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research-article2016
ACC0010.1177/2048872616687114European Heart Journal: Acute Cardiovascular CareHusebye et al.
EUROPEAN
SOCIETY OF
Original scientific paper CARDIOLOGY ®
Abstract
Background: Echocardiography is recommended for assessment of left ventricular systolic function in patients with
acute heart failure but few randomised trials have validated techniques like tissue Doppler (TDI) and speckle tracking
(STE) in patients with acute heart failure following ST-elevation myocardial infarction.
Methods: This was a substudy from the LEAF (LEvosimendan in Acute heart Failure following myocardial infarction)
trial (NCT00324766 ), which randomised 61 patients developing acute heart failure, including cardiogenic shock, within
48 hours after ST-elevation myocardial infarction, double-blind to a 25-hour infusion of levosimendan or placebo.
TDI-derived systolic mitral annulus velocity (S′), STE-derived global longitudinal strain (Sl) and strain rate (SRl) were
measured at baseline, day 1, day 5 and after 42 days.
Results: Datasets rejected for analyses were 2% (TDI) and 17% (STE). S′ increased by 23% in the levosimendan group
versus 8% in the placebo group from baseline to day 1 (p= 0.011) and by 30% vs. 3% from baseline to day 5 (p <0.0005).
Significant, but less pronounced, improvements in global Sl (p = 0.025 and p = 0.032) and in global SRl (p = 0.046 and p
= 0.001) in favour of levosimendan were also present.
Conclusion: S′ by TDI and STE-derived Sl and SRl were sensitive indices for changes in left ventricular systolic function
related to treatment with levosimendan. However, S′ by TDI was more feasible and sensitive and might be preferred
for assessment of changes in left ventricular systolic function in critically ill patients with acute heart failure receiving
inotropic therapy.
Keywords
Systolic mitral annulus velocity, global longitudinal strain, acute heart failure, levosimendan, myocardial contractility
Introduction
1Department of Cardiology, Oslo University Hospital Ullevål, Norway
Echocardiography is the image modality of choice in 2Centre for Heart Failure Research, University of Oslo, Norway
patients with heart failure due to its availability, safety and 3Faculty of Medicine, University of Oslo, Norway
low-cost.1 However, use of echocardiography in patients 4Centre for Clinical Heart Research, Oslo University Hospital Ullevål,
with acute heart failure (AHF) is less well defined, both in Norway
clinical practice and in clinical trials.2
Corresponding author:
Assessment of left ventricle (LV) systolic function by Trygve Husebye, Department of Cardiology, Oslo University Hospital
indices like wall motion score index (WMSI) and LV ejec- Ullevål Hospital, P.O. Box 4950, Nydalen N-0424, Oslo, Norway.
tion fraction are largely based on visual judgement and Email: tr-huse@online.no
2 European Heart Journal: Acute Cardiovascular Care
their user-dependency represents a major limitation, espe- organ hypoperfusion such as oliguria, cold and clammy
cially in clinical trials. Less user-dependent indices such as extremities or reduced consciousness.
peak systolic velocity of the mitral annulus (S′) by tissue All patients received standard medical therapy accord-
Doppler imaging (TDI), and global longitudinal strain (Sl) ing to current guidelines. The use of intravenous inotropic
and strain rate (SRl) by speckle tracking echocardiography drugs was restricted to patients with cardiogenic shock,
(STE), offer both objective, quantitative and validated except noradrenaline in the setting of hypotension not
measurement of LV function.3,4 These indices have been responding to volume therapy and reduction in study drug
studied in patients with chronic heart failure (CHF).5,6 infusion.
However, no data exist regarding the feasibility of these
indices in patients with advanced AHF complicating
Echocardiography
ST-elevation myocardial infarction (STEMI).
We have previously reported results from the ran- Examinations were performed with two digital ultrasonic
domised, placebo-controlled LEAF (LEvosimendan in device systems from the same vendor (GE Vingmed
Acute heart Failure following myocardial infarction) trial Ultrasound, Horten, Norway), Vivid i at baseline and on
on patients with AHF following a percutaneous coronary day 1 immediately after end of study drug infusion and
intervention (PCI)-treated STEMI.7 We were able to dem- Vivid 7 on day 5 and after 42 days (four echocardiograms
onstrate that levosimendan improved the primary endpoint in each patient). All recordings were analysed with the
WMSI from baseline to day 5 compared with placebo. same software (GE Echopac v 108.15). Two experienced
The main objective of this substudy of the LEAF trial echocardiographers (TH, GØA) performed all the record-
was to elucidate whether repetitive measurements of S′ by ings and a single one (TH) performed all the analyses.
TDI and global Sl and SRl by STE were feasible and sensi- Interobserver reproducibility was tested by an independent
tive indices for changes in LV systolic function during ino- echocardiographer blinded to the results of the performed
tropic stimulation by levosimendan in STEMI patients with analyses. Three consecutive cardiac cycles were recorded,
AHF including cardiogenic shock. five if atrial fibrillation was present. Recordings included
the standard parasternal and apical four-chamber, two-
chamber and long-axis views.
Methods TDI-recordings were obtained by colour tissue Doppler
The LEAF trial was an investigator initiated, manufacturer with a mean frame rate of 146 (±30)/s. Care was taken to
independent study conducted at Oslo University Hospital avoid an angle of incidence >20° between the ultrasound
Ullevål. The Regional Ethics Committee approved the beam and the direction of the motion of the basal segment
study, which was conducted in accordance with the princi- of the LV walls. A sampling area of 6 mm × 6 mm was
ples of the Declaration of Helsinki. All patients provided positioned in the basal segment of the LV wall within 1
written informed consent. The study was registered at cm of the insertion of the mitral leaflets (Figure 1). S′
www.clinicaltrial.gov; NCT00324766. (TDI) was measured as the average of the velocities
acquired from the base of the septal, lateral, anterior and
inferior walls over three consecutive cycles (five if atrial
Study design and patient population fibrillation).
The LEAF trial was a randomised, double-blind, placebo- Recordings for STE analyses were obtained from grey-
controlled, single-centre, parallel-group study. Details on scale images in the three apical views with a mean frame
study design and main results have been published previ- rate of 76 (±13)/s. Only the cycle with the best image qual-
ously.7 Patients were included in an intensive care (ICCU) ity was chosen for the analyses. Tracking of the myocardial
setting and assigned to an infusion of 0.2 µg/kg per min for walls was automatically performed by the software (GE
1 h followed by 0.1 µg/kg per min for 24 h of levosimendan Vingmed Ultrasound). Segments with suboptimal tracking
or placebo. Included in the study were patients with AHF were discarded. If ≥3 segments were discarded or if atrial
(including stratified randomisation of patients in cardio- fibrillation was present, the whole dataset was rejected for
genic shock) complicating a PCI-treated STEMI. The analysis. End-systole was defined as closure of the aortic
inclusion criteria were: (a) opening of an occluded or dila- valve determined from the apical long-axis view. Peak Sl
tion of a stenotic coronary artery presumed to be the was defined as the maximal shortening before end-systole
infarct-related artery, (b) signs of decreased wall-motion in and by the software given as a mean value in each of the
at least three of 16 segments of the LV assessed by echo- three apical views. Global Sl was then calculated as the
cardiography, (c) clinical HF. Additional criteria in the car- average value of the whole LV. Correspondingly, global SRl
diogenic shock subgroup were: (a) systolic blood pressure was calculated as the average of the mean values of the
(SBP) < 90 mmHg after 60 min of adequate volume ther- maximal systolic strain rate.
apy or SBP between 90 and 100 mmHg in spite of ino- WMSI was measured using a 16-segments model.8 LV
tropic support by catecholamine infusion and (b) signs of ejection fraction was measured by Simpson’s biplane
Husebye et al. 3
Figure 1. Measurements of left ventricular function by colour tissue Doppler imaging. Placement of sample volume for
measurement of mitral annulus velocities in apical four-chamber view (arrows to the left) and the corresponding maximal velocities
(arrows to the right) are shown.
Figure 2. Echocardiograms analysed in the levosimendan and placebo group. Total number and the number rejected from analyses
by TDI and STE from baseline until day 42 are shown.
