A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients.

PURPOSE: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF). METHODS: Healthy adults (Parts A/B) and HF patients (Part C) aged 18-85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). PRIMARY ENDPOINT: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function. RESULTS: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler). CONCLUSIONS: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03276728. DATE OF REGISTRATION: September 8, 2017.

Dual Vasopressin Receptor Antagonism to Improve Congestion in Patients With Acute Heart Failure: Design of the AVANTI Trial.

BACKGROUND: Loop diuretics are the main treatment for patients with acute heart failure, but are associated with neurohormonal stimulation and worsening renal function and do not improve long-term outcomes. Antagonists to arginine vasopressin may provide an alternative strategy to avoid these effects. The AVANTI study will investigate the efficacy and safety of pecavaptan, a novel, balanced dual-acting V1a/V2 vasopressin antagonist, both as adjunctive therapy to loop diuretics after admission for acute heart failure, and later as monotherapy. METHODS AND RESULTS: AVANTI is a double-blind, randomized phase II study in 571 patients hospitalized with acute heart failure and signs of persistent congestion before discharge. In part A, patients will receive either pecavaptan 30 mg/d or placebo with standard of care for 30 days. In part B, eligible patients will continue treatment or receive pecavaptan or diuretics as monotherapy for another 30 days. The primary end points for part A are changes in body weight and serum creatinine; for part B, changes in body weight and blood urea nitrogen/creatinine ratio. CONCLUSIONS: This study will provide the first evidence that a balanced V1a/V2 antagonist may safely enhance decongestion, both as an adjunct to loop diuretics and as an alternative strategy. TRIAL REGISTRATION NUMBER: NCT03901729.

Dual Vasopressin V1a/V2 Antagonism: The Next Step in Neurohormonal Modulation in Patients With Heart Failure?

Stimulation of the V1a receptor for arginine vasopressin produces myocardial and vascular effects similar to those of angiotensin II while stimulation of the V2 receptor causes fluid retention. There are no data with sustained blockade of the V1a receptor while single-dose experiments suggest benefit. Acute and chronic administration of selective V2 receptor antagonists reliably relieves dyspnea and produces diuresis without adverse effects on renal function or neurohormonal stimulation, either as adjunctive or alternative therapy to loop diuretics, but has not been shown to improve outcomes as adjunctive therapy. Combined antagonism has been tried only in single-dose studies in stable patients or over the short-term in acute heart failure, with encouraging results. Based on the both the pathophysiologic rationale for additional neurohormonal blockade and these results, chronically blocking both receptors, particularly in more congested patients, may offer significant benefit either as adjunctive or alternative therapy to standard diuretics.

Prognostic importance of sodium level trajectory in acute heart failure.

Low sodium levels are strongly associated with poor prognosis in acute heart failure (AHF); however, the prognostic impact of the sodium level trajectory overtime has not been determined. A secondary analysis of the AQUAMARINE study in which patients with AHF and renal impairment were randomized to receive either tolvaptan or conventional treatment was performed. Sodium levels were evaluated at the baseline and at 6, 12, 24, and 48 h. We defined 'sodium dipping' as sodium level falling below the baseline level at any time point. The primary endpoint was the combined event of all-cause death and heart failure rehospitalization during follow-up. The analysis included 184 patients with a median follow-up of 21.1 months. Sodium levels more steeply increased during the 48 h in patients without events as compared to sodium levels in patients with events (P = 0.018 in linear-mixed effect model). The sodium dipping group (n = 100; 54.3%) demonstrated significantly less urine output, less body weight reduction, and poorer diuretic response within 48 h compared to the non-dipping group. The sodium dipping group was also significantly associated with a low combined-event-free survival after adjustment for other prognostic factors (HR 1.97; 95% CI 1.06-3.38; P = 0.033). The trajectory of sodium levels during the acute phase is associated with the prognosis of patients with AHF independently of the baseline sodium level.

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study.

BACKGROUND: Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. METHODS AND RESULTS: We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, -4.2 [-4.9, -3.5] mg/dL and -3.5 [-4.2, -2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36). CONCLUSIONS: In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415.

Clinical Effectiveness of Tolvaptan in Patients With Acute Heart Failure and Renal Dysfunction.

