Publications by authors named "Alexandros Protonotarios"

30 Publications

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High-Resolution Imaging for the Analysis and Reconstruction of 3D Microenvironments for Regenerative Medicine: An Application-Focused Review.

Bioengineering (Basel) 2021 Nov 10;8(11). Epub 2021 Nov 10.

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

The rapid evolution of regenerative medicine and its associated scientific fields, such as tissue engineering, has provided great promise for multiple applications where replacement and regeneration of damaged or lost tissue is required. In order to evaluate and optimise the tissue engineering techniques, visualisation of the material of interest is crucial. This includes monitoring of the cellular behaviour, extracellular matrix composition, scaffold structure, and other crucial elements of biomaterials. Non-invasive visualisation of artificial tissues is important at all stages of development and clinical translation. A variety of preclinical and clinical imaging methods-including confocal multiphoton microscopy, optical coherence tomography, magnetic resonance imaging (MRI), and computed tomography (CT)-have been used for the evaluation of artificial tissues. This review attempts to present the imaging methods available to assess the composition and quality of 3D microenvironments, as well as their integration with human tissues once implanted in the human body. The review provides tissue-specific application examples to demonstrate the applicability of such methods on cardiovascular, musculoskeletal, and neural tissue engineering.
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http://dx.doi.org/10.3390/bioengineering8110182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614770PMC
November 2021

Clinical and Molecular Aspects of Naxos Disease.

Heart Fail Clin 2022 Jan 22;18(1):89-99. Epub 2021 Oct 22.

Paediatric Clinic, Hora Naxos 84300, Greece. Electronic address:

Naxos disease is a recessively inherited pattern of arrhythmogenic cardiomyopathy with palmoplantar keratoderma and woolly hair. The causative mutation identified in plakoglobin protein gene indicated a potential role of the desmosomal protein complex as culprit for cardiomyopathy. In the context of a family, the early evident cutaneous features may serve as a clinical screening tool to spot arrhythmogenic cardiomyopathy in subclinical stage. "Myocarditis-like episodes" may step up the disease evolution or mark a transition from concealed to symptomatic cardiomyopathy phase. Arrhythmogenic cardiomyopathy in Naxos disease shows increased penetrance and phenotypic expression but its arrhythmic risk is analogous to dominant forms.
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http://dx.doi.org/10.1016/j.hfc.2021.07.010DOI Listing
January 2022

The prevalence of left and right bundle branch block morphology ventricular tachycardia amongst patients with arrhythmogenic cardiomyopathy and sustained ventricular tachycardia: insights from the European Survey on Arrhythmogenic Cardiomyopathy.

Europace 2021 Sep 7. Epub 2021 Sep 7.

Second Department of Medicine-Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Kateřinská 1660/32, 121 08 Nové Město, Prague, Czech Republic.

Aims: In arrhythmogenic cardiomyopathy (ACM), sustained ventricular tachycardia (VT) typically displays a left bundle branch block (LBBB) morphology while a right bundle branch block (RBBB) morphology is rare. The present study assesses the VT morphology in ACM patients with sustained VT and their clinical and genetic characteristics.

Methods And Results: Twenty-six centres from 11 European countries provided information on 954 ACM patients who had ≥1 episode of sustained VT spontaneously documented during patients' clinical course. Arrhythmogenic cardiomyopathy was defined according to the 2010 Task Force Criteria, and VT morphology according to the QRS pattern in V1. Overall, 882 (92.5%) patients displayed LBBB-VT alone and 72 (7.5%) RBBB-VT [alone in 42 (4.4%) or in combination with LBBB-VT in 30 (3.1%)]. Male sex prevalence was 79.3%, 88.1%, and 56.7% in the LBBB-VT, RBBB-VT, and LBBB + RBBB-VT groups, respectively (P = 0.007). First RBBB-VT occurred 5 years after the first LBBB-VT (46.5 ± 14.4 vs 41.1 ± 15.8 years, P = 0.011). An implanted cardioverter-defibrillator was more frequently implanted in the RBBB-VT (92.9%) and the LBBB + RBBB-VT groups (90%) than in the LBBB-VT group (68.1%) (P < 0.001). Mutations in PKP2 predominated in the LBBB-VT (65.2%) and the LBBB + RBBB-VT (41.7%) groups while DSP mutations predominated in the RBBB-VT group (45.5%). By multivariable analysis, female sex was associated with LBBB + RBBB-VT (P = 0.011) while DSP mutations were associated with RBBB-VT (P < 0.001). After a median follow-up of 103 (51-185) months, death occurred in 106 (11.1%) patients with no intergroup difference (P = 0.176).

