Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice.

Aims: Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice. Methods and results: Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8 weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Conclusions: Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.

Estudo da função ventricular na técnica de plicatura da parede livre do ventrículo esquerdo em cães / Left ventricular function after plication of the left ventricular free wall in dogs

OBJETIVO: Avaliar os efeitos da técnica na função ventricular esquerda em cães hígidos e com cardiomiopatia dilatada induzida pela doxorrubicina. MÉTODO: De 13 cães, oito receberam doxorrubicina até que a fração de encurtamento (FE) fosse menor que 20 por cento. Destes, quatro animais e os cinco não induzidos foram submetidos à plicatura da parede livre do ventrículo esquerdo (PPLVE). Os demais cães não foram operados. Foram avaliados débito cardíaco (DC), pressão arterial, exame físico, eletrocardiografia, sistema "Holter" e ecocardiografia, por 180 dias. RESULTADOS: Houve redução do volume ventricular esquerdo. Os cães induzidos melhoraram após a operação e a fração de ejeção (FEj) retornou aos valores normais para a espécie. O DC e a FE aumentaram após a operação. Um cão foi a óbito. Nos cães não operados, a FE diminuiu e foram a óbito em torno de 40 dias após a indução; nos cães não induzidos, esta não se alterou. Houve extra-sístoles ventriculares, que se resolveram espontaneamente. CONCLUSÕES: A PPLVE sem circulação extracorpórea reduz o volume ventricular esquerdo e melhora a função cardíaca dos cães com cardiomiopatia dilatada induzida pela doxorrubicina, demonstrando baixa morbidade e mortalidade tardia.

[Comparison of the prothrombin levels between the patients with atrial fibrillation and patients with cardiac pacemaker implantation due to sick sinus syndrome during anticoagulation therapy with warfarin].

We measured the fully carboxylated prothrombin levels using the Carinactivase-1 (CA-1) test and thus compared prothrombin levels between patients having atrial fibrillation (Af) without pacemaking and those having sick sinus syndrome due to Af with cardiac pacemaker implantation during anticoagulation therapy with warfarin. Total plasma samples were assayed for the CA-1 test, the prothrombin time international normalized ratio (PT-INR) and the thrombotest (TT). This prospective randomized study was carried out on 641 samples obtained at the Fukuoka University Hospital Department of Cardiovascular Surgery between May 1997 and March 1999. The patients were divided into 2 groups consisting of: group A; 144 patients having sick sinus syndrome due to Af implanted with a cardiac pacemaker who were treated with warfarin, group B; 497 patients atrial fibrillation without pacemaking who were treated with warfarin. The prothrombin levels in each group were 65.5 +/- 25.2 and 76.1 +/- 47.7 micrograms/ml, respectively. The normal prothrombin levels of group A decreased more significantly than in group B. Therefore, the PT-INR and TT were not significantly different between groups A and B. The dose of warfarin in each group was 2.4 +/- 1.0 and 2.6 +/- 1.4 g/day, respectively. The dose of warfarin in group A therefore decreased significantly different more than in group B. In conclusion, the normal prothrombin levels of patients atrial fibrillation increased more significantly than patients having sick sinus syndrome due to Af implanted with a cardiac pacemaker.

[The effect of ventricular pacing on plasma atrial natriuretic factor levels and its clinical significance].

The effects of increasing pacing rate on cardiac hemodynamics and the release of atrial natriuretic factor (ANF), cGMP and cAMP were studied in 21 patients underwent ventricular pacing. ANF levels elevated insignificantly in patients without VA conduction, but elevated significantly in patients with VA conduction at pacing rate of 90,110 and 160 beat/min. The intracardiac pressure between these two groups of patients did not show significant difference. The conclusions are: (1) elevation of ANF levels at increasing pacing rate is mainly due to atrial distension rather than atrial pressure per se. (2) The elevation of ANF levels may reflect the changes of hemodynamics, the higher the ANF level, the more increase in intracardiac pressure. (3) marked elevation of ANF level may suggest presence of VA conduction in patients during ventricular pacing.

Cardiodynamic and neurohormonal importance of atrial contribution in rate-responsive pacing.

To elucidate the physiologic importance of atrial contribution in recently developed rate-responsive pacing, changes in cardiodynamics and neurohormonal factors were analyzed during exercise in patients with respiratory rate-dependent, rate-responsive atrial (AAIR; n = 6) and ventricular (VVIR; n = 9) demand mode pacemakers implanted for sick sinus syndrome. With increasing pacing rate during bicycle ergometer exercise, the AAIR group had significant increases in cardiac index (p < 0.05), left ventricular ejection fraction (p < 0.05), and ejection (p < 0.05) and peak filling (p < 0.05) rates; however, the VVIR group had a significant decrease in ejection fraction (p < 0.05), and an increase in cardiac index (p < 0.05) that was significantly less than in the AAIR group. At rest, the mean plasma concentrations of atrial natriuretic peptide (p < 0.005) and cyclic guanosine monophosphate (p < 0.05) were significantly greater in the VVIR group than in the AAIR group and normal subjects (n = 8). Atrial natriuretic peptide, norepinephrine, and cyclic adenosine and guanosine monophosphates were significantly greater (p < 0.05) during exercise, and atrial natriuretic peptide was significantly greater in the VVIR group (207.5 +/- 8.3 pg/ml) than in the AAIR group (116.4 +/- 51.5) and normal subjects (30.8 +/- 19.2; p < 0.05); this suggested a further increase in the nonphysiologic atrial overload with VVIR pacing. The data show both the neurohormonal and cardiodynamic importance of atrioventricular synchrony in rate-responsive pacing.