Padang R.,Centenary Institute |
Padang R.,University of Sydney |
Padang R.,Royal Prince Alfred Hospital |
Padang R.,Baird Institute |
And 10 more authors.
Physiological Genomics | Year: 2015
Intrinsic valvular degeneration and dysfunction is the most common complication of bicuspid aortic valve (BAV) disease. Phenotypically, it ranges from calcific aortic stenosis to redundant or prolapsing regurgitant leaflets. The underlying molecular mechanism underpinning phenotype heterogeneity of valvular degeneration in BAV is poorly understood. We used RNA sequencing (RNA-seq) to identify genes and pathways responsible for the development of valvular degeneration in BAV, compared with tricuspid aortic valve (TAV). Comparative transcriptome analysis was performed on total RNA of aortic valve tissues of patients with diseased BAV (n = 5) and calcified TAV (n = 3). RNA-seq findings were validated by RT-qPCR. A total of 59 and 177 genes were significantly up- and downregulated, respectively, in BAV compared with TAV. Hierarchical clustering indicated heterogeneity within the BAV group, separating those with heavy calcification (BAVc) from those with redundant leaflets and/or minimal calcification (BAVr). Interestingly, the gene expression profile of the BAVc group closely resembled the TAV, with shared up- and downregulation of inflammatory andNOTCH1signaling pathways, respectively. Downregulation of matrix protease ADAMTS9 and protein aggrecan were observed in BAVr compared with TAV. Dysregulation of fetal gene programs were also present, with notable downregulation ofSEMA6BandSEMA3Fin BAVr and BAVc compared with TAV, respectively. Upregulation ofTBX20was observed exclusively in BAVr compared with BAVc. In conclusion, diverging molecular mechanisms underpin phenotype heterogeneity of valvular degeneration in BAV and data from the present study suggest that there may be shared mechanisms leading to calcification in BAV and TAV. Recognition of these pathways is fundamental to improve our understanding of the molecular basis of human BAV disease. © 2015 the American Physiological Society
Dignan R.,University of New South Wales |
Keech A.C.,University of Sydney |
Gebski V.J.,University of Sydney |
Mann K.P.,University of Sydney |
And 2 more authors.
International Journal of Cardiology | Year: 2013
Aims The Warfarin Self-Management Anticoagulation Research Trial (Warfarin SMART) was designed to determine whether patients self-managing warfarin (PSM) using the CoaguChek device and a dosing algorithm developed for the trial could keep the INR (International Normalised Ratio) test in target range at least as often as patients managed by usual care by the family doctor or hospital clinic. Methods and results 310 patients were randomly assigned to PSM or usual care. The PSM group was trained to perform home INR testing and warfarin dosing using a validated ColourChart algorithm. The primary endpoint was the proportion of times over 12 months that a monthly, blinded "outcome INR test", measured in a central laboratory, was outside the patient's target therapeutic range. The rate of out-of-range outcome INRs was lower in PSM, and non-inferior to the usual care group (PSM: 36% vs. usual care: 41%, P < 0.001 for non-inferiority; P = 0.08 for superiority in closed-loop testing). The deviations from the patient's midpoint of target INR range (P = 0.02) and number of extreme INRs (P = 0.03) were significantly less in the PSM group than the usual-care group. There was no significant difference between groups in rates of bleeding or thrombotic adverse events. Conclusion Patient self-management performed at least as well as usual care in maintaining the INR within the target range, without any safety concerns. This treatment modality for the long-term use of warfarin has the potential to change current local and international practice. © 2013 Elsevier Ireland Ltd © 2013 Published by Elsevier Ireland Ltd.
Vallely M.P.,Royal Prince Alfred Hospital |
Vallely M.P.,Baird Institute |
Vallely M.P.,University of Sydney |
Edelman J.J.B.,Royal Prince Alfred Hospital |
And 2 more authors.
Interventional Cardiology (London) | Year: 2013
Recent trials have shown that coronary artery bypass grafting remains the standard-of-care for multivessel coronary artery disease. However, the main criticism of surgery in these trials has been the higher rate of stroke. Off-pump coronary artery bypass grafting (OPCAB) has been suggested as a technique to reduce the rate of stroke. However, large randomized trials comparing coronary artery bypass grafting with OPCAB have failed to show any neurological benefit, most probably because surgeons in these trials fail to avoid manipulation of the ascending aorta. Herein, the authors review a technique of OPCAB surgery where manipulation of the ascending aorta is completely avoided - 'anaortic OPCAB - facilitated by the use of composite and in situ grafts using bilateral internal mammary arteries. © 2013 Future Medicine Ltd.
Wise S.G.,Heart Research Institute |
Wise S.G.,University of Sydney |
Byrom M.J.,University of Sydney |
Waterhouse A.,Baird Institute |
And 4 more authors.
Acta Biomaterialia | Year: 2011
Small-diameter synthetic vascular graft materials fail to match the patency of human tissue conduits used in vascular bypass surgery. The foreign surface retards endothelialization and is highly thrombogenic, while the mismatch in mechanical properties induces intimal hyperplasia. Using recombinant human tropoelastin, we have developed a synthetic vascular conduit for small-diameter applications. We show that tropoelastin enhances endothelial cell attachment (threefold vs. control) and proliferation by 54.7 ± 1.1% (3 days vs. control). Tropoelastin, when presented as a monomer and when cross-linked into synthetic elastin for biomaterials applications, had low thrombogenicity. Activation of the intrinsic pathway of coagulation, measured by plasma clotting time, was reduced for tropoelastin (60.4 ± 8.2% vs. control). Platelet attachment was also reduced compared to collagen. Reductions in platelet interactions were mirrored on cross-linked synthetic elastin scaffolds. Tropoelastin was subsequently incorporated into a synthetic elastin/ polycaprolactone conduit with mechanical properties optimized to mimic the human internal mammary artery, including permeability, compliance, elastic modulus and burst pressure. Further, this multilayered conduit presented a synthetic elastin internal lamina to circulating blood and demonstrated suturability and mechanical durability in a small scale rabbit carotid interposition model. © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.