RESUMEN
S-Limonene (s-Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s-Lim exerts its antiarrhythmic effect, focusing on the blockade of ß-adrenoceptor (ß-AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the ß-adrenergic pathway, sarcomeric shortening and L-type calcium current (ICa,L). In isolated hearts, 10 µM of s-Lim did not alter the ECG profile or LVPD. s-Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 µM and reduced heart rate at the concentrations of 30 (12.4%) and 50 µM (16.6%). s-Lim (10 µM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 µM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s-Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker ß1-AR). In vivo, s-Lim antagonized the effect of ISO (agonists ß1-AR), presenting a similar effect to propranolol (a non-selective blocker ß-AR). In ventricular cardiomyocyte, s-Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s-Lim did not affect changes in the ECG effect mediated by 5 µM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO-induced arrhythmia model, s-Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s-Lim is related to blockade of ß-AR in the heart.
Asunto(s)
Antiarrítmicos , Limoneno , Ratas Wistar , Receptores Adrenérgicos beta , Transducción de Señal , Animales , Ratas , Antiarrítmicos/farmacología , Masculino , Receptores Adrenérgicos beta/metabolismo , Limoneno/farmacología , Transducción de Señal/efectos de los fármacos , Terpenos/farmacología , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ciclohexenos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/fisiopatología , Isoproterenol/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismoRESUMEN
The chemical structure of piperidine has a unique ability to combine with other molecular fragments. This fact makes it possible to actively use it as an effective basis for the creation of new drug-like substances. Thus, the aim of the current investigation was to study the acute toxicity, local anesthetic potency, and antiarrhythmic activity of the two new synthesized piperidine derivatives under laboratory codes LAS-286 and LAS-294 (local anesthetic substances). The Bulbring & Wajda animal model and method of determining the nociception threshold during electrical stimulation was used to investigate the action of the substance during infiltration anesthesia. An antiarrhythmic activity was observed by the aconitine-induced rat arrhythmia model. Additionally, these compounds were studied in relation to molecular docking to delineate the structure-activity relationships. The tested piperidine derivatives had a low toxicity in the subcutaneous and intravenous administration routes. The experimental results showed a higher prolonged and pronounced local anesthetic activity for LAS-286 at a 0.5% concentration, compared to the reference preparations. The low dosage of 0.1 mg/kg of LAS-294 demonstrated a pronounced preventive antiarrhythmic effect in 90% of cases on the development of mixed arrhythmia, caused by aconitine. The results of molecular docking confirmed a higher binding affinity of the tested piperidines with the Nav1.4 and Nav1.5 macromolecules. The results of the present study are very promising, because these piperidines have shown a high biological activity, which can suggest a potential therapeutic application in the future.
Asunto(s)
Anestésicos Locales , Antiarrítmicos , Simulación del Acoplamiento Molecular , Piperidinas , Animales , Antiarrítmicos/farmacología , Anestésicos Locales/farmacología , Piperidinas/farmacología , Piperidinas/química , Ratas , Masculino , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/tratamiento farmacológico , Relación Estructura-Actividad , Ratas Wistar , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Amiodarone (AMIO) is an antiarrhythmic drug with the pKa in the physiological range. Here, we explored how mild extracellular pH (pHe) changes shape the interaction of AMIO with atrial tissue and impact its pharmacological properties in the classical model of sea anemone sodium channel neurotoxin type 2 (ATX) induced late sodium current (INa-Late) and arrhythmias. METHOD: Isolated atrial cardiomyocytes from male Wistar rats and human embryonic kidney cells expressing SCN5A Na+ channels were used for patch-clamp experiments. Isolated right atria (RA) and left atria (LA) tissue were used for bath organ experiments. RESULTS: A more acidophilic pHe caused negative inotropic effects on isolated RA and LA atrial tissue, without modification of the pharmacological properties of AMIO. A pHe of 7.0 changed the sodium current (INa) related components of the action potential (AP), which was enhanced in the presence of AMIO. ATXinduced arrhythmias in isolated RA and LA. Also, ATX prolonged the AP duration and enhanced repolarization dispersion in isolated cardiomyocytes in both pHe 7.4 and pHe 7.0. Pre-incubation of the isolated RA and LA and isolated atrial cardiomyocytes with AMIO prevented arrhythmias induced by ATX only at a pHe of 7.0. Moreover, AMIO was able to block INa-Late induced by ATX only at a pHe of 7.0. CONCLUSION: The pharmacological properties of AMIO concerning healthy rat atrial tissue are not dependent on pHe. However, the prevention of arrhythmias induced by INa-Late is pHe-dependent. The development of drugs analogous to AMIO with charge stabilization may help to create more effective drugs to treat arrhythmias related to the INa-Late.
Asunto(s)
Potenciales de Acción , Amiodarona , Antiarrítmicos , Arritmias Cardíacas , Atrios Cardíacos , Miocitos Cardíacos , Ratas Wistar , Animales , Amiodarona/farmacología , Antiarrítmicos/farmacología , Masculino , Humanos , Ratas , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Potenciales de Acción/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Concentración de Iones de Hidrógeno , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/inducido químicamente , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Células HEK293 , Sodio/metabolismo , Técnicas de Placa-Clamp , Venenos de Cnidarios/farmacologíaRESUMEN
Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a vehicle (control) revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.
Asunto(s)
Arritmias Cardíacas , Dobutamina , Triazoles , Humanos , Ratas , Animales , Masculino , Especies Reactivas de Oxígeno , Ratas Wistar , Arritmias Cardíacas/inducido químicamente , Acetilcisteína , Miocitos CardíacosRESUMEN
BACKGROUND: The high incidence of atrial arrhythmias in pulmonary hypertension (PH) might be associated with poor prognosis, and the left atrium (LA) may play a role in this. An important finding in PH studies is that LA remodeling is underestimated. OBJECTIVE: This study investigated LA morphology and mechanical function, as well as the susceptibility to develop arrhythmias in a monocrotaline-induced PH (MCT-PH) model. METHODS: Wistar rats aged 4 weeks received 50 mg/kg of MCT. Electrocardiography and histology analysis were performed to evaluate the establishment of the MCT-PH model. The tissue was mounted in an isolated organ bath to characterize the LA mechanical function. RESULTS: Compared with the control group (CTRL), the MCT-PH model presented LA hypertrophy and changes in cardiac electrical activity, as evidenced by increased P wave duration, PR and QT interval in MCT-PH rats. In LA isolated from MCT-PH rats, no alteration in inotropism was observed; however, the time to peak contraction was delayed in the experimental MCT-PH group. Finally, there was no difference in arrhythmia susceptibility of LA from MCT-PH animals after the burst pacing protocol. CONCLUSION: The morphofunctional remodeling of the LA did not lead to increased susceptibility to ex vivo arrhythmia after application of the burst pacing protocol.
FUNDAMENTO: A alta incidência de arritmias atriais na hipertensão pulmonar (HP) pode estar associada a um prognóstico ruim, e o átrio esquerdo (AE) pode desempenhar um papel neste quadro. Um achado importante nos estudos de HP é que a remodelação do AE é subestimada. OBJETIVO: Este estudo investigou a morfologia e a função mecânica do AE, bem como a suscetibilidade ao desenvolvimento de arritmias em um modelo de HP induzida por monocrotalina (HP-MCT). MÉTODOS: Ratos Wistar com 4 semanas de idade receberam 50 mg/kg de MCT. Foram realizadas análises eletrocardiográficas e histológicas para avaliar o estabelecimento do modelo de HP-MCT. O tecido foi montado em banho de órgão isolado para caracterizar a função mecânica do AE. RESULTADOS: Em comparação com o grupo controle, o modelo de HP-MCT apresentou hipertrofia do AE e alterações da atividade elétrica cardíaca, conforme evidenciadas pelo aumento da duração da onda P, PR e intervalo QT. Não foi observada alteração no inotropismo do AE isolado de ratos com HP-MCT; no entanto, o tempo para atingir a contração máxima foi atrasado. Finalmente, não observamos diferença na suscetibilidade à arritmia no AE dos ratos com HP-MCT após o protocolo de estimulação intermitente. CONCLUSÃO: A remodelação morfofuncional do AE não levou ao aumento da suscetibilidade à arritmia ex vivo após a aplicação do protocolo de estimulação intermitente.
