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European Journal of Heart Failure 2007 9(12):1172-1177; doi:10.1016/j.ejheart.2007.10.002
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© 2007 European Society of Cardiology

Effects of levosimendan on coronary artery flow and cardiac performance in patients with advanced heart failure

Ignatios Ikonomidis*, John T. Parissis, Ioannis Paraskevaidis, Kallirrhoe Kourea, Vasiliki Bistola, John Lekakis, Gerasimos Filippatos and Dimitrios Th. Kremastinos

Second Cardiology Department and Heart Failure Unit, University of Athens Medical School, Attikon University Hospital Athens, Greece

* Corresponding author. University of Athens, Attikon Hospital Perikleous 19, N. Chalkidona, Athens, 14343, Greece. Tel.: +30 6944805732; fax: +30 210 5832351. ignoik{at}otenet.gr (I. Ikonomidis).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Levosimendan has inotropic and vasodilatory effects. We investigated the effects of levosimendan on coronary flow and associated changes in neurohormonal activation and cardiac performance in patients with advanced heart failure.

Methods: Forty-two patients with NYHA III–IV and a left ventricular ejection fraction (EF) 25±6%, were randomised to levosimendan 0.1 µg/kg/min (n=21) or placebo for 24 h. Before and 24 h after each treatment, we assessed: the maximal velocity (Vmax), time integral (VTI) and deceleration time (DT) of the diastolic coronary flow wave (CF) in LAD using transthoracic Doppler echocardiography, pulmonary artery systolic pressure by Doppler echocardiography, E/E' ratio using Doppler imaging of mitral inflow velocity, tissue Doppler imaging of the mitral annulus and B-type natriuretic peptide (BNP) levels.

Results: By ANOVA, there was a greater increase in CF-Vmax (43±23 vs.25±8 cm/s), CF-DT (904±250 vs. 667±151 ms), and EF and a greater decrease in BNP, pulmonary artery systolic pressure and E/E' after levosimendan than after placebo (p<0.05). Compared to baseline, the percent changes in CF-VTI were related to the concomitant changes in EF, E/E', and BNP after treatment with levosimendan (r=0.69, r=–0.51 and r=–0.80, p<0.05 respectively).

Conclusion: Treatment with levosimendan improves coronary flow and microcirculation in parallel with an improvement in cardiac performance and neurohormonal activation in patients with advanced heart failure.

Key Words: Levosimendan • Coronary flow • Echocardiography • Deceleration time microcirculation

Received June 13, 2007; Revised August 9, 2007; Accepted October 8, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Levosimendan is a novel agent that has been shown to have a unique dual mode of action, increasing myocardial contractility and producing at the same time arterial and venous dilation. Experimental studies have shown that levosimendan increases coronary flow by improving endothelial function through increased nitric oxide production [1] and/or by opening the adenosine triphosphate-sensitive potassium channels [2-4]. Recently, Erdei et al reported that the levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. The investigators suggested that OR-1896 contributes to the long-term haemodynamic effects of levosimendan. [5] Thus, the majority of data support the theory that activation of adenosine triphosphate-sensitive potassium channels is a major mechanism of levosimendan-induced coronary vasodilation.

