{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T15:26:40Z","timestamp":1789572400350,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>A retrospective study was conducted on pathologically diagnosed arrhythmogenic cardiomyopathy (ACM) from consecutive cases over the past 34 years (n = 1109). The anatomo-pathological analyses were performed on 23 hearts diagnosed as ACM (2.07%) from a series of 1109 suspected cases, while histopathological data of cardiac conduction system (CCS) were available for 15 out of 23 cases. The CCS was removed in two blocks, containing the following structures: Sino-atrial node (SAN), atrio-ventricular junction (AVJ) including the atrio-ventricular node (AVN), the His bundle (HB), the bifurcation (BIF), the left bundle branch (LBB) and the right bundle branch (RBB). The ACM cases consisted of 20 (86.96%) sudden unexpected cardiac death (SUCD) and 3 (13.04%) native explanted hearts; 16 (69.56%) were males and 7 (30.44%) were females, ranging in age from 5 to 65 (mean age \u00b1 SD, 36.13 \u00b1 16.06) years. The following anomalies of the CCS, displayed as percentages of the 15 ACM SUCD cases in which the CCS has been fully analyzed, have been detected: Hypoplasia of SAN (80%) and\/or AVJ (86.67%) due to fatty-fibrous involvement, AVJ dispersion and\/or septation (46.67%), central fibrous body (CFB) hypoplasia (33.33%), fibromuscular dysplasia of SAN (20%) and\/or AVN (26.67%) arteries, hemorrhage and infarct-like lesions of CCS (13.33%), islands of conduction tissue in CFB (13.33%), Mahaim fibers (13.33%), LBB block by fibrosis (13.33%), AVN tongue (13.33%), HB duplicity (6.67%%), CFB cartilaginous meta-hyperplasia (6.67%), and right sided HB (6.67%). Arrhythmias are the hallmark of ACM, not only from the fatty-fibrous disruption of the ventricular myocardium that accounts for reentrant ventricular tachycardia, but also from the fatty-fibrous involvement of CCS itself. Future research should focus on application of these knowledge on CCS anomalies to be added to diagnostic criteria or at least to be useful to detect the patients with higher sudden death risks.<\/jats:p>","DOI":"10.3390\/diagnostics11081323","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T10:31:44Z","timestamp":1627036304000},"page":"1323","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Sudden Unexpected Death Associated with Arrhythmogenic Cardiomyopathy: Study of the Cardiac Conduction System"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6982-170X","authenticated-orcid":false,"given":"Giulia","family":"Ottaviani","sequence":"first","affiliation":[{"name":"Lino Rossi Research Center, Anatomic Pathology, Department of Biomedical, Surgical and Dental Sciences, Universit\u00e0 Degli Studi di Milano, 20122 Milan, Italy"},{"name":"Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"Alfonsi","sequence":"additional","affiliation":[{"name":"Lino Rossi Research Center, Anatomic Pathology, Department of Biomedical, Surgical and Dental Sciences, Universit\u00e0 Degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone G.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Pathology and Forensic Medicine, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Maximilian","family":"Buja","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1161\/CIRCRESAHA.117.309345","article-title":"Arrhythmogenic cardiomyopathy","volume":"121","author":"Corrado","year":"2017","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ijcard.2020.06.005","article-title":"Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria","volume":"319","author":"Corrado","year":"2020","journal-title":"Int. J. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e373","DOI":"10.1016\/j.hrthm.2019.09.019","article-title":"2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: Executive summary","volume":"16","author":"Towbin","year":"2019","journal-title":"Hear. Rhythm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.carpath.2016.08.005","article-title":"Anatomopathological changes of the cardiac conduction system in sudden cardiac death, particularly in infants: Advances over the last 25 years","volume":"25","author":"Ottaviani","year":"2016","journal-title":"Cardiovasc. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.carpath.2019.06.002","article-title":"Pathobiology of cardiovascular diseases: An update","volume":"42","author":"Buja","year":"2019","journal-title":"Cardiovasc. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Thiene, G., Corrado, M., and Basso, C. (2016). Sudden Cardiac Death in the Young and Athletes, Springer Science and Business Media LLC.","DOI":"10.1007\/978-88-470-5776-0"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra1509267","article-title":"Arrhythmogenic right ventricular cardiomyopathy","volume":"376","author":"Corrado","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart disease and stroke statistics\u20142021 update: A report from the American Heart Association","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e002123","DOI":"10.1161\/CIRCGEN.118.002123","article-title":"Whole-exome sequencing identifies pathogenic variants in TJP1 gene associated with arrhythmogenic cardiomyopathy","volume":"11","author":"Postma","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e003273","DOI":"10.1161\/CIRCGEN.120.003273","article-title":"International evidence based reappraisal of genes associated with arrhythmogenic right ventricular cardiomyopathy using the clinical genome resource framework","volume":"14","author":"James","year":"2021","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1161\/01.CIR.65.2.384","article-title":"Right ventricular dysplasia: A report of 24 adult cases","volume":"65","author":"Marcus","year":"1982","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1161\/01.CIR.93.5.841","article-title":"Report of the 1995 World Health Organization\/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies","volume":"93","author":"Richardson","year":"1996","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1161\/CIRCULATIONAHA.106.174287","article-title":"Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention","volume":"113","author":"Maron","year":"2006","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/eurheartj\/ehm342","article-title":"Classification of the cardiomyopathies: A position statement from the European society of cardiology working group on myocardial and pericardial diseases","volume":"29","author":"Elliott","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1161\/CIRCULATIONAHA.108.840827","article-title":"Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy\/Dysplasia: Proposed modification of the task force criteria","volume":"121","author":"Marcus","year":"2010","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1093\/eurheartj\/ehz669","article-title":"Arrhythmogenic right ventricular cardiomyopathy: Evaluation of the current diagnostic criteria and differential diagnosis","volume":"41","author":"Corrado","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e014628","DOI":"10.1161\/JAHA.119.014628","article-title":"Arrhythmogenic right ventricular cardiomyopathy: Characterization of left ventricular phenotype and differential diagnosis with dilated cardiomyopathy","volume":"9","author":"Cipriani","year":"2020","journal-title":"J. Am. Hear. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1309\/J6AREY41HKBEYVHX","article-title":"Techniques and criteria in pathologic and forensic-medical diagnostics in sudden unexpected infant and perinatal death","volume":"124","author":"Matturri","year":"2005","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00428-007-0527-z","article-title":"Guidelines for neuropathologic diagnostics of perinatal unexpected loss and sudden infant death syndrome (SIDS)\u2014A technical protocol","volume":"452","author":"Matturri","year":"2007","journal-title":"Virchows Arch."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ottaviani, G. (2014). Crib Death\u2014Sudden Infant Death Syndrome (SIDS): Sudden Infant and Perinatal Unexplained Death: The Pathologist\u2019s Viewpoint, Springer International Publishing. [2nd ed.].","DOI":"10.1007\/978-3-319-08347-6"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.carpath.2007.07.009","article-title":"Histopathology of the cardiac conduction system in sudden intrauterine unexplained death","volume":"17","author":"Ottaviani","year":"2008","journal-title":"Cardiovasc. Pathol."},{"key":"ref_22","unstructured":"Centro Scientifico Editore (1990). Clinicopathological Approach to Cardiac Arrhythmias. A Color Atlas, Futura Publishing Company."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S1054-8807(00)00035-1","article-title":"Sudden Infant Death Syndrome (SIDS): A study of cardiac conduction system","volume":"9","author":"Matturri","year":"2000","journal-title":"Cardiovasc. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0167-5273(03)00043-3","article-title":"Crib death: Further support for the concept of fatal cardiac electrical instability as the final common pathway","volume":"92","author":"Ottaviani","year":"2003","journal-title":"Int. J. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.carpath.2004.05.003","article-title":"Early atherosclerotic lesions of the cardiac conduction system arteries in infants","volume":"13","author":"Matturri","year":"2004","journal-title":"Cardiovasc. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1007\/s00134-003-1772-5","article-title":"Cardiac massage in infants","volume":"29","author":"Matturri","year":"2003","journal-title":"Intensive Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1056\/NEJM198801213180301","article-title":"Right ventricular cardiomyopathy and sudden death in young people","volume":"318","author":"Thiene","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_28","unstructured":"Nava, A., Rossi, L., and Thiene, G. (1997). Arrhythmogenic Right Ventricular Cardiomyopathy\/Dysplasia, Elsevier."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.hfc.2018.01.002","article-title":"Diagnostic criteria, genetics, and molecular basis of arrhythmogenic cardiomyopathy","volume":"14","author":"Basso","year":"2018","journal-title":"Heart Fail. Clin."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1161\/01.CIR.0000108396.65446.21","article-title":"Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and\/or dysplasia","volume":"108","author":"Tabib","year":"2003","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.carpath.2015.06.002","article-title":"Pathological assessment of end-stage heart failure in explanted hearts in correlation with hemodynamics in patients undergoing orthotopic heart transplantation","volume":"24","author":"Ottaviani","year":"2015","journal-title":"Cardiovasc. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1097\/MD.0000000000000038","article-title":"Morphologic features of the recipient heart in patients having cardiac transplantation and analysis of the congruence or incongruence between the clinical and morphologic diagnoses","volume":"93","author":"Roberts","year":"2014","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/0002-9149(86)90089-5","article-title":"Familial arrhythmogenic right ventricular disease","volume":"58","author":"Rakovec","year":"1986","journal-title":"Am. J. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1016\/S0735-1097(97)00332-X","article-title":"Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy\/dysplasia: A multicenter study","volume":"30","author":"Corrado","year":"1997","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e319","DOI":"10.1002\/ctm2.319","article-title":"Deciphering DSC2 arrhythmogenic cardiomyopathy electrical instability: From ion channels to ECG and tailored drug therapy","volume":"11","author":"Moreau","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1093\/cvr\/cvaa010","article-title":"Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases","volume":"116","author":"Hayashi","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mattesi, G., Zorzi, A., Corrado, D., and Cipriani, A. (2020). Natural history of arrhythmogenic cardiomyopathy. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030878"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1161\/01.CIR.94.5.983","article-title":"Arrhythmogenic right ventricular cardiomyopathy: Dysplasia, dystrophy, or myocarditis?","volume":"94","author":"Basso","year":"1996","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.carpath.2017.11.001","article-title":"Cardiac sarcoidosis presenting as arrhythmogenic right ventricular cardiomyopathy\/dysplasia with ventricular aneurysms: A case report","volume":"33","author":"Petrovic","year":"2018","journal-title":"Cardiovasc. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107190","DOI":"10.1016\/j.carpath.2019.107190","article-title":"Clinicopathological manifestations of myocarditis in a heart failure population","volume":"45","author":"Buja","year":"2020","journal-title":"Cardiovasc. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1161\/CIRCRESAHA.115.308136","article-title":"Cardiac fibro-adipocyte progenitors express Desmosome proteins and preferentially differentiate to adipocytes upon deletion of the Desmoplakin Gene","volume":"119","author":"Lombardi","year":"2016","journal-title":"Circ. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1093\/eurheartj\/ehv579","article-title":"Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy","volume":"37","author":"Sommariva","year":"2016","journal-title":"Eur. Hear. J."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Maione, A., Stadiotti, I., Pilato, C., Perrucci, G., Saverio, V., Catto, V., Vettor, G., Casella, M., Guarino, A., and Polvani, G. (2021). Excess TGF-\u03b21 drives cardiac mesenchymal stromal cells to a pro-fibrotic commitment in arrhythmogenic cardiomyopathy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052673"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4920","DOI":"10.1016\/j.ijcard.2013.07.093","article-title":"Conduction abnormalities in arrhythmogenic right ventricular cardiomyopathy","volume":"168","author":"Peters","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/1054-8807(94)90042-6","article-title":"Sudden death in athletes\u2014Conduction system: Practical approach to dissection and pertinent pathology","volume":"3","author":"Bharati","year":"1994","journal-title":"Cardiovasc. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/1054-8807(94)90040-X","article-title":"Exercise as a factor in sudden cardiac death","volume":"3","author":"Burke","year":"1994","journal-title":"Cardiovasc. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3109\/15419061.2014.905928","article-title":"Cell junctions in the specialized conduction system of the heart","volume":"21","author":"Mezzano","year":"2014","journal-title":"Cell Commun. Adhes."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1161\/01.CIR.103.5.710","article-title":"Right bundle branch block, right precordial st-segment elevation, and sudden death in young people","volume":"103","author":"Corrado","year":"2001","journal-title":"Circulation"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Grassi, S., Vidal, M., Campuzano, O., Arena, V., Alfonsetti, A., Rossi, S., Scarnicci, F., Iglesias, A., Brugada, R., and Oliva, A. (2021). Sudden Death without a clear cause after comprehensive investigation: An example of forensic approach to atypical\/uncertain findings. Diagnostics, 11.","DOI":"10.3390\/diagnostics11050886"},{"key":"ref_50","first-page":"79","article-title":"Expression of apoptosis and proliferating cell nuclear antigen (PCNA) in the cardiac conduction system of crib death (SIDS)","volume":"5","author":"Matturri","year":"2001","journal-title":"Adv. Clin. Path."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1146\/annurev.physiol.60.1.309","article-title":"Normal and abnormal consequences of apoptosis in the human heart","volume":"60","author":"James","year":"1998","journal-title":"Annu. Rev. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-88109-7","article-title":"First in situ 3D visualization of the human cardiac conduction system and its transformation associated with heart contour and inclination","volume":"11","author":"Kawashima","year":"2021","journal-title":"Sci. Rep."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/8\/1323\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:33:47Z","timestamp":1760164427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/8\/1323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,23]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["diagnostics11081323"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics11081323","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202106.0246.v1","asserted-by":"object"}]},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,23]]}}}