The current and future managment of ahf

CLINICAL REVIEW
Frontiers in cardiovascular medicine
The current and future management of acute
heart failure syndromes
Peter S. Pang1,3, Michel Komajda2, and Mihai Gheorghiade3*
1
Department of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2
Department of Cardiology, Hopital Pitie-Salpetriere and University
Pierre et Marie Curie, Paris, France; and 3
Center for Cardiovascular Quality and Outcomes, Department of Medicine, Northwestern University, Feinberg School of Medicine, 645 N
Michigan Ave, Suite 1006, Chicago, IL 60611, USA
Received 12 January 2010; accepted 2 February 2010; online publish-ahead-of-print 5 March 2010
Hospitalization for heart failure (HF) marks a substantial crossroad for patients, as greater than one-third will be re-hospitalized or dead
within 90 days post-discharge. For patients with chronic HF who present with acute heart failure syndromes (AHFS), they transition
from an arena of well-established and life-saving evidence-based therapies to one where early pharmacological management has
changed little over the last 40 years. Traditional therapies, such as oxygen, loop diuretics, nitrates, and morphine remain the cornerstone
of early management today. Despite earlier initiation of chronic HF therapies during hospitalization, post-discharge event rates remain
high. Optimizing management of known targets with proven evidence-based therapy has the potential to reduce post-discharge event
rates. In this inaugural issue of the Frontiers in Cardiovascular Therapy, we briefly review current in-hospital management of AHFS, introduce
the concept of cardiac reconstruction, and focus on the potential of future management strategies and therapeutics to improve outcomes
in AHFS.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Acute heart failure syndromes † Management
Introduction
Hospitalization for heart failure (HF) marks a substantial crossroad for
patients, as greater than one-third will be re-hospitalized or dead
within 90 days post-discharge.1
For those patients with chronic HF,
it represents a transition from an arena of well-established and life-
saving evidence-based therapies to one where early pharmacological
management has changed little over the last 40 years.2
Traditional
therapies for acute heart failure syndromes (AHFS), such as oxygen,
loop diuretics, nitrates, and morphine remain the cornerstone of
early management today.2,3
Despite earlier initiation of evidence-
based chronic HF therapies during hospitalization, post-discharge
re-hospitalization and mortality event rates remain high.1,3,4
Such high post-discharge event rates represent a societal burden
giventhe numberofpatientswhopresentwithAHFSandthe resultant
cost.
In the USA, over one million hospitalizations occur each year for
HF, an increase of over 175% in the last 25 years.5,6
These hospi-
talizations account for the bulk of the 39 billion USD spent each
year for HF care.6
Similar rates of hospitalization occur in the
countries represented by the European Society of Cardiology
(ESC), although with geographical variations in the length of stay,
re-hospitalization rates, and in-hospital mortality.4,7,8
Although
the incidence of first hospitalization for HF appears to be decreas-
ing,9
it is projected that the overall numbers of patients who
present with HF will increase, due to the ageing of the population,
combined with those living longer due to advances in cardiovascu-
lar disease management.5,10
The cost of hospitalization in terms of
human life is grim: death occurs in 25–35% of patients within 1
year of hospitalization and this risk increases substantially with
each subsequent hospitalization.11 –15
There is a clear need to improve outcomes for patients who
present with AHFS. Although progress has been made in terms
of characterizing the AHFS patient, there remains limited evidence
linking hospital management with reduced post-discharge event
rates.16
In this inaugural issue of the Frontiers of Cardiovascular
Therapy, we briefly review current in-hospital management of
AHFS and discuss the potential of future interventions and strat-
egies to improve outcomes.
* Corresponding author. Tel: þ1 312 695 0051, Fax: þ1 312 695 1434, Email: m-gheorghiade@northwestern.edu
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: journals.permissions@oxfordjournals.org.
European Heart Journal (2010) 31, 784–793
doi:10.1093/eurheartj/ehq040
byguestonNovember14,2013http://eurheartj.oxfordjournals.org/Downloadedfrom

Definition and classification
Acuteheart failure syndromes have been definedasthe new onset or
recurrence of gradual or rapidly worsening signs and symptoms of
HF requiring urgent or emergent therapy.7,17
The vast majority of
patients present with congestion, however heterogeneity of under-
lying cardiac and non-cardiac co-morbidities and phenotypic vari-
ations in clinical presentations is a hallmark of patients with AHFS.18
Multiple AHFS classification schemes have been previously pro-
posed based on patients’ clinical presentation or past
history.17,19,20
The ESC divides patients into six clinical profiles:
(i) worsening or decompensated chronic HF, (ii) pulmonary
oedema, (iii) hypertensive HF, (iv) cardiogenic shock, (v) isolated
right HF, (vi) ACS and HF, with the explicit acknowledgement
that there is overlap between groups.7
The ACCF/AHA divides
patients based on presenting clinical profile into three main
groups: (i) volume overload, manifested by pulmonary and/or sys-
temic congestion, usually due to increases in blood pressure (BP),
(ii) severely reduced cardiac output often with hypotension, and
(iii) combined volume overload and cardiogenic shock.21
Another schema accounts for both historical and structural fea-
tures, classifying patients as follows: worsening chronic HF (75%),
de novo or new onset (20%), and advanced or refractory HF
(5%).17,22
These patients may present with high, normal, or low
BP, with reduced or preserved systolic function, and with or
without coronary artery disease (CAD).22
We propose a classification framework utilizing the ACCF/AHA
stages of development of HF (Table 1)21
, which outlines thera-
peutic goals and options based on cardiac structure and/or func-
tion. In addition, clinical profiles, as defined by the ESC
guidelines, will represent further discriminating factors. Patients
with de novo HF would be classified as Stage A or B ACCF/AHA
class. Patients with worsening chronic HF or end-stage HF would
be ACCF/AHA Stage C or D. Whether management by profile
or classification or combined leads to improved outcomes requires
further research.
Pathophysiological concepts
related to future management
The main reasons for admission and readmission in AHFS are
related to pulmonary and systemic congestion, rather than a low
cardiac output. Yet our current understanding of the pathophysiol-
ogy of AHFS is incomplete. An analogy to acute coronary syn-
drome (ACS) will be used as an illustrative example.
In ACS, symptoms of chest discomfort occur with various
clinical profiles (i.e. hypertensive, normotensive, or hypotensive,
complicated by AHFS, etc.) with different electrocardiographic
presentations [e.g. ST-elevation myocardial infarction (STEMI),
ST-depressions, etc.]. The underlying pathophysiology is related to
the rupture of an atherosclerotic plaque causing acute intravascular
thrombosis (the ‘clot’) leading to ischaemia and myocyte necrosis.
In AHFS, patients most commonly present with dyspnoea or
breathlessness with variable clinical profiles. The pathophysiology
may be dominated by a single precipitating or aetiological mechan-
ism or by multiple ‘clots,’ (e.g. hypertension, neurohormonal acti-
vation, myocardial dysfunction, arrhythmias, valvular disease, ACS,
reduced systolic function, etc.) with the resulting pathophysiological
process of increased pulmonary capillary wedge pressure (PCWP)
and/or low cardiac output. A unifying pathophysiological construct
encompassing all AHFS presentations has not yet been determined.
The apparent uncoupling of symptom improvement to out-
comes not only highlights a management paradox, but suggests
that altering symptoms does not appear to affect the pathophysiol-
ogy which relates to outcomes. Patients with the most severe pres-
entation, flash pulmonary oedema, appear to do well
post-discharge. In contrast, those with severe chronic HF may
have a less dramatic presentation (e.g. worsening fatigue) and by
comparison appear less acutely sick, yet have a much worse prog-
nosis. Current therapies make patients feel better, yet in spite of
hospital use of evidence-based therapies such as angiotensin-
converting enzyme inhibitors (ACE-I) or beta-blockers, the post-
discharge event rate remains high.
Importantly, only a small percentage of all HF patients have
advanced or end-stage HF, defined as persistent signs and symp-
toms despite maximal medical, surgical, and electrical therapy.17
Short of transplantation or other novel discoveries, the prognosis
for these patients remains grim. For the remaining patients who
comprise the vast majority of AHFS presentations, preserving or
safely improving myocardial function, the concept of cardiac
‘reconstruction’ may be critical to improve outcomes in the future.
As the pathophysiology of AHFS has been extensively reviewed
elsewhere,7,23
we focus on specific pathophysiological concepts
related to preservation and/or restoration of cardiac function,
myocardial injury, the importance of CAD, viability, metabolic
modulation, as well as renal function.
Myocardial injury
Acute heart failure syndromes are associated with elevated serum
troponin levels, which may represent myocyte injury, even when
ACS is not suspected. However, troponin release occurs in only
...............................................................................................................................................................................
Table 1 Proposed classification for patients who present with acute heart failure syndromes
ACCF/AHA stage Explanation of stage
Worsening chronic HF (75%) Stage C C: structural heart disease with prior or current symptoms of HF
Advanced HF (5%) Stage D D: refractory HF requiring specialized interventions
De novo HF (20%) Stage B most common, but also Stage A B: structural heart disease but without signs or symptoms of HF
Also neither A nor B A: at high risk for HF but without structural heart disease or symptoms of HF
Reconstructing the failing heart 785