Asunto(s)
Hipertensión Pulmonar , Ratas , Animales , Hipertensión Pulmonar/inducido químicamente , Ratas Sprague-Dawley , Ratas Wistar , Atrios Cardíacos , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/complicaciones , Monocrotalina/efectos adversos , Arteria PulmonarRESUMEN
BACKGROUND: Arrhythmias are one manifestation of the cardiotoxicity that results from doxorubicin (Doxo) administration. Although cardiotoxicity is an anticipated outcome in anticancer therapies, there is still a lack of treatment options available for its effective management. This study sought to evaluate the possible cardioprotective effect of complex d-limonene (DL) plus hydroxypropyl-ß-cyclodextrin (HßDL) during treatment with Doxo, focusing on the arrhythmic feature. METHODS: Cardiotoxicity was induced in Swiss mice with Doxo 20 mg/kg, with 10 mg/kg of HßDL being administered 30 min before the Doxo. Plasma CK-MB and LDH levels were analyzed. Cellular excitability and susceptibility to cardiac and cardiomyocyte arrhythmias were evaluated using in vivo (pharmacological cardiac stress) and in vitro (burst pacing) ECG protocols. Ca2+ dynamics were also investigated. The expression of CaMKII and its activation by phosphorylation and oxidation were evaluated by western blot, and molecular docking was used to analyze the possible interaction between DL and CaMKII. RESULTS: Electrocardiograms showed that administration of 10 mg/kg of HßDL prevented Doxo-induced widening of the QRS complex and QT interval. HßDL also prevented cardiomyocyte electrophysiological changes that trigger cellular arrhythmias, such as increases in action potential duration and variability; decreased the occurrence of delayed afterdepolarizations (DADs) and triggered activities (TAs), and reduced the incidence of arrhythmia in vivo. Ca2+ waves and CaMKII overactivation caused by phosphorylation and oxidation were also decreased. In the in silico study, DL showed potential inhibitory interaction with CaMKII. CONCLUSION: Our results show that 10 mg/kg of ßDL protects the heart against Doxo-induced cardiotoxicity arrhythmias, and that this is probably due to its inhibitory effect on CaMKII hyperactivation.
Asunto(s)
Calcio , Ciclodextrinas , Ratones , Animales , Limoneno/efectos adversos , Limoneno/metabolismo , Calcio/metabolismo , Cardiotoxicidad/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Simulación del Acoplamiento Molecular , Doxorrubicina/efectos adversos , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/prevención & control , Arritmias Cardíacas/metabolismo , Miocitos CardíacosRESUMEN
Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is widely used in agriculture and its use has experienced a tremendous increase in the last decade. The long-term exposure of humans to this pesticide is a real threat because it is stable in water and soil. The association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity is evident, however, acute toxicological studies to reveal the toxicity of TEB are limited. This research paper addressed the acute exposure of TEB in murine hearts, cardiomyocytes, and human cardiomyocytes derived from an induced pluripotent stem cell (hiPSC-CMs), spelling out TEB's impact on electromechanical properties of the cardiac tissue. In ex vivo experiments, TEB dose dependently, caused significant electrocardiogram (ECG) remodeling with prolonged PR and QTc interval duration. The TEB was also able to change the action potential waveform in murine cardiomyocytes and hiPSC-CMs. These effects were associated with the ability of the compound to block the L-type calcium current (IC50 = 33.2 ± 7.4 µmol.l-1) and total outward potassium current (IC50 = 5.7 ± 1.5 µmol.l-1). TEB also increased the sodium/calcium exchanger current in its forward and reverse modes. Additionally, sarcomere shortening and calcium transient in isolated cardiomyocytes were enhanced when cells were exposed to TEB at 30 µmol.l-1. Combined, our results demonstrated that acute TEB exposure affects the cardiomyocyte's electro-contractile properties and triggers the appearance of ECG abnormalities.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Arritmias Cardíacas/inducido químicamente , Cardiotoxicidad/etiología , Fungicidas Industriales/toxicidad , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Triazoles/toxicidad , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
In the present study, we investigated the cardiotoxic potential of Micrurus frontalis venom. Twelve guinea pigs (Cavia porcellus) were distributed in two groups (n = 6), named control and envenomed. Control groups received 0.2 ml of PBS/BSA, while envenomed group received 0.2 ml of the same solution containing 450 µg/kg of M. frontalis venom. Both were intramuscular injections. Electrocardiography, echocardiogram, blood count, and serum biochemistry were performed before and 2 h after inoculation. Necropsy was performed, and histological and ultrastructural analysis of the heart were conducted. First clinical signs were presented as early as 18 min after venom inoculation. All poisoned animals presented flaccid paralysis of both hind and forelimbs, followed by fasciculations and respiratory arrythmia. However, the animals did not die in the first 2 h of poisoning. ECG of the poisoned animals revealed severe ventricular arrythmias, corroborated by reduction of both ejection and shortening fractions, increase in CK, CK-MB, troponin, cardiomyocyte degeneration, fragmentation and mitochondrial damage. M. frontalis venom causes severe heart damage, eliciting both morphological and arrhythmogenic effects after only 2 h of envenomation.
