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(Chest. 2005;128:2633-2639.)
© 2005 American College of Chest Physicians

Effects of Levosimendan on Restrictive Left Ventricular Filling in Severe Heart Failure*

A Combined Hemodynamic and Doppler Echocardiographic Study

John Dernellis, MD and Maria Panaretou, MD

* From the Department of Cardiology, Vostanion Hospital, Mytilini, Greece.

Correspondence to: John Dernellis, MD, 1 Kathigitou Karakatsani St, 811 00 Mytilini, Greece; e-mail: dernellis{at}yahoo.gr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Background: A restrictive pattern of left ventricular filling is often present in patients with severe heart failure. Although the hemodynamic effects of levosimendan have been studied, the effects of levosimendan on LV filling pattern have not been investigated.

Methods: Pulsed-wave Doppler mitral (transthoracic) and pulmonary venous flow (transesophageal) velocity curves were recorded in 30 patients with a restrictive pattern of left ventricular filling with New York Heart Association class III or IV heart failure who had a documented left ventricular ejection fraction < 30% by echocardiography and received a 0.1 µg/kg/min infusion of levosimendan for 24 h.

Results: Levosimendan caused significant (p < 0.001) increases in stroke volume (from 46 ± 4 to 57 ± 4 mL) and decreases in pulmonary capillary wedge pressure (from 21 ± 1 to 15 ± 1 mm Hg). The E wave decreased (from 96 ± 7 to 71 ± 5 cm/s), and the A wave increased (from 40 ± 4 to 46 ± 4 cm/s). Moreover, deceleration time was increased (from 112 ± 7 to 189 ± 14 ms). The S wave of pulmonary venous flow was increased (from 38 ± 3 to 60 ± 3 cm/s), and atrial reversal was decreased (from 36 ± 2 to 29 ± 2 cm/s). All changes were significant (p < 0.001). Using stepwise linear regression analysis, we found that the percentage changes of the early/late transmitral diastolic peak flow velocity (E/A) ratio and the percentage changes of the isovolumetric relaxation time were independent predictors of the increase in cardiac output. Furthermore, the percentage changes of the systolic/diastolic ratio and the percentage changes of the E/A ratio were independent predictors of the decrease in pulmonary capillary wedge pressure.

Conclusions: Treatment with levosimendan improved measures of left ventricular diastolic function. Consequently, left ventricular stroke volume was increased.

Key Words: diastolic function • heart failure • levosimendan • pulmonary vein flow


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Favorable hemodynamic effects of levosimendan infusion have been shown in patients with congestive heart failure.123 Treatment with levosimendan increased stroke volume and cardiac index along with a decrease in left-heart and right-heart filling pressures and systemic arterial pressure. However, little is known about the effects of levosimendan on left ventricular diastolic function. It is well known that restrictive left ventricular filling as assessed by pulsed-wave Doppler echocardiography of the mitral flow usually identifies advanced heart failure associated with a poor prognosis.456 In this respect, assessment of the effects of levosimendan on restrictive left ventricular filling in severe heart failure may provide valid information complementary to that of hemodynamic effects of levosimendan on left ventricular systolic function.

Furthermore, levosimendan a Ca2+-sensitizer drug, provokes a general enhancement of calcium sensitivity that might have negative effects on left ventricular filling in light of the impaired left ventricular diastolic function that accompanies systolic dysfunction.78 For this reason, it would be extremely important to study the effects of levosimendan on left ventricular filling in patients with severe heart failure.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patient Selection
Study subjects were recruited from patients with systolic left ventricular dysfunction and New York Heart Association functional class III or IV symptoms of heart failure who were admitted to the hospital for management of decompensated heart failure. Patients were screened for the study if they had documented left ventricular ejection fraction of < 30% by echocardiography and a restrictive pattern of left ventricular filling with the transmitral Doppler E wave markedly increased and a small A wave and shortened deceleration time (DT) in the preceding 6 months. Patients were required to be in sinus rhythm and not have an acute need for IV inotropics.

