William J. McKenna

University of London · University College London (UCL)

Background Recent studies have shown the promise of new approaches to the management of hypertrophic cardiomyopathy (HCM) symptoms. However, as HCM is a chronic disorder that evolves slowly over decades with low annual event rates, therapeutic trials in the disease rely on surrogate measures of disease severity and progression rather than hard endp...

Background: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood. Objectives: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients. Methods: A total of 487 DCM...

Myoarchitectural disarray-the multiscalar disorganisation of myocytes, is a recognised histopathological hallmark of adult human hypertrophic cardiomyopathy (HCM). It occurs before the establishment of left ventricular hypertrophy (LVH) but its early origins and evolution around the time of birth are unknown. Our aim is to investigate whether myoar...

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder. The incidence of heart failure (HF) in ARVC has been reported at 5-13%. We aimed to define the genotype and disease progression of ARVC patients with HF. Methods: Patients with a definite diagnosis of ARVC who underwent genetic t...

It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnosti...

致心律失常性心肌病 (AC) 是一种相对罕见的心肌遗传性疾病,可能导致患者(通常低于 35 岁)猝死。AC 对于医生可能难以诊断,因为初始症状通常轻微,以至于可能被忽视。在一种罕见形式的 AC 中,受累患者还可能有明显的卷发和掌跖部皮肤异常增厚。这可能使诊断变得较为容易。这项来自英国伦敦的研究调查了存在一种由于桥斑蛋白突变导致的更为常见形式 AC 的家族,桥斑蛋白在心脏和皮肤中作为细胞之间的“胶水”发挥作用。我们证实,大多数 AC 家族成员有卷发,相当比例的患者还有导致皮肤增厚的问题。来自 AC 患者的皮肤活检显示,多种负责细胞间彼此连接的蛋白存在异常,这些蛋白对于心肌中的脉冲传导和收缩信号传导也至关重要。早期诊断和家族筛查是 AC 管理的关键目标。这项研究还在 AC 中发现了桥斑蛋白突变导...

Arrhythmogenic Cardiomyopathy (AC) is a relatively rare inherited disorder of the heart muscle and can lead to sudden death in patients, often under 35 years of age. AC can be very difficult for doctors to diagnose because the initial symptoms are often subtle so they can go unnoticed. In a rare form of AC, affected patients also have striking curl...

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder associated with an increased risk of life-threatening arrhythmias in some patients. Risk stratification remains challenging. Therefore, we sought a non-invasive, easily applicable risk score to predict sustained ventricular arrhythmias in...

Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy,...

New techniques change perceptions of disease. The translation of in vivo quantification of myocardial disarray brings closer together the domains of genetic, histological, and clinical HCM definitions. The desire to understand heart muscle, its architecture, pathways, and processes in health and disease with multitechnique approaches, is the ground...

Importance Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective To determine the effect of oral therapy with tri...

Background Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the postgenomic phenotype. Methods Label-free proteomic analysis was used initially to compa...

Background: Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the postgenomic phenotype. Methods: Label-free proteomic analysis was used initially to c...

Aims Arrhythmogenic Cardiomyopathy (AC) is an inherited, frequently under diagnosed disorder, predisposing to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported as cardiac specific. Causative mutations frequently occur in desmosom...

Aims: There are very few studies comparing epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) in different ethnic groups. Previous ethnicity studies have mostly determined OHCA differences between African American and Caucasian populations. The aim of this study was to compare epidemiology, clinical presentation, and outcomes of OHC...

Background: The comparative efficacy of antiarrhythmic drug (AAD) therapy vs ventricular tachycardia (VT) ablation in arrhythmogenic right ventricular cardiomyopathy (ARVC) is unknown. Objective: We compared outcomes of AAD and/or β-blocker (BB) therapy with those of VT ablation (with AAD/BB) in patients with ARVC who had recurrent VT. Methods:...

Objective Two LMNA genotype–phenotype cardiac correlations are reported: first, that cardiac involvement in multisystem laminopathies prevails with mutations upstream of the nuclear localisation signal (NLS); second, that worse outcomes occur with non-missense (compared with missense) mutations. We tested whether LMNA mutation DNA location and muta...

Aims Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLE...

Rare or novel PLEC variants identified in the ARVC cohort (n = 359). (XLSX)

PLEC + ARVC-associated variant versus only ARVC-associated variant. (XLSX)

ARVC cohort (n = 359): Ethnicities. (XLSX)

Rare PLEC variants identified in the ExAC Eu cohort. (XLSX)

Inter-observer analysis of immunostained myocardium and percent agreement between observers. (XLSX)

Dutch cohort (n = 79): Genes analysed. (XLSX)

Information on variant status of patients for whom immunofluorescence staining of heart tissue was performed. (XLSX)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited heart-muscle disorder, which is the most common cause of life-threatening arrhythmias and sudden cardiac death (SCD) in young adults and athletes. Early and accurate diagnosis can be crucial in effective ARVC management and prevention of SCD. The genome Aggregation Database...

