Arrhythmogenic Cardiomyopathy Research Articles

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

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

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 NaV1.5membrane 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 NaV1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.

Detection of gene mutation in the prognosis of a patient with arrhythmogenic right ventricular cardiomyopathy: a case report

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC), or more recently known as arrhythmogenic cardiomyopathy (ACM), is an heritable disorder of the myocardium characterized by progressive fibrofatty replacement the heart muscle and risk of ventricular arrhythmias and sudden cardiac death (SCD). We report a case study to demonstrate the role of gene mutation detection in risk stratification for primary prevention of SCD in a young patient diagnosed with ARVC.Case presentationA 15-year-old Asian (Vietnamese) male patient with no history of documented tachyarrhythmia or syncope and a family history of potential SCD was admitted due to palpitations. Clinical findings and work-up including cardiac magnetic resonance imaging (MRI) were highly suggestive of ARVC. Gene sequencing was performed for SCD risk stratification, during which PKP2 gene mutation was found. Based on the individualized risk stratification, an ICD was implanted for primary prevention of SCD. At 6 months post ICD implantation, the device detected and successfully delivered an appropriate shock to terminate an episode of potentially fatal ventricular arrhythmia. ICD implantation was therefore proven to be appropriate in this patient.ConclusionsWhile gene mutations are known to be an important factor in the diagnosis of ARVC according to the 2010 Task Force Criteria and recent clinical guidelines, their role in risk stratification of SCD remains controversial. Our case demonstrated that when used with other clinical factors and family history, this information could be helpful in identifying appropriate indication for ICD implantation.

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

Introduction
 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.
 Methods
 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.
 Results
 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.
 Discussion/Conclusion
 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.

Filamin C Deficiency Impairs Sarcomere Stability and Activates Focal Adhesion Kinase through PDGFRA Signaling in Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Truncating mutations in filamin C (FLNC) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell adhesion, cytoskeletal organization, sarcomere structural integrity, and likely nuclear function. Our previous study showed that the transcriptional profiles of FLNC homozygous deletions in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are highly comparable to the transcriptome profiles of hiPSC-CMs from patients with FLNC truncating mutations. Therefore, in this study, we used CRISPR-Cas-engineered hiPSC-derived FLNC knockout cardiac myocytes as a model of FLNC cardiomyopathy to determine pathogenic mechanisms and to examine structural changes caused by FLNC deficiency. RNA sequencing data indicated the significant upregulation of focal adhesion signaling and the dysregulation of thin filament genes in FLNC-knockout (FLNCKO) hiPSC-CMs compared to isogenic hiPSC-CMs. Furthermore, our findings suggest that the complete loss of FLNC in cardiomyocytes led to cytoskeletal defects and the activation of focal adhesion kinase. Pharmacological inhibition of PDGFRA signaling using crenolanib (an FDA-approved drug) reduced focal adhesion kinase activation and partially normalized the focal adhesion signaling pathway. The findings from this study suggest the opportunity in repurposing FDA-approved drug as a therapeutic strategy to treat FLNC cardiomyopathy.

P 024: Arrhythmogenic cardiomyopathy in a young man: Navigating diagnosis and management

P 024: Arrhythmogenic cardiomyopathy in a young man: Navigating diagnosis and management

Disputation on the power and efficacy of phenotypical classification in arrhythmogenic cardiomyopathy: Time for a reformation?!

Disputation on the power and efficacy of phenotypical classification in arrhythmogenic cardiomyopathy: Time for a reformation?!

Cardiac Sarcoidosis: A Comprehensive Clinical Review.

