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1.
J Vis Exp ; (160)2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32628173

RESUMO

The electrocardiogram is a valuable tool for evaluating the cardiac conduction system. Animal research has helped generate novel genetic and pharmacological information regarding the electrocardiogram. However, making electrocardiogram measurements in small animals in vivo, such as mice, has been challenging. To this end, we used an electrocardiogram recording method in anesthetized mice with many advantages: it is a technically simple procedure, is inexpensive, has short measuring time, and is affordable, even in young mice. Despite the limitations with using anesthesia, comparisons between control and experimental groups can be performed with enhanced sensitivity. We treated mice with agonists and antagonists of the autonomic nervous system to determine the validity of this protocol and compared our results with previous reports. Our ECG protocol detected increased heart rates and QTc intervals on treatment with atropine, decreased heart rates and QTc intervals after carbachol treatment, and higher heart rates and QTc intervals with isoprenaline but did not note any change in ECG parameters on administration of propranolol. These results are supported by previous reports, confirming the reliability of this ECG protocol. Thus, this method can be used as a screening approach to making ECG measurements that otherwise would not be attempted due to high cost and technical difficulties.


Assuntos
Adjuvantes Anestésicos/farmacologia , Sistema Nervoso Autônomo/fisiologia , Eletrocardiografia/métodos , Sistema de Condução Cardíaco/fisiologia , Frequência Cardíaca/fisiologia , Monitorização Fisiológica/métodos , Antagonistas Adrenérgicos beta/farmacologia , Animais , Atropina/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Propranolol/farmacologia , Reprodutibilidade dos Testes
2.
Medicine (Baltimore) ; 99(28): e21190, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664162

RESUMO

The effects of thyrotropin (TSH) suppressive therapy on autonomic regulation and ventricular repolarization in patients with differentiated thyroid cancer (DTC) have not been elucidated. The aim of present study was to evaluate variation in heart rate variability (HRV) and QT dispersion after TSH suppressive therapy in patients with DTC.Cases, defined as 271 patients with DTC within 1 year of exogenous levothyroxine, and all patients underwent a full history, physical examination, including standard 12 lead electrocardiogram (ECG), and 24 h ambulatory ECG monitoring (Holter) with normal free thyroxine (FT4) and free triiodothyronine (FT3) with levothyroxine. To evaluate effects of TSH suppressive therapy on HRV and QT dispersion, patients were divided into three groups according to different levels of TSH: TSH < 0.1 mIU/L group and 0.1 ≤ TSH < 0.5 mIU/L group were as TSH suppression groups, and 0.5 ≤ TSH < 2.0 mIU/L group was as TSH replacement group.Comparing with 0.5 ≤ TSH < 2.0 mIU/L group, significant changes in both time and frequency domain of HRV and QT dispersion were observed in TSH < 0.1 mIU/L group (P < .001: SDNN, SDANN, HF, LF/HF, QTd, and QTcd; P < .05: rMSSD) and 0.1 ≤ TSH < 0.5 mIU/L group (P < .001: SDNN, HF, LF/HF, QTd, and QTcd), and especially were more pronounced in TSH < 0.1 mIU/L group. Moreover, we found that TSH level was proportional to SDNN (ß = 15.829, P < .001), but inversely proportional to LF/HF (ß = -0.671, P < .001), QTd (ß = -16.674, P < .001) and QTcd (ß = -18.314, P < .001) in DTC patients with exogenous levothyroxine.Compared with euthyroid state, patients with suppressed serum TSH have increased sympathetic activity in the presence of diminished vagal tone, ultimately showed sympathovagal imbalance and with an increased inhomogeneity of ventricular recovery times. These findings revealed that TSH suppression therapy had a significant impact on cardiovascular system and had certain guiding role in the treatment and management of patients with DTC.