Lamins A and C are intermediate filament nuclear envelope proteins encoded by the LMNA gene. Mutations in LMNA cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than o...

In the past 25 years, major advances were achieved in the nosography of cardiomyopathies, influencing the definition and taxonomy of this important chapter of cardiovascular disease. Nearly, 50% of patients dying suddenly in childhood or adolescence or undergoing cardiac transplantation are affected by cardiomyopathies. Novel cardiomyopathies have...

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease with an increased risk for ventricular arrhythmias. The condition, which occurs in Boxer dogs, shares phenotypic features with the human disease arrhythmogenic cardiomyopathy (ACM) suggesting its potential as a natural animal model. However, there are curren...

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a significant cause of sudden cardiac death in the young. Improved noninvasive assessment of ARVC and better understanding of the disease substrate are important for improving patient outcomes. Methods and results: We studied 20 genotyped ARVC patients with a broad spectrum of...

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is traditionally considered as primarily affecting the right ventricle. Mutations in genes encoding desmosomal proteins account for 40-60% of cases. Genotype-phenotype correlations are scant and mostly non gene-specific. Accordingly, we assessed the genotype-phenotype correlation f...

Arrhythmogenic cardiomyopathy (AC) is a progressive disease with high risk of life-threatening ventricular arrhythmias. A genetic mutation is found in up to 50-60% of probands, mostly affecting desmosomal genes. Diagnosis of AC is made by a combination of data from different modalities including imaging, electrocardiogram, Holter monitoring, family...

Objectives Atrial fibrillation (AF) is associated with increased morbidity and mortality in patients with hypertrophic cardiomyopathy (HCM). The primary aim of this study (HCM Risk-AF) was to determine the predictors of AF in a large multicentre cohort of patients with HCM. Exploratory analyses were performed to investigate the association between...

Background Severe left ventricular (LV) systolic dysfunction is an uncommon complication of hypertrophic cardiomyopathy (HCM) that is associated with poor prognosis. Small observational series suggest that patients with rare causes of HCM are more likely to develop systolic impairment than those with idiopathic disease or mutations in cardiac sarco...

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 individuals worldwide. Existing epidemiological studies might have underestimated the prevalence of HCM, however, owing to limited inclusion of individuals with early, incomplete phenotypic expression. Clinical manifestations of HCM include di...

Aims The differentiation between idiopathic right ventricular outflow tract (RVOT) arrhythmias and early arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging. We aimed to assess whether QRS morphological features and coupling interval of ventricular ectopic beats (VEBs) can improve differentiation between the two conditions. M...

Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomeric proteins, the commonest being MYBPC3 encoding myosin-binding protein C. It is characterised by left ventricular hypertrophy but there is an important pre-hypertrophic phenotype with features including crypts, abnormal mitral leaflets and trabeculae. We investigated these during...

Background: Hypertrophic cardiomyopathy is associated with sudden cardiac death (SCD). Some studies have shown an association between risk of sudden death and left ventricular maximal wall thickness (MWT), but there are few data in patients with extreme hypertrophy. The aim of this study was to determine the relation between MWT and the risk of SC...

Background: Outcomes of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients post-heart transplantation have not been well studied. Diagnostic criteria were established in 1994 and subsequently revised in 2010. We sought to better characterize this population in a national cohort. Methods: 35 138 heart transplant-only recipients were...

The aim of this cohort study was to evaluate the value of echocardiographic multilayer strain analysis in the identification of arrhythmogenic cardiomyopathy (AC) in its earliest stages in which sudden cardiac death can occurs. Twenty seven asymptomatic relatives of AC probands (mean age 39.6 ± 19.5 years, 37 % male) with a desmosomal pathogenic mu...

Background: The ventricular ectopic QRS interval (VEQSI) has been shown to identify structural heart disease and predict mortality. In arrhythmogenic right ventricular cardiomyopathy (ARVC) early diagnosis is difficult with current methods and life-threatening arrhythmias are common and difficult to predict. Objectives: To assess the utility of...

Objective: We hypothesised that abnormal global longitudinal strain (GLS) would predict outcome in hypertrophic cardiomyopathy (HCM) better than current echocardiographic measures. Methods: Retrospective analysis of risk markers in relation to outcomes in 472 patients with HCM at a single tertiary institution (2006-2012). Exclusion criteria were...

Background: The prevalence and clinical characteristics of familial dilated cardiomyopathy (FDCM) among patients with end stage heart failure (ESHF) has yet to be elucidated. We sought to determine the prevalence of FDCM in ESHF in the United Network for Organ Sharing (UNOS) registry and compare this with center specific data from a large tertiary...

This editorial refers to ‘European Cardiomyopathy Pilot Registry: EURObservational Research Programme of the European Society of Cardiology’[†][1], by P.M. Elliott et al ., on page 164. Cardiomyopathies represent a heterogeneous group of uncommon diseases which are associated with significant morbidity and mortality. Because they are uncommon, mu...

Aims The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing famili...

The REGENERATE-DCM trial is the first phase II randomized, placebo-controlled trial aiming to assess if granulocyte colony-stimulating factor (G-CSF) administration with or without adjunctive intracoronary (IC) delivery of autologous bone marrow-derived cells (BMCs) improves global left ventricular (LV) function in patients with dilated cardiomyopa...

Myocarditis, simply defined as inflammation of the heart muscle, is a commonly encountered cardiac disease in primary and secondary care, both in the UK and on Operational deployments. In the UK Armed Forces, myocarditis results in deaths as well as the premature termination of military careers on medical grounds. The aetiology is usually the resul...

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inheritable heart muscle disease that predominantly affects the right ventricle (RV) and predisposes to ventricular arrhythmias and sudden cardiac death (SCD).1–17 In the last three decades, there have been a significant number of studies defining the pathogenesis, genetic as...

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Atrial fibrillation (AF) and thrombo-embolism (TE) are associated with reduced survival in hypertrophic cardiomyopathy (HCM), but the absolute risk of TE in patients with and without AF is unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Exploratory analyses were performed to determine...

Epsilon waves are hallmark features of arrhythmogenic cardiomyopathy (ACM) but information about their clinical significance is variable. We evaluated epsilon wave prevalence, characteristics and their clinical significance in an ACM population. Eighty-six unselected patients fulfilling the 2010 Task Force criteria were enrolled. Seventy-six of the...

Sarcomeric gene mutations cause hypertrophic cardiomyopathy (HCM). In gene mutation carriers without left ventricular (LV) hypertrophy (G + LVH-), subclinical imaging biomarkers are recognized as predictors of overt HCM, consisting of anterior mitral valve leaflet elongation, myocardial crypts, hyperdynamic LV ejection fraction, and abnormal apical...

Purpose: To quantitatively determine the population variation and relationship of left ventricular (LV) trabeculation to LV function, structure, and clinical variables. Materials and methods: This HIPAA-compliant multicenter study was approved by institutional review boards of participating centers. All participants provided written informed con...

Sudden death and stroke afflicted a family from rural Quebec with such frequency as to be called the Coaticook curse by the local community. In Montreal in the late 1950s, a team of physicians led by J.A.P. Paré investigated this family for inherited cardiovascular disease. Their efforts resulted in an extensive and now classic description of famil...

The prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of β myosin heavy chain (MYH7). Clinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compare...

Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a genetically determined disorder, mostly caused by mutations in genes encoding desmosomal proteins. We evaluated phenotype/genotype characteristics to predict the risk for the first major arrhythmic event in desmosomal-mutation-associated ARVC families. A cohort of 105 desmosomal-mutation c...

Diagnosis of apical HCM utilizes conventional wall thickness criteria. The normal left ventricular wall thins towards the apex such that normal values are lower in the apical versus the basal segments. The impact of this on the diagnosis of apical hypertrophic cardiomyopathy has not been evaluated.

Background: Sarcomeric gene mutations cause hypertrophic cardiomyopathy (HCM). In gene mutation carriers without left ventricular (LV) hypertrophy (G + LVH-), subclinical imaging biomarkers are recognized as predictors of overt HCM, consisting of anterior mitral valve leaflet elongation, myocardial crypts, hyperdynamic LV ejection fraction, and abn...

Contribuyente adicional: Constantinos O’Mahony (Reino Unido) Comité de la ESC para las Guías de Práctica Clínica (GPC): Jose Luis Zamorano (presidente) (España), Stephan Achenbach (Alemania), Helmut Baumgartner (Alemania), Jeroen J. Bax (Países Bajos), Héctor Bueno (España), Veronica Dean (Francia), Christi Deaton (Reino Unido), Çetin Erol (Turquía...

Preclinical diagnosis in hypertrophic cardiomyopathy (HCM) refers to the detection of functional or histopathological abnormalities in subjects who carry any HCM-causing gene mutation, before or even without the development of left ventricular hypertrophy [genotype(+) /phenotype(-) subjects]. The concept that HCM pathology, may exist in the absence...