REVIEWS

Pathophysiology and clinical

evaluation of acute heart failure
Robert J. Mentz1 and Christopher M. O’Connor2
Abstract | Acute heart failure (AHF) is a complex syndrome characterized by worsening heart
failure (HF) symptoms that requires escalation of therapy. Intrinsic cardiac abnormalities and
comorbid conditions, including lung and renal disease, and sleep-disordered breathing, can
contribute to the development of AHF. In this Review, we summarize and discuss the literature on
the clinical evaluation and underlying pathophysiology of AHF. Important features of AHF
evaluation include identification of precipitating factors to the disease, and assessment of
circulatory–renal limitations associated with use of HF medications, prior HF hospitalizations,
congestion and perfusion profiles, and end-organ dysfunction. The pathophysiological
contributions of endothelial dysfunction, neurohormonal activation, venous congestion, and
myocardial injury to the development of AHF are also discussed. These potential causative
mechanisms provide a framework for clinicians to evaluate and manage patients with AHF
and highlight possible future targets for therapies designed to improve clinical outcomes.

Heart failure (HF) is a major public health problem Clinical evaluation

affecting >25 million patients worldwide1. The majority Clinical history
of patients with HF experience an acute worsening of Clinical evaluation of patients with AHF typically
symptoms during the course of their disease. An increase involves a focused history and physical examination
in the severity of chronic HF symptoms that requires an along with ancillary data from laboratory and diagnos-
escalation of therapy and hospitalization is known as tic tests (BOX 1). The majority of patients hospitalized
acute heart failure (AHF)2. The development of AHF is with AHF have a history of HF; patients who develop
complex and is associated with primary cardiac abnor- de novo AHF require extra assessment in addition to the
malities and systemic perturbations, such as labile blood tests explained below. Potential contributing factors to
pressure and inflammation, and comorbid conditions, worsening HF symptoms should be elucidated from the
including lung and renal disease, and sleep-disordered patient’s clinical history. Data from the OPTIMIZE-HF
breathing 3. Despite marked advances in the treatment of registry 9 indicate that in the majority of patients with
chronic HF in the past three decades, the management AHF, precipitating causes such as a concomitant respira-
of AHF has largely remained unchanged and outcomes tory processes or pneumonia, ischaemia, arrhythmia,
after discharge from hospital continue to be poor 4–6. The worsening renal function (WRF), and hypertension can
primary treatment for AHF includes intravenous diuret- be identified. In OPTIMIZE-HF9, precipitating factors
ics, vasodilators, and inotropes, although regional differ- were also independently associated with in-hospital and
ences exist in prescribing patterns7,8. The paucity of novel postdischarge outcomes. Thus, identification of spe-
1
Duke Clinical Research therapies for AHF suggests the need for recharacter­ cific factors that can induce or exacerbate the disease
Institute and Department of
Medicine, Division
ization of the population of patients with AHF. In this can help to individualize treatment targets and might
of Cardiology, Duke Review, we highlight the literature on the clinical evalu­ offer prognostic insight. Additional relevant historical
University Medical Center, ation of AHF and summarize the pathophysiological data include recurrent hospitalizations for AHF and a
2400 Pratt Street, Durham, mechanisms underlying its development. We also dis- progressive inability to tolerate guideline-directed med-
NC 27705, USA.
cuss the contributions of endothelial dysfunction, neuro­ ical therapy. For example, an individual who is unable
2
Inova Heart and Vascular
Institute, 3300 Gallows Road, hormonal activation, venous congestion, myo­cardial to tolerate medications such as angiotensin-convert-
Falls Church, VA 22042, USA. injury, and renal dysfunction to the development of ing-enzyme (ACE) inhibitors owing to symptomatic low
Correspondence to R.J.M. AHF. A review of these topics highlights potential future blood pressure, WRF, or electrolyte disturbances, can be
robert.mentz@duke.edu targets for the treatment of AHF. A description of the identified as being at very high risk for adverse events10.
doi:10.1038/nrcardio.2015.134 current treatment strategies for AHF has been reviewed Similarly, patients with multiple AHF hospitalizations
Published online 15 Sep 2015 ­previously 4, and is beyond the scope of the present article. are at increased risk of poor outcomes, particularly in

