Arrhythmogenic Cardiomyopathy Research Articles

Abstract 4137272: The Impact of Genotype in Dilated and Arrhythmogenic Cardiomyopathy: Insights from the SHaRE Registry

Background: The impact of genotype on the risk of arrhythmia and heart failure in dilated and arrhythmogenic cardiomyopathy (DCM/ACM) is not well defined. Better understanding of genetic risk factors is needed to improve patient risk stratification, management, and outcomes. Methods: In this observational study, we leveraged the international Sarcomeric Human Cardiomyopathy Registry (SHaRe) to analyze the effect of arrhythmic gene variants on clinical events in patients with DCM/ACM (excluding arrhythmogenic right ventricular cardiomyopathy). Patients were stratified by the presence of pathogenic variants in 8 genes most commonly associated with ACM (AR(+): LMNA , DSP , FLNC , RBM20 , PLN , SCN5A , DES , and TMEM43 ). We assessed for risk of clinical events including ventricular arrhythmia (VA), atrial fibrillation (AF), heart failure (HF), death, and the overall composite of any of these events. Analyses were adjusted for age at diagnosis, sex, and baseline left ventricular ejection fraction (EF). Patients were also stratified by EF ≥50% in subgroup analyses. Results: A total of 1373 genotyped adults with DCM/ACM from 6 centers were included with median follow-up of 5.5 (IQR 2.4-10.4) years. Mean diagnosis age was 48 (± 15) years, and 39.5% were female. The cohort included 185 (13.5%) AR(+) patients. AR(+) compared to genotype-negative patients (N=486, 35.4%) had increased risk of VA (HR 5.02, 95% CI 3.46-7.29) and AF (HR 3.02, 95% CI 2.20-4.10). Risk of HF (HR 2.32, 95% CI 1.55-3.49) and the overall composite (HR 2.12, 95% CI 1.68-2.67) were also increased ( Figure ). Risk of each event remained significant after adjusting for age, sex, and baseline EF ( Table ). AR(+) patients with EF ≥50% also had increased risk of VA (HR 4.56, 95% CI 2.16-9.63), AF (HR 2.94, 95% CI 1.72-5.03), and the overall composite (HR 2.15, 95% CI 1.41-3.28). Conclusions: Genetic testing enables powerful risk stratification for both arrhythmias and heart failure in DCM/ACM independent of age, sex, or EF.

Abstract 4136452: Acute Cardiac Function Change After Catheter Ablation of Ventricular Arrhythmias in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterized by fibrofatty replacement of myocardial tissue, creating areas of electrical heterogeneity and increasing the risk of ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Catheter ablation is commonly performed in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) for management of ventricular arrhythmias (VAs). Whether catheter ablation affects cardiac function post-procedurally is uncertain. Research Question: Does catheter ablation for ARVC result in acute change in cardiac function? Goals/Aims: To assess the impact of catheter ablation for VAs on cardiac function in the acute post-procedure setting. Methods: This retrospective study included patients with ARVC who underwent catheter ablation for VAs at Mayo Clinic. Cardiac function was assessed on pre- and post-procedure transthoracic echocardiograms (TTEs). Post-procedure TTEs were obtained within 4 weeks after the ablation procedure. Right ventricular (RV) enlargement and systolic dysfunction were evaluated as continuous variables (0=none, 1=mild, 2=mild-moderate, 3=moderate, 4=moderate-severe, 5=severe). Results: The study included 32 patients who underwent a total of 44 ablations. Mean age at the time of ablation was 49±16 years, and 24 (75%) were male. After a mean follow-up duration of 2.6±5.5 days, there was a significant worsening in mean RV dysfunction (1.6±1.5 to 2.0±1.4, P = 0.001). There were no significant changes in mean left ventricular ejection fraction (LVEF), left ventricular (LV) dimensions, and RV size. 6 (14%) patients had a >5% decline in LVEF, and 14 (32%) patients had worsening RV function. Transient inotropic support was required in 4 (9%) patients. Conclusion(s): This study is the first to assess the acute impact of catheter ablation for VAs on cardiac function in ARVC patients. These results underscore the importance of careful post-procedure monitoring and planning of the ablation target in these patients to avoid excessive ablation and therefore impairment in cardiac function.

Abstract 4119187: Association of CMR derived Global Longitudinal Strain with adverse Outcomes in Arrhythmogenic Cardiomyopathy.

