The challenge to detect heart transplant rejection and transplant vasculopathy non-invasively - a pilot study

<p>Abstract</p> <p>Background</p> <p>Cardiac allograft rejection and vasculopathy are the main factors limiting long-term survival after heart transplantation.</p> <p>In this pilot study we investigated whether non-invasive methods are beneficial to detect cardiac allograft rejection (Grade 03 R) and cardiac allograft vasculopathy. Thus we compared multi-slice computed tomography and magnetic resonance imaging with invasive methods like coronary angiography and left endomyocardial biopsy.</p> <p>Methods</p> <p>10 asymptomatic long-term survivors after heart transplantation (8 male, 2 female, mean age 52.1 ± 12 years, 73 ± 11 months after transplantation) were included. In a blinded fashion, coronary angiography and multi-slice computed tomography and ventricular endomyocardial biopsy and magnetic resonance imaging were compared against each other.</p> <p>Results</p> <p>Cardiac allograft vasculopathy and atherosclerosis were correctly detected by multi-slice computed tomography and coronary angiography with positive correlation (r = 1). Late contrast enchancement found by magnetic resonance imaging correlated positively (r = 0.92, r²= 0.85, p < 0.05) with the histological diagnosis of transplant rejection revealed by myocardial biopsy. None of the examined endomyocardial specimen revealed cardiac allograft rejection greater than Grade 1 R.</p> <p>Conclusion</p> <p>A combined non-invasive approach using multi-slice computed tomography and magnetic resonance imaging may help to assess cardiac allograft vasculopathy and cardiac allograft rejection after heart transplantation before applying more invasive methods.</p

Endothelial Tissue-Type Plasminogen Activator Release in Coronary Heart Disease Transient Reduction in Endothelial Fibrinolytic Reserve in Patients With Unstable Angina Pectoris or Acute Myocardial Infarction

AbstractObjectives. We sought to examine whether the disturbed fibrinolytic system in patients with an acute coronary syndrome is associated with a reduced endothelial fibrinolytic capacity.Background. Intracoronary thrombus formation is a frequent finding in acute coronary syndromes. Systemic alterations of coagulation and fibrinolysis are known to occur, but possible disturbances of endothelial fibrinolytic function have not been investigated.Methods. We compared 42 patients with an acute coronary syndrome (acute myocardial infarction in 11 and unstable angina pectoris in 31) with 25 patients with stable angina. Venous blood was sampled serially for determination of markers of the fibrinolytic system and of hypercoagulability from admission to day 10. An occlusion test to determine the maximal endothelial tissue-type plasminogen activator (t-PA) release was also performed.Results. Both on day 0 and day 10, patients with an acute coronary syndrome had a marked elevation of t-PA mass concentration (mean value ± SEM 14.4 ± 1.6 [day 0], 18.9 ± 2.5 ng/ml [day 10]) and of plasminogen activator inhibitor (PAI) (9.4 ± 2.2 [day 0], 11.3 ± 2.6 AU/liter [day 10], p < 0.05 vs. patients with stable angina). There was also a hypercoagulative state with elevated thrombin activity and increased D-dimers (p < 0.05 vs. patients with stable angina). Maximal endothelial t-PA release was initially reduced (p < 0.05 vs. patients with stable angina) to 2.3 ± 0.9 ng/ml, but levels recovered during follow-up to 4.4 ± 1.4 ng/ml (vs. 5.7 ± 1.5 ng/ml in patients with stable angina).Conclusions. Despite the known prolonged systemic alteration of fibrinolysis in acute coronary syndromes, endothelial fibrinolytic capacity is reduced only during the acute phase and becomes normalized during follow-up, and thus is linked more to intravascular thrombus formation than to steady state levels of markers of the fibrinolytic system

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9

Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS) has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit 14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroid differentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice) and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts. This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss of hematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9. S100a8—whose expression was increased in mutant erythroblasts, monocytes and macrophages—is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect