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1.
Cells ; 10(10)2021 09 28.
Article in English | MEDLINE | ID: mdl-34685557

ABSTRACT

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.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Biomarkers/metabolism , Cardiomyopathies/genetics , MicroRNAs/metabolism , Adult , Case-Control Studies , Female , Humans , Male , Pilot Projects
2.
Heart Rhythm ; 16(5): 773-780, 2019 05.
Article in English | MEDLINE | ID: mdl-30453078

ABSTRACT

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.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Adult , Apoptosis Regulatory Proteins/genetics , Codon, Nonsense , Desmosomes/genetics , Female , Genetic Predisposition to Disease , Heterozygote , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Repressor Proteins/genetics
3.
Circ Genom Precis Med ; 11(10): e002123, 2018 10.
Article in English | MEDLINE | ID: mdl-30354300

ABSTRACT

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.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Zonula Occludens-1 Protein/genetics , Adult , Arrhythmogenic Right Ventricular Dysplasia/epidemiology , Arrhythmogenic Right Ventricular Dysplasia/metabolism , Arrhythmogenic Right Ventricular Dysplasia/pathology , Female , Germany/epidemiology , Humans , Male , Myocardium/metabolism , Myocardium/pathology , Netherlands/epidemiology , Prevalence , Exome Sequencing , Zonula Occludens-1 Protein/metabolism
4.
Article in English | MEDLINE | ID: mdl-29038103

ABSTRACT

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members. METHODS AND RESULTS: A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification. Nine heterozygous CNVs were identified in 11 (6.9%) of the 160 probands. Five carried a deletion of the entire plakophilin-2 (PKP2) gene, 2 a deletion of only PKP2 exon 4, 1 a deletion of the PKP2 exons 6 to 11, 1 a PKP2 duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 (DSC2) duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both DSC2 and desmoglein-2 genes. All probands were affected by moderate-severe forms of the disease, whereas 10 (32%) of the 31 family members carrying one of these deletions fulfilled the diagnostic criteria. CONCLUSIONS: Genomic rearrangements were detected in ≈7% of AC probands negative for pathogenic point mutations in desmosomal genes, highlighting the potential of CNVs analysis to substantially increase the diagnostic yield of genetic testing. Genotype-phenotype correlation demonstrated the presence of the disease in about one third of family members carrying the CNV, underlying the role of other factors in the development and progression of the disease.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Desmosomes/genetics , Gene Rearrangement , Action Potentials , Adolescent , Adult , Aged , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/physiopathology , DNA Copy Number Variations , DNA Mutational Analysis , Desmocollins/genetics , Desmoglein 2/genetics , Desmoplakins/genetics , Electrocardiography , Electrophysiologic Techniques, Cardiac , Female , Gene Deletion , Gene Dosage , Gene Duplication , Genetic Association Studies , Genetic Markers , Genetic Predisposition to Disease , Heart Rate , Heredity , Humans , Italy , Male , Middle Aged , Multiplex Polymerase Chain Reaction , Pedigree , Phenotype , Plakophilins/genetics , Point Mutation , Risk Factors , Young Adult , gamma Catenin
5.
Biomed Res Int ; 2017: 4139635, 2017.
Article in English | MEDLINE | ID: mdl-28904957

ABSTRACT

Cardiovascular diseases (CVD) represent the leading cause of maternal mortality and morbidity. Knowledge of CVD in women is constantly evolving and data are emerging that female-specific risk factors as complications of pregnancy are conditions associated with an increased risk for the long-term development of CVD. Echocardiography is a safe and effective imaging technique indicated in symptomatic or asymptomatic pregnant women with congenital heart diseases who require close monitoring of cardiac function. Deformation imaging is an echocardiographic technique used to assess myocardial function by measuring the actual deformation of the myocardium through the cardiac cycle. Speckle-tracking echocardiography (STE) is a two-dimensional (2D) technique which has been found to be more accurate than tissue Doppler to assess both left ventricular (LV) and right ventricular (RV) myocardial function. The use of 2D STE however might present some technical issues due to the tomographic nature of the technique and the motion in the three-dimensional space of the myocardial speckles. This has promoted the use of 3D STE to track the motion of the speckles in the 3D space. This review will focus on the clinical value of the new echocardiographic techniques of deformation imaging used to assess the maternal cardiovascular system in complicated pregnancies.


