Fibrofatty Replacement Of Myocardium Research Articles

Description of the Two-Dimensional Layer-Specific Strain Echocardiography Phenotype of Arrhythmogenic Left Ventricular Cardiomyopathy

Arrhythmogenic left ventricular cardiomyopathy (ALVC) is characterized by fibrofatty myocardial replacement demonstrated on cardiac magnetic resonance by late gadolinium enhancement (LGE) mainly involving the subepicardium. The aims of this study were to describe the layer-specific strain (LSS) echocardiography phenotype of ALVC and to compare it with LGE features. All consecutive ALVC pathogenic genetic variant carriers and noncarrier relatives were separated into four prespecified groups (overt ALVC [group 1], isolated LGE [group 2], pathogenic genetic variant carrier without ALVC phenotype [group 3], and no genetic variant carrier [group 4]) and studied accordingly using cardiac magnetic resonance and LSS echocardiography. Eighty-five individuals were included. Endocardial global longitudinal strain (GLS)-epicardial GLS (GLSepi) gradient was altered predominantly in group 1, illustrating transmural strain alteration in overt ALVC (3.8±1.1 in group 1, 4.3±2.2 in group 2, 5.2±1.2 in group 3, and 5.4±1.6 in group 4; P=.0017), whereas GLSepi was impaired predominantly in group 2 (endocardial GLS and GLSepi were 15.0±4.1% and 11.2±3.3%, respectively, in group 1; 20.5±2.8% and 16.2±5.5% in group 2; 23.4±3.3% and 18.2±2.7% in group 3; and 24.6±2.8% and 19.2±1.9% in group 4; P<.0001 for all). GLSepi was able to detect subepicardial LGE in genetic variant carriers without overt ALVC with an area under curve of 0.84 (95% CI, 0.73-0.95). However, segmental epicardial and endocardial strain behaved similarly and showed comparable diagnostic values for segmental LGE detection (areas under the curve, 0.72; [95% CI, 0.69-0.76] and 0.73 [95% CI, 0.70-0.76], respectively, P=.40). LSS alteration in ALVC progresses from the epicardium to the endocardium along with disease severity. Irrespective of LSS analysis, which did not provide incremental diagnostic value for the detection and localization of LGE, strain echocardiography was shown to be a potential surrogate marker of LGE, including in apparently healthy individuals with isolated LV fibrosis.

Risk of cardioembolic ischemic events and relation to atrial fibrillation/flutter in patients with arrhythmogenic cardiomyopathy during a long-term follow-up

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by fibro-fatty replacement of myocardium. Limited data is available concerning cardioembolic stroke. This study sought to determine the occurrence of cardioembolic ischemic events (CIEs) in ACM patients and to identify clinical and imaging predictors of CIEs. Every consecutive ACM patient was enrolled. ECG, Holter monitoring or implantable cardiac devices were used to detect atrial arrhythmias (AAs). CIEs were defined according to TOAST classification. In our cohort of 111 patients, CIEs were observed in eleven (10%) over a 12.9-year median follow-up, with an incidence of 7.9 event/1000 patient-year (HR 4.12 compared to general population). Mean age at the event was 42±9years. Female sex (p=0.03), T-wave inversion (p=0.03), RVOT dilatation (p=0.006) and lower LVEF (p=0.006) were associated with CIEs. Among patients with AAs (23/111, 20.7%), 5 (21.7%) experienced CIEs. CHA2DS2-VASc did not prove useful to define patients at higher risk of CIEs (p=0.098). 60% of stroke suffering patients had a pre-event score between 0 and 1 (if female). In ACM patients, CIEs are much more common than in general population and present a high burden at younger age. AAs relate to less than half of these events. In AAs patients, CHA2DS2-VASc is not useful to stratify those requiring oral anticoagulation. As a hypothesis-generating study, our research proposes the role of atrial myopathy, irrespective of AAs, as a pivotal factor in thrombogenesis risk, pointing out a definite unmet need in ACM therapeutic algorithm.