Background: Arrhythmogenic cardiomyopathy (ACM) is associated with high risk of ventricular arrhythmias (VA) and heart failure (HF). Different predictive models and diagnostic criteria include parameters related to myocardial structural abnormalities and right ventricular (RV) ejection fraction (EF). Nevertheless, the value of global longitudinal strain (GLS) ascertained from cardiac magnetic resonance (CMR) for risk-stratification in the context of ACM is unknown. Aim: We aim to study the association of low CMR-derived GLS with adverse outcomes in ACM patients. Methods: This was a retrospective cohort study of ACM patients seen at a single quaternary center. ACM diagnosis followed the modified 2010 ARVC modified task force criteria. Primary outcome was a composite of life-threatening VAs, heart transplant or HF hospitalization during follow up. We excluded patients who suffered events prior to diagnosis, and those with missing or inadequate CMR protocol. Imaging parameters were acquired by CMR including EF, GLS, and late gadolinium enhancement (LGE). Results: A total of 82 patients with suspected ACM were included, with a median age of 40 years, and 43 (52.4%) were females. Most common reason of initial visit was family history of genetic cardiomyopathy in 46 (56%), while 16 (20%) patients visited our clinic due to history of syncope. Out of 60 patients who had genetic testing, 21 (35%) had mutations of DSP gene. Left ventricular involvement (non-ischemic LV-LGE by CMR) was present in 42 (56.8%) out of 74 patients who had CMR with gadolinium. Median LVEF was 62% (56, 66), and RVEF of 53% (48, 59), both by CMR. Median LVGLS was -17.01% (-14.71, -18.43), while median RVGLS was -20.5% (-18.3, -24.4). A total of 15 (18%) patients suffered the composite endpoint during an average follow up period of 8 years. Patients who suffered the composite endpoint had significantly lower mean LVGLS (-15.04% vs -16.70%, p= 0.048), and lower average RVGLS (-18.45% vs -21.33%, p=0.035) compared to patients free from the adverse outcome. Meanwhile there was no significant difference in LVEF (60.13% vs 61.18%, p=0.67), nor in RVEF (49.13% vs 54.01%, p=0.065) between the two groups. Conclusion: Lower GLS was significantly associated with VAs and HF hospitalizations in our patient population. CMR derived GLS can be used as an important prognostic parameter of adverse outcomes in patients with suspected ACM. Especially in those with LV involvement and high genetic predisposition as our cohort.

Abstract 4140148: Genetic Influence in Patients Transplanted for Myocarditis in the TOPMed-TOPCHeF Cohort of Explanted Hearts

Background: Myocarditis is a leading cause of secondary cardiomyopathy and stems from infection, medications, or immune etiologies. Recent reports identify an overlap between myocarditis and pathogenic / likely pathogenic (P/LP) genetic variants of dilated and arrhythmogenic cardiomyopathies (DCM/ACM). Hypothesis: We hypothesized that myocarditis leading to heart failure and transplantation could be influenced by P/LP mutations for DCM/ACM. Aims: To evaluate the impact of genetics in myocarditis, we investigated a series of patients presenting with symptoms consistent with myocarditis who were found to have P/LP genetic signatures for dilated and arrhythmogenic cardiomyopathies DCM/ACM. Methods: Patients with myocarditis, defined by retrospective clinical diagnosis, were selected from the NHLBI Trans-Omics for Precision Medicine (TOPMed) - Trans-Omics for Precision Medicine for Congestive Heart Failure (TOPCHeF) cohort. After informed consent, patients’ explanted hearts were collected in the University of Colorado Heart Tissue Bank. A total of 837 hearts (697 failing and 140 control hearts) underwent whole genome DNA sequencing (WGS). Results: 11 patients had a diagnosis of myocarditis based on clinical history. None had acute myocarditis at time of transplantation. P/LP variants in DCM/ACM genes were found in 6 patients. The average age at transplantation was 42.8 years for patients with genetic variants and 38.9 without. Demographics are included in table 1. The most common genetic variants were Titin truncations. Full genetic data are included in table 2. Conclusion: 50% of patients undergoing transplantation with a clinical diagnosis of myocarditis in the TOPMed-TOPCHeF population had P/LP variants in DCM/ACM genes. This underscores the importance of genetic testing in patients with a clinical presentation of myocarditis for future management implications.

Abstract 4136394: Elucidation of a novel genetic substrate responsible for genetically elusive ring-like arrhythmogenic cardiomyopathy

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart disease characterized by fibrofatty replacement of ventricular myocardium. Arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) is a phenotypic variant of ACM predominantly involving the LV. Mutations in genes encoding for desmosome proteins and filamin C have been implicated in ALVC, especially in the setting of a ring-like late gadolinium enhancement (LGE) imaging pattern. Objective: To identify the underlying genetic substrate responsible for genetically elusive ring-like ALVC in a patient with seemingly sporadic/recessive disease. Methods: A 38-year-old male was referred for genetic investigation to determine the underlying genetic substrate responsible for his ALVC phenotype. The patient fulfilled both electrocardiographic (low voltage in the limb leads and anterolateral T-wave inversions) and imaging (>1 segment of subepicardial LGE) criteria for ALVC. Additionally, the patient experienced unexplained episodes of tachycardia, shakiness, sweating, and nausea prompting concern for an underlying neuromuscular disease. Genome sequencing (GS) was performed on DNA isolated from the affected patient and both of his unaffected parents. Variants were filtered assuming either a sporadic de novo occurrence or an autosomal recessive inheritance pattern. Results: GS identified compound heterozygous GNPTAB variants in the affected patient. A previously reported maternally derived p.Leu257Leu (c.771G>A) variant involving the last nucleotide of exon 7 of the GNPTAB gene and a novel paternally inherited Lys834fs*5 frame-shift variant were identified. The p.Leu257Leu variant has been reported to cause aberrant splicing and exon skipping of the GNPTAB mRNA transcript. Pathogenic variants in the GNPTAB encoded N-acetylglucosamine-1 (GlcNAc)-phosphotransferase subunits alpha/beta cause mucolipidosis type III, a rare recessive lysosomal storage disease characterized by coarse facial features, developmental delay, short stature, skeletal deformities, and cardiac involvement including valvular thickening and cardiomyopathy. Conclusions: Here, using a genome sequencing trio analysis we identified a compound heterozygous GNPTAB pathogenic variants as the underlying genetic substrate in a patient with ring-like ALVC and concomitant neuromuscular disease manifestation. Genome sequencing may identify the genetic etiology responsible for an otherwise undifferentiated diagnosis of cardiomyopathy.

