Diagnostic yield from cardiac gene testing for inherited cardiac conditions and re-evaluation of pre-ACMG variants of uncertain significance.

BACKGROUND: Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives. AIMS: We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020. RESULTS: Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively. CONCLUSION: Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families.

A report from the Irish women in cardiology survey, exploring Europe's largest gender gap in cardiology.

Aims: In Ireland, 8% of public cardiology consultants are female; this is the lowest proportion in Europe. We sought to understand perceptions amongst Irish trainees and consultants regarding aspects of working in cardiology in order to identify areas that can be targeted to improve gender equality. Methods and Results: In September 2021, the Irish Cardiac Society distributed a questionnaire to trainees and consultants in the Republic and Northern Ireland. Ethical approval was obtained from the University College Dublin, Ireland. There were 94 respondents (50% male, 50% consultants) which equates to ∼30% of all trainees and consultants in all Ireland. Although females were more likely to be single, overall, they had additional child-care responsibilities compared with male counterparts. Despite 53% of the respondents preferring to work less than full time, 64% reported a perceived lack of support from their departments. Males were significantly more likely to go into procedural/high radiation sub-specialities. Bullying was reported by 53% of females. Almost 80% of females experienced sexism and 30% reported being overlooked for professional advancement based on their sex. Females also rated their career prospects lower than males. Key challenges for women were: sexism, maternity leave/child-care responsibilities, cardiology as a 'boys club' and lack of flexible training. There was interest from both males and females in a mentorship programme and support for women in leadership positions. Conclusion: Discrimination including sexism, bullying, and equal opportunity for professional advancement are key aspects that need to be addressed to improve gender balance in cardiology within Ireland and Northern Ireland.

The evidence for the implantable loop recorder in patients with inherited arrhythmia syndromes: a review of the literature.

Risk stratification of patients with inherited arrhythmia syndromes (IASs) can be challenging. Recent guidelines acknowledge a place for considering the implantable loop recorder (ILR) to outrule malignant arrhythmia as a cause of syncope in certain inherited arrhythmia patients who are at low risk of sudden cardiac death. In this comprehensive literature review, we evaluate the available evidence for the use of the ILR in the IASs and in relatives of victims of sudden arrhythmic death syndrome.

Derivation and characterization of two human induced pluripotent stem cell lines (NUIGi004-A) and (NUIGi012-A) from two patients with LQT2 disease.

Long QT syndrome type 2 (LQT2) is associated with KCNH2, which encodes the α subunit of the ion channel that controls the K+ current in the heart. Mutations of KCNH2 cause loss of Kv11.1 channel function by disrupting subunit folding, assembly, or trafficking of the channel to the cell surface. Here we generated two induced pluripotent stem cell (iPSC) lines from two patients carrying mutation in KCNH2 gene. These iPSCs express the pluripotent markers and have the capacity of differentiation into other cell types. These patient-derived iPSCs are useful for investigating the disease pathology and identifying the therapeutic target.

Inherited Cerebellar Ataxias: 5-Year Experience of the Irish National Ataxia Clinic.

Establishing a molecular diagnosis in patients with progressive ataxia is often challenging due to significant genetic and clinical heterogeneity and requires a methodical approach with expert clinical evaluation and investigations. We describe the 5-year experience of the National Ataxia Clinic (NAC), Ireland. All adults with ataxia attending the NAC between 2014 and 2019 were evaluated. All individuals underwent detailed clinical assessment and investigations including, where appropriate, genetic testing using next-generation sequencing. For all patients, acquired causes were ruled out. A total of 254 patients from 196 families were assessed; with growth of the clinic cohort by 82% from 133 to 242 over the 5-year period. The underlying genetic cause was identified in 128/196 probands (65.3%). The detection rate for repeat expansion disorder gene testing was 47.7% (82/172) and using NGS gene panel, a genetic diagnosis was obtained in 30/84 (35.7%). Whole exome sequencing identified the molecular diagnosis in 4/20 (20%), and whole genome sequencing provided genetic diagnosis in 1/5 (20%). The commonest diagnosis was Friedreich's ataxia (68/128, 53.1%). SPG7-associated ataxia was the second most common diagnosis (21/128, 16.4%), followed by ANO10-associated spastic ataxia, ataxia telangiectasia (AT), and other rarer phenotypes. Our results highlight that careful clinical phenotyping in a dedicated ataxia clinic is crucial for appropriate genetic testing in selected patients in a timely manner. Advanced genetic testing has significantly improved the diagnostic yield in patients with suspected genetic ataxia and should be considered in all individuals with negative repeat expansion testing.

