Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report.

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 late­gadolinium 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.

Clinical significance of small nerve fiber involvement in the early diagnosis and treatment of patients with Fabry disease.

INTRODUCTION: Peripheral nervous system is early involved in Fabry disease (FD) and preferentially the small nerve fibers, causing the characteristic neuropathic pain crises usually beginning in childhood. Early detection of this likely underdiagnosed disease is an important approach because causal therapies are available. METHODS: We conducted a case-series study to investigate the small nerve fiber involvement in FD and its contribution to the diagnosis of the disease but also to the timely effective therapy administration. We used specific structured scales of symptoms and signs to detect peripheral neuropathy, as well as suitable functional and structural tests to diagnose the small fiber neuropathy (SFN). RESULTS: Twenty-seven consecutive patients (14 men, mean age 44.62 ± 10.70 years) with suspected FD were included in this study. Most of the patients presented symptoms of small nerve fiber involvement, which were accompanied by abnormal test results, fulfilling the criteria for SFN. The detection of SFN in our patients allowed the completion of the FD diagnostic criteria and thus the initiation of therapy. In five patients the SFN diagnosis determined the administration of therapy, whereas in two others it might be considered. CONCLUSION: Our results further suggest the importance of early diagnosis of peripheral neuropathy, especially of small nerve fiber involvement, in patients with suspected FD as it contributes crucially not only to the diagnosis but also to the timely effective initiation of FD therapy.

Transthyretin (Pro24Ser) variant amyloidosis: A case report of the first patient in Greece.

OBJECTIVE: Transthyretin cardiac amyloidosis (ATTR-CA) is a rare and potentially fatal disease caused by the accumulation of insoluble transthyretin (TTR) amyloid fibrils in the heart. The symptoms of ATTR-CA are often non-specific, often leading to underdiagnosis. Early diagnosis and treatment have a significant impact on disease progression and mortality. CASE PRESENTATION: In this case we report a 73-year-old male presented with dyspnea on exertion. The patient had a medical history of peripheral neuropathy, bilateral carpal tunnel syndrome, spinal fusion, and a family history of coronary artery disease. Upon his presentation at the Cardiology department, cardiac echo study revealed left and right ventricular hypertrophy with pulmonary hypertension, diastolic dysfunction and a restrictive pattern. Because of the high probability of amyloidosis, the patient underwent a technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphic study, which confirmed the diagnosis of ATTR-CA. Transthyretin gene sequencing analysis revealed the rare p. Pro24Ser pathogenic variant. Final diagnosis was ATTR-CA associated with the proline replaced by serine at position 24 (Pro24Ser) TTR variant, which is rare and only a few cases have been reported worldwide. The patient was treated with tafamidis and inotersen and followed up. CONCLUSION: This case highlights the importance of considering amyloidosis as a differential diagnosis for non-specific symptoms and the need for early diagnosis and management of ATTR-CA.

A truncating variant altering the extreme C-terminal region of desmoplakin (DSP) suggests the crucial functional role of the region: a case report study.

BACKGROUND: Homozygous truncating mutations located in the C-terminal region of the desmoplakin gene (DSP) are known to mainly cause Carvajal syndrome, an autosomal recessive syndromic form of arrhythmogenic cardiomyopathy with an extra-cardiac cutaneous phenotype. CASE PRESENTATION: Here we describe a female proband with a documented arrhythmogenic left ventricular cardiomyopathy and a syncopal episode at the age of 13, who was found homozygous for the novel DSP variant: NM_004415.4:c.8586delC, p.(Ser2863Hisfs*20) at the extreme C-terminal region of the protein, just 8 amino acids upstream the stop codon. She did not have any of the typical dermatological symptoms that characterize Carvajal syndrome. Her brother had died suddenly at the age of 18 during exercise and was found homozygous for the same variant at the post-mortem, while their parents were heterozygous. The region of origin of both parents was the same geographic area of Greece, but they were not aware of any common ancestor. Detailed clinical examination revealed that the mother displayed a mild arrhythmic phenotype, while the father was asymptomatic. CONCLUSION: These observations pinpoint to a significant functional role of the extreme C-terminal tail of the protein.

