Anti-Inflammatory Effect of Izalpinin Derived from Chromolaena leivensis: λ-Carrageenan-Induced Paw Edema and In Silico Model.

The flavonoid izalpinin was isolated from the aerial parts of Chromolaena leivensis. Its structural determination was carried out using MS and NMR spectroscopic techniques (1H, 13C). This compound was evaluated for its anti-inflammatory effect in a rat model on λ-carrageenan-induced plantar edema. Paw inflammation was measured at one-hour intervals for seven hours following the administration of λ-carrageenan. Serum creatine kinase (CK) levels were evaluated, obtaining statistically significant results with the treatments at doses of 10 mg/kg (* p < 0.01) and 20 mg/kg (** p < 0.005). The anti-inflammatory effect of the compound was evaluated by using plethysmography, and the results showed significant differences at the three concentrations (10 mg/kg, 20 mg/kg, 40 mg/kg) in the first and third hours after treatment. * p < 0.05; ** p < 0.001; **** p < 0.0001 vs. the negative control group treated with vehicle (DMSO). Lastly, molecular docking analyses reveal that izalpinin has a strong binding affinity with five target proteins involved in the inflammatory process. The analysis using molecular dynamics allowed demonstrating that the ligand-protein complexes present acceptable stability, with RMSD values within the allowed range.

Endocarditis infecciosa en canino con diagnóstico previo de síndrome vestibular periférico secundario a probable otitis media-interna: reporte de caso / Infectious Endocarditis in Dogs with a Previous Diagnosis of Peripheral Vestibular Syndrome Secondary to Probable Otitis Media-Interna: A Case Report

Resumen La endocarditis infecciosa es un proceso patológico de baja incidencia en la clínica diaria; su principal etiología son los agentes bacterianos, los cuales colonizan con mayor prevalencia de válvula mitral y aortica. En este artículo se presenta el estudio de un perro con diagnóstico previo de síndrome vestibular periférico secundario a probable otitis media-interna. Se presenta con un soplo de aparición súbita, claudicaciones intermitentes, inapetencia, depresión y fiebre, por lo cual se hace la valoración ecocardiográfica, donde se evidencia engrosamiento valvular mitral, acompañado de estructuras hiperecoicas en el borde libre que corresponden a lesiones vegetativas. Por medio de los criterios de Duke modificados se obtiene un diagnóstico definitivo de endocarditis infecciosa, para lo cual se realiza manejo médico intrahospitalario, sin evolución favorable. Los hallazgos clínicos y paraclínicos coinciden con lo reportado en la literatura. Los criterios de Duke modificados permiten orientar el diagnóstico y evidenciar signos clínicos de alarma. El manejo médico antimicrobiano deberá realizarse con base en hemocultivos y pruebas de sensibilidad, siempre teniendo en cuenta la prevalencia de patógenos y el origen primario de la infección. Se debe considerar como una patología con un pronóstico malo y un porcentaje de fatalidad alto. Finalmente, se concluye que la principal limitación del caso es la falta de confirmación histopatológica.

Abstract Infectious endocarditis is a pathological process with low incidence in the daily clinical practice. The main etiology are the bacterial agents that colonize with higher prevalence the mitral and aortic valves. This paper reports the case of a dog with a previous diagnosis of peripheral vestibular syndrome secondary to probable otitis media-interna. The dog has a sudden heart murmur, intermittent claudications, lack of appetite, depression and temperatures. It is performed an echocardiographic assessment that shows mitral valve thickening with hyperecoic structures in the free border that indicates vegetations. Using the Modified Duke Criteria, a definitive diagnosis of infectious endocarditis is concluded. The dog is provided a medical treatment at the clinic without success. The clinical and paraclinical findings match the background found in the literature. Modified Duke Criteria allow guiding the diagnosis process and uncovering the alarm clinical signs. Antimicrobial clinical treatment must be administered based on blood cultures and sensitivity tests and considering both the pathogen prevalence and infection primary origin. Doctors must deem this condition as a bad prognosis pathology with a high mortality percentage. Finally, it is concluded that the main limitation in this case is a lack of histopathological confirmation.

