Ventricular Cardiomyopathy Research Articles

Translation of Electrocardiography and Genetics in Arrhythmogenic Left Ventricular Cardiomyopathy

Translational cardiology combines different techniques in order to get a correct diagnosis (precision medicine). In a rare disease called arrhythmogenic left ventricular cardiomyopathy caused by non-desmosonal gene mutations 12-lead ECG and results of genetics were combined and analyzed. In a few gene mutations ECG findings were highly specific and predicts gene mutation, like desmoplakin, phospholamban, desmoglein-2, desmocollin-2, TMEM43, lamin A/C, and probably filamin C mutation. With the help of simple 12-lead ECG technique a precise prediction of specific gene mutation can be made.

Right Ventricular Strain Derived from Cardiac MRI Feature Tracking for the Diagnosis and Prognosis of Arrhythmogenic Right Ventricular Cardiomyopathy.

Purpose To demonstrate the myocardial strain characteristics of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), based on revised Task Force Criteria (rTFC), and to explore the prognostic value of strain analysis in ARVC. Materials and Methods This retrospective study included 247 patients (median age, 38 years [IQR, 28-48 years]; 167 male, 80 female) diagnosed with ARVC, based on rTFC, between 2014 and 2018. Patients were divided into "possible" (n =25), "borderline" (n = 40), and "definite" (n = 182) ARVC groups following rTFC. Biventricular global strain parameters were calculated using cardiac MRI feature tracking (FT). The primary outcome was defined as a composite of cardiovascular events, including cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator discharge. Univariable and multivariable cumulative logistic regression and Cox proportional hazards regression analysis were used to evaluate the diagnostic and prognostic value of right ventricle (RV) strain parameters. Results Patients with definite ARVC had significantly reduced RV global strain in all three directions compared with possible or borderline groups (all P < .001). RV global longitudinal strain (GLS) was an independent predictor for disease (odds ratio, 1.09 [95% CI: 1.02, 1.16]; P = .009). During a median follow-up of 3.4 years (IQR, 2.0-4.9 years), 55 patients developed primary end point events. Multivariable analysis showed that RV GLS was independently associated with the occurrence of cardiovascular events (hazard ratio, 1.15 [95% CI: 1.07, 1.24]; P < .001). Kaplan-Meier analysis showed that patients with RV GLS worse than median had a higher risk of combined cardiovascular events (log-rank P < .001). Conclusion RV GLS derived from cardiac MRI FT demonstrated good diagnostic and prognostic value in ARVC. Keywords: MR Imaging, Image Postprocessing, Cardiac, Right Ventricle, Cardiomyopathies, Arrhythmogenic Right Ventricular Cardiomyopathy, Revised Task Force Criteria, Cardiovascular MR, Feature Tracking, Cardiovascular Events Supplemental material is available for this article. © RSNA, 2024.

Cardiomyopathy in children: a single-centre, retrospective study of genetic and clinical characteristics

ObjectivesThis study aimed to describe the genetic and clinical characteristics of paediatric cardiomyopathy in a cohort of Chinese patients.MethodsWe retrospectively reviewed the clinical history and mutation spectrum of 75 unrelated...

Arrhythmogenic right ventricular cardiomyopathy with sustained ventricular tachycardia: a case report

IntroductionArrhythmogenic right ventricular cardiomyopathy (ARVC) is an infrequent hereditary disorder distinguished by fibrofatty replacement of the myocardium in the right ventricular, which predisposes individuals to life-threatening arrhythmias. This case delineates an ARVC patient who suffered recurrent bouts of sustained ventricular tachycardia (VT). In this case, we mainly discuss the application of myocardial contrast echocardiography (MCE) in displaying myocardial fibrosis in patients with ARVC.Case presentationA 43-year-old male experienced three episodes of unexplained VT over an eight-year period, accompanied by symptoms of chest discomfort, palpitations and dizziness. Coronary angiography revealed no significant coronary stenosis. The electrocardiogram (ECG) results indicated characteristic epsilon waves in right precordial leads, and subsequent echocardiography identified right ventricular enlargement and right ventricular systolic dysfunction. MCE further disclosed regional myocardial ischemia at the epicardium of the left ventricular apex. Ultimately, cardiovascular magnetic resonance imaging (CMR) corroborated the ARVC diagnosis, highlighting linear intensification in the right ventricle during the delayed enhancement.ConclusionPrompt identification of ARVC is crucial for timely intervention and management. MCE may offer an effective and valuable technique for the detection of myocardial involvement in ARVC patient.