Asunto(s)
Arritmias Cardíacas/inducido químicamente , Cardiomiopatías/inducido químicamente , Venenos Elapídicos/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Miocardio/patología , Disfunción Ventricular Izquierda/inducido químicamente , Función Ventricular Izquierda/efectos de los fármacos , Animales , Arritmias Cardíacas/sangre , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Biomarcadores/sangre , Cardiomiopatías/sangre , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Cardiotoxicidad , Serpientes de Coral , Cobayas , Masculino , Miocardio/metabolismo , Necrosis , Factores de Tiempo , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/patologíaRESUMEN
Air pollution exposure is a risk factor for arrhythmia. The atrioventricular (AV) conduction axis is key for the passage of electrical signals to ventricles. We investigated whether environmental nanoparticles (NPs) reach the AV axis and whether they are associated with ultrastructural cell damage. Here, we demonstrate the detection of the shape, size, and composition of NPs by transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometry (EDX) in 10 subjects from Metropolitan Mexico City (MMC) with a mean age of 25.3 ± 5.9 and a 71-year-old subject without cardiac pathology. We found that in every case, Fe, Ti, Al, Hg, Cu, Bi, and/or Si spherical or acicular NPs with a mean size of 36 ± 17 nm were present in the AV axis in situ, freely and as conglomerates, within the mitochondria, sarcomeres, lysosomes, lipofuscin, and/or intercalated disks and gap junctions of Purkinje and transitional cells, telocytes, macrophages, endothelium, and adjacent atrial and ventricular fibers. Erythrocytes were found to transfer NPs to the endothelium. Purkinje fibers with increased lysosomal activity and totally disordered myofilaments and fragmented Z-disks exhibited NP conglomerates in association with gap junctions and intercalated disks. AV conduction axis pathology caused by environmental NPs is a plausible and modifiable risk factor for understanding common arrhythmias and reentrant tachycardia. Anthropogenic, industrial, e-waste, and indoor NPs reach pacemaker regions, thereby increasing potential mechanisms that disrupt the electrical impulse pathways of the heart. The cardiotoxic, oxidative, and abnormal electric performance effects of NPs in pacemaker locations warrant extensive research. Cardiac arrhythmias associated with nanoparticle effects could be preventable.
Asunto(s)
Residuos Electrónicos , Mercurio , Nanopartículas , Taquicardia por Reentrada en el Nodo Atrioventricular , Anciano , Arritmias Cardíacas/inducido químicamente , Nodo Atrioventricular , Humanos , Residuos Industriales , México , TitanioRESUMEN
Micrurus surinamensis is a coral snake from the Elapidae family of wide distribution in Amazonia Forest. Its venom contains neurotoxins that induce muscular and respiratory paralysis; however, its cardiovascular action is not yet characterized. The aim of this study was to investigate the cardiotoxic effects caused by M. surinamensis poisoning in rodents. Twelve guinea pigs (Cavia porcellus) were distributed in two groups (n = 6) named as control and envenomed. The control group received 0.2 ml of PBS/BSA via intramuscular injection (IM), while envenomed animals received 0.75 µg of venom per g of body weight, also via IM. Electrocardiographic examination (ECG) and biochemical serum tests were conducted before and 2 h after inoculation. ECG of the envenomed animals revealed severe progressive arrhythmias including atrioventricular block, supraventricular, and ventricular extrasystoles. Serum biochemistry showed significant increase in CK, CK-MB, and LDH enzymes corroborating the skeletal and cardiac muscle damage. Myonecrosis and degeneration were observed in both skeletal and heart muscle; nevertheless, transmission electron microscopy revealed cardiac muscle fibers fragmentation. In conclusion, M. surinamensis venom has a potent cardiotoxic activity eliciting arrhythmogenic effects and heart damage after only 2 h of envenomation.
