Acute effects of levosimendan and dobutamine on QRS duration in patients with heart failure

Abstracts

FUNDAMENTO: A levosimendana é um novo agente inotrópico que aumenta a contratilidade cardíaca sem aumentar a captação celular de cálcio, de forma a não causar sobrecarga de cálcio e arritmias relacionadas. Em pacientes com insuficiência cardíaca (IC), a duração prolongada do QRS está associada com um aumento no risco de mortalidade e morte súbita cardíaca. Mudanças estruturais no ventrículo esquerdo podem levar à contração assíncrona, causando atraso de condução e um QRS prolongado no ECG de superfície. OBJETIVO: O objetivo do presente estudo foi comparar os efeitos agudos de levosimendana e dobutamina na duração do QRS em pacientes com IC grave e ritmo sinusal. MÉTODOS: 60 pacientes consecutivos com IC isquêmica foram incluídos no estudo e randomizados em dois grupos para infusão de levosimendana (n=37) ou dobutamina (n=23). 67,2 % eram homens; a média da idade era 66,4 ± 9,2 anos para todos os pacientes. A duração basal do QRS nos grupos levosimendana e dobutamina foi 120,44 ± 23,82 ms vs 116,59 ± 13,80 ms respectivamente. A fração de ejeção do ventrículo esquerdo (FEVE) estava diminuída em ambos os grupos (23,15 ± 8,3 vs 24,56 ± 7,5%). RESULTADOS: No grupo levosimendana, a duração do QRS diminuiu do valor basal para 116,47 ± 24,56 ms (p=0,006), enquanto não houve diferença significante no grupo dobutamina (p=0,605). Ambos os medicamentos causaram um aumento na FEVE, mas este foi significante apenas no grupo levosimendana (27,95 ± 8,9% p=0,003 vs 26,67 ± 7,6%, p=0,315). CONCLUSÃO: O estudo sugere que a administração de levosimendana, mas não de dobutamina, encurta a duração do QRS no ECG de superfície, possivelmente por causar uma contração coletiva nas fibras do músculo do ventrículo esquerdo. A base molecular desse efeito ainda precisa ser esclarecida.

Insuficiência cardíaca; cardiotônicos; levosimendana; dobutamina

FUNDAMENTO: La levosimendana es un nuevo agente inotrópico que aumenta la contractibilidad cardíaca sin aumentar la captación celular de calcio, de forma de no causar sobrecarga de calcio y arritmias relacionadas. En pacientes con insuficiencia cardíaca (IC), la duración prolongada del QRS está asociada a un aumento en el riesgo de mortalidad y muerte súbita cardíaca. Cambios estructurales en el ventrículo izquierdo pueden llevar a la contracción asíncrona, causando atraso de conducción y un QRS prolongado en el ECG de superficie. OBJETIVO: EL objetivo del presente estudio fue comparar los efectos agudos de levosimendana y dobutamina en la duración del QRS en pacientes con IC grave y ritmo sinusal. MÉTODOS: 60 pacientes consecutivos con IC isquémica fueron incluidos en el estudio y randomizados en dos grupos para infusión de levosimendana (n=37) o dobutamina (n=23). 67,2 % eran hombres; la media de la edad era 66,4±9,2 para todos los pacientes. La duración basal del QRS en los grupos levosimendana y dobutamina fue 120,44±23,82 vs. 116,59±13,80 respectivamente. La fracción de eyección del ventrículo izquierdo (FEVI) estaba disminuida en ambos grupos (23,15±8,3 vs. 24,56±7,5). RESULTADOS: En el grupo levosimendana, la duración del QRS disminuyó del valor basal para 116,47±24,56 ms (p=0,006), en cuanto no hubo diferencia significativa en el grupo dobutamina (p=0,605). Ambos medicamentos causaron un aumento en la FEVI, pero este fue significativo apenas en el grupo levosimendana (27,95±8,9 p=0,003 vs. 26,67±7,6, p=0,315). CONCLUSIÓN: El estudio sugiere que la administración de levosimendana, pero no de dobutamina, acorta la duración del QRS en el ECG de superficie, posiblemente por causar una contracción colectiva en las fibras del músculo del ventrículo izquierdo. La base molecular de ese efecto aun precisa ser aclarada.

