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• Biomarkers to distinguish pathological cardiorenal dysfunction are needed in HF. • Urine galectin-3 may be more specific to renal fibrosis than plasma galectin-3. • Urine galectin-3 distinguished all-cause mortality risk at equal low eGFR values. • Urine galectin-3 correlated with P3NP, indicating specificity for renal fibrosis. • Urine galectin-3 may distinguish cardiorenal risk profiles. Approaches to distinguishing pathological cardiorenal dysfunction in heart failure (HF) from functional/hemodynamically mediated changes in serum creatinine are needed. We investigated urine galectin-3 as a candidate biomarker of renal fibrosis and a prognostic indicator of cardiorenal dysfunction phenotypes. We measured urine galectin-3 in 2 contemporary HF cohorts: the Yale Transitional Care Clinic (YTCC) cohort (n = 132) and the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial (n = 434). We assessed the association of urine galectin-3 with all-cause mortality in both cohorts and the association with an established marker of renal tissue fibrosis, urinary amino-terminal propeptide of type III procollagen (PIIINP) in TOPCAT. In the YTCC cohort, there was significant effect modification between higher urine galectin-3 and lower estimated glomerular filtration rates (eGFRs) (P interaction = 0.046), such that low eGFR levels had minimal prognostic importance if urine galectin-3 levels were low, but they were important and indicated high risk if urine galectin-3 levels were high. Similar observations were noted in the TOPCAT study (P interaction = 0.002). In TOPCAT, urine galectin-3 also positively correlated with urine PIIINP at both baseline (r = 0.43; P < 0.001) and at 12 months (r = 0.42; P < 0.001). Urine galectin-3 levels correlated with an established biomarker of renal fibrosis in 2 cohorts and was able to differentiate high- vs low-risk phenotypes of chronic kidney disease in HF. These proof-of-concept results indicate that additional biomarker research to differentiate cardiorenal phenotypes is warranted. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Congestion is central to the pathophysiology of heart failure (HF); thus, tracking congestion is crucial for the management of patients with HF. In this study we aimed to compare changes in inferior vena cava diameter (IVCD) with venous pressure following manipulation of volume status during ultrafiltration in patients with cardiac dysfunction.Methods and Results: Patients with stable hemodialysis and with systolic or diastolic dysfunction were studied. Central venous pressure (CVP) and peripheral venous pressure (PVP) were measured before and after hemodialysis. IVCD and PVP were measured simultaneously just before dialysis, 3 times during dialysis and immediately after dialysis. Changes in IVCD and PVP were compared at each timepoint with ultrafiltration volumes. We analyzed 30 hemodialysis sessions from 20 patients. PVP was validated as a surrogate for CVP. Mean ultrafiltration volume was 2102 ± 667 mL. IVCD discriminated better ultrafiltration volumes ≤ 500 mL or ≤ 750 mL than PVP (AUC 0.80 vs 0.62, and 0.80 vs 0.56, respectively; both P< 0.01). IVCD appeared to track better ultrafiltration volume (P< 0.01) and hemoconcentration (P< 0.05) than PVP. Changes in IVCD were of greater magnitude than those of PVP (average change from predialysis: -58 ± 30% vs -28 ± 21%; P< 0.001).Conclusions: In patients undergoing ultrafiltration, changes in IVCD tracked changes in volume status better than venous pressure. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) is used to support patients in severe cardiogenic shock. In the absence of recovery, these patients may need to be listed for heart transplant (HT), which offers the best long-term prognosis. However, posttransplantation mortality is significantly elevated in patients who receive ECMO. The objective of the present study was to describe and risk-stratify different profiles of patients listed for HT supported by ECMO. Patients listed for HT in the United Network for Organ Sharing database were analyzed. The primary outcome was 1-year survival and was assessed in patients bridged to transplant with ECMO (ECMO BTT) and patients who were previously supported on ECMO but had it removed before HT (ECMO REMOVED). Among 65,636 adult candidates listed for HT (between 2001 and 2017), 712 were supported on ECMO, 292 of whom (41%) underwent HT (ECMO BTT , n = 202; ECMO REMOVED , n = 90). Most of the patients with ECMO REMOVED were transplanted with a ventricular assist device. In ECMO BTT , recipient age (each 10-year increase), time on the waitlist (both defined as minor risk factors), need for dialysis, and need for mechanical ventilation (both defined as major risk factors) were independent predictors of mortality. ECMO REMOVED and ECMO BTT with no risk factors showed 1-year survival comparable to that in patients who were never supported on ECMO. Compared with patients who were never on ECMO, patients in ECMO BTT group with minor risk factors, 1 major risk factor, and 2 major risk factors had ~2-, ~5-, and >10-fold greater 1-year mortality, respectively (P <.05). The HT recipients in the ECMO REMOVED and ECMO BTT groups with no risk factors showed similar survival as the HT recipients who were never supported on ECMO. In the ECMO BTT group, posttransplantation mortality increased significantly with increasing risk factors. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF.Methods: In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5).Results: The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only.Conclusions: A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile. [ABSTRACT FROM AUTHOR]

Background: The concept of multinephron segment diuretic therapy (MSDT) has been recommended in severe diuretic resistance with only expert opinion and case-level evidence. The purpose of this study was to investigate the safety and efficacy of MSDT, combining 4 diuretic classes, in acute heart failure (AHF) complicated by diuretic resistance.Methods and Results: A retrospective analysis was conducted in patients hospitalized with AHF at a single medical center who received MSDT, including concomitant carbonic anhydrase inhibitor, loop, thiazide, and mineralocorticoid receptor antagonist diuretics. Subjects served as their own controls with efficacy evaluated as urine output and weight change before and after MSDT. Serum chemistries, renal replacement therapies, and in-hospital mortality were evaluated for safety. Patients with severe diuretic resistance before MSDT were analyzed as a subcohort. A total of 167 patients with AHF and diuretic resistance received MSDT. MSDT was associated with increased median 24-hour urine output in the first day of therapy compared with the previous day (2.16 L [0.95-4.14 L] to 3.08 L [1.74-4.86 L], P = .003) in the total cohort and in the Severe diuretic resistance cohort (0.91 L [0.43-1.43 L] to 2.08 L [1.13-3.96 L], P < .001). The median cumulative weight loss at day 7 or discharge was -7.4 kg (-15.3 to -3.4 kg) (P = .02). Neither serum sodium, chloride, potassium, bicarbonate, or creatinine changed significantly relative to baseline (P > .05 for all).Conclusions: In an AHF cohort with diuretic resistance, MSDT was associated with increased diuresis without changes in serum chemistries or kidney function. Prospective studies of MSDT in AHF and diuretic resistance are warranted. [ABSTRACT FROM AUTHOR]

Background: Decongestion is a primary goal during hospitalizations for decompensated heart failure (HF). However, data surrounding the preferred route and strategy of diuretic administration are limited with varying results in prior studies.Methods: This is a retrospective analysis using patients from ASCEND-HF with a stable diuretic strategy in the first 24 hours following randomization. Patients were divided into three groups: intravenous (IV) continuous, IV bolus and oral strategy. Baseline characteristics, in-hospital outcomes, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality were compared across groups. Inverse propensity weighted modeling was used for adjustment.Results: Among 5,738 patients with a stable diuretic regimen in the first 24 hours (80% of overall ASCEND trial), 3,944 (68.7%) patients received IV intermittent bolus administration of diuretics, 799 (13.9%) patients received IV continuous therapy and 995 (17.3%) patients with oral administration. Patients in the IV continuous group had a higher baseline creatinine (IV continuous 1.4 [1.1-1.7]; intermittent bolus 1.2 [1.0-1.6]; oral 1.2 [1.0-1.4] mg/dL; P <0.001) and high NTproBNP (IV continuous 5,216 [2,599-11,603]; intermittent bolus 4,944 [2,339-9,970]; oral 3,344 [1,570-7,077] pg/mL; P <0.001). There was no difference between IV continuous and intermittent bolus group in weight change, total urine output and change in renal function till 10 days/discharge (adjusted P >0.05 for all). There was no difference in 30 day mortality and HF readmission (adjusted OR 1.08 [95%CI: 0.74, 1.57]; P = 0.701) and 180 days mortality (adjusted OR 1.04 [95%CI: 0.75, 1.43]; P = 0.832).Conclusion: In a large cohort of patients with decompensated HF, there were no significant differences in diuretic-related in-hospital, or post-discharge outcomes between IV continuous and intermittent bolus administration. Tailoring appropriate diuretic strategy to different states of acute HF and congestion phenotypes needs to be further investigated. [ABSTRACT FROM AUTHOR]

