Early effects of arterial hemodynamic conditions on human saphenous veins perfused ex vivo

Exposure to the arterial hemodynamic environment is thought to be a potential trigger for the pathological remodeling of saphenous vein grafts. Using matched pairs of freshly isolated human saphenous vein, we analyzed the early effects of ex vivo hemodynamic conditions mimicking the venous (native) compared with arterial (graft) environment on the key components of vascular remodeling, ie, matrix metalloproteinase (MMP)-9 and MMP-2 and cell proliferation. Interestingly, we found that arterial conditions halved latent MMP-9 (50+/-11%, P=0.01) and MMP-2 (44+/-6%, P=0.005) levels relative to matched vein pairs maintained ex vivo under venous perfusion for up to 3 days. Immunostaining supported decreased MMP levels in the innermost area of arterially perfused veins. Either decreased synthesis or increased posttranslational processing may decrease MMP zymogen levels. Biosynthetic radiolabeling showed that arterial perfusion actually increased MMP-9 and MMP-2 production. When we then examined potential pathways for MMP zymogen processing, we found that arterial conditions did not affect the expression of MT-MMP-1, a cell-associated MMP activator, but that they significantly increased the levels of superoxide, another MMP activator, suggesting redox-dependent MMP processing. Additional experiments indicated that increased superoxide under arterial conditions was due to diminished scavenging by decreased extracellular superoxide dismutase. Arterial perfusion also stimulated cell proliferation (by 220% to 750%) in the majority of vein segments investigated. Our observations support the hypothesis that arterial hemodynamic conditions stimulate early vein graft remodeling. Furthermore, physiological arterial flow may work to prevent pathological remodeling, particularly the formation of intimal hyperplasia, through rapid inactivation of secreted MMPs and, possibly, through preferential stimulation of cell proliferation in the outer layers of the vein wall.     

D-dimer testing: the role of the clinical laboratory in the diagnosis of pulmonary embolism

Pulmonary embolism is a common, yet often unsuspected and unrecognised disease associated with a high mortality. New, objective, "user friendly" and cost effective diagnostic strategies are being explored. D-dimers, the fibrinolytic degradation products of crosslinked fibrin, have emerged as the most useful of the procoagulant activity and ongoing fibrinolysis markers. D-dimer measurements are very sensitive in excluding a diagnosis of pulmonary embolism in the setting of normal values, a low clinical suspicion, and non-diagnostic lung scans. Several assays have been developed and are reviewed.     

Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial

Context  No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. Objective  To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. Design, Setting, and Participants  Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. Interventions  A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. Main Outcome Measure  Change in percent atheroma volume (PAV) from baseline to study completion. Results  Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, –0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (–0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA_1c levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, –0.68% to –0.42%) with pioglitazone and 0.36% (95% CI, –0.48% to –0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, –0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, –27.7 to –11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, –10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. Conclusion  In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. Trial Registration  clinicaltrials.gov Identifier: NCT00225277      

Mechanical stretching of human saphenous vein grafts induces expression and activation of matrix-degrading enzymes associated with vascular tissue injury and repair.

After coronary artery bypass surgery, saphenous vein graft occlusion occurs through tissue remodeling. Although a likely trigger, the role of preparative mechanical injury incurred by the graft is not yet understood. We studied the early effects of simple mechanical injury on human saphenous vein grafts by exposing them to longitudinal stretch, a deformation which potentially occurs during surgery. We then maintained ex vivo for up to 7 days matched pairs of experimentally stretched and nonstretched (control) vein segments and examined the expression and activation of matrix metalloproteinases (MMPs) and integrin alphav, molecules implicated in vascular remodeling. At peak expression on day 3, stretched vein secreted 177 +/- 16% active MMP-2 (P < 0.01), 161 +/- 36% (P < 0.05) pro-MMP-9, and contained 206 +/- 18% (P < 0.01) alphav, a receptor for active MMP-2, compared to control. In situ gelatinase activity was present in the intima and adventitia of stretched veins, but not of control, and correlated spatially with expression of alphav. Stretch also increased severalfold cell proliferation (1.27 +/- 0.4 vs. 0.23 +/- 0.05% in control, P < 0.05), as assessed by bromodeoxyuridine incorporation. Furthermore, we found that cell proliferation colocalized with gelatinase activity and alphav in the adventitia. Our results show that a single longitudinal stretch of vein grafts produces significant changes in the expression and activation of key molecules in vascular remodeling. We also found support for the notion that the adventitial layer contributes to vein graft remodeling.     

