Publications by authors named "Barbara Bauce"

89 Publications

A NOVEL PATHOGENIC ROLE FOR GALECTIN-3 IN EARLY DISEASE STAGES OF ARRHYTHMOGENIC CARDIOMYOPATHY.

Heart Rhythm 2021 Apr 12. Epub 2021 Apr 12.

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Background: Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations, whose pathogenesis remains incompletely understood.

Objective: To identify molecular pathways underlying early AC by gene expression profiling in both humans and animal models.

Methods: RNA sequencing for differentially expressed genes (DEGs) was performed on the myocardium of transgenic mice over-expressing the Desmoglein2-N271S mutation before phenotype onset. Zebrafish signaling reporters were used for in vivo validation. Whole exome sequencing was undertaken in 10 genotype-negative AC patients and subsequent direct sequencing in 140 AC index cases.

Results: Among 29 DEGs identified at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) showed reduced cardiac expression in transgenic mice and in 3 AC patients who suffered sudden cardiac death without overt structural remodeling. Four rare missense variants of LGALS3 were identified in 5 human AC probands. Pharmacological inhibition of Lgals3 in zebrafish reduced Wnt and TGFβ signaling, increased Hippo/YAP-TAZ signaling, and induced alterations in desmoplakin membrane localization, desmosome integrity and stability. Increased LGALS3 plasma expression in genotype-positive AC patients and CD98 activation supported the GAL3 release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions.

Conclusions: GAL3 plays a crucial role in early AC onset through regulation of Wnt/β-catenin signaling and intercellular adhesion.
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http://dx.doi.org/10.1016/j.hrthm.2021.04.006DOI Listing
April 2021

'Hot phase' clinical presentation in arrhythmogenic cardiomyopathy.

Europace 2020 Dec 13. Epub 2020 Dec 13.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Via Giustiniani, 2, 35121 Padua, Italy.

Aims: The aim of this study is to evaluate the clinical features of patients affected by arrhythmogenic cardiomyopathy (AC), presenting with chest pain and myocardial enzyme release in the setting of normal coronary arteries ('hot phase').

Methods And Results: We collected detailed anamnestic, clinical, instrumental, genetic, and histopathological findings as well as follow-up data in a series of AC patients who experienced a hot phase. A total of 23 subjects (12 males, mean age at the first episode 27 ± 16 years) were identified among 560 AC probands and family members (5%). At first episode, 10 patients (43%) already fulfilled AC diagnostic criteria. Twelve-lead electrocardiogram recorded during symptoms showed ST-segment elevation in 11 patients (48%). Endomyocardial biopsy was performed in 11 patients, 8 of them during the acute phase showing histologic evidence of virus-negative myocarditis in 88%. Cardiac magnetic resonance was performed in 21 patients, 12 of them during the acute phase; oedema and/or hyperaemia were detected in 7 (58%) and late gadolinium enhancement in 11 (92%). At the end of follow-up (mean 17 years, range 1-32), 12 additional patients achieved an AC diagnosis. Genetic testing was positive in 77% of cases and pathogenic mutations in desmoplakin gene were the most frequent. No patient complained of sustained ventricular arrhythmias or died suddenly during the 'hot phase'.

Conclusion: 'Hot phase' represents an uncommon clinical presentation of AC, which often occurs in paediatric patients and carriers of desmoplakin gene mutations. Tissue characterization, family history, and genetic test represent fundamental diagnostic tools for differential diagnosis.
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http://dx.doi.org/10.1093/europace/euaa343DOI Listing
December 2020

Ventricular arrhythmias in mitral valve prolapse: new explanations for an old problem.

Heart 2021 Mar 25;107(5):353-354. Epub 2020 Nov 25.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padova, Italy

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http://dx.doi.org/10.1136/heartjnl-2020-318086DOI Listing
March 2021

Arrhythmogenic Cardiomyopathy.

Eur Heart J 2020 12;41(47):4457-4462

Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padua Medical School, Padua, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehaa719DOI Listing
December 2020

Management of nonischemic-dilated cardiomyopathies in clinical practice: a position paper of the working group on myocardial and pericardial diseases of Italian Society of Cardiology.