Evolution of surface and endocavitary signals in patients with arrhythmogenic cardiomyopathy at 1 and 5 years

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Small fee from Boston Scientific. Background The use of subcutaneous defibrillator (S-ICD) is a viable alternative to transvenous ICD in patients with Arrhythmogenic Cardiomyopathy (ACM). In transvenous ICD recipients low sensing values may exist at the time of implantation and a progressive decline of signal amplitude may occur later on due to the progressive myocardial fibrofatty replacement. Similarly to what happens at the intracavitary level, in patients with ACM there is a progressive modification of the surface ECG over time. Data on the impact of ECG evolution on S-ICD sensing are still lacking, particularly for different ACM phenotypes. Purpose This study aims to analyze the evolution of surface electrocardiogram (ECG), focusing on R-wave amplitude variation, and intracavitary electrograms (EGMs) in ACM different phenotypes during a 1-year and a 5 five-year follow-up. Methods This study is a retrospective analysis of the data of consecutive patients with ACM who were referred to our centre from January 1992 to October 2021. Using a dedicated software, the ECG analysis was performed in 7 leads: DI, DII, aVF (in view of the similar orientation with the three S-ICD vectors) and V1, V2, V3 and V5. Results We included 69 ACM patients: 28 patients (41%) had a right ventricular involvement (ARVC), 19 (27%) had a dominant LV involvement (ALVC) and 22 (32%) had biventricular involvement. 58 patients (84%) were ICD recipients; 45/58 patients (78%) had a transvenous ICD, and 13/58 (22%) had an S-ICD. During 5-year follow-up, in the whole ACM population, there were no significant changes in the amplitude of the R-wave, S-wave and T-wave. Phenotypic subgroups showed a different R-wave amplitude at baseline: biventricular ACM and ALVC patients had a lower R-wave amplitude in DII (p=0.04; p=0.05) and aVF (p=0.01; p=0.01) compared to ARVC patients. However, within each group, no difference was observed in R-wave amplitude at 1 and 5 years compared to baseline ECG (Figure 1). In the transvenous ICD recipients (45/69 patients) mean sensing decreased progressively over time (9,38 ± 4,24 mV at baseline, 7,70 ± 2,91 mV at 1 year, 1,85 ± 6,86 mV at 5 years). The reduction was not statistically significant at the first year of follow-up (p=0.239) but it reached significance at 5 years (p&amp;lt;0.001). Patients with biventricular ACM had lower sensing values at baseline than ARVC and ALVC (p&amp;lt;0,001). Sensing values in the biventricular patients did not decrease significantly during the 5-year follow-up (p=0.21), whereas in the ARVC and ALVC groups a reduction in sensing values was observed albeit not statistically significant in ALVC (p=0.01 in ARVC and p =0.06 in ALVC) (Figure2). Conclusions These data suggest that surface ECG may be more stable over time compared to EGM, therefore if a patient is suitable for S-ICD implantation S-ICD sensing may remain stable over time. Despite these findings, further studies are needed to support these hypotheses.

Electrocardiogram in arrhytmogenic cardiomyopathy.

Criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) were first proposed in 1994 and subsequently revised in 2010 and in 2020 by an international task force. According to the last consensus of 2020, ACM is defined as a heart muscle disease affecting right ventricle, left ventricle or both, whose principal pathologic feature is fibrofatty myocardial replacement that impairs systolic ventricular function and predisposes to lethal ventricular arrhythmias. ECG findings not only could help to early recognize affected patients but also could identify the ones with maximum risk of ventricular arrhythmias and sudden cardiac death.

Modeling incomplete penetrance in arrhythmogenic cardiomyopathy by human induced pluripotent stem cell derived cardiomyocytes

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are commonly used to model arrhythmogenic cardiomyopathy (ACM), a heritable cardiac disease characterized by severe ventricular arrhythmias, fibrofatty myocardial replacement and progressive ventricular dysfunction. Although ACM is inherited as an autosomal dominant disease, incomplete penetrance and variable expressivity are extremely common, resulting in different clinical manifestations. Here, we propose hiPSC-CMs as a powerful in vitro model to study incomplete penetrance in ACM. Six hiPSC lines were generated from blood samples of three ACM patients carrying a heterozygous deletion of exon 4 in the PKP2 gene, two asymptomatic (ASY) carriers of the same mutation and one healthy control (CTR), all belonging to the same family. Whole exome sequencing was performed in all family members and hiPSC-CMs were examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp, immunofluorescence and RNASeq. Our results show molecular and functional differences between ACM and ASY hiPSC-CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation and sarcomere disorganization in ACM compared to ASY hiPSC-CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. These data indicate that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.