BACKGROUND: More efficacious and/or safer decongestive therapy is clearly needed in acute heart failure (AHF) patients complicated by renal dysfunction. We tested the hypothesis that adding tolvaptan, an oral vasopressin-2 receptor antagonist, to conventional therapy with loop diuretics would be more effective treatment in this population. METHODS AND RESULTS: A multicenter, open-label, randomized control trial was performed, and 217 AHF patients with renal dysfunction (estimated glomerular filtration rate 15-60 mL • min(-1) • 1.73 m(-2)) were randomized 1:1 to treatment with tolvaptan (n=108) or conventional treatment (n=109). The primary end point was 48-hour urine volume. The tolvaptan group showed more diuresis than the conventional treatment group (6464.4 vs 4999.2 mL; P <.001) despite significantly lower amounts of loop diuretic use (80 mg vs 120 mg; P <.001). Dyspnea relief was achieved significantly more frequently in the tolvaptan group at all time points within 48 hours except 6 hours after enrollment. The rate of worsening of renal function (≥0.3 mg/dL increase from baseline) was similar between the tolvaptan and conventional treatment groups (24.1% vs 27.8%, respectively; P =.642). CONCLUSIONS: Adding tolvaptan to conventional treatment achieved more diuresis and relieved dyspnea symptoms in AHF patients with renal dysfunction. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index/htm/ Unique identifier: UMIN000007109.

Ultrafiltration in decompensated heart failure with cardiorenal syndrome.

BACKGROUND: Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS: We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS: Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 µmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 µmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). CONCLUSIONS: In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Diuretic strategies in patients with acute decompensated heart failure.

BACKGROUND: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. METHODS: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. RESULTS: In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 µmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 µmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 µmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 µmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. CONCLUSIONS: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

Vasopressin receptor antagonists: from pivotal trials to current practice.

Heart failure is a growing health and economic problem in America, and outcomes continue to remain dismal, particularly for those presenting with acute heart failure syndrome (AHFS). In theory, arginine vasopressin antagonists (VRAs) could be useful in both acute and chronic heart failure, depending on which vasopressin receptor is targeted. Most studies of VRAs in heart failure have focused on V2 receptor antagonism, and to a lesser extent on combined V1a/V2 antagonism, due to the availability of appropriate agents and the unmet need of improving outcomes in AHFS. These agents are particularly attractive as adjunctive or alterative agents in AHFS because of their ability to produce a substantial diuresis without some of the drawbacks intrinsic to loop diuretics. While VRAs have been shown to ameliorate signs and symptoms of congestion when added to standard care, the largest trial of these agents showed no improvement in long-term morbidity, mortality, or hospitalization rates when added to standard care. This article reviews the mechanism of action of VRAs, the relevant clinical trials data, and current recommendations for clinical use, and suggests future directions for study of these agents in patients with heart failure.

Exploring spatial and temporal symptoms of the freshwater salinization syndrome in a rural to urban watershed.

The freshwater salinization syndrome (FSS), a concomitant watershed-scale increase in salinity, alkalinity, and major-cation and trace-metal concentrations, over recent decades, has been described for major rivers draining extensive urban areas, yet few studies have evaluated temporal and spatial FSS variations, or causal factors, at the subwatershed scale in mixed-use landscapes. This study examines the potential influence of land-use practices and wastewater treatment plant (WWTP) effluent on the export of major ions and trace metals from the mixed-use East Branch Brandywine Creek watershed in southeastern Pennsylvania, during the 2019 water year. Separate analysis of baseflow and stormflow subsets revealed similar correlations among land-use characteristics and streamwater chemistry. Positive associations between percent impervious surface cover, which ranged from 1.26 % to 21.9 % for the 13 sites sampled, and concentrations of Ca2+, Mg2+, Na+, and Cl- are consistent with road-salt driven reverse cation exchange and weathering of the built environment. The relative volume of upstream WWTP was correlated with Cu and Zn, which may be derived in part from corroded water-conveyance infrastructure; chloride to sulfate mass ratios (CSMR) ranged from ~6.3 to ~7.7× the 0.5 threshold indicating serious corrosivity potential. Observed exceedances of U.S. Environmental Protection Agency Na+ and Cl- drinking water and aquatic life criteria occurred in winter months. Finally, correlations between percent cultivated cropland and As and Pb concentrations may be explained by the persistence of agricultural pesticides that had been used historically. Study results contribute to the understanding of FSS solute origin, fate, and transport in mixed-use watersheds, particularly those in road salt-affected regions. Study results also emphasize the complexity of trace-metal source attribution and explore the potential for FSS solutes to affect human health, aquatic life, and infrastructure.

Metal accumulation in salt marsh soils along the East Coast of the United States.

