Transmission of angiosarcomas from a common multiorgan donor to four transplant recipients.

We describe the donor tumor transmission of metastatic angiosarcomas to four transplant recipients through transplantation of deceased-donor organs, i.e. kidneys, lung and liver, from an apparently unaffected common female multiorgan donor. Fluorescent in situ hybridization of angiosarcoma cells confirmed that the tumor was of female donor's origin in male kidney recipients. Recent literature associated increased urokinase-plasminogen-activator-receptor (uPAR) and plasma soluble urokinase-plasminogen-activator-receptor (suPAR) levels with metastatic malignancies. Now we found that, compared to baseline levels, both deceased-donor kidney recipients showed increased uPAR transcripts in mononuclear cells as well as increased plasma suPAR levels after the diagnosis of metastatic angiosarcomas, i.e. 4 months after donor tumor transmission. These results show an association of uPAR/suPAR in donor tumor transmission of metastatic angiosarcomas in humans.

Possibilities and limitations of capillary electropherosis in pharmaceutical analysis.

Capillary electropherosis (CE) has been proved to be an important alternative to high-performance liquid chromatography (HPLC) in pharmaceutical analysis. However, when it comes to the analysis of compounds, e.g. impurities or metabolites, of very different polarity and water solubility CE and the related techniques come to its limits. This is demonstrated for the antipsychotic drug quetiapine and its impurities. A nonaqueous capillary electrophoresis (NACE) method was developed using a background electrolyte (BGE) composed of ammonium acetate dissolved in a mixture of acetonitrile and methanol including acetic acid to protonate the substances. The NACE method gave an excellent separation of all components. Since the conductivity of the BGE used in the NACE method is quite low and problems with current occurred, an additional aqueous capillary zone electrophoresis (CZE) method was developed for quetiapine and the two water soluble derivatives, using phosphate buffer as BGE. The method was validated with regard to repeatability and limit of detection.

Distribution of Chlamydia pneumoniae in the human arterial system and its relation to the local amount of atherosclerosis within the individual.

BACKGROUND: Chlamydia pneumoniae has been suggested to play a role in the origin of atherosclerosis. We studied the prevalence of C pneumoniae at multiple locations in the arterial system within the same individual. Studying the association between atherosclerosis and C pneumoniae within the individual excludes confounding by interindividual variability. METHODS AND RESULTS: Postmortem, the presence in the intima/plaque and media of C pneumoniae membrane protein was determined by use of a C pneumoniae-specific monoclonal antibody. In 24 individuals, 33 arterial locations were studied (n=738 segments). Area stenosis was determined in adjacent cross sections. In all individuals, immunostaining of C pneumoniae was observed in >/=1 artery. The highest prevalences were observed in the abdominal aorta (67%), internal and common iliac arteries (41%), and coronary arteries (33%). The lowest prevalences were observed in the radial (0%) and cerebral (2%) arteries. Within the individual, area stenosis was larger in cross sections with immunoreactivity compared with cross sections without immunoreactivity (31.0+/-11.9% versus 14.3+/-6.1%, respectively; P:<0.001). In the individual, immunoreactivity was observed in 15+/-10% of the arteries (range, 3% to 45%). Between individuals, the percentage of arteries with immunoreactivity to C pneumoniae was associated with the average area stenosis throughout the arterial system (r(2)=0.56, P:<0.001). CONCLUSIONS: C pneumoniae was mostly observed at locations that are related to clinically relevant features. Within the individual, the distribution of C pneumoniae is associated with the distribution of atherosclerosis. The role of the microorganism in atherosclerotic disease remains to be elucidated.

Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig.

