Intest Res.  2025 Jan;23(1):23-36. 10.5217/ir.2023.00104.

Cardiovascular disease: extraintestinal manifestation of inflammatory bowel disease

• Lakhanpal S
• Aggarwal K
• Kaur H
• Kanwar K
• Gupta V
• Bhavsar J
• Jain R

• KMID: 2564394
• DOI: http://doi.org/10.5217/ir.2023.00104

Abstract

Inflammatory bowel disease (IBD) is a spectrum of diseases characterized by the interplay of the aberrant immune system, genetic factors, environmental factors, and intestinal microbiota, resulting in relapsing inflammation of the gastrointestinal tract. Underlying pro-inflammatory state and immune dysregulation act as a catalyst for increasing the likelihood of developing extraintestinal manifestations, including cardiovascular diseases (CVD) like atherosclerosis, pericarditis, myocarditis, venous and arterial thromboembolism, arrhythmias, despite a lower prevalence of classic CVD risk factors, like high body mass index or dyslipidemia compared to the general population. Chronic inflammation damages endothelium resulting in the recruitment of inflammatory cells, which induce cytotoxicity, lipoprotein oxidation, and matrix degradation, which increases the risk of atherosclerosis. Additionally, intestinal dysbiosis disrupts the intestinal mucosal barrier, releasing endotoxins and lipopolysaccharides into circulation, further exaggerating the atherosclerotic process. Abnormal collagen metabolism and alteration of nitric oxide-mediated vasodilation lead to blood pressure dysregulation in patients with IBD. Therefore, it is essential to make lifestyle modifications like smoking cessation, dietary changes, and increasing physical activity with adherence to medication to mitigate the risk of developing CVD in patients with IBD. This article reviews the potential links between IBD and the increased risk of CVD in such individuals.

Keyword

Inflammatory bowel disease; Intestinal dysbiosis; Cardiovascular diseases; Immune dysregulation

Figure

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  Fig. 1. Inflammatory bowel disease gut microbiome abnormalities may link to atherosclerotic cardiovascular disease. LPS, lipoprotein lipase; IL, interleukin; TNF, tumor necrosis factor; LDL, low-density lipoprotein; CCR, chemokine receptor; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule 1; ICAM-1, intercellular adhesion molecule 1.

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  Fig. 2. Intestinal dysbiosis and cardiovascular disease. IBD, inflammatory bowel disease; TMA, trimethylamine; TMAO, trimethylamine-N-oxide; LPS, lipoprotein lipase; TLR, Toll-like receptor; NF-kB; nuclear factor kappa light chain enhancer of activated B cells.

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  Fig. 3. Schematic presentation showing the link between inflammatory bowel disease (IBD) and cardiovascular disease. Elevated pro-inflammatory mediators promote cardiovascular events through endothelial dysfunction, intestinal dysbiosis, pro-inflammatory state, and lipid dysfunction. UC, ulcerative colitis; CD, Crohn’s disease; NO, nitric oxide; LPS, lipoprotein lipase; VEGF, vascular endothelial growth factor; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

Reference

1. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015; 12:720–727.

2. Barnes EL, Loftus EV, Kappelman MD. Effects of race and ethnicity on diagnosis and management of inflammatory bowel diseases. Gastroenterology. 2021; 160:677–689.

3. Dahlhamer JM, Zammitti EP, Ward BW, Wheaton AG, Croft JB. Prevalence of inflammatory bowel disease among adults aged ≥18 years: United States, 2015. MMWR Morb Mortal Wkly Rep. 2016; 65:1166–1169.

4. Ghouri YA, Tahan V, Shen B. Secondary causes of inflammatory bowel diseases. World J Gastroenterol. 2020; 26:3998–4017.

5. Fabián O, Kamaradová K. Morphology of inflammatory bowel diseases (IBD). Cesk Patol. 2022; 58:27–37.

6. Bunu DM, Timofte CE, Ciocoiu M, et al. Cardiovascular manifestations of inflammatory bowel disease: pathogenesis, diagnosis, and preventive strategies. Gastroenterol Res Pract. 2019; 2019:3012509.

7. Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res. 2018; 16:26–42.

8. Vizzardi E, Sciatti E, Bonadei I, et al. Subclinical cardiac involvement in Crohn’s disease and ulcerative colitis: an echocardiographic case-control study. Panminerva Med. 2016; 58:115–120.

