Arrhythmogenic Ventricular Cardiomyopathy Research Articles

WEARABLE CARDIOVERTER DEFIBRILLATOR IN PATIENT WITH TRANSIENT RISK OF SUDDEN CARDIAC DEATH : SINGLE CENTRE EXPERIENCE

Abstract Background Cardiovascular disease is still the first cause of death, with sudden cardiac death ( SCD) as a first presentation in 25% of cases, related to coronary artery disease. Implantable cardioverter defibrillator (ICD) demontrated a reduction of SCD in high risk patients with good functional status. However the risk of SCD should be transient, so the use of a wearable cardioverter defibrillator (WCD) is considered in current guidelines and in clinical practice. The purpose of this study was to investigate the safety and the adherence to WCD in a real world population; moreover we reviewed the rate of ICD implantation after WCD use. Methods We considered consecutively 96 patients discharged from Piacenza cardiology department for potentially transient high risk of SCD, weared a WCD from August 2017 to June 2023. The patients were discharged in high risk mode of SCD with WCD protection and followed through remote monitoring or outpatient.A clinical and echocardiographic evalutation was performed at baseline and repeated at the end of the WCD use period. Results Out of 95 patients , with average age 66,0 ±11,1 years old and baseline average left ventricular ejection fraction (LVEF) 28,6±7,5, 81,2% were males, 72,9% suffered from arterial hypertension, 26% diabetes mellitus, 13,5% peripheral vascular disease, 14,6% chronic renal failure, 4,1% previous stroke.66% of these patients weared WCD for severe systolic disfunction in ischemic cardiac disease after recent myocardial infarction, after percutaneous coronary intervention or coronary artery bypass graft, 4% after removal of an infected ICD, 6% whilst awaiting completion of diagnostic tests (chanalopathies/right arrhythmogenic ventricular cardiomyopathy), 24% newly diagnosed cardiomyopathy. The average wearing time of WCD was 22,7±3,1 hours daily. We received these events: 1 sustained ventricular tachicardia, 2 non sustained ventricular tachicardia, 5 atrial fibrillation with 3 T wave oversensing. One patient recedived inappropriate shock. One death was detected due to severe heart failure. After 56,0±37,8 days of average wearing time 52% of patients were scheduled for ICD implantation. Conclusions In our experience we may consider that WCD use is effective, safe and with a good adherence in all patients. The WCD allows saving resources preventing inapprpriate ICD implantation in patient with transient SCD risk.

Arrhythmogenic Left Ventricular Cardiomyopathy: From Diagnosis to Risk Management.

Left ventricular arrhythmogenic cardiomyopathy (ALVC) is a rare and poorly characterized cardiomyopathy that has recently been reclassified in the group of non-dilated left ventricular cardiomyopathies. This review aims to summarize the background, diagnosis, and sudden cardiac death risk in patients presenting this cardiomyopathy. Although there is currently a lack of data on this condition, arrhythmogenic left ventricular dysplasia can be considered a specific disease of the left ventricle (LV). We have collected the latest evidence about the management and the risks associated with this cardiomyopathy. Left ventricular arrhythmogenic cardiomyopathy is still poorly characterized. ALVC is characterized by fibrofatty replacement in the left ventricular myocardium, with variable phenotypic expression. Diagnosis is based on a multiparametric approach, including cardiac magnetic resonance (CMR) and genetic testing, and is important for sudden cardiac death (SCD) risk stratification and management. Recent guidelines have improved the management of left ventricular arrhythmogenic cardiomyopathy. Further studies are necessary to improve knowledge of this cardiomyopathy.

Inflammation on Endomyocardial Biopsy Predicts Risk of MACE in Undefined Left Ventricular Arrhythmogenic Cardiomyopathy

BackgroundPredictors of major adverse cardiovascular events (MACE) in patients with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM) have not been described. ObjectivesThe purpose of this study was to investigate the prognostic value of genetic testing and histology in a cohort of ULVACM patients. MethodsWe identified 313 patients with ULVACM defined by new-onset ventricular arrhythmia (VA), nonischemic pattern of late gadolinium enhancement limited to the left ventricle (LV), and no severe dilated cardiomyopathy (LV ejection fraction ≥40%) from a retrospective multicenter registry. Patients undergoing next generation sequencing (NGS) for cardiomyopathy genes and endomyocardial biopsy (EMB) were compared with subjects without these studies. The primary endpoint was the occurrence of MACE, defined as the composite of cardiac death, heart transplantation, and malignant VA (ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter-defibrillator treatment), at 60 months after clinical presentation. ResultsOf the whole cohort (age 46 ± 14 years, 63% men, LV ejection fraction 55% ± 7%), 160 (51%) and 198 patients (63%), respectively, underwent NGS and EMB. NGS identified pathogenic or likely-pathogenic cardiomyopathy variants (pathogenic variants/likely pathogenic variants) in 25 of 160 cases (16%). EMB showed active myocardial inflammation (AM) in 102 of 198 patients (52%), 47 of whom (46%) received immunosuppressive therapy. After 58-month median follow-up, 93 of 313 patients (30%) experienced MACE. On multivariable analysis, presentation with malignant VA and EMB-proven AM were positively associated with the primary endpoint (HR: 2.8; 95% CI: 1.4-5.5; P = 0.003; and HR: 3.9; 95% CI: 1.9-7.5; P < 0.001, respectively), whereas immunosuppressive therapy showed a reverse association with MACE at 60 months (HR: 0.10; 95% CI: 0.05-0.40; P < 0.001). ConclusionsPresentation with malignant VA or AM associates with MACE in ULVACM patients.

