Background: Anthracycline cardiotoxicity is a well-known complication of cancer treatment, and miRNAs have emerged as a key driver in the pathogenesis of cardiovascular diseases. This study aimed to investigate the expression of miRNAs in the myocardium in early and late stages of chronic anthracycline induced cardiotoxicity to determine whether this expression is associated with the severity of cardiac damage. Method: Cardiotoxicity was induced in rabbits via daunorubicin administration (daunorubicin, 3 mg/kg/week; for five and 10 weeks), while the control group received saline solution. Myocardial miRNA expression was first screened using TaqMan Advanced miRNA microfluidic card assays, after which 32 miRNAs were selected for targeted analysis using qRT-PCR. Results: The first subclinical signs of cardiotoxicity (significant increase in plasma cardiac troponin T) were observed after 5 weeks of daunorubicin treatment. At this time point, 10 miRNAs (including members of the miRNA-34 and 21 families) showed significant upregulation relative to the control group, with the most intense change observed for miRNA-1298-5p (29-fold change, p < 0.01). After 10 weeks of daunorubicin treatment, when a further rise in cTnT was accompanied by significant left ventricle systolic dysfunction, only miR-504-5p was significantly (p < 0.01) downregulated, whereas 10 miRNAs were significantly upregulated relative to the control group; at this time-point, the most intense change was observed for miR-34a-5p (76-fold change). Strong correlations were found between the expression of multiple miRNAs (including miR-34 and mir-21 family and miR-1298-5p) and quantitative indices of toxic damage in both the early and late phases of cardiotoxicity development. Furthermore, plasma levels of miR-34a-5p were strongly correlated with the myocardial expression of this miRNA. Conclusion: To the best of our knowledge, this is the first study that describes alterations in miRNA expression in the myocardium during the transition from subclinical, ANT-induced cardiotoxicity to an overt cardiotoxic phenotype; we also revealed how these changes in miRNA expression are strongly correlated with quantitative markers of cardiotoxicity.
- Publikační typ
- časopisecké články MeSH
Úvod: Ponechání pacienta na místě zásahu v přednemocniční neodkladné péči (PNP) je aktuální problematika. Na národní úrovní nejsou dostupná komparativní data ohledně ponechání pacienta na místě zásahu ani hodnocení bezpečnosti postupu. Cíl: Zjistit četnost ponechání pacienta na místě z rozhodnutí zdravotnických pracovníků a popsat charakteristiky těchto případů. Zhodnotit míru opakovaných výjezdů k pacientům ponechaným na místě zásahu. Metodika: Data byla sbírána z databáze výjezdové činnosti Zdravotnické záchranné služby Karlovarského kraje (ZZS KVK) za měsíc leden 2023. Celkem bylo identifikováno 335 pacientů ponechaných na místě z rozhodnutí výjezdové skupiny (z 3005 pacientů). Výsledky: Pacienti z primárních výjezdů jsou ponechávání na místě v 11,1 % (335/3005). Dominuje rozhodnutí zdravotnických záchranářů, kteří konzultují stav pacienta po telefonu s lékařem (90 % případů) nad ponecháním na místě výjezdovou skupinou rychlé lékařské pomoci. Mezi pacienty, kteří jsou ponecháváni na místě, převažují nespecifické zdravotní obtíže, ebrieta a psychiatrické stavy. Opakované výjezdy se uskutečnily k pacientům ponechaným na místě v 11,0 % (n = 37). Nejvíce opakovaných výjezdů se uskuteční do 24 hodin (51 % (n = 19)), respektive do 72 hodin (87 % (n = 32)). Vyšší četnost opakovaného výjezdu k těmto pacientům byla u starších pacientů. Exitus pacienta ponechaného na místě nebyl zaznamenán. Závěr: V Karlovarském kraji je ponecháváno na místě přes jedenáct procent pacientů z primárních výjezdů. Ponechání pacienta na místě zásahu lze považovat za bezpečnou součást poskytování PNP. Chybí doporučený postup na národní úrovni, který by zohledňoval stratifikaci rizik pro ponechávání pacientů na místě zásahů.
