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\begin{document}

\title{Assessment of serum prolidase levels in coronary artery stent restenosis}



\author[1]{Tolga Memioglu}%
\author[1]{Selim Ayhan}%
\author[1]{Ibrahim Donmez}%
\affil[1]{Bolu Abant İzzet Baysal University}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Coronary artery in-stent restenosis is the negative response
caused by the decrease in the artery diameters. Prolidase is an enzyme,
whichplays a role in the formation of new matrix, collagen metabolism
and cell development. There is no study evaluating the serum levels of
prolidase enzyme in patients developing in-stent restenosis. Therefore,
the objective of our study was to reveal the relationship between serum
prolidase levels and in-stent restenosis. Methods: A total of 70
patients who were at medium-to-high risk based on non-invasive tests or
clinical evaluation, and who underwent a coronary angiography in the
cardiology and emergency polyclinics of our hospital from 2013 through
2014 were included in the study. In-stent restenosis was identified in
40 patients. In the other 30 patients, there was no angiographically
determined critical lesion. Serum prolidase levels were measured in all
patients. Results: The mean serum level of prolidase was found to be
statistically significantly higher in the in-stent restenosis group
compared to restenosis free group (p=0.02). The mean serum level of
prolidase level was significantly higher in smokers compared to the
non-smoker patients (p=0.04). It was observed that serum prolidase
levels statistically significantly increased proportionally to the
in-stent restenosis percentage (p=0.04). Conclusions: The results of
this study indicate that, prolidase enzyme levels may enable timely and
and correct assessment of in-stent restenosis, and may contribute to the
decision for changing the treatment or timing to increase intensity of
the treatment in patients undergoing percutaneous coronary intervention
(PCI) with coronary stenting.%
\end{abstract}%



\sloppy


\textbf{Title:} Assessment of serum prolidase levels in coronary artery
stent restenosis

\textbf{Running Title:} Serum prolidase levels in stent restenosis

\textbf{Authors:} Tolga Memio\selectlanguage{polish}ğ\selectlanguage{english}lu, Selim Ayhan, Ibrahim D\selectlanguage{ngerman}önmez

\textbf{Affiliations:}

\textbf{Tolga Memioglu}

Abant Izzet Baysal University Medical Faculty, Department of Cardiology,
Bolu, Turkey

e-mail:\emph{tolgaptca@hotmail.com}

ORCID ID: 0000-0002-3183-5815

\textbf{Selim Ayhan}

Abant Izzet Baysal University Medical Faculty, Department of Cardiology,
Bolu, Turkey

e-mail:\emph{drselimayhan@gmail.com}

ORCID ID: 0000-0002-3363-4697

\textbf{Ibrahim Dönmez}

Abant Izzet Baysal University Medical Faculty, Department of Cardiology,
Bolu, Turkey

e-mail:\emph{dr\_ibrahimdonmez@hotmail.com}

ORCID ID: 0000-0002-6913-9073

\textbf{Correspondence:}

\textbf{Tolga Memioglu}

Izzet Baysal State Hospital, Department of Cardiology, Bolu, Turkey

e-mail:\emph{tolgaptca@hotmail.com}

Phone: +90 374 270 45 75

Fax: +90 374 270 45 85

Mobile: +90 5531193323

Address: Saglik Mahallesi, Sehitler Cd., No:20 14300 Bolu, Turkey

\textbf{Assessment of serum prolidase levels in coronary artery in-stent
restenosis}

\textbf{Abstract:}

\textbf{Background:} Coronary artery in-stent restenosis is the negative
response caused by the decrease in the artery diameters. Prolidase is an
enzyme, whichplays a role in the formation of new matrix, collagen
metabolism and cell development. There is no study evaluating the serum
levels of prolidase enzyme in patients developing in-stent restenosis.
Therefore, the objective of our study was to reveal the relationship
between serum prolidase levels and in-stent restenosis.

\textbf{Methods:} A total of 70 patients who were at medium-to-high risk
based on non-invasive tests or clinical evaluation, and who underwent a
coronary angiography in the cardiology and emergency polyclinics of our
hospital from 2013 through 2014 were included in the study. In-stent
restenosis was identified in 40 patients. In the other 30 patients,
there was no angiographically determined critical lesion. Serum
prolidase levels were measured in all patients.