136 A SHOCKING CASE OF MYOCARDITIS?

Abstract Background Cardiac involvement is common in systemic sclerosis (SSc), being a poor prognostic factor and the leading cause of mortality. Cardiac involvement ranges from a serendipitous diagnosis to relevant cardiac manifestations such as arrhythmias, pericardial effusion, myocardial dysfunction, and valvular diseases. Case report A 39-year-old female without remarkable medical history, on estroprogestinic therapy was admitted to our hospital in June 2020 after an out-of-hospital cardiovascular arrest due to ventricular fibrillation (VF). A coronary angiography ruled out coronary artery disease. Magnetic resonance imaging (MRI) showed a picture of acute myopericarditis characterized by late linear and nodular intramyocardial and subepicardial gadolinium enhancement of the septal and inferior segments of the left ventricle, with trivial oedema in the same location in turbo inversion recovery magnitude (TIRM) sequences. A subcutaneous-implantable cardiac defibrillator (S-ICD) was positioned for secondary prevention. At the 5 months ICD interrogation, 3 episodes of VF detected and treated by the device were documented. In December 2020 two more appropriate device interventions on polymorphic VT/VF occurred. A septal myocardial biopsy was then performed showing diffused replacement fibrosis in the absence of signs of acute inflammation or virus on the molecular investigation. In March 2021 the patient was referred to our institution after experiencing several ventricular arrhythmia episodes successfully treated by the ICD. A myocardial positron emission tomography (PET) scan documented the uptake of 18-fluorodeoxyglucose at middle and basal septum. A 'targeted' myocardial biopsy showed a substitutive fibroadiposis with sporadic inflammatory cells, in absence of cardiotropic viruses on the molecular investigation. We then initiated Anakinra, an anti-IL1 agent with an anti-inflammatory effect to prevent further development of "inflammation-driven fibrosis". Given the Raynaud's phenomenon reported by the patient, a capillaroscopy was performed, confirming isolated megacapillaries and apical haemorrhages, compatible with early pattern scleroderma. Immunologic examinations found homogeneous ANA 1:320 and anti-RNA polymerase III, while other autoantibodies, viral serologies and tubercular analysis were negative. In October 2021, the patient was readmitted to our hospital for recurrence of arrhythmic storm. A radiofrequency catheter-based ablation was performed. After a new episode of VT properly treated by the S-ICD in May 2022, the device was explanted, and a cardiac resynchronization therapy defibrillator was implanted. The genetic analysis identified a heterozygous deletion (c1262_1263del) of Lamin A (LMNA) classified as probably pathogenic in left ventricular arrhythmogenic cardiomyopathy or dilated cardiomyopathy. Conclusion A diagnosis of borderline myocarditis in anti-RNA-polymerase III+ systemic sclerosis with heterozygous deletion of LMNA was finally formulated, after having excluded pulmonary (PET, forced vital capacity, and CO lung diffusion in normal range), cutaneous, musculoskeletal and gastro-oesophageal involvement as well as a paraneoplastic nature (by total body PET) given the positivity for antiRNA-polymerase III.

433 A PRO-ARRHYTHMIC DOUBLE HIT

Abstract A 42-year-old man went to the emergency room complaining about dyspnea and palpitations. He reported an episode of atrial fibrillation (AF) with symptoms of dizziness 8 years before. He had a family history of ischemic cardiopathy, his father has suffered from AF since a young age.Acute course: The ECG revealed AF at high ventricular frequency. The echocardiography demonstrated mild reduction of the left ventricular function (EF 45%) with diffuse hypokinesis, and mitral valve prolapse (MVP) with mild mitral regurgitation. The blood tests showed a troponin peak of 750 ng/L (n.v. 0–34 ng/L). The suspect was acute coronary syndrome. Thus, he was treated with dual antiplatet therapy and low doses of beta-blockers, and he underwent coronarography, which demonstrated no significant lesions. So, after a transesophageal echocardiography that excluded thrombosis, and a loading dose of amiodarone, a successful electrical cardioversion was performed. The discharge diagnosis was AF with mild left ventricular disfunction. Three months later: He came back to the emergency room because of suffering some days of progressive epigastric and retrosternal pain radiating to the shoulders. The ECG and the echocardiography were unchanged, the troponin-I values were 79 ng/L-74 ng/L. Therefore, he underwent cardiac magnetic resonance (CMR), which showed normal biventricular dimensions and function (LVEF 64%, LVEDV 80 ml/mq), MVP with mitral annular disjunction (MAD) and curling of the infero-lateral basal wall (Figure A). The native T1, T2 and ECV values were increased, and there was a wide left ventricular subepicardial late gadolinium enhancement (LGE). The conclusion was MVP and active myocarditis. Moreover, he underwent endomyocardial biopsy that revealed focal lymphocytic infiltration, PCRs for common cardiotropic viruses or bacteria were negative. Six months later: The basal ECG was characterized by low QRS voltages in limb leads (Figure B). The CMR revealed a wide left ventricular non-ischemic fibrosis with a ring-like pattern (Figure C). The 24-hours Holter ECG showed premature ventricular beats with a right bundle branch block/superior and inferior axis morphology (Figure D), in keeping with MVP. The next step was the genetic testing that resulted positive for a Filamin-C (FLNC) mutation associated with cardiomyopathy. The final diagnosis was “Hot-phase of Left Ventricular Arrhythmogenic Cardiomyopathy (ACM), MVP and paroxysmal AF”. Discussion: The ACM is a rare hereditary heart muscle disease, and the “hot phase” represents its uncommon clinical presentation. Mutations in FLNC gene could be involved in the pathogenesis of ACM. Moreover, there are few cases in literature about the correlation between FLNC mutations and MVP. FLNC mutation may be a cross-sectional substrate for both these pro-arrhythmic conditions.