9. Balakumar P, Maung-U K, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res. 2016; 113:600–609.

10. Łykowska-Szuber L, Rychter AM, Dudek M, et al. What links an increased cardiovascular risk and inflammatory bowel disease? A narrative review. Nutrients. 2021; 13:2661.

11. Nguyen GC, Bernstein CN, Bitton A, et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology. 2014; 146:835–848.

12. Siti HN, Kamisah Y, Kamsiah J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul Pharmacol. 2015; 71:40–56.

13. Andersohn F, Waring M, Garbe E. Risk of ischemic stroke in patients with Crohn’s disease: a population-based nested case-control study. Inflamm Bowel Dis. 2010; 16:1387–1392.

14. Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol. 2011; 106:741–747.

15. Haapamäki J, Roine RP, Turunen U, Färkkilä MA, Arkkila PE. Increased risk for coronary heart disease, asthma, and connective tissue diseases in inflammatory bowel disease. J Crohns Colitis. 2011; 5:41–47.

16. Sridhar AR, Parasa S, Navaneethan U, Crowell MD, Olden K. Comprehensive study of cardiovascular morbidity in hospitalized inflammatory bowel disease patients. J Crohns Colitis. 2011; 5:287–294.

17. Rungoe C, Basit S, Ranthe MF, Wohlfahrt J, Langholz E, Jess T. Risk of ischaemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study. Gut. 2013; 62:689–694.

18. Kristensen SL, Ahlehoff O, Lindhardsen J, et al. Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death: a Danish nationwide cohort study. PLoS One. 2013; 8:e56944.

19. Kristensen SL, Ahlehoff O, Lindhardsen J, et al. Inflammatory bowel disease is associated with an increased risk of hospitalization for heart failure: a Danish Nationwide Cohort study. Circ Heart Fail. 2014; 7:717–722.

20. Panhwar MS, Mansoor E, Al-Kindi SG, et al. Risk of myocardial infarction in inflammatory bowel disease: a population-based national study. Inflamm Bowel Dis. 2019; 25:1080–1087.

21. Biondi RB, Salmazo PS, Bazan SG, Hueb JC, de Paiva SA, Sassaki LY. Cardiovascular risk in individuals with inflammatory bowel disease. Clin Exp Gastroenterol. 2020; 13:107–113.

22. Kondo T, Nakano Y, Adachi S, Murohara T. Effects of tobacco smoking on cardiovascular disease. Circ J. 2019; 83:1980–1985.

23. Raftery AL, Tsantikos E, Harris NL, Hibbs ML. Links between inflammatory bowel disease and chronic obstructive pulmonary disease. Front Immunol. 2020; 11:2144.

24. Cosnes J. Smoking, physical activity, nutrition and lifestyle: environmental factors and their impact on IBD. Dig Dis. 2010; 28:411–417.

25. Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci. 1989; 34:1841–1854.

26. Cottone M, Rosselli M, Orlando A, et al. Smoking habits and recurrence in Crohn’s disease. Gastroenterology. 1994; 106:643–648.

27. Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015; 12:205–217.

28. Stein R, Ferrari F, Scolari F. Genetics, dyslipidemia, and cardiovascular disease: new insights. Curr Cardiol Rep. 2019; 21:68.

29. Karaahmet F, Basar O, Coban S, Yuksel I. Dyslipidemia and inflammation in patients with inflammatory bowel disease. Dig Dis Sci. 2013; 58:1806–1807.

30. Wang D, Zhao XJ, Cui XF, Li LZ, Zhang HJ. Correlation of serum lipid profile and disease activity in patients with inflammatory bowel disease. Zhonghua Nei Ke Za Zhi. 2021; 60:834–836.

31. Sappati Biyyani RS, Fahmy NM, Baum E, Nelson KM, King JF. Inflammatory bowel disease and coronary artery disease. Indian J Gastroenterol. 2009; 28:28–30.

32. Moon JM, Kang EA, Han K, et al. Trends and risk factors of elderly-onset Crohn’s disease: a nationwide cohort study. World J Gastroenterol. 2020; 26:404–415.

