Download The pathophysiology of acute heart failure—Is it

Curriculum in Cardiology
The pathophysiology of acute heart failure—Is it all
about fluid accumulation?
Gad Cotter, MD,a G. Michael Felker, MD,a Kirkwood F. Adams, MD,b Olga Milo-Cotter, MD,a and
Christopher M. O’Connor, MDa Durham and Chapel Hill, NC
Despite significant advancement in chronic heart failure (HF), no breakthroughs have occurred in the last 2 decades in our
understanding of the pathophysiology, classification, and treatment of acute HF (AHF). Traditional thinking, which has been
that this disorder is a result of gradual fluid accumulation on a background of chronic HF, has been called into question by
recent large registries enrolling less selected patient populations. It is increasingly recognized that many patients with this
syndrome are elderly, have relatively preserved ejection fraction, and have mild or no preexisting chronic HF. In this review,
we propose 2 primary subtypes of AHF: (1) acute decompensated cardiac failure, characterized by deterioration of cardiac
performance over days to weeks leading to decompensation; and (2) acute vascular failure, characterized by acute
hypertension and increased vascular stiffness. Registry data suggest that the latter is the more common form of AHF in the
general population, although the former is often overrepresented in studies focused in academic tertiary care centers.
Regardless of the clinical subtype, a variety of pathophysiologic mechanisms may play a role in this disorder, many of which
remain poorly understood. In this review, we describe current understanding of the pathophysiology of AHF, including a
critical evaluation of the data supporting both traditional and novel mechanisms, and suggest a framework for integrating these
mechanisms into an overall model of AHF. (Am Heart J 2008;155:9-18.)
Acute heart failure (AHF) is the most common cause for
hospital admission in patients N65 years. 1 There are
approximately 1 000 000 admissions to US hospitals for
AHF each year, accounting for N6 000 000 hospital days
and $12 billion in costs. Moreover, the prognosis of
patients admitted with AHF is dismal, with N20% of
patients being readmitted with heart failure (HF) and
N20% dying during the first year after admission. 2 This
outcome is worse than that reported for patients with
stage D severe chronic systolic HF enrolled in the
Copernicus study, 3 suggesting that an AHF event is
associated with an abrupt worsening in HF prognosis.
Despite this, data regarding the pathogenesis, etiologic
factors, subclassification into specific disorders, risk
stratification, and effective treatment of AHF are lacking.
Most studies on the epidemiology of AHF have been
small, retrospective, or highly selective. Although larger
registries have recently been performed, these data are
limited by lack of detail and short-term follow-up. 4-6 In
these registries, the mean age of patients admitted with
AHF is 71 to 76 years, half are women, and half have
preserved ejection fraction (EF; N40%). These results are
in contrast to data on patients with chronic HF, in which
the mean age is lower, most patients are men, and the EF
is significantly lower. 7 Notably, AHF frequently occurs
even when chronic HF symptoms are mild or absent—in
the European registry 4 and the ADHERE registry, 5 the
index admission was the first time HF was diagnosed in
25% to 27% of the patients. In the recent IMPACT-HF
study and registry, 70% of patients at 1-month follow-up
were in New York Heart Association class I or II. 8 Clearly,
in some patients, AHF may be the result of a specific
pathologic process (in the absence of chronic HF),
whereas in others, it is the end result of a slow
deterioration in severe chronic HF. At present, our ability
to define and distinguish various clinical subtypes of AHF
is limited by the paucity of data and limitations in our
understanding of the pathophysiology of AHF.
Two general categories of AHF have been previously
suggested by us and used in the recently published
European Society of Cardiology guidelines on the
diagnosis and treatment of AHF. 9,10
From the aDuke University Medical Center, the Duke Clinical Research Institute, Durham,
NC, and bUniversity of North Carolina, Chapel Hill, NC.
Submitted October 19, 2005; accepted February 12, 2006.
1. Acute decompensated cardiac failure: In many
patients, AHF is the end result of a relatively slow
(days to weeks) deterioration of severe chronic HF.
This deterioration has traditionally been attributed
to nonadherence with diet, pharmacologic therapy,
or fluid restriction or to decreased contractility due
to ongoing myocardial injury (eg, ischemia). This
Reprint requests: Gad Cotter, MD, Duke Clinical Research Institute, 2400 Pratt St, Durham,
NC 27715, USA.
E-mail: [email protected]
0002-8703/$ - see front matter
© 2008, Published by Mosby, Inc.
doi:10.1016/j.ahj.2006.02.038
10 Cotter et al
type of AHF may be able to be managed in the
outpatient setting by administration of diuretics,
resumption of proper diet and fluid restriction, and
improved pharmacotherapy or other interventions
(such as revascularization, resynchronization).
2. Acute vascular failure: This rapidly progressive
disorder of high blood pressure (BP) accompanied
by severe acute dyspnea is commonly encountered
in emergency settings. It is most likely caused by
a combination of increased vascular resistance
superimposed on decreased cardiac contractility
(in many cases despite relatively preserved EF),
leading to severe hypertension, afterload mismatch,
and increased diastolic left ventricular (LV) failure.
Very importantly, data from recent registries such
as ADHERE5 have suggested that this presentation is the most common type of AHF in
unselected populations.
Pathophysiology of AHF
The existing paradigm for understanding AHF has
focused primarily on acute decompensated cardiac failure rather than vascular failure. This paradigm suggests
that AHF is caused by either an acute or chronic decrease
in LV contractility (typically induced by ischemia or
arrhythmia) or progressive fluid accumulation. Although
these triggers almost certainly play a role in some patients
with AHF, data to support the relative importance of
different AHF triggers are lacking. Here we will review
existing data on both traditional and novel mechanisms
that may contribute to the pathogenesis of AHF (of either
category) and suggest a framework for integrating them
into a comprehensive disease model.
Traditional mechanisms of AHF
Fluid overload
Volume overload is considered a hallmark of AHF, and
almost all patients hospitalized with AHF receive diuretic
therapy. A simplistic view of AHF pathophysiology
suggests that gradual increase in total body volume leads
to symptoms of congestion and that normalization of
volume status through treatment with diuretics results in
restoration of homeostasis. Surprisingly, available data do
not provide abundant support for this simplified model of
AHF pathophysiology.
In a recent small study, Verwey et al 11 have
demonstrated that even in patients with severe chronic
HF monitored by invasive and noninvasive measures,
worsening symptoms of HF (fatigue and increased
shortness of breath) and increase in pulmonary pressure
occurred days to weeks before weight gain was first
observed. Furthermore, when weight gain did occur, it
was in the range of only 2 kg. Similarly, Lewin et al 12
have demonstrated that weight gain did not differ in a
American Heart Journal
January 2008
prospective cohort of patients between patients developing AHF and those who did not. Recent data using
chronically implanted hemodynamic monitors have
confirmed that a dramatic rise in cardiac filling
pressures often occurs preceding an AHF hospitalization, even in the absence of any significant change in
weight (R. Bourge, MD, personal communication 2006).
Studies of hospitalization for AHF have generally
demonstrated only modest degrees of weight loss
(approximately 2 kg) during AHF hospitalization. 13 We
have recently analyzed the amount of weight loss in the
IMPACT-HF study and registry (W. Gattis-Stough,
unpublished data, 2005). Comparing patients with
weight loss above and below median, these data
suggest that the degree of weight loss was not
associated with the degree of improvement in fatigue,
paroxysmal nocturnal dyspnea, or rest dyspnea. Only
orthopnea (P b .001) and dyspnea on exercise (P =
.028) improved more in patients who lost more weight.
A greater degree of weight loss during hospitalization
was not associated with a reduction in recurrent HF or
death at 60 days. In support of the hypotheses of
limited fluid accumulation in most patients admitted
with AHF, the use of more aggressive diuretic treatment
either during the initial stabilization period or as
continuous maintenance therapy has not been associated with improved outcome. 14 Moreover, aggressive
diuretic treatment of AHF has been has correlated with
more adverse events, especially renal failure. 15 Taken
together, these data suggest that the pathogenesis of
AHF (and thus the optimal treatment) is substantially
more complicated than volume overload alone.
Nonadherence
Nonadherence may be a significant precipitating
factor in some patients with AHF, especially those with
severe chronic HF. Data on this topic are limited because
of the inability to measure adherence reliably. Nonadherence is reported in 20% to 60% of patients with
chronic HF and is often quoted as the leading cause for
hospital admission. In a prospective study, higher readmission rates, more hospitalization days, and a lower
EF after 6 years were found in HF patients who were
noncompliant with digoxin (which suggests higher
noncompliance with other aspects of the medical
regimen 16 ). Cline et al 17 reported that half of a cohort
of patients with chronic HF could not recall the correct
dose of the prescribed medication, and more than half
could not remember the correct time for taking the
medication. We have examined compliance by pill count
in patients post-MI who required captopril treatment
for HF and prospectively found nonadherence to be
associated with more adverse outcome and readmission
due to AHF. 18 Similar findings are reported for nonadherence with fluid and diet recommendations. 19 In
a large prospective study, even nonadherence with
American Heart Journal
Volume 155, Number 1
placebo was associated with worst outcome in patients
with CHF. 20 To date, the importance of nonadherence in
AHF pathophysiology remains poorly defined because
no large prospective studies have directly addressed the
role of nonadherence in an unselected cohort of patients
with AHF. This distinction is important because, as noted,
AHF may frequently occur on a background of minimal or
mild chronic HF. Although such patients may be less
sensitive to nonadherence with diet or diuretic therapy,
nonadherence to other treatments (such as hypertension)
may still be a significant factor in the genesis of AHF.
Myocardial ischemia
Most patients admitted for AHF have a history of
chronic ischemic heart disease, and ischemia is often
invoked as an important trigger for AHF. Surprisingly,
however, little data exist on the incidence of acute
ischemia during an AHF event. However, in the large
European registry, 4 only 32% of patients admitted with
AHF had chest pain at admission, and acute myocardial
infarction was diagnosed in only 12%. Surprisingly, few
other data exist on the occurrence of frank acute
coronary syndrome (ACS) during an AHF event. This
may be related in part to the fact that electrocardiographic changes and troponin release may occur in
patients with HF without coronary disease (and may be
the result rather than the cause of the AHF syndrome). 21,22 Available data suggest that the incidence of
troponin above the threshold for ACS diagnosis in
patients with AHF is approximately 20%. 23,24 In the
PRESERVED-HF study, a multicenter, prospective, randomized, open-label trial of nesiritide or dobutamine in
51 patients with chronic ischemic (but not acute) heart
disease admitted with AHF, detectable troponin T was
present in 43.5%, and troponin I was present in 73.9%
of patients at baseline. 24 In the patients with undetectable baseline troponin, 7.7% developed detectable
troponin T, and 41.7% developed detectable troponin I
during the hospitalization. Only 15% of patients
completed the study without evidence of troponin I
release. Although the study was not powered to
evaluate clinical events, baseline and peak values of
troponin were significantly higher in patients experiencing death or worsening HF as compared with
patients with no event. However, as alluded to
previously, low levels of detectable troponin may not
be direct evidence of ACS because they may also be
seen in patients with AHF without coronary disease.