Identification of Potential lncRNA-miRNA-mRNA Regulatory Network Contributing to Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) can lead to sudden cardiac death and life-threatening heart failure. Due to its high fatality rate and limited therapies, the pathogenesis and diagnosis biomarker of ARVC needs to be explored urgently. This study aimed to explore the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network in ARVC. The mRNA and lncRNA expression datasets obtained from the Gene Expression Omnibus (GEO) database were used to analyze differentially expressed mRNA (DEM) and lncRNA (DElnc) between ARVC and non-failing controls. Differentially expressed miRNAs (DEmiRs) were obtained from the previous profiling work. Using starBase to predict targets of DEmiRs and intersecting with DEM and DElnc, a ceRNA network of lncRNA-miRNA-mRNA was constructed. The DEM and DElnc were validated by real-time quantitative PCR in human heart tissue. Protein-protein interaction network and weighted gene co-expression network analyses were used to identify hub genes. A logistic regression model for ARVC diagnostic prediction was established with the hub genes and their ceRNA pairs in the network. A total of 448 DEMs (282 upregulated and 166 downregulated) were identified, mainly enriched in extracellular matrix and fibrosis-related GO terms and KEGG pathways, such as extracellular matrix organization and collagen fibril organization. Four mRNAs and two lncRNAs, including COL1A1, COL5A1, FBN1, BGN, XIST, and LINC00173 identified through the ceRNA network, were validated by real-time quantitative PCR in human heart tissue and used to construct a logistic regression model. Good ARVC diagnostic prediction performance for the model was shown in both the training set and the validation set. The potential lncRNA-miRNA-mRNA regulatory network and logistic regression model established in our study may provide promising diagnostic methods for ARVC.

Combination of arrythmogenic right ventricular cardiomyopathy with Loeys-Dietz syndrome: case report

Arrhythmogenic right ventricular dysplasia is a hereditary cardiomyopathy - a common cause of sudden cardiac death in children and young adults. Loeys-Dietz syndrome is an ultra-rare connective tissue disorder characterized by aneurysms of the aorta and other large arteries, arterial tortuosity, and joint hypermobility and is associated with pathogenic variants in genes encoding protein components TGF-β pathway. We present a rare case of a two-abovementioned genetic disorders combination in a proband with a complex and rapidly progressive cardiovascular syndrome.

Leaky RyR2 channels as pro-arrhythmic trigger in the PKP2-deficient atrial myocardium

