Risk stratification for arrhythmic events in patients with nonischemic dilated cardiomyopathy and nonsustained ventricular tachycardia: Role of programmed ventricular stimulation and the signal-averaged electrocardiogram

AbstractObjectives. This study investigated prediction of arrhythmic events by the signal-averaged electrocardiogram (ECG) and programmed stimulation in patients with nonischemic dilated cardiomyopathy.Background. Risk stratification in patients with nonischemic dilated cardiomyopathy remains controversial.Methods. Eighty patients with nonischemic dilated cardiomyopathy and spontaneous nonsustained ventricular tachycardia underwent signal-averaged electrocardiography (both time-domain and spectral turbulence analysis) and programmed stimulation. All patients were followed up for a mean of 22 ± 26 months.Results. Sustained monomorphic ventricular tachycardia was induced in 10 patients (13%), who all received amiodarone. The remaining 70 patients were followed up without antiarrhythmic therapy. Of the 80 patients, 15% had abnormal findings on the time-domain signal-averaged ECG, and 39% had abnormal findings on spectral turbulence analysis. Time-domain signal-averaged electrocardiography had a better predictive accuracy for induced ventricular tachycardia than spectral turbulence analysis (88% vs. 66%, p < 0.01). During follow-up, there were 9 arrhythmic events (5 sudden deaths, 4 spontaneous ventricular tachycardia/fibrillation) and 10 nonsudden cardiac deaths. Cox regression analysis showed that no variables predicted arrhythmic events or total cardiac deaths. The 2-year actuarial survival free of arrhythmic events was similar in patients with or without abnormal findings on the signal-averaged ECG or induced ventricular tachycardia.Conclusions. In patients with nonischemic dilated cardiomyopathy, 1) there is a strong correlation between abnormal findings on the time-domain signal-averaged ECG and induced ventricular tachycardia, but both findings are uncommon; and 2) normal findings on the signal-averaged ECG, as well as failure to induce ventricular tachycardia, do not imply a benign outcome

Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration.

Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration

Mithramycin Is a Gene-Selective Sp1 Inhibitor That Identifies a Biological Intersection between Cancer and Neurodegeneration

Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington’s disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration