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AIMS: The concept of atrial cardiomyopathy (AtCM) had been percolating through the literature since its first mention in 1972. Since then, publications using the term were sporadic until the decision was made to convene an expert working group with representation from four multinational arrhythmia organizations to prepare a consensus document on atrial cardiomyopathy in 2016 (EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication). Subsequently, publications on AtCM have increased progressively. METHODS AND RESULTS: The present consensus document elaborates the 2016 AtCM document further to implement a simple AtCM staging system (AtCM stages 1-3) by integrating biomarkers, atrial geometry, and electrophysiological changes. However, the proposed AtCM staging needs clinical validation. Importantly, it is clearly stated that the presence of AtCM might serve as a substrate for the development of atrial fibrillation (AF) and AF may accelerates AtCM substantially, but AtCM per se needs to be viewed as a separate entity. CONCLUSION: Thus, the present document serves as a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) to contribute to the evolution of the AtCM concept.

In recent years, society become much more interested in nature disasters that cause damage. The consequences of these destructive processes of a meteorological, hydrological and geological nature sometimes remain for years until the affected areas are recultivated, restored and recovered. These natural processes work together, often following each other or triggering each other to create a massive system of destruction that causes a lot of damage and often leads to death and numerous casualties.Moreover, with the changes in the global climate of the Planet, leading to the more frequent manifestation of more destructive natural phenomena - cyclones, storms, huge amounts of precipitation - lead to intensify and manifest in larger scales and volumes geological phenomena such as landslides, mudflows, mud - stone torrents, rockfalls, collapses of different character of slopes, linear and planar erosion etc.This is extremely relevant for Bulgaria, the territory for which is no exception to the manifestation of catastrophic natural phenomena. The country is located in an active orogenic zone as part of the Alpo-Himalayan tectonic belt, characterised by a complex tectonic structure, variable and diverse geological formations and rapid topographical changes.The main focus in the study is to present an advanced, multi-faceted framework for natural disaster risk assessment, integrating biodiversity and archaeological sites. Moreover, the assessments of natural risks made so far do not include sufficient attention to biotopes and archaeological and historical sites.The presented methodology is applied to landslide hazards in a pre-selected area along the northern Bulgarian Black Sea coast. The main goal of this paper is to identify socio-environmental risks in the studied region, as well as to construct risk profiles and visually represent both qualitative and quantitative risk levels in the socio-ecological system and biodiversity.

Cyclodextrins (CDs) are host systems with inherent capability for inclusion complex formation with various molecular entities, mostly hydrophobic substances. Host CDs are highly accommodative to water molecules as well and usually contain water in the native state. There is still an ongoing discussion on both the total number of water molecules and their preferred binding position inside the cavities of the CDs. To understand the hydration/dehydration properties of γ-CD (the largest of the three most abundant native CDs), the main experimental methods applied in this study were differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). By coupling these techniques with density functional theory (DFT) calculations we try to shed some light on the mechanism of the γ-CD hydration and to address some unanswered questions: (i) what are the preferable locations for water molecules in the macrocyclic cavity (“hot spots”); (ii) what are the major factors contributing to the stability of the water cluster in the CD interior; (iii) what type of interactions (i.e., water–water and/or water–CD walls) contribute to the stability of the water assemble; (iv) how does the mechanism of the γ-CD hydration compare with those of its α-CD and β-CD counterparts.

AimsAtrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodelling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex pathophysiological network, which renders AF resistant to existing pharmacotherapies that predominantly target transmembrane ion channels. Developing innovative therapeutic strategies requires a systems approach to disentangle quantitatively the pro-arrhythmic contributions of individual AF-induced alterations.Methods and resultsHere, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signalling pathways [i.e. protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinase II (CaMKII)] involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signalling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII- and PKA-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis.ConclusionsOur analysis reveals potential mechanisms by which the stress-associated adaptive changes turn into maladaptive pro-arrhythmic triggers at the cellular and tissue levels and identifies potential anti-AF targets. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches moving beyond the traditional ion channel-based strategy.

BackgroundAtrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.MethodsRight atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies.ResultsIn human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (P=2.0×10-2; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (P=1.4×10-6; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10-2 and 6.7×10-3, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (P=5.0×10-6; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (P=1.8×10-2 and 4.1×10-2, respectively; n=6, 6, and 5).ConclusionsPatients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

BackgroundSmall-conductance Ca2+-activated K+ (SK)-channel inhibitors have antiarrhythmic effects in animal models of atrial fibrillation (AF), presenting a potential novel antiarrhythmic option. However, the regulation of SK-channels in human atrial cardiomyocytes and its modification in patients with AF are poorly understood and were the object of this study.MethodsApamin-sensitive SK-channel current (ISK) and action potentials were recorded in human right-atrial cardiomyocytes from sinus rhythm control (Ctl) patients or patients with (long-standing persistent) chronic AF (cAF).ResultsISK was significantly higher, and apamin caused larger action potential prolongation in cAF- versus Ctl-cardiomyocytes. Sensitivity analyses in an in silico human atrial cardiomyocyte model identified IK1 and ISK as major regulators of repolarization. Increased ISK in cAF was not associated with increases in mRNA/protein levels of SK-channel subunits in either right- or left-atrial tissue homogenates or right-atrial cardiomyocytes, but the abundance of SK2 at the sarcolemma was larger in cAF versus Ctl in both tissue-slices and cardiomyocytes. Latrunculin-A and primaquine (anterograde and retrograde protein-trafficking inhibitors) eliminated the differences in SK2 membrane levels and ISK between Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced ISK amplitude and abolished the difference between Ctl- and cAF-cardiomyocytes, indicating that reduced calmodulin-Thr80 phosphorylation due to increased protein phosphatase-2A levels in the SK-channel complex likely contribute to the greater ISK in cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased ISK and reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced ISK-upregulation.ConclusionsISK is upregulated in patients with cAF due to enhanced channel function, mediated by phosphatase-2A-dependent calmodulin-Thr80 dephosphorylation and tachycardia-dependent enhanced trafficking and targeting of SK-channel subunits to the sarcolemma. The observed AF-associated increases in ISK, which promote reentry-stabilizing action potential duration shortening, suggest an important role for SK-channels in AF auto-promotion and provide a rationale for pursuing the antiarrhythmic effects of SK-channel inhibition in humans.

Background: Pulmonary vein isolation (PVI) using pulsed field ablation (PFA) or cryoballoon ablation (CBA) are commonly used single-shot techniques for the treatment of patients with atrial fibrillation (AF). The number of overweight (BMI 25–30 kg/m2) and obese (BMI>30 kg/m2) patients undergoing PVI is increasing, but data on this patient population is limited. Methods: Consecutive AF patients with a BMI ≥25 kg/m2 undergoing PFA- or CBA-PVI were included in this retrospective analysis. Baseline characteristics, procedural parameters and 1-year AF-freedom were retrospectively analyzed and compared for both ablation modalities. Results: Of 115 patients (66 % men, 64 years [IQR: 58–71 years], 57 % overweight and 43 % obese) PFA- was performed in 68 % and CBA-PVI in 32 %. Contrast-dye volume (PFA: 80 ml [IQR: 60 − 117 ml] vs. CBA: 130 ml [IQR: 95 − 200 ml], P=0.001) and radiation exposure (PFA: 2196 cGy·cm2 [IQR: 1398 − 2973 cGy·cm2] vs. CBA: 3239 cGy·cm2 [IQR: 1288 − 5062 cGy·cm2], P=0.009) was lower in patients undergoing PFA-PVI. Logistic regression analysis identified obesity (OR: 5.58, 95 % CI: 1.63–19.06; P=0.006) and CBA-PVI (OR: 12.93, 95 % CI: 3.51–47.68; P

Common centaury (Centaurium eryhtraea Rafn) is a medicinal plant species with vigorous morphogenic potential in vitro. The process of spontaneous shoot regeneration in a solid root culture is characteristic for this plant species. In this context, the aim of this work was to investigate the dynamic changes of endogenous phytohormones and carbohydrates content in root explants at different time points (0, 2, 4, 7, 14, 21, 28, and 60 days) during spontaneous centaury morphogenesis in vitro. Detailed analysis of cytokinins (CKs) showed that trans-zeatin (tZ) was the major bioactive CK at all time points. The corresponding riboside, tZ9R, was also determined in the majority of the identified transport forms, at all time-points. Further analysis of endogenous auxin revealed a significant increase in endogenous indole-3-acetic acid (IAA) after 21 days, when a huge jump in the ratio of IAA/bioactive CKs was also observed. The maximum total soluble sugar content was measured after 14 days, while a significant decrease was determined after 21 days, when the first regenerated adventitious shoots appeared. This undoubtedly indicates an increased energy requirement prior to the actual regeneration of the shoots. The obtained results indicate that the period from day 14 to day 21 involves the most dramatic disturbances in endogenous bioactive CKs, IAA and carbohydrate balance, which are very important and valuable factors for the onset of shoot regeneration.