Impaired cerebral autoregulation in Fabry disease: A case-control study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is a common manifestation among patients with Fabry disease (FD). As a biomarker of cerebral small vessel disease, the prevalence of impaired cerebral autoregulation as assessed by transcranial Doppler (TCD) ultrasonography was evaluated in FD patients and healthy controls. METHODS: TCD was performed to assess pulsatility index (PI) and vasomotor reactivity expressed by breath-holding index (BHI) for the middle cerebral arteries of included FD patients and healthy controls. Prevalence of increased PI (>1.2) and decreased BHI (<0.69) and ultrasound indices of cerebral autoregulation were compared in FD patients and controls. The potential association of ultrasound indices of impaired cerebral autoregulation with white matter lesions and leukoencephalopathy on brain MRI in FD patients was also evaluated. RESULTS: Demographics and vascular risk factors were similar in 23 FD patients (43% women, mean age: 51 ± 13 years) and 46 healthy controls (43% women, mean age: 51 ± 13 years). The prevalence of increased PI (39%; 95% confidence interval [CI]: 20%-61%), decreased BHI (39%; 95% CI: 20%-61%), and the combination of increased PI and/or decreased BHI (61%; 95% CI: 39%-80%) was significantly (p < .001) higher in FD patients compared to healthy controls (2% [95% CI: 0.1%-12%], 2% [95% CI: 0.1%-12%], and 4% [95% CI: 0.1%-15%], respectively). However, indices of abnormal cerebral autoregulation were not associated independently with white matter hyperintensities and presented a low-to-moderate predictive ability for the discrimination of FD patients with and without white matter hyperintensities. CONCLUSIONS: Impaired cerebral autoregulation as assessed by TCD appears to be highly more prevalent among FD patients compared to healthy controls.

Cardiomyopathies in children: An overview.

Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. Mostly inherited as a dominant or occasionally recessive trait, they might be part of a syndromic disorder of underlying metabolic or neuromuscular defects or combine early developing extracardiac abnormalities (i.e., Naxos disease). The annual incidence of 1 per 100,000 children appears higher during the first two years of life. Dilated and hypertrophic cardiomyopathy phenotypes share an incidence of 60% and 25%, respectively. Arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy, and left ventricular noncompaction are less commonly diagnosed. Adverse events such as severe heart failure, heart transplantation, or death usually appear early after the initial presentation. In ARVC patients, high-intensity aerobic exercise has been associated with worse clinical outcomes and increased penetrance in at-risk genotype-positive relatives. Acute myocarditis in children has an incidence of 1.4-2.1 cases/per 100,000 children per year, with a 6-14% mortality rate during the acute phase. A genetic defect is considered responsible for the progression to dilated cardiomyopathy phenotype. Similarly, a dilated or arrhythmogenic cardiomyopathy phenotype might emerge with an episode of acute myocarditis in childhood or adolescence. This review provides an overview of childhood cardiomyopathies focusing on clinical presentation, outcome, and pathology.

D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha (GLA) gene. Among them, the potential pathogenicity and clinical relevance of D313Y variation in patients with FD remain debated. METHODS: We performed a systematic review and meta-analysis of studies reporting D313Y as single occurring variant in the GLA gene and sought to evaluate (1) the prevalence of D313Y variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in D313Y-positive patients, and (3) the proportion of D313Y-positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). RESULTS: Forty cohorts comprising 211 individuals with D313Y variation among 42,723 participants with available GLA gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of D313Y variation (4.9%, 95% CI 1.6%-9.9%; I2 = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I2 = 1.9%; p = 0.004). The prevalence of D313Y variation was 0.6% (95% CI 0.3%-1%; I2 = 74.1%), 0.4% (95% CI 0.2%-0.7%; I2 = 0%), and 0.3% (95% CI 0.2%-0.4%; I2 = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. D313Y was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I2 = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I2 = 34%) and 16.2% (95% CI 8%-26.4%; I2 = 35%) of cases, respectively. D313Y-positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I2 = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I2 = 51%) and 28.5% (95% CI 17.8%-40.5%; I2 = 61%) of cases, respectively. DISCUSSION: D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify D313Y-positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment.

Risk and Protective Factors for Sudden Cardiac Death: An Umbrella Review of Meta-Analyses.

