Aims We compared the effects of 'ablate and pace' to pharmacological therapy on mortality and left ventricular ejection fraction (LVEF) in patients with atrial fibrillation (AF), with or without heart failure (HF). Methods and results Articles were identified by searching PubMed, Central, and Embase until 30 June 2024. Inclusion criteria encompassed observational and randomized controlled trials (RCTs) comparing 'ablate and pace' with pharmacological therapy and investigating outcomes of mortality and LVEF in patients with AF. An exclusion criterion was lack of a parallel study design. The primary outcomes were all-cause mortality and the mean difference (MD) in LVEF. Endpoints were assessed through meta-analyses computing relative risks (RRs) and MDs. The clinical diagnosis of HF was used to distinguish between patients with and without HF. Initially, 3837 studies were identified, of which 24 (n = 4292 patients) fulfilled the inclusion criteria, including 17 (n = 3261 patients) that focused on HF. Follow-up time varied from 3 to 96 months. Only in HF patients, 'ablate and pace' reduced mortality significantly with a risk reduction of 36% [RR, 0.64; 95% confidence interval (CI), 0.49-0.85; P < 0.01; n = 10] as compared with pharmacological therapy. Except for two studies, cardiac resynchronization therapy (CRT) was the chosen pace mode. The mortality reduction was independent of study design: RCTs (RR, 0.41; 95% CI, 0.18-0.94; P = 0.04; n = 2) and observational studies (RR, 0.70; 95% CI, 0.55-0.90; P = 0.01; n = 8). 'Ablate and pace' and pharmacological therapy were similar for the LVEF outcome (MD, 1.1; 95% CI, -1.6-3.8; P = 0.39; n = 16), which was independent of both HF and study designs (results not shown). Conclusion 'Ablate and CRT' reduced mortality in HF patients as compared with pharmacological therapy, which was supported by statistical associations in observational studies. A single RCT corroborated the finding.

AIMS:Iron deficiency (ID) is common in chronic heart failure (HF) and may disturb bone metabolism.We investigated the association of ID with bone mineral density (BMD), and the potential mediating roles of fibroblast growth factor 23 (FGF-23) and 1,25-dihydroxy vitamin D (1,25(OH)2 vitamin D) in patients with chronic HF from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). METHODS AND RESULTS:ID was defined as a transferrin saturation (TSAT) <20%. Among 198 patients (69 [61-76] years, 80% men), TSAT was <20% in 29.8% and associated with higher BMD (1.25 vs. 1.20 g/cm2, p=0.009), with a graded dose-response across TSAT quartiles (p for trend=0.0009). ID was also associated with higher serum FGF-23 (pg/mL; adjusted β=0.20, p=0.0009) and lower plasma 1,25(OH)2 vitamin D (30 vs. 35 pg/mL, p=0.03). In multivariable analyses, both TSAT <20% (adjusted odds ratio (aOR) 3.45, p=0.01) and lower plasma 1,25(OH)2 vitamin D (aOR 0.54, p=0.002) were associated with BMD above sex-specific medians. CONCLUSIONS:In HF, a TSAT <20% is associated with disturbed bone metabolism, possibly mediated by increases in serum FGF-23 and reductions in 1,25(OH)2 vitamin D concentrations. Detailed analyses of bone microstructure in HF are warranted.

Background:Patient-reported outcomes (PROs) are increasingly used as endpoints in clinical trials. However, the magnitude of observed changes in control arms attributable to placebo effects, as compared with other benefits of trial participation, has not been described.This study seeks to estimate the magnitude of the placebo effect by calculating changes in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores, which quantify the impact of heart failure on patients' symptoms, function, and quality of life, after participants were unblinded to treatment. Methods:REDUCE LAP-HF II randomized participants to atrial shunt or sham procedure, with unblinding after 2 years. The KCCQ was collected at baseline, 2, and 3 years after randomization. KCCQ-OS change from baseline to 2 years (placebo effect plus other benefits from trial participation) and the change from 2 to 3 years (placebo effect loss after unblinding) were calculated in sham-treated patients using mean±SD, as were changes from 2 to 3 years in shunt-treated patients (placebo effect benefit). Results:The analytic cohort included 421 participants (median age 72 years, 65.6% female). Among sham-treated participants (N=182), the mean±SD KCCQ-OS 2-year improvement from baseline was +9.3±22.4 points, with a decrement after unblinding of -1.7±18.2 points from 2 to 3 years. Among shunt-treated patients (N=239), mean±SD KCCQ-OS 2-year improvement was +12.7±22.8 points, with an improvement after unblinding of +1.9±18.2 points. In a hypothetical unblinded trial where placebo effect benefit would be expected in the active intervention arm, and none in the untreated arm, the combined effects would be 3.6 points. Conclusions:In a sham-controlled device trial that collected PRO data during blinded allocation to treatment or sham and after unblinding, the estimated mean placebo effect benefit and loss on the KCCQ-OS were small (≤2 points). Finding a modest placebo effect on PROs may increase confidence in their use as clinical trial outcomes.