Generation and characterization of an induced pluripotent stem cell (iPSC) line (NUIGi003-A) from a long QT syndrome type 2 (LQT2) patient harbouring the KCNH2 c.2464G>A pathogenic variant.

Long QT syndrome (LQTS), an inherited cardiac ion channelopathy, is associated with ventricular arrhythmias and risk of sudden death. LQTS sub-type 2 (LQT2) is caused by pathogenic variants in KCNH2 encoding the α-subunit of Kv11.1, thus affecting the rapid component of delayed rectifier K+ current (IKr) channel during the action potential. In this study, non-integrational Sendai reprogramming method was used to generate an induced-pluripotent-stem-cell (iPSC) line carrying the KCNH2 c.2464G>A (p.Val822Met) pathogenic variant from a LQT2 patient. This patient-specific iPSC line NUIGi003-A harbouring the c.2464G>A variant expressed pluripotency markers and demonstrated the differentiation potential to all three germ layers.

Long QT Syndrome: Genetics and Future Perspective.

Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classically torsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnormal cellular membrane repolarization. Severely affected phenotypes administered current standard of care therapies may not be fully protected from the occurrence of cardiac arrhythmias. There are 17 different subtypes of LQTS associated with monogenic mutations of 15 autosomal dominant genes. It is now possible to model the various LQTS phenotypes through the generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes. RNA interference can silence or suppress the expression of mutant genes. Thus, RNA interference can be a potential therapeutic intervention that may be employed in LQTS to knock out mutant mRNAs which code for the defective proteins. CRISPR/Cas9 is a genome editing technology that offers great potential in elucidating gene function and a potential therapeutic strategy for monogenic disease. Further studies are required to determine whether CRISPR/Cas9 can be employed as an efficacious and safe rescue of the LQTS phenotype. Current progress has raised opportunities to generate in vitro human cardiomyocyte models for drug screening and to explore gene therapy through genome editing.

Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria.

BACKGROUND: With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. METHODS AND RESULTS: The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (P=0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P=0.04). CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy.

Prophylactic implantable defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation or sustained ventricular tachycardia.

BACKGROUND: The role of implantable cardioverter-defibrillator (ICD) in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation (VF) or sustained ventricular tachycardia is an unsolved issue. METHODS AND RESULTS: We studied 106 consecutive patients (62 men and 44 women; age, 35.6±18 years) with arrhythmogenic right ventricular cardiomyopathy/dysplasia who received an ICD based on 1 or more arrhythmic risk factors such as syncope, nonsustained ventricular tachycardia, familial sudden death, and inducibility at programmed ventricular stimulation. During follow-up of 58±35 months, 25 patients (24%) had appropriate ICD interventions and 17 (16%) had shocks for life-threatening VF or ventricular flutter. At 48 months, the actual survival rate was 100% compared with the VF/ventricular flutter-free survival rate of 77% (log-rank P=0.01). Syncope significantly predicted any appropriate ICD interventions (hazard ratio, 2.94; 95% confidence interval, 1.83 to 4.67; P=0.013) and shocks for VF/ventricular flutter (hazard ratio, 3.16; 95% confidence interval, 1.39 to 5.63; P=0.005). The positive predictive value of programmed ventricular stimulation was 35% for any appropriate ICD intervention and 20% for shocks for VF/ventricular flutter, with a negative predictive value of 70% and 74%. None of the 27 asymptomatic patients with isolated familial sudden death had appropriate ICD therapy. Twenty patients (19%) had inappropriate ICD interventions, and 18 (17%) had device-related complications. CONCLUSIONS: One fourth of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior sustained ventricular tachycardia or VF had appropriate ICD interventions. Syncope was an important predictor of life-saving ICD intervention and is an indication for ICD. Prophylactic ICD may not be indicated in asymptomatic patients because of their low arrhythmic risk regardless of familial sudden death and programmed ventricular stimulation findings. Programmed ventricular stimulation had a low predictive accuracy for ICD therapy.

