Microvascular Research 97 (2015) 25–30

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Impaired coronary microvascular and left ventricular diastolic function in patients with inflammatory bowel disease Zuhal Caliskan a,⁎, Huseyin Savas Gokturk a, Mustafa Caliskan b, Hakan Gullu b, Ozgur Ciftci b, Gülsüm Teke Ozgur a, Aytekin Guven b, Haldun Selcuk a a b

Baskent University, Konya Teaching and Medical Research Center, Gastroenterology Department, Konya, Turkey Baskent University, Konya Teaching and Medical Research Center, Cardiology Department, Konya, Turkey

a r t i c l e

i n f o

Article history: Accepted 7 August 2014 Available online 14 August 2014 Keywords: Inflammatory bowel disease Coronary flow reserve Echocardiography Atherosclerosis Microvascular function

a b s t r a c t Background and aim: Increased incidence of coronary vascular events in patients with inflammatory bowel disease (IBD) is known. However, the association between coronary microvascular function and IBD has not been fully defined. We aimed to investigate whether coronary flow reserve (CFR) and left ventricular diastolic function were impaired in IBD patients. Methods: Seventy-two patients with IBD (36 patients with ulcerative colitis [UC] and 36 Crohn's disease [CD]) were registered. Each subject was evaluated after a minimum 15-day attack-free period. For the control group, 36 age- and sex-matched healthy volunteers were included into the study. IBD clinical disease activity in UC was assessed by the Truelove–Witts Index (TWAS) and in CD by the Crohn's Disease Activity Index (CDAI). In each subject, CFR was measured through transthoracic Doppler echocardiography. Results: Compared to the controls, the CD group and UC group had significantly higher high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate. Baseline diastolic peak flow velocity (DPFV) of the left anterior descending artery (LAD) was significantly higher in the IBD group (24.1 ± 3.9 vs. 22. 4 ± 2.9, p b 0.05), and hyperemic DPFV (56.1 ± 12.5 vs. 70.6 ± 15.3, p b 0.05) and CFR (2.34 ± 0.44 vs. 3.14 ± 0.54, p b 0.05) were significantly lower in the IBD group than in the control group. In stepwise linear regression analysis, hs-CRP and lateral Em/Am ratio were independently correlated with CFR. Conclusion: CFR, reflecting coronary microvascular function, is impaired in patients with IBD. CFR and left ventricular diastolic function parameters are well correlated with hs-CRP. © 2014 Published by Elsevier Inc.

Introduction Inflammatory bowel disease (IBD) is a group of chronic relapsing conditions characterized by ulceration of the intestinal mucosa with chronic microvascular and endothelial dysfunction (Hatoum et al., 2005; Hatoum et al., 2003). These disorders are also characterized by systemic inflammation that may affect a number of organ systems, including the cardiovascular (CV) system (Yarur et al., 2011). Hypercoagulable state and venous thromboembolisms are more prevalent in patients with IBD, and represent an important cause of morbidity and mortality (Irving et al., 2005; Talbot et al., 1986). An increased incidence of coronary artery disease events was also noted in patients with IBD despite having a lower burden of traditional CV risk factors (Yarur et al., 2011). The excess CV risk observed in IBD appears to be driven by the damaging effects of

Abbreviations: IBD, Inflammatory bowel disease. ⁎ Corresponding author at: Baskent University, Konya Teaching and Medical Research Center, Gastroenterology Department, Hoca Cihan Mah., Saray Cad., No: 1, Selcuklu, Konya, Turkey. Fax: +90 332 2476886. E-mail address: [email protected] (Z. Caliskan).

http://dx.doi.org/10.1016/j.mvr.2014.08.003 0026-2862/© 2014 Published by Elsevier Inc.

systemic inflammation on the vascular system, and thus the concept of inflammation as a CV risk factor has arisen (Willerson and Ridker, 2004). Furthermore, the role of inflammation in the pathogenesis of atherosclerosis has been demonstrated both experimentally and clinically (Ross 1999; Libby et al., 2002). Atherosclerosis is also a result of an active inflammatory and immune-mediated process in which leukocytes and soluble factors play a role in accelerating vessel pathology. IBD is usually diagnosed in young adulthood and accompanies patients throughout their lives (Aloi et al., 2012). The association between chronic inflammation and atherosclerosis is well established; however, the possible association between IBD and coronary microvascular function is currently unknown. Coronary flow reserve (CFR) measurement is used both to assess epicardial coronary arteries and to examine the integrity of the coronary microvascular circulation. The term coronary microvascular dysfunction refers to abnormal regulation of myocardial blood flow that has not been explained by epicardial coronary artery disease [3]. It is thought to result from vasomotor dysregulation or endothelial function of the small coronary arterioles, and represents one of the earliest signs of coronary atherosclerosis (Goel et al., 2001). As