Asunto(s)
Arritmias Cardíacas/inducido químicamente , Serpientes de Coral , Venenos Elapídicos/toxicidad , Animales , Arritmias Cardíacas/fisiopatología , Complejos Atriales Prematuros/inducido químicamente , Complejos Atriales Prematuros/fisiopatología , Bloqueo Atrioventricular/inducido químicamente , Bloqueo Atrioventricular/fisiopatología , Cardiotoxicidad , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Necrosis , Factores de Tiempo , Complejos Prematuros Ventriculares/inducido químicamente , Complejos Prematuros Ventriculares/fisiopatologíaRESUMEN
Paraquat (PQT) herbicide is widely used in agricultural practices despite being highly toxic to humans. It has been proposed that PQT exposure may promote cardiorespiratory impairment. However, the physiological mechanisms involved in cardiorespiratory dysfunction following PQT exposure are poorly known. We aimed to determine the effects of PQT on ventilatory chemoreflex control, cardiac autonomic control, and cardiac function in rats. Male Sprague-Dawley rats received two injections/week of PQT (5 mg·kg-1 ip) for 4 wk. Cardiac function was assessed through echocardiography and pressure-volume loops. Ventilatory function was evaluated using whole body plethysmography. Autonomic control was indirectly evaluated by heart rate variability (HRV). Cardiac electrophysiology (EKG) and exercise capacity were also measured. Four weeks of PQT administration markedly enlarged the heart as evidenced by increases in ventricular volumes and induced cardiac diastolic dysfunction. Indeed, end-diastolic pressure was significantly higher in PQT rats compared with control (2.42 ± 0.90 vs. 4.01 ± 0.92 mmHg, PQT vs. control, P < 0.05). In addition, PQT significantly reduced both the hypercapnic and hypoxic ventilatory chemoreflex response and induced irregular breathing. Also, PQT induced autonomic imbalance and reductions in the amplitude of EKG waves. Finally, PQT administration impaired exercise capacity in rats as evidenced by a â¼2-fold decrease in times-to-fatigue compared with control rats. Our results showed that 4 wk of PQT treatment induces cardiorespiratory dysfunction in rats and suggests that repetitive exposure to PQT may induce harmful mid/long-term cardiovascular, respiratory, and cardiac consequences.NEW & NOREWORTHY Paraquat herbicide is still employed in agricultural practices in several countries. Here, we showed for the first time that 1 mo paraquat administration results in cardiac adverse remodeling, blunts ventilatory chemoreflex drive, and promotes irregular breathing at rest in previously healthy rats. In addition, paraquat exposure induced cardiac autonomic imbalance and cardiac electrophysiology alterations. Lastly, cardiac diastolic dysfunction was overt in rats following 1 mo of paraquat treatment.
Asunto(s)
Arritmias Cardíacas/inducido químicamente , Sistema Nervioso Autónomo/efectos de los fármacos , Células Quimiorreceptoras/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Corazón/inervación , Herbicidas/toxicidad , Hipertrofia Ventricular Izquierda/inducido químicamente , Pulmón/inervación , Paraquat/toxicidad , Ventilación Pulmonar/efectos de los fármacos , Reflejo/efectos de los fármacos , Animales , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Células Quimiorreceptoras/metabolismo , Tolerancia al Ejercicio/efectos de los fármacos , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratas Sprague-Dawley , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosAsunto(s)
Arritmias Cardíacas/inducido químicamente , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Arritmias Cardíacas/prevención & control , COVID-19 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Ventrículos Cardíacos/fisiopatología , Humanos , Pandemias , Tratamiento Farmacológico de COVID-19RESUMEN
The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness. The use of chloroquine/hydroxychloroquine, azithromycin and antiviral treatment and has been proposed by various groups, supported by in-vitro studies and limited patient series, without the adequate scientific rigor that precedes drug prescription. Although it may represent the only hope for many patients, it is important to know the main adverse effects associated with the use of these drugs and to better select patients who may benefit from them.
