Download Inotropes in the management of acute heart failure

Inotropes in the management of acute heart failure
John W. Petersen, MD; G. Michael Felker, MD, MHS, FACC
Impaired cardiac contractility is a fundamental component of
the heart failure syndrome, initiating the cycle of vasoconstriction, neurohormonal and inflammatory activation, and adverse
ventricular remodeling that leads to heart failure progression.
Based on this core paradigm, drugs that increase cardiac contractility (positive inotropes) are theoretically appealing as a heart
failure therapy, and such agents have been extensively investigated in both acute and chronic heart failure. Although these
agents clearly improve cardiac output, their use in heart failure
has consistently been associated with increased myocardial oxygen demand, cardiac arrhythmias, and mortality in a variety of
clinical settings. Based on these data, the routine use of inotropes
as heart failure therapy is not indicated in either the acute or
chronic setting. Inotropes may be a necessary evil in a subset of
T
he term acute heart failure
(AHF) encompasses a group of
related clinical syndromes
broadly defined as new or
worsening symptoms or signs of heart
failure leading to hospitalization or unscheduled medical care (1). Data from a
variety of sources support the idea that
AHF is the most common and morbid
acute cardiovascular condition in the
Western world, with ⬎1 million hospitalizations per year in the United States and
a 50% rate of recurrence or death within
6 months (2– 4). Within the broad spectrum of AHF syndromes, there are a variety of clinical presentations (e.g., acute
pulmonary edema vs. gradual volume
overload) and patient subtypes (e.g., impaired vs. preserved ventricular systolic
function) (5). The severity of AHF may
range from mild volume overload in the
setting of nonadherence to diet or pharmacotherapy to life-threatening cardiogenic shock and multiorgan failure. Var-
From the Division of Cardiovascular Medicine,
Duke University Medical Center, Durham, NC.
Dr. Petersen has not disclosed any potential conflicts of interest. Dr. Felker holds a consultancy with
Cytokinetics.
For information regarding this article, E-mail:
[email protected]
Copyright © 2007 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000296273.72952.39
S106
acute heart failure patients, such as those with acute heart failure
decompensation in the setting of clinically evident hypoperfusion
or shock, or as a bridge to more definitive treatment, such as
revascularization or cardiac transplantation. Currently available inotropes, such as dobutamine and milrinone, act (directly
or indirectly) by increasing cyclic adenylate monophosphate
and therefore intracellular calcium flux. Whether newer inotropes with differing mechanisms of action will realize the potential clinical benefits of inotropic therapy without the risk
remains a subject of ongoing investigation. (Crit Care Med 2008;
36[Suppl.]:S106–S111)
KEY WORDS: cardiac contractility; heart failure syndrome; cardiac output
ious clinical syndromes within the
umbrella of AHF may differ significantly
with regard to pathophysiology, appropriate clinical care, and outcomes. Despite
these differences, several overriding therapeutic goals apply to most patients with
AHF. Chief among these are relieving
acute symptoms, restoring euvolemia, restoring or preserving end-organ function,
limiting length of stay and resource utilization, and decreasing rehospitalization
and short-term mortality. No available
therapy for AHF is able to achieve all of
these goals, but they provide a helpful
framework for considering the appropriateness of a given therapy in various patient types. In this review, we discuss the
data supporting (or rejecting) the efficacy
of inotropic therapy for AHF patients,
with an emphasis on applying the principles of evidence-based medicine.
Rationale for Inotropic Therapy
in Acute Heart Failure
Until the 1980s, the predominant
framework for understanding heart failure was based on a hemodynamic model.
Within this model of heart failure pathophysiology, impaired cardiac contractility
and decreases in cardiac output were considered the central abnormalities and
thus the most logical target for therapy.
