Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

OBJECTIVES: The purpose of our study was to characterize the penetrance of PKP2 mutations among family members of people with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to examine clinical features and predictors of disease among PKP2 mutation carriers. BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy characterized by fatty-fibrous myocardial replacement of the right ventricle, ventricular arrhythmias, and right ventricular dysfunction. Mutations in PKP2, the gene encoding plakophilin-2, are found in 11% to 43% of ARVD/C probands. METHODS: The study population was composed of 64 individuals in 9 families with an ARVD/C proband previously shown to carry a pathogenic PKP2 mutation. The diagnosis of ARVD/C was established based on task force criteria (TFC) set by the European Society of Cardiology. RESULTS: In addition to the probands, PKP2 mutations were present in 52% of relatives screened. Forty-nine percent of PKP2 mutation carriers met TFC. Among mutation carriers who did not meet full TFC, 50% met at least some TFC criteria besides family history. Pedigrees showed wide intra-familial variability, ranging from severe disease with early death to individuals who were completely asymptomatic late in life. Male PKP2 mutation carriers were more likely to have structural and conduction abnormalities as determined by imaging studies, signal-averaged electrocardiography, and 24-h ambulatory electrocardiography (p < 0.05). CONCLUSIONS: PKP2 mutations in a group of North American families with ARVD/C have both reduced penetrance and variable expressivity. Gender may have an influence on penetrance of PKP2 mutations, with male mutation carriers more likely to develop specific phenotypic manifestations of this disease.     

Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon?

PURPOSE OF REVIEW: Recent developments in the elucidation of genes underlying arrhythmogenic right ventricular cardiomyopathy and possible pathogenic mechanisms will be highlighted. RECENT FINDINGS: The cardiac desmosome is a multiprotein structure involved in cell-cell interactions. Mutations in genes encoding desmosomal proteins such as PKP2, DSP, JUP, DSC2 and DSG2 underlie arrhythmogenic right ventricular cardiomyopathy, which can therefore be considered a desmosome cardiomyopathy. Mutations in the plakophilin-2 gene are most prevalent. Current pathophysiological insights suggest a final common pathway in which plakoglobin release from the desmosome, independent of the primarily affected desmosomal protein, results in desmosome impairment, intercalated disc remodeling and Wnt/beta-catenin pathway signaling defects. The recognition of left ventricular involvement associated with mutations in desmosomal protein genes and low penetrance suggests that formal criteria should not be followed too closely in selecting patients for DNA analysis, because finding a mutation may have important implications for clinical practice. SUMMARY: Recent developments have demonstrated that arrhythmogenic right ventricular cardiomyopathy can be considered a desmosome cardiomyopathy. Left ventricular involvement is not uncommon in this type of cardiomyopathy. Such findings are important for diagnostics and family screening and form a starting-point for the elucidation of other (non)-genetic factors influencing disease progression and outcome.     

致心律失常性右室心肌病的研究进展

致心律失常性右室心肌病或致心律失常性右室发育不良/心肌病是一种主要累及右室的心肌疾病,表现为室性心动过速和猝死。新近研究证明这种疾病不是一种少见疾病,患病率约为1/1000,50%~80%有家族史,是一种常染色体遗传性疾病。1994年的诊断标准导致诊断率较低。目前对诊断指标进行了修改,如胸前导联QRS时限延长。通过改进ECG记录方式可以发现更多的epsilon波。应用新的诊断标准将发现更多的有症状和无症状致心律失常性右室心肌病的患者。基因筛查特别是plakophil-in-2突变筛查将成为疾病重要的早期诊断工具。致心律失常性右室心肌病的治疗应在改变生活方式(包括限制参加竞技运动)的基础上,根据病情应用β阻滞剂、胺碘酮、索他洛尔和/或ICD治疗预防猝死。     

Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis.