J Cardiovasc Med (Hagerstown) 2020 Dec;21(12):927-943

Cardiothoracovascular Department , Center for Diagnosis and Management of Cardiomyopathies, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), University of Trieste, Trieste.

: Nonischemic-dilated cardiomyopathy (NIDCM) is an entity that gathers extremely heterogeneous diseases. This awareness, although leading to continuous improvement in survival, has increased the complexity of NIDCM patients' management. Even though the endorsed 'red-flags' approach helps clinicians in pursuing an accurate etiological definition in clinical practice, it is not clear when and how peripheral centers should interact with referral centers with specific expertise in challenging scenarios (e.g. postmyocarditis and genetically determined dilated cardiomyopathy) and with easier access to second-line diagnostic tools and therapies. This position paper will summarize each step in NIDCM management, highlighting the multiple interactions between peripheral and referral centers, from first-line diagnostic workup and therapy to advanced heart failure management and long-term follow-up.
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http://dx.doi.org/10.2459/JCM.0000000000001050DOI Listing
December 2020

Differential diagnosis of arrhythmogenic cardiomyopathy: phenocopies versus disease variants.

Minerva Med 2021 Apr 22;112(2):269-280. Epub 2020 Jul 22.

Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy -

Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease caused by mutations of desmosomal genes in about 50% of patients. Affected patients may have defective non-desmosomal genes. The ACM phenotype may occur in other genetic cardiomyopathies, cardio-cutaneous syndromes or neuromuscular disorders. A sizeable proportion of patients have non-genetic diseases with clinical features resembling ACM (phenocopies). The identification of biventricular and left-dominant phenotypic variants has made differential diagnosis more difficult because of the broader spectrum of phenocopies which requires a detailed clinical study with appropriate evaluation of most prominent and discriminatory disease features. Conditions that enter into differential diagnosis of ACM include heart muscle diseases affecting the right ventricle, the left ventricle, or both. To confirm a conclusive diagnosis of ACM, these differential possibilities need to be reasonably excluded by an accurate and targeted clinical evaluation. This article reviews the clinical and imaging features of major phenocopies of ACM and provides indications for differential diagnosis. The recent etiologic classification of Arrhythmogenic Cardiomyopathies, whose common denominator is the distinctive phenotype characterized by a hypokinetic and non-dilated ventricle with a large amount of myocardial fibrosis underlying its propensity to generate ventricular arrhythmias is also addressed.
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http://dx.doi.org/10.23736/S0026-4806.20.06782-8DOI Listing
April 2021

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

Int J Cardiol 2020 11 16;319:106-114. Epub 2020 Jun 16.

Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Italy.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.06.005DOI Listing
November 2020

Arrhythmogenic Right Ventricular Cardiomyopathy: Characterization of Left Ventricular Phenotype and Differential Diagnosis With Dilated Cardiomyopathy.

J Am Heart Assoc 2020 03 2;9(5):e014628. Epub 2020 Mar 2.

Department of Cardio-Thoraco-Vascular Sciences and Public Health University of Padua Italy.

Background This study assessed the prevalence of left ventricular (LV) involvement and characterized the clinical, electrocardiographic, and imaging features of LV phenotype in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Differential diagnosis between ARVC-LV phenotype and dilated cardiomyopathy (DCM) was evaluated. Methods and Results The study population included 87 ARVC patients (median age 34 years) and 153 DCM patients (median age 51 years). All underwent cardiac magnetic resonance with quantitative tissue characterization. Fifty-eight ARVC patients (67%) had LV involvement, with both LV systolic dysfunction and LV late gadolinium enhancement (LGE) in 41/58 (71%) and LV-LGE in isolation in 17 (29%). Compared with DCM, the ARVC-LV phenotype was statistically significantly more often characterized by low QRS voltages in limb leads, T-wave inversion in the inferolateral leads and major ventricular arrhythmias. LV-LGE was found in all ARVC patients with LV systolic dysfunction and in 69/153 (45%) of DCM patients. Patients with ARVC and LV systolic dysfunction had a greater amount of LV-LGE (25% versus 13% of LV mass; <0.01), mostly localized in the subepicardial LV wall layers. An LV-LGE ≥20% had a 100% specificity for diagnosis of ARVC-LV phenotype. An inverse correlation between LV ejection fraction and LV-LGE extent was found in the ARVC-LV phenotype (=-0.63; <0.01), but not in DCM (=-0.01; =0.94). Conclusions LV involvement in ARVC is common and characterized by clinical and cardiac magnetic resonance features which differ from those seen in DCM. The most distinctive feature of ARVC-LV phenotype is the large amount of LV-LGE/fibrosis, which impacts directly and negatively on the LV systolic function.
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http://dx.doi.org/10.1161/JAHA.119.014628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335583PMC
March 2020