Assuntos
Doenças do Sistema Nervoso Autônomo/induzido quimicamente , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Neoplasias da Glândula Tireoide/fisiopatologia , Tiroxina/efeitos adversos , Adulto , Eletrocardiografia Ambulatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tireotropina/sangue
5.
Ideggyogy Sz ; 73(3-4): 121-127, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32364339

RESUMO

Background and purpose: To evaluate P-wave dispersion before and after antiepileptic drug (AED) treatment as well as to investigate the risk of ventricular repolarization using the Tpeak-Tend (Tp-e) interval and Tp-e/QT ratio in patients with epileptic disorder. Methods: A total of 63 patients receiving AED therapy and 35 healthy adults were included. ECG recordings were obtained before and 3 months after anti-epileptic treatment among patients with epilepsy. For both groups, Tp-e and Tp-e/QT ratio were measured using a 12-lead ECG device. Results: Tp-e interval, Tpe/QT and Tp-e/QTc ratios were found to be higher in the patient group than in the control group (p<0.05, for all), while QTmax ratio was significantly lower in the patient group. After 3 months of AED therapy, significant increases in QT max, QTc max, QTcd, Tp-e, Tp-e/QT, and Tp-e/QTc were found among the patients (p<0.05). When the arrhythmic effects of the drugs before and after treatment were compared, especially in the valproic acid group, there were significant increases in Tp-e interval, Tp-e/QT and Tp-e/QTc values after three months of treatment (p<0.05). Carbamazepine and levetiracetam groups were not statistically significant in terms of pre- and post-treatment values. Conclusion: It was concluded that an arrhythmogenic environment may be associated with the disease, and patients who received AED monotherapy may need to be followed up more closely for arrhythmia.


Assuntos
Anticonvulsivantes/uso terapêutico , Arritmias Cardíacas/diagnóstico , Carbamazepina/uso terapêutico , Epilepsia/tratamento farmacológico , Sistema de Condução Cardíaco/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Levetiracetam/uso terapêutico , Ácido Valproico/uso terapêutico , Adulto , Arritmias Cardíacas/fisiopatologia , Estudos de Casos e Controles , Eletrocardiografia/métodos , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos
6.
Angiology ; 71(6): 498-519, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32233780

RESUMO

Growing evidence suggests that atrial fibrillation (AF), in addition to its thromboembolic risk, is a risk factor for cognitive impairment (CI) via several pathways and mechanisms, further contributing to morbidity/mortality. Prior stroke is a contributor to CI, but AF is also associated with CI independently from prior stroke. Silent brain infarctions, microemboli and microbleeds, brain atrophy, cerebral hypoperfusion from widely fluctuating ventricular rates, altered hemostatic function, vascular oxidative stress, and inflammation may all exacerbate CI, particularly in patients with persistent/permanent rather than paroxysmal AF and with increased duration/burden of the arrhythmia. Brain magnetic resonance imaging is an important screening tool in eliciting and monitoring vascular and nonvascular lesions contributing to CI. Evidence is also emerging about the role of genetics in CI development. Anticoagulation and rhythm/rate control strategies may protect against CI preventing or slowing its progression or conversion to dementia, particularly at the early stages when CI may still be a treatable condition. Importantly, AF and CI share many common risk factors. Thus, screening for these 2 conditions and searching for and managing modifiable risk factors and potentially reversible causes for both AF and CI remains an important step toward prevention or amelioration of the impact incurred by these 2 conditions.


Assuntos
Fibrilação Atrial/epidemiologia , Encéfalo/efeitos dos fármacos , Cognição , Disfunção Cognitiva/epidemiologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca , Acidente Vascular Cerebral/epidemiologia , Antiarrítmicos/uso terapêutico , Anticoagulantes/uso terapêutico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Encéfalo/fisiopatologia , Tomada de Decisão Clínica , Cognição/efeitos dos fármacos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Técnicas de Apoio para a Decisão , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Prognóstico , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia
7.
PLoS Med ; 17(3): e1003040, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32134952

RESUMO

BACKGROUND: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. CONCLUSIONS: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.


