Introduction
Inflammatory bowel disease (IBD): [Crohn’s disease (CD) or ulcerative colitis (UC)] is the result of an immune response in individuals with genetic predisposition. It is thought that luminal antigens cause systemic immunoreaction due to increased intestinal permeability. Triggered systemic inflammation results in fibrosis and dysfunction in the extraintestinal organs (1,2). Inflammation has effects on cardiac structures either in an occult or overt manner. In acute exacerbation periods, pericarditis, myocarditis, arteritis, valvular regurgitation and tromboembolic events can be seen (3-5). Subtle myocardial involvement was shown in a few studies due to ongoing chronic low grade inflammation (6-8). We studied myocardial functions with conventional echocardiography and strain echocardiography, which gives more reliable information about global and segmental myocardial function. We investigated the effect of the severity of disease activity at the time of diagnosis on current myocardial functions by strain echocardiography. Patients in a remission period were chosen to exclude the effects of any increased inflammation of the active disease on myocardium.
Materials and Methods
Of the 42 IBD patients followed up in two different paediatric gastroenterology centres, 34 patients in remission were included in this study. Additionally, twenty-one healthy children were evaluated as a control group. The control group comprised patients referred to a paediatric gastroenterology clinic with non-specific abdominal pain with no systemic or cardiovascular disease. The diagnosis of 16 patients in the study group was CD and 18 of them were UC. The inclusion criteria of the study group was being in a remission period. IBD diagnosis was made based on clinical symptoms, radiological, endoscopic, and histopathological features according to the Montreal Classification and revised Porto Criteria (9,10). Paediatric CD activity index and paediatric UC activity index were recorded from the patients’ medical records (11,12). The actual height, weight and blood pressure of all the patients were recorded. Body mass index (BMI) was obtained by means of the formula weight (kg)/height2 (m). Patients groups were established according to disease activity at the time of diagnosis as either mild or severe disease activity. There were no patients with moderate disease activity at the time of diagnosis. Written consent for the study was obtained from the parents of all the patients and this study was approved by the local ethics committee of the University of Health Sciences Turkey, Kanuni Sultan Süleyman Training and Research Hospital (approval no: 06, date: 29.06.2018).
Echocardiographic Protocols and Definitions
Echocardiographic evaluation was performed using a Philips Affiniti 50C (Release 2.0.2 3000 Minuteman Road Andover, MA 01810 USA) echocardiography machine and 8-4 Mhz transducer in all subjects. Left ventricular diameters and systolic functions were assessed by M-mode echocardiography at a parasternal long axis view. Pulsed wave Doppler was performed to determine the mitral inflow parameters, namely, mitral E velocity, mitral A velocity, interventricular contraction time and deceleration time (DT).
For strain analysis, standard 2D grayscale images of LV were performed. Apical 4-chamber, 3-chamber and 2-chamber (AP4, AP3 AP2, respectively) views were obtained for the longitudinal strain of LV as previously described (13). Circumferential strain was obtained by parasternal short-axis views at the mitral valve plane, papillary muscle plane and apical plane (SAXB, SAXM, SAXA, respectively).
Synchronized with continuous electrocardiography, five consecutive cardiac cycles were recorded with frame rate of 60 and 90 frames per second. At end-systole, seven segments for longitudinal strain and six segments for circumferential strain were assessed by tracing the endocardial border line manually. Global longitudinal strain was obtained from the apical four-three-two chamber views and circumferential strain was obtained from the basal, mid-cavity, apical short axis views using speckle-tracking echocardiography software package (QLAB advanced ultrasound quantification soft release 10.4).
Statistical Analysis
Twenty-two software package (IBM Corp., Armonk, NY, USA) was used for the analysis of the data. The Kolmogorov-Smirnov test was used to determine the distribution of normality. Data is expressed as mean ± standard deviation for variables; number and percentages (%) are given for categorical variables, Mann-Whitney U and Student’s t-test were used for the comparison of groups, whichever being more appropriate. For the analysis of correlations, the Spearman rank correlation coefficient was used. Statistical significance was considered at a p-value <0.05.
