clinical presentation of acute heart failure

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Article Contents

Introduction, pathophysiology of acute heart failure, diagnosis of acute heart failure.

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Understanding acute heart failure: pathophysiology and diagnosis

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Mattia Arrigo, John T. Parissis, Eiichi Akiyama, Alexandre Mebazaa, Understanding acute heart failure: pathophysiology and diagnosis, European Heart Journal Supplements , Volume 18, Issue suppl_G, December 2016, Pages G11–G18, https://doi.org/10.1093/eurheartj/suw044

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Acute heart failure (AHF) is a relevant public health problem causing the majority of unplanned hospital admissions in patients aged of 65 years or more. AHF was historically described as a pump failure causing downstream hypoperfusion and upstream congestion. During the last decades a more complex network of interactions has been added to the simplistic haemodynamic model for explaining the pathophysiology of AHF. In addition, AHF is not a specific disease but the shared clinical presentation of different, heterogeneous cardiac abnormalities. Persistence of poor outcomes in AHF might be related to the paucity of improvements 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 pathophysiological particularities. Therefore, there is an unmet need for increased individualization 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.

Acute heart failure (AHF) is a relevant public health problem causing the majority of unplanned hospital admissions in patients aged of 65 years or more. 1 Despite major achievements in the treatment of chronic heart failure (HF) over the last decades, which led to marked improvement in long-term survival, outcomes of AHF remain poor with 90-day rehospitalization and 1-year mortality rates reaching 10–30%. 2 Persistence of poor outcomes in AHF might be related to the paucity of improvements in the acute management of those patients. Despite lacking evidence of beneficial effects on outcome, acute treatment of AHF still mainly consists of non-invasive ventilation in case of pulmonary oedema, intravenous diuretics and/or vasodilators. These interventions are tailored according to the initial haemodynamic status with little regard to the underlying pathophysiological particularities. 3–5

Acute heart failure was historically described as a pump failure causing downstream hypoperfusion and upstream congestion. During the last decades a more complex network of interactions has been added to the simplistic haemodynamic model for explaining the pathophysiology of AHF. 6 In addition, AHF is not a specific disease but the shared clinical presentation of different, heterogeneous cardiac abnormalities. Therefore, there is an unmet need for increased individualization of AHF treatment according to the predominant underlying pathophysiological mechanisms to, hopefully, improve patient’s outcome.

Acute heart failure is defined as new-onset or worsening of symptoms and signs of HF, 5 often requiring rapid escalation of therapy and hospital admission. The clinical presentation of AHF typically includes symptoms or signs related to congestion and volume overload rather than to hypoperfusion. 7 Since congestion plays a central role for the vast majority of AHF cases, understanding of the underlying pathophysiological mechanisms related to congestion is essential for treating AHF patients. 8 More importantly, the level of congestion and the number of congested organs have prognostic relevance in HF patients. 8

Mechanisms of congestion: fluid accumulation and fluid redistribution

Congestion in heart failure.

Tissue oedema occurs when the transudation from capillaries into the interstitium exceeds the maximal drainage of the lymphatic system. Transudation of plasma fluid into the interstitium results from the relation between hydrostatic and oncotic pressures in the capillaries and in the interstitium as well as interstitial compliance. Increased transcapillary hydrostatic pressure gradient, decreased transcapillary oncotic pressure gradient and increased interstitial compliance promote oedema formation.

In healthy individuals, increased total body sodium is usually not accompanied by oedema formation since a large quantity of sodium may be buffered by interstitial glycosaminoglycan networks without compensatory water retention. 14 Moreover, the interstitial glycosaminoglycan networks display low compliance which prevents fluid accumulation in the interstitium. 15

In HF, when sodium accumulation persists, the glycosaminoglycan networks may become dysfunctional resulting in reduced buffering capacity and increased compliance. In AHF the presence of pulmonary or peripheral oedema correlates poorly with left- and right-sided filling pressures, 16 , 17 but in patients with dysfunctional glycosaminoglycan networks even mildly elevated venous pressures might lead to pulmonary and peripheral oedemas. 9 In addition, since a large amount of sodium is stored in the interstitial glycosaminoglycan networks and does not reach the kidneys, it escapes renal clearance and is particularly difficult to remove from the body. 9

