Background
We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes.
...Methods
We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure.
Results
Improvement in renal function was more frequently observed with serelaxin when compared with placebo OR 1.88 (95% CI 1.64–2.15,
p
< 0.0001), but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin OR 0.70 (95% CI 0.60–0.83,
p
< 0.0001) and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin CVD HR 1.01 (0.99–1.04), ACM HR 1.01 (0.99–1.03), HF/renal failure hospitalization HR 0.99 (0.97–1.00).
Conclusions
Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF.
Graphical abstract
Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.
Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment ...with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure.
In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days.
A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval CI, 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups.
In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).
Human exposure to airborne ultrafine (≪1 μm) particulate pollution may pose substantial hazards to human health, particularly in urban roadside environments where very large numbers of people are ...frequently exposed to vehicle-derived ultrafine particles (UFPs). For mitigation purposes, it is timely and important to quantify the deposition of traffic-derived UFPs onto leaves of selected plant species, with particularly efficient particle capture (high deposition velocity), which can be installed curbside, proximal to the emitting vehicular sources. Here, we quantify the size-resolved capture efficiency of UFPs from diesel vehicle exhaust by nine temperate-zone plant species, in wind tunnel experiments. The results show that silver birch (79% UFP removal), yew (71%), and elder (70.5%) have very high capabilities for capture of airborne UFPs. Metal concentrations and metal enrichment ratios in leaf leachates were also highest for the postexposure silver birch leaves; scanning electron microscopy showed that UFPs were concentrated along the hairs of these leaves. For all but two species, magnetic measurements demonstrated substantial increases in the concentration of magnetic particles deposited on the leaves after exposure to the exhaust particulates. Together, these new data show that leaf-deposition of UFPs is chiefly responsible for the substantial reductions in particle numbers measured downwind of the vegetation. It is critical to recognize that the deposition velocity of airborne particulate matter (PM) to leaves is species-specific and often substantially higher (∼10 to 50 times higher) than the “standard” V d values (e.g., 0.1–0.64 cm s–1 for PM2.5) used in most modeling studies. The use of such low V d values in models results in a major under-estimation of PM removal by roadside vegetation and thus misrepresents the efficacy of selected vegetation species in the substantial (≫20%) removal of PM. Given the potential hazard to health posed by UFPs and the removal efficiencies shown here (and by previous roadside measurements), roadside planting (maintained at or below head height) of selected species at PM “hotspots” can contribute substantially and quickly to improve in urban air quality and reductions in human exposure. These findings can contribute to the development and implementation of mitigation policies of traffic-derived PM on an international scale.
Genomic microarrays have been implemented in the diagnosis of patients with unexplained mental retardation. This method, although revolutionizing cytogenetics, is still limited to the detection of ...rare de novo copy number variants (CNVs). Genome-wide single nucleotide polymorphism (SNP) microarrays provide high-resolution genotype as well as CNV information in a single experiment. We hypothesize that the widespread use of these microarray platforms can be exploited to greatly improve our understanding of the genetic causes of mental retardation and many other common disorders, while already providing a robust platform for routine diagnostics. Here we report a detailed validation of Affymetrix 500k SNP microarrays for the detection of CNVs associated to mental retardation. After this validation we applied the same platform in a multicenter study to test a total of 120 patients with unexplained mental retardation and their parents. Rare de novo CNVs were identified in 15% of cases, showing the importance of this approach in daily clinical practice. In addition, much more genomic variation was observed in these patients as well as their parents. We provide all of these data for the scientific community to jointly enhance our understanding of these genomic variants and their potential role in this common disorder. Hum Mutat 30:1-11, 2009.
Aims
Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of ...evidence-based therapies in this population, we evaluated the effects of serelaxin according to EF in RELAX-AHF trial.