BACKGROUND: Arterial remodeling after balloon angioplasty has been recognized as a major determinant of restenosis. Perturbation of collagen metabolism might be important. After balloon injury, matrix metalloproteinase (MMP) expression is upregulated. We investigated the effect of Batimastat, a nonspecific MMP inhibitor, on late lumen loss, arterial remodeling, and neointima formation after balloon dilation. METHODS AND RESULTS: In atherosclerotic iliac arteries of 12 Yucatan micropigs, balloon dilation was performed, with intravascular ultrasound and quantitative angiography used before and after balloon dilation and at 42-day follow-up. The animals were randomly divided into 2 groups, the Batimastat group (n=6) and the vehicle group (n=6). All animals were intraperitoneally injected with either Batimastat or a vehicle immediately after balloon dilation and at 2 weeks and 4 weeks after balloon dilation. Angiographic and echographic late lumen loss in the Batimastat group versus the vehicle group was 0.3+/-0.1 versus 0.8+/-0.1 mm (P=0.01) and 2.2+/-0.5 versus 4.9+/-0.7 mm(2) (P=0.004), respectively. Late media-bounded area loss was used as a measure of remodeling after balloon dilation and was 0.9+/-0.6 mm(2) in the Batimastat group compared with 3.8+/-0.8 mm(2) in the vehicle group (P=0.003, mixed model analysis P=0.01). Neointima formation was 1.3+/-0.3 mm(2) in the Batimastat group and 1.0+/-0.2 mm(2) in the vehicle group (P=0. 542). CONCLUSIONS: Metalloproteinase inhibition by Batimastat significantly reduced late lumen loss after balloon angioplasty by inhibition of constrictive arterial remodeling, whereas neointima formation was not inhibited by MMP inhibition.

Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition.

BACKGROUND: Constrictive vascular remodeling (VR) is the most significant component of restenosis after balloon angioplasty (PTA). Whereas in physiological conditions VR is associated with normalization of shear stress (SS) and wall stress (WS), after PTA the role of SS and WS in VR is unknown. Furthermore, whereas matrix metalloproteinase inhibition (MMPI) has been shown to modulate VR after PTA, its effect on the SS and WS control mechanisms after PTA is unknown. METHODS AND RESULTS: PTA was performed in external iliac arteries of 12 atherosclerotic Yucatan pigs, of which 6 pigs (7 vessels) received the MMPI batimastat and 6 pigs (10 vessels) served as controls. Before and after the intervention and at 6-week follow-up, intravascular ultrasound pullback was performed, allowing 3D reconstruction of the treated segment and computational fluid dynamics to calculate the media-bounded area and SS. WS was derived from the Laplace formula. Immediately after PTA, media-bounded area, WS, and SS changed by 20%, 16%, and -49%, respectively, in both groups. VR was predicted by SS and WS. In the control group, SS and WS had been normalized at follow-up with respect to the reference segment. In contrast, for the batimastat group, the SS had been normalized, but not the WS. The latter is attributed to an increase in wall area at follow-up. CONCLUSIONS: Vascular remodeling after PTA is controlled by both SS and WS. MMPI inhibited the WS control system.

Early outcome after off-pump versus on-pump coronary bypass surgery: results from a randomized study.

BACKGROUND: The use of cardiopulmonary bypass during coronary artery bypass surgery (CABG) has been associated with substantial morbidity. The recent introduction of cardiac stabilizers facilitates CABG without cardiopulmonary bypass (off-pump CABG), but it is unknown whether cardiac outcome after off-pump surgery is similar to that for the on-pump procedure. METHODS AND RESULTS: In a multicenter trial, 281 patients (mean age 61 years, SD 9 years) were randomly assigned to off-pump or on-pump CABG. In-hospital results and cardiac outcome and quality of life after 1 month are presented. Cardiac outcome was defined as survival free of stroke, myocardial infarction, and coronary reintervention. The mean numbers of distal anastomoses per patient were 2.4 (SD 1.0) and 2.6 (SD 1.1) in the off-pump and on-pump groups, respectively. Completeness of revascularization was similar in both groups. Blood products were needed during 3% of the off-pump procedures and 13% of the on-pump procedures (P<0.01). Release of creatine kinase muscle-brain isoenzyme was 41% less in the off-pump group (P<0.01). Otherwise, no differences in complications were found postoperatively. Off-pump patients were discharged 1 day earlier. At 1 month, operative mortality was zero in both groups, and quality of life had improved similarly. In both groups, 4% of the patients had recurrent angina. The proportions of patients surviving free of cardiovascular events were 93.0% in the off-pump group and 94.2% in the on-pump group (P=0.66). CONCLUSIONS: In selected patients, off-pump CABG is safe and yields a short-term cardiac outcome comparable to that of on-pump CABG.

Techniques characterizing the coronary atherosclerotic plaque: influence on clinical decision making?

The composition of the atherosclerotic lesion rather than the degree of stenosis is currently considered to be the most important determinant for acute clinical events. Modalities capable of characterizing the atherosclerotic lesion may be helpful in understanding its natural history and detecting lesions with high risk for acute events. Speaking grossly, three histologic features of the vulnerable plaque have been reported: size of the atheroma, thickness of the fibrous cap, and inflammation. Imaging techniques are currently being deployed and are under development to aid visualization of the vulnerable coronary plaque. Most of these diagnostic modalities have the potential to detect locally one or more of the three histologically defined features of vulnerable plaque. This review will focus on imaging techniques that have been developed to characterize the atherosclerotic lesion. Most catheter-based visualization techniques will provide insight into components of the local atherosclerotic plaque which may limit their predictive value for the occurrence of a clinical event. Therefore, the clinical relevance of these imaging tools will be discussed.

Proarrhythmic effects of ventricular electrical catheter ablation in dogs.

Electrical catheter ablation of arrhythmogenic sites is a new therapy for ventricular tachycardia that is still being investigated. Recent studies have shown, however, that the procedure itself can provoke serious ventricular arrhythmias. The incidence, course and mechanism of these arrhythmias were studied in 10 beagles treated with a single R wave-synchronized cathodal shock delivered to the endocardial ventricular wall (5 dogs left ventricular, 5 dogs right ventricular). Shocks were delivered at 30 (four dogs), 80 (two dogs) or 250 J (four dogs). Each dog underwent programmed electrical stimulation at or near the ablation site before, within 1 hour after and 1 week after the shock. Holter electrocardiographic monitoring (24 hours) was performed during day 1 and 7 after the shock in all the dogs, and extended Holter monitoring was done during the first 5 days in four dogs. All dogs survived for 1 week. Within 10 minutes after the shock, a sustained ventricular tachycardia was recorded in nine dogs; deterioration into ventricular fibrillation occurred in two dogs. In nine dogs, 60 to 169 monomorphic ventricular tachycardia episodes (mean 101) occurred on day 1 and 0 to 11 (mean 3) occurred on day 7; Holter monitoring failed for technical reasons in one dog. Extended Holter monitoring showed a marked decline in the incidence of tachycardia during the first 3 days. Early activation during ventricular tachycardia was always derived at or near the ablation site, and the QRS configuration during pre- and postablation pacing at this site was identical to the tachycardia configuration. Ventricular tachycardia was never inducible with programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrical catheter ablation in the left and right ventricular wall in dogs: relation between delivered energy and histopathologic changes.

Electrical catheter ablation of arrhythmogenic sites is now being used for the treatment of ventricular tachycardias. However, the extent and type of the ablation lesion in relation to energy level are controversial and not well known. In 10 beagles, single cathodal shocks of 30 (4 dogs), 80 (2 dogs) or 250 J (4 dogs) were delivered to the endocardial ventricular wall (5 dogs left ventricular, 5 dogs right ventricular). One week after ablation the dogs were killed for histopathologic examination. In the left ventricular wall, ablation lesion volumes calculated from measured extensions in three perpendicular directions were 0.4 and 0.9 cc at 30 J, 1.9 cc at 80 J and 2.8 and 3.4 cc at 250 J; in the right ventricular wall they were 0.4 and 0.5 cc at 30 J, 1.3 cc at 80 J and 2.5 and 4.2 cc at 250 J. In the right ventricular wall all 30 to 250 J lesions were transmural, whereas in the left ventricular wall only 250 J lesions were transmural. All lesions showed a necrotic area surrounded by granulation tissue with degenerated myofibrils. Thus, the size of the ablation lesion depends on delivered energy, whereas the pattern of histopathologic change is identical in the 30 to 250 J energy range. These results suggest that with accurate localization of the arrhythmogenic site one low energy shock may be successful with less myocardial damage.

Nonrandom ventricular rhythm in horses with atrial fibrillation and its significance for patients.

