Ulla-Stina Salminen

Biodegradation of the copolymeric polylactide stent : Long-term follow-up in a rabbit aorta model

The behavior of biodegradable polylactide as a stent material has not yet been fully established in small vessels such as arteries with a diameter <3 mm. The aim of this study was to investigate the long-term effect of a copolymeric polylactide (PLA96) stent. Appropriately sized spiral PLA96 stents were implanted into the infrarenal aortas of 20 rabbits. Intraoperative systemic heparinization (150 IU/kg), perioperative subcutaneous enoxaheparin sodium (10 mg), ticlopidine (250 mg/day) for 1 month, and acetosalicylic acid (12.5 mg/day) were continuously administered. Animals were euthanized according to a fixed timetable for up to 34 months for histologic and scanning-electron-microscopic assessment. Endothelialization was complete within 1 month. In 2 of the 3 aortas sampled 3 months after implantation, a mild inflammatory reaction was visible, with no sign of granulomatous or foreign-body reaction in the vessel wall. Instead, in 1 sample examined at the same time point, neointimal chondroid metaplasia was detected. After 6 months, inflammatory reaction declined in the vessel wall. Hydrolyzation of the stent was histologically evident at 12 months, with mild foreign-body reaction detectable in 2 of 5 aortas sampled at this time point. The stent disintegrated without fragmentation by 24 months, as it was gradually replaced by fibrosis. The vessel lumen remained patent at all time points. We conclude that the PLA96 stent degraded with minimal tissue response within 24 months. PLA96 may thus be a promising stent core material for small vessels in the future, although further investigation is needed to establish its final biocompatibility.

Reperfusion injury associated with one-fourth of deaths after coronary artery bypass grafting.

BACKGROUND This study of reperfusion injury after coronary artery bypass grafting focuses on its contribution to fatal outcome, on its connection with myocardial infarction (MI) and on risk factors. METHODS A consecutive series of 190 patients (mean age 61.7+/-8.9 years) dying within 30 days following coronary artery bypass grafting was autopsied with concomitant postmortem angiography during 1980 to 1993. RESULTS Reperfusion injury was revealed in 49 (25.8%) patients, with concomitant MI in almost all (46 of 49) (p < 0.01). Reperfusion injury occurred in association with preoperative New York Heart Association (NYHA) III classification (p < 0.05), coronary endarterectomy (p < 0.01), long aortic clamping time (p < 0.01), and short postoperative survival (p < 0.05). CONCLUSIONS Reperfusion injury was observed in one fourth of the deaths in association with MI. It occurred more often in patients with preoperative NYHA III symptoms and in those in whom endarterectomy was carried out and the anoxic time of the myocardium was longer. The shorter postoperative survival time indicates the lethal nature of this complication.

Tumor necrosis factor-?? in a porcine bronchial model of obliterative bronchiolitis1

Background. In posttransplant obliterative bronchiolitis (OB), the major pathologic features are inflammation, epithelial cell injury, fibrosis, and obliteration of the small airways. Tumor necrosis factor (TNF)-&agr; is a cytokine known to mediate and augment the inflammatory reaction and to enhance fibroblast proliferation. We assessed the role of TNF-&agr; in the development of OB in our heterotopic porcine bronchial transplantation model. Methods. Three groups were formed: autografts, nontreated allografts, and allografts treated with preoperative anti–TNF-&agr; monoclonal antibody (infliximab) infusion. The implants were harvested on days 2, 4, 7, 11, 14, 21, and 28 for histologic and immunohistochemical analysis. Results. TNF-&agr; inhibition reduced inflammation, rate of epithelial loss, fibrosis, and obliteration early in the development of OB. In the epithelium, the numbers of TNF-&agr;–positive epithelial and inflammatory cells and macrophages were significantly lower in treated than in nontreated allografts on day 4; furthermore, in the epithelium and in the bronchial wall, invasion of CD8+ lymphocytes was significantly decreased during the first week. Conclusions. These results indicate that TNF-&agr; promotes the development of OB, and inhibition of TNF-&agr; may prove beneficial in a clinical setting.

