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Aims: Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2–3), but this group is not well‐characterized. Methods and results: Patients with PH enrolled in the prospective, NHLBI‐sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2–3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2–3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2–3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2–3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N‐terminal pro‐B‐type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2–3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6‐min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30–0.86), and patients with G2–3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38–0.86). Conclusions: Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2–3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. Clinical Trial Registration: ClinicalTrials.gov NCT02980887. [ABSTRACT FROM AUTHOR]

Aim: Among patients discharged after hospitalization for heart failure (HF), a strategy of torsemide versus furosemide showed no difference in all‐cause mortality or hospitalization. Clinicians have traditionally favoured torsemide in the setting of kidney dysfunction due to better oral bioavailability and longer half‐life, but direct supportive evidence is lacking. Methods and results: The TRANSFORM‐HF trial randomized patients hospitalized for HF to a long‐term strategy of torsemide versus furosemide, and enrolled patients across the spectrum of renal function (without dialysis). In this post‐hoc analysis, baseline renal function during the index hospitalization was assessed as categories of estimated glomerular filtration rate (eGFR; <30, 30–<60, ≥60 ml/min/1.73 m2). The interaction between baseline renal function and treatment effect of torsemide versus furosemide was assessed with respect to mortality and hospitalization outcomes, and the change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS). Of 2859 patients randomized, 336 (11.8%) had eGFR <30 ml/min/1.73 m2, 1138 (39.8%) had eGFR 30–<60 ml/min/1.73 m2, and 1385 (48.4%) had eGFR ≥60 ml/min/1.73 m2. Baseline eGFR did not modify treatment effects of torsemide versus furosemide on all adverse clinical outcomes including individual components or composites of all‐cause mortality and all‐cause (re)‐hospitalizations, both when assessing eGFR categorically or continuously (p‐value for interaction all >0.108). Similarly, no treatment effect modification by eGFR was found for the change in KCCQ‐CSS (p‐value for interaction all >0.052) when assessing eGFR categorically or continuously. Conclusion: Among patients discharged after hospitalization for HF, there was no significant difference in clinical and patient‐reported outcomes between torsemide and furosemide, irrespective of renal function. [ABSTRACT FROM AUTHOR]

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]

This article examines the use of comprehensive heart failure (HF) medical therapy in a large, diverse health system. The study utilized an electronic health record (EHR)-based patient registry to evaluate factors that impact the use of guideline-directed medical therapy (GDMT) for HF. The findings showed that cardiology engagement within the last 12 months was strongly associated with higher GDMT scores. HF hospitalization and all-cause hospitalizations were associated with worse GDMT use, although HF hospitalization was linked to an increased likelihood of prescription for certain medications. The study also found no difference in GDMT scores based on patient race or sex when certain medications were excluded from the analysis. The authors suggest that this EHR-based approach can be used to evaluate GDMT opportunities in other health systems, but acknowledge the limitations of the study and the need for further research. [Extracted from the article]

This article discusses the renal perturbations that can occur with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF). Worsening renal function is commonly observed in patients with heart failure and can have adverse outcomes. SGLT2 inhibitors have emerged as a therapeutic advance in cardio-renal-metabolic diseases, but they can also cause acute changes in estimated glomerular filtration rate (eGFR) and extrarenal haemodynamic shifts. The article emphasizes the need for careful monitoring and individualized management strategies when initiating SGLT2 inhibitor therapy in patients with HFpEF to optimize therapeutic outcomes and mitigate adverse renal events. [Extracted from the article]

Aims: Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide. Methods and results: This is a pre‐specified sub‐analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1 ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm. Hypokalaemia (<3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatraemia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatraemia (p = 0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non‐significant over time (p = 0.053) and had no significant impact on hypokalaemia incidence (p = 0.061). Severe hypokalaemia (<3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p = 0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels. Conclusions: Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatraemia and improves decongestion over the entire range of baseline serum potassium and sodium levels. [ABSTRACT FROM AUTHOR]

