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Aims: Evidence on the relative impact of diverse genetic backgrounds associated with non-ischaemic dilated cardiomyopathy (DCM) remains contradictory. This study sought to synthesize the available data regarding long-term outcomes of different gene groups in DCM., Methods and Results: Electronic databases were systematically screened to identify studies reporting prognostic data on pre-specified gene groups. Those included pathogenic/likely pathogenic (P/LP) variants, truncating titin variants (TTNtv), lamin A/C variants (LMNA), and desmosomal proteins. Outcomes were divided into composite adverse events (CAEs), malignant ventricular arrhythmic events (MVAEs) and heart failure events (HFEs). A total of 26 studies (n = 7255) were included in the meta-analysis and 6791 patients with genotyped DCM were analysed. Patients with P/LP variants had a higher risk for CAEs (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.67-2.65), MVAEs (OR 1.86, 95% CI 1.52-2.26), and HFEs (OR 2.01, 95% CI 1.08-3.73) than genotype-negative patients. The presence of TTNtv was linked to a higher risk for CAEs (OR 1.78, 95% CI 1.20-2.63), but not MVAEs or HFEs. LMNA and desmosomal groups suffered a higher risk for CAEs, MVAEs, and HFEs compared to non-LMNA and non-desmosomal groups, respectively. When genes were indirectly compared, the presence of LMNA resulted in a more detrimental effect that TTNtv, with respect to all composite outcomes but no significant difference was found between LMNA and desmosomal genes. Desmosomal genes harboured a higher risk for MVAEs compared to TTNtv., Conclusions: Different genetic substrates associated with DCM result in divergent natural histories. Routine utilization of genetic testing should be employed to refine risk stratification and inform therapeutic strategies in DCM., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce., Objectives: This study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort., Methods: We collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM., Results: Of 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants., Conclusions: DES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals., Competing Interests: Funding Support and Author Disclosures Dr Bermudez-Jimenez has received grants from Instituto de Salud Carlos III (ISCIII) through the project JR21/00031 (cofounded by European Regional Development Fund). Dr Zorio has received grants from the Instituto de Salud Carlos III through the projects PI18/01582 and PI21/01282 (co-funded by European Regional Development Fund “A way to make Europe”). Dr Brodehl has received grants from the Medical Faculty of the Ruhr-University Bochum (FoRUM, F1074-2023) and the ‘Deutsche Herzstiftung e.V. (Frankfurt a.M., Germany); and is a shareholder with Tenaya Therapeutics. Dr Lopes has received grants from a Medical Research Council (MRC) Clinical Academic Research Partnership (CARP) award (MR/T005181/1). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy (LVH), with wall thickness ≥ 1.5 cm, is a phenotype in search of a diagnosis, which is most often a genetically determined, cardiac exclusive, or systemic disorder. Familial evaluation and genetic testing are required for definitive diagnosis. The role of genetic findings in predicting development of disease, outcomes, and increasingly to guide management is evolving with access to larger data sets. The specific mutation and sex of the patient are important determinants that ultimately are likely to guide management. The genetic/familial evaluation is influenced by the accuracy of the clinical diagnosis and the extent/expertise of the genetic laboratory. Genetic testing in a patient with unexplained LVH without systemic manifestations will yield a definite/likely pathogenetic mutation in a sarcomere (30%-50%), regulatory/functional (10%-15%) or metabolic/syndromic (< 5%) gene associated with Mendelian inheritance. The importance of oligo- and polygenic determinants, usually in the absence of Mendelian inheritance, is under investigation with important implications, particularly related to familial evaluation and definition of risk of disease development in relatives of probands. The results of genetic testing are increasingly important in management strategies related to the use of the implantable cardioverter defibrillator for prevention of sudden death, use of myosin inhibitors for refractory symptoms in patients with and without outflow tract obstruction, and-on the immediate horizon-gene therapy. This review will focus on genetic and outcome data in sarcomeric HCM, and minor causative genes with robust evidence of their association will also be considered., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late‑gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Successful therapy in a cohort with early onset Danon disease (DD) highlights the potential importance of earlier disease recognition. We present experience from the largest National Pediatric Center in Russia for cardiomyopathy patients. This report focuses on identification of early clinical features of DD in the pediatric population by detailed pedigree analysis and review of medical records. RESULTS: Nine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health ("National Pediatric Center") aged birth to 16 years. At presentation/evaluation: all patients had left ventricular hypertrophy (LVH), ECG features of Wolff-Parkinson-White (WPW), and an increase in hepatic enzymes (particularly lactate dehydrogenase (LDH)); three had marked increase in NT-proBNP; two had HCM with impaired LV function; one had LVH with LV noncompaction; five had arrhythmia with paroxysmal supraventricular and/or ventricular tachycardia. Two teenagers died at ages 16-17 from refractory heart failure and two underwent heart transplantation. All patients were found to have a pathogenic/likely pathogenic variant in the LAMP2 gene, six patients had no family history and a de novo evolvement was documented in 4/6 of those available for genetic tested. Retrospective review related to family background and earlier clinical evaluations revealed a definitive or highly suspicious family history of DD in 3, early clinical presentation with cardiac abnormalities (ECG, echo) in 3, and cerebral, hepatic and/or neuromuscular symptoms in 5. Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center. CONCLUSION: The earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown., Objective: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity., Design, Setting, and Participants: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled., Exposures: Amount and intensity of physical activity., Main Outcomes and Measures: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient's exercise category., Results: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority., Conclusions and Relevance: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Background: Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM., Methods: A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve., Results: Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers ( P <0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (β-coefficient, -0.031 mL/g per min [CI, -0.06 to -0.01]; P =0.013), higher ejection fraction (-0.025 mL/g per min [CI, -0.04 to -0.01]; P <0.005), and ECG maximum R-wave height (-0.023 mL/g per min [CI, -0.04 to -0.01]; P <0.005)., Conclusions: Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease associated with an increased risk of life-threatening arrhythmias. The aim of the present study was to evaluate the association of ventricular arrhythmias (VA) with circadian and seasonal variation in ARVC. One hundred two ARVC patients with an implantable cardioverter defibrillator (ICD) were enrolled in the study. Arrhythmic events included (a) any initial ventricular tachycardia (VT) or fibrillation (VF) prompting ICD implantation, (b) any VT or non-sustained VT (NSVT) recorded by the ICD, and (c) appropriate ICD shocks/therapy. Differences in the annual incidence of events across seasons (winter, spring, summer, autumn) and period of the day (night, morning, afternoon, evening) were assessed both for all cardiac events and major arrhythmic events. In total, 67 events prior to implantation and 263 ICD events were recorded. These included 135 major (58 ICD therapies, 57 self-terminating VT, 20 sustained VT) and 148 minor (NSVT) events. A significant increase in the frequency of events was observed in the afternoon versus in the nights and mornings ( p = 0.016). The lowest number of events was registered in the summer, with a peak in the winter ( p < 0.001). Results were also confirmed when excluding NSVT. Arrhythmic events in ARVC follow a seasonal variation and a circadian rhythm. They are more prevalent in the late afternoon, the most active period of the day, and in the winter, supporting the role of physical activity and inflammation as triggers of events.

The finding of a genotype-negative hypertrophic cardiomyopathy (HCM) pedigree with several affected members indicating a familial origin of the disease has driven this study to discover causative gene variants. Genetic testing of the proband and subsequent family screening revealed the presence of a rare variant in the MYBPC3 gene, c.3331-26T>G in intron 30, with evidence supporting cosegregation with the disease in the family. An analysis of potential splice-altering activity using several splicing algorithms consistently yielded low scores. Minigene expression analysis at the mRNA and protein levels revealed that c.3331-26T>G is a spliceogenic variant with major splice-altering activity leading to undetectable levels of properly spliced transcripts or the corresponding protein. Minigene and patient mRNA analyses indicated that this variant induces complete and partial retention of intron 30, which was expected to lead to haploinsufficiency in carrier patients. As most spliceogenic MYBPC3 variants, c.3331-26T>G appears to be non-recurrent, since it was identified in only two additional unrelated probands in our large HCM cohort. In fact, the frequency analysis of 46 known splice-altering MYBPC3 intronic nucleotide substitutions in our HCM cohort revealed 9 recurrent and 16 non-recurrent variants present in a few probands (≤ 4), while 21 were not detected. The identification of non-recurrent elusive MYBPC3 spliceogenic variants that escape detection by in silico algorithms represents a challenge for genetic diagnosis of HCM and contributes to solving a fraction of genotype-negative HCM cases., (© 2022. The Author(s).)

The best studied of the inherited cardiomyopathies-hypertrophic (HCM), dilated (DCM) and arrhythmogenic (ACM)-present overlapping clinical phenotypes with varying, often unrecognized, risk of sudden death. Risk assessment is informed by patient sex and by the specific disease-causing variant. HCM and arrhythmogenic right ventricular cardiomyopathy (ARVC) remain important causes of sudden death. A phenotype mimicking DCM in patients with inherited ACM is associated with premature sudden death in families with overlapping DCM and ACM phenotypes. The role of inflammation as a determinant of disease development and progression and sudden death is poorly understood but potentially important. Sudden death registries report myocarditis as the cause in 5% to 13%; examination of 30 hearts from victims of ARVC sudden death found focal myocarditis in areas of myocyte necrosis in 20 (67%). The link to specific disease-causing variants remains to be explored, including genetic determinants of the immune response. Clinical and experimental studies support immune- and autoimmune-mediated disease in DCM and ACM. Immunosuppression in biopsy-proven noninfectious myocarditis and inflammatory DCM is a treatment option. Recognition of ACM requires greater focus on distinguishing ACM from DCM. The potential to recognize disease before adverse events and to characterize patients who may benefit from immunosuppression or device therapy highlights the importance of more comprehensive genetic and immunologic characterization of patients with myocarditis and in those with a family history or clinical presentation of an inherited cardiomyopathy. This review will examine from a predominantly clinical perspective the potential importance of myocardial inflammation as a determinant of sudden death in inherited HCM, DCM, and ACM., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Filamin C truncating variants ( FLNCtv ) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers., Methods: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP -related arrhythmogenic cardiomyopathies were used for prognostic comparison., Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD., Conclusions: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

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 OHCA between the local Middle Eastern Gulf Cooperation Council (GCC) Arab and the migrant North African populations living in Qatar. Methods: This was a retrospective cohort study of Middle Eastern GCC Arabs and migrant North African patients with presumed cardiac origin OHCA resuscitated by Emergency Medical Services (EMS) in Qatar, between June 2012 and May 2015. Results: There were 285 Middle Eastern GCC Arabs and 112 North African OHCA patients enrolled during the study period. Compared with the local GCC Arabs, univariate analysis showed that the migrant North African OHCA patients were younger and had higher odds of initial shockable rhythm, pre-hospital interventions (defibrillation and amioderone), pre-hospital scene time, and decreased odds of risk factors (hypertension, respiratory disease, and diabetes) and pre-hospital response time. The survival to hospital discharge had greater odds for North African OHCA patients which did not persist after adjustment. Multivariable logistic regression showed that North Africans were associated with lower odds of diabetes (OR 0.48, 95% CI 0.25-0.91, p  = 0.03), and higher odds of initial shockable rhythm (OR 2.86, 95% CI 1.30-6.33, p  = 0.01) and greater scene time (OR 1.02 95% CI 1.0-1.04, p  = 0.02). Conclusions: North African migrant OHCA patients were younger, had decreased risk factors and favourable OHCA rhythm and received greater ACLS interventions with shorter pre-hospital response times and longer scene times leading to better survival.

In the absence of contemporary, population-based epidemiological studies, estimates of the incidence and prevalence of the inherited cardiomyopathies have been derived from screening studies, most often of young adult populations, to assess cardiovascular risk or to detect the presence of disease in athletes or military recruits. The global estimates for hypertrophic cardiomyopathy (1/500 individuals), dilated cardiomyopathy (1/250) and arrhythmogenic right ventricular cardiomyopathy (1/5,000) are probably conservative given that only individuals who fulfil diagnostic criteria would have been included. This caveat is highly relevant because a substantial minority or even a majority of individuals who carry disease-causing genetic variants and are at risk of disease complications have incomplete and/or late-onset disease expression. The genetic literature on cardiomyopathy, which is often focused on the identification of genetic variants, has been biased in favour of pedigrees with higher penetrance. In clinical practice, an abnormal electrocardiogram with normal or non-diagnostic imaging results is a common finding for the sarcomere variants that cause hypertrophic cardiomyopathy, the titin and sarcomere variants that cause dilated cardiomyopathy and the desmosomal variants that cause either arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy. Therefore, defining the genetic epidemiology is also challenging given the overlapping phenotypes, incomplete and age-related expression, and highly variable penetrance even within individual families carrying the same genetic variant.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Treatment options for patients with non-obstructive hypertrophic cardiomyopathy (HCM) are limited. We sought to determine whether biventricular (BiV) pacing improves exercise capacity in HCM patients, and whether this is via augmented diastolic filling., Methods and Results: Thirty-one patients with symptomatic non-obstructive HCM were enrolled. Following device implantation, patients underwent detailed assessment of exercise diastolic filling using radionuclide ventriculography in BiV and sham pacing modes. Patients then entered an 8-month crossover study of BiV and sham pacing in random order, to assess the effect on exercise capacity [peak oxygen consumption (VO 2 )]. Patients were grouped on pre-specified analysis according to whether left ventricular end-diastolic volume increased (+LVEDV) or was unchanged/decreased (-LVEDV) with exercise at baseline. Twenty-nine patients (20 male, mean age 55 years) completed the study. There were 14 +LVEDV patients and 15 -LVEDV patients. Baseline peak VO 2 was lower in -LVEDV patients vs. +LVEDV patients (16.2 ± 0.9 vs. 19.9 ± 1.1 mL/kg/min, P = 0.04). BiV pacing significantly increased exercise ΔLVEDV (P = 0.004) and Δstroke volume (P = 0.008) in -LVEDV patients, but not in +LVEDV patients. Left ventricular ejection fraction and end-systolic elastance did not increase with BiV pacing in either group. This translated into significantly greater improvements in exercise capacity (peak VO 2  + 1.4 mL/kg/min, P = 0.03) and quality of life scores (P = 0.02) in -LVEDV patients during the crossover study. There was no effect on left ventricular mechanical dyssynchrony in either group., Conclusion: Symptomatic patients with non-obstructive HCM may benefit from BiV pacing via augmentation of diastolic filling on exercise rather than contractile improvement. This may be due to relief of diastolic ventricular interaction., Clinical Trial Registration: ClinicalTrials.gov NCT00504647., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level., Methods: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry., Results: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle., Conclusions: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations., Competing Interests: Declaration of competing interest None., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background This study assessed the prevalence of left ventricular (LV) involvement and characterized the clinical, electrocardiographic, and imaging features of LV phenotype in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Differential diagnosis between ARVC-LV phenotype and dilated cardiomyopathy (DCM) was evaluated. Methods and Results The study population included 87 ARVC patients (median age 34 years) and 153 DCM patients (median age 51 years). All underwent cardiac magnetic resonance with quantitative tissue characterization. Fifty-eight ARVC patients (67%) had LV involvement, with both LV systolic dysfunction and LV late gadolinium enhancement (LGE) in 41/58 (71%) and LV-LGE in isolation in 17 (29%). Compared with DCM, the ARVC-LV phenotype was statistically significantly more often characterized by low QRS voltages in limb leads, T-wave inversion in the inferolateral leads and major ventricular arrhythmias. LV-LGE was found in all ARVC patients with LV systolic dysfunction and in 69/153 (45%) of DCM patients. Patients with ARVC and LV systolic dysfunction had a greater amount of LV-LGE (25% versus 13% of LV mass; P <0.01), mostly localized in the subepicardial LV wall layers. An LV-LGE ≥20% had a 100% specificity for diagnosis of ARVC-LV phenotype. An inverse correlation between LV ejection fraction and LV-LGE extent was found in the ARVC-LV phenotype ( r =-0.63; P <0.01), but not in DCM ( r =-0.01; P =0.94). Conclusions LV involvement in ARVC is common and characterized by clinical and cardiac magnetic resonance features which differ from those seen in DCM. The most distinctive feature of ARVC-LV phenotype is the large amount of LV-LGE/fibrosis, which impacts directly and negatively on the LV systolic function.

Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM. RNA was extracted from seven paraffin-embedded left ventricular tissue samples from deceased ACM patients carrying FLNC variants and sequenced. Transcript levels of 623 genes were upregulated and 486 genes were reduced in ACM in comparison to control samples. The cell adhesion pathway and ILK signalling were among the prominent dysregulated pathways in ACM. Consistent with these findings, transcript levels of cell adhesion genes JAM2, NEO1, VCAM1 and PTPRC were upregulated in ACM samples. Moreover, several actin-associated genes, including FLNC, VCL, PARVB and MYL7, were suppressed, suggesting dysregulation of the actin cytoskeleton. Analysis of the transcriptome for dysregulated biological pathways predicted activation of inflammation and apoptosis and suppression of oxidative phosphorylation and MTORC1 signalling in ACM. Our data suggests dysregulated cell adhesion and ILK signalling as novel putative pathogenic mechanisms of ACM caused by FLNC variants which are distinct from the postulated disease mechanism of classic ARVC caused by desmosomal gene mutations. This knowledge could help in the design of future gene therapy strategies which would target specific components of these pathways and potentially lead to novel treatments for ACM., Competing Interests: Declaration of competing interest None., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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 myoarchitectural abnormalities in HCM are present in the fetal heart. We used wild-type, heterozygous and homozygous hearts (n = 56) from a Mybpc3-targeted knock-out HCM mouse model and imaged the 3D micro-structure by high-resolution episcopic microscopy. We developed a novel structure tensor approach to extract, display and quantify myocyte orientation and its local angular uniformity by helical angle, angle of intrusion and myoarchitectural disarray index, respectively, immediately before and after birth. In wild-type, we demonstrate uniformity of orientation of cardiomyocytes with smooth transitions of helical angle transmurally both before and after birth but with traces of disarray at the septal insertion points of the right ventricle. In comparison, heterozygous mice free of LVH, and homozygous mice showed not only loss of the normal linear helical angulation transmural profiles observed in wild-type but also fewer circumferentially arranged myocytes at birth. Heterozygous and homozygous showed more disarray with a wider distribution than in wild-type before birth. In heterozygous mice, disarray was seen in the anterior, septal and inferior walls irrespective of stage, whereas in homozygous mice it extended to the whole LV circumference including the lateral wall. In conclusion, myoarchitectural disarray is detectable in the fetal heart of an HCM mouse model before the development of LVH., (© 2019 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

