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Aims: Sodium restriction was not associated with improved outcomes in heart failure patients in recent trials. The skin might act as a sodium buffer, potentially explaining tolerance to fluctuations in sodium intake without volume overload, but this is insufficiently understood. Therefore, we studied the handling of an increased sodium load in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: Twenty‐one ambulatory, stable HFrEF patients and 10 healthy controls underwent a 2‐week run‐in phase, followed by a 4‐week period of daily 1.2 g (51 mmol) sodium intake increment. Clinical, echocardiographic, 24‐h urine collection, and bioelectrical impedance data were collected every 2 weeks. Blood volume, skin sodium content, and skin glycosaminoglycan content were assessed before and after sodium loading. Sodium loading did not significantly affect weight, blood pressure, congestion score, N‐terminal pro‐brain natriuretic peptide, echocardiographic indices of congestion, or total body water in HFrEF (all p > 0.09). There was no change in total blood volume (4748 ml vs. 4885 ml; p = 0.327). Natriuresis increased from 150 mmol/24 h to 173 mmol/24 h (p = 0.024), while plasma renin decreased from 286 to 88 μU/L (p = 0.002). There were no significant changes in skin sodium content, total glycosaminoglycan content, or sulfated glycosaminoglycan content (all p > 0.265). Healthy controls had no change in volume status, but a higher increase in natriuresis without any change in renin. Conclusions: Selected HFrEF patients can tolerate sodium loading, with increased renal sodium excretion and decreased neurohormonal activation. [ABSTRACT FROM AUTHOR]

Aim: Phenylacetylglutamine (PAGln) is a phenylalanine‐derived metabolite produced by gut microbiota with mechanistic links to heart failure (HF)‐relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF. Methods and results: Fasting plasma PAGln levels were measured by stable‐isotope‐dilution liquid chromatography–tandem mass spectrometry (LC‐MS/MS) in patients with stable HF from two large cohorts. All‐cause mortality was assessed at 5‐year follow‐up in the Cleveland cohort, and HF, hospitalization, or mortality were assessed at 3‐year follow‐up in the Berlin cohort. Within the Cleveland cohort, median PAGln levels were 4.2 (interquartile range [IQR] 2.4–6.9) μM. Highest quartile of PAGln was associated with 3.09‐fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, estimated glomerular filtration rate, amino‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, left ventricular ejection fraction, ischaemic aetiology, and HF drug treatment, elevated PAGln levels remained predictive of 5‐year mortality in quartile comparisons (adjusted hazard ratio [HR] [95% confidence interval, CI] for Q4 vs Q1: 1.64 [1.07–2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 [IQR 2.0–4.8] μM), and PAGln levels were associated with a 1.92‐fold increase in 3‐year HF hospitalization or all‐cause mortality risk (adjusted HR [95% CI] for Q4 vs Q1: 1.92 [1.02‐3.61]). Prognostic value of PAGln appears to be independent of trimethylamine N‐oxide levels. Conclusion: High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio‐renal risk markers. [ABSTRACT FROM AUTHOR]

Novel pharmacologic treatment options reduce mortality and morbidity in a cost‐effective manner in patients with heart failure (HF). Undisputedly, the effective implementation of these agents is an essential element of good clinical practice, which is endorsed by the European Society of Cardiology (ESC) guidelines on acute and chronic HF. Yet, physicians struggle to implement these therapies as they have to balance the true and/or perceived risks versus their substantial benefits in clinical practice. Any worsening of biomarkers of renal function is often perceived as being disadvantageous and is in clinical practice one of the most common reasons for ineffective drug implementation. However, even in this context, they clearly reduce mortality and morbidity in HF with reduced ejection fraction (HFrEF) patients, even in patients with poor renal function. Furthermore these agents are also beneficial in HF with mildly reduced ejection fraction (HFmrEF) and sodium–glucose cotransporter 2 (SGLT2) inhibitors more recently demonstrated a beneficial effect in HF with preserved ejection fraction (HFpEF). The emerge of several new classes (angiotensin receptor–neprilysin inhibitor [ARNI], SGLT2 inhibitors, vericiguat, omecamtiv mecarbil) and the recommendation by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF of early initiation and titration of quadruple disease‐modifying therapies (ARNI/angiotensin‐converting enzyme inhibitor + beta‐blocker + mineralocorticoid receptor antagonist and SGLT2 inhibitor) in HFrEF increases the likelihood of treatment‐induced changes in renal function. This may be (incorrectly) perceived as deleterious, resulting in inertia of starting and uptitrating these lifesaving therapies. Therefore, the objective of this consensus document is to provide advice of the effect HF drugs on renal function. [ABSTRACT FROM AUTHOR]