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this type of dysfunction is, at least in part, reversible (Kaufmann et al., 2000), its assessment can be used to guide pharmacological interventions aimed at reducing the risk burden and progression to established coronary artery disease. The use of transthoracic second harmonic Doppler echocardiography (TTDE) for evaluating CFR has become very popular, and its feasibility in evaluating CFR in the mid to distal portion of the left anterior descending coronary artery (LAD) has been validated (Goel et al., 2001; Pirat et al., 2008). Impairment in endothelial function and reduced CFR, which reflects coronary microvascular dysfunction, have been shown to be early manifestations of atherosclerosis and coronary artery disease (Britten et al., 2004; Goel et al., 2001). In the present study, we hypothesized that subclinical inflammation in IBD patients might affect coronary microcirculation and impair myocardial diastolic function. Therefore, we aimed to investigate whether CFR and left ventricular (LV) diastolic function were impaired in IBD patients compared to normal control subjects.

Methods Study population We enrolled patients with IBD who were 18–60 years of age. Diagnosis of IBD was based on the established criteria of clinical, radiological, endoscopic, and histological findings. Exclusion criteria were: presence of valvular or congenital heart disease; any evidence of cardiac involvement; cardiac rhythm other than sinus; previous myocardial infarction; hypo- or hyperthyroidism; chronic obstructive pulmonary disease and/or cor-pulmonale; systemic diseases such as collagenosis: hemolytic, hepatic, and renal diseases or any disease that could impair CFR (e.g., hypertrophic cardiomyopathy and diabetes mellitus: fasting plasma glucose level measured on 3 separate days in a week N 126 mg/dl [7.0 mmol/l] or impaired oral glucose tolerance test: fasting plasma glucose b 126 mg/dl [7.0 mmol/l] but 2-h plasma glucose after a 75-g oral glucose challenge N 140 mg/dl [7.8 mmol/l]); family history of coronary artery disease; and excessive alcohol consumption (N120 g/day). Subjects were excluded from the study if they used any vasoactive drug, were current smokers, or had ST segment or T wave changes specific for myocardial ischemia, Q waves, or incidental left bundle branch block on ECG. Individuals were also excluded if they had triglyceride levels N4.56 mmol/l (400 mg/dl), body mass index (BMI) N35 kg/m2, or left ventricular mass index (LVMI) ≥ 125 g/m2 for men and N110 g/m2 for women. Fulfilling all inclusion and exclusion criteria, 72 patients with IBD (36 with ulcerative colitis [UC] and 36 with Crohn's disease [CD]) were consecutively registered for the study in the gastroenterology outpatient clinic. Each subject was evaluated after a minimum 15-day attack-free period (Crohn's Disease Activity Index [CDAI] b 150 and Truelove– Witts Index [TWAS] b 4). For the control group, 36 age- and sexmatched healthy volunteers were included into the study from among our hospital staff and/or healthy volunteers. In each subject, age, gender and BMI were recorded. IBD clinical disease activity was assessed in UC by the TWAS (Truelove and Witts, 1955) and in CD by the CDAI (Best et al., 1976). Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride levels, erythrocyte sedimentation rate (ESR), and fasting blood glucose were measured. Plasma levels of high-sensitivity C-reactive protein (hs-CRP) were measured using a highly sensitive sandwich ELISA technique. The study was conducted according to the recommendations set forth by the Declaration of Helsinki on Biomedical Research involving Human Subjects. Written informed consent was obtained from each subject, and the institutional ethics committee approved the study protocol.

