Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular- and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced INa, ICa,L, Ito, IKr and IKur, dual effects on IK1 and IK,ACh (inhibition at low and augmentation at high concentrations), and increased INCX and SR Ca2+ leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.
- MeSH
- akční potenciály účinky léků MeSH
- elektrofyziologické jevy účinky léků MeSH
- ethanol škodlivé účinky MeSH
- fibróza MeSH
- iontové kanály metabolismus MeSH
- kardiomyocyty účinky léků metabolismus MeSH
- lidé MeSH
- mezerový spoj účinky léků metabolismus MeSH
- počítačová simulace MeSH
- remodelace cév účinky léků MeSH
- srdce účinky léků patofyziologie MeSH
- srdeční arytmie patologie patofyziologie MeSH
- srdeční síně účinky léků patologie patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Gigantic left atrium is defined in the current literature as an excessive dilatation of the left atrium above 65mm. Chronic mitral valve disease is associated with the development of thrombus in the left atrium in up to 19% of all cases of mitral insufficiency and appropriate treatment must be initiated to prevent thromboembolic events. In order to diagnose thrombi in the left atrium or left atrial appendage, various imaging methods may be used, including cardiac magnetic resonance. CASE PRESENTATION: The case report describes a 73-year-old male who developed recurrent sessile thrombus on the posterior wall of the gigantic left atrium. A large thrombus was first detected following mitral valve surgery despite effective vitamin K antagonist anticoagulation therapy. Echocardiography and cardiac magnetic resonance were used within the diagnostic procedure and to monitor the treatment outcomes. Cardiac magnetic resonance was shown to be beneficial as it provided a more precise description of the intra-atrial masses located on the posterior left atrial wall, and in such situations, is of greater benefit than standard echocardiography. This led to the surgical removal of the intra-atrial mass; nevertheless, it was quickly followed by the recurrence of the thrombus. The anticoagulant therapy was adjusted and fortified by the introduction of acetylsalicylic acid and sequentially clopidogrel, but this also did not resolve the thrombus formation. Finally, employing a combination of rivaroxaban and clopidogrel resulted in partial thrombus regression. Therefore, various pathophysiological aspects of thrombus formation and used anticoagulation strategies are discussed. CONCLUSIONS: We describe a unique case of a recurrent thrombus located on the posterior wall of the gigantic left atrium. Cardiac magnetic resonance was shown to be beneficial in providing a more precise description of the intra-atrial masses located on the posterior left atrial wall as compared to standard echocardiographic examination. Development of a thrombus after mitral valve surgery despite effective anticoagulant therapy and its final resolution by introducing a combination of rivaroxaban and clopidogrel highlights the complex etiopathogenesis of thrombus formation. This supports the potential use of this combination in tailoring an individual personalized therapy for patients with recurrent atrial thrombi.
- MeSH
- anuloplastika mitrální chlopně škodlivé účinky MeSH
- chirurgická náhrada chlopně škodlivé účinky MeSH
- inhibitory agregace trombocytů aplikace a dávkování MeSH
- inhibitory faktoru Xa aplikace a dávkování MeSH
- klopidogrel aplikace a dávkování MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- mitrální insuficience diagnostické zobrazování chirurgie MeSH
- nemoci srdce diagnostické zobrazování farmakoterapie etiologie chirurgie MeSH
- recidiva MeSH
- rivaroxaban aplikace a dávkování MeSH
- senioři MeSH
- srdeční síně diagnostické zobrazování účinky léků chirurgie MeSH
- trombektomie MeSH
- trombóza diagnostické zobrazování farmakoterapie etiologie chirurgie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
Atrial fibrillation (AF) is the most common sustained arrhythmia associated with significant morbidity and mortality. The mechanisms underlying the pathogenesis of AF are poorly understood, although electrophysiological remodeling has been described as an important initiating step. There is growing evidence that oxidative stress is involved in the pathogenesis of AF. Many known triggers of oxidative stress, such as age, diabetes, smoking, and inflammation, are linked with an increased risk of arrhythmia. Numerous preclinical studies and clinical trials reported the importance of antioxidant therapy in the prevention of AF, using vitamins C and E, polyunsaturated fatty acids, statins, or nitric oxide donors. The aim of our work is to give a current overview and analysis of opportunities, challenges, and benefits of antioxidant therapy in AF.
