Arrhythmogenic Right Ventricular Cardiomyopathy Patients Research Articles

Ventricular arrhythmia burden during different physical activities in patients with arrhythmogenic right ventricular cardiomyopathy: preliminary analysis

Abstract Background Patients suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC) should avoid intense endurance exercise to reduce the risk of adverse cardiac events and disease progression. While an active lifestyle would be preferable to a sedentary one, evidence for safe levels of physical activity in ARVC, however, is scarce. Purpose This study aimed to describe the ventricular arrhythmia burden experienced during exercise and immediate recovery - estimated as the prevalence of premature ventricular contractions (PVC) - of different exercise modalities and intensities on ARVC patients. Methods This preliminary analysis includes four (1F, 33±12 yrs, BMI 24±4 kg/m2) ARVC patients harboring a pathogenic plakophilin-2 variant and carrying an implantable cardioverter-defibrillator that performed different exercises while monitored via 12-lead ECG. The order of modalities was randomized and participants instructed to stop when surpassing perceived exertion of 15 on the Borg 6-20 scale. Resistance exercises included two-legged squats and single arm biceps curls (20 repetitions and 2 min duration). Endurance exercise included 5 min of treadmill walking and 3-min cycling bouts at heart rates (HR) of 80, 100 and 120 bpm, as well as cycling at 120 bpm with 2 additional min of active cool down. Blood lactate concentration was assessed after each cycling bout. Results No adverse cardiac event or early termination for medical reasons occurred. Figure 1 summarizes the relationship between HR, perceived exertion and PVC burden. During walking (HR 76 ± 8 bpm), PVC burden was 11 ± 6% (range 4 – 18%). Cycling at 82 ± 4 bpm induced a PVC burden of 7 ± 5% (range 3 – 14%), which increased to 13 ± 8% (range 3 – 21%) at 93 ± 2 bpm and increased further to 16 ± 16% (range 7 – 37%) at 105 ± 3 bpm. In all three intensities the PVC burden was higher in the first 3 min of recovery than during the activity itself. Adding a 2-min active cool down increased the PVC burden to 25 ± 16% (range 6 – 45%). 2-legged squats (HR 101 ± 15 bpm) had a PVC burden of 9 ± 12%, which increased to 19 ± 14% at recovery. One arm biceps curls (HR 75 ± 13 bpm) had a PVC burden of 4 ± 3% during the activity and 9 ± 5% during recovery. Perception of effort varied widely when cycling at 80 bpm (range 6 – 12) or 100 bpm (range 8 – 14), but less so at 120 bpm (range 13 – 15). Blood lactate concentration when cycling at 120 bpm ranged between 2.2 and 3.5 mmol/L, typically associated with exercise in the "heavy" intensity domain. Conclusions PVC burden was high and seemingly intensity-dependent during exercise and immediate recovery. The wide range of PVC burden for physiological or subjective markers of effort call for personalized recommendations on physical activity. Exercises with small muscle mass such as biceps curls seem to minimize the PVC burden, thus, training the different muscles separately could be an interesting avenue to maintain physical fitness in ARVC patients.

PKP2 gene therapy reduces ventricular arrhythmias, reverses ventricular remodeling, improves heart function, and reduces mortality in a mouse model of arrhythmogenic right ventricular cardiomyopathy

Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Purpose Mutations in desmosome gene Plakophilin-2 (PKP2) account for approximately 40% of ARVC cases and result in reduced gene expression. Our goal is to examine the feasibility and the efficacy of restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Methods Adeno-associated virus 9 (AAV9) was used to deliver a wild-type copy of PKP2 gene that is driven by a cardiac-selective promoter and expressed selectively in cardiomyocytes. Results We demonstrated that a single-dose AAV9-mediated PKP2 gene therapy effectively prevented disease onset before overt cardiomyopathy and attenuated disease progression after overt cardiomyopathy. Restoration of PKP2 expression led to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, attenuating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. Additional RNA sequencing analyses showed that durable restoration of PKP2 expression led to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusion These results indicate that a cardiac-selective AAV9-mediated PKP2 gene therapy may be a promising one-time treatment for ARVC patients with PKP2 mutations.

