Prospects for histomorphological and genetic diagnosis of autopsy-negative sudden cardiac death
- Authors: Kulbitskiy B.N.1, Vladykina O.A.2, Bogomolov D.V.1, Kadykova A.I.3, Deev R.V.1,3
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Affiliations:
- Petrovsky National Research Centre of Surgery
- North-Western State Medical University named after I.I. Mechnikov
- Federal Research and Clinical Center of Sports Medicine and Rehabilitation
- Issue: Vol 10, No 4 (2024)
- Pages: 589-601
- Section: Reviews
- Submitted: 23.10.2024
- Accepted: 11.12.2024
- Published: 05.12.2024
- URL: https://for-medex.ru/jour/article/view/16192
- DOI: https://doi.org/10.17816/fm16192
- ID: 16192
Cite item
Abstract
This article presents the prospects of histological and genetic diagnosis in cases of sudden cardiac death where primary autopsy findings do not reveal obvious pathological changes.
In recent years, the number of autopsy-negative sudden cardiac deaths has increased, creating a need for more precise diagnostic methods to determine the cause of death and potentially prevent such cases in the future. The article examines modern histological examination techniques for cardiac tissues, as well as molecular genetic testing approaches that may be useful in identifying subclinical conditions leading to sudden cardiac death.
Molecular genetic methods for investigating sudden cardiac death remain underexplored. To date, large-scale studies on the molecular genetic causes of such fatalities are lacking in Russia, highlighting the need for further research at the intersection of medical genetics, pathological anatomy, and forensic medicine.
This article provides a brief review of histological and genetic diagnosis of sudden cardiac death, where the authors propose integrating these methods into the diagnostic process to enhance their effectiveness in pathological and forensic medical practice. The authors emphasize the necessity of further research, including the application of advanced technologies in histological and genetic analysis, as well as big data analytics to identify new pathological mechanisms of sudden cardiac death.
Medical genetic counseling on predisposition to sudden cardiac death can help identify at-risk individuals and reduce mortality. In the future, it may become possible to establish links between genetic predictors of sudden cardiac death and defects in myocardial contractile protein expression, with subsequent confirmation using immunohistochemical analysis.
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About the authors
Boris N. Kulbitskiy
Petrovsky National Research Centre of Surgery
Email: kulbitskiybn@rambler.ru
ORCID iD: 0000-0001-7791-3041
SPIN-code: 7785-0838
MD, Cand. Sci. (Medicine)
Россия, MoscowOlga A. Vladykina
North-Western State Medical University named after I.I. Mechnikov
Email: olavtryggvason@yandex.ru
ORCID iD: 0009-0001-4136-8691
Россия, Saint Petersburg
Dmitry V. Bogomolov
Petrovsky National Research Centre of Surgery
Email: usicc@yandex.ru
ORCID iD: 0000-0002-9111-8623
SPIN-code: 2777-2674
MD, Dr. Sci. (Medicine)
Россия, MoscowAnastasya I. Kadykova
Federal Research and Clinical Center of Sports Medicine and Rehabilitation
Email: KadykovaAI@sportfmba.ru
ORCID iD: 0000-0003-2996-6194
SPIN-code: 8764-6577
Россия, Moscow
Roman V. Deev
Petrovsky National Research Centre of Surgery; Federal Research and Clinical Center of Sports Medicine and Rehabilitation
Author for correspondence.
Email: romdey@gmail.com
ORCID iD: 0000-0001-8389-3841
SPIN-code: 2957-1687
MD, Cand. Sci. (Medicine), Assistant Professor
Россия, Moscow; MoscowReferences
- Shlyakhto EV, Arutyunov GP, Belenkov YN, et al. National recommendations on the determination of risk and prevention of sudden cardiac death. 2nd ed. Moscow: Medpraktika-M; 2018. 247 р. (In Russ.) EDN: OGIVYR
- Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death ― executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J. 2006;27(17):2099–2140. doi: 10.1093/eurheartj/ehl199
- Priori SG, Blomstrom-Lundqvist C. 2015 European Society of Cardiology Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs. Eur Heart J. 2015;36(41):2757–2759. doi: 10.1093/eurheartj/ehv445
- Bayes de Luna A, Elosua R. Sudden death (In English, Spanish). Rev Esp Cardiol (Engl Ed). 2012;65(11):1039–1052. doi: 10.1016/j.recesp.2012.03.032
- Zimmerman DS, Tan HL. Epidemiology and risk factors of sudden cardiac arrest. Curr Opin Crit Care. 2021;27(6):613–616. doi: 10.1097/MCC.0000000000000896
- Stiles MK, Wilde AA, Abrams DJ, et al. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. Heart Rhythm. 2021;18(1):e1–e50. doi: 10.1016/j.hrthm.2020.10.010
