Levosimedan-Editorial

Levosimendan in Cardiac Surgery: A
Unique Drug for the Treatment of
Perioperative Left Ventricular
Dysfunction or Just Another Inodilator
Searching for a Clinical Application?
Paul S. Pagel, MD, PhD The myofilament calcium (Ca2
) sensitizers are a class of positive inotropic,
vasodilating drugs ("inodilators") that augment myocardial contractility by
increasing the Ca2
sensitivity of the contractile apparatus without altering
intracellular Ca2
concentration (1). Ca2
sensitizers (including levosimendan,
pimobendan, sulmazole, EMD 57033, and MCI-154) have received
considerable attention for the treatment of acute and chronic congestive heart
failure because, unlike
1-adrenoceptor agonists or cardiac phosphodiesterase
(PDE) III inhibitors that stimulate cyclic adenosine monophosphate (cAMP)-
mediated signaling and increase intracellular Ca2
concentration, these drugs
do not adversely affect myocardial oxygen supply-demand relations (2),
produce cardiotoxicity, or predispose to the development of arrhythmias (3).
Levosimendan was developed over a decade ago, and based on a large body
of accumulated experimental and clinical evidence, appears to be the most
promising of these drugs. Levosimendan has already been approved for the
treatment of acute exacerbation of chronic heart failure in several European
countries following European Society of Cardiology guidelines (4,5). The
drug is currently undergoing Phase III clinical trials in the United States
(REVIVE study) to evaluate its utility for the acute or chronic management
of heart failure, and has received "fast-track" status from the Food and
Drug Administration.
The mechanisms by which levosimendan enhances the inotropic state and
produces vasodilation have been extensively studied (1). Briefly, levosimendan
binds to the regulatory protein troponin C (TnC) (6) and stabilizes the
Ca2
-bound conformation of TnC, thereby allowing unopposed interaction
between actin and myosin filaments and enhancing the rate and extent of
myocyte contraction (7). A unique feature of levosimendan-TnC binding is its
dependence on intracellular Ca2
concentration that facilitates the interaction
between TnC and Ca2
during systole, while simultaneously allowing Ca2
to
dissociate from the protein during diastole (8). This Ca2
-dependence of TnC
binding prevents deleterious abnormalities in relaxation that would otherwise
be expected to occur (9). Preservation of lusitropic function is also facilitated
by the PDE-inhibiting properties of levosimendan that occur at higher doses
of the drug (10). Levosimendan-induced systemic, pulmonary, and coronary
vasodilation occurs as a result of at least three distinct mechanisms. Levosimendan
opens several types of potassium (K
) channels (including voltagedependent,
ATP-sensitive, and Ca2
-activated forms) in conductance and
resistance vessels, actions that reduce intracellular Ca2
concentration in
vascular smooth muscle (11). Levosimendan induces Ca2
desensitization of
the contractile apparatus in vascular smooth muscle that does not contain TnC
independent of intracellular Ca2
concentration (12). PDE inhibition may also
play a role in vasodilation produced by higher doses of the drug.
Unlike other inotropic drugs, levosimendan may exert important antiischemic
effects by virtue of its actions as a KATP channel opener. Levosimendan
From the Anesthesia Service, the Clement
J. Zablocki Veterans Affairs Medical Center,
Milwaukee, Wisconsin.
Accepted for publication December 7,
2006.
Address correspondence to Paul S. Pagel,
MD, PhD, Clement J. Zablocki Veterans Affairs
Medical Center, Anesthesia Service, 5000
W. National Ave., Milwaukee, WI 53295. Address
e-mail to paul.pagel@med.va.gov.
Copyright © 2007 International Anesthesia
Research Society
DOI: 10.1213/01.ane.0000256864.75206.6d
Vol. 104, No. 4, April 2007 759
activates sarcolemmal (13) and mitochondrial (14) KATP
channels in vitro, and these channels play a critical role in
myocardial protection against reversible and irreversible
ischemic injury (15). Levosimendan reduced myocardial
infarct size in a canine model of ischemia and reperfusion
in vivo, independent of alterations in systemic
hemodynamics or coronary collateral blood flow, and
this beneficial action was abolished by the nonselective
KATP channel antagonist glyburide (16). Levosimendan
enhanced the functional recovery of stunned myocardium
after percutaneous transluminal coronary angioplasty
in patients with acute myocardial ischemia (17)
and was also beneficial for the treatment of cardiogenic
shock resulting from stunning of border zone myocardium
during infarction (18). Brief administration of levosimendan
to patients undergoing coronary artery bypass graft
surgery before cardiopulmonary bypass was associated
with lower postoperative troponin I concentrations (19).
These latter data suggested that levosimendan may be
capable of producing pharmacological preconditioning in
humans, presumably as a consequence of its actions on the
KATP channel.
