Predictors of Congestive Heart Failure after Treatment with an Endothelin Receptor Antagonist

Background and objectives

The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess of congestive heart failure (CHF) events in the avosentan arms, likely due to fluid retention. The aim of this study was to identify risk markers of CHF after treatment with avosentan.

Design, setting, participants, & measurements

In a post hoc analysis of the ASCEND trial (N=1392 participants), we assessed which baseline characteristics predicted CHF risk during avosentan treatment. Furthermore, postrandomization changes between baseline and the first available measurement of body weight and hemoglobin were examined as potential clinical indicators of fluid retention for their relationship with CHF development.

Results

Relative to placebo, avosentan increased CHF risk (hazard ratio, 2.76; 95% confidence interval, 1.68 to 4.54). The avosentan-related CHF risk was higher with lower baseline cholesterol levels (P interaction=0.003) and concomitant statin use (P interaction=0.06), whereas it was lower with a lower estimated GFR (P interaction=0.04). Patients allocated to avosentan had a median body weight increase of 0.6 kg (interquartile range, 0.0 to 2.0 kg) and a median hemoglobin decrease of 1.4 g/dl (interquartile range, −2.1 to −0.7 g/dl) at the first postrandomization measurement. The body weight increase induced by avosentan was associated with CHF development (P interaction=0.04), whereas hemoglobin decrease was not (P interaction=0.64). The increase in body weight was particularly pronounced in patients with a cardiovascular disease history and in patients using statins.

Conclusions

In avosentan-treated patients, body weight increase, but not hemoglobin decrease, was associated with CHF development, indicating that close body weight monitoring could provide an early signal of CHF development in future trials with endothelin receptor antagonists.     

Association of Anti-PLA2R Antibodies with Outcomes after Immunosuppressive Therapy in Idiopathic Membranous Nephropathy

Background

The optimal timing and duration of immunosuppressive therapy for idiopathic membranous nephropathy (iMN) have been debated. This study aimed to evaluate whether measuring the antibody against the phospholipase A₂ receptor (PLA₂R-ab) at start and end of therapy predicts long-term outcome and therefore may inform this debate.

Design, setting, participants, & measurements

This observational study included all consecutive high-risk patients with progressive iMN observed from 1997 to 2005 and treated with oral cyclophosphamide (CP) or mycophenolate mofetil (MMF) in combination with corticosteroids for 12 months. Patients were prospectively followed, and outcome was ascertained up to 5 years after completion of immunosuppressive therapy. Serum samples were collected before and after completion of therapy. PLA₂R antibodies were determined retrospectively in stored samples using ELISA.

Results

In total, 48 patients (37 men) were included. The median age was 55 years (range, 34–75), and the median serum creatinine level was 1.60 mg/dl (range, 0.98–3.37 mg/dl). Twenty-two patients received MMF and 26 received CP. At baseline, PLA₂R-abs were present in 34 patients (71%). Baseline characteristics and outcome did not significantly differ between patients negative or positive for PLA₂R-ab. In PLA₂R-ab–positive patients, treatment resulted in a rapid decrease of antibodies: median anti–PLA₂R-ab, 428 U/ml (range, 41–16,260 U/ml) at baseline and 24 U/ml (range, 0–505 U/ml) after 2 months. The PLA₂R-ab levels at baseline did not predict initial response, but antibody status at end of therapy predicted long-term outcome: After 5 years, 14 of 24 (58%) antibody-negative patients were in persistent remission compared with 0 of 9 (0%) antibody-positive patients (P=0.003).

Conclusions

These data suggest that in PLA₂R-ab–positive patients, measuring PLA₂R-abs at the end of therapy predicts the subsequent course.     

Long-Term Maintenance Therapy Using Rituximab-Induced Continuous B-Cell Depletion in Patients with ANCA Vasculitis

Background and objectives

Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission.

Design, setting, participants, & measurements

A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined.

Results

In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase–ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS]=0) was achieved in all patients. Major relapse (BVAS≥3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population.

Conclusion

This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted.     

