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© 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. Todos os direitos reservados., Introduction: We report the results of the Portuguese Registry of Hypertrophic Cardiomyopathy, an initiative that reflects the current spectrum of cardiology centers throughout the territory of Portugal. Methods: A direct invitation to participate was sent to cardiology departments. Baseline and outcome data were collected. Results: A total of 29 centers participated and 1042 patients were recruited. Four centers recruited 49% of the patients, of whom 59% were male, and mean age at diagnosis was 53±16 years. Hypertrophic cardiomyopathy (HCM) was identified as familial in 33%. The major reason for diagnosis was symptoms (53%). HCM was obstructive in 35% of cases and genetic testing was performed in 51%. Invasive septal reduction therapy was offered to 8% (23% of obstructive patients). Most patients (84%) had an estimated five-year risk of sudden death of, Objectivo: Apresentação dos resultados do Registo Português de Miocardiopatia Hipertrófica. Metodologia: Convite direto aos diferentes centros de cardiologia de Portugal, com análise de dados basais e de seguimento. Resultados: Foram 29 os centros participantes e 1042 doentes incluídos. Quatro centros incluíram 49% dos doentes, 59% do sexo masculino, idade média de diagnóstico 53 ± 16 anos. A doença foi considerada familiar em 33% e a presença de sintomas foi a principal causa de diagnóstico (53%). A miocardiopatia hipertrófica foi obstrutiva em 35%. O estudo genético foi efetuado em 51%. Oito por cento dos doentes fizeram terapêutica invasiva de redução septal (23% dos doentes com obstrução). A maioria dos doentes (84%) apresentava um risco estimado de morte súbita aos 5 anos < 6%. Em 13% foi colocado desfibrilhador cardioversor implantável. Após um seguimento de 3,3 anos, intervalo interquartil (P25-P75) 1,3-6,5 anos, 31% estavam assintomáticos. A mortalidade total foi de 1,19%/ano e a cardiovascular de 0,65%/ano. A incidência de morte por insuficiência cardiaca foi de 0,25%/ano, a de morte súbita de 0,22%/ano e a de morte por acidente vascular cerebal de 0,04%/ano. A mortalidade por insuficiência cardíaca e transplante cardíaco foi de 0,27%/ano e a de morte súbita e equivalentes de 0,53%/ano. Conclusões: A miocardiopatia hipertrófica em Portugal apresenta idade de diagnóstico elevada e é frequente o tratamento invasivo de formas obstrutivas. A mortalidade é baixa, a insuficiência cardíaca é a principal causa de morte, seguida pela morte súbita. A doença apresenta elevada morbilidade, realça a necessidade do desenvolvimento de tratamentos específicos com impacto na sua história natural.

Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994889.

Aims To perform a systematic literature review and meta-analysis of clinical risk factors for sudden cardiac death (SCD) in childhood hypertrophic cardiomyopathy. Methods Medline and PubMed databases were searched for original articles published in English from 1963 through to December 2015 that included patients under 18 years of age with a primary or secondary end-point of either SCD or SCD-equivalent events (aborted cardiac arrest or appropriate implantable cardioverter-defibrillator discharge) or cardiovascular death (CVD). Results Twenty-five studies (3394 patients) met the inclusion criteria. We identified four conventional major risk factors that were evaluated in at least four studies and that we found to be statistically associated with an increased risk of death in at least two studies: previous adverse cardiac event (pooled hazard ratio [HR] 5.4, 95% confidence interval [CI] 3.67-7.95, p

Background Vascular complications in homocystinuria have been known for many years, but there have been no reports to date on involvement of the ascending aorta. Methods We conducted a cross-sectional study of patients with homocystinuria, known to a single metabolic centre, and evaluated in 2016 with a transthoracic echocardiogram. Aortic root dilation was defined as Z-score ≥ 2.0 SD, and graded mild (Z-score 2.0–3.0), moderate (Z-score 3.01–4.0) and severe (Z-score > 4.0). Results The study population included 34 patients, median age of 44.3 years (IQR 33.3–52.2), 50% males, 69% diagnosed aged