AIMS: To evaluate clinical disease expression, non-invasive diagnosis, and prognosis in families with dominant vs. recessive arrhythmogenic right ventricular cardiomyopathy (ARVC) due to mutations in related desmosomal proteins plakophilin-2 (PKP2) and plakoglobin (JUP), respectively. METHODS AND RESULTS: One hundred and eighty-seven individuals belonging to ARVC families, four with dominant PKP2 mutations and 12 with recessive JUP mutation underwent serial non-invasive cardiac assessment. Survival and arrhythmic events were evaluated prospectively up to 21 years (median 8.5 years). Sixteen of 22 PKP2 carriers and all 26 homozygous JUP carriers fulfilled the diagnostic criteria for ARVC, the youngest by the age of 13 years. Clinical disease expression did not differ significantly between PKP2 and JUP carriers. T-wave inversion in leads V1-V3, right ventricular wall motion abnormalities, and frequent ventricular extrasystoles were the most sensitive/specific markers for identification of mutation carriers. QRS dispersion > or =40 ms was an independent predictor of syncope but not of sudden death. CONCLUSION: Mutations in PKP2 and JUP express similar cardiac phenotype. Non-invasive family screening may largely be based on T-wave inversion, right ventricular wall motion abnormalities, and frequent ventricular extrasystoles to identify mutation carriers.     

Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations.

AIMS: To characterize the clinical profile of patients belonging to families affected with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) due to mutations of the gene encoding for the cell-to-cell adhesion protein desmoplakin (DSP). METHODS AND RESULTS: Thirty-eight subjects belonging to four families showing different DSP mutations (three missense and one in the intron-exon splicing region) underwent clinical and genetic investigation, including annual 12-lead ECG, signal averaged ECG, 24 h Holter ECG, and two-dimensional echocardiography. Twenty-six family members (11 males and 15 females) were found to carry a DSP mutation. After a follow-up of 1-24 years, median 6, 14 (54%) fulfilled (mean age at diagnosis 33+/-15 years) and 12 (mean age 43+/-24 years at the last follow-up) did not fulfil the established diagnostic criteria of ARVC, although five of them had some cardiac abnormalities. Clinical presentations were palpitations in six, sudden death (SD) in three, syncope in one, and chest pain with increased myocardial enzymes in two. Abnormal 12-lead ECG findings were present in 15 cases (58%), ventricular arrhythmias in 12 (46%), and late potentials in 11 (42%). Fourteen (54%) had abnormal echocardiographic findings, with left ventricular involvement in seven of them. SD occurred in six subjects and in three it was the first symptom of the disease; moreover, one subject died due to heart failure. The annual disease-related death and SD/aborted SD were 0.028 and 0.023 patient/year, respectively. CONCLUSION: Familial ARVC caused by DSP mutations is characterized by a high occurrence of SD even as first clinical manifestation. Left ventricular involvement is not a rare feature of the disease, which frequently escapes clinical diagnosis by applying the currently available criteria. Genetic screening is mandatory for early identification of asymptomatic carriers and preventive strategies within a family with a genotyped index case.     

Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: Wide spectrum of disease in mutation carriers within a family

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disease, with male preponderance, characterized by progressive fibrofatty replacement of the right ventricle and ventricular arrhythmias. Mutations in plakophilin-2 (PKP2), a desmosomal protein, have been reported to underlie familial ARVC. We report a novel ARVC PKP2 mutation and present the clinical findings in three female mutation carriers. METHODS: We sequenced PKP2 from genomic DNA isolated from peripheral blood lymphocytes in a female proband who presented with cardiac arrest and in her four first-degree relatives. Clinical testing and diagnosis of ARVC was based on International Task Force criteria. RESULTS: The proband was diagnosed with ARVC due to right ventricular enlargement and regional hypokinesis, along with repolarization abnormalities and frequent ventricular ectopy. A novel 28 bp insertion in exon 11 of the PKP2 gene was found which causes a frameshift in the coding region. This results in a change in the amino acid sequence of the protein with a premature stop codon at position 740. Of the four relatives, only the mother and younger sister were identified as mutation carriers. The mother was phenotypically normal, while the younger sister has repolarization abnormalities and frequent ventricular ectopy. CONCLUSIONS: We report a novel PKP2 mutation that causes familial ARVC. All mutation carriers in this kindred group were women, and the family showed incomplete penetrance and variable expression of ARVC. Premature truncation of the plakophilin-2 protein appears to be the predominant mechanism whereby PKP2 mutations elicit the ARVC phenotype.     

Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin.

