Is activation in inflammatory bowel diseases associated with further impairment of coronary microcirculation?

    Is Activation in Inflammatory Bowel Diseases Associated with Further Impairment of Coronary Microcirculation? Zuhal Caliskan, Nursen Keles, Huseyin Savas Gokturk, Kamil Ozdil, Feyza Aksu, Oguzhan Ozturk, Resul Kahraman, Osman Kostek, Ahmet S. Tekin, Gulsum Teke Ozgur, Mustafa Caliskan PII: DOI: Reference:

S0167-5273(16)31847-2 doi: 10.1016/j.ijcard.2016.08.141 IJCA 23408

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

24 April 2016 5 August 2016 6 August 2016

Please cite this article as: Caliskan Zuhal, Keles Nursen, Gokturk Huseyin Savas, Ozdil Kamil, Aksu Feyza, Ozturk Oguzhan, Kahraman Resul, Kostek Osman, Tekin Ahmet S., Ozgur Gulsum Teke, Caliskan Mustafa, Is Activation in Inflammatory Bowel Diseases Associated with Further Impairment of Coronary Microcirculation?, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.08.141

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Full Title: Is Activation in Inflammatory Bowel Diseases Associated with Further Impairment of Coronary Microcirculation?

SC R

Authors’ names, academic degrees and affiliations:

IP

T

RunningTitle: Flare in Inflammatory Bowel Diseases and Coronary Microcirculation

Zuhal Caliskan, [1]; Nursen Keles [2]; Huseyin Savas Gokturk, [1]; Kamil Ozdil [3]; Feyza Aksu [2]; Oguzhan Ozturk [3]; Resul Kahraman, [3]; Osman Kostek, [4]; Ahmet

NU

S Tekin, [2]; Gulsum Teke Ozgur [1], ;Mustafa Caliskan [2].

MA

Authors’ names, academic degrees and affiliations:

D

[ 1 ] Baskent University Department of Gastroenterology, Konya,Turkey

TE

[ 2 ] Istanbul Medeniyet University Goztepe Training and Research Hospital, Department of

CE P

Cardiology,Istanbul,Turkey

[3] Umraniye Training and Research Hospital Department of Gastroenterology,

AC

Istanbul,Turkey

[4] Istanbul Medeniyet University Goztepe Training and Research Hospital, Department of Internal Medicine, Istanbul,Turkey

Correspondence author and address: NURSEN KELES ,M.D. [Corresponding author] Adress: Istanbul Medeniyet University, Goztepe Training and Research Hospital, Department of Cardiology, Istanbul, Turkey

ACCEPTED MANUSCRIPT Doktor Erkin Caddesi, Kadıköy /Istanbul, TURKEY Tel: [90]507 987 7745

IP

T

Fax: [90] 216 344 0093

AC

CE P

TE

D

MA

NU

SC R

e-mail: [email protected]

ACCEPTED MANUSCRIPT ABSTRACT:

Background: Inflammatory bowel disease [IBD] includes a number of chronic

T

relapsing diseases. In IBD intestinal microvascular endothelial cells are damaged by an

IP

abnormal immune response. Several studies have shown that IBD may cause increment in risk

SC R

of developing atherosclerosis. IBD in activation were related to enhanced risks of worse cardiovascular [CV] outcome, on the other hand no risk increment was seen in remission comparing to control group in those studies. Coronary Flow Reserve [CFR] reflects coronary

NU

microvascular circulation. Coronary microvascular dysfunction may be defined as a predictor of CV outcome combined with previous described atherosclerotic risk factors. The present

MA

study was purposed to further evaluate whether or not CFR in the left anterior descending artery [LAD] is disturbed in IBD patients with activation in comparison to remission and

TE

D

healthy subjects.

Methods: 62 patients with IBD and 39 healthy volunteers were enrolled into the

CE P

study. Patients’ demographics were recorded. CFR evaluation of patients with IBD in both activation and remission period and control group were performed with transthoracic

AC

echocardiography.

Results: CFR was significantly lowest in the active period of the IBD [2.26 [2.082.55] vs. 2.55 [2.18-3.00] and 3.10 [2.85-3.29] p < 0.001]. CFR is negatively correlated with disease activity scores of IBD. Conclusion: This study showed that CFR is more prominently disturbed in patients with IBD in activation. The activation of disease may have a major role in the progression of coronary microcirculatory dysfunction and future cardiovascular events. Key Words: Inflammatory Bowel Diseases, Activation, Coronary Flow Reserve. HIGHLIGHTS:

ACCEPTED MANUSCRIPT  The coronary microcirculation is more prominently impaired in IBD patients throughout active period of the disease.

progression of coronary microcirculatory

IP

significant role in the

T

 The active inflammation process during active episode may have an

SC R

function impairment and future cardiovascular events.  Monitoring firmly and suppressing the flare of IBD might improve

AC

CE P

TE

D

MA

NU

cardiovascular prognosis in patients with IBD.

1. INTRODUCTION: Inflammatory bowel diseases [IBD] includes two major chronic relapsing diseases named as Crohn’s disease [CD] and ulcerative colitis [UC]. An abnormal immune response damages intestinal microvascular endothelial cells in IBD. That immune response also causes both acute inflammatory flares throughout the periodic reactivation of the disease [relapse] and chronic low-grade inflammation. Although IBD generally are a group of diseases of

ACCEPTED MANUSCRIPT gastrointestinal system, they can also affect extra intestinal organs and tissues including cardiovascular system. Several studies have shown that IBD patients may have a higher risk

T

of developing atherosclerosis [1]. The rate of adverse cardiovascular events is increased

IP

among patients with IBD, even when the presence of conventional atherosclerotic risk factors

SC R

is low. [1]. The incidence of traditional atherosclerotic risk factors is not increased in IBD patients, therefore this increment in risk could be ascribable to inflammation-mediated atherosclerosis [1,2,3].

NU

The course of the disease is composed of activation and remission periods and the

MA

major target of the therapy is to suppress the activation periods. In nationwide registries, Kristensen et al. [4] examined the effect of active IBD on major adverse cardiovascular outcomes after myocardial infarction [MI]. When compared with the non-IBD group, IBD

TE

D

flares, in particular, were associated with increased risks of recurrent MI, all-cause mortality, and the composite end point, whereas no risk was identified in remission. Some of studies

CE P

have suggested endothelial dysfunction in patients with IBD through measurement of flowmediated dilation (FMD) of brachial artery [5,6]. The presence of endothelial dysfunction was

AC

further considered in active phases of the diseases; however this observation has been reached by comparing of active phase of the diseases with control group. There is no data about direct comparison of active and remission phases of the diseases. Furthermore, evaluation of endothelial dysfunction by measurement of FMD from brachial artery might not accurately reflect the alterations in coronary arteries. Recent studies show that evaluation of coronary flow reserve [CFR] in the middle to distal portion of the left anterior descending artery [LAD] using transthoracic Doppler echocardiography [TTDE] is feasible [7-9]. Coronary flow reserve [CFR] reflects both blood flow in epicardial coronary arteries and coronary microcirculatory function. Data from recent trials also have proved that coronary microcirculatory impairment is significantly connected

ACCEPTED MANUSCRIPT with increased risk for future cardiovascular [CV] outcomes and that coronary microvascular dysfunction may be defined as a predictor of CV events with conventional and non-

T

conventional risk factors [10]. In previous studies a CFR ≤ 2 by transthoracic dipyridamole

IP

stress echocardiography was associated with worse cardiovascular outcome including death in

SC R

both dilated cardiomyopathy patients with normal epicardial arteries and coronary artery disease patients [11,12]. Therefore; CFR ≤ 2 by transthoracic stress echocardiography is accepted as the indicator of coronary microvascular dysfunction.

NU

We have hypothesized that an activation episode of IBD may have more harmful

MA

effects on the cardiovascular system. Accordingly, this study was designed to investigate whether CFR of LAD artery is more prominently impaired in IBD patients during activation episode in comparison to remission period and healthy control subjects.

2.1.

TE

D

2. MATERIALS AND METHODS: Study population:

CE P

The inflammatory bowel diseases were diagnosed in accordance with endoscopic, clinical, histological and radiological criteria. The patients aged 18–60 years were enrolled in

AC

the study. Each participant was examined for main atherosclerotic risk factors, including diabetes mellitus, a family history of coronary artery disease [CAD], alcohol consumpiton and smoking. The exclusion criteria were a history of CAD congestive heart failure, stroke, obstructive sleep apnoea, hypertension [HTN], systemic diseases such as disturbed glucose tolerance, familial dyslipidemia, hepatic, haemolytic and renal disease, morbid obesity [body mass index >35 kg/m²] and alcohol abuse [>120 g/d] and smoking. Patients who have a history of vasoactive drug use, the presence of Q waves and left bundle branch block, ST segment or T wave changes specific to myocardial ischemiae on an ECG were not included in the study. 2.2.

IBD Activity:

ACCEPTED MANUSCRIPT The definitions of the remission and activation periods of the disease were based on the disease’s activity indexes and inflammatory markers [Truelove-Witts index [TWAS] and

T

Crohn’s Disease Activity Index [CDAI]] [13,14]. The remission period was described as 12

IP

months after last disease activity [IBD hospitalization, with biologic agent treatment, or

SC R

glucocorticoid prescription], and continuation of remission in the absence of further disease activity. We described episodes of activity of CD according to ECCO 2010 Crohn’s Disease definitions and diagnosis guideline including CDA Index [ CDAI ≥ 150] [14,15]. The activity

NU

of UC was defined with respect to TWAS index [TWAS index > 4] [13].

MA

Sixty-two IBD patients [30 patients with CD and 32 patient with UC] were consecutively included in the study according to all inclusion and exclusion criteria, from gastroenterology out patient clinic. Each IBD patient was examined in both remission and

TE

D

active periods of the disease. The clinical severities of disease activity of the patients with IBD were mild to moderate according to CDAI [13] and the TWAS index [14]. Any patients

CE P

were not used immunosuppressive and biologic agents such as TNFα blockers. For the control group, 39 healthy volunteers were enrolled the study. Age, body mass

2.3.