Transbrachial intra-aortic balloon pumping for high-risk percutaneous coronary intervention

The beneficial effect of placement of intra-aortic balloon (IAB) pump before revascularization in patients with high-risk coronary anatomy and impaired left ventricular systolic function is documented. However, the conventional insertion of IAB pump via the common femoral artery may be contraindicated or may be even impossible in patients with severe vascular disease. Recently, the percutaneous insertion of IAB via the brachial artery has been shown to be effective and safe in small series of patients with vascular disease undergoing coronary artery bypass surgery. The authors report their experience with a patient with aortobifemoral bypass grafts who underwent successful stenting of a trifurcating distal left main stenosis after placement of a 7.5-Fr IAB pump via the left brachial artery.     

Is inflammation a significant predictor of bile duct injury during laparoscopic cholecystectomy?

Background  Bile duct injuries (BDI) have been reported to occur more frequently during laparoscopic cholecystectomy (LC) compared to open cholecystectomy (OC). Several studies have demonstrated various potential predisposing factors for BDI. However, there is a controversy as to whether gallbladder inflammation is a significant predictor for BDI. Therefore, out primary aim was to investigate the relationship between inflammation and BDI at LC, and secondarily to present the management and clinical outcome of BDI. Methods  We recorded all consecutive LC performed between 1993 and 2005 in our institution by nine staff surgeons. BDI were classified according to Strasberg’s classification. Simple and multivariate logistic regression analysis was performed to evaluate the association between inflammation and BDI occurrence during LC. Results  There were 2,184 patients. Among those, 344 had inflammation (16%). The conversion rate was 5% and was higher among male, elder patients, and those with inflammation. The BDI incidence was 0.69% (0.14% for major and 0.55% for minor injuries) and it was significantly higher in those with inflammation compared to those without inflammation (p = 0.01). In particular, the risk for BDI was almost 3.5 times higher in those with inflammation (OR = 3.61, 95% CI 1.27–10.21). Inflammation remained an independent risk factor for BDI even after adjustment for potential confounders. Among patients sustaining injury, one died and two have recurrent cholangitis. No association was observed between clinical outcome and management of BDI, time of diagnosis, sex, and inflammation. Conclusion  We revealed that inflammation is an independent predictor of BDI occurrence during LC. Therefore, it would be advisable for surgeons to not hesitate to convert a LC to an OC in the presence of inflammation.     

Food-dependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing's syndrome: in vivo and in vitro studies

Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilaterally hyperplastic adrenals or unilateral adrenal adenomas is a rare form of adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-dependent manner, leading to the development of non-ACTH-dependent Cushing's syndrome. In the present study, we describe a novel case of a GIP receptor-expressive adrenocortical adenomatous nodule, detected incidentally by computed tomography scanning in a 41-yr-old lady with hirsutism but no clinical signs of Cushing's syndrome, on physical examination. Hormonal investigations in morning fasting samples showed slightly elevated androgen levels, low-normal baseline cortisol, normal suppression of cortisol after dexamethasone administration, and ACTH levels that were not suppressed and did stimulate after CRH administration. The elevated urinary free cortisol excretion, in conjunction with an atypical cortisol diurnal rhythm, raised the possibility of an aberrant stimulation of cortisol production by the adrenal tumor. Further studies demonstrated food-dependent secretion of cortisol, which was abolished by prior octreotide administration. Notably, substantial amounts of adrenal androgens were also secreted after food consumption. Removal of the tumor resulted in undetectable cortisol and androgen levels that did not respond to food consumption. Histological examination of the excised tumor revealed an adrenocortical adenomatous nodule originating from the inner zona reticularis, consisting mainly of compact cells. A steroidogenic secretory pattern, indicating the concomitant release of adrenal androgens and cortisol, was also observed in vitro from tumor cells cultured in the presence of GIP. The in vitro secretory response to GIP was higher for the adrenal androgen DHEA, compared with cortisol. The expression of the GIP receptor in tumor cells, but not in the adjacent normal adrenal, was demonstrated by RT-PCR), using specific oligonucleotide probes for this receptor. In summary, we describe a patient with a GIP-expressive cortisol and androgen oversecreting adrenocortical nodule with the unusual presentation of hirsutism and not the typical clinical signs of Cushing's syndrome. It is of note that food intake in this patient provoked a substantial increase in both adrenal androgen and cortisol levels that, together with the histological appearance of this nodule, was compatible with a zona reticularis-derived tumor. Thus, aberrant expression of the GIP receptor does not exclusively involve cells of a zona fasciculata phenotype, as previously reported, but may also occur in other types of differentiated adrenocortical cells.