a small percentage of patients admitted with AHFS.24,25
Troponin
release is associated with worse outcomes. Subsequently, myocar-
dial injury has been suggested to accelerate the progression of
heart failure.25 – 27
The mechanisms to explain troponin release
have not been fully elucidated, however, preventing myocyte
injury may be an important target for future management.
Coronary artery disease
Approximately 60% of AHFS patients have underlying CAD and
have a worse prognosis.3
They may present with ACS complicated
by AHFS or more commonly with AHFS and underlying CAD.28
Despite the prevalence of CAD in AHFS, whether management
should change based on the presence of CAD in AHFS has not
been well studied.28
Retrospective analysis suggests an association
between revascularization and improved outcomes.29
Given the
known effectiveness of therapies for CAD in general, CAD in
AHFS may be an important target.
Viable but dysfunctional myocardium
In patients with systolic dysfunction, the majority of patients have
viable but dysfunctional myocardium, which may be potentially sal-
vagable.30
Most commonly recognized in patients with underlying
CAD, described as hibernating myocardium due to chronic ischae-
mia, a significant number of HF patients without CAD also have
viable but dysfunctional myocardium. Even in CAD patients,
viable but dysfunctional myocardium may not always be related
to chronic ischaemia. Although there are multiple reasons for
viable but dysfunctional myocardium, such as excessive sympath-
etic stimulation or micronutrient deficiencies, this represents an
important target for restoring contractility as well as prevention
of further myocardial loss.31 – 36
When properly identified and
measured, revascularization and beta-blocker therapy will restore
function in the area of viable but non-contractile myocardium
due to ischaemia or metabolic reasons, respectively.30,31,33
Importantly, in patients with severe systolic dysfunction hospital-
ized for HF, the extent and severity of viable but dysfunctional
myocardium may divide patients in two groups; those with salvage-
able myocardium vs. those in whom myocardial function cannot be
improved. However, the presence, extent, and causes of viable but
dysfunctional myocardium in patients with reduced systolic func-
tion have not been well studied and remain an important area
for further investigation.
Metabolic factors contributing to left
ventricular dysfunction
The heart pumps over 7000 L of blood a day, utilizing more than
6 kg of adenosine tri-phosphate (ATP) to fuel this activity. The
heart also renews its protein components every 30 days.36
There-
fore, it is not surprising that the heart’s metabolic needs are enor-
mous. This creates the potential for a mismatch between energy
consumption and energy production. Inadequate or improper util-
ization of energy has been suggested to contribute to the patho-
physiology of HF.37 –39
Briefly, metabolism of free fatty acids and
glucose allows for the generation of ATP, which is utilized by myo-
cytes to power mechanical contraction. Lack of appropriate
substrate to convert to energy, impaired metabolism of existing
substrate or fuel, and/or dysfunctional utilization of released
energy represent multiple pathophysiological processes.37,38
Current inotropes are a therapeutic example of misapplied
energetics:short-term cardiac performance is improved, however,
the mismatch between supply and demand may lead to myocardial
injury.37
Agents that stimulate the heart without addressing cardiac
metabolism may be one reason why certain haemodynamic agents
have been associated with neutral or worse outcomes. Addressing
cardiac metabolism, or energetics, is emerging as an important
future target for intervention.
Renal impairment
Renal impairment at time of admission (defined as glomerular fil-
tration rate ,60 mL/min/1.73 m2
) is common in AHFS.40
A
wealth of data have shown that baseline renal impairment as well
as worsening renal function (WRF) during AHFS hospitalization
are independent predictors of mortality.40 – 43
Pathophysiological
investigations have indicated a strong interdependence between
myocardial and renal function, which is at least in part mediated
by neurohumoral and haemodynamic factors. The existence of a
cardiorenal syndrome (CRS) has therefore been postulated to
explain the abnormalities in renal function often observed in
patients with AHFS. Even if progress is being made, a universally
accepted definition of CRS has not yet been established,44
reflect-
ing the heterogeneity of pathophysiological processes that lead to
WRF. Importantly, WRF may occur despite clinical improvement.
Worsening renal function may be medication related (i.e. ACE-I),
reflect intravascular dehydration due to high diuretic use, due to
venous congestion with decreased or preserved cardiac output,
or a combination of all three.44 –46
As a result, treatment may
require specific targeting (e.g. venous congestion). Although
renal function is a major predictor of prognosis, it is not clear
whether addressing renal function alone without improving the
‘pump’ will be sufficient to substantially improve outcomes.
The concept of cardiac reconstruction
The traditional view of HF is as a progressive and irreversible
process, despite only a small proportion of HF patients with end-
stage HF. Many patients have potentially correctable causes that if
treated per established guideline recommendations, such as valvu-
lar disease, obstructive CAD, and ventricular dyssynchrony, may
improve or restore cardiac function. Preventing myocardial
injury, optimizing metabolism, and preservation of renal function
represent other possible targets. Determining the extent of
viable myocardium is an objective way to delineate patients with
salvageable myocardium, since its present in the majority of
patients with reduced ejection fraction. Identifying potential
‘responders’ to therapy will be important to tailor future manage-
ment to restore cardiac function.
Acute heart failure syndromes
management—phases of care
There are two primary phases of AHFS care, which may be further
subdivided (Table 2). Phase I is the stabilization phase, which com-
monly begins in the emergency department (ED). Safely improving
P.S. Pang et al.786

signs and symptoms, haemodynamics, and correction of volume
overload are the primary goals. Phase II continues with stabilization
during hospitalization and continues into the post-discharge period.
The primary goal is to prevent progression, recover cardiac function
or even reconstruct the heart through focused implementation of
evidence-based guidelines.
Stabilization phase of acute heart failure
syndromes
Identify and treat life-threatening conditions
Airway management, support of breathing, and circulatory support
remain the cornerstone of initial resuscitative efforts and may be
necessary in dramatic presentations of AHFS (e.g. flash pulmonary
oedema or cardiogenic shock). Other life threatening conditions
requiring timely intervention, such as ST-elevation MI, malignant
arrhythmia, or hypertensive emergency should be promptly ident-
ified and treated. Treatment and diagnosis often proceeds in parallel.
Diagnosis of heart failure
Diagnosis of HF is made clinically. A thorough history, assessment
of symptoms, and physical exam for signs of HF (JVD, s3, rales, per-
ipheral oedema) should be carefully performed. Radiographic evi-
dence of pulmonary congestion may aid in diagnosis as well as
rule in or rule out other diagnoses (e.g. pneumonia). However,
absence of radiographic pulmonary congestion does not exclude
a high filling pressure in patients with chronic HF.47
Measurement
of natriuretic peptide levels in conjunction with the clinical
impression is helpful when the diagnosis is in question.48
Determine and treat the clinical profile
The clinical profile prompts initial management (Figure 1 and
Table 3). Whether short- or long-term outcomes are improved
as a result of initial management requires further study. In patients
with elevated BP, proportional greater use of nitrate therapy with
lower dose diuretic therapy vs. low-dose nitrates and high-dose
diuretics has been suggested to improve outcomes.49
Improvement of LV filling pressures and/or cardiac output, leading
to symptomatic improvement are goals of early management.
...............................................................................................................................................................................
...............................................................................................................................................................................
...............................................................................................................................................................................
Table 2 Phases of acute heart failure syndromes management
PHASES GOALS Available Tools
Initial or emergency
department phase of
management
Treat life threatening conditions Examples: STEMI ! reperfusion therapy
Establish the diagnosis History, physical exam, EKG, X-ray, natriuretic peptide level
Determine the clinical profile BP, HR, signs (e.g. pulmonary oedema), ECG, X-ray,
laboratory analysis, echocardiography
Identify and treat precipitant History, physical exam, X-ray, ECG, laboratory analysis
Disposition No universally accepted risk-stratification method
In-hospital phase Monitoring and reassessment Signs/symptoms, HR, SBP, ECG, orthostatic changes, body
weight, laboratory analysis (BUN/Cr, electrolytes),
potentially BNP
Assess right and left ventricular pressures SBP (orthostatic changes, valsalva manoeuvre),
echocardiography, BNP/NT-proBNP, PA catheter
Assess and treat (in the right patient) other cardiac and
non-cardiac conditions
Echo-Doppler, cardiac catheterization, electrophysiology
testing
Assess for myocardial viability MRI, stress testing, echocardiography, radionuclear studies
Discharge phase Assess functional capacity 6 min walk test
Re-evaluate exacerbating factors (e.g. non-adherance,
infection, anaemia, arrhythmias, hypertension) and
treat accordingly
Examples: physical therapy, education for diet control and
medication, evaluation for sleep apnoea
Optimize pharmacological therapy ACCF/AHA and ESC guidelines
Establish post-discharge planning Discharge instructions including body weight monitoring,
smoking cessation, medication adherance, follow-up
Adapted and reproduced with permission from Khan et al.67
Figure 1 Presenting clinical profiles. Reproduced with per-
mission from Dickstein et al., modified from Filippatos/Zannad
Heart Fail Rev (2007) 12:87–907
. AHF, acute heart failure, ACS,
acute coronary syndrome, HF, heart failure.