142 ADVANCED HEART FAILURE IN PATIENTS WITH ARRHYTHMOGENIC CARDIOMYOPATHY

Abstract Background Arrhythmogenic Cardiomyopathy (ACM) is a primary disease of the heart muscle, characterized by fibro-fatty myocardial replacement. Improvements in the clinical diagnosis and antiarrhythmic therapy, including the use of the defibrillator (ICD) and endo-epicardial catheter ablation, have increased the survival of these patients, who experience late complications such as advanced heart failure, which sometimes requires cardiac transplantation. Aim of the study To evaluate clinical, instrumental and genetic features of patients affected with ACM who developed heart failure (HF) and to sought for possible predictive factors of HF. Methods From the entire cohort of probands and family members followed at the Cardiomyopathy unit of our University (555 patients), 34 patients (29%), both probands (n= 26, 77%) and family members who experienced HF (6%) were selected (24 males, 71%). Their anamnestic, clinical, and instrumental data were compared with those without episodes of HF (n-HF). Results The mean age at diagnosis in HF cohort was 45.2 (±18) years. In 14 patients (41%) HF was the first symptom that led to diagnosis. According to 2010 TFC 30 patients (88%) had a definite diagnosis of ACM. The most frequently observed phenotype was the biventricular ACM (n=27, 79%). A disease-related genetic variant was found in 18 (53%) and DSP was the more common disease-gene, accounting for 24% of cases. The mean duration of follow-up was 12.6 (±11.0) years (min-max, 1-20 years). During this period a total of 14 subjects (41.2%) experienced life-threatening arrhythmias (LTA), while 13 patients (38.2%) died, of whom 11 (84.6%) because of refractory HF. Eighteen patients (53%) underwent cardiac transplantation (mean age 43±17 years), approximately 4 (±3.5) years after the onset of symptoms. Comparison with the n-HF cohort of ACM patients showed a significant difference on presence of T-wave inversion (TWI) in V1-V3 (p=0.001), TWI in V4-V6 (p=0.010), low QRS voltages both in precordial and limb leads (both p&amp;lt;0.001) and presence of left bundle-branch block and right bundle-branch block (both p&amp;lt;0.001). Regarding CMR, HF cohort was characterized by a significantly more dilated right and left ventricle EDV (both p&amp;lt;0.001), EF reduction (both p&amp;lt;0.001), presence of wall motion alterations (respectively, p=0.007 and p&amp;lt;0.001) and LGE (respectively, p=0.002 and p=0.005) compared to n-HF group. Regarding outcomes evaluation, the HF group showed more frequently LTA (HF=41.2% vs n-HF 21.5%, p=0.008). Finally, the presence of right bundle-branch block at ECG (OR=20.562, CI 1.884-224.413, p=0.013) and of impaired RV ejection fraction (OR=0.821, CI 0.719-0.937, p=0.004) were found to be independent predictors of HF. Conclusions Heart failure is a rare complication in patients affected with ACM, with a prevalence of 6% in our study. The mean age of onset of HF was 45.2 (±18) years. Furthermore, 18 patients (53%) had an unfavorable progression to heart transplantation. The presence of right bundle branch block at ECG and an impaired CMR RV-EF were found to be predictors of HF. Our results suggest the importance of scheduling a close follow-up in ACM patients who show initial signs and/or symptoms of HF, taking into consideration the fast rate of progression to refractory HF, once established.

Clinical and echocardiographic evolution of patients with arrhythmogenic cardiomyopathy before heart transplantation.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by fibrofatty myocardial replacement, and accurate diagnosis can be challenging. The clinical course of patients expressing a severe phenotype of the disease needing heart transplantation (HTx) is not well described in the literature. Therefore, this study aims to describe the clinical and echocardiographic evolution of patients with ACM necessitating HTx. We retrospectively studied all patients who underwent HTx in our institution between 1998 and 2019 with a definite diagnosis of ACM according to the explanted heart examination. Ten patients with confirmed ACM underwent HTx. Only four of them had a diagnosis of ACM before HTx. These patients were 28 ± 15 years old at the time of their first symptoms. Patients received a diagnosis of heart failure (HF) after 5.9 ± 8.7 years of symptom evolution. The mean age at transplantation was 40 ± 17 years old. All the patients experienced ventricular tachycardia (VT) at least once before their HTx and 50% were resuscitated after sudden death. The mean left ventricular ejection at diagnosis and before transplantation was similar (32%±21% vs. 35.0%±19.3%, p=NS). Right ventricular dysfunction was present in all patients at the time of transplantation. Patients with ACM necessitating HTx show a high burden of ventricular arrhythmias and frequently present a biventricular involvement phenotype, making early diagnosis challenging. HF symptoms are the most frequent reason leading to the decision to transplant.

