Evaluation and experience from routine use of chemiluminescence assays for serological screening of blood and plasma donations on the Alinity s system and the Alinity i system, two new fully-automated immunoassay systems in Poland.

In Poland, independent evaluations under the auspices of the Institute of Hematology and Transfusion Medicine (IHTM) are mandated for any new device, assay, systems for screening samples from whole blood and plasma donors prior to implementation by Blood Transfusion Center (BTC). In last 5 years, two new systems were introduced to the market by Abbott GmbH, namely the Alinity s and the Alinity i. The evaluations performed for these two systems included the assessment of sensitivity, specificity and precision for each of the four mandatory serological screening markers in Poland: Hepatitis B Surface Antigen (HBsAg), Hepatitis C virus antibodies (Anti-HCV), HIV antibodies (anti-HIV) and Syphilis antibodies (anti-Treponema pallidum, anti-TP). Sensitivity was assessed by testing seroconversion panels, HBsAg international reference standard, well characterized local samples, and dilution panels. Specificity was assessed by testing routine donor samples. The results from Alinity i assays were compared to the results from Abbott ARCHITECT i2000SR and Ortho VITROS 3600 assays, while the results from Alinity s assays were compared to the results of ARCHITECT i2000SR assays. The evaluation of the Alinity s and Alinity i assays for sensitivity (100 %), specificity (99,92-100 %) and precision generated results that were as good as or better than generated by routinely used systems, were within acceptance criteria, and met all requirements for screening blood donor samples in accordance with Polish regulations. The specificity of the assays in routine use by BTCs, analyzed after approximately 150,000 donations on both systems, was comparable to the specificity observed during the evaluations at IHTM.

Coagulation Factor Xa Has No Effects on the Expression of PAR1, PAR2, and PAR4 and No Proinflammatory Effects on HL-1 Cells.

Atrial fibrillation (AF), characterised by irregular high-frequency contractions of the atria of the heart, is of increasing clinical importance. The reasons are the increasing prevalence and thromboembolic complications caused by AF. So-called atrial remodelling is characterised, among other things, by atrial dilatation and fibrotic remodelling. As a result, AF is self-sustaining and forms a procoagulant state. But hypercoagulation not only appears to be the consequence of AF. Coagulation factors can exert influence on cells via protease-activated receptors (PAR) and thereby the procoagulation state could contribute to the development and maintenance of AF. In this work, the influence of FXa on Heart Like-1 (HL-1) cells, which are murine adult atrial cardiomyocytes (immortalized), was investigated. PAR1, PAR2, and PAR4 expression was detected. After incubations with FXa (5-50 nM; 4-24 h) or PAR1- and PAR2-agonists (20 µM; 4-24 h), no changes occurred in PAR expression or in the inflammatory signalling cascade. There were no time- or concentration-dependent changes in the phosphorylation of the MAP kinases ERK1/2 or the p65 subunit of NF-κB. In addition, there was no change in the mRNA expression of the cell adhesion molecules (ICAM-1, VCAM-1, fibronectin). Thus, FXa has no direct PAR-dependent effects on HL-1 cells. Future studies should investigate the influence of FXa on human cardiomyocytes or on other cardiac cell types like fibroblasts.

Effects and Safety of Convalescent Plasma Administration in a Group of Polish Pediatric Patients with COVID-19: A Case Series.

Despite the enormous advances in knowledge about the SARS-CoV-2 infection, the optimal treatment for COVID-19 is still not well defined. The use of convalescent plasma seems to be a promising method of treatment but requires further evaluation. Although it is usually mild, in children with underlying chronic diseases, the course of SARS-CoV-2 infection may be very severe. We described a series of 13 pediatric patients (mean age 10.4 years, median 12) treated with convalescent plasma as a method of COVID-19 therapy. Medical history, with particular emphasis on comorbidities, clinical course, laboratory parameters, supportive treatment and virus elimination time, were analyzed. The mean hospitalization time was 22.6 days (median 20). The most common abnormalities included increased levels of C-reactive protein, D-dimer, and lymphopenia. Median time from symptom onset to convalescent plasma transfusion was 10.6 days (median 7 days). Six patients (46.2%) had a viral clearance on RT-PCR method from a nasopharyngeal swab within 3 days of transfusion, while in the remaining patients the mean elimination time was 12.1 days (median 6 days). Clinical improvement was achieved in all patients; no adverse effects were found in any of the cases. Convalescent plasma may be a promising treatment for COVID-19 in children.