Moreover, persistent neuro-humoral activation induces maladaptive processes resulting in detrimental ventricular remodelling and organ dysfunction. Based on that, pharmacological therapies that inhibit the sympathetic and renin-angiotensin-aldosterone systems, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists and more recently the angiotensin receptor neprilysin inhibitor LCZ696 have become the mainstays of chronic HF therapy. 18–33

Fluid accumulation alone cannot explain the whole pathophysiology of AHF. Indeed, the majority of AHF patients display only a minor increase in body weight (<1 kg) before hospital admission. 11–13

In those patients, congestion is precipitated by fluid redistribution, rather than accumulation. Sympathetic stimulation has been shown to induce a transient vasoconstriction leading to a sudden displacement of volume from the splanchnic and peripheral venous system to the pulmonary circulation, without exogenous fluid retention. 34 , 35 Nonetheless, the prerequisite for fluid redistribution is the presence of a certain amount of peripheral and splanchnic congestion.

In physiological states, capacitance veins contain one fourth of the total blood volume and stabilize cardiac preload, buffering volume overload. 36 , 37 In hypertensive AHF, the primary alteration is a mismatch in the ventricular-vascular coupling relationship with increased afterload and decreased venous capacitance (increased preload). 38

Fluid accumulation and fluid redistribution both produce an increase in cardiac load and congestion in AHF, but their relevance is likely to vary according to different clinical scenarios. While fluid accumulation might be more common in decompensations of congestive heart failure (CHF) with reduced ejection fraction, fluid redistribution might be the predominant pathophysiological mechanism in AHF with preserved ejection fraction. 39 Accordingly, the decongestive therapy should be tailored. While diuretics might be useful in presence of fluid accumulation, vasodilators might be more appropriate in presence of fluid redistribution to modulate ventricular-vascular coupling.

Furthermore, recent experimental data from human models suggest that venous congestion is not simply an epiphenomenon secondary to cardiac dysfunction but rather plays an active detrimental role in the pathophysiology of AHF inducing pro-oxidant, pro-inflammatory and haemodynamic stimuli that contribute to acute decompensation. 40 How these pathophysiological changes are induced remains incompletely understood but the biomechanical forces generated by congestion significantly contribute to endothelial and neuro-humoral activation. Indeed, endothelial stretch triggers an intracellular signalling cascade and causes endothelial cells to undergo a phenotypic switch to a pro-oxidant, pro-inflammatory vasoconstricted state. 41

Congestion-induced organ dysfunction

Overview of congestion-induced organ dysfunction and clinical manifestations

The close interaction between cardiac and renal dysfunction is known as the cardio-renal syndrome. 42 Historically, renal dysfunction in HF was described as consequence of reduced cardiac index and arterial underfilling both causing renal hypoperfusion. 43 More recent data showed that venous congestion (assessed as increased central venous pressure) was the strongest haemodynamic determinant for the development of renal dysfunction and low cardiac index alone in AHF has minor effects on renal function. 44 , 45 However, the combination of elevated central venous pressure and low cardiac index is particularly unfavourable for renal function.

Visceral congestion may increase intra-abdominal pressure in HF, which further negatively affects renal function in HF. Recent data showed that reducing central venous and intra-abdominal pressures by decongestive therapy may ameliorate serum creatinine, presumably by alleviating renal and abdominal congestion. 46

Cardiac dysfunction is frequently associated with liver abnormalities (cardio-hepatic syndrome) and negatively influences prognosis in AHF. 47 , 48 Cholestatic liver dysfunction is common in HF and is mainly related to right-sided congestion, while rapid and marked elevation in transaminases in AHF indicates hypoxic hepatitis related to hypoperfusion. 49 , 50 Finally, bowel congestion may contribute to development of cachexia in patients with advanced HF. 51

Assessment of congestion

Detection of congestion at an early (asymptomatic) stage is still an unmet need. Improved diagnostic methods would be highly valuable to enable early initiation of appropriate therapy following the ‘time to therapy’ approach recently introduced into HF guidelines. 5 The guidelines emphasize the potentially greater benefit of early treatment in the setting of AHF, as has long been the case for acute coronary syndromes. Indeed, the congestive cascade often begins several days or weeks before symptom onset and includes a sub-clinical increase of cardiac filling and venous pressures (‘haemodynamic congestion’) which may further lead to redistribution of fluids within the lungs and visceral organs (‘organ congestion’) and finally to overt signs and symptoms of volume overload (‘clinical congestion’). 12 , 52 Clinical congestion may be the ‘tip of the iceberg’ of the congestive cascade 8 . Although organ congestion is usually related to haemodynamic congestion, this might not be always true: indeed, several mechanisms might prevent oedema formation despite increased venous pressures and conversely, oedema might develop even in absence of increased hydrostatic pressure. 53