Insights on the canine mitral valve in the course of myxomatous mitral valve disease / Información sobre la válvula mitral canina en el curso de la degeneración mixomatosa valvular mitral / Percepções sobre a válvula mitral canina no curso da doença mitral mixomatosa

Abstract Myxomatous mitral valve disease (MMVD) is the most common heart alteration in dogs. A vast extent of research has been focused on echocardiographic tissue Doppler and strain indices and the medical treatment of this condition, which are beyond the scope of this article. This review intends to include less known information of the mitral valve, acknowledge the American College of Veterinary Internal Medicine (ACVIM) consensus on MMVD and state different surgical approaches and devices, all valuable information for small animal clinicians and cardiologists. Also, during the last decade studies have been oriented towards to understand valve's mechanical structure and function, genes involved in the etiology and molecular signaling pathways. Advances have been made in understanding the mitral valve, but more assessment and efforts are needed in this specific area.

Resumen La degeneración mixomatosa valvular mitral (MMVD) es la alteración cardíaca más común en perros. Una gran parte de la investigación se ha cen-trado en índices ecocardiográficos de doppler tisular y strain y la terapéutica médica de esta afección, aspectos que están más allá del alcance de este artículo. Esta revisión pretende incluir información menos difundida de la válvula mitral, señalar el consenso del Colegio Americano de Medicina Interna Veterinaria (ACVIM) sobre el MMVD y conocer diferentes métodos y dispositivos quirúrgicos, toda información valiosa para clínicos de caninos y felinos y cardiólogos. Adicionalmente, durante la última década, los estudios se han orientado a comprender la biomecánica y la función de las válvulas, los genes involucrados en la etiología y las vías de señalización molecular. Se ha avanzado en el entendimiento de la válvula mitral, pero más revisiones y esfuerzos son necesarios en esta área específica.

Resumo A doença valvar mitral mixomatosa (DMVM) é a alteração cardíaca mais comum em cães. Uma vasta extensão da pesquisa tem sido focada nos índices de Doppler tecidual e de strain ecocardiográfico e no tratamento médico dessa condição, que estão além do escopo deste artigo. Esta revisão pretende incluir informações menos conhecidas sobre a válvula mitral, reconhecer o Consenso do Colégio Americano de Medicina Interna Veterinária (ACVIM) sobre MMVD e indicar diferentes abordagens e dispositivos cirúrgicos, todas informações valiosas para clínicos e cardiologistas de pequenos animais. Além disso, durante a última década, os estudos foram orientados para entender a estrutura mecânica e a função da válvula, genes envolvidos nas vias de etiologia e sinalização molecular. Avanços foram feitos no entendimento da valva mitral, mas mais avaliações e esforços são necessários nessa área específica.

Exploración ecográfica ocular básica en perros (modo B tiempo real) / Basic ocular ultrasound examination in dogs (real-time B-mode) / Exploração por meio de ultrassonografia ocular básica em cachorros (modo B tempo real)

Resumen: En las últimas décadas, la ecografía veterinaria ha vivido un gran avance tecnológico y técnico. Los médicos veterinarios no solo la utilizan para las valoraciones comunes de abdomen, o incluso corazón, sino que han descrito técnicas para exploraciones más especiales, como para el sistema musculoesquelético, el vascular, el ocular, entre otros. La literatura sobre el tema ha reseñado el desarrollo y aplicación de la ecografía ocular modo A, específica para la valoración oftalmológica por parte veterinarios especializados en esta área. Actualmente, un gran número de clínicas veterinarias cuenta con ecógrafos con modo B tiempo real, que permiten una excelente valoración descriptiva de la anatomía ocular para orientar posibles diagnósticos. Este artículo de revisión presenta de forma concisa las principales indicaciones de la ecografía ocular modo B y la técnica de realización, y describe cualitativamente las imágenes normales de la exploración de este órgano de los sentidos.

Abstract: In recent decades, veterinary ultrasound has experienced a great technological and technical progress. Veterinary doctors not only use it for common evaluation of abdomen, or even heart, but techniques have been described for more special examinations, such as for the musculoskeletal, vascular, and ocular systems, among others. Literature on the subject has reviewed the development and application of A-mode ocular ultrasound, specific for ophthalmologic evaluation by veterinarians specialized in this area. Currently, a large number of veterinary clinics has real-time B-mode ultrasound scanners, which allow an excellent descriptive evaluation of the ocular anatomy to guide possible diagnoses. This review article concisely presents the main indications and realization technique for B-mode ocular ultrasound, as well as qualitatively describes normal scan images of this sense organ.

