Circulating miR-185-5p as a Potential Biomarker for Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by progressive myocardial fibro-fatty replacement, arrhythmias and risk of sudden death. Its diagnosis is challenging and often it is achieved after disease onset or postmortem. In this study, we sought to identify circulating microRNAs (miRNAs) differentially expressed in ARVC patients compared to healthy controls. In the pilot study, we screened the expression of 754 miRNAs from 21 ARVC patients and 20 healthy controls. After filtering the miRNAs considering a log fold-change cut-off of ±1, p-value < 0.05, we selected five candidate miRNAs for a subsequent validation study in which we used TaqMan-based real-time PCR to analyse samples from 37 ARVC patients and 30 healthy controls. We found miR-185-5p significantly upregulated in ARVC patients. Receiver operating characteristic analysis indicated an area under the curve of 0.854, corroborating the link of this miRNA and ARVC pathophysiology.

A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for ∼60% of ACM cases, but the remaining 40% is still genetically elusive. OBJECTIVE: The purpose of this study was to identify the underlying genetic cause in probands with ACM. METHODS: DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes-DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes. RESULTS: About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed ≥1 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency. CONCLUSION: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined.

Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by progressive fibro-fatty myocardial replacement, ventricular arrhythmia, heart failure, and sudden death. Causative mutations can be identified in 60% of patients, and most of them are found in genes encoding mechanical junction proteins of the intercalated disk. METHODS: Whole-exome sequencing was performed on the proband of an ACM family. Sanger sequencing was used to screen for mutations the tight junction protein 1 ( TJP1) gene in unrelated patients. Predictions of local structure content and molecular dynamics simulations were performed to investigate the structural impact of the variants. RESULTS: A novel c.2006A>G p.(Y669C) variant in TJP1 gene was identified by whole-exome sequencing in a patient with ACM. TJP1 encodes zonula occludens 1, an intercalated disk protein interacting with proteins of gap junctions and area composita. Additional rare TJP1 variants have been identified in 1 of 40 Italian probands (c.793C>T p.(R265W)) with arrhythmogenic right ventricular cardiomyopathy and in 2 of 43 Dutch/German patients (c. 986C>T, p.(S329L) and c.1079A>T, p.(D360V)) with dilated cardiomyopathy and recurrent ventricular tachycardia. The p.(D360V) variant was identified in a proband also carrying the p.(I156N) pathogenic variant in DSP. All 4 TJP1 variants are predicted to be deleterious and affect highly conserved amino acids, either at the GUK (guanylate kinase)-like domain (p.(Y669C)) or at the disordered region of the protein between the PDZ2 and PDZ3 domains (p.(R265W), p.(S329L), and p.(D360V)). The local unfolding induced by the former promotes structural rearrangements of the GUK domain, whereas the others are predicted to impair the function of the disordered region. Furthermore, rare variants in TJP1 are statistically enriched in patients with ACM relative to controls. CONCLUSIONS: We provide here the first evidence linking likely pathogenic TJP1 variants to ACM. Prevalence and pathogenic mechanism of TJP1-mediated ACM remain to be determined.

Co-inheritance of mutations associated with arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. Here we describe for the first time co-inheritance of mutations in genes associated with ACM or HCM in two families with recurrence of both cardiomyopathies. Among the double heterozygotes for mutations in desmoplakin (DSP) and myosin binding protein C (MYBPC3) genes identified in Family A, two were diagnosed with ACM and two with HCM. In Family B, one patient was identified to carry mutations in α-T-catenin (CTTNA3) and ß-myosin (MYH7) genes, but he does not fulfill the current diagnostic criteria neither for ACM nor for HCM. Interestingly, the double heterozygotes showed a variable clinical expression of both cardiomyopathies and they do not exhibit a more severe phenotype than family members carrying only one of the two mutations.

