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Gabriella Captur,
Vivek Muthurangu,
Christopher Cook,
Andrew S Flett,
Robert Wilson,
Andrea Barison,
Daniel M Sado,
Sarah Anderson,
William J McKenna,
Timothy J Mohun, Perry M Elliott,
James C Moon
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ABSTRACT: BACKGROUND: Left ventricular noncompaction (LVNC) is a myocardial disorder characterized by excessive left ventricular (LV) trabeculae. Current methods for quantification of LV trabeculae have limitations. The aim of this study is to describe a novel technique for quantifying LV trabeculation using cardiovascular magnetic resonance (CMR) and fractal geometry. Observing that trabeculae appear complex and irregular, we hypothesize that measuring the fractal dimension (FD) of the endocardial border provides a quantitative parameter that can be used to distinguish normal from abnormal trabecular patterns. METHODS: Fractal analysis is a method of quantifying complex geometric patterns in biological structures. The resulting FD is a unitless measure index of how completely the object fills space. FD increases with increased structural complexity. LV FD was measured using a box-counting method on CMR short-axis cine stacks. Three groups were studied: LVNC (defined by Jenni criteria), n=30(age 41+/-13; men, 16); healthy whites, n=75(age, 46+/-16; men, 36); healthy blacks, n=30(age, 40+/-11; men, 15). RESULTS: In healthy volunteers FD varied in a characteristic pattern from base to apex along the LV. This pattern was altered in LVNC where apical FD were abnormally elevated. In healthy volunteers, blacks had higher FD than whites in the apical third of the LV (maximal apical FD: 1.253+/-0.005 vs. 1.235+/-0.004, p<0.01)(mean+/-s.e.m.). Comparing LVNC with healthy volunteers, maximal apical FD was higher in LVNC (1.392+/-0.010, p<0.00001). The fractal method was more accurate and reproducible (ICC, 0.97 and 0.96 for intra and inter-observer readings) than two other CMR criteria for LVNC (Petersen and Jacquier). CONCLUSIONS: FD is higher in LVNC patients compared to healthy volunteers and is higher in healthy blacks than in whites. Fractal analysis provides a quantitative measure of trabeculation and has high reproducibility and accuracy for LVNC diagnosis when compared to current CMR criteria.
Journal of Cardiovascular Magnetic Resonance 05/2013; 15(1):36. · 3.72 Impact Factor
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Heart (British Cardiac Society) 04/2013; · 4.22 Impact Factor
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Daniel M Sado,
Steven K White,
Stefan K Piechnik,
Sanjay M Banypersad,
Thomas Treibel,
Gabriella Captur,
Marianna Fontana,
Viviana Maestrini,
Andrew S Flett,
Matthew D Robson,
Robin H Lachmann,
Elaine Murphy,
Atul Mehta,
Derralynn Hughes,
Stefan Neubauer, Perry M Elliott,
James C Moon
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ABSTRACT: BACKGROUND: -Anderson Fabry disease (AFD) is a rare but under-diagnosed intracellular lipid disorder which can cause left ventricular hypertrophy (LVH). Lipid is known to shorten the MRI parameter T1. We hypothesised that non-contrast T1 mapping by cardiovascular magnetic resonance would provide a novel and useful measure in this disease with potential to detect early cardiac involvement and distinguish AFD LVH from other causes. METHODS AND RESULTS: -227 subjects were studied: AFD patients (n=44, 55% with LVH), healthy volunteers (n=67, 0% with LVH), hypertension (n=41, 24% with LVH), hypertrophic cardiomyopathy (n=34, 100% with LVH), severe aortic stenosis (n=21, 81% with LVH) and definite AL cardiac amyloidosis (n=20, 100% with LVH). T1 mapping was performed using the Sh-MOLLI sequence on a 1.5T magnet before gadolinium administration with primary results derived from the basal and mid septum. Compared to health volunteers, septal T1 was lower in AFD and higher in other diseases (AFD vs healthy volunteers vs other patients, 882±47ms, 968±32ms, 1018±74ms, P<0.0001). In patients with LVH (n=105), T1 discriminated completely between AFD and other diseases with no overlap. In AFD, T1 correlated inversely with wall thickness (R=-0.51, P=0.0004) and was abnormal in 40% of subjects who did not have LVH. Segmentally, AFD showed pseudo-normalisation or elevation of T1 in the LV infero-lateral wall, correlating with the presence or absence of late gadolinium enhancement (1001±82ms vs 891±38ms, P<0.0001) CONCLUSIONS: -Non-contrast T1 mapping shows potential as a unique and powerful measurement in the imaging assessment of left ventricular hypertrophy and Anderson Fabry disease.
