European Heart Journal Supplements (2016) 18(Supplement G), G11–G18

The Heart of the Matter

doi:10.1093/eurheartj/suw044

Understanding acute heart failure: pathophysiology

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and diagnosis
Mattia Arrigo1,2, John T. Parissis3, Eiichi Akiyama4, and Alexandre Mebazaa1*
1
Department of Anaesthesiology and Critical Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals,
2 rue A. Paré, 75010 Paris, France
2
Department of Cardiology, University Heart Center, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland
3
Heart Failure Clinic, Attikon University Hospital, 1 Rimini street, 12462 Athens, Greece
4
Division of Cardiology, Yokohama City University Medical Center, 4–57 Urafune, Minami-ku, Yokohama 232–0024, Japan

KEYWORDS Acute heart failure (AHF) is a relevant public health problem causing the majority of
Acute heart failure; unplanned hospital admissions in patients aged of 65 years or more. AHF was histori-
Congestion; cally described as a pump failure causing downstream hypoperfusion and upstream
Pathophysiology; congestion. During the last decades a more complex network of interactions has
Diagnosis; been added to the simplistic haemodynamic model for explaining the pathophysiol-
Management
ogy of AHF. In addition, AHF is not a specific disease but the shared clinical presenta-
tion of different, heterogeneous cardiac abnormalities.
Persistence of poor outcomes in AHF might be related to the paucity of improve-
ments in the acute management of those patients. Indeed, acute treatment of AHF
still mainly consists of intravenous diuretics and/or vasodilators, tailored according
to the initial haemodynamic status with little regard to the underlying pathophysio-
logical particularities. Therefore, there is an unmet need for increased individualiza-
tion of AHF treatment according to the predominant underlying pathophysiological
mechanisms to, hopefully, improve patient’s outcome.
In this article we review current knowledge on pathophysiology and initial diagnosis
of AHF.

Introduction of AHF still mainly consists of non-invasive ventilation in

case of pulmonary oedema, intravenous diuretics and/or
Acute heart failure (AHF) is a relevant public health prob- vasodilators. These interventions are tailored according to
lem causing the majority of unplanned hospital admissions the initial haemodynamic status with little regard to the
in patients aged of 65 years or more.1 Despite major underlying pathophysiological particularities.3–5
achievements in the treatment of chronic heart failure Acute heart failure was historically described as a
(HF) over the last decades, which led to marked improve- pump failure causing downstream hypoperfusion and up-
ment in long-term survival, outcomes of AHF remain poor stream congestion. During the last decades a more com-
with 90-day rehospitalization and 1-year mortality rates plex network of interactions has been added to the
reaching 10–30%.2 Persistence of poor outcomes in AHF simplistic haemodynamic model for explaining the path-
might be related to the paucity of improvements in the ophysiology of AHF.6 In addition, AHF is not a specific dis-
acute management of those patients. Despite lacking evi- ease but the shared clinical presentation of different,
dence of beneficial effects on outcome, acute treatment heterogeneous cardiac abnormalities. Therefore, there
is an unmet need for increased individualization of AHF
treatment according to the predominant underlying
*Corresponding author. Tel: þ 33 1 49 95 80 71, Fax: þ 33 1 49 95 80 73, pathophysiological mechanisms to, hopefully, improve
Email: [email protected] patient’s outcome.

Published on behalf of the European Society of Cardiology. All rights reserved. V

C The Author 2016.

For permissions please email: [email protected]

G12 M. Arrigo et al.

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Figure 1 Congestion in heart failure.