OBJECTIVES: The purpose of this study was to examine the genotype-phenotype relation with respect to penetrance, age and severity of expression, disease progression and prognosis in a recessively inherited arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Naxos disease is a recessively inherited ARVC caused by a mutation in the gene encoding plakoglobin (cell adhesion protein) in which the cardiac phenotype is associated with palmoplantar keratoderma and woolly hair. METHODS: Twelve families with Naxos disease underwent cardiac and molecular genetic investigation. Serial cardiac assessment with annual resting 12-lead and 24-h ambulatory electrocardiogram (ECG) and two-dimensional echocardiography was performed during 1 to 16 years, median 7 +/- 6 years in all 78 surviving members. RESULTS: Twenty-eight surviving members were homozygous and 40 were heterozygous for the mutation. All adults who were homozygous (n = 26) fulfilled the diagnostic criteria for ARVC, the youngest by the age of 13 years. In eight who were heterozygous, minor ECG or echocardiographic abnormalities were observed. Of the 26 subjects who were affected homozygotes, 92% showed ECG abnormalities, 92% ventricular arrhythmias, 100% right ventricular structural alterations and 27% left ventricular involvement. During follow-up (10 +/- 6 years), 16 (62%) developed structural progression, 12 (46%) arrhythmic events and 7 (27%) heart failure. The annual disease-related and sudden death mortality was 3% and 2.3%, respectively. CONCLUSIONS: Autosomal recessive ARVC caused by a mutation in plakoglobin was 100% penetrant by adolescence. Affected subjects who were homozygous experienced progressive disease with adverse prognosis. A minority of subjects who were heterozygous showed minor ECG/echocardiographic changes, but clinically significant disease did not develop.     

Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1

OBJECTIVE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous disorder characterized by fibro-fatty replacement of the right ventricular myocardium, associated with high risk of sudden death. The objective of this study is to identify the gene involved in ARVD1, which has been elusive ever since its locus was mapped to chromosome 14q24.3. METHODS AND RESULTS: Mutation screening of the promoter and untranslated regions (UTRs) of the transforming growth factor-beta3 (TGFbeta3) gene was performed by direct sequencing of genomic DNA of one index case belonging to an ARVD1 family including 38 members in four generations. We detected a nucleotide substitution (c.-36G>A) in 5' UTR of TGFbeta3 gene, invariably associated with the typical ARVC clinical phenotype in the affected family members, according to the established diagnostic criteria. Investigation extended to 30 unrelated ARVC patients, performed by denaturing high-performance liquid chromatography (DHPLC), led to the identification of an additional mutation (c.1723C>T) in the 3' UTR of one proband. Neither nucleotide change was found in 300 control subjects. In vitro expression assays with constructs containing the mutations showed that mutated UTRs were twofold more active than wild-types. CONCLUSION: We identified TGFbeta3 as the disease gene involved in ARVD1. The identification of a novel ARVC gene will increase the power of the genetic screening for early diagnosis of asymptomatic carriers among relatives of ARVC patients.     

家族史在致心律失常性右心室心肌病危险分层中的地位

目的 探讨家族史在致心律失常性右心室心肌病(ARVC)危险分层中的地位.方法 根据1994年ARVC诊断标准,纳入34例ARVC先证者,男性26例,女性8例,平均年龄(38±15)岁.对其家族成员行临床筛查,项目包括:(1)心电图V1～V3导联QRS≥110 ms、V1～V3导联S波升支≥55 ms、Epsilon波、T波倒置(V1～V3导联倒置)、(V1+V2+V3)/(V4+V5+V6)QRS≥1.2、V1～V3导联与V6导联QRS差值≥25 ms,QRS离散度≥40 ms,QT离散度≥65 ms;(2)动态心电图记录室性早搏≥2000个/24 h或室性心动过速(VT);(3)超声心动图记录双心房、双心室及右心室流出道、流人道内径大小.比较ARVC家族史和上述各项临床参数的关系.分类变量用Fisher检验,连续变量使用t检验.P≤0.05为差异有统计学意义.结果 34例ARVC先证者中55个家族成员接受评估,男性28例(6例诊断ARVC)、女性27例(3例诊断ARVC),平均年龄(35±16)岁.8例先证者有家庭成员受累,其中5例有左束支阻滞形室性心动过速(LBBB-VT,63%);26例先证者家庭成员无受累,其中20例有LBBB-VT(77%),P=0.649.家族史和室性心动过速的发生筹异无统计学意义.结论 家族史并不能反映ARVC的危险程度.     

Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies.