Abstract 12450: Identifying Differential Proteins of the Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Associated Mutation in Transmembrane Protein 43 Ser358Leu by Proteomics and Interaction Studies Using TurboID

Introduction: Transmembrane protein 43 (TMEM43) is localized in the nuclear envelope and endoplasmic reticulum (ER). TMEM43- c.1073C&gt;T, p.S358L leads to a rare fully penetrant type 5 arrhythmogenic right ventricular cardiomyopathy (ARVC5). The molecular pathomechanism of ARVC5 is not well understood. Methods: TurboID cloned to N- and C-terminal of TMEM43 WT and p.S358L were transfected in HEK293 cells. Biotinylation assay was performed and biotinylated proteins were immunoprecipitated using streptavidin-beads. After on beads-digestion, peptide fragments were analyzed by Orbitrap mass-spectrometry (MS). Furthermore, we cultivated primary dermal fibroblasts of three TMEM43 p.S358L carriers. Proteins were isolated from cell cultures and analyzed by MS. Additionally, TMEM43-p.S358L and control fibroblasts were investigated by transmission electron microscopy (TEM). Results: TurboID proteome data shows differences in the interacting proteome of TMEM43 WT and p.S358L. VDAC2, which is involved in metabolic regulation of lipids and part of the ER-mitochondrion contact site, was one of the prominent interacting proteins less represented in TMEM43 p.S358L. The proteome of fibroblasts show 11 proteins upregulated in TMEM43-p.S358L (p&lt;0.003). Of note, proteins involved in fatty acid metabolism, such as acyl-coenzym A thioesterase 1 encoded by the gene ACOT1, and Malonate-CoA ligase encoded by ACSF3 were strongly upregulated. ACOT1 and ACSF3 regulate intracellular levels of free fatty acids and are expressed in human cardiomyocytes. TEM images of TMEM43 p.S358L carriers show accumulation of multilamellar bodies, which may support the dysregulation of the lipid metabolism as a prominent pathomechanism. Conclusions: The altered interaction of TMEM43 p.S358L with VDAC2 is a plausible mechanism for miscommunication of ER and mitochondria perturbing the lipid homeostasis. Additionally, the differentially regulated proteins in dermal fibroblasts and the accumulation of multilamellar bodies also suggest a dysregulation of the lipid metabolism by TMEM43 p.S358L, which may explain the development of myocardial fibrofatty replacement contributing to ARVC5.

New Diagnostic Approach to Arrhythmogenic Cardiomyopathy: The Padua Criteria

Arrhythmogenic cardiomyopathy (ACM) is a rare heart muscle disease characterized by a progressive fibro-fatty myocardial replacement, ventricular arrhythmias, and increased risk of sudden cardiac death. The first diagnostic criteria were proposed by an International Task Force of experts in 1994 and revised in 2010. At that time, ACM was mainly considered a right ventricle disease, with left ventricle involvement only in the late stages. Since 2010, several pathological and clinical studies using cardiac magnetic resonance (CMR) imaging have allowed to understand the phenotypic expression of the disease and to reach the current idea that ACM may affect both ventricles. Indeed, left ventricular involvement may parallel or exceed right ventricular involvement. The main limitations of the 2010 criteria included the poor sensitivity for left ventricular involvement and the lack of inclusion of tissue characterization by CMR. The 2020 International criteria (the Padua criteria) were developed to overcome these shortcomings. The most important innovations are the introduction of a set of criteria for identifying left ventricular variants and the use of CMR for tissue characterization. Moreover, criteria for right ventricular involvement were also updated taking into account new evidence. According to the number of criteria for right and/or left ventricular involvement, the 2020 Padua criteria allows diagnosing three ACM phenotypic variants: right-dominant, biventricular and left-dominant. This review discusses the evolving approach to diagnosis of ACM, from the 1994 International Criteria to the 2020 Padua criteria.