Background: Initiation of re-entrant ventricular tachycardia (VT) involves complex interactions between activation (AT) and repolarization times (RT). The re-entry vulnerability index (RVI) is a recently proposed activation-repolarization metric designed to quantify tissue susceptibility to re-entry. Objectives: The study aimed to test the feasibility of an RVI-based algorithm to predict the breakout site of VT and occurrence of clinical events. Methods: Patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (n=11), Brugada Syndrome (BrS) (n=13) and focal RV outflow tract VT (n=9) underwent programmed stimulation with unipolar electrograms recorded from a non-contact array. The distance between region of lowest RVI and site of VT breakout (Dmin), and global minimum RVI (RVIG) were computed to assess prediction of site of VT breakout and occurrence of clinical events, respectively. Results: Lowest values of RVI, representing sites of highest susceptibility to re-entry, co-localised with site of VT breakout in ARVC/BrS but not in focal VT and Dmin values were lower in ARVC/BrS. ARVC/BrS patients with inducible VT had lower RVIG than those who were non-inducible or those with focal VT. Patients were followed up for 112 +/- 19 months; those with clinical VT events had lower RVIG than those without VT or those with focal VT. Conclusions: The proposed methodology based on RVI localises the origin of re-entrant but not focal ventricular arrhythmias and predicts clinical events. This index could be applied to target ablation for arrhythmias which are difficult to induce or are haemodynamically unstable and also risk stratify patients for ICD prophylaxis.

Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity.In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post-operatively from 71.9 ± 39.6 mmHg to 13.4 ± 18.5 mmHg (P 0.05). Overall, 72.4% of patients improved by1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P 0.05). Long-term (30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years.Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients.

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 AF and survival and the efficacy of antiarrhythmic therapy in maintaining sinus rhythm (SR). Methods A retrospective, longitudinal cohort of patients recruited between 1986 and 2008 in seven centres was used to develop multivariable Cox regression models fitted with preselected predictors. HCM was defined as unexplained hypertrophy (maximum left ventricular wall thickness of ≥15 mm or in accordance with published criteria for the diagnosis of familial disease). 28% of patients (n=1171) had coexistent hypertension. The primary end point was paroxysmal, permanent or persistent AF detected on ECG, Holter monitoring or implantable device interrogation. Results Of the 4248 patients with HCM without pre-existing AF, 740 (17.4%) reached the primary end point. Multivariable Cox regression revealed an association between AF and female sex, age, left atrial diameter, New York Heart Association (NYHA) class, hypertension and vascular disease. The proportion of patients with cardiovascular death at 10 years was 4.9% in the SR group and 10.9% in the AF group (difference in proportions=5.9%; 95% CI (4.1% to 7.8%)). The proportion of patients with non-cardiovascular death at 10 years was 3.2% in the SR group and 5.9% in the AF group (difference in proportions=2.8%; 95% CI (0.1% to 4.2%)). An intention-to-treat propensity score analysis demonstrated that β-blockers, calcium channel antagonists and disopyramide initially maintained SR during follow-up, but their protective effect diminished with time. Amiodarone therapy did not prevent AF during follow-up. Conclusion This study shows that patients with HCM who are at risk of AF development can be identified using readily available clinical parameters. The development of AF is associated with a poor prognosis but there was no evidence that antiarrhythmic therapy prevents AF in the long term.

Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis in everyday clinical practice, but the diagnosis continues to be made in patients with late-stage disease, suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. Light chain cardiac amyloidosis, in particular, if recognized early and treated with targeted plasma cell therapy, can be managed very effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are currently in late-phase clinical trials. In this review, we address common questions encountered in clinical practice regarding etiology, clinical presentation, diagnosis, and management of cardiac amyloidosis, focusing on recent important developments in cardiac imaging and biochemical diagnosis. The aim is to show how a systematic approach to the evaluation of suspected cardiac amyloidosis can impact the prognosis of patients in the modern era.

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR 90. In addition, men with classical disease and a baseline eGFR 60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.

Background— Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH−]). Methods and Results— A multicenter case–control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH− sample (n=73) was 29±13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5–4.4; P =0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8–7.9; P =0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7–3.1; P P P =0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8–0.9). In this G+LVH− population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1–7.9; P =0.045). Conclusions— The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study.

