-

1. Article
Comparison of the Effects of Levosimendan
Dobutamine and Vasodilator Therapy
on Ongoing Myocardial Injury in Acute
Decompensated Heart Failure
Erkan Gencer, MD1
, Volkan Dog˘an, MD2
, Mu¨jgan Tek O¨ ztu¨rk, MD3
, Aydın Nadir, MD4
,
Ahmet Musmul, MD5
, and Yu¨ksel Cavus¸og˘lu, MD, FESC6
Abstract
Background: Cardiac troponins (cTn) are reliable and the most sensitive biomarker in the setting of acute decompensated heart
failure (ADHF). Acute decompensated heart failure is usually associated with worsening chronic heart failure, and it may be caused
by ongoing minor myocardial cell damage that may occur without any reported precipitating factors. Methods: We compared
the short-term effect of levosimendan (LEV), dobutamine (DOB), and vasodilator treatment (nitroglycerin [NTG]) on myocardial
injury with hemodynamic, neurohumoral, and inflammatory indicators. One hundred twenty-two patients with a mean age of 66
+ 9 years were treated with LEV (n ¼ 40), DOB (n ¼ 42), and NTG (n ¼ 40) and examined retrospectively. Blood samples (cTnI,
N-terminal probrain natriuretic peptide [NT-proBNP], highly sensitive C-reactive protein [HsCRP], and others), left ventricular
ejection fraction (LVEF), systolic pulmonary artery pressure (sPAP), and 6-minute walk distance (6MWD) were compared before
and after treatment. Results: At admission, detectable levels of cTnI were observed in 53% of patients (!0.05 ng/mL). Serial
changes in the mean cTnI levels were not significantly different between the groups (LEV 0.04 + 0.01 to 0.03 + 0.01 ng/mL; DOB
0.145 + 0.08 to 0.08 + 0.03 ng/mL; NTG 0.1 + 0.03 to 0.09 + 0.02 ng/mL; overall P ¼ .859). Favourable effects on the
NT-proBNP, sPAP values, LVEF, 6MWD, and HsCRP were observed overall, especially in the LEV groups. Conclusion: Beneficial
effects of short-term use of LEV, DOB, and NTG on ongoing myocardial injury were demonstrated. These findings can be
attributed to the anti-ischemic properties as well as the hemodynamic, neurohumoral, and functional benefits from the positive
inotropes, especially LEV, in patients with ADHF.
Keywords
heart failure, levosimendan, dobutamine, troponin
Introduction
There is increasing evidence that cardiac troponins (cTn) are
reliable and sensitive biomarkers for identifying high-risk
patients and good prognostic markers in the setting of acute
decompensated heart failure (ADHF).1-4
Ongoing myocardial
ischemia, inflammation, and apoptosis are associated with
myocyte degeneration in the cardiomyopathic myocardium,
and they may be responsible for worsening heart failure and
cTn release.5
Positive inotropic treatment may be given to patients who
are refractory to optimal medical treatment and intravenous
diuretics or who have evidence of low cardiac output, such as
hypotension or hypoperfusion in patients presenting with
ADHF.
Dobutamine (DOB) is a potent inotropic and weak chrono-
tropic agent that acts on the b1-2 and a1 adrenergic receptors.6
Levosimendan (LEV) is a parenteral inodilatory and so-called
calcium-sensitizing agent used for treating ADHF. In contrast
to DOB, it is suggested that LEV does not change the intracel-
lular calcium levels or oxygen consumption, and it may also
1
Department of Cardiology, Cardiology Clinic, Kilis State Hospital, Kilis, Turkey
2
Department of Cardiology, Department of Cardiology, Mugla Sıtkı Kocman
University, Mugla, Turkey
3
Department of Cardiology, Cardiology Clinic, Kecioren Education and
Research Hospital, Ankara, Turkey
4
Department of Cardiology, Cardiology Clinic, Bozuyuk State Hospital, Bilecik,
Turkey
5
Department of Biostatistics, Faculty of Medicine, Eskisehir Osmangazi
University, Eskisehir, Turkey
6
Department of Cardiology, Faculty of Medicine, Eskisehir Osmangazi
University, Eskisehir, Turkey
Manuscript submitted: March 29, 2016; accepted: May 09, 2016.