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): American Heart Association National Institutes of Health Introduction Atrial arrhythmias, like atrial fibrillation, occur in 20–40% of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Atrial fibrillation in ARVC patients is often associated with an increased risk of sustained ventricular arrhythmias and inappropriate ICD shocks. However, the pathophysiology behind the development of atrial arrhythmias in ARVC is far from clear. A genome-wide association study, based on UK-biobank data, revealed a link between atrial fibrillation and variants in the desmosomal gene plakophilin-2 (PKP2). Previous studies show that PKP2 is necessary to maintain the transcription of genes that control intracellular calcium (Ca2+) cycling and that loss of PKP2 expression in adult mouse ventricular tissue leads to disruption of intracellular Ca2+ homeostasis. In this study, we test the hypothesis that loss of PKP2 expression leads to pro-arrhythmic changes in atrial myocytes. Methods Experiments were carried out using a cardiac-specific, tamoxifen (TAM)-activated PKP2 knockout murine model (PKP2-cKO). Cre-negative, flox-positive, TAM-injected littermates were used as controls. We used RNA sequencing, quantitative imaging modalities, as well as biochemical and electrophysiological methods to study the functional and structural properties of atrial PKP2cKO tissue. Studies were carried out 21 days post-tamoxifen injection, a time point at which an arrhythmogenic cardiomyopathy of right ventricular predominance is manifest. Results In contrast to the previously-reported observations in PKP2cKO ventricular myocytes, atrial PKP2cKO myocytes presented no significant differences in Ca2+ transient dynamics, SR load and action potential duration. However, PKP2cKO atrial myocytes showed an increased frequency and amplitude of Ca2+ sparks, in combination with increased diastolic Ca2+ levels as well as an increase in cellular ROS levels. RNAseq data showed an under-representation of mRNA for Integrinα7, a stabilizer of Ryr2 that reduces its phosphorylation. Separate studies showed that PKP2cKO atrial myocytes present impaired relaxation and enhanced sarcomere shortening, a finding consistent with a downregulation in the expression of Myosin Binding Protein C. Isoproterenol (ISO) exposure further increased the frequency of Ca2+ sparks and the levels of diastolic Ca2+, and these effects were reversed by acute (30 minute) in vivo treatment with Ryanodex (medical grade Dantrolene), a known RyR blocker. Conclusion Loss of PKP2 expression affects cellular Ca2+ handling and electrophysiology differently in the atrial versus ventricular myocardium. We speculate that an increased probability of opening of Ryr2 channels, caused by ROS-induced RyR2 oxidation and/or Integrinα7-induced RyR2 phosphorylation, serve as pro-arrhythmic trigger in the PKP2-deficient atrial myocardium, that these effects can be amplified by a catecholaminergic input and that RyR blockers can dampen these pro-arrhythmic effects.

Generation of an induced pluripotent stem cell line from a patient with arrhythmogenic right ventricular cardiomyopathy harboring a TMEM43 splice-site variant

Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy that is predominantly inherited and characterized by cardiac arrhythmias and structural abnormalities. TMEM43 (transmembrane protein 43) is one of the well-known genetic culprits behind ACM. In this study, we successfully generated an induced pluripotent stem cell (iPSC) line, YCMi010-A, derived from a male patient diagnosed with ACM. Although these iPSCs harbored a heterozygous intronic splice variant, TMEM43 c.443-2A > G, they still displayed normal cellular morphology and were confirmed to express pluripotency markers. YCMi010-A iPSC line is a promising model for investigating the pathomechanisms associated with ACM and exploring potential therapeutic strategies.

Use of 18F-fluorodeoxyglucose positron emission tomography in the differential diagnosis of arrhythmogenic right ventricular cardiomyopathy and cardiac sarcoidosis

Abstract Introduction Arrhythmogenic Cardiomyopathy (ACM) is defined as an arrhythmogenic heart muscle disorder not explained by ischemic, hypertensive, or valvular heart disease, which ranges from a systemic immunologic disorder such as cardiac sarcoidosis (CS), to a genetically determined one (arrhythmogenic right ventricular cardiomyopathy=ARVC). The aim of this study was to assess the utility of 18F-fluordeoxyglucose positron emission tomography /computer tomography (18F-FDG-PET/CT) in the differential diagnosis of ACM. Methods This study included 45 patients with a definite diagnosis of ARVC, in whom 18F-FDG-PET/CT was performed to screen for CS. Following a positive PET, diagnosis of CS was pursued according to the 2014 HRS consensus document. The patients were divided into two cohorts: the ARVC Cohort (ARVC-C) and the Cardiac Sarcoidosis Cohort (CS-C). Results All 45 patients received an 18F-FDG-PET/CT, of these 5 had a positive PET showing myocardial hypermetabolism. All 5 patients with a positive PET had a final diagnosis of histologically confirmed CS, as such the 18F-FDG-PET/CT had a negative predictive value (NPV) of 100%. All 45 patients also received genetic testing (cardiomyopathy panel). In the ARVC-C, 23 (58%) patients harbored a pathogenic (P)/likely pathogenic (LP) variant (40% in PKP2). In the CS-C, 1 (20%) patient with histologically confirmed CS harbored a LP DSG2 variant. Nine (23%) subjects in the ARVC-C presented with atrioventricular block (AVB) (grade I) and 7 (18%) with QRS fragmentation, whereas 5 (100%) patients in the CS-C presented with AVB (grade I and higher) and 4 (80%) with QRS fragmentation. On TTE, left ventricular (LV) involvement was less frequent in the ARVC-C (LVEF 52.2 +/- 8.7%; wall motion abnormalities in 19 patients (48%)), while LV-involvement in the CS-C was more frequent (LVEF 44.0 +/- 16.2%; wall motion abnormalities in 3 (60%). On cardiac magnetic resonance imaging (cMRI), late gadolinium enhancement was present in the ARVC-C in 14 (35%) in the RV and 15 (38%) in the LV, while it was present in 3 (60%) patients in the RV and 3 (60%) in the LV in the CS-C. Conclusions CS is an underdiagnosed clinical entity, which can be challenging to differentiate from ARVC. 18F-FDG-PET/CT has a high NPV to exclude CS in patients fulfilling definite ARVC criteria. Hence, we recommend to offer 18F-FDG-PET/CT to patients fulfilling definite ARVC criteria who present with AVB, QRS fragmentation, or biventricular involvement to screen for CS, especially to those who do not have an LP/P variant in the PKP2 gene.