Objective A predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this study were to examine the phenotypes associated with sarcomere protein (SP) gene mutations and test the hypothesis that variation in non-sarcomere genes modifies the phenotype. Methods Unrelated and consecutive patients were clinically evaluated and prospectively followed in a specialist clinic. High-throughput sequencing was used to analyse 41 genes implicated in inherited cardiac conditions. Variants in SP and non-SP genes were tested for associations with phenotype and survival. Results 874 patients (49.6±15.4 years, 67.8% men) were studied; likely disease-causing SP gene variants were detected in 383 (43.8%). Patients with SP variants were characterised by younger age and higher prevalence of family history of HCM, family history of sudden cardiac death, asymmetric septal hypertrophy, greater maximum LV wall thickness (all p values

The sarcomere is the principal contractile unit of striated muscle. Mutations in genes encoding sarcomeric proteins are responsible for a range of diseases including hypertrophic, dilated and restrictive cardiomyopathies and ventricular non-compaction. The downstream molecular pathways leading to these heterogeneous phenotypes include changes in acto-myosin cross-bridge kinetics, altered mechanosensation, disturbed calcium sensitivity, de-regulated signalling pathways, inefficient energetics, myocardial ischaemia and fibrosis. The elucidation of the genetic causes of cardiomyopathy has helped in understanding the structure and function of the sarcomere and a more detailed knowledge of the sarcomere and its associated proteins has suggested additional gene candidates. The new hope is that these advances will stimulate the discovery of disease-modifying drugs.

Introduction Left ventricular noncompaction (LVNC) is characterised by prominent ventricular myocardial trabeculations, composed of sheets of cardiomyocytes. They form early during cardiogenesis but their development is complex. Measuring trabecular complexity in animal models of cardiac disease is important as abnormal trabecular patterns are increasingly been recognised to coexist with several other cardiac conditions, not just LVNC. We describe an innovative approach that utilises fractal algorithms and high-resolution episcopic microscopy (HREM) to study the developmental timing of myocardial trabeculation in mouse and we validate it using a recently described LVNC mouse model (NOTCH pathway regulator Mib1 mutant). Methods HREM (2–3 μm resolution) analysis was performed prospectively on 123 embryonic mouse hearts consisting of wild-type (WT) NIMR:Parkes, WT C57BL/6 and Mib1 flox ; cTnT-cre mutant and WT littermates. HREM permits the 2D/3D imaging of tissue samples as they are physically sectioned. Datasets underwent fractal analysis using a box-counting approach (Figure 1). Results LV trabecular complexity showed a significant drop between E14.5 and E18.5 (Figure 2). Across all embryonic stages, the apical half of the LV retained the highest fractal dimensions (FD) when compared to the base. By E18.5 the myocardium was almost fully compacted registering the lowest FD. For the first time, we demonstrate that strain-specific differences in LV trabecular patterning exist in mouse because NIMR:Parkes compacts earlier than C57BL/6 (Figure 3). Reslicing experiments (Figure 4) and separate validation tests on Mib1 mutants and WT littermates (Fig.5) confirmed how the proposed methodology is a reliable and effective tool for the detection of mutagenesis-related differences in trabeculation. Conclusion Reported here is a method in which sequential, 2D sections of mouse embryo hearts may be analysed using a fractal algorithm to calculate ventricular trabecular complexity – a technique so sensitive, that small inter-strain differences in somitogenesis are detectable in mouse pups. Precise knowledge of the trabecular architecture as it presents itself in WT, is a prerequisite for the correct identification of pathological trabecular phenotypes in mouse models of cardiac disease, explaining the need for a quantitative fractal atlas of trabecular development. Fractal mathematics in combination with HREM has the potential to answer to many developmental biology questions in the heart, with future applicability to other organ systems and to other species.

