Search

Aims Cardiac allograft vasculopathy (CAV) continues to be an unsolved clinical problem requiring the development of new therapeutic strategies. We have previously demonstrated that ex vivo donor allograft treatment with decoy oligodeoxynucleotides (ODN) targeting the transcription factors, activator protein-1 (AP-1) or signal transducer and activator of transcription-1 (STAT-1), delays acute rejection and prolongs cardiac allograft survival. Here, we investigated whether this treatment regime also prevents the occurrence of CAV in a fully allogeneic rat heart transplantation model. Methods and results Wistar-Furth rat cardiac allografts were perfused ex vivo with AP-1 decoy ODN, STAT-1 decoy ODN, or buffer solution and transplanted into the abdomen of Lewis rats immunosuppressed with cyclosporine. Treatment with both decoy ODNs but not vehicle significantly attenuated the incidence and severity of CAV. Laser-assisted microdissection/real-time polymerase chain reaction as well as immunohistochemistry analyses revealed a significant increase in CD40 abundance in the coronary endothelial cells and medial smooth muscle cells on day 1 post transplantation which was virtually abolished upon AP-1 or STAT-1 decoy ODN treatment. While the AP-1 decoy ODN primarily attenuated basal CD40 expression, the STAT-1 decoy ODN suppressed tumour necrosis factor-a-/interferon-gstimulated expression of CD40 in rat native endothelial cells. Conclusion Treating donor hearts with decoy ODNs neutralizing AP-1 or STAT-1 at the time of transplantation prevents upregulation of CD40 expression in the graft coronary arteries and effectively inhibits CAV.

Objective: Acute myocardial rejection is a cell-mediated process characterized by increased leukocyte recruitment into the graft myocardial tissue. Transcription factors like STAT-1 and AP-1 are critically involved in this process by regulating vascular adhesion molecule expression. The aim of our study was to investigate the effect of decoy oligodeoxynucleotide (dODN) treatment targeting transcription factors AP-1 and STAT-1 on acute cardiac allograft rejection in a rat transplant model. Methods Wistar–Furth (WF) cardiac allografts were transplanted into Lewis (LEW) rats after perfusion with STAT-1 or AP-1 dODN solution (5 μmol/l), buffer or the corresponding mutant control ODNs. Grafts were harvested and processed for histologic and immunohistochemical evaluation. Results: As demonstrated by fluorescence dye-labelled dODN, exposure of the grafts to the dODNs during 45 min of warm ischemia resulted in a dominant uptake of naked DNA by the graft endothelium. Treatment with AP-1 and STAT-1 dODNs, but not with vehicle or the control dODNs, significantly prolonged cardiac allograft survival by approximately 40% from 5.6±0.5 days to 7.8±1.3 days and 7.4±0.5 days, respectively (mean±S.D., p

Coronary atherectomy specimens from 50 patients with coronary heart disease were examined for the presence of Chlamydia pneumoniae by two different methods of polymerase chain reaction (PCR) and by in situ hybridization. C. pneumoniae DNA was detected by PCR in atherosclerotic plaques of four patients (8%). Two patients' coronary atheromas were positive, both by a single-step 16S rRNA-based PCR and by an omp1-based nested PCR. The other two patients' specimens were positive only by the nested PCR. In contrast, C. pneumoniae was not detected by in situ hybridization in any of the cardiovascular tissues tested. Of three patients with evidence of C. pneumoniae in coronary atheromas, two had an antibody titer of 1:32 and the third had no specific antibodies detectable. Results of this study demonstrate a low prevalence of C. pneumoniae DNA in coronary atheromas. These findings do not support the hypothesis that the organism plays a major role in atherogenesis.

Background There are conflicting results on the relationship of N5,N10-methylenetetrahydrofolate reductase C677T gene variation in coronary artery disease and myocardial infarction. Methods and Results We analysed this gene variation in 2453 male Caucasians whose coronary anatomy was defined by coronary angiography. In the total sample, the C677T gene polymorphism was not associated with the presence or the extent of coronary artery disease (defined by the degree of vessel disease or by the coronary heart disease score according to Gensini). However, after excluding individuals with low risk profiles, an association between the C677T TT genotype and the Gensini score was found. This observation applies only to individuals (i) with high glucose levels, (ii) with low apolipoprotein Al/apolipoprotein B ratios, (iii) with low apolipoprotein Al/apolipoprotein B ratios and high lipoprotein (a) levels and (iv) with low apolipoprotein Al/apolipoprotein B ratios and high glucose concentrations. In patients with high glucose levels, the paraoxonase 191 A/B gene variation presupposed whether differences in Gensini scores between C677T C allele carriers and TT homozygotes became apparent, since only in paraoxonase 191 AA homoxygotes, but not in paraoxonase 191 B allele carriers, did C677T TT homozygotes have clearly higher Gensini scores than C allele carriers (two-way interaction; P =0·013). The MTHFR C677T gene polymorphism was not associated with non-fatal myocardial infarction. Conclusion The present study extends previous observations by the finding that carriers of the N5,N10-methylenetetrahydrofolate reductase C677T TT genotype with various coronary high risk profiles had clearly higher coronary heart disease scores than individuals with at least one C677T C allele.

Aim There is evidence that interaction between angiotensin II type 1 receptor A1166C gene polymorphism and angio-tensin I-converting enzyme Insertion/Deletion gene variation might have an effect on the risk of myocardial infarction. The study was carried out in a population of 2244 male Caucasians, whose coronary anatomy was defined by means of coronary angiography. We analysed the relationship, on the risk of ischaemic heart disease, of angiotensin II type 1 receptor A1166C gene variation, not only to myocardial infarction but also to coronary artery disease, and its potential interaction with angio-tensin I-converting enzyme Insertion/Deletion gene polymorphism. Methods and Results No association was detected between angiotensin II type 1 receptor A1166C gene polymorphism and coronary artery disease. Similarly, there was no link to myocardial infarction, either in the total population or in low risk groups. In addition, most importantly, we found no interaction between angiotensin II type 1 receptor A1166C gene variation and angiotensin I-converting Insertion/Deletion polymorphism, either in connection with the risk of coronary artery disease or myocardial infarction. Conclusion This angiotensin II type 1 receptor A1166C gene variation is not associated with any detectable increase in risk of ischaemic heart disease. The findings of the present study do not suggest that, as regards risk of coronary artery disease and myocardial infarction, there is interaction between gene polymorphism and angiotensin I-converting enzyme Insertion/Deletion gene variation. The European Society of Cardiology

The aim of this study was to assess the effect of two different calcium channel blockers on myocardial blood flow and function in a rat model of myocardial 'stunning' by repeated short episodes of ischaemia ('repetitive ischaemia'). In an open chest rat model, the left anterior descending coronary artery was ligated for 10 min followed by 15 min reperfusion. In total, five periods of ischaemia and reperfusion were performed. Myocardial blood flow was assessed by the hydrogen clearance technique and systolic thickening fraction by pulsed Doppler. After five episodes of ischaemia, myocardial blood flow adn myocardial thickening in the ischaemic area were reduced by 60 +/- 8% and 52 +/- 7% (n=9), respectively, as compared to baseline. Continuous intravenous infusion of the calcium channel blockers nifedipine (n=6) and gallopamil (n=6), started 20 min prior to onset of ischaemia, attenuated the ischaemia-induced decrease of myocardial perfusion. Nifedipine was the most effective with only 5 +/- 2% reduction in blood flow after five ischaemic episodes, whereas reduction of myocardial blood flow was 30 +/- 4% in the presence of gallopamil. However, neither nifedipine nor gallopamil were able to prevent regional ventricular dysfunction induced by repetitive ischaemia. Despite the preservation of myocardial blood flow following repetitive ischaemia, calcium channel blockers do not prevent ischaemia-induced reduction of myocardial function in the ischaemic area.

Multiprogrammable, automatic internal defibrillators with (n = 45) and without (n = 15) antitachycardia pacing features were implanted in 60 consecutive patients with refractory, malignant ventricular tachycardia (VT) (n = 42) or fibrillation (VF) (n = 18). Left ventricular (LV) ejection fraction was reduced to 39% +/- 12% as a result of structural heart disease in 56 patients. The complexity of the systems caused no additional risks to the surgical procedure or postoperative management. VT/VF detection parameters were individually adjusted to the arrhythmia type (detection cycle length 323 +/- 40 ms in patients with VF vs 405 +/- 40 ms for VT patients, P0.05) and incidence (longer detection periods if frequent nonsustained VT was also present). Shock energy was reduced in patients with VT as compared to VF (11J vs 24J, P0.05). Antitachycardia pacing was activated in 19/28 (68%) patients with well tolerated VT. Signal, telemetry, as detected by the device, combined with programmability allowed the device to be checked for correct decisions (these were inappropriate in four patients in three of whom corrections were non-invasive) prior to discharge. In conclusion, in the automatic tachyarrhythmia control devices we studied, programmability and flexibility appeared to be clinically safe and useful. Prolonged observation periods are required, however, to evaluate the true clinical safety and persistent efficacy of device programmability and flexibility.