Background: The estimated glomerular filtration rate (eGFR) from cystatin C (eGFRcys) is often considered a more accurate method to assess GFR compared with an eGFR from creatinine (eGFRcr) in the setting of heart failure (HF) and sarcopenia, because cystatin C is hypothesized to be less affected by muscle mass than creatinine. We evaluated (1) the association of muscle mass with cystatin C, (2) the accuracy of eGFRcys, and (3) the association of eGFRcys with mortality given muscle mass.Methods and Results: We included 293 patients admitted with HF. Muscle mass was estimated with a validated creatinine excretion-based equation. Accuracy of eGFRcys and eGFRcr was compared with measured creatinine clearance. Cystatin C and creatinine were 31.7% and 59.9% higher per 14 kg higher muscle mass at multivariable analysis (both P < .001). At lower muscle mass, eGFRcys and eGFRcr overestimated the measured creatinine clearance. At higher muscle mass, eGFRcys underestimated the measured creatinine clearance, but eGFRcr did not. After adjusting for muscle mass, neither eGFRcys nor eGFRcr were associated with mortality (both P > .19).Conclusions: Cystatin C levels were associated with muscle mass in patients with HF, which could potentially decrease the accuracy of eGFRcys. In HF where aberrations in body composition are common, eGFRcys, like eGFRcr, may not provide accurate GFR estimations and results should be interpreted cautiously. [ABSTRACT FROM AUTHOR]

Background: Sensitized patients awaiting heart transplantation spend a longer time on the waitlist and have higher mortality. We are now able to further characterize sensitization by discriminating antibodies against class I and II, but the differential impact of these has not been assessed systematically.Methods and Results: Using United Network for Organ Sharing data (2004-2015), we analyzed 17,361 adult heart transplant patients whose class I and II panel reactive antibodies were reported. Patients were divided into 4 groups: class I and II ≤25% (group 1); class I ≤25% and class II ˃25% (group 2); class II ≤25% and class I >25% (group 3); and both class I and II >25% (group 4). Outcomes assessed were treated rejection at 1-year mortality, all-cause mortality, and rejection-related mortality. Compared with group 1, only group 4 was associated with a higher risk of treated rejection at 1 year (odds ratio 1.31, 95% confidence interval [CI] 1.05-1.64), all-cause mortality (hazard ratio 1.24, 95% CI 1.06-1.46), and mortality owing to rejection (subhazard ratio 1.84, 95% CI 1.18-2.85), whereas groups 2 and 3 were not (P > .05).Conclusions: Combined elevation in class I and II panel reactive antibodies seem to increase the risk of treated rejection and all-cause mortality, whereas risk with isolated elevation is unclear. [ABSTRACT FROM AUTHOR]