ObjectiveReduction of left ventricular outflow tract obstruction (LVOTO) often improves symptoms in hypertrophic cardiomyopathy (HCM), but the correlation between exercise performance and measured LVOT gradients is weak. We investigated the relationship between LVOTO and cardiorespiratory responses during exercise.MethodsThe study cohort included 70 patients with HCM (32 with LVOTO, 55 male, age 47±13) attending a dedicated cardiomyopathy clinic and 28 normal volunteers. All underwent cardiopulmonary exercise testing with simultaneous non-invasive haemodynamic assessment using finger plethysmography. Main outcome measures were peak oxygen consumption, cardiac index and arteriovenous oxygen difference.ResultsWhen compared with controls, patients had reduced peak exercise oxygen consumption (22.4±6.1 vs 34.7±7.7 mL/kg/min, p2, pConclusionsCardiac reserve is reduced in HCM because of failure of SV augmentation. LVOTO exacerbates this abnormal response, but haemodynamic responses vary significantly. Non-invasive exercise haemodynamic assessment may improve understanding of symptoms and help tailor therapy.

Aims Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality. Methods and results In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8–5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2–4.3). Conclusions This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure.

Item does not contain fulltext BACKGROUND: Screening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the alpha-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment. We developed a diagnostic algorithm for adults with LVH (maximal wall thickness (MWT) of >12mm), GLA GVUS and an uncertain diagnosis of FD. METHODS: A Delphi method was used to reach a consensus between FD experts. We performed a systematic review selecting criteria on electrocardiogram, MRI and echocardiography to confirm or exclude FD. Criteria for a definite or uncertain diagnosis and a gold standard were defined. RESULTS: A definite diagnosis of FD was defined as follows: a GLA mutation with /=1 characteristic FD symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso)Gb3 (classical male range) or family members with definite FD. Subjects with LVH failing these criteria have a GVUS and an uncertain diagnosis. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. Abnormally low voltages on ECG and severe LVH (MWT>15mm)

Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.

Importance: Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk.Objective: To develop and validate an SCD risk prediction model that provides individualized risk estimates.Design, Setting, and Participants: A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017.Exposures: The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping.Main Outcomes and Measures: A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise).Results: Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95%, CI 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years.Conclusions and Relevance: This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations.

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 trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro–brain natriuretic peptide level, and troponin T level. Results Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, −2.58 to −0.11 mL/kg per minute;P = .03) in the intervention group after 3 months. Conclusions and Relevance In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration ClinicalTrials.gov identifier:NCT01696370

Heart failure (HF) occurs when the cardiac output, no longer compensated by endogenous mechanisms, fails to meet the metabolic demands of the body. In most populations, the prevalence of heart failure continues to rise, constituting a major public health burden, especially in developed countries. There is some evidence that the risk of HF in the general population depends on genetic predisposition, necessarily characterised by a very complex architecture. In a small, but probably underestimated proportion, HF is caused by Mendelian inherited forms of myocardial disease. The genetic background of these genetic conditions is a matter of intensive research that is already shedding light onto the genetics of common sporadic forms of HF. In this review, we briefly review the insights provided by candidate gene and genome-wide association approaches in common HF and then describe the main genetic causes of inherited heart muscle disease. Finally we present the current challenges and future research needs for both forms of HF. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.

Sudden cardiac death (SCD) is a tragic outcome in hypertrophic cardiomyopathy, but it occurs at a low frequency overall and is challenging to predict accurately. Many important predictors of SCD have emerged over the past 50 years, one of which is a family history of SCD. The available data are limited by their retrospective nature and variability in the definition of family history across studies. We advocate a novel model of risk stratification in which no individual predictor has primacy; rather the overall clinical picture of the patient is used to determine their SCD risk.