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY AND CARDIAC SARCOIDOSIS: THE GREY ZONE

Abstract Cardiac sarcoidosis (CS) is a rare multisystem disorder characterized by granulomatous infiltration of the myocardium, whose clinical manifestations can be extremely heterogeneus. We report the case of a 47–year–old man with a previous diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVD). In history he had a marked arrhythmic pattern with multiple episodes of sustained ventricular arrhythmias, biventricular disfunction (LVEF 37%, RVEF 32%) and extensive biventricular transmural late–gadolinium enhancement (greater than 50%) at cardiac RMN. At EKG epsilon wave mainly seen in precordial leads. In November 2022 he was implanted with bicameral defibrillator and in March 2023 he underwent ablation procedure for ventricular tachycardia with RF with endo–epicardial approach. In May 2023 he arrived at our Centre for acute decompensated heart failure. At restored hemodynamic stability, screening for the possible inclusion in transplant list was started. Right heart catheterization (RHC) showed low cardiac index with no pulmonary hypertension. Chest CT unexpectedly showed the presence of multiple micronodules with perilymphatic distribution with confluent appearance compatible with pulmonary sarcoidosis. In consideration of this result, the transplant program was temporarily postponed and investigations for possible cardiac involvement of an inflammatory nature were started. 18F–FDG PET–CT showed pulmonary, splenic, lymphonodal and especially cardiac uptake in the mid–distal segment of the lateral wall of the left ventricle and in the inferior–apical site suspicious for inflammatory pathology. Unfortunately, both lymphonodal and cardiac biopsies were inconclusive because of insufficient material. Nevertheless, the clinical scenario satisfied the Japanese criteria for possible CS; therefore, treatment with prednisone 1 mg/kg was started and a 18F–FDG PET–CT was planned after 3 months of steroid therapy. CS can disguise as a phenocopy of arrhythmogenic right ventricular cardiomyopathy because of several common characteristics, especially arrhythmic presentation. Due to these similarities, a careful overall evaluation of each patient with ARVD is mandatory as several transplant centers have reported cases of CS in explanted heart with a pretransplant misdiagnosis of ARVD or dilated cardiomiopathy. Performing a chest CT in all ARVD patients as part of transplant screening may be considered.

Long-Term Freedom From Ventricular Arrhythmias in ARVC With Endocardial Only Ablation: Predictors of Success

BackgroundAlthough the epicardial predominance of substrate abnormalities has been well demonstrated in early stages of arrhythmogenic right ventricular cardiomyopathy (ARVC), endocardial (ENDO) ablation may suffice to eliminate ventricular tachycardia (VT) in some patients. ObjectivesThis study aimed to report the long-term outcomes of ENDO-only ablation in ARVC patients and factors that predict VT-free survival. MethodsWe included consecutive patients with Task Force Criteria diagnosis of ARVC undergoing a first ENDO-only VT ablation between 1998 and 2020. Ablation was predominantly guided by activation/entrainment mapping for mappable VTs and pace mapping/targeting abnormal electrograms for unmappable VTs. The primary endpoint was freedom from any recurrent sustained VT after the last ENDO-only ablation. ResultsSeventy-four ARVC patients underwent ENDO-only VT ablation. VT noninducibility was achieved in 49 (66%) patients. During median follow-up of 6.6 years (Q1-Q3: 3.4-11.2 years), 40 (54.1%) patients remained free from any VT recurrence with rare VT ≤2 episodes in additional 12.2%. Among patients with noninducibility, VT-free survival was 75.5% during long-term follow-up. In multivariable analysis, >45 y of age at diagnosis (HR: 0.41; 95% CI: 0.17-0.98) and VT noninducibility (HR: 0.36; 95% CI: 0.16-0.80) were predictors of VT-free survival. ConclusionsLong-term VT-free survival can be achieved in over half of ARVC patients following ENDO-only VT ablation, increasing to over 75% if VT noninducibility is achieved. Our results support consideration of a stepwise ENDO-only approach before proceeding to epicardial ablation if VT noninducibility can be achieved particularly in older patients.

Right ventricular scalloping index as cardiac magnetic resonance-derived marker for diagnosis of arrhythmogenic right ventricular cardiomyopathy.