Background: Fractional excretion of urea (FEUrea) is often used to understand the etiology of acute kidney injury (AKI) in patients receiving diuretics. Although FEUrea demonstrates diagnostic superiority over fractional excretion of sodium (FENa), clinicians often assume FEUrea is not affected by diuretics.Objective: To assess the intravenous loop diuretic effect on FEUrea.Methods: We analyzed a prospective cohort (n=297) hospitalized with hypervolemic heart failure at Yale New Haven Hospital System. FENa and FEUrea were calculated at baseline and serially after diuretics. The change in FEUrea at peak diuresis was compared with the pre-diuretic baseline.Results: Mean baseline FEUrea was 35.2% ± 10.5% and increased by a mean 5.6% ± 10.5% following 80 mg (40-160 mg) of furosemide equivalents (P < .001). The magnitude of change in FEUrea was clinically important as the distribution of change in FEUrea was similar to the overall distribution of baseline FEUrea. Change in FEUrea was related to the diuretic response (r = 0.61, P < .001), with a larger FEUrea increase in diuretic responders (8.8%, interquartile range [IQR]: 1.8-16.9) than non-responders (1.2%, IQR: -3.2 to 5.5; P < .001). Diuretic administration reclassified 27% of patients between low and high FEUrea groups across a 35% threshold. Neither change in FEUrea nor percentage reclassified out of a low FEUrea category differed between patients with and without AKI (P > .63 for both).Conclusions: FEUrea is meaningfully affected by loop diuretics. The degree of change in FEUrea is highly variable between patients and commonly of a magnitude that could reclassify across categories of FEUrea. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity display a number of pathophysiologic features that may render them more or less vulnerable to negative effects of decongestion on renal function, including greater right ventricular remodeling, plasma volume expansion and pericardial restraint. We aimed to contrast the renal response to decongestion in obese compared to nonobese patients with HFpEF METHODS AND RESULTS: National Institutes of Health heart failure network studies that enrolled patients with acute decompensated HFpEF (EF ≥ 50%) were included (DOSE, CARRESS, ROSE, and ATHENA). Obese HFpEF was defined as a body mass index ≥ 30 kg/m2. Compared to nonobese HFpEF (n = 118), patients with obese HFpEF (n = 214) were an average of 9 years younger (71 vs 80 years,< 0.001), were more likely to have diabetes (64% vs 31%, P< 0.001) but had less atrial fibrillation (56% vs 75%, P< 0.001). Renal dysfunction (glomerular filtration rate < 60 mL/min/1.73m2) was present in 82% of patients, and there was no difference at baseline between obese and nonobese patients. Despite similar weight loss through decongestive therapies, obese patients with HFpEF demonstrated greater rise in creatinine (Cr) and decline in glomerular filtration rate, with a 2-fold higher incidence of mild worsening renal function (rise in Cr ≥ 0.3 mg/dL) (28 vs 14%, P = 0.008) and a substantially greater increase in severe worsening of renal function (rise in Cr > 0.5 mg/dL) (9 vs 0%, P = 0.002).Conclusions: Despite being nearly a decade younger, obese patients with HFpEF experience greater deterioration in renal function during decongestion than do nonobese patients with HFpEF. Further study to elucidate the complex relationships between volume distribution, cardiorenal hemodynamics and adiposity in HFpEF is needed. [ABSTRACT FROM AUTHOR]

Background: Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies.Methods and Results: We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001).Conclusion: The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies. [ABSTRACT FROM AUTHOR]

Background: Renal dysfunction (RD) is a potent risk factor for death in patients with cardiovascular disease. This relationship may be causal; experimentally induced RD produces findings such as myocardial necrosis and apoptosis in animals. Cardiac transplantation provides an opportunity to investigate this hypothesis in humans.Methods and Results: Cardiac transplantations from the United Network for Organ Sharing registry were studied (n = 23,056). RD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2). RD was present in 17.9% of donors and 39.4% of recipients. Unlike multiple donor characteristics, such as older age, hypertension, or diabetes, donor RD was not associated with recipient death or retransplantation (age-adjusted hazard ratio [HR] = 1.00, 95% confidence interval [CI] 0.94-1.07, P = .92). Moreover, in recipients with RD the highest risk for death or retransplantation occurred immediately posttransplant (0-30 day HR = 1.8, 95% CI 1.54-2.02, P < .001) with subsequent attenuation of the risk over time (30-365 day HR = 0.92, 95% CI 0.77-1.09, P = .33).Conclusions: The risk for adverse recipient outcomes associated with RD does not appear to be transferrable from donor to recipient via the cardiac allograft, and the risk associated with recipient RD is greatest immediately following transplant. These observations suggest that the risk for adverse outcomes associated with RD is likely primarily driven by nonmyocardial factors. [ABSTRACT FROM AUTHOR]

Background Differentiating heart failure (HF) induced renal dysfunction (RD) from intrinsic kidney disease is challenging. It has been demonstrated that biomarkers such as B-type natriuretic peptide (BNP) or the blood urea nitrogen to creatinine ratio (BUN/creat) can identify high- vs low-risk RD. Our objective was to determine if combining these biomarkers could further improve risk stratification and clinical phenotyping of patients with RD and HF. Methods and Results A total of 908 patients with a discharge diagnosis of HF were included. Median values were used to define elevated BNP (>1296 pg/mL) and BUN/creat (>17). In the group without RD, survival was similar regardless of BNP and BUN/creat (n = 430, adjusted P = .52). Similarly, in patients with both a low BNP and BUN/creat, RD was not associated with mortality (n = 250, adjusted hazard ratio [HR] = 1.0, 95% confidence interval [CI] 0.6–1.6, P = .99). However, in patients with both an elevated BNP and BUN/creat those with RD had a cardiorenal profile characterized by venous congestion, diuretic resistance, hypotension, hyponatremia, longer length of stay, greater inotrope use, and substantially worse survival compared with patients without RD (n = 249, adjusted HR = 1.8, 95% CI 1.2–2.7, P = .008, P interaction = .005). Conclusions In the setting of decompensated HF, the combined use of BNP and BUN/creat stratifies patients with RD into groups with significantly different clinical phenotypes and prognosis. [ABSTRACT FROM AUTHOR]