Abstract 4120763: Predicting Disease Risk Among Variants in Cardiomyopathy-Associated Genes Across Diverse Genetic Ancestries

Background: Many cases of cardiomyopathy (CM) are genetically inherited, and the expansion of broad genomic sequencing has opened the door for predicting those at risk for developing disease. However, genetic tools that help determine variant pathogenicity employ genetic data from predominantly European genetic ancestries. Understanding the full diversity of genetic variants in cardiomyopathy genes is central to identifying which variants will cause disease. Hypothesis: Participants of non-European genetic ancestry will have a higher burden of cardiomyopathy gene variants with "VUS" designation in ClinVar but will have equivalent/less penetrance of clinical cardiomyopathy compared to a European ancestry group. Methods: Participants in the AllofUs database with exome sequencing (ES) were queried and a cohort of 230,013 participants were retained after sample quality control filters. Participant genetic ancestry was based on the designated ancestry group determined via AllofUs as previously described (1). Participants were queried for variants in genes with definitive or moderate evidence of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (ACM) in ClinGen. Variants were filtered by ClinVar status (1* and above P/LP, 1* and above B/LB, and VUS). Participant CM disease status was determined via ICD-9/10 code. Results: For each ancestry group, prevalence of cardiomyopathy ranged from 0.34% in the Latino/admixed American ancestry group to 1.09% in the African group, with an average prevalence of 0.91% across all groups. The European group had a statistically significant lower percentage of ClinVar VUS variants at 26%, while all other non-European ancestry groups had a combined VUS prevalence rate of 35% (****p<0.0001). The penetrance of CM in participants with CM VUS variants was lower in combined non-European ancestry groups (0.84%) than European ancestry (1.02%) (*p=0.0156). Conclusion: Prevalence of ClinVar VUS variants varies across different genetic ancestry groups, with European ancestry having a lower burden of VUS variants compared to non-European groups. However, non-European ancestry groups with increased burden of VUS variants have lower disease penetrance. Citations: (1) The All of Us Research Program Genomics Investigators. Genomic data in the All of Us Research Program. Nature 627 , 340–346 (2024). https://doi.org/10.1038/s41586-023-06957-x

Abstract 4128590: Identical Twins, Non-Identical Results: Genetic Testing for Cardiomyopathy

Case: A 58-year-old male (Twin A) with no medical history presented with syncope while playing paddle ball. TTE showed LVEF 15-20%. Cardiac MRI (CMR) identified transmural late gadolinium enhancement (LGE) in the inferolateral wall of the LV, but angiography showed non-obstructive CAD. Four years later, his monozygotic twin (Twin B), also with no medical history, suffered cardiac arrest while playing paddle ball. TTE showed LVEF 5-10%. CMR revealed inferolateral LGE (Figure 1) with angiography showing non-obstructive CAD. Genetic testing was performed by different companies. Twin A was found to be heterozygous for myosin light chain kinase 3 ( MYLK3 ) p.R380H (c.1139C>A), a variant of uncertain significance (VUS). While rare (gnomAD allele frequency 2.7e -4 ), MYLK3 p.R380H is not conserved across species, exchanges amino acids with similar biochemical properties, and is predicted to be benign by in silico pathogenicity tools. Notably, MYLK3 was not sequenced in Twin B, who was instead found to be heterozygous for desmoplakin ( DSP ) p.R1002W (c.3004C>T). DSP p.R1002W is highly conserved, exchanges amino acids with dissimilar properties, and is very rare (gnomAD allele frequency 2.8e -5 ). In silico testing yielded conflicting results with some tools predicting it to be damaging to protein function. Interestingly, the variant was present in both twins but was classified differently by each company: likely benign for Twin A (and therefore not reported) and VUS for Twin B. First degree relatives are advised to undergo clinical screening and cascade genetic testing for DSP p.R1002W. Discussion: The presentation described is consistent with arrhythmogenic cardiomyopathy (ACM) and the family history strongly supports a genetic etiology. DSP is a causal gene for ACM with unique clinical features that are strikingly similar to those observed herein. The differences in genes tested and variant adjudication between companies has left diagnostic uncertainty; hence, definitive pathogenicity cannot be attributed to either variant without cosegregation analysis, which is ongoing. In summary, this case illustrates the challenges of variant interpretation, and the impact that this can have on genetic counseling and family screening.