A microRNA Expression Profile as Non-Invasive Biomarker in a Large Arrhythmogenic Cardiomyopathy Cohort.

Int J Mol Sci 2020 Feb 24;21(4). Epub 2020 Feb 24.

Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Cardiovascular Pathology, Cardiology and Biostatistics Units, 35121 Padua, Italy.

Arrhythmogenic Cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease. Half of AC patients harbour private desmosomal gene variants. Although microRNAs (miRNAs) have emerged as key regulator molecules in cardiovascular diseases and their involvement, correlated to phenotypic variability or to non-invasive biomarkers, has been advanced also in AC, no data are available in larger disease cohorts. Here, we propose the largest AC cohort unbiased by technical and biological factors. MiRNA profiling on nine right ventricular tissue, nine blood samples of AC patients, and four controls highlighted 10 differentially expressed miRNAs in common. Six of these were validated in a 90-AC patient cohort independent from genetic status: miR-122-5p, miR-133a-3p, miR-133b, miR-142-3p, miR-182-5p, and miR-183-5p. This six-miRNA set showed high discriminatory diagnostic power in AC patients when compared to controls (AUC-0.995), non-affected family members of AC probands carrying a desmosomal pathogenic variant (AUC-0.825), and other cardiomyopathy groups (Hypertrophic Cardiomyopathy: AUC-0.804, Dilated Cardiomyopathy: AUC-0.917, Brugada Syndrome: AUC-0.981, myocarditis: AUC-0.978). AC-related signalling pathways were targeted by this set of miRNAs. A unique set of six-miRNAs was found both in heart-tissue and blood samples of AC probands, supporting its involvement in disease pathogenesis and its possible role as a non-invasive AC diagnostic biomarker.
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http://dx.doi.org/10.3390/ijms21041536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073183PMC
February 2020

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report.

Eur J Heart Fail 2019 08 18;21(8):955-964. Epub 2019 Jun 18.

Department of Clinical Genetics, Amsterdam Cardiovascular Sciences, University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.
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http://dx.doi.org/10.1002/ejhf.1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685753PMC
August 2019

Subcutaneous implantable cardioverter defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy: Results from an Italian multicenter registry.

Int J Cardiol 2019 04 12;280:74-79. Epub 2019 Jan 12.

Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Italy. Electronic address:

Background: Despite expanding indication of the subcutaneous implantable cardioverter defibrillator (S-ICD) in clinical practice, limited data exists on safety and efficacy of S-ICD in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. The aim of this multicenter study was to evaluate the safety and efficacy of S-ICD in ARVC patients.

Methods: The study population included 44 consecutive patients with definite ARVC diagnosis according to the 2010 ITF criteria (57% male, mean age 37 ± 17 years [range 10-75 years]) who received an S-ICD. Eighteen (41%) patients were implanted for secondary prevention.

Results: At implant, all inducible patients (34/44) had conversion of ventricular fibrillation at 65 J. No early complications occurred. During a median follow-up of 12 months (7-19), 3 (6.8%) patients experienced complications requiring surgical revision. No local or systemic device-related infections were observed. Six patients (14%) received a total of 61 appropriate and successful shocks on ventricular arrhythmias. Six (14%) patients experienced 8 inappropriate shocks for oversensing of cardiac signal (4 cases) and non-cardiac signal (4 cases) with one patient requiring device explantation. No patients had the device explanted due to the need for antitachycardia pacing.