Background: Sudden cardiac death (SCD) is a global public health issue, accounting for 10-20% of deaths in industrialized countries. Identification of modifiable risk factors may reduce SCD incidence. Methods: This umbrella review systematically evaluates published meta-analyses of observational and randomized controlled trials (RCT) for the association of modifiable risk and protective factors of SCD. Results: Fifty-five meta-analyses were included in the final analysis, of which 31 analyzed observational studies and 24 analyzed RCTs. Five associations of meta-analyses of observational studies presented convincing evidence, including three risk factors [diabetes mellitus (DM), smoking, and early repolarization pattern (ERP)] and two protective factors [implanted cardiac defibrillator (ICD) and physical activity]. Meta-analyses of RCTs identified five protective factors with a high level of evidence: ICDs, mineralocorticoid receptor antagonist (MRA), beta-blockers, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with HF. On the contrary, other established, significant protective agents [i.e., amiodarone and statins along with angiotensin-converting enzyme (ACE) inhibitors in heart failure (HF)], did not show credibility. Likewise, risk factors as left ventricular ejection fraction in HF, and left ventricular hypertrophy, non-sustain ventricular tachycardia, history of syncope or aborted SCD in pediatric patients with hypertrophic cardiomyopathy, presented weak or no evidence. Conclusions: Lifestyle risk factors (physical activity, smoking), comorbidities like DM, and electrocardiographic features like ERP constitute modifiable risk factors of SCD. Alternatively, the use of MRA, beta-blockers, SGLT-2 inhibitors, and ICD in patients with HF are credible protective factors. Further investigation targeted in specific populations will be important for reducing the burden of SCD. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020216363, PROSPERO CRD42020216363.

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

AIMS: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. CONCLUSION: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

Variant transthyretin amyloidosis (ATTRv) polyneuropathy in Greece: a broad overview with a focus on non-endemic unexplored regions of the country.

Comprehensive data on variant transthyretin amyloidosis polyneuropathy (ATTRv-PN) in Greece are lacking. We presently provide an overview of ATTRv-PN in Greece, focusing on unexplored non-endemic regions of the country. In total, we identified 57 cases of ATTRv-PN diagnosed over the past 25 years, including 30 from the island of Crete, an apparent endemic region. Patients carried 10 different TTR mutations (C10R; P24S; V30M; R34G; R34T; I68L; A81T; E89Q; E89K and V94A). Carriers of the common V30M mutation constituted 54.3 % of the cohort. A known founder effect for the V30M mutation was present on the island of Crete. Non-endemic cases identified outside the island of Crete are presently reported in more detail. The age of onset ranged from 25 to 77 years, with a mean of 51.1 years. A mean diagnostic delay of 3.2 years was observed. V30M patients had earlier onset and less cardiac involvement than patients carrying other mutations. Genotype-phenotype correlations were largely consistent with published data. We conclude that, with the exception of the Cretan cluster, ATTRv-PN is not endemic in the Greek population. This makes timely diagnosis more challenging, yet absolutely essential given the availability of therapies that can alter the long-term course of the disease.

Practical recommendations for the diagnosis and management of transthyretin cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by accumulation in the heart interstitium of amyloid fibrils formed by misfolded proteins. Most common CA types are light chain amyloidosis (AL) caused by monoclonal immunoglobulin light chains and transthyretin amyloidosis (ATTR) caused by either mutated or wild-type transthyretin aggregates. Previously considered a rare disease, CA is increasingly recognized among patients who may be misdiagnosed as undifferentiated heart failure with preserved ejection fraction (HFPEF), paradoxical low-flow/low-gradient aortic stenosis, or otherwise unexplained left ventricular hypertrophy. Progress in diagnosis has been due to the refinement of cardiac echocardiographic techniques (speckle tracking imaging) and magnetic resonance (T1 mapping) and mostly due to the advent of bone scintigraphy that has enabled noninvasive diagnosis of ATTR, limiting the need for endomyocardial biopsy. Importantly, proper management of CA starts from early recognition of suspected cases among high prevalence populations, followed by advanced diagnostic evaluation to confirm diagnosis and typing, preferentially in experienced amyloidosis centers. Differentiating ATTR from other types of amyloidosis, especially AL, is critical. Emerging targeted ATTR therapies offer the potential to improve outcomes of these patients previously treated only palliatively.

