Small Intestinal Bacterial Overgrowth Syndrome as a Risk Factor for Ventricular Tachycardia in Chronic Heart Failure with Left Ventricular Systolic Dysfunction

Aim. To identify the relationship between rhythm disturbances, including ventricular tachycardia (VT), and the small intestinal bowel bacterial overgrowth syndrome in chronic heart failure (CHF) with left ventricular systolic dysfunction.

Materials and methods. The study included 60 patients with CHF with systolic dysfunction of the left ventricle (left ventricular ejection fraction less than 50 %). Conventional biochemical and hematological tests , ECG and echocardiography were performed. The level of the N-terminal fragment of the brain natriuretic peptide (NT-proBNP) and nonspecific inflammatory markers (C-reactive protein (CRP), fibrinogen, leukocytes, lymphocytes, neutrophil to lymphocyte ratio) were studied. Lactulose hydrogen breath test was fulfiled to detect the small intestinal bowel bacterial overgrowth syndrome (SIBOS). In the presence of complaints of palpitation and interruptions in the heart work or other indications, Holter ECG monitoring was performed. The control group consisted of 20 patients comparable to the main group by sex, age and major diseases in the absence of CHF and SIBOS.

Results. The prevalence of SIBOS among patients with CHF significantly exceeded its prevalence in the group of patients without CHF (SIBOS was detected in 25 of 60 patients with CHF (42 %) and in 2 of 22 patients without CHF (9 %); p = 0.0034). The small bowel bacterial overgrowth syndrome with CHF did not have a significant impact on the functional class and the indicators of clinical and biochemical analysis of blood as well as on echocardiographic data and the number of supraventricular and ventricular extrasystoles. However, in patients with SIBOS, higher CRP values were observed (median and interquartile range: 3.6 (2.5; 4.1) vs 2.15 (0.4; 5.1); p = 0.041). In addition, among patients with CHF and a positive SIBOS test, ventricular tachycardia was significantly more common (in 45 % of patients with SIBOS and in 10.71 % of patients without SIBOS; p = 0.01555). The presence of SIBOS increased the risk of VT in patients with CHF (OR = 6.818, 95 % CI: 1.542 - 30.153; P = 0.011)). The development of VT in patients with SIBOS was associated rather with systemic inflammation than with the severity of CHF characterized by high NTproBNP numbers, while in the absence of SIBOS the opposite trend was noted.

Conclusion. The development of VT in patients with SIBOS is associated rather with systemic inflammation rather than with the severity of CHF. SIBOS can be considered as an additional risk factor in the development of systemic inflammation and ventricular tachycardia in patients with CHF. 

1. Qin J., Li R., Raes J., Arumugam M., Burgdorf K. S., Manichanh C., Nielsen T., Pons N., Levenez F., Yamada T., Mende D. R., Li J., Xu J., Li S., Li D., Cao J., Wang B., Liang H., Zheng H., Xie Y., Tap J., Lepage P., Bertalan M., Batto J. M., Hansen T., Le Paslier D., Linneberg A., Nielsen H. B., Pelletier E., Renault P. A human gut microbial gene catalogue. Nature. 2010;464:59–65.

2. Turnbaugh P.J., Quince C., Faith J.J., Mchardy A.C., Yatsunenko T., Niazi F., Affourtit J., Egholm M., Henrissat B., Knight R., Gordon J.I. Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc Natl Acad Sci U S A. 2010;107(16):7503–8.

3. Gill S.R., Pop M., Deboy R.T., Eckburg P.B., Turnbaugh P.J., Samuel B.S., Gordon J.I., Relman D.A., Fraser-Liggett C.M., Nelson K.E. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312(5778):1355–9.

4. Issacs P. E., Kim Y.S. Blind loop syndrome and small bowel bacterial contamination. Clin Gastroenterol. 1983;12:395–414.

5. Andrew C. Dukowicz, Brian E. Lacy, Gary M. Levine. Small Intestinal Bacterial Overgrowth: A Comprehensive Review. Gastroenterology & Hepatology. 2007;3(2):112–20.

6. Lauritano E.C., Valenza V., Sparano L., Scarpellini E., Gabrielli M., Cazzato A., Ferraro P.M., Gasbarrini A. Small intestinal bacterial overgrowth and intestinal permeability. Scand J Gastroenterol. 2010;45(9):1131–2.

7. Mollar A., Villanueva M. P., Nunez E., Carratala A., Mora F., Bayes-Genis A., Minguez M., Marrachelli V. G., Monleon D., Navarro D., Sanchis J., Nunez J. Hydrogen- and Methane-Based Breath Testing and Outcomes in Patients with Heart Failure. J Card Fail. 2018; [Epub ahead of print]

8. Çakıcı M., Çetin M., Dogan A., Oylumlu M., Aktürk E., Polat M., Suner A., Abuş S. Neutrophil to lymphocyte ratio predicts poor functional capacity in patients with heart failure. Turk Kardiyol Dern Ars. 2014;42(7):612–20.

9. Wang X., Fan X., Ji S., Ma A., Wang T. Prognostic value of neutrophil to lymphocyte ratio in heart failure patients. Clin Chim Acta. 2018;485:44–9. doi: 10.1016/j. cca.2018.06.021

10. Bures J., Cyrany J., Kohoutov D., Forstl M., Rejchrt S., Kvetina J., Vorisek V., Kopacova M. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol. 2010;16(24):2978–90.

11. Cevikel M. H., Ozgun H., Boylu S., Demirkiran A. E., Aydin N., Sari C., Erkus M. C-reactive protein may be a marker of bacterial translocation in experimental intestinal obstruction. ANZ Journal of Surgery. 2004;74(10):900–4.

12. Niebauer J., Volk H.D., Kemp M., Dominguez M., Schumann R.R., Rauchhaus M., Poole-Wilson P.A., Coats A.J., Anker S.D. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353:1838–42.

13. Sandek A., Bjarnason I., Volk H. D., Crane R., Meddings J. B., Niebauer J., Kalra P. R., Buhner S., Herrmann R., Springer J., Doehner W., Von Haehling S., Anker S.D., Rauchhaus M. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. International Journal of Cardiology. 2010;57(1):80–5.

14. Matsumori A., Yamada T., Suzuki H., Matoba Y., Sasayama S. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J. 1994;72(6):561–6.

15. Satoh M., Tamura G., Segawa I., Tashiro A., Hiramori K., Satodate R. Expression of cytokine genes and presence of enteroviral genomic RNA in endomyocardial biopsy tissues of myocarditis and dilated cardiomyopathy. Virchows Arch. 1996;427(5):503–9.

16. Izumi T., Nishii M. Diagnostic and prognostic biomarkers in acute myocarditis. Interleukin-10. Herz. 2012;37(6):627–31.

17. Kanda T., Tanaka T., Sekiguchi K., Seta Y., Kurimoto M., Wilson McManus J. E., Nagai R., Yang D., McManus B. M., Kobayashi I. Effect of interleukin-18 on viral myocarditis: enhancement of interferon- gamma and natural killer cell activity. J Mol Cell Cardiol. 2000; 32(12):2163–71.

18. Yoshida A., Kand T., Tanaka T., Yokoyama T., Kurimoto M., Tamura J., Kobayashi I. Interleukin-18 reduces expression of cardiac tumor necrosis factor-alpha and atrial natriuretic peptide in a murine model of viral myocarditis. Life Sci. 2002;70(11):1225–34.

19. Glück B., Schmidtke M., Merkle I., Stelzner A., Gemsa D. Persistent expression of cytokines in the chronic stage of CVB3-induced myocarditis in NMRI mice. J Mol Cell Cardiol. 2001;33(9):1615–26.

20. Fairweather D., Yusung S., Frisancho S., Barrett M., Gatewood S., Steele R., Rose N.R. IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication. J Immunol. 2003;170(9):4731–7.

21. Dong M., Liu T., Li G. Association between acute infections and risk of acute coronary syndrome: a meta-analysis. Int J Cardiol. 2011;147(3):479–82.

22. Warren-Gash C., Smeeth L., Hayward A.C. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect Dis. 2009;9(10):601–10.

23. Yalta K., Sivri N., Yetkin E. Acute coronary syndromes in the setting of acute infections: is there an overdiagnosis with overtreatment? Int J Cardiol. 2011;149(3):383.

24. Monden Y., Kubota T., Inoue T., Tsutsumi T., Kawano S., Ide T., Tsutsui H., Sunagawa K. Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction. Am J Physiol Heart Circ Physiol. 2007;293(1):H743–53.

25. Kragel A.H., Travis W.D., Steis R.G., Rosenberg S.A., Roberts W.C. Myocarditis or acute myocardial infarction associated with interleukin-2 therapy for cancer. Cancer. 1990;66(7):1513–6.

26. Eisner R. M., Husain A., Clark J.I. Case report and brief review: IL-2-induced myocarditis. Cancer Investig. 2004;22(3):401–4.

27. Yan W., Song Y., Zhou L., Jiang J., Yang F., Duan Q., Che L., Shen Y., Song H., Wang L. Immune cell repertoire and their mediators in patients with acute myocardial infarction or stable angina pectoris. Int J Med Sci. 2017;14(2):181–90.

28. Abe Y., Kawakami M., Kuroki M., Yamamoto T., Fujii M., Kobayashi H., Yaginuma T., Kashii A., Saito M., Matsushima K. Transient rise in serum interleukin-8 concentration during acute myocardial infarction. Br Heart J. 1993;70(2):132–4.

29. Dybdahl B., Slørdahl S. A., Waage A., Kierulf P., Espevik T., Sundan A. Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart. 2005;91(3):299–304.

30. Kukielka G.L., Smith C.W., LaRosa G.J. et al. Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo. J Clin Invest. 1995;95(1):89–103.

31. Ruiz-Baile´n M., Romero-Bermejo F. J., Rucabado-Aguilar L., Pearez-Valenzuela J., Ferrezuelo-Mata A., Ramírez Sánchez M., Ramos Cuadra, J. A., Martinez Ramírez M.J. Myocardial dysfunction in the critically ill patient: is it really reversible? Int J Cardiol. 2010;145(3):615–6.

32. Okazaki R., Iwasaki Y. K., Miyauchi Y., Hirayama Y., Kobayashi Y., Katoh T., Mizuno K., Sekiguchi A., Yamashita T. Lipopolysaccharide induces atrial arrhythmogenesis via down-regulation of L-type Ca2- channel genes in rats. Int Heart J. 2009;50(3):353–63.

33. Court O., Kumar A., Parrillo J. E., Kumar A. Clinical review: myocardial depression in sepsis and septic shock. Crit Care. 2002; 6(6):500–8.

34. Khalil H., Kanisicak O., Prasad V., Correll R. N., Fu X., Schips T., Vagnozzi R. J., Liu R., Huynh T., Lee S. J., Karch J., Molkentin J.D. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest. 2017;127(10):3770–83.

35. Lijnen P.J., Petrov V.V., Fagard R.H. Induction of cardiac fibrosis by transforming growth factor-beta1. Mol Genet Metab. 2000;71(1–2):418–35.

36. Roselló-Lletí E., Rivera M., Bertomeu V., Cortés R., Jordán A., González-Molina A. Interleukin-4 and cardiac fibrosis in patients with heart failure. Rev Esp Cardiol. 2007;60(7):777–80.

37. Peng H., Sarwar Z., Yang X.P., Peterson E.L, Xu J., Janic B., Rhaleb N., Carretero O.A., Rhaleb N.E. Profibrotic role for interleukin-4 in cardiac remodeling and dysfunction. Hypertension. 2015;66(3):582–9.

38. Streitner F., Kuschyk J., Veltmann C., Brueckmann M., Streitner I., Brade J., Neumaier M., Bertsch T., Schumacher B., Borggrefe M., Wolpert C. Prospective study of interleukin-6 and the risk of malignant ventricular tachyarrhythmia in ICD-recipients—a pilot study. Cytokine. 2007;40(1):30–4.

39. Konstantino Y, Kusniec J, Reshef T,. David-Zadeh O., Mazur A., Strasberg B., Battler A., Haim M. Inflammatory biomarkers are not predictive of intermediate-term risk of ventricular tachyarrhythmias in stable CHF patients. Clin Cardiol. 2007; 30(8):408–13.

40. Szydlowski L., Skierska A., Markiewicz-Loskot G., Mazurek B., Morka A., Undas A. The role of Interleukin-6, its -174 G>C polymorphism and C-reactive protein in idiopathic cardiac arrhythmias in children. Adv Med Sci. 2013;58(2):320–5.

41. Xiao H., Liao Y. H., Chen Z. J. Tumor necrosis factoralpha: a new mechanism of ischemic ventricular fibrillation? Chin Med J. 2008;121(18):1848–1851.

42. Zhong J., Hwang T.C., Adams H.R., Rubin L.J. Reduced L-type calcium current in ventricular myocytes from endotoxemic guineapigs. Am J Physiol. 1997;273(5 Pt 2):H2312–24.

43. Lew W.Y., Yasuda S., Yuan T., Hammond H.K. Endotoxin-induced cardiac depression is associated with decreased cardiac dihydropyridine receptors in rabbits.JMolCellCardiol. 1996;28(6):1367–71.