Aşkın ŞEN, Celal AKDENİZ, Volkan TUZCU, Ertuğrul KÖK, Yavuz ŞAHİN, Kadir DEMİRCAN, Recep FEDAKAR

Ani Kardiyak Ölümlerde Moleküler Otopsinin Önemi

Ani kardiyak ölümler, sağlıklı genç yaştaki kişilerdeki ölümlerin önemli bir nedenidir. Adli otopsi uygulamaları ile ani kardiyak ölümün nedeni sıklıkla saptanamamaktadır. Ölüm sonrası [post mortem] yapılan genetik testler moleküler otopsi olarak adlandırılmaktadır ve moleküler otopsi ani kardiyak ölüme neden olan genetik geçişli hastalıkların önemini göstermistir. Ani kardiyak ölümlere neden olan genetik hastalıklara hipertrofik kardiyomiyopati gibi miyokardiyal hastalıklar ve uzun QT sendromu gibi kanalopatiler örnek verilebilir. Bu tür genetik geçişli hastalıklar kalıtım özellikleri nedenleriyle risk altındaki akrabaları için dikkate alınmalıdır. Ani kardiyak ölümlerde, postmortem rutin toksikolojik ve patolojik inceleme ile herhangi bir ölüm nedeni saptanamadı- ğında, postmortem kandan genetik testler ile birlikte özel multidisipliner yaklaşım tanı için kritiktir. Kesin tanı konulduktan sonra vakanın yaşayan akrabalarını genetik kökenli ani kardiyak ölüm olaylarına karşı korumak gereklidir. Görüntüleme teknolojisindeki ve genetik dünyasındaki gelişmeler ani kardiyak ölümlerin tanısal sürecini kolaylaştıracaktır.

The Importance of Molecular Autopsy at Sudden Cardiac Deaths

Sudden cardiac deaths are an important cause of deaths in healthy adults. In generally, the cause of sudden cardiac death cannot be determined with forensic medicine methods. Post mortem genetic tests known as molecular autopsy showed the inherited genetic disorders causing sudden cardiac deaths significance. Myocardial disease as hypertrophic cardiomyopathy and channelopathies as long QT syndrome can be an example of the genetic disorders causing sudden cardiac deaths. Because of inheritance pattern of that genetic disorders must be taken into consideration for at risk family members. In sudden cardiac death cases where no cause of death is identified at postmortem rutin toxicological and pathological examination, coupled with genetic testing of postmortem blood in specialized multidisciplinary clinic setting, are critical for diagnosis. After establishing final diagnosis, preventing genetic sudden cardiac events in surviving relatives is necessary. Imaging technologies and advances in the world of genetics may refine diagnostic process for sudden cardiac deaths.