The exclusion criteria were acute coronary syndromes and stroke; heart failure due to uncorrected stenotic valvular disease; systolic BP < 100 mm Hg; heart rate > 100 beats/min; atrioventricular block of second or third degree; severe renal failure; hepatic failure; and cardiac tamponade. Oral nitrates and digitalis glycosides were withheld during the study day, and calcium antagonists were withheld 1 week before the study day. Patients were allowed to take ß-blockers during the study at half the dose used previously. Patients were required to have been receiving stable angiotensin-converting enzyme inhibitor doses for at least 5 days before entering the study. Amiodarone use was allowed as long as the patient had been receiving a stable dose for at least 2 months before study entry. IV diuretics had to be administered at least 6 h before baseline measurements, between 4 h and 18 h of the study period, and after the end of the levosimendan infusion. Written informed consent was obtained at the time of initial screening before any hemodynamic or transesophageal echocardiographic assessment.

Study Protocol
Treatment with levosimendan was started with a loading dose administered as an infusion of 24 µg/kg over 10 min, followed by a continuous infusion of 0.1 µg/kg/min. The infusion was maintained at a constant rate for 24 h unless the patient had a major cardiovascular event or had a serious adverse reaction. In addition, study treatment was discontinued if symptomatic ischemia, sustained ventricular tachycardia, or clinically more severe arrhythmia was recorded. The study protocol was reviewed and approved by our hospital ethics committee.

Baseline hemodynamic parameters were measured 2 h after the introduction of a Swan-Ganz catheter (Abbott Critical Care Systems; North Chicago, IL) and 30 min before starting the levosimendan infusion. Hemodynamic and echocardiographic data were obtained simultaneously without sedation.

Noninvasive hemodynamic (systolic and diastolic BP), ECG (heart rate), and transthoracic echocardiograms (left ventricular volumes and transmitral Doppler flow velocities) were repeated 72 h after the beginning (48 h after the cessation) of the levosimendan infusion in all patients. Cardiac output was calculated as the product of heart rate and left ventricular stroke volume.

Echocardiographic and Doppler Studies
Echocardiographic studies were performed with the patient in the supine position (Image Point, equipped with 2.5-MHz transducer; Hewlett-Packard; Andover, MA). Two-dimensional images were obtained in the standard parasternal and apical views. To quantify left ventricular volume, the biplane method of discs was used from the apical four-chamber view. Special attention was focused on displaying the true left ventricular apex, showing neither the aorta nor the coronary sinus while maximizing right ventricular size.9 All Doppler recordings were obtained at a sweep speed of 50 mm/s.

A pulsed Doppler sample volume was placed at the tips of the mitral valve and the transmitral velocity recorded during five cardiac cycles. The Doppler cursor was then positioned between the mitral valve and the left ventricular outflow, and a continuous-wave Doppler recording was obtained to allow measurement of the isovolumic relaxation time (IVRT).101112 After induction of topical anesthesia, a 5-MHz transesophageal echocardiographic probe was inserted into the esophagus. The transducer was manipulated to obtain a clear view of the left upper pulmonary vein as it emptied into the left atrium. A sample volume was then placed 1 to 2 cm into the pulmonary vein from its junction with the left atrium. Color flow imaging was used to obtain a beam direction as parallel as possible to pulmonary vein flow.1314

Pressure Measurements
The auscultatory method of BP measurement with a properly calibrated and validated instrument was used. The average value of three measurements were obtained as the reference BP.15

A flow-directed pulmonary-artery thermodilution catheter was placed in the pulmonary artery through the right subclavian vein. All pressures were referenced to 50% of the transthoracic diameter and were obtained at end-tidal volume apnea. They were recorded on a physiologic recorder (Life Scope 9; Nihon Kohden; Tokyo, Japan). We verified occlusive pressure by comparing the pressure tracing waveforms to the waveforms observed in the pulmonary artery position and by looking for the expected rise in oxygen saturation. The pressures reported represented an average of five cardiac cycles. Recordings were obtained when all hemodynamics parameters were stable. Hemodynamic and echocardiographic measurements were done at baseline and 24 h after the start of the infusion.

Derivative Parameters
From the cardiac output, cardiac index and stroke volume were estimated. From the transmitral Doppler flow velocity, the E wave and A wave as well as the DT were measured and the early/late transmitral diastolic peak flow velocity (E/A) ratio was calculated.14 From the pulmonary venous flow, the peak velocities of the systolic, diastolic, and atrial reversal (AR) waves were measured; the systolic/diastolic (S/D) ratio was calculated.