Symptom improvement, however, should not cause downstream
harm, such as myocardial or renal injury, decreased coronary per-
fusion, increased heart rate, and/or further neurohormonal acti-
vation.50–52
Carefulattentiontoheartrate,rhythm,andBPisessential.
Traditional medications such as loop diuretics and nitrates have
not been rigorously studied. Thus, dosing and goals of such thera-
pies remain largely empiric. Safely improving symptoms and hae-
modynamics during the stabilization phase of management
remains an unmet therapeutic need.
Identify and treat precipitating/contributing factors
According to data from the Euro Heart Failure Survey II, the
most common precipitants for AHFS differ between de novo
and worsening chronic HF admissions.8
For those with de novo
HF, ACS, valvular causes, and arrhythmias were the most
common precipitants. Arrhythmias and valvular causes were
also common precipitants for patients with decompensated
chronic HF, but medication non-compliance was more common
than ACS.8
Analysis from OPTIMIZE-HF highlight pneumonia/
respiratory process, ischaemia, and arrhythmias, as the most
common precipitants.53
Disposition
Evidence-based data to guide and facilitate risk-stratification/disposi-
tion after early management is lacking. Although the high-risk patient
has been characterized, absence of high-risk does not necessarily
equate to a low-risk patient.19,54 –58
Systolic BP may represent a
broadly applicable method to rapidly discriminate in-hospital mor-
tality risk.1
Initial studies support stratification of patients to the
observation unit setting (Figure 2).59
Current NHLBI funded
studies are exploring risk stratification from the ED.60
Role of the emergency department
Preliminary signals suggest the importance of early (e.g. ED) manage-
ment.19,61 – 63
Rapid and accurate diagnosis and management (e.g.
flash pulmonary oedema, malignant dysrhythmias, STEMI, etc.) is life-
saving. For the vast majority of patients who present with worsening
HF, a greater understanding of the early pathophysiology of AHFS is
Figure 2 In-hospital mortality rates by admission systolic blood pressure deciles (n ¼ 48 567). Reproduced with permission from JAMA,
296(18):2223. Copyright 2006. American Medical Association. All rights reserved.1
...............................................................................................................................................................................
Table 3 Initial therapeutic management
Target Therapeutic example Mechanism of action Side effects
Alleviate congestion IV furosemide Water and sodium excretion Electrolyte abnormalities
Reduce elevated LV filling
pressures
IV nitrates Direct relaxation of vascular smooth
muscle cells through various
mechanisms
Hypotension, decreased coronary
perfusion pressure
Poor cardiac performance Inotropes Activate camp or calcium sensitization
resulting in improved contractility;
also powerful vasodilators: in effect,
inodilators
Hypotension, arrhythmias, myocardial
damage, association with increased
morbid events
Tachycardia and increased
systemic blood pressure (i.e.
in cases of excessive
sympathetic tone)
Beta-blockers: IV esmolol may be
used when HF is related to AF
with RVR and/or severe
hypertension
Blockade of beta-1 and beta-2
receptors
Bradycardia, hypotension, negative
inotropy; however given short
half-life of esmolol, these side effects
should be short lived
Adopted and reproduced with permission from Khan et al.67
P.S. Pang et al.788

needed, including greater evidence regarding therapies used routi-
nely in daily practice. Whether AHFS management and outcomes
are time-sensitive is an area in need of further research.
Therapeutic management
As traditional AHFS therapies have been extensively reviewed
elsewhere (e.g. ESC Guidelines), we refer the reader to those
reviews/guidelines.7
Future management
Future management encompasses three primary domains: (i)
implementation of evidence-based therapy for HF and other
cardiac and non-cardiac conditions, (ii) systems re-engineering to
optimize implementation of evidence-based surgical, electrical,
medical therapies as well as socio-economic and psychosocial
considerations, and (iii) novel therapeutic development including
novel application of existing therapies.
Comprehensive assessment and
implementation of evidence-based
therapy
The majority of patients admitted with AHFS have chronic HF,
however once hospitalized, in spite of initial improvement, patients
continue to have severe haemodynamic and neurohumoral abnorm-
alities during hospitalization as well as post-discharge. These
abnormalities are likely to contribute to post-discharge outcomes
and should be aggressively targeted.18
After initial stabilization and
in-hospital management, available data suggest a lack of uptake of
guideline recommended therapy.64,65
Initiation of existing guideline
therapy is recommended in order to treat those pathologies that
are amenable to intervention. This applies not only for HF guidelines,
Figure 3 Comprehensive assessment and cardiac reconstruction. Modified and reproduced with permission from Gheorghiade and Pang.22
AHFS, acute heart failure syndromes, JVP, jugular venous pulse, LV, left ventricle, CAD, coronary artery disease, ACE-I, angiotensin converting
enzyme inhibitor, ARB, angiotensin receptor blocker, ICD, implantable cardiac defibrillator, CRT, chronic resynchronization therapy, Hydral,
hydralazine, ISDN, isosorbide dinitrate, CABG, coronary artery bypass grafting, AF, atrial fibrillation. *Select patients. **Investigational
agents. #
Viable but dysfunctional myocardium.