BACKGROUND:With evolving therapy for heart failure with reduced ejection fraction, the benefits of adding a defibrillator in patients undergoing cardiac resynchronization therapy (CRT) remain unclear, particularly for nonischemic cardiomyopathy (NICM). This study evaluates long-term survival among patients with NICM treated with CRT defibrillator (CRT-D) versus CRT pacemaker (CRT-P). METHODS:DECIDE-CRT (Cardiac Resynchronization With or Without Defibrillator in Non-Ischemic Cardiomyopathy) is a multicenter cohort study across 170 US Veterans Affairs hospitals. We identified patients with NICM receiving primary-prevention CRT-P or CRT-D between January 1, 2006, and December 31, 2020. Using a propensity score approach, we applied inverse probability of treatment weighting to balance baseline characteristics between the CRT-P and CRT-D groups. An inverse probability of treatment weighting-weighted Cox model estimated hazards for all-cause mortality. Secondary outcomes included generator replacement, device-related infections, hospitalization for heart failure, and ventricular arrhythmias. RESULTS:Of 16 609 CRT recipients, 3965 met NICM primary-prevention criteria (CRT-D=3158; CRT-P=807). At baseline, patients with NICM receiving CRT-P were much older, with more cardiovascular and noncardiovascular comorbidities compared with the CRT-D group. During the median follow-up of 5.2 years, the mortality rate for CRT-P versus CRT-D was 9.46 versus 9.21 per 100 person-years (RR, 0.97 [95% CI, 0.71-1.13]; P=0.66). The adjusted hazard ratio for all-cause mortality using the inverse probability of treatment weighting-Cox model was 0.90 (95% CI, 0.71-1.13; P=0.34). There was no difference in adjusted hazard for heart failure hospitalization (hazard ratio, 1.27 [95% CI, 0.86-1.87]), while the CRT-D group had higher rates of generator replacement and device-related infections. CONCLUSIONS:This nationwide observational study from the Veterans Affairs Health system did not demonstrate a clear survival advantage with the addition of a defibrillator among patients with NICM receiving CRT although residual confounding cannot be excluded. Given the uncertainty surrounding the incremental benefit of the defibrillator in this setting, a randomized trial is needed to test the incremental value of CRT-D over CRT-P in NICM.

Renal artery stenosis due to atherosclerotic renovascular disease (ARVD) is common but under-recognized amongst patients with heart failure and chronic kidney disease (CKD). Whether renal artery stenosis is just a manifestation of widespread atherosclerotic disease or a driver of heart failure symptoms, disease progression, and prognosis is controversial and may depend on distinguishing anatomic from functional renal artery stenosis. Anatomical renal artery stenosis can cause nephron damage due to micro-embolization/infarction or activation of inflammatory pathway, leading to a decline in estimated glomerular filtration rate (eGFR) and albuminuria. Functionally significant renal artery stenosis will, in addition, alter renal haemodynamics, favouring water and salt retention, and may cause nephron ischaemia. Clinical manifestations of renal artery stenosis include hypertension, a progressive decline in renal function, worsening heart failure, and 'flash pulmonary oedema'. Anatomical renal artery stenosis can be identified non-invasively using various methods but confirming functional significance may be difficult, creating uncertainty about which patients are likely to benefit from revascularization. If there is a large decline in eGFR after initiating renin-angiotensin-aldosterone system inhibitors (RAASi), this should raise the suspicion of functionally important renal artery stenosis. However, RAASi are an important first line therapy for both ARVD and heart failure. For patients with ARVD and heart failure, RAASi and other guideline-recommended therapies should be initiated with appropriate monitoring of renal function. Further randomized trials investigating the effects of renal revascularization of functionally significant renal artery stenosis on symptoms, renal function, diuretic efficacy, and prognosis in patients with heart failure are required.