Resumo: Nas últimas décadas, a ecografia veterinária tem vivido um grande avanço tecnológico e técnico. Os médicos veterinários não somente a utilizam para as avaliações comuns de abdômen, ou, inclusive o coração, mas também têm descrito técnicas para explorações mais especiais, como para o sistema musculoesquelético, o vascular, o ocular, entre outros. A literatura sobre o tema resenhou o desenvolvimento e aplicação da ultrassonografia ocular modo A, específica para a avaliação oftalmológica por parte de veterinários especializados nesta área. Atualmente, um grande número de clínicas veterinárias conta com scanners com modo B tempo real, que permitem uma excelente avaliação descritiva da anatomia ocular para orientar possíveis diagnósticos. Este artigo de revisão apresenta de forma concisa as principais indicações da ultrassonografia ocular modo B e a técnica de realização, e descreve qualitativamente as imagens normais da exploração deste órgão dos sentidos.

Chronic Omega-3 Polyunsaturated Fatty Acid Treatment Variably Affects Cellular Repolarization in a Healed Post-MI Arrhythmia Model.

INTRODUCTION: Over the last 40 years omega-3 polyunsaturated fatty acids (PUFAs) have been shown to be anti-arrhythmic or pro-arrhythmic depending on the method and duration of administration and model studied. We previously reported that omega-3 PUFAs do not confer anti-arrhythmic properties and are pro-arrhythmic in canine model of sudden cardiac death (SCD). Here, we evaluated the effects of chronic omega-3 PUFA treatment in post-MI animals susceptible (VF+) or resistant (VF-) to ventricular tachyarrhythmias. METHODS: Perforated patch clamp techniques were used to measure cardiomyocyte action potential durations (APD) at 50 and 90% repolarization and short term variability of repolarization. The early repolarizing transient outward potassium current Ito was also studied. RESULTS: Omega-3 PUFAs prolonged the action potential in VF- myocytes at both 50 and 90% repolarization. Short term variability of repolarization was increased in both untreated and treated VF- myocytes vs. CONTROLS: Ito was unaffected by omega-3 PUFA treatment. Omega-3 PUFA treatment attenuated the action potential prolongation in VF+ myocytes, but did not return repolarization to control values. CONCLUSIONS: Omega-3 PUFAs do not confer anti-arrhythmic properties in the setting of healed myocardial infarction in a canine model of SCD. In canines previously resistant to ventricular fibrillation (VF-), omega-3 PUFA treatment prolonged the action potential in VF- myocytes, and may contribute to pro-arrhythmic responses.

Electrocardiographic parameters in captive, clinically healthy, Amazona ochrocephala / Parámetros electrocardiográficos en Amazona ochrocephala clínicamente sanas en cautiverio

Objective. To stablish the electrocardiographic parameters of individuals of the species Amazona ochrocephala, from the Unidad de Rescate y Rehabilitacion de Animales Silvestres at the Universidad Nacional de Colombia. Materials and methods. The electrocardiographic examination was performed under inhaled anesthesia with isoflurane. Leads I, II, III, aVL, aVR and aVF were measured. Results. Electrocardiographic parameters obtained in Lead II. P wave Duration: 0.015-0.044 s, P wave amplitude: 0.031 to 0.6 mv, R wave duration: 0.015-0.022 s, amplitude R: 0.034-0.038 mv, S wave Duration: 0.019- 0.042 s, amplitude S: 0.194-0.815 mv, T wave Duration: 0.025-0.064 s, T-wave amplitude: 0.010 to 0.5 mv, PQ Duration: 0.021-0.076 s, QRS Duration: 0.036-0.068 s, QT Duration: 0.070-0.015 s, RR Duration: 0.104-0.324 s, EEM: -111° to -80°, FC: 240-600 ppm. Conclusions. The results showed different values for amplitude and duration of the P, R and T waves in comparison to those obtained in other studies. However, they were similar for heart rate, MEA and duration of the PQ/R, QT and QRS segments.