RITZ 4 is the only prospective study that evaluated
patients admitted with AHF who also have ACS,
randomizing 200 patients admitted with AHF accompanied by ACS to placebo or the endothelin antagonist
tezosentan. 25 During the first 72 hours after enrollment,
3% of patients died, 12% sustained a recurrent event
of HF, and 12% had recurrent ischemia, of which 3%
were frank myocardial infarctions. In these patients,
Cotter et al 11
troponin increase was a strong predictor of adverse
outcome. 26 More data exist on the occurrence of AHF
during admission for ACS. Khot et al 27 reported on the
incidence and outcome of clinical HF (by Killip class) in
a large cohort of patients (n N 20 000) with non–STelevation ACS enrolled in the GUSTO IIb, Paragon A
and B, and PURSUIT studies. Acute HF (Killip class ≥2)
was observed in 11% of the patients, leading to a 9%
one-month mortality and 16% six-month mortality—
more than triple the mortality observed in patients
without HF. Acute HF was correlated with 30% of the
overall mortality in the study, being the strongest
independent negative prognostic factor in the cohort.
The exact incidence of frank myocardial ischemia in
AHF remains unknown, in part because of difficulty of
diagnosing ischemia in patients admitted with AHF.
Although observational data cited suggest ischemic
complications in 20% of AHF admissions, this number
may be lower (troponin spillage can occur even when
ischemic heart disease is not present) or higher (ischemia
may occur without significant troponin leakage). Clearly,
patients with both ACS and AHF have a poor prognosis,
and more study of this patient group is needed. 28
Arrhythmias
The contribution of arrhythmias to the pathophysiology
of AHF has not been studied in detail. Most registries have
reported that atrial fibrillation occurs in 30% to 42% of
patients admitted with AHF. 4-6 In a large study by Cleland
et al, 4 42% of patients had atrial fibrillation at admission, of
whom approximately half did not previously have chronic
atrial fibrillation. A quarter of these patients had atrial
fibrillation that was judged to be rapid and presumably the
cause of the AHF event. In the same study, malignant
ventricular arrhythmias were reported in 8% of patients.
Because of the retrospective nature of the study, the
investigators were not able to demonstrate a cause-andeffect relationship between arrhythmias and the occurrence of AHF or its outcome. Recently, Benza et al 29 have
shown that the occurrence of new arrhythmias, mainly
atrial fibrillation, was a strong predictor of recurrent
events and death in patients admitted for AHF. Conceptually, transient arrhythmias may result in steep decreases
in cardiac contractility and deterioration in diastolic
dysfunction, both of which could contribute to an AHF
event. Given that such transient events may be difficult to
detect, the precise role of arrhythmia in the pathogenesis
of AHF remains unknown. The proliferation of implantable devices in patients with chronic HF may provide
important insights into the role of arrhythmia in AHF.
Mechanical lesions
In some patients, the decreased myocardial effective
contractility leading to AHF may be caused by a
significant mechanical lesion that evolves or deteriorates
rapidly. The most common such mechanical lesion is
American Heart Journal
January 2008
12 Cotter et al
acute mitral regurgitation. In a recent study on patients
with recent acute pulmonary edema, stress echocardiographic evaluation revealed significant stress-induced
mitral regurgitation in comparison with control patients
with similar degrees of HF but no pulmonary edema. 30
These findings are in contrast with those of Gandhi
et al, 31 who did not observe significant new valvular
lesions in serial echocardiographic evaluations performed
in patients admitted with AHF and high BP. Other causes
of mechanical lesions that may cause an AHF event are
ischemic or nonischemic papillary muscle rupture,
mechanical valve malfunction due to thrombosis or
pannus, infective endocarditis, ventricular septal rupture,
and aortic dissection causing severe ischemia or aortic
regurgitation. Although no large prospective echocardiographic study was performed in patients admitted for
AHF, the prevalence of such mechanical lesions as the
primary cause of AHF appears to be low.
Novel mechanisms of AHF
Vascular resistance and afterload mismatch
Our knowledge of the hemodynamic events preceding
AHF is limited by the selective use of right heart
catheterization. In unselected registries such as ADHERE,
the main hemodynamic observation related to AHF onset
is a significant increase in BP. 5 In ADHERE, the median
first systolic BP reported (in many cases after some
treatment was administered by emergency medical
services) was 143 mm Hg. We have recently completed a
registry of 341 consecutive patients who were admitted
during a period of 3 months to a community hospital, in
which initial BP measured before treatment by EMS was
164/88 mm Hg. 32 Mean BP in the highest quartile was
212/115 mm Hg. Similar findings have been reported in
other studies enrolling patients in whom BP was
measured early in the course of AHF, suggesting that high
BP is a key feature in most patients with AHF. 33,34 Such
findings suggest the hypothesis that a steep increase in
systemic vascular resistance (SVR) may be an important
trigger for AHF.
In recent years, accumulated evidence has suggested
that measurements of forward contractility power and
flow are significant predictors of short- and long-term
outcome in patients with AHF. The calculation of cardiac
power output (CPo; the product of simultaneously
measured cardiac output [CO] and mean arterial pressure
[MAP]; CPo = MAP × CO) and SVR might be important in
the diagnosis, risk stratification, and monitoring of
patients with both chronic HF and AHF. 35 Cardiac power
output integrates considerations of both contractility
(CO) and afterload (MAP), potentially providing an
integrated means of assessing hemodynamic state in AHF.