Aim: Intrinsic renal sodium avidity (IRSA) is a hallmark feature of acute heart failure (AHF) and can be measured by evaluating the urinary sodium (UNa) concentration. The aim of this study is to assess the role of measuring IRSA through a random Una‐sample and its association with decongestive response. Methods and results: A post‐hoc analysis of the ROSE‐AHF trial was performed in all patients with a random UNa spot sample before randomization (n = 339/360). Patients were categorized according to tertiles of UNa as high (range 19–40 mmol/L), intermediate (range 41–68 mmol/L), or low (range 69–139 mmol/L) IRSA. Linear mixed effect models and ANCOVA were used to assess the relation with decongestive effectiveness measured by: (i) weight change, (ii) visual analogue scale (VAS) improvement, (iii) N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) change, (iv) natriuretic response (UNa in mmol/L), (v) 72 h natriuresis (mmol), (vi) oedema resolution, and (vii) length of stay. High IRSA patients had less improvement in decongestive metrics, including weight loss (p = 0.028), VAS improvement, NT‐proBNP decrease, natriuretic response (p‐time interaction <0.001 for all), had lower total natriuresis (high IRSA 438 ± 141 mmol, intermediate IRSA 526 ± 320 mmol, and low IRSA 603 ± 276 mmol; p < 0.001), exhibited more oedema at 72 h (p = 0.005), and had a longer length of stay (p = 0.015). Incremental loop diuretic dose titration (± 4 times home dose) after >24 h, resulted in an increase in natriuretic response in the high IRSA group, however cumulative natriuresis still remained lower at 72 h (p < 0.001). Longitudinal UNa profiling of patients with low IRSA showed physiologic breaking in the UNa pattern, associated with attaining decongestion and slight increase in creatinine and cystatin C, forming a potential signal of complete decongestion. Conclusions: A simple random UNa sample at the time of AHF, gives insight into IRSA which is consistently associated with decongestive effectiveness across multiple metrics, offering an opportunity for early AHF care improvement. [ABSTRACT FROM AUTHOR]

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

Aims: To evaluate the performance of the WATCH‐DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). Methods and results: Adults with diabetes/pre‐diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning‐ [WATCH‐DM(ml)] and integer‐based [WATCH‐DM(i)] scores were used to estimate the 5‐year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C‐index) and calibration by the Greenwood–Nam–D'Agostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C‐index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH‐DM(ml) and WATCH‐DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C‐indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P ≥0.10). The C‐index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (<13) vs. high (≥13) WATCH‐DM(i) scores [0.71 (95% confidence interval 0.68–0.74) vs. 0.64 (95% confidence interval 0.61–0.66)]. When NP levels were combined with the WATCH‐DM(i) score, HF risk discrimination improvement and NRI varied across the spectrum of risk with greater improvement observed at low/intermediate risk [WATCH‐DM(i) <13] vs. high risk [WATCH‐DM(i) ≥13] (C‐index = 0.73 vs. 0.71; NRI = 0.45 vs. 0.17). Conclusion: The WATCH‐DM risk score can accurately predict incident HF risk in community‐based individuals with dysglycaemia. The addition of NP levels is associated with greater improvement in the HF risk prediction performance among individuals with low/intermediate risk than those with high risk. [ABSTRACT FROM AUTHOR]

