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Background: Diuretic resistance is a relevant clinical issue in acute heart failure (AHF), but a standardized, quantitative definition is still missing. The aim of this analysis was to highlight discrepancies between previously proposed definitions of diuretic response and to propose a new urinary sodium (NaU)-based definition of diuretic efficiency (DE) to identify diuretic resistant (DR) patients., Methods: Three historical definitions of diuretic response and a new NaU-based DE definition, evaluating total NaU after the first diuretic bolus per 40 mg furosemide administered, were applied in a retrospective analysis to an AHF population treated with intravenous (i.v.) loop diuretics. Baseline characteristics, in-hospital clinical data and outcomes at discharge and mid-term follow-up were collected and compared among DR and non-DR patients for each definition., Results: Among 53 patients, 39 (73.6%), 51 (96.2%) and 3 (5.7%) were DR according to weight-derived, diuresis-derived, and spot NaU definition, respectively. The median value of the new NaU-based definition was 31 mmol/40 mg and patients were stratified accordingly. DR patients showed lower cumulative diuresis (5200 mL, 3300-6700 vs 9825 mL, 6200-12200, p = 0.007) and weight loss (4 kg, 1-5 vs 6 kg, 3-8.5, p = 0.023), higher BNP levels (808 pg/mL, 443-1037 vs 351 pg/mL, 209-859, p = 0.062) at the conclusion of protocol-guided i.v diuretic therapy, which was less frequently stopped due to decongestion in DR as compared to non-DR patients (57.7% vs 85.2%, p = 0.026). Six-months mortality or HF hospitalizations were more frequent in DR patients (OR 18.6, 95% CI 2.1-161.2, p = 0.008)., Conclusions: The NaU-based DE definition might solve discrepancies of other previously proposed definitions., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple approaches have been tried to achieve adequate decongestion rapidly while minimizing adverse effects, no single diuretic strategy has shown superiority, and there is a paucity of data and guidelines to utilize in making these decisions. Observational cohort studies have shown associations between urine sodium excretion and outcomes after hospitalization for ADHF. Urine chemistries (urine sodium ± urine creatinine) may guide diuretic titration during ADHF, and multiple randomized clinical trials have been designed to compare a strategy of urine chemistry-guided diuresis to usual care. This review will summarize current literature for diuretic monitoring and titration strategies, outline evidence gaps, and describe the recently completed and ongoing clinical trials to address these gaps in patients with ADHF with a particular focus on the utility of urine sodium-guided strategies., (© 2024. The Author(s).)

Aims: Early evaluation of the natriuretic response is recommended to guide diuretic therapy in acute decompensated heart failure (ADHF). However, its implementation in daily practice is hampered by implementation barriers and increased time constraints. The Readily Available Urinary Sodium Analysis in Patients with Acute Decompensated Heart Failure (EASY-HF) study assessed the feasibility, efficacy and safety of a nurse-led urinary sodium-based diuretic titration protocol with the use of a point-of-care urinary sodium sensor., Methods and Results: The EASY-HF study was a single-centre, randomized, open-label study comparing diuretic management at the treating physician's discretion as standard of care (SOC) with a nurse-led natriuresis-guided protocol in patients with ADHF. The LAQUAtwin Sodium Meter (HORIBA) was used as point-of-care sensor to measure urine sodium concentration. The primary endpoint was natriuresis after 48 h. Secondary endpoints included safety profile and user-friendliness of both the protocol and the point-of-care sensor. Sixty patients were randomized towards SOC (n = 30) versus protocolized care (n = 30). The mean age was 80 ± 8 years, 25% were women and median N-terminal pro-B-type natriuretic peptide was 4667 (2667-7709) ng/L. Natriuresis after 48 h was significantly higher in the protocolized versus SOC group (820 ± 279 vs. 657 ± 273 mmol; p = 0.027). Pre-defined safety endpoints were similar among both groups. The sensor-based protocol was evaluated as easy to use by the nursing staff, and preferred over urinary collections., Conclusion: A nurse-led diuretic titration protocol via a point-of-care urinary sodium sensor was feasible, safe and resulted in an increased natriuresis in ADHF compared to SOC., (© 2024 European Society of Cardiology.)

Aims: We aim to identify the most accurate marker for early prediction of poor diuretic response in acute heart failure (AHF) patients with signs of congestion requiring intravenous diuretic treatment., Methods: In this single-centre, prospective observational study, AHF patients with signs of congestion received a standardized intravenous furosemide dose (1 mg/kg of body weight; 40 mg in bolus and remaining dose in 2 h continuous infusion). Subsequently, we assessed spot urine composition at 2 h post-administration, comparing it with total urine output at 6 h. Various potential urine markers were analysed for predicting urine output using receiver operating characteristic (ROC) curves and logistic regression models. We investigated guideline-recommended markers, including spot urine sodium (UNa + ) and its cut-off, and introduced the UNa + /UCr (urine creatinine concentration) ratio adjusting UNa + for urine dilution., Results: Out of 111 patients (85% males, 66.4 ± 13.9 years old, NTproBNP 7290 [4493-14 582] pg/ml), there were 18 (16%) with a poor diuretic response (cumulative urine output <600 ml during the first 6 h). The mean 6 h cumulative diuresis in patients with poor and good diuretic response was 406 ± 142 and 2114 ± 1164 ml, respectively, P < 0.005. After an initial evaluation of several potential biomarkers, only UNa + , UCr and UNa + /UCr were selected as candidates with the highest predictive value. The cut-off for UNa + adjusted for urine dilution: UNa + /UCr ratio <0.167 mmol/mg × 10 -1 was determined by ROC analysis with the highest area under the curve (95% confidence interval): 0.956 (0.915-0.997), P < 0.001. When compared with the guideline-recommended cut-off (UNa + <50 mmol/L as a reference, specificity-0.97; sensitivity-0.83), the odds ratio (OR) for UNa + /UCreat to identify a poor diuretic response was 2.5 times greater, regardless of kidney function (OR for estimated glomerular filtration rate in the logistic regression model was 0.978 [0.945-1.013, P = 0.222])., Conclusions: The UNa + /UCr ratio in a spot urine sample 2 h after intravenous diuretic administration is a simple, highly predictive marker for the identification of AHF patients with poor diuretic response, surpassing guidelines-recommended markers like UNa + ., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The clinical use of N-terminal pro-brain natriuretic peptide (NT-proBNP) and blood concentrations of heart-type fatty acid-binding protein (HFABP) is well-established in diagnosing heart conditions. However, their applicability in forensics is controversial due to postmortem changes. NT-proBNP and HFABP are excreted in the urine due to their small molecular weights and may be found in postmortem urine samples; however, their correlation has not been evaluated. In this study, we compared the concentrations of urinary NT-proBNP and HFABP in 386 forensic autopsy cases. The urinary NT-proBNP levels were significantly higher in acute myocardial infarction (AMI), congestive heart failure (CHF), sepsis, and hyperthermia cases, with the highest levels in CHF cases. Similarly, HFABP concentration was significantly higher in CHF, sepsis, and hyperthermia cases, with the highest level observed in hyperthermia cases. However, the difference in urinary HFABP levels between the AMI and control cases was not significant. Our analysis revealed a correlation between postmortem urine NT-proBNP and HFABP levels, and the NT-proBNP/HFABP ratio was high in patients with CHF and sepsis cases and low in those with hyperthermia. The difference between the ratios was possibly due to the combined release of ventricular myocardial cells in response to ventricular wall stress and myocardial injury for NT-proBNP, as well as myocardial and skeletal muscle injuries for HFABP. This study, for the first time, demonstrates the utility of postmortem measurements of urinary NT-proBNP and HFABP levels, offering valuable insights for improving the accuracy of postmortem diagnosis in forensic medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In our retrospective study, we aimed to investigate the relationship between urinary chloride (uCl - ) and selected clinical and laboratory biomarkers, renal function, and patient outcomes in the acute heart failure (AHF) population. We divided 248 adult patients (≥ 18 years) with AHF into two groups: low uCl - (< 115 mmol/L) and high uCl - . The mean age of the patient group was 70.2 ± 12.6, and 182 patients were male (73.4%). Clinical endpoints included in-hospital mortality, one-year mortality, and a composite endpoint of one-year mortality and rehospitalization for heart failure. Patients were followed up for at least one year. Relevant clinical and baseline biomarker data were collected, including markers concerning inflammation, liver and kidney function, perfusion and congestion, iron status, cardiac remodeling, gasometry, renin and aldosterone. Low uCl - was associated with worse in-hospital outcomes, including higher in-hospital mortality (7.7% vs. 1.4%, p = 0.014), the need for inotropic support (20.19% vs. 2.08%, p ≤ 0.001), worsening of HF during therapy (17.31% vs. 4.86%, p ≤ 0.001), and the need for treatment in an intensive cardiac care unit (33.65% vs. 15.28%, p ≤ 0.001). Low uCl - was a significant predictor of one-year mortality (40.4% vs. 16.7%, p < 0.05) and the composite outcome (HR 2.42, 95% CI 1.43-4.08, p < 0.001). In the multivariable analysis, uCl - was independently associated with the risk of one-year mortality (HR 0.92, 95% CI 0.87-0.98, p < 0.05) and the composite outcome (HR 0.95, 95% CI 0.92-0.99, p < 0.05). Our findings suggest that low uCl - is a marker of more advanced heart failure, activation of the renin-angiotensin-aldosterone system and is related to worse one-year outcomes., (© 2024. The Author(s).)