Objetivo. Establecer los parámetros electrocardiográficos en individuos de la especie Amazona ochrocephala, de la Unidad de Rescate y Rehabilitación de Animales Silvestres de la Universidad Nacional de Colombia sede Bogotá. Materiales y Métodos. El examen electrocardiográfico se realizó bajo anestesia inhalada con Isoflurano. Se tomaron derivadas I, II, III, aVL, aVR y aVF y posterior medición de ondas e intervalos usando magnificación con lupa. Resultados. Parámetros electrocardiográficos de la segunda derivada. Duración onda P: 0.015-0.044 s, amplitud onda P: 0.031-0.6 mv, duración onda R: 0.015-0.022 s, amplitud R: 0.034-0.038 mv, Duración onda S: 0.019- 0.042 s, Amplitud S: 0.194-0.815 mv, Duración onda T: 0.025-0.064 s, Amplitud onda T: 0.010-0.5 mv, Duración PQ: 0.021-0.076 s, Duración QRS: 0.036-0.068 s, Duración QT: 0.070-0.015 s, Duración R-R: 0.104-0.324 s, EEM: -111° a -80°, FC: 240-600 ppm. Conclusiones. Los resultados mostraron valores diferentes para los rangos de amplitud y duración de las deflexiones P, R y T en comparación a los obtenidos en otros estudios pero similares en cuanto al rango de frecuencia cardiaca, EEM y a la duración de los segmentos PQ/R, QT y QRS.

Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling.

AIMS: Ventricular arrhythmias are a common cause of death in patients with heart failure (HF). Structural and electrical abnormalities in the heart provide a substrate for such arrhythmias. Canine tachypacing-induced HF models of 4-6 weeks duration are often used to study pathophysiology and therapies for HF. We hypothesized that a chronic canine model of HF would result in greater electrical and structural remodeling than a short term model, leading to a more arrhythmogenic substrate. MAIN METHODS: HF was induced by ventricular tachypacing for one (short-term) or four (chronic) months to study remodeling. KEY FINDINGS: Left ventricular contractility was progressively reduced, while ventricular hypertrophy and interstitial fibrosis were evident at 4 month but not 1 month of HF. Left ventricular myocyte action potentials were prolonged after 4 (p<0.05) but not 1 month of HF. Repolarization instability and early afterdepolarizations were evident only after 4 months of HF (p<0.05), coinciding with a prolonged QTc interval (p<0.05). The transient outward potassium current was reduced in both HF groups (p<0.05). The outward component of the inward rectifier potassium current was reduced only in the 4 month HF group (p<0.05). The delayed rectifier potassium currents were reduced in 4 (p<0.05) but not 1 month of HF. Reactive oxygen species were increased at both 1 and 4 months of HF (p<0.05). SIGNIFICANCE: Reduced Ito, outward IK1, IKs, and IKr in HF contribute to EAD formation. Chronic, but not short term canine HF, results in the altered electrophysiology and repolarization instability characteristic of end-stage human HF.

Enfermedad valvular degenerativa canina: reporte de caso / Canine Degenerative Valve Disease: A Case Report / Doença valvular degenerativa canina: repórter de caso

En caninos, la enfermedad valvular degenerativa o endocardiosis es la patología cardiovascular con mayor prevalencia. Se caracteriza por regurgitación de la sangre hacia las aurículas, con disminución del gasto cardiaco, lo que lleva a sobrecarga de volumen con hipertrofia excéntrica e insuficiencia cardiaca congestiva. Este reporte tiene como objetivo describir los hallazgos clínicos y de necropsia de un canino, sugestivos de una endocardiosis valvular. El paciente ingresó por consulta externa a la Clínica Veterinaria Carlos Martínez Hoyos, de la Universidad de Nariño (Pasto, Colombia). Su propietario lo reportó enfermo desde hacía dos meses, con signos de enfermedad respiratoria, pérdida de peso y decaimiento. En el examen clínico se encontraron membranas mucosas muy pálidas, disnea inspiratoria, estertores, desdoblamiento de S2, soplo de regurgitación mesosistólico grado 4 y dilatación abdominal con signo de choque de onda positivo. En la necropsia se evidenció abundante cantidad de material de aspecto acuoso traslúcido en cavidad abdominal, torácica y pericárdica, corazón severamente aumentado de tamaño, redondeado, con engrosamiento de válvulas atrioventriculares, hígado con moderada disminución de tamaño y evidencia de lobulillación, riñones severamente disminuidos de tamaño y pálidos de superficie irregular con presencia de múltiples áreas quísticas en región corticomedular. Se tomaron muestras de estos tejidos y se fijaron en formol bufferado al 10%, para después ser procesadas para análisis histopatólogico en el Laboratorio de Patología de la Universidad de Nariño, mediante la técnica de hematoxilina y eosina de rutina. De esta manera se diagnostica como enfermedad valvular degenerativa.