The cardiac magnetic resonance (CMR) evaluation of right ventricular (RV) morphologic abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is subjective. Here, we aimed to use a quantitative index, the right ventricular scalloping index (RVSI), to standardize the measurement of RV free wall scalloping and aid in the imaging diagnosis. We retrospectively included 15 patients with definite ARVC and 45 age- and sex-matched patients with idiopathic right ventricular outflow tract ventricular arrhythmia (RVOT-VA) as controls. The RVSI was measured from cine images on four-chamber view to evaluate its ability to distinguish between ARVC and RVOT-VA patients. Other cardiac functional parameters including strain analysis were also performed. The RVSI was significantly higher in the ARVC than RVOT-VA group (1.56 ± 0.23 vs 1.30 ± 0.08, p < 0.001). The diagnostic performance of the RVSI was superior to the RV global longitudinal, circumferential, and radial strains, RV ejection fraction, and RV end-diastolic volume index. The RVSI demonstrated high intraobserver and interobserver reliability (intraclass correlation coefficient, 0.94 and 0.96, respectively). RVSI was a strong discriminator between ARVC and RVOT-VA patients (area under curve [AUC], 0.91; 95% CI, 0.82-0.99). A cutoff value of RVSI ≥1.49 provided an accuracy of 90.0%, specificity of 97.8%, sensitivity of 66.7%, positive predictive value (PPV) of 90.9%, and a negative predictive value (NPV) of 89.8%. In a multivariable analysis, a family history of ARVC or sudden cardiac death (odds ratio, 38.71; 95% CI, 1.48-1011.05; p = 0.028) and an RVSI ≥1.49 (odds ratio, 64.72; 95% CI, 4.58-914.63; p = 0.002) remained predictive of definite ARVC. RVSI is a quantitative method with good performance for the diagnosis of definite ARVC.

Evaluating Catheter Ablation Versus Conventional Management for Ventricular Arrhythmias in Arrhythmogenic Right Ventricular Cardiomyopathy: A Five-Year Retrospective Cohort Study.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a challenging genetic disorder marked by ventricular arrhythmias and sudden cardiac death, particularly in athletes and young adults. Despite its clinical significance, the relative effectiveness and safety of catheter ablation versus conventional management in ARVC are not fully delineated. Objective This study evaluates the efficacy and safety of catheter ablation compared to conventional management in reducing ventricular arrhythmias and improving patient outcomes over five years in ARVC patients. Methods In a retrospective cohort design at Lady Reading Hospital, Peshawar, we analyzed 120 ARVC patients from January 2018 to December 2023. Patients were divided into two groups: those undergoing catheter ablation and those receiving conventional management. Primary outcomes assessed were recurrence of ventricular arrhythmias, procedural complications, hospitalization duration, and mortality rates. Logistic regression was adjusted for demographics and clinical variables. Results Catheter ablation significantly lowered the recurrence of ventricular arrhythmias (20% vs. 55%, p<0.01) and reduced hospital stay duration (4 ± 2 days vs. 7 ± 3 days, p<0.05). A trend toward reduced five-year mortality was observed in the catheter ablation group (5% vs. 15%, p=0.07). Age, New York Heart Association class, and exercise capacity emerged as significant predictors of outcomes. Conclusions Catheter ablation outperforms conventional management in reducing the recurrence of ventricular arrhythmias and hospitalization in ARVC patients, with a promising trend toward enhanced survival. These findings advocate for personalized management strategies in ARVC, highlighting the necessity for further research to establish the long-term benefits of catheter ablation.