High-resolution allele frequencies for NGS based HLA-A, B, C, DQB1 and DRB1 typing of 23,595 bone marrow donors recruited for the Polish central potential unrelated bone marrow donor registry.

Next-generation sequencing (NGS)-based typings of HLA-A, B, C, DQB1 and DRB1 loci were performed from 2018 to 2019 in 23 595 newly recruited or re-typed adult potential bone marrow donors registered in Poltransplant Registry to characterize allele and haplotype frequencies of HLA system for loci important for hematopoietic stem cell transplantation. The donors were recruited for registry and not for any other purpose including controls in a disease association study. The population sample was collected in various regions of Poland including all voivodships. The data regarding the degree of relatedness among individuals in the sample were not collected. Typings were supported by public funds as a part of the Polish National Program for Transplant Medicine Development. HLA frequency data are available in the Allele Frequencies Net Database.

Activated clotting factor X mediates mitochondrial alterations and inflammatory responses via protease-activated receptor signaling in alveolar epithelial cells.

There is growing evidence for the contribution of the activated coagulation factor X (FXa) in the development of chronic inflammatory lung diseases. Therefore, we aimed to investigate effects of exogenous FXa on mitochondrial and metabolic function as well as the induction of inflammatory molecules in type II alveolar epithelial cells. Effects of FXa on epithelial cells were investigated in A549 cell line. Activation of extracellular signal-regulated kinase (ERK) and induction of inflammatory molecules were examined by immunoblot and gene expression analysis. Mitochondrial function was assessed by the measurement of oxygen consumption during maximal oxidative phosphorylation and quantitative determination of cardiolipin oxidation. Apoptosis was tested using a caspase 3 antibody. Metabolic activity and lactate dehydrogenase assay were applied for the detection of cellular viability. FXa activated ERK1/2 and induced an increase in the expression of pro-inflammatory cytokines, which was prevented by an inhibitor of FXa, edoxaban, or an inhibitor of protease-activated receptor 1, vorapaxar. Exposure to FXa caused mitochondrial alteration with restricted capacity for ATP generation, which was effectively prevented by edoxaban, vorapaxar and GB83 (inhibitor of protease-activated receptor 2). Of note, exposure to FXa did not initiate apoptosis in epithelial cells. FXa-dependent pro-inflammatory state and impairment of mitochondria did not reach the level of significance in lung epithelial cells. However, these effects might limit regenerative potency of lung epithelial cells, particular under clinical circumstances where lung injury causes exposure to clotting factors.

The Potential Role of Circulating Endothelial Cells and Endothelial Progenitor Cells in the Prediction of Left Ventricular Hypertrophy in Hypertensive Patients.

BACKGROUND: The main aim of present study is to evaluate the potential role of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPCs) - representing specific markers of endothelial damage, in the prediction of left ventricular hypertrophy (LVH) in hypertensive patients categorized into two groups; mild (MH) and resistant hypertension (RH). MATERIALS AND METHODS: Thirty patients with MH and 28 subjects with RH were involved in the study. In both groups, patients were divided into an LVH and non-LVH group. The control group included 33 age and sex-matched normotensive volunteers. Physical examination, laboratory tests and echocardiography were conducted. RESULTS: In both the MH and RH group, patients with as well as without LVH demonstrated a higher number of CECs and a lower ratio of CEPCs/CECs as compared to the healthy control. Multiple linear regression analysis showed a positive association of CEPCs with left ventricular mass (LVM) and left ventricular mass index (LVMI), independently of other confounders. CONCLUSION: Our results suggest that endothelial injury observed as an elevated CECs number and its impaired regeneration, reflected by a lowered CEPCs/CECs ratio, precede LVH occurrence and may play a significant role in LVH development regardless of the clinical severity of hypertension. Moreover, independent correlation of CEPCs with echocardiographic (ECG) incidences of LVH suggests their potential use as a screening biomarker to stratify the risk of LVH development.

Association between Advanced Glycation End Products, Soluble RAGE Receptor, and Endothelium Dysfunction, Evaluated by Circulating Endothelial Cells and Endothelial Progenitor Cells in Patients with Mild and Resistant Hypertension.

