Endothelial progenitor cells mobilization after maximal exercise according to heart failure severity

BACKGROUNDVascular endothelial dysfunction is an underlying pathophysiological feature of chronic heart failure (CHF). Patients with CHF are characterized by impaired vasodilation and inflammation of the vascular endothelium. They also have low levels of endothelial progenitor cells (EPCs). EPCs are bone marrow derived cells involved in endothelium regeneration, homeostasis, and neovascularization. Exercise has been shown to improve vasodilation and stimulate the mobilization of EPCs in healthy people and patients with cardiovascular comorbidities. However, the effects of exercise on EPCs in different stages of CHF remain under investigation.AIMTo evaluate the effect of a symptom-limited maximal cardiopulmonary exercise testing (CPET) on EPCs in CHF patients of different severity.METHODSForty-nine consecutive patients (41 males) with stable CHF [mean age (years): 56 ± 10, ejection fraction (EF, %): 32 ± 8, peak oxygen uptake (VO₂, mL/kg/min): 18.1 ± 4.4] underwent a CPET on a cycle ergometer. Venous blood was sampled before and after CPET. Five circulating endothelial populations were quantified by flow cytometry: Three subgroups of EPCs [CD34⁺/CD45^-/CD133⁺, CD34⁺/CD45^-/CD133⁺/VEGFR₂ and CD34⁺/CD133⁺/vascular endothelial growth factor receptor 2 (VEGFR₂)] and two subgroups of circulating endothelial cells (CD34⁺/CD45^-/CD133^- and CD34⁺/CD45^-/CD133^-/VEGFR₂). Patients were divided in two groups of severity according to the median value of peak VO₂ (18.0 mL/kg/min), predicted peak VO₂ (65.5%), ventilation/carbon dioxide output slope (32.5) and EF (reduced and mid-ranged EF). EPCs values are expressed as median (25th-75th percentiles) in cells/10⁶ enucleated cells.RESULTSPatients with lower peak VO₂ increased the mobilization of CD34⁺/CD45^-/CD133⁺ [pre CPET: 60 (25-76) vs post CPET: 90 (70-103) cells/10⁶ enucleated cells, P < 0.001], CD34⁺/CD45^-/CD133⁺/VEGFR₂ [pre CPET: 1 (1-4) vs post CPET: 5 (3-8) cells/10⁶ enucleated cells, P < 0.001], CD34⁺/CD45^-/CD133^- [pre CPET: 186 (141-361) vs post CPET: 488 (247-658) cells/10⁶ enucleated cells, P < 0.001] and CD34⁺/CD45^-/CD133^-/VEGFR₂ [pre CPET: 2 (1-2) vs post CPET: 3 (2-5) cells/10⁶ enucleated cells, P < 0.001], while patients with higher VO₂ increased the mobilization of CD34⁺/CD45^-/CD133⁺ [pre CPET: 42 (19-73) vs post CPET: 90 (39-118) cells/10⁶ enucleated cells, P < 0.001], CD34⁺/CD45^-/CD133⁺/VEGFR₂ [pre CPET: 2 (1-3) vs post CPET: 6 (3-9) cells/10⁶ enucleated cells, P < 0.001], CD34⁺/CD133⁺/VEGFR₂ [pre CPET: 10 (7-18) vs post CPET: 14 (10-19) cells/10⁶ enucleated cells, P < 0.01], CD34⁺/CD45^-/CD133^- [pre CPET: 218 (158-247) vs post CPET: 311 (254-569) cells/10⁶ enucleated cells, P < 0.001] and CD34⁺/CD45^-/CD133^-/VEGFR₂ [pre CPET: 1 (1-2) vs post CPET: 4 (2-6) cells/10⁶ enucleated cells, P < 0.001]. A similar increase in the mobilization of at least four out of five cellular populations was observed after maximal exercise within each severity group regarding predicted peak, ventilation/carbon dioxide output slope and EF as well (P < 0.05). However, there were no statistically significant differences in the mobilization of endothelial cellular populations between severity groups in each comparison (P > 0.05).CONCLUSIONOur study has shown an increased EPCs and circulating endothelial cells mobilization after maximal exercise in CHF patients, but this increase was not associated with syndrome severity. Further investigation, however, is needed.     

The degree of kinship and its association with reciprocity and exchange in the relationships of visually impaired older adults

This study draws on an evolutionary model of exchange in relationships to examine the nature of perceived reciprocity in the context of kin and non-kin relationships among a sample of visually impaired older adults (age 63–99). Further, we examined the direct and moderating impact of functional impairment and adaptation to visual impairment on the nature of perceived reciprocity. Results showed that the greater the degree of genetic relatedness the more imbalanced the exchange. It was also found that degree of adaptation to visual impairment moderated the association between genetic relatedness and perceived exchange, such that the greater the degree of genetic relatedness the more people reported they gave rather than received except at very low levels of adaptation, when people received more than they gave the greater the degree of genetic relatedness. Thus, an evolutionary model was supported such that imbalanced exchange was found more with greater degrees of genetic relatedness, but the direction of exchange was different for high versus low levels of adaptation to vision impairment.     