Dynamic electrocardiographic changes in patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND AND OBJECTIVES: Electrocardiographic (ECG) abnormalities of depolarisation and repolarisation contribute to the diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC). The development of diagnostic ECG features were investigated in a genotyped cohort with ARVC to provide more sensitive markers of early disease. METHODS: T-wave inversion (TWI) in right precordial leads, epsilon waves, localised QRS prolongation greater than 110 ms in V1-V3 and QRS dispersion greater than 40 ms were analysed from 317 ECG from 68 genotyped patients (34 with disease-causing mutations) during follow-up of 34+/-28 months. RESULTS: 16 patients (23%) had changes during follow-up, with the appearance of new ECG abnormalities in seven (10%) and dynamic changes in nine (13%). Four developed new and persistent TWI and eight had dynamic TWI in right precordial leads. Three developed new and another three had dynamic epsilon waves. No changes were observed in 10 with and 58 patients without localised QRS prolongation and in six patients with and 61 without QRS dispersion greater than 40 ms. An additional patient with QRS dispersion at baseline had normal depolarisation dispersion during follow-up. None of the nine ARVC patients with dynamic ECG changes had major structural or functional right ventricular abnormalities, suggesting an early stage of the disease. CONCLUSIONS: New or dynamic ECG changes were observed in 23%. This underscores the importance of serial ECG in the diagnosis of individuals at risk of ARVC, in whom potentially lethal arrhythmia may develop before major abnormalities are detectable with conventional imaging.

Unique epidermolytic bullous dermatosis with associated lethal cardiomyopathy related to novel desmoplakin mutations.

BACKGROUND: Desmoplakin plays a vital role in cell adhesion, linking the transmembrane desmosomal complex to the cytoskeletal network. Clues to the biological significance of desmoplakin have emerged from the embryonic lethal phenotype of null mice and from naturally occurring human desmoplakin mutations, which cause cardiocutaneous phenotypes. INDEX CASE: In this study, we describe a child who presented with the unique constellation of bullous dermatosis, profound plantar keratoderma, alopecia totalis and cardiomyopathy leading to sudden cardiac death at the age of 9 years. RESULTS: This complex cardiocutaneous phenotype is associated with compound heterozygosity for two novel nonsense desmoplakin mutations. Histological examination of a plantar skin biopsy showed full thickness epidermal acantholysis with superimposed spongiosis, hyperorthokeratosis and focal parakeratosis. Immunohistochemistry and quantitative confocal microscopy showed abnormal tissue distribution and reduced levels of expression for plakoglobin, desmoplakin and connexin 43 at epidermal junctional sites. CONCLUSIONS: Interpretation of the changes in the context of the two mutations provides insight into the mechanism of clinical cell adhesion disease.

Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity.

OBJECTIVES: We sought to investigate the clinical-genetic profile of left-dominant arrhythmogenic cardiomyopathy (LDAC). BACKGROUND: In the absence of coronary disease and left ventricular (LV) systolic dysfunction, lateral T-wave inversion and arrhythmia of LV origin are often considered benign. Similarly, chest pain with enzyme release might be attributed to viral myocarditis. We hypothesized that these abnormalities might be manifestations of the "left-dominant" subtype of arrhythmogenic right ventricular cardiomyopathy. METHODS: The 42-patient cohort was established through clinical evaluation of individuals with unexplained (infero)lateral T-wave inversion, arrhythmia of LV origin, and/or proven LDAC/idiopathic myocardial fibrosis in the family. RESULTS: Patients presented from adolescence to age >80 years with arrhythmia or chest pain but not heart failure. Desmosomal mutations were identified in 8 of 24 families (15 of 33 patients). Magnetic resonance findings included LV late-enhancement in a subepicardial/midwall distribution, corresponding to fibrofatty replacement and fibrosis on histopathology. Fifty percent had previously been misdiagnosed with viral myocarditis, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy, or idiopathic ventricular tachycardia. Arrhythmic events included presentation with ventricular fibrillatory arrest in 1 patient and 2 instances of sudden cardiac death during follow-up. CONCLUSIONS: Arrhythmogenic cardiomyopathy is distinguished from DCM by a propensity towards arrhythmia exceeding the degree of ventricular dysfunction. The left-dominant subtype is under-recognized owing to misattribution to other disorders and lack of specific diagnostic criteria. Clinicians are alerted to the possibility of LDAC in patients of any age with unexplained arrhythmia of LV origin, (infero)lateral T-wave inversion, apparent DCM (with arrhythmic presentation), or myocarditis (chest pain and enzyme rise with unobstructed coronary arteries).

Asymmetric dimethylarginine independently predicts fatal and nonfatal myocardial infarction and stroke in women: 24-year follow-up of the population study of women in Gothenburg.