The aim of the present study was to evaluate advanced glycation end products (AGEs) and soluble form of receptor RAGE (sRAGE) concentrations as well as the AGEs/sRAGE ratio in mild (MH) and resistant (RH) hypertensive patients in comparison with normotensive individuals. We also evaluated the association between AGEs, sRAGE as well as AGEs/sRAGE ratio and circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPCs). The MH group consisted of 30 patients, whereas 30 patients were classified for the RH group. The control group (C) included 25 normotensive volunteers. AGEs and sRAGE were measured using enzyme-linked-immunosorbent assay (ELISA). The multicolor flow cytometry was used for analysis of CECs and CEPCs. Significantly higher levels of AGEs in RH cohort were observed as compared to C cohort. Furthermore, significantly lower sRAGE levels as well as a higher AGEs/sRAGE ratio were observed between MH and RH cohorts. Significant correlations were found in the MH cohort for sRAGE and CECs, and CEPCs. The elevation of AGEs levels suggests that oxidative modification of proteins occurs in hypertension pathogenesis. The decrease in sRAGE levels and elevation of the AGEs/sRAGE ratio in MH and RH groups may suggest that hypertensive patients are less protected against the side effects of AGEs as a consequence of an insufficient competitive role of sRAGE against the AGEs-RAGE axis. Finally, it may be concluded that the level of AGEs may be an independent predictor of the condition and function of the endothelium. Furthermore, sRAGE may be classified as a potential biomarker of inflammation and endothelium dysfunction.

The endothelial status reflected by circulating endothelial cells, circulating endothelial progenitor cells and soluble thrombomodulin in patients with mild and resistant hypertension.

BACKGROUND: The aim of the present study was to evaluate endothelial status by measuring the concentration of novel markers of endothelial dysfunction (ED): a number of circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPCs) and their ratio (CEPCs/CECs) as well as a traditional parameter - soluble thrombomodulin (sTM) in patients with resistant (RH) and mild hypertension (MH). MATERIALS AND METHODS: Thirty patients with MH and thirty subjects with RH were involved in the study. The control group included thirty-three age and sex-matched normotensive volunteers. We used multicolor flow cytometry for CECs and CEPCs analysis and the commercial human sTM ELISA kit to measure plasma sTM concentration. RESULTS: An elevated CECs number and a decreased CEPCs/CECs ratio was found in MH as well as in RH patients in comparison with normotensive volunteers. CECs correlated positively with an increased triglycerides in MH patients and an elevated LDL-cholesterol and hsCRP in RH group. Positive correlation between CEPCs and LDL-cholesterol level was observed in both types of hypertension. CONCLUSIONS: The results of the present study suggest that an endothelial alteration accompanies hypertension. The number of CECs reflecting the extent of endothelial damage does not appear to be related to the severity of disease. The drastically decreased ratio between CEPCs and CECs observed in both groups of patients suggests an inadequate process of endothelial regeneration. Among analyzed factors inflammation and lipid abnormalities may have significant contribution in endothelial pathology in hypertension.

Integration of "omics" techniques: Dronedarone affects cardiac remodeling in the infarction border zone.

Dronedarone improves microvascular flow during atrial fibrillation and reduces the infarct size in acute models of myocardial infarction. However, dronedarone might be harmful in patients with recent decompensated heart failure and increases mortality in patients with permanent atrial fibrillation. A pathophysiological explanation for these discrepant data is lacking. This study investigated the effects of dronedarone on gene and protein expression in the infarcted area and border zone in pigs subjected to anterior ischemia/reperfusion myocardial infarction. The ischemia/reperfusion myocardial infarction was induced in 16 pigs. Eight pigs were treated with dronedarone for 28 days after myocardial infarction, the remaining pigs served as control. Microarray-based transcriptome profiling and 2D-DIGE-based proteome analysis were used to assess the effects of dronedarone on left ventricular gene expression in healthy (LV), infarcted (MI), and border zone tissue. Selected targets were validated by RT-qPCR or immunoblot analyses, with special emphasize given to the transcriptome/proteome overlap. Combined "omics" analysis was performed to identify most significant disease and function charts affected by dronedarone and to establish an integrated network. The levels of 879 (BZ) or 7 (MI) transcripts and 51 (LV) or 15 (BZ) proteins were significantly altered by dronedarone, pointing to a substantial efficacy of dronedarone in the border zone. Transcriptome and proteome data indicate that dronedarone influences post-infarction remodeling processes and identify matricellular proteins as major targets of dronedarone in this setting. This finding is fully supported by the disease and function charts as well as by the integrated network established by combined "omics". Dronedarone therapy alters myocardial gene expression after acute myocardial infarction with pronounced effects in the border zone. Dronedarone promotes infarct healing via regulation of periostin and might contribute to the limitation of its expansion as well as cardiac rupture. Thus, there are no experimental hints that dronedarone per se has direct harmful effects after MI in ventricular tissue. Impact statement Dronedarone reduced the infarct size in models of acute myocardial infarction (MI). Here, we show that dronedarone attenuates many of the substantial changes in gene expression that are provoked by acute myocardial infarction (AMI) in pigs. Dronedarone modifies the expression of gene panels related to post-infarction cardiac healing and remodeling processes and, most remarkably, this occurs predominantly in the infarction border-zone and much less so in the vital or infarcted myocardium. Combined "omics" identified matricellular proteins and ECM as major dronedarone-regulated targets and emphasizes their relevance for Disease Charts and Tox Function Charts associated with tissue remodeling and cellular movement. The results demonstrate dronedarone's capability of regulating cardiac repair and remodeling processes specifically in the infarction border zone and identify underlying mechanisms and pathways that might be employed in future therapeutic strategies to improve long-term cardiac tissue function and stability.

