TF contributes to the procoagulant activity of most atherosclerotic lesions treated with DCA. The association of immunohistochemically detectable TF with plaque thrombus suggests that TF plays a role in coronary thrombosis. Diminished TF expression in restenotic lesions may in part account for the lower complication rate that has been associated with DCA of restenotic versus de novo lesions. Inhibition of TF may represent a therapeutic goal for the prevention of thrombotic complications associated with percutaneous coronary interventions.

Heart transplant rejection is characterized pathologically by myocyte necrosis and apoptosis associated with interstitial mononuclear cell infiltration. Any one of these components can be targeted for noninvasive detection of transplant rejection. During apoptotic cell death, phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, gets exteriorized. Technetium-99m-labeled annexin-V, an endogenous protein that has high affinity for binding to phosphatidylserine, has been administered intravenously for noninvasive identification of apoptotic cell death. In the present study of 18 cardiac allograft recipients, 13 patients had negative and five had positive myocardial uptake of annexin. These latter five demonstrated at least moderate transplant rejection and caspase-3 staining, suggesting apoptosis in their biopsy specimens. This study reveals the clinical feasibility and safety of annexin-V imaging for noninvasive detection of transplant rejection by targeting cell membrane phospholipid alterations that are commonly associated with the process of apoptosis.

The molecular basis of human heart failure is unknown. Alterations in calcium homeostasis have been observed in failing human heart muscles. Intracellular calcium-release channels regulate the calcium flux required for muscle contraction. Two forms of intracellular calcium-release channels are expressed in the heart: the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (LP3R).In the present study we showed that these two cardiac intracellular calcium release channels were regulated in opposite directions in failing human hearts. In the left ventricle, RyR mRNA levels were decreased by 31% (P < 0.025) whereas IP3R mRNA levels were increased by 123% (P < 0.005). In situ hybridization localized both RyR and IP3R mRNAs to human cardiac myocytes. The relative amounts of IP3 binding sites increased -40% compared with ryanodine binding sites in the failing heart. RyR down-regulation could contribute to impaired contractility; IP3R up regulation may be a compensatory'response providing an alternative'pathway for mobilizing intracellular calcium release, possibly contributing to the increased. diastolic tone associated with heart failure and the hypertrophic response of failing myocardium. (J. Clin. Invest. 1995. 95:888-894.)

Thrombosis is integral to the development and progression and clinical sequelae of atherosclerosis. Acute thrombosis can occur spontaneously, leading to catastrophic arterial occlusion and resulting in myocardial infarction, unstable angina, stroke, and sudden death (1,2). Acute thrombosis also occurs as a complication of arterial bypass surgery, balloon angioplasty, atherectomy, or coronary artery stenting (3-5). Non-occlusive thrombus is an important component of the atherosclerotic plaque. Thrombus is comprised principally of platelets and fibrin. White blood cells and circulating proteins are also trapped within the platelet-fibrin thrombus. Activated platelets release a variety of growth factors and cytokines that have been implicated in vessel inflammation and in vascular smooth muscle cell (SMC) proliferation and migration (6,7). Thrombin (8) and factor XlXa (9,10) also have direct effects on SMC and may play a role in the development of intimal hyperplasia. In addition, products secreted by leukocytes trapped within the thrombus may have direct effects on the vessel wall. Tissue factor (TF) is a membrane-bound glycoprotein that initiates coagulation (11,12).Human TF consists of three domains: a short cytoplasmic domain of 19 residues, a single transmembrane domain of 23 residues, and a large extracellular domain of 219 residues. In addition, there is a 32 residue amino-terminal leader sequence which is cleaved to produce the mature molecule. TF binds to factor VIIA/IIa, and the resulting complex acts as a catalyst for the conversion of factors IX and X to IXa and Xa respectively, triggering the clotting cascade. This ultimately leads to the generation of thrombin, which in turn cleaves fibrinogen to fibrin, the major ingredient of the thrombus. Recent studies suggest that the accumulation of TF in atherosclerotic plaques plays a major role in determining plaque thrombogenicity. TF is also rapidly induced in the vessel wall as a consequence of acute arterial injury. Both phenomena may be important in the thrombotic complications of atherosclerotic heart disease.

Tissue factor (TF) is a major activator of the coagulation cascade and may play a role in initiating thrombosis after intravascular injury. To investigate whether medial vascular smooth muscle provides a source of TF following arterial injury, the induction of TF mRNA and protein was studied in balloon-injured rat aorta. After full length aortic injury, aortas were harvested at various times and the media and adventitia separated using collagenase digestion and microscopic dissection. In uninjured aortic media, TF mRNA was undetectable by RNA blot hybridization. 2 h after balloon injury TF mRNA levels increased markedly. Return to near baseline levels occurred at 24 h. In situ hybridization with a 35S-labeled antisense rat TF cRNA probe detected TF mRNA in the adventitia but not in the media or endothelium of uninjured aorta. 2 h after balloon dilatation, a marked induction of TF mRNA was observed in the adventitia and media. Using a functional clotting assay, TF procoagulant activity was detected at low levels in uninjured rat aortic media and rose by 10-fold 2 h after balloon dilatation.Return to baseline occurred within 4 d. These data demonstrate that vascular injury rapidly induces active TF in arterial smooth muscle, providing a procoagulant that may result in thrombus initiation or propagation. (J. Clin. Invest. 1993.

No abstract

Two-day steroid withdrawal in kidney transplant recipients did not affect BPAR, SCAR, CAN, graft function and patient and graft survival compared to control group up to 3 years. NODM was significantly less in steroid withdrawal group. Two-day steroid withdrawal is safe and beneficial in kidney transplant recipients.

Transplantation of kidneys from selected deceased donors with ARF provides comparable survival and function compared to kidneys from non-ARF donors and may be considered for transplantation to expand the donor pool to overcome the current acute shortage of kidneys.