POST-MORTEM CAST ANGIOGRAPHY IN THE DIAGNOSTICS OF GRAFT COMPLICATIONS IN PATIENTS WITH FATAL OUTCOME FOLLOWING CORONARY ARTERY BYPASS GRAFTING (CABG)

Abstract The advantages and limitations of a novel post-mortem angiographic method using solidifying silicone rubber and lead oxide as a contrast medium in detecting coronary artery graft complications on a routine basis were evaluated in a series of 223 consecutive patients with fatal outcome within 30 days following coronary artery bypass grafting (CABG). Of these patients, 166 (74.4%) were male and 57 (25.6%) female (mean age 61.9 ± 9). Coronary grafts totalled 660 (3.0 per patient) with 517 aortic and 838 coronary anastomoses. At autopsy, the rubber cast model of the grafts and coronary arterial tree was exposed by a bend scalpel and sites of possible complications were examined. Post-mortem angiographs were re-evaluated and compared with preoperative angiographs and dissection findings. By combining the findings of angiography and heart dissection, 122 (54.7%) of the 223 patients were found to have some type of complication of the graft or the anastomosis. The diagnostic sensitivity and specificity of postmortem angiography was 100% in assessing narrowing or twisting of the graft as well as narrowing of the aortal anastomosis, whereas these findings were revealed with difficulty by autopsy dissection only. In cases with correct x-ray projection, narrowing and occlusion of the proximal aortal and distal coronary anastomosis were also reliably revealed by angiography. In contrast, graft thrombosis was clearly overdiagnosed by angiography, leading to a lower specificity (84%) but high sensitivity (100%) in detecting this complication. Post-mortem angiography also failed to detect dissection of the wall of the graft or anastomosis. Technical problems with this angiographic method were due to too low perfusion pressure, too rapid polymerizing of the silicone rubber, leakage of contrast medium into the ventricles, or faulty x-ray projections. These results suggest that our post-mortem angiographic technique, yielding a permanent rubber- cast model of the graft and anastomosis site, improves the accuracy of diagnostics of postoperative CABG complications and eases postoperative autopsy dissection, which can now be directed to confirm suspected complications.

Prevention of small airway obliteration in a swine heterotopic lung allograft model

BACKGROUND In our swine model of obliterative bronchiolitis preventing obliteration by the standard immunosuppression with cyclosporine, methylprednisolone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmune reaction and obliteration of the allografts. This regimen includes the novel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin. METHODS Donor lung allografts of 1 cm3 were implanted sub-cutaneously into 11 random-bred non-related domestic pigs receiving daily oral cyclosporine (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals received either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/kg) (Group 2). Histologic alterations were graded from 0 to 3 based on repeatedly removed implants during a follow-up period of 3 months. RESULTS Total epithelial destruction and permanent luminal obliteration occurred within 37 days in Group 1. After an initial grade of 2.3+/-0.3 destruction, epithelial recovery was evident in Group 2 (P < 0.01), and the bronchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0.05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were destroyed in Group 1, but preserved in Group 2 with total recovery after a mild-grade initial necrosis. CONCLUSIONS Unlike the standard triple therapy, SDZ RAD combined with cyclosporine and methylprednisolone preserves the pulmonary allografts and prevents epithelial destruction and subsequent luminal obliteration. This suggests that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.

Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis.

BACKGROUND To study obliterative bronchiolitis (OB), we have developed a porcine heterotopic bronchial model. Allografts obliterate within 3 weeks, the immunosuppression cyclosporine (CsA)-azathioprine (AZA)-methylprednisolone (MP) delays OB, but OB is prevented when AZA is switched to 40-0-(2-hydroxyethyl)-rapamycin (RAD). To characterize our model, we studied immune cells under various immunosuppressive conditions. METHODS The groups studied were autografts (U), allografts (A), and allografts given either CsA-RAD-MP (R), or CsA-AZA-MP (C). The implants were harvested at 3, 7, 10, 14, 21, 30, 60, and 90 days after transplantation. Epithelial damage and obliteration were graded histologically, and the number of CD4, CD8, MHC class II expressing cells, macrophages, and B lymphocytes were counted (mean+SEM)/high-power visual field. RESULTS In group U, normal epithelium was regained with no obliteration and only few immune cells. In group A, consistent with initially acute ejection, an influx of CD4 (105+23), CD8 (166+23), and class II (92+20) cells was seen up to day 21, when total obliteration preceded by epithelial destruction had already developed. Some macrophages were seen and B cells were scarce. In group R, epithelial damage and obliteration were insignificant, but moderate numbers of CD4, CD8, and class II cells were seen. In group C, epithelial damage and obliteration were only delayed, but the immune cell response was clearly blunted. CONCLUSIONS In our model, rejection with significant immune cell influx was still active when obliteration was total in nontreated allografts. In immunosuppressed allografts, decrease in the number of immune cells alone did prevent OB. These results support OB being T-cell mediated. RAD may have additional important effects on growth factors and proliferation in prevention of OB.

Recurrence and Malignant Transformation of Endotracheal Chondroma

An endotracheal chondroma with recurrent course and malignant transformation is described. The first chondroma recurrence appeared 5 years after the primary operation, with no histopathological signs of malignancy. A second recurrence after a further 6 years showed obvious histological evidence of malignant chondrosarcoma. A third recurrence after 1 more year metastasized to various organs and led to the patients death 14 years from the date of primary diagnosis.