Normal aging results in a predictable decrease in glomerular filtration rate (GFR), and low GFR is associated with worsened survival. If this survival disadvantage is directly caused by the low GFR, as opposed to the disease causing the low GFR, the risk should be similar regardless of the underlying mechanism. Our objective was to determine if age-related decreases in estimated GFR (eGFR) carry the same prognostic importance as disease-attributable losses in patients with ventricular dysfunction. We analyzed the Studies Of Left Ventricular Dysfunction limited data set (n = 6,337). The primary analysis focused on determining if the eGFR-mortality relation differed by the extent to which the eGFR was consistent with normal aging. Mean eGFR was 65.7 ml/min/1.73 m(2) (SD = 19.0). Across the range of age in the population (27 to 80 years), baseline eGFR decreased by 0.67 ml/min/1.73 m(2)/year (95% confidence interval [CI] 0.63 to 0.71). The risk of death associated with eGFR was strongly modified by the degree to which the low eGFR could be explained by aging (p for interaction <0.0001). For example, in a model incorporating the interaction, uncorrected eGFR was no longer significantly related to mortality (adjusted hazard ratio 1.0 per 10 ml/min/1.73 m(2), 95% CI 0.97 to 1.1, p = 0.53), whereas a disease-attributable decrease in eGFR above the median carried significant risk (adjusted hazard ratio 2.8, 95% CI 1.6 to 4.7, p <0.001). In conclusion, in the setting of left ventricular dysfunction, renal dysfunction attributable to normal aging had a limited risk for mortality, suggesting that the mechanism underlying renal dysfunction is critical in determining prognosis. [ABSTRACT FROM AUTHOR]

Background: Differentiation of HF-induced renal dysfunction (RD) from irreversible intrinsic kidney disease is challenging, likely related to the multifactorial pathophysiology underlying HF-induced RD. In contrast, HF-induced liver dysfunction results in characteristic laboratory abnormalities. Given that similar pathophysiologic factors are thought to underlie both conditions, and that the liver and kidneys share a common circulatory environment, patients with laboratory evidence of HF-induced liver dysfunction may also have a high incidence of potentially reversible HF-induced RD. Methods and Results: Hospitalized patients with a discharge diagnosis of HF were reviewed (n = 823). Improvement in renal function (IRF) was denned as a 20% improvement in estimated glomerular filtration rate (eGFR). An elevated international normalized ratio (INR; odds ratio [OR] 2.8; P < .001), bilirubin (BIL; OR 2.2; P < .001), aspartate aminotransferase (AST; OR 1.8; P = .004), and alanine aminotransferase (ALT; OR 2.1; P = .001) were all significantly associated with IRF. Among patients with baseline RD (eGFR ≤45 mL min-1 1.73 m-2), associations between liver dysfunction and IRF were particularly strong (INR: OR 5.7 [P < .001]; BIL: OR 5.1 [P < .001]; AST: OR 2.9 [P = .005]; ALT: OR 4.8 [P < .001]). Conclusions: Biochemical evidence of mild liver dysfunction is associated with reversible RD in decompensated HF patients. In the absence of methodology to directly identify HF-induced RD, signs of HF-induced dysfunction of other organs may serve as an accessible method by which HF-induced RD is recognized. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to determine if the timing of hemoconcentration influences associated survival. Background: Indicating a reduction in intravascular volume, hemoconcentration during the treatment of decompensated heart failure has been associated with reduced mortality. However, it is unclear if this survival advantage stems from the improved intravascular volume or if healthier patients are simply more responsive to diuretics. Rapid diuresis early in the hospitalization should similarly identify diuretic responsiveness, but hemoconcentration this early would not indicate euvolemia if extravascular fluid has not yet equilibrated. Methods: Consecutive admissions at a single center with a primary discharge diagnosis of heart failure were reviewed (N = 845). Hemoconcentration was defined as an increase in both hemoglobin and hematocrit levels, then further dichotomized into early or late hemoconcentration by using the midway point of the hospitalization. Results: Hemoconcentration occurred in 422 (49.9%) patients (41.5% early and 58.5% late). Patients with late versus early hemoconcentration had similar baseline characteristics, cumulative in-hospital loop diuretic administered, and worsening of renal function. However, patients with late hemoconcentration versus early hemoconcentration had higher average daily loop diuretic doses (p = 0.001), greater weight loss (p < 0.001), later transition to oral diuretics (p = 0.03), and shorter length of stay (p < 0.001). Late hemoconcentration conferred a significant survival advantage (hazard ratio: 0.74 [95% confidence interval: 0.59 to 0.93]; p = 0.009), whereas early hemoconcentration offered no significant mortality benefit (hazard ratio: 1.0 [95% confidence interval: 0.80 to 1.3]; p = 0.93) over no hemoconcentration. Conclusions: Only hemoconcentration occurring late in the hospitalization was associated with improved survival. These results provide further support for the importance of achieving sustained decongestion during treatment of decompensated heart failure. [Copyright &y& Elsevier]