Systemic Effects of Intracoronary Nitroglycerin during Coronary Angiography in Children after Heart Transplantation

Coronary spasm during coronary angiography for vasculopathy in children can be prevented by the intracoronary administration of nitroglycerin. We reviewed the anesthesia and catheterization reports and charts for pediatric transplant recipients who underwent angiography from 2005 through 2010. Correlation analysis was used to study the relation of post-injection systolic blood pressure (SBP) to nitroglycerin dose. Forty-one angiographic evaluations were performed on 25 patients (13 male and 12 female). Mean age was 9.9 ± 3.2 years (range, 3.3–16.1 yr). The mean total dose of nitroglycerin was 2.93 ± 1.60 µg/kg (range, 1–8 µg/kg).There was a significant drop between the baseline SBP (mean, 106 ± 21.6 mmHg) and the lowest mean SBP before nitroglycerin administration (78 ± 13.2, P <0.0001, paired t test). There was no significant additional change in SBP (mean after nitroglycerin administration, 80.7 ± 13.1 mmHg; P = 0.2). There was a significant drop in lowest heart rate between baseline (109 ± 16.5 beats/min) and before nitroglycerin administration (89 ± 14.3 beats/min; P <0.0001, paired t test). There was no significant additional change in heart rate (mean heart rate after nitroglycerin, 84 ± 17.7 beats/min; P = 0.09). There were 2 interventions for SBP before nitroglycerin and 2 after nitroglycerin. One child experienced a transient ST-T–segment change during angiography after nitroglycerin. In the highest dose range, the additional decrease in SBP was 7.2 mmHg (P=0.03). Routine intracoronary nitroglycerin administration in this dose range produced no significant changes in SBP or heart rate in children.Key words: Child, coronary angiography, coronary vasospasm/etiology, dose-response relationship, drug, heart transplantation/adverse effects, hemodynamics/drug effects, nitroglycerin/administration & dosage/therapeutic use, postoperative complications/therapy, retrospective studies, vasodilation/drug effectsAllograft coronary disease in children occurs with increasing frequency after transplantation, as a function of time. In a multicenter study,¹ the incidence of coronary artery disease in children 5 years post-transplant was 17% of all recipients. Coronary angiography remains the gold standard in the detection of vasculopathy in heart-transplant recipients.² Coronary artery spasm can complicate selective coronary angiography and result in myocardial ischemia. Coronary spasm can simulate the angiographic appearance of graft vasculopathy and cause diagnostic confusion.³ The spasm can arise from manipulation of the arterial wall by the catheter or from intraluminal injection of contrast material. In cardiac transplant recipients, coronary artery spasm has been reported in as many as 4.9% of coronary angiograms.³In adults, intracoronary nitroglycerin is routinely administered during coronary angiography to prevent coronary artery spasm.⁴ In children, however, safety and dosage guidelines for intracoronary nitroglycerin have not yet been firmly established. A dose of 3 µg/kg can be extrapolated by weight from the established adult dose of 200 µg; this dose was used in a study of children after the arterial switch operation and was shown to produce coronary vasodilation—with a small reduction in systolic blood pressure (SBP) and no noteworthy change in heart rate—in a control group of patients.^5,6We previously reported a case of coronary artery spasm during routine coronary angiographic monitoring in a 9-year-old boy who had undergone heart transplantation as an infant.⁷ After left main coronary artery injection of contrast material, the patient''s left anterior descending and left circumflex coronary arteries appeared to be diffusely narrow, and he developed marked ST-segment elevation, hypotension, and ventricular tachycardia. After cardiopulmonary resuscitation, he recovered uneventfully and displayed normal systolic function. Coronary angiography one month later, with the administration of intracoronary nitroglycerin before the injection of contrast material, revealed normal coronary artery diameter and was accomplished without complication.Since 2005, intracoronary nitroglycerin has routinely been used in pediatric transplant patients during biennial selective coronary angiographic monitoring at our institution. The purpose of the study is to report our experience with the routine use of intracoronary nitroglycerin for coronary angiography in children: its effects on blood pressure, on heart rate, and on the occurrence of arrhythmia and ST-segment elevation.     

Listeria monocytogenes meningoencephalitis in adults: analysis of factors related to unfavourable outcome

Purpose

To analyse the short-term outcome in patients with Listeria monocytogenes meningoencephalitis (LMME) to improve management and outcome.

Methods

Observational study with adult patients with LMME between 1977 and 2009 at a tertiary hospital in Barcelona, Spain. Parameters that predicted outcome were assessed with univariate and logistic regression analysis.

