Inflammatory bowel disease (Crohn’s disease, ulcerative colitis) is characterised by chronic inflammation of the intestine. Inflammation of gut causes increased intestinal permeability, which triggers immune response to the luminal antigens.Reference Conrad, Roggenbuck and Laass1, Reference Laass, Roggenbuck and Conrad2 Therefore, inflammatory bowel disease is a systemic disorder that is not restricted to the intestinal tract solely. Extraintestinal involvement is seen in 20–40% inflammatory bowel disease patients.Reference Yu and Rodriguez3, Reference Agrawal, Rukkannagari and Kethu4
Myocardial, pericardial, valvular, and vascular involvement can be seen in inflammatory bowel disease.Reference Dubowitz and Gorard5, Reference Gaduputi, Tariq and Kanneganti6 Venous thromboembolism and ischemic heart disease are the other problems.Reference Branchford and Carpenter7, Reference Le Gall, Kirchgesner and Bejaoui8
Besides acute inflammatory exacerbations of inflammatory bowel disease, there is an ongoing chronic inflammation in remission periods. Classical cardiovascular risk factors such as obesity, diabetes, dyslipidemia, and hypertension are lower in inflammatory bowel disease patients than normal population.Reference Levy, Rizwan and Thibault9, Reference Jahnsen, Falch and Mowinckel10 This gives an opportunity to evaluate the effects of chronic inflammation on myocardial function and elasticity of the great vessels in inflammatory bowel disease ideally. Subclinical myocardial systolic and diastolic dysfunctions were shown by strain echocardiography in both paediatric and adult inflammatory bowel disease patients.Reference Kıvrak, Sunbul and Cincin11 Elasticity of aorta was shown to be related to the disease activity in adult inflammatory bowel disease patients.Reference Zanoli, Ozturk and Cappello12 Also, there is no study investigating aortic elasticity in remission periods either in adults or in children.
It is known that age at diagnosis in inflammatory bowel disease has a prognostic effect on disease progression. Diagnosis of inflammatory bowel disease before 10 years of age causes differences in disease location and treatment.Reference Levine, Griffiths and Markowitz13 These differences were related to genetic factors. Myocardial involvement or aortic elasticity properties are not known in this patient group. We subgrouped inflammatory bowel disease patients according to disease onset and studied left ventricular dimensions, systolic and diastolic functions, and aortic elasticity.
Method
Patients
Patients in remission period followed with diagnosis of inflammatory bowel disease in paediatric gastroenterology clinic were admitted to the study. Patients were in remission period for at least 1 year. There were 33 inflammatory bowel disease patients (17 male/16 female; 5–18 years of age, mean age 13.3 ± 3.9; 15 Chron’s disease and 18 ulcerative colitis) in study group and 25 patients (13 male/12 female; 6–18 years of age, mean age 11.6 ± 4) in control group. Patients were divided into subgroups according to age at diagnosis (early-onset inflammatory bowel disease was defined as the patients diagnosed under 10 years of age and late-onset inflammatory bowel disease was defined as the patients diagnosed over 10 years of age). There were 14 early-onset inflammatory bowel disease patients (mean age 9.5 ± 2.9) and 19 late-onset inflammatory bowel disease patients (mean age 16.1 ± 1.25) in study group. Comparison between these groups was not susceptible as mean ages of early and late onset were not similar to each other. Left ventricular dimensions and Doppler measurements are age-dependent, so statistical evaluation was performed within early-onset inflammatory bowel disease versus control group and late-onset inflammatory bowel disease versus control group. Inflammatory bowel disease was diagnosed by using clinical symptoms, radiological, endoscopic, and histopathological findings. The duration of disease, disease activity index according to paediatric ulcerative colitis activity index, and paediatric Crohn’s disease activity index were obtained from patients’ medical recordings.Reference Turner, Otley and Mack14, Reference Hyams, Markowitz and Otley15 All patients had no other systemic or cardiac disease. Blood pressure of all patients was measured by sphygmomanometry before echocardiographic evaluation. Serum glucose level and lipid profile were examined. None of them had diagnosis of diabetes mellitus, hypertension, and hyperlipidemia.
Control patients were healthy children who referred to paediatric cardiology clinic with innocent murmur. Patients gave written consents for the study and the study was approved by the local ethics committee in Istanbul University of Health Sciences, Umraniye Education and Research Hospital on 25 June, 2018.