Statistical Analysis
The paired-samples t test procedure was used to compare the means of the variables measured before and after treatment with levosimendan. Stepwise linear regression analysis was used to estimate the coefficients of the linear equation, involving the independent variables that best predict the value of the dependent variable. As dependent variables, the percentage changes of cardiac output and the percentage changes of pulmonary capillary wedge pressure were used. These dependent variables were used as the most important hemodynamic parameters in congestive heart failure that were measured in the present study. As independent variables, the percentage changes of all parameters derived from the transmitral flow and from the pulmonary flow velocities and their derivative parameters were used. These independent variables are measures of left ventricular diastolic function; E/A ratio is the most commonly used diastolic index derived from transmitral Doppler flow velocity. All independent variables selected were added to a single regression model in order to explore the association between hemodynamic parameters and left ventricular diastolic function indexes. In the stepwise selection method, the equation starts as "empty," and independent variables are added one at a time provided the statistical criteria for entry (stepping method criteria: F probability for entry, 0.05; F probability for removal, 0.1) are met.15 Analysis was performed using statistical software (SPSS Regression with Collinearity Diagnostics option, with SPSS Explore for evaluation of regression assumptions; SPSS; Chicago, IL). All statistical assumptions were met, and no multicolinearity problems were found to exist in our analysis. Scatterplots indicate that the dependent variable and the adjusted predicted values are linearly related. Statistical significance was defined by an {alpha} value ≤ 0.05 in two-tailed tests.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Thirty patients were enrolled in the study. Baseline hemodynamics and echocardiographic data of patients are summarized in Table 1 . Mean age ± SD was 59 ± 12 years. The cause of heart failure was ischemic heart disease in 18 patients. Twenty-three patients were admitted for deterioration of chronic heart failure, and 7 patients presented with acute heart failure. Digoxin was administered in 24 patients, diuretics and angiotensin-converting enzyme inhibitors in all patients, ß-blockers in 14 patients, amiodarone in 11 patients, and calcium-channel blockers in 4 patients. Diuretics resulted in significant loss of body water (minimum to maximum, 0.5 to 9.8 L; median, 3.2 L). The above treatment resulted in stabilization of the patients’ state at the time they were enrolled into the study. All patients completed the protocol study successfully. No patient had events leading to discontinuation of levosimendan infusion. The minor adverse events recorded in levosimendan-treated patients were headache (n = 1) and nausea (n = 1). Sinus tachycardia (heart rate increase > 20% from baseline) occurred in two patients. Low systolic BP (< 90 mm Hg) was recorded in one patient.


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  		Table 1.. Hemodynamic, Transmitral Flow, and Pulmonary Venous Flow Parameters at Baseline and After 24 h of Levosimendan Infusion*

 
The hemodynamics presented in Table 1 indicates a moderate congestive heart failure group. The mean pulmonary capillary wedge pressure was 21 mm Hg (range, 19 to 23 mm Hg), indicating that several subjects had near-normal filling pressures. The average wedge pressure at the end of the study period was almost normal. Thus, the population of patients was well compensated regarding the cardiac function at the time they were enrolled into the study.

Hemodynamic Effects
Systolic BP did not change, while there was a significant reduction of 8% in diastolic BP (p < 0.01). Cardiac output (29%) and stroke volume (24%) were significantly increased after 24 h of levosimendan infusion; heart rate (5%) did not change significantly; pulmonary capillary wedge pressure (– 29%) significantly decreased. All changes were significant at p < 0.001 (Table 1).

Left Ventricular Volumes
Levosimendan after 24-h infusion decreased left ventricular end-systolic volume by 13% (p = 0.003) and increased left ventricular ejection fraction by 26% (p < 0.001). However, left ventricular end-diastolic volume did not change (p = not significant [NS]).

Transmitral Flow Velocities
Levosimendan treatment had a significant effect on transmitral flow velocities. The E wave was decreased (– 26%) while the A wave was increased (+ 13%), so that E/A ratio was decreased (– 35%). Furthermore, DT (70%) and IVRT (71%) were increased in order that the restrictive pattern of left ventricular filling was transformed to pseudonormal pattern (Table 1, Fig 1 ).



