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Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project

The epsilon wave of the electrocardiogram (ECG) together with fragmented QRS (fQRS), the terminal conduction delay, incomplete right bundle branch block (IRBBB) and complete/advanced RBBB (CRBBB) of peripheral origin are part of a spectrum of ventricular depolarization abnormalities of arrhythmogenic cardiomyopathy (AC). Although the epsilon wave is considered a major diagnostic criterion for AC since 2010 (AC Task Force Criteria), its diagnostic value is limited because it is a sign of the later stage of the disease. It would be more appropriate to say that the epsilon wave is a “hallmark” of AC, but is of low diagnostic sensitivity. Although the epsilon wave has high specificity for AC, it can be present in other pathological conditions. In this update we will cover the nomenclature, association with disease states and electrocardiographic aspects of the epsilon wave. Keywords: Epsilon wave, Ventricular post-excitation wave, Fontaine wave

Advances in technology have reshaped the practice of medicine. These changes have greatly benefited our patients. However, in the setting of these advances, the importance of basic clinical tools is more pertinent than ever. Despite the growing reliance on technology, the physical exam remains valuable and cost effective, often enabling the well-trained clinician to arrive at the diagnosis, rapidly and accurately. The physical exam must not become a relic of a distant past. We aim to investigate current competency and proficiency, proposals for change in teaching curriculums, and the relationship with technology such as hand-held echocardiography. A skillful exam provides both emotional and intellectual satisfaction. It may be a lost art but it is well worth the effort to restore.

Excellence in recording and interpretation of electrocardiogram (ECG) is a necessity for optimal electrocardiography. This includes data to properly interpret the ECG, including data on age, gender, cardiovascular diagnosis, medications, abnormal laboratory findings (eg, data on electrolytes), and the indications for the electrocardiogram. The ECG needs to be performed by a qualified technician and interpreted by an experienced physician.

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Objective Changes in heart rate variability (HRV) associated with breathing (respiratory sinus arrhythmia) are known to be parasympathetically (vagally) mediated when the breathing rate is within the typical frequency range (9-24 breaths per minute [bpm]; high-frequency HRV). Slow yogic breathing occurs at rates below this range and increases low-frequency HRV power, which may additionally reflect a significant sympathetic component. Yogic breathing techniques are hypothesized to confer health benefits by increasing cardiac vagal control, but increases in low-frequency HRV power cannot unambiguously distinguish sympathetic from parasympathetic contributions. The aim of this study was to investigate the autonomic origins of changes in low-frequency HRV power due to slow-paced breathing. Methods Six healthy young adults completed slow-paced breathing with a cadence derived from yogic breathing patterns. The paced breathing took place under conditions of sympathetic blockade, parasympathetic (vagal) blockade, and placebo. HRV spectral power was compared under 11 breathing rates during each session, in counterbalanced order with frequencies spanning the low-frequency range (4-9 bpm). Results HRV power across the low-frequency range (4-9 bpm) was nearly eliminated (p = .016) by parasympathetic blockade (mean (SD) spectral power at breathing frequency = 4.1 (2.1)) compared with placebo (69.5 (8.1)). In contrast, spectral power during sympathetic blockade 70.2 (9.1) and placebo (69.5 (8.1)) was statistically indistinguishable (p = .671). Conclusions These findings clarify the interpretation of changes in HRV that occur during slow-paced breathing by showing that changes in low-frequency power under these conditions are almost entirely vagally mediated. Slow-paced breathing is an effective tool for cardiac vagal activation.

International audience; Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.

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International audience; Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.