AIMS: The ultrastructural features of the myocardium in arrhythmogenic right ventricular cardiomyopathy (ARVC) have not been systematically investigated so far. The recent discovery of gene mutations encoding intercalated disc proteins prompted us to perform a transmission electron microscopy study on endomyocardial biopsies. METHODS AND RESULTS: Twenty-one ARVC probands who fulfilled the international Task Force diagnostic criteria underwent right ventricular endomyocardial biopsy and screening of desmosome (D) protein encoding genes. Myocyte intercalated discs were analysed by transmission electron microscope and the data were compared with those of 10 controls and 10 patients with idiopathic dilated cardiomyopathy. Extensive fibro-fatty replacement with a residual myocardium of 59+/-23% was found in ARVC biopsy samples. Pathogenic D gene mutations were identified in 10 (48%): desmoglein-2 in four, desmoplakin in three and plakophilin-2 in three. Mean D length and D percent length of intercalated disc were significantly higher, D number was significantly lower and D gap was widened in ARVC. Moreover, abnormally located D in 75%, abnormal small junctions in 52%, and pale internal plaques in 32% of ARVC patients were found in the presence of a normal intercalated disc convolution index. CONCLUSION: The ultrastructural evidence of intercalated discs remodelling in ARVC, together with the positive screening of D protein encoding genes in half of probands, are in keeping with an intercellular junction cardiomyopathy.     

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 genotype-phenotype “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 minor criteria 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.     

Clinical profile of arrhythmogenic right ventricular cardiomyopathy in Chinese patients.

OBJECTIVE: To study the clinical profile of Chinese patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). PATIENTS: Chinese patients who fulfilled the diagnostic criteria of ARVC proposed by the Task Force of the European Society of Cardiology and of the scientific council on cardiomyopathy of the International Society and Federation of Cardiology were recruited for analysis. METHODS: Clinical data of patients with ARVC including age, sex, family history, presenting symptoms, electrocardiograph (ECG), echocardiography, cardiac catheterization, magnetic resonance imaging (MRI), electrophysiology study (EPS) and therapeutic intervention were analyzed. RESULTS: Eleven patients (seven males) were diagnosed with ARVC. Mean age at clinical presentation was 42.6+/-14.8 years. Two patients (18.1%) had positive family history of ARVC or premature sudden cardiac death. The commonest presenting symptoms were palpitation (73%) and dizziness (46%). Spontaneous ventricular tachycardia (VT) was the presenting arrhythmia in 54% and 1 (9%) with ventricular fibrillation and cardiac arrest. Seven patients (64%) had the ECG abnormality as defined by the Task Force. Echocardiography showed right ventricular (RV) dilatation in five patients (46%) and all patients had normal left ventricular function. Nine patients (90%) had RV wall thinning or fibrofatty replacement on MRI examination. Inducible monomorphic VT was detected in four out of nine patients at EPS. All eight patients had normal coronary arteries and left ventriculogram but RV dilatation and global hypokinesia was seen in three patients. Implantable cardioverter defibrillators were implanted in five patients and two of them had shocks delivered during the follow-up period. CONCLUSION: In this study, familial incidence of premature sudden death in patients with ARVC appears to be low and left ventricular involvement in affected individuals is uncommon. MRI is still the best investigation for ARVC.     

The other side of arrhythmogenic right ventricular cardiomyopathy

Knowledge regarding arrhythmogenic right ventricular cardiomyopathy (ARVC) has increased dramatically since the publication of the original International Task Force diagnostic criteria in 1994. Based on symptomatic index cases and sudden cardiac death victims, the Task Force criteria emphasized manifestations observed only at the most severe end of the clinical spectrum of ARVC. It is now known that the phenotypic expression of the disease may vary considerably both in its severity and in the pattern of myocardial involvement. Recent familial studies have emphasized that, despite its name, the abnormalities of ARVC are not limited to the right ventricle. In recognition of the prevalence and clinical significance of left ventricular involvement in ARVC, a proposed modification to the original International Task Force criteria was recently published. We herein describe 3 cases of patients with ARVC who presented with left ventricular involvement as manifested by nonischemic pattern of delayed enhancement in the left ventricle.     