To achieve early detection of congestion, several strategies including cardiac biomarkers, intrathoracic impedance monitoring and implantable haemodynamic monitoring have been proposed. 54–59 However, the use of classical biomarkers, in particular natriuretic peptides (NPs), which are released by the failing heart, reflect the severity of myocardial dysfunction and only indirectly haemodynamic congestion. 60 , 61 Novel vascular biomarkers (e.g. soluble CD146, CA125) might better correlate with congestion than NPs. 62–65

Early management of AHF.

Clinical evaluation

The initial clinical evaluation of dyspnoeic patients should help to (i) assess severity of AHF (ii) confirm the diagnosis of AHF and (iii) identify precipitating factors of AHF.

Since congestion is a typical feature of AHF, patient history and physical examination should primarily focus on the presence of congestion which would support the diagnosis of AHF. Left-sided congestion may cause dyspnoea, orthopnoea, bendopnoea, paroxysmal nocturnal dyspnoea, cough, tachypnoea, pathological lung auscultation (rales, crackles, wheezing) and hypoxia. 8 The absence of rales and a normal chest radiography do not exclude the presence of left-sided congestion. Indeed, 40–50% of patients with elevated pulmonary-artery wedge pressure may have a normal chest radiography. 66 Right-sided congestion may cause increased body weight, bilateral peripheral oedema, decreased urine output, abdominal pain, nausea and vomiting, jugular vein distension or positive hepato-jugular reflux, ascites, hepatomegaly, icterus. 8

Symptoms and signs of hypoperfusion indicate severity and may include hypotension, tachycardia, weak pulse, mental confusion, anxiety, fatigue, cold sweated extremities, decreased urine output and angina due to myocardial ischaemia. The presence of inappropriate stroke volume and clinical and biological signs of hypoperfusion in AHF defines cardiogenic shock, the most severe form of cardiac dysfunction. 67 Cardiogenic shock is most frequently related to acute myocardial infarction and accounts for less than 10% of AHF cases but is associated with in-hospital mortality rates of 40–50%. 39 , 68

However, given the limited sensitivity and specificity of symptoms and signs of AHF, the clinical evaluation should integrate information from additional tests. 69 , 70

According to the presence of clinical symptoms or signs of organ congestion (‘wet’ vs. ‘dry’) and/or peripheral hypoperfusion (‘cold’ vs. ‘warm’), patients may be classified in four groups. 67 , 71 About two of three AHF patients are classified ‘wet-warm’ (congested but well perfused), about one of four are ‘wet-cold’ (congested and hypoperfused) and only a minority are ‘dry-cold’ (not congested and hypoperfused). The fourth group ‘dry-warm’ represent the compensated (decongested, well-perfused) status. This classification may help to guide initial therapy (mostly vasodilators and/or diuretics) and carries prognostic information. 70 Patients with cardiopulmonary distress should be managed in intensive cardiac care units.

Notably, the use of inotropes should be restricted to patients with cardiogenic shock or AHF resulting in hypotension and hypoperfusion to maintain end-organ function, 5 since their often inappropriate use is associated with increased morbidity and mortality. 72

Acute heart failure usually consists of acute decompensation of chronic HF (ADHF) or, less frequently, may arise in patients without previous history of symptomatic HF ( de novo AHF). 68 The distinction of these two scenarios is important because the underlying mechanisms leading to AHF are significantly different. Indeed, while pre-existing pathophysiological derangements predispose CHF patients to ADHF, de novo AHF is typically induced by severe haemodynamic alterations secondary to the initial insult. Common causes of de novo AHF include acute myocardial infarction, severe myocarditis, acute valve regurgitation and pericardial tamponade. 68 On the other hand, ADHF may be precipitated by several clinical conditions, while in some patients, no precipitant can be identified. 2 , 73 , – 75