\textbf{Results:} The mean serum level of prolidase was found to be
statistically significantly higher in the in-stent restenosis group
compared to restenosis free group (p=0.02). The mean serum level of
prolidase level was significantly higher in smokers compared to the
non-smoker patients (p=0.04). It was observed that serum prolidase
levels statistically significantly increased proportionally to the
in-stent restenosis percentage (p=0.04).

\textbf{Conclusions:} The results of this study indicate that, prolidase
enzyme levels may enable timely and and correct assessment of in-stent
restenosis, and may contribute to the decision for changing the
treatment or timing to increase intensity of the treatment in patients
undergoing percutaneous coronary intervention (PCI) with coronary
stenting.

\textbf{Keywords:} Percutaneous coronary intervention, coronary stent,
in-stent restenosis, prolidase

\textbf{WHAT IS KNOWN?}

\begin{itemize}
\tightlist
\item
  Mortality rates of cardiovascular diseases remains high.
\item
  The most commonly used interventional techniques include percutaneous
  transluminal coronary angioplasty (PTCA), coronary stent implantation
  and some therapeutic coronary devices in the treatment of CAD.
\item
  In-stent restenosis has always been considered and ``enemy'' for
  interventional cardiologists.
\end{itemize}

\textbf{WHAT IS NEW?}

\begin{itemize}
\tightlist
\item
  Serum prolidase enzym level is closed associated with in-stent
  restenosis.
\item
  These level can be helpful in early identification of the risk for
  in-stent restenosis.
\item
  Proliase level can be guiding for changing the treatment of
  restenosis, if necessary.
\end{itemize}

\textbf{INTRODUCTION}

In developed countries, cardiovascular diseases are the most frequently
cause of morbidity and mortality (1). Despite novel modern treatment
methods and the use of complex interventional and surgical techniques,
mortality rates of these diseases remain high (2). CVDs involve coronary
arterial diseases (CAD), peripheral vascular diseases, hypertension
(HT), cerebrovascular diseases, congestive heart failure (CHF), and
congenital and valvular heart diseases. Whereas, CADs include angina,
myocardial infarction (MI), coronary failure, and coronary death (3).
The known most important risk factors of CAD are age, diabetes mellitus
(DM), HT, smoking, dyslipidemia, obesity and sedentary lifestyle (4).
CADs more than 1.2 million myocardial infarction (MI) cases and more
than 500.000 deaths every year in the USA (5).

In the treatment of CAD, the most commonly used interventional
techniques include percutaneous transluminal coronary angioplasty
(PTCA), coronary stent implantation and some therapeutic coronary
devices. These methods are collected under the umbrella of percutaneous
coronary intervention (PCI) (6). Today, approximately 1.000.000 PCI
procedures are performed annually in the USA (7).

Coronary stent implantation is now more widely used since it leads to
less complications and provides better long-term clinical outcomes
compared to PTCA.

One of the most important problems encountered following coronary stent
implantation is restenosis of coronary arterial stent. Coronary arterial
stent restenosis can be defined as a decrease in the arterydiameter
caused by the damage occurring during coronary revascularization and the
resultant negative response against this condition (8).

Coronary arterial restenosis often occurs in the form of in-stent
restenosis (ISR). ISR has always been considered the ``enemy'' for the
interventional cardiologists, thus many technical advancements (bare
metal, drug-eluting stents, drug coated balloons) aimed at the
prevention of ISR (9). ISR has been shown to be an independent predictor
for mortality during follow-up together with the other clinical risk
factors including age, sex, DM, smoking, prevous by-pass operation, and
left ventricular ejection fraction (10).

Today, the rate of ISR may reach high values such as 60\% to 80\%. This
rate may rise to 70\% in patients with risk factors such as diabetes
mellitus (11). Coronary stent implantation has decreased the incidence
of ISR compared to PTCA. Today, coronary stent implantation is the most
frequently used method in the treatment obstructive CAD in order to
reduce ISR and is a better option compared to surgical
revascularization. Despite advancements in medical and technological
fields, ISR is a still not fully resolved problem. Smooth muscle cell
proliferation and neointimal hyperplasia are the most important causes
of ISR. This study was planned considering that serum prolidase enzyme,
which plays a role in collagen formation, may be effective also in ISR.

