Publications (49)301.4 Total impact
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Article: Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada.
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ABSTRACT: AimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.Conclusion Although the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation.European Heart Journal 11/2012; · 10.48 Impact Factor -
Article: Sudden Cardiac Death in Hypertrophic Cardiomyopathy.
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ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a common disorder of cardiac muscle associated with sudden cardiac death (SCD). HCM is defined by increased left ventricular wall thickness or mass, in the absence of abnormal loading conditions to account for the observed abnormality.(1) In most adults, the disease is inherited as an autosomal dominant trait and is caused by mutations in cardiac sarcomere protein genes.1 Histologically HCM is characterised by myocardial disarray, fibrosis and small vessel disease.(2) Macroscopically the hypertrophy is typically asymmetric and 25% of patients have resting left ventricular outflow tract obstruction (LVOTO).(3)...Circulation Arrhythmia and Electrophysiology 09/2012; · 6.46 Impact Factor -
Article: The collapsing pulse.
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ABSTRACT: In modern medicine, reliance on clinical signs is rapidly diminishing. Although the cornerstone of valvular heart disease assessment is the history and echocardiographic findings, physical examination remains an important part of the diagnostic work-up to identify patients who require further investigation. Assessment of the pulse remains a fundamental skill for all doctors. This article reviews how to elicit and interpret a 'collapsing' pulse, and hopefully allay some fear in those sitting exams.British journal of hospital medicine (London, England: 2005) 05/2012; 73(5):C78-80. · 0.19 Impact Factor -
Article: Equilibrium contrast CMR for the measurement of diffuse myocardial fibrosis
Journal of Cardiovascular Magnetic Resonance 05/2012; 12:1-2. · 3.72 Impact Factor -
Article: Interstitial expansion in health and disease - an equilibrium contrast CMR study.
Journal of Cardiovascular Magnetic Resonance 02/2012; 14 Suppl 1:O23. · 3.72 Impact Factor -
Article: Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene.
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ABSTRACT: Hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene (TNNT2) has been associated with a high risk of sudden cardiac death (SCD) and mild left ventricular hypertrophy. However, previous studies are limited by sample size, cross-sectional design, and few data in relatives. Five hundred fifty-two unrelated hypertrophic cardiomyopathy probands were screened for TNNT2 mutations. First-degree relatives were invited for clinical and genetic evaluation. Ninety-two individuals (20 probands and 72 relatives) carried TNNT2 mutations (51 [55%] male; 30±17 years). ECGs and echo were available in 87 (95%) and 88 (96%) individuals, respectively. ECG was normal in 13 (68%) children (<16 years) and 13 (19%) adults. Echo was normal in 18 (90%) children and 16 (24%) adults; 7 (10%) adults had a normal ECG and echo. Thirteen (65%) of 20 families had a history of SCD. Follow-up was available for 75 patients (mean, 9.9±5.2 years); 2 of 16 adults and 2 of 18 children with normal echoes developed left ventricular hypertrophy. Twenty-three (22%) received an implantable cardioverter-defibrillator (20 for primary prophylaxis). One child and 3 adults died of SCD and 2 adults were resuscitated from ventricular fibrillation. One patient had an appropriate implantable cardioverter-defibrillator discharge. The rate of cardiovascular death, transplant, and implantable cardioverter-defibrillator discharge was 1.6% (0.016 person/y; 95% confidence interval, 0.83-2.79%), and SCD 0.93% (0.0093 person/y; 95% confidence interval, 0.37-1.92%). Left ventricular hypertrophy is rare in children with TNNT2 mutations. Left ventricular hypertrophy is absent in the minority of adults, but most have an abnormal ECG. Despite adverse family histories, the rate of cardiovascular death during follow-up was similar to that reported in large referral populations.Circulation Cardiovascular Genetics 12/2011; 5(1):10-7. · 6.11 Impact Factor -
Article: The relation of ventricular arrhythmia electrophysiological characteristics to cardiac phenotype and circadian patterns in hypertrophic cardiomyopathy.