In addition, clinical studies have shown improvement of coronary flow acutely after treatment with levosimendan in patients with angiographically documented coronary artery disease [6], after coronary interventions [7] and early after coronary by-pass surgery [8]. However, the effects of levosimendan on coronary flow in patients with advanced chronic heart failure compared to traditional medication have not been fully investigated. The aim of our study was therefore to assess the effects levosimendan on coronary flow, as assessed non-invasively by transthoracic Doppler echocardiography, compared to the effects of traditional medication, in patients with advanced chronic heart failure. The aim was also to assess the relationship between changes in coronary flow after treatment with levosimendan and the reciprocal changes in left ventricular (LV) function and B-type natriuretic peptide (BNP).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The study population consisted of 50 consecutive patients with heart failure who were admitted to hospital due to new-onset clinical deterioration, despite medical therapy (including diuretics, ACE inhibitors, b-blockers, and/or spironolactone), poor functional status with New York Heart Association III-IV symptoms, and severe LV systolic dysfunction (Ejection Fraction (EF) <35%). Exclusion criteria were: significant mitral regurgitation (>2/4) at baseline echocardiography, acute or chronic infectious or inflammatory diseases, recent myocardial infarction (<8 weeks) or active myocardial ischaemia, hepatic or renal impairment (creatinine >2.5 mg/dl), use of anti-inflammatory agents, serious arrhythmias, and supine systolic blood pressure <90 mmHg. All patients had <40% narrowing in the LAD at coronary angiography and absence of ischaemia at thallium scintigraphy or dobutamine stress echocardiography. However, 8 patients were also excluded because of inadequate quality of coronary flow Doppler signals. Thus, the final study cohort included 42 patients. Patients did not receive other intravenous inotropic therapies at admission except for levosimendan or placebo. All patients received the above treatment in addition to intravenous furosemide in order to achieve symptomatic improvement.

Patients were randomised (1:1) to receive either levosimendan (n=21) or placebo (Dextrose 5%) (n=21). Levosimendan was given as a continuous 24-hour infusion, initially at a rate of 0.1 µg/kg/min, with no a loading dose. In two non-responding patients, in whom there was no symptomatic improvement in the first 6 h, up-titration to a maximum infusion rate of 0.2 µg/kg/min, was performed.

Twenty-four hours after the placebo infusion, and after completion of the echocardiographic and BNP measurements, four non-responding placebo patients were also treated with levosimendan or dobutamine in addition to diuretic treatment. These patients were included in the placebo group for analysis. All echocardiographic and biochemical variables were measured at baseline before initiation of the drug infusion and 24 h after completion of levosimendan or placebo infusion and were conducted by staff who were blinded to the treatment status of individual patients. Any modifications in treatment were performed after the echocardiographic and BNP measurements had been completed.

We decided to use the 24 h interval after the end of the infusion to assess the effects of the study drugs because clinical studies have shown that the maximum haemodynamic effect of levosimendan is observed 1 to 3 days after starting the infusion [9]. The study was approved by the institutional ethics committee, and written consent was given by each patient.

2.1. Laboratory assays
Plasma B-type natriuretic peptide (BNP) was measured using the rapid Triage BNP assay (Biosite Inc., San Diego, California, USA) at admission and 24-hours after the end of the placebo or levosimendan infusion. Tests were performed simultaneously with the echocardiographic evaluation. As blood sampling was performed before initiation and 24-hours after the end of the infusion (placebo or levosimendan), the laboratory personnel were unaware of the patient's treatment.

2.2. Echocardiography
Studies were performed using a Vivid 7 (GE Medical Systems, Horten, Norway) phased array ultrasound system using second harmonic imaging. All studies were digitally stored and were analyzed using a computerized station (Echopac GE, Horten, Norway) by a single observer who was blinded to clinical and laboratory data. All patients had adequate images for analysis.

Pulmonary artery systolic pressure was calculated from the sum of the mean right atrial pressure, as estimated by the diameter of the inferior vena cava and its respiratory variation [10], and the maximal pressure difference between the right ventricle and the right atrium, as calculated by the continuous-wave Doppler flow velocity of the tricuspid regurgitation, applying the simplified Bernoulli equation (p=4 V2) [10]. LV end-diastolic and end-systolic volumes and ejection fraction were estimated using Simpson's method. The correlation coefficient of the measurements between the two observers (II and JP) was 0.96 for LV ejection fraction, 0.97 for LV end-diastolic volume, 0.95 for LV end-systolic volume, and 0.96 for pulmonary artery systolic pressure.

