Arrhythmogenic Left Ventricular Cardiomyopathy Research Articles

Epicardial catheter ablation of ventricular tachycardia in patients of acm - from a university hospital report in switzerland

Abstract Background Arrhythmogenic left ventricular cardiomyopathy (ALVC) as a subtype of arrhythmogenic cardiomyopathy (ACM) is increasingly being recognized. Cardiac magnetic resonance (CMR) has emerged as the primary imaging modality for the diagnosis of ACM. In patients with right-dominant ACM (ARVC) and recurrent sustained ventricular tachycardia (VT), endocardial +/-epicardial ablation yields good clinical outcomes in the long-term. However, studies on VT ablation in ACM with LV involvement are scarce. Purpose We sought to investigate clinical outcomes of VT ablation in ACM patients with LV involvement. Methods The study included patients from the Zurich ACM Registry who met 2020 "Padua Criteria" for ACM and underwent VT ablation between January 2018 and July 2023. Epicardial ablation was performed in patients with recurrent sustained VT despite endocardial ablation, those lacking and endocardial substrate or if the ECG of the VT / substrate on CMR was suggestive of an epicardial origin. Catheter ablation was guided by activation/entrainment mapping for mappable VT, and pace mapping/voltage mapping during sinus rhythm for unmappable VT. Consecutive follow-up of all patients was performed according to our protocol. Results Twenty-one ACM patients underwent n=24 VT ablation procedures. Of those 20 patients, 6 patients (30%) had LV involvement on CMR. Eight (33%) patients underwent epicardial +/- endocardial ablation. Among patients receiving epicardial ablation, 3 patients (38%) had LV involvement. These three underwent a single ablation procedure, which was epicardial only. Total follow-up was 30 months (range 4-43). Three-month sustained VT/VF recurrence rates were 12% in the ACM group with LV involvement vs 25% in ACM without LV involvement. All patients with sustained VT/VF recurrence underwent repeat ablation via an epicardial approach within 3 months and were free of sustained VT/VF thereafter during a median follow-up of 12 months. One-year recurrence rate did not differ between ACM patients with LV involvement vs. without LV involvement (7.7% vs 8.3%, P＝0.117). Seven out of eight epicardial ablations achieved freedom from VT/VF after one-year follow-up. One ARVC patient with previous endocardial ablation had recurrent VT one month after epicardial ablation, which was free of VT after Flecainide combined with beta-blocker. No significant differences were found in the use of beta-blockers and antiarrhythmic drugs between both groups (ACM with LV involvement vs. without LV involvement) at baseline and during one-year follow-up. Conclusions Single or adjuvant epicardial substrate ablation of VT in arrhythmogenic cardiomyopathy is promising in terms of postprocedural VT free survival, especially in patients with left ventricular involvement demonstrated by CMR.Figure 1Figure 2

Ser194Leu DSG2 mutation, associated with arrhythmogenic left ventricular cardiomyopathy and ventricular tachycardia.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members. Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample. Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample. Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy.

Influence of left ventricular ejection fraction, type of mutation and sex on malignant ventricular arrhythmias in dsp and flnc mutations