Appropriate interpretation of changes in markers of kidney function is essential during the treatment of acute and chronic heart failure. Historically, kidney function was primarily assessed by serum creatinine and the calculation of estimated glomerular filtration rate. An increase in serum creatinine, also termed worsening renal function, commonly occurs in patients with heart failure, especially during acute heart failure episodes. Even though worsening renal function is associated with worse outcome on a population level, the interpretation of such changes within the appropriate clinical context helps to correctly assess risk and determine further treatment strategies. Additionally, it is becoming increasingly recognized that assessment of kidney function is more than just glomerular filtration rate alone. As such, a better evaluation of sodium and water handling by the renal tubules allows to determine the efficiency of loop diuretics (loop diuretic response and efficiency). Also, though neurohumoral blockers may induce modest deteriorations in glomerular filtration rate, their use is associated with improved long-term outcome. Therefore, a better understanding of the role of cardio-renal interactions in heart failure in symptom development, disease progression and prognosis is essential. Indeed, perhaps even misinterpretation of kidney function is a leading cause of not attaining decongestion in acute heart failure and insufficient dosing of guideline-directed medical therapy in general. This position paper of the Heart Failure Association Working Group on Cardio-Renal Dysfunction aims at improving insights into the interpretation of renal function assessment in the different heart failure states, with the goal of improving heart failure care. [ABSTRACT FROM AUTHOR]

Aim: To identify distinct phenotypic subgroups in a highly-dimensional, mixed-data cohort of individuals with heart failure (HF) with preserved ejection fraction (HFpEF) using unsupervised clustering analysis.Methods and Results: The study included all Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) participants from the Americas (n = 1767). In the subset of participants with available echocardiographic data (derivation cohort, n = 654), we characterized three mutually exclusive phenogroups of HFpEF participants using penalized finite mixture model-based clustering analysis on 61 mixed-data phenotypic variables. Phenogroup 1 had higher burden of co-morbidities, natriuretic peptides, and abnormalities in left ventricular structure and function; phenogroup 2 had lower prevalence of cardiovascular and non-cardiac co-morbidities but higher burden of diastolic dysfunction; and phenogroup 3 had lower natriuretic peptide levels, intermediate co-morbidity burden, and the most favourable diastolic function profile. In adjusted Cox models, participants in phenogroup 1 (vs. phenogroup 3) had significantly higher risk for all adverse clinical events including the primary composite endpoint, all-cause mortality, and HF hospitalization. Phenogroup 2 (vs. phenogroup 3) was significantly associated with higher risk of HF hospitalization but a lower risk of atherosclerotic event (myocardial infarction, stroke, or cardiovascular death), and comparable risk of mortality. Similar patterns of association were also observed in the non-echocardiographic TOPCAT cohort (internal validation cohort, n = 1113) and an external cohort of patients with HFpEF [Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial cohort, n = 198], with the highest risk of adverse outcome noted in phenogroup 1 participants.Conclusions: Machine learning-based cluster analysis can identify phenogroups of patients with HFpEF with distinct clinical characteristics and long-term outcomes. [ABSTRACT FROM AUTHOR]

