Background Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure (ADHF) and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed. Methods and Results Based on well-established renal physiologic principles an equation was derived to predict net sodium output using a spot urine sample obtained one or two hours following loop diuretic administration. This equation was then prospectively validated in 50 ADHF patients using meticulously obtained timed 6-hour urine collections to quantitate loop diuretic induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2–4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (r=0.91, p<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (AUC=0.95, 95% CI 0.89–1.0, p<0.0001). Clinically recorded net fluid output had a weaker correlation (r=0.66, p<0.001) and lesser ability to predict poor natriuretic response (AUC=0.76, 95% CI 0.63–0.89, p=0.002). Conclusions In patients being treated for ADHF, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.

Background Recent epidemiologic studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure (HF). Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiologic literature. Methods and Results Two HF cohorts were included: (1) Observational: Patients receiving loop diuretics at the Yale Transitional Care Center (YTCC; N=162); (2) Interventional Pilot: Stable outpatients receiving ≥80mg furosemide equivalents were studied before and after three days of 115 mmol/d supplemental lysine chloride (N=10). In YTCC, 31.5% of patients had hypochloremia (chloride ≤96 mmol/L). Plasma renin concentration correlated with serum chloride (r=−0.46, p<0.001) with no incremental contribution from serum sodium (p=0.49). Hypochloremic vs. non-hypochloremic patients exhibited renal wasting of chloride (p=0.04) and of chloride relative to sodium (p=0.01), despite better renal free water excretion (urine osmolality 372±94 mOsm/kg vs. 507±118, p<0.001). Hypochloremia was associated with poor diuretic response (OR=7.3, 95% CI 3.3–16.1, p<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in NT-proBNP, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio. Conclusions Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardio-renal parameters. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.

AIDS vaccine and pathogenesis research will benefit from a more diverse array of cloned SIV challenge stocks from which to choose. Toward this end, 20 envelope genes were cloned from an extensively used, primary stock of uncloned SIVmac251. Each of the 20 clones had a unique sequence. Their translated sequences differed by as many as 26 amino acids from one another and by as many as 45 amino acids from the commonly used clone SIVmac239. Envelope sequences up to and including the membrane-spanning domain were exchanged into the infectious pathogenic SIVmac239 clone and virus stocks were produced by HEK293T cell transfection. Seventeen of the 20 recombinants were replication competent. The infectivities per ng p27 of the 17 new replication-competent recombinants in C8166-SEAP cells and in TZM-bl cells ranged from minus 32-fold to plus 7.6-fold relative to SIVmac239. A range of sensitivities to neutralization by sCD4 and by sera from SIV-infected macaques was observed but none was as sensitive to these neutralizing agents as SIVmac316, the highly macrophage-competent derivative of SIVmac239. Four strains that were most sensitive to sCD4 inhibition were also among the most sensitive to antibody-mediated neutralization. None of the new recombinant viruses replicated as well as SIVmac316 in primary alveolar macrophage cultures from rhesus monkeys but three of the strains did exhibit significant levels of delayed replication in these primary macrophages, reaching peak levels of virus production of ≥50 ng/ml p27 compared to 600-800 ng/ml p27 with SIVmac316. These new SIV clones are being contributed to the NIH AIDS Reagent Repository and are available to the scientific community.

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 combination these biomarkers could further improve risk stratification and clinical phenotyping of patients with RD and HF. Methods and Results 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=0.52). Similarly, in patients with both a low BNP and BUN/Creat, RD was not associated with mortality (n=250, adjusted HR=1.0, 95% CI 0.6-1.6, p=0.99). However, in patients with both an elevated BNP and BUN/Creat those with RD had a cardio-renal profile characterized by venous congestion, diuretic resistance, hypotension, hyponatremia, longer length of stay, greater inotrope use, and substantially worse survival compared to patients without RD (n=249, adjusted HR=1.8, 95% CI 1.2-2.7, p=0.008, p interaction=0.005). 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.

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BACKGROUND The prevalence and clinical characteristics of familial dilated cardiomyopathy (FDCM) among patients with end stage heart failure (ESHF) has yet to be elucidated. We sought to determine the prevalence of FDCM in ESHF in the United Network for Organ Sharing (UNOS) registry and compare this with center specific data from a large tertiary teaching hospital. Patients with a banked UNOS diagnosis of dilated cardiomyopathy (DCM) whose care originated at our center then underwent detailed pedigree analysis in order to determine the true prevalence of FDCM. METHODS AND RESULTS A total of 16,091 patients with DCM from all centers were identified in the UNOS registry of whom 492 carried the diagnosis of FDCM (3.1%). Patients with the diagnosis of FDCM tended to be younger (42 versus 49 years old in idiopathic dilated cardiomyopathy (IDCM), p=0.001), were less likely to have diabetes (7.8% versus 16.5% in IDCM, p<0.0001), had slightly lower creatinine (1.2 versus 1.4 in IDCM, p=0.0001) and were more likely to have a panel reactive antibody level ≥ 20% (62.1% versus 44.7% in IDCM, p<0.0001). Consecutive living adult patients with ESHF were identified from the UNOS registry that had been treated at the Yale Center for Advanced Heart Failure (YCAHF). After excluding all diagnoses that did not include any form of non-ischemic DCM, 73 patients met the inclusion criteria. Center-specific UNOS data showed pre-pedigree analysis diagnosis of FDCM in 4.12% of patients (3 out of 73), consistent with that found in the UNOS database for all centers. However, after detailed family history and pedigree analysis, 19 (26%) of 73 patients were found to have FDCM, while the remaining 54 were found to have IDCM. Echocardiographic findings including mitral regurgitation, mitral valve annulus and left ventricular end diastolic dimension were not significantly different between groups when adjusting for multiple testing. CONCLUSIONS The diagnosis of FDCM was missed in the majority of patients with end stage heart failure enrolled in the UNOS database, as sampled from a large, tertiary care teaching hospital in the United States. Echocardiographic findings are unlikely to aid in the differentiation between DCM and FDCM. Detailed pedigree analysis can successfully identify undiagnosed FDCM and should be encouraged prior to transplant listing as it has important implications for early detection and treatment of disease in family members.

Background Renal dysfunction (RD) is a potent risk factor for death in patients with cardiovascular disease. This relationship may be causal since 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 UNOS registry were studied (n=23,056). RD was defined as an estimated glomerular filtration rate < 60 ml/min/1.73m2. 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 HR=1.00, 95% CI 0.94–1.07, p=0.92). Moreover, in recipients with RD the highest risk for death or retransplantation occurred immediately post-transplant (0–30 day HR=1.8, 95% CI 1.54–2.02, p<0.001) with subsequent attenuation of the risk over time (30–365 day HR=0.92, 95% CI 0.77–1.09, p=0.33). 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 non-myocardial factors.

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