In a recent study, CPo and vascular resistance were
invasively measured in 100 patients with AHF at baseline
and for 30 hours. 9 Patients who experienced a recurrent
Figure 1
Recurrent acute HF by baseline cardiac power quartiles.
AHF episode during invasive hemodynamic monitoring
had lower CPo at baseline and deterioration in CPo
leading up to the acute event (Figure 1). Superimposed
on this low and decreasing CPo, we observed a steep
increase in SVR immediately before the AHF event.
These core hemodynamic events lead to an acute
“mismatch” between rapidly increasing afterload and
impaired systolic performance, resulting in an acute
increase in LV end-diastolic pressure and a decrease in
CO. This hemodynamic model may explain the presence
of pulmonary congestion despite modest fluid accumulation. Afterload mismatch and reduced contractility
can lead to fluid redistribution from the peripheral
circulation to the pulmonary circulation due to increased
pulmonary venous pressure transferred backward to the
alveoli, overwhelming the absorptive capabilities of the
alveolar cells, inducing pulmonary congestion and low
peripheral perfusion, the main symptoms of AHF.
The exact causes for the observed sudden increases in
SVR are not known. Some studies have suggested that
in patients with chronic HF, increased arterial stiffness
may be one of the causes of increased vascular
resistance. 36 This mechanism may also be important in
AHF. The incidence of both AHF and arterial stiffness
increases with age. 37 Inflammatory activation, which
has been suggested as a potential trigger of AHF, has
recently been demonstrated to result in an abrupt
increase in arterial stiffness. 38 Regardless of cause, the
paradigm of acute rise in SVR, leading to afterload
mismatch and decreasing cardiac performance, appears
to fit the observational data about the epidemiology of
AHF. Future prospective studies are needed to further
evaluate this hypothesis.
Diastolic dysfunction
Traditionally, EF measured by echocardiography has
been regarded as an important measure of LV contractility. Surprisingly, detailed data on echocardiographic
parameters in patients with AHF are sparse. In the only
American Heart Journal
Volume 155, Number 1
Figure 2
No change in LV EF between admission and 3 days' follow-up in
patients admitted with AHF (Gandhi et al 31).
significant prospective study reported to date, Gandhi
et al 31 assessed EF, valvular function, and simple measures
of diastolic function in 38 patients admitted with AHF
accompanied by high BP. Comparing admission measurements to 3-day follow-up, there was no change in EF
or valvular function (Figure 2), whereas some measures
of diastolic dysfunction were more severe at admission
than at 3-day follow-up. A retrospective study of clinical,
hemodynamic, and neurohormonal correlations of EF in
patients with AHF showed that EF was only weakly
correlated with hemodynamic measures of contractility
(ie, cardiac power) as well as outcome. 39 In another
study, Logeart et al 40 demonstrated that EF had no value
in predicting the short-term prognosis of patients with
AHF. The studies of both Gandhi et al 31 and Logeart et al 40
did demonstrate a correlation between measures of
diastolic (rather than systolic) function and outcome in
AHF. 31,40 In a recent review, Banerjee et al 41 suggested
that acute exacerbation of diastolic dysfunction may be
one of the core echocardiographic findings in patients
with AHF. It is unknown whether diastolic dysfunction
represents a primary mechanism of AHF or a secondary
phenomenon to the acute increases in afterload
described. Regardless, deterioration in diastolic function
may clearly contribute to increases in LV filling pressure,
with subsequent pulmonary congestion due to fluid
redistribution rather than fluid accumulation.
Cardiorenal syndrome
In patients with chronic HF, the presence of concomitant chronic renal dysfunction has been one of the
Cotter et al 13
strongest risk factors for mortality. 42 Although renal
dysfunction predicts all-cause mortality, it is most
predictive of death from progressive HF, suggesting that
in chronic HF, renal dysfunction may be a marker of HF
severity. 43 Indeed, the strongest predictor of creatinine
clearance in patients with chronic HF is CO. 44 In the
setting of hospitalization for AHF, multiple analyses have
confirmed the prognostic value of renal dysfunction as
measured by increase in serum urea nitrogen level and/or
creatinine. 6,45,46 Although the relationship between renal
dysfunction and adverse outcomes appears to be linear,
several studies have used a threshold of a 0.3-mg/dL rise
in serum creatinine over baseline to define this
phenomenon. 47 Changes of this magnitude generally
occur in about a third of patients admitted for AHF and
are associated with a prolonged and complicated hospital
course as well as high rates of morbidity and mortality.
In one multicenter cohort study, a creatinine level
increase of 0.3 mg/dL had a sensitivity of 65% and
specificity of 81% for predicting inhospital mortality. 47
The exact cause for the association between renal
dysfunction and poor outcome in patients with AHF is
not known. On one hand, renal dysfunction may occur
more frequently in patients with more severe AHF and,
therefore, may be a marker of severity. In support of this
concept, increased serum urea nitrogen level, which
integrates both renal perfusion and intrinsic impairment,
was found to be a stronger predictor of adverse outcome
than creatinine in most analyses. 45,48 Alternatively,
greater degrees of renal dysfunction may represent
greater burden of comorbidity (such as diabetes and
hypertension), resulting in acute deterioration in renal
function despite relatively modest hemodynamic insult.
Regardless of cause, worsening renal function may play
an important role in the progression and propagation of
an AHF episode by leading to greater fluid and sodium
retention and neurohormonal activation.