Prolidase is an enzyme that breaks the peptide bonds in
proline-containing dipeptides (X-Pro) and is found in many tissues such
as bone, connective tissue, kidney, heart, intestinal mucosa, liver,
brain, uterus, timus, erythrocytes, leukocytes, fibroblasts and plasma.
It contributes to the formation of new matrixand cellular growth in
collagen metabolism.

Prolidase plays a role in the catabolism of proteins containing
procollagen, collagen, proline and hydroxyproline inside the cell (12).
Proline and hydroxyproline amino acids released by the prolidase enzyme
make up about 25\% of the collagen tissue and help maintain the
continuity of connective tissue. Increased destruction of collagen
causes an increase in serum prolidase activity (13). In a study about
prolidase, it was aimed to determine the relationship between serum
prolidase activity and ischemia time in different ischemia types. In
conclusion, it was found that serum prolidase enzyme activity may be an
important biomarker in predicting ischemia time (14).

To our knowledge, so far there is no study investigating the value of
serum prolidase in patients with in-stent restenosis. Therefore, the
objective of this study is to reveal the relationship between ISR and
serum prolidase level.

\textbf{Material \& Methods}

This study included a total of 70 patients who were identified to be at
a moderate and high risk as a result of clinical or non-invasive tests
in the cardiology and emergency clinics of the Abant Izzet Baysal
University training and Research Hospital, and who underwent angiography
between 2013 through 2014. Forty patients with in-stent restenosis were
assigned to the study group and the remaining 30patients without ISR to
the control group, and the results were compared between both groups.

Before the beginning of the study, the necessary approval was received
from the local ethics committee of our hospital with the 23/12/2013
dated and 2013/08-249 numbered decision, in accordance with the Patient
Rights Regulation and ethical principles. This study received support
from the Abant Izzet Baysal University, Scientific Research Projects
Unitwith the Project No: BAP -- 2014.08.31.731. All participants signed
written informed consent forms.

Patients with acute coronary syndrome, serious valvular diseases, severe
coronary artery disease that may affect serum prolidase level, collagen
tissue disease, chronic kidney and liver failure and rheumatological
disease were excluded from the study.

Patients' age, gender, presence of DM, HT, cholesterol levels, smoking
status, history of PCI, ejection fraction (\%EF), biochemical and
hematologic parameters, drugs used, angiography outcomes, ISR stenosis
rates, stent types (bare metal stent / drug-eluting stent) and serum
prolidase levels were investigated in details and recorded.

All angiography and PCI procedures were performed by cardiologists
experienced on interventional procedures using the Siemens Axiom Artis
angiography device with standard methods. A narrowing \selectlanguage{english}[?]50\% in the lumen
diameter in the stent area was considered as restenosis. Venous blood
sample of 8 cc was drawn to a biochemical tube, centrifuged at 4000 ppm
for 10 minutes and the obtained serum sample was stored at
-72\textsuperscript{o}C until the analysis. Serum prolidase level was
then studied in this sample by the laboratory of AIBU Medical Faculty
Biochemistry Department. The measurements were done with the ELISA
method using the Cusabio kit.

Statistical Analysis:

Data obtained in this study were statistically analyzed using SPSS
(15.0, Inc, Chicago, IL, USA) statistical software. Categorical
variables were expressed as frequency and percentage. Continuous
variables were given as mean +- standard deviation or median values.
Student's t-test was used to compared continuous variables between the
groups, while Chi-square test was used to compared categorical
variables. In order to calculate the correlations between continuous
variables, Pearson's analysis was used in parametric data and Spearman's
method in non-parametric data. A linear regression analysis was
performed to determine independent predictors of stent restenosis.
p\textless{}0.05 values considered statistically significant.

\textbf{Results:}

A total of 70 patients who had stents in their coronary arteries within
the last year and underwent coronary angiography due to any indication
other than acute coronary syndrome were included in this study. ISR was
found in 40 patients.

The mean age was found as 63.3+-10.3 years in the patient and 61.7+-11.1
years in the control group (p=0.5). In the patient group, 9 were female
and 31 male, whereas in the control group, 11 were female and 19 male
(p=0.19). The incidence of ISR was significantly higher in smokers
compared to nonsmoker patients (Figure 1) (p=0.04). No statistically
significant difference was found between ISR and control groups in terms
of DM and HT (for all; p\textgreater{}0.05).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1.} Rate of smokers in ISR and control groups.