Hypertrophic cardiomyopathy (HCM) is a heart muscle disease that affects an estimated 1 in 500 adults in the general population. Many people with HCM live healthy lives, but its association with premature death in the young and heart failure in the middle aged raises its profile in the mind of the general public and make it a common cause for concern among healthcare professionals. To assist practitioners and patients manage the condition, The European Society of Cardiology (ESC) has recently published a new clinical practice guideline on HCM that replaces an earlier document produced jointly with the American College of Cardiology in 2003.1 From the outset, all members of the ESC writing committee agreed to three guiding principles while preparing their recommendations. The first was that guidance should be practical and firmly rooted in real-life clinical practice; second, there was a determination that recommendations should, where humanly possible, innovate and not slavishly reproduce previous statements; and finally–and perhaps most challenging of all—recommendations should, whenever possible, be based on the best scientific evidence. At first glance, the absence of large randomised clinical trials and the relative paucity of large cohort studies in this area of medicine might seem to render such ideals futile, but the experts on the committee were able to achieve consensus on an approach to diagnosis and management that shifts the emphasis towards multidisciplinary working and individualisation of patient care. Some of the most important areas covered in the guideline are discussed below. HCM is defined by a simple measurement of LV wall thickness on cardiac imaging. While this has been shown to be a robust and reproducible approach to clinical classification, it fails to describe the spectrum of genetic and non-genetic disorders than can present with LV thickening. One approach to rationalising this complexity is to …

HCM is commonly associated with AF. Current guidelines for AF management omit detailed advice for HCM because of a lack of clinical prediction tools that estimate the risk of developing AF and an absence of adequately powered treatment studies.To critically review current literature on atrial fibrillation (AF) and thromboembolism in hypertrophic cardiomyopathy (HCM) and meta-analyse prevalence and incidence.PubMed and Web of Science.Studies investigating AF and stroke in HCM as primary or secondary endpoint.Two investigators independently reviewed and extracted data from the identified articles. A random effect meta-regression model and I(2) statistics were used for analysis.A population of 7381 patients (33 studies) revealed overall AF prevalence of 22.45% (95% CI 20.13% to 24.77%), I(2)=78.9% (p0.001). Overall prevalence of thromboembolism in HCM patients with AF was 27.09% (95% CI 20.94% to 33.25%), I(2)=61.4% ( p0.01). Overall AF incidence was 3.08% per 100 patients per year (95% CI 2.63% to 3.54%, I(2)=86.5%, p0.001) and incidence of thromboembolism in HCM patients with AF was 3.75% per 100 patients per year (95% CI 2.88% to 4.61%), I(2)=37.9% (p=0.1). Left atrial (LA) dimension and age were common predictors for AF and thromboembolism. Meta-analysis revealed an LA diameter of 38.03 mm (95% CI 34.62% to 41.44%) in sinus rhythm and 45.37 mm (95% CI 41.64% to 49.04%) in AF. There were no randomised controlled trials of therapy; anticoagulation was associated with lower stroke incidence but data on other interventions were limited and contradictory.AF is common in HCM and associated with high thromboembolic risk. LA dimension and age are independently associated with AF but the literature is insufficient to create robust clinical tools to predict AF or thromboembolism. Most data suggest that AF patients should be anticoagulated.

Hypertrophic cardiomyopathy is a common inherited heart muscle disorder associated with sudden cardiac death, arrhythmias and heart failure. Genetic mutations can be identified in approximately 60% of patients; these are commonest in genes that encode proteins of the cardiac sarcomere. Similar to other Mendelian diseases these mutations are characterized by incomplete penetrance and variable clinical expression. Our knowledge of this genetic diversity is rapidly evolving as high-throughput DNA sequencing technology is now used to characterize an individual patient’s disease. In addition, the genomic basis of several multisystem diseases associated with a hypertrophic cardiomyopathy phenotype has been elucidated. Genetic biomarkers can be helpful in making an accurate diagnosis and in identifying relatives at risk of developing the condition. In the clinical setting, genetic testing and genetic screening should be used pragmatically with appropriate counseling. Here we review the current role of genetic biomarkers in hypertrophic cardiomyopathy, highlight recent progress in the field and discuss future challenges.

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 (C2H2) 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 C2H2uptake 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-1for finger plethysmography and C2H2,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-1for finger plethysmography and C2H2,respectively, P = 0·898. Mean difference between techniques was 0·1 ± 1·5 l min-1. The overall correlation between finger plethysmography and C2H2data obtained during rest and exercise was r2= 0·872, P

Takotsubo cardiomyopathy (TTC) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. Recent experimental and clinical observation has suggested a role for genetics in the pathogenesis of TTC. Ethnic as well as seasonal variation in the prevalence of TTC is well described, but it is only recently that familial cases of TTC have been reported. In recent years technological advances in exome capture and DNA sequencing have offered clinicians a new opportunity to discover genetics-related disease. This article explores the role of genetic mechanisms that might explain or modulate the pathogenesis of TTC.