TDI: colour tissue Doppler imaging; STE: speckle tracking echocardiography.
to baseline characteristics (Table 1). Patients were charac- increased significantly at day 1 (p = 0.046) and day 5 (p =
terised by large infarct size (peak troponin T ~ 12,000 0.001) in favour of levosimendan (Figure 3(c)). Significant
ng/l) and severe heart failure at inclusion (28% treated improvements in LVOT peak velocity from baseline to day
with an intra-aortic balloon pump and 15% were in car- 1 (p = 0.030) and day 5 (p = 0.002) in favour of levosi-
diogenic shock). mendan were also found (Figure 3(d)).
Table 1. Baseline characteristics of the study population according to treatment arms.
Continuous data are presented as median (25th, 75th percentiles) unless indicated otherwise.
aDifferences between treatment groups.
IABP: intra-aortic balloon counter-pulsation; PCI: percutaneous coronary intervention; TnT: troponin T; NT-proBNP: N-terminal pro B-type natri-
uretic peptide; WMSI: wall motion score index; LVEF: left ventricular ejection fraction
levosimendan and placebo groups was found (p = 0.72). received noradrenaline due to transient hypotension during
Both S′ and Sl at baseline were associated with the com- the study drug infusion (first 25 h). This treatment was dis-
posite endpoint in univariate analyses, while LVEF only continued in all patients >30 min before the end of the drug
reached borderline significance (Table 3). The HRs were infusion and did not affect the subsequent echo-recordings
significant after adjusting for age (S′, HR 0.58 (0.37–0.91) on day 1 or day 5.
p = 0.018), (Sl, HR 1.68 (1.27–2.21) p < 0.0005) and
(LVEF (0.87–0.99) p = 0.016).
Discussion
The principal finding of this prospective clinical study is
Use of beta-blockers and inotropic drugs that S′ measured by TDI was a feasible and sensitive
other than levosimendan marker of inotropic effect of levosimendan in patients
No significant differences in the use of beta blockers with advanced AHF. This is, to our best knowledge, the
between the levosimendan and placebo groups were found; first report of the use of this echocardiographic index to
baseline: 6/30 vs. 6/31, day 1: 3/29 vs. 2/30, day 5: 18/29 vs. quantify effects of inotropic stimulation in patients with
18/29, day 42: 29/30 vs. 24/25, respectively. All patients in AHF complicating STEMI. It was more feasible and sen-
the cardiogenic shock group (n = 9) received inotropic sitive than STE-derived Sl and SRl in an ICCU setting
drugs (dopamine or dobutamine) before inclusion and dur- with critically ill patients, including patients on a
ing the first day of the study. After five days, one patient in mechanical ventilator. The randomised, placebo-con-
the levosimendan group and two patients in the placebo trolled study design ensured that changes in myocardial
group received dopamine. A total of four patients in the function related to inotropic stimulation and not to effects
levosimendan group and one patient in the placebo group related to time per se were measured.
6 European Heart Journal: Acute Cardiovascular Care
Figure 3. Changes from baseline in echocardiographic indices in patients treated with a 25 h infusion of levosimendan or placebo
S′ by colour tissue Doppler (a), Sl by speckle tracking (b), SRl by speckle tracking (c) and LVOT peak (d). Mean values ± SEM ((a),
(b) and (d)) or median values with 25th,75th percentiles (c). p-values (* p <0.05, **p <0.005, *** p <0.0005) are given for differences
between treatment groups.
S′: peak systolic mitral annulus velocity; Sl: global longitudinal strain; SRl: global longitudinal strain rate; LVOT peak: left ventricular outflow tract peak velocity.
SV: stroke volume; CO: cardiac output; HR: heart rate; SBP: systolic blood pressure; Ea: effective arterial elastance
Husebye et al. 7
Table 3. Cox regression analyses for the association between pressure and systemic vascular resistance in 179 patients
baseline factors and future adverse events (all-cause death, during dobutamine stress echocardiography.22
heart transplantation or implantable cardioverter-defibrillator Differences in the relative changes in global Sl between
implantation after surviving cardiac arrest).