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, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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 patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF)., Results: A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction., Conclusions: Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 these patients., Methods: Cohort of Patients who fulfilled the 2010 ARVC task force criteria were consecutively recruited. Detailed clinical data were collected at baseline and during follow up. The clinical endpoint was a composite of recurrent sustained ventricular arrhythmias and hospitalization due to ventricular arrhythmias. Multivariable logistic regression was used to develop models to predict the arrhythmic risk. A cohort including patients from other registries in UK, Canada and Switzerland was used as a validation population., Results: One hundred and thirty-five patients were included of whom 35 patients (31.9%) reached the endpoint. A model consisting of filtered QRS duration on signal-averaged ECG, non-sustained VT (NSVT) on 24 h-ECG, and absence of negative T waves in lead aVR on 12‑lead surface ECG was able to predict arrhythmic events with a sensitivity of 81.8%, specificity of 84.0% and a negative predictive value of 95.5% at the first presentation of the disease. This risk score was validated in international ARVC registry patients., Conclusion: A risk score consisting of a filtered QRS duration ≥117 ms, presence of NSVT on 24 h-ECG and absence of negative T waves in lead aVR was able to predict arrhythmic events at first presentation of the disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

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 testing were consecutively recruited. Detailed clinical data was collected at baseline and during follow up. Clinical endpoint was a composite of heart transplantation and death due to HF., Results: 135 patients were included. 8 (5.9%) patients reached the endpoint. Patients reaching the endpoint were significantly more likely to carry a Plakophilin 2 mutation than patients without HF, and 50% had multiple variants, however only one patient had 2 pathogenic mutations., Conclusions: HF is a rare but significant outcome of patients with a definite diagnosis of ARVC. Patients with HF predominantly carried Plakophilin 2 mutations and often had multiple variants. RV dysfunction appears to be a determinant of heart transplantation and death., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals 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 to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP)., Objectives: In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC., Methods: Six AC pedigrees with 38 carriers of a dominant loss-of-function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping., Results: All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin., Conclusions: This study identifies a highly recognizable cutaneous phenotype associated with dominant loss-of-function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features., (© 2018 British Association of Dermatologists.)

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: In a multicenter retrospective study, 110 patients with ARVC (mean age 38 ± 17 years; 91[83%] men) with a minimum of 3 VT episodes were included; 77 (70%) were initially treated with AAD/BB and 32 (29%) underwent ablation. Subsequently, 43 of the 77 patients treated with AAD/BB alone also underwent ablation. Overall, 75 patients underwent ablation., Results: When comparing initial AAD/BB therapy (n = 77) and VT ablation (n = 32) after ≥3 VT episodes, a single ablation procedure rendered 35% of patients free of VT at 3 years compared with 28% of AAD/BB-only-treated patients (P = .46). Of the 77 AAD/BB-only-treated patients, 43 subsequently underwent ablation. For all 75 patients who underwent ablation, 56% were VT-free at 3 years after the last ablation procedure. Epicardial ablation was used in 40/75 (53%) and was associated with lower VT recurrence after the last ablation procedure (endocardial/epicardial vs endocardial-only; 71% vs 47% 3-year VT-free survival; P = .05). Importantly, there was no difference in survival free of death or transplantation between the ablation- and AAD/BB-only-treated patients (P = .61)., Conclusion: In patients with ARVC and a high VT burden, mortality and transplantation-free survival are not significantly different between drug- and ablation-treated patients. These patients have a high risk of recurrent VT despite drug therapy. Combined endocardial/epicardial ablation is associated with reduced VT recurrence as compared with endocardial-only ablation., (Copyright © 2018. Published by Elsevier Inc.)

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.