Corresponding Author:
Erkan Gencer, Cardiology Clinic, Kilis State Hospital, 79000 Kilis, Turkey.
Email: egencer45@gmail.com
Journal of Cardiovascular
Pharmacology and Therapeutics
1-6
ª The Author(s) 2016
Reprints and permission:
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DOI: 10.1177/1074248416657612
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2. exhibit protective properties against cardiac ischemia, inflam-
mation, and apoptosis.7-10
On the other hand, positive inotropic
therapy, including LEV and DOB treatment, may have adverse
hemodynamic, intracellular, and arrhythmogenic effects and
they should be used carefully in this patient-group.11-13
This retrospective study was designed to elucidate the
effects of LEV, DOB, and nitroglycerin (NTG) treatment on
ongoing myocardial injury as well as hemodynamic, neurohu-
moral, and inflammatory indicators in patients with ADHF.
Methods
Study Population
The patients who were admitted to the hospital of Osmangazi
University (Eskis¸ehir, Turkey) between June 2008 and May
2010 and those examined retrospectively were included in the
study. A total of 122 patients with ADHF included in the study
with a mean age of 66 + 9 years were treated with LEV, DOB,
or NTG; all patients had received standard heart failure therapy
including optimal oral medication and diuretics and left ven-
tricular ejection fraction (LVEF) of 35% or less as measured by
transthoracic echocardiography. LEV or DOB infusion was
administered to patients who have evidence of low cardiac
output such as peripheral hypoperfusion and hypotension or
who are refractory to optimal medical treatment according to
the clinician’s decision. NTG was administered preferably to
patients who have had hypertension or normotension with pul-
monary and/or peripheral edema in patient with ADHF. In
patients presenting with restrictive or hypertrophic cardiomyo-
pathy, uncorrected valvular disease, cardiogenic shock, sepsis,
severe hepatic impairment, severe renal impairment (glomeru-
lar filtration rate <30 mL/kg/1.73 m2
), chest pain or electro-
cardiogram changes with increased cTn values in serial
measurement, cTnI levels of !5Â cutoff, second- and third-
degree atrioventricular block, coexistence of acute respiratory
distress syndrome, recently with a history of cardiac arrest, and
any positive inotropes received last 4 weeks were excluded.
Study Design and Protocol
In all patients, cTnI, N-terminal probrain natriuretic peptide
(NT-proBNP), highly sensitive C-reactive protein (HsCRP),
echocardiographic estimation of LVEF, systolic pulmonary
artery pressure (sPAP) estimated by Doppler echocardiogra-
phy, 6-minute walk distance (6MWD), and other laboratory
findings were recorded before and after treatment. The mean
time of follow-up postinitiation of treatment was 48 hours. In
the all patients had been received of blood plasma samples
before treatment and postinitiation of 3 days. LEV with a load-
ing dose of 6 to 12 mg/kg over 10 minutes and followed by a
continuous infusion of 0.1 to 0.2 mg/kg/min was administered.
When there were adverse clinical effects, the dose was reduced
to 0.05 mg/kg/min. In the patients who have had received LEV,
5 patients of those had reduced dose of 0.05 mg/kg/min tempo-
rary. Dobutamine was infused at a rate of 10 mg/kg/min for
48 hours. Initial dose of NTG was 25 mg/kg/min and followed
by a continuous infusion up to 100 mg/kg/min when the dosage
adjusted according to blood pressure for 48 hours.
The baseline demographic, clinical, and hemodynamic char-
acteristics were recorded. Noninvasive measurements of the
blood pressure and heart rhythm during treatment were noted.
The results of invasive procedures that were performed at the
coronary care unit or catheterization laboratory were recorded
and compared.
Cardiac Troponin I Analysis
The control group consisted of healthy volunteers who were the
same age and gender in our clinic. Values of multiple cTnI
analyses of patients (Siemens Dimension cTnI Heterogeneous
Immunoassay Module) were recorded. The 99th percentiles of
the cTnI levels were established for optimal precision, and the
cTnI reference ranges were determined.14
Maximum 10%
coefficients of variation were applied to this level; in this way,
the cTnI reference intervals were determined with a lower
limit of detection of 0.05 ng/mL and upper reference limit
of 0.1 ng/mL (cutoff).