Rapid identification of precipitants of AHF is crucial to optimize patient management. The most common precipitants are myocardial ischaemia, arrhythmias (in particular paroxysmal atrial fibrillation), sepsis and/or pulmonary disease, uncontrolled hypertension, non-compliance with medical prescriptions, renal dysfunction and iatrogenic causes. The identification of precipitants of AHF aims at detecting reversible or treatable causes and at assisting prognostication. Indeed, the initial management should include, in addition to vasodilators and/or diuretics, also specific treatments directed towards the underlying causes of AHF. In particular, early coronary angiography with revascularization is recommended in AHF precipitated by acute coronary syndrome, antiarrhythmic treatment and/or electrical cardioversion are recommended in AHF precipitated by arrhythmia, rapid initiation of antimicrobial therapy is recommended for AHF precipitated by sepsis. 76–79 Furthermore, identification of precipitants of AHF may allow risk stratification of patients with AHF. Indeed, AHF precipitated by acute coronary syndrome or infection is associated with poorer outcomes whereas outcomes tend to be better in AHF precipitated by atrial fibrillation or uncontrolled hypertension. 73 , 74

Additional tests

Additional laboratory tests are helpful in the evaluation of patients with AHF. Natriuretic peptides, including B-type NP (BNP), amino-terminal pro-B-type NP (NT-proBNP) and mid-regional pro-atrial NPs (MR-proANP) show high accuracy and excellent negative predictive value in differentiating AHF from non-cardiac causes of acute dyspnoea. 80 Natriuretic peptide levels in HFpEF are lower than in HFrEF. Low circulating NPs (thresholds: BNP <100 pg/mL, NT-proBNP <300 pg/mL, MR-proANP <120 pmol/L) make the diagnosis of AHF unlikely. This is true for both HFrEF and HFpEF. A recent meta-analysis indicated that at these thresholds BNP and NT-proBNP have sensitivities of 0.95 and 0.99 and negative predictive values of 0.94 and 0.98, respectively, for a diagnosis of AHF. 80 MRproANP had a sensitivity ranging from 0.95 to 0.97 and a negative predictive value ranging from 0.90 to 0.97. 80

However, elevated levels of NPs do not automatically confirm the diagnosis of AHF, as they may also be associated with a wide variety of cardiac and non-cardiac causes. Among them, atrial fibrillation, age, and renal failure are the most important factors impeding the interpretation of NP measurements. On the other hand, NP levels may be disproportionally low in obese patients and in those with flash pulmonary oedema. Natriuretic peptides should be measured in all patients with suspected AHF upon presentation to the emergency department or intensive cardiac care units. 3–5

Cardiac troponin may be helpful to exclude myocardial ischaemia as precipitating factor of AHF. However, cardiac troponin, in particular when measured with high-sensitive assays, is frequently elevated in patients with AHF, often without obvious myocardial ischaemia or an acute coronary event. Indeed, AHF is characterized by accelerated myocardial necrosis and remodelling. Troponin measurement may be considered for prognostication as elevated levels are associated with poorer outcomes. 81 Numerous clinical variables and biomarkers are independent predictors of in-hospital complications and longer-term outcomes in AHF syndromes, but their impact on management has not been adequately established. The easy-to perform AHEAD score based on the analysis of co-morbidities has been shown to provide relevant information on short and long term prognosis of patients hospitalized for AHF. 82

An electrocardiography (ECG) may be helpful to identify potential precipitants of AHF (e.g. arrhythmia, ischaemia) and to exclude ST-elevation myocardial infarction requiring immediate revascularization. However, ECG is rarely normal in AHF patients. Current guidelines do not recommend immediate echocardiography in all patients presenting with AHF. 3–5 However, all patients presenting with cardiogenic shock or suspicion of acute life-threatening structural or functional cardiac abnormalities (mechanical complications, acute valve regurgitation, aortic dissection) should receive immediate echocardiography. Early echocardiography should be considered in all patients with de novo AHF and in those with unknown cardiac function, however, the optimal timing is unknown (preferably within 24–48 h from admission). 3–5

Thoracic ultrasound and chest X-ray may both be useful to assess the presence of interstitial pulmonary oedema. While chest X-ray may also be helpful to rule-out alternative causes of dyspnoea (e.g. pneumothorax, pneumonia), both techniques provide complementary information about the presence of pulmonary oedema or pleural effusion. Abdominal ultrasound may be useful to measure inferior vena cava diameter and collapsibility and exclude the presence of ascites. 3–5