Prognostic prediction of genotype versus phenotype in genetic cardiomyopathies

Abstract Background In cardiomyopathies (CMPs), the diverse genetic background often leads to phenotypic heterogeneity. Currently, genotype-phenotype studies are founded on clinical phenotype-based classification of CMPs, contributing possible biases due to the exclusion of specific and unascertained phenotypic expressions of CMP genes. Purpose We sought to define differences in outcome when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of CMP patients with positive genetic testing. Methods In this study, we included the whole spectrum of non-hypertrophic CMP phenotypes, genetically determined: dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular arrhythmogenic cardiomyopathy (ALVC) and biventricular ARVC (BiV). The primary and secondary outcomes were: 1) all-cause mortality/heart transplant (D/HT); 2) heart failure-related death/heart transplant/left ventricular assist device implantation (DHF/HT/VAD); and 3) sudden cardiac death/life-threatening ventricular arrhythmias (SCD/MVA). Results Two hundred and eighty-one patients (80% DCM) carrying pathogenic or likely pathogenic variants were included in this study. The phenotype was classified as DCM, ARVC, ALVC and BiV according to current consensus criteria. The median follow-up was 188 months. Variants in titin (TTN; 34%) and sarcomeric genes (SARC; 22%) were the most frequent genotypes and almost invariably associated with a DCM phenotype. DSP, LMNA and FLNC displayed more heterogeneous phenotypic presentations, including DCM, ARVC, ALVC, BiV. At survival analysis, the arrhythmic outcome occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA and FLNC variants. However, after adjustment for age and sex, the genotype-based classification but not the phenotype-based classification was predictive of the arrhythmic outcome. LMNA showed the worst trend in term of D/HT and DHF/HT/LVAD. Conclusions In genetic cardiomyopathies, genotype is associated with significant phenotypic heterogeneity. Nevertheless, in our study, the genotypic-based classification showed higher precision in predicting CMP patients' outcome in respect to the phenotype-based classification. These findings add to the current understanding of inherited CMPs and may implement the risk stratification of patients with positive genetic testing. Funding Acknowledgement Type of funding sources: None.

Epicardial mapping as first intention approach for structural ventricular tachycardia ablation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction In several structural arrhythmogenic diseases that comprise intricate endocardial, intramural and epicardial substrates, endocardial ablation of ventricular tachycardia (VT) is not sufficient and epicardial ablation has lately become a complementary and necessary tool. Purpose To evaluate the clinical characteristics of patients (pts) most suitable for first intention epicardial VT ablation. Methods Single-center prospective study of consecutive pts with structural heart disease undergoing first intention epicardial VT mapping between August 2015 and June 2021. Decision for epicardial approach was based on the etiology, VT electrocardiogram (ECG) and cardiac magnetic resonance (CMR) results. Under general anesthesia, subxiphoid access using a Tuhoy needle was done using fluoroscopic guidance and with high-density epicardial mapping was performed. Epicardial ablation was performed if relevant arrhythmogenic findings were locally confirmed. Results First intention epicardial VT ablation was attempted in 18 pts (mean age 59.8±12 years,94% male) of whom 16 had non-ischemic dilated cardiomyopathy (NICM,idiopathic:11; post-myocardis:4; hereditary:1) and 2 had right ventricular arrhythmogenic cardiomyopathy. Mean LVEF was 33% and 79% had a previous ICD (53% in primary prevenon). 69% were referred for ablation due to arrhythmic storm (1pt in cardiogenic shock). Epicardial access was achieved in 17 pts (94%), without acute complications. In 35% pts with NICM the decision for epicardial approach was based on the detection of subepicardial CMR delayed-hyperenhancement and relevant epicardial arrhythmic substrate was confirmed by mapping in all cases. In 3 pts radiofrequency (RF) applicaons were not performed at epicardium, as no abnormal electrograms were locally detected, and an addional endocardial approach was prosecuted. The mean overall procedure and fluoroscopic time were 123 and 28min, respectively, with a mean RF application me of 51min. After the procedure 1pt required pericardial drainage due to inflammatory pericardial effusion. No other acute complications occurred. During a mean follow-up of 2.8±1.8 years, only 3pts (17%) had VT recurrence; 5pts (28%) died due to end-stage heart failure and 2pts (11%) underwent heart transplantation. Conclusion In NICM a first intention epicardial VT ablation performed by experienced operators/centers is efficient, particularly if guided by CMR findings,and presents a safety profile.