Phenotypic expression is a prerequisite for malignant arrhythmic events and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Whether a desmosomal (DS)-gene defect may in itself induce life-threatening ventricular arrhythmias regardless of phenotypic expression of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still debated. This prospective study evaluated the long-term outcome of DS-gene mutation carriers in relation to the ARVC phenotypic expression. METHODS AND RESULTS: The study population included 116 DS-gene mutation carriers [49% males; median age 33 years (16-48 years)] without prior sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). The incidence of the arrhythmic endpoint, including sudden cardiac death (SCD), aborted SCD, sustained VT, and appropriate implantable cardioverter-defibrillator (ICD) intervention was evaluated prospectively and stratified by the presence of ARVC phenotype and risk factors (syncope, ventricular dysfunction, and non-sustained VT). At enrolment, 40 of 116 (34%) subjects fulfilled the criteria for definite ARVC while the remaining were either borderline or phenotype negatives. During a median follow-up of 8.5 (5-12) years, 10 patients (9%) had arrhythmic events (0.9%/year). The event rate was 2.3%/year among patients with definite ARVC and 0.2%/year among borderline or phenotype negative patients (P = 0.002). In patients with definite ARVC, the incidence of arrhythmias was higher in those with ≥1 risk factors (4.1%/year) than in those with no risk factors (0.4%/year, P = 0.02). Mortality was 0.2%/year (1 heart failure death and 1 SCD). CONCLUSIONS: The ARVC phenotypic expression is a prerequisite for the occurrence of life-threatening arrhythmias in DS-gene mutation carriers. The vast majority of malignant arrhythmic events occurred in patients with an overt disease phenotype and major risk factors suggesting that this subgroup most benefits from ICD therapy.

Homozygous Desmocollin-2 Mutations and Arrhythmogenic Cardiomyopathy.

Dominant mutations in desmocollin-2 (DSC2) gene cause arrhythmogenic cardiomyopathy (ACM), a progressive heart muscle disease characterized by ventricular tachyarrhythmias, heart failure, and risk of juvenile sudden death. Recessive mutations are rare and are associated with a cardiac or cardiocutaneous phenotype. Here, we evaluated the impact of a homozygous founder DSC2 mutation on clinical expression of ACM. An exon-by-exon analysis of the DSC2 coding region was performed in 94 ACM index patients. The c.536A>G (p.D179G) mutation was identified in 5 patients (5.3%), 4 of which resulted to be homozygous carriers. The 5 subjects shared a conserved haplotype, strongly indicating a common founder. Genetic and clinical investigation of probands' families revealed that p.D179G homozygous carriers displayed severe forms of biventricular cardiomyopathy without hair or skin abnormalities. The only heterozygous proband, who carried an additional variant of unknown significance in αT-catenin gene, showed a mild form of ACM without left ventricular involvement. All heterozygous family members were clinically asymptomatic. In conclusion, this is the first homozygous founder mutation in DSC2 gene identified among Italian ACM probands. Our findings provide further evidence of the occurrence of recessive DSC2 mutations in patients with ACM predominantly presenting with biventricular forms of the disease.

Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC. METHODS AND RESULTS: The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years [22-52]) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively. CONCLUSIONS: Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.

Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive myocardial loss, with fibro-fatty replacement, and high frequency of ventricular arrhythmias that can lead to sudden cardiac death. ARVC is a genetically determined disorder, usually caused by point mutations in components of the cardiac desmosome. Conventional mutation screening of ARVC genes fails to detect causative mutations in about 50% of index cases, suggesting a further genetic heterogeneity. We performed a genome-wide linkage study and a copy number variations (CNVs) analysis, using high-density SNP arrays, in an ARVC family showing no mutations in any of the desmosomal genes. The CNVs analysis identified a heterozygous deletion of about 122 kb on chromosome 12p11.21, including the entire plakophilin-2 gene and shared by all affected family members. It was not listed on any of available public CNVs databases and was confirmed by quantitative real-time PCR. This is the first SNP array-based genome-wide study leading to the identification of a CNV segregating with the disease phenotype in an ARVC family. This result underscores the importance of performing additional analysis for possible genomic deletions/duplications in ARVC patients without point mutations in known disease genes.

Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle. Mutations in several genes encoding desmosomal proteins have been identified in ARVC. We speculated that αT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients. Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes. METHODS AND RESULTS: We used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC. Mutations c.281T > A (p.V94D) and c.2293_2295delTTG (p.del765L) were identified in two probands. They are located in important domains of αT-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and ß-catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells. CONCLUSION: These findings might point to a causal relationship between CTNNA3 mutations and ARVC. This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes. Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.

Noninvasive cardiac screening in young athletes with ventricular arrhythmias.

The aim of this study was to analyze using noninvasive cardiac examinations a series of young athletes discovered to have ventricular arrhythmias (VAs) during the preparticipation screening program for competitive sports. One hundred forty-five athletes (mean age 17 ± 5 years) were evaluated. The study protocol included electrocardiography (ECG), exercise testing, 2-dimensional and Doppler echocardiography, 24-hour Holter monitoring, signal-averaged ECG, and in selected cases contrast-enhanced cardiac magnetic resonance imaging. Results of ECG were normal in most athletes (85%). VAs were initially detected prevalently during exercise testing (85%) and in the remaining cases on ECG and Holter monitoring. Premature ventricular complexes disappeared during exercise in 56% of subjects. Premature ventricular complexes during Holter monitoring averaged 4,700 per day, predominantly monomorphic (88%), single, and/or in couplets (79%). The most important echocardiographic findings were mitral valve prolapse in 29 patients (20%), congenital heart disease in 4 (3%), and right ventricular regional kinetic abnormalities in 5 (3.5%). On cardiac magnetic resonance imaging, right ventricular regional kinetic abnormalities were detected in 9 of 30 athletes and were diagnostic of arrhythmogenic right ventricular cardiomyopathy in only 1 athlete. Overall, 30% of athletes were judged to have potentially dangerous VAs. In asymptomatic athletes with prevalently normal ECG, most VAs can be identified by adding an exercise test during preparticipation screening. In conclusion, cardiac screening with noninvasive examinations remains a fundamental tool for the identification of a possible pathologic substrate and for the characterization of electrical instability.

Gender differences and role of pregnancy in the history of post-surgical women affected by tetralogy of Fallot.

BACKGROUND: The aim of this study was to describe gender differences in patients operated on for TOF and to define the impact of pregnancy in late post-surgical follow-up in women. METHODS: In this research, we studied 145 patients after correction of TOF: 66 male, 79 women, 41 of which reported history of 68 pregnancies, means age 37±10 years, age at operation 7±8 years, mean duration of post-surgical follow-up 30±7 years. Selected variables were compared according to sex and according to history of pregnancy with statistical tests. RESULTS: Men had more severe hemodynamic impairment and a higher number of cardiac reoperations than females. 41% of patients had at least one complication during pregnancy; there were 16 (67%) abortions and 39 (74%) Caesarian delivers; the recurrence of congenital heart defect was 10%. After pregnancy, there was a shift from first to second functional class: unique pregnancy determined no differences in term of morpho-functional ventricular features compared to nulliparous, but they complained fatigue and palpitation and echocardiographyc dysfunction. Left ventricular dysfunction and QRS duration at ECG were independent predictors of ventricular arrhythmias in all patients. CONCLUSIONS: There were no gender-specific differences in patients operated on for TOF using ventriculotomy. Pregnancy is an event in these patients at risk for the newborn, in terms of miscarriage, prematurity, and recurrence of birth defects, and for the mother in terms of ventricular dysfunction and electrical instability. At least a single pregnancy does not appear to significantly modify the natural history of post-surgical patients operated on for TOF.

Follow-up with exercise test of effort-induced ventricular arrhythmias linked to ryanodine receptor type 2 gene mutations.