Novel homozygous stop-gain pathogenic variant of PPP1R13L gene leads to arrhythmogenic cardiomyopathy

BackgroundArrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease with two main features: electric instability and myocardial fibro-fatty replacement. There is no defined treatment except for preventing arrhythmias and sudden death. Detecting causative mutations helps identify the disease pathogenesis and family members at risk. We used whole-exome sequencing to determine a genetic explanation for an ACM-positive patient from a consanguineous family.MethodsAfter clinical analysis, cardiac magnetic resonance, and pathology, WES was performed on a two-year-old ACM proband. Variant confirmation and segregation of available pedigree members were performed by PCR and Sanger sequencing. The PPP1R13L gene was also analyzed for possible causative variants and their hitherto reported conditions.ResultsWe found a novel homozygous stop-gain pathogenic variant, c.580C > T: p.Gln194Ter, in the PPP1R13L gene, which was confirmed and segregated by PCR and Sanger sequencing. This variant was not reported in any databases.ConclusionsWES is valuable for the identification of novel candidate genes. To our knowledge, this research is the first report of the PPP1R13L c.580C > T variant. The PPP1R13L variant was associated with ACM as confirmed by cardiac magnetic resonance and pathology. Our findings indicate that PPP1R13L should be included in ACM genetic testing to improve the identification of at-risk family members and the diagnostic yield.

Are human induced pluripotent stem cell derived cardiomyocytes a good cellular model for studying incomplete penetrance in arrhythmogenic cardiomyopathy?

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Regional Development Fund and Interreg V-A Italy-Austria 2014-2020 and Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol (Italy). Background Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were previously used to model several inherited heart diseases (1). Among these, arrhythmogenic cardiomyopathy (ACM) is characterized by a fibrofatty myocardial replacement and severe ventricular arrhythmias (2). ACM is mainly caused by mutations affecting proteins of intercalated discs (3) and shows incomplete penetrance and variable expressivity (4). Purpose To evaluate whether hiPSC-CMs provide a good in vitro model to study incomplete penetrance in ACM. Material and methods hiPSCs were generated from buffy coats of 6 close relatives. Three of them were ACM patients carrying a deletion of exon 4 in the PKP2 gene causing a premature stop codon, 2 were asymptomatic (ASY) PKP2 mutation carriers and 1 was a healthy control (CTR). Whole exome sequencing of the 6 individuals was performed. The purified hiPSC-CMs were cultured in basal and adipogenic medium and examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp and immunofluorescence. Results All family members tested negative for additional mutations in ACM genes. As expected, half the amount of wild type (wt) PKP2 mRNA was found in ACM and ASY than in CTR hiPSC-CMs (2.25±0.27vs4.29±0.70 wtPKP2/HPRT1; p=0.028) (2.08±0.38vs4.29±0.70 wtPKP2/HPRT1; p=0.052). Of note, the mutated (mut) PKP2 mRNA was detected and significantly more expressed in ACM than in ASY hiPSC-CMs (0.33±0.04vs0.11±0.06 mutPKP2/HPRT1; p=0.029). While we confirmed a reduced amount of wt plakophillin-2 protein in ACM and ASY compared to CTR hiPSC-CMs (0.19±0.07vs0.81±0.28 wtPKP2/GAPDH; p=0.016), (0.25±0.07vs0.81±0.28 wtPKP2/GAPDH; p=0.11), the truncated protein was not detected. Moreover, a significantly lower expression of the active form of β-catenin (ABC) has been shown in ACM and ASY than in CTR hiPSC-CMs (0.93±0.18vs1.30±0.09 ABC/GAPDH; p=0.057), (0.76±0.10vs1.30±0.09 ABC/GAPDH; p=0.0057). In basal medium, ACM hiPSC-CMs had a significant lower overall sodium current density compared to CTR (-49.82±2.8 vs -69.38±4.8 pA/pF; p&amp;lt;0.0001) and to ASY (-49.82±2.8 vs -68.92±4.3 pA/pF; p&amp;lt;0.0001) hiPSC-CMs. In adipogenic medium, ACM hiPSC-CMs showed a higher lipid accumulation and a higher sarcomere disorganization than CTR (1580±219vs615±199 intensity/nuclei; p=0.0351) (0.019±0.001vs0.028±0.003 myofibril alignment index; p=0.039) and ASY (1580±219vs689±146 intensity/nuclei; p=0.0059) (0.019±0.001vs0.027±0.001 myofibril alignment index; p=0.010) hiPSC-CMs. Conclusions Here we report that ACM express a significantly higher amount of mutated PKP2 mRNA than ASY iPSC-CMs. Even though no differences were detected for plakophilin-2 and active β-catenin proteins between ACM and ASY iPSCM-CMs, the ACM showed a fatty phenotype and altered electrical activity that differed significantly from the CTR as well as from the ASY hiPSC-CMs, demonstrating that these cells provide a valid model to study incomplete penetrance in ACM.