Echocardiographic examination Each subject was examined using an Acuson Sequoia C256® Echocardiography System equipped with a 3V2c and 5V2c broadband transducers with second harmonic capability (Acuson, Mountain View, CA, USA). Two-dimensional, M-mode, and subsequent standard and pulsed-tissue Doppler echocardiographic examinations were performed on each subject in the lateral decubitus position. The echocardiographic images were recorded on VHS videotapes. Diastolic and systolic interventricular septal (IVS) thickness, posterior wall (PW) thickness, and left ventricular enddiastolic (LVDD) and left ventricular end-systolic (LVSD) diameters were measured on the parasternal long-axis views. All measurements were performed on M-mode images. The pulsed Doppler sample volume was positioned at the mitral leaflet tips. Early diastolic peak flow velocity (E), late diastolic peak flow velocity (A), E/A ratio, and E-wave deceleration time (DT) were measured by transmitral Doppler imaging. The Doppler tissue imaging (DTI) program was set to the pulsedwave Doppler mode. Filters were set to exclude high-frequency signals, and the Nyquist limit was adjusted to a velocity range of − 15 to 20 cm/s. Gains were minimized to allow for a clear tissue signal with minimal background noise. All DTI recordings were obtained during normal respiration. A 5-mm sample volume was placed at the apical fourchamber view on the lateral corner of the mitral annulus (Caliskan et al., 2008). The resulting velocities were recorded for 5–10 cardiac cycles at a sweep speed of 100 mm/s, and stored on VHS videotape for later playback and analysis. The following measurements were determined as indexes of regional systolic function: peak velocities (cm/s) and time velocity integral of myocardial systolic (Sm) wave. Myocardial early (Em) and atrial (Am) peak velocities (cm/s) and Em/Am ratio, and SmEm duration (isovolumic relaxation time: IVRT), as the time interval occurring between the end of Sm and the onset of Em, were determined as diastolic measurements. All diastolic parameters were measured in three consecutive cardiac cycles and averaged. The same investigator, who was blinded to the clinical data, performed the echocardiography, and two cardiologists blinded to the subjects' data analyzed the echocardiogram recordings. CFR measurement All subjects were examined after a 12-hour fast and after they had abstained from caffeine- or xanthine derivative-containing drinks for at least 12 h before the measurements. Visualization of the distal LAD was performed using a modified, foreshortened, two-chamber view obtained by sliding the transducer on the upper part and medially from an apical two-chamber view to reach the best alignment to the interventricular sulcus. Subsequently, coronary flow in the distal LAD was examined by color Doppler flow mapping over the epicardial part of the anterior wall, with the color Doppler velocity range of 8.9–24.0 cm/s. The color gain was adjusted to provide optimal images. The acoustic window was placed at approximately the midclavicular line, in the fourth and fifth intercostal spaces, with the subject in the left lateral decubitus position (Pirat et al., 2008). The left ventricle was imaged on the long-axis cross-section, and the ultrasound beam was then inclined laterally. Next, coronary blood flow in the LAD (middle to distal) was searched by color Doppler flow mapping. All subjects had Doppler recordings of the LAD with a dipyridamole infusion at a rate of 0.56 mg/kg over 4 min. All subjects had continuous heart rate and electrocardiographic monitoring as well as blood pressure (BP) recordings at baseline, during dipyridamole infusion, and at recovery. Echocardiographic images were recorded on VHS videotapes. Two experienced echocardiographers, who had been blinded to the clinical data, analyzed the recordings. By placing the sample volume on the color signal, spectral Doppler of the LAD showed the characteristic biphasic flow pattern with larger diastolic and smaller systolic components. Coronary

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diastolic peak velocities were measured at baseline and after dipyridamole by averaging the highest three Doppler signals for each measurement (Caliskan et al., 2008). To test the coefficient of repeatability of the CFR measurement, the measurement was repeated in 10 control subjects two days later. Intraobserver intraclass correlation coefficient for coronary flow measurement was 0.847, and for CFR value it was 0.903.

significantly higher hs-CRP value (3.57 ± 2.80 vs. 1.87 ± 1.35; p b 0.05). Similarly, ESR was significantly higher in the CD group (18.8 ± 12.3 vs. 9.7 ± 3.1; p b 0.05) compared to the controls, while in UC patients, ESR was higher than in controls, but the difference did not reach statistical significance (15.7 ± 12.9 vs. 9.7 ± 3.1; p: 0.19).

Statistical analyses

IVS thickness, LV PW thickness, LVDD, LVSD, left ventricular ejection fraction (LVEF), left atrium diameter, and LVMI were similar between the IBD and control groups (Table 2).