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 REVIEWS

Key points part to the role of increased heart rate as a compensa-

tory mechanism to maintain cardiac output in the set-
• Acute heart failure (AHF) is a complex syndrome characterized by the worsening of ting of reduced stroke volume. A physiological increase
signs and symptoms of heart failure in heart rate, therefore, might be beneficial in some
• Clinical evaluation of patients with AHF involves a focused history and physical patients, while others with chronotropic incompetence
examination, along with ancillary data from laboratory and diagnostic tests might experience worse outcomes25.
• New team-based and device-based approaches to the clinical assessment and One potentially helpful strategy for categorizing
management of patients with AHF have improved outcomes and patients with AHF into haemodynamic profiles is the
reduced hospitalization classification system based on degree of congestion
• Neurohormonal activation, venous congestion, endothelial dysfunction, myocardial (wet or dry) and degree of perfusion (warm or cold;
injury, and renal dysfunction are central to the pathophysiology of AHF FIG. 1)26. Patients can be grouped into one of four cate-
• Studies are currently underway to investigate the utility of identifying specific AHF gories by integrating data from the examination of the
phenotypes for targeted therapeutic interventions neck veins, lungs, abdomen, and extremities. Signs and
symptoms of hypoperfusion can include narrow pulse
pressure, cool extremities, fatigue, and WRF, whereas
the weeks and months after hospital discharge11. The evidence of congestion (volume overload) can include
presence of comorbid lung and renal disease can also high jugular venous pressure, oedema, orthopnoea,
aid in prognostic estimates12, and can dictate the triage and the presence of abdominal ascites. Approximately
and management of patients with AHF13. These patients two-thirds of patients admitted to hospital with AHF
also often have a substantial burden of comorbidities,
which complicates HF management and is associated
with poor outcomes14. Box 1 | Clinical assessment of acute heart failure
Specific questions related to the symptom burden
Clinical history
of patients with AHF should also be addressed. For
• Precipitating factors (e.g. infection, ischaemia,
example, increased severity of baseline dyspnoea in arrhythmia, worsening renal function, hypertension,
these patients is associated with elevated morbidity and and medical and dietary noncompliance)
mortality, and increased financial costs15. In a study • Symptoms (e.g. dyspnoea severity, dyspnoea with
published in 2014, patient-reported bendopnoea, or forward bending, and angina)
shortness of breath when bending forwards, was shown
• Signs (e.g. orthopnoea, paroxysmal nocturnal
to be associated with elevated left ventricular filling dyspnoea, oedema, and weight gain)
pressures, particularly in the setting of reduced car-
• Intolerance to heart failure medication (e.g.
diac index 16. Patient-reported angina pectoris also had symptomatic hypotension, worsening renal function,
prognostic implications in HF with either reduced17 or and hyperkalaemia)
preserved18 ejection fraction that is related to increased • Prior hospitalizations for heart failure
risk of hospitalization and revascularization proce-
• Comorbidities (e.g. lung disease, anaemia, diabetes
dures. Furthermore, patients with AHF often experience mellitus, sleep-disordered breathing, obesity,
sleep-disordered breathing and depressive symptoms, depression, and frailty)
which can further complicate the clinical course of the
Physical examination
disease and its treatment 3,19. Thus, a patient’s clinical
• Global assessment
history is an important feature in the initial evaluation
of AHF. • Vital signs (e.g. pulse pressure and heart rate)
• Jugular venous distension, S3 gallop, and murmurs
Physical examination • Congestion and perfusion status
In addition to the clinical history, a comprehensive phys- Laboratory testing
ical examination is another critical component in the • Routine laboratory tests (e.g. serum sodium, blood urea
clinical evaluation of patients with AHF. The primary nitrogen, haemoglobin, and creatinine)
goals of the physical examination are to confirm the • Liver function testing
diagnosis of AHF, identify possible exacerbating fac- • Natriuretic peptide level
tors, and determine disease severity to guide triage and
• Troponin and lactate levels (in selected patients)
patient management. Physical examination begins with
• Potential novel biomarkers (e.g. ST‑2 and galectin‑3)
the global observation of a patient and a review of vital
signs. Low systolic blood pressure has been identified as Additional diagnostic testing
an important clinical variable associated with poor out- • Routine use of electrocardiography for the
comes in patients with AHF20,21. The prognostic relevance identification of ischaemia and arrhythmias, as well
of heart rate in the AHF setting, however, has not been as prognostic criteria, including QRS duration
as clearly defined. In the chronic HF setting, elevated • Consideration of echocardiography based on
heart rate is associated with poor outcomes; a reduction clinical context
in heart rate, therefore, is an important therapeutic tar- • Additional tests in selected patients: cardiac
get 22,23. However, in AHF, baseline elevation in heart rate catheterization (coronary evaluation or haemodynamic
might not be independently associated with outcomes24. assessment), endomyocardial biopsy, and cardiac CT
and MRI
The reason for this is not clear, but might be related in