Assuntos
Arritmias Cardíacas/fisiopatologia , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca , Malária/fisiopatologia , Potenciais de Ação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimaláricos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/diagnóstico por imagem , Arritmias Cardíacas/parasitologia , Regulação da Temperatura Corporal , Cardiotoxicidade , Criança , Pré-Escolar , Feminino , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/parasitologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Lactente , Malária/diagnóstico , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
8.
Balkan Med J ; 36(6): 301-310, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31648435

RESUMO

Parasympathetic overactivity may cause functional atrioventricular block episodes and necessitate pacemaker implantation in symptomatic cases and those refractory to conventional therapies. In these patients, if it can be clearly demonstrated that there is no structural damage in the conduction system, elimination of the vagal activity based on radiofrequency catheter ablation of main ganglionated plexi around the heart, which is called as cardioneuroablation, might be a rational approach. In this review article, we try to discuss patient selection and procedural steps suitable for cardioneuroablation based on two patients with functional atrioventricular block.


Assuntos
Bloqueio Atrioventricular/cirurgia , Ablação por Cateter/métodos , Ablação por Cateter/tendências , Eletrocardiografia Ambulatorial/métodos , Feminino , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade
9.
Circ Arrhythm Electrophysiol ; 12(10): e005557, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31594392

RESUMO

BACKGROUND: Ranolazine inhibits Na+ current (INa), but whether it can convert atrial fibrillation (AF) to sinus rhythm remains unclear. We investigated antiarrhythmic mechanisms of ranolazine in sheep models of paroxysmal (PxAF) and persistent AF (PsAF). METHODS: PxAF was maintained during acute stretch (N=8), and PsAF was induced by long-term atrial tachypacing (N=9). Isolated, Langendorff-perfused sheep hearts were optically mapped. RESULTS: In PxAF ranolazine (10 µmol/L) reduced dominant frequency from 8.3±0.4 to 6.2±0.5 Hz (P<0.01) before converting to sinus rhythm, decreased singularity point density from 0.070±0.007 to 0.039±0.005 cm-2 s-1 (P<0.001) in left atrial epicardium (LAepi), and prolonged AF cycle length (AFCL); rotor duration, tip trajectory, and variance of AFCL were unaltered. In PsAF, ranolazine reduced dominant frequency (8.3±0.5 to 6.5±0.4 Hz; P<0.01), prolonged AFCL, increased the variance of AFCL, had no effect on singularity point density (0.048±0.011 to 0.042±0.016 cm-2 s-1; P=ns) and failed to convert AF to sinus rhythm. Doubling the ranolazine concentration (20 µmol/L) or supplementing with dofetilide (1 µmol/L) failed to convert PsAF to sinus rhythm. In computer simulations of rotors, reducing INa decreased dominant frequency, increased tip meandering and produced vortex shedding on wave interaction with unexcitable regions. CONCLUSIONS: PxAF and PsAF respond differently to ranolazine. Cardioversion in the former can be attributed partly to decreased dominant frequency and singularity point density, and prolongation of AFCL. In the latter, increased dispersion of AFCL and likely vortex shedding contributes to rotor formation, compensating for any rotor loss, and may underlie the inefficacy of ranolazine to terminate PsAF.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Ranolazina/uso terapêutico , Animais , Fibrilação Atrial/fisiopatologia , Mapeamento Potencial de Superfície Corporal , Modelos Animais de Doenças , Sistema de Condução Cardíaco/efeitos dos fármacos , Masculino , Ovinos , Bloqueadores dos Canais de Sódio/uso terapêutico
10.
Int J Nanomedicine ; 14: 5595-5609, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413565