Exposure to hepatitis E virus, hepatitis A virus and Borrelia spp. infections in forest rangers from a single forest district in western Poland.

BACKGROUND: Hepatitis E virus (HEV) infection is an emerging problem in developed countries. At least 2 zoonotic genotypes of the virus (HEV-3 and HEV-4) infect human beings. There are some data suggesting that forest rangers (FRs) can be at a higher risk of contact with HEV. OBJECTIVES: The aim of this study was to assess the prevalence of HEV exposure markers in FRs from a single forest district in Greater Poland in relation to anti-HAV (hepatitis A virus) IgG, and anti-Borrelia spp. IgM and IgG antibodies. MATERIAL AND METHODS: In total, 138 participants (48 FRs and 90 blood donors - BDs) were tested for anti-HEV IgM and IgG (EUROIMMUN Medizinische Labordiagnostika AG, Luebeck, Germany) and 96 individuals (48 FRs and 48 BDs) were tested for anti-HAV IgG (ARCHITECT immunoassays, Abbott Laboratories, Wiesbaden, Germany); anti-Borrelia IgM and IgG (EUROIMMUN kits) were assessed in FRs only. RESULTS: Anti-HEV markers were detected in 3 participants (2.2%; IgM in 1 FR, IgG in 2 BDs), less frequently than anti-HAV (16 out of 96 individuals, about 17%; FRs 19% vs BDs 15%) or anti-Borrelia antibodies (18 out of 48 individuals, 37.5%) (p < 0.0001 for both). Older study participants (≥45 years of age) were more frequently HAV-seropositive (29% vs 4% of the younger individuals; p = 0.0012). CONCLUSIONS: We failed to unequivocally prove HEV exposure in FRs. The HAV seroprevalence in this study paralleled the situation in the general population. Exposure to Borrelia spp. in FRs was common.

Progressive impairment of atrial myocyte function during left ventricular hypertrophy and heart failure.

Hypertensive heart disease (HHD) can cause left ventricular (LV) hypertrophy and heart failure (HF). It is unclear, though, which factors may contribute to the transition from compensated LV hypertrophy to HF in HHD. We hypothesized that maladaptive atrial remodeling with impaired atrial myocyte function would occur in advanced HHD and may be associated with the emergence of HF. Experiments were performed on atrial myocytes and tissue from old (15-25months) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with advanced HHD. Based on the absence or presence of elevated lung weight, a sign of lung congestion and heart failure, SHR were divided into a non-failing (SHR-NF) and failing (SHR-HF) group. Compared with WKY, SHR exhibited elevated blood pressure, LV hypertrophy and left atrial (LA) hypertrophy with increased LA expression of markers of hypertrophy and fibrosis. SHR-HF were distinguished from SHR-NF by aggravated hypertrophy and fibrosis. SHR-HF atrial myocytes exhibited reduced contractility and impaired SR Ca2+ handling. Moreover, in SHR the expression and phosphorylation of SR Ca2+-regulating proteins (SERCA2a, calsequestrin, RyR2 and phospholamban) showed negative correlation with increasing lung weight. Increasing stimulation frequency (1-2-4Hz) of atrial myocytes caused a progressive increase in arrhythmogenic Ca2+ release (including alternans), which was observed most frequently in SHR-HF. Thus, in old SHR with advanced HHD there is profound structural and functional atrial remodeling. The occurrence of HF in SHR is associated with LA and RA hypertrophy, increased atrial fibrosis, impaired atrial myocyte contractility and SR Ca2+ handling and increased propensity for arrhythmogenic Ca2+ release. Therefore, functional remodeling intrinsic to atrial myocytes may contribute to the transition from compensated LV hypertrophy to HF in advanced HHD and an increased propensity of atrial arrhythmias in HF.