Methods and results
RELAX-AHF randomized 1161 AHF patients to 48-h serelaxin (30 μg/kg/day) or placebo within 16 h from presentation. We compared the effects of serelaxin on efficacy endpoints, safety endpoints, and biomarkers of organ damage between preserved (≥50%) and reduced (<50%, HFrEF) EF. HFpEF was present in 26% of patients. Serelaxin induced a similar dyspnoea relief in HFpEF vs. HFrEF patients by visual analogue scale-area under the curve (VAS-AUC) through Day 5 mean change, 461 (−195, 1117) vs. 397 (10, 783) mm h, P = 0.87, but had possibly different effects on the proportion of patients with moderately or markedly dyspnoea improvement by Likert scale at 6, 12, and 24 h odds ratio for favourable response, 1.70 (0.98, 2.95) vs. 0.85 (0.62, 1.15), interaction P = 0.030. No differences were encountered in the effect of serelaxin on short- or long-term outcome between HFpEF and HFrEF patients including cardiovascular death or hospitalization for heart/renal failure through Day 60, cardiovascular death through Day 180, and all-cause death through Day 180. Similar safety and changes in biomarkers (high-sensitivity troponin T, cystatin-C, and alanine/aspartate aminotransferases) were found in both groups.
Conclusions
In AHF patients with HFpEF compared with those with HFrEF, serelaxin was well tolerated and effective in relieving dyspnoea and had a similar effect on short- and long-term outcome, including survival improvement.
As a result of injury caused by chronic gastroesophageal reflux, Barrett's esophagus with high-grade dysplasia and esophageal adenocarcinoma are rapidly increasing problems in the United States. The ...current standard of care involves esophagectomy, a procedure associated with a high morbidity, a negative impact on long term quality of life, and a mortality rate of 1-6 percent. An entirely endoscopic technique for circumferential, long segment en bloc removal of the mucosa and submucosa with subsequent placement of a biologic scaffold material that promotes a constructive remodeling response and minimizes stricture is described herein. The results of this approach are reported for five patients with 4-24-month follow-up. Restoration of normal mature, K4+/K14+, squamous epithelium, and return to a normal diet without significant dysphagia is reported for all patients. Two of five patients show a small focus of recurrent Barrett's esophagus at the gastroesophageal junction, but the entire length and circumference of the reconstituted esophageal mucosa remains free of disease. This experience provides evidence that a regenerative medicine approach may, for the first time, enable aggressive endoscopic resection of early stage neoplasia without the need for esophagectomy and its associated complications.
Heart failure (HF) guidelines recommend initiation and optimization of guideline directed medical therapy (GDMT), including mineralocorticoid receptor antagonists (MRAs), before hospital discharge. ...However, scientific evidence for this recommendation is lacking. Our objective was to determine whether initiation of MRA prior to hospital discharge is associated with improved outcomes.
We performed a secondary analysis of 6197 patients enrolled in the RELAXin in AHF-2 (acute HF) study. Patients were divided into 4 groups according to MRA therapy at baseline and discharge. At baseline 30% of patients received MRA therapy, which increased to 50% of patients at discharge. In-hospital initiation of an MRA was observed in 1690 (27%) patients, 1438 (23%) patients remained on MRA therapy, 418 (7%) patients discontinued MRA treatment, and 2651 (42%) patients did not receive an MRA during hospital stay. Compared with patients who did not receive MRA therapy, in-hospital initiation of a MRA was independently associated with lower risks of mortality (multivariable hazard ratio (HR) 0.76 (0.60-0.96), p = 0.02), cardiovascular (CV) death (HR 0.77 (0.59-1.01), p = 0.06), hospitalization for HF or renal failure (HR 0.72 (0.60-0.86), p = 0.0003) and the composite endpoint of CV death and/or rehospitalization for HF or renal failure (HR 0.71 (0.61-0.83), p < 0.0001) at 180 days. These results were independent of baseline left ventricular ejection fraction.
In patients hospitalized for acute HF, in-hospital initiation of an MRA was associated with improved post-discharge outcomes, independent of LVEF and other potential confounders. This article is protected by copyright. All rights reserved.