All analyses were conducted using the Statistical Package for the Social Sciences (SPSS) 9.0 (SPSS for Windows 9.0, Chicago, IL). All group data are expressed as mean ± standard deviation. Considering the standard deviation of the control group measurements and accepting a 10% change in CFR measurement as clinically significant, power analysis revealed that at least 37 subjects should have been included into the study. Chi-square statistics were used to assess differences between categorical variables. Comparison analyses were made using independent samples t test and one-way ANOVA, followed by Scheffe test or Kruskal–Wallis test to compare continuous variables (comparison of a characteristic across the three study groups if that characteristic did not have a normal distribution, such as hs-CRP, ESR, mitral A-wave max, and lateral Am). The Pearson's and Spearman correlation analysis was used to test the possible associations between CFR and the study variables (such as age, fasting glucose, hs-CRP, ESR, disease duration, CDAI score, TWAS score, mitral A-wave max, and lateral Am), as appropriate. Prediction of independent variables was obtained by stepwise linear regression model including potential confounders. A P value of less than 0.05 was considered statistically significant. Results Clinical characteristics of the study population The general characteristics and risk factors for coronary artery disease of the study population are presented in Table 1. Age, sex, BMI, heart rate, systolic and diastolic BPs, lipid profiles, hemoglobin, and fasting glucose levels were similar among the groups. However, hsCRP and ESR were significantly higher in the patients with IBD as compared to the controls. Compared to the control group, the CD group had a higher hs-CRP value, although the difference was not significant (3.76 ± 3.62 vs. 1.87 ± 1.35; p: 0.15), and the UC group had

Analyses of the echocardiographic measurements

Standard and tissue Doppler echocardiographic analyses Mitral E-wave was similar among the groups. However, mitral Awave, E/A ratio, and IVRT were significantly different among the groups. Lateral Em did not differ among the groups, but lateral Am, lateral Em/ Am ratio and lateral IVRT were significantly higher in the IBD group than the control group (Table 2). Subgroup analysis of patient groups showed that LV diastolic function parameters of both the CD and UC groups were significantly impaired when compared to the controls. Analysis of CFR measurements Baseline and peak heart rate and BP were similar between the two groups. Baseline diastolic peak flow velocity (DPFV) of the LAD was significantly higher in the IBD group (24.1 ± 3.9 vs. 22. 4 ± 2.9, p b 0.05), while hyperemic DPFV (56.1 ± 12.5 vs. 70.6 ± 15.3, p b 0.05) and CFR (2.34 ± 0.44 vs. 3.14 ± 0.54, p b 0.05) were significantly lower in the IBD group than in the control group (Table 2). Moreover, when compared with controls, both the UC group and CD group also had significantly reduced CFR. Relationship of CFR and left ventricular diastolic function to study variables CFR was significantly and inversely correlated with age (r = −0.356, p b 0.001), TWAS score (r = −0.430, p = 0.009), hs-CRP (r = −0.392, p b 0.001), ESR (r = −0.435, p b 0.001), IVRT (r = −0.264, p = 0.01), and lateral Am (r = −0.331, p = 0.001), and significantly and positively correlated with mitral E/A ratio (r = 0.368, p b 0.001), lateral Em/Am ratio (r = 0.403, p b 0.001), and HDL-cholesterol levels (r = 0.229,

Table 1 Demographic and biochemical characteristics in patients with IBD and control subjects.

Age (years) Male/female (n/n) Body mass index (kg/m2) Fasting glucose (mg/dl) Total cholesterol (mg/dl)) Triglyceride (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Hemoglobin (mg/dl) hs-CRP (mg/dl) n ESR (mm/h)n Disease duration (years) Disease activity score (CDAI & TWAS)

Total IBD patients

CD patients

UC patients

Controls

(n = 72)

(n = 36)

(n = 36)

(n = 36)