Atrial thrombogenesis in atrial fibrillation : Results from atrial fibrillation models and AF-patients.

Atrial fibrillation (AF) is the most common cause of thromboembolic complications. The risk of suffering a thromboembolic complication depends on the accompanying cardiac risk factors and the patient's age. For patients who have an increased risk, which is now classified using the CHA2DS2-VASc score, initiation of long-term oral anticoagulation is the first-line treatment. In AF, thrombi arise in the left atrial appendage. The present review will summarize the basic pathophysiology of thrombogenesis in AF and will provide the molecular basis of a process called prothrombotic endocardial remodeling. Despite oral anticoagulation being a central component of therapy, the present results can be used to support concomitant therapy with statins, angiotensin II blockers, etc. to inhibit atrial thromogenesis.

Hepatitis E virus antibodies in HIV-infected patients and blood donors from western Poland: A preliminary report.

BACKGROUND: Hepatitis E virus (HEV) infection is an emerging problem in industrialized countries, including Europe. Little data exists on HEV seroprevalence in Poland. OBJECTIVES: The aim of this study was to assess the prevalence of anti-HEV IgG antibodies in Polish patients infected with the human immunodeficiency virus (HIV) and blood donors. MATERIAL AND METHODS: Two hundred and ten individuals (n = 105 of HIV-infected patients and n = 105 of ageand sex-matched blood donors from the same area; 178 men and 32 women), aged 18-50 (median age: 38 years), were tested for the presence of anti-HEV IgG antibodies with the EUROIMMUN Anti-Hepatitis E Virus (HEV) ELISA (IgG) tests (Lübeck, Germany). Additionally, some simple clinical and laboratory data was collected. RESULTS: The overall anti-HEV IgG prevalence was 2.4% (5/210). One HIV-positive patient (0.95%) and 4 blood donors (3.8%) were seropositive (p = 0.1745). All the HEV-exposed individuals were men with a history of travel abroad and no icteric disease in the past. CONCLUSIONS: Exposure to HEV infection among Polish HIV patients and blood donors seems to be uncommon. Data on this issue is scarce and conflicting for HIV-infected individuals. Further investigations applying different serological tests and concomitant HEV RNA testing are needed to reliably assess the risk and practical impact of HEV infection in Poland.

Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia.

The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.

Dronedarone does not affect infarct volume as assessed by magnetic resonance imaging in a porcine model of myocardial infarction.

Dronedarone has been demonstrated to be harmful in patients with recent decompensated heart failure. Furthermore, a PALLAS study reported that dronedarone therapy increases mortality rates in patients with permanent atrial fibrillation. Although a pathophysiological explanation for these finding remains to be elucidated, the long term effects of dronedarone on myocardial structure and stability have been suggested. The aim of the present study was to determine whether dronedarone therapy affects left ventricular (LV) function in a chronic model of myocardial infarction (MI). An anterior MI was induced in 16 pigs. Of these animals, eight pigs were then treated with dronedarone for 1 week prior to, and 4 weeks following MI, the remaining pigs served as controls. LV angiography was performed 4 weeks after MI to determine the LV ejection fraction (LVEF). A post­mortem magnetic resonance imaging scan of the LV was then performed on the two groups (n=6) to determine the volume and size of the induced MI. Dronedarone therapy did not affect systemic and intracardiac hemodynamic parameters or LVEF during the follow­up assessment. Of note, dronedarone had no negative effect on the total infarct volume and size and did not induce lethal proarrhythmic effects following the induced anterior MI. Therefore, the results suggested that dronedarone did not increase the volume or size of induced anterior MI and did not affect LV performance. Thus, dronedarone therapy was observed to be safe in a porcine model of anterior MI.

Early subcellular Ca2+ remodelling and increased propensity for Ca2+ alternans in left atrial myocytes from hypertensive rats.

