Cardiac Magnetic Resonance in Patients with Suspected Tachycardia-Induced Cardiomyopathy: The Impact of Late Gadolinium Enhancement and Epicardial Fat Tissue.

Tachycardia-induced cardiomyopathy (TIC) is a reversible subtype of dilated cardiomyopathy (DCM) resulting from sustained supraventricular or ventricular tachycardia and diagnosed by the normalization of left ventricular ejection fraction (LVEF) after stable sinus rhythm restoration. The aim of this study was to determine the contribution of cardiac magnetic resonance (CMR) to the differential diagnosis of TIC and DCM with persistent atrial arrythmias in patients hospitalized for the first time with heart failure (HF) with reduced LVEF of nonischemic origin. A total of 29 patients (age: 58.2 ± 16.9 years; males: 65.5%; average EF: 37.0 ± 9.5%) with persistent atrial tachyarrhythmia and first decompensation of HF without known coronary artery diseases were included in this study. The patients successfully underwent cardioversion and were observed for 30 days. The study population was divided into groups of responders (TIC patients; N = 16), which implies achieving FF > 50% or its increase > 10% in 30 days of TIC, and non-responders (N = 13). The increase in left ventricle (LV) volumes measured using CMR was significantly higher in the non-responder group when compared with the responders (114.8 mL ± 25.1 vs. 68.1 mL ± 10.5, respectively, p < 0.05). Non-responders also demonstrated decreased interventricular septum thickness (9.1 ± 0.8 vs.11.5 ± 1.3, respectively, p < 0.05). Late gadolinium enhancement (LGE) was observed in 12 patients (41.4%). The prevalence of LGE was increased in the non-responder group (25.0% vs. 65.1%, respectively, p = 0.046). Notably, a septal mid-wall LGE pattern was found exclusively in the non-responders. Epicardial adipose tissue thickness was decreased in the non-responder group versus the TIC patients. Conclusion: Patients with TIC were found to have smaller atrial and ventricular dimensions in comparison to patients with DCM. In addition, LGE was more common in DCM patients.

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus.

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.

Predictors of Progression and Mortality in Patients with Chronic Hypersensitivity Pneumonitis: Retrospective Analysis of Registry of Fibrosing Interstitial Lung Diseases.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) resulting from an immune-mediated response in susceptible and sensitized individuals to a large variety of inhaled antigens. Chronic HP with a fibrotic phenotype is characterized by disease progression and a dismal prognosis. The aim of this study was to identify predictors of progression and mortality in patients with chronic HP in real clinical practice. MATERIALS AND METHODS: This retrospective, multicenter, observational study used data from a registry of 1355 patients with fibrosing ILDs. The study included 292 patients diagnosed with chronic HP based on the conclusion of a multidisciplinary discussion (MDD). RESULTS: The patients were divided into groups with progressive (92 (30.3%) patients) and nonprogressive pulmonary fibrosis (200 (69.7%) patients). The most significant predictors of adverse outcomes were a DLco < 50% predicted, an SpO2 at the end of a six-minute walk test (6-MWT) < 85%, and a GAP score ≥ 4 points. CONCLUSION: Pulmonary fibrosis and a progressive fibrotic phenotype are common in patients with chronic HP. Early detection of the predictors of an adverse prognosis of chronic HP is necessary for the timely initiation of antifibrotic therapy.

Changes in the level of fatty acids in the brain of rats during memory acquisition.

Memory acquisition is accompanied by many cellular and molecular processes, and it is not always clear what role they play. Fatty acids (FAs) are known to be important for cognitive functions, but the details of their involvement in memory processes remain unknown. We investigated FAs in the prefrontal cortex and hippocampus of rats trained to perform a task with food reinforcement. The learning consisted of two training sessions, each of which included 10 trials. The results showed that such training altered individual FAs in the brains. The most significant changes were in the prefrontal cortex, where an increase in the level of many FAs occurred, especially after the second training session: palmitic (16:0), stearic (18:0), docosahexaenoic (22:6, n-3), arachidonic (22:4, n-6), docosapentaenoic (22:5, n-6) acids. Changes in the fatty acid level after training in rats were detected only in the left hippocampus, where the levels of palmitic, docosapentaenoic, and docosahexaenoic acids changed. The changes in the right hippocampus were not significant. In both the prefrontal cortex and the left hippocampus, 72 h after training, all FAs returned to control levels. We believe that the main role of a reversible increase in FA levels during memory acquisition is to support and protect cellular processes involved in memory acquisition. Consolidation of memory traces, which occurs mainly in the neocortex, requires protection from external influences, to which FAs makes a significant contribution. They are able to improve neuronal plasticity, enhance local blood flow, improve mitochondrial processes, and suppress pro-inflammatory signals.

