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Mehta A.,National Heart Research Institute Singapore | Ramachandra C.J.A.,National Heart Research Institute Singapore | Sequiera G.L.,National Heart Research Institute Singapore | Sudibyo Y.,National Heart Research Institute Singapore | And 5 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2014

Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) offer immense value in studying cardiovascular regenerative medicine. However, intrinsic biases and differential responsiveness of hPSCs towards cardiac differentiation pose significant technical and logistic hurdles that hamper human cardiomyocyte studies. Tandem modulation of canonical and non-canonical Wnt signaling pathways may play a crucial role in cardiac development that can efficiently generate cardiomyocytes from pluripotent stem cells. Our Wnt signaling expression profiles revealed that phasic modulation of canonical/non-canonical axis enabled orderly recapitulation of cardiac developmental ontogeny. Moreover, evaluation of 8 hPSC lines showed marked commitment towards cardiac-mesoderm during the early phase of differentiation, with elevated levels of canonical Wnts (Wnt3 and 3a) and Mesp1. Whereas continued activation of canonical Wnts was counterproductive, its discrete inhibition during the later phase of cardiac differentiation was accompanied by significant up-regulation of non-canonical Wnt expression (Wnt5a and 11) and enhanced Nkx2.5+ (up to 98%) populations. These Nkx2.5+ populations transited to contracting cardiac troponin T-positive CMs with up to 80% efficiency. Our results suggest that timely modulation of Wnt pathways would transcend intrinsic differentiation biases of hPSCs to consistently generate functional CMs that could facilitate their scalable production for meaningful clinical translation towards personalized regenerative medicine. © 2014 Elsevier B.V.


Serebruany V.L.,Johns Hopkins University | Cherepanov V.,Johns Hopkins University | Cabrera-Fuentes H.A.,Justus Liebig University | Cabrera-Fuentes H.A.,National University of Singapore | And 3 more authors.
Thrombosis and Haemostasis | Year: 2015

The role of anticoagulants and antiplatelet agents in tumour growth and prognosis is not new, and currently under intense investigation. Some randomised data strongly suggest that this association exists, but it is complex, and not necessarily pointed at the same direction. The potential mechanisms responsible for such harmful association include a direct hazard of novel antithrombotics on cancer, indirect promotion of tumour growth, easier metastatic dissemination due to instability of platelet-tumour cell aggregates, or/and inability to keep cancer cells locally in situ are considered. The latest randomised evidence ultimately rejected the drug-specific cancer risks, clearly indicating the class-effect. In lay terms “cancers follow bleeding”, which seems to be true for antithrombotic agents in general. Significant excess of solid cancers which was similar after prasugrel in TRITON, and with vorapaxar in TRACER trials was confirmed by the FDA reviews. Later, extra cancer deaths reported following clopidogrel and prasugrel in DAPT, and after ticagrelor in PEGASUS are also of concern. However, there are remaining controversies with regard to published cancer risks after ticagrelor (PLATO), or another vorapaxar trial (TRA2P), while full disclosure of separate clopidogrel and prasugrel cancer data in DAPT is still lacking. In short, if we apply moderate antiplatelet strategies for over two years, or aggressive regimens including triple therapy for much less than one year, the solid cancer risks emerge. Currently, more delicate platelet inhibition, and shorter exposure to dual oral antiplatelet agents should prevail. © Schattauer 2015.


Rear R.,University College London | Bell R.M.,University College London | Hausenloy D.J.,University College London | Hausenloy D.J.,National Heart Research Institute Singapore | Hausenloy D.J.,National University of Singapore
Heart | Year: 2016

CIN represents a significant clinical and health economic problem that may be under-recognised through limitations in the currently available biomarkers. Although often a transient injury, CIN may progress to significant persistent renal impairment, ESRF and adverse cardiovascular outcomes. There are a number of recognised risk factors, although the prediction of CIN, particularly prior to contrast administration, remains challenging. Current interventions are largely centred on the avoidance of dehydration, the withdrawal of nephrotoxic agents and minimisation of contrast load, which has limited efficacy in preventing CIN in vulnerable patients. The unmet clinical need in CIN therefore resides in accurate prediction, effective intervention and rapid detection to prevent adverse cardiorenal outcomes. Each of these areas, particularly predictive risk scoring systems, innovative pharmacological and mechanical interventions and novel biomarkers are currently the subject of intensive research and development that may lead to the future development effective strategies to mitigate the risk of CIN.


Ramachandra C.J.A.,National Heart Research Institute Singapore | Mehta A.,National Heart Research Institute Singapore | Lua C.H.,National Heart Research Institute Singapore | Chitre A.,National Heart Research Institute Singapore | And 2 more authors.
Stem Cells | Year: 2016

Abstract: Mechanisms determining intrinsic differentiation bias inherent to human pluripotent stem cells (hPSCs) toward cardiogenic fate remain elusive. We evaluated the interplay between ErbB4 and Epidemal growth factor receptor (EGFR or ErbB1) in determining cardiac differentiation in vitro as these receptor tyrosine kinases are key to heart and brain development in vivo. Our results demonstrate that during cardiac differentiation, cell fate biases exist in hPSCs due to cardiac/neuroectoderm divergence post cardiac mesoderm stage. Stage-specific up-regulation of EGFR in concert with persistent Wnt3a signaling post cardiac mesoderm favors commitment toward neural progenitor cells (NPCs). Inhibition of EGFR abrogates these effects with enhanced (>twofold) cardiac differentiation efficiencies by increasing proliferation of Nkx2-5 expressing cardiac progenitors while reducing proliferation of Sox2 expressing NPCs. Forced overexpression of ErbB4 rescued cardiac commitment by augmenting Wnt11 signaling. Convergence between EGFR/ErbB4 and canonical/noncanonical Wnt signaling determines cardiogenic fate in hPSCs. © 2016 AlphaMed Press.


Hausenloy D.J.,University College London | Hausenloy D.J.,National Health Research Institute | Hausenloy D.J.,National Heart Research Institute Singapore | Hausenloy D.J.,National University of Singapore | And 15 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic- preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P = 0.58). Furthermore, there were no significant between- group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. Copyright © 2015 Massachusetts Medical Society. All rights reserved.


Rosa V.,National University of Singapore | Toh W.S.,National University of Singapore | Cao T.,National University of Singapore | Shim W.,National Heart Research Institute Singapore
Expert Opinion on Biological Therapy | Year: 2014

Introduction: The induced pluripotent stem cells (iPSCs) have characteristics similar to embryonic stem cells, including the capability of self-renewal and large-scale expansion and the ability to differentiate into all types of cells including germ cells, which defines pluripotency. Using iPSC avoids problems of immunological rejection and ethical controversy. The possible future uses of iPSC are diverse and go beyond the differentiation into somatic cells for regeneration of damaged tissues.Areas covered: A unique feature of iPSC is the potential to generate patient disease-specific tissues. Thus, cells from patients can be differentiated into relevant cells of interest for drug screening, characterization of drug effects and cytotoxic assays. This review presents key aspects related to iPSC, such as their generation, potential for disease modeling, treatment, drug development and future contributions to the craniofacial complex.Expert opinion: It is undisputable that the evolution in iPSC knowledge will improve the approaches for drug screening and development, help to understand and treat disease origins and mechanisms and provide new strategies to clinical treatment. However, it is necessary to fine-tune protocols to establish iPSCs that are cost-effective and safe for clinical use. © Informa UK, Ltd.