Alloimmune injury preceding airway obliteration in porcine heterotopic lung implants: a histologic and immunohistologic study.

BACKGROUND Obliterative bronchiolitis (OB), the major long-term complication of lung transplantation, has thus far lacked a good large-animal model. Our goal was to develop such a model on the basis of previous rodent models with tracheal implants. METHODS Fragments of pulmonary tissue with structures of terminal bronchi were subcutaneously transplanted to four random-bred domestic piglets. Each animal received 10 autograft and 10 allograft implants. The histologic findings were graded from 0 to 3 for implants harvested repeatedly over 2 months. RESULTS In autografts, partial destruction of the respiratory epithelium and gradual luminal obliteration as well as mild damage to the cartilage and the bronchial wall underwent rapid reversal after initial ischemic injury. In the allografts, epithelial destruction and gradual obliteration were total within 14 days, the difference being statistically significant (P<0.05) in both. The histologic features of the obliterative plug were similar to those of human OB. In the allografts, cartilaginous destruction and pericartilaginous inflammation increased gradually to severe levels, significantly worse than in the autografts (P<0.05). Necrosis and inflammation of the bronchial wall were also more severe in the allografts (P<0.05). CONCLUSIONS At the end of follow-up, all autografts were vital, whereas the allografts were almost totally rejected and were without native structures. All bronchi in the allografts exhibited accelerated obliteration with histologic features characteristic of human OB, thus providing a model for research into OB and its prevention.

Indications for and risks in reoperation for coronary artery disease

Seventy-one coronary artery bypass grafting (CABG) reoperations were performed during a 17-year period, comprising 2.7% of all CABG operations. The main indication (in 87%) was vein graft failure alone or combined with other causes. Progression of disease in native coronary arteries was the sole indication in only 4 of the 71 cases. There were seven perioperative deaths, mainly due to myocardial infarction. Significant perioperative complications arose in 36 cases, including intraoperative lesion of a previous left internal mammary graft (16.2%) or of the right ventricle or anterior descending branch of the left coronary artery (2.8%). Postoperative low output syndrome appeared in 13 patients (18.3%), in seven of whom myocardial infarction was verified. Postoperative bleeding required resternotomy in six cases (9.1%). Because of the heightened operative mortality and morbidity risks, indications for redo CABG should be individualized. A well functioning internal mammary artery graft may be a relative contraindication. Accurate knowledge of the previous operation is essential and, especially in young patients, the possibility of reoperation should be taken into consideration at initial CABG.

Cyclooxygenase-2 expression in experimental post-transplant obliterative bronchiolitis

Epithelial cell injury, inflammation, progressive fibrosis, and airway obliteration are histological features of post‐transplant obliterative bronchiolitis (OB). Cyclooxygenase (COX)‐2 is expressed in acute and chronic inflammatory responses. Our aim was to elucidate the possible role of COX‐2 in post‐transplant OB by using a heterotopic bronchial porcine model. Bronchial allografts from non‐related donors were transplanted subcutaneously into 24 random‐bred domestic pigs, each weighing about 20 kg. Groups studied had grafts, non‐treated allografts, allografts given cyclosporine A (CsA), methylprednisolone (MP), and azathioprine (Aza), and allografts given CsA, MP, and everolimus. Grafts were serially harvested during a follow‐up period of 21 days for histology (H&E) and immunohistochemistry. Immunostaining was performed with monoclonal IgG against human COX‐2 peptide, and histological alterations and immunohistochemical positivity were graded on a scale from 0 to 5. Epithelial COX‐2 index was calculated by multiplying the percentage of positive cells by grade of epithelial COX‐2 intensity. Ischaemic epithelial loss, evident in all implants, recovered rapidly in autografts, and bronchi remained patent. Epithelial loss in non‐treated allografts preceded fibroblast proliferation, resulting in total luminal obliteration. In CsA‐, MP‐, and Aza‐treated allografts epithelial destruction and luminal obliteration were delayed, and these were prevented in CsA‐, MP‐, and everolimus‐treated allografts. COX‐2 expression due to operative ischaemia was evident in all implants on day 2. Thereafter, the epithelial COX‐2 index preceded epithelial injury and obliteration. During the inflammatory response and fibroblast proliferation, COX‐2 expression occurred in macrophages and fibroblasts. In conclusion, in the early stage of OB development, COX‐2 induction occurred in airway epithelial cells prior to luminal obliteration. In addition, the observation that COX‐2 expression in macrophages and fibroblasts paralleled the onset of inflammation and fibroblast proliferation indicates a role in OB development, but the causal relationships need further study. Copyright