ORCID Profile
0000-0002-5201-4856
Current Organisations
Westmead Hospital
,
University of New South Wales
,
University of Washington
,
University of Sydney
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Publisher: Springer Science and Business Media LLC
Date: 18-07-2016
DOI: 10.1038/CDDISCOVERY.2016.52
Abstract: Stem cell therapy is being investigated as an innovative and promising strategy to restore cardiac function in patients with heart failure. Several stem cell populations, including adult (multipotent) stem cells from developed organs and tissues, have been tested for cardiac repair with encouraging clinical and pre-clinical results. The heart has been traditionally considered a post-mitotic organ, however, this view has recently changed with the identification of stem rogenitor cells residing within the adult heart. Given their cardiac developmental origins, these endogenous cardiac progenitor cells (CPCs) may represent better candidates for cardiac cell therapy compared with stem cells from other organs such as the bone marrow and adipose tissue. This brief review will outline current research into CPC populations and their cardiac repair/regenerative potential.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.HLC.2016.04.011
Abstract: Atrial Fibrillation (AF) is one of the most common types of cardiac arrhythmias experienced in clinical practice, increasing the risk of stroke, dementia, myocardial infarction and death. Currently available options for the treatment of AF use either pharmacological agents or catheter-based ablation therapies to restore sinus rhythm or control the ventricular response rate. These current treatment options are suboptimal at best, motivating research into discovering more effective and innovative ways to treat AF. Gene therapy is being explored for its potential to treat various human conditions including cardiac arrhythmias. Gene transfer vectors with increasing transduction efficiency and biosafety have been developed and trialled for cardiovascular disease treatment. With an improved understanding of the molecular mechanisms of AF, several gene therapy targets have been identified and evaluated in an attempt to rate or rhythm control the heart during AF. This review will discuss the gene therapy vectors in use today and methods for delivery of these vectors to the atrium. Further, it will evaluate several gene therapy strategies and approaches for sinus rhythm restoration and ventricular rate control that have the potential to emerge as a therapy for AF.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Springer Science and Business Media LLC
Date: 20-07-2020
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.SCR.2014.09.008
Abstract: Mammalian hearts carry a number of primitive stem cell-like populations, although the magnitude of their contribution to tissue homeostasis and repair remains controversial. Recent CRE recombinase-based lineage tracing experiments suggest only a minor contribution to the formation of new cardiomyocytes from such cells, albeit one that might be augmented therapeutically. As the field explores clinical translation of cardiac stem cells, it will be important to understand the biology of these cells in great detail. In this review we document the various reported stem and progenitor cell populations in mammalian hearts and discuss the current state of knowledge on their origins and lineage capabilities.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.AMJCARD.2007.08.051
Abstract: Electrophysiologic studies predict the risk for sudden death after myocardial infarction (MI). Although primary angioplasty has become the preferred method of treatment for ST-elevation MI, intravenous thrombolysis remains the first-line treatment in 30% to 70% of cases worldwide. Rates of ventricular tachyarrhythmias may vary according to type of reperfusion treatment. This study was undertaken to examine the hypothesis that the left ventricular ejection fraction (LVEF) and rates of inducible ventricular tachycardia may be more favorable in treatment with primary angioplasty rather than thrombolysis. Consecutive patients receiving primary angioplasty (n = 225) or thrombolysis (n = 195) for ST-elevation MI were included. The mean LVEF was 48 +/- 12% for the primary angioplasty group and 46 +/- 13% for the thrombolysis group (p = 0.30). The proportion of patients with LVEFs <40% was 30% in the primary angioplasty group and 30% in the thrombolysis group (p = 0.98). Patients with LVEFs <40% underwent electrophysiologic studies. Ventricular tachycardia was inducible in 23 of 66 primary angioplasty patients (34.8%) compared with 21 of 55 (38.1%) thrombolysis patients (p = 0.69). Implantable cardiac defibrillators were inserted in 30 patients, of whom 8 (27%) had appropriate device activations. The mean time from MI to first spontaneous activation was 387 +/- 458 days. In conclusion, patients treated with thrombolysis or primary angioplasty for ST-elevation MIs had similar resultant LVEFs and rates of inducible ventricular tachycardia. There was a surprisingly high rate of spontaneous defibrillator activations, often occurring late after MI.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2022