39.7 0.40 24.8 92.6 184.3 118.4 43.1 117.9 13.7 3.67 17.2

38.1 0.51 24.8 92.9 179.2 115.2 42.4 113.7 13.9 3.76 18.8 3.5 63.7

41.2 0.40 24.7 92.4 189.6 121.7 43.9 122.4 13.4 3.57 15.7 6.5 3.52

37.2 0.40 25.6 90.9 180.8 128.4 42.6 111.7 14.1 1.87 9.7

± ± ± ± ± ± ± ± ± ± ±

12.1 0.49 4.2 10.2 27.1 40.5 7.1 22.2 1.6 3.21⁎⁎⁎ 12.6 ⁎⁎⁎

± ± ± ± ± ± ± ± ± ± ± ± ±

10.8 0.50 4.2 9.3 31.3 43.1 8.3 24.6 1.4 3.62 12.3⁎ 1.9 21.4

± ± ± ± ± ± ± ± ± ± ± ± ±

13.1 0.49 4.3 11.2 21.4 38.1 5.7 18.9 1.7 2.80⁎⁎ 12.9 6.9 0.69

± ± ± ± ± ± ± ± ± ± ±

5.1 0.49 1.7 5.8 27.1 52.2 10.4 23.2 1.1 1.35 3.1

Abbreviations: HDL: high-density lipoprotein; LDL: low-density lipoprotein; hs-CRP: high-sensitivity C-reactive protein; ESR: erythrocyte sedimentation rate; TWAS: Truelove–Witts Index, CDAI: Crohn's Disease Activity Index. ⁎ CD patients vs healthy controls, p value b0.05. ⁎⁎ UC patients vs healthy controls, p value b0.05. ⁎⁎⁎ Total IBD patients vs healthy controls, p value b0.05. n Nonparametric test (Mann–Whitney U). Bold indicates the significant correlations.

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Table 2 Echocardiographic findings and standard and tissue Doppler parameters of the left ventricle.

IVS thickness (cm) PW thickness (cm) LVDD (cm) LVSD (cm) EF (%) LAD (cm) LVMI (g/m2) Mitral E-wave max (cm/s) Mitral A-wave max (cm/s) n E/A ratio IVRT (ms) Lateral Em (cm/s) Lateral Am (cm/s) n Lateral IVRTm (ms) Lateral Em/Am ratio Systolic BP (mm Hg) Diastolic BP (mm Hg) Baseline HR (beats/min) Peak HR (beats/min) Basal DPFV (cm/sn) Hyperemic DPFV (cm/sn) CFR CFR b 2 (%)

Total IBD patients

CD patients

UC patients

Controls

(n = 72)

(n = 36)

(n = 36)

(n = 36)

0.92 ± 0.13 0.90 ± 0.14 4.66 ± 0.38 2.90 ± 0.30 67.3 ± 5.9 3.10 ± 0.49 83.3 ± 17.0 80.0 ± 18.5 73.3 ± 16.3⁎⁎⁎ 1.13 ± 0.33⁎⁎⁎ 109.4 ± 17.3⁎⁎⁎ 19.3 ± 4.7 17.1 ± 3.8⁎⁎⁎ 104.1 ± 21.1⁎⁎⁎ 1.16 ± 0.35⁎⁎⁎ 118.9 ± 11.0 74.9 ± 7.0 74.1 ± 7.8 98.6 ± 9.2 24.1 ± 3.9⁎⁎⁎ 56.1 ± 12.5⁎⁎⁎ 2.34 ± 0.44⁎⁎⁎ 24.16

0.92 ± 0.12 0.89 ± 0.14 4.68 ± 0.37 2.95 ± 0.34 66.9 ± 6.1 3.13 ± 0.47 83.4 ± 15.7 81.9 ± 17.4 71.4 ± 14.7⁎ 1.17 ± 0.25 107.4 ± 17.0 19.6 ± 3.7 17.2 ± 3.9⁎ 101.9 ± 18.8⁎ 1.19 ± 0.32⁎ 119.7 ± 12.8 74.4 ± 6.9 75.2 ± 7.9 100.1 ± 8.2 24.4 ± 4.4 56.1 ± 13.1⁎ 2.33 ± 0.49⁎ 33.33

0.92 ± 0.15 0.91 ± 0.14 4.63 ± 0.39 2.86 ± 0.26 67.6 ± 5.5 3.08 ± 0.51 83.1 ± 18.5 78.1 ± 19.5 75.1 ± 17.6⁎⁎ 1.09 ± 0.39⁎⁎ 111.3 ± 17.6⁎⁎ 18.9 ± 5.6 17.1 ± 3.7⁎⁎ 106.3 ± 23.2⁎⁎ 1.14 ± 0.38⁎⁎ 118.2 ± 9.1 75.5 ± 7.2 73.1 ± 7.7 97.1 ± 10.1 23.9 ± 3.4 56.2 ± 12.0⁎⁎ 2.35 ± 0.40⁎⁎ 25.00