Background and Aims: The urinary albumin‒creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are important markers of renal dysfunction, but few studies have simultaneously examined their impact on long-term mortality in patients with heart failure (HF)., Methods and Results: This study included patients with HF from the National Health and Nutrition Survey from 1999 to 2018. The fully adjusted Cox proportional risk model was adopted, and propensity score matching (PSM) was also used for risk adjustment. Among 988 patients, a median follow-up of 7.75 years was recorded. A higher UACR corresponded to a higher risk of cardiovascular death (P < 0.001 for trend). No statistically significant difference was found in the trend of eGFR risk stratification on the risk of cardiovascular death (P = 0.09 for trend). After PSM, the results showed that when grouped by UACR, the high-risk group had a higher risk of cardiovascular death regardless of a cutoff value of 30 or 300 mg/g (all P < 0.05). When grouped by eGFR, regardless of a cutoff value of 45 or 30 mL/min/1.73 m 2 , compared to the low-risk group, the high-risk group did not have a statistically significant increase in cardiovascular death (P = 0.086 and P = 0.093, respectively). The subgroup analysis of the main outcome showed an interaction between the UACR and eGFR (P = 0.044)., Conclusions: Both the UACR and eGFR are markers for predicting the progression of HF, but the UACR may be a more important indicator than the eGFR, and they synergistically and complementarily reflect the long-term cardiovascular risk of HF patients., Competing Interests: Declaration of competing interest The authors declare that they have no confict of interest., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction., Methods and Results: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P =3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P =0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P =0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission., Conclusions: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Aims: To provide real-world data on post-diuretic spot urine sodium concentration (UNa) assessment in acute heart failure (AHF) and its implications for treatment., Methods and Results: Automated query of the electronic medical record identified patients admitted to the cardiac intensive care unit of a single tertiary care hospital between November 2018 and December 2021, who received intravenous loop diuretics. Detailed manual chart review confirmed the AHF diagnosis. Stratification was performed based on whether post-diuretic UNa was assessed within 24 h of admission. AHF was confirmed in 340/380 identified patients. Post-diuretic UNa was assessed in 117 (34%), more frequently when ejection fraction was reduced and heart failure more advanced. Patients with versus without post-diuretic UNa assessment received higher doses of intravenous loop diuretics and more frequently acetazolamide and thiazide-like diuretics ( p  < 0.001 for all), resulting in similar urine output despite more advanced heart failure [2,488 mL (1,740-4,033 mL) vs. 2,400 mL (1,553-3,250 mL), respectively; p  = 0.170]. Diuretic therapy remained more intense at discharge in the post-diuretic UNa group, with also a higher prescription rate of angiotensin-neprilysin inhibitors ( p  = 0.021). Serum creatinine increases/decreases were similarly frequent irrespectively from UNa assessment, with more dynamic changes observed in patients with UNa ≤ 80 mmol/L versus ≥ 81 mmol/L. After adjustments for baseline characteristics, the risk for death or heart failure readmission was similar in patients with versus without UNa assessment [HR (95%CI) = 1.43 (0.88-2.32); p  = 0.150]., Conclusion: Post-diuretic UNa assessment in AHF was associated with more intense diuretic regimens, preserving urine output despite its use in a sicker population.

Introduction: This study aimed to evaluate the association between the NephroCheck® test AKIRisk® score, diuretic efficiency (DE), and the odds of worsening kidney function (WKF) within the first 72 h of admission in patients hospitalized for acute heart failure (AHF)., Methods: The study prospectively enrolled 125 patients admitted with AHF. NephroCheck® test was obtained within the first 24 h of admission. DE was defined as net fluid urine output per 40 mg of furosemide equivalents., Results: The median AKIRisk® score was 0.11 (IQR 0.06-0.34), and 38 (30.4%) patients had an AKIRisk® score &gt;0.3. The median cumulative DE at 72 h was 1,963 mL (IQR 1317-3,239 mL). At 72 h, a total of 10 (8%) patients developed an absolute increase in sCr ≥0.5 mg/dL (WKF). In a multivariable setting, there was an inverse association between the AKIRisk® score and DE within the first 72 h. In fact, the highest the AKIRisk® score (centered at 0.3), the higher the likelihood of poor DE (below the median) and WKF at 72 h (odds ratio [OR] 2.04; 95%; CI: 1.02-4.07; p = 0.043, and OR 3.31, 95% CI: 1.30-8.43; p = 0.012, respectively)., Conclusion: In patients with AHF, a higher NephroCheck® AKIRisk® score is associated with poorer DE and a higher risk of WKF at 72 h. Further research is needed to confirm the role of urinary cell cycle arrest biomarkers in the AHF scenario., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Albuminuria is prevalent in patients with chronic heart failure and is a risk factor for disease progression. However, its clinical meaning in acute heart failure remains elusive. This study analyzed the trajectory of urine albumin to creatinine ratio (UACR) between admission and discharge and its association with decongestion., Methods: In this prospective observational study, 63 patients were enrolled. UACR, B-type natriuretic peptide (BNP), and clinical congestion score (CCS) were obtained at admission and discharge. We used linear mixed regression analysis to compare changes in the natural logarithm of UACR (logUACR) and its association with changes in markers of decongestion. Estimates were reported as least squares mean with their respective 95% CIs., Results: The median age of the study population was 87 years, 68.5% were women, and 69.8% had a left ventricular ejection fraction &gt;50%. LogUACR at discharge significantly decreased in the overall population compared to admission (Δ -0.47, 95% CI: -0.78 to -0.15, p value = 0.003). The magnitude of UACR drop at discharge was associated with changes in surrogate markers of decongestion. Patients who showed a greater reduction in BNP at discharge exhibited a greater reduction in UACR (p = 0.016). The same trend was also found with clinical decongestion, as assessed by changes in CCS, however, without achieving statistical significance (p = 0.171). UACR change at discharge was not associated with changes in serum creatinine (p value = 0.923)., Conclusion: In elderly patients with AHF and volume overload, the level of UACR significantly decreased upon discharge compared to admission. This reduction in UACR was closely linked to decreases in BNP., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Acute decompensated heart failure (ADHF) is a life-threatening clinical syndrome involving multi-organ function deterioration. ADHF results from multifaceted, dysregulated pathways that remain poorly understood. Better characterization of proteins associated with heart failure decompensation is needed to gain understanding of the disease pathophysiology and support a more accurate disease phenotyping. In this study, we used an untargeted mass spectrometry (MS) proteomic approach to identify the differential urine protein signature in ADHF patients and examine its pathophysiological link to disease evolution. Urine samples were collected at hospital admission and compared with a group of healthy subjects by two-dimensional electrophoresis coupled to MALDI-TOF/TOF mass spectrometry. A differential pattern of 26 proteins (>1.5-fold change, p < 0.005), mostly of hepatic origin, was identified. The top four biological pathways ( p < 0.0001; in silico analysis) were associated to the differential ADHF proteome including retinol metabolism and transport, immune response/inflammation, extracellular matrix organization, and platelet degranulation. Transthyretin (TTR) was the protein most widely represented among them. Quantitative analysis by ELISA of TTR and its binding protein, retinol-binding protein 4 (RBP4), validated the proteomic results. ROC analysis evidenced that combining RBP4 and TTR urine levels highly discriminated ADHF patients with renal dysfunction (AUC: 0.826, p < 0.001) and significantly predicted poor disease evolution over 18-month follow-up. In conclusion, the MS proteomic approach enabled identification of a specific urine protein signature in ADHF at hospitalization, highlighting changes in hepatic proteins such as TTR and RBP4.