RR interval sequences during spontaneous atrial fibrillation in eight horses were analyzed as in previous studies in patients and dogs using histograms and serial auto-correlograms. In patients and dogs with spontaneous atrial fibrillation, ventricular rhythms were always random. In the horses, the histograms were skewed with median RR intervals of approximately 1,000 ms. A striking finding in these animals was the presence of long RR intervals up to 5,000 ms in duration. The shortest RR intervals lasted 400 to 600 ms. In contrast to findings in dogs and patients, the serial autocorrelograms showed periodicity that was reenforced by digitalis (n = 3), but eliminated by quinidine (n = 2) and atropine (n = 2). Quinidine and atropine eliminated the longer RR intervals, whereas digitalis increased the number of long RR intervals. In one horse, it was possible to measure intraarterial pressure, and large fluctuations in pressure were observed as the RR intervals varied from over 3,000 to less than 500 ms. It is postulated that these changes in blood pressure are associated with baroreceptor responses that may alter the electrophysiologic behavior of the atria and atrioventricular node. These changes cause the nonrandom patterns of ventricular rhythm in the horse. Because such very long RR intervals do not occur in human beings or dogs during atrial fibrillation, the random ventricular rhythm in these groups is maintained even during digitalis treatment.

Origin of arterial wall dissections induced by pulsed excimer and mid-infrared laser ablation in the pig.

To study adjacent tissue damage after delivery of holmium, thulium and excimer laser pulses, porcine thoracic aortas were irradiated in vivo. After 3 days, microscopic analysis of 67 craters produced by all three lasers demonstrated large dissections extending from the craters. The mean diameter of the dissections was smaller for excimer-induced craters (1.38 +/- 0.42 mm; n = 22) than for holmium-induced (2.7 +/- 0.87 mm; n = 22) and thulium-induced (2.37 +/- 0.42 mm; n = 14) craters (p less than 0.01 vs. mid-infrared dissections). In addition, microscopic analysis demonstrated necrosis adjacent to the crater. The lateral necrotic zones of the thulium-induced craters were smaller than the holmium- and excimer-induced necrotic zones (p less than 0.01). To identify the origin of the excessive tissue tearing, laser-saline and laser-tissue interaction were compared in vitro by time-resolved flash photography. In saline solution, the mid-infrared lasers showed bubble formation on a microsecond time scale. The excimer laser produced similar bubbles in the vicinity of tissue. For all three lasers, elevation of the tissue surface was shown during in vitro ablation. Dimension (diameter up to 4 mm) and time course (rise time of 100 to 300 microseconds) of bubble formation and tissue elevation were strikingly similar. Thus, tissue dissections are caused by the expansion of a vapor bubble within the target tissue. Coronary dissections after excimer and mid-infrared laser angioplasty might be related to the forceful bubble expansion.

Plaque burden, arterial remodeling and plaque vulnerability: determined by systemic factors?

OBJECTIVES: This study was designed to determine whether arterial remodeling and plaque vulnerability are influenced by systemic factors. BACKGROUND: Atherosclerotic luminal narrowing is caused by gradual plaque growth and arterial remodeling. In the acute phase, luminal narrowing may be accelerated by acute thrombus formation, usually precipitated by rupture of a vulnerable plaque. METHODS: Femoral arteries were obtained from elderly individuals at autopsy. Pairs of atherosclerotic femoral arteries from 42 individuals were examined. The arteries were divided in 1-cm intervals. Plaque size, the mode of arterial remodeling and histopathologic characteristics of plaque vulnerability (lipid-rich core and plaque inflammation) were compared between right and left femoral arteries obtained from the same individual. A role for systemic factors was assumed if a phenomenon was equally present in both arteries. RESULTS: There was concordance in average plaque size (r(2) = 0.5, p < 0.001), expansive remodeling (kappa = 0.42, p = 0.007) and occurrence of plaques containing a large lipid-rich core (kappa = 0.60, p = 0.001), but no concordance in plaque inflammation (kappa = 0.067, p = 0.61) between right and left arteries. CONCLUSIONS: These results suggest that not only the amount of atherosclerosis, but also arterial remodeling and lipid deposition in plaques, are influenced by systemic factors. The nonhomogeneous distribution of inflammation in atherosclerotic arteries supports the hypothesis that plaque inflammation is locally affected.

Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: the remodeling paradox.

OBJECTIVE: To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND: Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS: We obtained 1,521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS: Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections. Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION: Intraindividually, pathohistologic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.

Coronary artery bypass grafting without cardiopulmonary bypass and without interruption of native coronary flow using a novel anastomosis site restraining device ("Octopus").