Again, no statistically significant difference was found between the ISR
and control groups in age, echocardiographic parameters (left
ventricular diastolic diameter, left ventricular systolic diameter,
ejection fraction), urea, creatinine, hemoglobin, MCV, WBC, PLT, LDL,
and NON- HDL cholesterol levels (for all; p\textgreater{}0.05).

Table 1 shows demographic features and Table 2 describes
echocardiographic and laboratory parameters in patients with and without
ISR.

When the drugs used were evaluated between the groups; no statistically
significant difference was found between ISR and control groups in terms
of using beta blockers, statins, ACE inhibitors and/or angiotensin
receptor blockers (ARB) (fol all; p\textgreater{}0.05).

There was no significant difference between ISR and control groups in
terms of stent types and coronary arteries where the stent was inserted
(for all; p\textgreater{}0.05) (Table 3). Coronary arteries with ISR are
seen in Figure 2.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2.} Distribution of coronary arteries with ISR in the
patient group; n(\%)

In the comparison between increase of restenotic stent rate and serum
levels of prolidase; it was observed that serum prolidase level
increased as the rate of restenotic stents increased and this
relationship was statistically significant (p=0.04).

Angiographic GENSINI's score was statistically significantly higher in
the ISR group compared to the control group (35.7\selectlanguage{ngerman}±26.8 vs 19.8±17)
(p=0.002).

Serum level of prolidase was found to be statistically significantly
higher in ISR group than in the control group (993.18 ± 609.99 mU/mL vs
468.53 ± 258.92 mU/mL) (p=0.02). Comparison of serum prolidase levels
between ISR and control groups is seen in Figure 3. In the multivariate
lineer regression analysis, independent predictors of stent restenosis
are shown in Table 4.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3.} Comparison of serum prolidase levels (mU/mL) between
ISR and control groups

(Box-Plot).

When correlations between the parameters were evaluated; there was a
moderate correlation between prolidase level and restenotic stent rate
according to Pearson's correlation analysis (r: 0.44, p: 0.03). In the
linear regression analysis including serum prolidase level, age, LDL and
Gensini's score; serum prolidase level (\selectlanguage{greek}β: \selectlanguage{english}0.45, p: 0.02) and Gensini's
score (\selectlanguage{greek}β: \selectlanguage{english}0.56, p: 0.02) were found to be independent predictors of
in-stent restenosis.

\textbf{DISCUSSION}

In our study, serum prolidase level was found to be significantly higher
in the ISR group compared to the control group. In the correlation
analysis; prolidase level was correlated with the rate of restenosis. In
the linear regression analysis; we found that serum prolidase level and
Gensini's score were independent predictors of stent restenosis.

In-stent restenosis is defined as the gradual re-narrowing of the lesion
in the stent in the coronary artery as a result of arterial damage and
subsequent neointimal tissue proliferation (15). It has been shown that
coronary artery stent restenosis is a negative response caused by the
decrease in vascular diameter due to damage occurring during coronary
revascularization (8). Neointimal hyperplasia is known to be the most
important mechanism underlying ISR (16).

Neointimal hyperplasia is associated with collagen synthesis and matrix
proteins. Previous studies have shown that, because of the wide tissue
distribution, changes in serum prolidase enzyme levels may play a role
in the development and outcome of many diseases and is directly
associated with the synthesis of collagen, which is abundantly found in
the body (14, 17, 18).

Rabus et al. compared 26 patients who underwent valve replacement due to
rheumatic etiology, 24 patients due to degenerative etiology and 20
healthy volunteers in terms of prolidase enzyme levels. Serum level of
prolidase enzyme was statistically significantly higher in the control
group than in the patient group (p\textless{}0.001). No significant
difference was observed between rheumatic and degenerative valve
replacement groups in terms of prolidase enzyme levels. There was no
significant correlation between serum prolidase level and severity of
valvular disease (p\textgreater{}0.05). The authors stated that
rheumatic and degenerative valvular diseases were associated with
decreased serum prolidase enzyme level (19).

In a study by Akturk et al. evaluating serum prolidase levels in 40
patients with coronary artery ectasia (CEA) and 40 control subjects with
angiographically normal coronary arteries, serum prolidase level was
found to be significantly higher in CEA patients and was an independent
predictor of CEA (20).