Conclusion: RBBB-VT accounts for a significant proportion of sustained VTs in ACM. Sex and type of pathogenic mutations were associated with VT type, female sex with LBBB + RBBB-VT, and DSP mutation with RBBB-VT.
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http://dx.doi.org/10.1093/europace/euab190DOI Listing
September 2021

The genetic architecture of Plakophilin 2 cardiomyopathy.

Genet Med 2021 10 12;23(10):1961-1968. Epub 2021 Jun 12.

Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.

Purpose: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function.

Methods: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort.

Results: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants.

Conclusion: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.
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http://dx.doi.org/10.1038/s41436-021-01233-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486657PMC
October 2021

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

Circulation 2021 Jul 5;144(1):7-19. Epub 2021 May 5.

Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.

Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.

Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (, , , , , , , , , , ) or strong () evidence. Seven genes (14%; , , , , , , ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.

Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247549PMC
July 2021

International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework.

Circ Genom Precis Med 2021 06 8;14(3):e003273. Epub 2021 Apr 8.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, the Netherlands (R.L.D., J.P.v.T.).

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes.

Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework.

Results: Of 26 reported ARVC genes, only 6 (, , , , , and ) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, and . The remaining 18 genes had limited or no evidence. was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%).

Conclusions: Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (, , , , , , , and ) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.
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http://dx.doi.org/10.1161/CIRCGEN.120.003273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205996PMC
June 2021

The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy.

Can J Cardiol 2021 06 5;37(6):857-866. Epub 2020 Dec 5.

Institute of Cardiovascular Science, University College London, London, United Kingdom; Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, United Kingdom.

Background: Arrhythmogenic cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC but with insufficient evidence to support their pathogenicity.

Methods: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutations were prospectively screened by whole-exome sequencing.

Results: A single DES variant (p.Leu115Ile, c.343C>A) was identified in 3 index patients (2%). We assessed the clinical phenotypes within their families and confirmed cosegregation. One carrier required heart transplantation, 2 died suddenly, and 1 died of noncardiac causes. All cases had right- and left-ventricular (LV) involvement. LV late gadolinium enhancement was present in all, and circumferential subepicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically, but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells, and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short protofilaments and small fibrous aggregates.

Conclusions: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.
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http://dx.doi.org/10.1016/j.cjca.2020.11.017DOI Listing
June 2021

Myocardial strain analysis in family screening for genetic dilated cardiomyopathy: Testing the boundaries of normality?

Int J Cardiol 2021 01 23;323:201-202. Epub 2020 Oct 23.

Institute of Cardiovascular Science, University College London, London, UK; Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, UK; William Harvey Research Institute, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.1016/j.ijcard.2020.10.059DOI Listing
January 2021

State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy.

Int J Mol Sci 2020 Sep 10;21(18). Epub 2020 Sep 10.

Department of Cardiology, Royal Papworth Hospital, Cambridge CB2 0AY, UK.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM.
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http://dx.doi.org/10.3390/ijms21186615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554944PMC
September 2020

Influenza-associated cardiac injury: a disease of the cardiac conduction system?

Cardiovasc Res 2021 02;117(3):643-644

William Harvey Research Institute, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.1093/cvr/cvaa174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898940PMC
February 2021

Arrhythmogenic Cardiomyopathy: A Disease or Merely a Phenotype?

Eur Cardiol 2020 Feb 26;15:1-5. Epub 2020 Feb 26.

Institute of Cardiovascular Science, University College London, London, UK.