0.92 ± 0.14 0.92 ± 0.13 4.54 ± 0.41 2.85 ± 0.30 66.9 ± 2.3 3.04 ± 0.31 79.9 ± 11.5 77.1 ± 12.3 59.6 ± 11.2 1.31 ± 0.22 94.8 ± 18.0 19.3 ± 3.6 14.1 ± 2.7 85.3 ± 8.6 1.40 ± 0.32 119.5 ± 8.4 76.8 ± 5.4 73.6 ± 11.8 97.9 ± 13.0 22.4 ± 2.9 70.6 ± 15.3 3.14 ± 0.54 2.77

Abbreviations: IVS: interventricular septum; PW: posterior wall; LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; EF: ejection fraction; LAD: left atrium diameter; LVMI: left ventricular mass index; Em: early peak velocity; Am: atrial peak velocity; IVRTm: myocardial isovolumic relaxation time; BP: blood pressure; HR: heart rate; DPFV: diastolic peak flow velocity; CFR: coronary flow reserve. ⁎ CD patients vs healthy controls, p value b0.05. ⁎⁎ UC patients vs healthy controls, p value b0.05. ⁎⁎⁎ Total IBD patients vs healthy controls, p value b0.05. n Nonparametric test (Mann–Whitney U). Bold indicates the significant correlations.

p = 0.029). CFR was also inversely but not significantly correlated with CDAI score (r = −0.310, p = 0.062) (Table 3). In stepwise linear regression analysis, when CFR was taken as dependent and hs-CRP and other variables including age, sex, systolic and diastolic BP, LVMI, heart rate, glucose, and lipids (total cholesterol, LDL-cholesterol, and triglyceride) as independent, only hs-CRP (β = −0.280, p = 0.002) and lateral Em/Am (β = 0.280, p = 0.002) were independently correlated with CFR.

Table 3 Correlations of coronary flow reserve (CFR) with other study variables,. R value Age (years) BMI (kg/m2) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglyceride (mg/dl) LDL cholesterol (mg/dl) Glucose (mg/dl) Systolic BP (mm Hg) Diastolic BP (mm Hg) ESR (mm/h) Disease duration (years) hs-CRP (mg/l) CDAI score TWAS score Mitral A-wave max (cm/s) IVRT (ms) E/A ratio Lateral Am (cm/s) Lateral Em/Am ratio Lateral IVRTm (ms)

P value n

−0.356 −0.30 −0.17 0.229 0.16 −0.13 −0.064 −0.005 0.49 −0.435 n −0.321 n −0.392 n −0.310 n −0.430 n −0.410 n −0.264 0.368 −0.403 n 0.362 −0.256

b0.001 0.76 0.87 0.029 0.87 0.22 0.52 0.95 0.61 b0.001 0.01 b0.001 0.062 0.009 b0.001 0.01 b0.001 b0.001 b0.001 0.008

BMI: body mass index; HDL: high-density lipoprotein; LDL: low-density lipoprotein; BP: blood pressure; ESR: erythrocyte sedimentation rate; hs-CRP: high-sensitivity C-reactive protein; CDAI: Crohn's Disease Activity Index; TWAS: Truelove–Witts Index; IVRTm: myocardial isovolumic relaxation time. n Nonparametric correlation test (Spearman's). Bold indicates the significant correlations.

In addition, serum hs-CRP levels were inversely correlated with lateral Em/Am ratio (r = − 0.289, p = 0.003), whereas they were positively correlated with IVRT (r = 0.294, p = 0.003) and lateral Am (r = 0.238, p = 0.016). Discussion This preliminary study on coronary microvascular function in patients with IBD revealed that CFR, a reflection of coronary microvascular function, is significantly impaired in IBD patients. CFR impairment was found to be similar in both CD and UC patients while they were in remission and in the absence of manifest coronary artery disease and conventional CV risk factors. This finding is suggestive of coronary microvascular dysfunction in IBD patients, which might contribute to the increased CV morbidity and mortality (Kaufmann and Camici, 2005). Impairment in coronary microcirculation may compromise myocardial perfusion, and thus causes LV diastolic dysfunction. In the present study, we found that coronary microcirculatory function as expressed by CFR is associated with LV diastolic function parameters. Early atherosclerosis is a common finding in inflammatory immune-mediated disorders with pathogenetic mechanisms close to those of IBD, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), in which atherosclerotic complications are important causes of mortality and morbidity (Ciftci et al., 2008; Yılmaz et al., 2012). Previous studies have demonstrated impaired flow-mediated dilatation in the peripheral circulation of patients with chronic inflammation, including IBD (Roifman et al., 2009). However, data from flow-mediated dilatation in the brachial artery cannot be necessarily extrapolated to the coronary circulation (Roifman et al., 2009). Previous experimental and clinical studies have shown that early stage coronary atherosclerosis is frequently associated with abnormal resistance of the epicardial coronary arteries, before segmental stenosis is apparent on coronary angiography (Pirat et al., 2008; Saraste et al., 2001). The mechanism of the accelerated coronary atherosclerosis in IBD has not been fully defined and is related to IBD as well as unrelated factors (Yarur et al., 2011).