The aim of this study was to assess exercise test results and efficacy of therapy with a ß blocker (acebutolol) in ryanodine receptor type 2 (RyR2) mutation carriers with documented ventricular arrhythmias (VAs) and long-term follow-up. Twenty RyR2 mutation carriers belonging to 8 families and regularly followed at our center were analyzed using a study protocol involving electrocardiography, exercise tests off and on ß-blocker therapy, 2-dimensional echocardiography, and signal-averaged electrocardiography. Off-therapy exercise testing triggered the onset of VAs at different heart rates (mean 132 ± 13 beats/min) with various patterns that worsened while exercising and disappeared immediately after stopping. The most severe VAs detected were nonsustained ventricular tachycardia in 35% and ventricular couplets in 35%. In the remaining subjects single ventricular premature beats were recorded. In 15% of patients single monomorphic ventricular premature beats were detected and identified to be linked to RyR2 mutations owing to the presence of sudden deaths of their family members and subsequent family screening. Acebutolol made the VAs disappear completely in 20% of subjects and decreased their complexity in 50%, whereas it did not change VAs appreciably in 30% of patients with less complex VAs. After 11 ± 8 years of follow-up 2 patients developed syncope. In conclusion, exercise testing was a fundamental tool for assessing the clinical phenotype and efficacy of therapy in RyR2 mutation carriers and therapy with acebutolol led in most subjects to a decreased complexity of the arrhythmic pattern or to complete suppression.

Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease carrying a risk of sudden death. Information about the clinical features during childhood and the age at disease onset is scanty. OBJECTIVE: The aim of the study was to describe the ARVC phenotype as its initial clinical manifestation in a pediatric population (<18 years) with desmosomal gene mutations. METHODS: Fifty-three ARVC desmosomal gene mutation carriers (mean age 12.3 ± 3.9 years) were investigated by electrocardiogram (ECG), signal-averaged ECG, 24-hour Holter, echocardiogram, and contrast-enhanced cardiac magnetic resonance (CMR). RESULTS: None of the children ≤10 years old fulfilled the 1994 criteria, as opposed to six (33%) aged 11-14 years and eight aged >14 years (42%). At the end of follow-up (9 ± 7 years), 21 (40%) fulfilled the 1994 diagnostic criteria (mean age 16 ± 4 years). By using the 2010 criteria in subjects aged ≤18 years, 53% were unaffected, versus 62% by using the traditional criteria. More than two-thirds of affected subjects had moderate-severe forms of the disease. Contrast-enhanced CMR was performed in 21 (40%); of 13 unaffected gene mutation carriers, six showed ARVC morphological and/or tissue abnormalities. CONCLUSION: In pediatric ARVC mutation carriers, a diagnosis was achieved in 40% of cases, confirming that the disease usually develops during adolescence and young adulthood. The 2010 modified criteria seem to be more sensitive than the 1994 ones in identifying familial pediatric cases. Contrast-enhanced CMR can provide diagnostic information on gene mutation carriers not fulfilling either traditional or modified criteria. Management of asymptomatic gene mutation carriers remains the main clinical challenge.

Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses. OBJECTIVE: This study sought to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers. METHODS: Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing. RESULTS: Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers. CONCLUSION: Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.

Electrocardiographic pattern in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by progressive myocardial atrophy and fibrofatty replacement. Standard electrocardiograms (ECGs) and signal-averaged ECGs (SAECGs) were relatively low cost and repeatable diagnostic tools. In this study, ECGs and SAECGs of patients with ARVC were analyzed with the aim to assess the diagnostic capability of these noninvasive techniques. A total of 205 patients with ARVC were analyzed. ECGs were abnormal in 74% of patients and SAECGs were positive in 60%, with normal ECGs mostly related to mild forms of the disease. The most common electrocardiographic abnormalities were localized right QRS prolongation, poor r wave progression in the right precordial leads, incomplete right branch bundle block, prolonged S-wave upstroke in V(1) to V(3), parietal block, ST-segment elevation in V(1) to V(3), inversion of T waves beyond V(2), and epsilon wave. Low QRS voltages in the precordial leads were frequently present in all patients with ARVC compared with a group of 120 healthy subjects (p = 0.00001). T-wave inversion beyond V(3) characterized subjects with severe right ventricular dilatation, whereas in subjects with left ventricular involvement, T-wave inversion in lateral leads was more commonly detected. Overall, the extent of electrocardiographic abnormalities was related to disease extent. In conclusion, abnormalities in ECGs and SAECGs were frequent in patients with ARVC and correlated with disease extent, even if a stereotypical electrocardiographic pattern did not exist. ECGs and SAECGs remain an important tool for the diagnosis and assessment of ARVC extent. Nonetheless, a normal ECG does not exclude the presence of the disease.