One Heart, Two Problems: Cardiomyopathy and CPVT Secondary to RYR2 Mutation

<h3>Introduction</h3> RYR2 mutations are known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disorder with risk for life threatening atrial (AT) and ventricular (VT) arrhythmias. Individuals with RYR2 mutation less commonly exhibit arrhythmogenic right ventricular cardiomyopathy (ARVC). We report the first case of a pediatric patient with RYR2 mutation, manifesting with CPVT, ARVC, and severe dysfunction requiring heart transplant (HTx). <h3>Case Report</h3> A 4.5 year old male with developmental delay presented after multiple syncopal episodes both at rest and with activity. A Holter showed AT, and he was started on a beta adrenergic antagonist with decreased frequency of syncopal episodes. He then developed sinus bradycardia with marked sinus pauses, prompting dual chamber pacemaker placement at age 6 years. He later exhibited bidirectional VT and whole exome sequencing identified a de novo, likely pathogenic variant in RYR2. He was medically managed until 16 years of age when he had syncope with exercise and was found to have both frequent AT and moderately depressed ventricular function with an ejection fraction of 45%. Given recurrent syncope with exercise, he underwent uncomplicated sympathectomy and optimization of his medical antiarrhythmic management. Over the next few months, he developed progressive heart failure symptoms and was admitted with worsening biventricular dysfunction and tachyarrhythmias. During his admission, he had a cardiac arrest with initial monitoring demonstrating VT, and was placed on extracorporeal membrane oxygenation support. He was transitioned to a durable left ventricular assist device (VAD), and was eventually listed for HTx. His VAD course was complicated by RV dysfunction needing PDE5 inhibitor; his arrhythmia burden was managed on flecainide, sotalol, and nadolol. After 80 days of VAD support, he underwent HTx. Pathology of his explanted heart revealed biventricular fibrofatty myocardial replacement consistent with ARVC with prominent LV involvement. <h3>Summary</h3> This case highlights an expanded spectrum of RYR2 mutation related disease which may include prominent atrial arrhythmias, ARVC, and developmental delay. Patients with CPVT and RYR2 mutation warrant close monitoring for ventricular dysfunction, especially if there is a significant arrhythmia burden.

The 2020 "Padua Criteria" for Diagnosis and Phenotype Characterization of Arrhythmogenic Cardiomyopathy in Clinical Practice.

Arrhythmogenic Cardiomyopathy (ACM) is a heredo-familial cardiac disease characterized by fibro-fatty myocardial replacement and increased risk of sudden cardiac death. The diagnosis of ACM can be challenging due to the lack of a single gold-standard test: for this reason, it is required to satisfy a combination of multiple criteria from different categories including ventricular morpho-functional abnormalities, repolarization and depolarization ECG changes, ventricular arrhythmias, tissue characterization findings and positive family history/molecular genetics. The first diagnostic criteria were published by an International Task Force (ITF) of experts in 1994 and revised in 2010 with the aim to increase sensitivity for early diagnosis. Limitations of the 2010 ITF criteria include the absence of specific criteria for left ventricle (LV) involvement and the limited role of cardiac magnetic resonance (CMR) as the use of the late gadolinium enhancement technique for tissue characterization was not considered. In 2020, new diagnostic criteria (“the Padua criteria”) were proposed. The traditional organization in six categories of major/minor criteria was maintained. The criteria for identifying the right ventricular involvement were modified and a specific set of criteria for identifying LV involvement was created. Depending on the combination of criteria for right and LV involvement, a diagnosis of classic (right dominant) ACM, biventricular ACM or left-dominant ACM is then made. The article reviews the rationale of the Padua criteria, summarizes the main modifications compared to the previous 2010 ITF criteria and provides three examples of the application of the Padua criteria in clinical practice.

