Victor Tsang
University College London
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Circulation Research | 2009
Steven B. Marston; O’Neal Copeland; Adam Jacques; Karen Livesey; Victor Tsang; William J. McKenna; Shapour Jalilzadeh; Sebastian Carballo; Charles Redwood; Hugh Watkins
Rationale: Most sarcomere gene mutations that cause hypertrophic cardiomyopathy are missense alleles that encode dominant negative proteins. The potential exceptions are mutations in the MYBPC3 gene (encoding cardiac myosin-binding protein-C [MyBP-C]), which frequently encode truncated proteins. Objective: We sought to determine whether there was evidence of haploinsufficiency in hypertrophic cardiomyopathy caused by MYBPC3 mutations by comparing left ventricular muscle from patients undergoing surgical myectomy with samples from donor hearts. Methods and Results: MyBP-C protein and mRNA levels were quantitated using immunoblotting and RT-PCR. Nine of 37 myectomy samples had mutations in MYBPC3: 2 missense alleles (Glu258Lys, Arg502Trp) and 7 premature terminations. No specific truncated MyBP-C peptides were detected in whole muscle homogenates of hypertrophic cardiomyopathy tissue. However, the overall level of MyBP-C in myofibrils was significantly reduced (P<0.0005) in tissue containing either a truncation or missense MYBPC3 mutation: 0.76±0.03 compared with 1.00±0.05 in donor and 1.01±0.06 in non-MYBPC3 mutant myectomies. Conclusions: The absence of any detectable truncated MyBP-C argues against its incorporation in the myofiber and any dominant negative effect. In contrast, the lowered relative level of full length protein in both truncation and missense MYBPC3 mutations argues strongly that haploinsufficiency is sufficient to cause the disease.
Heart | 2004
Rajiv Chaturvedi; Duncan Macrae; Kate L. Brown; M Schindler; E C Smith; K B Davis; G Cohen; Victor Tsang; M. J. Elliott; M de Leval; Steve Gallivan; A P Goldman
Objective: To delineate predictors of hospital survival in a large series of children with biventricular physiology supported with extracorporeal membrane oxygenation (ECMO) after open heart surgery. Results: 81 children were placed on ECMO after open heart surgery. 58% (47 of 81) were transferred directly from cardiopulmonary bypass to ECMO. Hospital survival was 49% (40 of 81) but there were seven late deaths among these survivors (18%). Factors that improved the odds of survival were initiation of ECMO in theatre (64% survival (30 of 47)) rather than the cardiac intensive care unit (29% survival (10 of 34)) and initiation of ECMO for reactive pulmonary hypertension. Important adverse factors for hospital survival were serious mechanical ECMO circuit problems, renal support, residual lesions, and duration of ECMO. Conclusions: Hospital survival of children with biventricular physiology who require cardiac ECMO is similar to that found in series that include univentricular hearts, suggesting that successful cardiac ECMO is critically dependent on the identification of hearts with reversible ventricular dysfunction. In our experience of postoperative cardiac ECMO, the higher survival of patients cannulated in the operating room than in the cardiac intensive care unit is due to early effective support preventing prolonged hypoperfusion and the avoidance of a catastrophic cardiac arrest.
Journal of Molecular and Cellular Cardiology | 2008
Adam Jacques; O'Neal Copeland; Andrew E. Messer; Clare E. Gallon; Katie King; William J. McKenna; Victor Tsang; Steven B. Marston
Phosphorylation of myosin binding protein C (MyBP-C) was investigated in intraventricular septum samples taken from patients with hypertrophic cardiomyopathy undergoing surgical septal myectomy. These samples were compared with donor heart muscle, as a well-characterised control tissue, and with end-stage failing heart muscle. MyBP-C was partly purified from myofibrils using a modification of the phosphate-EDTA extraction of Hartzell and Glass. MyBP-C was separated by SDS-PAGE and stained for phosphoproteins using Pro-Q Diamond followed by total protein staining using Coomassie Blue. Relative phosphorylation level was determined from the ratio of Pro-Q Diamond to Coomassie Blue staining of MyBP-C bands as measured by densitometry. We compared 9 myectomy samples and 9 failing heart samples with 9 donor samples. MyBP-C phosphorylation in pathological muscle was lower than in donor (myectomy 40+/-2% of donor, P<0.0001; failing 45+/-3% of donor, P<0.0001). 6 myectomy samples were identified with MYBPC3 mutations, one with MYH7 mutation and two remained unknown, but there was no correlation between MYBPC3 mutation and MyBP-C phosphorylation level. In order to determine the number of phosphorylated sites in human cardiac MyBP-C samples, we phosphorylated the recombinant MyBP-C fragment, C0-C2 (1-453) with PKA using (gamma32)P-ATP up to 3.5 mol Pi/mol C0-C2. This measurement of phosphorylation was used to calibrate measurements of phosphorylation in SDS-PAGE using Pro-Q Diamond stain. The level of phosphorylation in donor heart MyBP-C was calculated to be 4.6+/-0.6 mol Pi/mol and 2.0+/-0.3 mol Pi/mol in myectomy samples. We conclude that MyBP-C is a highly phosphorylated protein in vivo and that diminished MyBP-C phosphorylation is a feature of both end-stage heart failure and hypertrophic cardiomyopathy.
Cardiovascular Research | 2008
Adam Jacques; N Briceno; Andrew E. Messer; Clare E. Gallon; S Jalilzadeh; E Garcia; G Kikonda-Kanda; J Goddard; Sian E. Harding; Hugh Watkins; Mt Esteban; Victor Tsang; William J. McKenna; Steven B. Marston
Abstract Aim The aim of the study was to compare the functional and structural properties of the motor protein, myosin, and isolated myocyte contractility in heart muscle excised from hypertrophic cardiomyopathy patients by surgical myectomy with explanted failing heart and non-failing donor heart muscle. Methods Myosin was isolated and studied using an in vitro motility assay. The distribution of myosin light chain-1 isoforms was measured by two-dimensional electrophoresis. Myosin light chain-2 phosphorylation was measured by sodium dodecyl sulphate–polyacrylamide gel electrophoresis using Pro-Q Diamond phosphoprotein stain. Results The fraction of actin filaments moving when powered by myectomy myosin was 21% less than with donor myosin (P = 0.006), whereas the sliding speed was not different (0.310 ± 0.034 for myectomy myosin vs. 0.305 ± 0.019 µm/s for donor myosin in six paired experiments). Failing heart myosin showed 18% reduced motility. One myectomy myosin sample produced a consistently higher sliding speed than donor heart myosin and was identified with a disease-causing heavy chain mutation (V606M). In myectomy myosin, the level of atrial light chain-1 relative to ventricular light chain-1 was 20 ± 5% compared with 11 ± 5% in donor heart myosin and the level of myosin light chain-2 phosphorylation was decreased by 30–45%. Isolated cardiomyocytes showed reduced contraction amplitude (1.61 ± 0.25 vs. 3.58 ± 0.40%) and reduced relaxation rates compared with donor myocytes (TT50% = 0.32 ± 0.09 vs. 0.17 ± 0.02 s). Conclusion Contractility in myectomy samples resembles the hypocontractile phenotype found in end-stage failing heart muscle irrespective of the primary stimulus, and this phenotype is not a direct effect of the hypertrophy-inducing mutation. The presence of a myosin heavy chain mutation causing hypertrophic cardiomyopathy can be predicted from a simple functional assay.
Journal of Molecular and Cellular Cardiology | 2010
Anita C. Hoskins; Adam Jacques; Sonya C. Bardswell; William J. McKenna; Victor Tsang; Cristobal G. dos Remedios; Elisabeth Ehler; Kim Adams; Shapour Jalilzadeh; Metin Avkiran; Hugh Watkins; Charles Redwood; Steven B. Marston; Jonathan C. Kentish
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, increased ventricular stiffness and impaired diastolic filling. We investigated to what extent myocardial functional defects can be explained by alterations in the passive and active properties of human cardiac myofibrils. Skinned ventricular myocytes were prepared from patients with obstructive HCM (two patients with MYBPC3 mutations, one with a MYH7 mutation, and three with no mutation in either gene) and from four donors. Passive stiffness, viscous properties, and titin isoform expression were similar in HCM myocytes and donor myocytes. Maximal Ca2+-activated force was much lower in HCM myocytes (14 ± 1 kN/m2) than in donor myocytes (23 ± 3 kN/m2; P < 0.01), though cross-bridge kinetics (ktr) during maximal Ca2+ activation were 10% faster in HCM myocytes. Myofibrillar Ca2+ sensitivity in HCM myocytes (pCa50 = 6.40 ± 0.05) was higher than for donor myocytes (pCa50 = 6.09 ± 0.02; P < 0.001) and was associated with reduced phosphorylation of troponin-I (ser-23/24) and MyBP-C (ser-282) in HCM myocytes. These characteristics were common to all six HCM patients and may therefore represent a secondary consequence of the known and unknown underlying genetic variants. Some HCM patients did however exhibit an altered relationship between force and cross-bridge kinetics at submaximal Ca2+ concentrations, which may reflect the primary mutation. We conclude that the passive viscoelastic properties of the myocytes are unlikely to account for the increased stiffness of the HCM ventricle. However, the low maximum Ca2+-activated force and high Ca2+ sensitivity of the myofilaments are likely to contribute substantially to any systolic and diastolic dysfunction, respectively, in hearts of HCM patients.
The Annals of Thoracic Surgery | 2002
Victor Tsang; Tain-Yen Hsia; Robert W.M Yates; Robert H. Anderson
BACKGROUNDnA distinct defect has been described within the apical part of the muscular ventricular septum, which has multiple orifices when seen from its right ventricular aspect. Closure has been suggested using umbrella devices introduced on a catheter. Such an intervention, however, can be technically difficult in small infants.nnnMETHODSnWe have recently seen two examples of this type of complex communication between the apexes of both left and right ventricles. Neither could be closed by catheterization. A surgical approach was used through a modified apical right ventriculotomy. We have also studied two autopsied specimens, which clarify the morphologic arrangement.nnnRESULTSnBoth patients were closed successfully, with trivial residual shunt and good biventricular functions. The patients were clinically well at 2-year follow-up.nnnCONCLUSIONSnSurgical division of right ventricular trabeculations makes it feasible to identify and repair the septal deficiency, which is a solitary hole. On the basis of our morphologic study, we offer an explanation for the anatomic arrangement that differs from the one proposed by recent previous investigators. If the ventricular incision is appropriately placed, our anatomic studies suggest that it is possible to visualize the solitary opening from its right ventricular aspect, and achieve surgical closure with a single patch.
The Journal of Thoracic and Cardiovascular Surgery | 2015
Michael Ibrahim; Victor Tsang; Maryanne Caruana; Marina Hughes; Synetta Jenkyns; Elodie Perdreau; Alessandro Giardini; Jan Marek
OBJECTIVEnCone reconstruction is advocated to treat severe tricuspid valve (TV) regurgitation associated with Ebsteins anomaly. Data on postoperative clinical status, ventricular adaptation, and objective cardiopulmonary testing are lacking in these patients.nnnMETHODSnThe clinical characteristics, echocardiography, magnetic resonance imaging, and exercise data from 27 consecutive cone reconstructions, undertaken from 2009 to 2013, were retrospectively compared between preoperative baseline and follow-up.nnnRESULTSnThere were no deaths. The cone TV functioned well in all but 1 patient with late dehiscence of inferior annuloplasty sutures that were subsequently repaired. Four patients required pacemaker insertion (3 for new complete heart block). At median follow-up of 2.7 ± 1.5 years, tricuspid regurgitation was reduced in all patients, without causing stenosis. Global left ventricle function remained unchanged (pre-operative fraction 60% ± 4% vs postoperative fraction 61% ± 3%; P = .96). MRI showed enhanced forward pulmonary flow (pre 26 ± 1 mL/beat vs post 36 ± 10 mL/beat; P < .005) and increased left ventricle filling (body surface area-indexed left ventricle end-diastolic volume pre 49 ± 14 mL/m(2) vs post 60 ± 14 mL/m(2); P < .005). New York Heart Association functional class improved (pre 2.5 ± 0.6 vs post 1.3 ± 0.6; P < .0001) and there was significant improvement in peak oxygen uptake (pre 54% ± 18% vs post 66% ± 22%; P = .02).nnnCONCLUSIONSnCone reconstruction of TV offers an effective repair in patients with severe regurgitation associated with Ebsteins anomaly. The patients clinical status improved with better left ventricle filling and objective exercise capacity. The durability of repair, and mechanisms by which the ventricles adapt to the new loading conditions, need longer-term study.
The Annals of Thoracic Surgery | 2005
Leisa J. Freeman; Marc R. de Leval; Victor Tsang
A 36-year-old woman has had an apical left ventricular to descending aortic valve conduit for 24 years that is functioning well and that is probably, to our knowledge, the longest surviving conduit. The patient had previously had a coarctation of the aorta resected at 2 years of age. In 1978, a prosthetic valve conduit was inserted through a left thoracotomy to relieve the left ventricular outflow tract obstruction caused by a monocusp aortic valve and hypoplastic aortic arch. Using cardiopulmonary bypass between the left atrium and the descending thoracic aorta, the apical aortic conduit was placed with a number 19 Hancock elbow-shaped ventricular splint at the apex of the left ventricle, and this was in turn attached to a number 20 Hancock valve conduit anastomosed to the descending aorta, just above the diaphragm. Recent angiography demonstrated no conduit stenosis or regurgitation. The computed tomography images are quite unique and showed the conduit from the left ventricular apex (Fig 1A, arrow) to the descending aorta (Fig 1B). The patient has limited exercise capacity requiring diuretics, and arrhythmia controlled with amiodarone. Despite the reported high incidence of conduit stenosis, apical left ventricular to aorta conduit can produce a good hemodynamic outcome and may be suitable for patients with severe hypertrophic subaortic stenosis thought unsuitable for Morrow’s operation or patients with critical aortic stenosis and “porcelain” ascending aorta. Address reprint requests to Dr Tsang, Cardiothoracic Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond St, London WC1N 3JH, UK; e-mail: [email protected]. Fig 1.