Conclusions: The study shows that S-ICD provides safe and effective therapy for termination of both induced and spontaneous malignant ventricular tachyarrhythmias with high energy shocks in ARVC patients, but the risk of inappropriate shocks and complications needing surgical revision should be considered.
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http://dx.doi.org/10.1016/j.ijcard.2019.01.041DOI Listing
April 2019

Relationship Between Electrocardiographic Findings and Cardiac Magnetic Resonance Phenotypes in Arrhythmogenic Cardiomyopathy.

J Am Heart Assoc 2018 11;7(22):e009855

1 Department of Cardiac, Thoracic and Vascular Sciences University of Padova Italy.

Background The new designation of arrhythmogenic cardiomyopathy defines a broader spectrum of disease phenotypes, which include right dominant, biventricular, and left dominant variants. We evaluated the relationship between electrocardiographic findings and contrast-enhanced cardiac magnetic resonance phenotypes in arrhythmogenic cardiomyopathy. Methods and Results We studied a consecutive cohort of patients with a definite diagnosis of arrhythmogenic cardiomyopathy, according to 2010 International Task Force criteria, who underwent electrocardiography and contrast-enhanced cardiac magnetic resonance. Both depolarization and repolarization electrocardiographic abnormalities were correlated with the severity of dilatation/dysfunction, either global or regional, of both ventricles and the presence and regional distribution of late gadolinium enhancement. The study population included 79 patients (60% men). There was a statistically significant relationship between the presence and extent of T-wave inversion across a 12-lead ECG and increasing values of median right ventricular ( RV ) end-diastolic volume ( P<0.001) and decreasing values of RV ejection fraction ( P<0.001). The extent of T-wave inversion to lateral leads predicted a more severe RV dilatation rather than a left ventricular involvement because of the leftward displacement of the dilated RV , as evidenced by contrast-enhanced cardiac magnetic resonance. A terminal activation delay of >55 ms in the right precordial leads (V1-V3) was associated with higher RV volume ( P=0.014) and lower RV ejection fraction ( P=0.053). Low QRS voltages in limb leads predicted the presence ( P=0.004) and amount ( P<0.001) of left ventricular late gadolinium enhancement. Conclusions The study results indicated that electrocardiographic abnormalities predict the arrhythmogenic cardiomyopathy phenotype in terms of severity of RV disease and left ventricular involvement, which are among the most important determinants of the disease outcome.
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http://dx.doi.org/10.1161/JAHA.118.009855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404435PMC
November 2018

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

Heart Rhythm 2019 05 17;16(5):773-780. Epub 2018 Nov 17.

Department of Biology, University of Padua, Padua, Italy.

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.
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http://dx.doi.org/10.1016/j.hrthm.2018.11.015DOI Listing
May 2019

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

Circ Genom Precis Med 2018 10;11(10):e002123

Departments of Biology (M.D.B., G.P., M.C., A.L., G.V., A.R.).

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.
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http://dx.doi.org/10.1161/CIRCGEN.118.002123DOI Listing
October 2018

Predictive value of exercise testing in athletes with ventricular ectopy evaluated by cardiac magnetic resonance.

Heart Rhythm 2019 02 30;16(2):239-248. Epub 2018 Aug 30.

Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy. Electronic address:

Background: Exercise-induced ventricular arrhythmias (EIVA) in young athletes raise the suspicion of an underlying heart disease at risk of sudden death.

Objective: We aimed to assess the prevalence and determinants of abnormal cardiac magnetic resonance (CMR) findings in athletes referred for EIVA vs non-EIVA with negative or inconclusive echocardiography.

Methods: We performed CMR in a consecutive series of athletes aged 15-50 years referred for frequent (>500 per day) or repetitive premature ventricular beats. Clinical and CMR findings were compared between athletes with EIVA and those with non-EIVA, and predictors of abnormal CMR were assessed.

