Y-ECCO Literature Review: Christina Kapizioni

Introduction

Cardiovascular disease (CVD) is the leading cause of death globally, despite the recent advances in diagnosis and therapy [1]. Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic Inflammatory Bowel Diseases (IBD) precipitated by genetic and environmental factors. Systemic inflammation is present in IBD and is known to be a risk factor for atherosclerosis as a result of the induction of many pathophysiological processes such as endothelial dysfunction, plaque formation and rupture as well as platelet activation [2]. Inflammatory biomarkers involved in IBD, including C-reactive protein, interleukin-6 and CD40 ligand, are also key mediators in the pathogenesis of atherosclerosis [3]. In addition, it has been shown that IBD patients have indirect surrogate markers of CVD such as increased arterial stiffness [4] and carotid intima-media thickness [5] in the absence of traditional risk factors, thus promoting the idea of early subclinical atherogenesis in patients with a chronic inflammatory burden. Considering the aforementioned data, it is plausible to assume that chronic systemic inflammation in patients with IBD may lead to increased risk of arterial events. Nonetheless, previous studies on the subject have not clarified the existence or absence of a causative relationship between IBD and CVD [6–8].

The nationwide French study published recently by Kirchgesner et al aimed to expand the data on this field by investigating the magnitude of arterial events in a large IBD cohort compared with the general population as well as to detect any possible risk factors promoting CVD in IBD patients.

Key findings

The study used the National Hospital Discharge Database of France and National Vital Statistics to recruit its subjects: patients older than 15 years old hospitalised during a 5-year period (2008–2013) and discharged with a diagnosis of IBD as well as all non-IBD patients over the same period, who served as control group. Arterial events, comprising ischaemic heart disease, cerebrovascular disease and peripheral artery disease, were retrieved in both groups. Patients with a history of a previous arterial event, cardiovascular disease or relevant cardiovascular procedures during hospitalisation were excluded. All traditional risk factors associated with CVD available in the database were recorded: hypertension, dyslipidaemia, diabetes mellitus, obesity, smoking and alcohol consumption. Disease activity was also assessed by considering hospitalisation for either active disease or IBD surgery as a surrogate marker.

In total, 210,162 IBD patients were included, constituting 595,202 person years; 46.5% had a diagnosis of CD and 53.5% a diagnosis of UC. Subjects were followed up for an average of 3.4 years. The risk of all acute arterial events in patients with IBD was significantly increased compared to the general population, with a standardised incidence ratio (SIR) of 1.19 (95% CI 1.16–1.22) and with CD patients being at a higher risk compared to UC patients (SIR 1.35 vs 1.10).

When the impact of age and sex on the incidence of arterial events was explored, it was observed that CD patients aged 15–34 and 35–54 were overall at the highest risk of arterial events (SIR 1.42 and 1.58 respectively), with peripheral artery disease accounting for the greater part of the risk. Similarly, UC patients aged 15–34 were at the highest risk (SIR 1.65) but the rest of the age groups had a similar risk to the general population. Additionally, females were more prone to arterial events than men, with female CD patients being at the highest risk.

When traditional risk factors for CVD were assessed, CD patients maintained a higher risk than the general population (SIR 1.26), while UC patients had a risk similar to that of the general population, a result possibly reflecting the increased systemic inflammation load of the former group.

Lastly, IBD activity seemed to play a pivotal role in increasing the risk of arterial events in both UC and CD patients. CD patients with an exacerbation of the disease were at an increased risk of all arterial diseases, with a hazard ratio (HR) of 1.74, while UC patients had an HR of 1.87. 

Conclusion

This study provides a valuable insight into the existing data regarding the association of IBD with CVD, suggesting that, similar to patients with rheumatoid arthritis and other chronic inflammatory disorders, IBD patients are at a high risk of acute arterial events.

When considering the inherent flaws of every administrative data-based study, one must point out the lack of information regarding several traditional CVD risk factors such as family history or physical activity. However, the authors corrected their results for every other important CVD risk factor available in the database – hypertension, dyslipidaemia, diabetes, obesity, smoking and alcohol consumption – an adjustment that many previous studies were not able to perform.

Furthermore, neither characteristics of intestinal disease, including extent and duration, nor treatment regimens used for IBD were available, thereby precluding more accurate estimates of the inflammatory burden carried by each subject and thus stratification of patients. A higher inflammatory milieu due to severe or extended disease would be expected to accelerate atherogenesis, which might translate into a different CVD risk.

Additionally, even though the retrospective nature of any study diminishes the strength of the results, prospective studies investigating CVD in IBD patients would need to enrol a great number of subjects in order to achieve the number of arterial events required to perform the analysis.

The impressive sample size of more than 210,000 IBD patients compensates in part for the shortcomings of the study’s design. The authors were able to perform subgroup analysis with large numbers of subjects and events, thus achieving quite accurate results. Young individuals and females were shown to be at the highest risk for arterial events, a fact that is in accordance with previous studies [7, 9].

Finally, it would be informative to attempt to relate disease severity, even with a surrogate marker of hospitalisation during a flare, to CVD risk. The great heterogeneity of the IBD population included in previous studies may have accounted for discordant results. It would be of interest to assess the impact of CVD events in IBD patients with mild or moderate disease exacerbations not requiring hospitalisation.

To conclude, although important evidence of the association between IBD and increased arterial events risk has emerged from the Kirchgesner et al study, it is true that a definite connection between IBD and CVD is still elusive. Both the true effect and the possibility of risk reduction along with inflammation reduction through successful treatment are points of interest that remain to be established in the future.  

Refrences

1. Top 10 causes of death [Internet]. World Health Organization. 2018 [cited 9 August 2018]. Available from: http://www.who.int/gho/mortality_burden_disease/causes_death/top_10/en/
2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–95.
3. Raggi P, Genest J, Giles JT, Rayner KJ, Dwivedi G, Beanlands RS, Gupta M. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions. Atherosclerosis. 2018;276:98–108.
4. Zanoli L, Cannavò M, Rastelli S, et al. Arterial stiffness is increased in patients with inflammatory bowel disease. J Hypertens. 2012;30:1775–81. 
5. Wu GC, Leng RX, Lu Q, Fan YG, Wang DG, Ye DQ. Subclinical atherosclerosis in patients with inflammatory bowel diseases: a systematic review and meta-analysis. Angiology. 2017;68:447–461.
6. Aniwan S, Pardi DS, Tremaine WJ, Loftus EV Jr. Increased risk of acute myocardial infarction and heart failure in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2018. pii: S1542-3565(18)30390-2. [Epub ahead of print]
7. Singh S, Singh H, Loftus EV Jr, Pardi DS. Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12:382–93.
8. Osterman MT, Yang YX, Brensinger C, et al. No increased risk of myocardial infarction among patients with ulcerative colitis or Crohn's disease. Clin Gastroenterol Hepatol. 2011;9:875–80.
9. Fumery M, Xiaocang C, Dauchet L, Gower-Rousseau C, Peyrin-Biroulet L, Colombel JF. Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: a meta-analysis of observational studies. J Crohns Colitis. 2014;8:469–79.

Christina Kapizioni is a gastroenterology trainee in Athens, Greece. She is also currently undertaking her PhD at the 2nd Department of Surgery, Aretaieion University Hospital in Athens. She is investigating blood and stool biomarkers of treatment response in IBD patients.

Christina Kapizioni  © Christina Kapizioni