Degenerative valvular disease or endocardiosis is the most common cardiovascular pathology in dogs. It is characterized by regurgitation of blood into the atria with decreased cardiac output, leading to volume overload with eccentric hypertrophy and congestive heart failure. This report describes the clinical and autopsy findings of a dog, suggestive of valvular endocardiosis. The patient was admitted to the outpatient Veterinary Clinic "Carlos Martínez Hoyos" at the University of Nariño (Pasto, Colombia). His owner said the dog was sick for two months, with signs of respiratory disease, weight loss, and decay. Clinical examination showed very pale mucous membranes, inspiratory dyspnea, rale, split S2, grade 4 mid-systolic murmur of regurgitation, and abdominal dilatation with sign of positive shock wave. Necropsy evidenced plenty of translucent watery material in the abdominal, chest and pericardium cavity, severely enlarged and rounded heart with thickened atrioventricular valves, moderate reduction in liver size and signs of lobulation, severely diminished and pale kidneys with irregular surface showing the presence of multiple cystic areas in corticomedullary region. Samples were taken from these tissues and fixed in 10% buffered formalin to be processed for histopathological analysis at the Laboratory of Pathology at the University of Nariño, using hematoxylin and eosin stain. This way, degenerative valvular disease was diagnosed.

Em caninos, a doença valvular degenerativa ou endocardiose é a patologia cardiovascular com maior prevalência. Caracteriza-se por regurgitação do sangue até as aurículas, com diminuição do gasto cardíaco, o que leva a sobrecarga de volume com hipertrofia excêntrica e insuficiência cardíaca congestiva. Este relatório tem como objetivo descrever os achados clínicos e de necropsia de um canino, sugestivos de uma endocardiose valvular. O paciente ingressou por consulta externa na Clínica Veterinária Carlos Martínez Hoyos, da Universidade de Nariño (Pasto, Colômbia). Seu proprietário o reportou doente há dois meses, com signos de doença respiratória, perda de peso e decaimento. No exame clínico se encontraram membranas mucosas muito pálidas, dispneia inspiratória, estertores, desdobramento de S2, sopro de regurgitação mesos sistólico grau 4 e dilatação abdominal com signo de choque de onda positivo. Na necropsia se evidenciou abundante quantidade de material de aspecto aquoso translúcido em cavidade abdominal, torácica e pericárdica, coração severamente aumentado de tamanho, redondeado, com engrossamento de válvulas atrioventriculares, fígado com moderada diminuição de tamanho e evidência lobular, rins severamente diminuídos de tamanho e pálidos, com superfície irregular com presença de múltiplas áreas císticas em região corticomedular. Tomaram-se amostras destes tecidos e se fixaram em formol tamponado a 10%, para depois ser processadas para análise histopatológica no Laboratório de Patologia da Universidade de Nariño, através de técnica de hematoxilina e eosina de rotina. Desta maneira se diagnostica como doença valvular degenerativa.

Arterial blood pressure as a predictor of the response to fluid administration in euvolemic nonhypotensive or hypotensive isoflurane-anesthetized dogs.