but also for all other guideline recommended therapies for
co-morbid cardiac and non-cardiac conditions (i.e. diabetes, hyper-
tension, etc.) (Figure 3). Evidence-based treatment of co-morbid
conditions is especially important for HF patients with preserved
ejection fraction, as evidence to treat HF in this large sub-group of
patients is limited.66
Hospitalization represents a unique opportunity for comprehen-
sive assessment, given limited time and resources available in the
outpatient setting.22,67
This assessment should not increase the
length of stay and should be tailored to each individual country,
as there are variations in length of stay and re-hospitalization
rates between countries as well as between the USA and
Europe overall.8
Thorough assessment and implementation of
evidence-based therapies during hospitalization or soon after and
may have significant socioeconomic benefit if re-hospitalizations
and/or mortality is decreased.
Quality measures
In the USA, hospital reported quality measures demonstrate differ-
ences in risk-adjusted re-hospitalization and mortality rates
between hospitals.68,69
Despite similar therapeutic options, out-
comes are different. Although explanations have varied, it is clear
that systems re-engineering may yield improved results.70,71
This
may involve improving communication between providers to
ensure safe and effective transitions of care or the creation or util-
ization of a comprehensive disease management program, which
have been shown to improve outcomes.70,71
Recent evidence suggests that in-patient HF quality measures
(measurement of EF, smoking cessation, discharge instructions,
ACE-I/ARB for LV systolic dysfunction, and anti-coagulation
for AF) are not associated with improved 60–90 days
re-hospitalization or mortality rates, with the exception of ACE-I/
ARB.72,73
The high post-discharge event rate combined with the
substantial cost for hospitals to achieve measures that do not
improve outcomes suggests that better measures are needed.73
Novel therapeutic development
Many clinical development programs in AHFS expect that a drug
will not only safely improve signs and symptoms but also positively
impact long-term outcomes. While not impossible, unless a sub-
stantial pathophysiological interruption occurs or that currently
used therapies cause sufficient downstream harm, it is doubtful
that a drug given for hours to days will impact longer-term out-
comes. Inotropic therapy may be one notable exception, given
the morbidity and mortality associated with current inotropes.
Rather, therapies may be divided into two general groups and
should focus on specific AHFS sub-groups rather than a
‘one-size-fits-all’ approach.
(1) Short term: Typically given for hours to days, these agents
target signs and symptoms, haemodynamic stabilization, poten-
tial protection/prevention of organ injury, and/or facilitate
implementation of known evidence-based therapies.
(2) Long-term: Typically given for weeks to months to improve
mortality and/or re-hospitalization.
Each group may be further divided into traditional (e.g. vasodila-
tors, fluid removal) vs. non-traditional (e.g. energetics, metabolic
modulators) therapeutic classes. In addition, therapies given
short term might also be continued long term. The majority of
novel therapies are being developed as short-term therapy
(Table 4).
Short-term traditional type therapies
Cinaciguat
This novel vasodilator is currently in the early stages of develop-
ment. From a pharmacodynamic standpoint, activation of soluble
guanylate cyclase (sGC) by cinaciguat in smooth muscle cells
leads to the synthesis of cyclic guanosine monophosphate
(cGMP) and subsequent vasodilation.74
The same pathway is also
activated by traditional nitrates; however, for nitrates to achieve
their effects, the Fe/heme complex of sGC needs to be in a
reduced state.75,76
During periods of increased stress, such as
AHFS, a significant proportion of heme Fe may become oxidized,
potentially blunting the effects of NO donors.75
In contrast, cinaci-
guat appears to be a heme-independent sGC activator, with more
predictable vasodilator response in conditions of elevated oxi-
dative stress. In accord with pharmacological data, preliminary
studies in patients with AHFS show a beneficial haemodynamic
profile of cinaciguat.74
At high doses, a substantial decrease in sys-
tolic blood pressure (SBP) was noted. However, this was not
associated with adverse effects on renal function,
re-hospitalization, or mortality suggesting a possible cardioprotec-
tive effect. Lower-dose trials are currently underway.
Chimeric natriuretic peptides
These molecules have been engineered to combine the beneficial
aspects of different natriuretic peptides into a single molecule
while minimizing potentially negative actions.77,78
CD-NP is a com-
bination of C-type natriuretic peptide (CNP) and Dendroapsis NP
(DNP).78
Although lacking natriuretic effects, CNP is a more selec-
tive venodilator than BNP, thus reducing the risk of significant
hypotension. On the other side, DNP possesses significant
natriuretic activity, at the expense of possible hypotensive
effects.78
The chimeric peptide CD-NP combines the favourable
natriuretic effects of DNP with the venodilatory profile of CNP,
reducing the risk for harmful side effects.77,78
Preliminary studies
in AHFS patients are ongoing.
................................................................................
Table 4 Short- and long-term novel therapies for
acute heart failure syndromes
Short term Long term Both
Cinaciguat Direct renin
inhibitors
Adenosine
antagonists
CD-NP Macronutrients Vasopressin
antagonists
Relaxin Micronutrients Digoxin
Adenosine regulating
agents
CRT/AICD
Stresscopin
Istaroxime
Cardiac myosin
activators
P.S. Pang et al.790

Relaxin
First identified as a pregnancy hormone with powerful vascular
effects, relaxin is currently under investigation for its systemic
and renal vasodilatory actions.63
In AHFS patients with high SBP,
data from a Phase II trial have demonstrated an improvement in
dyspnoea with a single dose.63
A Phase III clinical trial is currently
underway.
Istaroxime
A prototype of a new class of drugs, istaroxime exerts its actions
on the myocyte in two ways; stimulation of membrane-bound
Na-K/ATPase and by enhancing activity of sarcoendoplasmic reti-
culum Ca/ATPase type 2a. This mechanism results in inotropic
and lusitropic benefits without adverse haemodynamic conse-
quences.79
Preliminary data demonstrate that istaroxime increases
SBP, while reducing HR, improves diastolic function, decreases
PCWP, and improves CI, thus demonstrating significant potential
for patients presenting in cardiogenic shock or low-output
HF.79 –81
To date, no other approved inotropic therapy has such
a favourable haemodynamic profile.
Cardiac myosin activators
These new agents are cardiac-specific myosin ATPase activators
designed to improve myocardial contractility by accelerating the
productive phosphate-release step of the crossbridge cycle. In
animal studies, these drugs have been shown to improve the
indices of left ventricular systolic function by increasing the systolic
ejection time. Importantly, coronary blood flow, coronary sinus
oxygen content, and myocardial oxygen consumption did not
change at the time of drug administration. This apparent paradox
can be explained by an improved energy efficiency of the contrac-
tile apparatus induced by these drugs.82,83
Short-term non-traditional type therapies
Adenosine regulating agents
This new class of drugs, whose prototype is represented by acade-
sine, has been developed to mimic the protective effects of adeno-
sine during ischaemia. Acadesine exerts its pharmacological actions
by increasing adenosine bioavailability and by activating 50
adenosine
monophosphate (AMP) signalling cascade via its metabolite
5-aminoimidazole-4-carboxamide riboside (ZMP). The first mech-
anism leads to multiple anti-ischaemic effects (maintenance of endo-
thelial function and vasodilation, inhibition of platelet aggregation
and neutrophil activation), whereas the latter ameliorates glucose
uptake and free fatty acid oxidation thus increasing ATP synthesis.
Importantly, acadesine exerts its actions only in areas undergoing
net ATP catabolism (such as ischaemic tissues) thereby avoiding
potentially harmful peripheral vasodilator effects.84,85
Urocortins
Urocortins are a recently discovered group of peptide hormones
of the corticotropin releasing factor family. They bind with a
strong affinity to the CRH-R2 receptor, which is highly expressed
in the myocardium and in the vascular endothelium. Urocortins
exhibit potent inotropic and lusitropic effects on rat and sheep
hearts and activates a group of myocyte protective pathways col-
lectively known as ‘reperfusion injury salvage kinase’.86,87
Study in
healthy humans show that brief intravenous infusions of urocortin
2 in healthy humans induce pronounced dose-related increases in
cardiac output, heart rate, and left ventricular ejection fraction
while decreasing systemic vascular resistance; similar effects were
seen in HF patients.88,89
Long-term traditional type therapies
Direct renin inhibitors
The mechanism of action of this class of drugs involves the inhi-
bition of the first step in the renin–angiotensin–aldosterone
system (RAS) cascade, effectively suppressing this pathway.90
Given the role of RAS in the neurohormonal unbalance present
in patients with HF, aliskiren, an oral direct renin inhibitors (DRI)
currently approved for the treatment of hypertension, is currently
undergoing Phase III trials to test whether the addition of an DRI to
standard therapy delays time to events, including cardiovascular
death or HF re-hospitalization within 6 months in patients
hospitalized for AHFS and EF ,40%.91
Long-term non-traditional type therapies
Macronutrients
In the last few years, numerous epidemiological and interventional
studies have shown that dietary omega-3 fatty acids exert ben-
eficial CV effects. The recent publication of the GISSI-HF
(Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto mio-
cardico) trial has expanded these observations to patients with
chronic HF, showing mortality and morbidity benefits.92
The pro-
posed mechanisms include anti-inflammatory and haemodynamic
effects, as well as CV remodelling, neurohormonal inhibition, and
arrhythmia suppression.92,93
Whether treatment with omega-3
fatty acids may benefit patients with AHFS remains undetermined
and further research is warranted.
Micronutrients
Micronutrients are essential cofactors for energy transfer and
include molecules such as thiamine, amino acids, L-carnitine, and
coenzyme Q10.36
Effective utilization of macronutrients requires
micronutrients to ensure or optimize metabolism of energy sub-
strates.36,94
A recent comprehensive review by Soukoulis et al. high-
lights the state of the art in the role of micronutrients in HF. In
situations where the heart fails due to lackof optimal energy transfer,
micronutrient supplementation may correct known deficiencies
seen in HF. By optimizing energy utilization in conjunction with
evidence-based therapy may lead to improved outcomes.36
Therapies for both short and long term
Vasopressin antagonists
Vasopressin antagonists bind with various affinities to the arginine
vasopressin (AVP) receptors V1a, V1b, and V2. The V1a receptor
is the most widespread subtype of vasopressin receptor and is
found in vascular smooth muscle and many other structures.
V1b receptors have limited distribution. V2 receptors are
located predominantly in principal cells of the renal collecting-duct
system where they induce free water diuresis. Tolvaptan, an oral
V2 antagonist has been approved for use in patients with clinically
significant hypervolemic and euvolemic hyponatremia. In the
EVEREST trials, tolvaptan decreased serum sodium and body