AC

index [BMI] and gender of each participant were recorded. Biochemical Assesment:

The erythrocyte sedimentation rate [ESR] total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, triglyceride levels, and fasting blood glucose were evaluated in the study population. The plasma levels of high sensitive Creactive protein [hs-CRP] was detected by using of a sandwich Elisa technique.

The study was administered in accordance with the recommendations set forth by the Declaration of Helsinki on Biomedical Research involving Human Subjects. Written informed

ACCEPTED MANUSCRIPT consent was acquired from each participitant, and the study protocol was approved by institutional ethics committee. The Echocardiographic Analysis:

T

2.4.

IP

All echocardiographic measurements were done via a GE Vivid 7 [Horten, Norway] echocardiography machine. The echocardiographic examinations were conducted with

SC R

standard pulsed wave methods, tissue Doppler and two dimensional evaluations [16]. Left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) were achieved by the biplane method of disks summation(modified Simpson’s rule) on 2

2D

left atrial (LA)

NU

dimensional echocardiography[16].

volumetric measurements were done by

tracings of the

MA

bloodtissue interface on apical four- and two-chamber views. At the mitral valve level, the contour was closed by connecting the two opposite sections of the mitral annulus with a straight line. LA length L was defined as the shortest of the two long axes measured in the

D

apical two- and four-chamber views. Volumes were computed by using the area-length

TE

approximation [16]. All volume measurements were indexed to body surface area.

CE P

E wave deceleration time [DT] and early [E] and late [A] diastolic peak flow velocities were obtained on transmittal Doppler images.

AC

All tissue Doppler measurements were conducted at the apical 4-chamber aspect by positioning a 5-mm sample volume on the lateral side of the mitral annulus [17]. The recording of the velocities was performed for five to ten cardiac cycles at a sweep speed of 100 mm/s. The tissue Doppler measurements included myocardial early [E’] and atrial [A’] peak velocities [m/s], and isovolumic relaxation time [IVRT’]. IVRT’ was defined as the time interval between myocardial systolic wave and the onset of E’. All tissue Doppler enrolments were performed in the course of normal respiration. The intraclass coefficient of correlation was 0.90 for measurements of lateral mitral annular velocities in the study.

ACCEPTED MANUSCRIPT The measurements of diastolic parameters were performed in 5 consecutive cardiac cycles, which were then averaged. A single researcher conducted the echocardiography, and

T

two blinded investigators analysed the echocardiographic parameters.

IP

2.5.CFR measurement:

SC R

An expert in transthoracic Doppler echocardiography [TTDE] examined the coronary flow velocities. Previously described methods were used to acquire the CFR measurements

NU

[18]. Coronary blood flow velocities at rest and during hyperaemia according to dipyridamole infusion [0.56 mg/kg over 4-6 min] were obtained from control group and patients with IBD

MA

during both active and passive period [19-21]. If the increase in heart rate was not sufficient [10% increase from the baseline], an extra dose of dipyridamole infusion [0.28 mg/kg over a

D

2-min period] was used. For the measurement of coronary blood flow velocities, an acoustic

TE

window was placed near the mid clavicular line in the fourth and fifth intercostal spaces in the left lateral position. The left ventricle [LV] was visualized in the long-axis aspect by

CE P

conducting a lateral ultrasound beam. The coronary blood flow velocities were obtained throughout the mid to distal LAD artery using a pulsed Doppler method with colour guidance.

AC

Systolic and diastolic BPs and heart rates measurements were acquired and recorded at an interval of 4-6 minutes. ECG was continuously observed throughout the test. The five highest diastolic velocities from the pulsed Doppler signals both at rest and during hyperemia were averaged to obtain the diastolic peak flow velocities [DPFV]. CFR was described as the ratio of hyperaemic to resting DPFVs [22]. Intra observer intra-class correlation coefficient for CFR value was 0.903 and for coronary flow velocities measurement was 0.847. 2.6.

Statistical analyses:

Statistical analysis were perfromed using SPSS software version16.0. The variables

ACCEPTED MANUSCRIPT were investigated using visual (histograms, probabilityplots) and analytic methods (Kolmogorov-Simirnov/Shapiro-Wilk’s test) to determine whether or not they are normally

T

distributed. Categorical variables were shown as frequency and group percentage.

IP

Comparision of CFR values among groups were made post-hoc pairwise chi-square tests with

SC R

Bonferroni method. Descriptive analysis were presented using means and standart deviations fo rnormally distributed variables or medians with minimum and maximum for the nonnormally distributed variables, as appropriate. The Student’s t-test or Mann Whitney u test

NU

was used to compare parameters between groups, as appropriate. The Pearson’s correlation or Spearman’s rho correlation analyses were used to test the possible associations between CFR,

MA

TWAS, CDAI and CRP, as appropriate. Paired Student’s t-test or the Wilcoxon test was used to compare the change in study variables between disease active and remission stages, as

TE

D

appropriate. P values less than 0.05 in 2-sided tests were considered significant.