33. Wu K, Li A, Liu L, Shu T, Xia D, Sun X. Inflammatory bowel disease and cardiovascular disease: a two-sample Mendelian randomization analysis. Front Cardiovasc Med. 2022; 9:927120.

34. Lewis JD, Scott FI, Brensinger CM, et al. Increased mortality rates with prolonged corticosteroid therapy when compared with antitumor necrosis factor-α-directed therapy for inflammatory bowel disease. Am J Gastroenterol. 2018; 113:405–417.

35. Drapkina OM, Yafarova AA, Kaburova AN, Kiselev AR. Targeting gut microbiota as a novel strategy for prevention and treatment of hypertension, atrial fibrillation and heart failure: current knowledge and future perspectives. Biomedicines. 2022; 10:2019.

36. Czubkowski P, Osiecki M, Szymańska E, Kierkuś J. The risk of cardiovascular complications in inflammatory bowel disease. Clin Exp Med. 2020; 20:481–491.

37. Xu H, Jiang J, Chen W, Li W, Chen Z. Vascular macrophages in atherosclerosis. J Immunol Res. 2019; 2019:4354786.

38. Jaiswal V, Batra N, Dagar M, et al. Inflammatory bowel disease and associated cardiovascular disease outcomes: a systematic review. Medicine (Baltimore). 2023; 102:e32775.

39. Pussinen PJ, Kopra E, Pietiäinen M, et al. Periodontitis and cardiometabolic disorders: the role of lipopolysaccharide and endotoxemia. Periodontol 2000. 2022; 89:19–40.

40. Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019; 73:2089–2105.

41. Cason CA, Dolan KT, Sharma G, et al. Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. J Vasc Surg. 2018; 68:1552–1562.

42. Wu P, Jia F, Zhang B, Zhang P. Risk of cardiovascular disease in inflammatory bowel disease. Exp Ther Med. 2017; 13:395–400.

43. Barrington WT, Lusis AJ. Atherosclerosis: association between the gut microbiome and atherosclerosis. Nat Rev Cardiol. 2017; 14:699–700.

44. Chiang JY. Bile acid metabolism and signaling. Compr Physiol. 2013; 3:1191–1212.

45. Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. 2017; 56:54–65.

46. De Simone M, Cioffi U, Contessini-Avesani E, et al. Elevated serum procollagen type III peptide in splanchnic and peripheral circulation of patients with inflammatory bowel disease submitted to surgery. BMC Gastroenterol. 2004; 4:29.

47. Floege J, Ketteler M. Vascular calcification in patients with endstage renal disease. Nephrol Dial Transplant. 2004; 19 Suppl 5V59–V66.

48. Waśko-Czopnik D, Paradowski L. The influence of deficiencies of essential trace elements and vitamins on the course of Crohn’s disease. Adv Clin Exp Med. 2012; 21:5–11.

49. Rungoe C, Nyboe Andersen N, Jess T. Inflammatory bowel disease and risk of coronary heart disease. Trends Cardiovasc Med. 2015; 25:699–704.

50. Bornaun HA, Yılmaz N, Kutluk G, et al. Prolonged P-wave and QT dispersion in children with inflammatory bowel disease in remission. Biomed Res Int. 2017; 2017:6960810.

51. Lacey D, Bouillet P. Deregulation of TNF expression can also cause heart valve disease. Cytokine. 2016; 77:248–249.

52. Kamperidis N, Kamperidis V, Zegkos T, et al. Atherosclerosis and inflammatory bowel disease-shared pathogenesis and implications for treatment. Angiology. 2021; 72:303–314.

53. Negroni A, Pierdomenico M, Cucchiara S, Stronati L. NOD2 and inflammation: current insights. J Inflamm Res. 2018; 11:49–60.

54. Blander JM, Longman RS, Iliev ID, Sonnenberg GF, Artis D. Regulation of inflammation by microbiota interactions with the host. Nat Immunol. 2017; 18:851–860.

55. Gajendran M, Loganathan P, Catinella AP, Hashash JG. A comprehensive review and update on Crohn’s disease. Dis Mon. 2018; 64:20–57.

56. Bauer S, Hezinger L, Rexhepi F, Ramanathan S, Kufer TA. NOD-like receptors-emerging links to obesity and associated morbidities. Int J Mol Sci. 2023; 24:8595.