RESUMO

Background: Platinum nanoparticles (PtNPs) have been considered a nontoxic nanomaterial and been clinically used in cancer chemotherapy. PtNPs can also be vehicle exhausts and environmental pollutants. These situations increase the possibility of human exposure to PtNPs. However, the potential biotoxicities of PtNPs including that on cardiac electrophysiology have been poorly understood. Methods: Ion channel currents of cardiomyocytes were recorded by patch clamp. Heart rhythm was monitored by electrocardiogram recording. Morphology and characteristics of PtNPs were examined by transmission electron microscopy, dynamic light scattering and electrophoretic light scattering analyses. Results: In cultured neonatal mice ventricular cardiomyocytes, PtNPs with diameters 5 nm (PtNP-5) and 70 nm (PtNP-70) concentration-dependently (10-9 - 10-5 g/mL) depolarized the resting potentials, suppressed the depolarization of action potentials and delayed the repolarization of action potentials. At the ion channel level, PtNPs decreased the current densities of INa, IK1 and Ito channels, but did not affect the channel activity kinetics. In vivo, PtNP-5 and PtNP-70 dose-dependently (3-10 mg/kg, i.v.) decreased the heart rate and induced complete atrioventricular conduction block (AVB) at higher doses. Both PtNP-5 and PtNP-70 (10-9 - 10-5 g/mL) did not significantly increase the generation of ROS and leak of lactate dehydrogenase (LDH) from cardiomyocytes within 5 mins after exposure except that only very high PtNP-5 (10-5 g/mL) slightly increased LDH leak. The internalization of PtNP-5 and PtNP-70 did not occur within 5 mins but occurred 1 hr after exposure. Conclusion: PtNP-5 and PtNP-70 have similar acute toxic effects on cardiac electrophysiology and can induce threatening cardiac conduction block. These acute electrophysiological toxicities of PtNPs are most likely caused by a nanoscale interference of PtNPs on ion channels at the extracellular side, rather than by oxidative damage or other slower biological processes.


Assuntos
Frequência Cardíaca/efeitos dos fármacos , Canais Iônicos/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Miócitos Cardíacos/metabolismo , Platina/toxicidade , Testes de Toxicidade Aguda , Animais , Animais Recém-Nascidos , Células Cultivadas , Eletrocardiografia , Endocitose/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Ventrículos do Coração/citologia , Ativação do Canal Iônico/efeitos dos fármacos , Cinética , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Platina/administração & dosagem
11.
PLoS Negl Trop Dis ; 13(7): e0007602, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31365537

RESUMO

TGF-ß involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-ß signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TßR1/ALK5, on cardiac function in an experimental model of chronic Chagas' heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (102 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-ß signaling pathway reduced TGF-ß/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3+ cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-ß inhibitors.


Assuntos
Benzamidas/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Coração/efeitos dos fármacos , Pirazóis/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Tripanossomicidas/uso terapêutico , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença Crônica , Conexina 43/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Coração/parasitologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Carga Parasitária , Trypanosoma cruzi/efeitos dos fármacos
12.
Am Heart J ; 215: 52-61, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31279972

RESUMO

BACKGROUND: Although pulmonary vein isolation (PVI) is effective in the treatment of paroxysmal atrial fibrillation (AF), its success rates in persistent AF are suboptimal. Ablation strategies to improve outcomes including additional lesions beyond PVI have not consistently shown benefit. Recurrence as perimitral flutter (PMF) is a common form of ablation failure. The vein of Marshall (VOM) contains myocardial connections and abundant sympathetic and parasympathetic innervation implicated in the genesis and maintenance of AF, and is anatomically co-localized with the mitral isthmus, the ablation target of PMF. VOM ethanol infusion is effective in targeting these arrhythmia substrates. OBJECTIVE: To test the safety and efficacy of VOM ethanol infusion when added to PVI in patients undergoing either de novo ablation of persistent AF or after a previous ablation failure. STUDY DESIGN: VENUS-AF and MARS-AF are prospective, multicenter, randomized, controlled trials. VENUS-AF will enroll patients undergoing their first catheter ablation of persistent AF. MARS-AF will enroll patients undergoing ablation after previous ablation failure(s). Patients (n = 405) will be randomized to PVI alone or in combination with VOM ethanol infusion. The primary endpoints include procedural safety and freedom from AF or atrial tachycardia (AT) of more than 30 seconds on 30-day continuous event monitors at 6 and 12 months after randomization procedure (single-procedure success), off antiarrhythmic drugs. Key secondary endpoints include AF burden, freedom from AF/AT after repeat procedures and quality of life. CONCLUSIONS: The VENUS-AF and MARS-AF will determine the safety and potential rhythm control benefit of VOM ethanol infusion when added to PVI in patients with persistent AF undergoing de novo or repeat ablation, respectively.