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S3 gallop compensation by pulmonary lymphatics, and periph-

Orthopnea eral oedema is an insensitive measure of elevated filling
Peripheral oedema
Pulmonary oedema pressure32. Thus, physical examination might provide
Ascites insight into underlying abnormalities in patients with
Hepatojugular reflux
Elevated jugular venous pressure HF, but the overall clinical evaluation should integrate
information from both clinical history and diagnostic
Congested
‘Dry’ ‘wet’ testing, given the limited sensitivity and specificity of
individual examination findings.
Adequate
perfusion
Cool extremities ‘warm’ Laboratory testing
A B
Hypotension Baseline and serial laboratory data are a critical com-
Renal dysfunction ponent of the clinical evaluation of patients with AHF.
Altered mental status
Hyponatremia Routine laboratory test parameters, including serum
Narrow pulse pressure sodium levels, blood urea nitrogen levels, and creatinine
Pulsus alternans levels, can provide an indication of neurohormonal and
L C
Hypo- metabolic status, and can help to identify concomitant
perfusion
‘cold’ renal dysfunction12,33. In particular, an elevation in blood
urea nitrogen is one of the strongest laboratory predictors
Figure 1 | Assessment of haemodynamic profile using a colour gradient chart
for adverse outcomes in AHF33,34. Similarly, other routine
involving haemodynamic signs of patients presenting with heart
Nature failure.
Reviews Profile A
| Cardiology
represents the desired haemodynamic state, where patients with heart failure are both laboratory values, including low haemoglobin35, high red
decongested and warm. Patients who are categorized into the wet-and-cold profile cell distribution width36, and abnormal liver function val-
present with hypoperfusion and elevated filling pressures, while patients in the ues37, provide an indication of the degree of underlying
warm-and-wet profile display elevated filling pressures without reduced perfusion. inflammation and end-organ dysfunction in patients with
Abbreviations: A, clinical profile A (warm-and-dry); B, clinical profile B (warm-and-wet); AHF. Importantly, the natriuretic peptides have an estab-
C, clinical profile C (wet-and-cold); L, clinical profile L (dry-and-cold). lished role in both the diagnosis and prognosis of AHF,
but their measurement is often not required when clini­
cal presentation is consistent with AHF38,39. Natriuretic
are categorized into clinical profile B (warm-and-wet), peptides are valuable in cases of diagnostic uncertainty,
and more than one-quarter have features from profile C such as dyspnoea in the context of concomitant pulmo-
(wet-and-cold), whereas only a minority display traits nary disease. Additional novel biomarkers of myocardial
from profile L (dry-and-cold)27. Profile A represents the fibrosis, such as galectin‑3 and ST2, have been associated
desired state, where patients with HF are decongested with clinical outcomes in some analyses and might be
and warm. These profiles have different prognostic novel therapeutic targets40, but their role in the evaluation
implications and can aid in the management of patients of patients with AHF requires further study.
with AHF. An outcome analysis using the four haemod-
ynamic profiles found that patients with reduced perfu- Diagnostic testing
sion and increased congestion (wet-and-cold) had worse In addition to clinical history, and physical and labora-
outcomes than those with relatively preserved perfusion tory testing, diagnostic assessment also has a role in the
(warm-and-wet)27. clinical evaluation of AHF. Electrocardiography should
Specific data regarding the utility of physical exam- be routinely performed in patients with AHF to assess
ination in the setting of AHF are limited, and emphasis for ischaemia and arrhythmias, which can precipitate
has been placed primarily on the role of congestion on or exacerbate underlying HF symptoms41. For example,
patient outcomes. An analysis from the EVEREST trial28 the presence of ST-segment depression on electrocardio­
demonstrated that most patients with AHF have substan- graphy during AHF effectively reclassifies risk of 30‑day
tial congestion on admission that resolves after stan­dard mortality 42. In addition, prolonged QRS duration is an
decongestion therapy. However, postdischarge out­comes important predictor of increased postdischarge event
were poor despite decongestion, and patients with r­esid­ rates43. Echocardiography should be performed during
ual congestion on discharge were at ­p­articularly high the initial evaluation of patients with HF41, but might
risk of long-term morbidity and mortality 28. not be warranted during recurrent AHF hospitalization
In comparison to the AHF setting, the prognos- unless a suspected or potential change in the disease
tic utility of the physical examination in patients with occurs that would alter management 44. Contemporary
chronic HF has been characterized in greater detail29. echocardiographic techniques such as 3D imaging 45
Elevated jugular venous pressure and the presence of an and strain46 can also assist in the assessment of AHF.
S3 gallop are independently associated with increased Additional testing, such as cardiac catheterization for
morbidity and mortality in HF30. Importantly, the assess- evaluation of the coronary arteries, should be routinely
ment of these physical examination findings requires performed after initial HF diagnosis given the high prev-
some degree of experience and skill31, and a study has alence of ischaemic disease in this cohort of patients.
reported limitations related to the reliability of physi- Invasive haemodynamic assessment and myocardial
cal examination assessments compared with invasive biopsy should be reserved for specific circumstances,
haemodynamic testing 32. In addition, the majority of such as suspected myocarditis (particularly giant cell
patients with chronic HF do not have rales owing to myocarditis) or primary cardiac amyloidosis41,47,48.

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Myocardial remodelling A potential role for the use of device-based technol-

↑ Wall stress ogies in the assessment of patients with AHF has been
↑ Oxidative stress
↑ Inflammation suggested. However, to date, these devices have been
↑ Neurohormonal activation assessed only in the chronic HF population. Implantable
↑ Circulating levels of cardiac troponin pressure monitoring devices might allow for earlier
↑ Altered Ca2+ handling
identification of, and intervention for, fluid overload.
Investigators of the CHAMPION trial50 assessed the
utility of a wireless implantable haemodynamic pres-
sure monitoring system to measure pulmonary arterial
pressure compared with standard care50. Use of data
Endothelial dysfunction derived from this pressure monitoring system reduced
Impairment in endothelial
NO-dependent vasodilatation HF-related hospitalizations over a 6‑month period com-
Acute endothelitis pared with usual care. These findings support the poten-
Adverse effects on myocardial tial value of pulmonary artery pressure monitoring in
fibrosis and cardiac function,
haemodynamics, and coronary addition to clinical evaluation for the improvement of
Venous congestion
and renal circulation Episodic sympathetic- HF management and reduction of adverse events.
mediated fluid shifts from Wearable device-based technology might also pro-
vasoconstriction of the vide data on the activity level of patients with HF. Prior
splanchnic bed owing to
intermittent hypoxia studies have shown that accelerometry data correlate
with symptom class and functional status, and are asso-
ciated with clinical outcomes52–54. The efficacy of nitrates
in HF with preserved ejection fraction in improving
accelerometer-assessed daily activity compared with pla-
cebo is currently under investigation55. These data will
Worsening renal function help to assess the utility of wearable device-based tech-
RAAS stimulation nology to assess functional status, which might support
Sodium and fluid retention additional strategies to assess patients in the time period
Peripheral vasoconstriction
leading up to worsening of HF symptoms and possible
Figure 2 | Mechanisms of acute heart failure. Myocardial remodelling, endothelial AHF hospitalization.
Nature Reviews | Cardiology
dysfunction, venous congestion, and worsening renal function all contribute to
the pathophysiology of acute heart failure. Abbreviations: NO, nitric oxide; RAAS, Pathophysiology of AHF
renin–angiotensin–aldosterone system. In contrast to the improvement in the outcomes of
patients with chronic HF over the past three decades,
patients hospitalized for AHF continue to experience
Advances in assessment and diagnosis high event rates that have not changed in the past 2 dec-
Advances in the clinical evaluation of patients with ades1. With >1 million hospitalizations for AHF annually
AHF in the past decade include team-based approaches in the USA and Europe, as well as 90‑day re­hospitaliza-
to clinical assessment and management 49, as well as tion rates of 30% and 1‑year mortality at approximately
device-based approaches 50. The evaluation strate- 30%1, there is an unmet need for novel therapies to
gies discussed in this Review are often conducted by reduce the substantial morbidity and mortality associ-
a single clinician or nurse. However, the incremental ated with this syndrome. An improved understanding
value of a multi­disciplinary team-based approach in of the underlying pathophysiology of AHF provides
patients with HF has been demonstrated. Investigators a framework for clinicians to evaluate and manage
in the SMAC-HF trial49 assessed the utility of a multi­ patients with AHF and highlights possible future tar-
disciplinary health team approach in patients with AHF gets for therapies designed to improve clinical outcomes.
in reducing subsequent hospitalizations and improving FIGURE 2 details the pathophysiological contributions of
adherence to guideline-directed medical therapy. The endothelial dysfunction, neurohormonal activation,
SMAC-HF study involved scheduled group visits with venous congestion, and myocardial remodelling to the
a HF nurse practitioner, mental health nurse special- development of AHF.
ist, social worker, and dietician. The patients’ weight,
sodium and fluid intake, HF symptoms, physical activity, Neurohormonal activation and inflammation
current medications, vital signs, and depressive symp- Since the 1960s, neurohormonal activation has been rec-
toms were all assessed during the visit. This group-based ognized for its central role in cardiac performance and
assessment and management intervention improved has been emphasized in the mechanistic under­­pinnings
medication adherence and reduced HF hospitalization of HF56. During the early course of HF, acti­vation of the
compared with standard care. Larger studies will be nec- adrenergic nervous system and the renin–angiotensi­n–
essary to confirm and extend these results to support aldosterone system (RAAS) induces adaptive changes
broad application of a team-based clinical evaluation that allow for the maintenance of perfusion through
and management approach. Early routine follow-up mechanisms including enhanced cardiac contractility,
following discharge after AHF hospitalization has also sodium and fluid retention, and peripheral vasocon-
been shown to improve outcomes51. striction. However, over time these mechanisms become