2.2.1. Coronary flow
Coronary flow velocity profiles in the LAD were obtained using colour-guided pulse wave Doppler from long axis apical projections using a broad-band 7 MHz transducer as previously described [11,12]. The maximal velocity of the diastolic (CF-Vmax cm/sec) and the systolic waveform, the velocity time integral (VTI-cm) of the diastolic waveform (CF-VTId) [12] were measured at baseline and 24 h after levosimendan or placebo infusion. The deceleration time of basal diastolic velocity waveform (CF-DT-msec) was measured from the peak diastolic velocity along the decline in the velocity waveform contour and extrapolated to the baseline [13]. The ratio of the maximal velocity of the diastolic to the maximal velocity of the systolic waveform (CF-Vd/Vs) was also calculated. Measurements from 3 cardiac cycles were averaged. Each study was analyzed by one experienced investigator who was blinded to the treatment allocation. Inter-and intra-observer variability of these measurements in our laboratory was 5% and 2% respectively. The correlation coefficient of the measurements between the two observers (II and JP) was 0.95 for CF-Vmax, 0.93 for CF-VTId, 0.91 for CF-DT and 0.94 for the maximal velocity of systolic coronary waveform.

2.2.2. Mitral annulus velocities
Myocardial velocities were recorded using colour tissue Doppler (TDI) to record low-velocity, high-intensity myocardial signals at a high frame rate (120 MHz). A 5-mm sample volume was placed in septal, lateral, inferior and anterior corner of the mitral annulus in the apical 4 and 2 chamber views to record the systolic velocity (Sm), early diastolic velocity (Em), and late diastolic velocity (Am) as previously described [14,15]. The mean value of the Sm, Em and Am at all 4 sites of the annulus was used in the analysis. The ratio of E wave of the mitral inflow measured by pulsed wave Doppler to the mean Em was calculated as an index of LV diastolic filling pressures [12]. Inter-and intra-observer variability of these measurements in our laboratory was 3% and 1.7% respectively. The correlation coefficient of the measurements between 2 observers (II,JP) was 0.94 for Sm, 0.95 for Em, 0.96 for Am and 0.96 for E wave.

2.3. Statistical analysis
In a pilot study of 5 patients with levosimendan and 5 with placebo the mean difference±SD of coronary flow velocities between treatment and baseline was 9.8±10 and 0.8±1.1 respectively Thus, using an a=0.05 (2-sided) and a power=80% the sample size was calculated to 20 patients per group.

Categorical data were compared by means of the {chi}2-test or Fisher exact test where appropriate. Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Normally distributed variables are given as mean±standard deviation and compared by means of paired or unpaired t-test (2-tailed). Spearman correlation analysis was used to determine bivariate correlations. Data were analysed by analysis of variance for repeated measurements (General linear model, SPSS [11,5]) with time of measurement (baseline, 24 h after infusion of levosimendan or placebo) used as a within-subject factor and type of treatment (levosimendan vs. placebo) in all patients used as a between-subjects factor. The Greenhouse-Geisser correction was used when the sphericity assumption, as assessed by Mauchly's test, was not met. The F and corresponding p values of the interaction between time of measurement of the echocardiographic markers and medication were calculated. Post-hoc comparisons were performed using the Bonferroni correction.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The two study groups were well balanced with respect to baseline clinical characteristics and concomitant medications (Table 1). At baseline, a rapid deceleration time of the diastolic coronary flow (≤600 ms) [16] was present in 47% of our patients. Furthermore, patients treated with levosimendan or placebo had similar baseline LV end-diastolic and end-systolic volumes, ejection fraction, Sm, systolic pulmonary artery pressure, E/Em, BNP and coronary flow indices (Table 2, p=ns). Forty-eight hours after admission, patients who received levosimendan had a significant clinical improvement, as assessed by New York Heart Association functional class (NYHA III/IV: 17 /4 vs. 5/0, p<0.05). An improvement in New York Heart Association functional class was also detected in the placebo group (NYHA III/IV: 17 /4 vs. 9/2, p<0.05), though this improvement was less evident than in patients treated with levosimendan (10 (47%) in NYHA class II after placebo vs. 16 (76%) in NYHA class II after levosimendan, p<0.05).