Neurohormonal and inflammatory activation in AHF
Activation of neurohormonal pathways and inflammatory cascades is known to be a central feature of the
chronic HF syndrome. Blockade of neurohormonal
activation has been the major driver of therapeutic
success in drug development for chronic HF. The
interaction between neurohormones, inflammation, and
AHF is complex and has not been studied in detail. In
experimental models, acute increases in inflammatory
cytokines can recapitulate many aspects of the HF
phenotype, including decreased contractility, diastolic
dysfunction, and increased capillary permeability leading
to pulmonary edema. 48,49 Small observational studies
in patients with AHF support a potential role for acute
changes in inflammatory stress in the pathophysiology
of AHF. 50,51 In a study on 30 patients admitted with AHF,
we demonstrated that both classic neurohormones
(norepinephrine, brain natriuretic peptide, and
American Heart Journal
January 2008
14 Cotter et al
Figure 3
Figure 4
Changes in inflammatory markers in patients admitted with acute HF
(interleukin 6 pg/mL).
endothelin 1) and inflammatory markers (interleukin 6,
C-reactive protein) were significantly increased during
the acute phase of AHF both at time zero (before
treatment) and at 48 hours (Figure 3). 50 In a separate
study on 340 patients admitted with AHF, our group has
observed interactions between leukocytosis and lymphocyte ratio on admission and specific characteristics of
AHF (O. Milo-Cotter, unpublished data 2007). Higher
lymphocyte ratio was related to higher admission systolic
BP, whereas lower lymphocyte ratio was related to higher
troponin and more severe recurrent HF and death. The
correlation between increased systolic BP and increased
lymphocytes is in line with recent studies demonstrating
a possible interaction between inflammatory activation
and increased arterial stiffness, 38 suggesting a link
between inflammatory and hemodynamic events in AHF.
A notable finding in these studies has been the
persistence of inflammatory and neurohormonal activation beyond the acute event. In the study by Milo et al, 50
inflammatory and neurohormonal activation persisted
N48 hours and was still incompletely resolved at 60 days.
This pattern was also seen in analysis of data from the
PRESERVED-HF study, in which elevated values of
neurohormones and inflammatory markers persisted at
5 days of follow-up. 24 These data suggest that persistent
elevation of neurohormonal and inflammatory axes in
patients with AHF may explain the high (50%) short-term
rates of recurrence in this disorder.
Ventricular dyssynchrony
It has become apparent in recent years that the
synchronization of cardiac contraction including atrioventricular, interventricular (right ventricle and LV),
and intraventricular (different segments of the LV) is an
important determinant of cardiac contractility. 52,53
Dyssynchrony has been repeatedly shown to be
associated with adverse outcomes in patients with
chronic HF, an association that may be improved with
cardiac resynchronization therapy. 53,54 The importance
of dyssynchrony in patients with AHF has not been
examined. Theoretically, acute changes in cardiac
Plasma (10A) and platelet-bound (10B) P-selectin in patients with
acute HF versus controls.
contractility and conduction may induce dyssynchrony,
which could potentially contribute to the progression
of AHF after an initial insult. In support of this
concept, Brophy et al 55 found that intraventricular
conduction delay is associated with more adverse
outcome in patients admitted with AHF. To date, no
study has evaluated the interaction of AHF and
dyssynchrony in detail.
Platelet activation
In patients with chronic HF, many measures of
platelet activation (particularly P-selectin) have been
shown to be increased and related with outcome. In
AHF, platelet activation may lead to microvascular
reduction in myocardial blood flow, leading to
decreases in cardiac contractility and myocardial
ischemia. O'Connor et al 56 found a significant increase
in both soluble and platelet-bound P-selectin in
patients admitted with AHF as compared with controls
(Figure 4). In the second study, Milo et al 50 found the
same increase when comparing values during an AHF
event with values measured in the same patients at
2-month follow-up. These increases in platelet activation, which have been related to poor outcome,
American Heart Journal
Volume 155, Number 1
Cotter et al 15
Figure 5
Initiation phase of AHF.
suggest a possible avenue for the evaluation of
antiplatelet therapies in AHF.
Putting it together—initiation and
amplification of an AHF event
Consideration of the data summarized suggests a new
framework for understanding the pathophysiology of
AHF events. We suggest that AHF can be understood in
2 phases—an “initiation phase” that provides the initial
trigger and an “amplification phase” in which various
mechanisms contribute to the viscous cycle of deterioration leading to an AHF event.
Initiation phase
As described in Figure 5, our hypothesis suggests that
AHF is initiated by a combination of 2 pathways. The
“cardiac pathway” is fundamentally initiated by a low
cardiac contractility reserve. This low contractility
reserve can be amplified by an acute decrease in
cardiac contractility. A variety of mechanisms may
contribute to this decrease, including ischemia,
arrhythmia, inflammatory activation, or progressive
deterioration in myocardial dysfunction due to the
underlining mechanism causing the HF process. In
many cases, such decrease in contractility will be
accompanied by a plasma troponin leak. This leak
represents sometimes a true acute ischemic event,
although in many cases, it is the result of nonischemic
myocardial necrosis. Rarely, patients with low contractility reserve will develop AHF without a further
decrease in contractility, related to pure nonadherence
and fluid accumulation. As previously alluded to, such
cases are nowadays more commonly treated in out-
patient HF disease management programs by resumption of appropriate dietary and diuretic treatment. An
important inherent mechanism in the cardiac pathway
relates to renal impairment. A decrease in contractility
will invariably lead to lower renal perfusion and fluid
accumulation. Many clinicians will address the fluid
accumulation by an increase in diuretic therapy. Sometimes, this combination may lead to progressive renal
impairment, which, by numerous mechanisms, may
cause further deterioration in the HF process, instigating a viscous cycle of more HF.
