Publications

Pulmonary inflammation and episodes of bacterial colonisation are central to the pathogenesis of COPD. COPD patients show insensitivity to glucocorticosteroids and alternative anti-inflammatory therapies including p38 mitogen activated protein kinase (MAPK) inhibitors are currently being investigated in clinical trials. However, concerns still exist about off-target effects. We investigated the effect of two p38 MAPK inhibitors, VX745 and SCIO469 on macrophage innate immune cell function. Monocyte-derived macrophages (MDM), or alveolar macrophages (AM) from bronchoalveolar lavage (BAL) and lung sections from healthy volunteers or COPD patients were challenged with either fluorescently-labelled heat-killed or non-labelled live serotype 14 Streptococcus pneumoniae (Spn). Phagocytosis of Spn was assessed at 4 hours fluorometrically or by measuring intracellular viable bacteria at 4 hours by gentamicin protection assay. Opsonisation of bacteria increased Spn internalisation in healthy and COPD MDM (Healthy:3.2+/-0.3 vs 4.2+/-0.19 log10CFU/ml, n=7 p<0.01. COPD:2.9+/-0.5 vs 3.8+/-0.3 log10CFU/ml, n=8, p<0.01) but only healthy AM (3.7+/-0.5 vs 4.7+/-0.6, n=4, p<0.05). MDM and AM from COPD patients exhibited lower levels of internalisation compared to healthy controls (3.7+/-0.5 healthy AM, n=5 vs 2.8+/-0.3 COPD AM log10CFU/ml, n=7 p<0.01). The presence of VX745 or SCIO469 had no effect on internalisation of opsonised or non-opsonised bacteria in either healthy or COPD MDM or AM. In conclusion, COPD reduced bacterial internalisation but was not altered by modulation of p38 MAPK. Importantly, p38 MAPK inhibitors had no detrimental effect on bacterial phagocytosis.

Because many ongoing clinical restenosis prevention trials are using quantitative angiography to assess whether a drug is capable of reducing the amount of intimal hyperplasia, quantitative angiographic risk factors for angiographic luminal narrowing after balloon angioplasty were determined, including stretch and elastic recoil at the dilatation site. Quantitative analysis was performed on 666 lesions in 575 patients during angioplasty and at 6-month follow-up. Stretch was defined as balloon diameter minus minimal luminal diameter (MLD) before angioplasty/reference diameter, and recoil as balloon diameter minus MLD after angioplasty/reference diameter. Multivariate analysis was used to yield independent risk factors for luminal narrowing at follow-up. Predictors of absolute change in MLD were (1) relative gain at angioplasty (gain in millimeters normalized for reference diameter) and (2) lesion length. To allow risk stratification, logistic regression analysis was applied using the decrease in MLD as a binary outcome variable. A decrease in MLD at follow-up of ≥ 0.72 mm was considered significant. Variables retained in the model were: relative gain > 0.3 mm (rate ratio 2.9), relative gain 0.2 to 0.3 (rate ratio 2.1), stenosis length ≥ 6.8 (rate ratio 1.7), and thrombus after angioplasty (rate ratio 2.6). Although stretch was significantly related to luminal narrowing at univariate analysis, it was not retained in the multivariate models. A large gain in lumen diameter at angioplasty, dilation of long lesions, and angiographically determined thrombus after angioplasty were found to be accompanied by more severe luminal narrowing at follow-up.

No abstract is provided for this article.