KEY POINTS:Renin-angiotensin system inhibitors have less effect on decline in eGFR and no greater effect on delaying ESKD/KRT in patients receiving loop diuretics compared with those who do. Although loop diuretic use was not associated with higher rates of ESKD/KRT, it might be associated with a higher mortality. The decline in eGFR was slower in those taking loop diuretics. BACKGROUND:In the STOP-Angiotensin-Converting Enzyme Inhibitor trial, patients with advanced CKD were randomized to continue or stop renin-angiotensin system inhibitors (RASi) and showed no difference in kidney outcomes. This post hoc analysis investigates interactions with loop diuretic use. METHODS:Patients with eGFR <30 ml/min per 1.73 m 2 and progressive CKD were randomized to stop or continue RASi. Primary outcome was eGFR over 3 years using repeated-measures, mixed-effects linear regression, random-slope models. Cox models were used to calculate hazard ratios for time-to-event outcomes, including ESKD and KRT. RESULTS:At baseline, eGFR, arterial pressure, and proteinuria were similar for 133 patients taking loop diuretics and 278 who were not. Those receiving loop diuretics at randomization, least-squares mean (±SE) eGFR at 3 years was 12.3 (±1.1) for those stopping compared with 10.1 (±1.2) for those continuing RASi, trend favoring stopping RASi (+2.2; 95% confidence interval [CI], -0.9 to 5.4), but eGFR slope over 3 years was similar (-7.2 versus -7.7 ml/min per 1.73 m 2 ). Those not receiving loop diuretics, eGFR at 3-years was 8.8 (±0.8) and 11.6 (±0.8; discontinue and continue RASi groups), a difference favoring continuing RASi (-2.8; 95% CI, -4.9 to -0.8), and a steeper eGFR slope for those discontinuing RASi (-9.9 versus -7.6 ml/min per 1.73 m 2 ). The interaction between loop diuretic use and the effect of RASi on eGFR at 3 years and the three-way interaction between diuretic subgroup, effect of RASi, and time were both statistically significant ( P = 0.01 and P = 0.04, respectively). Of patients taking loop diuretics, 73 (55%) developed ESKD/KRT and 23 (17%) died. Of patients not taking loop diuretics, 170 (61%) developed ESKD/KRT and 19 (7%) died. CONCLUSIONS:Withdrawal of RASi was associated with a steeper decline in eGFR over 3 years in those not receiving loop diuretics, but this was not observed in those who were taking loop diuretics. Patients receiving loop diuretics had a high mortality. These data support the need for randomized trials investigating the efficacy and safety of loop diuretics in patients with advanced CKD.

BACKGROUND:Iron deficiency (ID) is common in patients with heart failure (HF). Current guidelines define ID based on serum ferritin and transferrin saturation (TSAT) rather than soluble transferrin receptor (STFR) or ratios such as iron/STFR or TSAT/STFR. We investigated the associations between these biomarkers and prognosis in patients with new-onset HF with reduced ejection fraction (HFrEF). METHODS:All patients hospitalised in 2016-2020 at Sahlgrenska University Hospital with new-onset HFrEF who had iron biomarkers measured within 6 months of discharge were included, with follow-up from the date of the iron biomarker test until 31 December 2021. The primary composite event of interest was first re-hospitalisation for HF (HHF) or all-cause mortality. The associations between ID biomarkers and endpoints were analysed using Cox regression adjusted for age, sex, previous HF, left ventricular ejection fraction, HF medications and comorbidity. Bonferroni-Holm correction was applied for multiple testing. RESULTS:Of 325 patients included (median age 68 (57-76) years, 70.2% men), 168 (52%) had ID using current guideline criteria and STFR was available for 224 (69%) patients. Median follow-up was 2.2 years. In the prespecified analysis plan, biomarkers of ID were not statistically significantly associated with the primary composite endpoint, although each SD increase in TSAT was associated with 56% lower risk of HHF (0.44 [0.27-0.71]) as were increased ratios of iron/STFR (0.58 [0.40-0.86]) and TSAT/STFR (0.55 [0.37-0.83]). However, in a post hoc sensitivity analysis in which patients with extreme values were excluded, each increase in SD of TSAT was associated with 47% lower risk of the primary composite endpoint (0.53 [0.35-0.79]). CONCLUSIONS:Lower TSAT is associated with a greater risk of clinical events in patients with new-onset HF, as were the ratios of iron/STFR and TSAT/STFR. However, neither ratio appeared to offer a substantial advantage compared with TSAT alone.