Prognostic role of myocardial inflammation in patients with undefined left ventricular arrhythmogenic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Etiology identification and risk stratification represent major issues for patients presenting with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM). Purpose To investigate the role of genetics and histology for ULVACM classification, management, and risk assessment. Methods We retrospectively analyzed a multicenter cohort of patients (screened n=1037) with ULVACM defined by ventricular arrhythmia (VA) onset, nonischemic late gadolinium enhancement (LGE) limited to the LV, and no severe dilated cardiomyopathy (LVEF≥40%). We selected patients undergoing both next generation sequencing (NGS) screening and endomyocardial biopsy (EMB) for etiology definition. When feasible, immunosuppressive therapy (IST) was used to target active myocardial inflammation (AMI). The study endpoint was a composite of cardiac death, heart transplantation and malignant VAs (VT, VF, appropriate ICD treatment). Results The study cohort is composed by 135 ULVACM patients (age 43±14 years, 63% males, LVEF 55±7 %). NGS identified pathogenic or likely-pathogenic variants (PVs/LPVs) consistent with ACM in 21 cases (16%), whereas EMB showed AMI in 78 patients (58%), including 13/21 PVs/LPVs+ (62%). After reclassification of 86 patients (64%), only 49 (36%) remained ULVACM. IST was started in 41/78 AMI patients (53%), including 9/13 PVs/LPVs+ (69%). Twenty patients (15%) met the study endpoint by 12 months, and 36 (27%) by the end of the study (60±27 months). Beyond malignant VT onset, AMI was the only predictor of events by 12 months (HR 5.0, 95%CI 1.4-18.1, p=0.007). No prognostic role was found for PVs/LPVs, except for the subgroup (n=77) with nonsustained VT onset. Among AMI patients, those treated by IST had a significantly lower occurrence of events, both by 12-months (1/41 vs. 16/37, p&amp;lt;0.001) and later (HR 0.05, 95%CI 0.01-0.21, p&amp;lt;0.001). Results were independently confirmed in PVs/LPVs+ and PVs/LPVs- cases. Excluding the IST population, the association of multiple factors among VT onset, PVs/LPVs, and AMI, resulted in an improved discrimination of arrhythmic risk profiles. Conclusion The combined genetic and histological workup allowed reclassification of up to 64% ULVACM patients, and substantially contributed into prognostic assessment. Furthermore, EMB identified suitable candidates for IST, who showed better outcomes irrespectively of their genotype.

P24 WEAREBLE CARDIOVERTER – DEFIBRILLATOR : UTILITY AND USER FRIENDLINESS

Abstract Background Worldwide, cardiovascular disease are still a major mode of death, being sudden arrhythmic death (SCD)25 % of total death. Implantable cardioverter defibrillator (ICD) is an effective weapon for SCD prevention in high risk patients with reasonable expectation of survival with good functional status for &amp;gt;1 year. However sometimes the risk of SCD can be transient, so the use of a wearable cardioverter defibrillator (WCD) is considered. Methods We considered consecutively 40 patients discharged from our cardiology department of Piacenza and Castel san Giovanni that, for potentially transient high risk of SCD, weared a WCD from August 2017 to September 2021, after a systematic education session lasting 30 – 45 minutes. They are followed through remote monitoring. Results Out of 40 patients, with average age 66 years old and average left ventricular ejection fraction (LVEF) 29%, 88% were males, 70 % suffered from arterial hypertension, 32% diabetes mellitus, 17,5 % peripheral vascular disease, 35 % chronic renal failure, 55% heart failure, 7,5% previous stroke. 56% of these patients weared WCD for severe systolic disfunction in ischemic cardiac disease after recent myocardial infarction, after percutaneous coronary intervention or coronary artery bypass graft, 7% after removal of an infected ICD, 9 % whilst awaiting completion of diagnostic tests (chanalopathies/right arrhythmogenic ventricular cardiomyopathy), 34% after newly diagnosed cardiomyopathy.The patients were discharged in high risk mode of SCD with WCD protection.The average wearing time of WCD was 51 days and 22,98 hours daily. We received 953 trasmissions, with 21 events: 7 ventricular tachicardia, 4 Sopraventricular tachicardia and 5 T wave oversensing .Neither inappropriate shock and neither death were detected .After wearing time and after clinical evaluation, only 52% of patients were subjected to ICD implantation. Conclusions In our experience we may consider that WCD use is effective, safe and with a good adherence in all patients, considering wearing time. The WCD allows saving resources with less hospitalization time.

P320 LEFT DOMINANT ARRHYTHMOGENIC CARDIOMYOPATHY: HOW TO STRATIFY THE ARRHYTHMIC RISK? EARLY ONSET CLINICAL CASE

Abstract Introduction Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by the progressive replacement of myocardiocytes by fibroadipose tissue that becomes a susbstrate for ventricular arrhythmias with risk of sudden cardiac death. Arrhythmogenic cardiomyopathy can manifest itself through three different phenotypes: the classic phenotype, the most frequent, involving only the right ventricle, the biventricular variant with possible right or left dominance and the rare variant involving only the left ventricle. We present a case of left ventricular arrhythmogenic cardiomyopathy. Case Report 16–year–old male patient in complete physical well–being, with no significant medical history and a negative family history of heart disease and/or sudden cardiac death (Fig. 1). He practiced competitive sports for years with periodic medical–sports visits. In 2017, ventricular extrasystole was detected on the electrocardiogram, for which he performed cardiological investigations. On electrocardiogram: sinus rhythm with QRS fragmented into DIII and aVL and negative T waves from V4 to V6 (Fig. 2). On transthoracic echocardiography, evidence of normal cavity dimensions, ejection fraction at lower normal limits (42%) and left ventricular trabeculation, in the absence of significant valvulopathy. He then performed a cardiac MRI that showed: left ventricle moderately dilated and hypokinetic with widespread alterations of myocardial signal secondary to fibroadipose replacement phenomena, configuring a picture of left ventricular dilation and dysfunction referable to arrhythmogenic left ventricular cardiomyopathy (Fig. 3). The patient was also subjected to genetic analysis aimed at searching for mutations of genes involved in arrhythmic heart disease, which was negative. In light of the absence of conclusive scientific evidence on the implantation of a defribrillator in primary prevention in clinical–instrumental cases such as the present, the risk of infection and the risk of inappropriate discharges, it was proposed the implantation of a loop–recorder in order to monitor and record any arrhythmic events, starting beta–blocker therapy. The possibility of continuing competitive physical activity was therefore denied. Conclusions Currently, guidelines on ACM and diagnostic criteria focus mainly on the right variant, so there are no clear indications to stratify arrhythmic risk in left ventricular ACM.