Objectives We sought to investigate whether plaques located in the left main stem (LMS) differ in terms of necrotic core content from those sited in the proximal tract of the left coronary artery. Background Plaque composition, favoring propensity to vulnerability, might be nonuniformly distributed along the vessel, which might explain the greater likelihood for plaque erosion or rupture to occur in the proximal but not in the distal tracts of the coronary artery or in LMS. Methods A total of 72 patients were included prospectively; 48 (32 men; mean age 57 ± 11 years; 25 with stable angina and 23 affected by acute coronary syndromes) underwent a satisfactory nonculprit vessel investigation through spectral analysis of intravascular ultrasound radiofrequency data (IVUS-Virtual Histology, Volcano Corp., Rancho Cordova, California). The region of interest was subsequently divided into LMS and LMS carina, followed by 6 consecutive nonoverlapping 6-mm segments in left anterior descending artery in 34 patients or in circumflex artery in 14 patients. Results Necrotic core content (%): 1) was minimal in LMS (median [interquartile range]: 4.6 [2 to 7]), peaked in the first 6-mm coronary segment (11.8 [8 to 16]; p < 0.01), and then progressively decreased distally; 2) was overall greater in patients with acute coronary syndromes (11.4 [5.5 to 19.8]) than stable angina (7.3 [3.2 to 12.9]; p < 0.001); 3) was largely independent from plaque size; and 4) did not correlate to systemic levels of C-reactive protein or lipid profile. Conclusions Plaques located in the LMS carry minimal necrotic content. Thus, they mimic the distal but not the proximal tract of the left coronary artery, where plaque rupture or vessel occlusion occurs more frequently.

No abstract is provided for this article.

Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality despite the widespread use of established medical therapies. This has prompted the search to identify new therapeutic approaches to achieve more effective prevention of cardiovascular events. Considerable interest has focused on the role of surrogate markers of therapeutic efficacy in the early evaluation of novel anti-atherosclerotic therapies. Monitoring changes in the extent of coronary atherosclerosis with intravascular ultrasound (IVUS) has been increasingly employed in clinical trials to assess progression and regression of atherosclerosis. This is based on the pivotal role that atherosclerotic plaque plays in the natural history of cardiovascular disease and the acceptance of validated arterial imaging approaches including coronary angiography and carotid intimal-medial thickness by regulatory authorities. The ability to generate high-resolution imaging of the entire thickness of the coronary artery wall permits evaluation of the entire burden of atherosclerotic plaque. In order to understand the differences, similarities, limitations and pitfalls of the IVUS technique among different academic core laboratories, a number of meetings of representatives from these groups were convened in 2007 and 2008. This document is the result of those IVUS methodology meetings that assembled experts from core laboratories to discuss standards for image acquisition, definitions, criteria, analyses, and primary and secondary endpoints.

In this first multicentre study we assessed the safety and efficacy of percutaneous transendocardial skeletal myoblast injection as a stand alone procedure in congestive heart failure patients.15 patients (14 male), age 63+/-7 (Mean+/-SD), NYHA class 2-4 were injected with 216+/-119 cells (81+/-19% Desmin+) using a NOGA or fluoroscopy guided injection catheter. The cells were injected in the scarred regions 6+/-4 years after myocardial infarction as a stand alone procedure. After treating the first 6 patients, the protocol was amended to require that remaining patients be fitted with an ICD prior to the cellular cardiomyoplasty procedure. Holter monitoring, ECG and ICD readings were obtained at multiple intervals. Stress echocardiography and LV angiography was performed at baseline, 3, 6 and 12 months post procedure.After 1 year follow-up 13 patients were still alive. Patient # 6 died suddenly 9 days post procedure. Patient #15 (ICD patient) survived an electrical storm 12 days post procedure, but died 2 days later due to cardiogenic shock. Two non-ICD patients received an ICD because of observed ventricular arrhythmias. It remains unknown whether these events are directly related to the cell injections.LV ejection fraction (%) changed from 34.4+/-10.3 to 36.6+/-10.4 (baseline versus 12 months FU, p=0.26). Wall motion score index improved both at rest (3.0+/-0.5 to 2.7+/-0.7, p=0.049) and under low-dose dobutamine stress (2.8+/-0.4 to 2.5+/-0.6, p=0.07, baseline versus 12 months FU).Percutaneous autologous skeletal myoblast injection is feasible, resulting in wall motion and functional class improvement, but is potentially associated with an increased risk for ventricular arrhythmias. Randomised studies are needed, however, to further assess overall safety, efficacy and the potential for initial increased risk for arrhythmia following cell injection in these high-risk patients.