CE P

3. RESULTS

3.1. Clinical characteristics of the study population: The demographic characteristics and risk factors for atherosclerosis of the study

AC

population are presented in Table 1. Many of the demographic, clinical properties and biochemical parameters including sex, age, heart rate, systolic and diastolic blood pressure [BP], lipid profiles, fasting glucose and hemoglobin levels were similar among patients with IBD active, remission period and control subsets [Table 1]. The BMI of the control group was significantly higher than the patients with IBD in both remission and active period [ 26.8 ± 1.7 vs. 24.3 ± 4.1, p<0.001 and 24.4±5.1, p = 0.001]. However, high-sensitive C-reactive protein was significantly higher in the patients with IBD in activation episode as compared to remission period and the controls [7.9 (3.4-13.0) vs. 2.5 (0.2-9.7), and 1.2 (0.5-5.8), p <0.001] . ESR was also higher in the patients with IBD in activation period as compared to remission period and the controls [31 (18-55) vs. 17 (1-55) , and 9 (5-16), p <0.001] [Table 1, Table 1].

ACCEPTED MANUSCRIPT 3.2. Analyses of the echocardiographic measurements: IVS and PW thickness, left ventricular ejection fraction [EF], LVEDV, LVESV, left

T

atrial volume index (LAVI) and LVMI were not significantly different among the active,

IP

remission period of the IBD and the control groups [Table 2].

SC R

Although mitral E-wave was not different among the groups, mitral A-wave, IVRT , IVRT’ and E/A ratio were significantly different among the active, passive period of the IBD and the control group. The left ventricular diastolic function parameters of both active and

MA

3.3. Analysis of CFR measurements:

NU

passive periods of the IBD were significantly disturbed compared to the controls. [Table 2].

Baseline and peak heart rate and blood pressure were similar among the study groups. Baseline DPFV measurement of the LAD was significantly higher in both the active and

TE

D

remission period of the IBD that healthy control group [24.1±3.1 vs. 22.2±2.8, p=0.002, 23.4±3.4 vs. 22.2±2.8, p= 0.05 ]; on the other hand CFR [2.33 (1.80-3.23) vs. 2.55 (1.83-

CE P

3.60) and 3.10 (2.00-4.83), p < 0.001] was significantly lowest in the active period of the IBD [Table 2], [figure 1]. The CFR values of patients in both active and remission period of IBD

AC

were significantly impaired compared to control group [Table 2]. The number of patients with CFR < 2 was higher in active episode of the disease than remission period. However; the difference of the number of the patients with CFR < 2 between active episode and the remission period of the disease was not significant [Table 2]. CFR is negatively correlated with TWAS [figure 2] and CDAI [figure 3] scores. Low CFR values were also related to high hs_CRP levels. 4. DISCUSSION This study demonstrated that CFR detected the coronary microcirculatory function is significantly reduced in active episode of the IBD compared to remission period of the IBD and the control group. The more prominent reduction in CFR was found in patients with IBD

ACCEPTED MANUSCRIPT in active period in the absence of obvious coronary artery disease and traditional

atherosclerotic predictors. These findings are suggestive of coronary microvascular

T

dysfunction [23], which may represent and contribute to the increased cardiovascular

IP

morbidity and mortality in these patients especially in the activation period.

SC R

Development of atherosclerosis is earlier and common widespread evidence in immunological inflammatory diseases with physiopathological mechanisms similar to those

cause of morbidity and mortality [24, 25].

NU

of IBD, such as Behcet Disese, RA and SLE, in which atherosclerotic complications are major

MA

Recently clinical trials have showed that FMD is impaired in the brachial arteries of patients with IBD [26]. However, FMD in the brachial artery cannot project the coronary circulation [27]. FMD generally is considered to project macrovascular endothelial function

TE

D

and thought that it is not sensitive to detect early microvascular endothelial dysfunction [29]. The association between FMD and cardiovascular risk factors is not very strong

[30].

CE P

However; impaired CFR has been assumed to be initial expression of atherosclerosis and cardiovascular diseases [7, 30]. Therefore, extensive atherosclerosis of the coronary arteries in

AC

the absence of stenotic lesions frequently causes decreased CFR, which may participate ischemiae of the myocardium and perfusion abnormality during pharmacological vasodilatation or exercise [9]. Britten et al. [30] reported the significance of CFR on prognosis in adults with non-stenotic coronary artery disease or normal coronary arteries. In addition, Wang et al. [31] demonstrated that coronary vasoreactivity is depressed in asymptomatic subjects who have higher atherosclerotic risk factors. The factors both related and unrelated to IBD which play major role in the mechanism of the accelerated atherosclerosis in patients with IBD has not been well known [1]. Conventional atherosclerotic risk factors may also conduce to the increased

ACCEPTED MANUSCRIPT atherosclerotic risk in IBD. In previous studies, disturbed lipid profile was reported in IBD patients [32, 33]. However in the study lipid profiles of the patients with IBD were normal.

T

In our previous study we detected decrement in coronary flow reserve and LV

IP

diastolic dysfunction in IBD patients during remission period without having a higher burden

SC R

of conventional atherosclerotic risk factors [34].

The present study also showed that the decrement of CFR was more considerable in IBD patients during active episode in spite of lower traditional cardiovascular risk burden.