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.

The evaluation of the efficacy of automated peak frequency annotation algorithm for the identification of critical isthmus of ventricular tachycardia and deceleration zones

Abstract Background Substrate modification techniques have widely been adopted due to hemodynamic instability and non-inducibility of clinical ventricular tachycardia (VT). Accurate annotation of local near field EGMs is paramount to better evaluate the ventricular substrate. Furthermore, annotation of late potentials (LP) necessitates substantial manual input and isochronal late activation mapping (ILAM) involves constant sensitivity adjustments, potentially affecting the accuracy of local ventricular signal representation. Objective This study aims to assess the utility of novel automated peak frequency (PF), which aims to determine near field local activity in low voltage regions in the prediction of the CI of scar related reentrant VTs. Furthermore, the effectiveness of automated PF annotation of near field EGMs to identify deceleration zone (DZ) during ILAM was also evaluated. Methods A total of 18 patients with scar-related VT were analyzed. In all patients, VT isthmuses were identified based on activation maps and acute termination achieved during radiofrequency ablation. Automated PF annotation using Ensite X system (Abbott) was retrospectively performed in all cases specifically in areas of low voltage with fractioned signals. The accuracy of applying the PF value and automated ILAM map for detecting VT isthmus was also assessed. Results Among the study group, 12 (66.7%) had ischemic cardiomyopathy, while 6 (33.3%) had nonischemic cardiomyopathy [3 (16.7%) with arrhythmogenic right ventricular cardiomyopathy, 2 (11.1%) with idiopathic dilated cardiomyopathy, and 1 (5.6%) with hypertrophic cardiomyopathy]. All identified isthmuses were located in areas exhibiting bipolar voltage below 0.5 mV and a PF of 250 Hz with fractionated EGMs Automated NF DZ annotation predicted the VT isthmus in 16/18 (88.9%) of the cases similar to the conventional ILAM with manual adjustment (88.9%). Conclusion Using high-density electroanatomical mapping with near field algorithm, a PF cutoff of 250 Hz accurately identified the low voltage regions to predict the CI of VT. In addition, automated annotation of EGMs during ILAM similarly identified the DZs compared with conventional last deflection algorithm with manual adjustments, which were colocalized with CI of VTs.

Impact of gender on the utilisation implantable cardioverter defibrillators and outcome: results from the German DEVICE registry