Abstract Introduction Pathogenic mutations in FLNC and DSP are a common cause of arrhythmogenic left ventricular cardiomyopathy and "arrhythmic dilated cardiomyopathy". We aimed to study demographic and clinical differences amongst these carriers. Purpose 1. To study the prevalence of malignant ventricular arrhythmias in DSP and FLNC mutation carriers in the studies and reports published in the literature. 2. To analyse the effect of age, left ventricular ejection fraction (LVEF), and sex on ventricular arrhythmias in both groups. Methods A systematic review of the human studies published in Medline and EMBASE until September 2022 was carried out. "Desmoplakin Mutations", "Filamin Mutations", "Arrhythmogenic Cardiomyopathy" and "Dilated Cardiomyopathy" were the keywords included in the search queries. Studies, family reports, and registries reporting on individual data of pathogenic or likely pathogenic mutation carriers were selected for analysis. Results Twenty-four articles published between 2002 and 2020 were selected from a total of 430 entries. 171 DSP carriers (from 16 studies) and 169 FLNC carriers (from 7 studies) were included in the analysis. Mean age was similar in both groups: 39.45±19.23 years in DSP vs 42.02±16.27 in the FLNC group (p:0.201). The proportion of females was higher among DSP carriers than that found among FLNC carriers: 101 (59%) vs 76 (45%), p: 0.012. Non-missense mutations were more frequent in both groups: 98 DSP carriers (57%) and 157 FLNC carriers (97%). LVEF was slightly more depressed amongst FLNC carriers: 47.75±14.94% vs 52.37±14.64%, p:0.014. A total of 81 major arrhythmic events (sudden death, ventricular fibrillation, sustained ventricular tachycardia were reported. The LVEF of the male patients that had suffered a major event was similar in both groups (39.13±18.20% in DSP vs 39.03±12.24% in FLNC, p:0.987). On the contrary, LVEF was significantly lower in female carriers of DSP mutations (32.33±15.65% in DSP vs 47.60±15.88% in FLNC, p:0.050). Male carriers show a worse prognosis than their female counterparts (log-rank 0.005) (Figure). The difference was not significant after adjusting for LVEF and type of mutation (missense vs non-missense). LVEF (HR 0.94 per percentage unit (0.91-0.96), p <0.001) and non-missense mutations (HR 0.21 (0.07-0.66), p:0.008) were inversely associated with adverse outcomes in DSP carriers in a multivariate analysis. LVEF was also associated with a better outcome in FLNC carriers (HR 0.97 (0.95-0.99), p: 0.019. Conclusion Moderate systolic dysfunction is a risk factor for malignant arrhythmias amongst DSP and FLNC mutation carriers. Female FLNC carriers with mild systolic dysfunction are at risk for sustained ventricular arrhythmias. Missense DSP mutations are associated with poor arrhythmic prognosis.Sex differences in survival

Abstract 15689: Ablation for Atrial Fibrillation in Patients With Rare Pathogenic Variants in Cardiomyopathy and Arrhythmia Genes

Introduction: Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF), with or without overt ventricular involvement. The efficacy of AF ablation in these patients is unknown. Research Questions/Hypothesis: To test the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have a higher risk of recurrence following AF ablation, and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM [ALVC], arrhythmogenic right ventricular CM [ARVC], dilated CM [DCM], hypertrophic CM [HCM], or a channelopathy) have a higher risk of recurrence. Methods: We performed a prospective observational cohort study in participants referred for AF catheter ablation who underwent whole exome sequencing. Our primary outcome was AF recurrence, defined as >30 seconds of AF, atrial flutter, or atrial tachycardia that occurred at least 90 days after AF ablation. Results: Among 1,366 participants, 109 (8.0%) had a pathogenic or likely-pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15 (0.84-1.60), p=0.53, Figure 1A ). When analyzed according to gene group, P/LP variants in the ALVC gene group, predominantly LMNA , were associated with increased recurrence (N=10; HR 3.75 (1.84-7.63), p<0.001), compared to those in the ARVC gene group (N=6; HR 1.97 (0.62-6.27), p=0.25), DCM gene group (N=50; HR 0.98 (0.59-1.63), p=0.94), HCM gene group (N=33; HR 1.28 (0.76-2.17), p=0.35), and channelopathy gene group (N=17; HR 0.58 (0.21-1.56), p=0.28), as shown in Figure 1B, 1C . Conclusions: Our results support the continued use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including TTN . However, patients with ALVC variants, such as in LMNA , may be at a significantly higher risk for arrhythmia recurrence.