Reassessment and allocation

Most of the patients presenting with AHF require hospital admission. The level of care (discharge, observation, ward, telemetry and intensive cardiac care unit) should be based on history (including symptom severity, precipitating factors), physical examination (haemodynamic and respiratory status, degree of congestion) and biomarkers (NPs, cardiac troponin, renal function, serum lactate). Forty to 50% of AHF patients require admission to intensive cardiac care units. 39 , 68 Low risk AHF patients (those with slightly elevated NP levels, normal blood pressure, stable renal failure, normal troponin) and with good response to initial therapy may be considered for early discharge. Follow-up plans must be in place prior to discharge and clearly communicated to the primary care team. 3–5

Pathophysiology-based management

According to current knowledge on the pathophysiology of AHF, the initial treatment of AHF patients should include decongestive therapy (e.g. vasodilators and/or diuretics) and specific therapy directed towards the underlying causes of AHF (e.g. revascularization, antiarrhythmic treatments, antimicrobial drugs). Moreover, early administration of oral disease-modifying HF therapy (beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and mineralocorticoid receptor antagonists), before hospital discharge is recommended in all patients with AHF.

Conflict of interest: MA is recipient of a fellowship of the Collège de Médecine des Hôpitaux de Paris. JP has received honoraria for lectures from Novartis, Orion Pharma and Roche Diagnostics. AM has received speaker honoraria from Abbott, Novartis, Orion, Roche and Servier and fee as member of advisory board and/or steering committee from Cardiorentis, Adrenomed, MyCartis, ZS Pharma and Critical Diagnostics. The other authors declare no conflict of interest.

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• heart failure, acute
• hemodynamics
• congenital heart defects
• vasodilators
• heterogeneity
• public health medicine
• hypoperfusion
• hospital admission

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Heart Failure Clinical Presentation

• Author: Ioana Dumitru, MD; Chief Editor: Gyanendra K Sharma, MD, FACC, FASE  more...
• Sections Heart Failure
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Predominant Right-Sided Heart Failure
• Heart Failure in Children
• Heart Failure Criteria, Classification, and Staging
• ACC/AHA Staging
• Approach Considerations
• Routine Laboratory Tests
• Natriuretic Peptides
• Genetic Testing
• Assessment of Hypoxemia
• Electrocardiography
• Chest Radiography
• Echocardiography
• CT Scanning and MRI
• Nuclear Imaging
• Catheterization and Angiography
• Assessment of Functional Capacity
• Nonpharmacologic Therapy
• Pharmacologic Therapy
• Acute Heart Failure Treatment
• Treatment of Heart Failure with Preserved LVEF
• Treatment of Right Ventricular Heart Failure
• Electrophysiologic Intervention
• Revascularization Procedures
• Valvular Surgery
• Ventricular Restoration
• Extracorporeal Membrane Oxygenation
• Ventricular Assist Devices
• Heart Transplantation
• Total Artificial Heart
• Guidelines Summary
• Screening and Genetic Testing
• Diagnostic Procedures
• Mechanical Circulatory Support Devices
• Management of Acute Decompensated Heart Failure (ADHF)
• 2024 ISHLT Guidelines on Heart Failure-Related Cardiogenic Shock
• 2024 ESC Guidelines on Management of Dietary Sodium and Fluid Intake in Heart Failure
• Medication Summary
• Beta-Blockers, Alpha Activity
• Beta-Blockers, Beta-1 Selective
• ACE Inhibitors
• Inotropic Agents
• Vasodilators
• B-type Natriuretic Peptides
• I(f) Inhibitors
• Angiotensin Receptor-Neprilysin Inhibitors (ARNi)
• Diuretics, Loop
• Diuretics, Thiazide
• Diuretics, Other
• Diuretics, Potassium-Sparing
• Aldosterone Antagonists, Selective
• SGLT2 Inhibitors
• Dual SGLT1/2 Inhibitors
• Soluble Guanylate Cyclase Stimulators
• Alpha/Beta Adrenergic Agonists
• Calcium Channel Blockers
• Anticoagulants, Cardiovascular
• Opioid Analgesics
• Questions & Answers
• Media Gallery

In evaluating patients with heart failure, the clinician should ask about the following comorbidities and/or risk factors:

• Previous myocardial infarction
• Valvular heart disease, familial heart disease
• Alcohol use
• Hypertension
• Dyslipidemia
• Coronary/peripheral vascular disease
• Sleep-disordered breathing
• Collagen vascular disease, rheumatic fever
• Pheochromocytoma
• Thyroid disease
• Substance abuse (previous/current history)
• History of chemotherapy/radiation to the chest

The New York Heart Association (NYHA) classification of heart failure is widely used in practice and in clinical studies to quantify clinical assessment of heart failure (see Heart Failure Criteria, Classification, and Staging ). Breathlessness, a cardinal symptom of left ventricular (LV) failure, may manifest with progressively increasing severity as the following:

Exertional dyspnea

Paroxysmal nocturnal dyspnea, dyspnea at rest.

