MARKERS OF INFLAMATION IN TROPONIN T

NEGATIVE UNSTABLE ANGINA PECTORIS

Zoran Koprivica, Dragić Banković, Nikola Čikiriz

Coronar unit of the cardiologic department- internal hospital ZC Gornji Milanovac,
Faculty of Science, Kragujevac, Medical Faculty, University of Kragijevac, kragujevac,
Serbia

MARKERI INFLAMACIJE U TROPONIN T NEGATIVNOJ

NESTABILNOJ ANGINI PEKTORIS

Zoran Koprivica, Dragić Banković, Nikola Čikiriz

Koronarna jedinica odeljenja za kardiologiju interne bolnice ZC Gornji Milanovac,
Srbija, PMF Kragujevac,Srbija, Medicinski Fakultet, Univerzitet u Kragujevcu,
Kragujevac, Srbija

SUMMARY

Unstable angina pectoris is nowadays defined as an acute coronar syndrome, often

followed by characteristic electro-cardiogram changes and that is why it represents a
differential – diagnostical problem.
Thanks to development of biochemical methods today it is possible , in a short
period of time to specify the rates of high specific cardio troponin T that will be helpful in
the approach to the patient with acute coronar syndrome ( ACS ) and in the short-term
prognosis. Biochemical cardiac markers play very important role in diagnosing and
treatment of the patients with acute coronar syndrome. Markers of necrosis myocytes,
troponins, are recommended in diagnisis and treatment of infarct myocard with
elevation of ST segment, and also infarct myocard without elevation of ST segment and
unstable angina pectoris. Values of troponin are almost the most important criteria at
stratification of the risk and making decisions about therapeutic approach to the patient
with acute coronar syndrome; it has been already written about their importance. Beside
markers of necrosis myocytes there are two other groups of hearth markers that are
becoming important: markers of inflammation and markers of hearth function.
Biochemic hearth markers play important role in diagnosing and treatment of the
patients with acute coronar syndrome. Three types of indicators are being used nowadays:
markers necrosis myocytes, markers of inflammation and markers of hearth function.
Markers of hearth necrosis, troponins, represent the part of the new world
recommendation for the patients with acute coronar syndrome and redefinition of infarct
myocard. Markers of heart function ,heart natriuretic peptides, are being used in
diagnosing and clinical estimating of heart insufficiency. Markers of inflammation in
acute coronar syndrome can help in stratification of the risk and identification of the
patients who may get the benefit of certain types of therapies. Some of them are common

1
indicators of inflammation: C-reactive protein, the number of white blood cells,
sedimentation of erythrocytes, fibrinogen and some of them are in the phase of research.
The aim of this study was to follow markers of inflammation in troponin negative
unstable angina pectoris, as early predictors in prevention of acute coronar event-infarct
myocard with permanent destruction of effective muscles quantity. The aim was also to
estimate the necessity of an early PCI.
Key words: markers of inflammation, acute coronar syndrome.

INTRODUCTION

It is estimated that today 1.7 million of patients are hospitalized annualy in the
USA because of ACS. 25% of them have STEMI and 75% have unstable angina pectoris.
Among the patients with unstable angina pectoris and NSTEMI, 40-60% have
evident myocardial necrosis with higher values of troponin.
Atherocshlerosis is etiological base for narrowing of coronary arteries but it is
accelerated by additional risk factors that increase the percentage of narrowing.
It is clinical manifestations of ACS, and it is manifested by pain in the chest or
some other usual locations, followed by dynamic ECG changes and without elevation of
ST- wave and increase of markers in the blood.
Classic manifestation of ischemia is angina that is described as difficult pain,
pressure, heating in the chest, heavy breathing and spreading of the difficulty in the neck,
left shoulder and arm. Unstable angina is defined on the basis of difficulties and character
of the “chest pain” and it has at least one of the three characteristics:
-angina at rest or at minimal effort in the duration of more than 20 minutes if it is
not previously stopped by sublingual nitro-glycerine.
-newly created heavy angina with clear “ chest pain”at little effort.
-crescendo angina with stronger and longer pain added to presend stable angina.
Women suffer from unstable angina more then men. Patients with this angina
usually have a history of infarction, angina, revascularization or exstracardiac vascular
disease. The pain is always present in patients with unstable angina but also in patients
with NSTEMI and accurs at rest or at minimal effort. In patients with stable angina the
pain occurs at less effort then previously. Its duration is less than 20 minutes and reaction
to sublingual nitro-glycerin is weaker. There may appear heavy breathing, nausea and
sweating that can be equivalent to pain.
Becouse of vagotonia, passing, bradycardia and hypotension are registered in
inferior ischemia; because or stimulation of sympathetic, passing tachycardia and
hypertension are registered in front ischemia.
Arrhythmia sometimes accurs and also the third and the fourth cardiac sound. The
apperance of systol murmur on apex is a sign of disfunction of papilar muscles. Large
ischemia may lead to heart insufficiensy.
Electrocardiogram; If during the pain the elevation of ST-wave accurs and goes
on without stop even after using sublingual nitro-glycerine, that is AIM. Depression of
ST-wave and T-wave changes are characteristic signs of myocardial ischemia. Significant
ST depression is depression from 0.1 mV and more, and it is registered in 20% of
patients. 20% of patients have ST-depression of 0.5 mV, so they should be followed up
becouse of worse prognosis than the previous ones. Prognosis is the worst in 10% of the