Objectives The primary objective of this study is risk stratification of patients with arrhythmic right ventricular cardiomyopathy (ARVC). Background There is a need to identify those who need an automatic implantable cardioverter-defibrillator (ICD) to prevent sudden death. Methods This is an analysis of 88 patients with ARVC from 3 centers and who were not treated with an ICD. Results Risk factors for subsequent arrhythmic deaths were pre-enrollment sustained or nonsustained ventricular tachycardia and decreased left ventricular function. Conclusions These factors serve as proposed guidelines for implantation of an ICD in patients with ARVC to prevent sudden death.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disorder pathologically characterized by progressive replacement of cardiac ventricular myocytes with fibrofatty tissue.1–3 Mutations in genes encoding cardiac desmosomal proteins located in the intercalated disks are responsible for ARVC.4 Mutations in five genes (plakophillin-2 [PKP2], desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin) account for the majority of index cases.5 These mutations result in electromechanical uncoupling of myocytes, triggering the histopathological changes in ARVC that create the substrate for ventricular dysfunction and ventricular arrhythmias that may lead to sudden death.1–3 The diagnosis of ARVC is based on international task force criteria that was originally published in 1994 and revised in 2010.2 Studies investigating sex-based differences in the incidence of ARVC are conflicting. European studies report that it is more common in males,6,7 whereas studies from the United States and the Dutch ARVC cohorts report similar incidence between males and females.8,9 Studies also suggest sex-based differences in clinical diagnostic features of ARVC, but no difference in the incidence of ventricular arrhythmias.6,7 The specific aims of the present investigation were (1) to compare the baseline clinical characteristics in men and women enrolled in the North American ARVC registry, (2) to compare the incidence and risk of cardiac events (death and ventricular arrhythmias) in males and females with ARVC, and (3) to identify unique risk stratifiers associated with adverse cardiac events by sex in ARVC patients enrolled in the North American ARVC registry.

Background—The risks of sports participation for implantable cardioverter-defibrillator (ICD) patients are unknown. Methods and Results—Athletes with ICDs (age, 10–60 years) participating in organized (n=328) or high-risk (n=44) sports were recruited. Sports-related and clinical data were obtained by phone interview and medical records. Follow-up occurred every 6 months. ICD shock data and clinical outcomes were adjudicated by 2 electrophysiologists. Median age was 33 years (89 subjects

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially lethal condition that poses diagnostic and prognostic challenges. Right ventricular (RV) strain has shown promise in the assessment of ARVC. We sought to evaluate the diagnostic and prognostic utility of RV strain in a

Objective Precordial ECG lead placement is difficult in obese patients with increased chest wall soft tissues due to inaccurate palpation of the intercostal spaces. We investigated whether the length of the sternum (distance between the sternal notch and xiphoid process) can accurately predict the location of the 4th intercostal space, which is the traditional location for V1 lead position. Materials and Methods Fifty-five consecutive adult chest computed tomography examinations were reviewed for measurements. Results The sternal notch to right 4th intercostal space distance was 67% of the sternal notch to xiphoid process length with an overall correlation of r = 0.600 (p Conclusion The above measurement may be utilized to locate the 4th intercostal space for accurate placement of the precordial electrodes in adults in whom the 4th intercostal space cannot be found by physical exam.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and an increased risk of sudden cardiac death. Although structural abnormalities of the right ventricle predominate, it is well recognized that left ventricular involvement is common, particularly in advanced disease, and that left-dominant forms occur. The pathological characteristic of ARVC is myocyte loss with fibrofatty replacement. Since the first detailed clinical description of the disorder in 1982, significant advances have been made in understanding this disease. Once the diagnosis of ARVC is established, the single most important clinical decision is whether a particular patient’s sudden cardiac death risk is sufficient to justify placement of an implantable cardioverter-defibrillator. The importance of this decision reflects the fact that ARVC is a common cause of sudden death in young people and that sudden death may be the first manifestation of the disease. This decision is particularly important because these are often young patients who are expected to live for many years. Although an implantable cardioverter-defibrillator can save lives in individuals with this disease, it is also well recognized that implantable cardioverter-defibrillator therapy is associated with both short- and long-term complications. Decisions about the placement of an implantable cardioverter-defibrillator are based on an estimate of a patient’s risk of sudden cardiac death, as well as their preferences and values. The primary purpose of this article is to provide a review of the literature that concerns risk stratification in patients with ARVC and to place this literature in the framework of the 3 authors’ considerable lifetime experiences in caring for patients with ARVC. The most important parameters to consider when determining arrhythmic risk include electric instability, including the frequency of premature ventricular contractions and sustained ventricular arrhythmia; proband status; extent of structural disease; cardiac syncope; male sex; the presence of multiple mutations or a mutation in TMEM43; and the patient’s willingness to restrict exercise and to eliminate participation in competitive or endurance exercise.

