Background-Cases of QT prolongation, torsades de pointes, and sudden death have been reported with arsenic trioxide (As 2 O 3 ), a highly effective agent for acute promyelocytic leukemia. In this study, we evaluated the effects of As 2 O 3 on repolarizing cardiac ion currents. Methods and Results-In HERG-or KCNQ1ϩKCNE1-transfected CHO cells (nϭ32; total), As 2 O 3 caused concentrationdependent block of both I Kr and I Ks , with an IC 50 for tail current block of 0.14Ϯ0.01 mol/L for I Kr and 1.13Ϯ0.06 mol/L for I Ks . In contrast to other QT-prolonging drugs, As 2 O 3 also activated a time-independent current that additional experiments identified as I K-ATP . Conclusions-As 2 O 3 blocks both I Kr and I Ks at clinically relevant concentrations. On the other hand, it also activates I K-ATP , which maintains normal repolarization. We infer that variability in the extent of QT interval prolongation and onset of ventricular arrhythmias during arsenic therapy represents competing effects to block and activate multiple repolarizing potassium currents. Key Words: torsades de pointes Ⅲ drugs Ⅲ ion channels A pproximately 20% to 30% of patients with acute promyelocytic leukemia (APL) relapse with current standard all-trans retinoic acid and anthracycline-based chemotherapy regimen. 1 In the mid-1990s, studies from China reported that arsenic trioxide (As 2 O 3 ) achieved complete remission in as many as 90% of patients with APL, 2,3 and additional trials have confirmed these results. 4,5 However, treatment has also been associated with QT prolongation, torsades de pointes, and sudden death. 4,6 -8 Because most of the patients receiving As 2 O 3 have been exposed to cardiotoxic chemotherapy, cardiac dysfunction is thought to be universal before As 2 O 3 therapy begins. 6,9 In addition, hypokalemia and hypomagnesemia are among the most common As 2 O 3 -related side effects. 1 Thus, it has been proposed that QT prolongation and ventricular arrhythmias associated with arsenic could be exacerbated by concurrent electrolyte disturbances or previous chemotherapy-induced cardiac damage. 4,6 -8 Recently, clinically relevant concentrations of As 2 O 3 (1 to 10 mol/L) have been reported to prolong the action potential duration in guinea pig papillary muscle. 9 In another study using rabbit hearts, polymorphic ventricular tachycardia was observed with As 2 O 3 30 mol/L. 10 In this study, we therefore investigated the effects of As 2 O 3 on cardiac repolarizing currents and identified an unexpectedly complex profile that may underlie variability in the arrhythmogenic potential of arsenic. MethodsExperiments were performed in CHO cells transfected with 2 g (each) of HERG, KCNQ1ϩKCNE1, or Kir6.2ϩSUR2A cDNAs. Kir6.2 and SUR2A cDNAs were kindly provided by Dr Joseph Bryan, Baylor College of Medicine, Houston, Tex. Cells were transfected using FuGENE 6 (Roche Applied Science). Green fluorescent protein (GFP) was coexpressed to identify transfected cells. All whole cell currents were recorded at 22°C to 23°C. Cells were held at Ϫ80 mV an...

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Inter-organ crosstalk plays an essential role in the physiological homeostasis of the heart and other organs, and requires a complex interaction between a host of cellular, molecular, and neural factors. Derangements in these interactions can initiate multi-organ dysfunction. This is the case, for instance, in the heart or kidneys where a pathological alteration in one organ can unfavorably affect function in another distant organ; attention is currently being paid to understanding the physiopathological consequences of kidney dysfunction on cardiac performance that lead to cardiorenal syndrome. Different cardiorenal connectors (renin–angiotensin or sympathetic nervous system activation, inflammation, uremia, etc.) and non-traditional risk factors potentially contribute to multi-organ failure. Of these, inflammation may be crucial as inflammatory cells contribute to over-production of eicosanoids and lipid second messengers that activate intracellular signaling pathways involved in pathogenesis. Indeed, inflammation biomarkers are often elevated in patients with cardiac or renal dysfunction. Epigenetics, a dynamic process that regulates gene expression and function, is also recognized as an important player in single-organ disease. Principal epigenetic modifications occur at the level of DNA (i.e., methylation) and histone proteins; aberrant DNA methylation is associated with pathogenesis of organ dysfunction through a number of mechanisms (inflammation, nitric oxide bioavailability, endothelin, etc.). Herein, we focus on the potential contribution of inflammation in pathogenesis of cardiorenal syndrome.

Background: Recognizing the importance of increased patient participation in healthcare decisions leads decision makers to consider effective ways to incorporate patient perspectives in Health Technology Assessment (HTA) processes. The implementation of local health HTA units in university hospitals in Quebec provides a unique opportunity to foster an increased participation of patients in decisions regarding health technologies and clinical interventions. This project explores strategies that could be effective in involving patients in HTA activities at the local level. To do so, three objectives are pursued: 1) To synthesise international knowledge and experiences on patient and public involvement in HTA activities; 2) To explore the perceptions of stakeholders (administrators, clinical managers, healthcare professionals, HTA producers, and patients) regarding strategies for involving patients in various HTA activities; and 3) To produce a consensual strategic framework that could guide interventions for involving patients in HTA activities at the local level.