Circulation Cardiovascular Imaging 04/2013; · 5.94 Impact Factor
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ABSTRACT: AIMS: We sought to determine the accuracy of finger plethysmography using pulse waveform analysis with brachial calibration for measurement of cardiac output during submaximal exercise by comparing it against an acetylene (C2 H2 ) uptake technique. METHODS: The study included 24 healthy volunteers (12 males, age 35 ± 8 years). Testing was performed on an upright cycle ergometer using an incremental protocol. Cardiac output measurements were performed at rest and during sub-maximal exercise using a single breath C2 H2 uptake technique and continuously using finger plethysmography with brachial calibration. RESULTS: Valid results at rest and during sub-maximal exercise were achieved in 20 of 24 participants. Cardiac output at rest was 5·3 ± 1·1 and 5·2 ± 1·2 l min(-1) for finger plethysmography and C2 H2, respectively, P = 0·712. Mean difference between techniques was -0·1 ± 0·5 l min(-1) . Cardiac output during submaximal exercise was 10·2 ± 2·3 and 10·3 ± 2·1 l min(-1) for finger plethysmography and C2 H2, respectively, P = 0·898. Mean difference between techniques was 0·1 ± 1·5 l min(-1) . The overall correlation between finger plethysmography and C2 H2 data obtained during rest and exercise was r(2) = 0·872, P<0·0001. Mean rise in cardiac output during exercise was 4·9 ± 1·5 (finger plethysmography) and 5·1 ± 1·5 l min(-1) (C2 H2 ), P = 0·64. CONCLUSION: Finger plethysmography determined cardiac output values both at rest and during sub-maximal exercise are comparable with those obtained using a single breath C2 H2 uptake technique.
Clinical Physiology and Functional Imaging 04/2013; · 1.33 Impact Factor
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ABSTRACT: Emery Dreifuss muscular dystrophy (EDMD) is a hereditary muscular disorder, characterized by contractures, progressive muscular wasting and cardiac involvement. The majority of EDMD patients harbor mutations in the lamin A/C (LMNA) and emerin (STA) genes. Emerging data implicate mutations in FHL1 (four and a half LIM protein 1) gene, located in chromosome Xq26, in EDMD pathogenesis. FHL1 is mainly expressed in striated and cardiac muscle, and plays important roles in sarcomeric protein synthesis, maintenance of cellular integrity, intracellular signaling and genetic transcription pathways. We report the identification of a novel nonsense mutation in FHL1 gene, associated with left ventricular hypertrophy and a family history of stroke and sudden cardiac death. The management implications of this diagnosis are also discussed.