Arrhythmogenic cardiomyopathy (AC) is a clinical entity that has evolved conceptually over the past 30 years. Advances in cardiac imaging and the introduction of genetics into everyday practice have revealed that AC comprises multiple phenotypes that are dependent on genetic or acquired factors. In this study, the authors summarise the approach to the identification of the AC phenotype and its underlying causes. They believe that AC represents a paradigm for personalised medicine in cardiology and that better stratification of the disease will enhance the development of mechanism-based treatments.
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http://dx.doi.org/10.15420/ecr.2019.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066858PMC
February 2020

Towards precision disease-modelling in experimental myocarditis.

Cardiovasc Res 2020 08;116(10):1656-1657

William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

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http://dx.doi.org/10.1093/cvr/cvaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380721PMC
August 2020

Short-term effects of angiotensin receptor-neprilysin inhibitors on diastolic strain and tissue doppler parameters in heart failure patients with reduced ejection fraction: A pilot trial.

Hellenic J Cardiol 2020 Nov-Dec;61(6):415-418. Epub 2019 Dec 19.

Department of Cardiology, Heraklion University Hospital, Greece.

Objective: Although sacubitril/valsartan has recently shown its long-term benefits on morbidity and mortality in symptomatic patients with chronic heart failure with reduced ejection fraction (HFrEF), its short-term effects on diastolic function remain uncertain. We sought to assess 30-day effects of sacubitril/valsartan on left ventricular (LV) diastolic paremeters determined by speckle tracking and tissue Doppler imaging (STI and TDI respectively) as well as their association with functional capacity change evaluated by peak oxygen uptake (VOmax) in stable patients with symptomatic HFrEF.

Methods: A total of 35 patients (aged 61 ± 9 years) eligible for sacubitril/valsartan underwent a complete two-dimension (2D) echocardiographic study and a cardiopulmonary exercise test at baseline and 30 days after the initiation of therapy.

Results: Significant improvements in ratio of trans-mitral inflow early diastolic velocity E to mitral annulus early diastolic velocity E' (ΔΕ//Ε' = -35.9%, p = 0.001), peak early diastolic strain rate SRE (ΔSRE = +22.5%, p = 0.024) and ratio E/SRE (ΔE/SRE = -33.2%, p = 0.025) were observed after 1-month therapy. Compared with baseline, VOmax also increased significantly by 16.7 % (p = 0.001). Baseline E/SRE and ΔE/SRE were the strongest independent predictors of VOmax improvement (beta = -0.43, p = 0.004 and beta = 0.45, p = 0.021 respectively) in the multivariate analysis.

Conclusion: Sacubitril/valsartan was associated with early improvement in LV diastolic function determined by TDI and 2D STI. Baseline E/SRE was stronger than standard echocardiographic parameters in predicting the early benefit of sacubitril/valsartan therapy.
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http://dx.doi.org/10.1016/j.hjc.2019.12.003DOI Listing
August 2021

Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype.

Int J Cardiol 2020 05 8;307:101-108. Epub 2019 Oct 8.

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.

Background: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level.

Methods: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry.

Results: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle.

Conclusions: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations.
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http://dx.doi.org/10.1016/j.ijcard.2019.09.048DOI Listing
May 2020

Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: a comprehensive genotype-imaging phenotype study.

Eur Heart J Cardiovasc Imaging 2020 03;21(3):326-336

Barts Heart Centre, St Bartholomew's Hospital, London, UK.

Aims: Myocardial scar detected by cardiovascular magnetic resonance has been associated with sudden cardiac death in dilated cardiomyopathy (DCM). Certain genetic causes of DCM may cause a malignant arrhythmogenic phenotype. The concepts of arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) and arrhythmogenic DCM are currently ill-defined. We hypothesized that a distinctive imaging phenotype defines ALVC.