Coastal salt marshes are depositional environments that can accumulate pollutants introduced to the environment from human activities. Metals are a contaminant of concern in coastal environments due to their longevity and toxicity. We assessed metal concentrations and accumulation rates in nine salt marsh sites along the U.S. East Coast from Maine to Georgia. Following a metal mobility assay in organic-rich and mineral dominated salt marsh soils under aerobic/anaerobic and freshwater/saltwater conditions, we focused on profiles of chromium, nickel, copper, zinc, cadmium, lead, and uranium in two soil cores from each of the nine marshes that had previously been dated using lead-210 radioisotope techniques. We examined how land cover and the spatial distribution of land cover, marsh vertical accretion, and other watershed characteristics correlated with metal concentrations and depth/time-integrated accumulation of metals. We found statistically significant differences in metal concentrations and/or inventories between sites, with accumulation of metals positively correlated with both developed land cover in the watershed and rates of vertical accretion in the tidal marsh. The accumulation of chromium, cadmium, and lead were significantly correlated with developed land cover while the accumulation of chromium, nickel, copper, zinc, and lead were correlated with factors that determine sediment delivery from the landscape (e.g., riverine suspended sediment, soil erodibility in the watershed, and agricultural land cover skewed towards the coast) and measured wetland accretion rates. We observed declines in the concentration of many metals since 1925 at sites along the U.S. East Coast, indicating pollution mitigation strategies have succeeded in reducing metal pollution and delivery to the coastal zone. However, increasing rates of salt marsh vertical accretion over recent decades largely offset reductions in metal concentrations, resulting in rates of metal accumulation in coastal salt marsh soils that have not changed or, in some instances, increased over time.

Prognostic implications of renal dysfunction in patients hospitalized with heart failure: data from the last decade of clinical investigations.

Numerous studies over the last decade have demonstrated that renal dysfunction and worsening renal function (WRF) are common in patients hospitalized for heart failure (HHF) and appear to be associated with poor in-hospital and post-discharge outcomes. Unfortunately, its etiology has not been completely understood, and its prediction during hospitalization remains challenging. The evaluation of renal impairment during hospitalization should take into consideration the underlying renal substrate (e.g., predisposing clinical comorbidities such as diabetes and hypertension), initiating mechanisms (e.g., in-hospital therapies such as diuretics), and amplifying factors (neurohormonal and hemodynamic profile changes). Various patterns of WRF may have different prognostic implications and may require different therapeutic approaches. WRF may be initially classified by duration (transient vs. persistent) and by etiology (elevated venous pressures vs. arterial underfilling). Other critical contributing factors during hospitalization include progressive left ventricular dysfunction, neurohormonal activation, and medications. Transient WRF as a result of aggressive therapy targeting congestion may not be associated with poor outcomes. Persistent WRF seen in patients with severe hemodynamic derangements may be associated with poor post-discharge prognosis. Future investigations must clarify the pathophysiological correlates of various patterns of WRF. To date, there is an unmet clinical need to achieve adequate control over congestion while preserving renal function in HHF patients. Thus, the aim of this review is to provide an in-depth and critical interpretation of the available data on the prognostic importance of RD and WRF during hospitalization in an effort to improve HF management.

Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

IMPORTANCE: Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). OBJECTIVE: To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. DESIGN: Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. INTERVENTIONS: Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. MAIN OUTCOME MEASURES: Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. RESULTS: Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). CONCLUSION AND RELEVANCE: Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00763867.

Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial.

IMPORTANCE: Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE: To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 µg/kg/min) or low-dose nesiritide (0.005 µg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS: Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES: Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS: Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE: In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01132846.

Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network.

BACKGROUND: Worsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function. METHODS AND RESULTS: The National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization in patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF). CONCLUSIONS: Treating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.

Obesity and the response to intensified diuretic treatment in decompensated heart failure: a DOSE trial substudy.

BACKGROUND: Obesity could attenuate diuretic effectiveness in treatment of acute decompensated heart failure (HF). METHODS AND RESULTS: The DOSE trial randomized 308 subjects with acute HF to low- versus high-intensification intravenous diuretic therapy. We tested for statistical interactions between obesity and dosing strategy across clinical end points. After 72 hours of treatment, obese subjects (body mass index >30 kg/m(2); n = 173) had greater volume loss than nonobese subjects (n = 119) but similar improvements in dyspnea and freedom from congestion. Both groups had greater fluid loss with high-intensification treatment. Obese subjects had a higher incidence of worsening renal function (WRF) at 72 hours with low-intensification treatment, compared with nonobese subjects. In contrast, nonobese and obese subjects had similar incidence of WRF with high-intensification treatment. There were no differences between obese and nonobese subjects in time to discharge and 60-day freedom from death, emergency department visit, or rehospitalization. CONCLUSIONS: The incidence of WRF was greater in obese than in nonobese subjects with low-intensification treatment. However, the frequency of WRF was equivalent in obese and nonobese subjects with high-intensification treatment. Additional studies are needed to assess whether obese patients with acute HF benefit from an initial high-intensification treatment strategy.

