Accepted Manuscript

Impaired coronary microvascular function and increased intima-media thickness inpreeclampsia

Faika Ceylan Ciftci, MD Mustafa Caliskan, Ass. Professor, M.D Ozgur Ciftci, Ass.Professor, M.D Hakan Gullu, Ass. Professor, M.D Ayla Uckuyu, Ass. Professor, M.DErzat Toprak, MD Filiz Yanik, Professor, M.D

PII: S1933-1711(14)00746-3

DOI: 10.1016/j.jash.2014.08.012

Reference: JASH 565

To appear in: Journal of the American Society of Hypertension

Received Date: 27 May 2014

Revised Date: 26 July 2014

Accepted Date: 18 August 2014

Please cite this article as: Ciftci FC, Caliskan M, Ciftci O, Gullu H, Uckuyu A, Toprak E, Yanik F,Impaired coronary microvascular function and increased intima-media thickness in preeclampsia,Journal of the American Society of Hypertension (2014), doi: 10.1016/j.jash.2014.08.012.

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

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JASH-D-14-00094R1 Impaired coronary microvascular function and increased intima-

media thickness in preeclampsia

Ciftci FC 1, M.D.; Caliskan M2, M.D.; Ciftci O2, M.D.; Gullu H2, M.D; Uckuyu A1 M.D.;

Toprak E1, M.D.; Yanik F1 M.D.

1 Department of Obstetrics and Gynocology, Baskent University Ankara, TURKEY

2 Department of Cardiology, Baskent University Ankara, TURKEY

Correspondence: Faika Ceylan Ciftci, M.D.,

Baskent University, Konya Application and Research Center, Department of Obstetrics and

Gynocology, Hoca Cihan Mah., Saray Cad., No:1, 42080, Selcuklu, Konya, TURKEY

Tel: +90 332 2570606-3300

Fax: +90 332 2570637

E-mail: faikaceylanciftci@gmail.com

Faika Ceylan CIFTCI, MD; Mustafa CALISKAN, Ass. Professor; Ozgur CIFTCI, Ass.

Professor; Hakan GULLU, Ass. Professor; Ayla UCKUYU, Ass. Professor; Erzat TOPRAK,

MD; Filiz YANIK, Professor

The authors report no conflict of interest.

During preparing this manuscript, we did not take any financial support. The word count of the abstract= 272 and main text= 3124

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Condensation

Condensed Abstract:

Coronary microvascular dysfunction was found in patients who had preeclampsia five years

ago, without the presence of any traditional cardiovascular risk factors.

Running title: Does Preeclampsia Effect Coronay Microvascular Function?

Author’s roles :

Faika Ceylan Ciftci and Mustafa Caliskan designed the study. Ozgur Ciftci was in charge of

statistical analysis and manuscript drafting. Ayla Uckuyu and Erzat Toprak were responsible

for carrying out of the study. Hakan Gullu and Filiz Yanik participated in the critical

discussion.

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ABSTRACT

Background: There is an association between preeclampsia (PE) and excessive morbidity and

mortality. Some recent studies have revealed the presence of endothelial dysfunction in PE

patients with inflammatory activity. Moreover, it has been argued that the chronic

inflammatory state involved in PE leads to an acceleration in atherosclerosis. Accordingly,

our goal in this study is to determine whether there is any coronary microvascular dysfunction

and increase in the intima-media thickness in patients who had mild PE five years before,

without the presence of any traditional cardiovascular risk factors.

Methods: The study included thirty three mild PE patients (Mild preeclampsia is classified as

a blood pressure (BP) of 140/90 mm Hg or higher with proteinuria of 0.3 to 3 g/day.) that

mean age was 33.7 years old , and 29 healthy women volunteers mean age was 36.1 years old.

Each subject was examined using transthoracic echocardiography five years after their

deliveries . During the echocardiographic examination coronary flow reserve (CFR) and

carotid intima-media thickness (IMT) were measured.

Results: There was a statistically lower CFR value in PE patients as compared to controls

(2,39±0,48 vs. 2,90±0,49, P < 0.001). On the other hand, there was a significant increase in

their IMT and high-sensitivity C-Reactive Protein (hs-CRP) values (respectively 0,59±0,15

vs. 0,46±0,10, P < 0.001; 3,80±2,10 vs. 2,33±1,79, p= 0,004). There was a negative

correlation between the CFR values of the PE patients and hs-CRP (r = -0.568, p = 0.001) and

IMT (r =−0.683, P < 0.001) results.