Results: We included 36 athletes with EIVA (median age 25 years; 27 (75%) males) and 24 with non-EIVA (median age 17 years; 18 (75%) males). CMR revealed cardiac abnormalities in 20 athletes with EIVA (56%) and in 5 with non-EIVA (21%) (P = .004). In particular, left ventricular late gadolinium enhancement was identified in 17 athletes with EIVA (47%) and in 3 with non-EIVA (13%) (P = .006), mostly with a nonischemic pattern. Predictors of abnormal CMR were T-wave inversion on electrocardiography (ECG) (odds ratio [OR] 5.2; 95% confidence interval [CI] 1.0-27.1; P = .05), complex ventricular arrhythmias on 24-hour ambulatory ECG monitoring (OR 4.5; 95% CI 1.1-18.7; P = .04), and complex EIVA with a right bundle branch block or polymorphic morphology on exercise testing (OR 5.3; 95% CI 1.4-19.4; P = .01).

Conclusion: Pathological myocardial substrates on CMR were observed significantly more often in athletes with EIVA than in those with non-EIVA. Repolarization abnormalities on baseline ECG and complex EIVA with a right bundle branch block or polymorphic morphology identified the subgroup of athletes with the highest probability of CMR abnormalities.
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http://dx.doi.org/10.1016/j.hrthm.2018.08.029DOI Listing
February 2019

Diagnostic Criteria, Genetics, and Molecular Basis of Arrhythmogenic Cardiomyopathy.

Heart Fail Clin 2018 Apr;14(2):201-213

Department of Cardiac, Thoracic, and Vascular Sciences, University of Padova Medical School, Padova, Italy.

Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease characterized by myocardial atrophy and fibrofatty replacement of the ventricular myocardium, at risk of sudden cardiac death, particularly in the young and athletes. Because there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined, including imaging, electrocardiographic changes, arrhythmias, tissue characterization, and family history. However, the routine use of contrast-enhanced cardiac magnetic resonance increasingly revealed left dominant AC, a variant that is not well addressed in the diagnostic criteria and still escapes clinical identification.
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http://dx.doi.org/10.1016/j.hfc.2018.01.002DOI Listing
April 2018

Anchoring Vignettes in EQ-5D-5L Questionnaire: Validation of a New Instrument.

Open Nurs J 2017 31;11:144-156. Epub 2017 Oct 31.

Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.

Background: Health Related Quality of Life (HRQoL) is an indicator of patient's physical, psychological and social life. HRQoL is influenced by experience, beliefs, perceptions and expectations, and measures subjective perspective of the patient himself. EQ-5D-5L and SF-12 questionnaires are validated instruments useful to measure HRQoL, increasingly administered in electronic formats.

Objective: The main purpose is to evaluate the feasibility of anchoring vignettes for the EQ-5D-5L questionnaire, with the aim to improve intergroup comparability of responses among different subjects. A comparison with SF-12 questionnaire is carried out.

Method: This is a cross-sectional study conducted at the ambulatories of cardiology of the University Hospital of Padova, in Italy. Thirty-eight subjects with a diagnosis of cardiovascular disease or at risk of cardiovascular disease were enrolled. A factorial analysis has been performed to assess the convergent validity of EQ-5D-5L questionnaire compared to Sf-12. Moreover, a compound Hierarchical Ordered Probit (Chopit) model has been estimated to evaluate if the questionnaire form affects the subjective evaluation process in order to compare EQ-5D-5L with and without vignettes.

Results: Correlation and factor analysis demonstrate that EQ_5D questionnaire is coherent with SF-12 in paper format. Chopit model estimation shows that questionnaire format does not affect the subjective question interpretation. Moreover, in a parametric model including vignettes, education attainment, disease severity, and gender are predictors of HRQoL status.

Conclusion: The EQ-5D including vignettes in electronic format seems to be a valid tool to measure HRQoL as compared to EQ-5D without vignettes in paper format and to SF-12 questionnaire.
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http://dx.doi.org/10.2174/1874434601711010144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712657PMC
October 2017

Large Genomic Rearrangements of Desmosomal Genes in Italian Arrhythmogenic Cardiomyopathy Patients.