Contrary to elderly patients with ischaemic-related acute heart failure (AHF) typically enrolled in North American and European registries, patients enrolled in the sub-Saharan Africa Survey of Heart ...Failure (THESUS-HF) were middle-aged with AHF due primarily to non-ischaemic causes. We sought to describe factors prognostic of re-admission and death in this developing population.
Prognostic models were developed from data collected on 1006 patients enrolled in THESUS-HF, a prospective registry of AHF patients in 12 hospitals in nine sub-Saharan African countries, mostly in Nigeria, Uganda, and South Africa. The main predictors of 60-day re-admission or death in a model excluding the geographic region were a history of malignancy and severe lung disease, admission systolic blood pressure, heart rate and signs of congestion (rales), kidney function (BUN), and echocardiographic ejection fraction. In a model including region, the Southern region had a higher risk. Age and admission sodium levels were not prognostic. Predictors of 180-day mortality included malignancy, severe lung disease, smoking history, systolic blood pressure, heart rate, and symptoms and signs of congestion (orthopnoea, peripheral oedema and rales) at admission, kidney dysfunction (BUN), anaemia, and HIV positivity. Discrimination was low for all models, similar to models for European and North American patients, suggesting that the main factors contributing to adverse outcomes are still unknown.
Despite the differences in age and disease characteristics, the main predictors for 6 months mortality and combined 60 days re-admission and death are largely similar in sub-Saharan Africa as in the rest of the world, with some exceptions such as the association of the HIV status with mortality.
Patients hospitalized for acute heart failure (AHF) differ with respect of many clinical characteristics which may influence their prognosis and response to treatment. We have assessed possible ...differences in the effects of serelaxin on dyspnoea relief, 60 Day outcomes and 180 Day mortality across patient subgroups in the RELAX-AHF trial.
Subgroups were based on pre-specified covariates (age, sex, race, geographic region, estimated glomerular filtration rate, time from presentation to randomization, baseline systolic blood pressure, history of diabetes, atrial fibrillation, ischaemic heart disease, cardiac devices, i.v. nitrates at randomization). Other covariates which may modify the efficacy of AHF treatment were also analysed. Subgroup analyses did not show any difference in the effects of serelaxin vs. placebo on dyspnoea relief or on the incidence of cardiovascular death or rehospitalizations for heart failure or renal failure at 60 days. Nominally significant interactions between some patient subgroups and the effects of serelaxin on 180 days cardiovascular and all-cause mortality were noted but should be interpreted cautiously due to the number of comparisons and the low incidence of deaths in the subgroups at lower risk.
The effects of serelaxin vs. placebo appeared to be similar across subgroups of patients in RELAX-AHF.
The BCM Search Launcher is an integrated set of World Wide Web (WWW) pages that organize molecular biology-related search and analysis services available on the WWW by function, and provide a single ...point of entry for related searches. The Protein Sequence Search Page, for example, provides a single sequence entry form for submitting sequences to WWW servers that offer remote access to a variety of different protein sequence search tools, including BLAST, FASTA, Smith-Waterman, BEAUTY, PROSITE, and BLOCKS searches. Other Launch pages provide access to (1) nucleic acid sequence searches, (2) multiple and pair-wise sequence alignments, (3) gene feature searches, (4) protein secondary structure prediction, and (5) miscellaneous sequence utilities (e.g., six-frame translation). The BCM Search Launcher also provides a mechanism to extend the utility of other WWW services by adding supplementary hypertext links to results returned by remote servers. For example, links to the NCBI's Entrez data base and to the Sequence Retrieval System (SRS) are added to search results returned by the NCBI's WWW BLAST server. These links provide easy access to auxiliary information, such as Medline abstracts, that can be extremely helpful when analyzing BLAST data base hits. For new or infrequent users of sequence data base search tools, we have preset the default search parameters to provide the most informative first-pass sequence analysis possible. We have also developed a batch client interface for Unix and Macintosh computers that allows multiple input sequences to be searched automatically as a background task, with the results returned as individual HTML documents directly to the user's system. The BCM Search Launcher and batch client are available on the WWW at URL http:@gc.bcm.tmc.edu:8088/search-launcher.html.
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