PDF

___

1.Knight B. The pathology of sudden death. In: Knight ed. Forensic Pathology 2nd Edition. New York: Oxford University Press, 1996:487—516.
2.Kolusay|n Ö, Koc S. Death. In: Soysal Z, Çakalır C, eds. Fo— rensic Autopsy Vol [in Turkish]. Istanbul: Istanbul University Press and Film Center, 1999: 93—151.
3.Yorulmaz AC. Natural Sudden Unexpected Deaths. In: Fo— rensic Medicine Textbook [in Turkish]. Istanbul: Istanbul Uni— versity Printing and Publishing Directorate, 2011: 129—43.
4. de Vreede—Swagemakers JJ, Gorgels AP, Dubois—Arbouw WI, van Ree JW, Daemen MJ,Houben LG, Wellens HJ. Out—of— hospitalcardiacarrest in the 1990's: population—basedstudy in the Maastricht area on incidence, characteristics and sur— vival. Am Coll Cardiol 1997;30[6]:1500—5.
5. Stecker EC, Reinier K, Marijon E, Narayanan K, Teodorescu C, Uy—Evanado A,Gunson K, Jui J, Chugh SS. Public health burden of sudden cardiac death in the United States. Circ Ar— rhythm Electrophysiol 2014;7[2]:212—7.
6. Hendrix A, Borleffs CJ, Vink A, Doevendans PA, Wilde AA, van Langen IM, van der Smagt JJ, Bots ML, Mosterd A. Car— diogeneticscreening of first—degree relatives after sudden cardiac death in theyoung: population—based approach. Eu— ropace 2011;13[5]:716—22.
7.Hofman N, Tan HL, Clur SA, Alders M, vanLangen IM, Wilde AA. Contribution of inherited heart disease to sudden cardiac death in childhood. Pediatrics 2007;120[4]:e967—73.
8.Campuzano O, Beltran—Alvarez P, Iglesias A, Scornik F, Pérez G, Brugada R. Genetics and cardiac channelopathies. Genet Med 2010;12[5]:260—7.
9.Hofer F, Fellmann F, Schlapfer J, Michaud K. Sudden car— diac death in the young [5—39 years] in the canton of Vaud, Switzerland. BMC Cardiovasc Disord 2014;14:140.
10. Risgaard B, Winkel BG, Jabbari R, Glinge C, Ingemann— Hansen 0, Thomsen JL, Ottesen GL, Haunso S, Holst AG, Tfelt—Hansen J. Sports—related sudden cardiac death in competitive and noncompetitive athlete population aged 12 to 49 years: Data from an unselected nationwide study in Den— mark. Heart Rhythm 2014;11[10]:1673—81.
11.Myerburg RJ, Castellanos A.Cardiac arrest and sudden cardiac death. Chapter 36. In: Libby P, Bonow RO, Mann DL, Zipes DP, Braunwald eds. Braunwald's Heart Disease: Textbook of Cardiovascular Medicine 8th Edition. Philadel— phia: Elsevier Saunders, 2008:933—74. Adli Tıp Dergisi Journal of Forensic Medicine, Cilt/Vol.:30, Sayı No:2
12.Eckart RE, Shry EA, Burke AP, McNear JA, Appel DA, Castillo—Rojas LM, Avedissian L, Pearse LA, Potter RN, Tre— maine L, Gentlesk PJ, Huffer L, Reich SS, Stevenson WG. Sudden death in young adults: an autopsy—based series of population under going active surveillance. Am Coll Cardiol 2011;58[12]:1254—61.
13.Takahashi M. Cardiacischemia in pediatricpatients. Pediatr Clin North Am 2010;57[6]:1261—80.
14.Kato H, Ichinose E, Kawasaki T. Myocardial infarction in Kawasaki disease: Clinical analyses in 195 cases. Pediatr 1986;108[6]:923—7.
15.Gogbashian A. Sudden death in young athletes. Engl Med 2003;349[25]:2464—5; authorreply —5.
16.Pilmer CM, Kirsh JA, Hildebrandt D, Krahn AD, Gow RM. Sudden cardiac death in children and adolescents between and 19 years of age. Heart Rhythm 2014;11[2]:239—45.
17. Margey R, Roy A, Tobin S, O'Keane CJ, McGorrian C, Mor— ris V, Jennings S, Galvin J. Sudden cardiac death in 14— to 35—year olds in Ireland from 2005 to 2007: retrospective reg— istry. Europace 2011;13[10]:1411—8.
18. Winkel BG, Holst AG, Theilade J, Kristensen IB, Thomsen JL, Ottesen GL, Bundgaard H, Svendsen JH, Haunso S, Tfelt— Hansen J. Nationwide study of sudden cardiac death in per— sons aged 1—35 years. Eur Heart 2011;32I8]:983—90.
19.Doolan A, Langlois N, Semsarian C. Causes of sudden car— diac death in young Australians. Med Aust 2004;180I3]:110—2.
20.McCrory PR, Berkovic SF, Cordner SM. Deaths due to brain injury among footballers in Victoria, 1968—1999. Med Aust 2000;172[5]:217—9.
21 .Fedakar R, Gök E, Çetin S, Baduroğlu E, Saka NE, Aslanhan N. Medicolegal aspect of the young sudden cardiac deaths: case report. Uludağ Medical Journal 2012;38[3]:201—5.
22.Link MS, Wang PJ, Pandian NG, Bharati S, Udelson JE, Lee MY, Vecchiotti MA, VanderBrink BA, Mirra G, Maron BJ, Estes NA 3rd. An experimental model of sudden death due to low— energy chest—wall impact [commotio cordis]. Engl Med 1998;338[25]:1805—11.
23.Fineschi V, Pomara C. Forensic Pathological Approach to Sudden Cardiac Death. In: Tsokos Ed. Forensic pathol— ogy reviews, Vol 1.Totowa, New Jersey: Humana Press Inc., 2004:139—68. 168 Şahin et al. The Importance of Molecular Autopsy at Sudden Cardiac Deaths
24.Madea B, Saukko P, Oliva A, Musshoff F. Molecular pa— thology in forensic medicine—Introduction. Forensic Sci Int 2010;203l1—3]:3—14.
25.Rodriguez—Calvo MS, Brion M, Allegue C, Concheiro L, Car— racedo A. Molecular genetics of sudden cardiac death. Foren— sic Sci Int 2008;182[1—3]:1—12.
26. Glinge C, Jabbari R, Risgaard B, Lynge TH, Engstrom T, Albert CM, Haunso S, Winkel BG, Tfelt—Hansen J. Symptoms Before Sudden Arrhythmic Death Syndrome: Nationwide Study Among the Young in Denmark. Cardiovasc Electro— physiol. 2015;26l7]:761—7.
27. Schwartz PJ, Stramba—Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Man— narino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long—QT syndrome. Circulation 2009;120[18]:1761—7.
28.Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long—QT syndrome: Clinical impact. Circulation 1999;99[4]:529—33.
29. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long—QT syndrome. NEngl Med 2003;348[19]:1866—74.
30. Goldenberg |, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Pla— tonov PJ, Priori SG, Qi M, Schwartz PJ, Shimizu W, Towbin JA, Vincent GM, Wilde AAM, Zhang L. Risk for life—threatening cardiac events in patients with genotype—confirmed long—OT syndrome and normal—range corrected QT intervals. Am Coll Cardiol 2011;57[1]:51—9.
31.Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Acker— man MJ. Targeted mutational analysis of the RyR2—encoded cardiac ryanodine receptor in sudden unexplained death: molecular autopsy of 49 medical examiner/coroner’s cases. Mayo Clin Proc 2004;79[11]:1380—4.
32.Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. Am Coll Cardiol 2007;49[2]:240—6.
33.Skinner JR, Crawford J, Smith W, Aitken A, Heaven D, Ev— ans CA, Hayes |, Neas KR, Stables S, Koelmeyer T, Denmark L, Vuletic J, Maxwell F, White K, Yang T, Roden DM, Leren TP, Shelling A, Love DR. Prospective, population—based long QT molecular autopsy study of postmortem negative sudden death in to 40 year olds.Heart Rhythm 2011;8[3]:412—9.
34.Tester DJ, Medeiros—Domingo A, Will ML, Haglund CM, Ackerman MJ. Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy—negative sudden unex— 169 plained death referred for postmortem genetic testing. Mayo Clin Proc 2012;87l6]:524—39.
35.Doolan A, Langlois N, Chiu C, Ingles J, Lind JM, Semsar— ian C. Postmortem molecular analysis of KCNQ1 and SCN5A genes in sudden unexplained death in young Australians. Int Cardiol 2008;127[1]:138—41.
36. Winkel BG, Larsen MK, Berge KE, Leren TP, Nissen PH, Olesen MS, Hollegaard MV, Jespersen T, Yuan L, Nielsen N, Haunso S, Svendsen JH, Wang Y, Kristensen |B, Jensen HK, Tfelt—Hansen J, Banner J. The prevalence of mutations in KCNO1, KCNHZ, and SCN5A in an unselected national cohort of young sudden unexplained death cases. Cardiovasc Elec— trophysiol 2012;23[10]:1092—8.
37.Bagnall RD, Molloy LK, Kalman JM, Semsarian C. Exome sequencingidentifies mutation in the ACTNZ gene in fam— ily with idiopathic ventricular fibrillation, left ventricular non— compaction, and sudden death. BMC Med Genet. 2014;15:99.
38.Semsarian C, Ingles J, Wilde AA. Sudden cardiac death in the young: the molecular autopsy and practical approach to surviving relatives. Eur Heart J. 2015;36[21]:1290—6.
39.Cerrone M, Priori SG. Genetics of sudden death: focus on inherited channelopathies. Eur Heart J. 2011;32[17]:2109—18.
40.Wilde AA, Behr ER. Genetic testing for inherited cardiac disease. Nat Rev Cardiol 2013;10l10]:571—83.
41. Behr ER, Dalageorgou C, Christiansen M, Syrris P, Hughes S, Tome Esteban MT, Rowland E, Jeffery S, McKenna WJ. Sud— den arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008;29[13]:1670—80.
42.Barsheshet A, Dotsenko 0, Goldenberg |. Congenitallong QT syndromes: prevalence, pathophysiology and manage— ment. Paediatr Drugs 2014;16[6]:447—56.
43. Barsheshet A, Dotsenko O, Goldenberg |. Genotype—spe— cific risk stratificationandmanagement of patients with long QT syndrome. Ann Noninvasive Electrocardiol 2013;18[6]:499— 509.
44.Brezina PR, Kutteh WH. Clinicalapplications of preimplan— tation genetic testingBMJ 2015;350:g7611.