Methods And Results: Eighty-nine patients with DCM-associated mutations [desmoplakin (DSP) n = 25, filamin C (FLNC) n = 7, titin n = 30, lamin A/C n = 12, bcl2-associated athanogene 3 n = 3, RNA binding motif protein 20 n = 3, cardiac sodium channel NAv1.5 n = 2, and sarcomeric genes n = 7] were comprehensively phenotyped. Clustering analysis resulted in two groups: 'DSP/FLNC genotypes' and 'non-DSP/FLNC'. There were no significant differences in age, sex, symptoms, baseline electrocardiography, arrhythmia burden, or ventricular volumes between the two groups. Subepicardial LV late gadolinium enhancement with ring-like pattern (at least three contiguous segments in the same short-axis slice) was observed in 78.1% of DSP/FLNC genotypes but was absent in the other DCM genotypes (P < 0.001). Left ventricular ejection fraction (LVEF) and global longitudinal strain were lower in other DCM genotypes (P = 0.053 and P = 0.015, respectively), but LV regional wall motion abnormalities were more common in DSP/FLNC genotypes (P < 0.001). DSP/FLNC patients with non-sustained ventricular tachycardia (NSVT) had more LV scar (P = 0.010), whereas other DCM genotypes patients with NSVT had lower LVEF (P = 0.001) than patients without NSVT.

Conclusion: DSP/FLNC genotypes cause more regionality in LV impairment. The most defining characteristic is a subepicardial ring-like scar pattern in DSP/FLNC, which should be considered in future diagnostic criteria for ALVC.
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http://dx.doi.org/10.1093/ehjci/jez188DOI Listing
March 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

Left ventricular non-compaction: have we reached the limits of conventional imaging?

Eur Heart J 2020 04;41(14):1437-1438

Institute of Cardiovascular Science, University College London, London, UK.

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http://dx.doi.org/10.1093/eurheartj/ehz352DOI Listing
April 2020

Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management.

Heart 2019 07 21;105(14):1117-1128. Epub 2019 Feb 21.

UCL Institute of Cardiovascular Science, University College London, London, UK.

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http://dx.doi.org/10.1136/heartjnl-2017-311160DOI Listing
July 2019

Effect of Trimetazidine Dihydrochloride Therapy on Exercise Capacity in Patients With Nonobstructive Hypertrophic Cardiomyopathy: A Randomized Clinical Trial.

JAMA Cardiol 2019 03;4(3):230-235

University College London Institute of Cardiovascular Science, London, United Kingdom.

Importance: Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy.

Objective: To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy.

Design, Setting, And Participants: This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018.

Interventions: Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months.

Main Outcomes And Measures: The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro-brain natriuretic peptide level, and troponin T level.

Results: Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, -2.58 to -0.11 mL/kg per minute; P = .03) in the intervention group after 3 months.

Conclusions And Relevance: In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited.

Trial Registration: ClinicalTrials.gov identifier: NCT01696370.
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http://dx.doi.org/10.1001/jamacardio.2018.4847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439550PMC
March 2019

Prevalence of F-fluorodeoxyglucose positron emission tomography abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy.

Int J Cardiol 2019 06 26;284:99-104. Epub 2018 Oct 26.

Institute for Cardiovascular Science, University College London, London, UK; Barts Heart Centre, St Bartholomew's Hospital, London, UK; NIHR University College London Hospitals Biomedical Research Centre, UK.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC using F-fluorodeoxyglucose positron emission tomography (FDG-PET).

Methods And Results: We performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 ± 13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake.

Conclusion: In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis.
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http://dx.doi.org/10.1016/j.ijcard.2018.10.083DOI Listing
June 2019

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy.

PLoS One 2018 30;13(8):e0203078. Epub 2018 Aug 30.

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Aims: Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure.

Methods: We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant.

Results: Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants.

Conclusions: Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117038PMC
February 2019

Arrhythmogenic right ventricular cardiomyopathy as a hidden cause of paediatric myocarditis presentation.

Int J Cardiol 2018 11 2;271:113-114. Epub 2018 Jul 2.

Institute for Cardiovascular Science, University College London, London, UK; Barts Heart Centre, St Bartholomew's Hospital, London, UK.

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http://dx.doi.org/10.1016/j.ijcard.2018.06.117DOI Listing
November 2018

Genetic basis of arrhythmogenic cardiomyopathy.

Curr Opin Cardiol 2018 05;33(3):276-281

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.

Purpose Of Review: To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM.

Recent Findings: Use of next-generation sequencing methods has resulted in the identification of novel causative variants and genes for ACM. The involvement of filamin C in ACM demonstrates the genetic overlap between ACM and other types of cardiomyopathy. Putative pathogenic variants have been detected in cadherin 2 gene, a protein involved in cell adhesion. Large genomic rearrangements in desmosome genes have been systematically investigated in a cohort of ACM patients.