Objective: Cardiac transplantation (OHT) using diabetic donors (DDs) is thought to adversely influence survival. We attempt to determine if adult OHT can be safely performed using selected DDs. Methods: The United Network for Organ Sharing (UNOS) database was examined for adult OHT from 2000 to 2010. Results: Of the 20,348 patients undergoing OHT, 496 (2.4%) were with DDs. DDs were older (39.6 vs 31.3 years; P < .001), more likely female (41.5% vs 28.3%; P < .001), and had a higher body mass index (BMI) (29.9 vs 26.4; P < .001). Recipients of DD hearts were older (53.4 vs 51.8; P = .004) and more likely to have diabetes (18.9% vs 14.9%; P = .024). The 2 groups were evenly matched with regard to recipient male gender (78.0% vs 76.1%; P = .312), ischemic time (3.3 vs 3.2 hours; P = .191), human leukocyte antigen mismatches (4.7 vs 4.6; P = .483), and requirement of extracorporeal membrane oxygenation (ECMO) as a bridge to transplant (0.8% vs 0.5%; P = .382). Median survival was similar (3799 vs 3798 days; P = .172). On multivariate analysis, DD was not associated with mortality (hazard ratio [HR], 1.155; 95% confidence interval [CI], 0.943-1.415; P = .164). As previously demonstrated, donor age, decreasing donor BMI, ischemic time, recipient creatinine, recipient black race, recipient diabetes, race mismatch, and mechanical ventilation or ECMO as a bridge to transplant were associated with mortality. On multivariate analysis of subgroups, neither insulin-dependent diabetes (1.173; 95% CI, 0.884-1.444; P = .268) nor duration of diabetes for more than 5 years (HR, 1.239; 95% CI, 0.914-1.016; P = .167) was associated with mortality. Conclusions: OHT can be safely performed using selected DDs. Consensus criteria for acceptable cardiac donors can likely be revised to include selected DDs. [Copyright &y& Elsevier]

Abstract: Background: Digitalis glycosides are known to improve the hemodynamic and neurohormonal perturbations that contribute to heart failure (HF)–induced renal dysfunction (RD). The objective of this study was to determine if randomization to digoxin is associated with improvement in renal function (IRF) and to evaluate if patients with digoxin-induced IRF have improved clinical outcomes. Methods and Results: Patients in the Digitalis Investigation Group (DIG) dataset with protocol-driven 1-year serum creatinine levels (performed in a central laboratory; n = 980) were studied. IRF was defined as a postrandomization ≥20% increase in estimated glomerular filtration rate (eGFR). IRF occurred in 15.5% of the population (mean improvement in eGFR 34.5 ± 15.4%) and was more common in patients randomized to digoxin (adjusted odds ratio 1.6; P = .02). In patients without IRF, digoxin was not associated with reduced death or hospitalization (adjusted hazard ratio [HR] 0.96, 95% CI 0.8–1.2; P = .67). However, in the group with IRF, digoxin was associated with substantially improved hospitalization-free survival (adjusted HR 0.49, 95% CI 0.3–0.8; P = .006; P interaction = .026). Conclusions: In this subset of the DIG trial, digoxin was associated with long-term improvement in kidney function and, in patients demonstrating this favorable renal response, reduction in death or hospitalization. Additional research is necessary to confirm these hypothesis-generating findings. [Copyright &y& Elsevier]