Arrhythmogenic left ventricular cardiomyopathy caused by a novel likely pathogenic DSP mutation, p.K1165Rfs*8, in a family with sudden cardiac death

ObjectiveWe conducted an investigation into the clinical and molecular characteristics of Arrhythmogenic left ventricular cardiomyopathy (ALVC) caused by a novel likely pathogenic mutation in an Iranian pedigree with sudden cardiac death (SCD).BackgroundALVC is a genetically inherited myocardial disease characterized by the substitution of fibro-fatty tissue in the left ventricular myocardium, predominantly inherited in an autosomal dominant pattern and is commonly associated with genes involved in encoding desmosomal proteins, specifically Desmoplakin (DSP).MethodsThe patient and available family members underwent a comprehensive clinical assessment, including Cardiac magnetic resonance (CMR) imaging, along with Whole-exome sequencing (WES). The identified variant was confirmed and segregated by Polymerase chain reaction (PCR) and Sanger sequencing in the family members.ResultsA novel likely pathogenic heterozygous variant, DSP (NM_004415.4), c.3492_3498del, p.K1165Rfs*8 was discovered in the proband. This variant is likely to be the primary reason for ALVC in this specific family. This variant was confirmed by Sanger sequencing and segregated in other affected members of the family.ConclusionWe identified a novel likely pathogenic variant in the DSP gene, which has been identified as the cause of ALVC in an Iranian family. Our investigation underscores the importance of genetic testing, specifically WES, for individuals suspected of ALVC and have a family history of SCD.

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 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.

The Diagnostic Value of the 12-Lead ECG in Arrhythmogenic Left Ventricular Cardiomyopathy: Novel ECG Signs

BackgroundElectrocardiographic (ECG) findings in arrhythmogenic left ventricular cardiomyopathy (ALVC) are limited to small case series. ObjectivesThis study aimed to analyze the ECG characteristics of ALVC patients and to correlate ECG with cardiac magnetic resonance and genotype data. MethodsWe reviewed data of 54 consecutive ALVC patients (32 men, age 39 ± 15 years) and compared them with 84 healthy controls with normal cardiac magnetic resonance. ResultsT-wave inversion was often noted (57.4%), particularly in the inferior and lateral leads. Low QRS voltages in limb leads were observed in 22.2% of patients. The following novel ECG findings were identified: left posterior fascicular block (LPFB) (20.4%), pathological Q waves (33.3%), and a prominent R-wave in V1 with a R/S ratio ≥0.5 (24.1%). The QRS voltages were lower in ALVC compared with controls, particularly in lead I and II. At receiver-operating characteristic analysis, the sum of the R-wave in I to II ≤8 mm (AUC: 0.909; P < 0.0001) and S-wave in V1 plus R-wave in V6 ≤12 mm (AUC: 0.784; P < 0.0001) effectively discriminated ALVC patients from controls. It is noteworthy that 4 of the 8 patients with an apparently normal ECG were recognized by these new signs. Transmural late gadolinium enhancement was associated to LPFB, a R/S ratio ≥0.5 in V1, and inferolateral T-wave inversion, and a ringlike pattern correlated to fragmented QRS, SV1+RV6 ≤12 mm, low QRS voltage, and desmoplakin alterations. ConclusionsPathological Q waves, LPFB, and a prominent R-wave in V1 were common ECG signs in ALVC. An R-wave sum in I to II ≤8 mm and SV1+RV6 ≤12 mm were specific findings for ALVC phenotypes compared with controls.

Genetic Risk Stratification in Arrhythmogenic Left Ventricular Cardiomyopathy.

Arrhythmogenic left ventricular cardiomyopathy is characterized by early malignant ventricular arrhythmia associated with varying degrees and times of onset of left ventricular dysfunction. Variants in numerous genes have been associated with this phenotype. Here, the authors review the literature on recent cohort studies of patients with variants in desmoplakin, lamin A/C, filamin-C, phospholamban, RBM20, TMEM43, and selected channelopathy genes also associated with structural disease. Unlike traditional sudden cardiac death risk assessment in nonischemic cardiomyopathy, left ventricular systolic function is an insensitive predictor of risk in patients with these genetic diagnoses.

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

BackgroundHomozygous 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 presentationHere 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.ConclusionThese observations pinpoint to a significant functional role of the extreme C-terminal tail of the protein.