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)-an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra-mass spectrometry (SWATH-MS) in kidney cortices from control sheep ( n = 5), sheep with established rapid-pacing-induced ADHF ( n = 8), and sheep after ~4 weeks recovery from ADHF ( n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2-2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.

Several circulating biomarkers have been found to play a role in the surveillance and risk stratification of heart failure without congenital heart disease, but these have not been widely studied in patients with single ventricles palliated with a Fontan operation. Imaging predictors of worse outcomes in this population include ventricular dilation and dysfunction. Patients who weighed >30 kg with a Fontan circulation referred for cardiac magnetic resonance imaging were invited to participate in the study. Blood and urine samples were obtained at the time of imaging and multiple conventional and novel biomarkers were measured. A total of 82 patients with a median age of 18 years were enrolled. Among the novel biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T had the strongest correlation with ventricular dilation and dysfunction. NT-ProBNP >100 pg/ml has a sensitivity of 91% for the detection of significant ventricular dilation (end-diastolic volume >120 ml/body surface area 1.3 ) and 82% for detection of ejection fraction <50%. The urinary neutrophil gelatinase-associated lipocalin-2 to creatinine ratio correlated with ejection fraction and estimated glomerular filteration rate. In conclusion, abnormalities in biomarkers of heart failure are common in ambulatory, largely asymptomatic patients with Fontan circulation. NT-ProBNP may serve as a sensitive marker for the identification of patients with significant ventricular dilation or dysfunction. Further work is needed to understand how these easily measured circulating biomarkers may be integrated into clinical care., Competing Interests: Disclosures Dr. Opotowsky has received grant funding from Roche Diagnostics. The authors have no other conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Low spot urinary creatinine concentration (SUCR) is a marker of muscle wasting and clinical outcome. The risk factors for low SUCR in heart failure (HF) remain poorly understood. We explored the risk factors for low SUCR related to poor outcomes. In 721 HF patients (age: 52.3 ± 11 years, female: 14%, NYHA: 2.7 ± 0.7) SUCR and Dexa body composition scans were performed. BMI prior HF-onset, weight loss, and appendicular muscle mass were obtained. Each patient was classified as malnutrition or normal by GLIM criteria and three other biochemical indices (CONUT, PNI, and GRNI). Sarcopenia index (SI) as creatinine to cystatin C ratio was also calculated. Within 1 year, 80 (11.1%) patients died. In ROC curve we identified a SUCR value of 0.628 g/L as optimally discriminating surviving from dead. In low SUCR group more advanced HF, higher weight loss and catabolic components of weight trajectory (CCWT), more frequent under-nutrition by GLIM, and lower SI were observed. In multivariate analysis the independent predictors of low SUCR were SI, CCWT, and GNRI score. In conclusion: the risk of low SUCR was associated with a worse outcome. Low SUCR was associated with greater catabolism and sarcopenia but not with biochemical indices of malnutrition.

The DAPA-HF trial demonstrated that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduced worsening heart failure (HF) events in chronic HF patients with or without type 2 diabetic mellitus (T2DM). However, it remains unclear whether the effectiveness of SGLT2i is also observed in patients with decompensated HF irrespective of HbA1c level. Eighty-one T2DM patients hospitalized due to decompensated HF were enrolled and divided into 2 groups according to their HbA1c levels (group H, HbA1c 6.9-13.0%, n = 41; group L, HbA1c < 6.9%, n = 40). After the initial management of HF, one of the SGLT2i (canagliflozin 100 mg/day or dapagliflozin 5 mg/day or empagliflozin 10 mg/day) was non-randomly administered, and clinical parameters associating with HF and T2DM were followed for 7 days. No symptomatic hypoglycemia was observed in any patient. In both groups, urine glucose excretion was increased significantly after the administration of SGLT2i. However, its amount was greater in group H than group L. Urine volume was increased significantly at day 1 in both groups. Urine volume returned to the baseline after one week in group L. In contrast, the increase in urine volume persisted at least for one week in group H. Of note, a decrease in B-type natriuretic peptide levels after the initiation of SGLT2i was observed in both groups similarly despite differences in urine output and excretion of urine glucose. In conclusion, SGLT2i can improve decompensated HF in patients with T2DM irrespective of the HbA1c level.

Background: Congestion predominates in exacerbations of heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), but evidence suggests that excess volume may be distributed differently in these 2 subgroups., Methods and Results: In this retrospective study, diuretic efficiency (DE, or net urine output per 40-mg of intravenous furosemide equivalent) during the first 72 hours was compared between patients hospitalized with HFrEF (n = 121) versus HFpEF (n = 120). Multivariate analysis was used to compare the 2 groups based on expected baseline differences (e.g., demographics, heart failure etiology, concomitant therapy). During the first 72 hours, mean daily diuretic doses were higher in patients with HFpEF versus HFrEF (172.0 vs. 159.9 mg, respectively, P = 0.026) but urine output was not significantly different (2603.3 mL vs. 2667.5 mL, respectively, adjusted P = 0.100). Similarly, mean cumulative DE did not differ (-673.5 vs. -637.8 mL/40-mg in the HFrEF and HFpEF groups, respectively, adjusted P = 0.884). An exploratory analysis of propensity-matched cohorts yielded similar findings. Correlations between the components of DE varied considerably and only became weak to moderately correlated toward the end of the observation period., Conclusions: Although cumulative DE did not differ between patients with HFrEF and HFpEF, variable correlations in the components of DE suggest there may be differences in diuretic response that warrant future analysis.

Carnosine is a naturally occurring dipeptide (β-alanine-L-histidine) which supports physiological homeostasis by buffering intracellular pH, chelating metals, and conjugating with and neutralizing toxic aldehydes such as acrolein. However, it is not clear if carnosine can support cardiovascular function or modify cardiovascular disease (CVD) risk. To examine this, we measured urinary levels of nonconjugated carnosine and its acrolein conjugates (carnosine-propanal and carnosine-propanol) in participants of the Louisville Healthy Heart Study and examined associations with indices of CVD risk. We found that nonconjugated carnosine was significantly associated with hypertension ( p = 0.011), heart failure ( p = 0.015), those categorized with high CVD risk ( p < 0.001), body mass index (BMI; p = 0.007), high sensitivity C-reactive protein (hsCRP; p = 0.026), high-density lipoprotein (HDL; p = 0.007) and certain medication uses. Levels of carnosine-propanal and carnosine-propanol demonstrated significant associations with BMI, blood glucose, HDL and diagnosis of diabetes. Carnosine-propanal was also associated with heart failure ( p = 0.045) and hyperlipidemia ( p = 0.002), but no associations with myocardial infarction or stroke were identified. We found that the positive associations of carnosine conjugates with diabetes and HDL remain statistically significant ( p < 0.05) in an adjusted, linear regression model. These findings suggest that urinary levels of nonconjugated carnosine, carnosine-propanal and carnosine-propanol may be informative biomarkers for the assessment of CVD risk-and particularly reflective of skeletal muscle injury and carnosine depletion in diabetes.