Conclusions: We determined in the study that there was impaired CFR and increased carotid

IMT in patients with PE, and moreover that these adverse effects were significantly correlated

with hs-CRP.

Key Words: Preeclampsia, CFR, IMT, endothelial function

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INTRODUCTION

Preeclampsia (PE) represents one of the most important causes of maternal morbidity

and mortality, affecting between 3-5% of all the pregnancies in the world, and is characterized

by the impairment of general vascular dilatation. (1,2) It is known that the insufficiency of

trophoblast invasion in early pregnancy leads to the impairment of angiogenesis in the

mother, as well as to the upsetting of the balance between nitric oxide and reactive oxygen

products which controls vascular tonus and the coagulation cascade, and that this situation

leads to the emergence of the clinical manifestations of the disease(3). The primary cause of

the impaired circulatory homeostasis in PE is endothelial dysfunction. As a result, there

occurs a maternal reaction that involves endothelial cell dysfunction caused by the stimulated

inflammatory response and hypertension develop (3,4). It has been shown recently that

patients with PE face a increased risk of developing cardiovascular diseases in later years

(5,6,7). Although coronary endothelium secretes many products, it has not yet proved possible

to develop a single blood test that could detect the early-stage changes in endothelium as well

as in the endothelial function. Many invasive and non-invasive methods are in use today to

assess the damages in coronary endothelium. Among these methods, transthoracic coronary

flow reserve (CFR) measurement is used to examine epicardial coronary arteries as well as to

evaluate the integrity of coronary microvascular circulation, non-invasively. Several studies

have validated the feasibility of this method in evaluating CFR in the middle to distal portion

of the Left Anterior Descending Artery(LAD)(8). Britten et al. have suggested that the

presence of CFR in normal to mildly diseased arteries is an independent predictor for the

development of atherosclerosis within the next decade (9).

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Transthoracic CFR correlated significantly with well-established noninvasive predictors of

atherosclerosis, and Gulu etal. suggest that it can be used as a surrogate for coronary

atherosclerosis..( 10) Our hypothesis in the study was that given PE’s role in the development

of several cardiovascular complications, it might also lead to coronary microvascular

dysfunction as well as to thicker carotid intima-media thickness (IMT). Our goal in this study

was to determine, excluding coronary risk factors, whether CFR and IMT are impaired in

patients with PE.

Methods

Study population: All the subjects met the inclusion and exclusion criteria and were recruited

from patients who delivered in Baskent University Obstetrics Clinic.

Inclusion criteria: the study included 46 patients between the ages of 18 and 40 who had had

PE at least five years before. The control group included otherwise having gestational

hypertension 38 healthy parous women who came to Baskent University Obstetrics and

Gynecology department in the same age group, with similar Body Mass Indes (BMI) and with

having normal blood pressures both during their daily lives and past in their pregnancies.

These women were recruited and studied between 2009-2013. Mild preeclampsia was

diagnosed as having a blood pressure (BP) of 140/90 mm Hg or higher and with proteinuria

of 0.3 to 3 g/day. The study excluded patients and controls with renal or any systemic disease,

smokers, those with thyroid dysfunction, chronic alcohol users(>50g/ day), pre-existing

cardiovascular disease, those who were current and recent smokers, those that were still

breastfeeding, and finally those who had undergone a heavy case of PE(Pronounced increase

in blood ressure(Systolic BP≥ 160 mmHg and/or Diastolic BP≥ 110 mmHg) and/or massive

proteinuria(≥ 5000mg/24 hours)), including the HELLP(Hemolyse Elevated Liver Enzymes

Low Platelets) syndrome, (11) Our study originally included 66 patients with PE. Because of

the consideration that smoking could impair the CFR and confound the results, current and

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recent smokers (12 subjects in all) were excluded from the study. Further 8 subjects were

excluded on account of their pre-existing heart disease The necessary measurements were

made in the 46 remaining patients with PE who met the criteria of the study. The study was

carried out in accordance with the Declaration of Helsinki and fulfilled as a single center

study in Baskent University Obstetrics and Gynocology Clinic. Informed consent of all the

participants was received beforehand, and the the institutional ethics committee approved the

study protocol (KA09/372).

