAT volume (OR: 0.885 [95%CI 0.822 ~ 0.947]) and higher density (OR: 1.845 [95%CI 1.023 ~ 3.437]) were both independently associated with the incidence of HFimpEF. Subgroup analysis revealed that the association between EAT properties and HFimpEF was not modified by HF etiology. Conclusions: This study reveals that lower EAT volume and higher EAT density are associated with development of HFimpEF. Therapies targeted at reducing EAT quantity and improving its quality might provide favorable effects on myocardial recovery in HF patients. [ABSTRACT FROM AUTHOR]

Aims: The utility of growth differentiation factor‐15 (GDF‐15) in predicting long‐term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF‐15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF‐15 into the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score‐based model. Methods and results: This single‐centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid‐range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0 years (range: 56.0–77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF‐15 concentration (P = 0.002) and a higher MAGGIC risk score (P < 0.001). We examined the associations between GDF‐15 levels and the risks of all‐cause mortality and HF rehospitalization using Cox regression models. The C‐index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4 year follow‐up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF‐15 levels were significantly associated with an increased risk of all‐cause mortality [hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.20–1.54; P < 0.001] and HF rehospitalization (HR = 1.75, 95% CI: 1.57–1.95; P < 0.001) across all HF phenotypes. This association remained significant when GDF‐15 was treated as a categorical variable (high GDF‐15 group: all‐cause death: HR = 1.73, 95% CI: 1.40–2.14; P < 0.001; HF rehospitalization: HR = 3.37, 95% CI: 2.73–4.15; P < 0.001). Inclusion of GDF‐15 in the MAGGIC risk score‐based model provided additional prognostic value for all HF patients (Δ C‐index = 0.021, 95% CI: 0.002–0.041; IDI = 0.011, 95% CI: 0.001–0.025; continuous NRI = 0.489, 95% CI: 0.174–0.629) and HF rehospitalization (Δ C‐index = 0.034, 95% CI: 0.005–0.063; IDI = 0.021, 95% CI: 0.007–0.032; continuous NRI = 0.307, 95% CI: 0.147–0.548), particularly in the HFpEF subgroup. Conclusions: GDF‐15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF‐15 into the MAGGIC risk score‐based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups. [ABSTRACT FROM AUTHOR]

Ivabradine, a pure bradycardic agent, can be given to heart failure reduced ejection fraction (HFrEF) patients with a sinus rhythm of ≥70 bpm on a maximum beta blocker dose, or when beta blockers are contraindicated. This study aimed to see how ivabradine affects the clinical and haemodynamic outcomes of HFrEF patients. This systematic review and meta-analysis searched ClinicalTrials.gov , OpenMD, ProQuest, PubMed, and ScienceDirect for potential articles. All relevant data were extracted. For all pooled effects, the random effect model was applied. A total of 18,972 heart failure (HF) patients from nine randomised clinical trials (RCTs) were involved in this study. Ivabradine decreased the risk of HF mortality (RR 0.79; 95% CI 0.64–0.98; p=0.03) and HF hospitalisation (RR 0.80; 95% CI 0.65–0.97; p=0.03). Ivabradine was related to a greater reduction in heart rate (MD -12.21; 95% CI -15.47 – -8.96; p<0.01) and left ventricular ejection fraction (LVEF) improvement (MD 3.24; 95% CI 2.17–4.31; p <0.01) compared with placebo. Asymptomatic bradycardia (RR 4.25; 95% CI 3.36–5.39; p<0.01) and symptomatic bradycardia (RR 3.99; 95% CI 3.17–5.03; p<0.01) were higher in the ivabradine group. Ivabradine can reduce the risk of HF mortality and HF hospitalisation in HFrEF patients. Ivabradine also effectively reduces resting heart rate and improves LVEF. However, ivabradine is associated with a greater risk of symptomatic and asymptomatic bradycardia. [ABSTRACT FROM AUTHOR]

Aims Many studies show the association between malnutrition and poor prognosis in heart failure (HF) patients. Our research aimed to analyse sex differences in patients with HF with reduced ejection fraction (HFrEF), emphasizing nutritional status and the influence of selected parameters on the prognosis. Methods and results We enrolled 276 consecutive patients diagnosed with HFrEF. Nutritional status was assessed using Mini Nutritional Assessment (MNA), geriatric nutritional risk index (GNRI), and body mass index (BMI). The mean follow-up period was 564.4 ± 346.3 days. The analysed group included 81.2% of men. The median age was 58, interquartile range (IQR) 49–64 years. Among all patients, almost 60% were classified as NYHA III or IV. Half of the participants were at risk of malnutrition, and 2.9% were malnourished. During follow-up, 72 (26.1%) patients died. The female sex was not associated with a higher occurrence of malnutrition (P = 0.99) or nutritional risk (P = 0.85), according to MNA. Coherently, GNRI scores did not differ significantly between the sexes (P = 0.29). In contrast, BMI was significantly higher in males (29.4 ± 5.3 vs. 25.9 ± 4.7; P < 0.001). Impaired nutritional status assessed with any method (MNA, GNRI, BMI) was not significantly associated with a worse prognosis. In multivariable analysis, NYHA class, lower estimated glomerular filtration rate, higher B-type natriuretic peptide (BNP), higher N-terminal fragment of proBNP, and higher uric acid were independent of sex and age predictors of all-cause mortality. Conclusion There were no sex differences in the nutritional status in the HFrEF patients, apart from lower BMI in females. Impaired nutritional status was not associated with mortality in both men and women. [ABSTRACT FROM AUTHOR]

Background and Objectives: Heart failure with reduced ejection fraction (HFrEF) remains a significant burden. Traditional herbal medicines have shown cardioprotective effects in treating HFrEF. However, the implications of herbal formulation considering the dynamic immunohistological changes in the myocardium following acute ischemic injury have been insufficiently discussed. This review investigated the efficacy and mechanisms reported in studies using rat or mouse models of HFrEF induced by left descending coronary artery ligation. Materials and Methods: A systematic search was conducted using PubMed, Embase, AMED, CINAHL, and CENTRAL databases. Information was extracted regarding study characteristics, disease model induction protocols, intervention characteristics, treatment protocols, outcomes, and suggested mechanisms. Hierarchical cluster analysis of test drugs was performed based on constituent herb similarities. The risk of bias (RoB) was assessed using the Systematic Review Center for Laboratory animal Experimentation RoB tool. Results: Overall, 26 studies met the eligibility criteria. HF model induction periods after LADCA ligation ranged from 1 day to 12 weeks. Most studies administered the test drug for four weeks. Commonly used herbs included Panax ginseng, Astragalus membranaceus, Salvia miltiorrhiza, Carthamus tinctorius, and Lepidium apetalum, which demonstrated anti-fibrotic, anti-inflammatory, and anti-apoptotic effects through various signaling pathways. The overall RoB was relatively high. No significant association was found between model induction periods and herbal formulations or examined mechanisms. Conclusions: Future research should consider the time-dependent immunohistological features of the myocardium during HF treatment. [ABSTRACT FROM AUTHOR]