The clinical efficacy of levosimendan in patients with
heart failure resulting from ischemic heart disease
(20,21), dilated cardiomyopathy (21), and acute myocardial
infarction (22) has been well documented. Levosimendan
causes dose-dependent improvements in
systemic and pulmonary hemodynamics in patients
with heart failure concomitant with a reduction in clinical
symptoms (21); but the myofilament Ca2
sensitizer
does not produce hypotension, exacerbate ongoing ischemia,
or contribute to mortality by increasing the incidence
of arrhythmias (22). In contrast, a major clinical
trial of the PDE III inhibitor, milrinone, in patients
admitted for an acute exacerbation of chronic heart
failure demonstrated that milrinone did not alter inhospital
or 60-day mortality when compared with placebo,
caused more frequent episodes of hypotension
requiring intervention, and increased the incidence of
arrhythmias as compared to placebo (23). When compared
with the
-adrenoceptor agonist, dobutamine,
levosimendan also produced more favorable alterations
in hemodynamics and reduced mortality in patients
with low-output heart failure (24) and in those with
cardiogenic shock after percutaneous coronary intervention
(25). The relative superiority of levosimendan when
compared with dobutamine described in these studies
(24,25) may be related to the antiinflammatory and
antiapoptotic effects of the myofilament Ca2
sensitizer
(26). Similar to the findings in the setting of heart failure,
levosimendan has also been shown to increase cardiac
performance concomitant with reductions in pulmonary
capillary occlusion pressure and systemic vascular resistance
in patients with normal (27) and depressed (28,29)
left ventricular (LV) function undergoing cardiac surgery
with or without (30) cardiopulmonary bypass.
In the current issue of Anesthesia & Analgesia, De
Hert et al. (31) provide further evidence that levosimendan
produces beneficial hemodynamic effects in
patients with preoperative LV dysfunction (ejection
fraction 30%) undergoing cardiac surgery who required
inotropic support after cardiopulmonary bypass.
Despite the inherent problems associated with a
strict comparison between drugs of differing pharmacological
action and relative potency, the authors
demonstrate that the combination of IV infusions of
levosimendan (0.1 g
kg1
min1) and dobutamine (5
g
kg1
min1) produces very similar cardiovascular
effects to those observed with the combination of milrinone
(0.5 g
kg1
min1) and dobutamine during the
first 24 h after cardiopulmonary bypass. The data
further suggest that levosimendan-dobutamine may
augment stroke volume index to a greater degree than
milrinone-dobutamine 12 and 24 h after bypass, although
these results may most likely be attributed to
the greater reductions in systemic vascular resistance
observed in patients receiving the combination of
levosimendan and dobutamine. Loading doses of levosimendan
or milrinone were not administered, but
infusions of these drugs were initiated upon removal
of the aortic cross-clamp preceding a prolonged reperfusion
before separation from bypass. Thus, steadystate
plasma concentrations of levosimendan and
milrinone were probably established before bypass
was discontinued. Perhaps of more importance, the
results indicate that the total doses of dobutamine and
norepinephrine (used to treat mean arterial blood
pressure 60 mm Hg) required during the first 48 h
after cardiopulmonary bypass, the total duration of
inotropic drug treatment, the duration of mechanical
circulatory support (intraaortic balloon counterpulsation
was required in four of 15 patients per group),
and time to tracheal extubation were significantly less in
patients receiving levosimendan-dobutamine when compared
with those treated with milrinone-dobutamine. The
beneficial hemodynamic effects of levosimendan have been
shown to persist for at least 24 h after discontinuation of
a continuous infusion as a result of a biologically active
metabolite (OR-1896) (32), and it is likely that the accumulation
and prolonged effect of this metabolite may, at
least partially, account for these dramatic differences
between levosimendan- and milrinone-treated patients.
PDE III inhibitors such as milrinone have been a
mainstay in the pharmacological management of LV
dysfunction after cardiopulmonary bypass for many
years. These drugs are commonly used in combination
with
1-adrenoceptor agonists to provide a synergistic
positive inotropic effect in the presence of bypassinduced
down regulation of the
1-adrenoceptor and
dysfunctional adenylyl cyclase-mediated signal transduction
(33). Because the mechanism of action of levosimendan
is not dependent on this signaling pathway, the
drug may have the distinct advantage of enhancing
myocardial contractility by acting directly at the level of
the contractile apparatus. In addition, levosimendan
may reduce the development of arrhythmias and the
incidence of cardiotoxicity that often occur with other
clinically used inotropic drugs, because increases in
760 Editorial ANESTHESIA & ANALGESIA
intracellular Ca2
concentration do not occur with the
myofilament Ca2
sensitizer at typical therapeutic doses.
KATP channel-mediated antiischemic effects and prolonged
drug action resulting from an active metabolite
also represent potentially important benefits of levosimendan
in patients with LV dysfunction after cardiac
surgery. Thus, the recent findings of De Hert et al. (31)
are certainly promising, and support the work of
previous investigations (28,29). Nevertheless, PDE III
inhibitors and
1-adrenoceptor agonists have a wellestablished
record of clinical efficacy in the treatment of
perioperative LV dysfunction. Given the success of these
drugs in this setting, a fundamental question remains: Is
another positive inotropic drug with vasodilating properties
truly required to successfully treat these patients?
Thus, whether the theoretical advantages of levosimendan
will ultimately translate into improved outcome in
cardiac surgical patients with LV dysfunction is
unknown and will require additional investigation to
define.