The role of chronic inflammation as a triggering factor for atherosclerotic cardiovascular disease (CVD) in systemic autoimmune diseases, such as rheumatoid arthritis and lupus erythematosus, is well established.
Inflammatory bowel disease (IBD) consisting of Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by a chronic relapsing-remitting or ongoing course leading to chronic intestinal and systemic inflammation.
Although subclinical markers of CVD, including inflammatory mediators such as CRP, or indices of endothelial dysfunction, are increased among IBD patients, a strong link between IBD and cardiovascular risk has not been demonstrated so far.
Cohort studies and a recent meta-analysis have shown that factors such as age, sex, and clinical characteristics, disease extent, and disease activity may be involved in the development of CVD, but robust data are lacking.
Disease severity reflects the overall disease burden since IBD diagnosis, including the impact of the disease on the patient’s symptoms and daily activities, fatigue, social and professional life, and also use of steroids or biological agents. , intestinal resections and hospitalizations.
Therefore, patients with more severe disease likely have a higher risk of cardiovascular complications.
The authors hypothesized that patients with IBD and coexisting CVD might have more severe disease compared to patients without CVD. Therefore, the aim of the present study was to investigate any possible effects of IBD-related inflammatory burden on the cardiovascular system by comparing disease severity parameters between IBD patients with or without a history of CVD.
Methods
We included 103 inflammatory bowel disease patients with concomitant cardiovascular disease compared to 206 age- and sex-matched inflammatory bowel disease patients without cardiovascular disease referred from three referral centers. Traditional cardiovascular disease factors and inflammatory bowel disease severity parameters were compared between the two groups.
Results
Among the 103 IBD patients with CVD, a history of ischemic heart disease (IHD) including myocardial infarction, angina or asymptomatic chronic coronary artery disease was reported in 63 (61.2%) patients, cerebrovascular diseases (ischemic stroke, hemorrhagic stroke or transient ischemic attack) in 29 (28.2%), peripheral arterial disease (PAD) in three (2.9%) and heart failure in 17 (16.5%) patients with IBD.
The combination of more than one CVD was found in four patients with IBD. The diagnosis of CVD followed the diagnosis of IBD in 56.6% of cases. No differences were found in the prevalence of severe disease, regardless of whether or not the IBD diagnosis preceded the CVD diagnosis (64.1% vs. 72.5%, p = 0.692).
Compared with patients in the control group, patients with IBD and concurrent CVD were more frequently obese (BMI > 30, P < 0.001) and former or current smokers. With respect to parameters related to disease severity, no statistically significant differences were observed between cases and controls for exposure to immunosuppressants, anti-TNF, and systemic corticosteroids, as well as in rates of IBD-related surgery.
Interestingly, patients with CVD trended toward lower rates of multiple hospitalizations (>3) for IBD exacerbations than patients without CVD. As expected, diabetes, dyslipidemia, high blood pressure, use of antiplatelets or antithrombotics were reported significantly more often in patients with CVD. The mean glucose value was higher in patients with CVD, who in turn had lower total cholesterol values than the control group (probably explained by the more frequent use of statins in this group).
PCR in terms of disease activity was available in 39.6% of IBD patients with a CV event after IBD diagnosis. Elevated CRP values were found only in 7 (30.4%) of them. Regarding clinical indices of disease activity, quality of life or biomarkers, no significant differences were found between the two groups.
Multivariate regression analysis revealed significantly higher rates of classic CV risk factors in the patient group, as expected. The number of IBD-related surgeries was lower in the CVD group, but it was not statistically significant.
There were no statistically significant differences between the UC or CD patient groups and the control groups in any parameter associated with disease severity, such as use of anti-TNF, immunomodulators or steroids, IBD-related surgery, hospitalizations for exacerbations or PCR at 3 years.
In line with previous findings, none of the subgroup analyzes of patients with a history of CVD after IBD diagnosis compared with the control group confirmed any association between CVD risk and factors related to IBD severity.
Discussion
This study represents the first effort to investigate the effect of IBD-related systemic inflammation on the cardiovascular system, taking into account not only traditional CV risk factors but also parameters associated with disease severity over time. , since the diagnosis of IBD. However, no differences were found in terms of disease severity between IBD patients with and without coexisting CVD.