In another study, serum level of prolidase enzyme was compared between
the patients with ischemic and idiopathic dilated cardiomyopathy (DCM)
and healthy individuals, and prolidase enzyme levels were found to be
significantly lower in patients with ischemic DCM compared to the other
two groups. The authors stated that the results obtained from this study
were the opposite of the predicted. Normally, serum prolidase level is
expected to be higher in patients with ischemic etiology, and the
authors proposed that lower serum prolidase levels found in patients
with ischemic etiology may be caused by decreased collagen cycle in
heart tissue and decreased physical activity in these patients (21).

Demirbag et al. compared hypertensive patients with and without left
ventricular hypertrophy and healthy individuals. In that study, serum
prolidase level was significantly higher in hypertensive patient groups
and was associated with the duration of hypertension. (22)

In a study evaluating CAD patients, Yildiz et al. compared 199 patients
with severe CAD and 122 healthy individuals. Serum prolidase activity
was found to be significantly higher in the CAD group (52.5\selectlanguage{ngerman}±5.6 U/L vs
46.7± 5.1 U/L, p\textless{}0.001). On the other hand, the authors stated
that serum prolidase level was an independent predictor of CAD (23).

In a study by A.Suner et al. the authors stated that increased prolidase
activity may contribute to the development of slow coronary flow. (24).

As we mentioned so far, prolidase enzyme levels have been evaluated in
various cardiac conditions such as valvular diseases, hypertension and
dilated cardiomyopathy, although there are no sufficient studies about
the value of prolidase in patient groups with CAD and stent restenosis.
Therefore, in the present study we found significantly higher serum
levels of prolidase in the patient group than in the control group
(993.18± 609.99 mU/mL vs 468,53± 258,92 mU/mL, p= 0.02).

In the current study, we demonstrated that serum prolidase levels were
moderately correlated with the severity of stent restenosis. On the
other hand, we found that serum prolidase level was an independent
factor in predicting the severity of in-stent restenosis (\selectlanguage{greek}β: \selectlanguage{english}0.45, p:
0.02).

We think that the reason underlying high serum prolidase level in the
patients with stent restenosis was associated with the prolidase's
direct role in collagen synthesis and thus, its indirect role in the
development of neointimal proliferation.

\textbf{Study Limitations}

Relatively small number of patients, lack of sufficient data about PCI
procedures performed in patients (stent diameters and sizes, duration
and pressure of balloon inflation etc.) and lack of the evaluation of
other biomarkers having a role in collagen mechanism arethe main
limitations of this study.

\textbf{Conclusion:}

Data obtained in this study indicate that serum prolidase enzyme level
is closely related with in-stent restenosis and is an independent factor
of predicting the severity of in-stent restenosis.

Our results suggest that serum prolidase enzyme levels will enable early
and correct evaluation of stent restenosis in patients undergoing PCI
with coronary stents and will contribute to determining the time of
altering or intensifying the existing treatment. Further comprehensive
clinical studies with a large number of patients are needed to support
our results.

\textbf{Declarations:}

\textbf{Acknowledgements:} We would like to thank Mehmet Tosun, MD from
Abant Izzet Baysal University Medical Faculty, Department of
Biochemistry, for his valuable support in biochemical analyses.

\textbf{Conflicts of interest/Competing interests:} ~\textbf{:} ~The
authors report no conflict of interest regarding this study.

\textbf{Funding:} This study was financially supported by the Abant
Izzet Baysal University, Scientific Research Projects Unit with the
Project No: BAP -- 2014.08.31.731.

\textbf{Informed Consent:} All participants were informed about
objectives of the study and signed informed consent forms.