European Journal of Echocardiography | 2018
Elodie Perdreau; Victor Tsang; Marina Hughes; M Ibrahim; S Kataria; K Janagarajan; X Iriart; Sachin Khambadkone; Jan Marek
AimsnThe Cone reconstruction in Ebsteins anomaly (EA) aims to reduce tricuspid valve regurgitation (TR) and reposition the valve to the anatomic annulus, but post-operative progress of ventricular function is poorly understood. This study evaluated biventricular function after Cone reconstruction using echocardiographic techniques.nnnMethods and resultsnA retrospective study assessing longitudinal change was conducted from 2009 to 2014. All symptomatic patients with EA and severe TR undergoing surgery were included. Transthoracic advanced echocardiography was performed pre- and post-operatively (at short-term (<30 days) and mid-term). Conventional and longitudinal 2D strain parameters were measured for left ventricle (LV) and right ventricle (RV). Paired analyses were compared using Wilcoxon Matched-pairs signed rank test. From the 38 patients operated for EA, the echocardiographic data of 17 patients, aged 15 (1-57u2009years) at operation could be analysed. Median follow up was 6u2009months (8 days-54u2009months). The tricuspid annular plane systolic excursion (26.42u2009±u20095.79u2009mm vs. 8.75u2009±u20093.18u2009mm, Pu2009<u20090.001), RV fractional area change (FAC) (45.00u2009±u20098.13% vs. 35.46u2009±u20095.76%, Pu2009=u20090.038) and LV 2D peak systolic strain were significantly reduced post-operatively (-20.49u2009±u20092.79 vs. -17.73u2009±u20092.76, Pu2009=u20090.041), with a trend to later recovery for LV 2D strain. There was no evidence of systolic mechanical dys-synchrony before or after operation.nnnConclusionnAlthough clinical outcome of Cone reconstruction for EA remains excellent, acute post-operative changes leads to reduction of myocardial function of both ventricles, with a trend to later recovery for LV. Continuing impairment of RV function is multifactorial but may reflect intrinsic myocardial deficiency.
Heart | 2018
Sylvia Krupickova; Gareth J. Morgan; Mun Hong Cheang; Michael Rigby; Rodney Franklin; Andrea Battista; Ariana Spanaki; Béatrice Bonello; Olivier Ghez; David Anderson; Victor Tsang; Guido Michielon; Jan Marek; Alain Fraisse
Objectives Infants with symptomatic partial and transitional atrioventricular septal defect undergoing early surgical repair are thought to be at greater risk. However, the outcome and risk profile of this cohort of patients are poorly defined. The aim of this study was to investigate the outcome of symptomatic infants undergoing early repair and to identify risk factors which may predict mortality and reoperation. Methods This multicentre study recruited 51 patients (24 female) in three tertiary centres between 2000 and 2015. The inclusion criteria were as follows: (1) partial and transitional atrioventricular septal defect, (2) heart failure unresponsive to treatment, (3) biventricular repair during the first year of life. Results Median age at definitive surgery was 179 (range 0–357) days. Sixteen patients (31%) had unfavourable anatomy of the left atrioventricular valve: dysplastic (n=7), double orifice (n=3), severely deficient valve leaflets (n=1), hypoplastic left atrioventricular orifice and/or mural leaflet (n=3), short/poorly defined chords (n=2). There were three inhospital deaths (5.9%) after primary repair. Eleven patients (22%) were reoperated at a median interval of 40 days (4u2009days to 5.1 years) for severe left atrioventricular valve regurgitation and/or stenosis. One patient required mechanical replacement of the left atrioventricular valve. After median follow-up of 3.8 years (0.1–11.4 years), all patients were in New York Heart Association (NYHA) class I. In multivariable analysis, unfavourable anatomy of the left atrioventricular valve was the only risk factor associated with left atrioventricular valve reoperation. Conclusions Although surgical repair is successful in the majority of the cases, patients with partial and transitional atrioventricular septal defect undergoing surgical repair during infancy experience significant morbidity and mortality. The reoperation rate is high with unfavourable left atrioventricular valve anatomy.