AIMS: Hypertension is a major risk factor for atrial fibrillation. We hypothesized that arterial hypertension would alter atrial myocyte calcium (Ca2+) handling and that these alterations would serve to trigger atrial tachyarrhythmias. METHODS AND RESULTS: Left atria or left atrial (LA) myocytes were isolated from spontaneously hypertensive rats (SHR) or normotensive Wistar-Kyoto (WKY) controls. Early after the onset of hypertension, at 3 months of age, there were no differences in Ca2+ transients (CaTs) or expression and phosphorylation of Ca2+ handling proteins between SHR and WKY. At 7 months of age, when left ventricular (LV) hypertrophy had progressed and markers of fibrosis were increased in left atrium, CaTs (at 1 Hz stimulation) were still unchanged. Subcellular alterations in Ca2+ handling were observed, however, in SHR atrial myocytes including (i) reduced expression of the α1C subunit of and reduced Ca2+ influx through L-type Ca2+ channels, (ii) reduced expression of ryanodine receptors with increased phosphorylation at Ser2808, (iii) decreased activity of the Na+ / Ca2+ exchanger (at unaltered intracellular Na+ concentration), and (iv) increased SR Ca2+ load with reduced fractional release. These changes were associated with an increased propensity of SHR atrial myocytes to develop frequency-dependent, arrhythmogenic Ca2+ alternans. CONCLUSIONS: In SHR, hypertension induces early subcellular LA myocyte Ca2+ remodelling during compensated LV hypertrophy. In basal conditions, atrial myocyte CaTs are not changed. At increased stimulation frequency, however, SHR atrial myocytes become more prone to arrhythmogenic Ca2+ alternans, suggesting a link between hypertension, atrial Ca2+ homeostasis, and development of atrial tachyarrhythmias.

Redox control of cardiac remodeling in atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a potential cause of thromboembolic events. AF induces significant changes in the electrophysiological properties of atrial myocytes and causes alterations in the structure, metabolism, and function of the atrial tissue. The molecular basis for the development of structural atrial remodeling of fibrillating human atria is still not fully understood. However, increased production of reactive oxygen or nitrogen species (ROS/RNS) and the activation of specific redox-sensitive signaling pathways observed both in patients with and animal models of AF are supposed to contribute to development, progression and self-perpetuation of AF. SCOPE OF REVIEW: The present review summarizes the sources and targets of ROS/RNS in the setting of AF and focuses on key redox-sensitive signaling pathways that are implicated in the pathogenesis of AF and function either to aggravate or protect from disease. MAJOR CONCLUSIONS: NADPH oxidases and various mitochondrial monooxygenases are major sources of ROS during AF. Besides direct oxidative modification of e.g. ion channels and ion handling proteins that are crucially involved in action potential generation and duration, AF leads to the reversible activation of redox-sensitive signaling pathways mediated by activation of redox-regulated proteins including Nrf2, NF-κB, and CaMKII. Both processes are recognized to contribute to the formation of a substrate for AF and, thus, to increase AF inducibility and duration. GENERAL SIGNIFICANCE: AF is a prevalent disease and due to the current demographic developments its socio-economic relevance will further increase. Improving our understanding of the role that ROS and redox-related (patho)-mechanisms play in the development and progression of AF may allow the development of a targeted therapy for AF that surpasses the efficacy of previous general anti-oxidative strategies. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.

[Upstream therapy for atrial fibrillation]. / Upstream-Therapie bei Vorhofflimmern.

In recent years a tremendous amount has been learned about the pathophysiology of atrial fibrillation (AF) which induces electrophysiological changes in the right and left atrium. Besides calcium-dependent tissue changes which are induced by activation of proteases and phosphatases, such as calpain and calcineurin, concomitant cardiac diseases activate the atrial angiotensin II system. Experiments have shown positive effects of statins in AF models. In contrast, clinical studies have provided heterogeneous results. Of note, several studies have shown that therapy with angiotensin II receptor blockers or statins does not influence the recurrence of AF.

Atrial Calpains: Mediators of Atrialmyopathies in Atrial Fibrillation.

Atrial fibrillation (AF) is associated with substantial structural changes at cell and tissue level. Cellular hypertrophy, disintegration of sarcomeres, mitochondrial swelling and apoptosis have been described as typical histo-morphologic alterations in AF. Main initiators for cellular alterations in fibrillating atrial myocytes are cytosolic calcium overload and oxidative stress. Calpains are intracellular Ca2+- activated proteases and important mediators of calcium overload. Activation of calpains and down-regulation of the calpain inhibitor, calpastatin, contribute to myocardial damage in fibrillating atria. Thus, deregulations of the expression, activity, or subcellular localization of calpain within atrial myocytes have been established as important mediators of atrial myopathy during AF.