To report the development of easy-to-use magnetic resonance imaging (MRI) fractal tools deployed on platforms accessible to all. The trabeculae of the left ventricle vary in health and disease but their measurement is difficult. Fractal analysis of cardiac MR images can measure trabecular complexity as a fractal dimension (FD).This Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by the local Institutional Review Board. Participants provided written informed consent. The original MatLab implementation (region-based level set segmentation and box-counting algorithm) was recoded for two platforms (OsiriX and a clinical MR reporting platform [cviFD by OsiriX and the clinical MR reporting platform showed high correlation with MatLab values (correlation coefficients: 0.96 [95% CI: 0.95-0.97] and 0.96 [0.95-0.96]) and high interstudy and intraplatform reproducibility. Semiautomated contours in OsiriX and the clinical MR reporting platform were highly correlated with ground truth contours evidenced by low P2C errors: 0.882 ± 0.76 mm and 0.709 ± 0.617 mm. Validity of ground truth contours was inferred from low P2C errors between readers (R1-R1: 0.798 ± 0.718 mm; R1-R2: 0.804 ± 0.649 mm).This set of accessible fractal tools that measure trabeculation in the heart have been validated and released to the cardiac MR community (http://j.mp/29xOw3B) to encourage novel clinical applications of fractals in the cardiac imaging domain.3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1082-1088.

BACKGROUND: Anderson-Fabry disease (AFD) is a disorder of glycosphingolipid metabolism resulting from deficiency of α-galactosidase A and accumulation of globotriaosylceramide. Presentation is heterogeneous and, despite guidelines for initiation of therapy, there is no basis for defining subgroups that will progress more rapidly, whether treated or not. The authors of this study used clinical and pathological data recorded on 1483 patients in the Fabry Outcome Survey, a large international registry, to develop a prognostic severity score. METHODS: Parameters relevant to disease progression or outcome were initially selected, using variables that are readily available in clinical practice. Individual end points for renal, cardiac, neurological disease, and death were selected, and a composite end point developed. Potential prognostic variables were correlated with each end point, before multivariate analysis. Variables retaining significance were then used to construct organ specific and composite prognostic scores. Kaplan-Meier (KM) analysis, according to score, was performed for each end point. RESULTS: Analysis demonstrated that it is possible to differentiate groups of patients with different outcome probabilities. Cardiac, renal and neurological end points could each be categorised into three separate groups. The 80% event-free survival for these groups differed by approximately 10 years. The overall composite score, the Fabry International Prognostic Index (FIPI), distinguished two distinct groups where the 50% event-free survival differed by 10 years. CONCLUSIONS: A prognostic scoring system for AFD has been developed and retrospective validation performed. The FIPI should prove to be a valuable tool in the counselling and management of AFD patients, and in comparative analyses of outcome using different therapies.

Background— Anderson-Fabry disease (AFD) is a rare but underdiagnosed intracellular lipid disorder that can cause left ventricular hypertrophy (LVH). Lipid is known to shorten the magnetic resonance imaging parameter T1. We hypothesized that noncontrast 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— Two hundred twenty-seven subjects were studied: patients with AFD (n=44; 55% with LVH), healthy volunteers (n=67; 0% with LVH), patients with hypertension (n=41; 24% with LVH), patients with hypertrophic cardiomyopathy (n=34; 100% with LVH), those with severe aortic stenosis (n=21; 81% with LVH), and patients with definite amyloid light-chain (AL) cardiac amyloidosis (n=20; 100% with LVH). T1 mapping was performed using the shortened modified Look-Locker inversion sequence on a 1.5-T magnet before gadolinium administration with primary results derived from the basal and midseptum. Compared with health volunteers, septal T1 was lower in AFD and higher in other diseases (AFD versus healthy volunteers versus other patients, 882±47, 968±32, 1018±74 milliseconds; P r =−0.51; P =0.0004) and was abnormal in 40% of subjects who did not have LVH. Segmentally, AFD showed pseudonormalization or elevation of T1 in the left ventricular inferolateral wall, correlating with the presence or absence of late gadolinium enhancement (1001±82 versus 891±38 milliseconds; P Conclusions— Noncontrast T1 mapping shows potential as a unique and powerful measurement in the imaging assessment of LVH and AFD.