Circ Arrhythm Electrophysiol 2017 Oct;10(10)

From the Departments of Cardiac, Thoracic, and Vascular Sciences (K.P., E.L., I.R., R.C., M.P.M., M.C., S.R., S.I., L.D., D.C., G. T., C.B., B.B.) and Medicine (D.R.), University of Padua, Italy; Department of Biology, University of Padua, Italy (M.D.B., M.C., G.P., A.R., A.L., G.O.); University Medical Center Groningen, University of Groningen, The Netherlands (J.J.); Cardiology Division, Casa di Cura Pederzoli, Peschiera del Garda, Italy (P.D.); and Department of Clinical Genetics, University of Amsterdam, The Netherlands (J.P.V.T.).

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 () gene, 2 a deletion of only exon 4, 1 a deletion of the exons 6 to 11, 1 a duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 () duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both and 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.
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http://dx.doi.org/10.1161/CIRCEP.117.005324DOI Listing
October 2017

The electrocardiographic "triangular QRS-ST-T waveform" pattern in patients with ST-segment elevation myocardial infarction: Incidence, pathophysiology and clinical implications.

J Electrocardiol 2018 Jan - Feb;51(1):8-14. Epub 2017 Aug 16.

Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy.

Background: A specific ECG pattern of presentation of ST-segment elevation acute myocardial infarction (STEMI), characterized by "triangular QRS-ST-T waveform" (TW), has been associated with poor in-hospital prognosis but longitudinal data on its incidence and clinical impact are lacking. We prospectively evaluated the incidence and prognostic meaning of the TW pattern in a cohort of consecutive STEMI patients.

Methods: All STEMI patients who presented within 12h of symptoms onset and showed no complete bundle branch block or paced ventricular rhythm were included. The TW pattern was defined as a unique, giant wave (amplitude≥1mV) resulting from the fusion of the QRS complex, the ST-segment and the T-wave and showing a "triangular" morphology with a positive polarity in the leads exploring the ischemic region.

Results: Among 428 consecutive STEMI patients, 367 fulfilled the enrollment criteria. The TW pattern was identified in 5 of 367 patients (1.4%) on the admission ECG. This subset of STEMI patients with TW pattern significantly more often showed a left main coronary artery involvement (2/4, 50% vs 2/322, 0.6%; p<0.001), experienced ventricular fibrillation (5/5, 100% vs 35/362, 9.6% p<0.001), had cardiogenic shock (4/5, 80% vs. 14/362, 3.8%, p<0.001) and died during hospitalization (2/5, 40% vs 15/362, 4.1% p=0.02), compared with those with other ST-segment elevation ECG patterns.

Conclusions: The TW pattern is an uncommon ECG finding, which reflects the presence of a large area of transmural myocardial ischemia and predicts cardiogenic shock accounting for high in-hospital mortality. When present, this ECG pattern should prompt aggressive therapeutic strategies, including mechanical support of circulation.
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http://dx.doi.org/10.1016/j.jelectrocard.2017.08.023DOI Listing
February 2019

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

Eur J Hum Genet 2017 10 12;25(10):1165-1169. Epub 2017 Jul 12.

Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua, Padua, Italy.

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 β-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.
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http://dx.doi.org/10.1038/ejhg.2017.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602010PMC
October 2017

Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral Valve Prolapse.

Circ Cardiovasc Imaging 2016 08;9(8):e005030

From the Department of Cardiac, Thoracic, and Vascular Sciences (M.P.M., C.B., M.D.L., S.R., A.C., I.R., F.M., K.P., L.C., E.B., A.C.F., B.B., D.C., G.T., S.I.), Department of Medicine (B.G.), and Department of Radiology (C.L.), Azienda Ospedaliera-University of Padua Medical School, Italy.

Background: Arrhythmic mitral valve prolapse (MVP) is characterized by myxomatous leaflets and left ventricular (LV) fibrosis of papillary muscles and inferobasal wall. We searched for morphofunctional abnormalities of the mitral valve that could explain a regional mechanical myocardial stretch.