Background: Some studies have reported that nitrate intake from vegetables was inversely associated with many vascular diseases, but few studies have paid attention to the relationship between urinary nitrate and cardiovascular diseases (CVDs). This cross-sectional study aimed to explore the connections between urinary nitrate and prevalence of CVDs., Methods: The data of this study was collected from National Health and Nutrition Examination Survey (NHANES). Finally, several years' data of NHANES were merged into 14,894 observations. Logistic regression models were used to examine the associations between urinary nitrate and CVDs by using the "survey" package in R software (version 3.2.3)., Results: In the univariable logistic analysis, significant association was discovered between urinary nitrate and congestive heart failure, coronary heart disease, angina pectoris, myocardial infarction (all P < 0.001). By adjusting related covariates, the multivariable logistic analysis showed that the significant association only existed between urinary nitrate and congestive heart failure (OR = 0.651, 95% CI 0.507-0.838, P < 0.001). Compared to Q1 urinary nitrate level as reference, the risk for prevalent heart failure diminished along with increasing levels of urinary nitrates, (OR of Q2 level = 0.633, 95% CI 0.403-0.994), (OR of Q3 level = 0.425, 95% CI 0.230-0.783), (OR of Q4 level = 0.375, 95% CI 0.210-0.661), respectively. Moreover, urinary nitrate levels were associated with congestive heart failure in a dose-dependent manner in both 20-60 years group, 60+ years group and male, female group (P < 0.001, P = 0.011 and P = 0.009, P = 0.004)., Conclusions: Independent of related covariates, higher urinary nitrate was associated with lower prevalent congestive heart failure.

Background: SGLT2 (sodium-glucose cotransporter-2) inhibitors improve heart failure-associated outcomes in patients with type 2 diabetes. In patients with heart failure, SGLT2 inhibitors will likely be coprescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics., Methods: The RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) was a randomized, double-blind, placebo-controlled, crossover trial of patients with type 2 diabetes and heart failure with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline to week 6., Results: Twenty-three participants (mean age, 69.8 years; 73.9% male; mean furosemide dose, 49.6±31.3 mg/d; mean HbA1c, 7.9±3.8%) were recruited. Compared with placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference, 535 mL [95% CI, 133-936]; P =0.005) and week 6 (mean difference, 545 mL [95% CI, 136-954]; P =0.005) after adjustment for treatment order, baseline 24-hour urine volume, and percentage change in loop diuretic dose. At 6 weeks, empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference, -7.85 mmol/L [95% CI, -2.43 to 6.73]; P =0.57). Empagliflozin caused a nonsignificant increase in fractional excretion of sodium at day 3, which was absent at week 6 (mean difference day 3, 0.30% [95% CI, -0.03 to 0.63]; P =0.09; week 6, 0.11% [95% CI, -0.22 to 0.44]; P >0.99), and a significant increase in electrolyte-free water clearance at week 6 (mean difference, 312 mL [95% CI, 26-598]; P =0.026) compared with placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6., Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03226457.

Background: Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations., Methods: Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated., Results: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours ( P <0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P =0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P =0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; P =0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; P =0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior ( P =0.02) and all other neurohormones were similar ( P <0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting ( P =0.20) or renal dysfunction ( P >0.11 for all biomarkers), whereas both serum magnesium ( P <0.001) and uric acid levels ( P =0.008) improved., Conclusions: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.

Trimethylamine (TMA) is a gut bacteria product oxidized by the liver to trimethylamine- N -oxide (TMAO). Clinical evidence suggests that cardiovascular disease is associated with increased plasma TMAO. However, little headway has been made in understanding this relationship on a mechanistic and molecular level. We investigated the mechanisms affecting plasma levels of TMAO in Spontaneously Hypertensive Heart Failure (SHHF) rats. Healthy Wistar Kyoto (WKY) and SHHF rats underwent metabolic, hemodynamic, histopathological and biochemical measurements, including tight junction proteins analysis. Stool, plasma and urine samples were evaluated for TMA and TMAO using ultra performance liquid chromatography-mass spectrometry. SHHF presented disturbances of the gut-blood barrier including reduced intestinal blood flow, decreased thickness of the colonic mucosa and alterations in tight junctions, such as claudin 1 and 3, and zonula occludens-1. This was associated with significantly higher plasma levels of TMA and TMAO and increased gut-to-blood penetration of TMA in SHHF compared to WKY. There was no difference in kidney function or liver oxidation of TMA to TMAO between WKY and SHHF. In conclusion, increased plasma TMAO in heart failure rats results from a perturbed gut-blood barrier and increased gut-to-blood passage of TMAO precursor, i.e., TMA. Increased gut-to-blood penetration of bacterial metabolites may be a marker and a mediator of cardiovascular pathology.

Background: The prognostic significance of urinary N -acetyl-β-D-glucosamidase in acute heart failure has not been fully elucidated. Accordingly, this study investigated whether urinary N -acetyl-β-D-glucosamidase could be associated with subsequent adverse events in acute heart failure patients., Methods: We studied 708 consecutive acute heart failure patients who had accessible N -acetyl-β-D-glucosamidase data on admission from the National Cerebral and Cardiovascular Center Acute Decompensated Heart Failure registry. We assessed the relationship between the admission N -acetyl-β-D-glucosamidase level and the combined endpoint of all-cause death and worsening heart failure. Worsening heart failure was defined as worsening symptoms and signs of heart failure requiring intensification of intravenous therapy such as diuretics, vasodilators and inotropes or initiation of mechanical support after stabilisation with initial treatment during hospitalisation, or readmission due to heart failure after discharge., Results: During a median follow-up period of 763 (interquartile range 431-1028) days, higher urinary N -acetyl-β-D-glucosamidase was significantly related to increased events of all-cause death and worsening heart failure. In addition, patients with higher urinary N -acetyl-β-D-glucosamidase and lower estimated glomerular filtration rate on admission had the worst clinical outcomes. In multivariable Cox regression, urinary N -acetyl-β-D-glucosamidase on admission was independently associated with adverse events (hazard ratio 1.19, 95% confidence interval 1.04-1.35) even after adjustment by covariates including the baseline estimated glomerular filtration rate., Conclusions: Higher urinary N -acetyl-β-D-glucosamidase level on admission was independently associated with worse clinical outcomes. Our findings indicate the potential value of assessing urinary N -acetyl-β-D-glucosamidase on admission for further risk stratification in patients with acute heart failure.

