Marjan Jahangiri

Coronary artery bypass graft surgery in dialysis patients.

Objective To examine the short term results and long term survival of patients on long term dialysis undergoing coronary artery bypass graft surgery. Methods A retrospective analysis of 19 patients on established dialysis who underwent coronary revascularisation between 1983 and 1995; 14 patients (73%) had class IV angina and five (25%) had unstable angina requiring heparin and nitrate infusions before surgery. Results The 30 day mortality was 5%. Follow up was completed in the remaining 18 patients. The mean follow up time was 34 months (range eight to 61). During the follow up period four patients died of cardiac causes. The actuarial survival at one, two, and three years was 87%, 78%, and 59%, respectively. The overall functional status was significantly improved compared to preoperative levels, with a mean Karnofsky score of 76% (p < 0.01) at three years. Conclusions Coronary artery bypass graft surgery can be performed with increased but acceptable morbidity and mortality in chronic dialysis patients. It results in considerable improvement in symptoms and functional status. However, long term survival is limited and this requires further investigation.

A surgical approach to coexistent coronary and carotid artery disease.

OBJECTIVE: To assess the early results of combined coronary artery bypass graft surgery and carotid endarterectomy. DESIGN: Retrospective and ongoing analysis of patients who underwent combined coronary artery bypass graft surgery and carotid endarterectomy. SETTING: Cardiothoracic unit in a London teaching hospital. PATIENTS: From June 1987 to March 1995, 64 patients were identified. They were patients who were scheduled to have coronary artery bypass graft surgery or required urgent coronary revascularisation and who were found to have significant coexistent carotid disease. (Unilateral carotid stenosis > 70%, bilateral carotid stenosis > 50%, or unilateral carotid stenosis > 50% with contralateral occlusion.) INTERVENTIONS: Both procedures were performed during one anaesthesia: the carotid endarterectomy was performed first without cardiopulmonary bypass. After completion of carotid endarterectomy, coronary artery bypass graft surgery was performed. MAIN OUTCOME MEASURES: The incidence of stroke, transient ischaemic attack, and myocardial infarction in the early postoperative period was analysed. RESULTS: Myocardial revascularisation was successful in all 64 patients. There were no perioperative infarcts. In three patients (4.7%) a new neurological deficit developed postoperatively: two recovered fully before hospital discharge. CONCLUSIONS: Combined coronary artery bypass graft surgery and carotid endarterectomy were performed safely and with good results.

BAS/BSCR9 Proteomic characterisation of extracellular space components in the human aorta

Rationale Proteomics has been previously applied to vascular tissues, but few studies have specifically targeted the vascular extracellular matrix. Methods and results In this study, we developed a novel methodology for the extraction and identification of extracellular proteins from human aortas. Our approach is based on (a) effective decellularisation to enrich for scarce extracellular proteins, (b) successful solubilisation and deglycosylation of matrix proteins and (c) relative estimation of protein abundance by liquid chromatography tandem mass spectrometry. This methodology resulted in the identification of 103 extracellular space proteins, of which one-third have never been reported in the proteomic literature of vascular tissues. In particular, our study revealed the presence of four novel glycoproteins in human aortas (podocan, sclerostin, agrin and asporin) and we confirmed their presence on the aortic extracellular matrix by independent methods. Although their function in the vasculature is currently unknown, we found that cholesterol loading regulated podocan and agrin expression in human aortic smooth muscle cells. Moreover, our methodology allowed us to investigate proteolytic activity within tissues, based on the identification of proteolytic enzymes and their corresponding degradation products. For instance, we were able to detect matrix metalloproteinase 9 by mass spectrometry and relate its presence to degradation of fibronectin. Conclusions We expect this new proteomic method to shed light on the composition and breakdown of extracellular matrix within cardiovascular tissues and provide insights into important pathological processes, such as plaque rupture, aneurysm formation and restenosis.

266 GLYCOPROTEOMICS ANALYSIS REVEALS A REDUCTION OF DECORIN FRAGMENTS WITH ANTI-MYOSTATIN ACTIVITY IN ATRIAL FIBRILLATION

Background A comprehensive characterisation of the cardiac extracellular matrix (ECM) is pertinent for a better understanding of cardiovascular disease processes. We have recently established a novel proteomic method to profile cardiac ECM proteins and applied it to a porcine model of ischemia-reperfusion injury (Barallobre-Barreiro et al, Circulation, 2012). In the present study, we analyzed human atrial tissue. Methods Left and right atrial specimen were obtained from five patients undergoing coronary bypass grafting. ECM proteins were enriched using a sequential extraction procedure followed by affinity capture of glycoproteins using concanavalin-A and wheat germ agglutinin before analyses by mass spectrometry. Results Few ECM-related glycoproteins, such as lumican, fibulin-2, latent TGFβ-binding protein 4 and clusterin were differentially expressed in left and right atria. Intriguingly, one glycoprotein was consistently identified in the non-glycosylated flow-through: decorin, a member of the small leucine-rich proteoglycan family (SLRPs), has three glycosylation sites in the C-terminal half of the protein. Only N-terminal fragments were detected in the flow-through. Mass spectrometry analyses of non-tryptic cleavage sites provided unambiguous evidence for decorin fragmentation in human atrial tissue. In contrast, other SLRPs, such as biglycan, were barely fragmented despite a high degree of sequence homology. Amongst the four most abundant decorin cleavage products were peptides with known anti-myostatin activity. Myostatin is a potent negative regulator of muscle growth. The mass spectrometry findings were confirmed using peptide-specific antibodies. Further analyses of atrial samples from patients with long-standing atrial fibrillation (AF) revealed that levels of full-length decorin increased during structural remodeling in AF. Its cleavage products with anti-myostatin activity, however, were reduced compared to atria from patients in sinus rhythm. Conclusions For the first time, cleavage products of decorin with known anti-myostatin activity were identified in human cardiac tissue and shown to be reduced in AF. The presence of these myostatin regulators could have important implications for the growth factor response in cardiac disease. Figure 1 A) Sequence coverage for decorin in the input, the glycoprotein-enriched and the flow-through fraction. No C-terminal peptides were detected in the flow-through (upper panel). Abundance of decorin cleavage sites according to ion intensities in mass spectrometry. Myostatin-binding domains are highlighted (bottom panel). B) Cleavage of decorin as determined by antibodies raised against the N-terminal (Ile36-Leu86), C- terminal (Phe312-Lys359) and internal domains (Leu136-Ile215). Note that increased expression of full-length decorin (45KD) in AF is associated with a reduction of its proteolytic fragments.