Guideline‐directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF) reduces morbidity and mortality, but its implementation is often poor in daily clinical practice. Barriers to implementation include clinical and organizational factors that might contribute to clinical inertia, i.e. avoidance/delay of recommended treatment initiation/optimization. The spectrum of strategies that might be applied to foster GDMT implementation is wide, and involves the organizational set‐up of heart failure care pathways, tailored drug initiation/optimization strategies increasing the chance of successful implementation, digital tools/telehealth interventions, educational activities and strategies targeting patient/physician awareness, and use of quality registries. This scientific statement by the Heart Failure Association of the ESC provides an overview of the current state of GDMT implementation in HFrEF, clinical and organizational barriers to implementation, and aims at suggesting a comprehensive framework on how to overcome clinical inertia and ultimately improve implementation of GDMT in HFrEF based on up‐to‐date evidence. [ABSTRACT FROM AUTHOR]

Aims: Recent guidelines recommend four core drug classes (renin–angiotensin system inhibitor/angiotensin receptor–neprilysin inhibitor [RASi/ARNi], beta‐blocker, mineralocorticoid receptor antagonist [MRA], and sodium–glucose cotransporter 2 inhibitor [SGLT2i]) for the pharmacological management of heart failure (HF) with reduced ejection fraction (HFrEF). We assessed physicians' perceived (i) comfort with implementing the recent HFrEF guideline recommendations; (ii) status of guideline‐directed medical therapy (GDMT) implementation; (iii) use of different GDMT sequencing strategies; and (iv) barriers and strategies for achieving implementation. Methods and results: A 26‐question survey was disseminated via bulletin, e‐mail and social channels directed to physicians with an interest in HF. Of 432 respondents representing 91 countries, 36% were female, 52% were aged <50 years, and 90% mainly practiced in cardiology (30% HF). Overall comfort with implementing quadruple therapy was high (87%). Only 12% estimated that >90% of patients with HFrEF without contraindications received quadruple therapy. The time required to initiate quadruple therapy was estimated at 1–2 weeks by 34% of respondents, 1 month by 36%, 3 months by 24%, and ≥6 months by 6%. The average respondent favoured traditional drug sequencing strategies (RASi/ARNi with/followed by beta‐blocker, and then MRA with/followed by SGLT2i) over simultaneous initiation or SGLT2i‐first sequences. The most frequently perceived clinical barriers to implementation were hypotension (70%), creatinine increase (47%), hyperkalaemia (45%) and patient adherence (42%). Conclusions: Although comfort with implementing all four core drug classes in patients with HFrEF was high among physicians, a majority estimated implementation of GDMT in HFrEF to be low. We identified several important perceived clinical and non‐clinical barriers that can be targeted to improve implementation. [ABSTRACT FROM AUTHOR]

Background: Despite the positive impact of implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) on prognosis, their implantation is often withheld especially in Japanese heart failure patients with reduced left ventricular ejection fraction (HFrEF) who have not experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) for uncertain reasons. Recent advancements in heart failure (HF) medications have significantly improved the prognosis for HFrEF. Given this context, a critical reassessment of the treatment and prognosis of ICDs and WCDs is essential, as it has the potential to reshape awareness and treatment strategies for these patients. Methods: We are initiating a prospective multicenter observational study for HFrEF patients eligible for ICD in primary and secondary prevention, and WCD, regardless of device use, including all consenting patients. Study subjects are to be enrolled from 31 participant hospitals located throughout Japan from April 1, 2023, to December 31, 2024, and each will be followed up for 1 year or more. The planned sample size is 651 cases. The primary endpoint is the rate of cardiac implantable electronic device implementation. Other endpoints include the incidence of VT/VF and sudden death, all-cause mortality, and HF hospitalization, other events. We will collect clinical background information plus each patient's symptoms, Clinical Frailty Scale score, laboratory test results, echocardiographic and electrocardiographic parameters, and serial changes will also be secondary endpoints. Results: Not applicable. Conclusion: This study offers invaluable insights into understanding the role of ICD/ WCD in Japanese HF patients in the new era of HF medication. [ABSTRACT FROM AUTHOR]

Aims: Chronic heart failure is associated with a bone‐catabolic state and increases the risk of osteoporosis and fractures. Prospective studies investigating the clinical relevance of bone disease in heart failure are lacking. We aimed to assess the prevalence and prognostic impact of osteoporosis and vertebral fractures (VFs) in chronic heart failure with reduced ejection fraction (HFrEF). Methods and results: Symptomatic outpatients with chronic heart failure and a previous diagnosis of overtly reduced left ventricular ejection fraction < 40% on stable, optimal HFrEF therapy and left ventricular ejection fraction < 50% at enrolment were included into a prospective single‐centre study. Osteoporosis was determined with dual‐energy X‐ray absorptiometry and defined as a T‐score ≤ 2.5 at any site. VFs were assessed using X‐ray of both thoracic and lumbar spine applying the semiquantitative Genant score. We enrolled 205 patients (22% women), with a median age of 66 (IQR 58–74) years. Median left ventricular ejection fraction was 37 (IQR 30–43) % and median N‐terminal pro B‐type natriuretic peptide was 964 (IQR 363–2173) pg/mL. Osteoporosis, as defined by bone mineral density, and at least one VF were prevalent in 31 (15%) and 29 patients (14%). Osteoporosis or VF were present in 55 patients (27%) and 5 patients (2%) had both osteoporosis and a VF. During a median follow‐up of 4.7 (IQR 4.0–5.3) years, 18 patients (9%) died due to cardiovascular (CV) cause, and 46 patients (22%) had a worsening heart failure (WHF) hospitalization. In multivariate Cox regression analyses, presence of VF independently predicted CV death (HR 2.82, 95% CI 1.04–7.65, P = 0.042), WHF hospitalizations (HR 2.39, 95% CI 1.18–4.82, P = 0.015), and a composite endpoint of CV death and WHF hospitalizations (HR 2.44, 95% CI 1.23–4.82, P = 0.011). Osteoporosis was not significantly associated with CV events. Conclusions: In a prospective study, bone disease affected every fourth patient with HFrEF, and patients with VF at baseline had a two‐fold risk of subsequent CV death or WHF hospitalization. Prevalent bone disease, particularly VF, should be considered as a clinically relevant comorbidity in HFrEF. [ABSTRACT FROM AUTHOR]

Aims: Achieving optimized guideline‐directed medical therapy (GDMT) is recommended prior to transcatheter mitral valve edge‐to‐edge repair (M‐TEER) for secondary mitral regurgitation (SMR). We aimed to propose and validate an easy‐to‐use score for assessing the quality of GDMT in patients with heart failure with reduced ejection fraction (HFrEF) undergoing M‐TEER. Methods and results: Among the 1641 EuroSMR patients enrolled in the EuroSMR Registry who underwent M‐TEER, a total of 1072 patients [median age 74, interquartile range (IQR) 67–79 years, 29% female] had complete data on GDMT and a left ventricular ejection fraction ≤ 40% and were included in the current study. We proposed a GDMT score that considers the dosage levels of three medication classes (angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor‐neprilysin inhibitors, beta‐blockers, and mineralocorticoid receptor antagonists), with a maximum score of 12 points indicating optimal GDMT. The primary outcome was all‐cause mortality. The median GDMT score was 4 points (IQR 3–6). All three domains of the scoring system were associated with all‐cause mortality (P < 0.05 for all). The overall GDMT score was associated with all‐cause mortality (hazard ratio 0.90, 95% confidence interval 0.86–0.95 for each 1‐point increase in the GDMT score). This association remained significant after adjusting for renal function and co‐morbidities. Conclusions: This study demonstrates the utility of a simple GDMT scoring system for assessing the adequacy of GDMT in HFrEF patients with relevant SMR undergoing M‐TEER. The GDMT score has potential applications in guiding the design of future clinical trials and aiding clinical decision‐making processes. [ABSTRACT FROM AUTHOR]