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 compare protein profiles in myocardial samples from 11 patients with HCM undergoing surgical myectomy with control samples from 6 healthy unused donor hearts. Differentially expressed proteins of interest were validated in myocardial samples from 65 unrelated individuals (HCM [n=51], controls [n=7], and aortic stenosis [n=7]) by the development and use of targeted multiple reaction monitoring-based triple quadrupole mass spectrometry., Results: In this exploratory study, 1586 proteins were identified with 151 proteins differentially expressed in HCM samples compared with controls ( P<0.05). Protein expression profiling showed that many proteins identified in the initial discovery study were associated with metabolism, muscle contraction, calcium regulation, and oxidative stress. Proteins downregulated in HCM versus controls included creatine kinase M-type, fructose-bisphosphate aldolase A, and phosphoglycerate mutase ( P<0.001). Proteins upregulated in HCM included lumican, carbonic anhydrase 3, desmin, α-actin skeletal, and FHL1 (four and a half LIM domain protein 1; P<0.01). Myocardial lumican concentration correlated with the left atrial area (ρ=0.34, P=0.015), late gadolinium enhancement on cardiac magnetic resonance imaging ( P=0.03) and the presence of a pathogenic sarcomere mutation ( P=0.04)., Conclusions: The myocardial proteome of HCM provides supporting evidence for dysregulation of metabolic and structural proteins. The finding that lumican is raised in HCM hearts provides insight into the myocardial fibrosis that characterizes this disease.

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 mutation subtype can predict phenotype severity in patients with lamin heart disease., Methods: We used a semantic workflow platform and manual electronic literature search to identify published LMNA mutations with cardiac-predominant phenotype. Hierarchical cluster analysis (HCA) assembled lamin heart disease into classes based on phenotype severity. 176 reported causative mutations were classified and any relationships to mutation location/subtype assessed by contingency analysis., Results: More adverse phenotype was associated with mutation location upstream of the NLS (p=0.014, OR 2.38, 95% CI 1.19 to 4.80) but not with non-missense mutations (p=0.337, OR 1.36, 95% CI 0.72 to 2.57), although an association with non-missense mutations was identified in a subcluster with malignant ventricular arrhythmia (p=0.005, OR 2.64, 95% CI 0.76 to 9.21). HCA limited to the 65 mutations described on ClinVar as pathogenic/likely pathogenic showed similar findings (upstream of NLS, p=0.030, OR 4.78, 95% CI 1.28 to 17.83; non-missense, p=0.121, OR 2.64, 95% CI 0.76 to 9.21) as did analysis limited to pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics standards., Conclusion: Cardiac patients with an LMNA mutation located upstream versus downstream of the NLS have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones., Competing Interests: Competing interests: None declared.

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 (gnomAD) population of 138,632 unrelated individuals was searched for previously identified ARVC variants, classified as pathogenic or unknown on the disease genetic variant database ( http://www.arvcdatabase.info/ ), in five most-commonly mutated genes: PKP2, DSP, DSG2, DSC2 and JUP, where variants account for 40-50% of all the ARVC cases. Minor allele frequency (MAF) of 0.001 was used to define variants as rare or common.The gnomAD data contained 117/364 (32%) of the previously reported pathogenic and 152/266 (57%) of the unknown ARVC variants. The cross-ethnic analysis of MAF revealed that 11 previously classified pathogenic and 57 unknown variants were common (MAF ≥ 0.001) in at least one ethnic gnomAD population and therefore unlikely to be ARVC causing.After applying our MAF analysis the overall frequency of pathogenic ARVC variants in gnomAD was one in 257 individuals, but a more stringent cut-off (MAF ≥ 0.0001) gave a frequency of one in 845, closer to the estimated phenotypic frequency of the disease.Our study demonstrates that the analysis of large cross-ethnic population sequencing data can significantly improve disease variant interpretation. Higher than expected frequency of ARVC variants suggests that a proportion of ARVC-causing variants may be inaccurately classified, implying reduced penetrance of some variants, and/or a polygenic aetiology of ARVC.

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 PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure., Methods: We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant., Results: Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants., Conclusions: Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development., Competing Interests: The authors have declared that no competing interests exist.

