Arrhythmogenic ventricular cardiomyopathy:A paradigm shift from right to biventricular disease

Arrhythmogenic ventricular cardiomyopathy(AVC) isgenerally referred to as arrhythmogenic right ventricu-lar(RV) cardiomyopathy/dysplasia and constitutesan inherited cardiomyopathy.Affected patients maysuccumb to sudden cardiac death(SCD),ventriculartachyarrhythmias(VTA) and heart failure.Geneticstudies have identified causative mutations in genesencoding proteins of the intercalated disk that lead toreduced myocardial electro-mechanical stability.Theterm arrhythmogenic RV cardiomyopathy is somewhatmisleading as biventricular involvement or isolated leftventricular(LV) involvement may be present and thus abroader term such as AVC should be preferred.The di-agnosis is established on a point score basis accordingto the revised 2010 task force criteria utilizing imagingmodalities,demonstrating fibrous replacement throughbiopsy,electrocardiographic abnormalities,ventricu-lar arrhythmias and a positive family history includingidentification of genetic mutations.Although severarisk factors for SCD such as previous cardiac arrest,syncope,documented VTA,severe RV/LV dysfunctionand young age at manifestation have been identified,risk stratification still needs improvement,especially inasymptomatic family members.Particularly,the roleof genetic testing and environmental factors has to befurther elucidated.Therapeutic interventions include re-striction from physical exercise,beta-blockers,sotalol,amiodarone,implantable cardioverter-defibrillators andcatheter ablation.Life-long follow-up is warranted insymptomatic patients,but also asymptomatic carriersof pathogenic mutations.

Arrhythmogenic right ventricular cardiomyopathy: From genetics to diagnostic and therapeutic challenges

Arrhythmogenic right ventricular cardiomyopathy(ARVC) is a genetic disease characterized by myocyte loss and fibro-fatty tissue replacement. Diagnosis of ARVC remains a clinical challenge mainly at its early stages and in patients with minimal echocardiographic right ventricular(RV) abnormalities. ARVC shares some common features with other cardiac diseases, such as RV outflow ventricular tachycardia, Brugada syndrome, and myocarditis, due to arrhythmic expressivity and biventricular involvement. The identification of ARVC can be often challenging, because of the heterogeneous clinical presentation, highly variable intra- and inter-family expressivity and incomplete penetrance. This genotypephenotype "plasticity" is largely unexplained. A familial history of ARVC is present in 30% to 50% of cases, and the disease is considered a genetic cardiomyopathy, usually inherited in an autosomal dominant pattern with variable penetrance and expressivity; in addition, autosomal recessive forms have been reported(Naxos disease and Carvajal syndrome). Diagnosis of ARVC relays on a scoring system, with major or minorcriteria on the Revised Task Force Criteria. Implantable cardioverter defibrillators(ICDs) are increasingly utilized in patients with ARVC who have survived sudden death(SD)(secondary prevention). However, there are few data available to help identifying ARVC patients in whom the prophylactic implantation of an ICD is truly warranted. Prevention of SD is the primary goal of management. Pharmacologic treatment of arrhythmias, catheter ablation of ventricular tachycardia, and ICD are the mainstay of treatment of ARVC.

Ablation strategies for arrhythmogenic right ventricular cardiomyopathy: a systematic review and meta-analysis