118 Undefined left ventricular arrhythmogenic cardiomyopathy: the value of genotyping and histological characterization

Abstract Aims Etiology identification and risk stratification represent major issues for patients presenting with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM). To investigate the role of genotyping and histology for ULVACM classification, management, and risk assessment. Methods and results We retrospectively analysed a multicentre cohort of patients (screened n = 1037) with ULVACM defined by ventricular arrhythmia (VA) onset, nonischaemic late gadolinium enhancement (LGE) limited to the LV, and no manifest dilated cardiomyopathy (LVEF ≥ 40%). We selected patients undergoing both next generation sequencing (NGS) genotyping and endomyocardial biopsy (EMB) for etiology definition. When feasible, immunosuppressive therapy (IST) was used to target active myocardial inflammation (AMI). The study endpoint was a composite of cardiac death, heart transplantation and malignant VAs (VT, VF, appropriate ICD treatment). The study cohort is composed by 135 ULVACM patients (age 43 ± 14 years, 63% males, LVEF 55 ± 7%). NGS identified pathogenic or likely-pathogenic variants (PVs/LPVs) consistent with ACM in 21 cases (16%), whereas EMB showed AMI in 78 patients (58%), including 13/21 PVs/LPVs + (62%). IST was started in 41/78 AMI patients (53%), including 9/13 PVs/LPVs + (69%). Twenty patients (15%) met the study endpoint by 12 months, and 36 (27%) by the end of the study (60 ± 27 months). Beyond malignant VT onset, AMI was the only predictor of events by 12 months (HR: 5.0, 95% CI: 1.4–18.1, P = 0.007). No prognostic role was found for PVs/LPVs, except for the subgroup (n = 77) with nonsustained VT onset. Among AMI patients, those treated by IST had a significantly lower occurrence of events, both by 12-months (1/41 vs. 16/37, P &amp;lt; 0.001) and later (HR: 0.05, 95% CI: 0.01–0.21, P &amp;lt; 0.001). Results were independently confirmed in PVs/LPVs+ and PVs/LPVs- cases. Excluding the IST population, the association of multiple factors among VT onset, PVs/LPVs, and AMI, resulted in an improved discrimination of arrhythmic risk profiles. Conclusions Despite its limited diagnostic yield, the combined genetic and histological workup substantially contributed into ULVACM prognostic assessment. Furthermore, EMB identified suitable candidates for IST, who showed better outcomes irrespectively of their genotype.

Investigating the Accuracy of Quantitative Echocardiographic-Modified Task Force Criteria for Arrhythmogenic Ventricular Cardiomyopathy in Adolescent Male Elite Athletes

Athlete preparticipation screening focuses on preventing sudden cardiac death (SCD) by detecting diseases such as arrhythmogenic ventricular cardiomyopathy (AVC), which affects primarily the right ventricular myocardium. Diagnosis may be obscured by physiological remodeling of the athlete heart. Healthy athletes may meet the 2010 Task Force Criteria right ventricular outflow tract (RVOT) dimension cut-offs, questioning the suitability of the modified Task Force Criteria (mTFC) in adolescent athletes. In this study, 67 male adolescent footballers undergoing preparticipation screening were reviewed. All athletes underwent a screening for resting ECG and echocardiogram according to the English FA protocol, as well as cardiopulmonary exercise testing, stress ECG, and exercise echocardiography. Athletes’ right ventricular outflow tract (RVOT) that met the major AVC diagnostic criteria for dilatation were identified. Of 67 evaluated athletes, 7 had RVOT dilatation that met the major criteria, all in the long axis parasternal view measurement. All had normal right ventricular systolic function, including normal free-wall longitudinal strain (ranging from − 21.5 to − 32.7%). Left ventricular ejection fraction ranged from 52 to 67%, without evidence of structural changes. Resting ECGs and cardiopulmonary exercise tests were normal in all individuals. In a series of healthy athletes meeting the major AVC diagnostic criteria for RVOT dilatation, none had any other pathological changes on a detailed screening including ECG, exercise testing, and echocardiography. This report highlights that current AVC echocardiographic diagnosis criteria have limitations in this population.

Arrhythmic risk stratification in patients with clinically-suspected left ventricular arrhythmogenic cardiomyopathy

Abstract Background Arrhythmic risk of patients with left ventricular arrhythmogenic cardiomyopathy (LVAC) is unpredictable. Purpose To identify risk facors associated with major ventricular tachyarrhythmias (VTA) in clinically-suspected LVAC patients. Methods We enrolled 127 consecutive patients (69% males, age 46±13 y, LVEF 54±7%) with clinically-suspected LVAC. All patients presented with either major (VT, VF) or minor VTA (NSVT, frequent VEB), and underwent extensive diagnostic workup to rule-out alternative diagnoses. Medical treatment and ICD implant were clinically-driven. Prospective follow-up was obtained via sequential 24h-Holter ECG (2–4/y) with or without continuous arrhythmia monitoring (ICD or implantable loop recorders, ILR). The primary endpoint was occurrence of major VTA (VT/VF/ICD therapy) by 24-month follow-up. Results At presentation, 56 (44%) and 71 patients (56%) had, respectively, major and minor VTA. Variants in desmosomal genes were identified in 7 of the 9 patients with clinically-indicated genetic test. Delayed gadolinium enhancement (DGE, average 23±12% of the LV mass) had anteroseptal distribution in 43 cases (34%). Monitoring strategy included ICD (n=64), ILR (n=33), or sequential Holer ECGs (n=30). By 24-month follow-up, major VTA occurred in 32 patients (25%). At univariable anlysis, major VTA onset (HR 16.8, 95% CI 5.4–52.2, p&amp;lt;0.001) and anteroseptal DGE (HR 3.0, 95% CI 1.3–6.9, p=0.010) were significantly associated with major VTA by 24-month follow-up. Among patients presenting with minor VTA, the only factor significantly associated with the primary endpoint was anteroseptal DGE (3/4 vs. 14/67, p=0.004). Conclusion Our preliminary experience suggests that, in patients with clinically-suspected LVAC, major VTA onset and anteroseptal DGE are relevant risk factors for major arrhythmic events by 24-month follow-up. Funding Acknowledgement Type of funding sources: None.

The Emerging Role of Epigenetics in Therapeutic Targeting of Cardiomyopathies.

Cardiomyopathies (CMPs) are a heterogeneous group of myocardial diseases accountable for the majority of cases of heart failure (HF) and/or sudden cardiac death (SCD) worldwide. With the recent advances in genomics, the original classification of CMPs on the basis of morphological and functional criteria (dilated (DCM), hypertrophic (HCM), restrictive (RCM), and arrhythmogenic ventricular cardiomyopathy (AVC)) was further refined into genetic (inherited or familial) and acquired (non-inherited or secondary) forms. Despite substantial progress in the identification of novel CMP-associated genetic variations, as well as improved clinical recognition diagnoses, the functional consequences of these mutations and the exact details of the signaling pathways leading to hypertrophy, dilation, and/or contractile impairment remain elusive. To date, global research has mainly focused on the genetic factors underlying CMP pathogenesis. However, growing evidence shows that alterations in molecular mediators associated with the diagnosis of CMPs are not always correlated with genetic mutations, suggesting that additional mechanisms, such as epigenetics, may play a role in the onset or progression of CMPs. This review summarizes published findings of inherited CMPs with a specific focus on the potential role of epigenetic mechanisms in regulating these cardiac disorders.

Diagnosing arrhythmogenic ventricular cardiomyopathy: a re-appraisal of the role and normal range of the signal-averaged ECG

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The 2010 Task Force Criteria (TFC) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (A(R)VC) in 1st degree relatives includes an abnormality in a single parameter of the signal averaged ECG (SAECG). SAECG normal ranges were derived predominately from ischaemic heart disease patients, so may not be applicable in an A(R)VC population. There remain concerns that the SAECG is not specific enough and its role in the diagnosis of A(R)VC is under scrutiny. Purpose to improve the diagnostic utility of the SAECG Methods Patients with an A(R)VC diagnosis and 1st degree family members (FM) under follow-up at a single inherited cardiac conditions (ICC) centre were included. All cases were independently reviewed by 3 cardiologists experienced in the diagnosis and management of A(R)VC. All SAECGs included were free from artefact. TFC clinical variables and genetic status were recorded for each patient. Where tests had been repeated the most recent values were used. Because of concerns about the use of a single abnormal SAECG parameter in making a clinical diagnosis we required ≥2 abnormal SAECG parameters, or a confirmed genetic mutation to make a diagnosis. A diagnosis of false positive SAECG was made with ≥2 abnormalities when the individual was known not to carry the familial pathogenic mutation. Results A study population of 160 patients (male 103 (64%), age 46yrs (range 18-85yrs); 41 pro-bands and 119 FM. 62(52%) FM had a clinical diagnosis of AVC, with ARVC the pre-dominant phenotype 51(82%). A pathogenic genetic variant was identified in 24(47%) of FM with ARVC. The SAECG data is presented graphically for each parameter. A clinical diagnosis of ARVC was made on the basis of an affected 1st degree FM and an abnormal SAECG in 24(47%) of FM. Of these, 16(67%) had three abnormal SAECG parameters, 6(25%) two and 2(8%) a single abnormal parameter. Both patients with only one abnormal SAECG parameter carry a pathogenic variant. In total 88% of FM with ARVC, and 32% of FM without AVC had an abnormal SAECG as per current TFC. False positive values were mainly in fQRS duration (17/18), but also LAS40 (5/18), and RMS40 (2/18). By redefining an abnormal fQRS duration to be ≥118ms, false positives are reduced from 17 to 4. In addition, if there is a requirement for a 2nd abnormality then the false positives are reduced to 2 (4%). By adjusting the diagnostic criteria to fQRS duration ≥118ms, with a 2nd abnormal parameter or known pathogenic gene carrier status none of the 24 FM with a clinical diagnosis on abnormal SAECG alone would change diagnostic classification. Conclusion The SAECG is useful in family screening as it is frequently the only test to show an abnormality. However, the current TFC reference values lack specificity. By redefining an abnormal fQRS as ≥118ms with the requirement of a 2nd abnormal parameter, specificity is increased to 96%, with no significant change in sensitivity. Abstract Figure. SAECG Parameters in Family Members