The age, gender and BMI data were recorded. Similarly, serum transaminase enzyme, serum

bilirubin, serum uric acid, fasting blood glucose, total cholesterol, HDL-cholesterol, LDL-

cholesterol, and triglyceride levels were measured using original kits, by the help of Abbott-

Aeroset autoanalyzer (Chicago, IL, USA). The plasma levels of hs-CRP were measured using

a highly sensitive sandwich Elisa technique, by the help of Abbott-Aeroset autoanalyzer

(Chicago, IL,USA).

Echocardiographic examination

An Acuson Sequoia C256® Echocardiography System, which was equipped with a 3V2c

broadband transducer with second harmonic capability (Acuson, Mountain View, CA, USA),

was used to examine each subject. Each subject assumed the lateral decubitus position to

undergo two-dimensional, M-mode, and Doppler echocardiographic examinations. The

echocardiographic images thus obtained were recorded on VHS videotapes. The pulsed

Doppler sample volume was positioned over the mitral leaflet tips. Transmitral Doppler

visualization was used to measure early diastolic peak flow velocity (E), late diastolic peak

flow velocity (A), E/A ratio and E-wave deceleration time (DT). The resulting velocities were

measured for the duration of 5–10 cardiac cycles, at a sweep speed of 100 mm/s. All the

diastolic parameters were measured in three consecutive cardiac cycles, and the average of

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these measurements was calculated. An investigator blinded for the clinical data performed

the echocardiography, while two cardiologists blinded for the data of the subjects analyzed

the echocardiogram recordings.

Coronary flow reserve measurement

An Acuson Sequoia C256® Echocardiography System (Acuson Corp, Mountain View, Calif,

USA), equipped with a high-resolution transducer with second harmonic capability (5V2c),

was used to perform transthoracic second harmonic Doppler echocardiography examination

on each subject. A high-frequency, 5-7 MHz probe was used for the visualization of the LAD

distal cross-section. The Nyquist limit was set to 0,16-0,50 m/sn in color Doppler imaging.

After the vein was visualized using color Doppler imaging, Pulse Wave Doppler was set to

the appropriate angle (not exceeding 60 degrees) to examine the coronary blood flow (12, 13).

Then color Doppler flow mapping over the epicardial part of the anterior wall was used to

examine the coronary flow in the distal LAD, with the color Doppler velocity set between 8.9

and 24.0 cm/second. The color gain was adjusted to obtain optimal image quality. In all

subjects, Doppler recordings of the LAD were made with a dipyridamole infusion at a rate of

0.84 mg/kg through 6 minutes. All subjects were continually monitored for heart rate and

electrocardiography, and their blood pressures were recorded at baseline, during dipyridamole

infusion, and at recovery. The definition of Coronary Flow Reserve (CFR) was made as

taking the ratio of hyperemic diastolic peak velocities to baseline velocities. The normal value

of CRF was defined as equal as or greater than two (12, 14). The CFR measurement hasn’t

got a unit because this is defined as a ratio. CFR measurement was successfully performed in

subjects (96%). Two days later CFR measurement was repeated in 10 subjects in order to test

its coefficient of reproducibility. The intra-observer intra-class correlation coefficient for CFR

was 0.910.

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Carotid Intima-Media Thickness Measurement:

According to the method described above, carotid IMT was measured on high-resolution,

two-dimensional ultrasound images that were obtained with a 7.5MHz linear-array transducer

attached to an ultrasound machine (Hitachi EUB 6500, Japan-2003).(10) While the subject lay

in the supine position, scanning was performed longitudinally from the common carotid artery

to the bifurcation point. After confirming the bifurcation of the common carotid artery, the

measurement of the carotid IMT was made from the far wall of the right carotid artery within

10 mm proximal to the bifurcation. On each scan three points were measured.

In order to avoid possible errors that may result from variable arterial compliance, the scans

were synchronized with the R-wave peaks on the ECG.

Mean carotid IMT was then calculated using the six measurements on two scans. An

investigator blinded to the subjects’ clinical data performed all the measurements. The

intraobserver intraclass correlation coefficient turned out to be 0.945 for the measurement of

carotid IMT.

Statistical analysis.

The SPSS software (Statistical Package for Social Sciences, version 10.0) was used to

perform the statistical analyses. The continuous variables were expressed in the form mean ±

standard deviation (SD) or median (interquartile range), while the categorical variables were

expressed as percentages. In order to test the normality of distribution, the Kolmogorov-

Smirnov test was used. In comparing the groups, the Student t-test was used for the

continuous variables, and the Chi-squared test for the categorical variables. Pearson’s

correlation test was used to find the correlations. Values of p < 0.05 were considered to be

statistically significant.