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 sarcomeric protein genes. The aim of this study was to test this hypothesis by comparing the prevalence of systolic dysfunction and its impact on prognosis in patients with different causes of HCM. METHODS AND RESULTS: 1697 patients (52 (40-63) years, 1160 (68%) males) with HCM followed at two European referral centres were studied. Diagnosis of specific aetiologies was made on the basis of clinical examination, cardiac imaging and targeted genetic and biochemical testing. The primary survival outcome was all-cause mortality or heart transplantation (HTx) for end-stage heart failure (HF). Secondary outcomes were HF-related death, sudden cardiac death, stroke-related death and non-cardiovascular death. Systolic dysfunction (LV ejection fraction

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 mouse cardiac development using high-resolution episcopic microscopy. In embryonic hearts from wildtype, homozygous (HO) and heterozygous (HET) Mybpc3-targeted knock-out (KO) mice we show that crypts (one or two) are a normal part of wildtype development but they almost all resolve by birth. By contrast, HO and HET embryos had increased crypt presence, abnormal mitral valve formation and alterations in the compaction process. In scarce normal human embryos, crypts were sometimes present. This study shows that features of the human pre-hypertrophic HCM phenotype occur in the mouse. In an animal model we demonstrate that there is an embryological HCM phenotype. Crypts are a normal part of cardiac development but, along with the mitral valve and trabeculae, their developmental trajectory is altered by the presence of HCM truncating Mybpc3 gene mutation.

In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance.

Aims Prevalence and clinical significance of right atrial enlargement (RAE) has been poorly characterized in hypertrophic cardiomyopathy.Methods One hundred and sixty consecutive patients with hypertrophic cardiomyopathy (35.5 +/- 20 years; 64% men) were studied. They underwent clinical examination, standard ECG, M-mode, 2D and Doppler echocardiography, stress test and ECG Holter monitoring. Major adverse cardiac events were considered: cardiac death (sudden death, heart failure death); cardiac transplant; resuscitated cardiac arrest or appropriate implantable cardioverter defibrillator discharge. Genetic analysis of eight sarcomeric genes was performed using Sanger sequencing.Results RAE was observed in 22 patients (14%), associated with left atrial enlargement in all cases. Patients with RAE were likely to have restrictive mitral pattern (P < 0.001) and had higher New York Heart Association (P < 0.001), N-terminal prohormone of brain natriuretic peptide (P< 0.001), left atrial volume index (P < 0.001), lateral (P=0.04) and septal (P=0.002) E/e', systolic pulmonary artery pressure (P< 0.001) and lower ejection fraction (all P < 0.001). On cardiopulmonary exercise testing, peak VO2 was lower and VE/VCO2 higher in patients with RAE (P < 0.001). During a mean follow-up of 4 +/- 2.1 years, 30 major adverse cardiac events in 24 patients (15%) were observed. Cox proportional hazards regression analysis identified RAE as an independent predictor of major adverse cardiac events (odds ratio=2.6; confidence interval 1.5-4.6; P=0.001). In patients with RAE who were genetically tested, there was a higher prevalence of sarcomeric genemutations (68%), doublemutations (16%) and troponin T mutations (21%).Conclusion RAE is present in a small subset of patients with hypertrophic cardiomyopathy, and largely reflects increased pulmonary pressures because of severe diastolic and/or systolic left ventricular dysfunction. Patients with RAE had a higher prevalence of sarcomeric gene mutations, troponin T mutations and complex genotypes. In conclusion, RAE may serve as a very useful marker of disease progression and adverse outcome in patients with sarcomeric hypertrophic cardiomyopathy.