Abstract Background Implantable cardioverter defibrillators (ICD) are an established therapy for the primary and secondary prevention of sudden cardiac death. Real world data regarding the impact of gender on ICD implantation and outcome are scarce. Purpose To determine the impact of gender on the ICD implantation and outcome. Methods The German DEVICE registry is a prospective, nationwide database of ICD and CRT devices implantation and revisions. Between March 2007 and February 2014, 3794 patients undergoing a single or dual chamber ICD implantation and revisions were prospectively included in 44 centres and monitored for a median of 17 months. Herein we conducted the gender-based analysis of the ICD recipients. Results A total of 688 (18,1%) women (mean age 62.5 ± 16.0, median BMI 26.7) and 3106 men (mean age 64.6 ± 12.9, median BMI 26.8) were included in this registry. Significantly less women had coronary artery disease (p&amp;lt;0.001), while more women had hypertrophic cardiomyopathy (p=0.024) and primary electrical heart disease (p&amp;lt;0.001), mainly because of a higher incidence of long QT syndrome and arrhythmogenic right ventricular cardiomyopathy. There was a trend towards a higher rate dual chamber ICD in the female population (31.7% vs. 28.1%; p=0.061). Women were less likely to undergo ambulatory interventions (6.4% vs. 9.0%; p=0.026) and had a trend towards higher rate of ICD implantation for secondary prevention (52.3% vs. 48.7%; p=0.086). Females were more likely to have a history of ventricular fibrillation (51.7% vs. 39.4%; p&amp;lt;0.001) and resuscitation (54.7% vs. 46.3%; p=0.006), but less likely to have a history of ventricular tachycardia (33.1% vs. 45.2%; p&amp;lt;0.001). The overall rate of in-hospital complications (5.3% vs. 2.7%; p=0.005) as well as the rate of major periprocedural complications (3.1% vs. 1.3%; p=0.002) was significantly higher among females, mainly driven by a higher incidence of pneumothorax (1.0% vs. 0.1%; p=0.004) and haemothorax (0.4% vs. 0%; p=0.02). The rate of in-hospital device revision and mortality were similar between genders. The Kaplan-Meier estimated 1-year all-cause mortality was 5.2% for women and 7.1% for men (p=0.073; Fig 1), while the estimated incidence of all-cause mortality or device shocks was significantly lower in the female population (15.1% vs. 19.0%; p=0.02). Women were more likely to undergo resuscitation during follow-up (FU; 1.3% vs. 0.3%; p&amp;lt;0.001) and showed a higher fear of receiving device shocks. There was no difference in terms of ICD-shocks, VT-storm and ablation rates at FU. The all- cause, device-related, and other cardiovascular rehospitalisation rates and the incidence of non-arrhythmic adverse events during FU were similar between genders. Conclusions In this real-life patient cohort only a minority of patients were females. Female patients had a higher risk of major periprocedural complications and in-hospital complications and a trend towards a lower all-cause mortality during FU.Fig 1. Kaplan-Meier estimated survival.

Left ventricular ejection fraction and myocardial fibrosis in survivors of ventricular fibrillation and ventricular tachycardia

Abstract Background Primary prevention implantable cardioverter defibrillator (ICD) therapy is indicated in patients with a LVEF&amp;lt;35%. Increasing evidence suggests that LVEF is a poor predictor or ventricular arrhythmias, such as ventricular tachycardia (VT) or fibrillation (VF). Methods Patients hospitalized for VF (55.4%) or VT with hemodynamic compromise underwent late gadolinium enhancement cardiovascular magnetic resonance (CMR). Patients with congenital heart disease, channelopathies, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and chemotherapy-induced cardiomyopathy were excluded. Results Among patients (n=111, aged 62.1 ± 14.6 years [mean ± SD]) hospitalized for VF (55.4%) or VT with hemodynamic compromise (44.5%) only 29/111 (43.6%) had a history of cardiac disease. At the index hospitalization, an ischemic cause was identified in 69.3%, a non-ischemic cause in 24.8% and no cause emerged in 5.9%. The LVEF (39.1 ± 17.2%) was ≤35% in 55.4% and &amp;gt;35% in 44.6%. Myocardial fibrosis was present in 85.1% (LVEF≤35%: 91.1%; LVEF&amp;gt;35%: 77.8%; p = 0.0619). Conclusions A large proportion of sustained VT or VF survivors would not have previously met LVEF primary prevention criteria for ICD therapy. In this 'ICD treatment gap', myocardial fibrosis was more prevalent than a LVEF≤35%. Further studies are needed to determine whether myocardial scar rather than LVEF≤35% should be used as an indication for primary prevention ICD therapy.