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 other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an LMNA mutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for LMNA , alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude LMNA mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our LMNA knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions., Competing Interests: Competing interests: AM is a member of the scientific advisory board of AlloMek Therapeutics, LLC, a privately held pharmaceutical company developing small molecules targeting ERK1/2 signalling. All other authors have declared no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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 for desmoplakin (DSP) missense and non-missense mutations causing ARVC., Methods and Results: We analyzed 27 ARVC patients carrying a missense or a non-missense DSP mutation, with complete clinical assessment. The two groups were compared for clinical parameters, basic demographics such as sex, age at diagnosis, age at disease onset, as well as prevalence of symptoms and arrhythmic events. Missense DSP variants were present in 10 patients and non-missense in 17. Mean age at diagnosis and at first arrhythmic event did not differ between the two groups. Also the prevalence of symptoms, either major (60% vs 59%, p=1) or all (80% vs 88%, p=0.61), did not differ. By contrast, left ventricular (LV) dysfunction was significantly more prevalent among patients with non-missense mutations (76.5% vs 10%, p=0.001), who were also much more likely to have a structural LV involvement by Cardiac Magnetic Resonance (CMR) (92% vs 22%, p=0.001)., Conclusions: For ARVC patients, both missense and non-missense DSP mutations carry a high arrhythmic risk. Non-missense mutations are specifically associated with left-dominant forms. The presence of DSP non-missense mutations should alert to the likely development of LV dysfunction. These findings highlight the clinical relevance of genetic testing even after the clinical diagnosis of ARVC and the growing clinical impact of genetics., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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 been discovered (arrhythmogenic, restrictive, and noncompacted) and added to update the World Health Organization classification. Myocarditis has also been named inflammatory cardiomyopathy. Extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed establishment of dilated cardiomyopathy as mostly cytoskeleton, force transmission disease; hypertrophic-restrictive cardiomyopathies as sarcomeric, force generation disease; and arrhythmogenic cardiomyopathy as desmosome, cell junction disease. Channelopathies (short and long QT, Brugada, and catecholaminergic polymorphic ventricular tachycardia syndromes) should also be considered cardiomyopathies because of electric myocyte dysfunction. Cardiomyopathies are easily diagnosed but treated only with palliative pharmacological or invasive therapy. Curative therapy, thanks to insights into the molecular pathogenesis, has to target the fundamental mechanisms involved in the onset and progression of these conditions., (© 2017 American Heart Association, Inc.)

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 currently no universally accepted clinical criteria to diagnose ARVC in Boxer dogs. We aimed to identify diagnostic criteria for ARVC in Boxer dogs defining a more uniform and consistent phenotype., Methods and Results: Clinical records from 264 Boxer dogs from a referral veterinary hospital were retrospectively analysed. ARVC was initially diagnosed according to the number of ventricular premature complexes (VPCs) in the 24-hour-Holter-ECG in the absence of another obvious cause. Dogs diagnosed this way had more VPCs, polymorphic VPCs, couplets, triplets, VTs and R-on-T-phenomenon and syncope, decreased right ventricular function and dilatation in comparison to a control group of all other Boxer dogs seen by the Cardiology Service over the same period. Presence of couplets and R-on-T-phenomenon on a 24h-ECG were identified as independent predictors of the diagnosis. A diagnosis based on ≥100 VPCs in 24 hours, presence of couplets and R-on-T phenomenon on a 24h-ECG was able to select Boxer dogs with a phenotype most similar to human ACM., Conclusion: We suggest the diagnosis of ARVC in Boxer dogs requires two out of the three following criteria: presence of ≥ 100 VPCs, presence of couplets or R-on-T-phenomenon on a 24 h-ECG. This results in a uniform phenotype similar to that described in human ACM and may result in the adoption of the term ACM for this analogous condition in Boxer dogs.

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 disease using electrocardiographic imaging (a method for noninvasive cardiac electrophysiology mapping) and advanced late gadolinium enhancement cardiac magnetic resonance scar imaging. Compared with 20 healthy controls, ARVC patients had longer ventricular activation duration (median, 52 versus 42 ms; P =0.007) and prolonged mean epicardial activation-recovery intervals (a surrogate for local action potential duration; median, 275 versus 241 ms; P =0.014). In these patients, we observed abnormal and varied epicardial activation breakthrough locations and regions of nonuniform conduction and fractionated electrograms. Nonuniform conduction and fractionated electrograms were present in the early concealed phase of ARVC. Electrophysiological abnormalities colocalized with late gadolinium enhancement scar, indicating a relationship with structural disease. Premature ventricular contractions were common in ARVC patients with variable initiation sites in both ventricles. Premature ventricular contraction rate increased with exercise, and within anatomic segments, it correlated with prolonged repolarization, electric markers of scar, and late gadolinium enhancement (all P <0.001)., Conclusions: Electrocardiographic imaging reveals electrophysiological substrate properties that differ in ARVC patients compared with healthy controls. A novel mechanistic finding is the presence of repolarization abnormalities in regions where ventricular ectopy originates. The results suggest a potential role for electrocardiographic imaging and late gadolinium enhancement in early diagnosis and noninvasive follow-up of ARVC patients., (© 2017 American Heart Association, Inc.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