• Acute pulmonary edema

Other cardiac symptoms of heart failure include chest pain/pressure and palpitations. Common noncardiac signs and symptoms of heart failure include anorexia, nausea, weight loss, bloating, fatigue, weakness, oliguria, nocturia, and cerebral symptoms of varying severity, ranging from anxiety to memory impairment and confusion. Findings from the Framingham Heart Study suggested that subclinical cardiac dysfunction and noncardiac comorbidities are associated with increased incidence of heart failure, supporting the idea that heart failure is a progressive syndrome and that noncardiac factors are extremely important. [ 31 , 32 , 58 ]

Older patients with heart failure frequently have preserved ejection fraction and an atypical and/or delayed presentation. [ 59 ]

The principal difference between exertional dyspnea in patients who are healthy and exertional dyspnea in patients with heart failure is the degree of activity necessary to induce the symptom. As heart failure first develops, exertional dyspnea may simply appear to be an aggravation of the breathlessness that occurs in healthy persons during activity, but as LV failure advances, the intensity of exercise resulting in breathlessness progressively declines; however, subjective exercise capacity and objective measures of LV performance at rest in patients with heart failure are not closely correlated. Exertional dyspnea, in fact, may be absent in sedentary patients.

Orthopnea is an early symptom of heart failure and may be defined as dyspnea that develops in the recumbent position and is relieved with elevation of the head with pillows. As in the case of exertional dyspnea, the change in the number of pillows required is important. In the recumbent position, decreased pooling of blood in the lower extremities and abdomen occurs. Blood is displaced from the extrathoracic compartment to the thoracic compartment. The failing LV, operating on the flat portion of the Frank-Starling curve, cannot accept and pump out the extra volume of blood delivered to it without dilating. As a result, pulmonary venous and capillary pressures rise further, causing interstitial pulmonary edema, reduced pulmonary compliance, increased airway resistance, and dyspnea.

Orthopnea occurs rapidly, often within a minute or two of recumbency, and develops when the patient is awake. Orthopnea may occur in any condition in which the vital capacity is low. Marked ascites, regardless of its etiology, is an important cause of orthopnea. In advanced LV failure, orthopnea may be so severe that the patient cannot lie down and must sleep sitting up in a chair or slumped over a table.

Cough, particularly during recumbency, may be an "orthopnea equivalent." This nonproductive cough may be caused by pulmonary congestion and is relieved by the treatment of heart failure.

Paroxysmal nocturnal dyspnea usually occurs at night and is defined as the sudden awakening of the patient, after a couple of hours of sleep, with a feeling of severe anxiety, breathlessness, and suffocation. The patient may bolt upright in bed and gasp for breath. Bronchospasm increases ventilatory difficulty and the work of breathing and is a common complicating factor of paroxysmal nocturnal dyspnea. On chest auscultation, the bronchospasm associated with a heart failure exacerbation can be difficult to distinguish from an acute asthma exacerbation, although other clues from the cardiovascular examination should lead the examiner to the correct diagnosis. Both types of bronchospasm can be present in a single individual.

In contrast to orthopnea, which may be relieved by immediately sitting up in bed, paroxysmal nocturnal dyspnea may require 30 minutes or longer in this position for relief. Episodes may be so frightening that the patient may be afraid to resume sleeping, even after the symptoms have subsided.