- Lou J, Chen H, Huang S, et al. Update on risk factors and biomarkers of sudden unexplained cardiac death. J Forensic Leg Med. 2022;87:102332. doi: 10.1016/j.jflm.2022.102332
- Fitzgerald DA, Jeffery H, Arbuckle S, et al. Sudden Unexpected Death in Infancy [SUDI]: What the clinician, pathologist, coroner and researchers want to know. Paediatr Respir Rev. 2022;41:14–20. doi: 10.1016/j.prrv.2021.08.002
- Grassi S, Vidal MC, Campuzano O, et al. Sudden death without a clear cause after comprehensive investigation: An example of forensic approach to atypical/uncertain findings. Diagnostics (Basel). 2021;11(5):886. doi: 10.3390/diagnostics11050886
- Revishvili ASh, Neminushchiy NM, Batalov RE, et al. All-Russian clinical recommendations on the control of the risk of sudden cardiac arrest and sudden cardiac death, prevention and first aid. J Arrhythmology. 2017;(89):2–104. (In Russ.) EDN: YPIPVV
- Shankar R, Donner EJ, McLean B, et al. Sudden unexpected death in epilepsy (SUDEP): What every neurologist should know. Epileptic Disord. 2017;19(1):1–9. doi: 10.1684/epd.2017.0891
- Sahly AN, Shevell M, Sadleir LG, Myers KA. SUDEP risk and autonomic dysfunction in genetic epilepsies. Auton Neurosci. 2022;237:102907. doi: 10.1016/j.autneu.2021.102907
- Van der Werf C, Hendrix A, Birnie E, et al. Improving usual care after sudden death in the young with focus on inherited cardiac diseases (the CAREFUL study): A community-based intervention study. Europace. 2016;18(4):592–601. doi: 10.1093/europace/euv059
- Gavrilova EA, Churganov OA, Belodedova MD. Autopsy-negative cardiac death in sports and its causes. Human Physiology. 2021;47(2):232–236. EDN: HMHOCI doi: 10.31857/S0131164621010045
- Sheppard MN. Aetiology of sudden cardiac death in sport: A histopathologist's perspective. Br J Sports Med. 2012;46(Suppl 1):i15–i21. doi: 10.1136/bjsports-2012-091415
- Marijon E, Uy-Evanado A, Reinier K, et al. Sudden cardiac arrest during sports activity in middle age. Circulation. 2015;131(16):1384–1391. doi: 10.1161/CIRCULATIONAHA.114.011988
- Harmon KG, Asif IM, Maleszewski JJ, et al. Incidence, cause, and comparative frequency of sudden cardiac death in national collegiate athletic association athletes: A decade in review. Circulation. 2015;132(1):10–19. doi: 10.1161/CIRCULATIONAHA.115.015431
- Finocchiaro G, Papadakis M, Robertus JL, et al. Etiology of sudden death in sports: Insights from a United Kingdom regional registry. J Am Coll Cardiol. 2016;67(18):2108–2115. doi: 10.1016/j.jacc.2016.02.062
- Emery MS, Kovacs RJ. Sudden cardiac death in athletes. JACC Heart Fail. 2018;6(1):30–40. doi: 10.1016/j.jchf.2017.07.014
- Pigolkin YuI, Shilova MA, Berezovsky DP, et al. Molecular and genetic basis of sudden cardiac death of young-aged individuals with cardiomyopathy of different genesis. Forensic Medical Examination. 2019;62(3):48–53. EDN: HSDZOZ doi: 10.17116/sudmed20196203148
- Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326(4):242–250. doi: 10.1056/NEJM199201233260406
- Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Circulation. 2018;138(20):e618–e651. doi: 10.1161/CIR.0000000000000617
- Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease [June 2, 2014]. 9th ed. Elsevier Health Sciences; 2014. 1472 р.
- Braunwald E. Cardiomyopathies: An overview. Circ Res. 2017;121(7):711–721. doi: 10.1161/CIRCRESAHA.117.311812
- Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. N Engl J Med. 1994;331(23):1564–1575. doi: 10.1056/NEJM199412083312307
- Bozkurt B, Colvin M, Cook J, et al. Current diagnostic and treatment strategies for specific dilated cardiomyopathies: A scientific statement from the American heart association. Circulation. 2016;134(23):e579–e646. doi: 10.1161/CIR.0000000000000455
- Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381(9862):242–255. doi: 10.1016/S0140-6736(12)60397-3
- Seidman JG, Seidman C. The genetic basis for cardiomyopathy: From mutation identification to mechanistic paradigms. Cell. 2001;104(4):557–567. doi: 10.1016/s0092-8674(01)00242-2
- Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2008;83(6):630–638. doi: 10.4065/83.6.630
- Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: A position statement from the European society of cardiology working group on myocardial and pericardial diseases. Eur Heart J. 2008;29(2):270–276. doi: 10.1093/eurheartj/ehm342
- Maron BJ, Ommen SR, Semsarian C, et al. Hypertrophic cardiomyopathy: Present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014;64(1):83–99. doi: 10.1016/j.jacc.2014.05.003
- Chandra A, Skali H, Claggett B, et al. Race- and gender-based differences in cardiac structure and function and risk of heart failure. J Am Coll Cardiol. 2022;79(4):355–368. doi: 10.1016/j.jacc.2021.11.024
- Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58(25):2703–2738. doi: 10.1016/j.jacc.2011.10.825
- Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009;10(8):iii23–33. doi: 10.1093/ejechocard/jep156
- Domínguez F, Adler E, García-Pavía P. Alcoholic cardiomyopathy: An updat. Eur Heart J. 2024;45(26):2294–2305. doi: 10.1093/eurheartj/ehae362
- Fernández-Solà J. The effects of ethanol on the heart: Alcoholic cardiomyopathy. Nutrients. 2020;12(2):572. doi: 10.3390/nu12020572
- Urbano-Marquez A, Estruch R, Navarro-Lopez F, et al. The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med. 1989;320(7):409–415. doi: 10.1056/NEJM198902163200701
- Corrado D, Link MS, Calkins H. Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med. 2017;376(1):61–72. doi: 10.1056/NEJMra1509267
- Fairweather D, Rose NR. Inflammatory heart disease: A role for cytokines. Lupus. 2005;14(9):646–651. doi: 10.1191/0961203305lu2192oa
- Duraes AR, de Souza Lima Bitar Y, Roever L, Neto MG. Endomyocardial fibrosis: Past, present, and future. Heart Fail Rev. 2020;25(5):725–730. doi: 10.1007/s10741-019-09848-4
- Sun R, Liu M, Lu L, et al. Congenital heart disease: Causes, diagnosis, symptoms, and treatments. Cell Biochem Biophys. 2015;72(3):857–860. doi: 10.1007/s12013-015-0551-6
- Campuzano O, Sarquella-Brugada G, Fernandez-Falgueras A, et al. Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes. EBioMedicine. 2020;54:102732. doi: 10.1016/j.ebiom.2020.102732
- Mitchell RN, Ashar FN, Jarvelin MR, et al. Effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death. J Am Heart Assoc. 2019;8(23):e013751. doi: 10.1161/JAHA.119.013751
- Huang J, Wang X, Hao B, et al. Genetic variants in KCNE1, KCNQ1, and NOS1AP in sudden unexplained death during daily activities in Chinese Han population. J Forensic Sci. 2015;60(2):351–356 [published correction appears in J Forensic Sci. 2018 Jan;63(1):349. doi: 10.1111/1556-4029.13725]. doi: 10.1111/1556-4029.12687
- Liu Z, Liu X, Yu H, et al. Common variants in TRDN and CALM1 are associated with risk of sudden cardiac death in chronic heart failure patients in Chinese Han population. PLoS One. 2015;10(7):e0132459. doi: 10.1371/journal.pone.0132459
- Wang S, Zhang Z, Yang Y, et al. An insertion/deletion polymorphism within 3'UTR of RYR2 modulates sudden unexplained death risk in Chinese populations. Forensic Sci Int. 2017;270:165–172. doi: 10.1016/j.forsciint.2016.12.005
- Albert CM, MacRae CA, Chasman DI, et al. Common variants in cardiac Ion channel genes are associated with sudden cardiac death. Circ Arrhythm Electrophysiol. 2010;3(3):222–229. doi: 10.1161/CIRCEP.110.944934
- Son MK, Ki CS, Park SJ, et al. Genetic mutation in Korean patients of sudden cardiac arrest as a surrogating marker of idiopathic ventricular arrhythmia. J Korean Med Sci. 2013;28(7):1021–1026. doi: 10.3346/jkms.2013.28.7.1021
- Wieneke H, Svendsen JH, Lande J, et al. Polymorphisms in the GNAS gene as predictors of ventricular tachyarrhythmias and sudden cardiac death: Results from the DISCOVERY trial and oregon sudden unexpected death study. J Am Heart Assoc. 2016;5(12):e003905. doi: 10.1161/JAHA.116.003905
- Reinier K, Stecker EC, Uy-Evanado A, et al. Sudden cardiac death as first manifestation of heart disease in women: The oregon sudden unexpected death study, 2004–2016. Circulation. 2020;141(7):606–608. doi: 10.1161/CIRCULATIONAHA.119.044169
- Adler A, Novelli V, Amin AS, et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation. 2020;141(6):418–428. doi: 10.1161/CIRCULATIONAHA.119.043132
- Ivanova AA, Maksimov VN. Molecular genetic aspects of sudden cardiac death: A review of the literature. Bulletin of Siberian Medicine. 2018;17(4):209–220. EDN: VQWTRY doi: 10.20538/1682-0363-2018-4-209-220
- Narula N, Tester DJ, Paulmichl A, et al. Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: A case series. Pediatr Cardiol. 2015;36(4):768–778. doi: 10.1007/s00246-014-1082-4
- Maksimov VN, Ivanova AA, Orlov PS, et al. Association study of new polymorphisms with sudden cardiac death in men. Russian Journal of Cardiology. 2018;23(10):70–75. EDN: VPZPCI doi: 10.15829/1560-4071-2018-10-70-75
- Ivanova AA, Maksimov VN, Moiseeva DI, et al. Single nucleotide variants RS6582147, RS10010305, RS2136810, RS17797829 as new molecular genetic markers of sudden cardiac death. Russian Journal of Cardiology. 2018;23(10):64–69. EDN: VPZPCB doi: 10.15829/1560-4071-2018-10-64-69
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