Multimodality Imaging in Arrhythmogenic Left Ventricular Cardiomyopathy

The term arrhythmogenic cardiomyopathy (ACM) describes a large spectrum of myocardial diseases characterized by progressive fibrotic or fibrofatty replacement, which gives the substrate for the occurrence of ventricular tachyarrhythmias and the development of ventricular dysfunction. This condition may exclusively affect the left ventricle, leading to the introduction of the term arrhythmogenic left ventricular cardiomyopathy (ALVC). The clinical features of ALVC are progressive fibrotic replacement with the absence or mild dilation of the LV and the occurrence of ventricular arrhythmias within the left ventricle. In 2019, the diagnostic criteria for the diagnosis of ALVC, based on family history and clinical, electrocardiographic, and imaging features, have been proposed. However, since the significant clinical and imaging overlap with other cardiac diseases, genetic testing with the demonstration of a pathogenic variant in an ACM-related gene is required for diagnostic confirmation. In ALVC, the multimodality imaging approach comprises different imaging techniques, such as echocardiography, cardiac magnetic resonance, and cardiac nuclear imaging. It provides essential information for the diagnosis, differential diagnosis, sudden cardiac death risk stratification, and management purposes. This review aims to elucidate the current role of the different multimodality imaging techniques in patients with ALVC.

Pregnancy in Women with Arrhythmogenic Left Ventricular Cardiomyopathy.

In the last few years, a phenotypic variant of arrhythmogenic cardiomyopathy (ACM) labeled arrhythmogenic left ventricular cardiomyopathy (ALVC) has been defined and researched. This type of cardiomyopathy is characterized by a predominant left ventricular (LV) involvement with no or minor right ventricular (RV) abnormalities. Data on the specific risk and management of pregnancy in women affected by ALVC are, thus far, not available. We have sought to characterize pregnancy course and outcomes in women affected by ALVC through the evaluation of a series of childbearing patients. A series of consecutive female ALVC patients were analyzed in a cross-sectional, retrospective study. Study protocol included 12-lead ECG assessments, 24-h Holter ECG evaluations, 2D-echocardiogram tests, cardiac magnetic resonance assessments, and genetic analysis. Furthermore, the long-term disease course of childbearing patients was compared with a group of nulliparous ALVC women. A total of 35 patients (mean age 45 ± 9 years, 51% probands) were analyzed. Sixteen women (46%) reported a pregnancy, for a total of 27 singleton viable pregnancies (mean age at first childbirth 30 ± 9 years). Before pregnancy, all patients were in the NYHA class I and none of the patients reported a previous heart failure (HF) episode. No significant differences were found between childbearing and nulliparous women regarding ECG features, LV dimensions, function, and extent of late enhancement. Overall, 7 patients (20%, 4 belonging to the childbearing group) experienced a sustained ventricular tachycardia and 2 (6%)-one for each group-showed heart failure (HF) episodes. The analysis of arrhythmia-free survival patients did not show significant differences between childbearing and nulliparous women. In a cohort of ALVC patients without previous episodes of HF, pregnancy was well tolerated, with no significant influence on disease progression and degree of electrical instability. Further studies on a larger cohort of women with different degrees of disease extent and genetic background are needed in order to achieve a more comprehensive knowledge regarding the outcome of pregnancy in ALVC patients.

Abstract 11772: Prevalence of Pathogenic Variants in Dilated Cardiomyopathy-Associated Genes in Patients Evaluated for Cardiac Sarcoidosis