Insuficiencia cardíaca; cardiotónicos; Levosimendana; Dobutamina

ORIGINAL ARTICLE

Cumhuriyet University, Faculty of Medicine, Department of Cardiology, Sivas - Turkey

Mailing address

ABSTRACT

BACKGROUND: Levosimendan is a novel inotropic agent that enhances cardiac contractility without increasing cellular calcium intake, so that it is not supposed to cause intracellular calcium overload and related arrhythmias. In patients with heart failure, prolonged QRS duration is associated with increased risk of mortality and sudden cardiac death. Structural changes in the left ventricle may lead to asynchronous contraction, causing conduction delay and a prolonged QRS on the surface electrocardiogram.

OBJECTIVE: We aimed to compare the acute effects of levosimendan and dobutamine on QRS duration in patients with severe heart failure and sinus rhythm.

METHODS: Sixty consecutive patients with ischemic heart failure were enrolled for the study and randomized into two groups for levosimendan (n=37) or dobutamine (n=23) infusions. 67.2 % were male; mean age was 66.4±9.2 years for all patients. Baseline QRS durations in levosimendan and dobutamine groups were, 120.44 ± 23.82 ms vs 116.59 ± 13.80 ms respectively. Baseline ejection fractions were both depressed (23.15 ± 8.3% vs 24.56 ± 7.5%).

RESULTS: In the levosimendan group, QRS duration shortened from baseline value to 116.47 ± 24.56 msec (p=0.006), whereas dobutamine group showed no significant change (p=0.605). Both drugs caused an increase in ejection fraction, but only the levosimendan group showed significance (27.95 ± 8.9% p=0.003 vs 26.67 ± 7.6%, p=0.315).

CONCLUSION: We suggest that the administration of levosimendan, not dobutamine, shortens QRS duration on the surface ECG, possibly by means of providing collective contraction in the left ventricle muscle fibers. The molecular basis of this effect remains to be clarified.

Key words: Heart failure; levosimendan; cardiotonic agents; dobutamine/adverses effects.

Introduction

Levosimendan is a novel inotropic agent that improves cardiac contractility without increasing myocardial oxygen consumption. Unlike other inotropic agents, levosimendan does not increase cellular calcium intake, so that it does not cause intracellular calcium overload and related arrhythmias¹. Levosimendan binds to the N-terminal domain of troponin C and stabilizes the troponin molecule with subsequent prolongation of its effect on contractile proteins². Studies have shown that 24-h infusion of levosimendan in patients with severe left ventricular dysfunction improves cardiac functions and relieves symptoms, as well as decreased short-term morbidity and mortality^3-5.

The QRS complex duration has been shown to be of prognostic importance in patients with heart failure. In this group of patients, prolonged QRS duration is associated with increased risk of mortality and sudden cardiac death⁶. A graded increase in mortality was correlated with ascending degrees of QRS prolongation. Increase in QRS duration is also correlated with impaired left ventricle systolic function⁷. Structural changes in the left ventricle may lead to asynchronous contraction, yielding conduction delay and a prolonged QRS on the surface electrocardiogram (ECG). In our study, we aimed to compare the acute effects of levosimendan and dobutamine on QRS duration in patients with severe heart failure and sinus rhythm.

Material and methods

1. Study population

A total of sixty consecutive patients in normal sinus rhythm with ischemic heart failure presenting New York Heart Association class III or IV symptoms and left ventricular systolic dysfunction of ischemic origin were enrolled into our study after giving their informed consent and assigned to levosimendan or dobutamine administration at the discretion of their primary physician. Exclusion criteria were: pregnancy and lactation; acute or chronic infectious or inflammatory diseases, recent myocardial infarction (< 8 weeks) or active myocardial ischemia; systolic blood pressure < 85 mmHg, hypersensitivity to levosimendan or any of its metabolites, severe renal failure (creatinine > 2.5 mg/dl), hepatic failure, 2^nd or 3^rd-degree atrioventricular blocks, overt bundle branch blocks, history of ventricular tachycardia or ventricular fibrillation, heart failure due to restrictive or hypertrophic cardiomyopathy or to uncorrected stenotic valvular disease. The investigation conforms to the principles outlined in the Declaration of Helsinki.

Patients received a loading dose of levosimendan (3 to 6 μg/kg) followed by a continuous infusion of 0.1 μg/kg per minute for 50 minutes; the rate was increased to 0.2 μg/kg per minute for an additional 23 hours as tolerated. Dobutamine was given at a 2.5 μg/kg, rate, which was subsequently increased to 5 μg/kg as tolerated, up to a 24-hour-period. Patients were also receiving similar and efficient doses of ACE-inhibitors, beta blockers, furosemide and spironolactone before admission. During admission the furosemide dose was fixed at 80 mg per day and was not increased. Moreover, other drugs' doses were not allowed to change.