the levosimendan and placebo group were modest, while
Univariate analysis differences in global SRl and LVOT peak velocity were
comparable to the relative differences in S′(TDI). SRl and
Hazard ratio (95% CI) p-value LVOT peak velocity are, as S′, markers of events that occur
Age 1.05 (1.01–1.09) 0.017 in the first half of the systole, as opposed to Sl, which is
Female 0.60 (0.22–1.66) 0.327 measured at or near end-systole.23 Previously, animal stud-
S′ 0.61 (0.41–0.91) 0.016 ies have shown that SRl correlated strongly with contractil-
Sl 1.57 (1.18–2.08) 0.002 ity, while Sl correlated best with SV.16,24 Also, in a study on
LVEF 0.94 (0.89–0.999) 0.045 healthy humans there was a significantly lower relative
TnT peak, µg/l 1.07 (0.096–1.16) 0.061 increase in global Sl than in global SRl, LVOT peak veloc-
ity and S′ during low-dose dobutamin infusion.25 Our find-
CI: confidence interval; S′: systolic mitral annulus velocity by colour tis-
sue Doppler; Sl: global longitudinal strain by speckle tracking; LVEF: left ings indicate that these relationships also apply during
ventricular ejection fraction; TnT peak: peak level of troponin T inotropic therapy in STEMI patients with AHF.
Levosimendan improved LV systolic function in post-
ischaemic myocardium measured as change in WMSI from
Feasibility of S′ by TDI and STE-derived Sl baseline to day 5 compared with placebo (p = 0.031, pri-
and SRl mary endpoint of the LEAF trial); however, no significant
S′(TDI) is easy to obtain, as visualisation of the mitral change was present the first day after start of drug infusion.7
annulus is possible in nearly all patients. It has a satisfac- WMSI is based on visual assessment and the semi-quantita-
tory reproducibility when measured as the average velocity tive scoring with only four levels makes it less sensitive to
from the septal, lateral, anterior and inferior mitral annu- detect minor changes in LV systolic function over time. In
lus.4,13 In our study, as demonstrated in Figure 2, S′(TDI) this substudy, the TDI and STE-derived indices were more
was analysed in all patients except one, confirming the fea- sensitive for such changes, probably because they measure
sibility of the index. on a continuous scale and are less user-dependent.
STE depends on good quality grey-scale images of the
whole LV.4 This may limit its application in different clini- Haemodynamic changes
cal settings such as an ICCU. This was confirmed in this
study on STEMI patients with AHF where many recordings Only a non-significant increase in SV related to levosi-
were discarded due to image quality reasons. Our results mendan treatment was found in the present study despite
indicate that STE may not be an ideal method for serial the improvement in LV function. A dose–response relation-
measurements in critically ill patients. ship between levosimendan treatment and changes in
haemodynamic indices after 23–24 h was reported in a pla-
cebo controlled study on patients with acute decompen-
Assessment of inotropic alterations sated HF.26 The main effect of levosimendan in the low-dose
The inotropic effects of levosimendan occur a few hours range (<0.2 µg/kg per min) seemed to be reduction in ven-
after start of the drug infusion and, due to its active tricular filling pressure and increase in cardiac output due
metabolites, last for several days.14 Due to systemic to increased HR, while a more modest increase in SV was
vasodilating properties, levosimendan may also improve observed. AHF in STEMI patients commonly is precipi-
LV function by afterload reduction.15 However, the tated by high filling pressures due to reduced contractility
changes in SBP and the calculated total afterload (Ea) and stiffness of ischaemic myocardium, more than reduced
were not significantly different between the two groups SV. Improvement of contractility of ischaemic myocardium
during the first five days after start of treatment in this consistent with anti-stunning effect of levosimendan has
study. Therefore, the observed changes in S′(TDI) been reported.27 An improvement in contractility of post-
between the levosimendan and placebo groups were ischaemic myocardium resulting in reduced filling pres-
probably mostly explained by the inotropic effects of sures, in spite of a modest increase in SV, might be of
levosimendan and not by its vasodilating properties. benefit in patients with AHF complicating PCI-treated
The capability of systolic velocity by TDI to detect STEMI and explain the results of our study.
minor alterations in LV contractility has been documented
in animal studies during dobutamine infusion.16-18 Although Outcome data
this index is influenced by LV load and elastic properties of
the myocardium,11,19-21 S′ was reported to be relatively Although the key message of the study was that measure-
independent of haemodynamic parameters like blood ments of S′ and Sl are sensitive indices for changes in LV
8 European Heart Journal: Acute Cardiovascular Care
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