This formed the rationale for treatment
of heart failure patients with drugs de-
signed to increase contractility and cardiac output (positive inotropes). Decades
of experience with the use of oral inotropic agents as chronic therapy have shown
convincingly that these agents lead to
increased mortality in chronic heart failure (6 – 8). The failure of chronic inotropic therapy, coupled with the success of
the neurohormonal model of chronic
heart failure in guiding the development
of angiotensin-converting enzyme inhibitors and ␤-blockers, led to the ascendancy of the neurohormonal model of
chronic heart failure and decreased emphasis on hemodynamic considerations
and contractility. No chronic oral inotropes are in routine clinical use in the
United States, and chronic inotropic
therapy is not covered by this review.
In contrast to the situation in chronic
heart failure, the hemodynamic considerations remain prominent in thinking
about AHF syndromes. A decrease in cardiac contractility (e.g., due to ischemia)
is often postulated to be the inciting
event that leads to a transition from compensated to decompensated heart failure
in at least some patients with AHF. The
recent European guidelines for the management of AHF state that “the final common denominator in the syndrome of
AHF is a critical inability of the myocardium to maintain a cardiac output sufficient to meet the demands of the periphCrit Care Med 2008 Vol. 36, No. 1 (Suppl.)
eral circulation” (9). This line of reasoning
has resulted in the continued (although
controversial) use of intravenous inotropic drugs in selected patients with AHF.
As with chronic heart failure, more recent attention has increasingly focused
on the role of various neurohormonal
pathways (such as the renin-angiotensinaldosterone system, inflammatory cytokines, and natriuretic peptides), the peripheral vasculature, and interactions with
other organ systems (such as the kidney)
in attempting to understand the pathogenesis of AHF (5, 10). Still, hemodynamic considerations have remained
prominent. Here we review the evidence
supporting the use of inotropic agents in
patients with AHF, the mechanisms of
action of available agents, and the development of novel agents with inotropic
properties.
Which Patients With AHF
Should Receive Inotropes?
Based on data from the Acute Decompensated Heart Failure National (ADHERE)
Registry, 9.6% of patients hospitalized for
AHF in the United States receive therapy
with an intravenous inotrope (either milrinone or dobutamine) (11). Patients in
ADHERE treated with inotropic agents
tended to have a clinical profile associated with more severe disease, including
lower blood pressure, lower ejection fraction, and higher blood urea nitrogen (11).
Is 10% an appropriate utilization of inotropes in a broad population of AHF patients?
Given the adverse outcomes seen with
inotropic therapy when given chronically
to heart failure patients, justification for
inotropic therapy in AHF must be based
on data supporting the ability of inotropes to achieve important therapeutic
goals that cannot be met by other, safer
therapies. As noted previously, two shortterm goals of therapy can be defined in the
initial management of AHF syndromes:
1. Rapid relief of symptoms (typically
dyspnea) by resolution of congestion
2. Maintenance or restoration of adequate end-organ perfusion and
function
Next, we outline the data addressing
the extent to which inotropes address
these two short-term goals of therapy in
specific patient subtypes.
Crit Care Med 2008 Vol. 36, No. 1 (Suppl.)
Inotropes in Patients Without
Clinical Hypoperfusion
Data from large multicenter registries
support the idea that the majority of patients presenting with AHF have congestion/volume overload, with relatively preserved end-organ function, normal to
elevated blood pressure, and no clinical
evidence of shock (3–5). This clinical profile includes patients with both impaired
and preserved ejection fraction and probably accounts for ⬎70% of all AHF hospitalizations, although it may be less
common in tertiary care centers where
advanced disease is more prevalent (5).