European journal of medical genetics 03/2013; · 1.57 Impact Factor
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ABSTRACT: AimsTo determine the relation between serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and prognosis in patients with hypertrophic cardiomyopathy (HCM).Methods and resultsIn total, 847 patients (53 ± 15 years; 67% male) with HCM (28% with left ventricular outflow tract obstruction ≥30 mmHg at rest) were followed for 3.5 years (IQR 2.5-4.5 years). The median NT-proBNP concentration was 78 pmol/L (range <5-1817 pmol/L and IQR 31-183 pmol/L). Sixty-eight patients (8%) reached the primary endpoint of all-cause mortality or cardiac transplantation. Plasma NT-proBNP concentration predicted long-term survival from the primary endpoint [area under the receiver operating characteristic curve of 0.78 (95% confidence interval 0.73-0.84)]. A serum concentration of ≥135 pmol/L was associated with an annual event rate of 6.1% (95% CI 4.4-7.7). Three independent predictors of primary outcome were identified in a multivariable Cox model: New York Heart Association class III/IV (HR 2.10, 95% CI 1.21-3.65, P = 0.008), ejection fraction (HR 0.98, 95% CI 0.96-1.00, P = 0.035), log NT-proBNP (HR 2.04, 95% CI 1.56-2.66, P < 0.001). Log NT-proBNP was a significant predictor of heart failure (HF) and transplant-related deaths (n = 23; HR 3.03, 95% CI 1.99-4.60, P < 0.001) but not sudden death or appropriate implantable cardioverter defibrillator shock (n = 11; HR 1.54, 95% CI 0.91-2.60, P = 0.111). In patients with ejection fraction ≥50% (n = 673), log NT-proBNP remained an independent predictor of the primary outcome (HR 2.11, 95% CI 1.54-2.90, P < 0.001).Conclusion
In patients with HCM, elevated NT-proBNP concentration is a strong predictor of overall prognosis, particularly HF-related death and transplantation.
European Heart Journal 03/2013; · 10.48 Impact Factor
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ABSTRACT: BACKGROUND: Clinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of a HTS strategy for patients with hypertrophic cardiomyopathy (HCM) using a targeted HTS methodology and workflow developed for patients with a range of inherited cardiovascular diseases. By comparing the sequencing results with published findings and with sequence data from a large-scale exome sequencing screen of UK individuals, we sought to quantify the strength of the evidence supporting causality for detected candidate variants. METHODS AND RESULTS: 223 unrelated patients with HCM (46±15 years at diagnosis, 74% males) were studied. In order to analyse coding, intronic and regulatory regions of 41 cardiovascular genes, we used solution-based sequence capture followed by massive parallel resequencing on Illumina GAIIx. Average read-depth in the 2.1 Mb target region was 120. Rare (frequency<0.5%) non-synonymous, loss-of-function and splice-site variants were defined as candidates. Excluding titin, we identified 152 distinct candidate variants in sarcomeric or associated genes (89 novel) in 143 patients (64%). Four sarcomeric genes (MYH7, MYBPC3, TNNI3, TNNT2) showed an excess of rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in cases compared to controls. The estimated probability that a nsSNP in these genes is pathogenic varied between 57% and near certainty depending on the location. We detected an additional 94 candidate variants (73 novel) in desmosomal, and ion-channel genes in 96 patients (43%). CONCLUSIONS: This study provides the first large-scale quantitative analysis of the prevalence of sarcomere protein gene variants in patients with HCM using HTS technology. Inclusion of other genes implicated in inherited cardiac disease identifies a large number of non-synonymous rare variants of unknown clinical significance.