Subject(s)
Cardiovascular System/diagnostic imaging , Echocardiography, Doppler , Pregnancy Complications, Cardiovascular/diagnosis , Female , Heart Ventricles/diagnostic imaging , Heart Ventricles/physiopathology , Humans , Image Interpretation, Computer-Assisted , Pregnancy , Pregnancy Complications, Cardiovascular/diagnostic imaging , Pregnancy Complications, Cardiovascular/physiopathology
6.
Eur J Hum Genet ; 25(10): 1165-1169, 2017 10.
Article in English | MEDLINE | ID: mdl-28699631

ABSTRACT

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.


Subject(s)
Arrhythmias, Cardiac/genetics , Cardiac Myosins/genetics , Cardiomyopathy, Hypertrophic/genetics , Carrier Proteins/genetics , Desmoplakins/genetics , Myosin Heavy Chains/genetics , Phenotype , alpha Catenin/genetics , Adolescent , Adult , Aged , Arrhythmias, Cardiac/diagnosis , Cardiomyopathy, Hypertrophic/diagnosis , Female , Heterozygote , Humans , Male , Middle Aged , Mutation , Pedigree , alpha Catenin/metabolism
7.
Orphanet J Rare Dis ; 11: 33, 2016 Apr 02.
Article in English | MEDLINE | ID: mdl-27038780

ABSTRACT

Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50% of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis.AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC.Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.


Subject(s)
Arrhythmias, Cardiac/metabolism , Cardiomyopathies/metabolism , Cardiomyopathies/pathology , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/pathology , Cardiomyopathies/genetics , Female , Heterozygote , Humans , Male , Mutation/genetics , beta Catenin/genetics
8.
Europace ; 18(7): 1086-94, 2016 Jul.
Article in English | MEDLINE | ID: mdl-26138720

ABSTRACT

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.


Subject(s)
Arrhythmias, Cardiac/epidemiology , Arrhythmogenic Right Ventricular Dysplasia/complications , Arrhythmogenic Right Ventricular Dysplasia/genetics , Cicatrix/pathology , Death, Sudden, Cardiac/epidemiology , Defibrillators, Implantable/adverse effects , Adolescent , Adult , Arrhythmogenic Right Ventricular Dysplasia/mortality , Desmoglein 2/genetics , Desmoplakins/genetics , Female , Heterozygote , Humans , Italy , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Phenotype , Plakophilins/genetics , Primary Prevention , Prospective Studies , Risk Factors , Young Adult
9.
Am J Cardiol ; 116(8): 1245-51, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26310507

ABSTRACT

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.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Desmocollins/genetics , Mutation/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Exons/genetics , Female , Founder Effect , Homozygote , Humans , Italy , Male , Middle Aged , Pedigree , Young Adult
10.
J Cardiovasc Med (Hagerstown) ; 16 Suppl 2: S89-91, 2015 Jan.
Article in English | MEDLINE | ID: mdl-23867911