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  		Table 1 Baseline demographics, clinical characteristics and concomitant medications in the levosimendan and placebo groups (mean±SD)

 


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  		Table 2 Effects of treatment with levosimendan or placebo on coronary flow and echocardiographic indices of LV function

 
Analysis of variance showed that LV ejection fraction, Sm and Em increased and LV end systolic volume, systolic pulmonary artery pressure, Em/Am, E/Em and BNP decreased 24 h after treatment with levosimendan compared to baseline, but remained unchanged after treatment with placebo (F for interaction=19, F=7.2, F=6.9, F=7, F=4.6, F=9.7, F=12.9, and F=12.9, respectively p<0.05, Table 2). At baseline patients treated with levosimendan or placebo had similar LV end-diastolic and end-systolic volumes, ejection fraction Sm, systolic pulmonary artery pressure, E/Em and BNP (p=ns). After levosimendan treatment, patients had improved LV ejection fraction, end-systolic volume, Sm, pulmonary artery systolic pressure, E/Em and BNP compared to patients on placebo (p<0.05).

Additionally in the levosimendan group, CF-Vmax, CF-VTId and CF-DT and Vd/VS increased post-treatment compared to baseline measurements but remained unchanged in the placebo group (F for interaction=28.9, F=32.2, F=24.3 and F=8.3, respectively, p<0.01, Table 2). After levosimendan treatment, patients had higher CF-Vmax, CF-VTId, CF-DT and Vd/VS compared to patients on placebo (p<0.05). Heart rate and blood pressure remained unchanged throughout the study in both treatment groups (Table 2).

In the levosimendan group, a positive correlation between the percent changes in CF-VTI-and LV ejection fraction was observed (r=0.69, p<0.05, Fig. 1A). Moreover, levosimendan-induced percent increase in CF-VTI was inversely correlated with the corresponding percent decrease in E/Em ratio (r=–0.51, p<0.05, Fig. 1B) and plasma BNP levels (r=–0.80, p<0.05, Fig. 1C). The percent increase in CF-DT was also significantly associated with the percent increase of LV ejection fraction (r=0.51, p<0.05) and the percent decrease in pulmonary artery systolic pressure (r=–0.52, p<0.05).


Figure 01
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  		Fig. 1 Correlations between levosimendan-induced percent (%) increase in the diastolic coronary flow velocity time integral CF-VTI with A) the percent (%) increase in left ventricular ejection fraction (EF), B) the percent (%) decrease in E/Em, C) the percent decrease (%) in plasma BNP levels.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this study of patients with advanced heart failure, we have shown that 24-hour treatment with levosimendan induced a greater increase in maximal velocity, velocity time integral and deceleration time of the diastolic coronary waveform as well as in the ratio of diastolic to systolic velocity of coronary flow as assessed by transthoracic echocardiography, 24-hours after the end of infusion compared to placebo. This beneficial effect was related to a concomitant improvement in ejection fraction, BNP, pulmonary artery systolic pressure and E/E'.

Experimental evidence suggests that levosimendan is a powerful vasodilator of coronary conductance and resistance arteries, and exerts its effect by improving endothelial function and/or by opening the adenosine triphosphate-sensitive potassium channels [1-9]. In a clinical study of 10 patients with coronary artery disease and a mean ejection fraction of 46%, Michaels et al [6] reported that coronary blood flow was increased after a 10 min infusion of levosimendan despite a decrease in coronary perfusion pressure during coronary angiography. In the above study by Michaels, the reduction in coronary vascular resistance and the increase in coronary sinus oxygen content despite the increase in contractility are indicative of primary coronary vasodilation by levosimendan.

