Should MRAs be at the front row in heart failure? A plea for the early use of mineralocorticoid receptor antagonists in medical therapy for heart failure based on clinical experience

The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in “third place,” i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper.     

Impact of increased venous pressure on kidney function and mortality in cardiovascular patients with preserved ejection fraction

Abstract

Background: Right but not left ventricular hemodynamic parameters have been found to be independently associated with adverse renal outcomes in patients with acute decompensated heart failure (HF).

Aim: To investigate the hemodynamic profile of patients without acute decompensated heart failure and left ventricular ejection fraction >50% referred for elective left and right heart catheterization and to correlate left and right filling pressures, stroke volume and arterial blood pressure to renal function parameters. Subsequently, we tested the hypothesis that right ventricle and left ventricle hemodynamic parameters can predict all-cause mortality in our non-HF subjects.

Methods: Between October 2009 and November 2010, 151 consecutive patients referred for elective left and right heart catheterization were studied and consequently followed up for a mean period of 8?years in order to identify all-cause mortality. Patient’s initial cohort was subdivided in two groups according to right atrial pressure. The RAPR_LOW group (Right Atrium Pressure ≤ 9?mmHg) and the RAPR_HIGH group (Right Atrium Pressure > 9mmHg)

Results: No correlation between blood pressure, pulmonary capillary wedges pressure, cardiac index, stroke volume and stroke volume index (SVI), and parameters of kidney function was observed. However, a weak, although, significant correlation between right atrial pressure (RAP) and modification of diet in renal disease (MDRD) (r = –0.202; p?=?.014) could be detected. RAPR_LOW patients had a statistically significant lower MDRD value of 16.6?mL/min/1.73 m² than RAPR_HIGH patients. Increased RAP (HR = 2.03; 95% [CI]: 1.05 to 3.9; p?=?.025) and age (HR = 1.08, 95% [CI] 1.04–1.12, p?<?.001) independently predicted all-cause mortality during follow up.

Conclusions: Our study demonstrates that right ventricular preload affects renal function in patients with preserved systolic function and that neither aortic systolic pressure nor left ventricle pressure indices were related to estimated glomerular filtration rate. Furthermore, we demonstrate for the first time that an increased RAP is able to predict a worse prognosis in patients with preserved ejection fraction independently of well-established risk factors, such as blood pressure and SVI.     

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.     

Effect of implant surface roughness and loading on peri-implant bone formation

BACKGROUND: Critical factors for the establishment of osseointegration are the implant surface microtopography and the local mechanical environment. The present study evaluated the bone response around a turned (T) and a roughened (R) implant for either an unloaded or a well-controlled loaded situation. METHODS: Bone chambers were installed in the tibia of 20 rabbits. In each of the chambers, two identical displacement-controlled loading experiments were performed: 30 microm for 400 cycles at 1 Hz, three times a week for 9 weeks versus 0-microm implant displacement. A linear mixed model and a logistic mixed model with alpha = 5% were set to study the significant effect of the surface texture on the peri-implant bone response in the unloaded (T-0 microm versus R-0 microm) and the loaded (T-30 microm versus R-30 microm) mode. RESULTS: Results indicated no microtopographic dependence of the bone response further away from the implant in unloaded and loaded conditions. For a load-free implant, osseointegration seemed to occur with a higher incidence at a roughened compared to a turned implant surface. In the presence of loading, the topographic dependency of the osteogenic activity at the interface was overruled by the loading-related bone response, revealing no significant differences in osseointegration incidence between T and R. CONCLUSION: A predominant effect of the interfacial mechanical environment over the implant surface characteristics on the differentiating cell population is suggested.     

Prevention of in vivo excitotoxicity by a family of trialkylglycines, a novel class of neuroprotectants

