Desmosomal Versus Non-Desmosomal Arrhythmogenic Cardiomyopathies: A State-of-the-Art Review

case presentation: A 48-year-old woman presents with exertional dyspnea and recurrent syncope. One year earlier, a permanent pacemaker was placed after she complained of fatigue and was found to have high-grade atrioventricular block. Now, she has echocardiographic evidence of moderate to severe left ventricular (LV) systolic dysfunction with regional wall-motion abnormalities. Nuclear imaging is notable for heterogeneous myocardial uptake of technetium Tc99m sestamibi, and coronary angiography reveals widely patent epicardial vessels. Multiple episodes of nonsustained ventricular tachycardia (VT) are documented on continuous ECG monitoring. What are the diagnostic considerations for this patient, and what further evaluations are indicated? This patient presents with dilated cardiomyopathy (DCM) with electric instability (DCM+E), which we define as conduction disease and arrhythmia out of proportion to the severity of LV systolic dysfunction. Diverse causes can result in DCM+E and fall into general categories of inflammatory, infectious, hereditary, and infiltrative processes. Cardiac presentation associated with these conditions is distinct from more common causes of DCM such as ischemic heart disease, viral myocarditis, valvular dysfunction, pregnancy, or substance abuse. Clinical features that are suggestive of DCM+E include supraventricular arrhythmias or conduction disease that precedes cardiomyopathy, multiple VT morphologies, and features suggestive of ischemic heart disease (Q waves, regional wall-motion abnormalities, perfusion defects, ventricular aneurysm) in the absence of epicardial stenoses. In this Clinician Update, we focus on the diagnostic approach to patients with DCM+E. Emphasis is placed on diagnoses that are relatively common or for which the clinical management would be impacted significantly by recognition of the underlying cause. Ischemic heart disease may present with conduction disease and a high burden of arrhythmia, especially in the setting of acute myocardial ischemia/infarction. The exclusion of obstructive coronary artery disease is strongly recommended in patients with DCM+E because atherosclerosis is so prevalent, evidence-based treatment is readily available, and the …

Sudden killer

AHA/ACCF Scientific Statement on the Evaluation of Syncope

Although multi-detector computed tomography (MDCT) and cardiac magnetic resonance (CMR) can assess the structural substrate of ventricular tachycardia (VT) in ischemic cardiomyopathy (ICM), non-ICM (NICM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), the usefulness of systematic image integration during VT ablation remains undetermined. A total of 116 consecutive patients (67 ICM; 30 NICM; 19 ARVC) underwent VT ablation with image integration (MDCT 91%; CMR 30%; both 22%). Substrate was defined as wall thinning on MDCT and late gadolinium-enhancement on CMR in ICM/NICM, and as myocardial hypo-attenuation on MDCT in ARVC. This substrate was compared to mapping and ablation results with the endpoint of complete elimination of local abnormal ventricular activity (LAVA), and the impact of image integration on procedural management was analyzed. Imaging-derived substrate identified 89% of critical VT isthmuses and 85% of LAVA, and was more efficient in identifying LAVA in ICM and ARVC than in NICM (90% and 90% vs. 72%, P < 0.0001), and when defined from CMR than MDCT (ICM: 92% vs. 88%, P = 0.026, NICM: 88% vs. 72%, P < 0.001). Image integration motivated additional mapping and epicardial access in 57% and 33% of patients. Coronary and phrenic nerve integration modified epicardial ablation strategy in 43% of patients. The impact of image integration on procedural management was higher in ARVC/NICM than in ICM (P < 0.01), and higher in case of epicardial approach (P < 0.0001). Image integration is feasible in large series of patients, provides information on VT substrate, and impacts procedural management, particularly in ARVC/NICM, and in case of epicardial approach.

Highlights From the Circulation Family of Journals.

The mystery behind recurrent pericardial effusions: A hidden case of arrhythmogenic right ventricular cardiomyopathy.

Comparison of radionuclide angiographic synchrony analysis to echocardiography and magnetic resonance imaging for the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an uncommon cardiac disease characterized by progressive right ventricular dysfunction due to fibrofatty replacement of myocytes and risk of sudden cardiac death from malignant arrhythmias. ARVC/D is a disease of the cardiac desmosome, with genetic mutations in genes encoding proteins critical to this structure found in the majority of patients. The diagnosis of ARVC/D is based on fulfilling a combination of clinical, imaging, pathologic, and/or genetic criteria set forth by the 2010 modified Task Force Criteria. Cardiac magnetic resonance (CMR) is included in these criteria and plays an important role in the management of ARVC/D, demonstrating pathologic structural changes in the right and left ventricles that provide both diagnostic and prognostic information. The purpose of this article is to provide a background on the pathophysiology and genetics of ARVC/D and focus on the role of CMR in management of ARVC/D including diagnosis, prognosis, and treatment decisions. Common CMR pitfalls that can lead to misdiagnosis will also be reviewed.