Aims: Guidelines recommend target doses (TD) of heart failure (HF) with reduced ejection fraction (HFrEF) medications regardless of sex. Differences in pharmacokinetics and pharmacodynamics may explain heterogeneity in treatment response, adverse reactions, and tolerability issues across sexes. The aim of this study was to explore sex‐based differences in the association between TD achievement and mortality/morbidity in HFrEF. Methods and results: Patients with HFrEF and HF duration ≥6 months registered in the Swedish HF Registry between May 2000 and December 2020 (follow‐up until December 2021) were analysed. Treatments of interest were renin–angiotensin system inhibitors (RASI) or angiotensin receptor–neprilysin inhibitors (ARNI), and beta‐blockers. Multivariable Cox regression models were performed to explore the risk of cardiovascular mortality or hospitalization for HF across dose categories in females versus males. A total of 17 912 patients were analysed (median age 77.0 years, interquartile range [IQR] 70.0–83.0), 29% were female. Over a median follow‐up of 1.33 years (IQR 0.29–3.22), for RASI/ARNI there was no significant difference in outcome for females achieving 50–99% versus 100% of TD (hazard ratio 0.92, 95% confidence interval 0.83–1.03), whereas males showed a gradual lowering in risk together with the achievement of higher % of TD (p‐interaction = 0.030). For beta‐blockers the achievement of TD was associated with the lowest risk of outcome regardless of sex. Conclusions: Our findings suggest that females and males might differently benefit from the same dose of RASI/ARNI, and do represent a general call for randomized controlled trials to consider sex‐specific up‐titration schemes when testing HFrEF treatments in need of up‐titration. [ABSTRACT FROM AUTHOR]

Background: Glycemic control, as measured by glycosylated hemoglobin (HbA1c), is an important biomarker to evaluate diabetes severity and is believed to be associated with heart failure development. Type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) commonly coexist, and the combination of these two diseases indicates a considerably poorer outcome than either disease alone. Therefore, glycemic control should be carefully managed. The present study aimed to explore the association between glycemic control and clinical outcomes, and to determine the optimal glycemic target in this specific population. Methods: A total of 262 patients who underwent cardiac MRI were included and were split by HbA1c levels [HbA1c < 6.5% (intensive control), HbA1c 6.5-7.5% (modest control), and HbA1c > 7.5% (poor control)]. The biventricular volume and function, as well as left ventricular (LV) systolic strains in patients in different HbA1c categories, were measured and compared. The primary and secondary outcomes were recorded. The association of different HbA1c levels with adverse outcomes was assessed. Results: Despite similar biventricular ejection fractions, both patients with intensive and poor glycemic control exhibited prominent deterioration of LV systolic strain in the longitudinal component (P = 0.004). After a median follow-up of 35.0 months, 55 patients (21.0%) experienced at least one confirmed endpoint event. Cox multivariable analysis indicated that both patients in the lowest and highest HbA1c categories exhibited a more than 2-fold increase in the risk for primary outcomes [HbA1c < 6.5%: hazard ratio (HR) = 2.42, 95% confidence interval (CI) = 1.07–5.45; P = 0.033; HbA1c > 7.5%: HR = 2.24, 95% CI = 1.01–4.99; P = 0.038] and secondary outcomes (HbA1c < 6.5%: HR = 2.84, 95% CI = 1.16–6.96; P = 0.022; HbA1c > 7.5%: HR = 2.65, 95% CI = 1.08–6.50; P = 0.038) compared with those in the middle HbA1c category. Conclusions: We showed a U-shaped association of glycemic control with clinical outcomes in patients with T2DM and HFrEF, with the lowest risk of adverse outcomes among patients with modest glycemic control. HbA1c between 6.5% and 7.5% may be served as the optimal hypoglycemic target in this specific population. [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium–glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood. Methods and results: The DAPA‐HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant‐level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate‐adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02–1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72–0.96) and without previous MI (HR 0.76, 95% CI 0.68–0.85; pinteraction = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI. Conclusion: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI. [ABSTRACT FROM AUTHOR]

Aims: The determinants and relevance of right ventricular (RV) mechanical dyssynchrony in heart failure with reduced ejection fraction (HFrEF) are poorly understood. We hypothesized that increased afterload may adversely affect the synchrony of RV contraction. Methods and results: A total of 148 patients with HFrEF and 36 controls underwent echocardiography, right heart catheterization, and gated single‐photon emission computed tomography to measure RV chamber volumes and mechanical dyssynchrony (phase standard deviation of systolic displacement timing). Exams were repeated after preload (N = 135) and afterload (N = 15) modulation. Patients with HFrEF showed higher RV dyssynchrony compared with controls (40.6 ± 17.5° vs. 27.8 ± 9.1°, P < 0.001). The magnitude of RV dyssynchrony in HFrEF correlated with larger RV and left ventricular (LV) volumes, lower RV ejection fraction (RVEF) and LV ejection fraction, reduced intrinsic contractility, increased heart rate, higher pulmonary artery (PA) load, and impaired RV–PA coupling (all P ≤ 0.01). Low RVEF was the strongest predictor of RV dyssynchrony. Left bundle branch block (BBB) was associated with greater RV dyssynchrony than right BBB, regardless of QRS duration. RV afterload reduction by sildenafil improved RV dyssynchrony (P = 0.004), whereas preload change with passive leg raise had modest effect. Patients in the highest tertiles of RV dyssynchrony had an increased risk of adverse clinical events compared with those in the lower tertile [T2/T3 vs. T1: hazard ratio 1.98 (95% confidence interval 1.20–3.24), P = 0.007]. Conclusions: RV dyssynchrony is associated with RV remodelling, dysfunction, adverse haemodynamics, and greater risk for adverse clinical events. RV dyssynchrony is mitigated by acute RV afterload reduction and could be a potential therapeutic target to improve RV performance in HFrEF. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the correlation between alterations in the distribution width of red blood cells (RDW) and the incidence of major adverse cardiovascular events (MACEs) in patients with heart failure with reduced ejection fraction (HFRF) receiving sacubitril/valsartan therapy. Implementing Methods: After obtaining permission from the Institutional Ethics Committee, the present study was initiated. This study retrospectively examined the medical records of hospitalized patients diagnosed with HFRF. The patients were allocated into two distinct groups, namely, the traditional group and the sacubitril/valsartan group, based on whether sacubitril/valsartan was incorporated into their individual pharmacological treatment regimen. The RDW values before and after treatment with sacubitril/valsartan are documented as RDW1 and RDW2, respectively. ΔRDW is defined as the value obtained by subtracting RDW1 from RDW2. Based on ΔRDW >0 or ≤0, patients in the sacubitril/valsartan group were categorized into two subgroups. MACEs, including mortality and readmission for myocardial infarction, acute myocardial infarction, and ischemic stroke, were documented in each cohort throughout the one-year follow-up period. Findings: Patients who received sacubitril/valsartan exhibited a reduced incidence of MACE compared to those who received conventional therapy (log-rank, P<0.001). During the follow-up period, the incidence of cardiac events was significantly higher in the ΔRDW >0 group than in the ΔRDW ≤ 0 group (Breslow, P<0.001). There was a significant positive correlation between increased RDW and a decreased likelihood of developing MACE (odds ratio [OR] = 3.044, 95% confidence interval [CI]:1.592-4.357). Furthermore, for every unit increase in RDW, the risk of developing MACE increased by 23.2% (OR=2.332, 95% CI:1.185-2.499). Treatment with sacubitril/valsartan effectively reduced the incidence of MACEs in HFRF patients. In addition, variations in RDW serve as predictors of MACEs after sacubitril/valsartan treatment. [ABSTRACT FROM AUTHOR]

Background and Objectives: In this study, we aimed to investigate the prognostic value of the C-reactive protein to albumin ratio (CAR) for all-cause mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF). Materials and Methods: In total, 404 chronic HFrEF patients were included in this observational and retrospective study. The CAR value of each patient included in this analysis was calculated. We stratified the study population into tertiles (T1, T2, and T3) according to CAR values. The primary outcome of the analysis was to determine all-cause mortality. Results: The median follow-up period in our study was 30 months. In the follow-up, 162 (40%) patients died. The median value of CAR was higher in patients who did not survive during the follow-up [6.7 (IQR = 1.6–20.4) vs. 0.6 (IQR = 0.1–2.6), p < 0.001]. In addition, patients in the T3 tertile (patients with the highest CAR) had a higher rate of all-cause mortality [n = 90 cases (66.2%), p < 0.001]. Multivariate Cox regression analysis revealed that CAR was an independent predictor of mortality in patients with HFrEF (hazard ratio: 1.852, 95% confidence interval: 1.124–2.581, p = 0.005). In a receiver operating characteristic curve analysis, the optimal cut-off value of CAR was >2.78, with a sensitivity of 66.7% and specificity of 76%. Furthermore, older age, elevated N-terminal pro-brain natriuretic peptide levels, and absence of a cardiac device were also independently associated with all-cause death in HFrEF patients after 2.5 years of follow-up. Conclusions: The present study revealed that CAR independently predicts long-term mortality in chronic HFrEF patients. CAR may be used to predict mortality among these patients as a simple and easily obtainable inflammatory marker. [ABSTRACT FROM AUTHOR]

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[Display omitted] [ABSTRACT FROM AUTHOR]

Trials evaluating implantable hemodynamic monitors to manage patients with heart failure (HF) have shown reductions in HF hospitalizations but not mortality. Prior meta-analyses assessing mortality have been limited in construct because of an absence of patient-level data, short-term follow-up duration, and evaluation across the combined spectrum of ejection fractions. The purpose of this meta-analysis was to determine whether management with implantable hemodynamic monitors reduces mortality in patients with heart failure and reduced ejection fraction (HFrEF) and to confirm the effect of hemodynamic-monitoring guided management on HF hospitalization reduction reported in previous studies. The patient-level pooled meta-analysis used 3 randomized studies (GUIDE-HF [Hemodynamic–Guided Management of Heart Failure], CHAMPION [CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients], and LAPTOP-HF [Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy]) of implantable hemodynamic monitors (2 measuring pulmonary artery pressures and 1 measuring left atrial pressure) to assess the effect on all-cause mortality and HF hospitalizations. A total of 1,350 patients with HFrEF were included. Hemodynamic-monitoring guided management significantly reduced overall mortality with an HR of 0.75 (95% CI: 0.57-0.99); P = 0.043. HF hospitalizations were significantly reduced with an HR of 0.64 (95% CI: 0.55-0.76); P < 0.0001. Management of patients with HFrEF using an implantable hemodynamic monitor significantly reduces both mortality and HF hospitalizations. The reduction in HF hospitalizations is seen early in the first year of monitoring and mortality benefits occur after the first year. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: The therapeutic mechanism of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on left cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF) is not well‐established. This study meta‐analysed the impact of SGLT2i on left cardiac structure and function in patients with HFrEF. Methods and results: Online databases were queried up to April 2023 for trials reporting indicators of left cardiac structure and function in patients with HFrEF treated with SGLT2i. Data from studies were pooled using a random‐effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). Six trials were included (n = 555). Compared with control, SGLT2i significantly improved left ventricular end‐diastolic volume (LVEDV; WMD: −17.07 ml [−23.84, −10.31]; p < 0.001), LVEDV index (WMD: −5.62 ml/m2 [−10.28, −0.97]; p = 0.02), left ventricular end‐systolic volume (LVESV; WMD: −15.63 ml [−26.15, −5.12]; p = 0.004), LVESV index (WMD: −6.90 ml/m2 [−10.68, −3.11]; p = 0.001), left ventricular ejection fraction (WMD: 2.71% [0.70, 4.72]; p = 0.008), and left atrial volume index (WMD: −2.19 ml/m2 [−4.26, −0.11]; p = 0.04) in patients with HFrEF. SGLT2i use was associated with a non‐significant trend towards a reduction in left ventricular mass index (WMD: −6.25 g/m2 [−12.79, 0.28]; p = 0.06). No significant impact on left ventricular global longitudinal strain was noted (WMD: 0.21% [−0.25, 0.67]; p = 0.38). Conclusions: Sodium–glucose cotransporter 2 inhibitors improve cardiac structure and function in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Aim: Persistent symptoms despite guideline‐directed medical therapy (GDMT) and poor tolerance of GDMT are hallmarks of patients with advanced heart failure (HF) with reduced ejection fraction (HFrEF). However, real‐world data on GDMT use, dose, and prognostic implications are lacking. Methods and results: We included 699 consecutive patients with HFrEF and at least one 'I NEED HELP' marker for advanced HF enrolled in a multicentre registry. Beta‐blockers (BB) were administered to 574 (82%) patients, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor–neprilysin inhibitors (ACEi/ARB/ARNI) were administered to 381 (55%) patients and 416 (60%) received mineralocorticoid receptor antagonists (MRA). Overall, ≥50% of target doses were reached in 41%, 22%, and 56% of the patients on BB, ACEi/ARB/ARNI and MRA, respectively. Hypotension, bradycardia, kidney dysfunction and hyperkalaemia were the main causes of underprescription and/or underdosing, but up to a half of the patients did not receive target doses for unknown causes (51%, 41%, and 55% for BB, ACEi/ARB/ARNI and MRA, respectively). The proportions of patients receiving BB and ACEi/ARB/ARNI were lower among those fulfilling the 2018 HFA‐ESC criteria for advanced HF. Treatment with BB and ACEi/ARB/ARNI were associated with a lower risk of death or HF hospitalizations (adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48–0.84, and HR 0.74, 95% CI 0.58–0.95, respectively). Conclusions: In a large, real‐world, contemporary cohort of patients with severe HFrEF, with at least one marker for advanced HF, prescription and uptitration of GDMT remained limited. A significant proportion of patients were undertreated due to unknown reasons suggesting a potential role of clinical inertia either by the prescribing healthcare professional or by the patient. Treatment with BB and ACEi/ARB/ARNI was associated with lower mortality/morbidity. [ABSTRACT FROM AUTHOR]