Exposure therapy triggers lasting reorganization of neural fear processing

A single session of exposure therapy can eliminate recalcitrant and disabling fear of phobogenic objects or situations. We studied neural mechanisms of this remarkable outcome by monitoring changes in brain activity as a result of successful 2-h treatment. Before treatment, phobogenic images excited activity in a network of regions, including amygdala, insula, and cingulate cortex, relative to neutral images. Successful therapy dampened responsiveness in this fear-sensitive network while concomitantly heightening prefrontal involvement. Six months later, dampened fear-network activity persisted but without prefrontal engagement. Additionally, individual differences in the magnitude of visual cortex activations recorded shortly after therapy predicted therapeutic outcomes 6 mo later, which involved persistently diminished visual responsiveness to phobogenic images. Successful therapy thus entailed stable reorganization of neural responses to initially feared stimuli. These effects were linked to fear-extinction mechanisms identified in animal models, thus opening new opportunities for the treatment and prevention of debilitating anxiety disorders.     

Limitations of biomarkers serum levels during pulmonary vein isolation

Introduction and objectives

Several biomarkers have been used for evaluation and quantification of myocardial injury after effective ablation. We studied possible different thermal stability and usability of the proteins released by cardiac cells injured by different energy sources.

Methods

Firstly, we tested in vitro thermal stability of creatinine kinase (CK), myocardial bound creatinine kinase (CKMB), cardiac troponins I (cTnI) and cardiac troponins T (cTnT) in collected blood samples from 15 patients (pts) with confirmed ST-segment elevated myocardial infarction (STEMI). Secondly, the biomarkers were collected and analyzed in 82 pts treated with radiofrequency ablation (RFA) and in 79 pts treated with cryo-balloon ablation (CBA).

Results

In vitro experiment showed that all biomarkers were stable in low temperature of -30^oC. Troponins were stable in the high temperatures analyzed. A substantial drop in CK and CKMB levels were measured at 50 °C and 40° C, respectively. In vivo study showed that the increase in CKMB levels was highly significant in CBA pts only. Pathological CKMB values were observed in 24% of RFA pts and 98% of CBA pts. Pathological cTnI values were observed in all pts and the rise in cTnI levels was highly significant in both groups after ablation.

Conclusions

Both in vitro and in vivo results show that CKMB cannot be used for quantitative determination of myocardial injury produced by radiofrequency energy. Only cardiac troponins reflect myocardial injury, regardless of energy source, and may be considered in future studies for comparison of biomarkers effects of cryo versus radiofrequency ablation.Full English text available from: www.revespcardiol.org     

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell–neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.Sensorineural hearing loss (SNHL) is diagnosed in approximately 1 per 500 newborns (1). A genetic etiology is present in more than half of the cases. Inner ear anomalies (IEAs), demonstrated with computerized tomography or magnetic resonance imaging, are associated with SNHL in about one-third of individuals (2). Although IEAs can be diagnosed in patients with other clinical manifestations, such as those seen in Waardenburg [Mendelian Inheritance in Man (MIM) 193500], Pendred (MIM 274600), or BOR (MIM 113650) syndromes, the majority of cases fall into the category of nonsyndromic deafness. Despite recent progress in identifying genes that determine many forms of hearing loss (hereditaryhearingloss.org/), the genetic basis of IEAs in humans remains largely unknown.The inner ear is a complex organ that is built from a simple structure, referred to as the otocyst, through a series of morphogenetic events. Roughly, it consists of a dorsal vestibular and a ventral auditory component (3). Studies in model organisms have identified a number of genes that play roles in proper development of the inner ear. Mouse models have been particularly relevant because the anatomy and physiology of the murine auditory system are similar to those of humans. Mutations in human orthologs of many of these genes have been reported to cause deafness in humans as well (4).Next-generation sequencing technologies have allowed rapid identification of novel human deafness genes. Approximately 85% of disease-causing mutations in Mendelian disorders have been found in the protein-coding regions, despite the fact that this portion accounts for less than 2% of the entire human genome (5). Accordingly, whole exome sequencing (WES) has been frequently used because it allows for a targeted enrichment and resequencing of nearly all exons of protein-coding genes.In this study, via WES, we detected a mutation in ROR1 (receptor tyrosine kinase-like orphan receptor 1; MIM 602336), encoding receptor tyrosine kinase-like orphan receptor 1, that associates with an IEA and nonsyndromic deafness in a family. Further characterization of Ror1 mutant mice revealed that Ror1 deficiency results in defective hair cell innervation and abnormal cochlear development.     

Trace of diffusion tensor differentiates the Parkinson variant of multiple system atrophy and Parkinson's disease

We have recently shown that diffusion-weighted magnetic resonance (MR) imaging (DWI) discriminates patients with the Parkinson variant of multiple system atrophy (MSA-P) from those with Parkinson's disease (PD) by regional apparent diffusion coefficients (rADC) in the putamen. Because rADCs measured in one direction may underestimate diffusion-related pathologic processes, we investigated the diffusivity in different brain areas by trace of diffusion tensor (Trace(D)) in a new cohort of patients with MSA-P and PD. We studied 11 MSA-P, 17 PD patients, and 10 healthy volunteers matched for age and disease duration. Regional ADCs in three orthogonal directions and Trace(D) values were determined in selected brain regions including the basal ganglia, gray matter, white matter, substantia nigra, and pons. MSA-P patients had significantly higher putaminal and pallidal rTrace(D) values as well as rADCs in y- and z-direction than both PD patients and healthy volunteers. Moreover, putaminal Trace(D) discriminated completely MSA-P from both PD and healthy volunteers. The rADCs in the y- and z-direction provided a complete or near complete separation. In conclusion, our study confirms the results of previous studies of our group that patients with MSA-P show an increased putaminal diffusivity due to neuronal loss and gliosis. Because rADCs in one direction are dependent on the slice orientation relative to the directions of fiber tracts, Trace(D) imaging appears to be more accurate in the separation of MSA-P from PD.