Prognostic Value of Magnetic Resonance Phenotype in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

BackgroundCardiac magnetic resonance (CMR) is widely used to assess tissue and functional abnormalities in arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a ARVC risk score was proposed to predict the 5-year risk of malignant ventricular arrhythmias in patients with ARVC. However, CMR features such as fibrosis, fat infiltration, and left ventricular (LV) involvement were not considered.ObjectivesThe authors sought to evaluate the prognostic role of CMR phenotype in patients with definite ARVC and to evaluate the effectiveness of the novel 5-year ARVC risk score to predict cardiac events in different CMR presentations.MethodsA total of 140 patients with definite ARVC were enrolled (mean age 42 ± 17 years, 97 males) in this multicenter prospective registry. As per study design, CMR was performed in all the patients at enrollment. The novel 5-year ARVC risk score was retrospectively calculated using the patient’s characteristics at the time of enrollment. During a median follow-up of 5 years (2 to 8 years), the combined endpoint of sudden cardiac death, appropriate implantable cardioverter-defibrillator intervention, and aborted cardiac arrest was considered.ResultsCMR was completely negative in 14 patients (10%), isolated right ventricular (RV) involvement was found in 58 (41%), biventricular in 52 (37%), and LV dominant in 16 (12%). During the follow-up, 48 patients (34%) had major events, but none occurred in patients with negative CMR. At Kaplan-Meier analysis, patients with LV involvement (LV dominant and biventricular) had a worse prognosis than those with lone RV (p < 0.0001). At multivariate analysis, the LV involvement, a LV-dominant phenotype, and the 5-year ARVC risk score were independent predictors of major events. The estimated 5-year risk was able to predict the observed risk in patients with lone RV but underestimated the risk in those with LV involvement.ConclusionsDifferent CMR presentations of ARVC are associated with different prognoses. The 5-year ARVC risk score is valid for the estimation of risk in patients with lone-RV presentation but underestimated the risk when LV is involved.     

Die arrhythmogene rechtsventrikuläre Kardiomyopathie

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder that is characterized by localized or diffuse atrophy of predominantly right ventricular myocardium with subsequent replacement by fatty and fibrous tissue. Arrhythmias of right ventricular origin are the main clinical manifestation. Affected patients present with ventricular premature beats and nonsustained or sustained ventricular tachycardia demonstrating a left bundle branch block pattern. However, since ventricular tachycardia may also degenerate into ventricular fibrillation, sudden death may be the first manifestation of ARVC.In recent years, ARVC has been more and more recognized as an important and frequent cause of ventricular tachyarrhythmias and sudden cardiac death, particularly in young patients and athletes, with apparently normal hearts. Evidence of the disease is found in 30-50% of family members. ARVC is a genetically heterogeneous disease.The diagnosis is based on electrocardiographic abnormalities and the identification of regional or global right ventricular dysfunction and fibrolipomatosis. Although several potentially causative genes have been identified, currently, genetic testing is not part of the routine diagnostic work-up.An implantable cardioverter-defibrillator is indicated in selected high-risk patients with ARVC (i. e., patients with life-threatening ventricular tachycardia or survivors of sudden cardiac death). The clinical course of the disease is often characterized by progression. In individual patients heart transplantation may become necessary.     

Compound and heterozygous mutations of DSG2 identified by Whole Exome Sequencing in arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular tachycardia

Backgrounds

This study was designed to identify the pathogenic mutations in two Chinese families of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using the Whole Exome Sequencing (WES).

Arrhythmogene rechtsventrikuläre Kardiomyopathie

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary, genetically determined heart muscle disease and a major cause of ventricular tachyarrhythmia and sudden cardiac death in young, apparently healthy individuals and athletes. In ARVC, mutations in genes encoding for desmosomal cell contact proteins result in myocardial atrophy with subsequent fibrofatty replacement, predominantly affecting the right ventricular myocardium. Left ventricular involvement can also occur early in the disease process. The structural abnormalities lead to global and/or regional dysfunction of the right or both ventricles and to the dominant clinical manifestation with ventricular tachyarrhythmia. A primary manifestation of ARVC with clinically relevant signs and symptoms of heart failure is rare. Genetic counselling is indicated in all index patients with ARVC and their families. Genetic testing, however, is recommended only under particular circumstances (e.g. cascade screening). An early and correct diagnosis is crucial for risk stratification, treatment and prognosis of ARVC. The catalogue of diagnostic criteria (major and minor criteria) includes electrocardiogram (ECG) findings of depolarization and repolarization, arrhythmia, morphological and functional imaging, histopathology and genetics. These diagnostic criteria are currently under prospective validation in clinical studies and registries.     