Summary: Recent studies have identified novel causes of ACM providing new insights into the genetic spectrum of the disease and highlighting an overlapping phenotype between ACM and dilated cardiomyopathy. Next-generation sequencing is a useful tool for research and genetic diagnostic screening but interpretation of identified sequence variants requires caution and should be performed in specialized centres.
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http://dx.doi.org/10.1097/HCO.0000000000000509DOI Listing
May 2018

Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells.

Circ Arrhythm Electrophysiol 2016 Feb;9(2):e003688

From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis).

Background: Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells.

Methods And Results: Buccal cells from patients, mutation carriers, and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathy patients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes.

Conclusions: Buccal mucosa cells from arrhythmogenic cardiomyopathy patients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCEP.115.003688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785796PMC
February 2016

Clinical Significance of Epsilon Waves in Arrhythmogenic Cardiomyopathy.

J Cardiovasc Electrophysiol 2015 Nov 6;26(11):1204-1210. Epub 2015 Sep 6.

Nikos Protonotarios Medical Centre, Naxos, Greece.

Introduction: Epsilon waves are hallmark features of arrhythmogenic cardiomyopathy (ACM) but information about their clinical significance is variable. We evaluated epsilon wave prevalence, characteristics, and their clinical significance in an ACM population.

Methods And Results: Eighty-six unselected patients fulfilling the 2010 Task Force criteria were enrolled. Seventy-six of them were carriers of desmosomal mutations. All subjects were serially evaluated with standard 12-lead ECG and 2-dimensional echocardiography. Epsilon waves were evaluated in all precordial and inferior leads. Novel parameters assessed included their duration and precordial/inferior lead extension. Twenty-five subjects (29%) had epsilon waves that were present in lead V3 and beyond in 9, and in the inferior leads in 7. Epsilon waves were associated with right ventricular outflow tract (RVOT) (P = 0.001) but not RV posterior wall (P = 0.21), RV apex (P = 0.30), or left ventricular (P = 0.94) wall motion abnormalities. Patients with epsilon waves had increased RVOT diameter (P < 0.0001). Extension of epsilon waves in lead V3 and beyond was associated with increased epsilon wave duration (P = 0.002) and RVOT diameter (P = 0.04). The duration of epsilon waves was positively correlated with RVOT diameter (r = 0.70, P = 0.0001). Epsilon waves were also associated with episodes of sustained ventricular tachycardia (P = 0.004) but not with heart failure (P = 0.41) or sudden cardiac death (P = 0.31).

Conclusion: Detection of epsilon waves on 12-lead ECG reflects significant RVOT involvement, which was associated with episodes of sustained ventricular tachycardia but not sudden cardiac death.
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http://dx.doi.org/10.1111/jce.12755DOI Listing
November 2015

Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy.

Europace 2016 Apr 29;18(4):610-6. Epub 2015 Mar 29.

Yannis Protonotarios Medical Centre, Naxos, Greece.

Aims: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a genetically determined disorder, mostly caused by mutations in genes encoding desmosomal proteins. We evaluated phenotype/genotype characteristics to predict the risk for the first major arrhythmic event in desmosomal-mutation-associated ARVC families.

Methods And Results: A cohort of 105 desmosomal-mutation carriers belonging to 39 consecutive ARVC families was evaluated. Serial clinical work-up consisting of history, physical examination, 12-lead/signal-averaged/24 h ambulatory ECG, and two-dimensional echocardiography was performed every 6-12 months. The predictive value of gender and genotype for the first major arrhythmic event was investigated within the cohort using time-to-event analysis. ECG/echocardiographic features were evaluated at the time of event and associated with the outcome using an age-matched nested case-control study within the cohort. Forty-three (41%) participants experienced the primary arrhythmic outcome at median age of 29 (21-46) years. The first event was sustained ventricular tachycardia in 31 and sudden cardiac death in 12. Definite diagnosis according to the 2010 Task Force criteria, showed 57% positive and 100% negative predictive value for the occurrence of arrhythmic outcome. Male gender (hazard ratio = 3.26, 95%CI, 1.63-6.51), predicted the first major arrhythmic event, independently of genotype, on multivariable analysis. Repolarization abnormalities and left-ventricular dysfunction independently associated with clinical disease profile at the time of event.