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 <50% by two-dimensional (2D) echocardiography) at first evaluation was more frequent in rare phenocopies than in idiopathic or sarcomeric HCM (105/409 (26%) vs 40/1288 (3%), respectively (p<0.0001)). All-cause death/HTx and HF-related death were more frequent in rare phenocopies compared with idiopathic or sarcomeric HCM (p<0.0001). All-cause mortality and HF-related death were highest in patients with cardiac amyloidosis (p<0.0001)., Conclusions: In adults with HCM, LV systolic dysfunction is more frequent in those with rare phenocopies. When combined with age at presentation, it is a marker for specific aetiologies and is associated with poorer long-term survival., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Outcomes of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients after 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: A total of 35,138 heart transplant-only recipients were identified from the United Network for Organ Sharing (UNOS) Thoracic Registry (1994-2011); 73 had ARVC. The non-ARVC group included ischemic cardiomyopathy, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and other. Survival was censored at 12 years. Multivariate Cox proportional hazard regression analysis was adjusted for age, sex, DM, race, ischemia time, dialysis, life support, wait time, and HLA mismatch., Results: There were 73 ARVC and 35,065 non-ARVC patients. The ARVC cohort was associated with less ventricular assist device use (P = .001) and significantly decreased pulmonary arterial and capillary wedge pressures (P < .001). Survivals at 1, 5, and 10 years were, respectively, ARVC 87%, 81%, and 77%, and non-ARVC 87%, 72%, and 53% (log rank P = .07). The ARVC unadjusted hazard ratio for all-cause mortality was 0.59 (95% confidence interval [CI] 0.34-1.04; P = .073). Multivariate analysis yielded a hazard ratio of 0.68 (95% CI 0.35-1.30; P = .25). ARVC survival was similar to restrictive, hypertrophic, and dilated cardiomyopathies and significantly better than ischemic cardiomyopathy., Conclusions: This is the largest reported series of ARVC after heart transplantation, of which 11% were pediatric. Survival was similar to the non-ARVC cohort, with improved survival over ischemic and restrictive etiologies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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 diastolic dysfunction, left ventricular outflow tract obstruction, ischaemia, atrial fibrillation, abnormal vascular responses and, in 5% of patients, progression to a 'burnt-out' phase characterized by systolic impairment. Disease-related mortality is most often attributable to sudden cardiac death, heart failure, and embolic stroke. The majority of individuals with HCM, however, have normal or near-normal life expectancy, owing in part to contemporary management strategies including family screening, risk stratification, thromboembolic prophylaxis, and implantation of cardioverter-defibrillators. The clinical guidelines for HCM issued by the ACC Foundation/AHA and the ESC facilitate evaluation and management of the disease. In this Review, we aim to assist clinicians in navigating the guidelines by highlighting important updates, current gaps in knowledge, differences in the recommendations, and challenges in implementing them, including aids and pitfalls in clinical and pathological evaluation. We also discuss the advances in genetics, imaging, and molecular research that will underpin future developments in diagnosis and therapy for HCM.

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 using current methods, and life-threatening arrhythmias are common and difficult to predict., Objective: The purpose of this study was to assess the utility of ventricular ectopic indices including VEQSI in ARVC diagnosis., Methods: We studied 70 patients with ARVC [30 with definite disease (age 47 ± 12 years; 60% male), 40 with incomplete disease expression (age 44 ± 18 years; 44% male)], 116 healthy controls (age 40 ± 15 years; 56% male), and 26 patients with normal heart right ventricular outflow tract (RVOT) ectopy (age 46 ± 17 years; 27% male). The duration of the broadest ventricular ectopic beat during 12-lead Holter monitoring was recorded as VEQSI max., Results: VEQSI max was associated with age and gender, but not with conducted QRS duration. Adjusted VEQSI max was greater in ARVC patients than in control groups. In healthy males (44.5 years), estimated VEQSI max was 163 ms (95% confidence interval [CI] 159-167 ms); in definite ARVC 212 ms (95% CI 206-217 ms); in incompletely expressed ARVC 204 ms (95% CI 199-210 ms); and in normal heart RVOT ectopy 171 ms (95% CI 165-178 ms). VEQSI max >180 ms had 98% sensitivity and specificity for diagnosis of ARVC (area under the curve 0.99, 95% CI 0.980-0.998). In our incompletely expressed ARVC patients, VEQSI max >180 ms identified 88% as affected., Conclusion: VEQSI max distinguishes ARVC patients, including those with incomplete disease expression, from healthy controls and patients with normal heart RVOT ectopy., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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.