Introduction: There is phenotypic and mechanistic overlap between arrhythmogenic right ventricular cardiomyopathy and cardiac sarcoidosis (CS). Whether CS and arrhythmogenic left ventricular cardiomyopathy (ALVC) similarly overlap has not been investigated. We aimed to evaluate the difference in proportions of disease-causing variants in ALVC-associated genes in patients with high clinical suspicion for CS. Methods: From a cohort of individuals with whole exome sequencing (WES) with linked electronic health record data in the Penn Medicine BioBank, we identified those who had and had not been referred for FDG-PET and cardiac MRI to evaluate for CS and compared demographics and carrier rates of predicted loss of function (pLOF) variants in genes causal for dilated cardiomyopathy (DCM) and ALVC. Results: Among 43,724 unrelated individuals with WES data, we identified 94 who had been referred for imaging to evaluate for CS. Those who had been referred for imaging were more often of self-reported Black race (50% vs. 25%, p&lt;0.001) and had atrial arrhythmias (62% vs. 30%, p&lt;0.001) and systolic heart failure (61% vs. 17%, p&lt;0.001). Among these 94 individuals, six (6.4%) carried a pLOF variant in at least one of 19 genes known to have strong causal evidence for DCM/ALVC, compared with 1.2% of the participants not referred for imaging. After adjustment for age, sex, and five genetic principal components of ancestry, individuals referred for FDG-PET and MRI were more likely to carry a pLOF variant in a DCM gene of interest compared with the remaining PMBB participants (OR 5.96; 95% CI 2.31, 12.6; p&lt;0.001). Conclusion: Individuals at high clinical suspicion for having CS have 6-fold higher odds of having a pLOF variant in a gene causal for DCM. There is under-recognized overlap between the clinical presentations of genetic ALVC/DCM and CS, and as such, the differential diagnosis for CS and inflammatory cardiomyopathy should be expanded to include these entities.

Abstract 15548: Rare Association of Arrhythmogenic Left Ventricular Cardiomyopathy Phenotype of Titin Mutation of Uncertain Significance

Case Presentation: A 67-year-old female presented to the office with exertional dyspnea, atypical chest pain, palpitations, and dizziness. She had a past medical history of hypertension, hyperlipidemia, mitral valve prolapse, and moderate mitral regurgitation. Her EKG identified multiple PVCs requiring the placement of a Holter monitor, a PVC burden of 31,441 beats (15%) was captured with variable morphology. TTE showed mild global hypokinesis of the left ventricle and ejection fraction (EF) of 40%. Coronary arteries were normal on cardiac catheterization. Cardiac magnetic resonance revealed epicardial late gadolinium enhancement suggestive of fatty infiltration of the distal lateral wall of the left ventricle (LV) indicative of Arrhythmogenic left ventricular cardiomyopathy (ALVC). The basal anterolateral wall of the LV appeared thin and dyskinetic, and the right ventricle was normal in size and function. Optimal medical therapy was initiated with metoprolol, sacubitril/valsartan, dapagliflozin, and spironolactone. A dual-chamber ICD was placed for primary prevention. Over time with medical management, her PVC burden reduced, and LVEF improved to 50%. A multigene panel for cardiomyopathies identified a mutation in titin (TTN) gene variant of unknown significance. Discussion: Previously thought to affect only the right ventricle, arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease characterized by fibrofatty replacement of the ventricular myocardium. ALVC refers to the predominant LV dominant phenotype of this disease. The most frequent genetic mutations occur in the genes plakophilin (PKP2), desmoplakin (DSP), and desmoglein (DSG2). However, we report a case of ALVC in the setting of titin (TTN) gene variant, which is a gene usually implicated in dilated cardiomyopathy. However, the clinical significance of the TTN gene variant identified in our patient remains unclear as more studies are needed to link it to the phenotypic findings.

Diagnostic pathways leading to arrhythmogenic left ventricular cardiomyopathy in a single center cohort