Aims: Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium-conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure.Methods and Results: Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride ≤96 mmol/L and hyponatraemia as serum sodium ≤135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P < 0.001). However, when both parameters were included in the same model, serum chloride remained strongly associated with mortality [hazard ratio (HR) 1.3 per standard deviation decrease, 95% confidence interval (CI) 1.18-1.42, P < 0.001], whereas sodium was not (HR 0.97 per standard deviation decrease, 95% CI 0.89-1.06, P = 0.52).Conclusion: Serum chloride is strongly and independently associated with worsened survival in patients with chronic heart failure and accounted for the majority of the risk otherwise attributable to hyponatraemia. Given the critical role of chloride in a number of regulatory pathways central to heart failure pathophysiology, additional research is warranted in this area. [ABSTRACT FROM AUTHOR]

Background Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear. Objectives This study investigated the potential pathophysiological contributions of intestinal microbiota in HF. Methods We examined the relationship between fasting plasma trimethylamine- N -oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF. Results The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001). Conclusions High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes. [ABSTRACT FROM AUTHOR]

Despite therapeutic advances, chronic heart failure (HF) is still associated with significant risk of morbidity and mortality. The course of disease and responses to therapies vary widely among individuals with HF, highlighting the need for precision medicine approaches. Gut microbiome stands to be an important aspect of precision medicine in HF. Exploratory clinical studies have revealed shared patterns of gut microbiome dysregulation in this disease, with mechanistic animal studies providing evidence for active involvement of the gut microbiome in development and pathophysiology of HF. Deeper insights into gut microbiome-host interactions in patients with HF promise to deliver novel disease biomarkers, preventative and therapeutic targets, and improve disease risk stratification. This knowledge may enable a paradigm shift in how we care for patients with HF, and pave the path toward improved clinical outcomes through personalized HF care. [Display omitted] • Gut microbiome modulates HF pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker. • Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with HF. • Interdisciplinary collaboration will facilitate translation of precision gut microbiomics to the clinical evaluation and management of patients with HF. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is increasingly prevalent in patients with chronic systolic heart failure. Therefore, evidence-based therapies are more and more being used in patients with some degree of renal dysfunction. However, most pivotal randomized clinical trials specifically excluded patients with (severe) renal dysfunction. The benefit of these evidence-based therapies in this high-risk patient group is largely unknown. This paper reviews data from randomized clinical trials in systolic heart failure and the interactions between baseline renal dysfunction and the effect of randomized treatment. It highlights that most evidence-based therapies show consistent outcome benefit in patients with moderate renal insufficiency (stage 3 CKD), whereas there are very scarce data on patients with severe (stage 4 to 5 CKD) renal insufficiency. If any, the outcome benefit might be even greater in stage 3 CKD compared with those with relatively preserved renal function. However, prescription of therapies should be individualized with consideration of possible harm and benefit, especially in those with stage 4 to 5 CKD where limited data are available. [Copyright &y& Elsevier]

The LHFRS is a simple score derived from three factors (history of hypertension, history of coronary artery disease/myocardial infarction, and red blood cell distribution width) deployed for the risk stratification of AHF in Greek population. This study aimed to validate the Larissa Heart Failure Risk Score (LHFRS) in patients with acute heart failure (AHF) in a Japanese population. We performed post-hoc analysis of 1670 consecutive patients enrolled in the REALITY-AHF. In all, 964 patients were finally enrolled. Exclusion criteria included patients with anemia, malignancies and sepsis. The primary outcome was defined as a composite of all-cause mortality and/or heart failure readmission, and the secondary outcome was defined as all-cause mortality. The median admission LHFRS value was 1 (interquartile range [IQR]: 0–2). During a median follow-up of 365 (IQR: 161–365) days, the primary and secondary outcomes were observed in 321 and 157 patients, respectively. LHFRS was an independent predictor of both the primary (adjusted hazard ratio per 1-point increase, 95% confidence interval: 1.17 [1.04–1.32], p = 0.011), and the secondary outcomes (1.31 [1.12–1.55], p = 0.001). Patients with higher LHFRS scores (≥2) exhibited significantly worse outcomes than those with lower scores (<2) both for the primary outcome (1.40 [1.07–1.83], p = 0.014) and the secondary outcome (1.60 [1.09–2.34], p = 0.015). Additionally, LHFRS revealed an excellent goodness of fit (observed versus predicted outcomes) for predicting both the primary and the secondary outcomes (p > 0.99 and p = 0.99, respectively). The simple LHFRS was proved as a reliable predictor of outcomes in patients with AHF. • Risk stratification is important during hospitalization for acute heart failure (AHF). • The Larissa Heart Failure Risk Score (LHFRS) is a simple score that easily and reliably risk stratifies AHF patients. • Close monitoring of high risk AHF patients is warranted. [ABSTRACT FROM AUTHOR]