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Traditional CV risk factors may contribute to the risk of atherosclerosis in IBD. In a previous study, an abnormal lipid profile was reported in patients with IBD (Ripollés Piquer et al., 2006). In this study, we intentionally excluded patients with a history of smoking, diabetes mellitus, hypertension, or known hypercholesterolemia. However, in our study, CFR was significantly and inversely correlated with age. Therefore, traditional CV risk factors might have a partial role in the impairment of CFR in IBD patients. Adenosine-induced hyperemic response incorporates both endothelium-dependent and endothelium-independent pathways (Schindler et al., 2007). Endothelium-derived nitric oxide is a key modulator of vascular tone and plays an important role in the regulation of the coronary microcirculation (Shimokawa and Yasuda, 2008). Inhibition of endothelial nitric oxide synthase by intravenous infusion of LNG-monomethyl arginine reduces the vasodilatory response to adenosine by approximately 25% as measured by positron emission tomography (PET), suggesting a role of the endothelium (Smits et al., 1995; Buus et al., 2001). Although the influence of inflammatory processes on coronary microvascular physiology and pathology has been studied less, our study suggests that similar processes are involved. Increased inflammation in the arterial wall may result from oxidative stress due to reduced endothelium-derived nitric oxide. For example, oxidative stress is critical for the activation of nuclear factor-kappa B (Mogensen et al., 2003), a transcription factor that increases the expression of proinflammatory cytokines, chemokines, and cell adhesion molecules through angiotensin-II stimulation. Increased inflammation may also reflect injury to the arterial wall in the early phases of the atherosclerotic process (Schindler et al., 2007). We were able to demonstrate that CAD risk factors did not explain the link between microvascular function and inflammation. As a whole, our data highlight the importance of inflammation in the early phases of the atherosclerotic process in asymptomatic individuals, because microvascular dysfunction appears to precede the development of frank coronary artery disease (Kaul and Ito, 2004). These results may also have implications for prevention, since microvascular dysfunction is potentially reversible and is associated with future CV events (Sinisalo et al., 2000). Maharshak et al. (2008) revealed that patients with CD in clinical remission present clearly elevated concentrations of inflammation-sensitive biomarkers including hs-CRP and ESR. In this study, we also found a significant negative correlation between hs-CRP and CFR. This study implicates that impaired coronary microvascular function in subjects with IBD is significantly associated with increased hs-CRP and ESR. Previous studies have indicated a significant association between hs-CRP and surrogate markers of atherosclerosis (Caliskan et al., 2008). In this study, we suggest that chronic inflammation represented by increased hs-CRP might partly explain the early development of coronary microvascular dysfunction in patients with IBD. In this study, measuring the mitral E/A ratio, mitral A wave, IVRT, lateral Am, Em/Am ratio, and lateral IVRT, we found a statistically significant impairment in LV diastolic function parameters in subjects with IBD. On the other hand, E/Em values were similar among the three groups. It is preferable to use the average Em velocity obtained from the septal and lateral sides of the mitral annulus for the prediction of LV filling pressures. Because septal Em is usually lower than lateral Em velocity, the E/Em ratio using septal signals is usually higher than the ratio derived by lateral Em, and different cutoff values should be applied on the basis of the LVEF, as well as Em location. In this study, the similar values of E/Em among the three groups might have been caused by the one-sided measurement of Em values (from only the lateral annulus of the mitral valve). Additionally, the small sample size of our study might also have contributed to the similar E/Em values among the three groups. Recent studies have noted that in patients with normal LVEF, lateral tissue Doppler signals (E/Em and Em/Am) have the best correlations with LV filling pressures and invasive indices of LV stiffness (Kasner et al., 2007). In our study, all of the subjects had normal LV systolic function.