Introduction We have observed electrocardiographic (ECG) changes primarily in women during tilt table testing. Methods We reviewed 12 lead ECGs during tilt studies between 2012 and 2016 for changes in ST segments and T waves during tilt table testing. Patients with distinctly abnormal baseline ECGs were excluded. Results Of the 180 tilt studies, 117 (65%) were in women. There were 32 patients with ECG changes during tilting. Of these, 28 (87.5%) were in women with an average age of 45 years. None had a history of CAD or exertional chest pain. Echocardiograms were available in 21 of the 28 women with tilt induced ECG changes and all were normal. ECG changes during tilt table testing were found in 4/64 (6.25%) of men. The occurrence of ST-T wave changes during tilt testing was significantly higher among women compared to men, with a p value of 0.008. Of the 28 women with ECG changes during tilt, 11 had T wave inversions alone. ST segment depression alone was noted in 7 women. There were 10 women who had both ST segment depression and T wave inversions. Changes occurred immediately upon tilting in 6. In the remaining, they occurred at an average of 4.8 ± 4 min after tilting. The slight increase in heart rate in patients with ECG changes was similar to that in the patients without new ECG changes. The ECG changes were not related to the presence of syncope. Conclusions ECG changes during the testing was observed at a relatively high incidence primarily in women. The clinical significance of these repolarization changes during tilt testing is unknown. These ECG changes during tilt testing may correlate with the high incidence of false positive ECGs in women during exercise testing but do not necessarily indicate the presence of ischemic coronary disease. Additional research is needed to explain this phenomenon.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with sudden cardiac death. However, the selection of patients for implanted cardioverter-defibrillators (ICDs), as well as programming of the ICD, is unclear. Objectives The objective of this study was to identify predictors, characteristics, and treatment of ventricular arrhythmias in patients with ARVC. Methods The Multidisciplinary Study of Right Ventricular Cardiomyopathy established the North American ARVC Registry and enrolled patients with a diagnosis of ARVC. Patients were followed prospectively. Results Of 137 patients enrolled, 108 received ICDs. Forty-eight patients had 502 sustained episodes of ventricular arrhythmias, including 489 that were monomorphic and 13 that were polymorphic. In the patients with ICDs, independent predictors of ventricular arrhythmias in follow-up included spontaneous sustained ventricular arrhythmias before ICD implantation and T-wave inversions inferiorly. The only independent predictor for life-threatening arrhythmias, defined as sustained ventricular tachycardia (VT) ≥240 beats/min or ventricular fibrillation, was a younger age at enrollment. Anti-tachycardia pacing (ATP), independent of the cycle length of the VT, was successful in terminating 92% of VT episodes. Conclusions In the North American ARVC Registry, the majority of ventricular arrhythmias in follow-up are monomorphic. Risk factors for ventricular arrhythmias were spontaneous ventricular arrhythmias before enrollment and a younger age at ICD implantation. ATP is highly successful in terminating VT, and all ICDs should be programmed for ATP, even for rapid VT.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically transmitted disease. However, the genetics are more complex than in other inherited conditions wherein a single gene abnormal mutation may be causative. In ARVC, 5 causative desmosomal genes have been identified, but because only 30% to 50% of patients with ARVC have 1 of these gene abnormalities, it is assumed that there are other genes not yet identified. Frequently, patients with ARVC have >1 genetic defect in the same gene (compound heterozygosity) or in a second complementary gene (digenic heterozygosity). In addition, a family member may have an ARVC gene defect and have development of the disease or have no or minimal manifestations of the disease. Clinical genetic testing is commercially available. It is beneficial for first-degree family members of a person with ARVC to have genetic testing but only if there is a known genetic abnormality in the affected person. If the affected family member (proband) with ARVC does not have a genetic defect identified, then it will not be identified in the family member. Genetic counseling is strongly advised for family members of the proband.