Motivation: High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes—in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7). Results: A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews’ correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction. Availability and Implementation: Analyses were implemented in Perl and C and used the Java-based Weka machine learning environment. Please contact the authors for availability. Contacts: andrew@bioinf.org.uk or andrew.martin@ucl.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

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 SCD. Methods and Results— This is a multicenter, retrospective, longitudinal cohort study of 3673 adult (≥16 years) patients, previously used to develop and validate a risk prediction model for SCD (HCM Risk-SCD [hypertrophic cardiomyopathy risk-SCD]). There was an inverted U-shaped relation between MWT and the estimated 5-year risk of SCD. In patients with MWT≥35 mm (n=47; mean age, 33 years; 81% men), there was a single SCD end point (annual rate, 0.2%; 95% confidence interval, 0.03–1.60) and 3 additional cardiovascular events during a median follow-up of 9.5 years. Compared with patients with MWT≤14 mm, those with MWT≥35 mm did not have a higher risk for SCD (hazard ratio, 0.22; 95% confidence interval, 0.03–1.65), cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.26–1.67), or all-cause mortality (hazard ratio, 0.73; 95% confidence interval, 0.32–1.69). Conclusions— The risk of SCD has a complex, nonlinear relationship to MWT. The pathophysiological mechanisms behind this observation require further study but implantable cardioverter defibrillator implantation should not be guided solely on the severity of left ventricular hypertrophy.

Metabolic disorders encompass a heterogeneous group of conditions that commonly affect the heart and contribute adversely to cardiovascular outcomes. As the heart is a metabolically active organ, inborn errors in metabolism (IEMs) often present with cardiac manifestations such as cardiomyopathy, arrhythmia, and valvular dysfunction. More than 40 IEMs are reported to cause cardiomyopathy, including fatty acid oxidation defects, glycogen, lysosomal and perioxisome storage diseases, mitochondrial cardiomyopathies, organic acidaemias, aminoacidopathies and congenital disorders of glycosylation. Studies suggest that IEM account for only 5% of cardiomyopathies; however, their diagnosis is imperative to enable the effective institution of disease-specific management strategies. This review describes the more common genetic defects that affect metabolic pathways and give rise to heart muscle disease.

Background— 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. Methods and Results— 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. Conclusions— 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.

Background— 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. Methods and Results— 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 ( Conclusions— 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.

OBJECTIVES: The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers. BACKGROUND: LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA. METHODS: In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment. RESULTS: In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction

Background— The features of the hypertrophic cardiomyopathy (HCM) ECG make it a challenge for subcutaneous implantable cardioverter-defibrillator (S-ICD) screening. We aimed to investigate the causes of screening failure at rest and on exercise to inform optimal S-ICD ECG vector development. Methods and Results— One hundred and thirty-one HCM patients (age, 50±16 years; 92 males and 39 females) with ≥1 HCM risk factor for sudden death underwent S-ICD ECG screening at rest and on exercise. Fifty patients (38%) were ineligible for S-ICD because of screening failure in every lead vector: 33 (66%) failed in the supine position, 12 (24%) failed in the standing position, and 5 (10%) failed on exercise. In patients who could exercise and passed screening at rest, 31 (44%) had 1 vector safety, 16 (23%) had 2 vector safety, and 24 (33%) had 3 vector safety. Increased R:T wave ratio in the S-ICD screening ECG (odds ratio, 4.0; confidence interval, 3.0–5.3; P P =0.006) and increasing age (odds ratio, 0.97; confidence interval, 0.95–0.99; P =0.03) was associated with reduced screening failure. European Society of Cardiology risk score was higher in those failing screening (risk score 5.5% [interquartile range, 3.2–8.7] in failed versus 4.5% [interquartile range, 2.9–7.4] in passed; P =0.04). Conclusions— HCM patients have a significant incidence of screening failure, which is determined primarily by the increased R:T ratio on the screening ECG and lead aVF. High-risk patients have an increased screening failure rate. Optimization of sensing algorithms is required to ensure that the highest risk HCM patients can benefit from S-ICD implantation.

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Background 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). Methods and results 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