Economic evaluation of screening for familiar form of arrhythmogenic right ventricular cardiomyopathy in Poland

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease associated with fibrofatty tissue replacement in heart muscle leading to arrhythmia, heart failure or sudden death (SCD) often being the first manifestation in probands. At least 50% of cases of ARVC are inherited. AIM: To evaluate costs and cost-effectiveness of diagnosis of the disease in asymptomatic relatives in Poland. METHODS: 239 asymptomatic subjects (mean age 35 years, 120 male) belonging to 42 families affected with ARVC were examined between May 2003 and May 2005. The costs of outpatient visits and additional diagnostic tests were included. Payer perspective was used. RESULTS: In all individuals ECG and transthoracic echocardiography were performed. Magnetic resonance imaging and signal-averaged ECG were performed in 35 patients suspected of having ARVC. The diagnostic criteria for ARVC were fulfilled in 29 patients and 57 subjects were recognised borderline. Total costs of screening amounted to 71 090 PLN (approximately 20,000 euro). The average cost per one case of detected ARVC was 2451 PLN (approximately 680 euro). CONCLUSIONS: Costs of early detection of ARVC in individuals with a family history of the disease in Polish settings are low. Due the avilability of primary prevention of SCD the family screening in asymptomatic subjects is a cost-effective procedure.     

Familial effort polymorphic ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy map to chromosome 1q42-43

In the present study we report on another cause of an arrhythmia associated with familial arrhythmogenic right ventricular cardiomyopathy (ARVC), which is linked to chromosome 1q42-43. Two families with 48 subjects were studied with 12-lead electrocardiography, 24-hour ambulatory electrocardiography, chest x-ray, M-mode and 2-dimensional echocardiography, signal-averaging electrocardiography, and exercise stress testing. Six subjects also underwent right and left ventricular angiography and electrophysiologic study. An endomyocardial biopsy was performed in 1 subject. The genetic study included pedigree reconstruction and linkage analysis with polymorphic DNA markers. Five young subjects died suddenly during exercise; autopsy was performed in 3 and showed segmental fibro-fatty replacement of the right ventricle, mostly at the apex. Two of them experienced syncopal attacks during effort. Sixteen living subjects, without arrhythmias at rest had polymorphic ventricular arrhythmias during effort; ARVC was diagnosed in 15, whereas 1 did not have any demonstrable cardiac abnormality. The remaining family members were healthy and did not have arrhythmias. The linkage study assigned the disease locus to chromosome 1q42-q43, in close proximity to the alpha-actinin 2 locus (maximal lod score was 5.754 at theta = 0) with a 95% penetrance. Thus, these data suggest that effort-induced polymorphic ventricular arrhythmias and juvenile sudden death can be due to adrenergic stimulation in a particular genetic group of ARVC patients. In these cases the pathology was segmental, mostly localized to the right ventricular apex. Ventricular arrhythmias that are present in these families differ from the monomorphic ones that are usually seen in patients with ARVC.     

Genetics of arrhythmogenic right ventricular cardiomyopathy--status quo and future perspectives

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder of unknown origin. In recent years, the disease has been recognized as a major cause of ventricular tachyarrhythmias and sudden cardiac death in young patients with apparently normal hearts. Although characteristic structural, imaging and electrocardiographic features are included in a proposed catalogue of diagnostic criteria, the correct diagnosis of ARVC often remains difficult. Much effort has been undertaken to enlarge the knowledge on pathophysiological mechanisms of the disease. The role of molecular genetics for the pathogenesis of ARVC is discussed in the following review. On the basis of linkage analyses in large families affected by ARVC, there is growing evidence for genetic alterations in ARVC, which, in the majority of chromosomal loci (seven) reported so far, follow a Mendelian autosomal-dominant pattern of inheritance with variable penetrance and polymorphic phenotype. Besides this, two autosomal-recessive forms of ARVC are known. These can be differentiated from the autosomal-dominant forms not only in terms of the mode of inheritance but also as to their specific phenotype: patients with Naxos disease exhibit characteristic hair and skin abnormalities and experience a more severe course of disease. Patients with another autosomal-recessive form display the typical but milder signs of ARVC together with opacifications of the crystalline lens. So far, two mutations in cardiac genes responsible for the development of ARVC have been reported. A homozygous two base pair deletion in the gene encoding for the cytoskeletal protein plakoglobin seems to account for the evolution of Naxos disease. The second mutation affecting the cardiac ryanodine receptor gene was found in patients with ARVC-2. Routine genetic testing of patients or relatives with a suspected diagnosis of ARVC is not available at present but may become the future gold standard with potential implications for a better understanding of the pathogenesis and management of the disease.