Prognostic value of right atrial strains in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty infiltration of atrial and ventricular myocardium resulting in adverse cardiac events. Atrial function has been increasingly recognized as prognostically important for cardiovascular disease. As the right atrial (RA) strain is a sensitive parameter to describe RA function, we aimed to analyze the prognostic value of the RA strain in ARVC. RA strain parameters were derived from cardiac magnetic resonance (CMR) images of 105 participants with definite ARVC. The endpoint was defined as a combination of sudden cardiac death, survival cardiac arrest, and appropriate implantable cardioverter-defibrillator intervention. Cox regression and Kaplan-Meier survival analyses were performed to evaluate the association between RA strain parameters and endpoint. Concordance index (C index), net reclassification index (NRI), and integrated discrimination improvement (IDI) were calculated to assess the incremental value of RA strain in predicting the endpoint. After a median follow-up of 5years, 36 (34.3%) reaching the endpoint displayed significantly reduced RA strain parameters. At Kaplan-Meier analysis, impaired RA reservoir (RARS) and booster strains (RABS) were associated with an increased risk of the endpoint. After adjusting for conventional risk factors, RARS (hazard ratio [HR], 0.956; p = 0.005) and RABS (HR, 0.906; p = 0.002) resulted as independent predictors for endpoint at Cox regression analyses. In addition, RARS and RABS improved prognostic value to clinical risk factors and CMR morphological and functional predictors (all p < 0.05). RARS and RABS were independent predictors for adverse cardiac events, which could provide incremental prognostic value for conventional predictors in ARVC. We evaluated the prognostic value of right atrial strain in ARVC patients and suggested cardiologists consider RA strain as a predictive parameter when evaluating the long-term outcome of ARVC patients in order to formulate better clinical therapy. • Patients with ARVC had significantly reduced RA strain and strain rates compared with healthy participants. • Participants with lower RA reservoir and booster stains were associated with a significantly higher risk of adverse cardiac events. • RA booster and reservoir strain provide incremental value to conventional parameters.

Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse.

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and Pwave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/- ), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated Pwave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV 1.5membrane clustering in Plako+/- atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone,might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and Pwave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to Pwave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized NaV 1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.

Ventricular arrhythmia burden during different physical activities in patients with arrhythmogenic right ventricular cardiomyopathy: Preliminary analysis

Introduction&#x0D; Patients suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC) should avoid intense endurance exercise to reduce the risk of adverse cardiac events and disease progression. On the other hand, an active lifestyle might be preferable to a sedentary one, which also brings a host of complications. Evidence for safe levels of physical activity in ARVC, however, is scarce. This is study aimed to describe the ventricular arrhythmia burden - estimated as the prevalence of premature ventricular contractions (PVC) - of different exercise modalities and intensities on ARVC patients.&#x0D; Methods&#x0D; The pilot analysis includes four (1F, 33 ± 12 yrs, BMI 24 ± 4 kg/m2) ARVC patients harboring a pathogenic plakophilin-2 variant and carrying an implantable cardioverter-defibrillator performed different exercises while monitored via 12-lead ECG. The order of modalities was randomized and participants instructed to stop when surpassing perceived exertion of 15 on the Borg 6-20 scale. Resistance exercises included two-legged squats and single arm biceps curls (each with 20 repetitions and 2 min duration) while endurance exercise included 5 min of treadmill walking, 3 min cycling bouts at heart rate (HR) of 80, 100 and 120 bpm as well as cycling at 120 bpm with 2 additional min of active cool down. Blood lactate concentration was assessed at the end of the cycling bouts.&#x0D; Results&#x0D; No adverse cardiac event were noted and no exercise was terminated for medical reasons. During walking HR was 76 ± 8 bpm, whereas PVC burden was 11 ± 6% (range 4-18%). Cycling at 82 ± 4 bpm induced a PVC burden of 7 ± 5% (range 3- 14%), which increased to 13 ± 8% (range 3- 21%) at 93 ± 2 bpm and further to 16 ± 16% (range 7-37%) at 105 ± 3 bpm. In all three modalities the PVC burden was higher in the first 3 min of recovery than during the activity itself. Adding a 2 min active cool down increased the PVC burden to 25 ± 16% (range 6-45%). 2-legged squats performed at 101 ± 15 bpm had a PVC burden of 9 ± 12%, which increased to 19 ± 14% at recovery. One arm biceps curls at 75 ± 13 bpm had a PVC burden of 4 ± 3% during the activity and 9 ± 5% during recovery. Perception of effort varied widely when cycling at 80 bpm (range 6-12) or 100 bpm (range 8-14), but less so at 120 bpm (range 13-15). Blood lactate concentration when cycling at 120 bpm ranged between 2.2 and 3.5 mmol/L, typically associated with exercise in the “heavy” intensity domain.&#x0D; Discussion/Conclusion&#x0D; ARVC patients present a high, intensity-dependent PVC burden during exercise and short-term recovery. However, we observed widely different PVC burdens and perceived exertion at a given HR during different exercise modalities, which calls for personalized recommendations on physical activity. Exercises with small muscle mass seem to minimize the PVC burden and training the different muscles separately could be an interesting avenue to maintain physical fitness in ARVC patients.