Statistical Analysis
The statistical analysis was performed using IBM SPSS Statis-
tics for Windows (version 20). The distribution forms of the
data were tested by Kolmogorov-Smirnov and Shapiro-Wilk
tests. Data for cross-sample comparisons were analyzed by
w2
tests and correlations. Comparison of the average of the data
was examined by t tests, and 1-way analysis of variance and
Tukey or Dunn test were used for post hoc analysis. Mean +
standard error values were used to summarize the data, and
P < .05 was considered as statistically significant.
Results
LEV (n ¼ 40), DOB (n ¼ 42), and NTG (n ¼ 40) groups were
compared in the study. Baseline clinical and demographic char-
acteristics are shown in Table 1. At admission, no significant
differences were observed between the groups in terms of these
characteristics.
Cardiac troponin Levels at Admission
and After Treatment
At admission, 53% of patients were found to exceed the lower
limit of detection of cTnI. The percentages of patients with
increased, decreased, and unchanged cTnI levels after treat-
ment were 36%, 44%, and 20%, respectively. After treatment
in all patients, decreasing trends were observed in the mean
cTnI levels, but statistically significant differences were not
found. After the treatment, no statistically significant effect
was observed with respect to serial changes in the cTnI
between the groups (overall P ¼ .859; Figure 1).
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3. Neurohumoral and Inflammatory Response
Overall, the mean NT-proBNP levels at admission of 9057 +
1052 pg/mL and after treatment of 5930 + 804 pg/mL were
observed (P < .001). In the post hoc analysis, no statistically
significant differences were found between the groups (P ¼
.207). Similarly, no significant differences were found in
terms of the mean change in HsCRP (P ¼ .487) as well as
total white blood cell count and its subtypes (P ¼ .173).
Hemodynamic and Functional Indicators
In each group with more pronounced LEV, statistically signif-
icant increases were found in the LVEF after treatment. In post
hoc analysis, the LVEF increase was significantly higher for
LEV and DOB compared to NTG (LEV DOB NTG,
.001). In each group, the sPAP values were significantly
decreased after treatment. This decrease tended to be greater
in the LEV group. Overall, statistically significant increases
were observed in terms of 6MWD after treatment, but no sta-
tistically significant difference was found between the groups
(P ¼ .087; Table 2). In all patients, statistically significant
increases were observed in the mean heart rate after treatment
(77.5 + 15 vs 84 + 16, P .001), but no statistically signif-
icant differences were found between the groups (P ¼ .124).
Discussion
ADHF is a clinical syndrome with increasing incidence that is
associated with frequent hospitalizations and high morbidity
and mortality. Although many different medications are used
in the effective treatment of acute and chronic heart failure,
inotropes may be required to improve hemodynamic stabiliza-
tion, peripheral perfusion, and cardiac output.15-17
However,
they should be used carefully because of safety concerns, such
as myocardial ischemia, atrial and ventricular tachyarrhyth-
mias, hypotension, and mortality risk.18-23
Many clinical studies on ADHF indicate that LEV improves
myocardial function, reduces the cTn levels, and suppresses
inflammation and apoptotic indicators of both intense myocar-
dial ischemia and stunned myocardium after myocardial infarc-
tion.24-27
In addition, lower levels of cTn release during LEV
administration and improving myocardial performance indica-
tors have been reported.28-30
An association between DOB and myocardial injury has
rarely been studied in patients with ADHF. DOB increases the
myocardial contractility, reducing the peripheral vascular resis-
tance and thus improving the cardiac output without seriously
affecting the blood pressure or sympathetic tone.31
In the pilot
randomized study of nesiritide versus dobutamine in heart fail-
ure (PRESERVED-HF) study, some patients developed cTn
release during hospitalization with DOB treatment.5
In several
studies that used DOB, there was no significant release of cTn
even for patients with a diffuse coronary artery disease or pre-
vious myocardial infarction.32-34
Table 1. Baseline and Clinical Characteristics of Patients at Admission.
Study Population (N ¼ 122) Levosimendan (n ¼ 40) Dobutamine (n ¼ 42) Nitroglycerin (n ¼ 40) P Value
Gender, male (%) 33 27 33 .08
Age, years 67.5 + 9.3 67.3 + 10.4 63.5 + 8.0 .097
Weight, kg 74.3 + 13.5 76.2 + 17.9 77.7 + 15.9 .622
Height, cm 168 + 7.5 167 + 8.5 170 + 6.6 .194
Atrial fibrillation, n (%) 6 (15) 7 (16.7) 12 (30) .189
Diabetes, n (%) 19 (47.5) 21 (50) 16 (40) .284
Hypertension, n (%) 19 (47.5) 26 (61.9) 27 (67.5) .171
Smoking, n (%) 12 (30) 6 (14.3) 14 (35) .083
Hyperlipidemia, n (%) 12 (30) 15 (35.7) 15 (37.5) .482
Heredity, n (%) 6 (15) 10 (23.8) 8 (20) .34
b-Blocker, n (%) 26 (65) 30 (71.4) 23 (57.5) .285
RAAS blocker, n (%) 20 (50) 21 (50) 23 (57.5) .738
Ischemic, n (%) 32 (88.6) 30 (78.4) 28 (73) .248
Single vessel, n 6 6 6 .967
Multivessel, n 26 24 22 .797
Abbreviation: RAAS, renin–angiotensin–aldosterone system.
Figure 1. Mean cTnI levels at admission and after treatment in all
groups. cTnI indicates cardiac troponin I.
Gencer et al 3
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4. At admission, detectable cTnI levels were found in 53% of
our patients. No significant changes were observed with the
mean cTnI levels after positive inotropic therapy or NTG. In
the present study, we observed that high levels of cTnI can
initially be detected regardless of the etiology of cardiomyo-
pathy and they tend to decrease, but did not change signifi-
cantly, after ADHF treatment. In inotropes, but more
pronounced in the LEV group, statistically significant improve-
ments were observed in the LVEF and 6MWD, and the
NT-proBNP and sPAP levels were more effectively decreased.
Overall, no significant differences were observed in the inflam-
mation indicators after treatment.
Recent studies suggest that positive inotropic therapy is not
associated with adverse events if eligible patients are treated.35
This may be associated with different causes, such as anti-
ischemic properties, hemodynamic, neurohumoral, and
functional benefits of positive inotropes, especially LEV.36
Furthermore, in previously reported studies, associations
between adverse events and using positive inotropes have not
inspired widespread use of implantable cardioverter defibrilla-
tors (ICDs) or the fact that the vast majority of mortality depends
on the sudden cardiac death.37
In the vicious cycle of congestive
heart failure and its progressive nature, it is already associated
with adverse outcomes in the absence of optimal medical ther-
apy, complete revascularization, and treatment of comorbidities,
which is exacerbated if an ICD is not implanted per the current
recommendations. Moreover, hospital admission with serious
clinical conditions, such as cardiogenic shock, pulmonary
edema, or end-organ dysfunctions caused by low cardiac output,
can be treated with commonly used positive inotropes, which
may be considered a lifesaving feature of ADHF.38
Conclusion
The present results indicate that beneficial effects were shown
by the short-term infusion of LEV, DOB, and NTG on ongoing
myocardial cell injury, which is considered as the main reason
of worsening heart failure. However, improvement in
hemodynamic, neurohumoral, and functional parameters is
more pronounced with LEV than those with DOB and NTG.
In addition, LEV, DOB, and vasodilator treatment might be
reliable options in the short term with eligible patients having
ADHF are treated. Further studies are needed to support this
conclusion.
Author Contributions
Volkan Dog˘an contributed to conception, design, and analysis.
Mu¨jgan Tek O¨ ztu¨rk, Aydın Nadir, Ahmet Musmul, and Yu¨ksel
Cavus¸og˘lu contributed to conception. Yu¨ksel Cavus¸og˘lu contributed
to design. All authors gave final approval and agree to be accountable
for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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Levosimendan (n ¼ 40) Dobutamine (n ¼ 42) Nitroglycerin (n ¼ 40)
Overall PAdmission
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WBC, 1/mL 12.4 + 2.6 10.5 + 2.1 .155 8.7 + 0.5 9 + 0.7 .101 8.7 + 0.7 8.7 + 0.7 .5 .173
PLTs, 1/mL 299 + 47 323 + 43 .352 215 + 20 235 + 15 .309 239 + 17 219 + 14 .052 .083
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