Echocardiography
Echocardiographic evaluation was performed in all subjects using Philips Affiniti 50C (22100 Bothell – Everett Highway Bothell, VVA 98021-8431) echocardiography machine and 8–4 MHz transducer. Left ventricular systolic and diastolic diameters (LVSd, LVDd), diameter of interventricular septum (IVSd), and left ventricular posterior wall (LVPWd) were measured by M-Mode echocardiography in parasternal long-axis view, and ejection fraction (EF) and shortening fraction (SF) were calculated from M-Mode measurements. Mitral inflow parameters, mitral E velocity, mitral A velocity, deceleration time (DT), and interventricular contraction time (IVRT) were evaluated by pulsed wave Doppler echocardiography. Mitral E′ wave, mitral A′ wave, isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT), and ejection time (ET) were measured by tissue Doppler echocaridography. Myocardial performance index was calculated according to formula IVCT + IVRT/ET. Systolic and diastolic diameters of ascending aorta and abdominal aorta were measured, and strain, distensibility (DIS), and stiffness index (SI) were calculated according to below formulas:
$${\rm{Aortic}}\,\,{\rm{strain}}\,{\rm{(\% ) = 100 \times }}\left( {{\rm{Systolic}}\,{\rm{diameter - Diastolic}}\,{\rm{diameter}}} \right)/{\rm{Diastolic}}\,{\rm{diameter}}$$
$${\rm{Aortic}}{\mkern 1mu} {\mkern 1mu} {\rm{stiffness}}{\mkern 1mu} {\mkern 1mu} {\rm{index = logarithm }}{\mkern 1mu} ({\rm{Systolic}}{\mkern 1mu} {\rm{blood}}{\mkern 1mu} \,{\rm{pressure/Diastolic}}{\mkern 1mu} {\rm{blood}}{\mkern 1mu} {\rm{pressure}}){\rm{/}}(({\rm{Systolic}}{\mkern 1mu} {\rm{diameter - Diastolic}}{\mkern 1mu} {\rm{diameter}}){\rm{/Diastolic}}{\mkern 1mu} {\rm{diameter}})$$
$${\rm{Aortic \,\,distensibility}}\,{\rm{(c}}{{\rm{m}}^{\rm{2}}}{\rm{/dy}}{{\rm{n}}^{\rm{2}}}{\rm{/1}}{{\rm{0}}^{ - {\rm{6}}}}{\rm{) = 2 \times }}\left( {{\rm{Systolic\, diameter}} - {\rm{Diastolic\, diameter}}} \right){\rm{/}}\left( {{\rm{Diastolic\, aortic\, diameter}}} \right){\rm{ \times }}\left( {{\rm{Systolic\, blood\, pressure}} - {\rm{Diastolic\, blood\, pressure}}} \right)$$
Statistical analysis
The data were analysed using SPSS 22 software package (IBM Corp., Armonk, New York, United States of America). The distribution of normality was analysed using Kolmogorov–Simirnov test. Data were expressed as mean ± standard deviation or median and range for continuous variables; for categorical variables, number and percentages (%) were expressed. Comparison of groups’ inflammatory bowel disease versus control and early-onset inflammatory bowel disease versus control and late-onset inflammatory bowel disease versus control was made by using Student t-test and Mann–Whitney U-test whichever is appropriate. Spearman rank correlation coefficient was used for analysis of correlations between variables. Statistical significance was considered a p <0.05.
Results
Patients
The mean duration of illness was 29.4 ± 23.4 months (3–96 months, median time = 2 months; 1–84 months, median time = 23 months). Activity index of patients at diagnosis was 51.3 ± 12.8 (35–85, median = 50) and activity index during the clinical evaluation of the study was 7.1 ± 8.4 (0–30, median = 5). The average age of the study group was 13.3 ± 3.9, the mean age was 9.5 ± 2.97 in early-onset inflammatory bowel disease, 16 ± 1.2 in late-onset inflammatory bowel disease, and 11.6 ± 4 in control group. There was statistically significant difference between early-onset inflammatory bowel disease and late-onset inflammatory bowel disease groups in terms of age (p = 0.04). However, there was no statistical significance in comparison of age in groups’ between early-onset inflammatory bowel disease versus control and late-onset inflammatory bowel disease versus control. One patient had perianal involvement and four patients had extraintestinal involvement. Nine of the patients were under Mesalamine treatment and 18 of them were treated with Mesalamine and Azathiopurine, 3 patients were taking Infliximab in addition to Mesalamine, and 3 patients were taking Infliximab, Mesalamine, and Azathiopurine therapy. Demographic and clinical data were shown in Table 1.
Table 1. Demographic and clinical data of IBD and control patients
BMI = body mass index; DBP = diastolic blood pressure; DT = desceleration time; ET = ejection time; IBD = inflammatory bowel disease; IVCT = isovolumetric contraction time; IVRT = isovolumetric relaxation time; IVSd = interventricular septal diameter; LVDd = left ventricular diastolic diameter; LVPWd = left ventricular posterior wall diameter; LVSd = left ventricular systolic diameter; m2 = body surface area; Mitral A = mitral peak late wave velocity; Mitral A′ = tissue Doppler imaging septal annular velocity during atrial contraction; Mitral E = mitral peak early wave velocity; Mitral E′ = tissue Doppler imaging mitral early diastolic septal annular velocity; MPI = myocardial performance index; PP = pulse pressure; SBP = systolic blood pressure; SI = stiffness index.
Echocardiography
M-mode echocardiography and mitral inflow parameters
In early-onset inflammatory bowel disease patients, interventricular septum (mm) was thicker (6.9 ± 1.2) than control patients (6.1 ± 1.27) (p = 0.050). Left ventricular end-systolic diameter (mm) was higher in early-onset inflammatory bowel disease patients (26.2 ± 4.6) than control patients (22.7 ± 4.12) (p = 0.050) (Table 2).
Table 2. Echocardiographic features and aortic elasticity parameters of early-onset and late-onset inflammatory bowel disease and control patients
DIS = distensibilite; DT = desceleration time; ET = ejection time; IBD = inflammatory bowel disease; IVCT = isovolumetric contraction time; IVRT = isovolumetric relaxation time; IVSd = interventricular septal diameter; LVDd = left ventricular diastolic diameter; LVPWd = left ventricular posterior wall diameter; LVSd = left ventricular systolic diameter; Mitral A = mitral peak late wave velocity; Mitral A′ = tissue Doppler imaging septal annular velocity during atrial contraction; Mitral E = mitral peak early wave velocity; Mitral E′ = tissue Doppler imaging mitral early diastolic septal annular velocity; MPI = myocardial performance index; SI = stiffness index.
* p: early-onset IBD versus control.
** p: late-onset IBD versus control.
Mitral E/A ratio was lower in inflammatory bowel disease patients (1.46 ± 0.32) than control patients (1.70 ± 0.27) (p = 0.013). DT (seconds) was longer in inflammatory bowel disease patients (151.1 ± 26.4 seconds) than control patients (127 ± 44.7 seconds) (p = 0.045).
Mitral A was higher in early-onset inflammatory bowel disease patients (68.3 ± 10.6) than control patients (59.1 ± 13.4) (p = 0.012). Mitral E/A ratio was lower in early-onset inflammatory bowel disease patients (1.4 ± 0.21) than control patients (1.70 ± 0.27) (p = 0.004). DT (seconds) was longer in early-onset inflammatory bowel disease patients (149.2 ± 28.3) than control patients (127 ± 44.7) (p = 0.012). Tissue Doppler echocardiography revealed increment of E/E′ ratio and myocardial performance index in inflammatory bowel disease and early-onset inflammatory bowel disease groups according to control group (p = 0.046, p = 0.04; p = 0.023, p = 0.033). E′ was decreased in early-onset inflammatory bowel disease than control group (p = 0.05) (Table 2).
Elasticity parameters
There was no statistically significant difference in aortic elasticity parameters of ascending and abdominal aorta between inflammatory bowel disease and control patients. Elasticity parameters did not differ between early-onset and control patients and between late-onset and control patients (Table 2).
Discussion
Inflammatory bowel disease is a chronic inflammatory disease with exacerbation and remission periods. During acute exacerbations, endocardial, myocardial, and pericardial involvement are expected.Reference Branchford and Carpenter7, Reference Kreuzpaintner, Horstkotte and Heyll16 In remission periods, inflammation continues at low grade.
It is well known that inflammation causes endothelial dysfunction and has effects on structure and function of arterial wall.Reference Roifman, Sun and Fedwick17, Reference Zieman, Melenovsky and Kass18 Endothelial dysfunction exists not only in the endothelium of gut in inflammatory bowel disease, it has arterial extent. Chronic systemic low-grade inflammation affects both endothelial function and elastic properties of the great vessels. Inflammatory mediators causes increased matrix metalloproteinase activity and elastin degradation in the arterial wall inducing impaired arterial stiffness.Reference Wang, Zhang and Jiang19 Arterial stiffness is a marker of the end organ damage of systemic inflammation and accepted as a predictor of cardiovascular mortality and morbidity.Reference Arnett, Evans and Riley20 Increased arterial stiffness was found in adult inflammatory bowel disease patients.Reference Zanoli, Rastelli and Granata21, Reference Zanoli, Boutouyrie and Fatuzzo22 Meta-analysis found a link between inflammation and aortic stiffness in inflammatory bowel disease patients and it was related to the duration of the disease.Reference Zanoli, Rastelli and Granata21 There is only one study evaluating the arterial stiffness in children which did not found a statistical difference between inflammatory bowel disease and control patients. In that study the remission rate of patients was 68%.Reference Lurz, Aeschbacher and Carman23 In our study, all of the patients were in remission and there was no statistically significant difference in the elasticity of ascending and abdominal aorta between groups and subgroups. As arterial stiffening is an early marker of cardiovascular risk, it should be followed up in young adulthood. Our study showed that arterial stiffening was not increased in children while they were in remission.
Endocardial endothelium which is a biologic barrier between blood and myocytes has effects on myocyte contractility and remodelling via endocrine signalling.Reference Noireaud and Andriantsitohaina24, Reference Balligand, Feron and Dessy25 Endocardial endothelial function was found to be impaired in inflammation.Reference Smiljić, Nestorović and Savić26–Reference Kensuke28 Endocardial endothelial dysfunction may explain the subclinical diastolic dysfunction in inflammatory bowel disease. In our study, decreased E/A ratio and prolonged DT in inflammatory bowel disease patients indicate impaired diastolic function. Tissue Doppler echocardiography revealed impaired myocardial performance index and E/E′ in inflammatory bowel disease and early onset-inflammatory bowel disease patients according to control patients. In previous studies, diastolic dysfunction was shown in both paediatric and adult inflammatory bowel disease patients.Reference Kıvrak, Sunbul and Cincin11, Reference Hensel, Abellan Schneyder and Wilke29 Also, diastolic dysfunction was found to be correlated to coronary microvascular dysfunction in adult patients with no coronary risk factors in inflammatory bowel disease patients.Reference Caliskan, Gokturk and Caliskan30
Early-onset inflammatory bowel disease defined as a monogenic inflammatory bowel disease group which is characterised with hyperinflammation and accompanied by autoinflammatory disorders. Monogenic disorders are more resistant to conventional therapy and have a high morbidity and mortality. Early-onset inflammatory bowel disease patients had impaired myocardial diastolic function when compared with control patients, while there was no difference between late-onset inflammatory bowel disease patients and control patients in our study.
Left ventricular EF was found to be depressed; left atrial enlargement and increased interventricular septum thickness were revealed in adult inflammatory bowel disease patients in previous studies.Reference Vizzardi, Sciatti and Bonadei31, Reference Bragagni, Brogna and Franceschetti32 Left ventricular end-systolic dimension has a prognostic importance on reverse remodelling in patients diagnosed with heart failure.Reference Pradeep, Bhat and Mahi33 Left ventricular myocardial performance parameters were found to be depressed by speckle tracking echocardiography in inflammatory bowel disease.Reference Kıvrak, Sunbul and Cincin11, Reference Hensel, Abellan Schneyder and Wilke29 In our study, we determined increase in septal and left ventricular end-systolic diameter in patients with early-onset inflammatory bowel disease. We can conclude that precaution in cardiac evaluation is necessary in early-onset inflammatory bowel disease subgroup.
Limitations
However, this study consisted of small participants’ number; it gives information of both aortic elasticity and cardiac function in early- and late-onset inflammatory bowel disease patients in remission period. Although pulse wave velocity is the recommended method for determination of aortic elasticity properties in both children and adults, transthoracic echocardiographic evaluation of aortic elasticity is feasible.Reference Pradeep, Bhat and Mahi33, Reference Hensel, Abellan Schneyder and Wilke29
Conclusion
We demonstrated diastolic dysfunction and enlargement of systolic left ventricular dimension in early-onset inflammatory bowel disease patients in remission period. Aortic elasticity was not impaired in remission in our study. Long-term follow-up of aortic elasticity parameters in inflammatory bowel disease patients and attention to cardiac involvement in early-onset inflammatory bowel disease subgroup are needed.
Acknowledgments
None.
Financial Statement
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Conflict of Interest
None.