430 Diagnosis and management of a case of biventricular arrhythmogenic cardiomyopathy: a case report

Abstract Arrhythmogenic cardiomyopathy (ACM) is a genetically determined heart muscle disorder characterized by fibro-fatty replacement of myocardium which may affect the right ventricle (‘dominant right’ variant), the left ventricle (‘dominant left’ variant) or both (‘biventricular disease’ variant). Despite of ACM is one of the main causes of sudden cardiac death (SCD) in young people and athletes as well, the diagnosis of this complex clinical entity still remains a challenge. We report on a case of a 29 years old non-athletic woman with family history of SCD and a long-standing personal history of palpitations leading to frequent accesses to the Accident &amp; Emergency Department. Her echocardiogram was normal while twelve leads ECG revealed negative T waves in the right precordial leads (V1–V3) and post-excitation epsilon waves. ECG Holter monitoring recorded frequent (up to 17 000 in 24 h) polymorphic premature ventricular contractions (PVCs) seldom organized in couplets or triplets. She was followed-up in our clinic and started on Propanolol 40 mg bid with slight relief of symptoms and reduction of PVCs. Cardiac magnetic resonance (CMR) showed regional dyskinesia of both ventricles and RV dilatation. Moreover, tissue characterization findings revealed the presence of diffuse subepicardial late gadolinium enhancement (LGE) of the LV. Genetic analysis was performed and a variant of uncertain significance (VUS) in Desmoplakin was identified. Non sustained monomorphic ventricular tachycardia was induced during electrophysiologic study by programmed ventricular stimulation. In light of these results, we diagnosed biventricular ACM and, after carefully discussion with the patient, a subcutaneous implantable cardioverter defibrillator (ICD) was implanted. The present case should be a persisting reminder that must be considered more than just a single diagnostic tool when dealing with arrhythmic presentations especially in young patients and the importance of contrast CMR along with genetic testing in order to aid clinicians in the demanding selection of the best candidates for ICD implantation.

Circulating miR-185-5p as a Potential Biomarker for Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by progressive myocardial fibro-fatty replacement, arrhythmias and risk of sudden death. Its diagnosis is challenging and often it is achieved after disease onset or postmortem. In this study, we sought to identify circulating microRNAs (miRNAs) differentially expressed in ARVC patients compared to healthy controls. In the pilot study, we screened the expression of 754 miRNAs from 21 ARVC patients and 20 healthy controls. After filtering the miRNAs considering a log fold-change cut-off of ±1, p-value < 0.05, we selected five candidate miRNAs for a subsequent validation study in which we used TaqMan-based real-time PCR to analyse samples from 37 ARVC patients and 30 healthy controls. We found miR-185-5p significantly upregulated in ARVC patients. Receiver operating characteristic analysis indicated an area under the curve of 0.854, corroborating the link of this miRNA and ARVC pathophysiology.

Neuropeptide Y promotes adipogenesis of human cardiac mesenchymal stromal cells in arrhythmogenic cardiomyopathy

BackgroundArrhythmogenic Cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes. AC hearts show fibro-fatty myocardial replacement, which favors stress-related life-threatening arrhythmias, predominantly in the young and athletes. AC lacks effective therapies, as its pathogenesis is poorly understood. Recently, we showed that cardiac Mesenchymal Stromal Cells (cMSCs) contribute to adipose tissue in human AC hearts, although the underlying mechanisms are still unclear. PurposeWe hypothesize that the sympathetic neurotransmitter, Neuropeptide Y (NPY), participates to cMSC adipogenesis in human AC. MethodsFor translation of our findings, we combined in vitro cytochemical, molecular and pharmacologic assays on human cMSCs, from myocardial biopsies of healthy controls and AC patients, with the use of existing drugs to interfere with the predicted AC mechanisms. Sympathetic innervation was inspected in human autoptic heart samples, and NPY plasma levels measured in healthy and AC subjects. ResultsAC cMSCs expressed higher levels of pro-adipogenic isotypes of NPY-receptors (i.e. Y1-R, Y5-R). Consistently, NPY enhanced adipogenesis in AC cMSCs, which was blocked by FDA-approved Y1-R and Y5-R antagonists. AC-associated PKP2 reduction directly caused NPY-dependent adipogenesis in cMSCs. In support of the involvement of sympathetic neurons (SNs) and NPY in AC myocardial remodeling, patients had elevated NPY plasma levels and, in human AC hearts, SNs accumulated in fatty areas and were close to cMSCs. ConclusionsIndependently from the disease origin, AC causes in cMSCs a targetable gain of responsiveness to NPY, which leads to increased adipogenesis, thus playing a role in AC myocardial remodeling.