RESULTS

The clinical characteristics of the study population

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Table 1 lists the general characteristics of the study population and their risk factors for

coronary artery disease. The groups were similar as regards age, BMI, heart rate, systolic

blood pressure, diastolic BP, uric acid levels, lipid profiles, and fasting glucose levels. The

levels of hs-CRP turned out to be higher in the PE group.

Analysis of the echocardiographic measurements

The PE and control groups were similar as regards left ventricular ejection fraction (EF), left

atrial diameter (LA), and LVMI (Table 2).

Standard and tissue Doppler echocardiographic analyses

The PE and control groups were similar as regards mitral E-wave and the E/A ratio. However,

there was a statistical difference between the two groups in mitral A-wave, mitral E-wave DT

and mitral isovolumetric relaxation time (IVRT) (Table 2).

Analysis of CFR and IMT measurements

The two groups were similar as regards baseline and peak BPs as well as baseline and peak

heart rate. Likewise, they were similar as regards the baseline and hyperemic diastolic peak

flow velocities of the LAD. In the PE group, CFR was significantly lower and IMT was

significantly higher than in the control group (Table 2).

Relationship of CFR and IMT to the study variables

There was a negative correlation between CFR on the one hand and IMT (r = - 0,683, P <

0.001) , hs-CRP(r =−0.581, P = 0.001) and basal coronary diastolic peak flow velocity of the

LAD coronary artery (r =−0.609, P < 0.001) on the other. There was a positive correlation

between IMT on the one hand and hs-CRP (r = 0.581, P < 0.001), peak systolic blood

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pressure (r = 0.376, P = 0.031), peak diastolic blood pressure (r =0.404, P = 0.02) and CFR

on the other.

CONCLUSION

The present study has revealed that the patients with PE have impaired CFR and

increased carotid artery IMT when compared with normotensive pregnancies. It has been

demonstrated in recent epidemiological studies that there exists an association between

preeclampsia and increased risk of cardiovascular disease in later life (14,16,17).

Accordingly, it could be argued that the main cause of mortality and morbidity in later years

is ischemic heart disease rather than preeclampsia itself (18). Endothelial dysfunction, one of

the major contributory factors of ischemic heart disease, is closely associated with nitric oxide

and oxidative stress (19). It has been shown that significant oxidative stress is produced even

before the beginning of PE, and that this may play an important role in vasoconstriction which

results in endothelial dysfunction(3).

In this study, instead of using invasive catheter-based methods to evaluate CFR, we made a

noninvasive assessment with transthoracic echocardiography. Previous studies have reported

that the assessment of CFR by transthoracic Doppler echocardiography constitutes a reliable

and reproducible marker of coronary microvascular function (19,20).

Carotid IMT serves as a general measure of the degree of severity of atherosclerosis,

and increased IMT is linked with generalized atherosclerosis.(10) The association of carotid

IMT with coronary atherosclerotic status has been demonstrated in several studies.(21,22)

Moreover, using a linear regression model adjusted for confounding factors, Gulu et al. have

shown that carotid IMT is an independent predictor of CFR. (10) This result may be taken to

mean that increased carotid IMT can be used as a predictor of impaired microvascular

functions, or perhaps more suitably that impaired CFR results from developing coronary

atherosclerosis and/or vascular aging in totally healthy individuals without any of the

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traditional risk factors of coronary atherosclerosis. Carotid IMT stands as the most established

surrogate marker of coronary atherosclerosis, and it is still the only noninvasive method to be

accepted as a surrogate marker of coronary atherosclerosis by AHA (23). Gullu et al. argue

that transthoracic CFR may help detect individuals at risk for coronary atherosclerosis before

the diagnosis of diabetes mellitus, hypertension or other traditional risk factors of coronary

atherosclerosis (10). As previously described, systolic blood pressure, fasting serum glucose,

fasting insulin, smoking, and body mass index are associated with intima-media thickness in

young age (24). In this study, we have not found any diffrence and correlation between the

groups in any manner. We excluded the prediabetics and smokers and overweight participants

and other confounding factors which might influence IMT and CFR results. Thanks to this we

can evaluate the preeclampsia effect on IMT and CFR.