Background: Pacemaker‐induced cardiomyopathy is a well described phenomenon in patients with preserved ejection fraction at the time of permanent pacemaker implant. One of the identified risk factors for pacemaker‐induced cardiomyopathy is the degree of ventricular pacing burden. However, it is unclear how a high right ventricular pacing burden affects patients with depressed left ventricular function at the time of pacemaker implantation. We sought to assess the relationship between right ventricular pacing and change in left ventricular function over time. Methods: We conducted an analysis of all patients who had received either a single or dual lead cardiac implantable electronic devices, excluding biventricular devices, and had a prior transthoracic echocardiogram demonstrating an ejection fraction of less than 50%. The primary end‐point was the correlation between the percentage of ventricular pacing and the change in LV ejection fraction. Results: Fifty eight patients with preceding heart failure had pacemakers implanted and had follow up echocardiograms. There was no correlation between the degree of ventricular pacing and the absolute change in LV function (r =.04, p =.979). None of the previously identified risk factors for pacemaker induced cardiomyopathy were predictive of a significant fall in ejection fraction. Conclusion: The degree of RV pacing and other established risk factors for pacemaker‐induced cardiomyopathy in patients with normal left ventricular function at the time of implantation do not appear to carry the same risk in patients with pre‐existing heart failure who receive either single or dual lead pacemakers. [ABSTRACT FROM AUTHOR]

Dapagliflozin was recently approved for use in adults with chronic heart failure with reduced ejection fraction (HFrEF) with/without type 2 diabetes mellitus (T2DM). The objectives of this analysis were to characterize dapagliflozin pharmacokinetics in patients with HFrEF and to compare dapagliflozin systemic exposure between adults with HFrEF with/without T2DM and adults with T2DM. A nonlinear mixed‐effects modelling approach was applied; the population‐pharmacokinetic model was developed using 9735 dapagliflozin plasma concentrations from 2744 patients. The final two‐compartmental model adequately described the observed dapagliflozin concentrations, with a similar estimated apparent clearance compared with a previous estimate in patients with T2DM without HF and in healthy subjects (23.0 [95% CI: 22.6–23.9] L/h vs. 22.9 [95% CI: 22.1–23.7] L/h). The model‐predicted median area under the dapagliflozin concentration–time profile was ≤1.2‐fold higher in patients with HFrEF vs. those with T2DM without HFrEF, which is not considered clinically relevant. Dapagliflozin exposure was similar between patients with HFrEF with/without T2DM and T2DM patients without HFrEF. [ABSTRACT FROM AUTHOR]

Background: Kidney dysfunction (KD) is a main limiting factor of applying guideline‐directed medical therapy (GDMT) and reaching the recommended target doses (TD) in heart failure (HF) with reduced ejection fraction (HFrEF). Hypothesis: We aimed to assess the success of optimization, long‐term applicability, and adherence of neurohormonal antagonist triple therapy (TT:RASi [ACEi/ARB/ARNI] + βB + MRA) according to the KD after a HF hospitalization and to investigate its impact on prognosis. Methods: The data of 247 real‐world, consecutive patients were analyzed who were hospitalized in 2019−2021 for HFrEF and then were followed‐up for 1 year. The application and the ratio of reached TD of TT at hospital discharge and at 1 year were assessed comparing KD categories (eGFR: ≥90, 60−89, 45−59, 30−44, <30 mL/min/1.73 m2). Moreover, 1‐year all‐cause mortality and rehospitalization rates in KD subgroups were investigated. Results: Majority of the patients received TT at hospital discharge (77%) and at 1 year (73%). More severe KD led to a lower application ratio (p <.05) of TT (92%, 88%, 80%, 73%, 31%) at discharge and at 1 year (81%, 76%, 76%, 68%, 40%). Patients with more severe KD were less likely (p <.05) to receive TD of MRA (81%, 68%, 78%, 61%, 52%) at discharge and a RASi (53%, 49%, 45%, 21%, 27%) at 1 year. One‐year all‐cause mortality (14%, 15%, 16%, 33%, 48%, p <.001), the ratio of all‐cause rehospitalizations (30%, 35%, 40%, 43%, 52%, p =.028), and rehospitalizations for HF (8%, 13%, 18%, 20%, 38%, p =.001) were significantly higher in more severe KD categories. Conclusions: KD unfavorably affects the application of TT in HFrEF, however poorer mortality and rehospitalization rates among them highlight the role of the conscious implementation and up‐titration of GDMT. [ABSTRACT FROM AUTHOR]

Background: Left ventricular remodeling (LVR) is a key factor leading to the onset and progression of heart failure with reduced ejection fraction (HFrEF). Improving LVR can delay the progression of HFrEF and improve quality of life. Objective: To evaluate the improvement effect of Astragalus membranaceus (A. membranaceus) on LVR in patients with HFrEF. Method: We retrieved randomized controlled trials (RCTs) of A. membranaceus in treating HFrEF from eight Chinese and English databases, up until 31 October 2023. To assess the quality of the literature, we utilized the bias risk tool from the Cochrane Handbook. For meta-analysis, we employed Review Manager 5.4.1 software. Additionally, we performed sensitivity analysis and publication bias assessment using Stata 17.0 software. Result: Totally 1,565 patients were included in 19 RCTs. Compared to conventional treatment (CT), the combination therapy of A. membranaceus with CT demonstrated significant improvements in LVR, specifically increasing left ventricular ejection fraction (LVEF, MD = 5.82, 95% CI: 4.61 to 7.03, p < 0.00001), decreasing left ventricular end-diastolic diameter (LVEDD, MD = -4.05, 95% CI: -6.09 to -2.01, p = 0.0001), and left ventricular end-systolic diameter (LVESD, MD = -12.24, 95% CI: -15.24 to -9.24, p < 0.00001). The combination therapy of A. membranaceus with CT also improved clinical efficacy (RR = 4.81, 95% CI: 3.31 to 7.00, p < 0.00001), reduced brain natriuretic peptide (BNP, MD = -113.57, 95% CI: -146.91 to -81.22, p < 0.00001) level, and increased 6-min walking distance (6-MWD, MD = 67.62, 95% CI: 41.63 to 93.60, p < 0.00001). In addition, the combination therapy of A. membranaceus with CT mitigated inflammatory responses by reducing tumor necrosis factor-alpha (TNF-a, MD = -16.83, 95% CI: -22.96 to -10.71, p < 0.00001), interleukin-6 (IL-6, MD = -29.19, 95% CI: -36.08 to -22.30, p < 0.00001), and high-sensitivity C-reactive protein (hs-CRP, MD = -0.98, 95% CI: -1.43 to -0.52, p < 0.0001). Notably, the combination therapy of A. membranaceus with CT did not increase the incidence of adverse reactions (RR = 0.86, 95% CI: 0.25 to 2.96, p = 0.81). Conclusion: This systematic review and meta-analysis revealed that the combination therapy of A. membranaceus with CT hasmore advantages thanCT alone in improving LVR and clinical efficacy in HFrEF patients, without increasing the incidence of adverse reactions. However, due to the limited quality of included studies, more high-quality investigations are required to provide reliable evidence for clinical use. [ABSTRACT FROM AUTHOR]