DOI: 10.1038/S41467-022-32946-1
Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of the adenoviral vector vaccines ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen) against COVID-19. The mechanisms involved in clot formation and thrombocytopenia in VITT are yet to be fully determined. Here we show neutrophils undergoing NETosis and confirm expression markers of NETs in VITT patients. VITT antibodies directly stimulate neutrophils to release NETs and induce thrombus formation containing abundant platelets, neutrophils, fibrin, extracellular DNA and citrullinated histone H3 in a flow microfluidics system and in vivo. Inhibition of NETosis prevents VITT-induced thrombosis in mice but not thrombocytopenia. In contrast, in vivo blockage of FcγRIIa abrogates both thrombosis and thrombocytopenia suggesting these are distinct processes. Our findings indicate that anti-PF4 antibodies activate blood cells via FcγRIIa and are responsible for thrombosis and thrombocytopenia in VITT. Future development of NETosis and FcγRIIa inhibitors are needed to treat VITT and similar immune thrombotic thrombocytopenia conditions more effectively, leading to better patient outcomes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-01-2023
DOI: 10.1161/CIRCRESAHA.122.321123
Abstract: Myocardial infarction (MI) is among the leading causes of death worldwide. Following MI, necrotic cardiomyocytes are replaced by a stiff collagen-rich scar. Compared to collagen, the extracellular matrix protein elastin has high elasticity and may have more favorable properties within the cardiac scar. We sought to improve post-MI healing by introducing tropoelastin, the soluble subunit of elastin, to alter scar mechanics early after MI. We developed an ultrasound-guided direct intramyocardial injection method to administer tropoelastin directly into the left ventricular anterior wall of rats subjected to induced MI. Experimental groups included shams and infarcted rats injected with either PBS vehicle control or tropoelastin. Compared to vehicle treated controls, echocardiography assessments showed tropoelastin significantly improved left ventricular ejection fraction (64.7±4.4% versus 46.0±3.1% control) and reduced left ventricular dyssynchrony (11.4±3.5 ms versus 31.1±5.8 ms control) 28 days post-MI. Additionally, tropoelastin reduced post-MI scar size (8.9±1.5% versus 20.9±2.7% control) and increased scar elastin (22±5.8% versus 6.2±1.5% control) as determined by histological assessments. RNA sequencing (RNAseq) analyses of rat infarcts showed that tropoelastin injection increased genes associated with elastic fiber formation 7 days post-MI and reduced genes associated with immune response 11 days post-MI. To show translational relevance, we performed immunohistochemical analyses on human ischemic heart disease cardiac s les and showed an increase in tropoelastin within fibrotic areas. Using RNA-seq we also demonstrated the tropoelastin gene ELN is upregulated in human ischemic heart disease and during human cardiac fibroblast-myofibroblast differentiation. Furthermore, we showed by immunocytochemistry that human cardiac fibroblast synthesize increased elastin in direct response to tropoelastin treatment. We demonstrate for the first time that purified human tropoelastin can significantly repair the infarcted heart in a rodent model of MI and that human cardiac fibroblast synthesize elastin. Since human cardiac fibroblasts are primarily responsible for post-MI scar synthesis, our findings suggest exciting future clinical translation options designed to therapeutically manipulate this synthesis.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2019
DOI: 10.1038/S41434-019-0097-0
Abstract: Differences between mouse and human hearts pose a significant limitation to the value of small animal models when predicting vector behavior following recombinant adeno-associated viral (rAAV) vector-mediated cardiac gene therapy. Hence, sheep have been adopted as a preclinical animal, as they better model the anatomy and cardiac physiological processes of humans. There is, however, no comprehensive data on the shedding profile of rAAV in sheep following intracoronary delivery, so as to understand biosafety risks in future preclinical and clinical applications. In this study, sheep received intracoronary delivery of rAAV serotypes 2/6 (2 × 10
Publisher: Elsevier BV
Date: 11-2015
Publisher: Research Square Platform LLC
Date: 30-09-2021
DOI: 10.21203/RS.3.RS-753825/V1
Abstract: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of adenoviral vector vaccines (AstraZeneca and Johnson & Johnson) against COVID-19 1 . Anti-platelet factor 4 (PF4) antibodies are present in VITT patients 2,3 . Although the current view suggests that platelet activation by anti-PF4 antibodies is the cause of thrombosis there is as yet no direct evidence that the antibodies induce clot formation and thrombocytopenia (reduction in platelet counts) in VITT and the mechanisms involved remain unknown 4 . Here we show that VITT antibodies induce thrombosis and thrombocytopenia, and that thrombus formation is mediated by neutrophil extracellular traps (NETs). We found markers of NETosis, abundance of neutrophil latelet aggregates and presence of neutrophils undergoing NETosis in patients with active VITT. VITT antibodies directly stimulate neutrophils to release NETs and induce thrombus formation containing abundant platelets, neutrophils, fibrin, extracellular DNA and citrullinated histone H3 using an in vitro blood flow microfluidic system. In transgenic mice expressing human PF4 and FcγRIIa, VITT antibodies lead to thrombosis, thrombocytopenia and formation of low density granulocytes. Pharmacological and genetic inhibition of NETosis prevents VITT-induced thrombosis in mice but not thrombocytopenia. In contrast, in vivo blockage of FcγRIIa abrogates both thrombosis and thrombocytopenia suggesting they are distinct processes. Our findings indicate that VITT antibodies activate cells via FcγRIIa and are responsible for thrombosis and thrombocytopenia. This study identifies NETosis as a pathogenic mechanism for thrombus formation in VITT. We anticipate our findings will motivate future development of NETosis and FcγRIIa inhibitors as potential specific therapies for VITT and consequently better patient outcomes.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2015
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.HLC.2016.11.002
Abstract: Numerous pharmacological and device therapies have improved adverse cardiac remodelling and mortality in heart failure. However, none are able to regenerate damaged cardiac tissue. Stem cell based therapies using multipotent (adult) stem cells and pluripotent stem cells are new approaches that could potentially achieve the elusive goal of true cardiac regeneration. Over the past two decades, various stem cell based approaches have been shown to improve left ventricular function in pre-clinical animal models. Promising results rapidly led to clinical trials, initially using bone marrow-derived mononuclear cells, then mesenchymal stromal cell populations and, more recently, progenitor cells from the adult heart itself. These have been shown to be safe and have advanced our understanding of potential suitable recipients, cell delivery routes, and possible mechanisms of action. However, efficacy in these trials has been inconsistent. Human pluripotent stem cells (hPSCs) are another potential source of stem cells for cardiac regeneration. They could theoretically provide an unlimited source of cardiomyocytes or cardiac progenitors. Pre-clinical studies in both small and large animal models have shown robust engraftment and improvements in cardiac function. The first clinical trial using hPSC-derived cardiac derivatives has now commenced and others are imminent. In this brief review article, we summarise recent developments in stem cell therapies aimed at cardiac regeneration, including discussion of types of cell and non-cell-based strategies being explored.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 2020
DOI: 10.1126/SCITRANSLMED.AAY2140
Abstract: Recombinant human platelet-derived growth factor-AB improves cardiac function and survival after myocardial infarction in a porcine model.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Research Square Platform LLC
Date: 07-09-2023
Publisher: Springer Science and Business Media LLC
Date: 19-08-2014
Publisher: MDPI AG
Date: 19-10-2018
DOI: 10.3390/JCDD5040050
Abstract: Bradycardia arising from pacemaker dysfunction can be debilitating and life threatening. Electronic pacemakers serve as effective treatment options for pacemaker dysfunction. They however present their own limitations and complications. This has motivated research into discovering more effective and innovative ways to treat pacemaker dysfunction. Gene therapy is being explored for its potential to treat various cardiac conditions including cardiac arrhythmias. Gene transfer vectors with increasing transduction efficiency and biosafety have been developed and trialed for cardiovascular disease treatment. With an improved understanding of the molecular mechanisms driving pacemaker development, several gene therapy targets have been identified to generate the phenotypic changes required to correct pacemaker dysfunction. This review will discuss the gene therapy vectors in use today along with methods for their delivery. Furthermore, it will evaluate several gene therapy strategies attempting to restore biological pacing, having the potential to emerge as viable therapies for pacemaker dysfunction.
Publisher: Mary Ann Liebert Inc
Date: 07-2013
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.HLC.2012.04.020
Abstract: Cell therapies specifically targeting heart failure could greatly decrease morbidity and burgeoning health care costs worldwide. Due to the great number of cell types being investigated, navigating the cardiovascular regeneration field can be difficult. This brief review gives an overview of the main cell types being explored for cardiac cell therapy. These include populations from extra-cardiac sources (skeletal myoblasts, bone marrow derived mononuclear cells, endothelial progenitor cells, bone marrow or adipose derived mesenchymal stem cells and embryonic or induced pluripotent stem cells as well as newly discovered cardiac stem cell populations (isl1(+), c-kit(+), sca1(+), sca1(+) dgfrα(+), cardiosphere derived, cardiac side-population and epicardium derived cells). Although clinical trials using both groups of cell sources have been performed, the vast majority of studies have used bone marrow mononuclear cells. The current wave of clinical trials includes large studies refining specifics of bone marrow mononuclear cell therapy and early phase trials of mesenchymal stem cell and cardiac stem cell populations. Embryonic stem cell derived therapies are being studied in large animal models with the aim of swift progression to clinical trials. Lessons learnt from the intense investigation in this infant field have resulted in rapid translational progress and it is likely that several clinical products rotocols for cardiac repair will be available in the not too distant future.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2019
DOI: 10.1038/S41598-019-47022-W
Abstract: We have previously reported a subpopulation of mesenchymal stromal cells (MSCs) within the platelet-derived growth factor receptor-alpha (PDGFRα)/CD90 co-expressing cardiac interstitial and adventitial cell fraction. Here we further characterise PDGFRα/CD90-expressing cardiac MSCs (PDGFRα + cMSCs) and use human telomerase reverse transcriptase (hTERT) over-expression to increase cMSCs ability to repair the heart after induced myocardial infarction. hTERT over-expression in PDGFRα + cardiac MSCs (hTERT + PDGFRα + cMSCs) modulates cell differentiation, proliferation, survival and angiogenesis related genes. In vivo , transplantation of hTERT + PDGFRα + cMSCs in athymic rats significantly increased left ventricular function, reduced scar size, increased angiogenesis and proliferation of both cardiomyocyte and non-myocyte cell fractions four weeks after myocardial infarction. In contrast, transplantation of mutant hTERT + PDGFRα + cMSCs (which generate catalytically-inactive telomerase) failed to replicate this cardiac functional improvement, indicating a telomerase-dependent mechanism. There was no hTERT + PDGFRα + cMSCs engraftment 14 days after transplantation indicating functional improvement occurred by paracrine mechanisms. Mass spectrometry on hTERT + PDGFRα + cMSCs conditioned media showed increased proteins associated with matrix modulation, angiogenesis, cell proliferation/survival/adhesion and innate immunity function. Our study shows that hTERT can activate pro-regenerative signalling within PDGFRα + cMSCs and enhance cardiac repair after myocardial infarction. An increased understanding of hTERT’s role in mesenchymal stromal cells from various organs will favourably impact clinical regenerative and anti-cancer therapies.
Publisher: Springer Science and Business Media LLC
Date: 30-04-2014
DOI: 10.1038/NATURE13233
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-10-2014
Publisher: Oxford University Press (OUP)
Date: 11-2006
DOI: 10.1016/J.EUJE.2006.09.001
Abstract: Melanoma is the most common form of cardiac metastases. Surgical excision has been shown to be an effective palliative measure. This requires detailed definition of cardiac anatomy in relation to the tumour. Two-dimensional (2D), three-dimensional (3D) transthoracic (TTE) and transoesophageal echocardiography (TEE), spiral computerised tomography (CT) and magnetic resonance imaging (MRI) have all been described in aiding surgical planning for excision of cardiac tumours. In this case report, 3D-TTE provided excellent anatomical definition for surgical planning of a large right atrial melanoma precluding the need for more invasive and expensive investigations.
No related grants have been discovered for James Chong.