Assuntos
Técnicas de Ablação/métodos , Fibrilação Atrial/terapia , Etanol/administração & dosagem , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Fibrilação Atrial/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Seguimentos , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Veias Pulmonares , Solventes/administração & dosagem , Resultado do Tratamento
13.
Circ Arrhythm Electrophysiol ; 12(7): e007294, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31248280

RESUMO

BACKGROUND: Phthalates are used as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients. METHODS: Optical mapping of transmembrane voltage and pacing studies were performed on isolated, Langendorff-perfused rat hearts to assess cardiac electrophysiology after MEHP exposure compared with controls. MEHP dose was chosen based on reported blood concentrations after an exchange transfusion procedure. RESULTS: Thirty-minute exposure to MEHP increased the atrioventricular node (147 versus 107 ms) and ventricular (117 versus 77.5 ms) effective refractory periods, compared with controls. Optical mapping revealed prolonged action potential duration at slower pacing cycle lengths, akin to reverse use dependence. The plateau phase of the action potential duration restitution curve steepened and became monophasic in MEHP-exposed hearts (0.18 versus 0.06 slope). Action potential duration lengthening occurred during late-phase repolarization resulting in triangulation (70.3 versus 56.6 ms). MEHP exposure also slowed epicardial conduction velocity (35 versus 60 cm/s), which may be partly explained by inhibition of Nav1.5 (874 and 231 µmol/L half-maximal inhibitory concentration, fast and late sodium current). CONCLUSIONS: This study highlights the impact of acute MEHP exposure, using a clinically relevant dose, on cardiac electrophysiology in the intact heart. Heightened clinical exposure to plasticized medical products may have cardiac safety implications-given that action potential triangulation and electrical restitution modifications are a risk factor for early after depolarizations and cardiac arrhythmias.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Arritmias Cardíacas/induzido quimicamente , Dietilexilftalato/análogos & derivados , Equipamentos e Provisões/efeitos adversos , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Plastificantes/toxicidade , Animais , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Simulação por Computador , Dietilexilftalato/toxicidade , Desenho de Equipamento , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Preparação de Coração Isolado , Masculino , Modelos Cardiovasculares , Ratos Sprague-Dawley , Período Refratário Eletrofisiológico/efeitos dos fármacos , Medição de Risco , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismo , Fatores de Tempo , Imagens com Corantes Sensíveis à Voltagem
14.
Anesth Analg ; 129(1): 63-72, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210652