NU

Several systemic inflammatory diseases such as Behcet’s disease [BD] have also

MA

activation and remission periods similar to IBD. In a previous study Caliskan et al. [35] demonstrated that the coronary microvascular dysfunction is more prominent in active period of BD. They concluded that BD patients are perhaps more tend to cardiovascular events

TE

D

during an active period of the disease. In present study we found that CFR is significantly reduced in active episode compared to passive period of the IBD and the control group. In

CE P

addition; the number of patients with CFR< 2 that reflects coronary microvascular dysfuction was higher in active episode of the disease than remission period close to Caliskan’ s study

AC

[35].

In the pathogenesis of atherosclerosis inflammation plays a complex role. Thus, It has been demonstrated that atherosclerosis is an active immune-mediated inflammatory process. The leukocytes and a number of soluble factors conduce to accelerating arterial pathology [36, 37]. Maharshak et al [38] reported that Crohn’s Disease patients in during remission period have prominently increased serum levels of inflammation markers including erythrocyte sedimentation rate [ESR] and hs - CRP. In our study we have also found that patients with IBD in both clinical remission and activation had significantly increased serum level of hs-CRP and ESR and there was a negatively correlation between inflammatory biomarker values and CFR. Increasing in concentrations of inflammatory markers was more

ACCEPTED MANUSCRIPT prominent in patients with IBD in clinical activation. Previous studies have shown significant relation between hs-CRP and substitute predictors of atherosclerosis [39]. In this study we

T

also implicated that more distinct impairment of coronary microcirculatory function in IBD

IP

patients during clinical activation have considerable association with elevated hs-CRP and

SC R

ESR value. 4.1. Strengths and limitations:

NU

The strengths and limitations of the data obtained from this study are deserved of

MA

consideration. The present study, obtaining data from comparison of CFR values of patients with IBD in active and remission periods, is the first cross sectional case control trial that was designed for evaluating cardiovascular risk in patients with IBD in activation period. This

TE

D

study was cross-sectional as mentioned above, and we did not perform a prospective observation. Therefore, we cannot theorize any reason-result relation. On the other hand, the

CE P

results point to a correlation between lower CFR levels and atherosclerosis in patients with IBD in activation period. Also, the study was limited in sample size, however its results may

AC

lead to further large prospective trials that will investigate the relation between activation in IBD and atherosclerotic risk.

4.2. Perspective and conclusion:

In conclusion, the present study demonstrated that coronary microcirculation is more prominently disturbed in IBD patients throughout active episode of the disease. Therefore, active inflammation cascades during active episode may have an significant role in the progression of coronary microcirculatory function impairement and future cardiovascular

ACCEPTED MANUSCRIPT events. Accordingly, firmly monitoring and suppressing the activation of IBD might improve

AC

CE P

TE

D

MA

NU

SC R

IP

T

cardiovascular prognosis in patients with IBD.

ACCEPTED MANUSCRIPT Funding: No financial support was received for this study.

IP

T

Declaration of Interest:

SC R

All of the authors have no conflict of interest.

Acknowledgements:

All of the authors contributed planning, conduct, and reporting of the work. All authors had

NU

full access to all data in the study and take responsibility for the integrity of the data and the accuracy

AC

CE P

TE

D

MA

of the data analysis.

ACCEPTED MANUSCRIPT REFERENCES: 1.

Yarur AJ, Deshpande AR, Pechman DM Tamariz L, Abreu MT, Sussman DA.

T

Inflammatory bowel disease is associated with an increased incidence of

Hatoum OA, Gauthier KM, Binion DG, Miura H, Telford G, Otterson MF,et

SC R

2.

IP

cardiovascular events. Am J Gastroenterol., 106 (2011), pp.741-747.

al. Novel mechanism of vasodilation in inflammatory bowel disease.

3.

NU

Arterioscler Thromb Vasc Biol., 25 (2005), pp.2355-2361. Hatoum OA, Binion DG, Otterson MF, Gutterman DD. Acquired

MA

microvascular dysfunction in inflammatory bowel disease: Loss of nitric oxide-mediated vasodilation. Gastroenterology, 125(2003), pp.58-69. Kristensen SL, Ahlehoff O, Lindhardsen J, Erichsen R, Lamberts M, Khalid U,

D

4.

TE

et al. PR Prognosis after first-time myocardial infarction in patients with inflammatory bowel disease according to disease activity: nationwide cohort

5.

CE P

study. irc Cardiovasc Qual Outcomes, 7 (2014), pp.857-862. Irving PM, Pasi KJ, Rampton DS. Thrombosis and inflammatory bowel

6.

AC

disease. Clin Gastroenterol Hepatol., 3 (2005), pp.617-628. Talbot RW, Heppell J, Dozois RR, Beart RW Jr. Vascular complications of inflammatory bowel disease. Mayo Clin Proc., 61 (1986), pp. 140-145.

7.

Goel PK, Gupta SK, Agarwal A, Kapoor A. Slow coronary flow: a distinct angiographic subgroup in syndrome X. Angiology, 52 (2001), pp.507-514.

8.

Pirat B, Bozbas H, Simsek V, Yildirir A, Sade LE, Gursoy Y, et al. Impaired coronary flow reserve in patients with metabolic syndrome. Atherosclerosis, 201 (2008), pp.112-116.

9.

Saraste M, Koskenvuo J, Knuuti J, Toikka J, Laine H, Niemi P, et al. Coronary flow reserve: measurement with transthoracic Doppler echocardiography is

ACCEPTED MANUSCRIPT reproducible and comparable with positron emission tomography. Clin Physiol., 21(2001), pp. 114–122. Caliskan M, Turan Y, Caliskan Z, Gullu H, Ciftci FC, Avci E, et al. Previous

T

10.

11.

SC R

reserve. Ann Med., 47 (2015), pp. 615-623.

IP

gestational diabetes history is associated with impaired coronary flow

Rigo F, Gherardi S, Galderisi M, Pratali L, Cortigiani L, Sicari R, et al. The prognostic impact of coronary flow-reserve assessed by Doppler

12.

MA

2006), pp. 1319-1323.

NU

echocardiography in non-ischaemic dilated cardiomyopathy. Eur Heart J 27(

Cortigiani L, Rigo F, Gherardi S, Sicari R, Galderisi M, Bovenzi F, et al. Additional prognostic value of coronary flow reserve in diabetic and

TE

D

nondiabetic patients with negative dipyridamole stress echocardiography by wall motion criteria. J Am Coll Cardiol 50 (2007), pp.1354-1361. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's

CE P

13.

disease activity index. National Cooperative Crohn's Disease Study.

14.

AC

Gastroenterology, 70 (1976), pp. 439-444. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on atherapeutic trial. Br Med J., 29 (1955), pp.1041-1048.

15.

Van Assche G., Dignass A., Panés J., Beaugerie L., Karagiannis J., Allez M., et al. Second European evidence-based consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. J Crohn's Colitis, 4 (2010).

16.

Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and

ACCEPTED MANUSCRIPT the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 28 (2015) , pp. 1-39 Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH,et al. Assessment of

T

17.

IP

mitral annulus velocity by Doppler tissue imaging in the evaluation of left

18.

SC R

ventricular diastolic function. J. Am. Coll. Cardiol., 30 (1997), pp.474-480. Takeuchi M, Lodato JA, Furlong KT, Lang RM, Yoshikawa J.Feasibility of measuring coronary flow velocity and reserve in the left anterior descending

NU

coronary artery by transthoracic Doppler echocardiography in a relatively

19.

MA

obese American population. Echocardiography, 22 (2005), pp.225–232. Lambertz H, Tries HP, Stein T, Lethen H. Noninvasive assessment of coronary flow reserve with transthoracic signal-enhanced Doppler echocardiography.

20.

TE

D

J Am Soc Echocardiogr.,12 (1999), pp.186–195. Korcarz CE, Stein JH. Noninvasive assessment of coronary flow reserve by

CE P

echocardiography: Technical considerations. J Am Soc Echocardiogr., 17 (2004), pp.704–707. Caliskan M, Caliskan Z, Gullu H, Keles N, Bulur S, Turan Y, et al. Increased

AC

21.

morning blood pressure surge and coronary microvascular dysfunction in patient with early stage hypertension. J Am Soc Hypertens.,8 (2014), pp.652-659.

22.

Caliskan M, Erdogan D, Gullu H, Yilmaz S, Gursoy Y, Yildirir A,et al. Impaired coronary microvascular and left ventricular diastolic functions in patients with ankylosing spondylitis. Atherosclerosis, 196 (2008), pp. 306312.

ACCEPTED MANUSCRIPT 23.

Kaufmann PA, Camici PG. Myocardial blood flow measurement by PET: technical aspects and clinical applications. J Nucl Med., 46 (2005), pp.75-

Ciftci O, Yilmaz S, Topcu S, Caliskan M, Gullu H, Erdogan D, et al. Impaired

IP

24.

T

88.

SC R

coronary microvascular function and increased intima-media thickness in rheumatoid arthritis. Atherosclerosis, 198 (2008), pp.332-337. 25.

Boros CA, Bradley TJ, Cheung MM, Bargman JM, Russell JL, McCrindle BW,

NU

et al. Early determinants of atherosclerosis in paediatric systemic lupus

26.

MA

erythematosus. Clin Exp Rheumatol.,29 (2011), pp.575-581. Roifman I, Sun YC, Fedwick JP, Panaccione R, Buret AG, Liu H, et al. Evidence of endothelial dysfunction in patients with inflammatory bowel

27.

TE

D

disease. Clin Gastroenterol Hepatol., 7(2009), pp. 175-182. Pitkanen OP, Nuutila P, Raitakari OT, Rönnemaa T, Koskinen PJ, Iida H, et al.

CE P

Coronary flow reserve is reduced in young men with IDDM. Diabetes, 47 (1998), pp.248-254. Kathiresan S, Gona P, Larson MG, Vita JA, Mitchell GF, Tofler GH, et al.

AC

28.

Cross-sectional relations of multiple biomarkers from distinct biological pathways to brachial artery endothelial function. Circulation, 21(2006), pp.938-945.

29.

Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endotheliumdependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol, 24 (1994), pp.1468-1474.

30.