OBJECTIVE: To determine the effects of rapid small-volume fluid administration on arterial blood pressure measurements and associated hemodynamic variables in isoflurane-anesthetized euvolemic dogs with or without experimentally induced hypotension. DESIGN: Prospective, randomized, controlled study. ANIMALS: 13 healthy dogs. PROCEDURES: Isoflurane-anesthetized dogs were randomly assigned to conditions of nonhypotension or hypotension (mean arterial blood pressure, 45 to 50 mm Hg) and treatment with lactated Ringer's solution (LRS) or hetastarch (3 or 10 mL/kg [1.4 or 4.5 mL/lb] dose in a 5-minute period or 3 mL/kg dose in a 1-minute period [4 or 5 dogs/treatment; ≥ 10-day interval between treatments]). Hemodynamic variables were recorded before and for up to 45 minutes after fluid administration. RESULTS: IV administration of 10 mL/kg doses of LRS or hetastarch in a 5-minute period increased right atrial and pulmonary arterial pressures and cardiac output (CO) when dogs were nonhypotensive or hypotensive, compared with findings before fluid administration; durations of these effects were greater after hetastarch administration. Intravenous administration of 3 mL of hetastarch/kg in a 5-minute period resulted in an increase in CO when dogs were nonhypotensive. Intravenous administration of 3 mL/kg doses of LRS or hetastarch in a 1-minute period increased right atrial pressure and CO when dogs were nonhypotensive or hypotensive. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of LRS or hetastarch (3 or 10 mL/kg dose in a 5-minute period or 3 mL/kg dose in a 1-minute period) improved CO in isoflurane-anesthetized euvolemic dogs with or without hypotension. Overall, arterial blood pressure measurements were a poor predictor of the hemodynamic response to fluid administration.

Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.

The role of I(KCa) in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of I(KCa) blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The I(KCa) blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by I(KCa) blockade in all of the groups studied. I(KCa) blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. I(KCa) blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, I(KCa) blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for I(KCa) in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.

Ibandronate and ventricular arrhythmia risk.

INTRODUCTION: Bisphosphonates, including ibandronate, are used in the prevention and treatment of osteoporosis. METHODS AND RESULTS: We report a case of suspected ibandronate-associated arrhythmia, following a single dose of ibandronate in a 55-year-old female. ECG at presentation revealed frequent ectopy and QT/QTc interval prolongation; at follow-up 9 months later the QT/QTc intervals were normalized. Proarrhythmic potential of ibandronate was assessed with a combination of in vivo and in vitro approaches in canines and canine ventricular myocytes. We observed late onset in vivo repolarization instability after ibandronate treatment. Myocytes superfused with ibandronate exhibited action potential duration (APD) prolongation and variability, increased early afterdepolarizations (EADs) and reduced Ito (P < 0.05), with no change in IKr . Ibandronate-induced APD changes and EADs were prevented by inhibition of intracellular calcium cycling. Ibandronate increased sarcoplasmic reticulum calcium load; during washout there was an increase in calcium spark frequency and spontaneous calcium waves. Computational modeling was used to examine the observed effects of ibandronate. While reductions in Ito alone had modest effects on APD, when combined with altered RyR inactivation kinetics, the model predicted effects on APD and SR Ca(2+) load consistent with observed experimental results. CONCLUSION: Ibandronate may increase the susceptibility to ventricular ectopy and arrhythmias. Collectively these data suggest that reduced Ito combined with abnormal RyR calcium handling may result in a previously unrecognized form of drug-induced proarrhythmia.

Sinoatrial node reentry in a canine chronic left ventricular infarct model: role of intranodal fibrosis and heterogeneity of refractoriness.

BACKGROUND: Reentrant arrhythmias involving the sinoatrial node (SAN), namely SAN reentry, remain one of the most intriguing enigmas of cardiac electrophysiology. The goal of the present study was to elucidate the mechanism of SAN micro-reentry in canine hearts with post-myocardial infarction (MI) structural remodeling. METHODS AND RESULTS: In vivo, Holter monitoring revealed ventricular arrhythmias and SAN dysfunctions in post-left ventricular MI (6-15 weeks) dogs (n=5) compared with control dogs (n=4). In vitro, high-resolution near-infrared optical mapping of intramural SAN activation was performed in coronary perfused atrial preparations from MI (n=5) and controls (n=4). Both SAN macro- (slow-fast; 16-28 mm) and micro-reentry (1-3 mm) were observed in 60% of the MI preparations during moderate autonomic stimulation (acetylcholine [0.1 µmol/L] or isoproterenol [0.01-0.1 µmol/L]) after termination of atrial tachypacing (5-8 Hz), a finding not seen in controls. The autonomic stimulation induced heterogeneous changes in the SAN refractoriness; thus, competing atrial or SAN pacemaker waves could produce unidirectional blocks and initiate intranodal micro-reentry. The micro-reentry pivot waves were anchored to the longitudinal block region and produced both tachycardia and paradoxical bradycardia (due to exit block), despite an atrial ECG morphology identical to regular sinus rhythm. Intranodal longitudinal conduction blocks coincided with interstitial fibrosis strands that were exaggerated in the MI SAN pacemaker complex (fibrosis density: 37±7% MI versus 23±6% control; P<0.001). CONCLUSIONS: Both tachy- and brady-arrhythmias can result from SAN micro-reentry. Postinfarction remodeling, including increased intranodal fibrosis and heterogeneity of refractoriness, provides substrates for SAN reentry.