Comparison of clinical features of arrhythmogenic right ventricular cardiomyopathy in men versus women.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease characterized by myocardial necrosis followed by fibrous-fatty replacement. The pathologic process constitutes the basis for ventricular arrhythmias due to re-entrant circuits. Even if this genetic disease is transmitted in the majority of cases with autosomal dominant trait, in all reported series ARVC is prevalent in men. In this study we investigate the impact that gender may have on clinical presentation in a large series of patients with ARVC. A total of 171 consecutive patients (mean 29 +/- 12 years, range 13 to 65) affected by ARVC were examined with family and personal history, 12-lead electrocardiogram (ECG), 24-hour ECG, signal-averaged ECG, and echocardiogram. Moreover, electrophysiological study and ventricular angiography were performed in selected cases. In the 171 subjects, 71% were men and 29% women (p = 0.02). No gender differences were found considering the age at the time of diagnosis and of study enrolment and the prevalence of index cases and family members. The genders differed in prevalence of abnormal ECG (69% vs 52%, p = 0.036) and presence of late potentials (60% vs 40%, p = 0.01). Moreover, men had larger right ventricular dimensions and practiced competitive sports more frequently (26% vs 14%, p <0.001). Nonetheless, gender was not associated with a high incidence of life-threatening ventricular arrhythmias or with a poor outcome. In conclusion, our data show that diagnosis of ARVC is less common in female patients, who present a higher prevalence of mild forms. Nonetheless, the degree of electrical instability does not differ significantly between genders in affected subjects. Even if ARVC remains mainly a male disease, gender does not have a role in patients' outcome. The cause of the under-representation of women is not clear, even if potentially important factors such as sexual hormones and physical activity could play a role.

Comparison between QRS duration at standard ECG and signal-averaging ECG for arrhythmic risk stratification after surgical repair of tetralogy of fallot.

INTRODUCTION: Surgical repair of tetralogy of Fallot is complicated by the occurrence of ventricular tachycardia (VT). Among different indexes proposed to assess prognosis of these patients, the study of QRS and repolarization provided useful information. Controversial results come from the analysis of signal-averaging ECG (SAECG). The aim of our study was to identify patients operated for tetralogy of Fallot at higher risk of sudden death by means of SAECG. METHODS AND RESULTS: Sixty-six consecutive patients, mean age 26 +/- 10 years, were studied 17.7 +/- 5.8 years after total correction for tetralogy of Fallot using standard ECG, 24-hour Holter recordings, SAECG, and echocardiography. The following variables were measured: standard QRS duration, filtered QRS duration (fQRS), high-frequency and low-amplitude signal duration (HFLA), root mean square of the mean voltage in the terminal portion of filtered QRS (RMS), left and right end-diastolic volumes, and ejection fractions. During a mean follow-up period of 7.3 +/- 3.1 years, 12 patients had episodes of sustained VT and two of them suddenly died. All patients had complete right bundle branch block. Patients with VT were characterized by a significantly longer fQRS duration at all filter settings. On the contrary, there was no difference in standard QRS duration in patients with or without VT. At a multivariate analysis, left ventricular ejection fraction and fQRS were independent predictors for VT. CONCLUSIONS: A longer fQRS duration is associated with an increased risk in developing malignant ventricular arrhythmias in asymptomatic patients after total correction of tetralogy of Fallot.

Autonomic profile and arrhythmic risk stratification after surgical repair of tetralogy of Fallot.