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REVIEWS

maladaptive, and result in further cardiac and end-organ induces AHF symptoms can vary between patients. In
dysfunction by increasing fibroblast proliferation, some patients, prominent right-sided cardiac dysfunc-
oxidative stress, and extracellular matrix d­eposition. tion results in backward congestion into the liver and
Pharmacological therapies that inhibit the RAAS and antecedent vessels, as indicated by the development of
adrenergic system are considered first-line therapies for ascites and peripheral oedema72. These patients tend
patients with chronic HF41. However, despite the well- to have a clinical disease course characterized by pro-
established role of neurohormonal activation in chronic gressive volume overload before AHF hospitalization72.
HF57, its role in the AHF setting is less clear. Previous Conversely, many patients do not have substantial weight
studies have demonstrated that levels of neurohormonal gain or have rapid symptom development before AHF
biomarkers, including plasma renin, aldosterone, nor- presentation. These patients have been hypothesized
epinephrine, and endothelin‑1, are elevated in AHF58,59. to have developed symptoms of congestion owing to
Whereas systemic levels of components of the RAAS can rapid fluid shifts from vasoconstriction of the splanch-
induce haemodynamic changes, tissue RAAS is thought nic bed mediated by increased sympathetic activity 73.
to contribute to the long-term effects of cardiac remod- Intermittent hypoxia can trigger episodic sympathetic
elling 60. Additionally, levels of inflammatory biomark- hyperactivity, resulting in the activation of the neuro-
ers, including those from the interleukin and tumour hormonal system, which subsequently leads to the trans-
necrosis factor classes as well as C‑reactive peptide, are location of blood into the effective circulating volume74.
elevated in AHF61–63, and might contribute to an under- Regardless of the mechanism causing venous conges-
lying prothrombotic and proapoptotic milieu64. Elevated tion, fluid overload, when established, leads to a cycle
levels of inflammatory cytokines induced by activation of neurohormonal activation through positive feedback
of the innate immune system have also been shown to be mechanisms that enhance angiotensinogen expression,
involved in the progression of HF65. In addition, ST2 and resulting in downstream maladaptive effects of fibrosis
galectin‑3 levels are increased in the setting of inflam- and apoptosis. Therefore, through sustained myocardial
mation and cardiomyocyte stretch, and are implicated stretch and local RAAS activation, venous congestion
in the development of cardiac dysfunction through their induces subendocardial ischaemia and adverse ventricu-
regulation of fibrosis40. lar remodelling 75, which further exacerbates cardiac dys-
Although biomarkers of RAAS activation might help function and is associated with declining renal function
in assessing the severity of disease and are therapeutic in AHF76,77.
targets in the chronic HF setting, their role in predict- Worsening congestion and compromised renal func-