Abstract 4135893: The Importance of Genetic Testing in Diagnosis and Management of Peripartum Cardiomyopathy: A Case Study

Introduction: At least 15% of women diagnosed with peripartum cardiomyopathy (PPCM) are found to have a pathogenic genetic variant associated with dilated cardiomyopathy. We present a patient with PPCM who required orthotopic heart transplantation (OHT) for cardiogenic shock. Her explant pathology and genetic testing played a critical role in identifying the etiology of her cardiomyopathy. Case Description: A 22-year-old primigravid woman with a history of asthma presented in labor and underwent a Cesarean delivery for non-reassuring fetal heart tones. She had noted exertional dyspnea, a dry cough, and orthopnea in her final weeks of pregnancy but had an otherwise uncomplicated pregnancy. Immediately following delivery, she suffered a cardiac arrest with pulseless electrical activity and developed cardiogenic shock. She was found to have severe biventricular systolic dysfunction with a left ventricular (LV) ejection fraction of 10%. She was cannulated on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and transferred to our center. She was transitioned from VA-ECMO to an axillary Impella 5.5 device but continued to require inotropic support without evidence of LV recovery. Therefore, she was listed for and successfully underwent OHT. Explant pathology (Figure 1) revealed arrhythmogenic cardiomyopathy (ACM). Her family history was significant for a maternal grandfather who died of an unspecified arrhythmia at age 57. Genetic testing via a commercial arrhythmia and cardiomyopathy panel revealed a pathogenic desmoplakin ( DSP) truncating variant ( DSP tv) p.Ser1894Leufs*34 in the N-terminal constitutive NMD-competent region, confirming the diagnosis of ACM. The patient had minor cutaneous findings, including curly hair, consistent with the clinical presentation of DSP -mediated ACM. Discussion: This case highlights the importance of genetic testing in all patients with PPCM, as well as attention to the explant pathology in those who undergo OHT. These practices can elucidate the mechanism of cardiomyopathy, inform the risks of disease progression and of relapse with subsequent pregnancy, and allow for cascade testing of family members.

Abstract 4125497: Diagnostic Discrepancies Revealed by Explant Pathology at the Time of Cardiac Transplant in Patients Clinically Diagnosed with Nonischemic Cardiomyopathy: Role of Cardiac Magnetic Resonance Imaging

Background: Differentiating between causes of non-ischemic cardiomyopathy is important for disease-directed treatment. Cardiac MRI (CMR) and the use of late gadolinium enhancement (LGE) have proven useful for enhancing diagnostic accuracy. Definitive assessment of cardiomyopathy etiology by explant pathology facilitates direct evaluation of CMR utility. Hypothesis: We hypothesized direct comparison between pre-transplant (Tx) CMR and explant pathology will improve the characterization of undifferentiated cardiomyopathy through examination of cases where pre- and post-Tx diagnoses were discordant. Aims: To evaluate discrepant cases to describe imaging patterns in relation to post-Tx diagnosis. Methods: Institutional Tx recipients between 2000 and June 2023 were queried for pre-Tx MRI (n=122). Discrepant cases were identified (n=8). Pre-Tx diagnostic modalities, including CMR, were reviewed, and CMR patterns were evaluated in association with ultimate explant diagnosis. Results: Of the eight patients with discrepant diagnoses, five carried clinical diagnosis of dilated cardiomyopathy, one hypertrophic cardiomyopathy, one peripartum cardiomyopathy, and one congenital heart disease having undergone tricuspid valve and ASD repair. Pathologic evaluation most frequently identified biventricular or left ventricular arrhythmogenic cardiomyopathy (ARVC) (n=6), where CMR disclosed a diffuse pattern of subepicardial LGE and pre-Tx diagnosis of DCM was most common. Two of these pathologic descriptions represented a different disease on genetic evaluation: one patient had Danon disease, another had a LMNA pathogenic variant. The presumed peripartum cardiomyopathy was identified as Fabry’s disease on pathology (however, genetic testing consistent with Danon disease). Both Danon disease patients had primarily subendocardial LGE on CMR. One patient with a DCM phenotype had HCM pathologically. Results summarized in Table 1. Conclusions: Cardiac MRI can be a useful modality for the evaluation of underlying cardiomyopathy and should prompt appropriate genetic testing. Diffuse subepicardial LGE frequently accompanied the diagnosis of ARVC whereas a non-subepicardial pattern reflected alternative etiologies identified only through genetic testing.

Gene Therapy in Cardiovascular Disease: Recent Advances and Future Directions in Science: A Science Advisory From the American Heart Association.

Cardiovascular disease remains the foremost cause of morbidity and mortality globally, affecting millions of individuals. Recent discoveries illuminate the substantial role of genetics in cardiovascular disease pathogenesis, encompassing both monogenic and polygenic mechanisms and identifying tangible targets for gene therapies. Innovative strategies have emerged to rectify pathogenic variants that cause monogenic disorders such as hypertrophic, dilated, and arrhythmogenic cardiomyopathies and hypercholesterolemia. These include delivery of exogenous genes to supplement insufficient protein levels caused by pathogenic variants or genome editing to correct, delete, or modify mutant sequences to restore protein function. However, effective delivery of gene therapy to specified cells presents formidable challenges. Viral vectors, notably adeno-associated viruses and nonviral vectors such as lipid and engineered nanoparticles, offer distinct advantages and limitations. Additional risks and obstacles remain, including treatment durability, tissue-specific targeting, vector-associated adverse events, and off-target effects. Addressing these challenges is an ongoing imperative; several clinical gene therapy trials are underway, and many more first-in-human studies are anticipated. This science advisory reviews core concepts of gene therapy, key obstacles, patient risks, and ongoing research endeavors to enable clinicians to understand the complex landscape of this emerging therapy and its remarkable therapeutic potential to benefit cardiovascular disease.

Desmoplakin Cardiomyopathy in Pediatric Patients: A Distinct, Underrecognized Cohort of Arrhythmogenic Cardiomyopathy.

DSP cardiomyopathy is a distinct subset of arrhythmogenic cardiomyopathy, reported primarily in adults, that has predominantly left ventricular involvement and features of myocarditis. Clinical characteristics, risk stratification, and management of pediatric patients with DSP variants are not well known. We sought to identify phenotypic features and prognosis of pediatric patients with DSP pathogenic or likely pathogenic variants. Multicenter, retrospective study of patients <21 years of age with DSP variants from 6 tertiary pediatric hospitals. Thirty-four patients, including 10 probands with clinical disease and 24 genotype-positive phenotype-negative patients, were included in the study. The majority of probands were initially diagnosed with myocarditis (50%) and had biventricular (60%) or left ventricular predominant (40%) disease. Chest pain was the most common symptom at presentation (30%), and all had troponin elevation. Probands with homozygous or compound heterozygous DSP variants were likely to present at an early age (<13 years) with symptoms of heart failure, severe biventricular involvement, and dermatologic abnormalities. Low-voltage QRS was the most prominent ECG abnormality. Of those who underwent implantable cardioverter defibrillator implantation, 50% received appropriate implantable cardioverter defibrillator therapy and were found to have significant biventricular involvement in addition to severe left ventricular dysfunction with an ejection fraction <35%. DSP cardiomyopathy in children and adolescents has varied phenotypic manifestations based on age and genotype and often can be diagnosed as myocarditis. Severe left ventricular dysfunction and biventricular involvement may be associated with a higher likelihood of malignant ventricular tachyarrhythmia.

Prevalence and Correlates of Anti-DSG2 Antibodies in Arrhythmogenic Right Ventricular Cardiomyopathy and Myocarditis: Immunological Insights from a Multicenter Study

Background: Autoantibodies against Desmoglein-2 desmosomal protein (anti-DSG2-ab) were identified in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) by Enzyme-Linked ImmunoSorbent Assay (ELISA); anti-intercalated disk autoantibodies (AIDAs) were identified in myocarditis and (ARVC) by indirect immunofluorescence (IFL). We aim to assess: (1) anti-DSG2-ab specificity in ARVC and myocarditis, (2) accuracy of anti-DSG2-ab detection by ELISA versus AIDA by IFL, and (3) clinical correlates of anti-DSG2-ab in ARVC. Methods: We included 77 patients with ARVC, 91 with myocarditis/dilated cardiomyopathy (DCM), 27 with systemic immune-mediated diseases, and 50 controls. Anti-heart antibodies (AHAs) and AIDAs were assessed by IFL, and anti-DSG2-ab by ELISA (assessed both by optical density, OD, and U/L). Receiving operator curve (ROC) analysis was used to assess ELISA diagnostic accuracy. Results: A relevant proportion (56%) of ARVC patients was anti-DSG2-ab-positive, with higher anti-DSG2-ab levels than controls. Anti-DSG2-ab titer was not different between ARVC and myocarditis/DCM patients (48% anti-DSG-ab positive). Frequency of anti-DSG2 positivity by ELISA was higher in AIDA-positive cases by IFL than AIDA-negative cases (p = 0.039 for OD, p = 0.023 for U/L). In ARVC, AIDA-positive patients were more likely to be AHA-positive (p &lt; 0.001), had pre-syncope (p = 0.025), and abnormalities in cardiac rhythm (p = 0.03) than ARVC AIDA-negative patients, while anti-DSG2-ab positivity did not have clinical correlates. Conclusions: Anti-DG2-ab detection in ARVC and myocarditis/DCM reflects immune-mediated pathogenesis to desmosomal proteins. Higher frequency of anti-DSG2-ab positivity by ELISA by U/L was higher in AIDA-positive cases by IFL than AIDA-negative cases, in keeping with the hypothesis that DSG2 is one of AIDA autoantigens. In ARVC, AIDA status but not anti-DSG2-ab showed distinct clinical correlates, possibly reflecting a wider AIDA autoantigenic spectrum.