Sarcoidosis is an inflammatory multisystemic disease of unknown etiology characterized by the formation of non-caseating granulomas. Sarcoidosis can affect any organ, predominantly the lungs, lymphatic system, skin and eyes. While 90% of patients with sarcoidosis have lung involvement, an estimated 5% of patients with sarcoidosis have clinically manifest cardiac sarcoidosis (CS), whereas approximately 25% have asymptomatic, clinically silent cardiac involvement verified by autopsy or imaging studies. CS can present with conduction disturbances, ventricular arrhythmias, heart failure or sudden cardiac death. Approximately 30% of 60-year-old patients presenting with unexplained high degree atrioventricular (AV) block or ventricular tachycardia are diagnosed with CS, therefore CS should be strongly considered in such patients. CS is the second leading cause of death among patients affected by sarcoidosis after pulmonary sarcoidosis, therefore its early recognition is important, because early treatment may prevent death from cardiovascular involvement. The establishment of isolated CS diagnosis sometimes can be quite difficult, when extracardiac disease cannot be verified. The other reason for the difficulty to diagnose CS is that CS is a chameleon of cardiology and it can mimic (completely or almost completely) different cardiac diseases, such as arrhythmogenic cardiomyopathy, giant cell myocarditis, dilated, restrictive and hypertrophic cardiomyopathies. In this review article we will discuss the current diagnosis and management of CS and delineate the potential difficulties and pitfalls of establishing the diagnosis in atypical cases of isolated CS.

Inflammation—A Possible Link between Myocarditis and Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy is a primary genetic disease caused by mutations in the desmosome genes. Ever since the introduction of new imaging techniques, like cardiovascular magnetic resonance, the diagnosis of arrhythmogenic cardiomyopathy has become more challenging as left ventricular or biventricular variants may have resemblance to other cardiomyopathies or myocarditis. Not only this but they may also share an acute phase, which might cause even more confusion and misdiagnoses and influence the prognosis and outcome. In this case report, we present a 31-year-old patient with multiple clinical pictures: his symptoms were acute chest pain, new onset of heart failure and arrhythmia symptoms, which determined a dynamic change in clinical diagnosis and management, ultimately taking into consideration arrhythmogenic cardiomyopathy. Through the article, we try to uncover and explain common pathophysiological pathways shared by arrhythmogenic cardiomyopathy and other clinical entities with a special focus on inflammation. The final question remains: “If there is more than one heart disorder that eventually leads to the same clinical image, one may wonder, is arrhythmogenic cardiomyopathy a syndrome rather than a specific condition?”.

Impact of genotype on clinical course in biventricular arrhythmogenic cardiomyopathy

Aim. To analyze the correlation between genotype and phenotype in patients with biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC).Methods. The clinical phenotype of 9 unrelated probands (89 % men, median age 35 [34; 37]) with biventricular ARVC were observed. The clinical and instrumental examination included a 12-lead ECG, 24-hour Holter ECG monitoring, transthoracic echocardiography and cardiac magnetic resonance imaging with late gadolinium enhancement. Biventricular variant of ARVC was diagnosed according to the 2020 Padua criteria for both right and left ventricles involvement. High-throughput sequencing was utilized to search for mutations in genes linked to the onset of cardiomyopathies and other inherited rhythm disorders. Statistical analysis procedures were performed using the STATISTICA-12 program.Results. In all patients with biventricular ARVC, according to late gadolinium enchansment magnetic resonance imaging, left ventricular involvement of varying degrees was detected, characterized by fibrous or fibrofatty infiltration of the myocardium, as well as regional or global systolic dysfunction. Genotyping in 9 patients with biventricular ARVC revealed 10 variants of the nucleotide sequence of III-V classes of pathogenicity according to the criteria of ACMG (2015) in 4 genes associated with ARVC (PKP2, DSP, DSC2, DSG2). Of these, 7 variants belonged to classes IV and V (PKP2 - 4 mutations, DSP - 2 mutations, DSG2 - 1 mutation); 3 nucleotide substitutions were variants with uncertain significance (VUS, class III) - 2 in DSC2 gene and 1 in DSP gene. A combination of nucleotide variants in two genes (DSP and DSC2) was detected in 1 patient. The findings highlight that mutations in DSP gene were associated with more severe systolic dysfunction and left ventricle dilation compared to carriers of mutations in PKP2 gene. In patients with variants of class III pathogenicity in DSC2 gene the most adverse clinical course of the disease was observed with the early onset of the first sustained ventricular tachycardia and the development of severe dysfunction and dilation of both ventricles requiring heart transplantation in comparison with carriers of mutations in other genes.Conclusion. The results obtained in a cohort of patients with biventricular ARVC demonstrate a specific correlation between genotype and clinical course and disease severity as well.