Britten MB, Zeiher AM, Schachinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts

ACCEPTED MANUSCRIPT adverse cardiovascular long-term outcome. Coron Artery Dis,15(2004), pp.259 -264. Wang L, Jerosch-Herold M, Jacobs DR Jr, Shahar E, Folsom AR. Coronary

T

31.

IP

risk factors and myocardial perfusion in asymptomatic adults: the Multi-

SC R

Ethnic Study of Atherosclerosis [MESA]. J Am Coll Cardiol, 47 (2006 ), pp.565-572. 32.

Ripollés Piquer B, Nazih H, Bourreille A, Segain JP, Huvelin JM, Galmiche

NU

JP, et al. Altered lipid, apolipoprotein, and lipoprotein profiles in

MA

inflammatory bowel disease: consequences on the cholesterol efflux capacity of serum using Fu5AH cell system. Metabolism, 55(2006), pp.980988.

D

van Leuven SI, Hezemans R, Levels JH, Snoek S, Stokkers PC, Hovingh GK,

TE

33.

et al. Enhanced atherogenesis and altered high density lipoprotein in patients

34.

CE P

with Crohn's disease. J Lipid Res,48( 2007), pp.2640-2646. Caliskan Z, Gokturk HS, Caliskan M, Gullu H, Ciftci O, Ozgur GT, et al.

AC

Impaired coronary microvascular and left ventricular diastolic function in patients with inflammatory bowel disease. Microvasc Res, 97 (2015), pp.2530.

35.

Gullu H, Caliskan M, Erdogan D, Yilmaz S, Dursun R, Ciftci O, et al. Patients with Behcet's disease carry a higher risk for microvascular involvement in active disease period. Ann Med, 39 (2007), pp.154-159.

36.

Ross R. Atherosclerosis an inflammatory disease. N Engl J Med, 14 (1999 ), pp.115-126.

37.

Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation, 205 (2002), pp.1135-1143.

ACCEPTED MANUSCRIPT 38.

Maharshak N, Zilberman L, Arbel Y, Shapira I, Berliner S, Arber N,et al. Microinflammation in patients with Crohn's disease in clinical remission. J

et al.

IP

Gullu H, Erdogan D, Caliskan M, Tok D, Yildirim E, Ulus T,

SC R

Interrelationship between noninvasive predictors of atherosclerosis: transthoracic coronary flow reserve, flow-mediated dilation, carotid intimamedia thickness, aortic stiffness, aortic distensibility, elastic modulus, and

CE P

TE

D

MA

NU

brachial artery diameter. Echocardiography, 23(2006), pp.835-842.

AC

39.

T

Crohns Colitis, 4 (2008), p.310-314.

ACCEPTED MANUSCRIPT

THE FIGURE LEGENDS: Figure 1.The comparison of the CFR values of the study subgroups.

T

Figure 2. The correlation between TWAS score and CFR.

AC

CE P

TE

D

MA

NU

SC R

IP

Figure 3. The correlation between CDAI score and CFR.

Figure 1

AC

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

AC

Figure 2

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

Figure 3

AC

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Table 1. Demographic and biochemical characteristics among patients with remission, active phase of IBD and control groups

period (n=62)

Age (years)

39 ± 11

Male/female

value

T

(n=39) active period (n=62) 39±11

37± 5

0.36

28/34

26/13

0.03

0.03

24.4±5.1

<0.001

0.001

0.87

26.8 ±

0.36

TE

Index

IP

in

(n/n)

24.3 ± 4.1

***

P3 value

Controls

28/34

Body-mass

**

P2 value

SC R

remission

patients

*

P1

NU

in

Healthy

MA

patients

IBD

D

IBD

1.7

Systolic BP

CE P

2

(kg/m )

119± 11

120± 8

0.72

0.82

0.88

76 ± 7

76 ± 5

0.34

0.94

0.32

93.3±9.1

90.7 ±

0.34

0.11

0.60

0.38

0.06

0.31

(mmHg) Diastolic BP

AC

119 ± 11

75 ± 7

(mmHg) Fasting

92.4 ± glucose

5.6 10.2

(mg/dl) Total

189.5 ±

179.4 ±

23.8

26.5

184.5 ± cholesterol 26.5 (mg/dl))

ACCEPTED MANUSCRIPT

(mg/dl)

135 (42-

143 (42-

125 (52-

219)

230)

240)

42 (39-

40 (30-

46)

65)

119.9 ±

110.9 ±

19.2

22.4

13.4 ±

14.1 ±

1.4

1.1

HDL 43 (28-61)

0.36

0.06

0.55

0.75

0.68

0.14

0.06

IP

cholesterol

0.37

T

Triglyceride

LDL 118.0 ± cholesterol (mg/dl) Hemoglobin

Hs-CRP

2.5 (0.2-

7.9 (3.4-

1.2 (0.5-

(mg/dl)

9.7)

13.0)

D

(mg/dl)

31 (1817 (1-55)

0.65

0.06

0.39

0.005

<0.001

<0.001

0.01

<0.001

<0.001

5.8)

TE

ESR (mm/h)

0.28

MA

13.7 ± 1.7

NU

21.6

SC R

(mg/dl)

9 (5-16)

activity

170

(155-

AC

Disease

CE P

55)

61 (50-73)

score

<0.001 <0.001

178)

4 (3-4)

(CDAI &

6 (5-7)

TWAS)

Data are shown as mean±standart deviation median (minumum -maximum) as appropriate. Comparison between IBD groups and control group was made by the student-t test or Mann-Whitney U and Chi-square test. Paired Student’s t-test or the Wilcoxon test was used to compare the change in study variables between disease active and remission stages. P value less than 0.05 was considered to show a statistically significant result (p< 0.05). * Comparison between IBD patients in remission period and healthy controls.