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ABSTRACT: The triggers of ventricular arrhythmias (VAs) leading to sudden cardiac death in hypertrophic cardiomyopathy (HCM) are ill defined. We sought to examine the electrophysiological characteristics of VAs in HCM and study their relation to cardiac phenotype and circadian patterns using stored intracardiac electrocardiograms from implantable cardioverter defibrillators (ICDs). A single centre, observational cohort study of 230 consecutively evaluated ICD recipients with HCM [median age 42 years, 97% primary prevention, 51% with anti-tachycardia pacing (ATP)]. Fifty-six non-clustered VAs (39 initially treated with ATP and 17 with shocks) from 29 patients were analysed. Monomorphic ventricular tachycardia was the culprit arrhythmia in 86% of cases, ventricular fibrillation/flutter in 9%, and polymorphic ventricular tachycardia in 5%. Prior to the onset of VA the rhythm was sinus in 67%, atrial fibrillation/flutter in 19%, and 15% were paced ventricularly; tachycardia (cycle length <600 ms) was present in 25%. Ventricular arrhythmias were triggered by premature ventricular complexes (PVCs) in 72%, which were late-coupled (84%). Short-long-short initiation was seen in 2% and 26% of VAs were sudden-onset without preceding PVCs. Ventricular arrhythmia peaked at midday (with 20% occurring between 2300 and 0700), on Sundays and in May. The cardiac phenotype and time of the day did not predict the mode of initiation. Age at ICD implantation was the only independent predictor of VA cycle length (linear regression coefficient 0.67, 95% CI 0.02-1.32, P= 0.04). Anti-tachycardia pacing terminated 67% of VAs, but patients with ATP therapy had a similar incidence of appropriate shocks (log-rank test P= 0.25) and syncope (log rank P= 0.23) to patients with shock as initial therapy. Most VAs are monomorphic ventricular tachycardias triggered by late-coupled PVCs. They are frequently terminated by ATP, but ATP does not reduce the frequency of ICD shocks. Younger HCM patients have more rapid VAs, which may explain the peak of sudden cardiac death in early adulthood. The circadian periodicity is different from that observed in ischaemic heart disease, and is likely to relate to the distinct character of the arrhythmogenic substrate in HCM and its modulators.Europace 11/2011; 14(5):724-33. · 1.98 Impact Factor -
Article: Pregnancy and its management in women with GSD type III - a single centre experience.
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ABSTRACT: We present a review of our experience and pregnancy outcome in patients with GSD III managed by our centre. Between 1997 and 2010 there were 15 pregnancies in seven women with GSD III. Four women had GSD IIIb (nine pregnancies) and three GSD IIIa (six pregnancies). There was a successful outcome in all 15 pregnancies with delivery of 15 liveborn infants. Four infants were of low birthweight (<2nd centile) but all have developed normally apart from one with behavioural/psychiatric problems. Three women had pre-existing cardiomyopathy prior to pregnancy. One of these women had deterioration of her cardiomyopathy during pregnancy and again in the post-partum period. Women with GSD III do not seem to have any issues with fertility. Overall the outcome of pregnancy for both mother and child is good. Care needs to be taken to avoid maternal hypoglycemia which may be associated with intrauterine growth restriction and low birth weight. Cardiac function should be monitored carefully particularly in those with pre-existing cardiomyopathy.Journal of Inherited Metabolic Disease 09/2011; 35(2):245-51. · 3.58 Impact Factor -
Article: Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson-Fabry Disease survey.
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ABSTRACT: The prevalence of Anderson-Fabry disease (AFD) in patients presenting with unexplained left ventricular hypertrophy (LVH) is controversial. The aim of this study was to determine the prevalence of AFD in a large, consecutive cohort of patients with hypertrophic cardiomyopathy (HCM) using rapid mutation screening. A European multicentre cross-sectional study involving 13 referral centres. Inclusion criteria for the study were: men aged at least 35 years and women aged at least 40 years with unexplained LVH (maximum left ventricular wall thickness ≥ 1.5 cm). All patients were screened using a denaturing high-performance liquid chromatography protocol for rapid mutation screening of the α-galactosidase A (α-Gal A) gene and, if a sequence variant was found, direct sequencing was performed. 1386 patients (63.9% men, mean age 57.9 ± 12.0 years) were enrolled in the study. Seven (0.5%) patients (age 57.4 ± 9.0 years (45-72); three (43%) men) had pathogenic α-galactosidase A mutations. Polymorphisms were identified in 283 patients (20.4%). Maximal left ventricular wall thickness in patients carrying a disease-causing mutation was 18 ± 2 mm (range 15-22); four patients had concentric LVH and the remainder had asymmetric septal hypertrophy. The prevalence of AFD gene mutations in a large, consecutive cohort of European patients with unexplained LVH is 0.5%.Heart (British Cardiac Society) 09/2011; 97(23):1957-60. · 4.22 Impact Factor -
Article: The long-term survival and the risks and benefits of implantable cardioverter defibrillators in patients with hypertrophic cardiomyopathy.
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ABSTRACT: Implantable cardioverter defibrillators (ICDs) are routinely used to prevent sudden cardiac death (SCD) in selected hypertrophic cardiomyopathy (HCM) patients, but the determinants of device-related complications, therapies and long-term cardiovascular mortality in ICD recipients are not known. Retrospective observational cohort study. Single-centre tertiary referral cardiomyopathy clinic. Patients 334 consecutively evaluated HCM patients (median age 40 years, 62% male, 92% primary prevention) at risk of SCD treated with ICD. Thirty-six patients (11%) received concurrent cardiac resynchronisation therapy for heart failure symptoms. During the 1286 patient-years of follow-up, cardiovascular mortality (including transplantation) occurred in 22 (7%) patients (1.7%/year) and was associated with New York Heart Association (NYHA) class III/IV (adjusted HR=9.38, 95% CI 3.31 to 26.55, p≤0.001), percentage fractional shortening (HR=0.92, 95% CI 0.87 to 0.96, p=0.001) and implantation for secondary prevention (HR=0.07, 95% CI 0.01 to 0.86, p=0.04). There were no SCD. Twenty-eight (8%) patients received appropriate shocks (2.3%/year), which were predicted by baseline fractional shortening (HR=0.96, 95% CI 0.92 to 0.99, p=0.04). Fifty-five (16%) patients received inappropriate shocks (4.6%/year). Sixty (18%) patients experienced implant-related complications (5.1%/year), including two deaths. Adverse ICD-related events (inappropriate shocks and/or implant complications) were seen in 101 (30%) patients (8.6%/year). Patients with cardiac resynchronisation therapy were more likely to develop implant complications than those with single-chamber ICDs (HR=4.39, 95% CI 1.44 to 13.35, p=0.009) and had a higher 5-year cardiovascular mortality than did the rest of the cohort (21% vs 6%, p<0.001). HCM patients with an ICD have a significant cardiovascular mortality and are exposed to frequent inappropriate shocks and implant complications. These data suggest that new strategies are required to improve patient selection for ICDs and to prevent disease progression in those that receive a device.Heart (British Cardiac Society) 07/2011; 98(2):116-25. · 4.22 Impact Factor -
Article: The quantification and role of diffuse myocardial fibrosis in familial dilated cardiomyopathy - an equilibrium contrast cmr study
Journal of Cardiovascular Magnetic Resonance. 01/2011; -
Article: The evolution and clinical importance of scar in hypertrophic cardiomyopathy - a 7 year CMR follow-up study
Journal of Cardiovascular Magnetic Resonance. 01/2011; -
Article: The distribution of hypertrophy in anderson fabry disease
Journal of Cardiovascular Magnetic Resonance. 01/2011; -
Article: Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
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ABSTRACT: Advances in molecular genetics present new opportunities and challenges for cardiologists who manage patients and families with cardiomyopathies. The aims of this position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases are to review the general issues related to genetic counselling, family screening and genetic testing in families with a cardiomyopathy, and to provide key messages and suggestions for clinicians involved in their management.European Heart Journal 11/2010; 31(22):2715-26. · 10.48 Impact Factor -
Article: Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.
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ABSTRACT: Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. Forty-six consecutive patients with symptomatic exercise limitation (peak Vo(2) <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to -0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak Vo(2)) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg(-1) · min(-1); P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo). In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy.Circulation 10/2010; 122(16):1562-9. · 14.74 Impact Factor -
Article: Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes.
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ABSTRACT: Whilst the decision regarding defibrillator implantation in a patient with a familial sudden cardiac death syndrome is likely to be most significant for any particular individual, the clinical decision-making process itself is complex and requires interpretation and extrapolation of information from a number of different sources. This document provides recommendations for adult patients with the congenital Long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although these specific conditions differ in terms of clinical features and prognosis, it is possible and logical to take an approach to determining a threshold for implantable cardioveter-defibrillator implantation that is common to all of the familial sudden cardiac death syndromes based on estimates of absolute risk of sudden death.Europace 08/2010; 12(8):1156-75. · 1.98 Impact Factor -
Article: Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy.