(1) Background: Besides the use of guideline-directed medical therapy (GDMT), multidisciplinary heart failure (HF) outpatient care (HFOC) is of strategic importance in HFrEF. (2) Methods: Data from 257 hospitalised HFrEF patients between 2019 and 2021 were retrospectively analysed. Application and target doses of GDMT were compared between HFOC and non-HFOC patients at discharge and at 1 year. 1-year all-cause mortality (ACM) and rehospitalisation (ACH) rates were compared using the Cox proportional hazard model. The effect of HFOC on GDMT and on prognosis after propensity score matching (PSM) of 168 patients and the independent predictors of 1-year ACM and ACH were also evaluated. (3) Results: At 1 year, the application of RASi, MRA and triple therapy (TT: RASi + βB + MRA) was higher (p < 0.05) in the HFOC group, as was the proportion of target doses of ARNI, βB, MRA and TT. After PSM, the composite of 1-year ACM or ACH was more favourable with HFOC (propensity-adjusted HR = 0.625, 95% CI = 0.401–0.974, p = 0.038). Independent predictors of 1-year ACM were age, systolic blood pressure, application of TT and HFOC, while 1-year ACH was influenced by the application of TT. (4) Conclusions: HFOC may positively impact GDMT use and prognosis in HFrEF even within the first year of its initiation. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is frequently found in patients with heart failure with reduced ejection fraction (HFrEF) and is associated with reduced exercise capacity, poor quality of life and adverse outcomes. Recent evidence suggests that axial thoracic skeletal muscle size could be used as a surrogate to assess sarcopenia in HFrEF. Since diabetes mellitus (DM) is one of the most common comorbidities with HFrEF, we aimed to explore the potential association of axial thoracic skeletal muscle size with left ventricular (LV) remodeling and determine its prognostic significance in this condition. Methods: A total of 243 diabetes patients with HFrEF were included in this study. Bilateral axial thoracic skeletal muscle size was obtained using cardiac MRI. Patients were stratified by the tertiles of axial thoracic skeletal muscle index (SMI). LV structural and functional indices, as well as amino-terminal pro-B-type natriuretic peptide (NT-proBNP), were measured. The determinants of elevated NT-proBNP were assessed using linear regression analysis. The associations between thoracic SMI and clinical outcomes were assessed using a multivariable Cox proportional hazards model. Results: Patients in the lowest tertile of thoracic SMI displayed a deterioration in LV systolic strain in three components, together with an increase in LV mass and a heavier burden of myocardial fibrosis (all P < 0.05). Moreover, thoracic SMI (β = -0.25; P < 0.001), rather than body mass index (β = -0.04; P = 0.55), was independently associated with the level of NT-proBNP. The median follow-up duration was 33.6 months (IQR, 20.4–52.8 months). Patients with adverse outcomes showed a lower thoracic SMI (40.1 [34.3, 47.9] cm2/m2 vs. 45.3 [37.3, 55.0] cm2/m2; P < 0.05) but a similar BMI (P = 0.76) compared with those without adverse outcomes. A higher thoracic SMI indicated a lower risk of adverse outcomes (hazard ratio: 0.96; 95% confidence interval: 0.92–0.99; P = 0.01). Conclusions: With respect to diabetes patients with HFrEF, thoracic SMI is a novel alternative for evaluating muscle wasting in sarcopenia that can be obtained by a readily available routine cardiac MRI protocol. A reduction in thoracic skeletal muscle size predicts poor outcomes in the context of DM with HFrEF. [ABSTRACT FROM AUTHOR]

The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Iron deficiency correction with ferric carboxymaltose improves symptoms and reduces rehospitalization in patients with reduced left ventricular ejection fraction. The mechanisms underlying these improvements are poorly understood. This study aimed to determine changes in left ventricular contractility after iron treatment as reflected in global longitudinal strain. Methods: Prospective single‐center study including 43 adults with reduced ejection fraction, non‐anemic iron deficiency, and functional class II‐III heart failure despite optimal medical treatment. Global longitudinal strain through speckle‐tracking echocardiography was measured at baseline and 4 weeks after ferric carboxymaltose. Results: A significant improvement in global longitudinal strain was detected (from −12.3% ± 4.0% at baseline to −15.6% ± 4.1%, p <.001); ferritin and transferrin saturation index had increased, but ejection fraction presented no significant changes (baseline 35.7% ± 4.6%, follow‐up 37.2% ± 6.6%, p =.073). Conclusions: In patients with heart failure and reduced ejection fraction, the correction of iron deficiency with ferric carboxymaltose is associated with an early improvement in global longitudinal strain, possibly suggesting a direct effect of iron correction on myocardial contractility. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Hospital Pharmacy / Journal Canadien de la Pharmacie Hospitalière is the property of Canadian Society of Hospital Pharmacists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Hospital Pharmacy / Journal Canadien de la Pharmacie Hospitalière is the property of Canadian Society of Hospital Pharmacists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim of the Study: To estimate the prevalence of iron deficiency in patients of heart failure with reduced ejection fraction & response to injectable iron therapy in patients with iron deficiency anemia in heart failure with reduced ejection fraction. Materials and Methods: 1000 patients with heart failure with reduced ejection fraction (HFrEF; left ventricular ejection fraction <40%) who met the prespecified inclusion and exclusion criteria were chosen. A detailed history was taken and clinical examination was performed. Peripheral venous blood was drawn, and a complete hemogram along with iron studies (iron, ferritin, transferrin saturation and total iron binding capacity) were performedResults: Prevalence of iron deficiency among patients of heart failure with reduced ejection fraction was 63%. Most of the patients (71.42%) had absolute iron deficiency whereas 28.57% cases had functional iron deficiency status. 520(82.53%) patients were found to be anemic and 110(17.46%) patients were non anemic which was statistically significant, suggesting that the prevalence of iron deficiency was higher among all anaemic patients with heart failure with reduced ejection fraction, as compared to non-anaemic individuals. The use of injectable iron therapy significantly improved the NYHA functional status among all the patients of heart failure with reduced ejection fraction. Conclusion: Our study showed that there is a large burden of iron deficiency in patients of heart failure with reduced ejection fraction irrespective of anemia status. The correction of iron deficiency, irrespective of the presence or absence of concomitant anemia, improves the NYHA functional status and quality of life. It may therefore be prudent to assess and use iron status as a therapeutic target in all patients with heart failure even with normal hemoglobin levels. [ABSTRACT FROM AUTHOR]

The guidelines released by the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) in 2022 and those released in 2021 by the European Society of Cardiology (ESC) play a crucial role in offering evidence-based recommendations for the diagnosis and management of heart failure (HF). This comprehensive review aims to provide an overview of these guidelines, incorporating insights from relevant clinical trials. While there is considerable alignment between the two sets of guidelines, certain notable differences arise due to variations in publication timelines, which we will outline. By presenting this summary, our objective is to empower clinicians to make informed decisions regarding HF management in their own practice, and facilitate the development of more harmonized guidelines in the future. [ABSTRACT FROM AUTHOR]