Background Catheter ablation for ventricular tachycardia(VT) in patients with arrhythmogenic right ventricular cardiomyopathy(ARVC) has significantly evolved over the past decade. However, different ablation strategies showed inconsistency in acute and long-term outcomes. Methods We searched the databases of Medline, Embase and Cochrane Library through October 17, 2019 for studies describing the clinical outcomes of VT ablation in ARVC. Data including VT recurrence, all-cause mortality, acute procedural efficacy and major procedural complications were extracted. A meta-analysis with trial sequential analysis was further performed in comparative studies of endo-epicardial versus endocardial-only ablation. Results A total of 24 studies with 717 participants were enrolled. The literatures of epicardial ablation were mainly published after 2010 with total ICD implantation of 73.7%, acute efficacy of 89.8%, major complication of 5.2%, follow-up of 28.9 months, VT freedom of 75.3%, all-cause mortality of 1.1% and heart transplantation of 0.6%. Meta-analysis of 10 comparative studies revealed that compared with endocardial-only approach, epicardial ablation significantly decreased VT recurrence(OR: 0.50;95% CI: 0.30–0.85;P = 0.010), but somehow increased major procedural complications(OR: 4.64;95% CI: 1.28–16.92;P = 0.02), with not evident improvement of acute efficacy(OR: 2.74;95% CI: 0.98–7.65;P = 0.051) or all-cause mortality(OR: 0.87;95% CI: 0.09–8.31;P = 0.90). Conclusion Catheter ablation for VT in ARVC is feasible and effective. Epicardial ablation is associated with better long-term VT freedom, but with more major complications and unremarkable survival or acute efficacy benefit.

Arrhythmogenic epilepsy and pacing need: A matter of controversy

There is increasing awareness among the cardiology community regarding ictal bradyarrhythmias as a cause of loss of consciousness. A high degree of suspicion is necessary when diagnosing ictal bradyarrhythmias, and delay in diagnosing this condition may lead to morbidity associated with falls and trauma. Ictal bradyarrhythmias have also been suggested to be associated with sudden unexplained death in epilepsy, although evidence related to this association is limited. There is no guidelinedirected therapy for symptomatic ictal bradyarrhythmias due to a lack of randomized, controlled trials. Cardiac pacemaker therapy is commonly used for these patients; however, currently, there is no universal agreement on the pacing indications for these patients. In this review, we focus on the pathophysiology and clinical presentation of ictal bradyarrhythmias and then discuss the pacing need based on the available literature data.

Seeking candidate variants of arrhythmogenic cardiomyopathy in sarcomere genes

ObjectiveTo seek potential pathogenic variants in sarcomere genes in arrhythmogenic cardiomyopathy(ACM)and describe the characteristics.Methods and Results We performed targeted sequencing of 14sarcomere genes in 118 cases with the clinical diagnosis of ARVC and Sanger sequencing of the specific variants in family members of the probands.

Is cardiac MRI an effective test for arrhythmogenic right ventricular cardiomyopathy diagnosis?

AIM:To evaluate the referrals with suspected arrhythmogenic right ventricular cardiomyopathy(ARVC)and compare cardiac MR(cMR)findings against clinical diagnosis.METHODS:A retrospective analysis of 114(age range16 to 83,males 55%and females 45%)patients referred for cMR with a suspected diagnosis of ARVC between May 2006 and February 2010 was performed after obtaining institutional approval for service evaluation.Reasons for referral including clinical symptoms and family history of sudden death,electrocardiogram and echo abnormalities,cMR findings,final clinical diagnosis and information about clinical management were obtained.The results of cMR were classified as major,minor,non-specific or negative depending on both functional and tissue characterisation and the cMR results were compared against the final clinical diagnosis.RESULTS:The most common reasons for referral included arrhythmias(30%)and a family history of sudden death(20%).Of the total cohort of 114 patients:4 patients(4%)had major cMR findings for ARVC,13patients(11%)had minor cMR findings,2 patients had non-specific cMR findings relating to the right ventricle and 95 patients had a negative cMR.Of the 4 patients who had major cMR findings,3(75%)had a positive clinical diagnosis.In contrast,of the 13 patients who had minor cMR findings,only 2(15%)had a positive clinical diagnosis.Out of the 95 negative patients,clinical details were available for 81 patients and none of them had ARVC.Excluding the 14 patients with no clinical data and final diagnosis,the sensitivity of the test was 100%,specificity 87%,positive predictive value29%and the negative predictive value 100%.CONCLUSION:CMR is a useful tool for ARVC evaluation because of the high negative predictive value as the outcome has a significant impact on the clinical decision-making.