OBJECTIVE: Asymmetrical dimethylarginine (ADMA) reduces nitric oxide by inhibiting nitric oxide synthase is associated with cardiovascular disease (CVD). Our study examined the association of ADMA with CVD prospectively in a healthy population-based cohort of women. METHODS AND RESULTS: We measured baseline ADMA of 880 women in the Population Study of Women in Gothenburg using high-performance liquid chromatography. After adjustment for traditional risk factors, creatinine clearance, and homocysteine using Cox models, the HR (95% CI in parentheses) of CVD end points at 24 years for a 0.15 micromol/L (1 SD) increase in ADMA were: all-cause mortality 1.12 (0.96, 1.32), fatal CVD 1.30 (1.04, 1.62), total CVD events 1.29 (1.09, 1.53). The top quintile (ADMA >or=0.71 micromol/L) compared with the bottom four-fifths, conferred a cumulative risk 22 versus 14%, relative risk 1.75 (95% CI 1.18, 2.59) and population attributable risk 12.7% of total CVD events, and further identified individuals who are at higher than expected risk based on the SCORE and Framingham systems. CONCLUSIONS: A 0.15 mumol/L increase in baseline ADMA levels is associated with approximately 30% increase in incident cardiovascular risk at 24 years in women after adjustment. ADMA levels >or=0.71 micromol/L enhances CVD risk assessment in women.

Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression.

BACKGROUND: According to clinical-pathological correlation studies, the natural history of arrhythmogenic right ventricular dysplasia/cardiomyopathy is purported to progress from localized to global right ventricular dysfunction, followed by left ventricular (LV) involvement and biventricular pump failure. The inevitable focus on sudden death victims and transplant recipients may, however, have created a skewed perspective of a genetic disease. We hypothesized that unbiased representation of the spectrum of disease expression in arrhythmogenic right ventricular dysplasia/cardiomyopathy would require in vivo assessment of families in a genetically heterogeneous population. METHODS AND RESULTS: A cohort of 200 probands and relatives satisfying task force or modified diagnostic criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy underwent comprehensive clinical evaluation. Desmosomal mutations were identified in 39 individuals from 20 different families. Indices of structural severity correlated with advancing age and were increased in long-term endurance athletes. Fulfillment of modified criteria indicated phenotypically mild disease, whereas asymptomatic status did not. In >80%, ECG, rhythm monitoring, and/or gadolinium-enhanced cardiovascular magnetic resonance were suggestive of LV involvement, the extent of which often was marked among individuals with chain-termination mutations and/or desmoplakin disease. Three patterns of disease expression were identified: (1) classic, with isolated right ventricular disease or LV involvement in association with significant right ventricular impairment; (2) left dominant, with early and prominent LV manifestations and relatively mild right-sided disease; and (3) biventricular, characterized by parallel involvement of both ventricles. CONCLUSIONS: LV involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy may precede the onset of significant right ventricular dysfunction. Recognition of disease variants with early and/or predominant LV involvement supports adoption of the broader term arrhythmogenic cardiomyopathy.

Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease.

AIMS: Mutations in the desmoglein-2 (DSG2) gene have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) but clinical information regarding the associated phenotype is at present limited. In this study, we aimed to clinically characterize probands and family members carrying a DSG2 mutation. METHODS AND RESULTS: We investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands. Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Morphological abnormalities of the right ventricle were evident in 66% of gene carriers, left ventricular (LV) involvement in 25%, and classical right precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death/aborted sudden death in 66%. CONCLUSION: Mutations in DSG2 display a high degree of penetrance. Disease expression was of variable severity with LV involvement a prominent feature. The low prevalence of classical ECG changes highlights the need to expand current diagnostic criteria to take account of LV disease, childhood disease expression, and incomplete penetrance.

Cardiovascular magnetic resonance in arrhythmogenic right ventricular cardiomyopathy revisited: comparison with task force criteria and genotype.