Each patient's primary physician decided to administer the inotropic agent. All the patients were submitted to electrocardiography and echocardiography, before and 24 hours after the start of administration. Patients were hospitalized at coronary care unit and were monitored by means of ECG, 24-hour urine output, blood pressure. Additionally, all patients' biochemical work up was performed before and after the inotrope administration. During infusions, no nephrotoxic agent was allowed (nesiritide is not available in the country) and no increase in the dose of continuous loop diuretics (only furosemide is available in the country), as well as no change in the intravenous fluid administration, unless the patient had hypotension, were allowed. Other drug therapy and discharge decisions, determined by patient's status, were left to the discretion of the primary physicians, who were totally blinded to the study outcomes, including clinical parameters. The study was approved by the institutional ethics committee and written informed consent was obtained before randomization.

2. Electrocardiography

Patients' electrocardiographic examination was performed with the available ECG equipment (ELI-250, Mortara Instruments, Wisconsin, USA) at baseline and 24 hours after the start of the administration. ECGs were recorded at a speed of 50 mm/second. QRS duration was measured manually using a digital caliper and magnifying lens in the electrocardiograms performed on admission. QRS duration was determined in the single lead which had the longest QRS. Maximal QRS width in any lead was measured from the first to the last sharp vector crossing the isoelectric line. Electrocardiographic data were analyzed by 2 independent observers blinded to all other patient's data, and an average of two measurements was accepted as final result.

3. Echocardiography

Patients' echocardiographic examination was performed with available ultrasound equipment (GE-Vivid 4 with a 3.5 MHz transducer, Wisconsin, USA) Left ventricular ejection fraction (LVEF) was measured by Simpson's rule⁸. Examination was performed by two blinded echocardiographists, thirty minutes before and twenty four hours after the start of the administration and an average of two values were obtained for each examination.

4. Statistical analysis

Parametric data were expressed as means (Standard deviation) and categorical data as percentages. SPSS 15.0 (SPSS, Inc., Chicago, Illinois) was used to perform statistical procedures. Independent parametric data were evaluated by Mann Whitney U test. Temporal change of parametric data was evaluated by Wilcoxon's signed rank test, and categorical data via Chi square test. Correlation was evaluated by Spearman's correlation test. A p value <0.05 was accepted as significant.

Results

Sixty patients were enrolled in the study and randomized into two groups. Two patients died (due to pump failure) during inotrope infusions, one for each group. The remaining fifty-eight patients (levosimendan n=36, dobutamine n=22) underwent complete treatment and statistical evaluation. All patients had NYHA Class IV symptoms before the infusions. In the whole group, 67.2 % were male (n: 39), 32.8 % were female (n: 19). Mean age for all patients was 66.4±9.2 years (66.1±10.5 for levosimendan, 67.0±6.9 for dobutamine). All patients' baseline rhythms were sinus before inotrope administration, with no alteration after that. In the levosimendan group, baseline mean QRS duration was 120.44±23.82 ms. Following infusion, mean QRS duration significantly decreased to 116.47±24.56 ms (p = 0.006) on the 24^th hour. On the other hand, dobutamine infusion yielded no significant effect on QRS duration (Table 1 and 2, figure 1).

After both infusions, ejection fractions in both groups increased. Left ventricular systolic and diastolic diameters did not show any significant change in both groups (Table 1). No significant correlation was detected between ejection fraction and QRS duration (r:0,398, p=0.082) in the levosimendan group. Additionally, heart rate slightly increased in levosimendan group, but showed no significant change compared to baseline values (Table 1). Patients' baseline body weights were similar, no difference occurred between both groups, after the administration of the drug. Moreover, absolute weight loss, which is a surrogate for improved edematous state, was similar in both groups (Table 1). No patient experienced electrolyte abnormality, both before and after the infusions.