Objectives To verify accurate placement of the precordial ECG leads by identifying the 4th and 5th intercostal spaces as a function of the length of the sternum. This should decrease the percentage of lead misplacement leading to misdiagnoses. Methods The population consisted of patients and healthy volunteers. The proposed method compared palpation of the 4th and 5th intercostal spaces to a percentile of the sternal length. Location of the 4th and 5th intercostal space using a simple device was evaluated to assist in proper placement of the precordial leads to obtain accurate diagnosis. Results The location of the 4th and 5th intercostal space is related to the length of the sternum. It is 77% of the sternal length that measures 15 cm for the 4th intercostal space. The position of the V1 and V2 electrodes decreases to 57% when the sternal length is 26 cm. Similar data was obtained to locate the 5th intercostal space with proper position of V4-V6 electrodes. Tables are provided to facilitate this process. An instrument was designed to measure the 4th and 5th intercostal space as a function of the sternal length. Conclusions The location of the 4th and 5th intercostal space is identified based on the length of the sternum.

We appreciated the interest of Barison and colleagues in our International Consensus Statement on the treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).1 Our document provided a comprehensive overview and recommendations for risk stratification and therapy of patients fulfilling the diagnostic criteria for ARVC/D. These criteria had been addressed by a previous International Task Force consensus document dedicated to diagnosis of ARVC/D.2 According to the revised criteria proposed by the International Task Force in 2010, the diagnosis of ARVC/D is based on the presence of major and minor criteria encompassing electrocardiographic, arrhythmic, morphological, histopathologic, and genetic factors. Diagnosis of definite ARVC/D is fulfilled in the presence of 2 major criteria or 1 major plus 2 minor or 4 minor criteria from different groups; the ARVC/D diagnosis is possible or borderline in the presence of insufficient criteria. In their Letter to the Editor, Barison and colleagues emphasized the valuable role of cardiac magnetic resonance (CMR) for diagnosis of ARVC/D, which relies on its ability to combine evaluation of ventricular size, function, and regional wall motion with characterization by late-gadolinium enhancement (LGE) of fibro-fatty myocardial scar, which is the hallmark lesion of ARVC/D. We totally agree that CMR is becoming the gold standard tool for detection of structural and functional ventricular abnormalities in ARVC/D. In the 2010 International Task Force consensus document, CMR was appropriately included among the diagnostic imaging techniques, and specific CMR reference values for normal (and abnormal) ventricular size, systolic function, and regional dyssynergy were provided. Tissue characterization by LGE was not included among these diagnostic criteria because of the potential risk of misdiagnosis of ARVC/D related to the difficulty of assessing LGE at the level of the thin right ventricular wall and possible confusion with normal epicardial fat tissue. More recently, the frequent involvement by the disease of the left ventricular wall in the form of epicardial-mediomural LGE has been recognized. As pointed out by the authors, LV LGE may enhance sensitivity for early/minor or predominant left variants of the ARVC/D; however, its diagnostic accuracy remains to be established. The prognostic role of CMR and, in particular, of postcontrast sequences for tissue characterization in patients with a diagnosis of definitive ARVC/D remains elusive. In our consensus statement on the treatment of ARVC/D, we performed a systematic review of outcome studies on ARVC/D available in the literature to identify predictor variables that were associated with an increased risk of major arrhythmic events (ie, sudden cardiac death, appropriate defibrillator interventions, or defibrillator therapy on fast ventricular tachycardia/ventricular fibrillation), nonsudden cardiac death, or heart transplantation in at least 1 published multivariable analysis. Although the predicting value of CMR for worse arrhythmic outcome was shown in the general population of patients showing premature ventricular beats with a left bundle branch morphology4 and in patients with suspected diagnosis of ARVC/D,5 no specific features of CMR, either alone or in combination, have been reported yet as independent predictors of life-threatening arrhythmic events in patients with a definite diagnosis of ARVC/D. This lack of evidence underscores the importance of undertaking future studies on this field.