OBJECTIVES: We sought to assess the utility of cardiovascular magnetic resonance (CMR) in the evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) in relation to diagnostic criteria and genotype. BACKGROUND: Timely diagnosis of ARVC is difficult as clinical findings may be subtle and nonspecific in early disease. The role of CMR is controversial owing to the absence of a standardized protocol, insufficient experience with the modality, and inherent difficulties in imaging the right ventricle. METHODS: Comprehensive CMR examination was performed in 232 patients undergoing evaluation for suspected ARVC. CMR outcomes were compared with: 1) prospective clinical diagnosis using Task Force guidelines, with and without the proposed modifications for familial ARVC; and 2) gene-carrier status in 35 individuals from genotyped families. RESULTS: CMR studies were positive in all 64 patients who prospectively fulfilled Task Force criteria, resulting in 100% sensitivity. Specificity in relation to Task Force criteria was low (29%). Of the 119 apparent false positives detected by CMR, however, 63 fulfilled modified diagnostic criteria for familial ARVC and 7 were obligate gene carriers, suggesting that CMR frequently identifies individuals with early disease, in whom Task Force criteria are relatively insensitive. This was borne out by evaluation of genotyped individuals (26 gene-positive and 9 gene-negative), in whom CMR had a sensitivity of 96% and a specificity of 78%. CONCLUSIONS: CMR is a valuable component of the diagnostic workup for ARVC when performed with a dedicated protocol by specialists with experience in analysis of volumes, right ventricular wall motion, and delayed-enhancement imaging.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited myocardial disorder associated with arrhythmias, heart failure, and sudden death. To date, mutations in four genes encoding major desmosomal proteins (plakoglobin, desmoplakin, plakophilin-2, and desmoglein-2) have been implicated in the pathogenesis of ARVD/C. We screened 77 probands with ARVD/C for mutations in desmocollin-2 (DSC2), a gene coding for a desmosomal cadherin. Two heterozygous mutations--a deletion and an insertion--were identified in four probands. Both mutations result in frameshifts and premature truncation of the desmocollin-2 protein. For the first time, we have identified mutations in desmocollin-2 in patients with ARVD/C, a finding that is consistent with the hypothesis that ARVD/C is a disease of the desmosome.

Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy.

AIMS: Left ventricular outflow tract obstruction (LVOTO) is associated with reduced survival in patients with hypertrophic cardiomyopathy (HCM). The influence of LVOTO on survival from SD in relation to other recognized clinical risk markers is unknown. METHODS AND RESULTS: A total of 917 patients with HCM (554 males, 43+/-15 years) were studied; 288 (31.4%) had LVOTO at rest (> or =30 mmHg). During follow-up [median 61 (30;99) months], 54 (5.9%) patients died suddenly (SD), survived ventricular fibrillation, or had an appropriate ICD discharge; 25 (2.7%) died from heart failure or were transplanted; 17 (1.8%) died from other cardiovascular causes. Five-year survival from all-cause death or cardiac transplantation was lower in patients with LVOTO [86.5% (95% CI: 81.7-91.2) vs. 90.1% (95% CI: 87.3-92.8), P=0.006], with a trend towards higher all-cause death and transplantation with increasing LVOTO [(RR per 20 mmHg=1.24 (95% CI: 1.08-1.42), P=0.003)]. In patients with obstruction, there was a significant relation between 5-year survival from all-cause death and functional limitation (NYHA class I: 91.0%; NYHA class II: 83.3%; NYHA class III/IV: 82.6%, P=0.002). LVOTO was associated with reduced survival from SD and ICD discharge (SD/ICD) [91.4% (95% CI: 87.4-95.3) vs. 95.7% (95% CI: 93.8-97.6), P=0.0004]. Magnitude of LVOTO was related to a higher occurrence of SD/ICD [RR per 20 mmHg=1.36 (95% CI: 1.12-1.65), P=0.001]. There was no relation between survival from SD/ICD, LVOTO, and NYHA class. The annual rate of SD/ICD in patients with LVOTO and no risk factors was 0.37% (95%CI: 0.05-1.35). There was a trend towards lower survival from SD/ICD, with increasing numbers of risk factors in patients with and without LVOTO (P=0.002 and P=0.002, respectively). Multivariable analysis demonstrated that LVOTO was an independent predictor of SD/ICD, with a 2.4-fold (P=0.003) increase in the risk of SD/ICD. CONCLUSION: LVOTO is associated with an increased risk of SD/ICD that is related to the severity of obstruction and the presence of other recognized risk factors for SD. The low sudden death mortality in asymptomatic patients with LVOTO and no other SD risk markers suggests that aggressive interventions to reduce LVOTO are unwarranted in this group. Further studies are required to determine the most appropriate treatment strategies (ICD or gradient reduction) in patients with additional risk factors.

Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC. METHODS AND RESULTS: We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC. CONCLUSIONS: In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC.