Hostname: page-component-848d4c4894-hfldf Total loading time: 0 Render date: 2024-06-09T17:28:36.845Z Has data issue: false hasContentIssue false

The association between pro-arrhythmic agents and aortic stenosis in young adults: is it sufficient to clarify the sudden unexpected deaths?

Published online by Cambridge University Press:  08 November 2016

Bojana Radnic
Affiliation:
Institute of Forensic Medicine “Milovan Milovanovic”, School of Medicine, University of Belgrade, Belgrade, Serbia
Nemanja Radojevic*
Affiliation:
Department of Forensic Medicine, Clinical Centre of Montenegro, Podgorica, Montenegro
Jelena Vucinic
Affiliation:
Department of Pathology, Centre for Pathology and Forensic Medicine, Clinical Centre of Montenegro, Podgorica, Montenegro
Natasa Duborija-Kovacevic
Affiliation:
Department of Pharmacology and Clinical Pharmacology, School of Medicine, University of Montenegro, Podgorica, Montenegro
*
Correspondence to: N. Radojevic, MD, Forensic Pathologist, Department of Forensic Medicine, Clinical Centre of Montenegro, Ljubljanska 1, 81000 Podgorica, Montenegro. Tel: +382 69 340 510; Fax: +382 20 246 409; E-mail: com_nr@yahoo.com

Abstract

Most young patients with mild-to-moderate aortic stenosis show no symptoms, and sudden death appears only occasionally. We hypothesised that malignant ventricular arrhythmias could be responsible for the high incidence of sudden death in such patients. If multiple factors such as asymptomatic aortic stenosis in association with arrhythmia-provoking agents are involved, could it be sufficient to account for sudden unexpected death? In this study, eight cases of sudden death in young adults, with ages ranging from 22 to 36 years, who had never reported any symptoms that could be related to aortic stenosis, were investigated. Full autopsies were performed, and congenital aortic stenosis in all eight cases was confirmed. DNA testing for channelopathies was negative. Comprehensive toxicological analyses found an electrolyte imbalance, or non-toxic concentrations of amitriptyline, terfenadine, caffeine, and ethanol. Collectively, these results suggest that congenital asymptomatic aortic stenosis without cardiac hypertrophy in young adults is not sufficient to cause sudden death merely on its own; rather, an additional provoking factor is necessary. According to our findings, the provoking factor may be a state of physical or emotional stress, a state of electrolyte imbalance, or even taking a therapeutic dose of a particular drug.