Catov et al.’s study, dated 2013, assessed carotid IMT, FMD (flow mediated

dilatation) and arterial stiffness in PE patients twelve years after giving birth. Although they

encountered impaired IMT values, higher blood pressures and atherogenic lipid profiles in PE

patients, as compared with the subjects with healthy pregnancies, they found no significant

difference in the FMD values (25). In our research as well, IMT and CFR values were found

to be impaired in comparison with the control group (Table 2). Moreover, there was an

increase in the mitral DT, mitral A wave velocity and mitral IVRT values, which was found to

agree with left ventricular diastolic dysfunction. However, no difference was found between

the two groups as regards blood pressure and lipid values (Table 1). On the other hand, the

hs-CRP values of the PE patients included in our study turned out to be higher than those of

the controls, and were found to be correlated with the IMT and CFR values. This situation

shows that impaired CFR and IMT values, predictors of atherosclerosis development, are

associated with increased chronic inflammatory process.Yuan et al. were in agreement with

our own study, both the augmentation index and the carotid IMT were found to be

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significantly impaired 18 months after giving birth (26). Similarly, Verissimo et al. (27)

detected increased carotid IMT values in PE patients six months after giving birth, a result in

agreement with our own findings.

Sandvik et al. found no difference between the control group and the PE patients as regards

the FMD and IMT values, they detected an association between preeclampsia and certain

changes in circulating markers that could be pointing to early endothelial dysfunction.

However, both the PE and the control groups in their study included smokers, patients still

receiving treatment for hypertension, and those with a family history of premature

atherosclerosis. This state of affairs may have concealed any possible differences in the FMD

and IMT values. Moreover, despite these confounding factors involved in the selection of

patients, the biochemical factors of atherosclerosis were found to be negatively different in

the PE group (28). Our study excluded all the patients with risk factors that cause

predisposition for atherosclerosis, as well as all patients receiving medication, and thus

prevented the confounding factors from concealing such differences.

In our study we observed a significant impairment in both IMT and CFR results and in

hs-CRP values, and found furthermore that hs-CRP values were correlated with the impaired

IMT and CFR results. This corroborates the suggestion that inflammation plays a central role

in PE patients. Based on these findings, it may be argued that inflammation-driven

atherogenesis is potentially associated with the excess CAD risk in PE. In agreement with

these results, we demonstrated that CFR was impaired and IMT increased in patients with PE,

and that the IMT values were correlated with the CFR results. This result may be taken to

mean that impaired CFR in patients with PE constitutes an early manifestation of coronary

vascular involvement and developing coronary atherosclerosis. It is possible to defer the

unfavorable effects of PE on the cardiovascular system by changing the other atherosclerosis

risk factors. In patients with PE, we should carefully manage risk factors for CAD in the

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presence of impaired CFR. For this reason, in consideration of the fact that CFR may help

detect individuals facing the risk of coronary atherosclerosis before the diagnosis of coronary

artery disease, patients with PE and impaired CFR need to be examined carefully to detect

and change any preexisting coronary risk factors.

In conclusion, the present study has demonstrated that coronary microvascular

function, represented by CFR, is impaired and carotid IMT is increased in PE patients.

Furthermore, our results indicate a significant relationship between hs-CRP, CFR and IMT.

According to the increased hs-CRP values in the PE patients that chronic inflammation may

constitutes an important contributing mechanism in the development of endothelial

dysfunction as well as of pre-atherosclerotic state in PE. Despite the fact that the number of

patients included in the present study was limited, the results in question suggest that impaired

CFR may constitute an early manifestation of cardiac involvement in patients with PE.

Limitations of the study

The present study excluded subjects with the confounding factors for CFR generally found in

the normal population, so as to examine the independent effects of PE on CFR. Accordingly,

the study does not offer any information about the effects of PE on the CFR of patients who

have the risk factors of coronary heart disease, and its results are not valid for the population

at large.

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Legends

Table 1. Demographic, biochemical, and echocardiographic characteristics of the study

groups

Table 2. Hemodynamic and coronary flow measurements of the groups

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9378(13)00756-4. 10.1016/j.ajog.2013.07.024. [Epub ahead of print]

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ACCEPTED MANUSCRIPTTable 1. Demographic, biochemical, and echocardiographic characteristics of the study

groups.