La pandemia por el virus SARS-COV-2 causante de la enfermedad COVID-19 representa un reto mundial dada su alta tasa de transmisión y ausencia de una terapia efectiva o vacuna. Este escenario ha propiciado el uso de diversos fármacos que in vitro han demostrado un potencial efecto contra el virus. Sin embargo, el tiempo no ha sido suficiente para evaluar su efectividad clínica con el adecuado rigor científico que precede a la prescripción de medicamentos. El uso de cloroquina/hidroxicloroquina, azitromicina y esquemas antivirales ha sido propuesto por diversos grupos, apoyado por series de pacientes limitada en número. Si bien puede representar la única esperanza para muchos enfermos, es importante conocer los principales efectos adversos asociados al uso de estas drogas y seleccionar mejor a los pacientes que puedan beneficiarse de ellas. El riesgo de arritmias ventriculares incrementa tanto por el uso de fármacos como por la gravedad de la propia enfermedad viral.
Asunto(s)
Arritmias Cardíacas/inducido químicamente , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Antivirales/efectos adversos , Antivirales/uso terapéutico , Azitromicina/efectos adversos , Azitromicina/uso terapéutico , COVID-19 , Cloroquina/efectos adversos , Cloroquina/uso terapéutico , Infecciones por Coronavirus/epidemiología , Humanos , Hidroxicloroquina/efectos adversos , Hidroxicloroquina/uso terapéutico , Pandemias , Neumonía Viral/epidemiología , Tratamiento Farmacológico de COVID-19RESUMEN
COVID-19 infection has shown rapid growth worldwide, and different therapies have been proposed for treatment, in particular, the combination of immune response modulating drugs such as chloroquine and hydroxychloroquine (antimalarials) alone or in combination with azithromycin. Although the clinical evidence supporting their use is scarce, the off label use of these drugs has spread very quickly in face of the progression of the epidemic and the high mortality rate in susceptible populations. However, these medications can pathologically prolong the QT interval and lead to malignant ventricular arrhythmias such that organized guidance on QT evaluation and management strategies are important to reduce morbidity associated with the potential large-scale use.
Asunto(s)
Antimaláricos/efectos adversos , Infecciones por Coronavirus/tratamiento farmacológico , Electrocardiografía , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/diagnóstico por imagen , Neumonía Viral/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Adulto , Anciano , Antimaláricos/administración & dosificación , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/epidemiología , Azitromicina/administración & dosificación , Azitromicina/efectos adversos , COVID-19 , Cloroquina/administración & dosificación , Cloroquina/efectos adversos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/efectos adversos , Incidencia , Masculino , Persona de Mediana Edad , Pandemias/prevención & control , Pandemias/estadística & datos numéricos , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Pronóstico , Medición de Riesgo , Tratamiento Farmacológico de COVID-19RESUMEN
Dexamethasone is the most clinically used glucocorticoid with an established role in the treatment of a wide spectrum of inflammatory-related diseases. While the therapeutic actions are well known, dexamethasone treatment causes a number of cardiovascular side effects, which are complex, frequent and, in some cases, clinically unnoticeable. Here, we investigated whether a therapeutic regimen of dexamethasone affects cardiac arrhythmogenesis, focusing on the contribution of Nox-derived reactive oxygen species (ROS). Male Wistar rats were treated with dexamethasone (2 mg/kg, i.p.) for 7 days. Afterward, hemodynamic measurements, autonomic modulation, left ventricular function, cardiac fibrosis, reactive oxygen species (ROS) generation, Nox protein expression, superoxide dismutase (SOD) and catalase activities, and arrhythmias incidence were evaluated. Here, we show that dexamethasone increases blood pressure, associated with enhanced cardiac and vascular sympathetic modulation. Moreover, a marked increase in the cardiac ROS generation was observed, whereas the enhanced SOD activity did not prevent the higher levels of lipid peroxidation in the dexamethasone group. On the other hand, increased cardiac Nox 4 expression and hydrogen peroxide decomposition rate was observed in dexamethasone-treated rats, while Nox 2 remained unchanged. Interestingly, although preserved ventricular contractility and ß-adrenergic responsiveness, we found that dexamethasone-treated rats displayed greater interstitial and perivascular fibrosis than control. Surprisingly, despite the absence of arrhythmias at basal condition, we demonstrated, by in vivo and ex vivo approaches, that dexamethasone-treated rats are more susceptible to develop harmful forms of ventricular arrhythmias when challenged with pharmacological drugs or burst pacing-induced arrhythmias. Notably, concomitant treatment with apocynin, an inhibitor of NADPH oxidase, prevented these ectopic ventricular events. Together, our results reveal that hearts become arrhythmogenic during dexamethasone treatment, uncovering the pivotal role of ROS-generating NADPH oxidases for arrhythmias vulnerability.