Type
Original Articles
Copyright
© Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. DiMaio, VJM, DiMaio, D. Forensic Pathology, 2nd edn. CRC Press, Boca Raton, FL, 2001.Google Scholar
2. Matthews, AW, Barritt, DW, Keen, GE, et al. Preoperative mortality in aortic stenosis. Br Heart J 1974; 36: 101103.Google Scholar
3. Chizner, MA, Pearle, DL, deLeon, AC Jr. The natural history of aortic stenosis in adults. Am Heart J 1980; 99: 419424.CrossRefGoogle ScholarPubMed
4. Ross, J Jr, Braunwald, E. Aortic stenosis. Circulation 1968; 38 (Suppl.): V61V67.Google Scholar
5. Kelly, TA, Rothbart, RM, Cooper, CM, et al. Comparison of outcome of asymptomatic to symptomatic patients older than 20 years of age with valvular aortic stenosis. Am J Cardiol 1988; 61: 123130.CrossRefGoogle ScholarPubMed
6. Pellikka, PA, Nishimura, RA, Bailey, KR, et al. The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis. J Am Coll Cardiol 1990; 15: 10121017.Google Scholar
7. Makkar, RR, Fromm, BS, Steinman, RT, Meissner, MD, Lehmann, MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270: 25902597.CrossRefGoogle ScholarPubMed
8. Bednar, MM, Harrigan, EP, Ruskin, JN. Torsades de pointes associated with non-antiarrhythmic drugs and observations on gender and QTc. Am J Cardiol 2002; 89: 13161319.Google Scholar
9. Antzelevitch, C, Shimizu, W. Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol 2002; 17: 4351.Google Scholar
10. Heist, EK, Ruskin, JN. Drug-induced arrhytmia. Circulation 2010; 122: 14261435.Google Scholar
11. Roden, DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350: 10131022.Google ScholarPubMed
12. Kay, GN, Plumb, VJ, Arciniegas, JG, Henthorn, RW, Waldo, AL. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol 1983; 2: 806817.Google Scholar
13. Bednar, MM, Edmund, P, Harrigan, EP, Anziano, RJ, Camm, AJ, Ruskin, JN. The QT interval. Prog Cardiovasc Dis 2001; 43: 145.Google Scholar
14. Roden, DM, Woosley, RL, Primm, RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986; 111: 10881093.Google Scholar
15. Capps, SB, Elkins, RC, Fronk, DM. Body surface area as a predictor of aortic and pulmonary valve diameter. J Thorac Cardiovasc Surg 2000; 119: 975982.Google Scholar
16. Haycock, GB, Schwartz, GJ, Wisotsky, DH. Geometric method for measuring body surface area: a height weight formula validated in infants, children and adults. J Pediatr 1978; 93: 6266.Google Scholar
17. Basso, C, Burke, M, Fornes, P, et al. Association for European Cardiovascular Pathology Guidelines for autopsy investigation of sudden cardiac death. Pathologica 2010; 102: 391404.Google Scholar
18. Basso, C, Carturan, E, Pilichou, K, Rizzo, S, Corrado, D, Thiene, G. Sudden cardiac death with normal heart: molecular autopsy. Cardiovasc Pathol 2010; 19: 321325.Google Scholar
19. Molina, DK, DiMaio, VJM. Normal organ weights in men, Part I – the heart. Am J Forensic Med Pathol 2012; 33: 362367.Google Scholar
20. Fagard, R. Athlete’s heart. Heart 2003; 89: 14551461.CrossRefGoogle ScholarPubMed
21. Fananapazir, L, Tracy, CM, Leon, MB, et al. Electrophysiologic abnormalities in patients with hypertrophic cardiomyopathy consecutive analysis of 155 patients. Circulation 1989; 80: 12591268.Google Scholar
22. Anderson, KP, Stinson, EB, Derby, GC, et al. Vulnerability of patients with obstructive hypertrophic cardiomyopathy to ventricular arrhythmia induction in the operating room: analysis of 17 patients. Am J Cardiol 1983; 51: 811816.Google Scholar
23. Von Olshausen, K, Witt, T, Pop, T, et al. Sudden cardiac death while wearing Holter monitor. Am J Cardiol 1991; 67: 381386.CrossRefGoogle Scholar
24. Nikolic, G, Haffty, BG, Bishop, RL, et al. Sudden death in aortic stenosis monitored by ear densitographic pulse and ECG. Am Heart J 1982; 104: 311312.CrossRefGoogle ScholarPubMed
25. Schulz, M, Iwersen-Bergmann, S, Andersen, H, Schmoldt, A. Therapeutic and toxic blood concentrations or nearly 1000 drugs and other xenobiotics. Crit Care 2012; 16: R136, [Epub ahead of print].Google Scholar
26. Pratt, CM, Hertz, RP, Ellis, BE, Crowell, SP, Louv, W, Moye, L. Risk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. Am J Cardiol 1994; 73: 346352.Google Scholar
27. Hanrahan, JP, Choo, PW, Carlson, W, Greineder, D, Faich, GA, Platt, R. Terfenadine-associated ventricular arrhythmias and QTc interval prolongation: a retrospective cohort comparison with other antihistamines among members of a health maintenance organization. Ann Epidemiol 1995; 5: 201209.Google Scholar
28. Monahan, BP, Ferguson, CL, Killeavy, ES, Lloyd, BK, Troy, J, Cantilena, LR Jr. Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264: 27882790.Google Scholar
29. Honig, PK, Woosley, RL, Zamani, K, Conner, DP, Cantilena, LR Jr. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52: 231238.Google Scholar
30. Jurima-Romet, M, Crawford, K, Cyr, T, Inaba, T. Terfenadine metabolism in human liver. Drug Metab Dispos 1994; 22: 849857.Google Scholar
31. Honig, PK, Wortham, DC, Zamani, K, Conner, DP, Mullin, J, Cantilena, LR. Terfenadine-ketoconazole interaction. JAMA 1993; 269: 15131518.Google Scholar
32. Mihailovic, Z, Atanasijevic, T, Popovic, V, Milosevic, MB, Sperhake, JP. Estimation of the postmortem interval by analyzing potassium in the vitreous humor: could repetitive sampling enhance accuracy? Am J Forensic Med Pathol 2012; 33: 400403.Google Scholar
33. Palmiere, C, Mangin, P. Postmortem chemistry update part I. Int J Legal Med 2012; 126: 187198.Google Scholar
34. Higgins, JP, Tuttle, TD, Higgins, CL. Energy beverages: content and safety. Mayo Clin Proc 2010; 85: 10331041.Google Scholar
35. Gunja, N, Brown, JA. Energy drinks: health risks and toxicity. Med J Aust 2012; 196: 4649.Google Scholar
36. McCusker, RR, Goldberger, BA, Cone, EJ. Caffeine content of energy drinks, carbonated sodas, and other beverages. J Anal Toxicol 2006; 30: 112114.Google Scholar
37. Klatsky, AL, Hasan, AS, Armstrong, MA, Udaltsova, N, Morton, C. Coffee, caffeine, and risk of hospitalization for arrhythmias. Perm J 2011; 15: 1925.Google Scholar
38. Denison, H, Jern, S, Jagenburg, R, Wendestam, C, Wallerstedt, S. Influence of increased adrenergic activity and magnesium depletion on cardiac rhythm in alcohol withdrawal. Br Heart J 1994; 72: 554560.Google Scholar
39. Maki, T, Toivonen, L, Koskinen, P, Naveri, H, Harkonen, M, Leinonen, H. Effect of ethanol drinking, hangover, and exercise on adrenergic activity and heart rate variability in patients with a history of alcohol induced atrial fibrillation. Am J Cardiol 1998; 82: 317322.Google Scholar
40. Preedy, VR, Siddiq, T, Why, H, Richardson, PJ. The deleterious effects of alcohol on the heart: involvement of protein turnover. Alcohol Alcohol 1994; 29: 141147.Google ScholarPubMed
41. Marcus, GM, Smith, LM, Whiteman, D, et al. Alcohol intake is significantly associated with atrial flutter in patients under 60 years of age and a shorter right atrial effective refractory period. Pacing Clin Electrophysiol 2008; 31: 266272.Google Scholar
42. Steinbigler, P, Haberl, R, Konig, B, Steinbeck, G. P-wave signal averaging identifies patients prone to alcohol-induced paroxysmal atrial fibrillation. Am J Cardiol 2003; 91: 491494.Google Scholar
43. Habuchi, Y, Furukawa, T, Tanaka, H, Lu, LL, Morikawa, J, Yoshimura, M. Ethanol inhibition of Ca2+ and Na+ currents in the guinea-pig heart. Eur J Pharmacol 1995; 292: 143149.Google Scholar
44. Buckingham, TA, Kennedy, HL, Goenjian, AK, et al. Cardiac arrhythmias in a population admitted to an acute alcoholic detoxification center. Am Heart J 1985; 110: 961965.CrossRefGoogle Scholar
45. Liu, J, Wang, Y, Shan, Z, Guo, H. Influence of acute stress on cardiac electrophysiological stability in male goats. Acta Cardiol 2012; 67: 325330.Google Scholar
46. Itabashi, H, et al. Forensic Neuropathology: A Practical Review of the Fundamentals, 1st edn. Elsevier, London, 2007.Google Scholar
47. Hirvonen, J, Huttunen, P. Postmortem changes in serum noradrenaline and adrenaline concentrations in rabbit and human cadavers. Int J Legal Med 1996; 109: 143146.CrossRefGoogle ScholarPubMed
48. Wilke, N, Janssen, H, Fahrenhorst, C, et al. Post-mortem determination of concentrations of stress hormones in various body fluids – is there a dependency between adrenaline/noradrenaline quotient, cause of death and agony time? Int J Legal Med 2007; 121: 385394.Google Scholar