Acetylation and methylation of histones alter the chromatin structure and accessibility that affect transcriptional regulators binding to enhancers and promoters. The binding of transcriptional regulators enables the interaction between enhancers and promoters, thus affecting gene expression. However, our knowledge of these epigenetic alternations in patients with heart failure remains limited. From the comprehensive analysis of major histone modifications, 3-dimensional chromatin interactions, and transcriptome in left ventricular (LV) tissues from dilated cardiomyopathy (DCM) patients and non-heart failure (NF) donors, differential active enhancer and promoter regions were identified between NF and DCM. Moreover, the genome-wide average promoter signal is significantly lower in DCM than in NF. Super-enhancer (SE) analysis revealed that fewer SEs were found in DCM LVs than in NF ones, and three unique SE-associated genes between NF and DCM were identified. Moreover, SEs are enriched within the genomic region associated with long-range chromatin interactions. The differential enhancer-promoter interactions were observed in the known heart failure gene loci and are correlated with the gene expression levels. Motif analysis identified known cardiac factors and possible novel players for DCM. We have established the cistrome of four histone modifications and chromatin interactome for enhancers and promoters in NF and DCM tissues. Differential histone modifications and enhancer-promoter interactions were found in DCM, which were associated with gene expression levels of a subset of disease-associated genes in human heart failure. Unlabelled Image • We establish the genomic cistrome and chromatin interactome in NF and DCM. • Global H3K4me3 enrichment is reduced in DCM heart. • Super-enhancers are enriched in genomic regions associated with long-range chromatin interaction. [ABSTRACT FROM AUTHOR]

Background: The necessity of neurohumoral blockers in patients with heart failure who demonstrate normalized ejection fractions after cardiac resynchronization therapy remains unclear.Objectives: The aim of this study was to investigate the feasibility and safety of neurohumoral blocker withdrawal in patients with normalized ejection fractions after cardiac resynchronization therapy.Methods: In this prospective, open-label, randomized controlled pilot trial with a 2 × 2 factorial design, subjects were randomized to withdrawal of renin-angiotensin-aldosterone system inhibitors and/or beta-blockers versus continuation of treatment. The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular end-systolic volume index of >15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure-related hospitalizations, and incidence of sustained ventricular arrhythmias at 24 months.Results: Eighty subjects were consecutively enrolled and randomized among 4 groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). Of the 80 subjects, 6 (7.5%) met the primary and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 subjects because of hypertension or supraventricular arrhythmias.Conclusions: The incidence of the primary and secondary endpoints over a follow-up period of 2 years was low in both the control group and in the groups in which neurohumoral blockers were discontinued. However, neurohumoral blocker withdrawal was hampered by cardiac comorbidities. (Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients [STOP-CRT]; NCT02200822). [ABSTRACT FROM AUTHOR]