ACCEPTED MANUSCRIPT ** Comparison between IBD patients in active period and healthy controls.

AC

CE P

TE

D

MA

NU

SC R

IP

T

*** Comparison between IBD patients in active and remission period

ACCEPTED MANUSCRIPT Table 2. Echocardiographic findings and standard and tissue Doppler parameters of the left ventricle among patients with remission, active period of IBD and control groups

remission

active period

Healthy

*

value

(n=62)

(n=39)

55.6 ± 10.1

52.8 ±

LVEDVI

55.6 ± 10.0 2

NU

(n=62)

P2 value

SC R

Controls

period

**

P1

***

P3

T

IBD patients in

IP

IBD patients in

0.20

0.21

0.99

11.3

17.8 ± 4.2

17.8 ± 4.3

17.4 ± 4.7

0.71

0.66

0.94

EF (%)

67.8 ± 5.6

67.8 ± 5.6

66.8 ± 2.2

0.27

0.34

0.88

21.4 ± 3.2

21.6 ± 3.9

0.83

0.83

0.99

90.0±20.6

86.1±19.7

0.47

0.34

0.80

78.2 ± 14.5

85.9 ±

0.20

0.01

0.30

72.5 ± 16.1

75.9 ± 16.9

<0.001

<0.001

0.25

<0.001

<0.001

0.07

2

LVMI (g/m )

89.1±21.4

Mitral E-wave

Mitral A-wave

E/A ratio

81.4 ± 18.9

AC

max (cm/s)

max (cm/s)

21.4 ± 3.2

TE

2

LAVI (mL/m )

D

LVESVI(mL/m )

CE P

2

MA

(mL/m )

1.16 ± 0.33

14.0 60.3 ± 10.8 1.06 ± 0.24

1.45 ± 0.28

IVRT (ms)

108.7 ± 17.6

108.9 ± 17.6

94.9±15.4

0.01

0.01

0.94

E’(cm/s)

11.1 (6.0-19.8)

10.2 (5.4 -15.0)

12.0(7.8-

0.45

0.03

0.03

15.6)

value

ACCEPTED MANUSCRIPT A’ (cm/s)

17 (8-26)

16 (8-26)

14 (11-

0.71

0.49

0.49

<0.001

0.86

102.2 ± 19.2

102.7 ± 18.9

85.1 ± 8.3

<0.001

E’/A’ ratio

0.68 (0.33-1.14)

0.63 (0.33-1.20)

0.87(0.56-

0.70

SC R

1.15) Systolic BP

120± 8

0.82

0.87

0.34

0.94

0.31

73 ± 10

0.62

0.31

0.40

99± 9

97 ± 13

0.64

0.30

0.42

24.1±3.1

22.2±2.8

0.05

0.002

0.25

60.5±12.8

56.1±10.5

69.7±15.2

0.001

<0.001

0.04

2.55 (1.83-3.60)

2.33 (1.80-3.23)

3.10(2.00-

<0.001

<0.001

0.013

0.80

119 ± 10

75 ± 7

76 ± 7

72 ± 4

72 ± 4

NU

Diastolic BP

76 ± 5

MA

(mmHg)

Peak HR

98± 9

CE P

(beats/min)

TE

D

(beats/min)

Basal DPFV

23.4±3.4

AC

(cm/sn) Hyperemic

0.17

0.72

119 ± 11 (mmHg)

Baseline HR

0.18

IP

IVRT’ (ms)

T

22)

DPFV (cm/sn) CFR

CFR< 2 (%)

7 (11.2)

9 (14.5)

4.83)

<0.001

0

0.03

Data are shown as mean±standart deviation median (minumum -maximum) as appropriate. Comparison between IBD groups and control group was made by the student-t test or Mann-Whitney U and Chi-square test. Paired Student’s t-test or the Wilcoxon test was used to compare the change in study variables between disease active and remission stages. Comparision of CFR <2 values among groups were made post-hoc pairwise chi-square tests with Bonferroni method. P value less than 0.05 was considered to show a statistically significant result (p< 0.05).

ACCEPTED MANUSCRIPT * Comparison between IBD patients in remission period and healthy controls. ** Comparison between IBD patients in active period and healthy controls.

AC

CE P

TE

D

MA

NU

SC R

IP

T

*** Comparison between IBD patients in active and remission period.

AC

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT HIGHLIGHTS:  The coronary microcirculation is more prominently impaired in active

T

IBD.

IP

 The acute inflammation may account for microvascular dysfunction in

SC R

active IBD.

 Monitoring firmly, suppressing flare may improve cardiovascular

AC

CE P

TE

D

MA

NU

prognosis in IBD.