Results

Of 59 cases of LMME, 28 occurred in the last decade. Since 1987, a new protocol has been used and 29/45 patients (64 %) treated since then received adjuvant dexamethasone. In patients who received this treatment there was a trend towards fewer neurological sequelae (5 vs 33 %; p = 0.052). Antiseizure prophylaxis with phenytoin was administered in 13/45 (28 %) patients. Seizures occurred in 7/45 (16 %) patients, all in the group who did not receive phenytoin. Hydrocephalus presented in 8/59 (14 %). It was never present at admission and five patients needed neurosurgical procedures. Sequelae after 3 months were present in 8/45 (18 %), mostly cranial nerve palsy. Rhombencephalitis (RE) was related to the presence of neurologic sequelae (OR: 20.4, 95 % CI: 1.76–236). Overall mortality was 14/59 (24 %), 9/59 (15 %) due to neurological causes related to hydrocephalus or seizures. Mortality was defined as early in 36 % and late in 64 %. In the multivariate analysis, independent risk factors for mortality were presence of hydrocephalus (OR: 17.8, 95 % CI: 2.753–114) and inappropriate empirical antibiotic therapy (OR: 6.5, 95 % CI: 1.201–35).

Conclusions

Outcome of LMME may be improved by appropriate empirical antibiotic therapy, suspicion and careful management of hydrocephalus. Use of adjuvant dexamethasone or phenytoin in a subgroup of these patients might have a benefit.     

Bmi1, stem cells, and senescence regulation

Stem cells generate the differentiated cell types within many organs throughout the lifespan of an organism and are thus ultimately responsible for the longevity of multicellular organisms. Therefore, senescence of stem cells must be prevented. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death.     

Iron mediates production of a neutrophil chemoattractant by rat hepatocytes metabolizing ethanol.

Ethanol metabolism in hepatocytes is accompanied by release of a potent lipid chemoattractant for neutrophils. Production of the factor may initiate the inflammation associated with alcoholic hepatitis. In previous studies with a cytosol system from liver, production was blocked by iron chelators as well as by catalase and superoxide dismutase, suggesting the involvement of oxyradicals in formation of the chemoattractant. These studies have examined the role of iron in intact hepatocytes using cells from rats fed an iron-deficient diet, a control diet or a diet containing 3% carbonyl iron. The iron content averaged 1.4 nmol/mg protein in iron-deficient cells, 6.3 in controls and 135.3 in iron-loaded cells. Hepatocytes from all groups were established in primary culture and incubated with ethanol (10 mM); the medium was assayed for chemoattractant activity for human neutrophils. Cultures from chow-fed or iron-loaded animals produced chemoattractant as previously reported. By contrast, chemoattractant production was undetectable in the iron-deficient cultures. Addition of ferric citrate (10 microM) restored chemoattractant production while increasing cellular iron in the deficient cells less than 50% (to 2.3 nmol/mg protein). Addition of desferrioxamine mesylate to cultures of iron-loaded cells ablated chemoattractant production. The data provide evidence for the importance of hepatocellular iron in production of this alcohol-related lipid chemoattractant and suggest that a small intracellular pool of "free" iron plays a critical role.     

Activation of protein kinase C results in the displacement of its myristoylated, alanine-rich substrate from punctate structures in macrophage filopodia

The myristoylated, alanine-rich C kinase substrate (MARCKS) is a prominent substrate for protein kinase C (PKC) in a variety of cells, and has been implicated in diverse cellular processes including neurosecretion, fibroblast mitogenesis, and macrophage activation. In macrophages that have spread on the substratum, MARCKS has a punctate distribution at the cell-substratum interface of pseudopodia and filopodia. At these points, MARCKS co-localizes with vinculin and talin. Activation of PKC with phorbol esters results in the rapid disappearance of punctate staining of MARCKS, but not vinculin or talin, and is accompanied by cell spreading and loss of filopodia. The morphological changes and disappearance of punctate staining follow a time-course that closely approximates both the PKC-dependent phosphorylation of MARCKS, and its phosphorylation-dependent release from the plasma membrane. Our results suggest a role for PKC-dependent phosphorylation of MARCKS in the regulation of the membrane cytoskeleton.