Background: Type 2 sodium-glucose cotransporter inhibitors (SGLT2i) are among the main therapeutic options for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the effects of SGLT2i on the echocardiographic parameters of left (LV) and right (RV) ventricular function among outpatients with a long history of HFrEF, in optimized therapy. Methods: We evaluated consecutive patients affected by HFrEF in whom the SGLT2i therapy was prescribed. Following a baseline evaluation (T0), in which SGLT2i was prescribed, patients were re-evaluated at 3 (T3), 6 (T6), and 12 (T12) months. Results: We considered 60 patients for the analysis with a median history of HFrEF of more than seven years in optimal medical and electrical therapy. After SGLT2i therapy, LV ejection fraction and LV global longitudinal strain improved from baseline at T3, T6, and T12. Analogously, RV global and free wall longitudinal strain improved at T3 and T6. Conclusions: Our study shows that the addition of SGLT2i to the optimized therapy for HFrEF was associated with a significant improvement in both LV and RV function, thus highlighting a possible mechanism responsible for the benefit obtained with this class of drugs. [ABSTRACT FROM AUTHOR]

Aims: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but remain underused and are often discontinued especially in patients with chronic kidney disease (CKD) due to concerns on renal safety. Therefore, in a real‐world HFrEF population we investigated the safety of MRA use, in terms of risk of renal events, any mortality and any hospitalization, across the estimated glomerular filtration rate (eGFR) spectrum including severe CKD. Methods and results: We analysed patients with HFrEF (ejection fraction <40%), not on dialysis, from the Swedish Heart Failure Registry. We performed multivariable logistic regression models to investigate patient characteristics independently associated with MRA use, and univariable and multivariable Cox regression models to assess the associations between MRA use and outcomes. Of 33 942 patients, 17 489 (51%) received MRA, 32%, 45%, 54%, 54% with eGFR <30, 30–44, 45–59 or ≥60 ml/min/1.73 m2, respectively. An eGFR ≥60 ml/min/1.73 m2 and patient characteristics linked with more severe HF were independently associated with more likely MRA use. In multivariable analyses, MRA use was consistently not associated with a higher risk of renal events (i.e. composite of dialysis/renal death/hospitalization for renal failure or hyperkalaemia) (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.98–1.10), all‐cause death (HR 1.02, 95% CI 0.97–1.08) as well as of all‐cause hospitalization (HR 0.99, 95% CI 0.95–1.02) across the eGFR spectrum including also severe CKD. Conclusions: The use of MRAs in patients with HFrEF decreased with worse renal function; however their safety profile was demonstrated to be consistent across the entire eGFR spectrum. [ABSTRACT FROM AUTHOR]

Whether sodium–glucose cotransporter-2 inhibitors (SGLT2is) reduce ventricular arrhythmias and sudden cardiac death is controversial. Ventricular repolarization heterogeneity is associated with ventricular arrhythmias; however, the effect of SGLT2is on ventricular repolarization in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully investigated. We prospectively evaluated 31 HFrEF patients in sinus rhythm who were newly started on dapagliflozin 10 mg/day. Changes in QT interval, corrected QT interval (QTc), QT dispersion (QTD), corrected QTD (QTcD), T peak to T end (TpTe), TpTe/QT ratio, and TpTe/QTc ratio were evaluated at 1-year follow-up. QT interval, QTc interval, QTD, QTcD, TpTe, and TpTe/QTc ratio decreased significantly at 1-year follow-up (427.6 ± 52.6 ms vs. 415.4 ± 35.1 ms; p = 0.047, 437.1 ± 37.3 ms vs. 425.6 ± 22.7 ms; p = 0.019, 54.1 ± 11.8 ms vs. 47.6 ± 14.7 ms; p = 0.003, 56.0 ± 11.2 ms vs. 49.4 ± 12.3 ms; p = 0.004, 98.0 ± 15.6 ms vs. 85.5 ± 20.9 ms; p = 0.018, and 0.225 ± 0.035 vs. 0.202 ± 0.051; p = 0.044, respectively). TpTe/QT ratio did not change significantly (0.231 ± 0.040 vs. 0.208 ± 0.054; p = 0.052). QT interval, QTD, and TpTe were significantly reduced 1 year after dapagliflozin treatment in patients with HFrEF. The beneficial effect of dapagliflozin on the heterogeneity of ventricular repolarization may contribute to the suppression of ventricular arrhythmias. Registry informationhttps://center6.umin.ac.jp/cgi-open-bin/ctr/ctr%5fview.cgi?recptno=R000049428. Registry number: UMIN000044902. [ABSTRACT FROM AUTHOR]

The development of implantable cardiac devices brought a spectacular improvement in the prognosis of patients with heart failure with reduced ejection fraction, reducing the risk of sudden cardiac death by implanting a cardiac defibrillator, improving ventricular remodeling through cardiac resynchronization and, at the same time, increasing the pa-tient's functional capacity, reducing decompensation episodes and hospitalization. Phys-ical training at moderate exercise intensity is safe and effective in patients with heart fail-ure and cardiac implantable devices; even if they have a severely impaired effort capacity and device-related issues, the assessment of the disease status and of the device parame-ters before the enrollment in the training program warrants the improvement of physical performance and disease outcomes without notable adverse events. [ABSTRACT FROM AUTHOR]

Background: Limited evidence regarding the use of guideline directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) undergoing coronary artery bypass grafting (CABG) is available. Objective: The purpose of this study was to characterize prescription of HFrEF GDMT use before and after CABG. Methods: A retrospective analysis of adult patients with an ejection fraction ≤40% undergoing CABG was performed. The primary objective was to evaluate patients receiving HFrEF GDMT, defined as a heart failure beta-blocker (HFBB) and a renin-angiotensin inhibitor preoperatively and postoperatively. Secondary outcomes included dosing, percent of patients on each individual therapy, mineralocorticoid receptor antagonist (MRA) use, and the combination thereof. The follow up period was 1 year. Results: Thirty-eight patients met criteria for inclusion. Prior to CABG, 52.6% of patients were receiving HFrEF GDMT. The prescribing rate of HFrEF GDMT was not significantly higher at any point within 1 year postoperatively (P =.299). The rate of renin-angiotensin inhibitors, HFBB, and aldosterone antagonists use significantly increased from 13.2% preoperatively to 36.8% at 1 year after CABG (P =.022). Doses of individual therapies were not significantly different across all time points preoperatively and postoperatively. Conclusion: HFrEF GDMT use and doses of individual therapies after CABG were not maximized. Collaborative efforts between cardiac surgeons, heart failure cardiologists, and pharmacists could be used to optimize HFrEF GDMT use and dose titration. [ABSTRACT FROM AUTHOR]

Background: Transthyretin cardiac amyloidosis (ATTR-CM) is classically thought of as a progressive disease with preserved systolic function. The longitudinal clinical trajectories of ATTR-CM with impaired left ventricular ejection fraction (LVEF) remain unclear. Methods: This is a single-center retrospective cohort study of consecutive patients with ATTR-CM who underwent two or more echocardiograms with baseline LVEF < 50%. Patients were stratified according to the presence of ≥5% change in LVEF. A Cox proportional hazard model examined hazard of a composite outcome of death, transplant, or LVAD insertion over the two years following diagnosis. Results: In our study cohort of 179 patients, 62 patients (34.6%) experienced an increase in LVEF while 33 (18.4%) experienced a decrease in LVEF. After adjusting for covariates, patients with a decrease in EF experienced increased hazard of death (HR 2.15, 95% CI 1.05–4.40, p = 0.038) compared to those with stable or an increase in LVEF. Changes in LVEF corresponded with significant differences in NT proBNP trajectories, but initial biomarker levels or clinical staging were not predictive of LVEF trajectory. Conclusions: in ATTR-CM patients with impaired LVEF, over a third demonstrated improved LVEF over time, while those with a decrease in LVEF had worse long-term outcomes. [ABSTRACT FROM AUTHOR]