Background and Aims: Potassium-wasting (loop diuretics [LD]) and potassium-sparing (spironolactone) medications used for heart failure (HF) may alter renal potassium handling and confound the use of twenty-four-hour (24-h) urine collections as a surrogate marker for potassium intake, an effect that has been observed with dietary sodium assessment. The objective was to determine the strength of association between 24-h urine collections and weighed food records in assessing potassium intake in HF patients stratified by LD usage and spironolactone usage., Methods and Results: Stable outpatients with HF simultaneously completed two 24-h urine collections and two weighed food records on consecutive days. Analyses compared patients stratified by LD and/or spironolactone use. Pearson's correlation and the Bland-Altman method of agreement assessed the relationship between the techniques. Overall, 109 patients (61 ± 11 yrs, 74% male) were included. The mean difference in dietary potassium estimated between 24-h urine collections and food records was -353 ± 1043 mg (p < 0.01) for all patients, with no differences between measures among subgroups. The association between the two methods was r = 0.551 (95% CI, 0.373 to 0.852, p < 0.001) for LD users; r = 0.287 (95% CI, 0.01 to 0.570, p = 0.050) for LD non-users; r = 0.321 (95% CI, 0.13 to 0.798, p = 0.043) for spironolactone users, and; r = 0.534 (95% CI, 0.331 to 0.747, p < 0.001) for spironolactone non-users. There were no significant mean biases identified as part of the Bland-Altman analysis., Conclusion: Among HF patients, potassium-wasting and potassium-sparing medications do not influence the agreement between the two methods in the assessment of potassium intake., Competing Interests: Declaration of Competing Interest All the authors confirmed that they have no conflicts of interest., (Copyright © 2020 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Urinary albumin to creatinine ratio (UACR) is common in patients with heart failure (HF) and may have an impact on clinical outcome. We evaluated the effect of UACR on clinical outcome in a real-world cohort of patients with HF., Methods: All patients with HF at a health maintenance organization were followed for cardiac-related hospitalizations and death., Results: The study cohort included 4668 patients with HF and was divided into 3 groups based on UACR: normal-range albuminuria (2085 patients; 45%), microalbuminuria (1769 patients; 38%), and macroalbuminuria (814 patients; 17%). Microalbuminuria and macroalbuminuria were both associated with increasing age, diabetes mellitus, hypertension, peripheral vascular disease, atrial fibrillation, and New York Heart Association class III/IV. Microalbuminuria and macroalbuminuria were directly associated with decreased event-free survival from death and death and cardiovascular hospitalizations. Cox regression analysis after adjustment for significant predictors demonstrated that microalbuminuria was associated with increase in mortality (hazard ratio, 1.18; 95% confidence interval, 1.18-1.38; P = 0.03) and macroalbuminuria (hazard ratio, 1.33; 95% confidence interval, 1.10-1.61; P < 0.001). Albuminuria was also an independent predictor of death and cardiovascular hospitalizations. Analysis of albuminuria as a continuous parameter (natural logarithm transformed) showed that UACR was an independent predictor of mortality, and cardiovascular hospitalizations. Subclinical albuminuria (UACR 12-29 μg/mg) was directly associated with reduced survival. Cox regression analysis using restricted cubic splines demonstrated an independent continuous increase in mortality with increasing albuminuria (P < 0.0001 adjusted linear model)., Conclusion: Albuminuria provides important information regarding several detrimental processes in HF and is a significant predictor of a worse outcome., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Nonadrenal diseases (NAD), including congestive heart failure (CHF), can affect the conversion of cortisone to cortisol favoring the production of cortisol's urinary downstream metabolites 5α/5β-tetrahydrocortisol (THF) relative to tetrahydrocortisone (THE). We hypothesized that healthy dogs would have lower urinary levels of cortisol, cortisone, THF, and THE than dogs with hypercortisolism (HC) or CHF, and the latter would have higher urinary levels of THF and lower THE than dogs with HC. Four, 9, and 8 dogs with HC, CHF, and normal health, respectively, were included in a pilot prospective cross-sectional study. A single morning voided urine sample was analyzed for urinary cortisol metabolites by liquid chromatography-mass spectrometry. The percentages of conjugated urinary metabolites were significantly higher in dogs with CHF than in healthy dogs ( p  = 0.001), and not different in HC dogs ( p  = 0.07). Log-transformed urine cortisol metabolites-to-creatinine ratios in healthy dogs were significantly lower than the 2 other groups ( p  < 0.001). The urinary free THE:THF ratio was significantly higher ( p  < 0.001) than the urinary total and conjugated THE:THF ratios. Health status did not affect the total, conjugated, and free THE:THF ratios ( p  = 0.61). Additional studies are needed to investigate differences in cortisol metabolites between dogs with HC and NAD to accurately discriminate between the groups.

Background: The optimal diuretic treatment strategy for patients with acute heart failure and renal dysfunction remains unclear. Plasma carbohydrate antigen 125 (CA125) is a surrogate of fluid overload and a potentially valuable tool for guiding decongestion therapy. The aim of this study was to determine if a CA125-guided diuretic strategy is superior to usual care in terms of short-term renal function in patients with acute heart failure and renal dysfunction at presentation., Methods: This multicenter, open-label study randomized 160 patients with acute heart failure and renal dysfunction into 2 groups (1:1). Loop diuretics doses were established according to CA125 levels in the CA125-guided group (n = 79) and in clinical evaluation in the usual-care group (n = 81). Changes in estimated glomerular filtration rate (eGFR) at 72 and 24 hours were the co-primary endpoints, respectively., Results: The mean age was 78 ± 8 years, the median amino-terminal pro-brain natriuretic peptide was 7765 pg/mL, and the mean eGFR was 33.7 ± 11.3 mL/min/1.73m 2 . Over 72 hours, the CA125-guided group received higher furosemide equivalent dose compared to usual care (P = 0.011), which translated into higher urine volume (P = 0.042). Moreover, patients in the active arm with CA125 >35 U/mL received the highest furosemide equivalent dose (P <0.001) and had higher diuresis (P = 0.013). At 72 hours, eGFR (mL/min/1.73m 2 ) significantly improved in the CA125-guided group (37.5 vs 34.8, P = 0.036), with no significant changes at 24 hours (35.8 vs 39.5, P = 0.391)., Conclusion: A CA125-guided diuretic strategy significantly improved eGFR and other renal function parameters at 72 hours in patients with acute heart failure and renal dysfunction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Men with heart failure are reported to be less adherent to low-sodium diets than women are. One potential reason may be that men consume more food and, consequently, more sodium than women do., Objectives: The aims of this study were to compare dietary sodium intake, urine sodium excretion, and sodium density of diet consumed between men and women with heart failure and to determine whether sex moderated the relationship of kilocalories (kcals) consumed with dietary and urine sodium., Methods: A total of 223 patients with heart failure (mean age, 62 ± 12 years; 70% men, 46% New York Heart Association class III-IV) completed detailed 4-day food diaries and provided 24-hour urine sodium samples. To account for sodium density of food, dietary sodium and urine sodium were referenced to sodium per 1000 kcal., Results: On an absolute basis, men consumed 23% more kcals and 28% more sodium than women did; 24-hour sodium excretion was 16% higher in men than in women. There were no differences between men and women when dietary sodium and urinary sodium were referenced to 1000 kcal, indicating they consumed foods with similar sodium density. However, both moderation analyses showed that the dietary sodium intake of men and women with lower kcal intake was similar, whereas men with higher kcal intake consumed more sodium-dense foods than women did., Conclusion: The results suggest that the men with higher sodium intake than women had 2 reasons for nonadherence. They consumed more food and foods with higher sodium density than women did.

Kidney dysfunction (KD) is closely associated with poor clinical outcome in patients with heart failure (HF). KD is classified as intrinsic and pre-renal KD. However, the impact of each KD on the clinical outcome in patients with HF has not yet been fully elucidated. We measured the urinary to serum creatinine (UC/SC) ratio, a marker for intrinsic and pre-renal KD, in 1009 consecutive patients with HF at admission. There were 314 cardio-renal events including HF and advanced end-stage renal dysfunction during the median follow-up period of 1154 days. There were 63 (6%) patients with intrinsic KD (UC/SC ratio < 20), 118 (12%) patients with intermediate KD (UC/SC ratio 20-40), 607 (60%) patients with pre-renal KD (UC/SC ratio > 40), and 221 (22%) patients with no KD. Multivariate Cox's proportional hazard regression analysis demonstrated that intrinsic and intermediate KDs were significantly associated with poor clinical outcome. The prediction model for cardio-renal events was significantly improved by the addition of UC/SC ratio to the confounding risk factors. Subgroup analysis in patients with HF with severely reduced glomerular filtration rates showed that the prevalence rates of intrinsic, intermediate, and pre-renal KDs were 23%, 30%, and 47%, respectively. The cardio-renal event rate was the highest in the intrinsic KD group compared with that in the other groups. Intrinsic KD was closely associated with extremely poor clinical outcome in patients with HF. The UC/SC ratio could provide important clinical information for the treatment and management of KD in patients with HF.