Impacts of Road Deicing Application on Sodium and Chloride Concentrations in Philadelphia Region Drinking Water.

Historical application of roadway deicing agents (e.g., road salt and brines) has led to an increase in sodium and chloride concentrations in surface water over time. Numerous studies have explored the impacts of road salt on freshwater aquatic organisms such as amphibians and benthic macroinvertebrates; however, the public health risk associated with consuming drinking water with elevated sodium has been largely unexplored in the literature. Yet, sodium ingestion, primarily through diet, has been linked to adverse human health conditions, such as hypertension. This study documents weekly sodium and chloride concentrations in municipal tap water from three municipalities within the Philadelphia metropolitan area during winter 2018-2019 (November through March). A late winter peak in sodium and chloride concentrations was observed for all three municipalities immediately following successive snow events coupled with daily high temperatures above 0°C. Among municipalities, mean and peak sodium and chloride concentrations were associated with relatively higher development in upstream areas. Observed sodium concentrations ranged from 1 to 6.4x the USEPA recommended guideline of 20 mg/L for individuals restricted to a total sodium intake of 500 mg/day. Additionally, the contribution of sodium ingestion from water consumption to the recommended daily sodium intake limits for adults ranged from 3.5% to 18.8% for non-restricted and 4.2%-33.3% for "low salt" (i.e., <1,500 mg/day) diets, respectively. The study results coupled with a records review for 40 U.S. municipalities in snow affected regions indicate the need for real-time communication between water utilities and the general public regarding sodium exposure risk during winter months.

Long-term impacts of impervious surface cover change and roadway deicing agent application on chloride concentrations in exurban and suburban watersheds.

Roadway deicing agents, including rock salt and brine containing NaCl, have had a profound impact on the water quality and aquatic health of rivers and streams in urbanized areas with temperate climates. Yet, few studies evaluate impacts to watersheds characterized by relatively low impervious surface cover (ISC; < 15 %). Here, we use long-term (1997-2019), monthly streamwater quality data combined with daily streamflow for six exurban and suburban watersheds in southeastern Pennsylvania to examine the relations among chloride (Cl-) concentrations and ISC. Both flow-normalized Cl- concentrations and ISC increased over time in each of the six watersheds, consistent with changes in watershed management (e.g., ISC, road salt application, etc.). The watersheds that experienced the greatest changes in percent ISC (e.g., agriculture replaced by residential and commercial development) experienced the greatest changes in flow-normalized Cl- concentrations. We also utilized a comprehensive mass-balance model (2011-2018) that indicated Cl- inputs exceeded the outputs for the study watersheds. Road salt applied to state roads, non-state roads, and other impervious surfaces accounted for the majority of Cl- inputs to the six watersheds. Furthermore, increasing Cl- concentrations during baseflow conditions confirm impacts to shallow groundwater. Although flow-normalized Cl- concentrations are below the U.S. Environmental Protection Agency's chronic threshold value for impacts to aquatic organisms, year-round exceedances may result before the end of this century based on current trends. Though reduced Cl- loading to streams may be achieved by limiting the expansion of impervious surfaces in exurban and suburban watersheds, changes in baseflow concentrations are likely to be gradual because of the accumulated Cl- in groundwater.

Bioaccumulation of trace metals in two oyster species from southwest Puerto Rico.

As coastal ecosystems are impacted by land use change and anthropogenic activities, oysters can be an important tool for monitoring local water quality. We collected oysters (Crassostrea rhizophorae and Isognomon alatus) from coastal sites near Guánica and La Parguera in southwest Puerto Rico and analyzed their tissue for concentrations of Ag, As, Cd, Co, Cr, Cu, Ni, Pb, V, and Zn. All trace metals were found in both species, with high bioaccumulation factors for Ag, Cd, and Zn in both species and Cr in C. rhizophorae. Some trace metals are likely associated with anthropogenic sources, including paints and vehicles (Cu and Zn), oil (Ni and V), and wood preservatives (As). Cr in oysters near Guánica is most likely associated with sediment from erosion in the watershed. Both species could be used to monitor changes in trace metal concentrations and the influence of future watershed management strategies in the region.