3D Fractal Dimension Analysis: Prognostic Value of Right Ventricular Trabecular Complexity in Participants with Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive myocardial fibro-fatty infiltration accompanied by trabecular disarray. Traditionally, two-dimensional (2D) instead of 3D fractal dimension (FD) analysis has been used to evaluate trabecular disarray. However, the prognostic value of trabecular disorder assessed by 3D FD measurement remains unclear. To investigate the prognostic value of right ventricular trabecular complexity in ACM patients using 3D FD analysis based on cardiac MR cine images. Retrospective. 85 ACM patients (mean age: 45 ± 17 years, 52 male). 3.0T/cine imaging, T2-short tau inversion recovery (T2-STIR), and late gadolinium enhancement (LGE). Using cine images, RV (right ventricular) volumetric and functional parameters were obtained. RV trabecular complexity was measured with 3D fractal analysis by box-counting method to calculate 3D-FD. Cox and logistic regression models were established to evaluate the prognostic value of 3D-FD for major adverse cardiac events (MACE). Cox regression and logistic regression to explore the prognostic value of 3D-FD. C-index, time-dependent receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) to evaluate the incremental value of 3D-FD. Intraclass correlation coefficient for interobserver variability. P < 0.05 indicated statistical significance. 26 MACE were recorded during the 60 month follow-up (interquartile range: 48-67 months). RV 3D-FD significantly differed between ACM patients with MACE (2.67, interquartile range: 2.51 ~ 2.81) and without (2.52, interquartile range: 2.40 ~ 2.67) and was a significant independent risk factor for MACE (hazard ratio, 1.02; 95% confidence interval: 1.01, 1.04). In addition, prognostic model fitness was significantly improved after adding 3D-FD to RV global longitudinal strain, LV involvement, and 5-year risk score separately. The myocardial trabecular complexity assessed through 3D FD analysis was found associated with MACE and provided incremental prognostic value beyond conventional ACM risk factors. 4 TECHNICAL EFFICACY: Stage 1.

A missense variant in MYOF is associated with ARVC and sudden cardiac death

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is rare autosomal dominant genetic disorder that leads to severe arrhythmia and sudden cardiac death. Although previous studies in clinical, pathological and genetics of ARVC established consensus diagnostic criteria and expanded the spectrum of pathogenic genes, there is still a proportion of patients with unclear causative factors.Here, whole-exome sequencing was employed to investigate the genetic etiology of a 15-year-old sudden cardiac death female caused by ARVC. A novel variant of MYOF (NM_013451.3: c.4723G > C: p.D1575H) was identified, which is a member of the Ferlin family of proteins is associated with cardiomyopathy. And the bioinformatics analysis predicted the pathogenicity of this variant. We report the first variant of MYOF in ARVC, which imply a vital role of MYOF in cardiomyopathy.

Prevalence and clinical significance of low QRS voltages in healthy individuals, athletes, and patients with cardiomyopathy: implications for sports pre-participation cardiovascular screening.