Tachy-brady arrhythmias: the critical role of adenosine-induced sinoatrial conduction block in post-tachycardia pauses.

BACKGROUND: In patients with sinoatrial nodal (SAN) dysfunction, atrial pauses lasting several seconds may follow rapid atrial pacing or paroxysmal tachycardia (tachy-brady arrhythmias). Clinical studies suggest that adenosine may play an important role in SAN dysfunction, but the mechanism remains unclear. OBJECTIVE: To define the mechanism of SAN dysfunction induced by the combination of adenosine and tachycardia. METHODS: We studied the mechanism of SAN dysfunction produced by a combination of adenosine and rapid atrial pacing in isolated coronary-perfused canine atrial preparations by using high-resolution optical mapping (n = 9). Sinus cycle length and sinoatrial conduction time (SACT) were measured during adenosine (1-100 µM) and DPCPX (1 µM; A1 receptor antagonist; n = 7) perfusion. Sinoatrial node recovery time was measured after 1 minute of "slow" pacing (3.3 Hz) or tachypacing (7-9 Hz). RESULTS: Adenosine significantly increased sinus cycle length (477 ± 62 ms vs 778 ± 114 ms; P<.01) and SACT during sinus rhythm (41 ± 11 ms vs 86 ± 16 ms; P<.01) in a dose-dependent manner. Adenosine dramatically affected SACT of the first SAN beat after tachypacing (41 ± 5 ms vs 221 ± 98 ms; P<.01). Moreover, at high concentrations of adenosine (10-100 µM), termination of tachypacing or atrial flutter/fibrillation produced atrial pauses of 4.2 ± 3.4 seconds (n = 5) owing to conduction block between the SAN and the atria, despite a stable SAN intrinsic rate. Conduction block was preferentially related to depressed excitability in SAN conduction pathways. Adenosine-induced changes were reversible on washout or DPCPX treatment. CONCLUSIONS: These data directly demonstrate that adenosine contributes to post-tachycardia atrial pauses through SAN exit block rather than slowed pacemaker automaticity. Thus, these data suggest an important modulatory role of adenosine in tachy-brady syndrome.

Differential regulation of EHD3 in human and mammalian heart failure.

Electrical and structural remodeling during the progression of cardiovascular disease is associated with adverse outcomes subjecting affected patients to overt heart failure (HF) and/or sudden death. Dysfunction in integral membrane protein trafficking has long been linked with maladaptive electrical remodeling. However, little is known regarding the molecular identity or function of these intracellular targeting pathways in the heart. Eps15 homology domain-containing (EHD) gene products (EHD1-4) are polypeptides linked with endosomal trafficking, membrane protein recycling, and lipid homeostasis in a wide variety of cell types. EHD3 was recently established as a critical mediator of membrane protein trafficking in the heart. Here, we investigate the potential link between EHD3 function and heart disease. Using four different HF models including ischemic rat heart, pressure overloaded mouse heart, chronic pacing-induced canine heart, and non-ischemic failing human myocardium we provide the first evidence that EHD3 levels are consistently increased in HF. Notably, the expression of the Na/Ca exchanger (NCX1), targeted by EHD3 in heart is similarly elevated in HF. Finally, we identify a molecular pathway for EHD3 regulation in heart failure downstream of reactive oxygen species and angiotensin II signaling. Together, our new data identify EHD3 as a previously unrecognized component of the cardiac remodeling pathway.