Pathophysiology of acute heart failure In healthy individuals, increased total body sodium is
usually not accompanied by oedema formation since a
Acute heart failure is defined as new-onset or worsening of large quantity of sodium may be buffered by interstitial
symptoms and signs of HF,5 often requiring rapid escalation glycosaminoglycan networks without compensatory water
of therapy and hospital admission. The clinical presenta- retention.14 Moreover, the interstitial glycosaminoglycan
tion of AHF typically includes symptoms or signs related to networks display low compliance which prevents fluid ac-
congestion and volume overload rather than to hypoperfu- cumulation in the interstitium.15
sion.7 Since congestion plays a central role for the vast ma- In HF, when sodium accumulation persists, the glycos-
jority of AHF cases, understanding of the underlying aminoglycan networks may become dysfunctional resulting
pathophysiological mechanisms related to congestion is es- in reduced buffering capacity and increased compliance.
sential for treating AHF patients.8 More importantly, the In AHF the presence of pulmonary or peripheral oedema
level of congestion and the number of congested organs correlates poorly with left- and right-sided filling pres-
have prognostic relevance in HF patients.8 sures,16,17 but in patients with dysfunctional glycosamino-
glycan networks even mildly elevated venous pressures
might lead to pulmonary and peripheral oedemas.9 In addi-
Mechanisms of congestion: fluid accumulation tion, since a large amount of sodium is stored in the inter-
and fluid redistribution stitial glycosaminoglycan networks and does not reach the
kidneys, it escapes renal clearance and is particularly diffi-
In presence of cardiac dysfunction, several neuro-humoral cult to remove from the body.9
pathways, including the sympathetic nervous system, the Moreover, persistent neuro-humoral activation induces
renin-angiotensin-aldosterone system and the arginine- maladaptive processes resulting in detrimental ventricular
vasopressin system, are activated to counter the negative remodelling and organ dysfunction. Based on that, pharma-
effects of HF on oxygen delivery to the peripheral tissues. cological therapies that inhibit the sympathetic and renin-
Neuro-humoral activation in HF leads to impaired regulation angiotensin-aldosterone systems, including beta-blockers,
of sodium excretion through the kidneys which results in so- angiotensin-converting enzyme inhibitors, angiotensin
dium and, secondarily, fluid accumulation9,10 (see Figure 1). receptor blockers, aldosterone antagonists and more re-
Indeed, significantly increased cardiac filling pressures and cently the angiotensin receptor neprilysin inhibitor LCZ696
venous congestion are frequently observed days or weeks have become the mainstays of chronic HF therapy.18–33
before the overt clinical decompensation.11–13 Fluid accumulation alone cannot explain the whole path-
Tissue oedema occurs when the transudation from ophysiology of AHF. Indeed, the majority of AHF patients
capillaries into the interstitium exceeds the maximal drain- display only a minor increase in body weight (<1 kg) before
age of the lymphatic system. Transudation of plasma fluid hospital admission.11–13
into the interstitium results from the relation between hy- In those patients, congestion is precipitated by fluid redis-
drostatic and oncotic pressures in the capillaries and in the tribution, rather than accumulation. Sympathetic stimula-
interstitium as well as interstitial compliance. Increased tion has been shown to induce a transient vasoconstriction
transcapillary hydrostatic pressure gradient, decreased leading to a sudden displacement of volume from the
transcapillary oncotic pressure gradient and increased in- splanchnic and peripheral venous system to the pulmonary
terstitial compliance promote oedema formation. circulation, without exogenous fluid retention.34,35
Understanding acute heart failure G13

Table 1 Overview of congestion-induced organ dysfunction and clinical manifestations

Congested organ Clinical manifestation References

83–85
Heart Third heart sound, jugular vein distension, positive hepato-jugular reflux
Functional mitral and tricuspid regurgitation
Elevated NPs: BNP >100 pg/mL, NT-proBNP >300 pg/mL, MR-proANP >120 pmol/L
8,66
Lung Dyspnoea, orthopnoea, bendopnoea, paroxysmal nocturnal dyspnoea
Auscultatory rales, crackles, wheezing; tachypnoea and hypoxia
Pathological chest radiography (interstitial/alveolar oedema, pleural effusion)

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B-lines (‘comets’) on lung ultrasound
44,45
Kidney Decreased urine output
Elevated creatinine levels, hyponatraemia
47,48
Liver Right-sided upper abdominal discomfort, hepatomegaly, icterus
Elevated parameters of cholestasis
46,51
Bowel Nausea, vomiting, abdominal pain
Ascites, increased abdominal pressure
Cachexia