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A high oxidative stress in IBD has been proven to be a cause of endothelial dysfunction, which can stimulate fibroblast and myocyte proliferation with collagen deposition. In fact, CD is associated with an increased collagen deposition in the different tissues, as well as in the bowel wall, where various types of collagen build-up have been described (Kjeldsen et al., 2001; Kjeldsen, et al., 1995). LV structure and function in IBD were studied with conventional echocardiographic techniques. Bragagni et al. (Bragagni et al., 2007) previously reported evidence of cardiac alterations in patients with IBD. Confirming these results, we found that LV diastolic function was impaired in patients with IBD, and severity of changes in diastolic parameters was well correlated with the degree of inflammation. In addition, it has been demonstrated previously that LV diastolic dysfunction is associated with CFR impairment and/or coronary microvascular dysfunction even in the absence of LV hypertrophy (Erdogan et al., 2005). In line with these findings, we have shown that CFR was inversely and significantly correlated with mitral A-wave, IVRT, and lateral Am, and positively and significantly correlated with mitral E/A ratio and lateral Em/Am ratio. Impairment in coronary microcirculation may compromise myocardial perfusion, and thus may cause LV diastolic dysfunction. Conclusion The present study demonstrated that CFR, reflecting coronary microvascular function and LV diastolic function, is impaired in patients with IBD. CFR and LV diastolic function parameters were well correlated with hs-CRP. Our results also indicate a strong significant association between LV diastolic function parameters and CFR. Although the number of patients included in this study was limited, these results suggest that impaired CFR may be an early manifestation of coronary vascular involvement in patients with IBD. Conflict of interest None of the authors has any personal or financial relationship that has any potential to inappropriately bias his or her actions or manuscript, and no financial or other potential conflicts of interest regarding the manuscript exist (including involvement with any organization with a direct financial, intellectual, or other interest in the subject of the manuscript). In addition, no grants or sources of financial support related to the topics of the manuscript were received for this study. References Aloi, M., Tromba, L., Di Nardo, G., Dilillo, A., Del Giudice, E., Marocchi, E., Viola, F., Civitelli, F., Berni, A., Cucchiara, S., 2012. Premature subclinical atherosclerosis in pediatric inflammatory bowel disease. J. Pediatr. 161, 589–594 (Oct, e1). Best, W.R., Becktel, J.M., Singleton, J.W., Kern Jr., F., 1976. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 70, 439–444 (Mar). Bragagni, G., Brogna, R., Franceschetti, P., Zoli, G., 2007. Cardiac involvement in Crohn's disease: echocardiographic study. J. Gastroenterol. Hepatol. 22 (1), 18–22 (Jan). Britten, M.B., Zeiher, A.M., Schachinger, V., 2004. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron. Artery Dis. 15, 259–264. Buus, N.H., Bøttcher, M., Hermansen, F., Sander, M., Nielsen, T.T., Mulvany, M.J., 2001. Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia. Circulation 104 (19), 2305–2310 (Nov 6). Caliskan, M., Erdogan, D., Gullu, H., Yilmaz, S., Gursoy, Y., Yildirir, A., Yucel, E., Muderrisoglu, H., 2008. Impaired coronary microvascular and left ventricular diastolic functions in patients with ankylosing spondylitis. Atherosclerosis 196 (1), 306–312 (Jan). Ciftci, O., Yilmaz, S., Topcu, S., Caliskan, M., Gullu, H., Erdogan, D., Pamuk, B.O., Yildirir, A., Muderrisoglu, H., 2008. Impaired coronary microvascular function and increased intima-media thickness in rheumatoid arthritis. Atherosclerosis 198 (2), 332–337 (Jun). Erdogan, D., Gullu, H., Caliskan, M., Yildirim, I., Ulus, T., Bilgi, M., Muderrisoglu, H., 2005. Coronary flow reserve in dipper and non-dipper hypertensive patients. Blood Press. 14, 345–352. Goel, P.K., Gupta, S.K., Agarwal, A., Kapoor, A., 2001. Slow coronary flow: a distinct angiographic subgroup in syndrome X. Angiology 52, 507–514.

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Impaired coronary microvascular and left ventricular diastolic function in patients with inflammatory bowel disease.

Increased incidence of coronary vascular events in patients with inflammatory bowel disease (IBD) is known. However, the association between coronary ...
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