OBJECTIVE: This study assessed the feasibility of coronary artery bypass grafting on the beating heart without interruption of native coronary blood flow using a novel anastomosis site restraining device. BACKGROUND: Recently, an end-to-side bypass technique was described that does not require interruption of flow in the recipient artery. METHODS: By means of a suction device ("Octopus"), in 31 pigs the epicardium was grasped and immobilized through an arm contraption fixed to the operating table. In the first 15 consecutive pigs (study I), the two-dimensional motion of an epicardial beacon was monitored. In 16 subsequent pigs (study II), an internal mammary artery was grafted under the microscope in two steps to a proximal coronary artery segment, without cardiopulmonary bypass. First, the internal mammary artery was sutured end-to-side to the outside of the coronary artery. Secondly, an orifice was punched in the partitioning coronary wall by an excimer laser catheter introduced through a temporary side-branch of the internal mammary artery. RESULTS: Study II: During 43 suction periods in four anastomosis areas, immobilization was achieved for 15 to 169 min (>30 h in total) in 13 open- and 9 closed-chest procedures without hemodynamic deterioration. The area circumscribed by the edges of the beacon trajectory (area in which the anastomosis is to be tracked) was reduced from 73.0 +/- 43.0 mm(2) (mean +/- SD) to 1.3 +/- 0.5 mm(2) (p<0.001) in the open-chest and to 0.2 +/- 0.2 mm(2) in the closed-chest procedure. At 6 weeks, no myocardial or coronary suction lesions were found. Study II: Nonocclusive anastomosis surgery required 25 +/- 3 min. No leakage, serious arrhythmias, graft closure or hemodynamic deterioration occurred during the procedure or for 2 h after ligating the coronary artery proximally. At 6 weeks, all seven grafts were patent. CONCLUSIONS: Coronary bypass on the beating heart without interruption of coronary flow is feasible. In both open- and in closed-chest procedures, the "Octopus" reduced anastomosis site motion to about 1 X 1 mm without adverse consequences.

Remodeling of De Novo atherosclerotic lesions in femoral arteries: impact on mechanism of balloon angioplasty.

OBJECTIVES: Using 30-MHz intravascular ultrasound in the human femoral artery, we related the mode of arterial remodeling to the immediate result and the mechanism of balloon angioplasty. BACKGROUND: The atherosclerotic femoral artery may undergo three modes of remodeling in response to plaque formation: compensatory enlargement, failure of compensatory enlargement and paradoxic shrinkage. METHODS: In 83 patients an ultrasound catheter pullback maneuver was performed before and after balloon angioplasty. For each lesion (n = 121), the cross section with the narrowest lumen was selected for further analysis. For each cross section, the lumen area stenosis was expressed as percent of the lumen area at an adjacent reference site. Similarly, the media-bounded area was expressed as percent of the media-bounded area at the reference site. Cross sections were classified into one of three groups based on percent relative media-bounded area: 1) > 105% (group A, compensatory enlargement, n = 24); 2) 95% to 105% (group B, failure of compensatory enlargement, n = 26); and 3) < 95% (group C, arterial wall shrinkage, n = 71). The power of the present study was 99.3% to demonstrate a difference in lumen gain of 2.5 mm2 among groups. RESULTS: The gain in lumen area induced by balloon angioplasty did not differ significantly among the three groups (group A, 7.0 +/- 4.0 mm2 [mean +/- SD]; group B, 8.6 +/- 4.8 mm2; group C, 8.9 +/- 4.9 mm2). Stretch of the media-bounded area was observed in all three groups, but it was significantly larger in group C (7.5 +/- 5.2 mm2) than in the other two groups (group A, 3.9 +/- 5.1 mm2; group B, 5.1 +/- 4.1 mm2). A significantly positive correlation between balloon/media-bounded area ratio and elastic recoil was observed for cross sections in groups A and B (r = 0.71 and r = 0.69, respectively). However, no correlation was observed between balloon/media-bounded area ratio and elastic recoil for cross sections in group C (r = 0.17). CONCLUSIONS: We conclude that lumen gain by balloon angioplasty is not related to the mode of atherosclerotic arterial remodeling. However, the mode of arterial remodeling affects the dilation mechanism.

Nonmuscle myosin heavy chain-B expression in balloon-dilated and stented arteries: a study in the atherosclerotic Yucatan micropig.