The diagnosis of arrhythmic right ventricular cardiomyopathy (ARVC) can be difficult, particularly in patients who have early manifestations of the disease. Modification of the 1994 Diagnostic Test Task Force criteria has recently been published. The most frequent cause for misdiagnosis is incorrect interpretation of a cardiac imaging test, particularly magnetic resonance imaging. The results of genetic testing must be interpreted with caution. Genetic abnormalities may be absent in 50% of patients with ARVC and penetrance is variable.

The issue of ARVC/D in children and use of diagnostic modalities (such as CMR) in the pediatric population remain controversial. In this chapter, we are discussing some of the most recently published research providing an evidence and understanding of the most beneficial follow-up protocol in childhood. The majority of longitudinal studies in ARSVC/D indicate that electrical abnormalities on ECG or Holter monitoring are more prevalent than structural changes defined by either echocardiography or CMR. Based on published data, we believe it is reasonable to suggest that ECGs and Holter monitoring be performed at yearly intervals after the age of 8 or 10 years, supplemented by CMR studies if electrical abnormalities are present. We also provide our clinical algorithm of the ECG, Holter and CMR utilization in the population with positive genotype, and/or positive family history of ARVC/D, allowing to screen for phenotypic presentations in case of potentially fatal disorder. In addition to a close clinical follow-up, we recommend considering an evidence suggesting that frequent, prolonged, and vigorous athletic activity may represent a risk factor for sudden cardiac death and can exacerbate the rate of progression of the ARVC/D. Therefore, these types of activity should be avoided by probands or by family members who are prone to develop the disease.

In this chapter, we present several cases from our practice with known or suspected ARVC/D, with representative imaging (CMR, ECHO) and ECG data where available, in the form of a short clinical vignette along with an important “teaching point” we created based on the analysis of these cases. ARVC/D is a disease requiring significant systematic process of considering all the clinical data, as there is no single “gold standard” in the diagnosis and management of the disorder. Our cases include typical patients with definitive ARVC/D, cases where the findings are borderline for the disease, cases with positive family history of ARVC/D, and/or genotype-positive family member. These cases were not previously published. We hope these vignettes would help our readers in understanding the diagnostic process and our clinical approach to the ARVC/D patients.

This chapter will summarize the most important CMR features of ARVC/D. Diagnostic accuracy of CMR in the diagnosis of ARVC/D has been evaluated in numerous studies and is an integral part of the 2010 Modified Task Force ARVC/D criteria. CMR can identify not only the advanced disease but also subtle early changes of ARVC/D with a high diagnostic accuracy; CMR also has incremental value in risk stratifying asymptomatic ARVC/D-associated desmosomal mutation carriers. Typical CMR findings in ARVC/D include RV dilatation and global RV systolic dysfunction, wall motion abnormalities, trabecular disarray, fatty infiltration of the RV (and in some cases - the LV) myocardium demonstrated by T1 signal, thinned and remodeled RV myocardium due to fibrofatty replacement, aneurysms of the RV and RVOT, and delayed hyperenhancement of the involved myocardium on gadolinium-enhanced sequences. This review will help the readers to recognize patterns of the CMR abnormalities consistent with ARVC/D.

In this chapter, we will describe in detail, the mimics of the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). There are several disorders predominantly involving the right ventricular myocardium and leading to structural abnormalities that could be easily interpreted by inexperienced imager as these are consistent with the ARVC/D. We will focus on some of these pathologic conditions associated with the RV changes reminding those of the RV dysplasia and frequently reaching extent and severity requiring review of task force criteria. Disorders such as cardiac sarcoidosis, myocarditis, pulmonary hypertension, and some congenital abnormalities may be easily mixed up with the ARVC/D. Moreover, these disorders may lead to a significant RV and left ventricular (LV) fibrosis, and subsequent ventricular arrhythmias mimicking electrocardiography-based criteria of the ARVC/D. Serious diagnostic skills and knowledge are needed to carefully review the entire clinical picture and create a differential diagnosis list for all the cases when the ARVC/D is suspected. In this chapter, we will also describe normal variants and a few benign clinical conditions that may have CMR appearance of the ARVC/D. It is especially important in this regard to distinguish the disorder with a normal variant of the “athlete’s heart.” We provide a simple approach allowing to utilize the entirety of the clinical data in each case in order to come up with an understanding of the “posttest likelihood” of the ARVC/D vs. the ARVC/D mimic. Several clinical examples from the published evidence demonstrate diagnostic dilemmas and difficulty in differential diagnosis of ARVC/D, as well as the most effective approach to diagnosis in these patients.