Arrhythmogenic right ventricular cardiomyopathy patients with desmoglein-2 variants are characterized by recessive inheritance and progressive heart failure:clinical and genetic features of a Chinese ARVC cohort

Background Arrhythmogenic right ventricular cardiomyopathy(ARVC)is an inherited primary cardiomyopathy characterized by myocardial degeneration with fibro-fatty replacement.Clinical and genetic features of ARVC were well identified in Caucasian cohorts,but seldom examined in Chinese cohort.Our aim is to examine the genetic factor,genotype-phenotype correlations,and inheritance patterns of ARVC in a Chinese cohort.

Arrhythmogenic right ventricular cardiomyopathy characterized by recurrent syncope during exercise:A case report

BACKGROUND Arrhythmogenic right ventricular(RV)cardiomyopathy is a rare and currently underrecognized cardiomyopathy characterized by the replacement of RV myocardium by fibrofatty tissue.It may be asymptomatic or symptomatic(palpitations or syncope)and may induce sudden cardiac death,especially during exercise.To prevent adverse events such as sudden cardiac death and heart failure,early diagnosis and treatment of arrhythmogenic RV cardiomyopathy(ARVC)are crucial.We report a patient with ARVC characterized by recurrent syncope during exercise who was successfully treated with combined endocardial and epicardial catheter ablation.CASE SUMMARY A 43-year-old man was referred for an episode of syncope during exercise.Previously,the patient experienced two episodes of syncope without a firm etiological diagnosis.An electrocardiogram obtained at admission indicated ventricular tachycardia originating from the inferior wall of the right ventricle.The ventricular tachycardia was terminated with intravenous propafenone.A repeat electrocardiogram showed a regular sinus rhythm with negative T waves and a delayed S-wave upstroke from leads V1 to V4.Cardiac magnetic resonance imaging showed RV free wall thinning,regional RV akinesia,RV dilatation and fibrofatty infiltration(RV ejection fraction of 38%).An electrophysiological study showed multiple inducible ventricular tachycardia as of a focal mechanism from the right ventricle.Endocardial and epicardial voltage mapping demonstrated scar tissue in the anterior wall,free wall and posterior wall of the right ventricle.Late potentials were also recorded.The patient was diagnosed with ARVC and treated with combined endocardial and epicardial catheter ablation with a very satisfactory follow-up result.CONCLUSION Clinicians should be aware of ARVC,and further workup,including imaging with multiple modalities,should be pursued.The combination of epicardial and endocardial catheter ablation can lead to a good outcome.

Dilated left ventricle with multiple outpouchings—a severe congenital ventricular diverticulum or left-dominant arrhythmogenic cardiomyopathy:A case report

BACKGROUND Left-dominant arrhythmogenic cardiomyopathy(LDAC)is a relatively rare disease characterized by poor prognosis that exacerbates the incidence of sudden cardiac death and ventricular arrhythmias.Clinically,LDAC is constantly overlooked or misdiagnosed as myocardial infarction,myocarditis,and dilated cardiomyopathy,owing to atypical and nonspecific clinical manifestations at an early stage.CASE SUMMARY A 57-year-old woman was diagnosed with sinus bradycardia and chronic bifascicular block during a health check.She occasionally experienced mild chest pain and paroxysmal palpitation during activity in the past 2 years.Comprehensive auxiliary examinations,including electrocardiogram,echocardiography,coronary computerized tomography angiography,and magnetic resonance imaging,revealed that she had LDAC instead of congenital ventricular diverticulum.The physicians prescribed standard oral therapy for heart failure and implantable cardioverter-defibrillator.Consequently,her left ventricular systolic function and symptoms remained stable at the 2-year follow-up after discharge.CONCLUSION Based on this case,clinicians need to be aware of LDAC in patients with localized left ventricular lesions and multiple electrocardiographic abnormalities.Multimodality cardiovascular imaging is effective in identification of multiple types of cardiomyopathy and cardiac inner structures.