Journal of Medical Genetics 02/2013; · 6.36 Impact Factor
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ABSTRACT: AIMS: Sudden cardiac death (SCD) is a common mode of death in hypertrophic cardiomyopathy (HCM), but identification of patients who are at a high risk of SCD is challenging as current risk stratification guidelines have never been formally validated. The objective of this study was to assess the power of the 2003 American College of Cardiology (ACC)/European Society of Cardiology (ESC) and 2011 ACC Foundation (ACCF)/American Heart Association (AHA) SCD risk stratification algorithms to distinguish high risk patients who might be eligible for an implantable cardioverter defibrillator (ICD) from low risk individuals. METHODS AND RESULTS: We studied 1606 consecutively evaluated HCM patients in an observational, retrospective cohort study. Five risk factors (RF) for SCD were assessed: non-sustained ventricular tachycardia, severe left ventricular hypertrophy, family history of SCD, unexplained syncope and abnormal blood pressure response to exercise. During a follow-up period of 11 712 patient years (median 6.6 years), SCD/appropriate ICD shock occurred in 20 (3%) of 660 patients without RF (annual rate 0.45%), 31 (4.8%) of 636 patients with 1 RF (annual rate 0.65%), 27 (10.8%) of 249 patients with 2 RF (annual rate 1.3%), 7 (13.7%) of 51 patients with 3 RF (annual rate 1.9%) and 4 (40%) of 10 patients with ≥4 RF (annual rate 5.0%). The risk of SCD increased with multiple RF (2 RF: HR 2.87, p≤0.001; 3 RF: HR 4.32, p=0.001; ≥4 RF: HR 11.37, p<0.0001), but not with a single RF (HR 1.43 p=0.21). The area under time-dependent receiver operating characteristic curves (representing the probability of correctly identifying a patient at risk of SCD on the basis of RF profile) was 0.63 at 1 year and 0.64 at 5 years for the 2003 ACC/ESC algorithm and 0.61 at 1 year and 0.63 at 5 years for the 2011 ACCF/AHA algorithm. CONCLUSIONS: The risk of SCD increases with the aggregation of RF. The 2003 ACC/ESC and 2011 ACCF/AHA guidelines distinguish high from low risk individuals with limited power.
Heart (British Cardiac Society) 01/2013; · 4.22 Impact Factor
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Luis R Lopes,
Anna Zekavati,
Petros Syrris,
Mike Hubank,
Claudia Giambartolomei,
Chrysoula Dalageorgou,
Sharon Jenkins,
William McKenna,
UK10K,
Vincent Plagnol, Perry M. Elliott
Journal of Medical Genetics 01/2013; · 6.36 Impact Factor
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Claudio Rapezzi,
Eloisa Arbustini,
Alida L P Caforio,
Philippe Charron,
Juan Gimeno-Blanes,
Tiina Heliö,
Ales Linhart,
Jens Mogensen,
Yigal Pinto,
Arsen Ristic,
Hubert Seggewiss,
Gianfranco Sinagra,
Luigi Tavazzi, Perry M Elliott
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ABSTRACT: In 2008, The ESC Working Group on Myocardial and Pericardial Diseases proposed an updated classification of cardiomyopathies based on morphological and functional phenotypes and subcategories of familial/genetic and non-familial/non-genetic disease. In this position statement, we propose a framework for the clinical approach to diagnosis in cardiomyopathies based on the recognition of diagnostic 'red flags' that can be used to guide rational selection of specialized tests including genetic analysis. The basic premise is that the adoption of a cardiomyopathy-specific mindset which combines conventional cardiological assessment with non-cardiac and molecular parameters increases diagnostic accuracy and thus improves advice and treatment for patients and families.
European Heart Journal 12/2012; · 10.48 Impact Factor
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Caroline J Coats,
Valentina Parisi,
Monica Ramos,
Kalaiarasi Janagarajan,
Constantinos O'Mahony,
Anne Dawnay,
Robin H Lachmann,
Elaine Murphy,
Atul Mehta,
Derralynn Hughes, Perry M Elliott
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ABSTRACT: Enzyme replacement therapy has the potential to delay or reverse adverse cardiac remodeling in Anderson-Fabry disease (AFD); however, the current indications for enzyme replacement therapy rely on detecting relatively advanced features of the disease. We aimed to determine the relation between the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and cardiac abnormalities in patients with AFD. We hypothesized that it might help to detect early disease. NT-proBNP was measured under at rest conditions in 117 patients with AFD (age 48 ± 15 years, 46.2% men). All patients underwent clinical evaluation with electrocardiography and echocardiography. The median NT-proBNP concentration was 24 pmol/L (range <5 to 6,059). Of the 117 patients, 67 (57%) had elevated, age-corrected, NT-proBNP levels. In the 56 patients (48%) with normal echocardiographic findings, the NT-proBNP levels were greater than the age-predicted cutoffs in 10 of 25 patients with abnormal electrocardiographic findings and 3 of 31 patients with normal electrocardiographic findings (p <0.05). On multiple regression analysis, age, creatinine, left atrial volume index, E/Ea, and the presence of abnormal electrocardiographic findings were independently associated with log NT-proBNP (R(2) = 0.67, p <0.05). In conclusion, NT-proBNP concentrations were elevated in patients with AFD and early cardiac involvement, suggesting its measurement could assist in decisions regarding the timing of enzyme replacement therapy.
