Citations

OBJECTIVES To examine the impact of time to thrombolytic treatment on multiple acute outcome variables in a single trial of thrombolysis in acute myocardial infarction. DESIGN AND PATIENTS Mortality and reinfarction rate were measured in 2770 patients with acute myocardial infarction who received thrombolysis within 12 hours in CORE, an international, dose ranging trial of poloxamer 188. Tc-99m sestamibi infarct size and radionuclide angiographic ejection fraction substudies included 1099 and 1074 patients, respectively. RESULTS Time to thrombolysis, subgrouped by intervals (< 2, 2–4, ⩾ 4–6, and ⩾ 6 hours), was significantly associated with infarct size (median 15.0%, 18.5%, 22.0%, 18.5% of left ventricle; p = 0.033), mean (SD) ejection fraction (51.5 (12.0)%, 48.3 (13.9)%, 48.2 (13.3)%, 48.2 (15.0)%; p = 0.006), 35 day mortality (5.7%, 7.1%, 7.9%, 12.5%; p = 0.0004), six month mortality (7.3%, 8.6%, 10.4%, 15.5%; p < 0.0001), and 35 day reinfarction rate (6.1%, 3.2%, 4.0%, 0.9%; p = 0.0001). CONCLUSIONS In this single large trial, the beneficial effect of time to thrombolysis on infarct size and ejection fraction was restricted to treatment given within two hours of symptom onset, while the effect on mortality was evident over all time intervals. Reinfarction rate was higher in patients treated with earlier thrombolysis.

Presenilins mediate an unusual intramembranous proteolytic activity known as γ-secretase, two substrates of which are the Notch receptor (Notch) and the β-amyloid precursor protein (APP). γ-Secretase-mediated cleavage of APP, like that of Notch, yields an intracellular fragment [ A PP i ntra c ellular d omain (AICD)] that forms a transcriptively active complex. We now demonstrate a functional role for AICD in regulating phosphoinositide-mediated calcium signaling. Genetic ablation of the presenilins or pharmacological inhibition of γ-secretase activity (and thereby AICD production) attenuated calcium signaling in a dose-dependent and reversible manner through a mechanism involving the modulation of endoplasmic reticulum calcium stores. Cells lacking APP (and hence AICD) exhibited similar calcium signaling deficits, and—notably—these disturbances could be reversed by transfection with APP constructs containing an intact AICD, but not by constructs lacking this domain. Our findings indicate that the AICD regulates phosphoinositide-mediated calcium signaling through a γ-secretase-dependent signaling pathway, suggesting that the intramembranous proteolysis of APP may play a signaling role analogous to that of Notch.