Differences in underlying cardiac substrate among S-ICD recipients and its impact on long-term device-related outcomes: Real-world insights from the iSUSI registry

BackgroundOutcome comparisons among subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients with nonischemic cardiomyopathies are scarce. ObjectiveThe aim of this study was to evaluate differences in device-related outcomes among S-ICD recipients with different structural substrates. MethodsPatients enrolled in the i-SUSI (International SUbcutaneouS Implantable cardioverter defibrillator registry) project were grouped according to the underlying substrate (ischemic vs nonischemic) and subgrouped into dilated cardiomyopathy, hypertrophic cardiomyopathy, Brugada syndrome (BrS), arrhythmogenic right ventricular cardiomyopathy (ARVC). The main outcome of our study was to compare the rates of appropriate and inappropriate shocks and device-related complications. ResultsAmong 1698 patients, the most common underlying substrate was ischemic (31.7%), followed by dilated cardiomyopathy (20.5%), BrS (10.8%), hypertrophic cardiomyopathy (8.5%), and ARVC (4.4%). S-ICD for primary prevention was more common in the nonischemic cohort (70.9% vs 65.4%; P = .037). Over a median (interquartile range) follow-up of 26.5 (12.6–42.8) months, no differences were observed in appropriate shocks between ischemic and nonischemic patients (4.8%/y vs 3.9%/y; log-rank, P = .282). ARVC (9.0%/y; hazard ratio [HR] 2.492; P = .001) and BrS (1.8%/y; HR 0.396; P = .008) constituted the groups with the highest and lowest rates of appropriate shocks, respectively. Device-related complications did not differ between groups (ischemic: 6.4%/y vs nonischemic: 6.1%/y; log-rank, P = .666), nor among underlying substrates (log-rank, P = .089). Nonischemic patients experienced higher rates of inappropriate shocks than did ischemic S-ICD recipients (4.4%/y vs 3.0%/y; log-rank, P = .043), with patients with ARVC (9.9%/y; P = .001) having the highest risk, even after controlling for confounders (adjusted HR 2.243; confidence interval 1.338–4.267; P = .002). ConclusionMost S-ICD recipients were primary prevention nonischemic cardiomyopathy patients. Among those, patients with ARVC tend to receive the most frequent appropriate and inappropriate shocks and patients with BrS the least frequent appropriate shocks.

Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy

BackgroundDilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited.MethodsSingle-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster.ResultsRight ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model).ConclusionsThis study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.

Risk of atrial arrhythmias in patients with ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy

BackgroundIn arrhythmogenic right ventricular cardiomyopathy (ARVC), risk of atrial arrhythmias (AAs) persists after ventricular tachycardia (VT) ablation. ObjectiveThe purpose of this study was to determine the type, prevalence, outcome, and risk correlates of AA in ARVC in patients undergoing VT ablation. MethodsProspectively collected procedural and clinical data on ARVC patients undergoing VT ablation were analyzed. Risk score for typical atrial flutter was determined from univariate logistic regression analysis. ResultsOf 119 consecutive patients with ARVC and VT ablation, 40 (34%) had AA: atrial fibrillation (AF) in 31, typical isthmus-dependent atrial flutter (AFL) in 27, and atrial tachycardia/atypical flutter (AT) in 10. Seventeen patients (43%) with AA experienced inappropriate defibrillator therapy, with 15 patients experiencing shocks. Ablation was performed for typical AFL in 21 (53%), AT in 5 (13%), and pulmonary vein isolation for AF in 4 (10%) patients and prevented AA in 78% and all AFL during additional mean follow-up of 65 months. Risk score for typical flutter included age >40 years (1 point), ≥moderate right ventricular dysfunction (2 points), ≥moderate tricuspid regurgitation (2 points), ≥moderate right atrial dilation (2 points), and right ventricular volume >250 cc (3points), with score >4 identifying 50% prevalence of typical flutter. ConclusionAAs are common in patients with ARVC and VT, can result in inappropriate implantable cardioverter-defibrillator shocks, and typically are controlled with atrial ablation. A risk score can be used to identify patients at high risk for typical AFL who may be considered for isthmus ablation at the time of VT ablation.