Since these patients generally have preserved end-organ function, there is little
rationale for improving end-organ perfusion with inotropic therapy. Since the
main symptom complex of this group of
patients involves symptoms of dyspnea
and congestion, the primary question in
considering inotropic therapy in such patients is “Do inotropes lead to more rapid
resolution of symptoms/relief of congestion or earlier discharge?” In contrast to
many areas of AHF therapy, the use of an
inotropic agent in this patient population
has been evaluated in a placebo-controlled, double-blind randomized clinical
trial, the Outcomes of a Prospective Trial
of Intravenous Milrinone for Exacerbation of Chronic Heart Failure (OPTIMECHF) study (12). OPTIME-CHF randomized patients with AHF who were not
believed to have a clinical indication for
inotropic therapy (i.e., patients without
evidence of inadequate end-organ perfusion) to 48 hrs of milrinone infusion or
placebo. The proposed benefit of inotropes in this population was that inotropic therapy might speed the resolution of
acute symptoms, facilitate diuresis, and
enable treatment with higher doses of
chronic neurohormonal antagonists,
such as angiotensin-converting enzyme
inhibitors. It was hypothesized that these
effects would decrease length of stay and
rehospitalization for heart failure. At the
time the OPTIME-CHF therapy was designed, use of intravenous milrinone to
achieve these putative benefits was increasingly common in the management
of AHF in the United States.
Review of baseline characteristics of
the patients enrolled in the OPTIME
study suggests that the trial was generally
successful in enrolling a target population representative of most patients with
AHF, with a normal mean blood pressure
(120/71 mm Hg) and little evidence of
end-organ dysfunction (mean creatinine
1.5 mg/dL in the placebo group and 1.4
mg/dL in the treatment group). The primary end point of OPTIME was total
number of days hospitalized for cardiovascular causes or within 60 days of randomization. For the purposes of this end
point, patients who died during follow-up
were considered as hospitalized for the
days they were deceased. This end point
was chosen based on the hypothesis that
milrinone therapy would decrease the
length of stay of the index hospitalization
and potentially limit rehospitalization.
The primary end point did not differ significantly between those randomized to
milrinone and those to placebo (median
of 6 days for milrinone vs. 7 days for
placebo, p ⫽ .71). Other important secondary end points, such as the proportion
of patients reaching target doses of angiotensin-converting enzyme inhibitor
therapy, did not differ between the treatment groups. Mortality at 60 days (10.3%
for milrinone vs. 8.9% for placebo, p ⫽
.41) and 60-day rates of death or rehospitalization (35.0% for milrinone and
35.3% for placebo, p ⫽ .92) were similar
between the groups. Randomization to
milrinone was associated with more adverse events, with significantly higher incidence of atrial fibrillation or flutter
(4.6% vs. 1.5%, p ⫽ .004) and hypotension (10.7% vs. 3.2%, p ⬍ 0.001). Post
hoc secondary analyses of the OPTIME
data have suggested that the harmful effects of milrinone were primarily seen in
those patients with an ischemic etiology
of heart failure, potentially due to adverse
consequences of milrinone on myocardial
oxygen demand or to arrhythmogenesis
(Fig. 1) (13). Taken as a whole, the OPTIME
data strongly suggest that the routine use
of inotropes in patients without evidence
of impaired end-organ perfusion is not
indicated in AHF. Since such patients
represent the majority of AHF patients in
the United States, these data suggest a
limited role for inotropic therapy in AHF
management.
Inotropes in Patients With
Clinical Hypoperfusion
As noted previously, patients with
clinical evidence for end-organ hypoperfusion or shock are a minority of patients
hospitalized for AHF (probably ⬍10%).
This hemodynamic profile, often referred
to as a low output state, represents a very
high-risk group with significant shortterm mortality (14). Classically, hypotenS107
(%)
50
45
40
35
30
25
20
15
10
5
0
Placebo
Milrinone
Ischemic
Non-Ischemic
Figure 1. Rates of death or rehospitalization at 60 days stratified by heart failure etiology and treatment
assignment in the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbation of
Chronic Heart Failure (OPTIME-CHF) study. p ⫽ .01 for etiology ⫻ treatment interaction.
sion has been considered a powerful predictor of low output states, and lower
systolic blood pressure on admission has
consistently been shown to be a very powerful predictor of adverse outcomes in
AHF (15, 16). Importantly, however, clinical exam findings may be inaccurate in
identifying patients with low output
states, and not all such patients present
with hypotension (17). Particularly in patients with long-standing chronic heart
failure, low output states may be associated with more subtle clinical signs, such
as abdominal pain, nausea, fatigue, and
slowed mentation (18). A common clinical finding often believed to be suggestive
of marginal or impaired end-organ perfusion is worsening renal function, a finding that often occurs after initiation of
AHF treatment with intravenous loop diuretics (so-called cardiorenal syndrome)
(19). Although cardiorenal syndrome traditionally was thought to be related to
low cardiac output states, more recent
data have suggested a much more complex pathophysiology for cardiorenal syndrome, and many such patients appear to
have a relatively preserved cardiac output
and hypertension (20). Although the results of the ESCAPE trial (21) do not
support the routine use of invasive monitoring in AHF, pulmonary artery catheterization may be helpful in distinguishing which patients with low output states
may be amenable to treatment with inotropes.
In general, inotropic drugs appear effective in increasing cardiac output and
improving end-organ perfusion in patients with AHF and diminished cardiac
output. The utility of inotropic therapy in
restoring end-organ perfusion in these
patients is based primarily on clinical experience rather than randomized clinical
trial data, given the difficulty in performing randomized clinical trials in this very
sick group of patients. Other drugs, such
as vasodilators, may also be effective in
S108
this clinical scenario and may not be associated with some of the adverse effects
of inotropes. Some efforts have been
made to directly compare outcomes with
vasodilators and inotropes using observational data from large registries, although such analyses are highly confounded by indication (i.e., physicians
tend to use inotropic agents in patients
with more severe disease). Even after sophisticated statistical adjustment (such
as with propensity analysis) for baseline
differences, the possibility of unmeasured
confounders substantially weakens this
type of analysis. Given these caveats, data
from the ADHERE registry do suggest
worsened outcomes with inotropic drugs
compared with vasodilator therapy in
AHF patients treated with intravenous vasoactive medications (11). In general, use
of vasodilators in this population of patients is often limited by hypotension and
may require invasive hemodynamic monitoring in an intensive care setting to be
done safely. In patients with significant
hypotension, even traditional inotropes,
such as milrinone or dobutamine, may be
poorly tolerated due to their vasodilatory
effects, and peripherally acting agents,
such as dopamine, may be transiently required to support the blood pressure during the initiation of inotropic therapy in
patients with severe hypotension and cardiogenic shock.
If inotropic drugs are used in AHF
patients, these agents should be seen as
the initial phase of treatment, leading to
hemodynamic stabilization and restoration of adequate organ perfusion. If inotropic therapy is not sufficient to restore
hemodynamic stability, adjunctive mechanical support (such as with an intraaortic balloon pump) may be required
and may be useful even in patients with
nonischemic cardiomyopathy. Once
short-term hemodynamic stabilization is
achieved, an important goal of therapy
should be to identify a strategy for tran-
sitioning the patient off of inotropic support. This ultimate “destination” for a
given patient depends on the clinical scenario. In patients in whom the pathophysiology of hemodynamic compromise
is related to potentially reversible insults
(such as acute myocardial infarction or
fulminant myocarditis), inotropic therapy can serve as a bridge to more definitive therapy (such as revascularization)
or recovery. In patients without obvious
reversible causes, inotropic therapy can
stabilize the patient sufficiently to consider the suitability of other treatments,
such as cardiac transplantation or ventricular assist device therapy. In a small
number of end-stage patients in whom
other therapies are not appropriate,
chronic intravenous inotropes may be
considered as a palliative option as part of
end-of-life care. In sum, use of intravenous inotropes in patients with AHF
should be limited to short-term treatment of patients with clinical evidence of
impaired end-organ perfusion, with a
goal or restoring hemodynamic stability
and end-organ function.
Choice of Inotropes
Mechanism of Action. The most commonly used intravenous inotropes for the
management of AHF are dobutamine and
milrinone. Both agents increase contractility by increasing intracellular levels of
cyclic adenylate monophosphate (cAMP),
although they affect cAMP by differing
mechanisms. Elevated levels of cAMP
lead to increased calcium release from
the sarcoplasmic reticulum and increased
force generation by the actin-myosin apparatus, with a resulting increase in cardiac contractility. In addition to increasing contractile function, the elevated
levels of intracellular calcium resulting
from cAMP increases may partially explain the side effects of these agents, especially arrhythmogenesis. Dobutamine
increases cAMP production by ␤-adrenergic-mediated stimulation of adenylate cyclase, which leads to cAMP production.