Quantifying Cardiac Tissue Composition using QuPath and Cellpose: An Accessible Approach to Postmortem Diagnosis SAE

Sudden death can be the first symptom of cardiac disease, and establishing a precise postmortem diagnosis is crucial for genetic testing and follow-up of relatives. Arrhythmogenic cardiomyopathy (ACM) is a structural cardiomyopathy that can be challenging to diagnose postmortem because of differences in structural findings and propagation of the disease at the time of death. Cases can have minimal or no structural findings and later be diagnosed according to genotype, known as concealed cardiomyopathy. Postmortem diagnosis often lacks clinical information, whereas antemortem diagnosis is based on paraclinical investigations that cannot be performed after death. However, the entire substrate is available, which is unique to postmortem diagnosis and research and can provide valuable insights when adding new methods. Reactive changes in the heart such as myocardial fibrosis and fat are significant findings. The patterns of these changes in various diseases are not yet fully understood and may be limited by sampling material and conventional microscopic diagnostics.We demonstrate an automated pipeline in QuPath for quantifying postmortem picrosirius red cardiac tissue for collagen, residual myocardium, and adipocytes, by integrating Cellpose into a versatile pipeline. This method was developed and tested using cardiac tissues from autopsied individuals. Cases diagnosed with ACM and age-matched controls were used for validation and testing.This approach is free and easy to implement by other research groups using this as a template. This can potentially lead to the development of quantitative diagnostic criteria for postmortem cardiac diseases, eliminating the need to rely on diagnostic criteria from endomyocardial biopsies that are not applicable to postmortem specimens. We propose that this approach serves as a template for creating a more efficient process for evaluating postmortem cardiac measurements in an unbiased manner, particularly for rare cardiac diseases.

Why the Athlete's heart matters: Insights into Arrhythmogenic cardiomyopathy

Why the Athlete's heart matters: Insights into Arrhythmogenic cardiomyopathy

A review of alternative measurements in strain imaging for ventricular arrhythmia prediction.

Global longitudinal strain has been established as a reliable tool to assess global left ventricular function and a marker of subclinical left ventricular dysfunction unrecognized by the ejection fraction. On the other hand, ventricular arrhythmias are the most common cause of sudden cardiac death. Their early detection is a challenge. Possible prognostic markers for the risk of ventricular arrhythmias are discussed in the literature - electrocardiographic, cardiac magnetic resonance, computed tomography, radionuclide imaging, and markers from new echocardiographic techniques. Of the latter, at this stage of knowledge, several markers have been discussed as informative for predicting ventricular arrhythmias - global longitudinal strain, radial strain and mechanical dispersion, and most recently, myocardial work. As far as we are informed, global longitudinal strain is particularly useful in patients with normal echocardiographic parameters such as left ventricular ejection fraction, left atrial diameter, left ventricular wall thickness, and aortic root. The relationship between mechanical dispersion and ventricular arrhythmias has been widely studied. The relationship has been studied more in some patient populations - heart failure, ischemic heart disease, long QT syndrome and arrhythmogenic cardiomyopathy, congenital heart disease. The role of mechanical dispersion as a predictor of ventricular arrhythmias in metabolic syndrome is scarce.

Targeting Wnt Pathways with Small Molecules as New Approach in Cardiovascular Disease.

The increasing incidences of morbidity and mortality associated with cardiovascular diseases represent significant difficulties for clinical treatment and have a major impact on patient health. Wnt signaling pathways are highly conserved and are well known for their regulatory roles in embryonic development, tissue regeneration, and adult tissue homeostasis. Wnt signaling is classified into two distinct pathways: canonical Wnt/β-catenin signaling and noncanonical pathways, including planar cell polarity and Wnt/Ca2+ pathways. A growing body of experimental evidence suggests the involvement of both canonical and non-canonical Wnt signaling pathways in the development of cardiovascular diseases, including myocardial hypertrophy, arrhythmias, diabetic cardiomyopathy, arrhythmogenic cardiomyopathy, and myocardial infarction. Thus, to enhance patient quality of life, diagnosing and treating cardiac illnesses may require a thorough understanding of the molecular functions played by the Wnt pathway in these disorders. Many small-molecule inhibitors specifically target various components within the Wnt signaling pathways, such as Frizzled, Disheveled, Porcupine, and Tankyrase. This study aims to present an overview of the latest findings regarding the functions of Wnt signaling in human cardiac disorders and possible inhibitors of Wnt, which could lead to novel approaches for treating cardiac ailments.