- MeSH
- akční potenciály MeSH
- antiarytmika farmakologie MeSH
- antioxidancia terapeutické užití MeSH
- fibrilace síní farmakoterapie genetika metabolismus patofyziologie MeSH
- genetická terapie metody MeSH
- lidé MeSH
- oxidační stres účinky léků genetika MeSH
- remodelace síní účinky léků MeSH
- rizikové faktory MeSH
- srdeční frekvence účinky léků MeSH
- srdeční síně účinky léků metabolismus patofyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Anthracyclines use is limited by profound cardiotoxicity. Involvement of miRNAs in anthracycline-induced cardiotoxicity (AIC) is still not completely understood. Thus, the expression of AIC-related microRNAs was determined in rat atria and ventricles after doxorubicin (DOX) and liposomal doxorubicin (L-DOX) administration. Vehiculum, DOX or L-DOX were applied intraperitoneally in a single dose to male Wistar rats (3 groups: control, DOX and L-DOX, respectively). Rats were sacrificed after 24 h, and samples from left atrium (LA)/ventricle (LV) and right atrium (RA)/ventricle (RV) were obtained. Expressions of miR-208a, let-7g and snU6 were determined using qRT-PCR. In the control group, miR-208a was highly abundant in the atria compared to the ventricles and in the left-sided structures compared to the right-sided structures, while let-7g showed only atrio-ventricular gradient with predominant expression in the atria. Administration of both DOX and L-DOX resulted in 38.87 and 23.57% reduction in miR-208a expression in the LV (p = 0.028) and in 13.79 and 14.70% reduction in let-7g expression in the LA (p = 0.015), respectively. Acute administration of DOX/L-DOX alters expression of miR-208a in LV and of let-7g in LA. These changes may partly contribute to the development of AIC.
- MeSH
- doxorubicin analogy a deriváty farmakologie MeSH
- exprese genu MeSH
- krysa rodu rattus MeSH
- mikro RNA biosyntéza genetika MeSH
- polyethylenglykoly farmakologie MeSH
- potkani Wistar MeSH
- srdeční komory účinky léků metabolismus MeSH
- srdeční síně účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Nicotine abuse is associated with variety of diseases including arrhythmias, most often atrial fibrillation (AF). Altered inward rectifier potassium currents including acetylcholine-sensitive current I K(Ach) are known to be related to AF pathogenesis. Since relevant data are missing, we aimed to investigate I K(Ach) changes at clinically relevant concentrations of nicotine. Experiments were performed by the whole cell patch clamp technique at 23 ± 1 °C on isolated rat atrial myocytes. Nicotine was applied at following concentrations: 4, 40 and 400 nM; ethanol at 20 mM (∼0.09%). Nicotine at 40 and 400 nM significantly activated constitutively active component of I K(Ach) with the maximum effect at 40 nM (an increase by ∼100%); similar effect was observed at -110 and -50 mV. Changes at 4 nM nicotine were negligible on average. Coapplication of 40 nM nicotine and 20 mM ethanol (which is also known to activate this current) did not show cumulative effect. In the case of acetylcholine-induced component of I K(Ach), a dual effect of nicotine and its correlation with the current magnitude in control were apparent: the current was increased by nicotine in the cells showing small current in control and vice versa. The effect of 40 and 400 nM nicotine on acetylcholine-induced component of I K(Ach) was significantly different at -110 and -50 mV. We conclude that nicotine at clinically relevant concentrations significantly increased constitutively active component of I K(Ach) and showed a dual effect on its acetylcholine-induced component, similarly as ethanol. Synchronous application of nicotine and ethanol did not cause additive effect.