Discussion

Heart failure is one of the most frequent causes of morbidity and mortality in a global scale. Despite improvements in medical therapies and surgical methods, its prevalence keeps rising⁹. QRS duration complex has been shown to be of prognostic importance in patients with heart failure. In this group of patients, prolonged QRS duration is associated with increased risk of mortality and sudden cardiac death. Bode-Schnurbus et al¹⁰ showed significant mortality and sudden cardiac death difference in patients with heart failure who had implantable cardioverter-defibrillators when compared by QRS prolongation, defined as > 150 msec¹⁰. In their retrospective study, Xiao et al¹¹ found that abnormal conduction, demonstrated as prolonged PR interval and QRS duration, of dilated cardiomyopathy patients appears to be a high risk for mortality¹¹. Iuliano et al⁶ conducted a retrospective analysis of 669 chronic heart failure patients according to QRS duration < 120 ms or > 120 ms. They showed a significant increase in mortality and sudden death in patients with prolonged QRS duration. In a subgroup of patients with LVEF < 30%, QRS prolongation was associated with a significant increase in mortality (51.6% versus 41.1%, p < 0.01) and sudden death (28.8% versus 21.1%, p < 0.02)⁴. These results were supported by another study, conducted by Shenkman et al⁷, in which 3,471 chronic heart failure patients were enrolled for the study. Prolonged QRS duration of 120 to 149 milliseconds was associated with an increased mortality at 60 months (p < 0.001)⁷.

In the light of the aforementioned studies, we decided to investigate the acute effects of levosimendan on QRS duration measured in surface ECG, in a group of patients who had severely depressed left ventricle functions. The drug caused an increase in left ventricle ejection fraction, as expected (p = 0.003), with a mild decrease in left ventricle diastolic diameters, without significance. QRS duration measured in surface ECG was also found to be decreased after drug administration (120.44±23.82 ms versus 116.47±24.56 ms, p = 0.006). A possible explanation of this novel effect might be a unique property of levosimendan, which enables the myocardium to contract as a syncytium through improved calcium handling. In our study group, we did not observe any arrhythmia or hypotensive effect, mostly associated with the high loading dose of levosimendan yielding arrhythmic and possibly mortal complications following infusion¹². We believe that this finding has not been fully investigated¹³ and it could be worth further investigating within this concept.

In the SURVIVE¹² study, levosimendan showed greater benefit in patients who received beta blocker therapy. Patients with acutely decompensated heart failure carry high risk for mortality and the use of beta blocking agents was suggested. This is a controversy regarding the use of beta adrenergic inotropes like dobutamine. Regarding this issue, a study in Brazil¹⁴ showed that beta adrenergic agonist-resistant patients responded well (55.8% of patients) to levosimendan administration. These data are important regarding the use of inotropic agents in patients who receive beta-blocker therapy and are beta-adrenergic agonist-resistant.

In terms of limitations, it is possible to speculate a causal link between relative decrease in left ventricular size and shortening of QRS duration. However, we did not observe such change in QRS duration among patients in the dobutamine arm, which also yielded almost similar improvements associated with the left ventricle. Hence, we suggest this could possibly be associated with the molecular properties of levosimendan. Another limitation is that baseline QRS width is greater in levosimendan group than dobutamine group. The baseline mean left ventricle diastolic diameter is also greater in the levosimendan group, so we may claim that levosimendan patients had slightly more severe heart failure to a certain degree and this may be related to the difference between baseline QRS durations. On the other hand, among a group of patients with ischemic heart failure, effect of dobutamine might have two phases. Effect at the initial phase might be towards the side of QRS shortening during the first few minutes or hours, because ischemic and nonischemic myocardial regions would probably contract to similar extent. However, ischemic regions cannot sustain increased contraction tempo due to extended beta mimetic stimulation; therefore the latter phase effect might result with poorer response than first phase just like those seen (biphasic response) during dobutamine stress echocardiography. This would lead contraction delay between myocardial regions.". However, this issue remains as a limitation. In this study, PR and QT durations were not mentioned, not because of lack of data, but because it is beyond the aim of this study; hence these could be a matter of another study, as we aimed to assess the possible relationship between myocardial cellular contraction and depolarization, not the conduction. That is the reason why we excluded those with overt bundle branch block, in whom it is not reasonable to expect to revert the QRS duration up on therapeutic interventions, due to established destruction of the conduction system.

In conclusion, we suggest that the administration of levosimendan, but not dobutamine, shortens QRS duration in the surface ECG, possibly by means of providing collective contraction in the left ventricle muscle fibers. The molecular mechanism responsible for this effect remains to be clarified with further trials enrolling a sufficient number of patients.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any post-graduation program.

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Acute effects of levosimendan and dobutamine on QRS duration in patients with heart failure

Osman Can Yontar; Mehmet Birhan Yilmaz; Kenan Yalta; Alim Erdem; Izzet Tandogan

Publication Dates

• Publication in this collection
  12 Nov 2010
• Date of issue
  Dec 2010

History

• Received
  15 Dec 2009
• Accepted
  26 May 2010
• Reviewed
  06 Mar 2010