Phosphodiesterase (PDE) inhibitors, such
as milrinone, increase cAMP levels by
blocking the enzyme that breaks down
cAMP.
Hemodynamic and Clinical Effects.
Milrinone and dobutamine have similar
hemodynamic effects with some potentially important differences (Table 1)
(22). Both agents lead to similar increases in cardiac output and decrease
cardiac filling pressures, although milriCrit Care Med 2008 Vol. 36, No. 1 (Suppl.)
Table 1. Effects of dobutamine and milrinone on systemic and coronary hemodynamics
Dobutamine
Milrinone
CI
HR
LVEDP
MPAP
PVR
SAP
SVR
CSBF
MOC
1
1
_
1
2
+
2
+
2
+
2/1
2
2
+
1
7
1
7
CI, cardiac index; HR, heart rate; LVEDP, left ventricular end-diastolic pressure; MPAP, mean
pulmonary artery pressure; PVR, pulmonary vascular resistance; SAP, systemic arterial pressure; SVR,
systemic vascular resistance; CSBF, coronary sinus blood flow; MOC, myocardial oxygen consumption.
none appears to lower filling pressures to
a greater degree than does dobutamine.
Milrinone has more significant vasodilatory effects than dobutamine (it is often
termed an inodilator), leading to a
greater decrease in systemic vascular resistance and systemic blood pressure
than is seen with dobutamine. Although
both agents can cause tachycardia, dobutamine in general leads to higher heart
rates (due to its effects on ␤-adrenergic
receptors) than milrinone. Both agents
increase myocardial oxygen demand, although dobutamine appears to do so to a
greater extent than milrinone.
Clinically, there are no high-quality
randomized data directly comparing the
efficacy of milrinone and dobutamine in
patients with AHF. A retrospective analysis of 329 patients admitted with AHF
compared the hemodynamic and clinical
effects of milrinone vs. dobutamine (23).
In this study, there were no differences in
baseline characteristics or hemodynamic
profiles between the two treatment
groups, except for a higher mean pulmonary arterial pressure in the milrinone
group (47 mm Hg vs. 42 mm Hg, p ⬍
.001). As compared with dobutamine,
milrinone did lead to lower systemic vascular resistance (p ⫽ .01), lower pulmonary artery occlusion pressure (p ⬍ .001),
and a larger change in the percentage
increase of cardiac index (p ⫽ .03), percentage decrease in pulmonary vascular
resistance (p ⫽ .0001), and percentage
decrease in mean pulmonary artery pressure (p ⫽ .002). Despite the more favorable hemodynamic response in patients
treated with milrinone, there was no statistically significant difference in the inhospital mortality rates between those
treated with milrinone (7.8%) or dobutamine (10%) in this small study. The cost
of drug was significantly higher in the
milrinone group compared with the dobutamine group ($1855 vs. $45, p ⬍
.0001). This cost imbalance, which was
primarily related to the costs of the drugs
themselves, would be much more comparable between the two therapies today
Crit Care Med 2008 Vol. 36, No. 1 (Suppl.)
Table 2. Preferred inotrope in different clinical
settings
Clinical Setting
Increased pulmonary
artery pressure
Need for ␤-blockade
Hypotension
Renal insufficiency
Preferred
Inotrope
Milrinone
Milrinone
Dobutamine
Dobutamine
due to the availability of generic milrinone.
In clinical use, hemodynamic differences may influence the choice of one
agent or the other for a given patient
(Table 2). Due to its greater vasodilator
activity, milrinone may be preferred in
patients with very elevated filling pressures, in particularly those patients with
elevated pulmonary artery pressures.