Abstract: Background: In the setting of acute decompensated heart failure, worsening renal function (WRF) and improved renal function (IRF) have been associated with similar hemodynamic derangements and poor prognosis. Our aim was to further characterize IRF and its associated mortality risk. Methods and Results: Consecutive patients with a discharge diagnosis of congestive heart failure at the Hospital of the University of Pennsylvania were reviewed. IRF was defined as a ≥20% improvement and WRF as a ≥20% deterioration in glomerular filtration rate. Overall, 903 patients met the eligibility criteria, with 31.4% experiencing IRF. Baseline venous congestion/right-side cardiac dysfunction was more common (P ≤ .04) and volume of diuresis (P = .003) was greater in patients with IRF. IRF was associated with a greater incidence of preadmission (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.6–6.7; P < .0001) and postdischarge (OR 1.8, 95% CI 1.2–2.7; P = .006) WRF. IRF was associated with increased mortality (adjusted hazard ratio 1.3, 95% CI, 1.1–1.7; P = .011), a finding largely restricted to patients with postdischarge recurrence of renal dysfunction (P interaction = .038). Conclusions: IRF is associated with significantly worsened survival and may represent the resolution of venous congestion–induced preadmission WRF. Unlike WRF, the renal dysfunction in IRF patients occurs independently from the confounding effects of acute decongestion and may provide incremental information for the study of cardiorenal interactions. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to investigate whether a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high-dose loop diuretics (HDLD). Background: Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and have been associated with worsened survival. Methods: Subjects in the BEST (Beta-Blocker Evaluation of Survival Trial) receiving loop diuretics at baseline were analyzed (N = 2,456). The primary outcome was the interaction between BUN- and HDLD-associated mortality. Results: In the overall cohort, HDLD use (≥160 mg/day) was associated with increased mortality (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR: 1.06; 95% CI: 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR: 1.59; 95% CI: 1.34 to 1.88) and adjusted (HR: 1.29; 95% CI: 1.07 to 1.60) risk of death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR: 0.99; 95% CI: 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR: 0.71; 95% CI: 0.49 to 0.96) (p interaction = 0.018). Conclusions: The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with an elevated BUN level and improved survival in patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop diuretic–associated mortality. [Copyright &y& Elsevier]

Background: Worsening renal function (WRF) commonly complicates the treatment of acute decompensated heart failure. Despite considerable investigation in this area, it remains unclear to what degree WRF is a reflection of treatment- versus patient-related factors. We hypothesized that if WRF is significantly influenced by factors intrinsic to the patient, then WRF during an index hospitalization should predict WRF during subsequent hospitalization. Methods: Consecutive admissions to the Hospital of the University of Pennsylvania with a discharge diagnosis of congestive heart failure were reviewed. Patients with >1 hospitalization were retained for analysis. Results: In total, 181 hospitalization pairs met the inclusion criteria. Baseline patient characteristics demonstrated significant correlation between hospitalizations (P ≤ .002 for all) but minimal association with WRF. In contrast, variables related to the aggressiveness of diuresis were weakly correlated between hospitalizations but significantly associated with WRF (P ≤ .024 for all). Consistent with the primary hypothesis, WRF during the index hospitalization was strongly associated with WRF during subsequent hospitalization (odds ratio [OR] 2.7, P = .003). This association was minimally altered after controlling for traditional baseline characteristics (OR 2.5, P = .006) and in-hospital treatment–related parameters (OR 2.8, P = .005). Conclusions: A prior history of WRF is strongly associated with subsequent episodes of WRF, independent of in-hospital treatment received. These results suggest that baseline factors intrinsic to the patient''s cardiorenal pathophysiology have substantial influence on the subsequent development of WRF. [Copyright &y& Elsevier]