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients' vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to determine the feasibility and value of a protocol-driven approach to patients with cardiac resynchronization therapy (CRT) who did not exhibit a positive response long after implant. Background: Up to one-third of patients with advanced heart failure do not exhibit a positive response to CRT. Methods: A total of 75 consecutive ambulatory patients with persistent advanced heart failure symptoms and/or adverse reverse remodeling and CRT implanted >6 months underwent a comprehensive protocol-driven evaluation to determine the potential reasons for a suboptimal response. Recommendations were made to maximize the potential of CRT, and adverse events were documented. Results: All patients (mean left ventricular [LV] ejection fraction 23 ± 9%, LV end-diastolic volume 275 ± 127 ml) underwent evaluation. Eighty-eight percent of patients had significantly better echocardiographic indexes of LV filling and LV ejection with optimal setting of their CRT compared with a temporary VVI back-up setting. Most patients had identifiable reasons for suboptimal response, including inadequate device settings (47%), suboptimal medical treatment (32%), arrhythmias (32%), inappropriate lead position (21%), or lack of baseline dyssynchrony (9%). Multidisciplinary recommendations led to changes in device settings and/or other therapy modifications in 74% of patients and were associated with fewer adverse events (13% vs. 50%, odds ratio: 0.2 [95% confidence interval: 0.07 to 0.56], p = 0.002) compared with those in which no recommendation could be made. Conclusions: Routine protocol-driven approach to evaluate ambulatory CRT patients who did not exhibit a positive response is feasible, and changes in device settings and/or other therapies after multidisciplinary evaluation may be associated with fewer adverse events. [Copyright &y& Elsevier]

Introduction: Patients who undergo transcatheter aortic valve replacement (TAVR) for severe, symptomatic aortic stenosis frequently have heart failure (HF). We investigated the predictors of mortality in patients with HF with preserved ejection fraction (HFpEF) versus reduced ejection fraction (HFrEF) who underwent TAVR. Methods: Patients were identified from the Nationwide Inpatient Sample database from January 2011 to September 2015 using the ICD-9. Patients with HF who underwent TAVR were classified according to whether they were diagnosed with HFrEF or HFpEF. The principal outcome of interest was in-hospital mortality. Multivariable analysis was used to adjust for potential baseline confounders including demographics, conventional risk factors (diabetes, hypertension, hyperlipidemia, and tobacco abuse), acute critical illnesses (sepsis, septic shock), acute coronary syndrome, stroke, and acute respiratory insufficiency. All analyses were conducted using R 3.4.0 and STATA/MP 14.2. Results: Among 61,630 patients undergoing TAVR, 28,369 (46.0%) had baseline HF, including 20,110 (70.9%) with HFpEF and 8,259 (29.1%) with HFrEF (P<0.0001). The mean age was 82.0 years in HFpEF and 81.2 years in HFrEF patients; 55.4% and 38.1% respectively were women. Overall in-hospital mortality after TAVR in patients without and with HF was 2.13% vs. 3.65% respectively (p=0.01). Among TAVR patients with HF, in-hospital mortality was greater in those with HFrEF compared with HFpEF (4.07% vs. 2.90%, p=0.01). Ethnicity, age, sex, stroke, chronic renal failure, sepsis, anxiety and depression did not predict in-hospital mortality in patients with HFpEF or HFrEF after TAVR. By multivariable analysis, among HFpEF patients baseline atrial fibrillation (AF) was an independent predictor of in-hospital mortality (adjusted odds ratio [OR] 1.75; 95% confidence intervals 1.15-2.66, p=0.009) while hypertension was associated with reduced mortality (OR 0.51; 95% CI 0.33-0.79, p=0.003). Among HFrEF patients, liver disease was an independent predictor of mortality (OR 5.10; 95% CI 1.36-19.1, p=0.01) while diabetes was associated with reduced mortality (OR 0.24; 95% CI 0.09-0.70, p=0.02). Conclusions: Baseline HF in patients with severe aortic stenosis undergoing TAVR is frequent and is more commonly due to HFpEF than HFrEF. In-hospital mortality is higher after TAVR in HFrEF compared with HFpEF. The predictors of mortality after TAVR are different in HFrEF and HFpEF, knowledge of which may be useful in patient selection and prognostic guidance. [ABSTRACT FROM AUTHOR]