Introduction: Non-conveyance of patients following prehospital emergency care is a current issue. There are no available national comparative data on non-conveyance of the patient from scene or evaluation of the safety of the procedure. Aim: To evaluate the frequency of non-conveyance of the patient by the decision of healthcare workers and describe the characteristics of these cases. To find out the rate of repeated visits to patients left at the scene of intervention. Methods: The data was collected from the database of the Emergency medical services of Karlovy Vary region from 1st to 31st January 2023. A total of 335 patients were left on the place based on the decision of the ambulance crew (out of 3005 patients). Results: The non-conveyance rate of patients from primary calls was 11.1% (335/3005). The decision of paramedics, who consult the patient‘s condition over the phone with physician (90% of cases) dominates over leaving the patient on site by the ambulance crew with physician. The most common reasons for non-transport of the patient are non-specific health conditions, alcohol intoxication and psychiatric conditions. Repeated visits occurred to these patients in 11.0% (n = 37). Most of the repeated calls took place within 24 hours (51% (n = 19)) or within 72 hours (87% (n = 32)). A higher frequency of repeated visits to these patients was more common in older patients. No death of the patient left on the scene was recorded. Conclusion: In the Karlovy Vary region, over eleven percent of patients from primary visits during January 2023 were left on place. Non-conveyance of the patient can be considered safe part of providing prehospital emergency care. However, there is a lack of a national recommendations or guidelines that would consider the risks stratification for non-transport of the patient. Key words: emergency medical services – pre-hospital emergency care – paramedic – non-conveyance of the patient.
Current knowledge on the renin-angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets.
- MeSH
- fibróza MeSH
- kardiomegalie genetika metabolismus patologie MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- myokard metabolismus patologie MeSH
- nemoci srdce genetika metabolismus patologie MeSH
- renin-angiotensin systém * MeSH
- signální transdukce * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Modern diagnostic strategies for early recognition of cancer therapeutics-related cardiac dysfunction involve cardiac troponins measurement. Still, the role of other markers of cardiotoxicity is still unclear. The present study was designed to investigate dynamics of response of human cardiomyocytes derived from induced pluripotent stem cells (hiPCS-CMs) to doxorubicin with the special emphasis on their morphological changes in relation to expression and organization of troponins. The hiPCS-CMs were treated with doxorubicin concentrations (1 and 0.3 µM) for 48 h and followed for next up to 6 days. Exposure of hiPCS-CMs to 1 µM doxorubicininduced suppression of both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) gene expression. Conversely, lower 0.3 µM doxorubicin concentration produced no significant changes in the expression of aforementioned genes. However, the intracellular topography, arrangement, and abundance of cardiac troponin proteins markedly changed after both doxorubicin concentrations. In particular, at 48 h of treatment, both cTnT and cTnI bundles started to reorganize, with some of them forming compacted shapes extending outwards and protruding outside the cells. At later intervals (72 h and onwards), the whole troponin network collapsed and became highly disorganized following, to some degree, overall changes in the cellular shape. Moreover, membrane permeability of cardiomyocytes was increased, and intracellular mitochondrial network rearranged and hypofunctional. Together, our results demonstrate complex effects of clinically relevant doxorubicin concentrations on hiPCS-CM cells including changes in cTnT and cTnI, but also in other cellular compartments contributing to the overall cytotoxicity of this class of cytostatics.
- MeSH
- buněčné linie MeSH
- doxorubicin farmakologie toxicita MeSH
- indukované pluripotentní kmenové buňky cytologie účinky léků MeSH
- kardiomyocyty cytologie účinky léků metabolismus MeSH
- kardiotoxicita MeSH
- lidé MeSH
- protinádorové látky farmakologie toxicita MeSH
- troponin metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Personalized medicine is partly based on biomarker-guided diagnostics, therapy and prognosis, which is becoming an unavoidable concept in modern cardiology. However, the clinical significance of single biomarker studies is rather limited. A promising novel approach involves combining multiple markers into a multiplex panel, which could refine the management of a particular patient with cardiovascular pathology. Two principally different assay formats have been developed to facilitate simultaneous quantification of multiple antigens: planar array assays and microbead assays. These approaches may help to better evaluate the complexity and dynamic nature of pathologic processes and offer substantial cost and sample savings compared with traditional enzyme-linked immunosorbent assay (ELISA) measurements. However, a multiplex multimarker approach cannot become a generally disseminated method until analytical problems are solved and further studies confirming improved clinical outcomes are accomplished. These drawbacks underlie the fact that a limited number of systematic studies are available regarding the use of a multiplex biomarker approach in cardiovascular medicine to date. Our perspective underscores the significant potential of the use of the multiplex approach in a wider conceptual framework under the close cooperation of clinical and experimental cardiologists, pathophysiologists and biochemists so that the personalized approach based on standardized multimarker testing may improve the management of various cardiovascular pathologies and become a ubiquitous partner of population-derived evidence-based medicine.