Progression of definite and non-definite Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and risk of major adverse cardiac events

Abstract Background In patients with Arrhythmogenic right ventricular cardiomyopathy (ARVC, also called"Arrhythmogenic Cardiomyopathy"), it is a challenge to predict those at greatest risk of major adverse cardiac events (MACE). Our hypothesis is that risk of arrhythmia may be preceded by change in ventricular structure and function. Purpose To assess the association between change in ventricular structure and function over time and risk of (MACE) in ARVC. Methods 101 definite and non-definite ARVC patients (defined as per Revised Task Force criteria (TFC)) were included with at least two sequential echocardiography and ECGs between 2010 and 2022. Structural progression was defined as development of new 2010 TFC on echocardiography during follow-up. MACE were defined as ventricular fibrillation (VF), sustained ventricular tachycardia (Sus VT), appropriate implantable cardio-defibrillator (ICD) therapy (shock/anti-tachycardia pacing (ATP)), heart failure, cardiac transplantation and death. Results Of the 101 patients, 51 had a definite diagnosis of ARVC, and 50 had a non-definite ‘early’ diagnosis, of whom a total of 66 (68%) carried a pathogenic variant associated with ARVC. Most were male 58 (57%), and the median age at presentation was 39 years (IQR: 27 - 53). Palpitations 41 (41%) and syncope 25 (25%) were the most common symptoms at baseline. 21 (23%) of the entire population were engaged in competitive exercise. At baseline, 22/101 (22%) patients presented with MACE, in which 20 (91%) definite patients met either minor or major imaging criteria at inclusion. During 4 years follow up (IQR: 2 – 6), 22 patients experienced MACE, in which 11 with history of MACE and 11 without, of those (15 (68%)) had structural progression. Additionally, 9 patients had structural progression of which 5 patients had history of MACE and no second event during follow up and 4 patients had no MACE at baseline or during follow up. Results showed that the odds of structural progression were significantly higher in patients with MACE than without (Table 1). Conclusion Structural progression was strongly associated with MACE events. This finding raises the possibility that tracking change over time identifies those patients at greatest risk of arrhythmia, with significant changes in right ventricular measurements.

Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient's disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (PKP2, n = 8) and gene-elusive (GE, n = 8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy for PKP2 patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while in PKP2 patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC.

Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient’s disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (PKP2, n = 8) and gene-elusive (GE, n = 8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy for PKP2 patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while in PKP2 patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC.

Abstract P3079: Integrating Existing Cardiac Single-cell RNA Sequencing Datasets To Uncover The Role Of B-cells In Heart Disease

Introduction: The role of B-cells in human heart failure remains unclear. To address this knowledge gap, we analyzed publicly available datasets of scRNAseq and snRNAseq from patients with various forms of cardiomyopathy. Methods and Results: We used two public datasets including single cells or single nuclei RNAseq data collected from the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), idiopathic cardiac diseases (ICD), or healthy controls. The first dataset comprised 30 healthy controls and 22 non-ischemic DCM; the second contained 18 controls and 61 with DCM, ARVC, or ICD. Data were normalized and scaled, a UMAP plot was generated, and cells were classified using ScType. B-cells were merged into a single matrix, and the final dataset contained 1100 cells from 32 healthy controls, 59 DCM, and 8 ARVC patients. Four different B-cell clusters were identified. The top 100 biomarkers from each cluster were used to identify B-cell subtypes. Cluster 1 was identified as transitional splenic B-cells; Cluster 2 as plasma cells; Cluster 3 as follicular splenic B-cells; Cluster 4, present only in DCM, as immature B cells. Ingenuity Pathway Analysis (IPA) of the genes enriched in each cluster highlighted that different B cell clusters displayed distinct biological activity, ranging from phagosome formation to B cell receptor signaling and cytokine production. Differentially expressed gene analysis comparing healthy controls to DCM and ARVC showed both similar and disease-specific gene expression patterns in the various B cell clusters. For instance, cluster 2 showed upregulation of oxidative phosphorylation in both DCM and ARVC. On the other hand, DCM cluster 2 showed downregulation of CD40 signaling, while in ARVC the same cluster showed downregulation of IL-6 signaling (Z score &gt;2, p&lt;0.05). Discussion: Our findings suggest that human heart failure is associated with perturbations in B cell gene expression, with both shared and disease-specific features. This data supports the notion that B cells likely play a role in human cardiomyopathy. Further, this data suggests that B-cells play distinct roles in disparate forms of cardiac disease.