\textbf{REFERENCES:}

\begin{enumerate}
\tightlist
\item
  The global burden of disease. 2004 update. World Health Organization
  2008.\emph{https://www.who.int/healthinfo/global\_burden\_disease/2004\_report\_update/en/}{[}Access
  Date: 15/10/2020{]}.
\item
  Chung M, Asher RC, Yamada D, Eagle KA. Arrhythmias after cardiac and
  non-cardiac surgery. In: Podrid P, Kowey PR, Editors. Cardiac
  arrhythmia: mechanisms, diagnosis, and management. Philadelphia, PA:
  Lippincott Williams \& Wilkins; 2001.
\item
  HURST'S, The HEART Fuster, Walsh, Harrington, Hunt, King III, Nash,
  Prystowsky, Roberts, Rose. B:2 S:17.
\item
  Global risk and objectives in cardiovascular diseases Gulec S. T\selectlanguage{ngerman}ürk
  Kardiyol Dern Ar\selectlanguage{polish}ş - \selectlanguage{english}Arch Turk Soc Cardiol 2009;37 Suppl 2:1-10
\item
  Lloyd-Jones D,Adams R, Carnethon M, et al. Heart disease and stroke
  statistics-2009 uptade: a report from the American Heart Association
  Statistics Committee and Stroke Statistics Subcommittee. Circulation.
  2009; 119(3):480-486.
\item
  Kardiyovask\selectlanguage{ngerman}üler Hastal\selectlanguage{polish}ı\selectlanguage{english}klar El Kitab\selectlanguage{polish}ı. \selectlanguage{english}Edt: Brian P. Griffin, B:65,
  S:1. Lippincott Williams\&Wilkins.
\item
  American Heart Association. 2004 Heart and Stroke Statistical
  Uptade.Dallas , TX; American Heart Association, 2003.
\item
  Schwartz RS. Animal Models of Human Coronary Restenosis. In: Topol EJ
  editor. Textbook of Interventional Cardiology. Philadelphia:
  Saunders,1994;365- 81.
\item
  Cortese B, Berti S, Biondi-Zoccai G, et al. Drug-coated balloon
  treatment of coronary artery disease: a position paper of the Italian
  Society of Interventional Cardiology. Catheter Cardiovasc Interv
  2014;83:427-35.
\item
  Cassese S, Byrne RA, Schulz S, et al. Prognostic role of restenosis in
  10 004 patients undergoing routine control angiography after coronary
  stenting. Eur Heart J 2015;36:94-9.
\item
  Batyraliev T, Av\selectlanguage{polish}ş\selectlanguage{english}ar \selectlanguage{ngerman}Ö. Stent \selectlanguage{polish}İ\selectlanguage{ngerman}çi Restenoz ve \selectlanguage{polish}İ\selectlanguage{english}la\selectlanguage{ngerman}çlarla Kapl\selectlanguage{polish}ı \selectlanguage{english}Stentler.
  T\selectlanguage{ngerman}ürk Giri\selectlanguage{polish}ş\selectlanguage{english}imsel Kardiyoloji Dergisi. 2007;11: 163-169.
\item
  Surazynski, A., Miltyk, W., Palka, J. and Phang, J.M. (2008b)
  Prolidase-dependent regulation of collagen biosynthesis. Amino Acids
  35, 731-- 738.
\item
  Kayadibi H, Gultepe M, Yasar B, Ince AT, Ozcan O, Ipcioglu OM, et al.
  Diagnostic value of serum prolidase enzyme activity to predict the
  liver histological lesions in non-alcoholic fatty liver disease: a
  surrogate marker to distinguish steatohepatitis from simple steatosis.
  Dig Dis Sci. 2009;54(8):1764--1771.
\item
  Can elevated prolidase activity predict the duration of ischemic
  exposure in different types of ischemia? T\selectlanguage{ngerman}ürk Gö\selectlanguage{polish}ğ\selectlanguage{ngerman}üs Kalp Damar