BACKGROUND: Restenosis after balloon angioplasty is in part due to remodelling, whereas restenosis after stenting is entirely due to neointima formation. Nonmuscle myosin heavy chain-B (NMMHC-B) is expressed by vascular smooth muscle cells and because of its overexpression in restenotic lesions after balloon angioplasty, NMMHC-B is proposed as a potential therapeutic target. Because the mechanisms underlying restenosis after balloon angioplasty or after stenting are different we hypothesised that the expression of NMMHC-B would differ in balloon-dilated versus stented arteries. METHODS: To study the localisation and time course of expression of NMMHC-B, we performed stenting or balloon dilation in peripheral arteries of 16 atherosclerotic Yucatan micropigs and used serial intravascular ultrasound (IVUS) and angiography to measure geometric dimensions following balloon angioplasty or stenting. In situ hybridisation techniques were used to detect NMMHC-B mRNA. 5'-bromo-2'-deoxyuridine (BrdU) was administered to detect proliferating cells. By counting the number of silver grains in the different layers of the artery, we could compare the amount of expression at the different time points between the groups. RESULTS: In intima and media, NMMHC-B expression increased after balloon dilation and stenting and peaked at 7 days. In stented arteries, the expression of NMMHC-B remained high for up to 42 days after injury, whereas in balloon-dilated arteries it had normalised. In the adventitia of balloon-dilated arteries, but not of stented arteries, NMMHC-B expression peaked at 7 days. NMMHC-B expression was not limited to proliferating cells. CONCLUSION: NMMHC-B is expressed near sites of active repair after arterial injury, but not limited to proliferating cells. The different pattern of NMMHC-B expression after balloon dilation compared with stenting may be related to arterial remodelling, because stented arteries that do not remodel lack this conspicuous adventitial expression at 7 days.

Off-pump coronary artery bypass surgery compared with stent implantation and on-pump bypass surgery: clinical outcome and cost-effectiveness at one year.

BACKGROUND: Coronary revascularisation by means of surgery or percutaneous intervention plays an important role in the management of patients with ischaemic heart disease. Coronary bypass surgery without cardiopulmonary bypass (off-pump surgery) has been reintroduced into clinical practice to avoid complications related to the use of cardiopulmonary bypass. It is unknown whether off-pump surgery can match the outcomes of bypass surgery with cardiopulmonary bypass (on-pump surgery) or intracoronary stent implantation. METHODS: The Octopus study comprised two multicentre randomised trials. In the Octopump trial, on-pump surgery was compared with off-pump surgery (139 vs. 142 patients). In the Octostent trial stent implantation was compared with off-pump surgery (138 vs. 142 patients). The primary cardiac endpoint was survival free from the following cardiovascular events: stroke, myocardial infarction and repeated coronary revascularisation. Secondary endpoints included quality of life and cost-effectiveness. The uncertainty surrounding the cost-effectiveness analysis was addressed by bootstrapping. RESULTS: Octopump trial: at one year, event-free survival in the on-pump group was 90.6% and in the off-pump group 88.0% (difference 2.6%, 95% CI-4.6 to 9.8). Quality-adjusted years of life were 0.83 and 0.82 (p=0.81), respectively. On-pump surgery was associated with €2089 (14.1%) additional direct medical costs per patient (p<0.01). Off-pump was more cost-effective than on-pump surgery in 95% of bootstrap estimates. Octostent trial: at one year, event-free survival in the stent group was 85.5% and in the off-pump surgery group 91.5% (difference -6.0%, 95% CI -13.5 to 1.4). Quality-adjusted years of life were 0.82 and 0.79 (p=0.09), respectively. Stent implantation reduced direct medical costs by €2813 (26.0%) per patient (p=0.01). Stent implantation was more cost-effective in 95% of bootstrap estimates. CONCLUSION: In selected patients eligible for bypass surgery, there was no difference in cardiac outcome between on-pump and off-pump surgery. Off-pump surgery, however, was more cost-effective than on-pump surgery and may be preferred from an economic perspective. In selected patients eligible for percutaneous coronary intervention, stent implantation was more cost-effective than off-pump surgery while maintaining comparable cardiac outcome. Therefore, stent implantation rather than off-pump surgery can be recommended as a first-choice revascularisation strategy.

Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications.

Arterial remodeling is currently being recognized as an important determinant in vascular pathology in which narrowing of the lumen is the predominant feature. Not only expansive remodeling (enlargement), but also constrictive remodeling (shrinkage) is observed in de novo atherosclerosis, in restenosis and in transplant vasculopathy. Expansive remodeling prevents and constrictive remodeling enhances luminal narrowing by plaque formation or intimal hyperplasia. The mechanisms of the opposite remodeling modes is unknown. Insight into the processes that determine the direction of local arterial remodeling may help to develop new strategies to prevent arterial occlusive disease. In the present paper the current status of research in the field of arterial remodeling in cardiovascular disease is reviewed. Mechanisms of arterial remodeling, potential interventions to influence the mode of remodeling as well as the methodological limitations of remodeling studies are discussed.

Angioscopic complex lesions are predominantly compensatory enlarged: an angioscopy and intracoronary ultrasound study.

OBJECTIVES: Atherosclerotic remodeling of the coronary artery may lead to compensatory enlargement or to shrinkage. Post-mortem data suggest a relation between compensatory enlargement and histopathological markers of plaque vulnerability. In patients that required a coronary intervention, we investigated retrospectively the relation between the angioscopic appearance and the remodeling mode of the culprit lesion. METHODS: In 34 patients, coronary angioscopy and intracoronary ultrasound (ICUS) imaging was performed across the culprit lesion before the intervention. Only single de novo lesions were included. With angioscopy, lesions with a smooth surface without thrombus were classified as smooth, whereas lesions with an irregular surface with or without thrombus were classified as complex. With ICUS, remodeling of the culprit lesions was determined by the relative cross-sectional vessel area (lesion vessel area/reference vessel area) x 100%. Lesions were divided into three groups: compensatory enlargement (relative vessel area > or = 105%), no-remodeling (relative vessel area between 95 and 105%) and shrinkage (relative vessel area < or = 95%). RESULTS: In 22 patients good images were obtained with both imaging modalities. More complex lesions were compensatory enlarged compared to shrunken lesions, whereas more smooth lesions were shrunken compared to compensatory enlarged lesions, 8/9 versus 2/7 and 5/7 versus 1/9, respectively (p = 0.035). CONCLUSIONS: In patients selected for coronary intervention, angioscopic complex atherosclerotic lesions were found predominantly in compensatory enlarged arterial segments, whereas smooth lesions were found predominantly in shrunken arterial segments.

The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: the natural history of remodeling.

OBJECTIVE: Remodeling in de novo atherosclerosis and in restenosis after balloon angioplasty constitutes a change in total arterial circumference which, together with plaque growth or neointimal formation, determines the lumen of the artery. To better understand the fundamental biology of neointimal formation, remodeling and their interaction, animal studies are needed. In this study, we described in detail the methodology used and the natural history of neointimal formation and remodeling after balloon angioplasty in atherosclerotic Yucatan micropigs. METHODS AND RESULTS: Atherosclerosis was induced in 60 peripheral arteries of sixteen Yucatan micropigs by a combination of denudation and atherogenic diet. Balloon angioplasty was performed in 38 arteries, with serial intravascular ultrasound (IVUS) and quantitative angiography before and after intervention and at 2, 4, 7, 14 or 42 days follow-up. Remodeling, expressed as late media-bounded area (MBA) loss, increased progressively over time. At 42 days, late MBA loss after balloon angioplasty was significantly different compared to late MBA loss in control arteries, 2.2 +/- 1.0 versus -0.3 +/- 1.1 mm2 and p = 0.02. Late lumen loss increased over time and was highest at 42 days after balloon angioplasty (2.8 +/- 0.7 mm2). The contribution of neointimal formation to late lumen loss decreased over time and the contribution of late MBA loss to late lumen increased over time and was highest at 42 days (78%). Medial necrosis was 48% at two days after balloon angioplasty and the repopulation of the media was almost completed at seven days. CONCLUSION: Remodeling following balloon angioplasty has an early onset and progresses with neointimal formation to cause restenosis over the standard 42-day time course for Yucatan micropigs. This correlates to six months renarrowing in humans. In this model, atherosclerosis and the natural history of restenosis, both with respect to neointimal formation and remodeling, resemble the human disease quite closely.