In contrast, the “vascular pathway” is commonly the
main pathophysiologic mechanism for AHF in patients
with mild to moderate decrease in cardiac contractility
reserve, which by itself would rarely lead to an AHF
episode. This vascular pathway is fundamentally
related to increased vascular resistance in the periphery associated with increased vascular stiffness. Again,
a variety of mechanisms (including neurohormonal
activation, inflammatory stress, and aging-associated
changes in vascular stiffness) may contribute to the
development of this component. This would lead to
an acute afterload mismatch impairing the forwardpumping ability of the heart and, hence, redistribution
of fluid to the pulmonary circulation and lungs. By
echocardiography this pathway will lead to a mild
decrease in LV EF and concomitant signs of significant,
sometimes acute, diastolic dysfunction.
Although one or the other of these pathways may
predominate in different clinical scenarios, in most
patients, both pathways are active in the initiation
phase of an AHF event. This combination will culminate
into reduction in both forward perfusion of many organ
systems as well as increased LV pressures. This
increased intracavitary pressure of the LV will manifest
as worsening diastolic dysfunction by echocardiography
and increased wedge pressure by right heart catheterization. Although these variables can be quantitated
relatively easily, for the large part these changes are
only epiphenomena related to the AHF event and not
its immediate cause.
Once initiated, multiple mechanisms contribute to the
amplification of the AHF event as described.
Amplification phase
Once initiated, the AHF process is amplified through
several mechanisms:
1. Myocardial necrosis and progressive LV failure:
Although in some cases, acute coronary syndrome
is the cause of the AHF event, in other cases,
AHF, by inducing hypoxia, acidosis, hypoperfusion, significant neurohormonal-inflammatory activation, or increased LV pressure causing
subendocardial ischemia or platelet activation, may
cause additional myocardial necrosis, leading to
American Heart Journal
January 2008
16 Cotter et al
2.
3.
4.
5.
6.
troponin release and further reduction in cardiac
contractility, amplifying the AHF syndrome.
Right ventricular failure: Although in some cases,
an acute event of RV failure is caused by
pulmonary embolism, triggering an AHF event, in
most cases, RV failure is the result rather than
the cause of AHF. During such an event,
increased fluid content in the lungs and decreased
oxygen saturation induce pulmonary vasoconstriction. This process leads to an increase in RV
pressure that further compromises LV function
through the ventricular interaction mechanism. 57
Respiratory failure: Decreased oxygenation, presence of acidosis, and reduced CO may lead to
depressed central respiratory drive, failure of the
respiratory muscles, and eventually respiratory failure superimposed on cardiovascular failure.
Leakage of the alveolar-capillary membrane and
decreased alveolar fluid clearance: The significant
hypoxia and possibly acute inflammatory process
related to AHF may depress the rate of alveolar
fluid clearance, further enhancing pulmonary
congestion.58
Renal failure: As previously described, patients
with AHF who develop acute renal failure during
the course of their admission (defined by an
increase of ≥0.3 mg/dL in serum creatinine) have
worse outcomes. 47 Although the exact reason for
this association is not known, it is possible that
renal failure is a marker of more severe HF but also
an important amplifier of the syndrome trough
fluid accumulation and activation of neurohormonal and inflammatory mechanisms.
Arrhythmias: Arrhythmias, especially atrial tachyarrhythmias, are very common in patients with AHF.
Recently, Benza et al29 have shown that the
occurrence of new arrhythmias, mainly atrial
arrhythmias, was a strong predictor of recurrent
events and death. Hence, development of arrhythmia during the AHF event is an important cause for
further deterioration in these patients.
Conclusions
Acute HF is a collection of clinical syndromes with
varying and poorly understood pathophysiologic
mechanisms. Despite its high prevalence and morbidity, limited understanding of the fundamental underlying pathophysiology has led to a lack of
development of new therapies in this field. Existing
data suggest that some traditional triggers, such as
fluid accumulation, ischemia, and arrhythmias, may
play a limited role in the initiation of this syndrome,
whereas other mechanisms such neurohormonal activation, increased vascular stiffness, and fluid redistribution may play a larger role. Further elucidation of
the role of these various mechanisms will require
carefully designed, prospective studies. Greater understanding of fundamental mechanisms contributing to
AHF may be helpful in defining subtypes that may be
amenable to specific therapies, leading to improved
care for this disorder.
References
1. American Heart Association. 2003 Heart and stroke statistical
update. Dallas (Tex): American Heart Association; 2002.
2. Lee DS, Mamdani MM, Austin PC, et al. Trends in heart failure
outcomes and pharmacotherapy: 1992 to 2000. Am J Med 2004;
116:581-9.
3. Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival
in severe chronic heart failure. N Engl J Med 2001;344:1651-8.
4. Cleland JGF, Swedberg K, Follath F, et al. 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;24:442-63.
5. Adams J, Fonarow GC, Emerman CL, et al. Characteristics and
outcomes 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;149:209-16.
6. Lee DS, Austin PC, Rouleau JL, et al. Predicting mortality among
patients hospitalized for heart failure: derivation and validation of a
clinical model. JAMA 2003;290:2581-7.
7. McMurray JJV, Ostergren J, Swedberg K, et al. Effects of candesartan
in patients with chronic heart failure and reduced left-ventricular
systolic function taking angiotensin-converting-enzyme inhibitors: the
CHARM-Added trial. Lancet 2003;362:767-71.
8. O'Connor CM, Stough WG, Gallup DS, et al. Demographics, clinical
characteristics, and outcomes of patients hospitalized for decompensated heart failure: observations from the IMPACT-HF Registry.