  Cerrahisi Dergisi 2013;21(4):1000-1004 doi:
  10.5606/tgkdc.dergisi.2013.7855
\item
  Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R.
  In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol.
  2010 Nov 30; 56(23):1897-907.
\item
  Zhou W,Lin PH,Bush RL,Peden EK,Guerrero MA,Kougias P,Lumsden AB,
  Management of in-sent restenosis after carotid artery stenting in
  high-risk patients. Journal of vascular surgery.
\item
  Türk Biyokimya Dergisi (Turkish Journal of Biochemistry-Turk J
  Biochem) 2007; 32 (1); 12-16.
\item
  Whang SH, Zhi QW, Sun MJ. (2006) Dual activities of human prolidase.
  Toxicol In Vitro. 20: 71-77.
\item
  Serum prolidase activity in patients with degenerative and rheumatic
  heart valve diseases Murat Bulent Rabu\selectlanguage{polish}ş, \selectlanguage{english}Recep Demirba\selectlanguage{polish}ğ, \selectlanguage{english}Yusuf Sezen,
  Mehmet Ta\selectlanguage{polish}ş\selectlanguage{english}ar, Abdullah Ta\selectlanguage{polish}ş\selectlanguage{english}k\selectlanguage{polish}ı\selectlanguage{english}n, Nurten Aksoy, Kaan K\selectlanguage{polish}ı\selectlanguage{english}rali, Cevat Yakut.
  Turk J Med Sci 2010; 40 (5): 687-692 TUB\selectlanguage{polish}İ\selectlanguage{english}TAK
\item
  Akt\selectlanguage{ngerman}ürk E, A\selectlanguage{polish}ş\selectlanguage{english}k\selectlanguage{polish}ı\selectlanguage{english}n L, Nacar H, Ta\selectlanguage{polish}ş\selectlanguage{english}olar MH, T\selectlanguage{ngerman}ürkmen S, Çetin M, Bozkurt M.
  Association of serum prolidase activity in patients with isolated
  coronary artery ectasia. Anatol J Cardiol. 2018 Feb;19(2):110-116.
\item
  Serum prolidase activity in idiopathic and ischemic cardiomyopathy
  patients.\emph{Yusuf Sezen},\emph{Memduh Bas},~\emph{Halil
  Altiparmak},~\emph{Ali Yildiz},~\emph{Hakan Buyukhatipoglu},\emph{Omer
  Faruk Dag},~\emph{Zekeriya Kaya},~\emph{Nurten Aksoy}. J Clin Lab
  Anal.~2010;24(4):213-8doi: 10.1002/jcla.20388.
\item
  Serum prolidase activity in patients with hypertension and its
  relation with left ventricular hypertrophy . Recep Demirbag , Ali
  Y\selectlanguage{polish}ı\selectlanguage{english}ld\selectlanguage{polish}ı\selectlanguage{english}z , Mustafa Gur , Remzi Yilmaz , Kevser El\selectlanguage{ngerman}çi , Nurten Aksoy, R.
  Demirbag et al. / Clinical Biochemistry 40 (2007) 1020--1025.
\item
  The association of serum prolidase activity with the presence and
  severity of coronary artery disease. Yildiz A, Demirbag R, Yilmaz R,
  Gur M, Altiparmak IH, Akyol S, Aksoy N, Ocak AR, Erel O. Coron Artery
  Dis 2008 Aug;19(5):319-25.doi: 10.1097/MCA.0b013e32830042ba.
\item
  Evaluation of serum prolidase activity in patients with slow coronary
  flow.\emph{Arif Suner},\emph{Abdullah Nurdag},~\emph{Mustafa
  Polat}\textsuperscript{~},~\emph{Hakan
  Kaya}\textsuperscript{~},\emph{Sedat
  Koroglu}\textsuperscript{~},\emph{Gurkan Acar},\emph{Hatice
  Sezen}\textsuperscript{.}Postepy Kardiol Interwencyjnej.
  2015;11(3):206-11.~doi: 10.5114/pwki.2015.54015.~Epub 2015 Sep 28.
\end{enumerate}

\textbf{TABLES:}

\textbf{Table 1.} Demographic features of ISR and control groups\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& & \textbf{ISR} & \textbf{CONTROL} & \textbf{TOTAL} &
\textbf{P}\tabularnewline
\midrule
\endhead
\textbf{AGE} & \textbf{AGE} & 63.3\selectlanguage{ngerman}±10.3 & 61.7\selectlanguage{ngerman}±11.1 & 70 &
0.50\tabularnewline
\textbf{FEMALE} & \textbf{FEMALE} & 9 (22\%) & 11 (37\%) & 20 &
0.19\tabularnewline
\textbf{MALE} & \textbf{MALE} & 31 (78\%) & 19 (63\%) & 50 &
0.19\tabularnewline
\textbf{HYPERTENSION} & \textbf{Yes} & 28 (70\%) & 16 (53\%) & 44 &
0.15\tabularnewline
& \textbf{No} & 12 (30\%) & 14 (47\%) & 26 &\tabularnewline
\textbf{DIABETES} & & & & &\tabularnewline
MELLITUS & \textbf{Yes} & 13 (32\%) & 12 (40\%) & 25 &
0.52\tabularnewline
& \textbf{No} & 27 (68\%) & 18 (60\%) & 45 &\tabularnewline
\textbf{SMOKING} & \textbf{Yes} & 10 (25\%) & 2 (7\%) & 12 &
0.04\tabularnewline
& \textbf{No} & 30 (75\%) & 28 (93\%) & 58 &\tabularnewline
Chi-square test. & & & & &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2.} Echocardiographic and laboratory parameters of ISR and
control groups\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{ISR} & \textbf{CONTROL} & \textbf{P}\tabularnewline
\midrule
\endhead
\textbf{LVDD (mm)} & 48.1\selectlanguage{ngerman}±5.9 & 49.9\selectlanguage{ngerman}±6.2 & 0,21\tabularnewline
\textbf{LVSD (mm)} & 32\selectlanguage{ngerman}±7.2 & 33.3\selectlanguage{ngerman}±7.6 & 0,43\tabularnewline
\textbf{EF (\%)} & 51.9\selectlanguage{ngerman}±10.3 & 53.2\selectlanguage{ngerman}±12.7 & 0,63\tabularnewline
\textbf{UREA (mg/dL)} & 34.8\selectlanguage{ngerman}±10.4 & 35.9\selectlanguage{ngerman}±13.2 & 0,69\tabularnewline
\textbf{CREATININE (mg/dL)} & 0.96\selectlanguage{ngerman}±0.18 & 1.07\selectlanguage{ngerman}±0.87 &
0,46\tabularnewline
\textbf{HGB (g/dL)} & 13.7\selectlanguage{ngerman}±1.54 & 13.8\selectlanguage{ngerman}±1.91 & 0,69\tabularnewline
\textbf{MCV (fL)} & 85.7\selectlanguage{ngerman}±4.77 & 83.2\selectlanguage{ngerman}±12.3 & 0,24\tabularnewline
\textbf{WBC (K/uL)} & 7.27\selectlanguage{ngerman}±2.27 & 7.89\selectlanguage{ngerman}±2.34 & 0,23\tabularnewline
\textbf{PLT (K/uL)} & 231\selectlanguage{ngerman}±46.1 & 246\selectlanguage{ngerman}±65.5 & 0,24\tabularnewline
\textbf{LDL (mg/dL)} & 101.8\selectlanguage{ngerman}±33.5 & 101.8\selectlanguage{ngerman}±38.2 & 0,99\tabularnewline
\textbf{NON HDL (mg/dL)} & 133.2\selectlanguage{ngerman}±42.7 & 135\selectlanguage{ngerman}±42.9 & 0,86\tabularnewline
Student's t test. & & &\tabularnewline
\bottomrule
\end{longtable}

LVDD: Left ventricular diastolic diameter; LVSD: Left ventricular
systolic diameter; EF: Ejection fraction; HGB: Hemoglobin; MCV: Mean
corpuscular volume; WBC: Leukocytes; PLT: Platelets;

LDL: Low density lipoprotein; NON HDL: Non high density lipoprotein
cholesterol

\textbf{Table 3.} Stent types and coronary arteries of stent
implantation according to the groups.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& & \textbf{ISR} & \textbf{CONTROL} & \textbf{TOTAL} &
\textbf{P}\tabularnewline
\midrule
\endhead
\textbf{Stent} & & & & &\tabularnewline
Type & \textbf{DES} & 13 (32\%) & 14 (46\%) & 27 & 0.23\tabularnewline
& \textbf{BMS} & 27 (68\%) & 16 (54\%) & 43 &\tabularnewline
\textbf{Coronary} & & & & &\tabularnewline
Artery of & & & & &\tabularnewline
Implantation & \textbf{RCA} & 13 (33\%) & 8 (25\%) & 21 &
0.87\tabularnewline
& \textbf{CX} & 5 (13\%) & 4 (15\%) & 9 &\tabularnewline
& \textbf{LAD} & 22 (54\%) & 18 (60\%) & 40 &\tabularnewline
Chi-square test. & & & & &\tabularnewline
\bottomrule
\end{longtable}

DES: Drug-eluting stent; BMS: Bare metal stent; RCA: Right coronary
artery; CX: Left circumflex artery; LAD: Left anterior descending artery

\textbf{Table 4.} Independent predictors of in-stent restenosis.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Beta} & \textbf{T} & \textbf{P}\tabularnewline
\midrule
\endhead
\textbf{PROLIDASE} & 0,45 & 2,54 & 0,02\tabularnewline
\textbf{AGE} & 0,22 & -0,93 & 0,37\tabularnewline
\textbf{LDL} & 0,35 & -1,72 & 0,11\tabularnewline
\textbf{GENSINI SCORE} & 0,56 & 2,70 & 0,02\tabularnewline
LDL: Low density lipoprotein & & &\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