RESUMO

BACKGROUND: Bupivacaine cardiotoxicity mainly manifests as inhibition of the cardiac sodium channel, which slows conduction, particularly at the ventricular level. Experimental studies have demonstrated that intravenous lipid emulsions (ILEs) can reduce the cardiotoxic effects of bupivacaine, but the extent of these effects is controversial. Sodium bicarbonate (B) represents the standard treatment of toxicity related to sodium channel-blocking drugs. The aim of this study was to compare the effects of ILEs and B on the speed of recovery from bupivacaine-induced effects on the electrocardiographic parameters. METHODS: Bupivacaine 4 mg/kg was administered to 24 anesthetized pigs. Three minutes after delivering the bupivacaine bolus, the animals were given the following: ILE 1.5 mL/kg followed by 0.25 mL/kg/min (ILE group) and B 2 mEq/kg followed by 1 mEq/kg/h (B group). Controls (C group) were given saline solution, 50 mL followed by 1 mL/kg/h. Electrophysiological parameters were evaluated in sinus rhythm and during right ventricular pacing at several time intervals up to 30 minutes. Data were analyzed as the area under the curve (AUC) for the first 10 minutes (AUC10) or 30 minutes (AUC30). RESULTS: Bupivacaine increased the sinus cycle length, PR interval, and QRS duration. AUC30 of the sinus rhythm QRS duration after antidote administration was significantly different among the 3 groups (P = .003). B group experienced faster recovery from intoxication than the C group (AUC10, P = .003; AUC30, P = .003) or the ILE group (AUC10, P = .018). During the first minute, 50% of the B group (versus 0% of the ILE and C groups) had recovered >30% of QRS duration (P = .011). The trend toward faster recovery in the ILE group than in the C group did not reach significance (AUC10, P = .23; AUC30, P = .06). Effects on the paced QRS duration at a rate of 150 bpm were more intense but with similar results (B versus C group: AUC10, P = .009; AUC30, P = .009; B versus ILE: AUC10, P = .015; AUC30, P = .024). The recovery process of the paced QRS tended to be slower for all antidotes. CONCLUSIONS: In a closed-chest swine model, B was an effective treatment for electrophysiological alterations caused by established bupivacaine toxicity. At clinical doses, B ameliorated bupivacaine electrocardiographic toxicity faster than ILE. Use-dependent effects of bupivacaine are prominent and delay the effects of both antidotes, but B produces faster recovery than ILE.


Assuntos
Anestésicos Locais , Antídotos/administração & dosagem , Arritmias Cardíacas/tratamento farmacológico , Bupivacaína , Emulsões Gordurosas Intravenosas/administração & dosagem , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Bicarbonato de Sódio/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Cardiotoxicidade , Modelos Animais de Doenças , Sistema de Condução Cardíaco/fisiopatologia , Recuperação de Função Fisiológica , Sus scrofa , Fatores de Tempo
16.
Neuropeptides ; 75: 65-74, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31047706

RESUMO

The heart receives sympathetic and parasympathetic innervation through the intrinsic cardiac nervous system. Although bradykinin (BK) has negative inotropic and chronotropic properties of cardiac contraction, the direct effect of BK on the intrinsic neural network of the heart is still unclear. In the present study, the effect of BK on the intracardiac ganglion neurons isolated from rats was investigated using the perforated patch-clamp technique. Under current-clamp conditions, application of 0.1 µM BK depolarized the membrane, accompanied by repetitive firing of action potentials. When BK was applied repeatedly, the second responses were considerably less intense than the first application. The BK action was fully inhibited by the B2 receptor antagonist Hoe-140, but not by the B1 receptor antagonist des-Arg9-[Leu8]-BK. The BK response was mimicked by the B2 agonist [Hyp3]-BK. The BK-induced depolarization was inhibited by the phospholipase C inhibitor U-73122. BK evoked inward currents under voltage-clamp conditions at a holding potential of -60 mV. Removal of extracellular Ca2+ markedly increased the BK-induced currents, suggesting an involvement of Ca2+-permeable non-selective cation channels. The muscarinic agonist oxotremorine-M (OxoM) also elicited the extracellular Ca2+-sensitive cationic currents. The OxoM response did not exhibit rundown with repeated agonist application. The amplitude of current evoked by 1 µM OxoM was comparable to that induced by 0.1 µM BK. Co-application of 0.1 µM BK and 1 µM OxoM elicited the current whose peak amplitude was almost the same as that elicited by OxoM alone, suggesting that BK and OxoM activate same cation channels. BK also reduced the amplitude of M-current, while the M-current inhibitor XE-991 affected neither resting membrane potential nor the BK-induced depolarization. From these results, we suggest that BK regulates excitability of intrinsic cardiac neurons by both an activation of non-selective cation channels and an inhibition of M-type K+ channels through B2 receptors.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Bradicinina/farmacologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Coração/inervação , Neurônios/efeitos dos fármacos , Animais , Técnicas de Patch-Clamp , Ratos , Ratos Wistar
17.
Anesth Analg ; 129(4): 1100-1108, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30985379