Aims: Patients with obesity and ischaemic heart failure may counter‐intuitively have better outcomes compared with patients with normal body weight due to an 'obesity paradox'. This study sought to determine if body mass index (BMI) impacts the treatment effects or safety outcomes of the treatment of ischaemic heart failure with coronary artery bypass grafting (CABG). Methods and results: We obtained and reviewed the Surgical Treatment of Ischaemic Heart Failure (STICHES) data for 1212 patients. We categorized obesity by the World Health Organization (WHO) classes to define baseline characteristics and test for treatment interactions for the primary and secondary STICHES outcomes by treatment groups. While CABG decreased the risk of death, there was no evidence of treatment interaction by BMI per 5 kg/m2 (P = 0.83) or WHO obesity class. For the overall cohort, there was no interaction by WHO obesity class for the cumulative incidence of death in either the medical therapy or CABG plus medical therapy (P‐interaction = 0.90). There was a non‐significant trend for higher BMI and a lower risk of death [hazard ratio 0.92, 95% confidence interval (CI) 0.85–1.00, P = 0.051]. Increasing body size (per 5 kg/m2) was associated with return to the operating room (odds ratio 2.48, 95% CI 1.45–4.26, P < 0.001) and infectious mediastinitis (odds ratio 2.09, 95% CI 1.10–3.97, P = 0.024) at 30 days but not other 30 day safety outcomes. Conclusions: The benefit of CABG vs. medical therapy for ischaemic heart failure was consistent regardless of BMI or WHO obesity class for death or secondary clinical outcomes. However, higher BMI was associated with some short‐term post‐CABG complications. [ABSTRACT FROM AUTHOR]

Aims: Current guidelines recommend beta‐blocker therapy in chronic heart failure with reduced ejection fraction (HFrEF) titrated according to tolerated target dose. The efficiency of this strategy to obtain adequate heart rate (HR) control remains unclear in clinical practice. The aim of this study was to determine, in a real‐world setting, the proportion of HFrEF patients who fail to achieve beta‐blocker target doses, whether target doses of beta‐blockers have a relationship with the adequacy in reducing resting HR over time. Methods and results: Beta‐blocker dose and resting HR of consecutive ambulatory patients with a diagnosis of HFrEF (ejection fraction ≤ 35%) in sinus rhythm were reviewed at the first outpatient contact in the Cleveland Clinic Health System from the year 2000 to 2015. Patients who did not receive beta‐blocker therapy, have congenital heart disease and hypertrophic cardiomyopathy, were not in sinus rhythm, or have a history of heart transplant were excluded. Patients were followed up until their last known visit at the Cleveland Clinic. Median resting HR was 71 b.p.m. [inter‐quartile range (IQR) 60–84 b.p.m.] in 8041 patients (median age 65; 68% male) with 67% on carvedilol, 32% on metoprolol succinate, and 1% on bisoprolol. In 3674 subjects (56%), resting HR was ≥70 b.p.m. At final follow‐up after a median of 21 months (IQR 0.1–7.2 years), resting HR was 72 b.p.m. (IQR 60–84 b.p.m.) in the subset of patients with persistently low ejection fraction ≤ 35%. HR ≥ 70 b.p.m. was observed in 55% of this group. Beta‐blocker target dose was achieved in 19%, 5%, and 15% of those receiving carvedilol, metoprolol succinate, and bisoprolol, respectively. In the subset of patients who experienced beta‐blocker up‐titration, reduced mortality or hospitalization due to heart failure was observed in patients who experienced the lowest HR after titration. Conclusions: In our single‐centre experience, the majority of patients with chronic HFrEF treated with beta‐blocker therapy did not achieve target doses over time, and a substantial proportion had inadequate control of resting HR. There was no relationship between achieved beta‐blocker target dose and resting HR control. [ABSTRACT FROM AUTHOR]

Aims: In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results.Methods and Results: In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naïve, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady-state concentrations had not been reached by 48 h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints.Conclusions: Lower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial. [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]

B This article refers to 'Renal profiling based on estimated glomerular filtration rate and spot urine sodium identifies high-risk acute heart failure patients' by J. Biegus I et al i ., published in this issue on pages 729-739. b Every era grapples with a medical riddle and the complexities underlying the interaction between heart and kidney physiology are no exception, as knowledge gaps regarding this complex interaction have persisted throughout much of medical history. Secondly, some patients received intravenous diuretics in the pre-hospital setting or had intensification of oral diuretics prior to admission, which may have affected baseline U SB Na sb values. It is also unclear whether I all i patients will need serial assessment of U SB Na sb (for example, a patient who has >3 L/day of urine output is likely diuretic responsive). [Extracted from the article]

Aims: Plasma volume expansion is clinically and prognostically relevant in individuals with heart failure. Prior cohorts either excluded or had limited representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between calculated plasma volume status (PVS) and outcomes in HFpEF.Methods and Results: We included enrollees from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) with available haematocrit and weight data (n = 3414). Plasma volume was derived from the Hakim formula and compared to estimates of ideal plasma volume to generate a relative PVS. Multivariable Cox proportional hazards models tested the association of PVS with clinical outcomes. The median PVS was -11.9% (25th-75th percentile: -17.2% to -6.4%) and the majority (91.1%) had PVS consistent with relative volume contraction (PVS ≤ 0%) as opposed to volume expansion (8.9%, PVS > 0%). After multivariable adjustment, each 5% increment in PVS was associated with a ∼11%, 14%, and 12% higher risk for the primary composite endpoint, all-cause death, and heart failure hospitalization, respectively (P < 0.002 for all), but not cardiovascular death (P = 0.051). After additional adjustment for natriuretic peptides, PVS only remained associated with heart failure hospitalization (HR 1.10, 95% confidence interval 1.001-1.21, P = 0.047). There were no significant interactions between spironolactone use and the PVS-risk relationship for any endpoint (P > 0.1 for all).Conclusion: Higher calculated estimates of PVS were independently associated with a higher risk of long-term clinical outcomes in HFpEF, and particularly, heart failure hospitalization. [ABSTRACT FROM AUTHOR]

The vast majority of acute heart failure episodes are characterized by increasing symptoms and signs of congestion with volume overload. The goal of therapy in those patients is the relief of congestion through achieving a state of euvolaemia, mainly through the use of diuretic therapy. The appropriate use of diuretics however remains challenging, especially when worsening renal function, diuretic resistance and electrolyte disturbances occur. This position paper focuses on the use of diuretics in heart failure with congestion. The manuscript addresses frequently encountered challenges, such as (i) evaluation of congestion and clinical euvolaemia, (ii) assessment of diuretic response/resistance in the treatment of acute heart failure, (iii) an approach towards stepped pharmacologic diuretic strategies, based upon diuretic response, and (iv) management of common electrolyte disturbances. Recommendations are made in line with available guidelines, evidence and expert opinion. [ABSTRACT FROM AUTHOR]

Aims: Prior cohorts demonstrating the importance of serum chloride levels in heart failure either excluded or had partial representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between serum chloride concentration and outcomes in HFpEF.Methods and Results: We included participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) who met the following criteria: met inclusion by the natriuretic peptide stratum, had recorded serum chloride levels, and were from the Americas (n = 942). Multivariable Cox proportional hazards models tested the association of serum chloride with clinical outcomes, and mixed effects modelling tested the association of spironolactone or loop diuretic on serial serum chloride levels. The median serum chloride level was 102 [25th-75th percentile 100-105 mmol/L (range 84-114 mmol/L)]. After multivariable adjustment, every standard deviation decrease in serum chloride (4.05 mmol/L) was associated with ∼50% increased risk for cardiovascular death [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.11-2.06, P = 0.008] and ∼30% increased risk for all-cause death (HR 1.29, 95% CI 1.02-1.62, P = 0.04), but not with the primary composite endpoint or heart failure hospitalization (P > 0.3 for both). There were no significant interactions between spironolactone use and the serum chloride-risk relationship (P > 0.1) for each endpoint. Spironolactone was not (P = 0.33) but loop diuretic use was associated with lower serial serum chloride levels (P < 0.001).Conclusion: Lower serum chloride was independently associated with increased risk of cardiovascular and all-cause death in HFpEF. Loop diuretic use, but not spironolactone, lead to a decrease in serum chloride levels over time. [ABSTRACT FROM AUTHOR]

Aims: Decreased arylesterase (ArylE) activity of paraoxonase-1, a HDL-associated protein with anti-inflammatory and antioxidant properties, has been associated with increased risk of cardiac events in patients with ischaemic heart failure (HF). We aim to investigate the prognostic significance of changes in serum ArylE activity over time.Methods and Results: We examined the association between baseline and follow-up serum ArylE activity and HF outcomes (death, cardiac transplantation, or ventricular assist device implantation) in 299 patients with HF enrolled in a prospective cohort study from January 2008 to July 2009, with 145 patients having available follow-up levels at 1 year. A significant drop in ArylE activity on follow-up was defined as a drop of ≥25% vs. baseline levels. Mean baseline and follow-up ArylE activity levels were 110.6 ± 29.9 µmol/min/mL and 106.2 ± 29.9 µmol/min/mL, respectively. After a mean follow-up of 2.8 ± 1.1 years, low baseline ArylE activity was associated with increased risk of adverse HF events [hazard ratio (HR; lowest vs highest tertile) 2.6, 95% confidence interval (CI) 1.3-5.5, P = 0.01] and HF-related hospitalization [incidence rate ratio (lowest vs. highest tertile) 2.1, 95% CI 1.2-4.1, P = 0.016], which remained significant after adjustment for age, male gender, systolic blood pressure, diabetes, creatinine clearance, CAD, and HDL-cholesterol levels. Patients who had a significant drop in ArylE activity on follow-up (n = 18) had a significantly increased risk of HF events (HR 4.9, 95% CI 1.6-14.6, P = 0.005), even after adjustment for baseline levels of ArylE activity.Conclusions: Reduced baseline ArylE activity and decreased levels on follow-up are associated with adverse outcomes in stable outpatients with HF. [ABSTRACT FROM AUTHOR]

Background QRS duration (QRSd) may be impacted by both left ventricular (LV) dilatation and conduction delay. It is possible therefore that the same QRSd may portend significantly different amounts of LV activation delay in patients with small versus large left ventricles. We hypothesized that LV size modifies the effect of QRSd on predicting outcomes in patients undergoing CRT implant. Methods We extracted data on consecutive patients presenting for initial CRT implant. In patients with a follow-up echocardiogram, response was defined as an absolute improvement in LV ejection fraction ≥5%. Multivariate models were created to determine if left ventricular end-diastolic diameter (LVEDD) modified the effect of QRSd on its association with both long-term survival free of left ventricular assist device (LVAD) and heart transplant and echocardiographic response. Results 464 patients met inclusion criteria. At a mean follow-up of 4.9 ± 2.6 years, there were 210 deaths, 13 heart transplants, and 12 LVAD placements. There was a weak but significant correlation between baseline QRSd and LVEDD (Spearman's Rho 0.106, P < 0.001). In a multivariate analysis, there was no evidence of effect modification of LVEDD on QRSd (LVEDDi*QRS interaction term HR 1.0 [0.995-1.006], P = 0.94). Note that 305 patients had a follow-up echocardiogram, of whom 193 met the criteria for response. In a multivariate analysis, there was no evidence of effect modification of LVEDD on QRSd (LVEDDi*QRS interaction term odds ratio 0.998 (0.988-1.008), P = 0.65). Conclusion LV size does not modify the effect of QRSd and its association with outcomes following CRT. The correlation between LV size and QRSd in patients with a QRSd ≥ 120 ms is weak. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) can be associated with a higher resting heart rate (HR), and an elevated HR is associated with adverse long-term events. However, the mechanistic and causal role of HR in HF is unclear. This study aimed to investigate changes in HR during hospitalization, and the association between discharge HR and clinical outcomes as well as an interaction with beta-blocker therapy in patients with acute decompensated HF (ADHF).Methods and Results: We studied 2906 patients with an LVEF ≤35%, without AF, who were enrolled in the ASCEND-HF trial. A total of 2492 (85.8%) patients had a HR ≥70 b.p.m. at baseline and 1580 (54.4%) patients were on beta-blocker treatment. Although HR was gradually reduced from baseline to discharge (85.5 ± 15.9 b.p.m. at baseline, 81.7 ± 14.1 b.p.m. at 24 h from treatment initiation, and 79.1 ± 12.2 b.p.m. at discharge), 80.2% of the patients still had a HR ≥70 b.p.m. at discharge. Patients with a HR ≥70 b.p.m. at discharge had significantly lower survival rates than those with a HR <70 b.p.m. (adjusted hazard ratio 1.02, 95% confidence interval 1.01-1.04, P = 0.002). Moreover, HR at discharge had a curvilinear association with mortality, and had no significant interaction effect with beta-blocker therapy at discharge (P = 0.82).Conclusions: Despite current beta-blocker therapy, many patients with hospitalized ADHF with reduced LVEF have relatively high discharge HR, and discharge HR is associated with higher mortality. Further studies are warranted to determine the optimal strategy for HR control to improve 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]

Aims: The aim of this study was to assess the haemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) up-titration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF).Methods and Results: Medical records of 147 consecutive ADHF patients who underwent placement of a pulmonary artery catheter and received intravenous vasodilator therapy were reviewed. Intravenous sodium nitroprusside and sodium nitroglycerin as first-line agent for those with preserved blood pressures were utilized in 143 and 32 patients, respectively. Sixty-one percent of patients were converted to oral HYD/ISDN combination therapy through a standardized conversion protocol. These patients had a significantly higher admission mean pulmonary arterial wedge pressure compared with patients not converted (28 ± 7 vs. 25 ± 8 mmHg, respectively; P-value 0.024). Beneficial haemodynamic response to decongestive therapy, defined as low cardiac filling pressures and cardiac index ≥2.20 L/min/m(2) without emergent hypotension, was achieved in 32% and 29% of patients who did or did not receive oral HYD/ISDN, respectively (P-value 0.762). HYD/ISDN dosing was progressively and consistently decreased up to the moment of hospital discharge and during outpatient follow-up, primarily due to incident hypotension.Conclusion: The use of a standardized haemodynamically guided up-titration protocol for conversion from intravenous to oral vasodilators may warrant subsequent dose reductions upon stabilization. [ABSTRACT FROM AUTHOR]

Aims Loop diuretics are a cornerstone of heart failure ( HF) treatment, but data regarding diuretic dose adjustments after a HF hospitalization and the association with subsequent outcomes are limited. This study was therefore conducted to determine these factors. Methods and results We analysed data from 6119 patients enrolled in ASCEND-HF, examining the association between loop diuretic use at the time of discharge, compared with admission, and the composite outcome of 30-day HF re-hospitalization or all-cause mortality. The majority of patients, 3921 (64%), were taking a loop diuretic on admission. At discharge, 3411 (56%) patients were prescribed higher doses compared with admission, including 1867 (31%) initiating daily outpatient diuretics; 1912 (31%) had no dose change and 795 (13%) were prescribed lower doses compared with admission. Initiation of an oral loop diuretic at discharge was independently associated with better 30-day outcomes compared with no dose change [adjusted odds ratio ( OR) 0.51, 95% confidence interval ( CI) 0.37-0.68]. However, for patients that were already established on a loop diuretic prior to admission, change in the dose at discharge was not associated with improved outcomes compared with no dose change (adjusted OR 0.92, 95% CI 0.79-1.07). Conclusions In a large multinational clinical trial, 56% of patients hospitalized with HF were either initiated on a daily loop diuretic at discharge or discharged on higher doses compared with admission. In patients established on diuretics prior to hospitalization, we found no association between changes to chronic doses at discharge and improved outcomes, whereas initiation of loop diuretic therapy was associated with better outcomes compared with no dose change. [ABSTRACT FROM AUTHOR]

Prediction Rule to Identify Patients at High Risk for Early Demise Following CRT Background In patients with advanced heart failure, the decision of whether to pursue cardiac resynchronization therapy (CRT) or to proceed directly to advanced heart failure therapies can be challenging. We sought to create a prediction rule to identify patients with advanced systolic heart failure at heightened risk of rapid deterioration despite receiving CRT. Methods Clinical data were collected on consecutive patients with advanced heart failure presenting for a new CRT device at the Cleveland Clinic between February 12, 2002 and July 8, 2008. Early demise was defined as death, left ventricular assist device, or heart transplant within 6 months following CRT implant. Using a multivariate model, variables associated with early demise were identified and a prediction rule created. Results A total of 879 patients were included of whom 47 met criteria for early demise. Using forward stepwise regression followed by a bootstrapping analysis, the final model included: left ventricular end-diastolic diameter ≥6.5 cm (OR 3.23 [1.72-6.06 g], P < 0.001), the presence of a non-left bundle branch block (non-LBBB) morphology (OR 2.18 [1.18-4.04, P = 0.013]), creatinine ≥1.5 mg/dL (OR 2.98 [1.52-5.49], P < 0.001), and lack of or intolerance to β-blocker use (OR 2.80 [1.46-5.39], P = 0.002). The specificity for ≥2 and ≥3 risk factors was 72.6% and 94.6%, respectively. Conclusions Left ventricular dilatation, the presence of a non-LBBB morphology, renal dysfunction, and lack of or intolerance to β-blockers are associated with early demise following CRT. In patients with at least 3 of these factors, bypassing CRT with early adoption of advanced heart failure therapies may be considered given the high specificity for rapid decline. [ABSTRACT FROM AUTHOR]

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate ( GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function. [ABSTRACT FROM AUTHOR]

Aims ‘Worsening renal function’ (WRF) and ‘improvement in renal function’ (IRF) monitored by changes in serum creatinine are frequently encountered during treatment of acute decompensated heart failure (ADHF). We sought to establish the important haemodynamic determinants of alterations in serum creatinine. Methods and results We reviewed data from 443 patients treated for ADHF with haemodynamic guidance in a single centre. WRF and IRF were defined as a 25% increase or decrease in estimated glomerular filtration rate (eGFR) from time of admission to pulmonary artery catheter removal, respectively. Of the 443 patients, 46 (10%) experienced WRF and 127 (29%) had IRF. Baseline eGFR was lower in patients with IRF when compared with stable patients or those with WRF (45 ± 25 vs. 63 ± 30 vs. 68 ± 27 mL/min/m2, respectively, P < 0.0001). In contrast, the relative decrease in mean blood pressure (BP) was more pronounced in patients with WRF when compared with stable patients or those with IRF (15 ± 15 vs. 9 ± 17 vs. 4 ± 15%, respectively, P = 0.003). With larger decreases in mean BP, there was greater likelihood of experiencing WRF (P = 0.04) but less likelihood of experiencing IRF (P = 0.01). In contrast, the degree of changes in right atrial pressure or cardiac index did not affect the propensity for developing WRF or IRF. There was no difference in adverse clinical outcomes (death, heart transplantation, LV assist device implantation, or readmission) between the three groups (P = 0.56). Conclusion Blood pressure decrease, rather than alterations in cardiac output or central venous pressure, were associated with changes in serum creatinine during treatment of ADHF. [ABSTRACT FROM PUBLISHER]

Aims Cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling, improved functional capacity, and better clinical outcome in patients with advanced chronic heart failure, reduced ejection fraction, and evidence of ventricular conduction delay, who are under optimal medical therapy. This study investigated whether these benefits can be extrapolated to older patients, typically not included in randomized clinical trials. Methods and results Consecutive patients who received a CRT device between October 2008 and June 2011, including optimization afterwards in a dedicated clinic, were stratified into 3 pre-specified groups, according to age: <70 years (n = 76); 70–79 years (n = 95); and ≥80 years (n = 49). Left ventricular remodelling, functional capacity, heart failure hospitalization, and mortality data were assessed during follow-up. Reverse left ventricular remodelling and improvement in New York Heart Association functional class were similar in all groups at 6 months after implantation. During mean follow-up of 20 months, 32 patients died and 66 were admitted for heart failure. Annualized mortality rates were significantly higher in elderly patients (6% vs. 8% vs. 15% in all groups, respectively; P < 0.001), but time to death or first heart failure admission was similar among age groups (P = 0.531). Progressive pump failure was the major cause of death (50%), with co-morbidity-related deaths also being frequent (41%). Conclusion Reverse left ventricular remodelling and functional capacity improvement after CRT are sustained at advanced age. Moreover, time to all-cause mortality or heart failure admission was similar, irrespective of age, in a context of maximized optimization including optimal medical therapy. [ABSTRACT FROM PUBLISHER]