Worse outcomes in patients with cardiac sarcoidosis and involvement of the right ventricle in cardiac magnetic resonance

Abstract Background Cardiac sarcoidosis (CS) can manifest with variety of unspecific symptoms. It can mimic all types of cardiomyopathies but most often it resembles dilated cardiomyopathy. Involvement of right ventricle (RV) is rare and may lead to a false diagnosis of arrhythmogenic right ventricular cardiomyopathy and delay of the immunosuppressive therapy. Purpose The aim of this research was to study the characteristics and the outcomes of this peculiar subtype of patients. Methods We analyzed 112 patients diagnosed with CS after elaborate work-up with cardiac magnetic resonance (CMR), FDG PET and endomyocardial biopsy (EMB). All patients underwent follow-up for occurrence of combined endpoint of death, LV assist device implantation or heart transplantation. Patients with evidence of late gadolinium enhancement (LGE) involving RV (RV group) were identified and compared to the rest (DCM group) for baseline clinical characteristics, arhythmic outcomes and combined endpoint. Results Involvement of the RV in CMR was observed in 19 (17%) patients. Patients in the RV group were more frequently male: 84% vs. 57%, P = 0.032. EMB confirmed CS in 63% vs. 19.4% in the DCM group; P= 0.0001. LV ejection fraction in the RV group was comparable to the DCM group: 42±14% vs. 45±14%; P = 0.3. Furthermore, in the RV group the rates of sustained ventricular tachycardia were significantly higher than the DCM: 68% vs. 34%; P = 0.009. Long-term immunosuppressive therapy was started in 74% in RV and in 70% of the DCM group; P=0.77. Despite this, during follow-up, the rate of death, LVAD implantation or heart transplantation was significantly higher in the RV than in the DCM group; 26.3% vs. 7.5%; P = 0.03. In binary logistic analysis, the OR for the combined endpoint was 4.4; 95% CI 1.2-15.7. Conclusions Patients with CS and RV involvement in CMR have worse outcomes as compared to patients presenting as DCM, despite the comparable LV EF and immunosuppressive therapy.

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.

Revealing functional-molecular parasympathetic dysfunction in PVC-induced cardiomyopathy via dual stressor PVC and exercise

Abstract Background Exercise intolerance is a common presentation of premature ventricular contractions-induced cardiomyopathy (PVC-CM). In a canine PVC-CM model, previous studies have shown cardiac autonomic nervous system remodeling, resulting in persistent sympathetic excess. Nevertheless, the molecular mechanisms and functional implications of this neural remodeling, as well as parasympathetic alterations, remain unclear. Purpose We aim to evaluate the functional-molecular mechanisms of parasympathetic remodeling and its potential contribution to exercise intolerance in an animal model of PVC-CM. Methods We studied 15 canines (8 experimental vs 7 sham controls) chronically instrumented with pacemakers and telemetry devices to deliver 12-weeks of bigeminal PVCs (200ms coupling) to induce PVC-CM and to record sympathetic (SNA), vagal nerve activity (VNA) and heart rate (HR) over this period. Exercise challenge was conducted in sinus rhythm (SR) and in the presence of bigeminal PVCs ("dual stressor") at baseline and after development of PVC-CM. Sympatho-vagal neural and HR responses were assessed during and after exercise at baseline and after PVC-CM development, with and without PVCs, thus comparing baseline SR, baseline with PVCs, CM SR and CM with PVCs. Western Blot was performed on intrinsic and extrinsic cardiac neural tissues to evaluate molecular mechanisms of neural remodeling. Results Compared to baseline, SNA was significantly higher in PVC-CM in all phases of exercise (rest, exercise, recovery, p=0.03). In contrast, VNA was significantly lower in PVC-CM than baseline during exercise recovery (P=0.014). After exercise, HR recovery (HRR) was impaired (p=0.001), VNA lower (p=0.014) and SNA (p=0.03) higher in PVC-CM compared with baseline. Tyrosine hydroxylase (TH) immunoreactivity in the left ventricle (LV, p=0.001) and stellate ganglia (SG, p=0.03) and trans-cardiac plasma NE levels (p=0.03) were higher in PVC-CM compared with sham. Choline Acetyltransferase (CHAT) was not significantly different in either vagus (p=0.33) or LV (p=0.8) between PVC-CM vs sham. Cardiac (LV) Nerve Growth Factor (NGF), Growth Associated Protein (GAP-43) and beta 1-adrenoreceptor levels were lower (p=0.042, p=0.003, p=0.002 respectively) whereas beta 2-adreno- and muscarinic M2-cholinergic receptors were higher (p=0.02, p&amp;lt;0.01 respectively) in PVC-CM compared with sham. Conclusion Neural remodeling in PVC-CM results in an imbalanced sympathetic excess and sympathetic-parasympathetic dysfunction characterized by a loss of sympathetic functional reserve during exercise and impaired parasympathetic activity and HRR after exercise. Adaptive downregulation of NGF might explain this imbalance and dysfunction. These data open the intriguing possibility of neural-targeted therapies to reverse remodeling and restore autonomic function disrupted by chronic PVCs.GraphsMolecular