Nonetheless, the prerequisite for fluid redistribution is the Historically, renal dysfunction in HF was described as con-
presence of a certain amount of peripheral and splanchnic sequence of reduced cardiac index and arterial underfilling
congestion. both causing renal hypoperfusion.43 More recent data
In physiological states, capacitance veins contain one showed that venous congestion (assessed as increased cen-
fourth of the total blood volume and stabilize cardiac pre- tral venous pressure) was the strongest haemodynamic de-
load, buffering volume overload.36,37 In hypertensive AHF, terminant for the development of renal dysfunction and
the primary alteration is a mismatch in the ventricular- low cardiac index alone in AHF has minor effects on renal
vascular coupling relationship with increased afterload and function.44,45 However, the combination of elevated cen-
decreased venous capacitance (increased preload).38 tral venous pressure and low cardiac index is particularly
Fluid accumulation and fluid redistribution both produce unfavourable for renal function.
an increase in cardiac load and congestion in AHF, but their Visceral congestion may increase intra-abdominal pres-
relevance is likely to vary according to different clinical sure in HF, which further negatively affects renal function
scenarios. While fluid accumulation might be more com- in HF. Recent data showed that reducing central venous
mon in decompensations of congestive heart failure (CHF) and intra-abdominal pressures by decongestive therapy
with reduced ejection fraction, fluid redistribution might may ameliorate serum creatinine, presumably by alleviat-
be the predominant pathophysiological mechanism in AHF ing renal and abdominal congestion.46
with preserved ejection fraction.39 Accordingly, the decon- Cardiac dysfunction is frequently associated with liver
gestive therapy should be tailored. While diuretics might abnormalities (cardio-hepatic syndrome) and negatively
be useful in presence of fluid accumulation, vasodilators influences prognosis in AHF.47,48 Cholestatic liver dysfunc-
might be more appropriate in presence of fluid redistribu- tion is common in HF and is mainly related to right-sided
tion to modulate ventricular-vascular coupling. congestion, while rapid and marked elevation in transami-
Furthermore, recent experimental data from human nases in AHF indicates hypoxic hepatitis related to hypo-
models suggest that venous congestion is not simply an perfusion.49,50 Finally, bowel congestion may contribute to
epiphenomenon secondary to cardiac dysfunction but development of cachexia in patients with advanced HF.51
rather plays an active detrimental role in the pathophysi-
ology of AHF inducing pro-oxidant, pro-inflammatory and
Assessment of congestion
haemodynamic stimuli that contribute to acute decom-
pensation.40 How these pathophysiological changes are Detection of congestion at an early (asymptomatic) stage is
induced remains incompletely understood but the biome- still an unmet need. Improved diagnostic methods would
chanical forces generated by congestion significantly be highly valuable to enable early initiation of appropriate
contribute to endothelial and neuro-humoral activation. therapy following the ‘time to therapy’ approach recently
Indeed, endothelial stretch triggers an intracellular sig- introduced into HF guidelines.5 The guidelines emphasize
nalling cascade and causes endothelial cells to undergo a the potentially greater benefit of early treatment in the
phenotypic switch to a pro-oxidant, pro-inflammatory setting of AHF, as has long been the case for acute coronary
vasoconstricted state.41 syndromes. Indeed, the congestive cascade often begins
several days or weeks before symptom onset and includes a
Congestion-induced organ dysfunction sub-clinical increase of cardiac filling and venous pressures
(‘haemodynamic congestion’) which may further lead to
Venous congestion significantly contributes to organ dys- redistribution of fluids within the lungs and visceral organs
function in both chronic and acute HF (see Table 1). (‘organ congestion’) and finally to overt signs and symp-
The close interaction between cardiac and renal dys- toms of volume overload (‘clinical congestion’).12,52
function is known as the cardio-renal syndrome.42 Clinical congestion may be the ‘tip of the iceberg’ of the
G14 M. Arrigo et al.

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Figure 2 Early management of AHF.

congestive cascade8. Although organ congestion is usually Since congestion is a typical feature of AHF, patient his-
related to haemodynamic congestion, this might not be al- tory and physical examination should primarily focus on
ways true: indeed, several mechanisms might prevent oe- the presence of congestion which would support the diag-
dema formation despite increased venous pressures and nosis of AHF. Left-sided congestion may cause dyspnoea,
conversely, oedema might develop even in absence of in- orthopnoea, bendopnoea, paroxysmal nocturnal dyspnoea,
creased hydrostatic pressure.53 cough, tachypnoea, pathological lung auscultation (rales,
To achieve early detection of congestion, several strate- crackles, wheezing) and hypoxia.8 The absence of rales
gies including cardiac biomarkers, intrathoracic impedance and a normal chest radiography do not exclude the pres-
monitoring and implantable haemodynamic monitoring have ence of left-sided congestion. Indeed, 40–50% of patients
been proposed.54–59 However, the use of classical bio- with elevated pulmonary-artery wedge pressure may have
markers, in particular natriuretic peptides (NPs), which are a normal chest radiography.66 Right-sided congestion may
released by the failing heart, reflect the severity of myocar- cause increased body weight, bilateral peripheral oedema,
dial dysfunction and only indirectly haemodynamic conges- decreased urine output, abdominal pain, nausea and vom-
tion.60,61 Novel vascular biomarkers (e.g. soluble CD146, iting, jugular vein distension or positive hepato-jugular re-
CA125) might better correlate with congestion than NPs.62–65 flux, ascites, hepatomegaly, icterus.8
Symptoms and signs of hypoperfusion indicate severity
and may include hypotension, tachycardia, weak pulse,
Diagnosis of acute heart failure mental confusion, anxiety, fatigue, cold sweated extremi-
ties, decreased urine output and angina due to myocardial
The early management of AHF should consist of three ischaemia. The presence of inappropriate stroke volume
parts: triage, diagnosis and initiation of treatment, and and clinical and biological signs of hypoperfusion in AHF de-
reassessment (see Figure 2). Since AHF is a life threatening fines cardiogenic shock, the most severe form of cardiac
condition, current guidelines for the management of AHF dysfunction.67 Cardiogenic shock is most frequently related
recommend that diagnosis and initiation of treatment to acute myocardial infarction and accounts for less than
should occur as early as possible, optimally during the first 10% of AHF cases but is associated with in-hospital mortal-
30–60 min after hospital admission.3–5 ity rates of 40–50%.39,68
However, given the limited sensitivity and specificity of
Clinical evaluation symptoms and signs of AHF, the clinical evaluation should
integrate information from additional tests.69,70
The initial clinical evaluation of dyspnoeic patients should According to the presence of clinical symptoms or signs of
help to (i) assess severity of AHF (ii) confirm the diagnosis organ congestion (‘wet’ vs. ‘dry’) and/or peripheral hypo-
of AHF and (iii) identify precipitating factors of AHF. perfusion (‘cold’ vs. ‘warm’), patients may be classified in
Understanding acute heart failure G15