Clinical Profile of Cardiac Involvement in Danon Disease: A Multicenter European Registry.

BACKGROUND: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe. METHODS: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. RESULTS: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P<0.003). Heart failure was the leading cause of death (10 of 17; 59%), and LV systolic dysfunction predicted an adverse outcome. Eight men and 8 women (28%) underwent heart transplantation or received an LV assist device. Our cohort suggests better prognosis of female compared with male heart transplant recipients. CONCLUSIONS: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.

An expert consensus document on the management of cardiovascular manifestations of Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (GLA) gene that leads to reduced or undetectable α-galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD-related heart disease and expert consensus recommendations for its management.

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

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.

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report.

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.

Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells.

BACKGROUND: Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells. METHODS AND RESULTS: Buccal cells from patients, mutation carriers, and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathy patients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes. CONCLUSIONS: Buccal mucosa cells from arrhythmogenic cardiomyopathy patients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.

Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a genetically determined disorder, mostly caused by mutations in genes encoding desmosomal proteins. We evaluated phenotype/genotype characteristics to predict the risk for the first major arrhythmic event in desmosomal-mutation-associated ARVC families. METHODS AND RESULTS: A cohort of 105 desmosomal-mutation carriers belonging to 39 consecutive ARVC families was evaluated. Serial clinical work-up consisting of history, physical examination, 12-lead/signal-averaged/24 h ambulatory ECG, and two-dimensional echocardiography was performed every 6-12 months. The predictive value of gender and genotype for the first major arrhythmic event was investigated within the cohort using time-to-event analysis. ECG/echocardiographic features were evaluated at the time of event and associated with the outcome using an age-matched nested case-control study within the cohort. Forty-three (41%) participants experienced the primary arrhythmic outcome at median age of 29 (21-46) years. The first event was sustained ventricular tachycardia in 31 and sudden cardiac death in 12. Definite diagnosis according to the 2010 Task Force criteria, showed 57% positive and 100% negative predictive value for the occurrence of arrhythmic outcome. Male gender (hazard ratio = 3.26, 95%CI, 1.63-6.51), predicted the first major arrhythmic event, independently of genotype, on multivariable analysis. Repolarization abnormalities and left-ventricular dysfunction independently associated with clinical disease profile at the time of event. CONCLUSION: Male gender, independently of genotype is an arrhythmic risk predictor in ARVC-associated desmosomal-mutation carriers. Repolarization abnormalities and left-ventricular dysfunction are important components of the first event-associated clinical disease profile.

Clinical Significance of Epsilon Waves in Arrhythmogenic Cardiomyopathy.

INTRODUCTION: Epsilon waves are hallmark features of arrhythmogenic cardiomyopathy (ACM) but information about their clinical significance is variable. We evaluated epsilon wave prevalence, characteristics, and their clinical significance in an ACM population. METHODS AND RESULTS: Eighty-six unselected patients fulfilling the 2010 Task Force criteria were enrolled. Seventy-six of them were carriers of desmosomal mutations. All subjects were serially evaluated with standard 12-lead ECG and 2-dimensional echocardiography. Epsilon waves were evaluated in all precordial and inferior leads. Novel parameters assessed included their duration and precordial/inferior lead extension. Twenty-five subjects (29%) had epsilon waves that were present in lead V3 and beyond in 9, and in the inferior leads in 7. Epsilon waves were associated with right ventricular outflow tract (RVOT) (P = 0.001) but not RV posterior wall (P = 0.21), RV apex (P = 0.30), or left ventricular (P = 0.94) wall motion abnormalities. Patients with epsilon waves had increased RVOT diameter (P < 0.0001). Extension of epsilon waves in lead V3 and beyond was associated with increased epsilon wave duration (P = 0.002) and RVOT diameter (P = 0.04). The duration of epsilon waves was positively correlated with RVOT diameter (r = 0.70, P = 0.0001). Epsilon waves were also associated with episodes of sustained ventricular tachycardia (P = 0.004) but not with heart failure (P = 0.41) or sudden cardiac death (P = 0.31). CONCLUSION: Detection of epsilon waves on 12-lead ECG reflects significant RVOT involvement, which was associated with episodes of sustained ventricular tachycardia but not sudden cardiac death.