Worsening renal function (RF) and improved RF during the treatment of decompensated heart failure have traditionally been thought of as hemodynamically distinct events. We hypothesized that if the pulmonary artery catheter-derived measures are relevant in the evaluation of cardiorenal interactions, the comparison of patients with improved versus worsening RF should highlight any important hemodynamic differences. All subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with admission and discharge creatinine values available were included (n = 401). No differences were found in the baseline, final, or change in pulmonary artery catheter-derived hemodynamic variables, inotrope and intravenous vasodilator use, or survival between patients with improved versus worsening RF (p = NS for all). Both groups were equally likely to be in the bottom quartile of cardiac index (p = 0.32), have a 25% improvement in cardiac index (p = 0.97), or have any worsening in cardiac index (p = 0.90). When patients with any significant change in renal function (positive or negative) were compared to those with stable renal function, strong associations between variables such as a reduced cardiac index (odds ratio 2.2, p = 0.02), increased intravenous inotrope and vasodilator use (odds ratio 2.9, p <0.001), and worsened all-cause mortality (hazard ratio 1.8, p = 0.01) became apparent. In contrast to traditionally held views, the patients with improved RF and those with worsening RF had similar hemodynamic parameters and outcomes. Combining these groups identified a hemodynamically compromised population with significantly worse survival than patients with stable renal function. In conclusion, the changes in renal function, regardless of the direction, likely identify a population with an advanced disease state and a poor prognosis. [ABSTRACT FROM AUTHOR]

The noninvasive estimation of pulmonary artery systolic pressure (PASP) has become a standard component of the echocardiographic examination. Our aim was to evaluate the accuracy of this modality in a large series of unselected studies obtained in clinical practice. All right heart catheterizations during a 4-year period were reviewed. Studies with echocardiographic findings available within 48 hours were evaluated for PASP agreement. In an effort to mirror clinical practice, the right heart catheterization findings were used as the reference standard and the PASP values were taken directly from the respective clinical reports. Overall, 792 right heart catheterization–echocardiogram pairs were identified. Echocardiographic PASP could not be estimated in 174 of these studies (22.0%). The correlation between modalities was moderate, but agreement was poor (bias 9.0%, 95% limits of agreement −53.2% to 71.2%, r = 0.52, p <0.001). Misclassification of clinical PASP categories occurred more often than not (54.4%). Multivariate analysis using multiple potential sources of error could only account for 3.2% of the total variation in the discrepancy between the study modalities (p = 0.003). In conclusion, noninvasively estimated PASP had limited agreement with the invasively determined PASP, and misclassification of PASP clinical categories occurred frequently. Given the widespread use of echocardiographically determined PASP, these data are in need of replication in a large prospective study. [Copyright &y& Elsevier]

Recent reports have demonstrated the adverse effects of venous congestion on renal function (RF) and challenged the assumption that worsening RF is driven by decreased cardiac output (CO). We hypothesized that diuresis in patients with right ventricular (RV) dysfunction, despite decreased CO, would lead to a decrease in venous congestion and resultant improvement in RF. We reviewed consecutive admissions with a discharge diagnosis of heart failure. RV function was assessed by multiple echocardiographic methods and those with ≥2 measurements of RV dysfunction were considered to have significant RV dysfunction. Worsening RF was defined as an increase in creatinine of ≥0.3 mg/dl and improved RF as improvement in glomerular filtration rate ≥25%. A total of 141 admissions met eligibility criteria; 34% developed worsening RF. Venous congestion was more common in those with RV dysfunction (odds ratio [OR] 3.3, p = 0.009). All measurements of RV dysfunction excluding RV dilation correlated with CO (p <0.05). Significant RV dysfunction predicted a lower incidence of worsening RF (OR 0.21, p <0.001) and a higher incidence of improved RF (OR 6.4, p <0.001). CO emerged as a significant predictor of change in glomerular filtration rate during hospitalization in those without significant RV dysfunction (r = 0.38, p <0.001). In conclusion, RV dysfunction is a strong predictor of improved renal outcomes in patients with acute decompensated heart failure, an effect likely mediated by relief of venous congestion. [Copyright &y& Elsevier]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown. These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status. SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4. Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (P trend = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017). Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934) [ABSTRACT FROM AUTHOR]

Background Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF. Methods Diuretic response , defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent. Results Mean diuretic response was −0.42 kg/40 mg of furosemide (interquartile range −1.0, −0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response ( P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide. Conclusions Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response. [ABSTRACT FROM AUTHOR]