Abstract Background Despite major advances, the recognition of arrhythmogenic left ventricular cardiomyopathy (ALVC) remains challenging, since this clinical entity is often concealed in different clinical settings both in terms of clinical onset and imaging phenotype, resulting in significant delays in diagnosis with prognostic implications. Purpose To describe a single Center cohort of ALVC patients, focusing on the spectrum of clinical presentation and diagnostic pathways. Methods Patients were retrospectively evaluated between January 2012 and January 2022. Diagnosis was based on 1) ≥3 contiguous segments with subepicardial/midwall LGE in the LV at cardiac magnetic resonance (CMR) plus a likely pathogenic/pathogenic arrhythmogenic cardiomyopathy (ACM) associated genetic mutation and/or familial history of ACM and/or red flags for ALVC (i.e, negative T waves in V4–6/aVL, low voltages in limb leads) or 2) pathology examination of explanted hearts/autoptic cases suffering from sudden cardiac death (SCD). Patients with significant right ventricular involvement were excluded. Results Sixty-six patients were evaluated for suspected ALVC: 8 phenocopies were excluded (6 acute myocarditis and 2 sarcoidosis) after a comprehensive clinical and multi-modality instrumental evaluation. The final study cohort was composed by 56 patients (55% males, median age 45 years), from 36 families. Diagnostic pathways leading to diagnosis were: SCD in 4 (7%), ventricular arrhythmias in 11 (20%), chest pain in 9 (16%), heart failure in 7 (12%), and familial screening in 25 (45%) (Figure 1). An echocardiogram was available for all but 2 patients with SCD: 25 (46%) had normal phenotype, 17 (32%) had a hypokinetic non dilated cardiomyopathy, and 12 (22%) had a dilated cardiomyopathy (DCM). Of the 49 tested patients, 31 (63%) had a pathogenic/likely pathogenic DNA variant: desmoplakin (DSP, N=21), filamin C (FLNC, N=4), SCN5A (N=3) were the most frequently involved genes; 8 patients had a double gene mutation. Twenty-four patients (43%) had previously received a diagnosis other than ALVC: 10 idiopathic DCM, 9 acute myocarditis, 4 post-myocarditis DCM, 2 acute myocardial injury/non-ST elevated myocardial infarction. In 13 patients ALVC was diagnosed with the introduction of CMR in the diagnostic work-up of a DCM, in 2 cases the diagnosis was done with the pathology examination after heart transplantation. The median diagnostic delay was of 8 years, with a maximum of 20 years. It is worth nothing that patients from the same family might have different diagnostic pathways and phenotypes of ALVC (Figure 2). Conclusions ALVC is a challenging diagnosis, hidden in different clinical scenarios. Five main clinical pathways leading to ALVC diagnosis may be identified: ventricular arrhythmias, chest pain, heart failure, SCD at first presentation, and clinical/instrumental familial screening. Funding Acknowledgement Type of funding sources: None.

Myocarditis-like Episodes in Patients with Arrhythmogenic Cardiomyopathy: A Systematic Review on the So-Called Hot-Phase of the Disease.

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease, characterized by myocytes necrosis with fibrofatty substitution and ventricular arrhythmias that can even lead to sudden cardiac death. The presence of inflammatory cell infiltrates in endomyocardial biopsies or in autoptic specimens of ACM patients has been reported, suggesting a possible role of inflammation in the pathophysiology of the disease. Furthermore, chest pain episodes accompanied by electrocardiographic changes and troponin release have been observed and defined as the “hot-phase” phenomenon. The aim of this critical systematic review was to assess the clinical features of ACM patients presenting with “hot-phase” episodes. According to PRISMA guidelines, a search was run in the PubMed, Scopus and Web of Science electronic databases using the following keywords: “arrhythmogenic cardiomyopathy”; “myocarditis” or “arrhythmogenic cardiomyopathy”; “troponin” or “arrhythmogenic cardiomyopathy”; and “hot-phase”. A total of 1433 titles were retrieved, of which 65 studies were potentially relevant to the topic. Through the application of inclusion and exclusion criteria, 9 papers reporting 103 ACM patients who had experienced hot-phase episodes were selected for this review. Age at time of episodes was available in 76% of cases, with the mean age reported being 26 years ± 14 years (min 2–max 71 years). Overall, 86% of patients showed left ventricular epicardial LGE. At the time of hot-phase episodes, 49% received a diagnosis of ACM (Arrhythmogenic left ventricular cardiomyopathy in the majority of cases), 19% of dilated cardiomyopathy and 26% of acute myocarditis. At the genetic study, Desmoplakin (DSP) was the more represented disease-gene (69%), followed by Plakophillin-2 (9%) and Desmoglein-2 (6%). In conclusion, ACM patients showing hot-phase episodes are usually young, and DSP is the most common disease gene, accounting for 69% of cases. Currently, the role of “hot-phase” episodes in disease progression and arrhythmic risk stratification remains to be clarified.

Clinical profile and long-term follow-up of a cohort of patients with desmoplakin cardiomyopathy.

Desmoplakin (DSP) genetic variants have been reported in arrhythmogenic cardiomyopathy with particular regard to predominant left ventricular (LV) involvement. The purpose of this study was to improve our understanding of clinical phenotype and outcome of DSP variant carriers. The clinical picture and outcome of 73 patients (36% probands) harboring a pathogenic/likely pathogenic DSP variant were evaluated. The phenotype during follow-up (mean 11 years; range 1-39 years) changed in 25 patients (35%), arrhythmogenic LV cardiomyopathy (ALVC) forms being the most frequent (n = 26 [36%]), followed by biventricular (BIV; n = 20 [27%]) and arrhythmogenic right ventricular cardiomyopathy (ARVC; n = 16 [22%]) forms. Major ventricular arrhythmias were detected in 21 patients (29%), and they were more common in ARVC (n = 6, 56%) and BIV forms (n = 8, 40%) than in ALVC forms (n = 4, 15%). In patients with ALVC, major ventricular arrhythmias occurred in the setting of a normal/mildly reduced systolic function. Heart failure (HF) occurred in 6patients(8%); none affected with ALVC. Females showed more commonly LV involvement, while ARVC forms were more frequently detected in males (21 [61%] vs 15 [38%]; P = .147). Males showed a higher incidence of major ventricular arrhythmias (18 [52%] vs 9 [24%]; P = .036), HF (11 [31%] vs 1 [3%]; P = .004), and cardiac death (11 [31%] vs 0 [0%]; P < .001). The clinical phenotype in pathogenic/likely pathogenic DSP variant carriers is wide. Although most patients show LV involvement, 16 (22%) has right ventricular abnormalities in keeping with a "classical" arrhythmogenic cardiomyopathy form. In ALVC, HF and major ventricular arrhythmias seem less common than in right ventricular and BIV variants. Females show more frequently LV involvement and a better outcome.

Genetic Background and Clinical Features in Arrhythmogenic Left Ventricular Cardiomyopathy: A Systematic Review.

In recent years a phenotypic variant of Arrhythmogenic cardiomyopathy has been described, characterized by predominant left ventricular (LV) involvement with no or minor right ventricular abnormalities, referred to as Arrhythmogenic left ventricular cardiomyopathy (ALVC). Different disease-genes have been identified in this form, such as Desmoplakin (DSP), Filamin C (FLNC), Phospholamban (PLN) and Desmin (DES). The main purpose of this critical systematic review was to assess the level of knowledge on genetic background and clinical features of ALVC. A search (updated to April 2022) was run in the PubMed, Scopus, and Web of Science electronic databases. The search terms used were “arrhythmogenic left ventricular cardiomyopathy” OR “arrhythmogenic cardiomyopathy” and “gene” OR “arrhythmogenic dysplasia” and “gene”. The most represented disease-gene turned out to be DSP, accounting for half of published cases, followed by FLNC. Overall, ECG abnormalities were reported in 58% of patients. Major ventricular arrhythmias were recorded in 26% of cases; an ICD was implanted in 29% of patients. A total of 6% of patients showed heart failure symptoms, and 15% had myocarditis-like episodes. DSP is confirmed to be the most represented disease-gene in ALVC patients. An analysis of reported clinical features of ALVC patients show an important degree of electrical instability, which frequently required an ICD implant. Moreover, myocarditis-like episodes are common.

Clinical characteristics and long-term follow-up results of radiofrequency ablation for the treatment of ventricular tachycardia in patients with arrhythmogenic left ventricular cardiomyopathy