Abstract P2135: A Novel Pkp2 Mouse Model Of Genetic Arrhythmogenic Right Ventricular Cardiomyopathy And Its Rescue By Gene Therapy

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder in which cardiomyocytes lack structural integrity and signaling is compromised resulting in the disruption of normal rhythms and formation of fibrosis. Patients suffer from arrhythmia and are at increased risk of sudden cardiac death and heart failure. Previous work has demonstrated that heterozygous mutations in the desmosomal gene, plakophilin-2 ( PKP2 ), are the most common cause of ARVC. Our objective was to investigate the mechanisms of ARVC development and test a potential ARVC gene therapy strategy using a novel mouse model of Pkp2. Methods: A knock-in (KI) mouse model with a point mutation corresponding to human PKP2 ( PKP2 c.2146-1G&gt;C or Pkp2 KI) was generated via CRISPR/Cas9 technology. High fat diet (HFD) was used to induce the ARVC phenotype in the Pkp2 KI heterozygous (het) mice. The Pkp2 KI het mice were crossed with a cardiac-specific Pkp2 cKO (αMHC-Cre ERT ) mouse to generate a tamoxifen inducible model (KIxKO). Cardiac function was assessed by echocardiography and arrhythmia burden by EKG. The KIxKO animals received AAV:PKP2 via retro-orbital injection. Results: Pkp2 KI het animals with normal chow had slow and mild ARVC development, and 50% decrease in PKP2 protein expression, with right ventricle (RV) dilation not occurring until animals were 9 months old. Induction with HFD from 8 weeks hastened and worsened the RV dilation. In contrast, the KIxKO mice exhibited &gt;90% decrease in PKP2 protein expression and a correspondingly severe ARVC phenotype starting from 3 weeks after Tamoxifen induction. This included a high arrhythmia burden and both RV area dilation and decreased ejection fraction, indicating the mice eventually progressed to biventricular heart failure. This resulted in 100% mortality in KIxKO animals by 9 weeks post-tamoxifen induction. A single dose of AAV:PKP2 gene therapy (6E13 vg/kg) maintained ejection fraction, prevented ARVC development and improved survival in the KIxKO mice after 9 weeks of treatment. Conclusion: The current results demonstrated that AAV:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations resulting in haploinsufficiency.

Exercise does not influence development of phenotype in PLN p.(Arg14del) cardiomyopathy.

Endurance and frequent exercise are associated with earlier onset of arrhythmogenic right ventricular cardiomyopathy (ARVC) and ventricular arrhythmias (VA) in desmosomal gene variant carriers. Individuals with the pathogenic c.40_42del; p.(Arg14del) variant in the PLN gene are frequently diagnosed with ARVC or dilated cardiomyopathy (DCM). The aim of this study was to evaluate the effect of exercise in PLN p.(Arg14del) carriers. In total, 207 adult PLN p.(Arg14del) carriers (39.1% male; mean age 53 ± 15years) were interviewed on their regular physical activity since the age of 10years. The association of exercise with diagnosis of ARVC, DCM, sustained VA and hospitalisation for heart failure (HF) was studied. Individuals participated in regular physical activities with amedian of 1661 metabolic equivalent of task (MET) hours per year (31.9MET-hours per week) until clinical presentation. The 50% most and least active individuals had asimilar frequency of sustained VA (18.3% vs 18.4%; p = 0.974) and hospitalisation for HF (9.6% vs 8.7%; p = 0.827). There was no relationship between exercise and survival free from (incident) sustained VA (p = 0.65), hospitalisation for HF (p = 0.81), diagnosis of ARVC (p = 0.67) or DCM (p = 0.39) during follow-up. In multivariate analyses, exercise was not associated with sustained VA or HF hospitalisation during follow-up in this relatively not-active cohort. There was no association between the amount of exercise and the susceptibility to develop ARVC, DCM, VA or HF in PLN p.(Arg14del) carriers. This suggested unaffected PLN p.(Arg14del) carriers can safely perform mild-moderate exercise, in contrast to desmosomal variant carriers and ARVC patients.

A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy.Graphical