Results
This study consisted of 34 IBD patients (median: 11 years, range: 5-17 years, 10.9±3.9 years of age; 16 CD and 18 UC) and 21 healthy children (median: 12.5 years, range: 5-18 years, 11.6±4 years of age) as a control group (p=0.15). All patients in the IBD and control groups and in the subgroups of severe or mild disease activity were comparable in terms of age, sex, height, weight and BMI. Their demographic data is shown in Table I.
Eleven patients were undergoing mesalamine therapy, 23 patients were receiving mesalamine and azathiopurine therapy, 3 patients were being treated with mesalamine and infliximab and 1 patient was receiving treatment with mesalamine, azathiopurine and infliximab. The duration of the disease was 29.4±23.4 months (median: 28 months; range: 3-96 months), the duration of treatment was 23.8±19.8 months (median: 23 months; range: 1-84 months), the activity index at the time of diagnosis was 51.3±12.8 (median: 50; range: 35-85), the activity index at the time of test was 7.1±8.4 (median: 5; range: 0-30). There were 3 patients who had perianal disease, 4 patients who had extra intestinal disease, and one patient who had perianal and extra intestinal disease.
Four CD and 12 UC patients had mild activity index and 12 CD and 6 UC patients had severe activity index at the time of diagnosis.
There were no statistically significant differences between the groups and subgroups in terms of left ventricular diameters, ejection fraction (EF%), and shortening fraction (SF%). Mitral inflow parameters revealed decreased mitral E and DT in IBD patients in comparison to the control patients (p=0.05, p=0.04) (Table II). DT was lower in IBD patients with severe disease activity in comparison to the control group and those IBD patients with mild disease activity (p=0.006, p=0.05) (Table III). Mitral E was lower in CD patients than in the control patients (p=0.038) and DT was lower in UC patients than in the control patients (p=0.02). Other conventional echocardiographic parameters were not statistically significantly different between the UC, CD and control group patients (Table IV).
Strain Echocardiography
There was no statistical difference between the IBD and control patients in terms of the strain parameters of the left ventricle (Table II).
The strain value of LVAP4 was lower in those patients with CD (-17.1±3.3) than in patients with UC (-19.1±2.3) (p=0.046) (Table IV). The GLLV, LVAP4, and LVAP3 strain values were lower in the CD group than in the control patients (p=0.046, p=0.048, p=0.046 respectively).
In patients with severe disease activity at diagnosis, the strain values of GLLV (-17.1±2.9 vs -18.7±1.79), LVAP3 (-16.4±3.24 vs -19±2.8) and LVAP4 (-17.8±3.5 vs -19±2.5) were lower than in those patients with mild disease activity at the time of diagnosis (p=0.043, p=0.032, p=0.028, respectively). In addition, the strain values of GLLV (-17.1±2.9, vs -18±2.04) LVAP3 (-16.4±3.24 vs -17.7±2.7), and LVAP4 (-17.8±3.5 vs -18.5±2.1) were lower in those IBD patients with severe disease activity than in the control patients (p=0.044, p=0.018, p=0.028, respectively) (Table III).
Disease activity at the time of diagnosis was inversely correlated to EF (%) (p=0.047 r=-0.50) and the strain values of GLLV (p=0.016, r=-0.57), LVAP3 (p=0.029, r=-0.53), and LVAP2 (p=0.011, r=-0.53) in UC patients.
Discussion
IBD is a chronic inflammatory immune mediated disease with acute exacerbation and remission periods. Chronic inflammation exists systemically, extending beyond the gut in addition to local inflammation. The status of chronic inflammation is the main cause of extra intestinal manifestations. Cardiac involvement is often in the form of pericarditis and myocarditis during acute exacerbation periods (14-16). Endocarditis, atrioventricular block and arrhythmias are the other forms of cardiac involvement in IBD (17,18). Subtle myocardial involvement in IBD patients was shown in a few studies via strain echocardiography (6-8). Subclinical myocardial involvement cannot be shown by standard conventional echocardiography because of its limitations, such as being angle and geometry dependent and also being affected by volume load. Strain echocardiography provides segmental myocardial wall functions and is not dependent on the angle or the user.
Hensel et al. (6) showed that the global strain rate was depressed in paediatric IBD patients who were in active or remission periods in comparison to control patients. We demonstrated that children with severe disease activity at diagnosis had worse global longitudinal strain than those children with mild disease activity at diagnosis.
It was revealed that the disease activity index of CD was inversely correlated to the global longitudinal strain of LV in adult IBD patients (7). In adult patients with CD and UC disease, the activity index was correlated inversely to the global longitudinal strain (7,8). Hensel et al. (6) found no difference in terms of myocardial functions shown by strain echocardiography between CD and UC patients. However, we showed that the longitudinal strain parameters were depressed in CD in comparison to both the control patients and the UC patients. On the other hand, we found that disease activity at diagnosis was inversely correlated to the EF% and global strain value of the left ventricle in paediatric UC patients.
Chronic inflammation is associated with increased collagen type I, III, and V in IBD patients (19-23). The increased synthesis of procollagen type 3 also plays a role in the fibrosis process of other organs such as the pancreas, lungs and liver in IBD (23-25). Abnormal collagen deposition (increased serum procollagen 3 peptides) in peripheral circulation and the degradation of type I collagen was shown in IBD cases (19,20). Increased procollagen type 3 is a marker used in the follow-up and prediction of the prognosis in dilated cardiomyopathy and heart failure (26,27). In the adult group, the risk of cardiac disease-related hospitalization was found to be 37%, especially in the acute exacerbation phase of the disease (28). Acute hyperinflammation is another important risk factor for myocardial decompensation. Fibrosis and fibrosis related abnormal collagen composition may be the cause of ventricular volume increases and myocardial dysfunction. Thickening of the mitral valve and mitral valve prolapse may be associated with this finding in IBD patients (29).
Altered endothelial dysfunction was shown in the gut of IBD patients (30). Endothelial dysfunction is not restricted to the gut endothelium, but it is seen in the entire endothelium as a marker of the systemic extent of the inflammation (31,32).
Decreased mitral E and DT shows impairment in the early filling of the left ventricle, especially in those patients with severe disease activity. The effect of both chronic inflammation and flares of acute exacerbations on myocardial function and cardiovascular health has been shown in studies in adult IBD patients. It has been shown that adult IBD patients have coronary microvascular dysfunction leading to myocardial systolic and diastolic dysfunction (33). A study conducted with the adult population revealed that for myocardial infarction, having IBD is an independent risk factor (34).
We demonstrated the effect of disease severity at the time of diagnosis on long-term myocardial function. In paediatric patients, the negative effects of systemic inflammation on myocardium at the time of diagnosis continue even after the patient is in remission. In our study, the myocardial functions of children with severe disease activity at the time of diagnosis, ascertained via strain echocardiography, were found to be impaired compared to those with mild disease activity at the time of diagnosis. We could not find any difference between the IBD and control patients in terms of myocardial functions via strain echocardiography. This may be due to the shortness of the follow-up period and the fact that the patients were in remission. We can conclude that “the more severe the inflammation is at the time of diagnosis, the more subclinical myocardial dysfunction there is in the long term”.
Conclusion
Our study revealed that the severity of disease activity at the time of diagnosis has long-lasting effects on myocardial functions in those children with IBD. In this study, the systolic dysfunction of our patients was assessed after a rather short follow-up period. A longer term follow-up study to observe myocardial functions in IBD patients with both mild and severe disease activity is needed in future studies.
Ethics
Ethics Committee Approval: This study was approved by the local ethics committee in University of Health Sciences Turkey, Kanuni Sultan Süleyman Training and Research Hospital (approval number: 06, date: 29.06.2018).
Informed Consent: Written consents for the study were taken from the parents of the all patients.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Design: E.P., E.E., N.G., H.A.C., Data Collection or Processing: N.G., H.A.C., Analysis or Interpretation: E.E., Literature Search: E.E., Writing: E.P., E.E.
Conflict of Interest: The authors declare that they have no conflict of interest.
Financial Disclosure: The authors declared that this study received no financial support.