Genetic Overlap of Acute Myocarditis and Inherited Cardiomyopathy

Background: Acute myocarditis is a complex inflammatory disease increasingly associated with dilated cardiomyopathy (DCM) and arrhythmogenic ventricular cardiomyopathy (ACM), but its underlying genetic basis is unknown. We sought to determine if there is a genetic overlap between myocarditis and inherited forms of cardiomyopathy. Methods: Population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA-sequencing for well-characterised cardiomyopathy-associated genes with comparison to healthy controls (n=1053). Case ascertainment was assessed against national admission data. Findings: Variants of known or likely pathogenicity were identified in 6% of cases compared to <1% of controls (∆+5%; p=0.0097). In London (n=230; median age 33years; 84% men), which was representative of national myocarditis admissions (median age 32years; 71% men; 66% case ascertainment), 4.8% of cases carried rare truncating variants (tv), particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin ( DSP )-tv in patients with normal LVEF and ventricular arrhythmia. In Maastricht (n=106; median age 54years; 61% men), there was enrichment of rare tv in DCM genes, particularly TTN -tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). DCM variants occurred in patients with LV dysfunction (median LVEF 39% vs 60%; p<0.0001). During a median follow-up of 1.9years, all-cause mortality was greatest with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004). Interpretation: One in 20 myocarditis cases had a DCM- or ACM-associated genetic variant that would potentially inform clinical management and need for family screening. This was dominated by DSP -tv in those with normal LVEF, and TTN -tv in those with reduced LVEF. Routine genetic testing may be beneficial in acute myocarditis. Funding: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital, Imperial College London, Wellcome Trust, Medical Research Council and Rosetrees Trust. Declaration of Interest: SKP has received honoraria from Bayer Schering and travel support from Circle 42, outside the submitted work. JSW has received personal fees from Myokardia, outside the submitted work. JSW also has a patent (US 62383189—Methods, systems and apparatus for identifying pathogenic gene variants) issued. DJP has received research support from Siemens and Bayer, and personal fees from Bayer and Chiesi, outside the submitted work. All other authors declare no competing interests. Ethical Approval: All participants in cohorts 1, 2 and 3 provided written informed consent as approved by the 23 National Research Ethics Service [references 09/H0504/104+5 and 09/H0707/69] or Medical Ethical Committee of Maastricht University.

Abstract 14797: Pediatric Arrhythmogenic Ventricular Cardiomyopathy Often Misclassified in End Stage Heart Failure Patients - A 30 Year Tertiary Care Center Experience

Introduction and Background: Arrhythmogenic ventricular cardiomyopathy (AVC) is a hereditable disorder characterized by fibro-fatty infiltration of the right ventricular myocardial wall. The purpose of this study was to describe the clinicopathologic phenotype of AVC in pediatric end-stage heart failure patients who underwent heart transplantation (HTx). Hypothesis: We hypothesized that AVC is misclassified in the young population who require heart transplant. Methods: We investigated 371 consecutive cases of primary pediatric (≤21 years) heart transplantation performed at Texas Children’s hospital between 1989 and 2018. Heart re-transplants were excluded from the study. Explanted hearts and tissue blocks were examined by a cardiac pathologist after HTx. Histological Diagnosis of AVC was based on the presence of major and minor diagnostic criteria according to the 2010 Revised Task Force Criteria. Results: Over half of the patients who underwent HTx had cardiomyopathy (212/371=57%) as the underlying primary diagnosis. After comprehensive histological evaluation of explanted hearts, 8 cases (8/212=3.8%) were diagnosed with AVC. Predominantly right ventricular disease was seen in 2/8 (25%), and biventricular involvement in 6/8 (75%) patients on pathological examination. Six out of 8 patients (6/8=75%) were misclassified, 4 as dilated cardiomyopathy, 1 as viral myocarditis, and 1 as restrictive cardiomyopathy. The median age at heart transplant (AVC cohort) was 11 years. Four of 8 (50%) were males. Six of 8 (75%) had a significant ventricular arrhythmia burden manifesting as non-sustained ventricular tachycardia requiring antiarrhythmic therapy. Genetic testing was undertaken in 3 of 8 (37.5%); all three were found to have pathogenic mutations in the PKP2 gene. Conclusion: Arrhythmogenic ventricular cardiomyopathy is often misclassified in the young population who require heart transplant. Pediatric dilated and restrictive cardiomyopathy phenotypes with end-stage heart failure waitlisted for a heart transplant (HT) who have a significant ventricular arrhythmia burden should be investigated for AVC.