ABSTRACT

This study describes the un-natural history of a 16-year-old patient, presenting with a critical bicuspid aortic valve stenosis, who was initially treated in the neonatal period and later with a valvuloplasty. This focused the attention on palliative interventions that, in young adulthood or middle age, are usually related to several complications, until heart transplantation. The other important aspect of this case is the presence of a coronary atherosclerotic plaque producing a significant obstruction, in the setting of haemodynamic acute postoperative failure caused by the sudden aortic valve laceration and insufficiency. This favoured the transmural myocardial antero-septal evolution of the myocardial ischaemic-reperfusion damage. This case is peculiar in that it presents two unrelated entities in their natural history. The coronary lesion was an unexpected finding in an adolescent with congenital heart disease. The severity of the coronary lesion became haemodynamically significant as a combination of the hypoperfusion due to the massive aortic valve regurgitation following the acute failure of the aortic valve plasty and the vasoconstriction of the eccentric speared segment. Once again, the complete understanding of grown-up patients with congenital hart disease is mandatory together with the point that a close collaboration of a multidisciplinary team is essential for appropriate operative timing and planning the most suitable treatment option. Acquired heart diseases can rarely present in association in this group of patients and need to be taken into account.


Subject(s)
Aortic Valve Stenosis/complications , Aortic Valve/abnormalities , Coronary Artery Disease/complications , Heart Valve Diseases/complications , Hypertrophy, Left Ventricular/complications , Adolescent , Aortic Valve/surgery , Aortic Valve Stenosis/surgery , Bicuspid Aortic Valve Disease , Heart Transplantation , Heart Valve Diseases/surgery , Heart Valve Prosthesis Implantation , Humans , Infant, Newborn , Male
11.
Circ Cardiovasc Genet ; 6(6): 533-42, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24070718

ABSTRACT

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.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Death, Sudden, Cardiac , Desmosomes/genetics , Mutation , Adult , Arrhythmogenic Right Ventricular Dysplasia/physiopathology , Desmocollins/genetics , Desmoglein 2/genetics , Desmoplakins/genetics , Female , Genotype , Heterozygote , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Plakophilins/genetics , Prognosis , Risk Factors , Sex Factors , Tachycardia, Ventricular/genetics , Tachycardia, Ventricular/physiopathology , Time Factors , Ventricular Fibrillation/genetics , Ventricular Fibrillation/physiopathology , Young Adult
12.
Eur J Hum Genet ; 21(11): 1226-31, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23486541

ABSTRACT

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.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Gene Deletion , Plakophilins/genetics , Adult , Aged , Aged, 80 and over , Arrhythmogenic Right Ventricular Dysplasia/diagnostic imaging , Chromosomes, Human, Pair 12/genetics , DNA Copy Number Variations , Family , Female , Gene Dosage/genetics , Genetic Linkage , Humans , Male , Middle Aged , Pedigree , Real-Time Polymerase Chain Reaction , Ultrasonography , Young Adult
13.
J Cardiovasc Med (Hagerstown) ; 14(8): 582-6, 2013 Aug.
Article in English | MEDLINE | ID: mdl-22964646

ABSTRACT

AIMS: Heterozygous mutations in the transcription factor Nkx2.5 indicate a genetic cause for congenital heart diseases (CHDs) in human beings. The present study aimed to assess the prevalence of NKX2.5 mutations in Italian patients with sporadic non-syndromic and syndromic CHD, as well as to appraise any genotype-phenotype correlations. METHODS: One hundred Italian patients affected with CHD (90 had sporadic non-syndromic CHD and 10 had syndromic CHD) were screened for NKX2.5 mutations. The coding region and flanking regions involved in gene splicing of the CSX/NKX2.5 gene were amplified from genomic DNA by PCR, and mutational analysis was performed using denaturing high performance liquid chromatography and DNA sequencing. RESULTS: One previously reported NKX2.5 mutation (c.73C>T, p.R25C) was identified in two of the 100 CHD patients (2%). We have detected the p.R25C alteration in a woman showing aneurysm of the membranous septum, aortic coarctation and bicuspid aortic valve, that was a different phenotype from those previously reported, and for the first time in a patient with syndromic CHD with Down's syndrome (posterior ventricular septal defect, atrial septal defect, left superior cava vein ' sinus, and patent ductus arteriosus). CONCLUSION: Our results confirm that NKX2.5 mutations are not a common cause of CHD; furthermore, the p.R25C variation may increase susceptibility to development of CHD in patients with and without chromosomal abnormalities.


Subject(s)
Heart Defects, Congenital/genetics , Homeodomain Proteins/genetics , Mutation , Transcription Factors/genetics , Adolescent , Adult , Aged , Amino Acid Sequence , Animals , Case-Control Studies , Child , Child, Preschool , DNA Mutational Analysis/methods , Dogs , Gene Frequency , Genetic Predisposition to Disease , Homeobox Protein Nkx-2.5 , Humans , Infant , Infant, Newborn , Mice , Middle Aged , Molecular Sequence Data , Pedigree , Rats , Sequence Alignment , Syndrome
14.
J Cardiovasc Med (Hagerstown) ; 14(5): 326-33, 2013 May.
Article in English | MEDLINE | ID: mdl-22609874

ABSTRACT

The number of adults with congenital heart disease (CHD) has constantly increased as medical and surgical treatment of CHD - either simple or complex - continues to improve. Over the past half century, advances in surgical techniques have continued with the evolution of traditional surgical repair and introduction of new surgical procedures for complex lesions which were previously considered to be irreparable. We sought to analyze the current role of cardiac surgery in the treatment of congenital anomalies of the heart in those patients who have reached adulthood with or without surgical repair or palliation, with particular attention to future directions and perspectives.


Subject(s)
Cardiac Surgical Procedures , Heart Defects, Congenital/surgery , Adult , Age Factors , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/surgery , Cardiac Surgical Procedures/adverse effects , Cardiac Surgical Procedures/mortality , Heart Defects, Congenital/complications , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/mortality , Heart Defects, Congenital/physiopathology , Heart Failure/etiology , Heart Failure/surgery , Humans , Risk Factors , Treatment Outcome
15.
Eur Heart J ; 34(3): 201-10, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23136403

ABSTRACT

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.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Death, Sudden, Cardiac/etiology , Gene Deletion , Mutation, Missense/genetics , alpha Catenin/genetics , Adult , Arrhythmias, Cardiac/genetics , Arrhythmogenic Right Ventricular Dysplasia/metabolism , Case-Control Studies , Electrocardiography , Female , Heterozygote , Humans , Male , Pedigree , alpha Catenin/metabolism
16.
Am J Cardiol ; 111(4): 557-62, 2013 Feb 15.
Article in English | MEDLINE | ID: mdl-23219000

ABSTRACT

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.


Subject(s)
Arrhythmias, Cardiac/diagnosis , Athletes , Echocardiography, Doppler/methods , Electrocardiography, Ambulatory/methods , Exercise Test/methods , Mass Screening/methods , Physical Examination/methods , Adolescent , Adult , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/physiopathology , Child , Female , Humans , Incidence , Italy/epidemiology , Male , Reproducibility of Results , Young Adult
17.
Amyloid ; 20(1): 56-7, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23237236

ABSTRACT

We report on a young pregnant woman developing distal leg edema and hypoalbuminemia, who was lately diagnosed with AL amyloidosis. Fetal growth retardation led to a caesarian section in the 27th week of gestation. A live birth healthy female, 710 g weight, was admitted to the neonatal intensive care unit and survived. Thereafter the mother underwent specific chemotherapy achieving only a partial and transient response, and eventually died due to sepsis. Interestingly, amyloidotic material was found on the maternal but not on the fetal side of the placenta. Experimental data show suppression of AA amyloid formation during pregnancy and suggest a protective role of the placenta on the offspring. However, most reported cases deal with pregnant women diagnosed with AA amyloidosis associated with Familial Mediterranean Fever and describe growth retardation of the fetus, worsening renal function and preeclampsia. To the best of our knowledge, this is the first report of AL amyloidosis diagnosed in a pregnant woman. In our patient, as well as in the other reported cases, amyloidosis during pregnancy has been confirmed to be an ominous condition. Therefore mild leg edema and proteinuria during pregnancy, though a common finding, may not be innocent.


