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 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.

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.

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.

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.

Screening of pathogenic genes in Chinese patients with arrhythmogenic right ventricular cardiomyopathy

Background Arrhythmogenic right ventricular cardiomyopathy （ARVC） is a heritable cardiac disease predominantly caused by mutations in desmosomal protein genes. Previous genetic analyses of the Chinese ARVC population are limited to small size and restriction to a single gene. This study was aimed to investigate the genotype in a large series of Chinese patients with ARVC through comprehensively screening nine ARVC-causing genes. Methods A total of 100 unrelated ARVC patients and 300 age, gender and ethnicity matched healthy controls were genetically tested with multiplexing targeted resequencing for nine previously reported ARVC-causing genes, including plakophilin-2, desmoplakin, desmoglein-2, desmocollin-2, plakoglobin, transforming growth factor beta-3, transmembrane protein 43, desmin and Lamin A/C. Results Fifty-nine mutations were identified in 64% of the patients, among which, 93% were located in desmosomal protein genes. Plakophilin-2 mutations accounted for 54% of the total and 58% of the desmosomal mutations, with a truncating mutation type making up about 2/3 of the plakophilin-2 mutations. Only four mutations were found in nondesmosomal genes; two in transmembrane protein 43 and two in transforming growth factor beta-3. Two of them （one of each gene） appeared as single missense mutations. No mutation was identified in desmin or Lamin A/C. Multiple mutations were found in 23% of the patients, with plakophilin-2 being found in 57% of the multi-mutation carriers. Conclusions Plakophilin-2 was the most common gene mutation that was identified in Chinese ARVC patients. Nondesmosomal genes should be added to desmosomal protein genes when performing molecular genetic screening in patients with suspected ARVC.

Unexpected sudden death in pregnancy–arrhythmogenic right ventricular cardiomyopathy/dysplasia:a case report

Cardiovascular disease is an important contributor to maternal mortality in both developing and developed countries.Systematic search for cardiac disease is usually not performed during pregnancy despite hypertensive disease,undiagnosed pulmonary hypertension and cardiomyopathies being recognized as major health problems in these settings.This article reported a 27-year-old female who was normal on clinical examination and basic investigations,and on an antenatal visit was found collapsed in the toilet of her house and was pronounced dead on admission to hospital.She was found to be in the 11th week of pregnancy and had no history of significant illness in the past.Autopsy did not reveal any obvious macroscopic pathology except for a significant amount of epicardial fat infiltrating into myocardium of right ventricle.Detailed histopathological examination of the heart demonstrated fibro-fatty replacement of the heart muscle.The cause of death was arrhythmogenic right ventricular cardiomyopathy/dysplasia(ARVC/D).ARVC/D can cause unexpected sudden death during pregnancy.Therefore,it is recommended that an ECG and echocardiogram be included as screening tests during antenatal follow-up to minimize preventable cardiac deaths like ARVC/D.

Linkage analysis of five Chinese families with arrhythmogenic right ventricular cardiomyopathy using microsatellite genetic markers

Objective To explore the linkage relationship between specific genetic markers and arrhythmogenic right ventricular cardiomyopathy (ARVC) in Chinese pedigrees.Methods The microsatellite genetic markers D2S152, D14S252, and D10S1664 were studied for their linkages to ARVC in five Chinese ARVC pedigrees and a normal population of 121 Chinese individuals. Genomic DNA of the pedigrees and normal population was amplified using PCR techniques. Denaturing polyacrylamide sequencing gel (4%) electrophoresis was used to detect microsatellite repeat polymorphisms. Gels were silver-stained. A classical linkage analysis program was used assuming models of autosomal dominance and recession.Results The logarithm of the odds (LOD) scores of D2S152 with ARVC in LW, WD, DS, LC and TY pedigrees were 2. 174, -0. 589, -∞, , - (indicating that linkage is not supported in this mode), and -∞ respectively in autosomal dominant model (recombination fraction =0. 000 respectively)and were -∞, -∞, -∞, -∞, and 0. 182 respectively in the autosomal recessive model. The LOD scores of D14S252 with ARVC in LW, WD, DS, LC and TY pedigrees were - , - , -∞ , - , and 0 respectively in autosomal dominant model, and were -∞ , -0.812, -∞ , -∞, and 0.087 respectively in autosomal recessive model. The LOD scores of D2S152 with ARVC in LW, WD, DS, LC and TY pedigrees were - , - 0. 539, - , and 0. 602 respectively in autosomal dominant model and were - , -∞, - ∞ , - ∞ , and -∞ respectively in autosomal recessive model.Conclusions The LOD score for D2S152 in the LW pedigree was 2.174, indicating that the chance of linkage is about 150:1. This suggests that there is a possible ARVC-related gene near this marker. There were no clear linkage relationships between ARVC and D10S1664 and D14S252 in this family, and no linkages between ARVC and any of the three genetic markers in the other four families. These results also suggest that there is genetic heterogeneity in LW and in the other pedigrees.

Evaluation of cardiac function in patients with arrhythmogenic right ventricular cardiomyopathy by echocardiography

Background Arrhythmogenic right ventricular cardiomyopathy （ARVC） mainly performs local myocardial abnormal movements and tissue Doppler and spot tracking technique can accurately reflect myocardial movement. However, the technique is still rarely used in research of ARVC. Methods The study enrolled 28 ARVC patients and 28 normal controls. Right ventricular parameters were measured by two-dimensional echocardiography, tissue Doppler imaging, speckle tracking imaging in order to compare the difference between two groups. Results Morphological indices （right ventricular inflow tract inner diameter and right ventricular outflow tract inner diameter） and functional indices （right ventricular peak S＇, right ventricular E＇/ A＇ ratio, tricuspid annular plane systolic excursion, right ventricular fractional area change and right ventricular inferior and lateral wall longitudinal strain） showed significant difference between the ARVC group and control group. All the above-mentioned indices were analyzed by receiver operating characteristic curve （ROC curves）. Area under the curve （AUC） of right ventricular inferior wall longitudinal strain was the largest one （AUC = 0.94） with an optimal cutoff value of -19.5%. Conclusion Compared with two- dimensional echocardiography and tissue Doppler imaging, right ventricular inferior wall longitudinal strain is a more sensitive predictor for changes of ARVC.

Long-term outcomes in patients with arrhythmogenic right ventricular cardiomyopathy

Background Arrhythmogenic right ventricular cardiomyopathy （ARVC） is a major cause for sudden cardiac death due to ventricular tachycardia. Litter is known about its long-term outcomes in Chinese ARVC patients. The purpose of this study was to evaluate the long-term clinical outcomes in patients with ARVC and to clarify the risk factors of cardiac events. Methods Forty subjects fulfilling modified Task Force criteria were included in this study. Information on clinical presentation, electrocardiographic and cardiac imaging findings, and long-term outcome of cases were investigated. Results Average follow-up period from onset was 57.5 ± 42.6 months. The mean age at onset of symptoms （32.2 ± 12.7 years） and male predominance （85.0%） were similar to that report- ed in other studies. Palpitations were the most frequent symptom （82.5%）. T-wave inversion was the most com- mon presenting abnormality on resting 12-lead ECG （75%）. Ventricular tachycardia with left bundle branch block morphology was subsequently documented in a total of 28（70%） subjects during a study period. The cu- mulative mortality rate was 7.5%. Conclusion Clinical presentation in Chinese ARVC patients was similar to that reported in other studies. ARVC is associated with early mortality that is different to other country popula- tion.

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

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.