- MeSH
- acetylcholin farmakologie MeSH
- časové faktory MeSH
- dovnitř usměrňující draslíkové kanály spřažené s G proteiny agonisté účinky léků MeSH
- ethanol toxicita MeSH
- hodnocení rizik MeSH
- kardiomyocyty účinky léků metabolismus MeSH
- membránové potenciály MeSH
- nikotin toxicita MeSH
- potkani Wistar MeSH
- srdeční arytmie chemicky indukované metabolismus MeSH
- srdeční síně účinky léků metabolismus MeSH
- techniky in vitro MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Alcohol intoxication tends to induce arrhythmias, most often the atrial fibrillation. To elucidate arrhythmogenic mechanisms related to alcohol consumption, the effect of ethanol on main components of the ionic membrane current is investigated step by step. Considering limited knowledge, we aimed to examine the effect of clinically relevant concentrations of ethanol (0.8-80 mM) on acetylcholine-sensitive inward rectifier potassium current I K(Ach). Experiments were performed by the whole-cell patch clamp technique at 23 ± 1 °C on isolated rat and guinea-pig atrial myocytes, and on expressed human Kir3.1/3.4 channels. Ethanol induced changes of I K(Ach) in the whole range of concentrations applied; the effect was not voltage dependent. The constitutively active component of I K(Ach) was significantly increased by ethanol with the maximum effect (an increase by ∼100 %) between 8 and 20 mM. The changes were comparable in rat and guinea-pig atrial myocytes and also in expressed human Kir3.1/3.4 channels (i.e., structural correlate of I K(Ach)). In the case of the acetylcholine-induced component of I K(Ach), a dual ethanol effect was apparent with a striking heterogeneity of changes in individual cells. The effect correlated with the current magnitude in control: the current was increased by eth-anol in the cells showing small current in control and vice versa. The average effect peaked at 20 mM ethanol (an increase of the current by ∼20 %). Observed changes of action potential duration agreed well with the voltage clamp data. Ethanol significantly affected both components of I K(Ach) even in concentrations corresponding to light alcohol consumption.
- MeSH
- acetylcholin farmakologie MeSH
- akční potenciály MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- dovnitř usměrňující draslíkové kanály spřažené s G proteiny účinky léků genetika metabolismus MeSH
- ethanol toxicita MeSH
- hodnocení rizik MeSH
- kardiomyocyty účinky léků metabolismus MeSH
- kinetika MeSH
- lidé MeSH
- modely kardiovaskulární MeSH
- morčata MeSH
- počítačová simulace MeSH
- potkani Wistar MeSH
- srdeční arytmie chemicky indukované metabolismus patofyziologie MeSH
- srdeční frekvence účinky léků MeSH
- srdeční síně účinky léků metabolismus patofyziologie MeSH
- transfekce MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the in vitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1 μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (< 5 μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (< 5 μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (> 5 μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime.
- MeSH
- antagonisté muskarinových receptorů farmakologie MeSH
- atropin farmakologie MeSH
- cholinesterasové inhibitory farmakologie MeSH
- diaminy farmakologie MeSH
- fysostigmin farmakologie MeSH
- interakce mezi receptory a ligandy MeSH
- krysa rodu rattus MeSH
- methacholinchlorid farmakologie MeSH
- močový měchýř účinky léků enzymologie metabolismus MeSH
- obidoxim chlorid farmakologie MeSH
- receptor muskarinový M2 antagonisté a inhibitory MeSH
- receptor muskarinový M3 antagonisté a inhibitory MeSH
- srdeční síně účinky léků enzymologie metabolismus MeSH
- svalová kontrakce účinky léků MeSH
- techniky in vitro MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Levá síň je relativně tenkostěnný srdeční oddíl s nízkým intraluminálním tlakem, který je z anatomického hlediska v úzkém kontaktu se strukturami v zadní části dolního mediastina, a to především s jícnem a descendentní aortou. Tyto charakteristické vlastnosti ji dělají náchylnější k zevní kompresi patologickými strukturami souvisejícími s gastrointestinálním traktem, mediastinem, plícemi, perikardem a aortou. Podle stupně útlaku levé síně může být pacient asymptomatický nebo se mohou objevit známky kardiální insuficience. V naší kasuistice popisujeme letálně probíhající útlak levé síně chronickým abscesem mediastina vzniklým rupturou zadní části jícnu při ulcerující ezofagitidě. Dle našeho zjištění jde o první podobný publikovaný případ, neboť ohraničený průběh mediastinitidy se vznikem abscesu je extrémně raritní.