Background: Heart failure (HF) and inflammation have a bidirectional relation leading to activation and adaptation of multiple cellular lines, including leucocyte subtypes and platelets. We aimed to assess and compare the predictive value of the neutrophil–lymphocyte (NLR), monocyte-lymphocyte (MLR) and platelet-lymphocyte (PLR) ratios for all-cause long-term mortality in HF. Methods: This is an observational retrospective cohort study that included patients from the HI-HF cohort that survived the initial hospitalization. Vital status and survival time were assessed in June 2020. Results: We analyzed 1018 HF patients with a mean age of 72.32 ± 10.29 years and 53.54 % women. All-cause long-term mortality was 38.21 % after a median follow-up time of 68 [38 – 82] months. NLR (AUC 0.667, 95 %CI 0.637 – 0.697), MLR (AUC 0.670, 95 %CI 0.640 – 0.700) and PLR (AUC 0.606, 95 %CI 0.574 – 0.636) were predictors of all-cause mortality. In multivariable Cox proportional hazards analysis, NLR≥3.56 was the only hematological index independent predictor of fatality (HR 1.36, 95 %CI 1.05 – 1.76). Conclusions: Of the three hematological indices, NLR was the only independent predictor of all-cause long-term mortality of HF patients. We suggest NLR≥3.56 as an auxiliary prognostic biomarker for the evaluation of HF patients.

Background: Atypical atrial flutter (AAF) is an increasingly relevant clinical problem. Despite advancements in mapping and ablation techniques, the general management of these patients remain challenging especially when mapping cannot be performed during ongoing arrhythmia. There are no data whether induction of AAF is a feasible approach in these cases. Methods: We retrospectively analyzed patients who underwent catheter ablation of AAF and compared procedural results between patients with ongoing tachycardia when starting the procedure and patients with induced AAF. Results: We analyzed 97 ablation procedures performed in 76 patients with a mean follow-up of 13.2 ± 12.2 months. In 68 procedures (70.1 %) AAF was ongoing at the beginning of the procedure and in 29 cases (29.9 %) AAF had to be induced.There was no statistically significant difference regarding acute procedural success. The recurrence rate of any arrhythmia during follow-up was significantly higher after ablation of ongoing AAF compared to induced AAF (63.2 % vs. 42.9 %; p = 0.047) driven by a significant higher rate of AAF-recurrence (57.4 % vs. 34.5 %; p = 0.039). The number of ablated tachycardias per patient as well as the number of de-novo tachycardias found during re-ablation showed no significant difference between both groups. Conclusion: Starting a procedure with ongoing arrhythmia did not result in better short- or mid-term outcome in patients undergoing AAF ablation. Furthermore, based on our results inducing AAF seems a legitimate approach for AAF ablation in patients presenting in sinus rhythm.

Introduction: postural balance is a concept that refers to the body's ability to maintain its center of gravity while relying on a support area. Purpose: to develop and implement a combined physiotherapy programme with sensorimotor exercises and to monitor its effectiveness after anterior cruciate ligament reconstruction. Material and methods: Material: 15 men (mean age 25.16) were observed after anterior cruciate ligament reconstruction. They underwent a physiotherapy programme combined with additional exercises for sensorimotor stimulation. The sensorimotor stimulation exercises were specifically tailored to overcome muscle imbalance and pathological proprioceptive information from the operated knee joint. Methods: Functional methods include lower extremity centimetry, range of motion in the knee joint, manual muscle testing, static and dynamic balance tests, and postural control tests. Statistical methods: statistical data grouping; Cronbach's test; descriptive method; statistical hypotheses testing; correlation analysis. The data was processed with SPSS v.24.0 for Windows. Results: according to the literature, the main cause of impaired proprioception and mechanoreception is the loss of mechanoreceptive afferency due to tissue damage in the knee joint. This requires an income of sensory information from neighboring healthy structures. The inclusion of sensorimotor exercises helps build new motor skills, activity, and regulation that require peripheral stimuli. The results from the static and dynamic portions of the test show the possibility of restoring impaired sensorimotor information. Conclusion: the combination of classic physiotherapy and sensorimotor stimulation influences the support and motor function of the lower extremities.