Dyspnea at rest in heart failure is the result of the following mechanisms:

• Decreased pulmonary function secondary to decreased compliance and increased airway resistance
• Increased ventilatory drive secondary to hypoxemia due to increased pulmonary capillary wedge pressure (PCWP); ventilation/perfusion (V/Q) mismatching due to increased PCWP and low cardiac output; and increased carbon dioxide production
• Respiratory muscle dysfunction, with decreased respiratory muscle strength, decreased endurance, and ischemia

Pulmonary edema

Acute pulmonary edema is defined as the sudden increase in PCWP (usually >25 mm Hg) as a result of acute and fulminant LV failure. It is a medical emergency and has a very dramatic clinical presentation. The patient appears extremely ill, poorly perfused, restless, sweaty, tachypneic, tachycardic, hypoxic, and coughing, with an increased work of breathing and using respiratory accessory muscles and with frothy sputum that on occasion is blood tinged.

Chest pain/pressure and palpitations

Chest pain/pressure may occur as a result of either primary myocardial ischemia from coronary disease or secondary myocardial ischemia from increased filling pressure, poor cardiac output (and, therefore, poor coronary diastolic filling), or hypotension and hypoxemia.

Palpitations are the sensation a patient has when the heart is racing. It can be secondary to sinus tachycardia due to decompensated heart failure, or more commonly, it is due to atrial or ventricular tachyarrhythmias.

Fatigue and weakness

Fatigue and weakness are often accompanied by a feeling of heaviness in the limbs and are generally related to poor perfusion of the skeletal muscles in patients with a lowered cardiac output. Although they are generally a constant feature of advanced heart failure, episodic fatigue and weakness are also common in earlier stages.

Nocturia and oliguria

Nocturia may occur relatively early in the course of heart failure. Recumbency reduces the deficit in cardiac output in relation to oxygen demand, renal vasoconstriction diminishes, and urine formation increases. Nocturia may be troublesome for patients with heart failure because it may prevent them from obtaining much-needed rest. Oliguria is a late finding in heart failure, and it is found in patients with markedly reduced cardiac output from severely reduced LV function.

Cerebral symptoms

The following may occur in elderly patients with advanced heart failure, particularly in those with cerebrovascular atherosclerosis:

• Memory impairment
• Bad dreams or nightmares
• Rarely, psychosis with disorientation, delirium, or hallucinations

Patients with mild heart failure appear to be in no distress after a few minutes of rest, but they may be obviously dyspneic during and immediately after moderate activity. Patients with left ventricular (LV) failure may be dyspneic when lying flat without elevation of the head for more than a few minutes. Those with severe heart failure appear anxious and may exhibit signs of air hunger in this position.

Patients with a recent onset of heart failure are generally well nourished, but those with chronic severe heart failure are often malnourished and sometimes even cachectic. Chronic marked elevation of the systemic venous pressure may produce exophthalmos and severe tricuspid regurgitation, and it may lead to visible pulsation of the eyes and of the neck veins. Central cyanosis, icterus, and malar flush may be evident in patients with severe heart failure.

In mild or moderate heart failure, stroke volume is normal at rest; in severe heart failure, it is reduced, as reflected by a diminished pulse pressure and a dusky discoloration of the skin. With very severe heart failure, particularly if cardiac output has declined acutely, systolic arterial pressure may be reduced. The pulse may be weak, rapid, and thready; the proportional pulse pressure (pulse pressure/systolic pressure) may be markedly reduced. The proportional pulse pressure correlates reasonably well with cardiac output. In one study, when pulse pressure was less than 25%, it usually reflected a cardiac index of less than 2.2 L/min/m 2 . [ 60 ]

Ascites occurs in patients with increased pressure in the hepatic veins and in the veins draining into the peritoneum; it usually reflects long-standing systemic venous hypertension. Fever may be present in severe decompensated heart failure because of cutaneous vasoconstriction and impairment of heat loss.

Increased adrenergic activity is manifested by tachycardia, diaphoresis, pallor, peripheral cyanosis with pallor and coldness of the extremities, and obvious distention of the peripheral veins secondary to venoconstriction. Diastolic arterial pressure may be slightly elevated.

Rales heard over the lung bases are characteristic of heart failure that is of at least moderate severity. With acute pulmonary edema, rales are frequently accompanied by wheezing and expectoration of frothy, blood-tinged sputum. The absence of rales does not exclude elevation of pulmonary capillary pressure due to LV failure.