BACKGROUND AND AIMS:Many patients with cancer develop heart failure (HF), and many patients with HF develop cancer. Inter-relationships between their natural histories are rarely reported. METHODS:Health records were obtained for a Scottish region. People aged >50 years were classified by the presence or absence of HF, loop diuretics (a pharmacological marker of congestion), and cancer. Incident cancer, mortality, and cause of death were recorded. RESULTS:Of 317 178 people aged >50 years, 11 268 (3.6%) had HF of whom 6276 were prescribed loop diuretics; a further 19 044 (6.0%) received loop diuretics. Thus, 30 312 (9.6%) people met an expanded definition of heart failure (HFexp). Annual cancer incidence was slightly higher for those with HFexp (incidence rate ratio 1.10; P < .001), varying amongst cancer types. For people with neither cancer nor HFexp, mortality was <3% annually; most deaths were cardiovascular. For those with cancer but not HFexp, annual mortality was 6.3% for women and 9.0% for men; most died of cancer. For those with HFexp but not cancer, annual mortality ranged from 6.6% to 18.4% depending on sex and HFexp criteria applied; most deaths were cardiovascular. For those with both cancer and HFexp, annual mortality ranged from 14.5% to 28.4%; cardiovascular and cancer mortality rates were similar. Few patients died at home (∼20%). CONCLUSIONS:Patients with HFexp have a slightly higher risk of cancer overall, but this may vary according to cancer type. Patients with both cancer and HFexp have a poor prognosis with a similar proportion of deaths attributed to cancer and cardiovascular disease.

Importance:Current guidelines do not recommend primary prevention implantable cardioverter-defibrillators (ICDs) unless a patient's left ventricular ejection fraction (LVEF) is 35% or less. Many sudden cardiac deaths (SCD) occur when LVEF is 36% to 50%. Myocardial scar (a key arrhythmic substrate) can be assessed by late gadolinium enhancement on cardiovascular magnetic resonance (CMR), but robust evidence is lacking regarding a scar-based approach to ICD insertion. Objective:To determine whether implantation of ICDs reduces SCD or hemodynamically significant ventricular arrhythmia (HSVA) in patients with an LVEF of 36% to 50% and myocardial scar. Design, Setting, and Participants:An open-label randomized clinical trial enrolled adults between 2015 and 2022 who had ischemic or nonischemic cardiomyopathy, an LVEF of 36% to 50%, CMR-defined myocardial scar, and were receiving guideline-directed medical therapy at 18 sites in Australia, Germany, and the UK. Follow-up assessments were completed in 2026. Interventions:A primary prevention ICD (n = 180) vs an implantable loop recorder (ILR) (n = 173). Main Outcomes and Measures:The primary composite outcome was SCD or HSVA. Five secondary outcomes were evaluated: SCD, HSVA, heart failure-related hospitalization, cardiovascular mortality, and all-cause mortality. Results:Of 353 patients randomized (median age, 65 years [IQR, 57-61 years]; 18% female; and 72% had an ischemic etiology), 70% had an LVEF of 40% or greater. The median follow-up was 6.3 years (IQR, 4.8-7.6 years). The primary composite outcome occurred in 14 patients (7.8%) in the ICD group compared with 16 patients (9.2%) in the ILR group (hazard ratio [HR], 0.76 [95% CI, 0.37-1.58]). For the individual components of the primary composite outcome, SCD occurred in 3 patients (1.7%) vs 10 patients (5.8%) in the ILR group (HR, 0.26 [95% CI, 0.07-0.95]) and HSVA occurred in 12 patients (6.7%) vs 6 patients (3.5%), respectively (HR, 1.77 [95% CI, 0.65-4.81]). The rates for all-cause mortality, cardiovascular mortality, and heart failure-related hospitalization were similar between groups. In a prespecified analysis of 6 subgroups, the primary outcome occurred less often in patients younger than 70 years in the ICD group (3.3%) vs patients in the ILR group (10.0%) (HR, 0.28 [95% CI, 0.09-0.89]) but not in those aged 70 years or older (16.9% vs 7.5%, respectively) (HR, 2.33 [95% CI, 0.75-7.26]; P = .01 for interaction). Conclusions and Relevance:Implantation of an ICD did not reduce the composite outcome of SCD or HSVA in patients with an LVEF of 36% to 50% and myocardial scar. Trial Registration:ClinicalTrials.gov Identifier: NCT01918215.