Conclusion: Male gender, independently of genotype is an arrhythmic risk predictor in ARVC-associated desmosomal-mutation carriers. Repolarization abnormalities and left-ventricular dysfunction are important components of the first event-associated clinical disease profile.
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http://dx.doi.org/10.1093/europace/euv061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841562PMC
April 2016

Left dominant arrhythmogenic cardiomyopathy: a morbid association of ventricular arrhythmias and unexplained infero-lateral T-wave inversion.

J Electrocardiol 2013 Jul-Aug;46(4):352-5. Epub 2013 Apr 18.

Department of Cardiology, University Hospital of Heraklion, Heraklion, Greece.

Left-dominant arrhythmogenic cardiomyopathy is a subtype of arrhythmogenic right ventricular cardiomyopathy characterized by early predominant left ventricular involvement. Α 34-year-old man presented with palpitations and a history of frequent ventricular extrasystoles of both LBBB and RBBB configuration. Cardiac workup revealed repolarization abnormalities at infero-lateral leads in the absence of diagnostic structural/functional alterations or obstructive coronary artery disease. Six months later he died suddenly. Histopathology was diagnostic for arrhythmogenic right ventricular cardiomyopathy affecting predominantly the left ventricle at subepicardial/midwall myocardial layers. Thus, ventricular arrhythmias accompanied by unexplained infero-lateral T-wave inversion should warn of a possible morbid association underlying left-dominant arrhythmogenic cardiomyopathy.
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http://dx.doi.org/10.1016/j.jelectrocard.2013.03.011DOI Listing
January 2014

Clear cell sarcoma of the jejunum: a case report.

World J Surg Oncol 2013 Jan 25;11:17. Epub 2013 Jan 25.

Department of General Surgery, University Hospital of Heraklion, Medical School of Heraklion, University of Crete, Heraklion, Greece.

Background: Clear cell sarcoma (CCS), also known as malignant melanoma of soft parts, is a rare type of soft tissue sarcoma which exhibits morphological, immunohistochemical and ultrastructural similarity with malignant melanoma. It is rarely localized in the intestine and the natural history of this tumor is not yet clear.

Case Report: A 49-year-old woman presented with diffuse abdominal colicky pain and vomitus over the previous seven days. An X-ray of the abdomen revealed obstruction of the small intestine. The patient underwent contrast enhanced abdominal computerized tomography (CT), which confirmed the obstruction at the jejunum and an associated circumferential wall thickening extending about 3 cm in length, causing concentric narrowing of the lumen. At laparotomy, a mass was recognized at the level of the jejunum in the small intestine, which caused almost complete obstruction of the lumen. At the point of obstruction, adhered loops of small intestine were found. A segmental small bowel resection was performed with 5 cm clear margins and its respective mesenteric lymph nodes.

Results: Histological examination of the specimen revealed a tumor (3×3×2 cm) with epithelioid cell characteristics and eosinophilic or clear cytoplasm and focal translucent nuclei. Immunohistochemistry was positive for S100, epithelial membrane antigen (EMA) and synaptophysin. The tumor was pankeratin AE1/AE2, GFAP, HMB45 and MART-1/Melan-A negative. Twelve lymph nodes were retrieved and were free of neoplastic infiltration. Cytogenetic examination revealed translocation of the EWSR1 gene. The patient had an uncomplicated postoperative course and left the hospital seven days after her admission in good general condition. After 20 months of follow-up the patient remains asymptomatic without any clinical or radiological evidence of recurrence.

Conclusion: CCS sarcoma can be rarely localized in the jejunum. Due to its morphological similarity to malignant melanoma, cytogenetic examination is necessary for its diagnosis. Wide resection of the tumor and its respective lymph nodes was associated with a 20-month disease free survival in this patient.
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http://dx.doi.org/10.1186/1477-7819-11-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598680PMC
January 2013
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