2
patients with unstable angina or NSTEMI who have a passing ST-elevation ( up to 20
minutes) T- wave changes are more sensitive but not specific for acute ischemia unless
they are of considerable values (> 0.3 mV).
Electrocardiogram examination is often done, and the changes are followed; it is
wery important to do this examination during the pain becouse the therapy and prognosis
dependon this.
Inflammation, sistematic or local, plays imprtant role in occurance of acute
coronary syndrome. Proces of inflammation determines stability or unstability of plaque.
Becouse of that we come to the question whether these workers of inflammation may
help in the stratification of the risk and identification of the patients who may have the
benefit of some types of therapeutic procedures.
Markers of inflammation used at present:
- C- reactive protein (CRP)
- number of leukocytes
- sedimentation of erythrocytes
- fibrinogen
C – reactive protein is a marker that has been alredy used in estimation of
inflammation in patients with atherosclerosis. Higher values of CRP occur in patients
who have faster progress of atherosclerosis. Disfunction of vasodilatation depending on
endothel occurs in atherosclerosis. Higher values of CRP go together with damaged
vasodilatation depending on endothel in patients with coronary disease. According to
some new studies, the values of CRP correlate with systematic bio-availability of azot
monoxide from endothel in patients with coronary disease.
Myocardial infarction, exitus and the need for revascularisation of myocard occur
more often in patients with unstable angina pectoris and increased values of CRP then in
patients without increased values og CRP.
The importance of prognosis of increased of CRP has no connection with positive
troponin. In patients with negative troponin, as a marker of mucite necrosis, increased
values of CRP meant the presence of higher risk for bad result of coronary event.
Increased values of CRP are united with bad short-term prognosis in patients with
unstable angina pectoris.
At present, increased values of CRP in acute coronary sundrome represent higher
risk for bad result in such patients. Increased values of CRP are united with faster
progress of atheroschlerosis, so decrease of CRP values leads to decrease of mortality
caused by coronary disease. It has been proved, in controlled randomiyed study of
Revesal, that the use of statin owing to its antiinflamatory action, leads to significant
decrease of CRP values.
The increase of the white blood cells in acute coronary syndrome is associated
with a worse prognosis and increased degree of mortality in such patients. The number of
leukocytes in acute infarction begins to grow 2 hours after the beginning of „angina
pain“; maximal values are obtained 2-4 days later, and it turns to normal during the first
week. Changes in relative LF often occur, with the increase on the part of
polimorfonucleaar leukocytes. Since this is wide-spread and simple method, it may be
very attractive in stratification of the risk in acute coronary syndrome. At present there
are no data about the adventages of some types of therapies in comparison with
positivness of this markers of inflamation.

3
 Sedimentation of erythrocytes is normal within first two days. Then it grows and
reaches the maximal values on the fourth and fifth day, maintaining the elevated values
during next several weeks.
Fibrinogen grows in acute myocardial infarction with the some dynamic like
sedimentation of erythrocytes. There is correlation between the values of fibrinogen and
the extent of infarction. For the time being it is not known that elevated values of
fibrinogen have any predictive importance.

PATIENTS AND METHODS

PLACE AND TIME OF THE STUDY

The study was made in Coronary Unit of the Internal Department of public
Hospital in Gornji Milanovac. The prospective study was done on the patients with T –
troponin negative unstable angina pectoris that were hospitalized from September to
November of 2008. According to the type of research, this is a „ pair-study“.

PATIENTS AND PARAMETRES OF THE RESEARCH

This study involved the patients with unstable angina pectoris T – troponin
negativ( T – troponin ≤ 0.03 ng/ml).
A total of 39 patients were treated, of whom 20 were the patients with unstable
angina pectoris T troponin negative ( examined group ) and 19 were the patients without
cardiovascular symphatology ( control group ). The criteria for diagnosis of this clinical
syndrome that represents one of the clinical manifestations of ACS are: „ chest – pain“
which lasts more than 20 minutes, and continues no matter previously made therapy or
sublingual nitro-glycerine therapy; dynamic changes on ECG without ST – elevation and
without increase of markers of heart necrosis followed by longer and stronger pain in the
sense of crescendo angina added to existing stable angina.
We formed the control group in such a manner that we joined one patient of the
same similar or the same age ( ± 2 year ) without unstable angina pectoris ( patients
without cardiovascular disease ) to every patient in our internal protocol. The youngest
patient was 36, and the oldest one was 82 years old.

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 STATISTICS REPORT

Descriptive Statistics
N Minimum Maximum Mean Std.
Deviation
STAROST 39 36,00 82,00 60,4615 10,6174
HOMOCIST 39 4,00 30,00 15,1282 7,9610
CRP 39 1,10 222,00 25,5821 44,1686
FIB 38 1,80 9,60 3,7842 1,6112
LEUK 38 2,60 96,00 11,0842 19,2872
SE 39 2,00 82,00 19,5744 23,3412
Valid N 37
(listwise)

Tests of Normality
Kolmogorov- Shapiro-
Smirnov Wilk
GRUPA Statistic df Sig. Statistic df Sig.
STAROST 1,00 ,121 17 ,200 ,984 17 ,971
2,00 ,097 20 ,200 ,986 20 ,981
HOMOCIST 1,00 ,129 17 ,200 ,953 17 ,492
2,00 ,160 20 ,192 ,928 20 ,179
CRP 1,00 ,200 17 ,068 ,819 17 ,010
2,00 ,112 20 ,200 ,971 20 ,747
FIB 1,00 ,138 17 ,200 ,934 17 ,318
2,00 ,127 20 ,200 ,940 20 ,307
LEUK 1,00 ,422 17 ,000 ,506 17 ,010
2,00 ,164 20 ,164 ,941 20 ,316
SE 1,00 ,201 17 ,066 ,841 17 ,010
2,00 ,129 20 ,200 ,921 20 ,112

* This is a lower bound of the true significance.

** This is an upper bound of the true significance.
a Lilliefors Significance Correction

5
 HOMOCISTEIN

Group Statistics
GRUPA N Mean Std. Deviation Std.
Error
Mean
HOMOCIST 1,00 19 22,4211 4,1809 ,9592
2,00 20 8,2000 2,5464 ,5694
P
= 0.000

Angina pektoris Kontrola p

HOMOCIST 22,42 ± 4,18 8,20 ± 2,57 0,000
Komentar: Razlika u homocisteinu između angine pectoris i kontrolne grupe je statistički
značajna (p = 0,000) (t test)

ROC Curve
1,00

,75

,50

,25
Sensitivity

0,00
0,00 ,25 ,50 ,75 1,00

1 - Specificity
Coment: Homocistein may be a marker for angina pectoris CUT OFF for
HOMOCISTEIN is 17

6
CRP
CRP
Percentiles

GRUPA 25 50 75
CRP 1,00 19,0000 23,0000 26,0000
2,00 6,0000 8,0000 10,7500

Angina pektoris Kontrola p

CRP 23,00 (19,00 – 26,00) 8,00 (6,00 – 10,75) 0,000
Komentar: Razlika u CRP-u između angine pectoris i kontrolne grupe je statistički značajna (p
= 0,000) (Mann-Whitney)

ROC Curve
1,00

,75

,50

,25
Sensitivity

0,00
0,00 ,25 ,50 ,75 1,00

1 - Specificity
CRP may be a marker for angina pectoris. CUT OFF for CRP is 6,45

RESULTS

Markers of inflammation in acute coronary sundrome have, for the time being,
such clinical importance that they help in establishing a diagnosis and estimation of
seriousness of inflammation. Since we know that atheroschlerosis is chronic,
inflammatory and destructive process which ruins triple endothel function
( antitrombogeny, vasodilatatory, anti-inflammatory).
Our work is specific because of the fact that we followed exactly determined
group of patients with acute coronary sundrome with T – troponin unstable negative

7
angina pectoris where we, in the moment of deterioration by following markers of
inflammation, warned the patients of the danger of future acute coronary event in the
sense of muocardial infarction which destroys effective work muscle surface.
Taking all this into account it leads to heart weakness and possible sudden exitus
coronary event. These patients were instructed to make an earlu PCI.

DISCUSSION

This study compared the values of C – reactive protein in serum in the patients
with unstable T – troponin negative angina pectoris and the values in the patients of
control group who matched those from the first group in sex and age ( ± 2 years ).
The study showed that the patients with unstable negative T – troponin angina
statistically had considerably higher values of CRP, Homocistein, Fibrinoghen,
Leukocytes and Sedimentation in plazma than the patients of control group. Our results
show that the values of markers of inflammation in serum of the patients with unstable T
– troponin negative angina are increased and they correspond to the results of in this
field.
One of these studies was by Auer and assoc. in 2002. The study involved 56
patients, of whom 25 patients were with unstable angina pectoris and acute muocard
infarction (mediana age 68.5 ± 14.3 )and 31 patients with clinical signs and symptoms of
stable coronary arthery disease ( median 64 ± 12.7 ). 43 of these patients were males, 13
were females. The values of CRP in serum in patients with unstable angina and
myocardial infarction statically were not significantly different from the values of CRP in
patients with stable coronary arthery disease. In the sub category patients with
myocardial infarction, the values of CRP in serum statistically were significantly higher
than those of the patients with stable coronary arthery disease. This proves that
inflammation plays important role in pathogenesis of atheroschlerosis. Chronic
inflamatory process can event by induction rupture of atheroschlerosial plaque.
Our research also showed that the values of CRP don`t depend on sex and age. In
2002. Riese and ass.compared the values of CRP in women that took oral contraceptive
pills with those of women that didn`t take such pills and men. They showed that women
who took oral contraceptive pills had the highest values of CRP, men had lower values,
and women who didn`t take oral contraceptive pills had the lowest values of CRP.
We noticed that the patients in control group had lower values of fibrinogen than the
patients with unstable T – troponin negative angina, and we also noticed that the patients
with higher values of CRP more often have higher values of fibrinogen than the patients
with normal values of CRP. Higher values of fibrinogen and CRP are connected with a
worse result in patients with acute coronary syndrome.
On the basis of this study and also the data of other studies we have come to the
conclusion that the patients with unstable T – troponin negative angina pectoris have
increased values of markers of inflammation.

REFERENCES

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 MARKERI INFLAMACIJE U TROPONIN T NEGATIVNOJ
NESTABILNOJ ANGINI PEKTORIS

Zoran Koprivica, Dragić Banković, Nikola Čikiriz

Koronarna jedinica odeljenja za kardiologiju interne bolnice ZC Gornji Milanovac,
Srbija, PMF Kragujevac,Srbija, Medicinski Fakultet, Univerzitet u Kragujevcu,
Kragujevac, Srbija
SAŽETAK
Nestabilna angina pektoris u današnje vreme se definiše kao akutni
koronarni sindrom često praćene karakterističnim
elektrokardiogramskim promenama zbog čega predstavlja
diferencijalno - dijagnostički problem.
Zahvaljujući razvoju biohemijskih metoda danas je u kratkom vremenskom intervalu
moguće odrediti nivoe visoko specifičnog kardio troponina T i time se brzo orijentisati u
prilazu pacijentu sa akutnim koronarnim sindromom (AKS) i kratkoročnoj
prognozi.Biohemijski srčani markeri igraju značajnu ulogu u dijagnozi i lečenju
bolesnika sa akutnim koronarnim sindromom. Markeri nekroze miocita, troponini, ušli su
u preporuke za dijagnozu i lečenje infarkta miokarda sa elevacijom ST segmenta, a i
infarkta miokarda bez elevacije ST segmenta i nestabilne angine pectoris. Vrednosti
troponina su jedan od odličujućih kriterijuma pri srtatifikaciji rizika i donošenju odluka
o terapijskom pristupu bolesniku sa akutnim koronarnim sindromom, i o njihovom
značaju je već pisano. Pored markera nekroze miocita postoje još dve grupe srčanih
markera koje dobijaju na značaju, a to su: markeri inflamacije i markeri srčane funkcije.
Biohemijski srčani markeri igraju značajnu ulogu u dijagnozi i lečenju bolesnika sa
akutnim koronarnom sindromom. Tri klase indikatora su sada u upotrebi: markeri
nekroze miocita, markeri inflamacije i markeri srčane funkcije. Markeri srčane nekroze,
troponini, ušli su u nove međunarodne preporuke za bolesnike sa akutnim koronarnim
sindromom i redefiniciju infarkta miokarda. Markeri srčane funkcije, srčani natriuretski peptidi,
koriste se u dijagnostikovanju i kliničkoj proceni srčane insuficijencije. Markeri inflamacije u
akutnom koronarnom sindromu mogu pomoći u stratifikaciji rizika i identifikovanju bolesnika,
koji mogu imati koristi od pojedinih vrsta terapija. Neki od njih su opšte poznati indikatori
inflamacije: C-reaktivni protein, broj belih krvnih zrnaca, sedmentacija eritrocita, fibrinogen, a
neki su u fazi istraživanja.
Ključne reči: markeri inflamacije, akutni koronarni sindrom
11