The Improvement of Functional State of Brain Mitochondria with Astaxanthin in Rats after Heart Failure.

The relationship between neurological damage and cardiovascular disease is often observed. This type of damage is both a cause and an effect of cardiovascular disease. Mitochondria are the key organelles of the cell and are primarily subject to oxidative stress. Mitochondrial dysfunctions are involved in the etiology of various diseases. A decrease in the efficiency of the heart muscle can lead to impaired blood flow and decreased oxygen supply to the brain. Astaxanthin (AST), a marine-derived xanthophyll carotenoid, has multiple functions and its effects have been shown in both experimental and clinical studies. We investigated the effects of AST on the functional state of brain mitochondria in rats after heart failure. Isoproterenol (ISO) was used to cause heart failure. In the present study, we found that ISO impaired the functional state of rat brain mitochondria (RBM), while the administration of AST resulted in an improvement in mitochondrial efficiency. The respiratory control index (RCI) in RBM decreased with the use of ISO, while AST administration led to an increase in this parameter. Ca2+ retention capacity (CRC) decreased in RBM isolated from rat brain after ISO injection, and AST enhanced CRC in RBM after heart failure. The study of changes in the content of regulatory proteins such as adenine nucleotide translocase 1 and 2 (ANT1/2), voltage dependent anion channel (VDAC), and cyclophilin D (CyP-D) of mitochondrial permeability transition pore (mPTP) showed that ISO reduced their level, while AST restored the content of these proteins almost to the control value. In general, AST improves the functional state of mitochondria and can be considered as a prophylactic drug in various therapeutic approaches.

Why Do Levels Of Anti-inflammatory Cytokines Increase During Memory Acquisition?

The role of anti-inflammatory cytokines in the mechanisms of learning and memory, modulation of synaptic plasticity in the mammalian brain has not received sufficient attention. These issues are discussed in this review, and among the many cytokines, attention is paid to the most studied in this respect IL-10, IL-4, IL-13 and TGF-ß. The level of anti-inflammatory cytokines in the brain tends to increase during memory acquisition, but the significance of such an increase is unclear. We hypothesize that anti-inflammatory cytokines primarily protect and optimize the functioning of neuronal circuits involved in information processing. The increased local activity of neurons during memory acquisition activates many signaling molecules, and some of them can trigger unwanted processes (including neuroinflammation), but increased levels of anti-inflammatory cytokines prevent this triggering. Each of the anti-inflammatory cytokines plays a specific role in supporting information processing. For example, the role of IL-4 and IL-13 in recruiting T cells to the meninges during training in healthy animals has been most studied. It has also been shown that TGF-ß is able to optimize late stage LTP in the hippocampus and support the consolidation of memory traces in behavioral studies. Cytokines have an effect on learning and memory through their influence on neuroplasticity, neurogenesis in the hippocampus and regulation of the neurovascular unit. Experiments have shown such an effect, and the data obtained create the prerequisites for new therapeutic approaches to the correction of cognitive impairments.

Prolongation of experimental diabetes mellitus increased susceptibility to reperfusion ventricular tachyarrhythmias.

Diabetes mellitus (DM) is associated with increased risk of sudden cardiac death, but its role in arrhythmogenesis is not clear. We evaluated contributions of DM duration and hyperglycemia level to development of proarrhythmic electrophysiological changes in the experimental ischemia/reperfusion model. Ventricular epicardial 64-lead mapping and arrhythmia susceptibility burst-pacing testing were performed in 43 healthy and 55 diabetic (alloxan model) anesthetized rabbits undergoing 15 min left anterior descending coronary artery occlusion, followed by 15 min reperfusion. During ischemia, arrhythmia inducibility did not differ between the groups, but the number of reperfusion ventricular tachycardias and (or) fibrillations (VT/VFs) were higher in the DM group (14 out of 55) as compared with control (3 out of 43, p = 0.017). In the diabetic animals, both DM duration and glucose concentration were associated with reperfusion VT/VF development in univariate logistic regression analysis (odds ratio (OR) 1.058, 95% confidence interval (CI) 1.025-1.092, p < 0.001; and OR 1.119, 95% CI 1.045-1.198, p = 0.001, respectively). Only the DM duration, however, remained an independent predictor of reperfusion VT/VF in multivariate logistic regression analysis (OR 1.060, 95% CI 1.006-1.117, p = 0.029). Among mapping parameters, DM duration was associated with the prolongation of total ventricular activation duration (regression coefficient 0.152, 95% CI 0.049-0.255, p = 0.005) and activation-repolarization intervals (ARIs) (regression coefficient 0.900, 95% CI 0.315-1.484, p = 0.003). The prolonged ARI was the only mapping characteristic predicting reperfusion VT/VF development (OR 1.028, 95% CI 1.009-1.048, p = 0.004). The DM duration-dependent prolongation of ventricular repolarization presents a link between DM development and reperfusion VT/VF inducibility.