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  		Figure 1.. Transmitral filling and pulmonary venous flow patterns at baseline and after 24 h of levosimendan infusion. The restrictive pattern of the E wave markedly increased; a small A wave with shortened DT and blunted pulmonary venous flow with an increased AR reversed into pseudonormal pattern with E wave greater than A wave, resembling a normal pattern; the pulmonary venous flow shows an increased systolic flow and reduced AR.

 
Pulmonary Venous Flow Velocities
Treatment with levosimendan produced a significant increase in systolic velocity (+ 60%) and a decrease in diastolic velocity (– 6%) and AR velocity (– 20%). The S/D ratio was significantly increased (+ 72%), supporting the conversion of restrictive pattern of left ventricular filling into pseudonormal pattern (Table 1, Fig 1).

Determinants of Hemodynamic Changes
We found that percentage changes of the E/A ratio (standardized coefficient, – 0.937; p < 0.001) and percentage changes of IVRT (standardized coefficient, 0.200; p < 0.005) were independent predictors of the increase in cardiac output. Furthermore, percentage changes of the S/D ratio (standardized coefficient, – 0.639; p < 0.001) and percentage changes of the E/A ratio (standardized coefficient, 0.319; p < 0.05) were independent predictors of the decrease in pulmonary capillary wedge pressure (Fig 2 ).



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  		Figure 2.. Scatterplots indicate that the dependent variable and the adjusted predicted values are linearly related. Top: The dependent variable is the percentage changes of cardiac output (CO), and the adjusted predicted values are the E/A ratio and the IVRT. Bottom: The dependent variable is the percentage changes of pulmonary capillary wedge pressure (PCWP), and the adjusted predicted values are the S/D ratio and the E/A ratio.

 
Measurements at 72 h
In Figure 3 , the hemodynamic and transmitral Doppler flow measurements 72 h after drug infusion are shown. At 72 h, heart rate, mean BP, cardiac index, DT, and IVRT were similar with the values at 24 h during levosimendan infusion cessation.



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  		Figure 3.. Effects of levosimendan during and after 24-h continuous infusion. The effects on left ventricular diastolic function indexes remained 48 h after the cessation of levosimendan infusion.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The main finding of this study, was the improvement of measures left ventricular diastolic function in patients with severe heart failure as a result of the levosimendan administration. By virtue of this change in left ventricular filling, cardiac output was increased while pulmonary capillary wedge pressure was decreased. Levosimendan improves both systolic and diastolic function in the severely failing left ventricle. Similar findings have been found in multicellular cardiac muscle preparations17 and in dogs with pacing-induced heart failure18; these studies have shown that levosimendan, despite its Ca2+-sensitizing properties, not only prevented a worsening of diastolic dysfunction, it improved the diastolic properties of the myocardium. Furthermore, Tachibana et al19 found that levosimendan decreases minimal left ventricular pressure and the time constant of left ventricular relaxation ({tau}). With levosimendan treatment during exercise, the early diastolic portion of the left ventricular pressure-volume loop was shifted downward with decreased minimal left ventricular pressure and {tau} values.19

Mechanism of Action
In vitro, levosimendan increases the sensitivity of myocardial filaments to calcium.20 It is thought that levosimendan increases calcium sensitivity by binding to troponin C.21 Consistent with this thesis is the observation that levosimendan does not impair myocardial relaxation. Unlike most other Ca2+ sensitizers, levosimendan acts through direct binding with troponin C, thereby increasing the affinity of troponin C for Ca2+ in a Ca2+-dependent manner. A lack of Ca2+ sensitization under low prevailing calcium concentrations during diastole might be of critical importance to prevent a worsening of diastolic dysfunction. In addition, it was shown that levosimendan increases activity of the Na+-Ca2+ exchanger that may also contribute to improved diastolic function.

Hemodynamic Effects
Hemodynamic performance was improved in all patients. Cardiac output was increased at an average of 29%, and stroke volume increased at an average of 24%. Moreover, mean pulmonary capillary wedge pressure was decreased by an average of 29%. These changes were achieved after 24-h infusion and were consistent with those of other studies.123 Levosimendan was well tolerated and did not cause serious cardiac adverse events.

Left Ventricular Filling Pattern
In severe heart failure, progressive shortening of the transmitral DT and increasing E/A ratio can be seen with decreasing ventricular compliance and increasing pulmonary capillary wedge pressure.9 The treatment of heart failure with levosimendan for 24 h produced significant changes in transmitral flow-velocity pattern (Fig 1). IVRT was prolonged, E velocity and E/A ratio decreased, and DT was prolonged. These findings show a reversal of the constrictive pattern of left ventricular filling into a pseudonormal left ventricular filling pattern.