As part of the Reimbursable Advisory Services on Accelerating Resilience to Disaster Risks, the World Bank worked with the Interior Ministry of Bulgaria to develop a proposal for the National Disaster Risk Profile of Bulgaria. The purpose of this document, which is the fourth technical annex to the proposal for the National Disaster Risk Profile, is to provide particular conclusions, information, and techniques that were utilised to evalu-ate the risk of landslides in Bulgaria. For the first time at the national level, landslide risk assessment procedures based on ISO/IEC 31010:2019 Risk assessment techniques are being developed and applied in Bulgaria. The five primary categories in which the results are presented are physical safety, economic security, social well-being, environmental security, and security of tangible assets and critical infrastructure. The uncertainty (confidence) parameter is utilised, and it is subdivided into the following three basic categories: low uncertainty, medium uncertainty, and high uncertainty. The produced results demonstrate consistent applicability to empirical data analysis and real-world situations.

Abstract The genomes of charophyte green algae, close relatives of land plants, typically do not show signs of developmental regulation by phytohormones. However, scattered reports of endogenous phytohormone production in these organisms exist. We performed a comprehensive analysis of multiple phytohormones in Viridiplantae, focusing mainly on charophytes. We show that auxin, salicylic acid, ethylene and tRNA-derived cytokinins including cis-zeatin are found ubiquitously in Viridiplantae. By contrast, land plants but not green algae contain the trans-zeatin type cytokinins as well as auxin and cytokinin conjugates. Charophytes occasionally produce jasmonates and abscisic acid, whereas the latter is detected consistently in land plants. Several phytohormones are excreted into the culture medium, including auxin by charophytes and cytokinins and salicylic acid by Viridiplantae in general. We note that the conservation of phytohormone biosynthesis and signaling pathways known from angiosperms does not match the capacity for phytohormone biosynthesis in Viridiplantae. Our phylogenetically guided analysis of established algal cultures provides an important insight into phytohormone biosynthesis and metabolism across Streptophyta.

Objective: Bleeding is frequent during transcatheter aortic valve implantation (TAVI), especially when performed through a transapical approach (TA), and is associated with a worse prognosis. The present study aims to test the implication of red blood cell (RBC) transfusion and the optimal transfusion strategy in this context. Methods: Among 11,265 participants in the multicenter TRITAVI (Transfusion Requirements in Transcatheter Aortic Valve Implantation) registry, 548 patients (4.9%) who received TA-TAVI at 19 European centers were included. One-to-one propensity score matching was performed to reduce treatment selection bias and potential confounding among transfused versus non-transfused patients. The primary endpoint of the study was the 30-day occurrence of all-cause mortality. Results: 209 patients (38 %) received RBC transfusions. The primary endpoint occurred in 47 (8.6 %) patients. Propensity score matching identified 188 pairs of patients with and without RBC transfusion. In the propensity score-matched analysis, RBC transfusion was associated with increased 30-day mortality (HR 3.35, 95 % CI 1.51 – 7.39; p = 0.002). At multivariable cox regression analysis, RBC transfusion was an independent predictor of 30-day mortality (HR 3.07, 95 % CI 1.01–9.41, p = 0.048), as well as baseline ejection fraction (HR 0.96, 95 % CI 0.92–0.99, p = 0.043), and acute kidney injury (HR 3.95, 95 % CI 1.11–14.05, p = 0.034). Conclusions: RBC transfusion is an independent predictor of short-term mortality in patients undergoing TA-TAVI, regardless of major bleeding.Clinical trial registration: https://www.clinicaltrials.gov Unique identifier: NCT03740425.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources. These important findings extend our understanding of the origin, biology, and function of fibroblasts and offer possibilities for therapeutic targeting of fibrosis in AF.

Background: Cardiac troponin I (cTnI) above the 99th percentile is associated with an increased risk of major adverse events. Patients with detectable cTnI below the 99th percentile are a heterogeneous group with a less well-defined risk profile. The purpose of this study is to investigate the prognostic relevance of detectable cTnI below the 99th percentile in patients undergoing coronary angiography. Methods: The study included 14,776 consecutive patients (mean age of 65.4 ± 12.7 years, 71.3 % male) from the Essen Coronary Artery Disease (ECAD) registry. Patients with cTnI levels above the 99th percentile and patients with ST-segment elevation acute myocardial infarction were excluded. All-cause mortality was defined as the primary endpoint. Results: Detectable cTnI below the 99th percentile was present in 2811 (19.0 %) patients, while 11,965 (81.0 %) patients were below detection limit of the employed assay. The mean follow-up was 4.25 ± 3.76 years. All-cause mortality was 20.8 % for patients with detectable cTnI below the 99th percentile and 15.0 % for those without detectable cTnI. In a multivariable Cox regression analysis, detectable cTnI was independently associated with all-cause mortality with a hazard ratio of 1.60 (95 % CI 1.45–1.76; p