- MeSH
- biologické markery analýza MeSH
- ELISA MeSH
- kardiovaskulární nemoci diagnóza farmakoterapie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Tato přehledová práce se zabývá významem experimentálního výzkumu pro pochopení mechanizmů kardiotoxicity protinádorových léčiv a možnostmi její kardioprotekce. Pozornost je věnována zejména léčivům s přímou toxicitou vůči kardiomyocytům, která ústí do dysfunkce levé komory. Diskutovány jsou charakteristické znaky kardiotoxicity I. typu (reprezentované antracykliny) a II. typu (reprezentované trastuzumabem a sunitinibem). Popsány jsou také in vivo modely pro experimentální studium antracyklinové kardiotoxicity.
This review article analyses the contribution of experimental research to the understanding of anti-cancer drug cardiotoxicity mechanisms and the options for cardioprotection. We focused on drugs inducing direct toxicity against cardiomyocytes resulting in left ventricular dysfunction. Typical features of Type I and Type II toxicity (represented by anthracyclines and trastuzumab/sunitinib, respectively) are discussed. The paper also describes in vivo models for experimental study of anthracycline cardiotoxicity.
- MeSH
- antracykliny škodlivé účinky terapeutické užití MeSH
- daunomycin aplikace a dávkování terapeutické užití MeSH
- doxorubicin aplikace a dávkování terapeutické užití MeSH
- indoly terapeutické užití MeSH
- kardiotoxicita * etiologie patofyziologie MeSH
- lidé MeSH
- preklinické hodnocení léčiv MeSH
- protinádorová antibiotika MeSH
- protinádorové látky * MeSH
- teoretické modely MeSH
- trastuzumab terapeutické užití MeSH
- tyrosinkinasy antagonisté a inhibitory škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- analýza rozptylu MeSH
- antracykliny terapeutické užití MeSH
- biologické markery krev metabolismus MeSH
- daunomycin toxicita MeSH
- echokardiografie MeSH
- funkční vyšetření srdce MeSH
- kardiomyopatie * chemicky indukované krev MeSH
- kardiotoxicita krev MeSH
- králíci MeSH
- modely u zvířat MeSH
- plocha pod křivkou MeSH
- protinádorová antibiotika * toxicita MeSH
- troponin T * krev MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Tn is a unique translational biomarker in cardiology whose potential has not been diminished in the new era of high sensitive assays. cTns can be valuable markers in cardiac diseases as well as in infectious diseases and respiratory diseases. Furthermore, the role of cTns is growing in the routine evaluation of cardioxicity and in determining the efficacy/safety ratio of novel cardioprotective strategies in clinical settings. cTns can detect myocardial injury not only in a wide spectrum of laboratory animals in experimental studies in vivo, but also in isolated heart models or cardiomyocytes in vitro. The crucial issue regarding the cross-species usage of cardiac troponin investigation remains the choice of cardiac troponin testing. This review summarizes the recent proteomic data on aminoacid sequences of cTnT and cTnI in various species, as well as selected analytical characteristics of human cardiac troponin high-sensitivity assays. Due to the highly phylogenetically conserved structure of troponins, the same bioindicator can be investigated using the same method in both clinical and experimental cardiology, thus contributing to a better understanding of the pathogenesis of cardiac diseases as well as to increased effectiveness of troponin use in clinical practice. Measuring cardiac troponins using commercially available human high-sensitivity cardiac troponin tests with convenient antibodies selected on the basis of adequate proteomic knowledge can solve many issues which would otherwise be difficult to address in clinical settings for various ethical and practical reasons. Our survey could help elaborate the practical guidelines for optimizing the choice of cTns assay in cardiology.
- MeSH
- biologické markery metabolismus MeSH
- biotest metody MeSH
- lidé MeSH
- myokard metabolismus patologie MeSH
- nemoci srdce diagnóza metabolismus patologie MeSH
- proteomika MeSH
- troponin I izolace a purifikace metabolismus MeSH
- troponin T izolace a purifikace metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