Furthermore, treatment with levosimendan was associated with a significant decrease in pulmonary venous diastolic velocity and a significant increase in systolic velocity and S/D ratio. The left atrium is considered to act like a conduit in diastole, and thus the pulmonary venous diastolic flow reflects mitral flow velocity pattern.22 Thus, a decrease in diastolic velocity was associated with a decrease in E-wave velocity.

Another important finding of our study was the reduction of AR flow velocity after levosimendan administration. This resulted from a reduction in left atrial afterload mismatch, which is closely linked to a decrease in the volume of blood ejected from the atrium backward into the pulmonary veins.23 We have already reported the left atrial afterload mismatch concept in severe heart failure: in end-stage heart failure, left atrial pump function is reduced leading to further impairment of atrioventricular coupling and eventual loss of left atrial compensation.24 The new finding in this study is that levosimendan may improve atrioventricular coupling. Levosimendan significantly reduced left ventricular stiffness expressed by the prolonged DT. Consequently, levosimendan reduced the afterload in the left atrium associated with an increase in left atrial ejection into the left ventricle and a decrease in backward flow volume into the pulmonary veins during atrial contraction. These effects lead to a pseudonormalization of the transmitral flow velocity pattern.

Doppler Predictors of Hemodynamic Changes
We found that the changes in transmitral flow velocities and pulmonary vein flow velocities in patients with severe heart failure were related to the changes in the hemodynamic parameters. Increase in cardiac output was predicted by the decrease in E/A ratio and the increase in IVRT. Decrease in pulmonary capillary wedge pressure was predicted by the increase in S/D ratio and the decrease in E/A ratio. Thus, the improvement in left ventricular diastolic function by levosimendan may enhance the hemodynamic amendment. These findings are expected, as a better filling of the left ventricle will result to an improved left ventricular systolic function as a result of the Starling law of the heart. Moreover, the positive inotropic action of levosimendan improves left ventricular contraction and consequently hemodynamic parameters.

Late Effects of Levosimendan on Left Ventricular Diastolic Function Indexes
Another interesting finding of this study was that the hemodynamic effects and the effects on left ventricular diastolic function indexes of levosimendan remained after the cessation of the drug infusion. The transmitral Doppler flow velocity pattern remained in the pseudonormal pattern. All E/A, DT, and IVRT indexes remained unchanged. These results may be explained by the active, potent acetylated metabolite of levosimendan with a long life (OR-1896), which is also a calcium sensitizer, which may be responsible for most of the longer-term effects of levosimendan.25 Formation of OR-1896 is slow, with peak metabolite concentrations occurring 1 to 2 days after cessation of a 24-h infusion of levosimendan.26 The elimination half-life of OR-1896 is approximately 80 h. Accordingly, the pharmacologic effects of metabolite may persist for approximately 1 week.27

Oral Levosimendan
Levosimendan is available in oral form in Europe. Our study was short, but the long-term effects of oral therapy in patients with congestive heart failure would be interesting for clinicians. It has been reported that oral levosimendan has favorable cardiac and hemodynamic effects in patients with severe congestive heart failure; these effects are similar to those seen after IV dosing with levosimendan.28 The 4- to 8-mg daily doses of oral levosimendan showed moderate inotropic effects.29 Both 6-h infusion and a 2-mg single dose of levosimendan showed that levosimendan has moderate inotropic and vasodilatory effects in patients with severe congestive heart failure.30 Thus, oral levosimendan may be used as substitute for IV inotropic support in end-stage heart failure, as pilot results on the use of oral levosimendan are encouraging.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Echocardiographic measures of diastolic function in patients with severe heart failure and a restrictive pattern of left ventricular filling were markedly improved with levosimendan treatment. Levosimendan may improve hemodynamics in patients with severe heart failure along with changes in left ventricular filling pattern.


   Footnotes
 
Abbreviations: AR = atrial reversal; DT = deceleration time; E/A = early/late transmitral diastolic peak flow velocity; IVRT = isovolumic relaxation time; NS = not significant

Received for publication March 23, 2005. Accepted for publication May 30, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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