ing prognosis and in the underlying pathophysiology tion shift the dose–response curve for loop diuretics
of AHF is incompletely understood. An elevation in downward and to the right, such that higher doses are
serum aldosterone level has been associated with long- needed to maintain adequate diuresis. Patients might
term outcomes after AHF hospitalization66. Studies have also experience diuretic resistance through renal adap-
demonstrated that therapies for AHF, such as loop diu- tations and escape mechanisms (such as aldosterone
retics, can induce a further increase in neurohormonal breakthrough and increased prorenin effects), which
activity 67,68, but the majority of these studies were per- is associated with poor outcomes78. Cardiorenal syn-
formed before contemporary use of RAAS inhibitors. dromes type 3 and 4 are characterized by acute and
Neurohormonal activation during AHF has also been chronic renal dysfunction, respectively, with concomi-
linked with WRF69. However, a study published in 2014 tant worsening of cardiac function owing to electrolyte
suggests that the changes in biomarkers of RAAS activa- and acid–base disturbances, sympathetic activation,
tion (such as plasma renin activity and serum aldoster- hypertension, inflammation, and myocardial ischae-
one level) might be similar when comparing high-dose mia79,80. In response to congestion-mediated vascular
versus low-dose loop diuretics, and that WRF occurred stretch, venous en­dothelial function also undergoes
in a similar percentage of patients in each treatment progressive impairment 81.
group, regardless of baseline RAAS activation level70. Endothelial dysfunction has also been associ-
Furthermore, baseline RAAS biomarker levels might ated with the development and progression of HF82.
not be independently associated with short-term out- Endothelial nitric oxide (NO) generation and metabo-
comes70. These data highlight the complexity in inter- lism, in addition to prostaglandins and cytokine levels,
preting RAAS biomarker level and predicting WRF can influence myocardial function, haemodynamics,
in the context of AHF. The ongoing BLAST trial71 is and coronary and renal circulation83. Severe impairment
designed to assess whether the introduction of RAAS in endothelial NO-dependent vasodilatation occurs in
inhibition during AHF hospitalization improves surro- AHF and has been described as an acute endothelitis84.
gate HF markers and clinical outcomes, and will provide An imbalance in NO levels and an increase in oxidative
additional data to support the role of neurohormonal stress are also involved in the development of cardio-
activation in AHF. renal syndrome69. Increasing venous arm pressure in
healthy individuals has been shown to alter endothelial
Venous congestion and endothelial dysfunction cell mRNA expression profiles and increase inflamma-
Venous congestion has a central role in the underlying tion and neurohormonal activation85. Together, these
pathophysiology of AHF through mechanisms involv- data suggest that venous congestion and endothe-
ing neurohormonal activation, endothelial cell activa- lial dysfunction both  contribute to the underlying
tion, and WRF. The process by which venous congestion pathophysiology of AHF.