This chapter discusses current evidence in the genotype to phenotype correlation of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Due to incomplete penetrance and variable expressivity, the genotype to phenotype relationship is often difficult to predict. ARVC/D is classically thought of as a disease of desmosomal proteins, as mutations in five desmosomal genes account for a majority of cases (DSP, DSG2, DSC2, JUP, and PKP2). Other non-desmosomal genes have also been implicated in disease pathogenesis (TGFB3, TMEM43, TP63, DES, LMNA, CTNNA3, PLN, and TTN), but their roles are less well understood due to insufficient data and overlap with other diseases. Emerging evidence is summarized and suggests an expanding role for ARVC/D genotype and the relationship to prognosis and management.

In their 1982 paper, Frank Marcus from the University of Arizona and Guy Fontaine with the group of investigators from the Hopital de La Salpetriere provided a detailed description of the disease they called “arrhythmogenic right ventricular dysplasia,” or ARVD. They defined ARVD as a disorder of a heart muscle, leading to arrhythmias, and predominantly involving the right ventricular (RV) myocardium, causing progressive fibro fatty replacement of the RV free wall and subsequent RV enlargement and focal regional wall motion abnormalities. The authors described in detail imaging-based features of this disorder; utilizing RV angiography and echocardiography. They revealed the most frequent an involvement of specific regions of the RV (RV inflow tract and outflow tract and RV apex) defining it as “the triangle of dysplasia.” In this Chapter, we provide historical overview of the changes in understanding and definition of ARVC/D. We also describe diagnostic approach utilizing the 2010 ARVC/D Task Force Criteria.

ARVC 2012. The most common presentation of arrhythmogenic right ventricular cardiomyopathy (ARVC) is palpitations or ventricular tachycardia (VT) of left bundle branch morphology in a young or middle-aged individual. The 12-lead electrocardiogram may be normal or have T-wave inversion beyond V1 in an otherwise healthy person who is suspected of having ARVC. The most frequent imaging abnormalities are an enlarged right ventricle, decrease in right ventricular (RV) function, and localized wall motion abnormalities. Risk factors for implantable cardioverter defibrillator include a history of aborted sudden death, syncope, young age, decreased left ventricular function, and marked decrease in RV function. Recent results of treatment with epicardial ablation are encouraging. (J Cardiovasc Electrophysiol, Vol. pp. 1-5) arrhythmogenic right ventricular cardiomyopathy, implantable cardioverter defibrillator, RV dysplasia, sudden death, ventricular tachycardia Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by the predominance of ventricular arrhythmias. 1 The presenting clinical manifestations usually consist of palpitations because of premature ventricular beats (PVCs), lightheadedness or syncope because of rapid monomorphic ventricular tachycardia (VT) or uncommonly sudden death as a result of ventricular fibrillation. Symptoms usually appear between the ages of 30‐50 but there is a wide range of the onset of symptoms from age 10 to the 80s. Because ventricular arrhythmias usually originate from the right ventricle, the ventricular arrhythmias have left bundle branch morphology. Therefore, suspicion for the diagnosis of ARVC is increased when the ventricular arrhythmias have left bundle branch block (LBBB) morphology and particularly when the QRS axis is superior. This is exemplified by a positive QRS complex in lead AVL indicating an origin from the body of the right ventricle rather than from the right ventricular (RV) outflow tract. Nevertheless, PVCs may arise from the RV outflow tract in ARVC. If so, the diagnosis must be differentiated from patients who have idiopathic VT (RVOT). Another interesting characteristic of these patients is that their sustained VT may be quite rapid, in the range of 200‐250 beats/minute, yet the patients may tolerate this for many hours because the left ventricle has normal or nearly

Background— Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a false-positive case in which plakoglobin signal was reduced in a patient initially believed to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC but has not been previously associated with altered desmosomal proteins. Methods and Results— We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 (cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β, in patients with ARVC (all P Conclusions— The results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.

Imaging of the right ventricle (RV) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is commonly performed by echocardiography or magnetic resonance imaging (MRI). Angiography is an alternative modality, particularly when MRI cannot be performed. We hypothesized that RV volume and ejection fraction computed by angiography would correlate with these quantities as computed by MRI. RV volumes and ejection fraction were computed for subjects enrolled in the North American ARVC/D Registry, with both RV angiography and MRI studies. Angiography was performed in the 30° right anterior oblique (RAO) and 60° left anterior oblique (LAO) views. Angiographic volumes were computed by RAO view and two-view (RAO and LAO) formulae. 17 subjects were analyzed (11 men and 6 women), with 15 subjects classified as affected, and two as unaffected by modified Task Force criteria. The correlation coefficient of MRI to the two-view angiographic analysis was 0.72 (P = 0.003) for end-diastolic volume and 0.68 (P = 0.005) for ejection fraction. Angiographically derived volumes were larger than MRI derived volume (P = 0.009) and with the slope in a linear relationship equal to 0.8 for end diastolic volume, and 0.9 for RV ejection fraction (P < 0.001), computed by the two view formula. End-diastolic volumes and ejection fractions of the RV obtained by dual view angiography correlate with these quantities by MRI. RV end-diastolic volumes are larger by RV angiography in comparison with MRI.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited disease that causes structural and functional abnormalities of the right ventricle (RV). The presence of late potentials as assessed by the signal-averaged electrocardiogram (SAECG) is a minor task force criterion.The purpose of this study was to examine the diagnostic and clinical value of the SAECG in a large population of genotyped ARVC/D probands.We compared the SAECGs of 87 ARVC/D probands (age 37 ± 13 years, 47 males) diagnosed as affected or borderline by task force criteria without using the SAECG criterion with 103 control subjects. The association of SAECG abnormalities was also correlated with clinical presentation, surface ECG, ventricular tachycardia (VT) inducibility at electrophysiologic testing, implantable cardioverter-defibrillator therapy for VT, and RV abnormalities as assessed by cardiac magnetic resonance imaging (cMRI).Compared with controls, all three components of the SAECG were highly associated with the diagnosis of ARVC/D (P.001). They include the filtered QRS duration (97.8 ± 8.7 ms vs 119.6 ± 23.8 ms), low-amplitude signal (24.4 ± 9.2 ms vs 46.2 ± 23.7 ms), and root mean square amplitude of the last 40 ms of the QRS (50.4 ± 26.9 μV vs 27.9 ± 36.3 μV). The sensitivity of using SAECG for diagnosis of ARVC/D was increased from 47% using the established 2 of 3 criteria (i.e., late potentials) to 69% by using a modified criterion of any 1 of 3 criteria, while maintaining a high specificity of 95%. Abnormal SAECG as defined by this modified criterion was associated with a dilated RV volume and decreased RV ejection fraction detected by cMRI (P.05). SAECG abnormalities did not vary with clinical presentation or reliably predict spontaneous or inducible VT and had limited correlation with ECG findings.Using 1 of 3 SAECG criteria contributed to increased sensitivity and specificity for the diagnosis of ARVC/D. This finding is incorporated in the recent modification of the task force criteria.