RESUMO

BACKGROUND: Dexmedetomidine is a highly selective α2-adrenergic agonist, which is increasingly used in pediatric anesthesia and intensive care. Potential adverse effects that have not been rigorously evaluated in children include its effects on myocardial repolarization, which is important given that the drug is listed as a possible risk factor for torsades de pointes. We investigated the effect of 3 different doses of dexmedetomidine on myocardial repolarization and transmural dispersion in children undergoing elective surgery with total IV anesthesia. METHODS: Sixty-four American Society of Anesthesiologists I-II children 3-10 years of age were randomized to receive dexmedetomidine 0.25 µg/kg, 0.5 µg/kg, 0.75 µg/kg, or 0 µg/kg (control), as a bolus administered over 60 seconds, after induction of anesthesia. Pre- and postintervention 12-lead electrocardiograms were recorded. The interval between the peak and the end of the electrocardiogram T wave (Tp-e; transmural dispersion) and heart rate-corrected QT intervals (myocardial repolarization) were measured by a pediatric electrophysiologist blinded to group allocation. Data were analyzed using an analysis of covariance regression model. The study was powered to detect a 25-millisecond difference in Tp-e. RESULTS: Forty-eight children completed the study, with data analyzed from 12 participants per group. There were no instances of dysrhythmias. Tp-e values were unaffected by dexmedetomidine administration at any of the studied doses (F = 0.09; P = .96). Mean (99% CI) within-group differences were all <2 milliseconds (-5 to 8). Postintervention, corrected QT interval increased in the control group, but decreased in some dexmedetomidine groups (F = 7.23; P < .001), specifically the dexmedetomidine 0.5 and 0.75 µg/kg doses. Within groups, the mean (99% CI) differences between pre- and postintervention corrected QT interval were 12.4 milliseconds (-5.8 to 30.6) in the control group, -9.0 milliseconds (-24.9 to 6.9) for dexmedetomidine 0.25 µg/kg, -18.6 milliseconds (-33.7 to -3.5) for dexmedetomidine 0.5 µg/kg, and -14.1 milliseconds (-27.4 to -0.8) for dexmedetomidine 0.75 µg/kg. CONCLUSIONS: Of the bolus doses of dexmedetomidine studied, none had an effect on Tp-e and the dexmedetomidine 0.5 and 0.75 µg/kg doses shortened corrected QT intervals when measured at 1 minute after dexmedetomidine bolus injection during total IV anesthesia. There is no evidence for an increased risk of torsades de pointes in this context.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Anestesia Geral , Dexmedetomidina/administração & dosagem , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Fatores Etários , Colúmbia Britânica , Criança , Pré-Escolar , Dexmedetomidina/efeitos adversos , Eletrocardiografia , Feminino , Humanos , Infusões Intravenosas , Masculino , Período Perioperatório , Medição de Risco , Fatores de Risco , Método Simples-Cego , Fatores de Tempo
18.
Cardiovasc Toxicol ; 19(5): 432-440, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30945064