Objective Home care is important in patients with heart failure (HF) in order to maintain their quality of life. A biomarker that can be measured noninvasively is needed to optimize the home care of patients with HF. Urinary angiotensinogen (uAGT) is an indicator of the intrarenal renin-angiotensin system activity, which may be augmented in HF. We hypothesized that uAGT might be a urinary biomarker in HF. Methods We measured uAGT by an enzyme-linked immunosorbent assay and uAGT normalized by urinary creatinine (uCr)-designated uAGT/uCr-at admission and discharge in 45 patients hospitalized for HF. Results We found that both uAGT/uCr [median (interquartile range): 65.5 (17.1-127.7) μg/g Cr at admission; 12.1 (6.0-37.0) μg/g Cr at discharge; p<0.01] and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels [5,422 (2,280-9,907) pg/mL at admission; 903 (510-1,729) pg/mL at discharge; p<0.01] significantly decreased between admission and discharge along with an improvement in patient's clinical status [New York Heart Association scores: 3 (3-4) at admission; 1 (1-1) at discharge; p<0.01]. The generalized least squares model revealed that the time course changes in uAGT/uCr also correlated with those in NT-proBNP levels between admission and readmission in five patients readmitted for HF. Conclusion The results indicated that the time course changes in uAGT/uCr correlated with those in the NT-proBNP levels in patients with HF who showed a clinical improvement. Further investigation and development of a kit for the rapid measurement of uAGT are needed to evaluate the clinical utility of uAGT as a biomarker in HF.

Background: In patients hospitalized with acute heart failure (AHF), low urine sodium concentration (U Na ) after diuretic treatment may identify patients at risk for longer length of stay (LOS) and adverse events. We investigated the prognostic significance of 24-hour cumulative postdiuretic urine sodium concentration in a multicenter clinical trial population., Methods: The Renal Optimization Strategies Evaluation AHF (ROSE AHF) trial randomized 360 patients with AHF and renal dysfunction receiving intravenous diuretic to dopamine, nesiritide, or placebo. Sodium concentration was measured in cumulative urine sample collected during the first 24 hours after randomization in 298 patients. Based on prior studies, lower U Na was defined as ≤60 mmol/L., Results: Lower U Na was present in 142 (48%) patients, who had longer LOS (7 days vs 5 days, P < .001) and less 72-hour weight loss (5.7 lb vs 9.0 lb, P < .001). These associations persisted after controlling for baseline estimated glomerular filtration rate and outpatient furosemide dose. Lower U Na did not modify the null effects of dopamine or nesiritide on clinical outcomes. Results were similar for spot rather than cumulative 24-hour U Na concentration., Conclusion: In patients hospitalized for AHF and renal dysfunction, U Na  ≤ 60 mmol/L during the first 24 hours of diuresis identifies patients at risk for prolonged hospitalization but does not provide an indication for adjunctive dopamine or nesiritide., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Previously we have shown that increased expression of renal epithelial sodium channels (ENaC) may contribute to the renal sodium and water retention observed during chronic heart failure (CHF). The goal of this study was to examine whether renal denervation (RDN) changed the expressions of renal sodium transporters ENaC, sodium-hydrogen exchanger-3 proteins (NHE3), and water channel aquaporin 2 (AQP2) in rats with CHF. CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, surgical bilateral RDN was performed. The expression of ENaC, NHE3, and AQP2 in both renal cortex and medulla were measured. As a functional test for ENaC activation, diuretic and natriuretic responses to ENaC inhibitor benzamil were monitored in four groups of rats (Sham, Sham+RDN, CHF, CHF+RDN). Western blot analysis indicated that RDN (1 wk later) significantly reduced protein levels of α-ENaC, β-ENaC, γ-ENaC, and AQP2 in the renal cortex of CHF rats. RDN had no significant effects on the protein expression of kidney NHE3 in both Sham and CHF rats. Immunofluorescence studies of kidney sections confirmed the reduced signaling of ENaC and AQP2 in the CHF+RDN rats compared with the CHF rats. There were increases in diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. RDN reduced the diuretic and natriuretic responses to benzamil in CHF rats. These findings suggest a critical role for renal nerves in the enhanced expression of ENaC and AQP2 and subsequent pathophysiology of renal sodium and water retention associated with CHF. NEW & NOTEWORTHY This is the first study to show in a comprehensive way that renal denervation initiated after a period of chronic heart failure reduces the expression of epithelial sodium channels and aquaporin 2 leading to reduced epithelial sodium channel function and sodium retention.

Background: Worsening renal function (WRF) during acute heart failure (AHF) occurs frequently and has been associated with adverse outcomes, though this association has been questioned. WRF is now evaluated by function and injury. We evaluated whether urine neutrophil gelatinase-associated lipocalin (uNGAL) is superior to creatinine for prediction and prognosis of WRF in patients with AHF., Methods and Results: We performed a multicenter, international, prospective cohort of patients with AHF requiring IV diuretics. The primary outcome was whether uNGAL predicted development of WRF, defined as a sustained increase in creatinine of 0.5 mg/dL or ≥50% above first value or initiation of renal replacement therapy, within the first 5 days. The main secondary outcome was a composite of in-hospital adverse events. We enrolled 927 patients (mean 68.5 years of age, 62% men). The primary outcome occurred in 72 patients (7.8%). The first, peak and the ratio of uNGAL to urine creatinine (area under curves (AUC) ≤ 0.613) did not have diagnostic utility over the first creatinine (AUC 0.662). There were 235 adverse events in 144 patients. uNGAL did not predict (AUCs ≤ 0.647) adverse clinical events better than creatinine (AUC 0.695)., Conclusions: uNGAL was not superior to creatinine for predicting WRF or adverse in-hospital outcomes and cannot be recommended for WRF in AHF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Congestive heart failure (CHF) entails a complex interaction between the heart and the kidney that represents a clinical entity called cardiorenal syndrome (CRS). One of the mechanisms underlying CRS includes increased intra-abdominal pressure (IAP). We examined the effect of elevated IAP on kidney function in rats with low- and high-output CHF., Methods and Results: Rats with compensated and decompensated CHF induced by means of aortocaval fistula, rats with myocardial infraction (MI) induced by means of left anterior descending artery ligation, and sham control rats were subjected to either 10 or 14 mm Hg IAP. Urine flow (V), Na + excretion (U Na V), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pretreatment with tadalafil (10 mg/kg orally for 4 days) on the adverse renal effects of IAP were examined in decompensated CHF and MI. Basal V and GFR were significantly lower in rats with decompensated CHF compared with sham control rats. Decompensated CHF rats and MI rats subjected to 10 and 14 mm Hg IAP exhibited more significant declines in V, U Na V, GFR and RPF than compensated and sham controls. Elevated IAP also induced tubular injury, as evidenced by significantly increased absolute urinary excretion of neutrophil gelatinase-associated lipocalin. In addition, in a nonquantitative histologic analysis, elevated IAP was associated with increase in necrosis and cell shedding to the tubule lumens, especially in the decompensated CHF subgroup. Pretreatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP., Conclusions: Elevated IAP contributes to kidney dysfunction in high- and low-cardiac output CHF. IAP induces both hemodynamic alterations and renal tubular dysfunction. These deleterious effects are potentially reversible and can be ameliorated with the use of phosphodiesterase-5 inhibition., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the relationship between urinary sodium (U na ) concentration and the pathophysiologic interaction with the development of acute heart failure (AHF) hospitalization., Background: No data are available on the longitudinal dynamics of U na concentration in patients with chronic heart failure (HF), including its temporal relationship with AHF hospitalization., Methods: Stable, chronic HF patients with either reduced or preserved ejection fraction were prospectively included to undergo prospective collection of morning spot U na samples for 30 consecutive weeks. Linear mixed modeling was used to assess the longitudinal changes in U na concentration. Patients were followed for the development of the clinical endpoint of AHF., Results: A total of 80 chronic HF patients (71 ± 11 years of age; an N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentration of 771 [interquartile range: 221 to 1,906] ng/l; left ventricular ejection fraction [LVEF] 33 ± 7%) prospectively submitted weekly pre-diuretic first void morning U na samples for 30 weeks. A total of 1,970 U na samples were collected, with mean U na concentration of 81.6 ± 41 mmol/l. Sodium excretion remained stable over time on a population level (time effect p = 0.663). However, interindividual differences revealed the presence of high (88 mmol/l U na [n = 39]) and low (73 mmol/l U na [n = 41]) sodium excreters. Only younger age was an independent predictor of high sodium excretion (odds ratio [OR]: 0.91; 95% confidence interval [CI]: 0.83 to 1.00; p = 0.045 per year). During 587 ± 54 days of follow-up, 21 patients were admitted for AHF. Patients who developed AHF had significantly lower U na concentrations (F [1.80]  = 24.063; p < 0.001). The discriminating capacity of U na concentration to detect AHF persisted after inclusion of NT-proBNP and estimated glomerular filtration rate (eGFR) measurements as random effects (p = 0.041). Furthermore, U na concentration dropped (U na  = 46 ± 16 mmol/l vs. 70 ± 32 mmol/l, respectively; p = 0.003) in the week preceding the hospitalization and returned to the individual's baseline (U na  = 71 ± 22 mmol/l; p = 0.002) following recompensation, while such early longitudinal changes in weight and dyspnea scores were not apparent in the week preceding decompensation., Conclusions: Overall, U na concentration remained relatively stable over time, but large interindividual differences existed in stable, chronic HF patients. Patients who developed AHF exhibited a chronically lower U na  concentration and exhibited a further drop in U na concentration during the week preceding hospitalization. Ambulatory U na sample collection is feasible and may offer additional prognostic and therapeutic information., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: PENK (proenkephalin) is a stable surrogate for enkephalins, endogenous opioid peptides, which exert cardiodepressive effects and improve renal function. PENK has been associated with heart failure (HF) severity and renal dysfunction. We therefore hypothesized that PENK could be associated with deterioration of kidney function and could have a role as a novel renal marker in HF., Methods and Results: In 2180 patients with HF of a large multicenter cohort (BIOSTAT-CHF [A Systems Biology Study to Tailored Treatment in Chronic Heart Failure]), the relationship between PENK and clinical variables, plasma and urinary biomarkers, and clinical end points was established. Data were validated in a separate cohort of 1703 patients with HF. PENK was elevated (>80 pmol/L, 99th percentile) in 1245 (57%) patients. Higher PENK was associated with more advanced HF and glomerular and tubular dysfunction. The strongest independent predictor of PENK was estimated glomerular filtration rate. Others were plasma NGAL (neutrophil gelatinase-associated lipocalin) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; all P<0.001). Using correlation heatmaps and hierarchical cluster analyses, PENK clustered with estimated glomerular filtration rate, creatinine, NGAL, galectin-3, and urea. Higher PENK was independently associated with increased risk of deterioration of kidney function between baseline and 9 months (odds ratio, 1.29 [1.02-1.65] per PENK doubling; P=0.038; defined as >25% decrease in estimated glomerular filtration rate) and mortality (hazard ratio, 1.23 [1.07-1.43] per doubling; P=0.004). Analyses in the validation cohort yielded comparable findings., Conclusions: Higher PENK levels are associated with more severe HF, with glomerular and tubular renal dysfunction, with incidence of a deterioration of kidney function, and with mortality. These findings suggest that the opioid system might be involved in deteriorating kidney function in HF.

Aims: The clinical significance of the measurement of urine sodium concentration (UNa + ) in response to loop diuretic administration in patients with acute heart failure (AHF) is still unsettled. We studied the association of serial measurements of spot UNa + during the first 48 h of AHF treatment with the indices of decongestion, renal function, and prognosis., Methods and Results: We enrolled 111 AHF patients, all of whom received intravenous furosemide on admission. The mean spot UNa + significantly increased in the 6 h sample (P < 0.05 vs. baseline) and returned to baseline values in the 24 and 48 h samples. Based on the increase or decrease/no change of UNa + in the 6 and 48 h samples vs. baseline, patients were divided into two groups at each time point, respectively. Patients did not differ in baseline clinical and laboratory characteristics. Patients with a decrease/no change of UNa + in the 6 and 48 h samples had a lower weight loss during hospitalization. Patients with a decrease/no change of UNa + in the 48 h sample had a poorer diuretic response and a significant increase in the urinary levels of the tubular biomarkers: kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Low UNa + and decrease/no change in UNa + in the 6 and 48 h samples were independent predictors of higher risk of all-cause mortality during 1-year follow-up (all P < 0.05)., Conclusion: In AHF, low spot UNa+ and lack to increase UNa + in response to intravenous diuretics are associated with poor diuretic response, markers of tubular injury and high risk of 1-year mortality., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Objectives: This study examined the association between urinary albumin excretion and incident heart failure (HF) hospitalization., Background: Excess urinary albumin excretion is more strongly associated with incident stroke and coronary heart disease risk in black than in white individuals. Whether similar associations extend to HF is unclear., Methods: This study examined the associations between the urinary albumin-to-creatinine ratio (ACR) and incident hospitalization for HF overall in 24,433 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants free of suspected HF at baseline; findings were stratified by race and HF subtype (preserved vs. reduced ejection fraction). Models were adjusted for sociodemographic, clinical, and laboratory variables including estimated glomerular filtration rate, and multiple imputation was used to account for missing covariate data., Results: After a median follow-up of 9.2 years, 881 incident HF events (332 preserved ejection fraction, 447 reduced ejection fraction, 102 unspecified) were observed. Compared to the lowest ACR category (<10 mg/g), the risk of incident HF increased with increasing ACR categories (10 to 29 mg/g hazard ratio [HR]: 1.49; 95% confidence interval [CI]: 1.26 to 1.78; 30 to 300 mg/g HR: 2.32; 95% CI: 1.93 to 2.78; >300 mg/g HR: 4.42; 95% CI: 3.36 to 5.83) in the fully adjusted model. Results did not differ by race. The magnitude of the association between ACR and HF with preserved ejection fraction was greater than with HF with reduced ejection fraction (HR comparing highest vs. lowest ACR category: 6.20; 95% CI: 4.15 to 9.26 vs. HR: 4.37; 95% CI: 3.00 to 6.25, respectively; p = 0.05)., Conclusions: Higher ACR was associated with greater risk of incident HF hospitalization in community-dwelling black and white adults., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review gives an overview of mechanisms of DR with a focus on loop diuretics and summarizes the current literature regarding the prognostic value of diuretic efficiency and predictors of natriuretic response in AHF., Recent Findings: The pharmacokinetics of diuretics are impaired in chronic heart failure, but little is known about mechanisms of DR in AHF. Almost all diuresis after administration of a loop diuretic dose occurs in the first few hours after administration and within-dose DR can develop. Recent studies suggest that DR at the level of the nephron may be more important than defects in diuretic delivery to the tubule. Because loop diuretics induce natriuresis, urine sodium (UNa) concentration may serve as a functional, physiological, and direct measure for diuretic responsiveness to a given loop diuretic dose. Identifying and targeting individuals with DR for more aggressive, tailored therapy represents an important opportunity to improve outcomes. A better understanding of the mechanistic underpinnings of DR in AHF is needed to identify additional biomarkers and guide future trials and therapies.