Bulluck H.,University College London | Yellon D.M.,University College London | Hausenloy D.J.,University College London | Hausenloy D.J.,National Heart Research Institute Singapore | Hausenloy D.J.,National University of Singapore
Heart | Year: 2016

Despite prompt reperfusion by primary percutaneous coronary intervention (PPCI), the mortality and morbidity of patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) remain significant with 9% death and 10% heart failure at 1 year. In these patients, one important neglected therapeutic target is 'myocardial reperfusion injury', a term given to the cardiomyocyte death and microvascular dysfunction which occurs on reperfusing ischaemic myocardium. A number of cardioprotective therapies (both mechanical and pharmacological), which are known to target myocardial reperfusion injury, have been shown to reduce myocardial infarct (MI) size in small proof-ofconcept clinical studies-however, being able to demonstrate improved clinical outcomes has been elusive. In this article, we review the challenges facing clinical cardioprotection research, and highlight future therapies for reducing MI size and preventing heart failure in patients presenting with STEMI at risk of myocardial reperfusion injury.


PubMed | National University of Singapore, National Heart Research Institute Singapore and Hebei Medical University
Type: Journal Article | Journal: PloS one | Year: 2017

Aconitine (ACO) is well-known for causing lethal ventricular tachyarrhythmias. While cardiac Na+ channel opening during repolarization has long been documented in animal cardiac myocytes, the cellular effects and mechanism of ACO in human remain unexplored. This study aimed to assess the proarrhythmic effects of ACO in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). ACO concentration-dependently (0.3 ~ 3.0 M) shortened the action potentials (AP) durations (APD) in ventricular-like hiPSC-CMs by > 40% and induced delayed after-depolarization. Laser-scanning confocal calcium imaging analysis showed that ACO decreased the duration and amplitude of [Ca2+]i transients and increased in the beating frequencies by over 60%. Moreover, ACO was found to markedly reduce the L-type calcium channel (LTCC) currents (ICa,L) in hiPSC-CMs associated with a positive-shift of activation and a negative shift of inactivation. ACO failed to alter the peak and late Na+ currents (INa) in hiPSC-CMs while it drastically increased the late INa in Guinea-pig ventricular myocytes associated with enhanced activation/delayed inactivation of INa at -55 mV~ -85 mV. Further, the effects of ACO on ICa,L, INa and the rapid delayed rectifier potassium current (Ikr) were validated in heterologous expression systems by automated voltage-clamping assays and a moderate suppression of Ikr was observed in addition to concentration-dependent ICa,L inhibition. Lastly, increased beating frequency, decreased Ca2+ wave and shortened field potential duration were recorded from hiPSC-CMs by microelectrode arrays assay. In summary, our data demonstrated that LTCC inhibition could play a main role in the proarrhythmic action of ACO in human cardiomyocytes.


Mann M.B.,Houston Methodist Research Institute | Mann M.B.,Institute of Molecular and Cell Biology | Black M.A.,University of Otago | Jones D.J.,Houston Methodist Research Institute | And 14 more authors.
Nature Genetics | Year: 2015

Although nearly half of human melanomas harbor oncogenic BRAF V600E mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in Braf V600E mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF V600E melanoma and discover new genes with potential clinical importance in human melanoma. © 2015 Nature America, Inc.


Murasato Y.,Cardiovascular Center | Murasato Y.,Clinical Research Center | Finet G.,University of Lyon | Foin N.,National Heart Research Institute Singapore
EuroIntervention | Year: 2015

Final kissing balloon inflation (KBI) after provisional bifurcation stenting has failed to provide clear clinical benefit except for a decrease in side branch stenosis, while a significant reduction of major adverse cardiac events has been documented in two-stent deployment. The optimisation of KBI in terms of proximal optimisation technique, appropriate guidewire re-crossing, minimal balloon overlapping, and balloon size selection may overcome the drawbacks of conventional KBI by: 1) correcting the proximal malapposition expected from fractal geometry; 2) optimising side branch ostium strut opening while conserving a bifurcation area free of malapposition at both the carina and the side branch ostium; and 3) optimising the geometry, velocity fields and shear rate. © 2015 Europa Digital & Publishing. All rights reserved.

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