B-PO03-204 DON’T THROW THE BABY OUT WITH THE BATHWATER - VOLTAGE MAPPING STILL MATTERS

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart condition characterized with fibrofatty replacement of myocardium with an increased risk of arrhythmia and sudden cardiac death. Multimodality imaging including cardiac magnetic resonance (CMR) can help deep phenotype cases. Clinical case where voltage mapping identified fibrofatty myocardium undetected by CMR. N/A A 46-year-old female presented with palpitations, ventricular tachycardia (VT) and premature ventricular contractions (PVCs) burden of 17%. The intrinsic sinus ECG was normal She preferred ablation and pre-procedure CMR showed dilated right ventricle without evidence of dyskinesia, inflammation, late gadolinium enhancement, or fatty infiltration. The patient underwent an EP study arriving in sinus rhythm and had dominant clinical PVC with a left bundle inferiorly directed axis, V5 transition and negative in lead I and aVL placing it at the anterior-septal right ventricular outflow tract. Having good pace maps there burst pacing with the ablation catheter induced clinical VT similar to the PVC; radiofrequency ablation slowed and terminated it under 10 seconds. After suppression of VT and PVCs, a detailed voltage map of the RV was obtained demonstrating significant bipolar and unipolar voltage abnormalities on the RV free wall where ablation had not been performed. This scar pattern was suggestive of ARVC Subsequent genetic testing confirmed pathogenic PKP2 mutation. Voltage mapping remains a useful adjunct tool for deep phenotyping and can detect diseased myocardium which may not be visualized with other imaging modalities.

Arrhythmogenic Cardiomyopathy-Current Treatment and Future Options.

Arrhythmogenic cardiomyopathy (ACM) is an inheritable heart muscle disease characterised pathologically by fibrofatty myocardial replacement and clinically by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Although, in its original description, the disease was believed to predominantly involve the right ventricle, biventricular and left-dominant variants, in which the myocardial lesions affect in parallel or even mostly the left ventricle, are nowadays commonly observed. The clinical management of these patients has two main purposes: the prevention of SCD and the control of arrhythmic and heart failure (HF) events. An implantable cardioverter defibrillator (ICD) is the only proven lifesaving treatment, despite significant morbidity because of device-related complications and inappropriate shocks. Selection of patients who can benefit the most from ICD therapy is one of the most challenging issues in clinical practice. Risk stratification in ACM patients is mostly based on arrhythmic burden and ventricular dysfunction severity, although other clinical features resulting from electrocardiogram and imaging modalities such as cardiac magnetic resonance may have a role. Medical therapy is crucial for treatment of VAs and the prevention of negative ventricular remodelling. In this regard, the efficacy of novel anti-HF molecules and drugs acting on the inflammatory pathway in patients with ACM is, to date, unknown. Catheter ablation represents an effective strategy to treat ventricular tachycardia relapses and recurrent ICD shocks. The present review will address the current strategies for prevention of SCD and treatment of VAs and HF in patients with ACM.

A Case Of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Presenting with Dizziness-A Rare Case Report

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder. Its hallmark is the fibrofatty replacement of myocardium leading to cardiomyopathy. It can have various presentations which can range from silent disease to sudden cardiac death. Here, we report a case of ARVC in a 42 years old female who presented to us with dizziness as her first clinical presentation. We clinched the diagnosis with the help of electrocardiogram, echocardiography and cardiac magnetic resonance imaging (CMR).

Arrhythmogenic Cardiomyopathy and Skeletal Muscle Dystrophies: Shared Histopathological Features and Pathogenic Mechanisms.

Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease characterized by fibrotic or fibrofatty myocardial replacement, associated with an increased risk of ventricular arrhythmias and sudden cardiac death. Originally described as a disease of the right ventricle, ACM is currently recognized as a biventricular entity, due to the increasing numbers of reports of predominant left ventricular or biventricular involvement. Research over the last 20 years has significantly advanced our knowledge of the etiology and pathogenesis of ACM. Several etiopathogenetic theories have been proposed; among them, the most attractive one is the dystrophic theory, based on the observation of similar histopathological features between ACM and skeletal muscle dystrophies (SMDs), such as progressive muscular degeneration, inflammation, and tissue replacement by fatty and fibrous tissue. This review will describe the pathophysiological and molecular similarities shared by ACM with SMDs.