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ABSTRACT: Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, but the genetic basis in the majority of cases remains unknown. Genes encoding desmosomal proteins, currently regarded as synonymous with another disorder, arrhythmogenic right ventricular cardiomyopathy, are known to cause left ventricular dysfunction, but their importance in unselected patients with unequivocal dilated cardiomyopathy is unknown. The objective of this study was to determine the prevalence of mutations in 5 desmosomal protein genes in patients with dilated cardiomyopathy. We studied 100 unrelated patients with idiopathic dilated cardiomyopathy consecutively referred to a dedicated cardiomyopathy unit. Patients underwent clinical evaluation, ECG, echocardiography, exercise testing, 24-hour ambulatory ECG monitoring, and mutation screening of 5 genes implicated in arrhythmogenic right ventricular cardiomyopathy: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Of the 100 patients (mean age at evaluation, 46.8+/-13.8 years; range, 17.0 to 72.8 years; male sex, 63%), 5 were found to carry pathogenic desmosomal protein gene mutations. An additional 13 patients had sequence variants of uncertain pathogenic significance and were excluded from further comparative analysis. Patients harboring desmosomal gene mutations had a phenotype indistinguishable from the 82 noncarriers, with the exception of exercise-induced ventricular ectopy, which was more frequent in the desmosomal mutation carriers (P=0.033). None of the 5 carriers of desmosomal mutations fulfilled current diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy, but 1 had fibrofatty change in the left ventricle at autopsy. Heart failure caused by a dilated, poorly contracting left ventricle and arrhythmogenic right ventricular cardiomyopathy have been considered distinct clinicopathologic entities. This study suggests that both clinical presentations can be caused by mutations in desmosomal protein genes.Circulation Cardiovascular Genetics 08/2010; 3(4):314-22. · 6.11 Impact Factor -
Article: Left ventricular strain and untwist in hypertrophic cardiomyopathy: relation to exercise capacity.
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ABSTRACT: Nonobstructive hypertrophic cardiomyopathy (nHCM) is often associated with reduced exercise capacity despite hyperdynamic systolic function as measured by left ventricular ejection fraction. We sought to examine the importance of left ventricular strain, twist, and untwist as predictors of exercise capacity in nHCM patients. Fifty-six nHCM patients (31 male and mean age of 52 years) and 43 age- and gender-matched controls were enrolled. We measured peak oxygen consumption (peak Vo(2)) and acquired standard echocardiographic images in all participants. Two-dimensional speckle tracking was applied to measure rotation, twist, untwist rate, strain, and strain rate. The nHCM patients exhibited marked exercise limitation compared with controls (peak Vo(2) 23.28 +/- 6.31 vs 37.70 +/- 7.99 mL/[kg min], P < .0001). Left ventricular ejection fraction in nHCM patients and controls was similar (62.76% +/- 9.05% vs 62.48% +/- 5.82%, P = .86). Longitudinal, radial, and circumferential strain and strain rate were all significantly reduced in nHCM patients compared with controls. There was a significant delay in 25% of untwist in nHCM compared with controls. Both systolic and diastolic apical rotation rates were lower in nHCM patients. Longitudinal systolic and diastolic strain rate correlated significantly with peak Vo(2) (r = -0.34, P = .01 and r = 0.36, P = .006, respectively). Twenty-five percent untwist correlated significantly with peak Vo(2) (r = 0.36, P = .006). In nHCM patients, there are widespread abnormalities of both systolic and diastolic function. Reduced strain and delayed untwist contribute significantly to exercise limitation in nHCM patients.American heart journal 05/2010; 159(5):825-32. · 4.65 Impact Factor -
Article: Equilibrium contrast CMR for the measurement of diffuse myocardial fibrosis
Journal of Cardiovascular Magnetic Resonance. 01/2010; -
Article: Right ventricular hypertrabeculation associated with double-outlet left ventricle: exaggeration of a normal pattern or right ventricular cardiomyopathy?
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ABSTRACT: We describe a rare case of double-outlet left ventricle, ventricular septal defect, and subpulmonary valve stenosis surgically corrected by Rastelli procedure, developing severe homograft obstruction with right ventricular dilation and extensive hypertrabeculation/noncompaction during follow-up. We briefly discuss the cause diagnosis, and clinical significance of right ventricular hypertrabeculation/noncompaction.Journal of Cardiovascular Medicine 12/2009; 11(3):193-5. · 1.51 Impact Factor
Top co-authors
Top Journals
Institutions
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2006–2012
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University College London Hospitals
London, ENG, United Kingdom
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2004–2011
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University College London
- Institute of Cardiovascular Science
London, ENG, United Kingdom
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2009
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Royal Brompton & Harefield NHS Foundation Trust
Harefield, ENG, United Kingdom
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2008
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Hadassah Medical Center
Jerusalem, Jerusalem District, Israel
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2002–2003
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St George Hospital
Sydney, New South Wales, Australia
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