Aims: The pathophysiology of pulmonary hypertension (PH) due to left‐sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left‐sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)–soluble guanylate cyclase–cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. Methods and results: This was a single‐centre, retrospective study with a median follow‐up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty‐four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: −2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all‐cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27–14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. Conclusions: Patients with Group 2 PH were tolerant of the inhaled NO test. NO‐induced PAWP is a novel prognostic indicator. [ABSTRACT FROM AUTHOR]

Aims: The long‐term effect of angiotensin receptor–neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1 year of heart failure (HF) treatment. Methods and results: The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1 year of undergoing index echocardiography. After 1 year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow‐up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all‐cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4 ± 14.1 years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow‐up (median follow‐up, 44 [interquartile range, 34–51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P = 0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs. Conclusions: Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1 year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Patients with an established diagnosis of heart failure (HF) with reduced ejection fraction (HFrEF) are prone to experience episodes of worsening symptoms and signs despite continued therapy, termed "worsening heart failure" (WHF). Despite guideline-directed medical therapy, worsening of chronic heart failure accounts for almost 50% of all hospital admissions for HF, and patients experiencing WHF carry a substantially higher risk of death and hospitalization than patients with "stable" HF. New drugs are emerging as arrows in the quiver for clinicians to address the residual risk of HF hospitalization and cardiovascular deaths in patients with WHF. This question-and-answer-based review will discuss the emerging definition of WHF in light of the recent clinical consensus released by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC), the new therapeutic approaches to treat WHF and then move on to their timing and safety concerns (i.e., renal profile). [ABSTRACT FROM AUTHOR]

Vitamin D emerged as an important prognostic biomarker in heart failure (HF), with currently highly debated therapeutic implications. Several trials on vitamin D supplementation in HF showed improvements in left ventricular (LV) remodeling and function and health-related quality of life (HRQoL), which did not translate into mid- to long-term beneficial effects regarding physical performance and mortality. We addressed total 25-hydroxyvitamin D (25(OH)D), serum albumin, and uric acid (UA) levels, focusing mainly on vitamin D deficiency, as potential markers of LV systolic dysfunction in HF with reduced and mildly reduced ejection fraction (HFrEF, HFmrEF). Seventy patients with LVEF < 50% were comprehensively evaluated using ECG, echocardiography, lung ultrasound (LUS), blood sampling, and the six-minute walk test (6MWT). HRQoL was also assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Statistically significant positive correlations were found between LVEF, 25(OH)D, serum UA, and albumin, respectively (p = 0.008, p = 0.009, and p = 0.001). Serum UA (7.4 ± 2.4 vs. 5.7 ± 2.1, p = 0.005), NT-proBNP levels (1090.4 (675.2–2664.9) vs. 759.0 (260.3–1474.8), p = 0.034), and MLHFQ scores (21.0 (14.0–47.0) vs. 14.5 (4.5–25.5), p = 0.012) were significantly higher, whereas 25(OH)D concentrations (17.6 (15.1–28.2) vs. 22.7 (19.5–33.8), p = 0.010) were lower in subjects with severely reduced LVEF. Also, 25(OH)D was independently associated with LVEF in univariate and multiple regression analysis, maintaining its significance even after adjusting for confounders such as age, NT-proBNP, the presence of chronic coronary syndrome, hypertension, and anemia. According to our current findings, 25(OH)D is closely associated with LVEF, further supporting the need to establish correct vitamin D supplementation schemes and dietary interventions in HF. The changes in LVEF, 25(OH)D, serum UA, and albumin levels in HFrEF and HFmrEF indicate a similar pathophysiological background. [ABSTRACT FROM AUTHOR]

Aims: Although trials have proven the group‐level effectiveness of various therapies for heart failure with reduced ejection fraction (HFrEF), important differences in absolute effectiveness exist between individuals. We developed and validated the LIFEtime‐perspective for Heart Failure (LIFE‐HF) model for the prediction of individual (lifetime) risk and treatment benefit in patients with HFrEF. Methods and results: Cox proportional hazards functions with age as the time scale were developed in the PARADIGM‐HF and ATMOSPHERE trials (n = 15 415). Outcomes were cardiovascular death, heart failure (HF) hospitalization or cardiovascular death, and non‐cardiovascular mortality. Predictors were age, sex, New York Heart Association class, prior HF hospitalization, diabetes mellitus, extracardiac vascular disease, systolic blood pressure, left ventricular ejection fraction, N‐terminal pro‐B‐type natriuretic peptide, and glomerular filtration rate. The functions were combined in life‐tables to predict individual overall and HF hospitalization‐free survival. External validation was performed in the SwedeHF registry, ASIAN‐HF registry, and DAPA‐HF trial (n = 51 286). Calibration of 2‐ to 10‐year risk was adequate, and c‐statistics were 0.65–0.74. An interactive tool was developed combining the model with hazard ratios from trials to allow estimation of an individual's (lifetime) risk and treatment benefit in clinical practice. Applying the tool to the development cohort, combined treatment with a mineralocorticoid receptor antagonist, sodium–glucose cotransporter 2 inhibitor, and angiotensin receptor–neprilysin inhibitor was estimated to afford a median of 2.5 (interquartile range [IQR] 1.7–3.7) and 3.7 (IQR 2.4–5.5) additional years of overall and HF hospitalization‐free survival, respectively. Conclusion: The LIFE‐HF model enables estimation of lifelong overall and HF hospitalization‐free survival, and (lifetime) treatment benefit for individual patients with HFrEF. It could serve as a tool to improve the management of HFrEF by facilitating personalized medicine and shared decision‐making. [ABSTRACT FROM AUTHOR]

Despite previous studies showing that patients with low systolic blood pressure (sBP) in heart failure with reduced ejection fraction (HFrEF) has a poor prognosis, it has few treatment options. This study aimed to investigate the efficacy and safety of sacubitril/valsartan (S/V) in HFrEF patients with hypotension. We included 43 consecutive HFrEF patients with sBP < 100 mmHg despite guideline-directed medical therapy for at least 3 months and who received S/V between September 2020 and July 2021. Patients admitted for acute heart failure were excluded and 29 patients were evaluated for safety endpoints. Furthermore, patients who performed non-pharmacological therapy or died within 1 month were excluded, finally, 25 patients were evaluated for efficacy endpoints. The mean initial S/V dose was 53.0 ± 20.5 mg/day and the mean dosage was increased to 84.0 ± 34.5 mg/day in 1 month. Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values significantly decreased from 2200 [interquartile range (IQR): 1462–3666] pg/ml to 1409 (IQR: 964–2451) pg/ml. (p < 0.0001). No significant change in sBP occurred (pre-sBP: 93.2 ± 4.9 mmHg, post-sBP: 93.4 ± 9.6 mmHg, p = 0.91), and no patients discontinued the S/V due to symptomatic hypotension in 1 month after S/V initiation. S/V can be safely introduced in HFrEF patients with hypotension to reduce serum NT-proBNP values. Thus, S/V may be useful for the treatment of HFrEF patients with hypotension. [ABSTRACT FROM AUTHOR]