four groups. 67,71 About two of three AHF patients are classi- Natriuretic peptide levels in HFpEF are lower than in HFrEF.
fied ‘wet-warm’ (congested but well perfused), about one Low circulating NPs (thresholds: BNP <100 pg/mL, NT-
of four are ‘wet-cold’ (congested and hypoperfused) proBNP <300 pg/mL, MR-proANP <120 pmol/L) make the
and only a minority are ‘dry-cold’ (not congested and hypo- diagnosis of AHF unlikely. This is true for both HFrEF and
perfused). The fourth group ‘dry-warm’ represent the HFpEF. A recent meta-analysis indicated that at these
compensated (decongested, well-perfused) status. This thresholds BNP and NT-proBNP have sensitivities of 0.95
classification may help to guide initial therapy (mostly vaso- and 0.99 and negative predictive values of 0.94 and 0.98,
dilators and/or diuretics) and carries prognostic informa- respectively, for a diagnosis of AHF.80 MRproANP had a sen-
tion.70 Patients with cardiopulmonary distress should be sitivity ranging from 0.95 to 0.97 and a negative predictive
managed in intensive cardiac care units. value ranging from 0.90 to 0.97.80

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Notably, the use of inotropes should be restricted to pa- However, elevated levels of NPs do not automatically
tients with cardiogenic shock or AHF resulting in hypoten- confirm the diagnosis of AHF, as they may also be associ-
sion and hypoperfusion to maintain end-organ function,5 ated with a wide variety of cardiac and non-cardiac causes.
since their often inappropriate use is associated with in- Among them, atrial fibrillation, age, and renal failure are
creased morbidity and mortality.72 the most important factors impeding the interpretation of
Acute heart failure usually consists of acute decompen- NP measurements. On the other hand, NP levels may be
sation of chronic HF (ADHF) or, less frequently, may arise in disproportionally low in obese patients and in those with
patients without previous history of symptomatic HF (de flash pulmonary oedema. Natriuretic peptides should be
novo AHF).68 The distinction of these two scenarios is im- measured in all patients with suspected AHF upon presen-
portant because the underlying mechanisms leading to AHF tation to the emergency department or intensive cardiac
are significantly different. Indeed, while pre-existing path- care units.3–5
ophysiological derangements predispose CHF patients to Cardiac troponin may be helpful to exclude myocardial
ADHF, de novo AHF is typically induced by severe haemody- ischaemia as precipitating factor of AHF. However, cardiac
namic alterations secondary to the initial insult. Common troponin, in particular when measured with high-sensitive
causes of de novo AHF include acute myocardial infarction, assays, is frequently elevated in patients with AHF, often
severe myocarditis, acute valve regurgitation and pericar- without obvious myocardial ischaemia or an acute coronary
dial tamponade.68 On the other hand, ADHF may be precip- event. Indeed, AHF is characterized by accelerated myo-
itated by several clinical conditions, while in some cardial necrosis and remodelling. Troponin measurement
patients, no precipitant can be identified.2,73–75 may be considered for prognostication as elevated levels
Rapid identification of precipitants of AHF is crucial to are associated with poorer outcomes.81 Numerous clinical
optimize patient management. The most common precipi- variables and biomarkers are independent predictors of in-
tants are myocardial ischaemia, arrhythmias (in particular hospital complications and longer-term outcomes in AHF
paroxysmal atrial fibrillation), sepsis and/or pulmonary syndromes, but their impact on management has not been
disease, uncontrolled hypertension, non-compliance with adequately established. The easy-to perform AHEAD score
medical prescriptions, renal dysfunction and iatrogenic based on the analysis of co-morbidities has been shown to
causes. The identification of precipitants of AHF aims at provide relevant information on short and long term prog-
detecting reversible or treatable causes and at assisting nosis of patients hospitalized for AHF.82
prognostication. Indeed, the initial management should in- An electrocardiography (ECG) may be helpful to identify