Methods And Results: Thirty-six (27 female patients; median age: 44 years) arrhythmic MVP patients with LV late gadolinium enhancement on cardiac magnetic resonance and no or trivial mitral regurgitation, and 16 (6 female patients; median age: 40 years) MVP patients without LV late gadolinium enhancement were investigated by morphofunctional cardiac magnetic resonance. Mitral annulus disjunction (median: 4.8 versus 1.8 mm; P<0.001), end-systolic mitral annular diameters (median: 41.2 versus 31.5; P=0.004) and end-diastolic mitral annular diameters (median: 35.5 versus 31.5; P=0.042), prevalence of posterior systolic curling (34 [94%] versus 3 [19%]; P<0.001), and basal to mid LV wall thickness ratio >1.5 (22 [61%] versus 4 [25%]; P=0.016) were higher in MVP patients with late gadolinium enhancement than in those without. A linear correlation was found between mitral annulus disjunction and curling (R=0.85). A higher prevalence of auscultatory midsystolic click (26 [72%] versus 6 [38%]; P=0.018) was also noted. Histology of the mitral annulus showed a longer mitral annulus disjunction in 50 sudden death patients with MVP and LV fibrosis than in 20 patients without MVP (median: 3 versus 1.5 mm; P<0.001).

Conclusions: Mitral annulus disjunction is a constant feature of arrhythmic MVP with LV fibrosis. The excessive mobility of the leaflets caused by posterior systolic curling accounts for a mechanical stretch of the inferobasal wall and papillary muscles, eventually leading to myocardial hypertrophy and scarring. These mitral annulus abnormalities, together with auscultatory midsystolic click, may identify MVP patients who would need arrhythmic risk stratification.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.005030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991345PMC
August 2016

Nonischemic Left Ventricular Scar as a Substrate of Life-Threatening Ventricular Arrhythmias and Sudden Cardiac Death in Competitive Athletes.

Circ Arrhythm Electrophysiol 2016 07;9(7)

From the Department of Cardiac, Thoracic, and Vascular Sciences (A.Z., M.P.M., I.R., M.D.L., A.S., A.N., K.P., F.M., S.R., C.B., B.B., S.I., G.T., D.C.) and Division of Radiology, Department of Medicine (B.G.), University of Padova, Padova, Italy; Department of Radiology, Azienda Ospedaliera di Padova, Padova, Italy (G.D.C.); Center for Sports Medicine, Treviso, Italy (P.S.); Unidad de Cardiologica del Deporte, Hospital Universitario Quiron, Madrid, Spain (L.S.); U.O. Cardiologia, Ospedale B.Ramazzini, Carpi (MO), Italy (G.P., E.D.M.); Center for Sports Medicine, CONI, Rome, Italy (A.P.); and Center for Sports Medicine, Padova, Italy (M.S.).

Background: The clinical profile and arrhythmic outcome of competitive athletes with isolated nonischemic left ventricular (LV) scar as evidenced by contrast-enhanced cardiac magnetic resonance remain to be elucidated.

Methods And Results: We compared 35 athletes (80% men, age: 14-48 years) with ventricular arrhythmias and isolated LV subepicardial/midmyocardial late gadolinium enhancement (LGE) on contrast-enhanced cardiac magnetic resonance (group A) with 38 athletes with ventricular arrhythmias and no LGE (group B) and 40 healthy control athletes (group C). A stria LGE pattern with subepicardial/midmyocardial distribution, mostly involving the lateral LV wall, was found in 27 (77%) of group A versus 0 controls (group C; P<0.001), whereas a spotty pattern of LGE localized at the junction of the right ventricle to the septum was respectively observed in 11 (31%) versus 10 (25%; P=0.52). All athletes with stria pattern showed ventricular arrhythmias with a predominant right bundle branch block morphology, 13 of 27 (48%) showed ECG repolarization abnormalities, and 5 of 27 (19%) showed echocardiographic hypokinesis of the lateral LV wall. The majority of athletes with no or spotty LGE pattern had ventricular arrhythmias with a predominant left bundle branch block morphology and no ECG or echocardiographic abnormalities. During a follow-up of 38±25 months, 6 of 27 (22%) athletes with stria pattern experienced malignant arrhythmic events such as appropriate implantable cardiac defibrillator shock (n=4), sustained ventricular tachycardia (n=1), or sudden death (n=1), compared with none of athletes with no or LGE spotty pattern and controls.