Aims We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF. Methods and results Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes. Baseline cTnI was undetectable in 22% and elevated above the 99th percentile URL in 50% of subjects. cTnI levels did not differ based on HF aetiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as length of stay (P = 0.01) and worsening HF during the index hospitalization (P = 0.01), but was not associated with worsened post-discharge outcomes at 30 or 180 days. The relationship between cTnI and outcomes was generally linear and there was no evidence of a threshold effect at any particular level of cTnI. Conclusion cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and predicts in-hospital outcome, but is not an independent predictor of long-term outcomes. [ABSTRACT FROM AUTHOR]

Aims Acute kidney injury (AKI) is a strong predictor of adverse events with an incompletely understood pathophysiology. Neutrophil gelatinase-associated lipocalin (NGAL) is proposed as an early marker of renal tubular injury. Our aim is to determine whether AKI during treatment of acute decompensated heart failure (ADHF) is accompanied by renal tubular injury. Methods and results Urinary NGAL (uNGAL) and urinary creatinine (uCreat) levels were measured in 141 consecutive patients hospitalized for ADHF and followed for 180 days for death or re-hospitalization. AKI was defined as a rise in serum creatinine ≥0.3 mg/dl in a 48 h period. Median uNGAL/uCreat levels on Day 1 (baseline) were similar between patients who did and did not develop AKI [22.8 (12.5–106.8) μg/g vs. 20.6 (12.4–52.0) μg/g, P = 0.55]. On Day 2 and beyond, the difference between the AKI and no AKI cohorts increased, but was only significant on Day 3 [36.2 (21.7–131.8) μg/g vs. 29.4 (11.4–54.6) μg/g, P = 0.02]. The area under the receiver operating characteristic curve for Day 2 uNGAL/uCreat (≥ or <32 µg/g) to predict AKI was 0.61. There was no difference in diuretic response between ‘uNGAL/uCreat + ’ (≥ 27 µg/g) and ‘uNGAL/uCreat–’ (<27 µg/g) patients. However ‘uNGAL/uCreat + ’ patients had more adverse events after 180 days (66% vs. 52%, P = 0.02). Conclusions In patients with ADHF who develop AKI following diuretic therapy, a minor rise in uNGAL precedes AKI. However, the degree of renal tubular insult was much lower than that observed in other forms of AKI. [ABSTRACT FROM PUBLISHER]

Aims Methods and results Conclusions The clinical utility of pulmonary hypertension (PH) risk scores in non‐group 1 PH with pulmonary vascular disease (PVD) remains unresolved.We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH‐related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c‐statistic to predict death was compared separately in (i) pre‐capillary PH groups 3/4/5, and (ii) combined post‐ and pre‐capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular–pulmonary artery (RV‐PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c‐statistic for predicting death (0.699, 95% confidence interval [CI] 0.660–0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656–0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c‐statistic difference −0.072, 95% CI −0.123 to −0.020, p = 0.006, and −0.043, 95% CI −0.067 to −0.018, p = 0.0007, respectively). RV function and RV‐PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non‐invasively identified non‐group 1 PH with more advanced PVD with worse exercise capacity, RV‐PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all).Non‐invasive REVEAL risk predicts mortality in non‐group 1 PH without incremental prognostic value from detailed RV function or RV‐PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non‐invasively identifies greater pulmonary vascular dysfunction and right heart‐related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non‐group 1 PH. [ABSTRACT FROM AUTHOR]

The authors discuss research on the impact of probiotics on trimethylamine-N-oxide (TMAO) in subjects on a hypercaloric high-fat diet. They reference the study "Probiotic Supplementation and Trimethylamine-n-Oxide Production Following a High Fat Diet" by N. E. Boutagy and colleagues published in the current issue of the journal. Topics covered include the role of probiotics in the treatment of obesity and link between TMAO levels and high-fat diet.