Host-Derived Smooth Muscle Cells Accumulate in Cardiac Allografts: Role of Inflammation and Monocyte Chemoattractant Protein 1

Transplant arteriosclerosis is characterized by inflammation and intimal thickening caused by accumulation of smooth muscle cells (SMCs) both from donor and recipient. We assessed the relationship between clinical factors and the presence of host-derived SMCs in 124 myocardial biopsies from 26 consecutive patients who received hearts from opposite-sex donors. Clinical and demographic information was obtained from the patients' medical records. Host-derived SMCs accounted for 3.35±2.3% of cells in arterioles (range, 0.08–12.51%). As shown by linear regression analysis, an increased number of SMCs was associated with rejection grade (mean, 1.41±1.03, p = 0.034) and the number of leukocytes (19.1±12.7 per 20 high-power fields, p = 0.01). The accumulation of host-derived SMCs was associated with an increased number of leukocytes in the allografts. In vitro, monocyte chemoattractant protein 1 (MCP-1) released from leukocytes was crucial for SMC migration. After heart allotransplantion, mice treated with MCP-1-specific antibodies had significantly fewer host-derived SMCs in the grafts than mice treated with isotypic antibody controls. We conclude that the number of host-derived SMCs in human cardiac allografts is associated with the rejection grade and that MCP-1 may play pivotal role in recruiting host-derived SMCs into cardiac allografts

ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of oxysterol by intact cells.

ATP Binding Cassette (ABC) transporter, ABCA1, plays a pivotal role in reverse cholesterol transport by mediating the cellular efflux of phospholipid and cholesterol. Studies using intact cells strongly suggest that ABCA1 acts as a phospholipid floppase, but there has been no direct demonstration that the protein is a primary active sterol transporter. Using membrane vesicles from insect Sf21 cells, we found that ABCA1 mediated ATP-dependent uptake of [(3)H]25-hydroxycholesterol with an apparent K(m) of 0.7 muM. Consistent with this high apparent affinity, expression of ABCA1 in human embryonic kidney cells both increased rapid efflux of 25-hydroxcholesterol and prevented oxysterol-mediated repression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNAs. Comparison of wild-type and ABCA1(-/-) murine fibroblasts indicates that 25-hydroxycholesterol is effluxed approximately 5-fold more rapidly by wild-type cells. In addition, the rate of efflux from the wild-type but not the ABCA1(-/-) fibroblasts is increased a further twofold by inducers of ABCA1 expression. Thus under the experimental conditions employed, endogenous ABCA1 is a major contributor to 25-hydroxycholesterol efflux from wild-type fibroblasts. Evidence from in vitro studies indicates that oxysterols are potent inducers of genes involved in cellular cholesterol efflux and metabolism, including the ABCA1 gene, and repressors of genes involved in cholesterol synthesis or uptake. Our observations raise the possibility that efflux of oxysterols by ABCA1 could contribute to a homeostatic mechanism, which both attenuates oxysterol-induced expression of its cognate gene and alleviates repression of genes encoding proteins, such as HMG-CoA reductase and LDL receptor

Accuracy of Electro Cardiogram (ECG) Interpretation and need for ECG Audit in Emergency Department, A prospective observational study from a tertiary care teaching hospital

In spite of much recent advancement, 12 lead electro cardiogram (ECG) is still the most relied upon tool for diagnosis of cardiac emergencies in the emergency departments, especially in resource poor settings. Studies on accuracy of ECG interpretations, their likely impact in the emergency departments are scarce from India. Objective:To assess the accuracy of the ECG interpretation by CMO/resident doctors and emergency physicians, in emergency department of a tertiary care teaching hospital in south India. Methodology:The study was a prospective observational study conducted in the emergency medicine department of tertiary care teaching hospital. ECG interpretations of CMO/resident doctor and emergency physicians are compared against the blinded, gold standard interpretation by a cardiologist panel. Results:A total of 2857 ECGs of the patients presenting with chest pain were analyzed. The overall concordance as assessed by mean pair agreement index (MPAI) was higher for emergency physician (MPAI=83.75%, Kappa statistic =0.50), compared to CMO/resident doctor (MPAI=75.95%, Kappa statistic =0.48). The concordance rate for abnormal ECG, as assessed by sensitivity of was only 67.2% for CMO/ resident doctor and was 78.3% for emergency physician. The concordance rate for normal ECGs, as assessed by specificity was 81.5% and 87.2% respectively for both the groups. Conclusions:ECG interpretation skills for both normal and abnormal ECGs are better in emergency physicians, compared to CMO/resident doctors and are better for normal ECGs, compared to abnormal ECGs. Many life threatening emergencies, which need immediate intervention, are being missed