Clinical overlap between healthy athletes and athletes with arrhythmogenic right ventricular cardiomyopathy

Abstract Introduction The extensive physiological cardiac remodelling that results from the haemodynamic stress of endurance exercise shares many features with the pathological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC), giving rise to a significant diagnostic challenge for clinicians. Contemporary discriminators of disease have been derived from comparisons between healthy athletes and non-athletic ARVC patients. Differentiation between healthy and diseased athletes may be more difficult. Purpose To assess published clinical differentiators of physiological remodelling from ARVC in a cohort of endurance athletes. Methods This project utilises data from the Pro@heart consortium comprising elite endurance athletes that have received comprehensive cardiac phenotyping using cardiac magnetic resonance imaging, echocardiography, resting and ambulatory electrocardiography and cardiopulmonary exercise testing. Measures of cardiac structure and function with potential to differentiate health and disease were assessed in healthy endurance athletes without symptoms or suspicion of ARVC, endurance athletes diagnosed with ARVC (meeting ARVC task force criteria) and athletes with suspected sub-clinical ARVC (complex ventricular arrhythmias and ≥1 task force criteria). One way ANOVA assessed differences in continuous variables, while Chi Square with pair wise Z test and Bonferroni p value correction were used to test for differences in nominal data. Results Athletes with ARVC and athletes with suspected ARVC displayed more clinical indicators of ARVC compared to healthy athletes (table 1). While a greater proportion of athletes with ARVC and suspected ARVC met ≥1 and ≥3 indicators of pathology compared to healthy athletes, it was relatively common for healthy athletes to meet ≥1 criteria (53%) and ≥3 criteria (14%) (table 2). Comparison of mean values showed right ventricular ejection fraction (RVEF) and right ventricular fractional area change (RV FAC) were lower in athletes with or suspected to have ARVC compared to healthy athletes, however no significant differences in burden of ventricular premature beats (VPB) were noted (table 1). A high burden of VPBs, evidence of ventricular arrhythmia, evidence of late gadolinium enhancement (LGE), a low RVEF, and a reduced RV FAC were more prevalent in athletes with ARVC compared to healthy athletes (table 2). However, there was clinically relevant overlap in all measures between healthy and diseased athletes (table 2). Right ventricular to left ventricular volume ratio was a particularly poor discriminator of pathology (table 1 &amp; 2). Conclusion Electrophysiological, structural and functional abnormalities are not uncommon in healthy athletes resulting in significant overlap with athletic ARVC patients. Future research is required to identify better clinical discriminators of disease, and to assess the clinical significance of abnormal measures in ostensibly healthy athletes

Arrhythmogenic right ventricular cardiomyopathy: the importance of biventricular strain in risk-stratification

Abstract Background Despite Arrhythmogenic right ventricular cardiomyopathy (ARVC) being a predominant right ventricle (RV) disease, concomitant left ventricle (LV) involvement has been recognized. ARVC diagnosis is made through the RV-centric 2010 Task Force Criteria (TFC), but previous studies already suggested the use of echocardiographic strain measures to better depict RV and LV dysfunction in these patients. No data however is available on the additional value of combining biventricular strain in ARVC for risk stratification. Purpose To assess the prognostic value of measuring both LV global longitudinal strain (GLS) and RV free wall strain (FWLS) analysis in patients with ARVC. Methods A total of 204 patients who met the TFC for the ARVC spectrum were included. Patients were categorized based on a cut-off of -18% for strain impairment in both ventricles. The end-point was a composite of all-cause mortality, arrhythmic events, ICD therapy and heart failure events. Results Patients (age 41 ± 17 years, 55% males) were divided into impaired (n=33), discordant (either RV or LV impaired, n=70), and normal (n=101) strain groups (Fig. 1A). Definite and borderline ARVC were diagnosed in 78% and 39%, respectively, at the time of first available echocardiography. During a follow-up of 87 [24-136] months, 60 (29%) experienced the combined outcome, and a significant difference in event-free survival was observed (p&amp;lt;0.001) between the 3 groups (Fig. 1B). In the multivariate analysis (Fig. 2), the strain grouping remained associated with outcome (p=0.040) after adjusting for age, gender, history of syncope and definite ARVC diagnosis, which were also significantly associated with the endpoint at the univariate analysis. A sub-analysis including only definite and borderline ARVC patients confirmed that the strain grouping was an independent predictor of the composite endpoint (p=0.027). Conclusion Biventricular involvement by strain analysis has additional prognostic value in ARVC patients and outcome is worse for those with both RV and LV involvement.Strain groups and Kaplan Meier curvesMultivariate analysis

Clinical value of anti-DSG2 antibodies in arrhythmogenic right ventricular cardiomyopathy: a real-life experience

Abstract Background/Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease leading to ventricular arrhythmias and heart failure. The diagnosis is challenging and currently based on a set of clinical criteria with limited sensitivity and specificity. Anti-desmoglein-2 (DSG2) antibodies were previously found in patients diagnosed with ARVC, while they were absent in both healthy controls and athletes. Purpose The study aimed to evaluate the diagnostic value of anti-DSG2 antibodies by comparing their concentration in patients with ARVC and other right ventricular diseases. Additionally, the prognostic value of the biomarker was assessed. Methods A cohort of 101 patients with a definite diagnosis of ARVC according to the 2010 Task Force criteria was enrolled (64 males, mean age 47 ± 16 years). The control group included patients with Ebstein anomaly and Eisenmenger syndrome (16 and 21 subjects, respectively). Anti-DSG2 antibody concentration was assessed using enzyme-linked immunosorbent assay (ELISA). After that, an ARVC cohort was followed for 3.9 ± 1.6 years for the occurrence of the primary endpoint of cardiac death or heart transplantation (HTx) and major arrhythmic events (MAEs) defined as ventricular fibrillation, sustained ventricular tachycardia (sVT) or appropriate implantable cardioverter-defibrillator intervention. Results The median anti-DSG2 antibody concentration presented as ELISA optical density (OD) reached 1.36 [0.54-2.15] in the ARVC cohort, while it was 0.4 [0.34-0.54] in Ebstein anomaly group and 0.36 [0.28-0.58] in the Eisenmenger syndrome group. There was a significant difference in antibody levels between ARVC and both control groups (p &amp;lt; 0.001, Figure 1). The cutoff value for the diagnosis of ARVC was 0.774, with 72.3% sensitivity and 100% specificity (AUC = 0.823). After dividing the ARVC cohort according to the designated cutoff point, the anti-DSG2-positive subgroup was significantly younger (44.5 ± 15.4 vs. 52.8 ± 15.5 years, p = 0.017) and more likely to have a history of sVT (68.5% vs. 46.4%, p = 0.041). There was no difference regarding sex, presence of PKP2 or DSG2 mutations, previous sports activities, history of sudden cardiac arrest or syncope, right ventricular dimensions and systolic function, left ventricular ejection fraction and heart failure symptoms. This threshold was not predictive for the primary endpoint and MAEs. However, a more stringent cutoff value for anti-DSG2 level (1.021) was found to predict death or HTx (HR [95% CI] 4.56 [1.05-19.76], p = 0.026, Figure 2). Conclusions The concentration of anti-DSG2 antibodies is significantly higher in ARVC compared to other right ventricular diseases. A high antibody level is prognostic for death or HTx in ARVC.Figure 1Figure 2

Vector Field Heterogeneity (VFH) as a novel quantitative marker of electrical disarray in Arrhythmogenic CardioMyopathy (ACM) with ventricular tachycardia

Abstract Background ACM is a hereditary condition characterized by fibrofatty infiltration and replacement of cardiac myocytes predominantly presenting with ventricular arrhythmias (VA). Cardiac imaging allows for detailed structural phenotyping of scar patterns in ACM. Yet, there is a lack of tools to objectively quantify the electrical substrate alterations that may enable a more precise identification of critical sites that predispose to VA. Purpose To quantify locally disorganized cardiac electrical propagation wavefronts using the Vector Field Heterogeneity (VFH) metric from high-density multi-electrodes in patients with ACM with VT and compare to healthy controls. Methods High density epicardial substrate maps acquired with a 16-pole grid catheter during SR or RV pacing in patients with ACM with VA, who underwent clinically indicated catheter ablation, were retrospectively reviewed. Patients with structurally normal heart and idiopathic VA with epicardial ablation were analysed as a control group. Unipolar contact mapping data was exported &amp; processed offline. From the 4×4 electrode array EGMs, vector maps of the directions of electrical propagation for recorded sites were computed. The VFH was then computed as a quantitative measure of local heterogeneity of propagation, with higher VFH expected to correlate with sites of (micro)structural tissue alterations. VFH was compared between ACM and control patients as well as at sites of normal, border zone &amp; scar based on omnipolar voltage in ACM patients (&amp;gt;1.5mV, 0.5mV–1.5mV, &amp;lt;0.5mV, respectively). Results 10 patients with ACM (70% male, aged 52 ±18 years, ARVC 70%, biventricular 30%, RVEF 40.7±4.7%, LVEF 66±12%) and 2 patients with structurally normal heart (female, 38 &amp; 61 years) were included. Epicardial maps had an average of 9258 ±5412 EGM points. Median VFH was statistically significantly higher in the ACM cohort compared to control for global maps (0.33±0.33 vs 0.13±0.22, p&amp;lt;0.001) and at sites with voltage &amp;gt;1.5mV (i.e. greater disorganization in ACM, p&amp;lt;0.001). In ACM, assessment of VFH according to omnipolar voltage sites (as a surrogate of scar) showed a quantifiable statistically significant increase in electrical disorganized propagation at sites of lower voltage (&amp;lt;0.5mV, median VFH 0.53±0.36) compared to borderzone (0.5-1.5mV, VFH 0.29±0.41) and normal voltage (&amp;gt;1.5mV, VFH 0.15±0.26), p &amp;lt;0.001 respectively. Conclusion Heterogenous electrical propagation as quantified by VFH is significantly increased in patients with ACM at sites of scar, but importantly also in areas of normal voltages when compared to non-ACM controls, possibly indicating microstructural alterations that are missed in traditional assessments of the arrhythmogenic substrate. Identifying and quantifying disorganized conduction patterns by VFH is a promising new mapping approach that could allow improved substrate characterization. Its diagnostic value to guide ablation therapy is currently being validated.VFH Metric ACM and ControlVFH Map Examples