Conclusions: Isolated nonischemic LV LGE with a stria pattern may be associated with life-threatening arrhythmias and sudden death in the athlete. Because of its subepicardial/midmyocardial location, LV scar is often not detected by echocardiography.
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http://dx.doi.org/10.1161/CIRCEP.116.004229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956679PMC
July 2016

Management of arrhythmogenic right ventricular cardiomyopathy.

Minerva Med 2016 Aug 17;107(4):194-216. Epub 2016 May 17.

Division of Cardiology, Department of Cardiac, Thoracic and Vascular Sciences, Medical School, University of Padua, Padua, Italy -

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder, predisposing to sudden cardiac death (SCD), particularly in young patients and athletes. Pathological features include loss of myocytes and fibrofatty replacement of right ventricular myocardium; a biventricular involvement is often observed. The diagnosis of ARVC (prevalence 1:5.000 in the general population) does not rely on a single gold standard test but is achieved using a scoring system, proposed in 2010 by an International Task Force, which encompasses familial and genetic factors, ECG abnormalities, arrhythmias, and structural/functional ventricular alterations. The main goal of treatment is the prevention of SCD. Implantable cardioverter defibrillator (ICD) is the only proven "lifesaving" therapy; however, it is associated with a significant morbidity due to device-related complications and inappropriate ICD interventions. Other treatment options such as life style changes, antiarrhythmic drugs, beta-blockers and catheter ablation may reduce the arrhythmic burden and alleviate symptoms, without evident impact on prevention of SCD. Selection of patient candidates to ICD implantation is the most challenging issue in the clinical management of ARVC. This article reviews the current perspective on management of ARVC, focusing on clinical manifestations, diagnostic criteria, risk stratification and therapeutic strategies of affected patients.
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August 2016

Arrhythmogenic Right Ventricular Cardiomyopathy: Risk Stratification and Indications for Defibrillator Therapy.

Curr Cardiol Rep 2016 06;18(6):57

Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined disease which predisposes to life-threatening ventricular arrhythmias. The main goal of ARVC therapy is prevention of sudden cardiac death (SCD). Implantable cardioverter defibrillator (ICD) is the most effective therapy for interruption of potentially lethal ventricular tachyarrhythmias. Despite its life-saving potential, ICD implantation is associated with a high rate of complications and significant impact on quality of life. Accurate risk stratification is needed to identify individuals who most benefit from the therapy. While there is general agreement that patients with a history of cardiac arrest or hemodynamically unstable ventricular tachycardia are at high risk of SCD and needs an ICD, indications for primary prevention remain a matter of debate. The article reviews the available scientific evidence and guidelines that may help to stratify the arrhythmic risk of ARVC patients and guide ICD implantation. Other therapeutic strategies, either alternative or additional to ICD, will be also addressed.
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http://dx.doi.org/10.1007/s11886-016-0734-9DOI Listing
June 2016

Arrhythmogenic cardiomyopathy.

Orphanet J Rare Dis 2016 Apr 2;11:33. Epub 2016 Apr 2.

Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.

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.
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http://dx.doi.org/10.1186/s13023-016-0407-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818879PMC
April 2016

Relationship Between Arrhythmogenic Right Ventricular Cardiomyopathy and Brugada Syndrome: New Insights From Molecular Biology and Clinical Implications.

Circ Arrhythm Electrophysiol 2016 Apr;9(4):e003631

From the Departments of Cardiac, Thoracic, and Vascular Sciences (D.C., A.Z., I.R., B.B.) and Biomedical Sciences (M.M.), University of Padua, Padova, Italy; and The Leon H. Charney Division of Cardiology, New York University School of Medicine (M.C., M.D.).

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http://dx.doi.org/10.1161/CIRCEP.115.003631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800833PMC
April 2016