Low QRS voltages (LQRSV), defined as a QRS amplitude from peak to nadir < 0.5 mV in all limb leads, are an emerging diagnostic finding on the electrocardiogram (ECG). In healthy individuals and athletes, LQRSV are rare (2.2-4% of elite athletes, 0.5% of recreational athletes, and 0.3% of sedentary individuals). LQRSV athletes commonly show ventricular arrhythmias (VAs) on exercise, and up to 40% of those with LQRSV and VAs have late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR). The prevalence of LQRSV in arrhythmogenic cardiomyopathy ranges from 17-40%, predicts left ventricular (LV) involvement, and is correlated with more extensive LGE replacement on CMR. In hypertrophic cardiomyopathy (HCM), LQRSV ranges from 0.7-11%. LQRSV-HCM patients have more segments with LGE, despite relatively smaller LV mass, suggesting a more advanced clinical stage and a worse prognosis. In dilated cardiomyopathy (DCM), LQRSV range from 6-7%, but may be higher (36%) in certain genetic forms of DCM. On a follow-up, LQRSV are independently associated with incident cardiac events, such as sudden death, sustained ventricular arrhythmia, or appropriate internal cardioverter defibrillator discharge. In cardiac amyloid, LQRSV range from 34-66% and demonstrate a negative prognostic value, with worse clinical outcomes regardless of underlying biologic, genetic, and clinical variables. In conclusion, LQRSV deserve careful consideration for exclusion of arrhythmogenic substrates in healthy individuals, athletes, and patients. While additional research is needed, it is reasonable that LQRSV should trigger clinical investigation to exclude underlying diseases at risk of life-threatening arrhythmias.

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.

Arrhythmogenic Cardiomyopathy: Definition, Classification and Arrhythmic Risk Stratification.

Arrhythmogenic cardiomyopathy (ACM) is a heart disease characterized by a fibrotic replacement of myocardial tissue and a consequent predisposition to ventricular arrhythmic events, especially in the young. Post-mortem studies and the subsequent diffusion of cardiac MRI have shown that left ventricular involvement in arrhythmogenic cardiomyopathy is common and often develops early. Regarding the arrhythmic risk stratification, the current scores underestimate the arrhythmic risk of patients with arrhythmogenic cardiomyopathy with left involvement. Indeed, the data on arrhythmic risk stratification in this group of patients are contradictory and not exhaustive, with the consequence of not correctly identifying patients at a high arrhythmic risk who deserve protection from arrhythmic death. We propose a literature review on arrhythmic risk stratification in patients with ACM and left involvement to identify the main features associated with an increased arrhythmic risk in this group of patients.

Arrhythmogenic Right Ventricular Cardiomyopathy in Children: A Systematic Review.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by the progressive replacement of the normal myocardium by fibroadipocytic tissue. The importance of an early diagnosis is supported by a higher risk of sudden cardiac death in the pediatric population. We reviewed the literature on diagnosis, risk stratification, and prognosis in the pediatric population with ARVC. In case reports which analyzed children with ARVC, the most common sign was ventricular tachycardia, frequently presenting as dizziness, syncope, or even cardiac arrest. Currently, there is no gold standard for diagnosing ARVC in children. Nevertheless, genetic analysis may provide a proper diagnosis tool for asymptomatic cases. Although risk stratification is recommended in patients with ARVC, a validated prediction model for risk stratification in children is still lacking; thus, it is a matter of further research. In consequence, even though ARVC is a relatively rare condition in children, it negatively impacts the survival and clinical outcomes of the patients. Therefore, appropriate and validated diagnostic and risk stratification tools are crucial for the early detection of children with ARVC, ensuring a prompt therapeutic intervention.

Early consequences of the phospholamban mutation PLN-R14del+/- in a transgenic mouse model.

The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/- ) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. "Superinhibition" of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected. Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8-12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated. The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress. (1) PLN R14del+/- loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model.

Case report on Arrhythmogenic Right Ventricular Dysplasia

Arrhythmogenic cardiomyopathy (AC) is a genetic disease characterized by fibro-fatty replacement of either ventricles in isolation or in combination. It may cause tachyarrhythmias to sudden cardiac death, especially in young adult. When ventricular tachycardia (VT) is the principal manifestation then the condition is termed as arrhythmogenic right ventricular dysplasia (ARVD). Here we present a case of ARVD in a 36 years old hypertensive male who presented with sudden onset of chest tightness, palpitations, breathing difficulty, dizziness for 20 minutes. In emergency department his electrocardiogram (ECG) showed sustained VT. After 200 joule DC cardioversion he was reverted to sinus rhythm, then resting ECG showed T-wave inversion (TWI) in V1-V3 along with epsilon wave. His echocardiogram also revealed dilated right ventricle (RV) along with hypertrabeculation, RV wall motion abnormality and low RV ejection fraction (EF), his coronaries were normal on coronary angiogram (CAG). He was discharged from the hospital after Implantable Cardioverter Defibrilator (ICD) implantation with beta-blocker and advised to restrict excessive physical activity. J Bangladesh Coll Phys Surg 2024; 42: 86-91

