Ventricular arrhythmias following thermal damage of epicardial tissue: possible causes and clinical implications

Epicardial heating may be used for ventricular tachycardia (VT) ablation and transmyocardial revascularization. However, the potential risks of thermal epicardial injury, including arrhythmia, have not been fully explored. This study relates the pathologic and arrhythmic sequellae of epicardial heating when applied with a diode laser at varying doses. Acute pathology and dosimetry were determined in a group of normal dogs using 2-3 W over 30-90 seconds. Another group received a similar dose range before undergoing 24-hour monitoring, and electrophysiological testing was done at 4 weeks. In this group, four dogs each received 12 lesions (90-180 J) according to a randomized block design. Another dog received nine lower dose lesions (30-120 J). Acute lesions measured 2.5-8.0-mm wide by 4-8.5-mm deep. Charring and vaporization were common when 3 W were applied over 45 seconds. Within 24 hours, VT with features of abnormal automaticity occurred in all dogs receiving this dose. The dog in whom lower doses induced coagulation only had no VT. Four weeks later, electrophysiological study induced no VT. At this time fibrosis and granulation tissue were organizing the contraction band necrosis seen acutely, and some lesion borders were becoming calcified. No major vessels had been damaged. Abnormal automaticity and VT may occur if thermal damage of the epicardium exceeds coagulation. This could be related to tissue injury caused by sudden water vaporization, and may have clinical relevance given the growing indications for myocardial heating.     

Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions

Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)-α production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (T_reg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN-α secretion potently (−64%) but TLR-9-induced IFN-α secretion only slightly (−20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN-γ and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4⁺forkhead box protein 3 (FoxP3)⁺ regulatory T cells, but did not affect the generation of suppressive CD8⁺CD38⁺lymphocyte activation gene (LAG)-3⁺ T_reg. In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4⁺ T cell proliferation and induce CD4⁺FoxP3⁺ regulatory T cell generation.     

IRON EXACERBATES ANILINE-ASSOCIATED SPLENIC TOXICITY

Our earlier studies have shown that aniline exposure in rats causes time- and dose-dependent accumulation of iron in the spleen, which may exacerbate aniline splenotoxicity by catalyzing free-radical reactions. The present studies were conducted to test whether aniline-induced splenic toxicity could be potentiated by iron overload. For 30 d male Sprague-Dawley rats received the following treatments: 0.5 mmol/kg/ d aniline hydrochloride (AH) by gavage (AH group); 3% carbonyl iron-supplemented diet (IR group); 0.5 mmol/kg/d AH by gavage and iron-supplemented diet (AH + IR group); or no treatments (controls). Treatment-related significant increases in total iron, low molecular weight chelatable iron, lipid peroxidation, and protein oxidation were observed in the spleens of all the groups compared to control. However, these changes were much greater in the combined AH + IR group. The aniline-induced morphological changes in the spleen were consistent with our earlier observations, but were more pronounced in the AH + IR group. The increased toxicity, as evident from greater oxidative stress and morphological changes in the AH + IR group, suggests that iron potentiates the splenic toxicity of aniline.