Prognostic value of ADAMTS13 in patients with severe sepsis and septic shock.

PURPOSE: ADAMTS13 level was evaluated as a predictor of mortality in patients with severe sepsis and septic shock, and compared with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. METHODS: This prospective observational study was conducted in the Medical and Surgical Intensive Care Units of King Khalid University Hospital. Detailed clinical evaluations were performed on 84 patients (56.08±18.18 years of age) with severe sepsis and septic shock. ADAMTS13 levels were determined (three blood samples at 24 hours intervals) and APACHE II scores, hematological profiles, indices of organ hypo-perfusion, renal functions and coagulation profiles were recorded. Primary outcome was 30 days ICU mortality and secondary outcomes were its comparison with APACHE II score, length of ICU stay and use of vasopressor agents. RESULTS: Hypertension (53.6%) and diabetic mellitus (45.2%) were the commonest comorbidities. The median ADAMTS13 levels were 336.65, 339.35 and 313.9, respectively. ROC analysis showed maximum area under the curve for second ADAMTS13 (AUC=0.760) compared with first (AUC=0.660) and third samples (AUC=0.707) and APACHE II scores (AUC=0.662). Patients were divided into low and high ADAMTS13 groups according to the best cut-off point. Mortality was high in the low ADAMTS13 level group [OR=4.5]and was significantly associated with age, DBP, ADAMTS13, APACHE II score, DIC score and platelet count. ADAMTS13 (OR=5.3), APACHE II (OR=4.13) and DIC scores (OR=7.32) were significant risk factors for mortality. CONCLUSIONS: Low ADAMTS13 was associated with increased mortality in patients with severe sepsis and septic shock and was comparable to APACHE II scores for predicting mortality.

Location of acute coronary artery thromboses in patients with and without chronic kidney disease.

Patients with chronic kidney disease have high rates of myocardial infarction and death following an initial attack. Proximal location of coronary atherosclerotic lesions has been linked to the risk of acute myocardial infarction and to infarction-associated mortality. To examine if the spatial distribution of lesions differs in patients with and without chronic kidney disease, we used quantitative coronary angiography to measure this in patients with acute coronary thromboses who were having angiography following acute myocardial infarction. Multivariable linear regression was used to adjust for differences in baseline characteristics. Among 82 patients with stage 3 or higher chronic kidney disease, 55.6% of lesions were located within 30 mm and 87.7% were within 50 mm of the coronary ostia. This compared to 34.7 and 71.8%, respectively, among 299 patients without significant kidney disease. Chronic kidney disease was independently and significantly associated with a 7.0 mm decrease in the distance from the coronary ostia to the problem lesion. Our study suggests that a causal link between a more proximal culprit lesion location in patients with chronic kidney disease and their high mortality rates after myocardial infarct is possible and may have important implications for interventions to prevent infarction.

Matrix metalloproteinase-9 modulation by resident arterial cells is responsible for injury-induced accelerated atherosclerotic plaque development in apolipoprotein E-deficient mice.

OBJECTIVE: Although matrix metalloproteinase-9 (MMP-9) has been implicated in atherosclerotic plaque instability, the exact role it plays in the plaque development and progression remains largely unknown. We generated apolipoprotein E (apoE)-deficient (apoE-/-) MMP-9-deficient (MMP-9-/-) mice to determine the mechanisms and the main cell source of MMP-9 responsible for the plaque composition during accelerated atherosclerotic plaque formation. METHODS AND RESULTS: Three weeks after temporary carotid artery ligation revealed that while on a Western-type diet, apoE-/- MMP-9-/- mice had a significant reduction in intimal plaque length and volume compared with apoE-/- MMP-9+/+ mice. The reduction in plaque volume correlated with a significantly lower number of intraplaque cells of resident cells and bone marrow-derived cells. To determine the cellular origin of MMP-9 in plaque development, bone marrow transplantation after total-body irradiation was performed with apoE-/- MMP-9+/+ and apoE-/- MMP-9-/- mice, which showed that only MMP-9 derived from resident arterial cells is required for plaque development. CONCLUSIONS: MMP-9 is derived from resident arterial cells and is required for early atherosclerotic plaque development and cellular accumulation in apoE-/- mice.