Preeclampsia group (n= 46)

Control group (n= 38)

P value

Age (year) 33.28 ± 7.34 34.00 ± 9.48 0.704

Post Partum Examination Time ( month) 63.54 ± 2.19 63.57 ± 2.77 0.949

Uric Asid 4.10 ± 0.77 3.79 ± 0.93 0.116

Creatinine 0.78 ± 0.16 0.82 ± 0.13 0.209

ALT(IU/mL) 21.00 ± 11.29 18.94 ± 7.32 0.319

AST(IU/mL) 20.08 ± 7.02 18.50 ± 6.66 0.293

hs-CRP(mg/L) 3.85 ± 2.14 2.83 ± 1.88 0.022

Fasting plasma Glucose (mg/dL)

94.76 ± 7.26 94.47 ± 7.80 0.863

Fasting Insulin(µU/ml) 7.16 ± 2.18 7.39 ± 3.92 0.750

Total cholesterol (mg/dL) 188.26 ± 33.97 189.26 ± 29.58 0.885

Triglyceride (mg/dL)

122.32 ± 51.04 122.55± 59.25 0.985

HDL-cholesterol (mg/dL) 48.52 ± 9.30 51.73 ± 11.76 0.176

LDL-cholesterol (mg/dL) 114.36 ± 27.67 112.57 ± 24.09 0.752

Body mass index (kg/m2) 28.79 ± 5.17 28.47 ± 4.85 0.771

Serum iron (µg/mL) 46.66 ± 33.66 57.21 ± 43.18 0.244

Ferritin (ng/mL) 37.24 ± 28.10 38.56 ± 28.83 0.842

Hemoglobin (g/dL) 13,57±3,57 13,15±1,22 0,461

Baseline systolic BP (mmHg) 118.02 ± 15.49 123.57 ± 14.91 0.101

Baseline diastolic BP (mmHg) 76.51 ± 12.15 78.18 ± 9.89 0.491

Peak systolic BP (mmHg) 123.60 ± 17.22 126.15 ± 16.26 0.488

Peak diastolic BP (mmHg) 76.97 ± 11.27 78.02 ± 9.26 0.641

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ACCEPTED MANUSCRIPTAbbreviations: ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; hs-CRP:

High sensitivity C-reactive protein; HDL: High-density lipoprotein; LDL: Low-density

lipoprotein; BP: Blood pressure. Data was presented as mean ± standard deviation.

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ACCEPTED MANUSCRIPTTable 2. Hemodynamic and coronary flow measurements of the groups.

Preeclampsia

group (n= 46)

Control group (n= 38)

P value

Left Atrium (cm) 22.07 ± 31.58 23.37 ± 35.46 0.861

LVMI (g/m) 58.08 ± 38.46 57.33 ± 36.11 0.928

EF (%) 105.46 ± 63.41 106.57 ± 69.86 0.940

Mitral E (cm/s) 99.89 ± 31.57 94.15 ± 33.57 0.426

Mitral A (cm/s) 59.08 ± 27.68 53.65 ± 19.09 0.293

E/A ratio 16.89 ± 25.84 18.97 ± 30.54 0.741

MDT (msn) 199.48 ± 65.83 176.72 ± 29.83 0.042

Mitral IVRT 104.13 ± 28.46 99.00 ± 11.87 0.276

Baseline heart rate (bpm) 74,52±13,23 77,28±16,26 0.402

Peak heart rate (bpm) 99.73 ± 16.73 101.71 ± 16.35 0.588

Baseline DPFV (cm/s) 27.01 ± 11.20 25.31 ± 4.67 0.355

Hyperemic DPFV (cm/s) 61.43 ± 12.51 69.23 ± 12.31 0.005

CFR ratio 2.38 ± 0.46 2.77 ± 0.48 <0,001

IMT(mm) 0.58 ± 0.14 0.50 ± 0.10 0.004

Abbreviations: LVMI: Left ventricular mass index; EF: Left ventricular ejection fraction;

IVRT: Isovolumic relaxation time; MDT: Mitral deceleration time; bpm: Beat per minute;

DPFV: Coronary diastolic peak flow velocity; CFR: Coronary flow reserve. Data was

presented as mean ± standard deviation.

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Significance of this study

What is already known about this subject?

• Reduced CFR has been shown to be early manifestation of atherosclerosis

• Several study showed an association between PE and atherosclerosis by measuring

IMT

What are new findings?

• This study revealed that CFR significantly impaired in PE patients.

• Impaired CFR may be an early manifestation of coronary vascular involvement in

patients with PE.

How might it impact on clinical practice in the foreseeable future?

• In patients with PE, the presence of impaired CFR should render the clinician aware of

the development of coronary artery disease.