Excitotoxicity has been implicated in the etiology of ischemic stroke and chronic neurodegenerative disorders. Hence, the development of novel neuroprotectant molecules that ameliorate excitotoxic brain damage is vigorously pursued. We used a neuroprotection-based cellular assay to screen a synthetic combinatorial library of N-alkylglycine trimers. Two compounds (6-1-2 and 6-1-10) that efficiently prevented excitotoxic neurodegeneration in vitro and in vivo were identified. Both molecules protected primary cultures of cerebellar neurons against glutamate-induced neuronal death with an efficiency equivalent to N-methyl-D-aspartate (NMDA) receptor antagonists. These trialkylglycines did not block appreciably the NMDA receptor channel, or attenuated glutamate-induced increase of Ca(2+), or affect the glutamate-nitric oxide-cGMP pathway. Intraperitoneal injection of both peptoids in mice attenuated > or = 80% ammonia-induced, NMDA receptor-mediated animal death. Furthermore, these two molecules reduced by > or = 50% the neurodegeneration in striatum in a rat model of cerebral ischemia. Neuroprotection against ischemia was associated with decreased activation of caspase-3, reflecting prevention of apoptotic neuronal death. Collectively, the results reported indicate that these trialkylglycines are new neuroprotectant leads with important in vivo activity against excitotoxicity, and that they act on a novel, yet-unrecognized cellular target. These lead compounds may become tolerated drugs for the treatment of acute and chronic neurodegenerative diseases with fewer side effects than NMDA receptor antagonists.     

Testosterone levels increase in association with recovery from acute fracture in men

Summary

In this longitudinal case–control study, acute fracture was associated with low serum testosterone, which was transient in 43 % of men. While assessment of gonadal status is part of the assessment of bone fragility, measurement of testosterone in the early period after fracture may overestimate the prevalence of androgen deficiency.

Introduction

Measurement of circulating testosterone is recommended in the evaluation of bone fragility in men. Since acute illness can transiently decrease circulating testosterone, we quantified the association of acute fracture and serum testosterone levels.

Methods

A case–control study was conducted involving 240 men with a radiologically confirmed minimal trauma fracture presenting to a tertiary referral hospital and 89 age-matched men without a history of minimal trauma fracture serving as controls. Follow-up testosterone levels 6 months after baseline were available for 98 cases and 27 controls. Results were expressed as the median and interquartile (IQR) range.

Results

Compared to controls, cases had lower total testosterone [TT, 7.2 (3.5, 10.8) vs 13.6 (10.9, 17.1) nmol/L, p?<?0.001]. The 143 cases treated as inpatients had lower testosterone levels than the 97 cases treated as outpatients [TT 4.7 (2.3, 8.1) vs 10.3 (7.5, 12.7) nmol/L, p?<?0.001]. Group differences in calculated free testosterone (cFT) were comparable to the group differences in TT. At follow-up, in 98 cases, median TT increased from 6.5 nmol/L (3.2, 8.5) to 9.6 nmol/L (6.9, 12.0) p?<?0.0001, and SHBG remained unchanged. Of cases with low testosterone, 43 % with TT <10 nmol/L and/or cFT <230 pmol/L at presentation were reclassified as androgen sufficient at follow-up. TT was unchanged in the controls.

Conclusions

Low testosterone levels in men presenting with an acute fracture may, at least in part, be due to an acute, fracture-associated, stress response. To avoid over diagnosis, evaluation for testosterone deficiency should be deferred until recovery from the acute event.     

Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5‐associated malformations include bottom‐of‐the‐sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway. Ann Neurol 2014;75:782–787     

Aquacel Ag dressing versus Acticoat™ dressing in partial thickness burns: A prospective,randomized, controlled study in 100 patients. Part 1: Burn wound healing

Introduction

Studies comparing contemporary silver dressings in burns are scarce.

Methods

In a prospective, randomized, controlled study, counting 50 patients/research group, we compared two frequently used silver dressings, Acticoat™ and Aquacel^® Ag, in the management of partial thickness burns with a predicted healing time between 7 and 21 days as assessed by laser Doppler imaging between 48 and 72 h after burn. Variables investigated were related to baseline research group characteristics, wound healing, bacteriology, economics, nurse, and patient experience.

Results

Both research groups were comparably composed taking into account gender, age and burn characteristics. Similar results were obtained as to healing time and bacterial control with both silver dressings. A statistically significant difference in favor of the Aquacel^® Ag dressing was found for average ease of use (p < 0.001), average ease of application (p = 0.001), patient pain (p < 0.001), patient comfort with the dressing (p = 0.017), silver staining (p < 0.001), and cost effectiveness (p < 0.001).

Conclusion

Both silver dressings resulted in comparable healing times and bacterial control but the Aquacel^® Ag dressing significantly increased comfort for patients as well as nurses and was significantly more cost-effective than the Acticoat™ dressing for the given indication.