Clinical and cardiovascular magnetic resonance profile of cardiomyopathy patients from South Africa: Pilot of the IMHOTEP study

BackgroundCardiomyopathy is an important cause of heart failure, however, there is notable lack of data on causes and manifestations of cardiomyopathy in Africa. AimsThe African Cardiomyopathy and Myocarditis Registry Program (IMHOTEP) aims to address the knowledge gap on etiology, treatment, and outcomes of cardiomyopathy in sub-Saharan Africa. Methods and resultsWe conducted a single-center pilot study to delineate the clinical and cardiovascular magnetic resonance (CMR) phenotypes of cardiomyopathy in South African patients. Assessment of the first 99 adult incident cases [mean age 36.8 ± 12.5 years; females 53.5%] enrolled in IMHOTEP showed that dilated cardiomyopathy (n = 77) was commonest, followed by hypertrophic (n = 13), restrictive (n = 5) and arrhythmogenic (n = 4) cardiomyopathies. A broad range of etiologies were encountered with secondary causes identified in 42% of patients. Onset of symptoms in the peripartum period was observed in 47% of women, and peripartum cardiomyopathy was diagnosed in 32.1% of women recruited. In addition to electrocardiography and echocardiography, CMR was performed in 67 cases and contributed diagnostically in a third of cases. Acute inflammation was rarely observed [2%] on CMR, however, late gadolinium enhancement (LGE) was noted in 92% of cases. ConclusionWe report a diverse spectrum of causes of cardiomyopathy in the South African population, with secondary, potentially treatable, etiologies in a significant proportion of cases. CMR was useful in delineating specific phenotypes and etiologies, influencing clinical care. A higher-than-expected burden of LGE was observed in this young patient cohort - the implications of which are yet to be determined.

Ventricular Tachycardia Ablation in Patients With Desmoplakin Cardiomyopathy

BackgroundDesmoplakin (DSP) pathogenic variants are rare causes of arrhythmogenic cardiomyopathy and often involve the right and left ventricles. Ventricular tachycardia (VT) ablations may be required in these patients, but procedural characteristics have not been reported. ObjectivesIn this study, the authors sought to report a multicenter experience of VT ablation in patients with DSP pathogenic variants. MethodsVT ablations performed in patients with known DSP pathogenic variants were analyzed across 6 centers in 3 countries. Patient characteristics and acute and long-term procedural outcomes were reported. ResultsA total of 20 patients (13 men, median age 43 years [Q1-Q3: 41.5-53.0 years], left ventricular ejection fraction 43.0% [Q1-Q3: 41.5%-53.0%], 11 previous failed ablations) were referred for VT ablation procedures. All patients had symptomatic VTs, with ICD therapy in 19 patients. Epicardial procedures were performed in 16 of the 20 patients. VT target sites were located in the right ventricular (RV) endocardium (n = 11), the RV epicardium (n = 4), the left ventricular (LV) endocardium (n = 2) and the LV epicardium (n = 7). In 3 patients, the VT target sites were in close proximity to coronary arteries, limiting ablation. During follow-up, VTs recurred in 11 patients, and repeated ablations were performed in 9 patients. Allowing for multiple procedures, 19 of the 20 patients remained free of VT recurrence after a median follow-up of 18 months [Q1-Q3: 5-60 months]. ConclusionsPatients with DSP cardiomyopathy often have biventricular involvement, and ablation procedures often require ablation in both ventricles and the epicardium. Recurrences are not uncommon, and the pathologic substrate can be located in close proximity to epicardial coronary arteries, limiting the success rate of ablations.