Abstract-Cytokine-induced NO production depresses myocardial contractility and has been shown to be cytotoxic to cardiac myocytes. However, the mechanisms of cytokine-induced cardiac myocyte cell death are unclear. To analyze these mechanisms in detail, we treated neonatal cardiac myocytes in serum-free culture with a combination of the macrophage-derived cytokines interleukin-1␤, tumor necrosis factor-␣, and interferon-␥. These cytokines caused a time-dependent induction of cardiac myocyte apoptosis, but not necrosis, beginning 72 hours after treatment, as determined by nuclear morphology, DNA internucleosomal cleavage, and cleavage of poly(ADP-ribose) polymerase, reflecting caspase activation. Apoptosis was preceded by a Ͼ50-fold induction of inducible NO synthase mRNA and the release of large amounts (5 to 8 nmol/g protein) of NO metabolites (NOx) into the medium. Cell death was completely blocked by an NO synthase inhibitor and attenuated by antioxidants (N-acetylcysteine and DTT) and the caspase inhibitor ZVAD-fmk. Cytokines also mediated an NO-dependent, sustained increase in myocyte expression of the Bcl-2 homologs Bak and Bcl-x(L). The NO donor S-nitrosoglutathione also induced apoptosis and cell levels of Bak, but not of Bcl-x(L). All effects of cytokines, including poly(ADP-ribose) polymerase cleavage, could be attributed to interleukin-1␤; interferon-␥ and tumor necrosis factor-␣ had no independent effects on apoptosis or on NOx production. We conclude that cytokine toxicity to neonatal cardiac myocytes results from the induction of NO and subsequent activation of apoptosis, at least in part through the generation of oxygen free radicals. The rate and extent of this apoptosis is modulated by alterations in the cellular balance of Bak and Bcl-x(L), which respond differentially to cytokine-induced and exogenous NO and by the availability of oxidant species. (Circ Res. 1999;84:21-33.)Key Words: poly(ADP-ribose) polymerase Ⅲ protein kinase G Ⅲ nitric oxide Ⅲ Bcl-x(L) Ⅲ oxidative stress

Investigation and utilization of molecularly targeted agents has induced a number of drug adverse effects that are not typically associated with conventional chemotherapy. QT interval prolongation, a cardiac toxicity that increases the risk of fatal arrhythmia, is associated with several novel oncology therapies. Classes of molecularly targeted agents with described QT effects include histone deacetylase inhibitors, multitargeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. Concurrently, guidelines for monitoring the QT-prolonging effects of drugs under development have become increasingly rigorous. Although these guidelines apply to anticancer agents, they were not specifically designed for the oncology patient population. This article will review the pathophysiology of QT prolongation, methods of preclinical QT assessment, and current guidelines for QT evaluation in early phase trials. Additionally, molecularly targeted agents with QT effects will be summarized, and mechanisms of addressing this toxicity in the context of oncology drug development will be explored.

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Background— An observational study determining the long-term impact of chronic kidney disease (CKD) on patients undergoing percutaneous coronary intervention at a tertiary cardiac referral center. CKD is associated with poor in-hospital outcomes after percutaneous coronary intervention, but its effect beyond 1 year, particularly in the drug-eluting stent (DES) era, has not been reported. Methods and Results— Baseline creatinine was available for 11 953 patients entered into a prospective registry (April 2000 to September 2007). Patients were stratified: those with or without at least moderate CKD (creatinine clearance, <60 mL/min). Follow-up data were obtained through linkage to a provincial registry. Kaplan–Meier analysis was performed. Cox multiple-regression analysis identified independent predictors of late mortality and major adverse cardiac events (MACE) and examined the association between DES use and late outcomes in the presence or absence of CKD. CKD was present in 3070 patients (25.7%). In-hospital mortality and MACE were significantly increased in CKD (3.34% versus 0.44%, P <0.001 and 5.73% versus 2.2%, P <0.001). Survival and MACE-free survival at 7 years were reduced (64.5�1.4% versus 89.4�0.5%, P <0.001; 44.0�1.4% versus 63.4�0.8%, P <0.001). CKD was an independent predictor of late mortality and MACE (hazard ratio [HR]: 2.18, CI: 1.90 to 2.49, P <0.0001; HR: 1.37, CI: 1.25 to 1.49, P <0.0001). DES use was associated with a significant reduction in both (HR: 0.71, CI: 0.60 to 0.83, P <0.0001; HR: 0.70, CI: 0.63 to 0.78, P <0.0001). In patients with CKD, DES use was associated with reduced revascularization (HR: 0.68, CI: 0.53 to 0.88, P =0.004) and reduced MACE (HR: 0.81, CI: 0.69 to 0.95, P =0.011) but not reduced mortality (HR: 0.85, CI: 0.69 to 1.05, P =0.1). Conclusion— In a large registry of “all comers” for percutaneous coronary intervention, CKD was an independent predictor of adverse late outcomes. DES use may be associated with improved long-term outcomes in this high-risk cohort, but further prospective studies are required.