Impact of functional gene groups on outcomes after ablation of ventricular tachycardia in patients with inherited left ventricular cardiomyopathy: an international multicentre study

Abstract Background Advances in genetic testing has enabled identification of pathogenic variants of different functional gene groups associated with non-dilated left ventricular cardiomyopathy (NDLCM)/dilated cardiomyopathy (DCM) and ventricular tachycardia (VT). However, there is limited data on the impact of functional groups on VT ablation outcome. Aim We aimed to assess the impact of likely pathogenic/pathogenic variants (LP/Pv) of different functional gene groups on heart failure (HF) outcomes and VT recurrence in patients with NDLCM/DCM after VT ablation. Methods Patients with NDLCM/DCM who underwent genetic testing (next-generation sequencing) and were referred for VT ablation were enrolled at 6 participating centers. Patients were followed for VT recurrence, HF-related adverse outcomes (death, left ventricular assist device [LVAD], or heart transplantation due to HF), and all-cause mortality. Results A total of 239 patients (age 55±14yrs; male n=193; LVEF 40±12%; amiodarone at admission n=103; ICD n=180) were included. LP/Pv were identified in 128 patients (54%), predominantly found in genes encoding sarcomeric (n=36/128, [28%]; titin n=20, myosin binding protein C n=12), followed by nuclear membrane (n=27/128, [22%]; lamin A/C; n=26), desmosomal (n=23/128, [18%]; desmoplakin n=11, plakophilin n=9), cytoskeleton (n=12/128, [9%]; filamin C n=8), and sarcoplasmic reticulum proteins (n=12/128, [9%]; phospholamban n=10). Variants of unknown significance (n=32) were grouped with patients who tested negative. Acute complete ablation success, defined as non-VT inducibility of any sustained monomorphic VT, was achieved in 113 patients (47%), 63 (56%) with LP/Pv. During a median follow-up of 32 months, 108 patients (45%) had VT recurrence, 41 (17%) had HF-related adverse outcomes (death with/without LVAD in 34, LVAD in 2, heart transplantation in 5) and 47 (20%) died. Patients with LP/Pv were more likely to have VT recurrence, HF-related adverse outcomes and had a higher mortality compared to those without (VT, 68 [53%] vs. 40 [36%]; HF-related adverse outcomes, 30 [23%] vs. 11 [10%]; mortality, 30 [23%] vs. 17 [15%]; log-rank, P&amp;lt;0.01 for all). As compared to patients without LP/Pv, those with LP/Pv in genes encoding nuclear membrane or sarcomeric proteins had significantly worse (P&amp;lt;0.01 for both) and those with LP/Pv in genes encoding desmosomal proteins had similar HF and VT recurrence outcomes (Figure). Of interest, patients with LP/Pv in genes encoding cytoskeleton proteins had favorable HF-related adverse outcomes, but worse VT recurrence (P=0.02) compared to those without LP/Pv (Figure). Conclusion In patients with NDLCM/DCM and VT, the impact of LP/Pv on HF and VT-recurrence outcomes after ablation differs across functional groups. Integrating genetic testing in the comprehensive evaluation of patients with NDLCM/DCM undergoing VT ablation may facilitate personalized ablation strategies and early consideration of alternative HF treatments.

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

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

Alterations of Myocardial Mitochondrial Morphology and Function in a Canine Model of Premature Ventricular Contractions-Induced Cardiomyopathy.

Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM. Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson's trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all p < 0.01 vs the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all p < 0.05). We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.

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.