Efficacy of epicardial and endocardial ablation in the prevention of ventricular tachycardia in arrythmogenic right ventricular cardiomyopathy- a meta analysis

Abstract Introduction Ventricular tachycardia is a major complication associated with increased risk of sudden cardiac death in arrhythmogenic ventricular cardiomyopathy. Recurrence of VT status post catheter endocardial ablation with conventional mapping is a evolving discussion in management of VT prevention in ARVC. With the evolution of new mapping techniques to locate ectopic foci of VT, a combination of endo- and epicardial catheter ablation have proven to be efficacious in the prevention of frequency of VT recurrence and its duration. Methods Using PubMed, Ovid (MEDLINE) and Cochrane database we searched using the MeSH terms including: “arrhythmogenic right ventricular cardiomyopathy”, “arrhythmogenic right ventricular dysplasia”, “monomorphic ventricular tachycardia”, “polymorphic ventricular Tachycardia”, “endocardial catheter ablation”, “epicardial catheter ablation”. The primary outcomes were to assess VT frequency and duration status post endocardial or epicardial or a combination of both types of ablation. The secondary outcome includes sudden cardiac arrest or sudden cardiac death after procedure. ANOVA with post HOC analysis was performed using SPSS v.26 (IBM Corp, NY, USA) Results A total of 33 studies included 1437 patients with a mean male=67%. The data analysis showed a mean VT prevention for endocardial ablation was 65%, epicardial 78%, and for combined epi-endocardial was 89% (figure-1). The mean procedural mortality rate was 2%. In order to test the hypothesis that combined epi-endocardial ablation was more successful in the prevention of VT recurrence, we performed a one-way analysis of variance (ANOVA). The analysis was statistically significant F(2,14)=5.879, 95% CI, p=0.014. Post Hoc test (Tukey HSD test) with multiple comparisons indicated that patients who underwent combined epi-endocardial ablation experienced a statistically significant difference in VT prevention of 89% (95% CI p=0.01) compared to only endocardial ablation, mean VT prevention of 65% (95% CI, p=0.189) or only epicardial, mean VT prevention of 78% (95% CI, p=0.353). Conclusion With new mapping techniques, use of endocardial, and epicardial ablation is linked to decrease VT frequency, duration, ICD shocks, and sudden cardiac death in patients with ARVC in cohorts with prior failure of antiarrhythmics. Total VT Prevention across target sites Funding Acknowledgement Type of funding source: None

Autoptic findings of sudden cardiac death (SCD) in patients with arrhythmogenic ventricular cardiomiopathy (AVC) from left ventricle and biventricular involvement

ObjectivesTo evaluate autoptic histopathological findings of arrhythmogenic ventricular cardiomyopathy (AVC) as major cause of sudden cardiac death (SCD) in young adults. BackgroundAccording to Heart Rhythm Society (HRS)’s international consensus, histological criteria for AVC diagnosis include a progressive myocardial atrophy of the right ventricle characterized by a transmural fatty or fibrofatty replacement in a segmental or diffuse pattern (residual myocytes <60 % vs 60–75 % by morphometric analysis) explaining the electrical instability with increased risk of SCD. However, there is increasing evidence for atypical patterns of localizations and percentage of fibrofatty replacement suggesting the need to update histopathological features of AVC. MethodsHistology examination of ventricles, atria, and septum was performed on 10 autopsy of SCD due to AVC. Staining with hematoxylin-eosin and PicroSirius Red/Fast Green were performed on the heart samples to identify specific fibrofatty patterns. ResultsOur analysis showed that: 1) myocardial replacement by a diffuse segmental fatty or fibro-fatty tissue characterized right and left ventricles as well as atrial walls; 2) the degree of fibrofatty tissue replacement was less than 40 % both in left ventricle (n = 4, 40 %) and biventricular (n = 6, 60 %) localization; 3) perivascular fibrosis, inflammatory infiltrate, areas of hypertrophy and/or areas of coagulative necrosis as signs of hypoxic damage in the first stage. ConclusionsWe confirmed prior evidence for fibrofatty replacement both in biventricular and septal localizations. Importantly, we observed a less degree (<40 %) of fibrofatty replacement as compared to current guidelines. This supports the need to further explore the histological patterns of fibrofatty infiltration in a larger study population to improve the histological diagnostic criteria of AVC.

Diagnosis, family screening, and treatment of inherited arrhythmogenic diseases in Europe: results of the European Heart Rhythm Association Survey.

The spectrum of inherited arrhythmogenic diseases (IADs) includes disorders without overt structural abnormalities (i.e. primary inherited arrhythmia syndromes) and structural heart diseases (i.e. arrhythmogenic ventricular cardiomyopathy, hypertrophic cardiomyopathy). The aim of this European Heart Rhythm Association (EHRA) survey was to evaluate current clinical practice and adherence to 2015 European Society of Cardiology Guidelines regarding the management of patients with IADs. A 24-item centre-based online questionnaire was presented to the EHRA Research Network Centres and the European Cardiac Arrhythmia Genetics Focus Group members. There were 46 responses from 20 different countries. The survey revealed that 37% of centres did not have any dedicated unit focusing on patients with IADs. Provocative drug challenges were widely used to rule-out Brugada syndrome (BrS) (91% of centres), while they were used in a minority of centres during the diagnostic assessment of long-QT syndrome (11%), early repolarization syndrome (12%), or catecholaminergic polymorphic ventricular tachycardia (18%). While all centres advised family clinical screening with electrocardiograms for all first-degree family members of patients with IADs, genetic testing was advised in family members of probands with positive genetic testing by 33% of centres. Sudden cardiac death risk stratification was straightforward and in line with current guidelines for hypertrophic cardiomyopathy, while it was controversial for other diseases (i.e. BrS). Finally, indications for ventricular mapping and ablation procedures in BrS were variable and not in agreement with current guidelines in up to 54% of centres.