Nationwide cohort studies in Denmark have shown an increased risk of IHD, especially during the first year after IBD diagnosis and during periods of IBD activity. In a more recent meta-analysis, female sex and age <50 years were associated with an increased risk of IHD in IBD patients. Regarding the extent of the disease, Aniwan et al. reported a three-fold increased risk of acute myocardial infarction in patients with CD with ileal/ileocecal location and patients with UC with extensive colitis.
Consequently, IHD, risk of cerebrovascular disease, risk of PAD, and overall rate of acute arterial events have been significantly increased during periods of IBD activity in female and younger patients. Recent studies have demonstrated an increased risk of hospitalization for heart failure during periods of active disease and a higher cumulative incidence of heart failure among patients with IBD.
The originality of this study is based on the comparison of IBD patients of similar sexes and ages with and without CVD in an attempt to isolate and examine the role of chronic disease inflammation in the atherosclerotic process.
The authors assume that chronic inflammation may be a possible additional CVD factor in both IBD groups and sought to identify whether patients with a history of IHD, cerebrovascular event, PAD, or heart failure had a more complicated disease course.
Contrary to the proposed hypothesis, the inflammatory load measured by selected markers related to the general course of IBD does not appear to affect the cardiovascular system. Our study confirmed that traditional risk factors for CVD play the main and fundamental role for atherosclerosis in patients with IBD.
The fact that CVD diagnosis followed IBD diagnosis in 56.6% of cases further weakens the assumption of a possible association between chronic inflammation in IBD and CV risk. With respect to inflammatory biomarkers, a minority of IBD patients with a CV event after IBD diagnosis had elevated CRP, but the small number does not allow us to draw firm conclusions.
In contrast to expected, CVD patients had a trend for even lower hospitalizations for exacerbations and IBD-related surgeries compared to controls. A possible explanation for this finding could be the influence of other factors, such as the immunomodulatory effect of drugs used in cardiovascular diseases on the intestinal epithelium.
Clinical studies have shown that statins commonly used in cardiovascular disease can improve disease activity scores, reduce rates of steroid use, and protect against de novo IBD .
Furthermore, studies in experimental colitis have also found that statins can improve macroscopic and microscopic inflammation, alter intestinal epithelium, induce changes in microflora, and mitigate intestinal fibrosis.
Furthermore, antihypertensive use was significantly higher among IBD patients with a history of CVD as expected. Given the antifibrotic and anti-inflammatory properties, especially for certain classes of antihypertensives such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in experimental models of colitis, antihypertensives could affect the course of IBD, but clinical studies have not investigated its role in IBD patients until now.
Limited studies examining the possible protective role of clopidogrel in the course of IBD have shown no effect in inducing clinical remission over placebo. In this study, antiplatelet use was significantly higher in IBD patients with a history of CVD, but their exact role in the course of IBD is unclear.
Biomarkers of inflammation and especially CRP have been linked to the development of atherosclerosis. In the present study, persistent elevation of CRP was not found to be different between patients with or without CVD. Markers of arterial stiffness associated with longer disease duration have recently been reported, suggesting a role for disease duration in atherosclerosis.
Limitations of the present study are the retrospective design of the study and the relatively small sample size corresponding to the low prevalence of CVD in patients with IBD. However, the authors believe that using CVD-free controls in a 2:1 ratio increases the strength of the study.
Considering that the diagnosis of CD and CVD leads to a considerable reduction in smoking rates, we have noted a remarkably high rate of ex-smokers (>50% in both groups). Therefore, the lack of quantification of smoking in pack years and the exact timing of cessation could likely underestimate its role as a risk factor for more severe disease.
Conclusion
This study showed no differences in disease severity measured with surrogate markers (persistent elevation of CRP, IBD-related surgeries, hospitalizations, and use of biologics or immunosuppressants) between patients with IBD and concomitant CVD and patients with IBD without CVD.
It could be suggested that inflammatory burden possibly plays a less important role in the development of CVD in IBD patients. On the other hand, traditional CVD risk factors seem to play a fundamental role for atherosclerosis in patients with IBD. Data from larger prospective studies are essential to confirm our findings.