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria. Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54-13.68; P=0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39-51.24; P<0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents. SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.

The dose-response association between physical activity and cardiovascular outcomes is well described (10). As little as 15 min·d−1 of moderate-intensity exercise significantly lowers the risk for cardiovascular morbidity and mortality. Greater volumes yield greater cardiovascular benefit. However, the impact of extreme volumes of exercise on cardiovascular health is under debate (9), because some studies present evidence of adverse clinical outcomes in endurance athletes who perform exercise volumes at the extreme upper end of the physical activity continuum. These observations raise the possibility that high doses of exercise have deleterious cardiac effects.

ABSTRACTArrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a relatively under-recognized hereditary cardiomyopathy. It is characterized pathologically by fibro-fatty infiltration of right ventricular (RV) myocardium and clinically by consequences of RV electrical instability. Timely intervention with device therapy and pharmacotherapy may help reduce the risk of arrhythmic events or sudden cardiac death. Here, we describe a classic case of a young adult with ARVC and a brief literature review. The patient presented with exertional palpitations and ARVC was suspected after his routine electrocardiogram (EKG) revealed symmetric T wave inversions and possible epsilon waves in right precordial leads. Subsequent work up showed fatty infiltration of RV myocardium on cardiac magnetic resonance imaging and inducible ventricular tachycardia from the right ventricle during electrophysiologic study. Those findings confirmed the diagnosis of ARVC and warranted treatment with implantable cardioverter defibrillator. It is always exciting to encounter rare pathological entities with classic clinical findings, especially when they present as a diagnostic challenge.We were able to provide correct diagnosis and management, thereby preventing the potentially lethal consequences. Therefore, it is important to recognize the possible EKG findings of ARVC and to know when to pursue further investigations and to implement therapies.

Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST‐T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene [NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9)] that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with increased risk of sudden cardiac death. It is a progressive disease that can already manifest itself during childhood and adolescence. Since little is known about the early stage in pediatric patients, this study sought to determine the influence of right and left ventricular findings from cardiac magnetic resonance imaging (CMR) in pediatric patients ≤ 18 years with suspected ARVC in conjunction with positive genetic testing.

Arrhythmogenic cardiomyopathy (ACM) is a cardiac disorder characterized by structural alterations of the myocardium, which predisposes individuals to ventricular arrhythmias and increases the risk of sudden cardiac death. Initially described as arrhythmogenic right ventricular cardiomyopathy, the involvement of the left ventricle (LV) has been subsequently recognized, leading to the classification of various phenotypes under LV non-dilated cardiomyopathy. The clinical spectrum of ACM ranges from life-threatening ventricular arrhythmias to overt heart failure, sometimes presenting with acute myocarditis-like episodes and extracardiac symptoms, further contributing to the disease's heterogeneity. Diagnosis relies on imaging modalities, such as echocardiogram and cardiac magnetic resonance imaging, to detect areas of fibro-fatty replacement and/or non-ischemic ventricular scarring, integrated with genetic analysis. The 2023 European Society of Cardiology guidelines on Cardiomyopathies underscore the importance of a comprehensive diagnostic approach, combining imaging and genetics for arrhythmic risk stratification and comprehensive patient management. Growing evidence on genotype-phenotype correlation, along with the validation of specific predictive scores, is improving ACM clinical management and promoting personalized treatment tailored to individual and familial characteristics.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart muscle disorder characterized by the progressive replacement of right ventricular myocardium with fibrofatty tissue. This condition predisposes individuals to arrhythmias and an elevated risk of sudden cardiac death (SCD). The etiology of ARVC is predominantly genetic, with mutations in genes encoding desmosomal proteins playing a crucial role. Physical exercise has a significant impact on the progression of ARVC, often exacerbating the disease's severity and increasing the likelihood of life-threatening arrhythmic events. Diagnosing ARVC remains challenging due to its variable clinical presentation and overlapping features with other cardiomyopathies. Advanced imaging techniques, electrocardiography, and genetic testing are essential tools in the diagnostic process. Treatment strategies for ARVC include lifestyle modifications, pharmacotherapy, implantable cardioverter-defibrillators (ICDs), and in some cases, catheter ablation or heart transplantation. Preventing disease progression and SCD involves a multidisciplinary approach, emphasizing early diagnosis, risk stratification, and tailored therapeutic interventions. This review comprehensively examines the etiology of ARVC, the detrimental effects of physical exercise on the disease, the associated SCD risk, and the challenges in diagnosis, while also discussing current treatment modalities and preventive measures to mitigate disease progression. Materials and Methods Review and summary of research studies available in databases on Google Scholar and PubMed. Databases such as PubMed and Google Scholar were searched using the keywords: ‘Arrhythmogenic right ventricular cardiomyopathy, ‘ARVC in athletes’, ‘Sudden cardiac death’, ‘impact of physical exercise on ARVC’.