J Card Fail 2005;11:200-5.
9. Cotter G, Moshkovitz Y, Milovanov O, et al. Acute heart failure: a
novel approach to its pathogenesis and treatment. Eur J Heart Fail
2002;4:227-34.
10. Endorsed by the European Society of Intensive Care Medicine, Task
FM, Nieminen MS, et al. Executive summary of the guidelines on the
diagnosis and treatment of acute heart failure: the Task Force on
Acute Heart Failure of the European Society of Cardiology. Eur Heart
J 2005;26:384-416.
11. Verwey HF, Molhoek SG, Sweeney R, et al. Patient symptoms and
device-based activity for decompensated vs. non-decompensated
heart failure patients. J Card Fail 2005;12:170.
12. Lewin J, Ledwidge M, O'Loughlin C, et al. Clinical deterioration in
established heart failure: what is the value of BNP and weight gain in
aiding diagnosis? Eur J Heart Fail 2005;7:953-7.
13. Gheorghiade M, Gattis WA, O'Connor CM, et al. Effects of
tolvaptan, a vasopressin antagonist, in patients hospitalized with
worsening heart failure: a randomized controlled trial. JAMA 2004;
291:1963-71.
14. Cotter G, Weissgarten J, Metzkor E, et al. Increased toxicity of highdose furosemide versus low-dose dopamine in the treatment of
refractory congestive heart failure. Clin Pharmacol Ther 1997;62:
187-93.
15. Butler J, Forman DE, Abraham WT, et al. Relationship between heart
failure treatment and development of worsening renal function
among hospitalized patients. Am Heart J 2004;147:331-8.
American Heart Journal
Volume 155, Number 1
16. Buckle J, Sharkey P, Myriski P, et al. Improving outcomes for patients
hospitalized with CHF. Manag Care Q 2002;10:30-40.
17. Cline CM, Bjorck-Linne AK, Israelsson BY, et al. Non-compliance and
knowledge of prescribed medication in elderly patients with heart
failure. Eur J Heart Fail 1999;1:145-9.
18. Shemesh E, Rudnick A, Kaluski E, et al. A prospective study of
posttraumatic stress symptoms and nonadherence in survivors of a
myocardial infarction (MI). Gen Hosp Psychiatry 2001;23:215-22.
19. van der Wal MH, Jaarsma T, van Veldhuisen DJ. Non-compliance in
patients with heart failure; how can we manage it? Eur J Heart Fail
2005;7:5–17.
20. Granger BB, Swedberg K, Ekman I, et al. Relationship of adherence to
candesartan and placebo with outcomes in chronic heart failure:
results from the CHARM programme. Lancet 2005;366:2005-11.
21. Littmann L. Large T wave inversion and QT prolongation associated
with pulmonary edema: a report of nine cases. J Am Coll Cardiol
1999;34:1106-10.
22. Sugiura T, Takase H, Toriyama T, et al. Circulating levels of
myocardial proteins predict future deterioration of congestive heart
failure. J Card Fail 2005;11:504-9.
23. Gattis WA, O'Connor CM, Gallup DS, et al. Predictors of 60-day
death or rehospitalization in patients admitted with decompensated
heart failure: insights from the IMPACT-HF Trial. J Am Coll Cardiol
2003;17:694.
24. Gheorghiade M, Gattis Stough W, Adams J, et al. The Pilot
Randomized Study of Nesiritide Versus Dobutamine in Heart Failure
(PRESERVD-HF). Am J Cardiol 2005;96:18-25.
25. O'Connor CM, Gattis WA, Adams Jr KF, et al. Tezosentan in patients
with acute heart failure and acute coronary syndromes: results of the
Randomized Intravenous TeZosentan Study (RITZ-4). J Am Coll
Cardiol 2003;41:1452-7.
26. Gattis WA, O'Connor CM, Hasselblad V, et al. Usefulness of an
elevated troponin-I in predicting clinical events in patients admitted
with acute heart failure and acute coronary syndrome (from the RITZ4 trial). Am J Cardiol 2004;93:1436-7.
27. Khot UN, Jia G, Moliterno DJ, et al. Prognostic importance of physical
examination for heart failure in non–ST-elevation acute coronary
syndromes: the enduring value of Killip classification. JAMA
2003;290:2174-81.
28. Velazquez EJ, Pfeffer MA. Acute heart failure complicating acute
coronary syndromes: a deadly intersection. Circulation
2004;109:440-2.
29. Benza RL, Felker GM, Zabel KM, et al. Arrhythmias in heart failure
exacerbations: the OPTIME-CHF study. Circulation 2001;104:525.
30. Pierard LA, Lancellotti P. The role of ischemic mitral regurgitation in
the pathogenesis of acute pulmonary edema. N Engl J Med
2004;351:1627-34.
31. Gandhi SK, Powers JC, Nomeir AM, et al. The pathogenesis of acute
pulmonary edema associated with hypertension. N Engl J Med
2001;344:17-22.
32. Milo-Cotter O, Adams KF, O'Connor CM, et al. Acute heart failure
associated with high admission blood pressure–a distinct vascular
disorder. Eur J Heart Fail 2007;9:178-83.
33. Cotter G, Metzkor E, Kaluski E, et al. Randomised 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;351:389-93.
34. Kaluski E, Kobrin I, Zimlichman R, et al. RITZ-5: randomized
intravenous tezosentan (an endothelin-A/B antagonist) for the
treatment of pulmonary edema: a prospective, multicenter, doubleblind, placebo-controlled study. J Am Coll Cardiol 2003;41:
204-10.