Asunto(s)
Arritmias Cardíacas , NADPH Oxidasas , Animales , Arritmias Cardíacas/inducido químicamente , Dexametasona/toxicidad , Masculino , NADPH Oxidasas/genética , Ratas , Ratas Wistar , Especies Reactivas de OxígenoRESUMEN
INTRODUCTION: T-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. METHODS: We have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. RESULTS: Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%-4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77-5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29-5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation. CONCLUSION: The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment.
Asunto(s)
Ado-Trastuzumab Emtansina/efectos adversos , Arritmias Cardíacas/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Insuficiencia Cardíaca/diagnóstico , Isquemia Miocárdica/diagnóstico , Ado-Trastuzumab Emtansina/uso terapéutico , Anciano , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Arritmias Cardíacas/inducido químicamente , Neoplasias de la Mama/metabolismo , Cardiotoxicidad/diagnóstico , Cardiotoxicidad/etiología , Cardiotoxicidad/fisiopatología , Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase III como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Femenino , Insuficiencia Cardíaca/inducido químicamente , Humanos , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/métodos , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Isquemia Miocárdica/inducido químicamente , Receptor ErbB-2/metabolismoRESUMEN
Resumen La pandemia por el virus SARS-COV-2 causante de la enfermedad COVID-19 representa un reto mundial dada su alta tasa de transmisión y ausencia de una terapia efectiva o vacuna. Este escenario ha propiciado el uso de diversos fármacos que in vitro han demostrado un potencial efecto contra el virus. Sin embargo, el tiempo no ha sido suficiente para evaluar su efectividad clínica con el adecuado rigor científico que precede a la prescripción de medicamentos. El uso de cloroquina/hidroxicloroquina, azitromicina y esquemas antivirales ha sido propuesto por diversos grupos, apoyado por series de pacientes limitada en número. Si bien puede representar la única esperanza para muchos enfermos, es importante conocer los principales efectos adversos asociados al uso de estas drogas y seleccionar mejor a los pacientes que puedan beneficiarse de ellas. El riesgo de arritmias ventriculares incrementa tanto por el uso de fármacos como por la gravedad de la propia enfermedad viral.
Abstract The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness. The use of chloroquine/hydroxychloroquine, azithromycin and antiviral treatment and has been proposed by various groups, supported by in-vitro studies and limited patient series, without the adequate scientific rigor that precedes drug prescription. Although it may represent the only hope for many patients, it is important to know the main adverse effects associated with the use of these drugs and to better select patients who may benefit from them.
Asunto(s)
Humanos , Neumonía Viral/tratamiento farmacológico , Arritmias Cardíacas/inducido químicamente , Infecciones por Coronavirus/tratamiento farmacológico , Antivirales/efectos adversos , Antivirales/uso terapéutico , Neumonía Viral/epidemiología , Cloroquina/efectos adversos , Azitromicina/efectos adversos , Azitromicina/uso terapéutico , Pandemias , COVID-19 , Hidroxicloroquina/efectos adversosAsunto(s)
Humanos , Neumonía Viral/tratamiento farmacológico , Arritmias Cardíacas/inducido químicamente , Infecciones por Coronavirus/tratamiento farmacológico , Arritmias Cardíacas/prevención & control , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Pandemias , COVID-19 , Ventrículos Cardíacos/fisiopatologíaRESUMEN
El autor aborda el caso de la cloroquina y la hidroxicloroquina en el contexto de la actual pandemia de COVID-19, a través de dos ejes centrales. Por un lado, el escándalo a nivel editorial y de comunicación de la evidencia, y por otro, el de la toma de decisiones en salud pública. Describe flagrantes debilidades en la cadena de generación, difusión y aplicación del nuevo conocimiento. Adicionalmente, explora iniciativas y propuestas que podrían contribuir a solucionar estos problemas. (AU)