This may be a particular issue for patients
being listed for cardiac transplantation,
where elevation of pulmonary vascular
resistance is a strong relative contraindication to transplantation. Conversely, the
use of milrinone may be limited in patients with low blood pressure due to its
greater tendency to cause hypotension.
The initial hypotensive effect of milrinone may be blunted by beginning at very
low infusion rates (0.125 ␮g/kg/min
without a bolus). Because it works independently of ␤-adrenergic receptor activation, milrinone retains its hemodynamic effects in the setting of ongoing
␤-blocker therapy. Indeed, some data
have suggested more potent hemodynamic effects for milrinone with ongoing
␤-blockade (24). Because milrinone has a
relatively long half-life (ⵑ4 – 6 hrs) and is
renally cleared, caution must be used
with prolonged milrinone therapy in patients with abnormal or changing renal
function. Both milrinone and dobutamine increase myocardial oxygen demand and therefore may exacerbate myocardial ischemia. Although dobutamine
leads to more sinus tachycardia, both
agents carry a significant risk of atrial
and ventricular arrhythmias, presumably
related to increases in intracellular calcium levels (25, 26). It has also been
suggested that inotropes may have direct
toxicity to the myocardium. Multiple
studies have established the adverse association between elevation of circulating
catecholamines and outcomes (27). Indirect data have suggested that exposure to
inotropic agents may lead to greater myocardial dysfunction after these agents are
discontinued, particularly in those patients with ischemic substrate (28, 29).
Newer Inotropes
Levosimendan. Despite the limitations of available inotropes, there have
been substantial efforts to develop agents
that improve cardiac contractility without the adverse consequences of currently available agents. Levosimendan,
which has been approved for use in treatment of AHF in Europe, has a primary
mechanism of action that differs from
that of the ␤-agonists and PDE inhibitors. It is a calcium sensitizer that stabilizes
the conformational change in troponin
C when it binds to calcium, facilitating
myocardial cross-bridging and thus improving contractility (30). At higher
doses, levosimendan also inhibits PDE,
similar to other PDE inhibitors, such as
milrinone. Finally, levosimendan has vasodilator effects through its action on
adenosine triphosphate-sensitive potassium channels.
Hemodynamic studies of levosimendan in normal volunteers and in patients
with heart failure demonstrate its ability
to increase cardiac output and lower ventricular filling pressures in a dosedependent manner (31, 32). At therapeutic doses, levosimendan does not appear
to have significant effects on myocardial
oxygen consumption (33).
A phase II study of levosimendan in
low-output heart failure, the Levosimendan Infusion or Dobutamine (LIDO)
study, randomized 203 patients with AHF
who were believed to require invasive hemodynamic monitoring and an inotropic
agent (34). Patients were randomized to a
24-hr continuous infusion of levosimendan (24 mg/kg bolus followed by 0.1 mg/
kg/min) or dobutamine (5 mg/kg/min),
with a primary end point of the proportion of patients with hemodynamic improvement (defined as a ⱖ30% increase
in cardiac output and a ⱖ25% decrease in
pulmonary artery occlusion pressure at
24 hrs). A greater proportion of patients
S109
in the levosimendan group than in the
dobutamine group achieved the primary
end point (p ⫽ .022). In this study population, ␤-blockade did not attenuate the
favorable hemodynamic effects of levosimendan. Those in the levosimendan
group had a greater median number of
days alive out of hospital and improved
mortality through the first 180 days compared with the dobutamine group. Another phase II investigation in patients
with acute myocardial infarction, the
Randomized Study on Safety and Effectiveness of Levosimendan in Patients
with Left Ventricular Failure after an
Acute Myocardial Infarct (RUSSLAN)
trial, also suggested that levosimendan
reduced mortality and worsening heart
failure in patients with AHF and myocardial infarction (35). These initial promising data led to the development of the
REVIVE and SURVIVE phase III studies.