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Renal dysfunction troponin levels102. Thus, recurrent AHF events involv-

The interdependence of the heart and kidneys is exem- ing serial insults to the myocardium (as identified by
plified through characterization of the cardiorenal low-level troponin elevations) might be an important
syndrome79,80. Renal dysfunction is a well-established mech­anism of disease progression as well as a target
risk factor for adverse events in patients with chronic for therapy. An increase in the expression of addi-
HF86,87. Many patients with AHF also present with renal tional markers of myocardial injury and extracellular
dysfunction on admission, which is independently matrix turnover 103 during AHF suggests that, compared
associated with worse in-hospital and postdischarge with chronic HF, AHF is characterized by a­ccelerated
outcomes88. Similarly, WRF during AHF hospitaliza- ­m­yocardial necrosis and myocardial remodelling.
tion portends poor prognosis89–92. However, studies pub-
lished in 2010 demonstrate that transient worsening of Comorbid disorders
renal function might not necessarily be associated with Comorbid disease such as lung disease, anaemia, dia-
adverse outcomes93,94, and that adequate decongestion betes mellitus, sleep-disordered breathing, depression,
might improve outcomes94. obesity, and frailty all contribute to the development of
The underlying pathways contributing to the devel- AHF3 through mechanisms that include inflammation
opment of renal dysfunction in the setting of AHF have and activation of the RAAS and sympathetic nervous
been reviewed previously 69,79. In brief, venous congestion, system14. For example, chronic obstructive pulmonary
neurohormonal activation, and inflammation are major disease promotes an inflammatory response that induces
contributors to baseline renal dysfunction and the devel- endothelial and cardiomyocyte dysfunction with fibro-
opment of WRF during AHF hospitalization, but the spe- sis, and resultant clinical HF104. Underlying lung disease
cific mechanisms leading to renal dysfunction remain can cause ventricular dysfunction through its effects on
poorly understood95. The historical hypothesis for renal the pulmonary and systemic vasculature105,106. In addi-
dysfunction in AHF was related to arterial underfilling tion, sleep-disordered breathing is also proinflamma-
and reduced forward flow 96, but studies from the past tory, as hypoxaemia and hypercapnoea can induce an
decade have suggested that venous congestion, rather increase in oxidative stress and sympathetic activation19.
than reduced cardiac output, was instead the primary These observations support a role for comorbidities in
driver of renal dysfunction76,77. However, conflicting altering ventricular–vascular coupling in AHF.
data that do not support the venous congestion model as
an isolated or unifying mechanism have since been pub- Advances in understanding
lished95. For example, investigators in one study assessing Advances in the understanding of pathophysiological
changes in renal function and haemodynamic measures mechanisms in AHF in the past decade include the con-
found no association between baseline or change in tributions of sympathetic-mediated fluid redistribution,
venous pressures with the development of WRF97. Venous venous congestion, inflammation, and endothelial dys-
congestion is hypothesized to be affected not only by vol- function63,73,76,82. However, these mechanisms might con-
ume, but also by changes in venous tone and sympathetic tribute to the development of AHF to different degrees
activation73,95. Thus, whereas the contemporary focus has in individual patients. As such, the haemodynamic pro-
been on venous congestion, the development of renal file model used to characterize a patient’s volume and