Background: There is no currently available technology to accurately predict ablation lesion size within seconds of onset of delivery of radiofrequency (RF) energy. Methods: Changes in several biophysical characteristics of cardiac tissue in vitro within 5–15 seconds of the onset of RF energy were evaluated to predict lesion formation at 120 seconds. RF energy was applied with a 50% duty cycle to measure heating and cooling behavior of the electrode temperature sensor. Changes in impedance, phase angle, and the resulting resistance and capacitance, power, and electrode temperature variation during RF ablation were analyzed. Results: A combination of electrical-based parameters measured online as early as 5, 10, and 15 seconds after onset of RF energy in vitro was found to explain 63, 75, and 76% of variability (R2) of lesion volume. These correlations were better than any single parameter, particularly impedance and target temperature. Conclusions: A combination of electrical-based parameters provides better correlation with lesion formation than a single parameter and may be useful to predict lesion size during RF ablation in vivo. These parameters appear to represent changes in the tissue during heating. (PACE 2010; 33:1082–1088)

Objectives This study sought to examine the efficacy of empiric antiarrhythmic drugs in a rigorously characterized cohort of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. Background Antiarrhythmic drugs are important in protecting against ventricular arrhythmias in ARVC, but no studies have provided data in a group rigorously screened for the disease. Methods Antiarrhythmic medicines were examined in all subjects with implantable cardioverter-defibrillators (ICDs) enrolled in the North American ARVC Registry. A Cox proportional hazards model was used to account for time on each drug, and a hierarchical analysis was performed for repeated measures within individuals. Results Ninety-five patients were studied, with a mean follow-up of 480 ± 389 days. Fifty-eight (61%) received beta-blockers, and these medicines were not associated with an increased or decreased risk of ventricular arrhythmias. Sotalol was associated with a greater risk of any clinically relevant ventricular arrhythmia as defined by sustained ventricular tachycardia or ICD therapy (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.02 to 6.39, p = 0.045), but this was not statistically significant after adjusting for potential confounders. An increased risk of any ICD shock and first clinically relevant ventricular arrhythmia while on sotalol remained significant after multivariable adjustment. Those on amiodarone (n = 10) had a significantly lower risk of any clinically relevant ventricular arrhythmia (HR: 0.25, 95% CI: 0.07 to 0.95, p = 0.041), a finding that remained significant after multivariable adjustment. Conclusions In a cohort of well-characterized ARVC subjects, neither beta-blockers nor sotalol seemed to be protective. Evidence from a small number of patients suggests that amiodarone has superior efficacy in preventing ventricular arrhythmias.

ObjectivesThis study sought to investigate the prevalence and mechanisms underlying right ventricular (RV) dyssynchrony in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using tissue Doppler echocardiography (TDE).BackgroundAn ARVD/C is characterized by fibrofatty replacement of RV myocardium and RV dilation. These pathologic changes may result in electromechanical dyssynchrony.MethodsEchocardiography, both conventional and TDE, was performed in 52 ARVD/C patients fulfilling Task Force criteria and 25 control subjects. The RV end-diastolic and -systolic areas, right ventricular fractional area change (RVFAC), and left ventricular (LV) volumes and function were assessed. Mechanical synchrony was assessed by measuring differences in time-to-peak systolic velocity (TSV) between the RV free wall, ventricular septum, and LV lateral wall. An RV dyssynchrony was defined as the difference in TSVbetween the RV free wall and the ventricular septum, >2 SD above the mean value for control subjects.ResultsThe mean difference in RV TSVwas higher in ARVD/C compared with control subjects (55 ± 34 ms vs. 26 ± 15 ms, p < 0.001). Significant RV dyssynchrony was not noted in any of the control subjects. Based on a cutoff value of 56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). Patients with RV dyssynchrony had a larger RV end-diastolic area (22 ± 5 cm2vs. 19 ± 4 cm2, p = 0.02), and lower RVFAC (29 ± 8% vs. 34 ± 8%, p = 0.03) compared with ARVD/C patients without RV dyssynchrony. No differences in QRS duration, LV volumes, or function were present between the 2 groups.ConclusionsAn RV dyssynchrony may occur in up to 50% of ARVD/C patients, and is associated with RV remodeling. This finding may have therapeutic and prognostic implications in ARVD/C.