Noninvasive Assessment of the Fractional Flow Reserve with the CT FFRc 1D Method: Final Results of a Pilot Study.

Background: Until recently, Russia did not utilize noninvasive fractional flow reserve (FFR) assessment. We developed an automated algorithm for noninvasive assessment of FFR based on a one-dimensional (1D) mathematical modeling. Objective: The research aims to evaluate the diagnostic accuracy of this algorithm. Methods: The study enrolled 80 patients: 16 of them underwent 64-slice computed tomography - included retrospectively, 64 - prospectively, with a 640-slice CT scan. Specialists processed CT images and evaluated noninvasive FFR. Ischemia was confirmed if FFR < 0.80 and disproved if FFR ≥ 0.80. The prospective group of patients was hospitalized for invasive FFR assessment as a reference standard. If ischemic, patients underwent stent implantation. In the retrospective group, patients already had invasive FFR values.Statistical analysis was performed using GraphPad Prism 8. We compared two methods using a Bland-Altman plot and per-vessel ROC curve analysis. Considering the abnormality of distribution by the Kolmogorov-Smirnov test, we have used Spearman's rank correlation coefficient. Results: During data processing, three patients of the retrospective and 46 patients of the prospective group were excluded. The sensitivity of our method was 66.67% (95% CI: 46.71-82.03); the specificity was 78.95% (95% CI: 56.67-91.49), p = 0.0052, in the per-vessel analysis. In per-patient analysis, the sensitivity was 69.57% (95% CI: 49.13-84.40); the specificity was 87.50% (95% CI: 52.91-99.36), p = 0.0109. The area under the ROC curve in the per-vessel analysis was 77.52% (95% CI: 66.97-88.08), p < 0.0001. Conclusion: The obtained indices of sensitivity, specificity, PPV, and NPV are, in general, comparable to those in other studies. Moreover, the noninvasive values of FFR yielded a high correlation coefficient with the invasive values. However, the AUC was not high enough, 77.52 (95% CI: 66.97-88.08), p < 0.0001. The discrepancy is probably attributed to the initial data heterogeneity and low statistical power.

Different Activation of IL-10 in the Hippocampus and Prefrontal Cortex During Neurodegeneration Caused by Trimethyltin Chloride.

Anti-inflammatory cytokine interleukin-10 (IL-10) plays a crucial role in controlling the resolution of inflammation. In this study, we aimed to assess gene expression and the level of IL-10 in the hippocampus and prefrontal cortex of rats, after a single injection of neurotoxicant trimethyltin chloride (TMT). It was shown that 4 weeks after the treatment with TMT, the level of IL-10 in the prefrontal cortex, but not in the hippocampus of TMT-treated rats, was increased. However, expression level of IL-10 mRNA was upregulated both in the hippocampus and in the prefrontal cortex 3 weeks after the injection. Concomitantly, within the same post-treatment period, the expression level of the cyclooxygenase-2 was upregulated in both brain structures, indicating the induction of neuroinflammation. Considering that TMT leads to the death of neurons mainly in the hippocampus, we assume that in contrast to the prefrontal cortex, the level of anti-inflammatory cytokine IL-10 in the hippocampus is not sufficiently increased to prevent the damaging effect of the neurotoxicant. Therefore, an exogenous increase in the level of IL-10 may be useful for the survival of neurons in conditions of neurotoxic damage to the hippocampus.

α9α10 nicotinic acetylcholine receptors regulate murine bone marrow granulocyte functions.

Polymorphonuclear neutrophilic granulocytes (PMNs) are extremely important in defense of the organism against infections and in inflammatory processes including neuroinflammation and pain sensation. Different subtypes of nicotinic acetylcholine receptors (nAChRs) are involved in modulation of PMN activities. Earlier we determined expression of α2-7, α9, ß3, ß4 subunits and regulatory role of α7 and α3ß2 nAChR subtypes in functions of inflammatory PMNs. Other authors detected mRNA of α9 subunit in bone marrow neutrophils (BM-PMNs). Murine BM-PMNs coming out from the bone marrow, where they develop, to blood were characterized as mature. There was no data for α10 and for the presence of functionally active α9α10 nAChRs in BM-PMNs. Here we detected for the first time mRNA expression of the α10 nAChR subunit in BM-PMNs and confirmed the expression of mRNA for α9 nAChR. With the help of α-conotoxins RgIA and Vc1.1, highly selective antagonists of α9α10 nAChRs, we have revealed participation of α9 and/or α9α10 nAChRs in regulation of cytosolic Ca2+ concentration, cell adhesion, and in generation of reactive oxygen species (ROS). Nicotine, choline, RgIA, and Vc1.1 induced Ca2+ transients in BM-PMNs, enhanced cell adhesiveness and decreased production of ROS indicating involvement of α9, possibly co-assembled with α10, nAChRs in the BM-PMN activity for recruitment and cytotoxicity.

The role of anti-inflammatory cytokines in memory processing in a healthy brain.

The purpose of the work was to study the role of anti-inflammatory cytokines in memory processing in a healthy brain. Wistar rats were trained to perform a task with positive (food) reinforcement; and then the task performance was tested after intraventricular injection of IL-10 or TGF-ß1. A microinjection into the brain of either of the two cytokines did not affect the performance of the task and did not have an anti-amnesic effect when the retrieval was deteriorated with scopolamine. In addition, endogenous levels of IL-10 and TGF-ß1 were determine in the prefrontal cortex and in the hippocampus after one and two training sessions, consisting of 10 runs each. The level of IL-10 did not change after training both in the prefrontal cortex and in the hippocampus. Endogenous level of TGF-ß1 increased in the neocortex after the first training session, the second session, and recovered to the normal level three days after training. In contrast, in the hippocampus, the level of TGF-ß1 was decreased: maximally after the first training session in the right hippocampus and after the second training session in the left one. Given the role of the prefrontal cortex in memory processing, we assume that a specific increase of TGF-ß1 in the prefrontal cortex may indicate involvement in memory trace consolidation.

Deficiency of transforming growth factor-ß signaling disrupts memory processes in rats.

Cytokines, in addition to their participation in immune and inflammatory processes, play an important role in synaptic plasticity, neoneurogenesis, and cognitive functions. In our work, we aimed to clarify the role of the transforming growth factor-ß (TGF-ß), which is recognized as a multifunctional cytokine, in memory processes. Behavioral experiments were carried out in rats using step-through passive avoidance test. The results obtained showed that the learning of animals after treatment with SB431542, a selective inhibitor of TGF-ß receptors, was impaired, which indicated a significant memory deterioration. Nevertheless, the memory of rats remained at the control level when TGF-ß and SB431542 were coadministered. Thus, the role of TGF-ß in memory retrieval after the passive avoidance test was revealed: memory in rats was weakened if the TGF-ß signaling pathway was inhibited during learning. Evidently, successful consolidation of at least some types of memory requires a normal level of TGF-ß, indicating the modulation of cognitive functions by cytokines under normal physiological conditions.

Delayed treatments with pharmacological modulators of pre- and postsynaptic mGlu receptors rescue the hippocampus from kainate-induced neurodegeneration.

Gene expression of mGluR2, mGluR3 and mGluR5 was evaluated in the hippocampus and frontal cortex in Wistar rats in 1 and 4 weeks after bilateral microinjection of kainic acid into the dorsal hippocampus. The time-course of the receptors' expression suggested their adaptive role in response on the induction of excitotoxicity. It was assumed that the decrease of kainate-induced neurodegeneration could be achieved through simultaneous activation of presynaptic mGluRs and inhibition of mGlu postsynaptic receptors. Both negative allosteric modulator of mGluR5, MPEP, and agonist of mGluR2, LY354740, were administered intraperitoneally 5 days after microinjection of kainic acid. As shown by histochemical studies with cresyl violet and Fluoro-Jade, kainate induced significant damage of hippocampal neurons in the CA3 and CA1 fields. Pharmacological treatment with the negative modulator of mGlu5 receptors in common with the agonist of mGluR2 decreased kainate-induced neurodegeneration in dorsal hippocampus.