Our results show that, compared to placebo, 24 hour levosimendan infusion is effective in increasing coronary flow 24 h after the infusion in patients with advanced heart failure with severely impaired systolic LV function as indicated by the low mean ejection fraction (25%) and adverse haemodynamic profile (elevated systolic pulmonary artery pressure, E/Em and BNP plasma levels).

In agreement with our previous studies [15], we have shown an increase in ejection fraction, systolic Sm, the early diastolic Em velocity of the mitral annulus, and of the Em/Am and a reduction in the E/Em after treatment with levosimendan compared to placebo, suggesting an improvement in LV diastolic and systolic performance. Furthermore, we have shown a concomitant decrease in pulmonary artery pressure and BNP levels after treatment with levosimendan compared to placebo.

We have also demonstrated that the levosimendan-induced percent changes in coronary flow indices were associated with respective beneficial changes in ejection fraction, E/Em and BNP levels. This finding suggests for the first time an association between improvement in coronary flow and improvement in haemodynamic profile and cardiac performance after treatment with levosimendan in patients with advanced heart failure.

A rapid diastolic deceleration time (DT) has been proposed as an index of impaired microvascular function [16,17]. A DT <600 ms after successful angioplasty, has been shown to predict the risk of long-term cardiac events after acute myocardial infarction [16]. Additionally, patients with a rapid diastolic DT were more likely than patients with a normal diastolic DT to develop congestive heart failure during long-term follow-up [16,17]. Studies have confirmed the presence of impaired coronary microcirculatory function in patients with ischaemic or dilated cardiomyopathy with advanced heart failure [18].

In the present study, we observed that a rapid deceleration time (<600 ms) was present in approximately half of our patients with advanced chronic heart failure. Furthermore, we found that deceleration time of diastolic coronary flow was significantly improved after treatment with levosimendan compared to placebo. Experimental findings indicate that levosimendan increases coronary flow by restoring endothelial function and increasing nitric oxide release [1]. Endothelial dysfunction leading to reduced production of nitric oxide is observed in patients with heart failure [19] and is an important determinant of impaired resting coronary flow and coronary microcirculation in these patients [20-22]. Thus, a possible explanation for our observations is that the levosimendan-induced increase in nitric oxide production [1] may have partially restored the impaired coronary microvascular function leading to an increased deceleration time of the diastolic coronary flow. Additionally, the reduction in elevated LV diastolic pressure by decreasing the extravascular compressive forces and resistance in the subendocardial coronary microcirculation [23] and/or vasodilation of the resistance coronary arterioles [6,23] after treatment with levosimendan may have contributed to the improved deceleration time and the coronary flow indices measured in our study.

4.1. Study limitations
Our results establish a close relation between changes in coronary flow indices and indices of cardiac performance after treatment with levosimendan. However, this study was not designed to establish whether this is a causative relation or whether improvement in coronary flow and cardiac performance are parallel effects caused by the vasodilatory and inotropic properties of levosimendan. Based on current evidence it is reasonable to suggest that improvement in coronary flow and coronary microcirculatory function may be an additional pathophysiologic mechanism that contributes to the drug-induced favourable effects on cardiac performance. The single assessment of our patients at 24 h following administration of the study drug does not allow evaluation of time-dependent changes in coronary flow. Other limitations of our study are the non-invasive measurement of coronary flow parameters and the relatively small sample size. However, using current technology, several studies have shown that assessment of coronary flow by means of echocardiography is reliable and closely related to invasive measurement of coronary flow [24,25]. Our study was not double-blind, though doctors performing the echocardiographic studies and laboratory assays were blinded to the patients medication.

In conclusion, 24-hour treatment with levosimendan improves echocardiographically estimated coronary flow indices 24 h after infusion in patients with advanced heart failure and this beneficial effect seems to be related to the concomitant improvement in LV diastolic and systolic function, and neurohormonal activation. The prognostic implications of these therapeutic advantages of short-term treatment with levosimendan should be tested in larger clinical trials especially in patients with coronary artery disease and LV dysfunction.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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