weight, and improved global clinical status and dyspnoea; however,
it failed to improve long-term mortality.95 – 97
Importantly, no sig-
nificant safety concerns were raised.
Conivaptan is an IV antagonist of V1a/V2 receptors approved for
the treatment of hospitalized patients with hypervolemic and euvo-
lemic hyponatremia resulting from inappropriate or excessive
secretion of AVP. Theoretically, the addition of V1a blockade
may result in additional haemodynamic benefits. However, coni-
vaptan, despite its V1 blockade in addition to V2, appears to
have similar haemodynamic activity as tolvaptan.98
Initial studies
also did not demonstrate significant improvement in signs or symp-
toms in patients with AHFS.99
Adenosine antagonists
Adenosine antagonists were developed for their potentially
renoprotective effects derived from preservation of glomerular
filtration through inhibition of adenosine-mediated tubuloglo-
merular feedback. Blockade of sodium re-absorption leading to
mild diuresis was considered an additional benefit.100,101
As base-
line renal function and changes in renal function during hospitaliz-
ation are predictors of post-discharge outcomes in AHFS,
preservation of renal function with adenosine agonists appears to
be a potential target to decrease adverse outcomes. Despite the
positive trends seen in a Phase II trial using rolofylline (PROTECT-
Pilot), the pivotal Phase III PROTECT trial failed to reach its
primary or secondary endpoints.102
In addition, there were non-
significant, but concerning CNS safety signals. Given the relatively
low proportion of patients with WRF, defined as a worsening crea-
tinine of 0.3 mg/dL or greater at two separate time points, it is
possible that the hypothesis for which PROTECT was designed
has yet to be thoroughly tested.
Re-evaluating existing therapies
Currently available evidence-based therapies for chronic HF, such
as ACE-I and beta-blockers, have not been well studied in AHFS.
The re-evaluation of these therapies in this setting is important
since the neurohumoral, haemodynamic, and renal abnormalities
of AHFS are different compared to the chronic state.
Cardiac glycosides
Cardiac glycosides have been used for thousands of years, yet with
the introduction of new chronic HF agents, their use has declined
substantially in the last 10 years (from 70 to 15%).103,104
Digoxin,
the most commonly used cardiac glycoside, appears to have many
ideal properties for an AHFS drug, including relatively rapid onset,
haemodynamic benefits, absence of negative effects on neurohor-
monal activation, BP, HR, or renal function.105,106
Unfortunately, it
has not yet been tested in the AHFS setting (Table 5).107
A new paradigm in clinical
development—T1 translational
research
Phase III trials in AHFS have, to date, largely failed. Although novel
clinical development continues to be promising, repeatedly suc-
cessful Phase II studies followed by unsuccessful Phase III studies
raises the question that repetition of past clinical development
pathways may not lead to different outcomes. In the past,
Phase II was considered the stage to best understand the mechan-
istic properties of a drug. However, it is possible that failure was
related to an incomplete understanding of the drug and/or the
drug was tested in a ‘wrong’ patient population given the diverse
pathophysiologic processes seen in AHFS. We propose a new
paradigm and have borrowed the phrase T1 Translational Research
to describe it. These would be small studies, but in multiple tightly
controlled, homogenous HF patient sub-groups to limit phenotypic
variability. Such an approach would maximize the signal-to-noise
ratio, allowing for a more thorough understanding of the mechan-
istic properties of the drug. Importantly, identification of early
‘failure’ is also beneficial.
Conclusion
Improving post-discharge outcomes for patients with AHFS is a
fundamental goal of therapy. Current management remains chal-
lenging, as the evidence for initial management is limited. A
better understanding of existing therapies is needed. In addition,
certain healthcare systems and institutions have better outcomes
despite a similar therapeutic armamentarium, suggesting the
benefits of optimization of therapies, including psychosocial and
socioeconomic considerations. Better measures of HF quality are
needed.
In spite of the commonly held belief that the high mortality and
morbidity seen post-discharge is inevitable, we believe future man-
agement holds great promise as many conditions that contribute to
progression of HF can be effectively treated (e.g. CAD, valvular
disease, ventricular dyssynchrony). In addition, since progression
of LV dysfunction contributes to the poor prognosis of HF, identi-
fying patients with viable but dysfunctional myocardium, which is
potentially salvageable, and for whom future therapies can be
identified, may be the last frontier in the treatment of AHFS.
Acknowledgement
The authors would like to thank Umberto Campia MD for his edi-
torial assistance and April York for her administrative support.
Table 5 Ideal properties for an acute heart failure
syndromes therapy
1. Improve signs and symptoms (e.g. dyspnoea)
2. Improve haemodynamics without adversely effecting heart rate and
blood pressure
3. Improve the neurohumoral profile
4. Do not cause myocardial and/or kidney damage
5. Be effective in the context of current evidence-based therapy such
as ACE-I and beta-blockers
6. Demonstrate efficacy in both the acute and chronic setting
7. Be affordable
8. Reduce both in-hospital and post-discharge morbidity and mortality.
Adapted and reproduced with permission from JAMA, 302(19):2146. Copyright
2009. American Medical Association. All rights reserved.107
P.S. Pang et al.792