RESUMO

Unintentional administration of bupivacaine may be associated with electrocardiogram changes that promote the development cardiac arrhythmias. Ventricular repolarization markers (corrected QT, QT dispersion, Tpeak-Tend and Tpeak-Tend dispersion) are useful to predict cardiac arrhythmias. We aim to investigate the effects of bupivacaine on the transmural dispersion of repolarization and their reversion following intravenous lipid emulsion (ILE) administration. Fourteen pigs were anaesthetized with thiopental and sevoflurane and underwent tracheal intubation. After instrumentation, a 4 mg kg-bolus of bupivacaine was administrated followed by an infusion of 100 µg kg-1 min-1. QT interval, QTc:QT corrected by heart rate, Tpeak-to-Tend interval and QT and Tpeak-to-Tend dispersion were determined in a sequential fashion: after bupivacaine (at 1 min, 5 min and 10 min) and after ILE (1.5 mL kg-1 over 1 min followed by an infusion of 0.25 mL kg-1 min-1). Three additional animals received only ILE (control group). Bupivacaine significantly prolonged QT interval (∆:36%), QT dispersion (∆:68%), Tpeak-to-Tend (∆:163%) and Tpeak-to-Tend dispersion (∆:98%), from baseline to 10 min. Dispersion of repolarization was related to lethal arrhythmias [three events, including asystole, sustained ventricular tachycardia (VT)] and repeated non-sustained VT (4/14, 28%). A Brugada-like-ECG pattern was visualized at V1-4 leads in 5/14 pigs (35%). ILE significantly decreased the alterations induced by bupivacaine, with the termination of VT within 10 min. No ECG changes were observed in control group. Bupivacaine toxicity is associated with an increase of transmural dispersion of repolarization, the occurrence of a Brugada-like pattern and malignant VA. ILE reverses the changes in dispersion of repolarization, favouring the disappearance of the Brugada-like pattern and VT.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Anestésicos Locais/toxicidade , Antídotos/administração & dosagem , Síndrome de Brugada/tratamento farmacológico , Bupivacaína/toxicidade , Emulsões Gordurosas Intravenosas/administração & dosagem , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Taquicardia Ventricular/tratamento farmacológico , Animais , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Sus scrofa , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo
19.
Clin Pharmacol Ther ; 106(3): 642-651, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30947366

RESUMO

Short QT syndrome (SQTS) predisposes afflicted patients to sudden cardiac death. Until now, only one drug-quinidine-has been shown to be effective in patients with SQTS type 1(SQTS1). The objective of this study was to use human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1 to search for potentially effective drugs for the treatment of SQTS1 patients. Patch clamp and single-cell contraction measurements were employed to assess drug effects. Ivabradine, mexiletine, and ajmaline but not flecainide, ranolazine, or amiodarone prolonged the action potential duration (APD) in hiPSC-CMs from an SQTS1 patient. Ivabradine, ajmaline, and mexiletine inhibited KCNH2 channel currents significantly, which may underlie their APD-prolonging effects. Under proarrhythmic epinephrine stimulation in spontaneously beating SQTS1 hiPSC-CMs, ivabradine, mexiletine, and ajmaline but not flecainide reduced the epinephrine-induced arrhythmic events. The results demonstrate that ivabradine, ajmaline, and mexiletine may be candidate drugs for preventing tachyarrhythmias in SQTS1 patients.


Assuntos
Fármacos Cardiovasculares/farmacologia , Canal de Potássio ERG1/metabolismo , Sistema de Condução Cardíaco/anormalidades , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Arritmias Cardíacas , Relação Dose-Resposta a Droga , Epinefrina/farmacologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Cardiopatias Congênitas , Humanos
20.
Cardiovasc Toxicol ; 19(3): 191-197, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31030341

RESUMO

Synthetic cannabinoids (SCBs) are widely used recreational substances especially among adults. Although they have been considered as safe during the marketing process, our knowledge about their adverse effects has evolved since years. SCBs are associated with various cardiac events including acute myocardial infarction and sudden cardiac death. There is also growing evidence that SCBs are associated with cardiac arrhythmia development both in acute and chronic exposure. SCBs have been shown to be associated with both supraventricular and ventricular arrhythmias. However, the exact mechanism of the SCB related arrhythmia remains unknown. Understanding the exact association and possible mechanisms may help us to identify high risk patients at an early stage and to develop treatment modalities to prevent or reverse the arrhythmic effects of SCBs.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Canabinoides/efeitos adversos , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/fisiopatologia , Canabinoides/síntese química , Cardiotoxicidade , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Medição de Risco
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