The American journal of cardiology 10/2012; · 3.58 Impact Factor
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Daniel M Sado,
Andrew S Flett,
Sanjay M Banypersad,
Steven K White,
Viviana Maestrini,
Giovanni Quarta,
Robin H Lachmann,
Elaine Murphy,
Atul Mehta,
Derralynn A Hughes,
William J McKenna,
Andrew M Taylor,
Derek J Hausenloy,
Philip N Hawkins, Perry M Elliott,
James C Moon
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ABSTRACT: To measure and assess the significance of myocardial extracellular volume (ECV), determined non-invasively by equilibrium contrast cardiovascular magnetic resonance, as a clinical biomarker in health and a number of cardiac diseases of varying pathophysiology.
Prospective study.
Tertiary referral cardiology centre in London, UK.
192 patients were mainly recruited from specialist clinics. We studied patients with Anderson-Fabry disease (AFD, n=17), dilated cardiomyopathy (DCM, n=31), hypertrophic cardiomyopathy (HCM, n=31), severe aortic stenosis (AS, n=66), cardiac AL amyloidosis (n=27) and myocardial infarction (MI, n=20). The results were compared with those for 81 normal subjects.
In normal subjects, ECV (mean (95% CI), measured in the septum) was slightly higher in women than men (0.273 (0.264 to 0.282 vs 0.233 (0.225 to 0.244), p<0.001), with no change with age. In disease, the ECV of AFD was the same as in normal subjects but higher in all other diseases (p<0.001). Mean ECV was the same in DCM, HCM and AS (0.280, 0.291, 0.276 respectively), but higher in cardiac AL amyloidosis and higher again in MI (0.466 and 0.585 respectively, each p<0.001). Where ECV was elevated, correlations were found with indexed left ventricular mass, end systolic volume, ejection fraction and left atrial area in apparent disease-specific patterns.
Myocardial ECV, assessed non-invasively in the septum with equilibrium contrast cardiovascular magnetic resonance, shows gender differences in normal individuals and disease-specific variability. Therefore, ECV shows early potential to be a useful biomarker in health and disease.
Heart (British Cardiac Society) 08/2012; 98(19):1436-41. · 4.22 Impact Factor
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European Heart Journal 06/2012; · 10.48 Impact Factor
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Revista Espanola de Cardiologia 05/2012; 65(7):599-605.
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Juan Pablo Kaski,
Petros Syrris,
Adam Shaw,
Krisztina Zuborne Alapi,
Viviana Cordeddu,
Maria Teresa Tome Esteban,
Sharon Jenkins,
Michael Ashworth,
Peter Hammond,
Marco Tartaglia,
William J McKenna, Perry M Elliott
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ABSTRACT: Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM.
Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ≤13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (PTPN11, SOS1, HRAS, KRAS, NRAS, BRAF, RAF1, MAP2K1, and MAP2K2), together with CBL (exons 8 and 9) and SHOC2 (4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in SOS1 (2 individuals), BRAF, MAP2K1, and MAP2K2. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in MYBPC.
This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.