Conflict of interest: P.S.P. is or has been in the last 5 years a con-
sultant to Astellas, Bayer, the Medicines Company, Nile Thera-
peutics, Otsuka, Palatin Technolgies, PDL BioPharma, PeriCor
Therapeutics, and Solvay Pharmaceuticals, has received honoraria
from BiogenIdec, Corthera, EKR Therapeutics, and research
support from Merck and PDL BioPharma. M.K. is a consultant
for Servier, a member of the steering committee for ASCEND,
SHIFT, HEAAL. A speaker for GSK, sanofi-aventis, Astra Zeneca,
Menarini, Bristol Meyers Squibb, Merck Sharpe Dohm, and
Boehringer Ingelheim. M.G. is or has been a consultant and/or
received honoraria from Astellas, Bayer, Corthera, DebioPharm,
ErreKappa Terapeutici, EKR Therapeutics, GlaxoSmithKline,
Medtronic, Merck, Nile Therapeutics, Novartis, Otsuka, Palatin
Technologies, PDL BioPharma, Pericor Therapeutics, Scios Inc.,
Solvay Pharmaceuticals, and SigmaTau.
References
1. Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O’Connor CM,
She L, Stough WG, Yancy CW, Young JB, Fonarow GC. Systolic blood pressure
at admission, clinical characteristics, and outcomes in patients hospitalized with
acute heart failure. J Am Med Assoc 2006;296:2217–2226.
2. Ramirez A, Abelmann WH. Cardiac decompensation. N Eng J Med 1974;290:
499–501.
3. Adams JKF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR,
Abraham WT, Berkowitz RL, Galvao M, Horton DP. Characteristics and out-
comes of patients hospitalized for heart failure in the United States: Rationale,
design, and preliminary observations from the first 100,000 cases in the Acute
Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;
149:209–216.
4. Cleland JGF, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC,
Dietz R, Gavazzi A, Hobbs R, Korewicki J, Madeira HC, Moiseyev VS, Preda I,
van Gilst WH, Widimsky J, Freemantle N, Eastaugh J, Mason J, for the Study
Group on Diagnosis of the Working Group on Heart Failure of the European
Society of C. The EuroHeart Failure survey programme—a survey on the
quality of care among patients with heart failure in Europe: Part 1: patient
characteristics and diagnosis. Eur Heart J 2003;24:442–463.
5. Fang J, Mensah GA, Croft JB, Keenan NL. Heart failure-related hospitalization in
the U.S., 1979 to 2004. J Am Coll Cardiol 2008;52:428–434.
6. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K,
Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V,
Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J,
Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R,
Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N,
Wylie-Rosett J, Hong Y. Heart disease and stroke statistics–2009 update: a
report from the American Heart Association Statistics Committee and Stroke
Statistics Subcommittee. Circulation 2009;119:480–486.
7. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P,
Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW,
Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, Vahanian A,
Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C,
Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M,
Widimsky P, Zamorano JL. ESC Guidelines for the diagnosis and treatment of
acute and chronic heart failure 2008: the Task Force for the Diagnosis and
Treatment of Acute and Chronic Heart Failure 2008 of the European Society
of Cardiology. Developed in collaboration with the Heart Failure Association
of the ESC (HFA) and endorsed by the European Society of Intensive Care
Medicine (ESICM). Eur Heart J 2008;29:2388–2442.
8. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP,
Hochadel M, Komajda M, Lassus J, Lopez-Sendon JL, Ponikowski P, Tavazzi L.
EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart
failure patients: description of population. Eur Heart J 2006;27:2725–2736.
9. Jhund PS, Macintyre K, Simpson CR, Lewsey JD, Stewart S, Redpath A,
Chalmers JW, Capewell S, McMurray JJ. Long-term trends in first hospitalization
for heart failure and subsequent survival between 1986 and 2003: a population
study of 5.1 million people. Circulation 2009;119:515–523.
10. Hugli O, Braun JE, Kim S, Pelletier AJ, Camargo CA Jr. United States emergency
department visits for acute decompensated heart failure, 1992 to 2001. Am J
Cardiol 2005;96:1537–1542.
11. Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW. Temporal
trends in clinical characteristics, treatments, and outcomes for heart failure
hospitalizations, 2002 to 2004: findings from Acute Decompensated Heart
Failure National Registry (ADHERE). Am Heart J 2007;153:1021–1028.
12. Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J, Kalman J,
Phillips RA, Steingart R, Brown EJ Jr, Berkowitz R, Moskowitz R, Soni A,
Mancini D, Bijou R, Sehhat K, Varshneya N, Kukin M, Katz SD, Sleeper LA, Le
Jemtel TH. Hospitalization for heart failure in the presence of a normal left ven-
tricular ejection fraction: results of the New York Heart Failure Registry. J Am
Coll Cardiol 2004;43:1432–1438.
13. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, Yusuf S,
Swedberg K, Young JB, Michelson EL, Pfeffer MA. Influence of nonfatal hospital-
ization for heart failure on subsequent mortality in patients with chronic heart
failure. Circulation 2007;116:1482–1487.
14. Ahmed A, Allman RM, Fonarow GC, Love TE, Zannad F, Dell’italia LJ, White M,
Gheorghiade M. Incident heart failure hospitalization and subsequent mortality
in chronic heart failure: a propensity-matched study. J Card Fail 2008;14:
211–218.
15. Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict
mortality in the community population with heart failure. Am Heart J 2007;
154:260–266.
16. Butler J, Kalogeropoulos A. Worsening heart failure hospitalization epidemic we
do not know how to prevent and we do not know how to treat!. J Am Coll
Cardiol 2008;52:435–437.
17. Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, Massie BM,
Roland E, Targum S, Collins SP, Filippatos G, Tavazzi L, for the International
Working Group on Acute Heart Failure S. Acute heart failure syndromes:
current state and framework for future research. Circulation 2005;112:
3958–3968.
18. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in acute heart
failure syndromes: an essential target of evaluation and treatment. Am J Med
2006;119 (12 Suppl. 1):S3–S10.
19. Collins S, Storrow AB, Kirk JD, Pang PS, Diercks DB, Gheorghiade M. Beyond
pulmonary edema: diagnostic, risk stratification, and treatment challenges of
acute heart failure management in the emergency department. Ann Emerg Med
2008;51:45–57.
20. Felker GM, Adams KF Jr, Konstam MA, O’Connor CM, Gheorghiade M. The
problem of decompensated heart failure: nomenclature, classification, and risk
stratification. Am Heart J 2003;145(2 Suppl):S18–S25.
21. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG,
Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson LW, Yancy CW.
2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Manage-
ment of Heart Failure in Adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines:
developed in collaboration with the International Society for Heart and Lung
Transplantation. Circulation 2009;119:1977–2016.
22. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;
53:557–573.
23. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG,
Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA,
Stevenson LW, Yancy CW. Focused update incorporated into the ACC/AHA
2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults
A Report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines Developed in Collaboration
With the International Society for Heart and Lung Transplantation. J Am Coll
Cardiol 2009;53:e1–e90.
24. Maytin M, Colucci WS. Cardioprotection: a new paradigm in the management of
acute heart failure syndromes. Am J Cardiol 2005;96:26G–31G.
25. Peacock WF, De Marco T, Fonarow GC, Diercks D, Wynne J, Apple FS,
Wu AHB, the AI. Cardiac troponin and outcome in acute heart failure. N Eng
J Med 2008;358:2117–2126.
26. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is associ-
ated with impaired hemodynamics, progressive left ventricular dysfunction, and
increased mortality rates in advanced heart failure. Circulation 2003;108:
833–838.
27. Gheorghiade M, Gattis Stough W, Adams KF Jr, Jaffe AS, Hasselblad V,
O’Connor CM. The Pilot Randomized Study of Nesiritide versus Dobutamine
in Heart Failure (PRESERVD-HF). Am J Cardiol 2005;96:18G–25G.
28. Flaherty JD, Bax JJ, De Luca L, Rossi JS, Davidson CJ, Filippatos G, Liu PP,
Konstam MA, Greenberg B, Mehra MR, Breithardt G, Pang PS, Young JB,
Fonarow GC, Bonow RO, Gheorghiade M. Acute heart failure syndromes in
patients with coronary artery disease early assessment and treatment. J Am
Coll Cardiol 2009;53:254–263.
29. Flaherty JD, Rossi J, Fonarow G, Nunez E, Stough WG, Abraham W, Albert NM,
Greenberg B, O’Connor CM, Yancy C, Young J, Davidson CJ, Gheorghiade M.
Influence of coronary angiography on the utilization of therapies in patients
with acute heart failure syndromes: a report from OPTIMIZE-HF (Organized

Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart
Failure) (presented as a Late Breaking Clinical Trial). Transcatheter Cardiovas-
cular Therapeutics Conference, Washington, DC. Am J Cardiol 2008;102:251.
30. Cleland JG, Pennell DJ, Ray SG, Coats AJ, Macfarlane PW, Murray GD, Mule JD,
Vered Z, Lahiri A. Myocardial viability as a determinant of the ejection fraction
response to carvedilol in patients with heart failure (CHRISTMAS trial): random-
ised controlled trial. Lancet 2003;362:14–21.
31. Bello D, Shah DJ, Farah GM, Di Luzio S, Parker M, Johnson MR, Cotts WG,
Klocke FJ, Bonow RO, Judd RM, Gheorghiade M, Kim RJ. Gadolinium cardiovas-
cular magnetic resonance predicts reversible myocardial dysfunction and remo-
deling in patients with heart failure undergoing beta-blocker therapy. Circulation
2003;108:1945–1953.
32. Gheorghiade M, De Luca L, Fonarow GC, Filippatos G, Metra M, Francis GS.
Pathophysiologic targets in the early phase of acute heart failure syndromes.
Am J Cardiol 2005;96:11G–17G.
33. Seghatol FF, Shah DJ, Diluzio S, Bello D, Johnson MR, Cotts WG, O’Donohue JA,
Bonow RO, Gheorghiade M, Rigolin VH. Relation between contractile reserve
and improvement in left ventricular function with beta-blocker therapy in
patients with heart failure secondary to ischemic or idiopathic dilated cardio-
myopathy. Am J Cardiol 2004;93:854–859.
34. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP,
Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC. Neurohumoral
features of myocardial stunning due to sudden emotional stress. N Engl J Med
2005;352:539–548.
35. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J, Longe TF,
Maron BJ. Acute and reversible cardiomyopathy provoked by stress in women
from the United States. Circulation 2005;111:472–479.
36. Soukoulis V, Dihu JB, Sole M, Anker SD, Cleland J, Fonarow GC, Metra M,
Pasini E, Strzelczyk T, Taegtmeyer H, Gheorghiade M. Micronutrient deficiencies
an unmet need in heart failure. J Am Coll Cardiol 2009;54:1660–1673.
37. Ingwall JS, Weiss RG. Is the failing heart energy starved? On using chemical
energy to support cardiac function. Circ Res 2004;95:135–145.
38. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med 2007;356:
1140–1151.
39. van Bilsen M, Smeets PJ, Gilde AJ, van der Vusse GJ. Metabolic remodelling of the
failing heart: the cardiac burn-out syndrome? Cardiovasc Res 2004;61:218–226.
40. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR,
Wynne J. High prevalence of renal dysfunction and its impact on outcome in
118,465 patients hospitalized with acute decompensated heart failure: a
report from the ADHERE database. J Card Fail 2007;13:422–430.
41. Damman K, Navis G, Voors AA, Asselbergs FW, Smilde TD, Cleland JG, van
Veldhuisen DJ, Hillege HL. Worsening renal function and prognosis in heart
failure: systematic review and meta-analysis. J Card Fail 2007;13:599–608.
42. Filippatos G, Rossi J, Lloyd-Jones DM, Stough WG, Ouyang J, Shin DD,
O’Connor C, Adams KF, Orlandi C, Gheorghiade M. Prognostic value of
blood urea nitrogen in patients hospitalized with worsening heart failure: insights
from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in
Chronic Heart Failure (ACTIV in CHF) study. J Card Fail 2007;13:360–364.
43. Klein L, Massie BM, Leimberger JD, O’Connor CM, Pina IL, Adams KF, Califf RM,
Gheorghiade M. Admission or changes in renal function during hospitalization
for worsening heart failure predict postdischarge survival: results from the Out-
comes of a Prospective Trial of Intravenous Milrinione for Exacerbation of
Chronic Heart Failure (OPTIME-CHF). Circulation: Heart Failure 2008;1:25–33.
44. Francis G. Acute decompensated heart failure: the cardiorenal syndrome. Cleve
Clin J Med 2006;73 (Suppl. 2):S8–S13. discussion S30-13.
45. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ,
Hillege HL. Increased central venous pressure is associated with impaired
renal function and mortality in a broad spectrum of patients with cardiovascular
disease. J Am Coll Cardiol 2009;53:582–588.
46. Jessup M, Costanzo MR. The cardiorenal syndrome: do we need a change of
strategy or a change of tactics? J Am Coll Cardiol 2009;53:597–599.
47. Mahdyoon H, Klein R, Eyler W, Lakier JB, Chakko SC, Gheorghiade M. Radio-
graphic pulmonary congestion in end-stage congestive heart failure. Am J
Cardiol 1989;63:625–627.
48. Maisel A, Mueller C, Adams K Jr, Anker SD, Aspromonte N, Cleland JG,
Cohen-Solal A, Dahlstrom U, Demaria A, Di Somma S, Filippatos GS,
Fonarow GC, Jourdain P, Komajda M, Liu PP, McDonagh T, McDonald K,
Mebazaa A, Nieminen MS, Peacock WF, Tubaro M, Valle R, Vanderhyden M,
Yancy CW, Zannad F, Braunwald E. State of the art: Using natriuretic peptide
levels in clinical practice. Eur J Heart Fail 2008;10:824–839.
49. Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, Simovitz A, Shaham O,
Marghitay D, Koren M, Blatt A, Moshkovitz Y, Zaidenstein R, Golik A. Random-
ised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-
dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary
oedema. Lancet 1998;351:389–393.
50. Beohar N, Erdogan AK, Lee DC, Sabbah HN, Kern MJ, Teerlink J, Bonow RO,
Gheorghiade M. Acute heart failure syndromes and coronary perfusion. J Am
Coll Cardiol 2008;52:13–16.
51. Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, Califf RM,
Gheorghiade M, O’Connor CM, Investigators O-C. Heart failure etiology and
response to milrinone in decompensated heart failure: results from the
OPTIME-CHF study. J Am Coll Cardiol 2003;41:997–1003.
52. Hasselblad V, Gattis Stough W, Shah MR, Lokhnygina Y, O’Connor CM,
Califf RM, Adams KF Jr. Relation between dose of loop diuretics and outcomes
in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail 2007;9:
1064–1069.
53. Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M,
Greenberg BH, O’Connor CM, Pieper K, Sun JL, Yancy CW, Young JB.
Factors identified as precipitating hospital admissions for heart failure and clinical
outcomes: findings from OPTIMIZE-HF. Arch Intern Med 2008;168:847–854.
54. Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M,
Greenberg BH, O’Connor CM, Sun JL, Yancy CW, Young JB. Predictors of
in-hospital mortality in patients hospitalized for heart failure: insights from the
Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients
with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol 2008;52:347–356.
55. Felker GM, Leimberger JD, Califf RM, Cuffe MS, Massie BM, Adams KF Jr,
Gheorghiade M, O’Connor CM. Risk stratification after hospitalization for
decompensated heart failure. J Card Fail 2004;10:460–466.
56. Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ, for the
Adhere Scientific Advisory Committee SGaI. Risk stratification for in-hospital
mortality in acutely decompensated heart failure: classification and regression
tree analysis. J Am Med Assoc 2005;293:572–580.
57. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting mortality
among patients hospitalized for heart failure: derivation and validation of a clini-
cal model. J Am Med Assoc 2003;290:2581–2587.
58. O’Connor CM, Abraham WT, Albert NM, Clare R, Gattis Stough W,
Gheorghiade M, Greenberg BH, Yancy CW, Young JB, Fonarow GC. Predictors
of mortality after discharge in patients hospitalized with heart failure: an analysis
from the Organized Program to Initiate Lifesaving Treatment in Hospitalized
Patients with Heart Failure (OPTIMIZE-HF). Am Heart J 2008;156:662–673.
59. Peacock WFt, Albert NM. Observation unit management of heart failure. Emerg
Med Clin North Am 2001;19:209–232.
60. Storrow AB, Collins S, Lindsell CJ, Disalvo T, Han J, Weintraub NL. Improving
heart failure risk stratification in the ED: Stratify 1R01HL088459-01; Treatment
Endpoints in Acute Decompensated Heart Failure 1K23HL085387-01A2.
Vanderbilt University and University of Cincinnati: NHLBI; 2007.
61. Maisel AS, Peacock WF, McMullin N, Jessie R, Fonarow GC, Wynne J, Mills RM.
Timing of immunoreactive B-type natriuretic peptide levels and treatment delay
in acute decompensated heart failure: an ADHERE (Acute Decompensated
Heart Failure National Registry) analysis. J Am Coll Cardiol 2008;52:534–540.
62. Collins SP, Levy PD, Lindsell CJ, Pang PS, Storrow AB, Miller CD, Naftilan AJ,
Thohan V, Abraham WT, Hiestand B, Filippatos G, Diercks DB, Hollander J,
Nowak R, Peacock WF, Gheorghiade M. The rationale for an acute heart
failure syndromes clinical trials network. J Card Fail 2009;15:467–474.
63. Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Weatherley BD,
Marmor A, Katz A, Grzybowski J, Unemori E, Teichman SL, Cotter G. Relaxin
for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multi-
centre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb
study. Lancet 2009;373:1429–1439.
64. Albert NM, Yancy CW, Liang L, Zhao X, Hernandez AF, Peterson ED,
Cannon CP, Fonarow GC. Use of aldosterone antagonists in heart failure.
J Am Med Assoc 2009;302:1658–1665.
65. Fonarow GC, Yancy CW, Heywood JT. Adherence to heart failure
quality-of-care indicators in US hospitals: analysis of the ADHERE Registry.
Arch Intern Med 2005;165:1469–1477.
66. Shah SJ, Gheorghiade M. Heart failure with preserved ejection fraction: treat
now by treating comorbidities. J Am Med Assoc 2008;300:431–433.
67. Khan SS, Gheorghiade M, Dunn JD, Pezalla E, Fonarow GC. Managed care inter-
ventions for improving outcomes in acute heart failure syndromes. Am J Manag
Care 2008;14 (Suppl. 12 Managed):S273–S286. quiz S287–291.
68. Krumholz HM, Normand SL. Public reporting of 30-day mortality for patients
hospitalized with acute myocardial infarction and heart failure. Circulation 2008;
118:1394–1397.
69. US Department of Heath and Human Services. Hospital compare. www.
hospitalcompare.hhs.gov (28 July 2009).
70. Fonarow GC, Abraham WT, Albert NM, Gattis Stough W, Gheorghiade M,
Greenberg BH, O’Connor CM, Pieper K, Sun JL, Yancy CW, Young JB. Influence
of a performance-improvement initiative on quality of care for patients hospital-
ized with heart failure: results of the Organized Program to Initiate Lifesaving
P.S. Pang et al.793a

Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). Arch
Intern Med 2007;167:1493–1502.
71. Fonarow GC, Yancy CW, Albert NM, Curtis AB, Stough WG, Gheorghiade M,
Heywood JT, Mehra M, O’Connor CM, Reynolds D, Walsh MN. Improving the
use of evidence-based heart failure therapies in the outpatient setting: the
IMPROVE HF performance improvement registry. Am Heart J 2007;154:12–38.
72. Fonarow GC, Abraham WT, Albert NM, Gattis WA, Gheorghiade M,
Greenberg B, O’Connor CM, Pieper K, Sun J-L, Yancy CW, Young J. Association
between performance measures and clinical outcomes for patients hospitalized
with heart failure. J Am Med Assoc 2007;297:61–70.
73. Fonarow GC, Peterson ED. Heart failure performance measures and outcomes:
real or illusory gains. J Am Med Assoc 2009;302:792–794.
74. Lapp H, Mitrovic V, Franz N, Heuer H, Buerke M, Wolfertz J, Mueck W, Unger S,
Wensing G, Frey R. Cinaciguat (BAY 58-2667) improves cardiopulmonary
hemodynamics in patients with acute decompensated heart failure. Circulation
2009;119:2781–2788.
75. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP.
NO-independent stimulators and activators of soluble guanylate cyclase: discov-
ery and therapeutic potential. Nat Rev Drug Discov 2006;5:755–768.
76. Mitrovic V, Hernandez AF, Meyer M, Gheorghiade M. Role of guanylate cyclase
modulators in decompensated heart failure. Heart Fail Rev 2009;14:309–319.
77. Lee CY, Chen HH, Lisy O, Swan S, Cannon C, Lieu HD, Burnett JC Jr. Pharma-
codynamics of a novel designer natriuretic peptide, CD-NP, in a first-in-human
clinical trial in healthy subjects. J Clin Pharmacol 2009;49:668–673.
78. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC Jr. Design, syn-
thesis, and actions of a novel chimeric natriuretic peptide: CD-NP. J Am Coll
Cardiol 2008;52:60–68.
79. Gheorghiade M, Blair JE, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J,
Bubenek-Turconi SI, Ceracchi M, Bianchetti M, Carminati P, Kremastinos D,
Valentini G, Sabbah HN. Hemodynamic, echocardiographic, and neurohormonal
effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a ran-
domized controlled trial in patients hospitalized with heart failure. J Am Coll
Cardiol 2008;51:2276–2285.
80. Dec GW. Istaroxime in heart failure new hope or more hype. J Am Coll Cardiol
2008;51:2286–2288.
81. Shah SJ, Blair JE, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J,
Bubenek-Turconi SI, Ceracchi M, Bianchetti M, Carminati P, Kremastinos D,
Grzybowski J, Valentini G, Sabbah HN, Gheorghiade M. Effects of istaroxime
on diastolic stiffness in acute heart failure syndromes: results from the Hemody-
namic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel
Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in
Patients Hospitalized with Heart Failure (HORIZON-HF) trial. Am Heart J
2009;157:1035–1041.
82. Cleland JGF. The Selective Cardiac Myosin Activator CK-1827452 Increases Sys-
tolic Function in a Concentration-Dependent Manner in Patients with Stable
Heart Failure (presented as a Late Breaking Clinical Trial). Heart Failure Society
of America Annual Meeting, Toronto, Canada, 2008.
83. Coletta AP, Cleland JG, Cullington D, Clark AL. Clinical trials update from Heart
Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART
and CK-1827452. Eur J Heart Fail 2008;10:917–920.
84. Drew BG, Kingwell BA. Acadesine, an adenosine-regulating agent with the
potential for widespread indications. Expert Opin Pharmacother 2008;9:
2137–2144.
85. Engler RL. Harnessing nature’s own cardiac defense mechanism with acadesine,
an adenosine regulating agent: importance of the endothelium. J Card Surg 1994;9
(Suppl. 3):482–492.
86. Davidson SM, Rybka AE, Townsend PA. The powerful cardioprotective effects
of urocortin and the corticotropin releasing hormone (CRH) family. Biochem
Pharmacol 2009;77:141–150.
87. Rademaker MT, Cameron VA, Charles CJ, Richards AM. Integrated hemody-
namic, hormonal, and renal actions of urocortin 2 in normal and paced sheep:
beneficial effects in heart failure. Circulation 2005;112:3624–3632.
88. Davis ME, Pemberton CJ, Yandle TG, Fisher SF, Lainchbury JG, Frampton CM,
Rademaker MT, Richards AM. Urocortin 2 infusion in healthy humans: hemody-
namic, neurohormonal, and renal responses. J Am Coll Cardiol 2007;49:461–471.
89. Davis ME, Pemberton CJ, Yandle TG, Fisher SF, Lainchbury JG, Frampton CM,
Rademaker MT, Richards M. Urocortin 2 infusion in human heart failure. Eur
Heart J 2007;28:2589–2597.
90. Andersen K, Weinberger MH, Egan B, Constance CM, Ali MA, Jin J, Keefe DL.
Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and
ramipril in hypertension: a 6-month, randomized, double-blind trial.
J Hypertens 2008;26:589–599.
91. Gheorghiade M, Maggioni AP, Bohm M, Fonarow G, Zannad F, Schober B,
Ghadanfar M, Armbrecht J, Gimpelewicz C, Rattunde H. ASTRONAUT: Alis-
kerin Trial on Acute Heart Failure Outcomes [ABSTRACT]. European Society
of Cardiology Heart Failure Association. Nice, France; 2009.
92. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D,
Nicolosi GL, Porcu M, Tognoni G. Effect of n-3 polyunsaturated fatty acids in
patients with chronic heart failure (the GISSI-HF trial): a randomised, double-
blind, placebo-controlled trial. Lancet 2008;372:1223–1230.
93. Lavie CJ, Milani RV, Mehra MR, Ventura HO. Omega-3 polyunsaturated fatty
acids and cardiovascular diseases. J Am Coll Cardiol 2009;54:585–594.
94. Witte KK, Clark AL. Micronutrients and their supplementation in chronic
cardiac failure. An update beyond theoretical perspectives. Heart Fail Rev
2006;11:65–74.
95. Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP,
Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C.
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients
hospitalized for heart failure: the EVEREST Clinical Status Trials. J A Med Assoc
2007;297:1332–1343.
96. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP,
Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C,
for the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study
With Tolvaptan I. Effects of oral tolvaptan in patients hospitalized for worsening
heart failure: The EVEREST outcome trial. J Am Med Assoc 2007;297:1319–1331.
97. Pang PS, Konstam MA, Krasa HB, Swedberg K, Zannad F, Blair JE, Zimmer C,
Teerlink JR, Maggioni AP, Burnett JC Jr, Grinfeld L, Ouyang J, Udelson JE,
Gheorghiade M. Effects of tolvaptan on dyspnoea relief from the EVEREST
trials. Eur Heart J 2009;30:2233–2240.
98. Finley JJt, Konstam MA, Udelson JE. Arginine vasopressin antagonists for the
treatment of heart failure and hyponatremia. Circulation 2008;118:410–421.
99. Goldsmith SR, Elkayam U, Haught WH, Barve A, He W. Efficacy and safety of
the vasopressin V1A/V2-receptor antagonist conivaptan in acute decompen-
sated heart failure: a dose-ranging pilot study. J Card Fail 2008;14:641–647.
100. Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O’Connor CM,
Metra M, Massie BM. The PROTECT pilot study: a randomized, placebo-
controlled, dose-finding study of the adenosine A1 receptor antagonist rolofyl-
line in patients with acute heart failure and renal impairment. J Card Fail 2008;14:
631–640.
101. Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, Dyer F,
Gomez M, Bennett D, Ticho B, Beckman E, Abraham WT. BG9719
(CVT-124), an A1 adenosine receptor antagonist, protects against the decline
in renal function observed with diuretic therapy. Circulation 2002;105:
1348–1353.
102. Cleland JG, Coletta AP, Yassin A, Buga L, Torabi A, Clark AL. Clinical trials
update from the European Society of Cardiology Meeting 2009: AAA, RELY,
PROTECT, ACTIVE-I, European CRT survey, German pre-SCD II registry, and
MADIT-CRT. Eur J Heart Fail 2009;11:1214–1219.
103. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H,
Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart
Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P. Ferric Carboxymaltose in
patients with heart failure and iron deficiency. N Engl J Med 2009;361:
2436–2448.
104. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, Massie BM,
O’Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M. Short-term intrave-
nous milrinone for acute exacerbation of chronic heart failure: a randomized
controlled trial. J Am Med Assoc 2002;287:1541–1547.
105. Ahmed A, Rich MW, Love TE, Lloyd-Jones DM, Aban IB, Colucci WS, Adams KF,
Gheorghiade M. Digoxin and reduction in mortality and hospitalization in heart
failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J 2006;27:
178–186.
106. Antonello A, Cargnielli G, Ferrari M, Melacini P, Montanaro D. Effect of digoxin
on plasma-renin-activity in man. Lancet 1976;2:850.
107. Gheorghiade M, Braunwald E. Reconsidering the Role for Digoxin in the Man-
agement of Acute Heart Failure Syndromes. J Am Med Assoc 2009;302:
2146–2147.
Reconstructing the failing heart 793b

The current and future managment of ahf

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (20)

Similar to The current and future managment of ahf

Similar to The current and future managment of ahf (20)

More from drucsamal

More from drucsamal (20)

Recently uploaded

Recently uploaded (20)

The current and future managment of ahf