Objective: To investigate the acute and long-term outcome of catheter ablation for the treatment of ventricular tachycardia (VT) in patients with arrhythmogenic left ventricular cardiomyopathy (ALVC). Methods: This retrospective, cross-sectional study enrolled ALVC patients undergoing radiofrequency ablation for the treatment of VT at the First Affiliated Hospital of Nanjing Medical University from January 2011 to December 2018 and collected their clinical characteristics and intraoperative electrophysiological examination. Patients were followed up every 6 months after radiofrequency ablation until August 2021. Echocardiographic results and VT recurrence post radiofrequency ablation were analysed. Results: Totally 12 patients were enrolled (mean age: (42±15) years, 11 males(11/12)). The mean of left ventricular end diastolic diameter (LVDd) and left ventricular ejection fraction (LVEF) were (51±5)mm and (65±5)%, respectively. Twelve VTs were induced in 10 patients during the electrophysiological study, and the mean tachycardia cycle length was (293±65) ms. Three-dimensional substrate mapping revealed the diseased area at endocardial site in one patient, at epicardial sites in the other 11 patients (involved endocardial sites in 2 cases) with the basal part near the mitral annulus being the predilection for the substrate (10/11). After the catheter ablation at the endocardial and epicardial sites respectively, the complete procedure endpoint was achieved in all patients (VT cannot be induced post ablation). The median follow-up time was 65 (25, 123) months. One patient was lost to follow-up, and the other 11 patients survived without VT. No significant cardiac function deterioration was detected by the echocardiographic examination ((51±5)mm vs. (52±5)mm, P>0.05 for LVDd, (65±5)% vs. (60±6)%, P>0.05 for LVEF) at the end of follow-up. Conclusion: After radiofrequency ablation, the complete procedure endpoint is achieved in ALVC patients, and the catheter ablation provides long-term ventricular tachycardia control during the long-term follow-up.

Phenotypic characteristics of patients with arrhythmogenic left ventricular cardiomyopathy and sustained ventricular tachycardias

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The Padua criteria proposed for the diagnostic approach to Arrhythmogenic Cardiomyopathy (AMC) introduced new diagnostic criteria to recognize patients with a phenotype of the left ventricular variants of AMC (ALVC). Unlike ARVC, the arrhythmogenicity of this left phenotype has not yet been established. Objectives This study aims to analyze the phenotypic characteristics in a group of patients with ALVC and ventricular arrhythmias (VA). Methods Thirty-seven related patients with ALVC and VA were included and these were evaluated at the Inherited Cardiac Disease Unit of a Tertiary Hospital. Results Between 2000 and 2021, a total of 207 patients were diagnosed with ALVC. Thirty-seven patients (18%) presented VA; 25 ( 67%) sustained ventricular tachycardia (SVT), 10 ( 27 %) non sustained ventricular tachycardia (NSVT) and 2 ventricular fibrillation (VF). Eighteen 18/37 (49%) biventricular and 19/37 (51%) dominant . Twenty-five, 67 % male, aged 41.8 ± 13.4 years. A genetic study was performed in 36 ( 97%), and the pathogenic mutations were identified in desmoplakin in eighteen, plakophilin-2, desmoglein-2 and phospholamb in three, titin and filamine in two; desmin, plakoglobin and lamin A in one. There was one variant of uncertain significance in desmocollin-2, desmoplakin and titin. A low amplitude QRS voltages (LAQRS) in limb leads was present in 14/33 patients . Inverted T waves in right (V1-V3) in 4/33 patients and in left precordial (V4-V6) were present in 9/33 patients. The average left ventricular ejection fraction (LVEF) was 41%± 14 and myocardial fibrosis evidenced by contrast-enhanced CMR as LGE was presented in 22 patients. Ventricular arrhythmias with a right bundle branch block (RBBB) morphology were most frequent (7/12 ), denoting the origin from LV. All VT with LBBB morphology appeared in biventricular cases (5/12). Reverse pattern break was present in three patients. EAM showed bipolar or unipolar endocardial scar left ventricle in 6/10 and bipolar or unipolar endocardial scar right ventricle in 3/10 patients. Epicardial scar was present in 4 patients ( 3 LV, 2 RV). An implantable cardioverted defibrillator (ICD) therapy was performed in 25 patients for primary or secondary prevention of sudden death. Heart transplantation was carried out for three patients. Conclusions A substancial number of patients with ALVC have presented ventricular arrhythmias. Ventricular arrhythmias with a right bundle branch block (RBBB) morphology were the most frequent. All of VT with LBBB morphology appeared in biventricular cases. The mutation in DSP was the most prevalent in patients with ALVC and VT. Patients with ALVC and VA are characterized by a ventricular function that is not significantly impaired; however, fibrosis in LGE is widespread.

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.