Subject(s)
Amyloidosis/diagnosis , Edema/diagnosis , Fetus , Pregnancy Complications/diagnosis , Adult , Amyloidosis/metabolism , Amyloidosis/pathology , Cesarean Section , Edema/metabolism , Edema/pathology , Female , Fetal Growth Retardation/diagnosis , Fetal Growth Retardation/pathology , Gestational Age , Humans , Immunoglobulin Light-chain Amyloidosis , Maternal Death , Placenta/metabolism , Placenta/pathology , Pregnancy , Pregnancy Complications/metabolism , Pregnancy Complications/pathology , Serum Amyloid A Protein/metabolism
18.
PLoS One ; 7(12): e49729, 2012.
Article in English | MEDLINE | ID: mdl-23239969

ABSTRACT

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.


Subject(s)
Heart Defects, Congenital , Sex Characteristics , Tetralogy of Fallot , Treatment Outcome , Adult , Arrhythmias, Cardiac/surgery , Electrocardiography , Female , Heart Defects, Congenital/surgery , Humans , Male , Middle Aged , Pregnancy , Reoperation , Tetralogy of Fallot/physiopathology , Tetralogy of Fallot/surgery
19.
Am J Cardiol ; 109(7): 1015-9, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22221940

ABSTRACT

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.


Subject(s)
Exercise Test , Genetic Testing , Mutation , Physical Exertion , Ryanodine Receptor Calcium Release Channel/genetics , Tachycardia, Ventricular/etiology , Acebutolol/therapeutic use , Adolescent , Adult , Anti-Arrhythmia Agents/therapeutic use , Cohort Studies , Death, Sudden, Cardiac/prevention & control , Echocardiography , Electrocardiography , Exercise Test/adverse effects , Family , Female , Follow-Up Studies , Genetic Markers/genetics , Heterozygote , Humans , Male , Pedigree , Phenotype , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/drug therapy , Tachycardia, Ventricular/genetics , Treatment Outcome
20.
PLoS One ; 6(12): e28313, 2011.
Article in English | MEDLINE | ID: mdl-22180780

ABSTRACT

BACKGROUND: Recent studies have reported that patients with end-stage heart disease can have cognitive deficits ranging from mild to severe. Little is known, however, about the relationship between cognitive performance, neurophysiological characteristics and relevant clinical and instrumental indexes for an extensive evaluation of patients with heart failure, such as: left ventricular ejection fraction (LVEF) and other haemodynamic measures, maximum oxygen uptake during cardiopulmonary exercise testing, comorbidities, major cardiovascular risk factors and disease duration. Our purpose was to outline the cognitive profiles of end-stage heart disease patients in order to identify the cognitive deficits that could compromise the quality of life and the therapeutic adherence in end-stage heart disease patients, and to identify the variables associated with an increased risk of cognitive deficits in these patients. METHODS: 207 patients with end-stage cardiac disease, candidates for heart transplant, were assessed by complete neuropsychological evaluation and by electroencephalographic recording with EEG spectral analysis. RESULTS: Pathological scores in one or more of the cognitive tests were obtained by 86% of the patients, while 36% performed within the impaired range on five or more tests, indicating poor performance across a broad range of cognitive domains. The executive functions were the cognitive domain most impaired (70%). Poor performances were not related to the aetiology of heart disease, but rather to cerebral dysfunction secondary to haemodynamic impairment and to comorbidities. CONCLUSIONS: Severe heart failure induces significant neurophysiological and neuropsychological alterations, which may produce an impairment of cognitive functioning and possibly compromise the quality of life of patients and the therapeutic adherence.


Subject(s)
Heart Transplantation , Neuropsychological Tests , Female , Heart Diseases/drug therapy , Heart Diseases/physiopathology , Heart Diseases/psychology , Humans , Male , Medication Adherence/statistics & numerical data , Memory, Short-Term , Middle Aged , Neurophysiology
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