Decoy oligodeoxynucleotide againstactivator protein-1 reducesneointimal proliferation after coronaryangioplasty in hypercholesterolemic minipigs

AbstractObjectivesWe sought to demonstrate, in an appropriate animal model, that co-medication with a transcription factor-blocking agent limits restenosis after percutaneous transluminal coronary angioplasty (PTCA).BackgroundEnhanced synthesis in the vessel wall of endothelin-1 (ET-1), a powerful co-mitogen for vascular smooth muscle cells, appears to be one mechanism that promotes restenosis after PTCA. Deformation-induced expression of prepro-ET-1 is governed by the transcription factor, activator protein-1 (AP-1).MethodsAn anti-AP-1 decoy oligodeoxynucleotide (dODN) strategy was devised in which the dODN-containing solution (20 nmol) was administered locally through a Dispatch catheter into the coronary arteries of hypercholesterolemic minipigs at the time of PTCA (AVE-GFX stent).ResultsTreatment with an AP-1 dODN, mimicking the consensus binding site of the transcription factor, significantly reduced neointimal formation in the coronary arteries of hypercholesterolemic minipigs (n = 10 to 12), compared with vehicle-treated coronary arteries, after four weeks of follow-up (neointimal area 2.64 ± 0.33 vs. 4.81 ± 1.04 mm2[mean ± SEM]; p < 0.05). This effect was maintained after eight weeks (neointimal area 2.04 ± 0.22 mm2; n = 3) and correlated with a reduction in both nuclear translocation of AP-1 and ET-1 synthesis in the vessel wall 48 h after PTCA (n = 4). In contrast, an AP-1 mutant dODN, to which the transcription factor does not bind, showed no effect on neointimal formation at either time point (n = 3 to 7). Moreover, a consensus dODN directed against CCAAT/enhancer binding protein (C/EBP), another deformation-sensitive transcription factor, did not significantly affect neointimal formation after four weeks (n = 3).ConclusionsThese findings demonstrate the feasibility, efficacy and specificity of the anti-AP-1 dODN approach to the treatment of restenosis, which principally but not exclusively targets deformation-induced ET-1 synthesis in the vessel wall. Provided that these findings can be extrapolated to the situation of patients with coronary artery disease, the observed extent of the inhibitory effect of the AP-1 dODN treatment suggests that this co-medication may greatly reduce the incidence of in-stent restenosis

Cardiac troponin I elevation in acute pulmonary embolism is associated with right ventricular dysfunction

AbstractOBJECTIVESThe purpose of this study was to evaluate the prevalence and diagnostic utility of cardiac troponin I to identify patients with right ventricular (RV) dysfunction in pulmonary embolism.BACKGROUNDRight ventricular overload resulting from elevated pulmonary resistance is a common finding in major pulmonary embolism. However, biochemical markers to assess the degree of RV dysfunction have not been evaluated so far.METHODSIn this prospective, double-blind study we included 36 study patients diagnosed as having acute pulmonary embolism.RESULTSAmong the whole study population, 14 patients (39%) had positive troponin I tests. Ten of 16 patients (62.5%) with RV dilatation had increased serum troponin I levels, while only 4 of 14 patients (28.6%) with elevated troponin I values had a normal RV diameter as assessed by echocardiography, indicating that positive troponin I tests were significantly associated with RV dilatation (p = 0.009). Patients with positive troponin I tests had significantly more segmental defects in ventilation/perfusion lung scans than patients with normal serum troponin I (p = 0.0002).CONCLUSIONSOur data demonstrate that more than one-third of patients clinically diagnosed as having pulmonary embolism presented with elevated serum troponin I concentrations. Troponin I tests helped to identify patients with RV dilatation who had significantly more segmental defects in lung scans. Thus, troponin I assays are useful to detect minor myocardial damage in pulmonary embolism