Arrhythmogenic Ventricular Dysplasia/Cardiomyopathy: Insights from the Rationale of Disease Nomenclature and Clinical Perspectives

“Arrhythmogenic right ventricular dysplasia” (ARVD), a heart muscle disorder characterized by the presence of fibro-fatty tissue and ventricular electrical vulnerability related to sudden death, was first described in 1977 by a French team. Since then, other terms such as “arrhythmogenic right ventricular cardiomyopathy” (ARVC), “arrhythmogenic cardiomyopathy” (AC), “left-dominant arrhythmogenic cardiomyopathy” (LDAC), and “arrhythmogenic left ventricular dysplasia” (ALVD) have been introduced. These changes in nomenclature of the same disease entity are based on different explanations of pathomorphologic patterns. The dysplasia theory claims cardiac growth “maldevelopment” whereas the cardiomyopathy has been seen as an atrophy from acquired injury (myocyte death) and repair (fibrofatty replacement). The other area of divergent opinion is with regards to involvement of both ventricles rather than being an isolated right ventricular anomaly that may result in increased likelihood of diagnosing the concealed form manifesting with pre-dominant left ventricular arrhythmias. Multiple line of evidences support common disease path-ways: Presence of fibro-fatty and superimposed myocarditis, desmosome mutations and malfunc-tion. These compelling data regarding the heart growth, and pathological, clinical, phenotype/ genotype correlates have advanced our understanding of arrhythmogenic ventricular dysplasia/ cardiomyopathy and increased the diagnostic accuracy as well as providing an avenue for future development of new mechanism-based therapies.

Confusing aspects of arrhythmogenic right ventricular dysplasia: Current clinical view

Arrhythmogenic right ventricular dysplasia is an inherited fatal cardiomyopathy causing fat and connective tissue infiltration of right ventricle. In advanced disease, it may also involve left ventricle. Heart failure, arrhythmias and sudden death are main clinical components. Many different genetic mutations can cause this cardiomyopathy. All mutations lead to the formation of the disease are not yet defined. Basis of pathogenetic event is corruption of physical connection as well as the electrical conduction between cardiomyocytes due to these genetic reasons. Genetical inheritance is frequently autosomal dominant but incomplete. Because of the many different phenotypes, there may be great heterogenity of clinical manifestations in same family. Diagnostic criteria are renovated lately. Current cardiac imaging techniques for the diagnosis is gradually progressing. A combination of several tests should be used for diagnosis. Early and accurate diagnosis will save lives and improve the patient’s quality of life. In this paper, after mentioning the features and diagnosis of ARVD, differential diagnosis of ARVD from other diseases which may cause fatty infiltration of heart, arrhythmias and sudden death will be focused.

Anaesthesia for patients with arrhythmogenic right ventricular dysplasia

Arrhythmogenic right ventricular dysplasia(ARVD) is an inherited heart muscle disease.Myocyte apoptosis and fibro-fatty scar tissue predisposes patients to malignant ventricular arrhythmias.Patients may present to variety of surgical procedures with diagnosed ARVD.Surgical insult,catecholamine surge and physiological disturbance can be hazardous on the vulnerable myocardium and may result in life-threatening ventricular tachycardia or sudden cardiac death in the perioperative period.Anaesthetists have particular role in perioperative management of this patient population,meticulous perioperative planning,close haemodynamic monitoring and maintenance of physiological stability throughout helps to avoid devastating perioperative loss.

Arrhythmogenic right ventricular cardiomyopathy associated ventricular tachycardia misdiagnosed as idiopathic right ventricular outflow tract origin and its management

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an autosomal dominant genetic form of cardiomyopathy (CM), which primarily affects the right ventricle (RV) and results in life threatening ventricular arrhythmias and sudden cardiac death (SCD). Diagnosis is difficult due to the broad spectrum of phenoltypic variations, especially in the early stage. Clinical suspicion should be raised in the setting of refractory ventricular tachycardia originating from the RV, and the final diagnosis could be made based on the combination of electrocardiography, echocardiography, cardiac magnetic resonance imaging (CMRI) and myocardial biopsy. Implantable cardioverter-defibrillator (ICD) implantation is an effective option for the treatment of ARVC.