clude, in addition to vasodilators and/or diuretics, also potential precipitants of AHF (e.g. arrhythmia, ischaemia)
specific treatments directed towards the underlying causes and to exclude ST-elevation myocardial infarction requiring
of AHF. In particular, early coronary angiography with immediate revascularization. However, ECG is rarely nor-
revascularization is recommended in AHF precipitated by mal in AHF patients. Current guidelines do not recommend
acute coronary syndrome, antiarrhythmic treatment and/ immediate echocardiography in all patients presenting
or electrical cardioversion are recommended in AHF with AHF.3–5 However, all patients presenting with cardio-
precipitated by arrhythmia, rapid initiation of antimicro- genic shock or suspicion of acute life-threatening structural
bial therapy is recommended for AHF precipitated by sep- or functional cardiac abnormalities (mechanical complica-
sis.76–79 Furthermore, identification of precipitants of AHF tions, acute valve regurgitation, aortic dissection) should
may allow risk stratification of patients with AHF. Indeed, receive immediate echocardiography. Early echocardiogra-
AHF precipitated by acute coronary syndrome or infection phy should be considered in all patients with de novo AHF
is associated with poorer outcomes whereas outcomes and in those with unknown cardiac function, however, the
tend to be better in AHF precipitated by atrial fibrillation optimal timing is unknown (preferably within 24–48 h from
or uncontrolled hypertension.73,74 admission).3–5
Thoracic ultrasound and chest X-ray may both be useful
Additional tests to assess the presence of interstitial pulmonary oedema.
While chest X-ray may also be helpful to rule-out alterna-
Additional laboratory tests are helpful in the evaluation of tive causes of dyspnoea (e.g. pneumothorax, pneumonia),
patients with AHF. Natriuretic peptides, including B-type both techniques provide complementary information about
NP (BNP), amino-terminal pro-B-type NP (NT-proBNP) and the presence of pulmonary oedema or pleural effusion.
mid-regional pro-atrial NPs (MR-proANP) show high accu- Abdominal ultrasound may be useful to measure inferior
racy and excellent negative predictive value in differenti- vena cava diameter and collapsibility and exclude the pres-
ating AHF from non-cardiac causes of acute dyspnoea.80 ence of ascites.3–5
G16 M. Arrigo et al.

Reassessment and allocation 5. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS,
Falk V, Gonza lez-Juanatey JR, Harjola V-P, Jankowska EA, Jessup M,
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Most of the patients presenting with AHF require hospital
GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/
admission. The level of care (discharge, observation, ward, Task Force Members, Document Reviewers. 2016 ESC Guidelines for
telemetry and intensive cardiac care unit) should be based the diagnosis and treatment of acute and chronic heart failure: The
on history (including symptom severity, precipitating fac- Task Force for the diagnosis and treatment of acute and chronic
tors), physical examination (haemodynamic and respira- heart failure of the European Society of Cardiology (ESC) Developed
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Conflict of interest: MA is recipient of a fellowship of the Collège 12. Chaudhry SI, Wang Y, Concato J, Gill TM, Krumholz HM. Patterns of
de Médecine des Hôpitaux de Paris. JP has received honoraria for weight change preceding hospitalization for heart failure.
lectures from Novartis, Orion Pharma and Roche Diagnostics. AM Circulation 2007;116:1549–1554.
has received speaker honoraria from Abbott, Novartis, Orion, 13. Zile MR, Bennett TD, St John Sutton M, Cho YK, Adamson PB, Aaron
Roche and Servier and fee as member of advisory board and/or MF, Aranda JM, Abraham WT, Smart FW, Stevenson LW, Kueffer FJ,
steering committee from Cardiorentis, Adrenomed, MyCartis, ZS Bourge RC. Transition from chronic compensated to acute decom-
pensated heart failure: pathophysiological insights obtained from
Pharma and Critical Diagnostics. The other authors declare no con-
continuous monitoring of intracardiac pressures. Circulation
flict of interest. 2008;118:1433–1441.
14. Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M,
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