This 2026 focused update of the original iCARDIO Alliance Global Implementation Guidelines on Heart Failure published in 2025 incorporates emerging evidence relevant to acute and chronic HF, including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and cardiomyopathies. When patients with HFrEF experience substantial improvement in LVEF they are commonly diagnosed as having HF with improved EF (HFimpEF). We define HFimpEF to be present, when in a patient who previously was diagnosed with HFrEF an improvement in the LVEF of at least 10 percentage points to an LVEF ≥50% is observed. The main updates in the therapeutic recommendations of the Global Implementation Guidelines on Heart Failure pertain to evolving data on the soluble guanylate cyclase stimulator vericiguat, cardiac glycosides, GLP-1 receptor agonists, cardiac myosin inhibitors, and preventive vaccination strategies. Revised recommendations were informed by recently published randomized trials, and selected additional post-hoc analyses and meta-analyses demonstrating improvements in symptoms, quality of life, HF hospitalization or mortality among patients receiving contemporary guideline-directed medical therapy (GDMT) regarding the approaches mentioned above. Consistent with the overarching iCARDIO Alliance framework, these recommendations additionally consider the feasibility, monitoring requirements, multidisciplinary expertise, and globally varying levels of healthcare resources. In selected cases, specific implementation guidance is provided for settings in which resources are somewhat limited or severely limited. Accordingly, this document provides a concise, evidence-informed, and globally applicable focused update to HF management strategies, aiming to support clinicians in optimizing HF care and improving patient outcomes across a broad range of healthcare systems worldwide.

BACKGROUND:Cancer and heart failure (HF) frequently coexist due to population ageing and improved survival for both conditions. HF is a well-recognised complication of oncologic therapies and a potential association between HF and subsequent cancer incidence has been recently noticed. We therefore conducted a meta-analysis to quantify cancer incidence and mortality in patients with and without HF. METHODS:Databases were searched from inception to 15 February 2026. Data from observational studies and randomised trials on individuals with and without HF and reporting cancer incidence and/or mortality during follow-up were included. The main outcome of interest was the incidence of any cancer; secondary outcomes included site-specific cancer incidence (lung, colorectal, breast, and prostate) and all-cause, cardiovascular, and cancer-related mortality. RESULTS:Twelve studies comprising 8,979,195 individuals were included. HF was associated with a higher incidence of cancer (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.14-1.54), with substantial heterogeneity (I2 = 99.7%). Cancer site-specific analyses showed increased incidences of lung (HR 1.70, 95% CI 1.26-2.29), colorectal (HR 1.28, 95% CI 1.11-1.48), and breast (HR 1.19, 95% CI 1.04-1.37), but not prostate, cancer. Effect estimates varied according to analytical strategy: matched HF and non-HF cohorts reported higher risk estimates than those using covariate adjustment without matching. Mortality data were sparse and heterogeneous. CONCLUSIONS:HF is associated with a higher incidence of cancer, although with marked heterogeneity among studies and cancer types. Mortality and cause of death were rarely reported. The observed HF-cancer association is influenced by statistical methodology, shared risk factors, differences in surveillance intensity and cancer type, that confound analyses investigating possible causal biological links. More granular and harmonised studies are required.

AIMS:Target-dose angiotensin-converting enzyme inhibitors (ACEIs), compared with below-target doses, have been associated with lower risks of death and kidney failure (KF) in patients with heart failure with reduced ejection fraction (HFrEF). We examined these associations in heart failure with preserved ejection fraction (HFpEF). METHODS:Among 96,473 Veterans with HFpEF (EF ≥ 50%) newly initiated on ACEIs (2000-2018), 32,728 received target doses recommended for HFrEF. Propensity scores for receiving target-dose ACEIs were used to assemble an outcome-blinded matched cohort of 61,160 patients (target-dose, n=30,580), balanced on 76 baseline characteristics. Outcomes were 5-year all-cause mortality, incident KF, and HF hospitalization. RESULTS:Compared with below-target-dose ACEIs, target-dose ACEIs were associated with a lower KF risk (HR, 0.89; 95% CI, 0.83-0.97), no mortality difference (HR, 0.99; 95% CI, 0.97-1.02), and a higher risk of HF hospitalization (HR, 1.08; 95% CI, 1.04-1.12). Among 16,735 patients with chronic kidney disease (CKD; eGFR 15-59 mL/min/1.73 m2), target-dose ACEIs were associated with a lower risk of KF (HR, 0.82; 95% CI, 0.75-0.90) and mortality (HR, 0.93; 95% CI, 0.89-0.96) without a higher HF hospitalization risk (HR, 0.95; 95% CI, 0.90-1.01). Each association differed significantly from those in patients with eGFR ≥ 60 mL/min/1.73 m2 (interaction p<0.001). CONCLUSION:In HFpEF, target-dose ACEIs were associated with a lower risk of KF, a higher risk of HF hospitalization, and no association with mortality. These associations were consistently more favorable in the subgroup with CKD. These findings underscore the importance of evaluating treatment strategies within biologically coherent HFpEF phenotypes.