The author addresses the case of chloroquine and hydroxychloroquine in the context of the current COVID-19 pandemic, through two central axes. On the one hand, the scandal at the editorial and communication level of the evidence, and on the other, that of decision-making in public health. He describes flagrant weaknesses in the chain of generation, diffusion,and application of new knowledge. Additionally, it explores initiatives and proposals that could contribute to solving these problems. (AU)
Asunto(s)
Humanos , Cloroquina/efectos adversos , Infecciones por Coronavirus/tratamiento farmacológico , Toma de Decisiones Clínicas , Hidroxicloroquina/efectos adversos , Arritmias Cardíacas/inducido químicamente , Bioética , Ensayos Clínicos Controlados Aleatorios como Asunto , Mala Conducta Científica , Cloroquina/uso terapéutico , Salud Pública , Paroxetina/uso terapéutico , Revisión de la Investigación por Pares/ética , Azitromicina/uso terapéutico , Medicina Basada en la Evidencia , Ética en Investigación , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Comunicación y Divulgación Científica , Estudios Observacionales como Asunto , Práctica Clínica Basada en la Evidencia , Comunicación en Salud , Pandemias , Hidroxicloroquina/uso terapéutico , Neuraminidasa/antagonistas & inhibidoresRESUMEN
Abstract Background: D-limonene (DL) is a monoterpene and is the major component in the essential oil of citrus fruit. It presents antihyperglycemic and vasodilatation activities. Objectives: This study evaluated the cardiovascular effects and potential antiarrhythmic of DL in rats. Methods: Hemodynamic and electrocardiographic (ECG) parameters were measured in male Wistar rats, which under anesthesia had been cannulated in the abdominal aorta and lower vena cava and had electrodes subcutaneously implanted. In the in vitro approach, the heart was removed and perfused using the Langendorff technique. The significance level adopted was 5% (p < 0.05). Results: DL, in doses of 10, 20, and 40 mg/kg (i.v), produced intense and persistent bradycardia associated with hypotension. Bradycardia with prolonged QTc was observed in the ECG in vivo recording. In the in vivo model of arrhythmia induced by Bay K8644, DL (10 mg/kg) decreased the arrhythmia score from 15.33 ± 3.52 to 4.0 ± 2.64 u.a (p < 0.05, n = 4). In isolated perfused hearts, DL (10-3 M) promoted significant reductions in heart rate (from 228.6 ± 8.5 ms to 196.0 ± 9.3 bpm; p < 0.05) and left ventricular development pressure (from 25.2 ± 3.4 to 5.9 ± 1.8 mmHg; n = 5, p < 0.05). Conclusions: DL produces bradycardia and antiarrhythmic activity in rat heart.
Resumo Fundamento: O D-limoneno (DL) é um monoterpeno e o principal componente do óleo essencial de frutas cítricas. Ele apresenta atividades anti-hiperglicêmicas e vasodilatadoras. Objetivos: Este estudo avaliou os efeitos cardiovasculares e antiarrítmicos potenciais do DL em ratos. Métodos: Os parâmetros hemodinâmicos e eletrocardiográficos (ECG) foram mensurados em ratos Wistar machos que, sob anestesia, tiveram a aorta abdominal e a veia cava inferior canuladas e receberam eletrodos implantados subcutaneamente. Na abordagem in vitro, o coração foi removido e perfundido utilizando a técnica de Langendorff. O nível de significância adotado foi de 5% (p < 0,05). Resultados: DL, nas doses de 10, 20 e 40 mg/kg (i.v), produziu bradicardia intensa e persistente associada à hipotensão. A bradicardia com QTc prolongado foi observada no registro in vivo do ECG. No modelo in vivo de arritmia induzida por Bay K8644, DL (10 mg / kg) houve diminuição do escore da arritmia de 15,33 ± 3,52 para 4,0 ± 2,64 u.a (p < 0,05, n = 4). Em corações perfundidos isolados, o DL (10-3 M) promoveu reduções significativas na frequência cardíaca (de 228,6 ± 8,5 ms para 196,0 ± 9,3 bpm; p < 0,05) e na pressão desenvolvida do ventrículo esquerdo (de 25,2 ± 3,4 para 5,9 ± 1,8 mmHg; n = 5, p < 0,05). Conclusões: O DL produz bradicardia e atividade antiarrítmica no coração de ratos.