Data from the phase III REVIVE and
SURVIVE studies have been presented but
not yet published. The REVIVE program
randomized 600 patients with AHF and
left ventricular systolic dysfunction to a
24-hr infusion of levosimendan or placebo (36). REVIVE used a unique clinical
composite end point, which evaluated the
clinical status at 6 hrs, 24 hrs, and 5 days
after randomization. The primary end
point was the proportion of patients classified as improved at 5 days. This end
point was significantly improved by treatment with levosimendan, with 33% more
patients in the levosimendan group improving and 30% fewer of them worsening compared with the control group
(p ⫽ .015 for both differences). Despite
the positive results with regard to the
primary end point, potentially significant
safety concerns were associated with levosimendan, including a trend toward increased mortality at 90 days (15.1% vs.
11.6% for placebo) and increased rates of
hypotension and ventricular arrhythmias.
The SURVIVE study compared levosimendan directly with dobutamine in patients with AHF due to left ventricular
dysfunction and a clinical indication for
inotropic therapy (36). In SURVIVE,
1,327 patients were randomized to infusion of dobutamine or levosimendan,
with a primary end point of all-cause
mortality at 6 months. There was no significant difference in the primary end
point between levosimendan (26% mortality) and dobutamine (28% mortality,
hazard ratio ⫽ 0.91, p not significant).
The phase III levosimendan experiS110
ence suggests that levosimendan appears
to improve symptoms more than placebo
in AHF (based on REVIVE) but with worrisome trends toward greater adverse
events and mortality (compared with placebo). Based on SURVIVE, levosimendan
appears to have similar mortality risk to
dobutamine in patients with AHF and a
clinical indication for inotropic therapy.
Levosimendan is currently approved for
use in AHF in Europe but not in the
United States. Future development of this
agent in the United States remains uncertain.
Cardiac Myosin Activators. Given the
impairment in cardiac contractile function that is a fundamental feature of the
heart failure syndrome, efforts to develop
inotropic agents with more favorable
safety profiles continue. Recently, insights into the molecular machinery of
cardiac contraction have led to the development of a new class of small molecules
that work by altering the relationship between actin and myosin. These agents,
termed cardiac myosin activators, directly target myocardial myosin adenosine triphosphatase. By increasing the efficiency of actin-myosin cross-bridge
formation, these agents may be able to
improve contractility without affecting
intracellular calcium concentrations. A
family of small-molecule myosin activators has been extensively evaluated in animal models, and one drug candidate
(CK1827452) has recently begun clinical
development in humans with heart failure. Animal data from this agent suggest
that it is able to increase the duration of
systolic ejection (and therefore the stroke
volume) without direct effects on intracellular calcium cycling, myocardial oxygen consumption, the sympathetic nervous system, or PDE activity (37, 38).
This appears to result in a significant
increase in myocardial efficiency (i.e.,
greater amount of external work without
an increase in energy consumption).
Such an agent may possibly allow the
clinical benefits of increasing cardiac
contractility without the costs in terms of
myocardial oxygen demand and arrhythmogenesis. Initial human studies of this
potentially promising new agent have recently been reported (39, 40).
CONCLUSION
AHF is a common, highly morbid condition, with few effective, evidence-based
therapies. This situation may explain the
persistent use of inotropes in a significant
minority of patients who are hospitalized
with AHF (41). For the majority of patients with AHF, with normal systemic
blood pressure and no clinical evidence of
hypoperfusion, there are no data to support a role for inotropic therapy. Although inotropes are often used in patients who develop the cardiorenal
syndrome, available data do not support
the effectiveness of this therapy, and indeed the emerging profile of patients with
cardiorenal syndrome is not generally
consistent with a low output state. Inotropic therapy continues to have a role in
the short-term stabilization of patients
with clear evidence of impaired organ
perfusion and low output state. If inotropic therapy is required, selection of a specific agent may depend on aspects of the
clinical profile of the patient, including
systemic blood pressure, underlying substrate (ischemic vs. nonischemic), and renal function. Despite the lack of general
success with inotropic therapy in heart
failure, efforts continue to develop novel
agents that will realize the potential clinical benefits of increased contractility,
but without the costs in terms of arrhythmogenesis and myocardial oxygen consumption.
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