Cotter et al 17
35. Cotter G, Moshkovitz Y, Kaluski E, et al. The role of cardiac power
and systemic vascular resistance in the pathophysiology and
diagnosis of patients with acute congestive heart failure. Eur J Heart
Fail 2003;5:443-51.
36. Kawaguchi M, Hay I, Fetics B, et al. Combined ventricular systolic and
arterial stiffening in patients with heart failure and preserved ejection
fraction: implications for systolic and diastolic reserve limitations.
Circulation 2003;107:714-20.
37. Redfield MM, Jacobsen SJ, Borlaug BA, et al. Age- and genderrelated ventricular-vascular stiffening: a community-based study.
Circulation 2005;112:2254-62.
38. Vlachopoulos C, Dima I, Aznaouridis K, et al. Acute systemic
inflammation increases arterial stiffness and decreases wave
reflections in healthy individuals. Circulation 2005;112:
2193-200.
39. Uriel N, Torre-Amione G, Milo O, et al. Echocardiographic ejection
fraction in patients with acute heart failure: correlations with
hemodynamic, clinical, and neurohormonal measures and short-term
outcome. Eur J Heart Fail 2005;7:815-9.
40. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type
natriuretic peptide assay for identifying patients at high risk of readmission after decompensated heart failure. J Am Coll Cardiol
2004;43:635-41.
41. Banerjee P, Clark AL, Nikitin N, et al. Diastolic heart failure.
Paroxysmal or chronic? Eur J Heart Fail 2004;6:427-31.
42. Al Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney
function and anemia as risk factors for mortality in patients with left
ventricular dysfunction. J Am Coll Cardiol 2001;38:955-62.
43. Dries DL, Exner DV, Domanski MJ, et al. The prognostic
implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll
Cardiol 2000;35:681-9.
44. Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive
heart failure: relationship of cardiac index to kidney function. Drugs
1990;39:10-21.
45. Fonarow GC, Adams Jr KF, Abraham WT, et al. Risk stratification
for in-hospital mortality in acutely decompensated heart failure:
classification and regression tree analysis. JAMA 2005;293:
572-80.
46. Felker GM, Leimberger JD, Califf RM, et al. Risk stratification after
hospitalization for decompensated heart failure. J Card Fail
2004;10:460-6.
47. Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of
different definitions of worsening renal function in congestive heart
failure. J Card Fail 2002;8:136-41.
48. Janssen SPM, Gayan-Ramirez G, Van Den Bergh A, et al. Interleukin6 causes myocardial failure and skeletal muscle atrophy in rats.
Circulation 2005;111:996–1005.
49. Pagani FD, Baker LS, Hsi C, et al. Left ventricular systolic and diastolic
dysfunction after infusion of tumor necrosis factor-alpha in conscious
dogs. J Clin Invest 1992;90:389-98.
50. Milo O, Cotter G, Kaluski E, et al. Comparison of inflammatory and
neurohormonal activation in cardiogenic pulmonary edema secondary to ischemic versus nonischemic causes. Am J Cardiol 2003;
92:222-6.
51. Sato Y, Takatsu Y, Kataoka K, et al. Serial circulating concentrations
of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute
left heart decompensation. Clin Cardiol 1999;22:811-3.
52. Sogaard P, Egeblad H, Kim WY, et al. Tissue Doppler imaging
predicts improved systolic performance and reversed left ventricular
remodeling during long-term cardiac resynchronization therapy.
J Am Coll Cardiol 2002;40:723-30.
American Heart Journal
January 2008
18 Cotter et al
53. Bader H, Garrigue S, Lafitte S, et al. Intra-left ventricular electromechanical asynchrony: a new independent predictor of severe cardiac
events in heart failure patients. J Am Coll Cardiol 2004;43:248-56.
54. Cleland JGF, Daubert JC, Erdmann E, et al. The effect of cardiac
resynchronization on morbidity and mortality in heart failure. N Engl
J Med 2005;352:1539-49.
55. Brophy JM, Deslauriers G, Rouleau JL. Long-term prognosis of
patients presenting to the emergency room with decompensated
congestive heart failure. Can J Cardiol 1994;10:543-7.
O
56. O'Connor CM, Gurbel PA, Serebruany VL. Usefulness of soluble and
surface-bound P-selectin in detecting heightened platelet activity
in patients with congestive heart failure. Am J Cardiol 1999;83:
1345-9.
57. Atherton JJ, Moore TD, Lele SS, et al. Diastolic ventricular interaction
in chronic heart failure. Lancet 1997;349:1720-4.
58. Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport
and the resolution of pulmonary edema. Physiol Rev 2002;82:
569-600.
N THE MOVE?
Send us your new address at least 6 weeks ahead
Don’t miss a single issue of the journal! To ensure prompt service when you change your address, please photocopy
and complete the form below.
Please send your change of address notification at least 6 weeks before your move to ensure continued service. We
regret we cannot guarantee replacement of issues missed because of late notification.
JOURNAL TITLE:
Fill in the title of the journal here.
__________________________________________________________
OLD ADDRESS:
NEW ADDRESS:
Affix the address label from a recent issue of the journal here.
Clearly print your new address here.
Name ____________________________________________________
Address __________________________________________________
City/State/ZIP _____________________________________________
COPY AND MAIL THIS FORM TO:
Elsevier Subscription Customer Service
6277 Sea Harbor Dr
Orlando, FL 32887
OR FAX TO:
OR PHONE:
OR E-MAIL:
407-363-9661
1-800-654-2452
Outside the U.S., call
407-345-4000
[email protected]