Objectives The aim of this study was to assess the 6-year clinical outcome after unrestricted use of sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) as compared with bare-metal stents (BMS) in consecutive de novo patients undergoing percutaneous coronary intervention (PCI). Background SES and PES have been shown to significantly decrease target vessel revascularization (TVR) rates compared with BMS in “real-world” registries. However, possible higher rates of very-late stent thrombosis and a restenosis “catch-up” trend might jeopardize the benefit. Methods Three PCI cohorts, each with exclusive use of 1 stent type (BMS = 450; SES = 508; PES = 576), were systematically followed for the occurrence of major adverse cardiac events (MACE). Results Very-late stent thrombosis was more common in SES and PES patients than BMS patients (2.4% vs. 0.9% vs. 0.4%, respectively; p = 0.02); however, there were no significant differences between the stent types for all-cause mortality and all-cause mortality/myocardial infarction at 6-year follow-up. Sixty-nine SES patients (Kaplan-Meier estimate 14%) and 72 PES patients (14%) had a TVR, as compared with 79 BMS patients (18%; log-rank p = 0.02), which maintained significance after adjustment for (potential) confounders. Multivariate analysis showed that DES implantation is associated with lower incidence of TVR and MACE than BMS implantation (hazard ratio: 0.65, 95% confidence interval: 0.49 to 0.86; p = 0.003; hazard ratio: 0.79, 95% confidence interval: 0.65 to 0.97; p = 0.02, respectively). Incidence of MACE was also lower in SES and PES patients (30% and 30%, respectively) than in BMS patients (34%); however, significance was borderline. Conclusions The unrestricted use of both DES resulted in a sustained advantage in decreasing TVR and, to a lesser extent, MACE compared with BMS at 6 years. The SES and PES are equally safe and effective in the treatment of coronary lesions.

Objectives. Late lumen narrowing after directional coronary atherectomy was assessed by quantitative coronary angiography and compared with that after balloon angioplasty. Background. Directional coronary atherectomy has been introduced as an alternative technique for balloon angioplasty and may reduce the incidence of restenosis. Methods. A prospectively collected consecutive series of 87 native coronary artery lesions successfully treated with atherectomy were matched with 87 coronary artery lesions selected from a consecutive series of lesions that had been successfully dilated by balloon angioplasty. Late angiographic analysis was performed in 158 lesions. The net gain index represents the ultimate gain in minimal lumen diameter at follow-up study, normalized for the vessel size. This index is the result of the relative gain attained during the procedure (the ratio of the change in minimal lumen diameter and reference diameter) and the relative loss observed during the follow-up period (the ratio of the change in minimal lumen diameter during the follow-up period and the reference diameter). Results. Matching for clinical and angiographic variables resulted in two comparable groups with similar baseline stenosis characteristics. Atherectomy resulted in a more pronounced increase in minimal lumen diameter than did balloon angioplasty (mean ± SD 1.17 ± 0.29 to 2.44 ± 0.42 mm vs. 1.21 ± 0.38 to 2.00 ± 0.36 mm, p < 0.001). However, this favorable immediate result was subsequently lost during late angiographic follow-up, so that the minimal lumen diameter at follow-up and the net gain index did not differ significantly between the two groups (1.76 ± 0.62 vs. 1.77 ± 0.59 nun, p = 0.93, and 0.18 ± 0.19 vs. 0.17 ± 0.17, p = 0.70). Consequently, ths relative gain and relative loss were higher in the atherectomy group. For both techniques, the relative gain was linearly related to the relative loss but the slope of the regression line was steeper for atherectomy, suggesting that the relative loss in the atherectomy group is proportionally even larger for a given relative gain compared with that in the angioplasty group. Conclusions. In matched groups of patients, atherectomy induces a greater initial gain in minimal lumen diameter than does balloon angioplasty. However, the vascular wall injury induced by the device is of a different nature (debulking vs. dilating) that leads to more relative loss over the follow-up period in the atherectomy group.