BACKGROUND: Severe ventricular arrhythmias represent one of the main causes of mortality after repair of tetralogy of Fallot. Their appearance is primarily caused by the large ventricular scar created by surgical intervention. However, the role of autonomic activity as a modulating factor should be considered. The aim of our study was to evaluate this activity in a low-risk group of patients operated on for TOF and its correlation with the occurrence of sustained ventricular tachycardia. METHODS AND RESULTS: The study group included 38 patients with a mean age of 31 +/- 10 years, selected out of 76 subjects operated on for total correction of tetralogy of Fallot. After a mean interval of 21.9 +/- 6 years from surgical procedure, they underwent electrocardiography, echocardiography, and time domain heart rate variability (HRV) analysis obtained by 24-hour Holter monitoring. Thirty-five healthy subjects comprised the control group for HRV analysis. During a mean follow-up of 6.2 +/- 3 years, 8 patients experienced episodes of sustained ventricular tachycardia. Among different HRV parameters, the standard deviation of all normal beat intervals showed a significant reduction in this group of patients (91.7 +/- 19 versus 133.4 +/- 46, P < .02). Echocardiographic examination demonstrated an increased left ventricular end diastolic volume (85.6 +/- 55 versus 61.3 +/- 13 mL/m(2), P < .05) and a reduced left ventricle ejection fraction (53.9 +/- 9 versus 61.0 +/- 6 %, P < .01) in arrhythmic patients. QRS duration was similar in patients with or without sustained ventricular tachycardia. CONCLUSIONS: Patients after surgical correction of tetralogy of Fallot, considered to be at low risk, showed a significant incidence of severe ventricular arrhythmias. HRV analysis seems to be a useful method for identifying arrhythmic patients, and the standard deviation of all normal beat intervals appears to be the more helpful index.

Life expectancy and quality of life in adult patients with congenital heart disease.

The survival and quality of life of patients with congenital heart disease have significantly improved in the last 20 years. This is due to more effective medical and surgical care. The new community of grown-up congenital heart patients consists of a few natural survivors with trivial congenital lesions or very rare complex cardiac abnormalities which are naturally compensated, and of more than 75% of patients who had been submitted to cardiac surgery during infancy or childhood. Clinical follow-up is however mandatory for many of them with scheduled times and types of exams to control the effects of sequelae and late complications, and to prevent deterioration and premature death because cardiac surgery may not have resulted in normality. Moreover, these patients have many needs and even more, many questions. Not giving a correct answer to each specific question reduces the entity of surgical success.

Fatal outcome in Eisenmenger syndrome.

AIM: To assess correlations between fatal outcome and histologic findings of pulmonary vascular disease in different situations of Eisenmenger syndrome, either during the natural course or early-late after surgery. MATERIAL AND METHODS: The clinical follow-up and fatal outcome of 20 patients affected by Eisenmenger syndrome were investigated. In addition to the pathologic report and gross reexamination of the heart, the lung tissue was studied by histology. Patients were divided into three groups: 6 non-operated patients who died during the natural course (Group 1), 11 patients who underwent correction of the congenital defect and died in the perioperative period (Group 2), and 3 patients who died late after surgery (Group 3). RESULTS: In Group 1, five patients (83%) died of cardiac arrest a few days after the onset of hypoxic attacks; in four patients histology showed Grade IV pulmonary vascular disease with diffuse fibrinoid necrosis in the distal pulmonary arterial vasculature. In Group 2, nine patients (82%) died on the first or second postoperative day after a refractory pulmonary hypertensive crisis, with histologic evidence in three patients of fibrinoid necrosis of the distal pulmonary small arteries and arterioles. In Group 3, two patients (67%) died suddenly, 6 and 18 years after cardiac surgery, following onset of dyspnea and cardiogenic shock; autopsy showed aneurysmal dilatation of the pulmonary artery with massive thrombosis in the setting of Grades III-IV pulmonary vascular disease without fibrinoid necrosis. CONCLUSION: Fatal outcome in Eisenmenger syndrome, either in the natural course or after refractory hypertensive attacks post surgery, is frequently associated with fibrinoid necrosis of the small pulmonary arteries and arterioles.