57. Galluzzo S, Patti G, Dicuonzo G, et al. Association between NOD2/CARD15 polymorphisms and coronary artery disease: a case-control study. Hum Immunol. 2011; 72:636–640.

58. Riis L, Vind I, Vermeire S, et al. The prevalence of genetic and serologic markers in an unselected European population-based cohort of IBD patients. Inflamm Bowel Dis. 2007; 13:24–32.

59. van der Linde K, Boor PP, Houwing-Duistermaat JJ, et al. CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies. Eur J Gastroenterol Hepatol. 2007; 19:449–459.

60. Leong RW, Armuzzi A, Ahmad T, et al. NOD2/CARD15 gene polymorphisms and Crohn’s disease in the Chinese population. Aliment Pharmacol Ther. 2003; 17:1465–1470.

61. Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet. 2002; 47:469–472.

62. Liu Y, Yang H, Liu LX, et al. NOD2 contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and inflammation. Life Sci. 2016; 149:10–17.

63. Singh S, Blanchard A, Walker JR, Graff LA, Miller N, Bernstein CN. Common symptoms and stressors among individuals with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2011; 9:769–775.

64. Schinzari F, Armuzzi A, De Pascalis B, et al. Tumor necrosis factor-alpha antagonism improves endothelial dysfunction in patients with Crohn’s disease. Clin Pharmacol Ther. 2008; 83:70–76.

65. Schoeler M, Caesar R. Dietary lipids, gut microbiota and lipid metabolism. Rev Endocr Metab Disord. 2019; 20:461–472.

66. Manea M, Marcu D, Motofei I, et al. Cardiovascular risk in patients with inflammatory bowel diseases: a review. Rom Biotechnol Lett. 2019; 24:366–373.

67. Gandhi S, Narula N, Marshall JK, Farkouh M. Are patients with inflammatory bowel disease at increased risk of coronary artery disease? Am J Med. 2012; 125:956–962.

68. Nikolaus S, Schulte B, Al-Massad N, et al. Increased tryptophan metabolism is associated with activity of inflammatory bowel diseases. Gastroenterology. 2017; 153:1504–1516.

69. Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013; 368:1575–1584.

70. Cainzos-Achirica M, Glassner K, Zawahir HS, et al. Inflammatory bowel disease and atherosclerotic cardiovascular disease: JACC review topic of the week. J Am Coll Cardiol. 2020; 76:2895–2905.

71. Hills RD, Pontefract BA, Mishcon HR, Black CA, Sutton SC, Theberge CR. Gut microbiome: profound implications for diet and disease. Nutrients. 2019; 11:1613.

72. Bendall CL, Mayr HL, Opie RS, Bes-Rastrollo M, Itsiopoulos C, Thomas CJ. Central obesity and the Mediterranean diet: a systematic review of intervention trials. Crit Rev Food Sci Nutr. 2018; 58:3070–3084.

73. Chicco F, Magrì S, Cingolani A, et al. Multidimensional impact of Mediterranean diet on IBD patients. Inflamm Bowel Dis. 2021; 27:1–9.

74. Wong MS, Delansorne R, Man RY, Vanhoutte PM. Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol. 2008; 295:H289–H296.

75. Bigeh A, Sanchez A, Maestas C, Gulati M. Inflammatory bowel disease and the risk for cardiovascular disease: does all inflammation lead to heart disease? Trends Cardiovasc Med. 2020; 30:463–469.

76. Yin K, You Y, Swier V, et al. Vitamin D protects against atherosclerosis via regulation of cholesterol efflux and macrophage polarization in hypercholesterolemic swine. Arterioscler Thromb Vasc Biol. 2015; 35:2432–2442.

77. Rai V, Agrawal DK. Role of vitamin D in cardiovascular diseases. Endocrinol Metab Clin N Am. 2017; 46:1039–1059.

78. Elnabawi YA, Oikonomou EK, Dey AK, et al. Association of biologic therapy with coronary inflammation in patients with psoriasis as assessed by perivascular fat attenuation index. JAMA Cardiol. 2019; 4:885–891.

79. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019; 68:s1–s106.

80. Crockett SD, Hansen RA, Stürmer T, et al. Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study. Inflamm Bowel Dis. 2012; 18:1048–1056.

81. Triantafillidis JK, Merikas E, Georgopoulos F. Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des Devel Ther. 2011; 5:185–210.