Arrhythmogenic Right Ventricular Disease on a Young Peaseant

Abstract

A Heterozygous Phospholamban Variant(p.R14del)Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy

This study aimed to determine the prevalence and clinical features of Arrhythmogenic Right Ventricular Cardiomyopathy(ARVC)caused by pathogenic mutations in the Phospholamban(PLN)gene.The study included 170 patients who had a confrmed diagnosis of ARVC and underwent PLN genetic screening using next-generation sequencing.The fndings of this study provide valuable insights into the association between PLN mutations and ARVC,which can aid in the development of more efective diagnostic and treatment strategies for ARVC patients.Out of the patients evaluated,six had a rare pathogenic mutation in PLN with the same p.R14del variant.Family screening revealed that heterozygous carriers of p.R14del exhibited a defnite ARVC phenotype.In clinical studies,individuals with the p.R14del mutation experienced a similar rate of malignant arrhythmia events as those with classic desmosome mutations.After adjusting for covariates,individuals with PLN mutations had a two point one seven times greater likelihood of experiencing transplant-related risks compared to those who did not possess PLN mutations(95%CI 1.08–6.82,p=0.035).The accumulation of left ventricular fat and fbers is a pathological marker for ARVC patients with p.R14del mutations.In a cohort of 170 Chinese ARVC patients,three point fve percent of probands had the PLN pathogenic variant(p.R14del)and all were female.Our data shows that PLN-related ARVC patients are at high risk for ventricular arrhythmias and heart failure,which requires clinical diferentiation from classic ARVC.Furthermore,carrying the p.R14del mutation can be an independent prognostic risk factor in ARVC patients.

Reactivation of PPARαalleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acidβ-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mutations in desmosome proteins,with Desmoglein-2(DSG2)mutations as a common etiology.However,the mechanism underlying the accumulation of fibrofatty in ACM remains unknown,which impedes the development of curative treatment.Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2(CS-Dsg2^(-/-)).Heart failure and cardiac lipid accumulation were observed in CSDsg2^(-/-)mice.We demonstrated that these phenotypes were caused by decline of fatty acid(FA)β-oxidation resulted from impaired mammalian target of rapamycin(m TOR)signaling.Rapamycin worsened while overexpression of m TOR and 4EBP1 rescued the FAβ-oxidation pathway in CS-Dsg2^(-/-)mice.Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function.Our results suggest that impaired m TOR-4EBP1-PPARa-dependent FAβ-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM.

A validation study of southern China for European prediction model about ventricular arrhythmias for arrhythmogenic right ventricular cardiomyopathy

Background Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy.European Society of Cardiology was devised a new prediction model to estimate ventricular arrhythmias and guide decisions regarding primary prevention ICDs.This paper aimed to conduct external validation of European prediction model in the South China.

Clinical and familial study of arrhythmogenic right ventricular cardiomyopathy

Objective To explore the characteristics of arrhythmogenic right ventricular cardiomyopathy (ARVC) Methods Seven patients with arrhythmogenic right ventricular cardiomyopathy and 34 members of three families were studied All patients and family members underwent history collection, clinical examination, electrocardiogram (ECG), two dimensional echocardiography (2 DE) and a signal averaging electrocardiogram Programmed ventricular stimulation was performed in five patients Results All patients and family members had normal morphologic characteristics and normal function of the left ventricular by 2 DE Fourteen persons had abnormal findings indicating ARVC Five had enlargement of the right ventricular with diffused hypocontractility, eight had thin and systolic bulging in the focal anterior wall with hypokinesia and one had bulging of the inferior wall Twenty five persons (seven patients and 18 family members) had abnormal findings in ECG Positive ventricular late potential was recorded in 13 persons (six patients) Two to three monomorphic ventricular tachycardia (VT) with left bundle branch block (LBBB) configurations were induced in five patients Ventricular fibrillation was induced in two patients during the electrophysiologic study (EPS) Five patients had very high pacing threshold and/or ineffective pacing in one or many regions of the right ventricle Two members of one family died suddenly One member was a dwarf with ARVC Spontaneous VT with a left bundle branch block (LBBB) configuration was recorded in five patients, polymorphic VT with extremely short coupling interval in one, and premature ventricular complexes with LBBB configuration in 12 (six patients) Conclusion Our familial study strongly suggests that ARVC may be a hereditary disease and it is helpful in the diagnosis and detection of ARVC The most common manifestations were abnormal structure and function of the right ventricle and abnormal ECG of repolarization and ventricular arrhythmia which originates from the right ventricle

Mutation of plakophUin-2 gene in arrhythmogenic right ventricular cardiomyopathy

Background Arrhythmogenic right ventricular cardiomyopathy （ARVC） is one of the leading causes of sudden cardiac death. Recent studies have shown that ARVC, which is an inheritable genetic change, results from mutations in genes encoding desmosomal proteins. Plakophilin-2 is an important component of the desmosome. Because the full range of genetic variations related to ARVC is unknown and no related studies of the Chinese population have been reported, we aimed to investigate the genetic variation of plakophilin-2 in ARVC patients from the Southern Region of China. Methods Genomic DNA was isolated from peripheral blood samples of all 34 ARVC patients, who were screened through a clinical evaluation. They were used to detect variations in the sequences of the plakophilin-2 genes by polymerase chain reaction amplification in combination with direct sequencing. Results In exon-1 of the plakophilin-2 gene, a deletion mutation （c.145_148 del GACA） was found in one family pedigree. The mutation was also found in exon-2, 4, and 11 of the plakophilin-2 gene. The QT interval dispersion of the ECG was considerably longer in the mutation group than in the non-mutation group of ARVC patients, and this result was statistically significant （P 〈0.05）. Conclusion We discovered a plakophilin-2 mutation that prolongs the QT interval dispersion in the southern Chinese ARVC population.

Clinical study of 39 Chinese patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy

Background There are few studies on the clinical profile of Chinese patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy （ARVD/C）. The purpose of this study was to describe the clinical characteristics of ARVD/C patients from China, particularly to define the features of electrocardiograph and treatment outcomes. Methods Thirty-nine patients hospitalized in Fu Wai Cardiovascular Hospital from 1998 to 2006 were included. The data were obtained from the medical archive and the follow-up records. Results Of these patients 33 were male and 6 female （age at the first presentation was （34.9 ± 9.8） years）. The most common symptoms were palpitation （62%） and syncope （44%）. Right precordial QRSd 〉 110 ms was detected in 69% of the patients, epsilon wave in 59%, and a ratio of QRSd in V1＋V2＋V3/V4＋V5＋V6 ≥ 1.2 in 82%. The most frequent features of electrocardiogram in patients without right bundle-branch block were T-wave inversions and S-wave upstroke in V1-V3 〉55 ms （96% and 90% of 28 patients, respectively）. Radiofrequency catheter ablation （RFCA） for ventricular tachycardia （VT） was successful in 15 （68%） of 22 patients. The recurrence rate of VT was 46% （7/15） during the follow-up of （16.7 ± 11.2） months. Seven patients had cardioverter/defibrillator （ICD） implanted plus drug therapy and 17 patients took antiarrhythmic drugs alone. During the follow-up of （35.6 ± 19.0） months, all patients with ICD implanted received at least one appropriate ICD shock. One patient died of ventricular fibrillation suddenly and one patient underwent heart transplantation for progressive biventricular heart failure during the drug therapy alone. Conclusions This study demonstrated the clinical and ECG features of the 39 ARVD/C Chinese patients. ICD provided life-saving protection by effectively terminating malignant arrhythmias, and the high recurrence of VT was the major problem of RFCA therapy.