The left atrium is a thin-walled cardiac chamber with a low intraluminal pressure. It is located in the inferoposterior part of mediastinum, near to structures such as the esophagus and descending aorta. This makes it vulnerable to compression by pathologic changes associated with the gastrointestinal tract, mediastinum, lungs, pericardium and aorta. Depending on the level of the compression the patient may be asymptomatic or develops signs of cardiac insufficiency. We describe a lethal course of left atrial compression due to a chronic mediastinal abscess secondary to a ruptured esophageal ulcer. To our knowledge this is the first such case described, in part because bordered mediastinitis with abscess development is very rare.
- MeSH
- absces * patologie MeSH
- cysty mediastina * komplikace mortalita patologie MeSH
- echokardiografie MeSH
- lidé MeSH
- peptická ezofagitida komplikace MeSH
- perforace peptického vředu komplikace mortalita MeSH
- senioři nad 80 let MeSH
- srdeční selhání etiologie farmakoterapie mortalita MeSH
- srdeční síně patofyziologie účinky léků MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Obidoxime, a well-known bis-pyridinium reactivator, is often the preferred antidote of organophosphorus poisoning caused by pesticides and tabun. It is also considered to be an allosteric modulator of muscarinic receptors, preferably M2 sub-type. This study compared the effect of obidoxime and atropine in vivo and in vitro on the cholinergic stimulation of the rat heart (M2) and the urinary bladder (M3). The results showed that obidoxime exerts anti-muscarinic effects, that may play an important role in the treatment of organophosphourus poisoning, and that the muscarinic receptor inhibition profile shows M2 receptor selectivity. This anti-muscarinic effect is much smaller that the effect of atropine and might be due to the allosteric inhibition of the receptors. The results also indicate that the acetylcholinesterase inhibition and the muscarinic receptor antagonism occur at different concentrations and dose levels.
- MeSH
- antagonisté muskarinových receptorů farmakologie MeSH
- atropin farmakologie MeSH
- cholinesterasové inhibitory farmakologie MeSH
- krysa rodu rattus MeSH
- močový měchýř účinky léků MeSH
- molekulární struktura MeSH
- obidoxim chlorid chemie farmakologie MeSH
- organofosforové sloučeniny MeSH
- otrava organofosfáty MeSH
- reaktivátory cholinesterázy chemie farmakologie MeSH
- srdeční frekvence účinky léků MeSH
- srdeční síně účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Numerous ligands of sigma receptors are known to prolong the QT interval and therefore cause a variety of arrhythmias. High affinity binding sites for the prototypical sigma ligand haloperidol were found in membranes of cardiac myocytes from adult rats. Activation of sigma 1 receptor leads to a release of calcium from the endoplasmic reticulum that follows increased synthesis of inositol 1,4,5-trisphosphate (IP3). We studied the effect of long-term haloperidol treatment on the expression of sigma 1 receptors, IP3 receptors of type 1 and 2 in the individual parts of the rat heart, in isolated rat cardiomyocytes and in PC12 cells. We have found that prolonged treatment with haloperidol significantly increased mRNA levels of sigma 1 receptors in both atria and ventricles. Sigma 1 receptor's mRNA was increased also in isolated cardiomyocytes. Haloperidol treatment affects the expression of IP3 receptors of type 1 and 2 in cardiac atria, but not in cardiac ventricles. We observed increase in IP3 receptors in differentiated PC12 cells, but not in isolated cardiomyocytes. We propose that this increase might participate in triggering cardiac arrhythmias during haloperidol treatment, which has to be further verified.
- MeSH
- antipsychotika farmakologie MeSH
- buňky PC12 MeSH
- haloperidol farmakologie MeSH
- inositol-1,4,5-trisfosfát - receptory genetika metabolismus MeSH
- kardiomyocyty účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- messenger RNA genetika metabolismus MeSH
- potkani Wistar MeSH
- regulace genové exprese účinky léků MeSH
- srdeční komory účinky léků metabolismus MeSH
- srdeční síně účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH