Article

Comparison of the Effects of LevosimendanDobutamine and Vasodilator Therapyon Ongoing Myocardial Injury in AcuteDecompensated Heart Failure

Erkan Gencer, MD1, Volkan Dogan, MD2, Mujgan Tek Ozturk, MD3, Aydın Nadir, MD4,Ahmet Musmul, MD5, and Yuksel Cavusoglu, MD, FESC6

AbstractBackground: Cardiac troponins (cTn) are reliable and the most sensitive biomarker in the setting of acute decompensated heartfailure (ADHF). Acute decompensated heart failure is usually associated with worsening chronic heart failure, and it may be causedby ongoing minor myocardial cell damage that may occur without any reported precipitating factors. Methods: We comparedthe short-term effect of levosimendan (LEV), dobutamine (DOB), and vasodilator treatment (nitroglycerin [NTG]) on myocardialinjury with hemodynamic, neurohumoral, and inflammatory indicators. One hundred twenty-two patients with a mean age of 66+ 9 years were treated with LEV (n¼ 40), DOB (n¼ 42), and NTG (n¼ 40) and examined retrospectively. Blood samples (cTnI,N-terminal probrain natriuretic peptide [NT-proBNP], highly sensitive C-reactive protein [HsCRP], and others), left ventricularejection fraction (LVEF), systolic pulmonary artery pressure (sPAP), and 6-minute walk distance (6MWD) were compared beforeand after treatment. Results: At admission, detectable levels of cTnI were observed in 53% of patients (�0.05 ng/mL). Serialchanges in the mean cTnI levels were not significantly different between the groups (LEV 0.04 + 0.01 to 0.03 + 0.01 ng/mL; DOB0.145 + 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 theNT-proBNP, sPAP values, LVEF, 6MWD, and HsCRP were observed overall, especially in the LEV groups. Conclusion: Beneficialeffects of short-term use of LEV, DOB, and NTG on ongoing myocardial injury were demonstrated. These findings can beattributed to the anti-ischemic properties as well as the hemodynamic, neurohumoral, and functional benefits from the positiveinotropes, especially LEV, in patients with ADHF.

Keywordsheart 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, Turkey2 Department of Cardiology, Department of Cardiology, Mugla Sıtkı Kocman

University, Mugla, Turkey3 Department of Cardiology, Cardiology Clinic, Kecioren Education and

Research Hospital, Ankara, Turkey4 Department of Cardiology, Cardiology Clinic, Bozuyuk State Hospital, Bilecik,

Turkey5 Department of Biostatistics, Faculty of Medicine, Eskisehir Osmangazi

University, Eskisehir, Turkey6 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 CardiovascularPharmacology and Therapeutics1-6ª The Author(s) 2016Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/1074248416657612cpt.sagepub.com

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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 (Eskisehir, 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 �5� 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 Admissionand 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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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 .08Age, years 67.5 + 9.3 67.3 + 10.4 63.5 + 8.0 .097Weight, kg 74.3 + 13.5 76.2 + 17.9 77.7 + 15.9 .622Height, cm 168 + 7.5 167 + 8.5 170 + 6.6 .194Atrial fibrillation, n (%) 6 (15) 7 (16.7) 12 (30) .189Diabetes, n (%) 19 (47.5) 21 (50) 16 (40) .284Hypertension, n (%) 19 (47.5) 26 (61.9) 27 (67.5) .171Smoking, n (%) 12 (30) 6 (14.3) 14 (35) .083Hyperlipidemia, n (%) 12 (30) 15 (35.7) 15 (37.5) .482Heredity, n (%) 6 (15) 10 (23.8) 8 (20) .34b-Blocker, n (%) 26 (65) 30 (71.4) 23 (57.5) .285RAAS blocker, n (%) 20 (50) 21 (50) 23 (57.5) .738Ischemic, n (%) 32 (88.6) 30 (78.4) 28 (73) .248Single vessel, n 6 6 6 .967Multivessel, n 26 24 22 .797

Abbreviation: RAAS, renin–angiotensin–aldosterone system.

Figure 1. Mean cTnI levels at admission and after treatment in allgroups. cTnI indicates cardiac troponin I.

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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 Dogan contributed to conception, design, and analysis.

Mujgan Tek Ozturk, Aydın Nadir, Ahmet Musmul, and Yuksel

Cavusoglu contributed to conception. Yuksel Cavusoglu 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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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 .173PLTs, 1/mL 299 + 47 323 + 43 .352 215 + 20 235 + 15 .309 239 + 17 219 + 14 .052 .083

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