Circulation Cardiovascular Genetics 05/2012; 5(3):317-26. · 6.11 Impact Factor
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Journal of the American College of Cardiology 05/2012; 59(18):1660-1. · 14.16 Impact Factor
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ABSTRACT: Small selected cohort studies suggest that mutations in the cardiac myosin binding protein-C (MYBPC3) gene cause late-onset, clinically benign hypertrophic cardiomyopathy (HCM). The aim of this study was to test this hypothesis in a large series of families with HCM associated with MYBPC3 mutations.
The initial study population comprised 57 probands with 42 mutations (26 [61.9%] novel) in MYBPC3. Missense mutations (15, 45.6%) were the most frequent, and multiple mutations occurred in 4 (7.0%) probands. Another 110 mutation carriers were identified during familial evaluation; 38 were clinically affected with left ventricular hypertrophy ≥13 mm. Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years, P<0.001), and was greater in males than females (65.1% versus 48.1%, P=0.03). In 9 families (25 individuals) with the R502W mutation, there was marked heterogeneity in age at diagnosis (5 to 80 years), pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric), and prognosis (premature sudden death in 2 individuals compared with survival to advanced age in 6 individuals). During follow up of 7.9+/-4.5 years, in 82 clinically affected individuals the annual risk of sudden death and all cause mortality was 0.46% and 0.93% per year, respectively.
Disease expression in families with HCM related to MYBPC3 mutations shows marked heterogeneity with incomplete, age-related, and gender specific penetrance. Importantly, complex genetic status is observed and should be considered when mutation analysis and cascade screening is used in the evaluation of at risk family members.
Circulation Cardiovascular Genetics 01/2012; 5(2):156-66. · 6.11 Impact Factor
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ABSTRACT: The mitochondrion is the main site of production of ATP that represents the source of energy for a large number of cellular processes. Mitochondrial diseases that result in a deficit in ATP production can affect almost every organ system with a large spectrum of clinical phenotypes. Cardiomyocytes are particularly vulnerable to limited ATP supply because of their large energy requirement. Abnormalities in the mitochondrial function are increasingly recognized in association with dilated and hypertrophic cardiomyopathy, cardiac conduction defects, endothelial dysfunction and coronary artery disease. Cardiologists should, therefore, be alerted to symptoms and signs suggestive of mitochondrial diseases and become familiar with the general issues related to multisystem disease management, genetic counseling and testing.
Future Cardiology 01/2012; 8(1):71-88.
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ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease predominantly caused by mutations in desmosomal protein genes. Lamin A/C gene (LMNA) mutations are associated with dilated cardiomyopathy, conduction abnormalities and high incidence of sudden cardiac death. In this study, we screened a large cohort of ARVC patients for LMNA mutations.
One hundred and eight patients from unrelated families with borderline (n = 27) or definite (n = 81) diagnosis of ARVC were genetically tested for five desmosomal genes and LMNA. Sixty-one (56.5%) were positive for desmosomal gene mutations. Standard polymerase chain reaction (PCR) amplification of the 12 protein-coding LMNA exons was performed and mutational screening performed by direct sequencing. Four patients (4%) without desmosomal gene mutations carried LMNA variants. Three had severe right ventricular involvement, and during follow-up three died (two suddenly and one from congestive heart failure); all three had conduction abnormalities on resting 12-lead electrocardiogram (ECG). Myocardial tissue from two patients showed myocyte loss and fibro-fatty replacement. In one of these, immunohistochemical staining with antibody to plakoglobin showed reduced/absent staining of the intercalated discs in the myocardium.
Lamin A/C gene mutations can be found in severe forms of ARVC. Lamin A/C gene should be added to desmosomal genes when genetically testing patients with suspected ARVC, particularly when they also have ECG evidence for conduction disease.
European Heart Journal 12/2011; 33(9):1128-36. · 10.48 Impact Factor
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JACC. Cardiovascular imaging 11/2011; 4(11):1221-3. · 14.29 Impact Factor