dysfunction in individual patients is varied and in some perfusion status might oversimplify the potential com-
cases might be attributable to ­neurohormonal-mediated plexity of the AHF population. Different phenotypes of
or inflammation-mediated mechanisms. patients with acute or chronic HF have been identified
using cluster analysis107,108 performed on baseline varia-
Myocardial injury bles, which were assessed for their utility in categorizing
Myocardial injury in the setting of HF is routinely iden- patients into different groups on the basis of demo-
tified by measuring the circulating levels of cardiac graphics, comorbidities, HF aetiology, biomarker data,
troponin98. The serum troponin level is elevated in the haemodynamic profile, quality of life, and functional
majority of patients with AHF even in the absence of status. The researchers found marked heterogeneity in
clinical ischaemia, owing to increased wall stress, oxi- disease characteristics between HF patient subgroups,
dative stress, inflammation, neurohormonal activation, which translated into differential clinical outcomes.
and altered calcium handling 98. The data on the prog- Future analyses in AHF populations should assess the
nostic utility of troponin in the setting of AHF have been potential utility of identifying specific phenotypes that
mixed. Several studies have suggested that positive (ele- might benefit from targeted therapeutic interventions.
vated) troponin at baseline or conversion to a positive The use of biomarker evaluations might be one potential
level is associated with adverse short-term outcomes99,100. strategy to further characterize the underlying dysfunc-
However, in a study employing the use of a contempor­ tion in individual patients with AHF in order to target
ary high-sensitivit­y assay for troponin, no association the causal mechanisms with specific therapeutics109. For
between baseline troponin elevation and postdischarge example, the novel therapeutic agent serelaxin has been
outcomes at 30 or 180 days was identified101. Therefore, shown to have favourable effects on biomarker profiles
the mechanisms by which myocardial injury contributes in patients with AHF102. Investigators in future studies
to underlying AHF pathophysiology remains unclear. could prospectively assess whether patients with specific
Interestingly, serelaxin, a novel pharmacological agent biomarker profiles at baseline receive a greater therapeu-
for AHF, reduced mortality at 180 days and reduced tic benefit from novel AHF medications. Furthermore,

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REVIEWS

the relationship between a short-term in-hospital infu- identification of precipitating factors, circulatory–renal
sion and improved post­discharge mortality, as well as limitations to HF medication use, prior HF hospitaliza-
the potential role of reduced time-to-treatmen­t (that tions, congestion and perfusion profiles, end-organ dys-
is, infusion within 16 h of presentation) might provide function, and comorbidities. Neurohormonal activation
important insights into specific AHF mechanisms for has long been appreciated as a prominent contributor
targeted intervention. to the mechanistic underpinnings of HF, and there is
an increasing understanding of the role of venous con-
Conclusions gestion, endothelial dysfunction, and myocardial injury
The clinical assessment of patients with AHF involves in the context of AHF. These observations should offer
a focused history and physical examination, along guidance to clinicians in the management of patients
with ancillary data from laboratory and diagnostic with AHF and highlight potential future targets for
tests. Important features of these evaluations include therapies designed to improve clinical outcomes.

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