Beta3-integrin mediates smooth muscle cell accumulation in neointima after carotid ligation in mice.

BACKGROUND: Pharmacological blockade of beta3-integrins inhibits neointimal lesion formation in nonmouse animal models of arterial injury. In contrast, beta3-integrin-deficient (beta3-/-) mice are not protected from neointimal lesion formation after arterial injury. We investigated this discrepancy in beta3-/- and wild-type (beta3+/+) mice using different models of injury. METHODS AND RESULTS: After disruption of the carotid with a transluminal probe, there was no significant difference in neointimal thickening between beta3-/- and beta3+/+ mice. However, after ligation of the carotid without medial disruption, there was reduced neointimal thickening in beta3-/- mice compared with beta3+/+ mice at intervals up to 3 months. Lesion reduction in beta3-/- mice was associated with fewer intimal smooth muscle cells (SMCs) without a difference in SMC apoptosis or proliferation rate compared with beta3+/+ mice, consistent with reduced SMC migration from the media into the intima of beta3-/- mice. Moreover, combined eccentric medial disruption and ligation of the carotid in beta3-/- mice resulted in neointimal lesion formation only at the site of medial disruption. Transplantation of bone marrow cells harvested from beta3+/+ mice into irradiated beta3-/- mice resulted in reduced neointimal lesion formation after carotid ligation injury, confirming the importance of alpha(v)beta3 and not alpha(IIb)beta3 in the attenuated response. CONCLUSIONS: The alpha(v)beta3-integrin mediates intimal SMC accumulation that contributes to neointimal thickening in the setting of arterial ligation.

A model of primary atherosclerosis and post-angioplasty restenosis in mice.

Although mice deficient in various genes are providing greater insight into the mechanisms of restenosis after angioplasty, there have been limitations with murine models not simulating human vascular disease. To develop a more clinically applicable model of primary atherosclerosis and restenosis following angioplasty of the primary lesion, we fed apolipoprotein E-deficient mice a Western diet and occluded the left common carotid artery for 2 days. Three weeks after flow was restored, the temporarily occluded carotids demonstrated atherosclerotic lesions containing foam cells, cholesterol clefts, necrotic cores, and fibrous capsules. The atherosclerotic carotids in other animals underwent angioplasty with a beaded probe, resulting in plaque and medial layer disruption. Three weeks after angioplasty, although there was significant neointimal lesion formation, the luminal narrowing did not change significantly secondary to overall vessel enlargement (positive remodeling). Neointimal lesions were composed of smooth-muscle cells and extracellular matrix observed adjacent to the original atherosclerotic plaques. Similarly, even at 3 months after the angioplasty the lumen was maintained despite greater neointimal lesion formation caused by progressive positive remodeling. This new murine model of primary atherosclerosis and postangioplasty intimal hyperplasia and remodeling mimics the human disease pattern of postangioplasty intimal hyperplasia. Used in transgenic animals, this model will likely facilitate understanding of the mechanisms of restenosis in humans.

Grb2 is required for the development of neointima in response to vascular injury.

OBJECTIVE: Neointima formation occurs in arteries in response to mechanical or chemical injury and is responsible for substantial morbidity. In this work, the role of the intracellular linker protein Grb2 in the pathogenesis of neointima formation was examined. Grb2 is a critical signaling protein that facilitates the activation of the small GTPase ras by receptor tyrosine kinases. METHODS AND RESULTS: Cultured rat aortic smooth muscle cells were treated with an antisense morpholino to Grb2 and these cells showed a reduced proliferative response to platelet-derived growth factor stimulation. Grb2-/- mice do not survive embryonic development. Grb2+/- mice appear normal at birth and are fertile but have defective signaling in several tissues. Cultured smooth muscle cells derived from Grb2+/- mice grew at a much slower rate than cells derived from Grb2+/+ mice. Grb2+/- and Grb2+/+ mice were subjected to carotid injury. After 21 days, Grb2+/+ mice developed robust neointima formation that, in some cases, resulted in an occlusive lesion. In contrast, Grb2+/- mice were resistant to the development of neointima CONCLUSIONS: Grb2 is an essential component of the signaling cascade resulting in neointima formation after arterial injury.