Aims: We conducted a prospective study of emergency department (ED) patients with acute heart failure (AHF) to determine if worsening HF (WHF) could be predicted based on urinary electrolytes during the first 1-2 h of ED care. Loop diuretics are standard therapy for AHF patients. A subset of patients hospitalized for AHF will develop a blunted natriuretic response to loop diuretics, termed diuretic resistance, which often leads to WHF. Early detection of diuretic resistance could facilitate escalation of therapy and prevention of WHF., Methods and Results: Patients were eligible if they had an ED AHF diagnosis, had not yet received intravenous diuretics, had a systolic blood pressure > 90 mmHg, and were not on dialysis. Urine electrolytes and urine output were collected at 1, 2, 4, and 6 h after diuretic administration. Worsening HF was defined as clinically persistent or WHF requiring escalation of diuretics or administration of intravenous vasoactives after the ED stay. Of the 61 patients who qualified in this pilot study, there were 10 (16.3%) patients who fulfilled our definition of WHF. At 1 h after diuretic administration, patients who developed WHF were more likely to have low urinary sodium (9.5 vs. 43.0 mmol; P < 0.001) and decreased urine sodium concentration (48 vs. 80 mmol/L; P = 0.004) than patients without WHF. All patients with WHF had a total urine sodium of <35.4 mmol at 1 h (100% sensitivity and 60% specificity)., Conclusions: One hour after diuretic administration, a urine sodium excretion of <35.4 mmol was highly suggestive of the development of WHF. These relationships require further testing to determine if early intervention with alternative agents can prevent WHF., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: In hospitalized heart failure patients, a poor diuretic response (DR) during the first days of hospital admission is associated with worse outcomes. However, it remains unknown whether DR in the first hours has similar prognostic value. Moreover, data on the sequential change in DR during hospital admission are lacking., Methods and Results: DR (urine output per 40-mg furosemide-equivalent diuretics dose) was measured from 0 to 6 hours (DR6), 6 to 48 hours (DR6-48), and 0 to 48 hours (DR48) of the patient's emergency department (ED) arrival in 1551 patients with acute heart failure (AHF; mean age 78 years, 56% male, and 48% de novo patients with heart failure). Patients with a poor DR within the first 6 hours were older age, had worse renal function, and were already on diuretic treatment before admission. DR6 was only weakly correlated with DR6-48 (Spearman's rho = 0.273; P < .001). DR6, DR6-48, and DR48 were all significantly associated with 60-day mortality independent of other prognostic factors. DR6 and DR48 showed comparable prognostic ability. However, the model combining DR6 with DR6-48 significantly exceeded both DR6 (net reclassification improvement 0.249; P = .032) and DR48 (net reclassification improvement 0.287; P = 0.025) with regard to 60-day mortality prediction., Conclusions: DR measured within the first 6 hours of ED arrival and DR measured during the first 48 hours in patients with AHF have similar prognostic value, although they were moderately correlated. Changes in DR over time provide additional prognostic information., (Copyright © 2018. Published by Elsevier Inc.)

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Recently, we and other group have reported that furosemide administration along with hypertonic saline solution enhanced diuretic efficiency of furosemide. However, little is known about factors which associated with high diuretic efficiency by hypertonic saline solution with furosemide therapy. To identify predictors of diuretic efficiency in the hypertonic saline solution with furosemide therapy, we recruited 30 consecutive hospitalized heart failure (HF) patients with volume overload (77 ± 10 years, systolic blood pressure > 90 mmHg, and estimated glomerular filtration rate > 15 ml/min/1.73 m 2 ). Hypertonic saline with furosemide solution, consisting of 500 ml of 1.7% hypertonic saline solution with 40 mg of furosemide, was administered continuously over 24 h. The patients were divided into two groups on the basis of 24-h urine volume (UV) after initiation of diuretic treatment ≥ 2000 ml (high urine volume: HUV) and < 2000 ml (low urine volume: LUV). The basal clinical characteristics of both groups were analyzed and the predictors of HUV after receiving the treatment were identified. There were not significant differences between two groups in baseline clinical characteristics and medication. Univariate logistic analysis revealed that blood urea nitrogen/creatinine ratio, urine urea nitrogen/creatinine ratio (UUN/UCre), fractional excretion of sodium, and tricuspid annular plane systolic excursion positively associated with HUV. Multivariate logistic regression analysis revealed that UUN/UCre at baseline was independently associated with HUV, and UUN/UCre best predicts HUV by the therapy with a cut-off value of 6.16 g/dl/g Cre (AUC 0.910, 95% CI 0.696-0.999, sensitivity 80%, specificity 87%). The Kaplan-Meier curves revealed significant difference for HF rehospitalization and death rate at 180 days between patients with UUN/UCre ≥ 6.16 g/dl/g Cre and those with UUN/UCre < 6.16 g/dl/g Cre (log-rank P = 0.0489). UUN/UCre at baseline strongly predicted of diuretic efficiency in the hypertonic saline solution with furosemide therapy, and was associated with HF prognosis.

Background: Relief of congestion is the primary goal of initial therapy for acute decompensated heart failure (ADHF). Early measurement of urine sodium concentration (UNa) may be useful to identify patients with diminished response to diuretics. The aim of this study was to determine if the first spot UNa after diuretic initiation could select patients likely to require more intensive therapy during hospitalization., Methods: At the time of admission, 103 patients with ADHF were identified prospectively, and UNa was measured after the first dose of intravenous diuretic. Clinical outcomes were compared for patients with UNa >60 mmol/L and UNa of ≤60 mmol/L, with the primary outcome of a composite of death at 90 days, mechanical circulatory support during admission, and requirement of inotropic support at discharge., Results: Patients with UNa ≤60 had lower admission blood pressure, had less chronic neurohormonal antagonist prior to admission, and were more than twice as likely to experience the primary end point (hazard ratio 2.40, 95% CI 1.02-5.66, P = .045), which was marginally significant after adjusting for renal function and baseline home loop diuretic. Worsening renal function was significantly more common in patients with UNa <60 (23.6% vs 6.5%, P = .05). Although the initial assessment of congestion was similar at admission, patients with low early UNa had a longer length of stay (11 vs 6 days, P < .006) than patients with UNa >60., Conclusions: Assessment of spot UNa after initial intravenous loop diuretic administration may facilitate identification and triage of a population of HF patients at increased risk for adverse events and prolonged hospitalization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: This study investigates spot urinary chloride concentration in euvolemic chronic heart failure (CHF) patients., Methods: This prospective cohort study included 50 ambulatory CHF patients on maintenance loop diuretics without recent hospital admission, clinical signs of volume overload, or adjustment in neurohumoral blocker or diuretic therapy. Spot urinary samples were collected immediately after loop diuretic intake. Subsequently, loop diuretic dose was reduced with 50% or stopped if ≤40 mg furosemide equivalents. Successful down-titration was defined as persistent dose reduction after 7 d without body weight increase >1.5 kg., Results: Urinary chloride concentration was 3045 ± 1271 mg/L overall. Patients with higher versus lower urinary chloride concentrations took the same dose of loop diuretics [40 mg (20-40 mg) furosemide equivalents; p value = .509] and had similar plasma NT-proBNP levels [1179 ng/L (311-2195 ng/L) versus 900 ng/L (255-1622 ng/L), respectively; p value = .461]. Down-titration was successful in 72% versus 76%, respectively (p value  = 1.000). At 30 d, loop diuretic dose remained reduced in 59% versus 76% of patients, respectively (p value = .238). The proportion of patients free from diuretic therapy was 45% versus 62% in the high versus low chloride concentration group (p value = .265)., Conclusions: Loop diuretic down-titration was successful in 3 out of 4 euvolemic CHF patients, irrespectively of urinary chloride concentration on spot samples collected after diuretic intake.

Background: Urinary liver-type fatty acid-binding protein (L-FABP) is a potential biomarker for acute kidney injury, and it in turn increases cardiovascular mortality. We tested whether the urinary L-FABP level predicted short- and mid-term outcomes in patients with acute heart failure., Methods and Results: We enrolled consecutive patients with acute heart failure, and measured their urinary L-FABP levels before acute treatment. Worsening renal function (WRF), defined as both an absolute increase in the serum creatinine level of ≥0.3mg/dL and a ≥25% relative increase in its level from baseline, occurred in 37 (26.8%) of 138 patients. Patients with a urinary L-FABP level above the upper normal limit (8.4 µg/g creatinine) (n = 49; 35.5%) were more likely than those with a urinary L-FABP level within normal limits (n = 89; 64.5%) to develop WRF (n = 26 [53.1%] vs n = 11 [12.4%]; P < .001). A urinary L-FABP level above the upper limit was independently associated with WRF (hazard ratio 1.8; P = .01). During 1 year of follow-up, 12 patients (8.7%) died, and urinary L-FABP level had no association with all-cause mortality. There was, however, a tendency toward a higher readmission rate in patients with a urinary L-FABP level above the upper normal limit who survived the index hospitalization (n = 46) than in those without an abnormal L-FABP level (n = 88; n = 13 [28.3%] vs n = 13 [14.8%]; log-rank P = .06)., Conclusions: Increased urinary L-FABP level before treatment may predict WRF in patients with acute heart failure. Further investigation is warranted for its predictive ability of adverse outcomes., (Copyright © 2018. Published by Elsevier Inc.)