Systemic venous hypertension is manifested by jugular venous distention. Normally, jugular venous pressure declines with respiration; however, it increases in patients with heart failure, a finding known as the Kussmaul sign (also found in constrictive pericarditis ). This reflects an increase in right atrial pressure and, therefore, right-sided heart failure. In general, elevated jugular venous pressure is the most reliable indicator of fluid volume overload in older patients, and thorough evaluation is needed. [ 59 ]

The hepatojugular reflux is the distention of the jugular vein induced by applying manual pressure over the liver; the patient's torso should be positioned at a 45° angle. The hepatojugular reflux occurs in patients with elevated left-sided filling pressures and reflects elevated capillary wedge pressure and left-sided heart failure.

Although edema is a cardinal manifestation of heart failure, it does not correlate well with the level of systemic venous pressure. In patients with chronic LV failure and low cardiac output, extracellular fluid volume may be sufficiently expanded to cause edema in the presence of only slight elevations in systemic venous pressure. Usually, a substantial gain of extracellular fluid volume (ie, a minimum of 5 L in adults) must occur before peripheral edema develops. Edema in the absence of dyspnea or other signs of LV or right ventricular (RV) failure is not solely indicative of heart failure and can be observed in many other conditions, including chronic venous insufficiency, nephrotic syndrome, or other syndromes of hypoproteinemia or osmotic imbalance.

Hepatomegaly is prominent in patients with chronic right-sided heart failure, but it may occur rapidly in acute heart failure. When hepatomegaly occurs acutely, the liver is usually tender. In patients with considerable tricuspid regurgitation, a prominent systolic pulsation of the liver, attributable to an enlarged right atrial V wave, is often noted. A presystolic pulsation of the liver, attributable to an enlarged right atrial A wave, can occur in tricuspid stenosis, constrictive pericarditis, restrictive cardiomyopathy involving the right ventricle, and pulmonary hypertension (primary or secondary).

Hydrothorax is most commonly observed in patients with hypertension involving both the systemic and pulmonary circulation. It is usually bilateral, although when unilateral, it is usually confined to the right side of the chest. When hydrothorax develops, dyspnea usually intensifies because of further reductions in vital capacity.

Cardiac findings

Protodiastolic (S 3 ) gallop is the earliest cardiac physical finding in decompensated heart failure in the absence of severe mitral or tricuspid regurgitation or left-to-right shunts. The presence of an S 3 gallop in adults is important, pathologic, and often the most apparent finding on cardiac auscultation in patients with significant heart failure.

Cardiomegaly is a nonspecific finding that nonetheless occurs in most patients with chronic heart failure. Notable exceptions include heart failure from acute myocardial infarction, constrictive pericarditis, restrictive cardiomyopathy, valve or chordae tendineae rupture, or heart failure due to tachyarrhythmias or bradyarrhythmias.

Pulsus alternans (during pulse palpation, this is the alternation of one strong and one weak beat without a change in the cycle length) occurs most commonly in heart failure due to increased resistance to LV ejection, as occurs in hypertension, aortic stenosis, coronary atherosclerosis, and dilated cardiomyopathy. Pulsus alternans is usually associated with an S 3 gallop, signifies advanced myocardial disease, and often disappears with treatment of heart failure.

Accentuation of the P 2 heart sound is a cardinal sign of increased pulmonary artery pressure; it disappears or improves after treatment of heart failure. Mitral and tricuspid regurgitation murmurs are often present in patients with decompensated heart failure because of ventricular dilatatation. These murmurs often disappear or diminish when compensation is restored. Note that the correlation is poor between the intensity of the murmur of mitral regurgitation and its significance in patients with heart failure. Severe mitral regurgitation may be accompanied by an unimpressively soft murmur.

Cardiac cachexia is found in long-standing heart failure, particularly of the RV, because of anorexia from hepatic and intestinal congestion and sometimes because of digitalis toxicity. Occasionally, impaired intestinal absorption of fat occurs and, rarely, protein-losing enteropathy occurs. Patients with heart failure may also exhibit increased total metabolism secondary to augmentation of myocardial oxygen consumption, excessive work of breathing, low-grade fever, and elevated levels of circulating tumor necrosis factor (TNF).

Ascites, congestive hepatomegaly, and anasarca due to elevated right-sided heart pressures transmitted backward into the portal vein circulation may result in increased abdominal girth and epigastric and right upper quadrant (RUQ) abdominal pain. Other gastrointestinal symptoms, caused by congestion of the hepatic and gastrointestinal venous circulation, include anorexia, bloating, nausea, and constipation. In preterminal heart failure, inadequate bowel perfusion can cause abdominal pain, distention, and bloody stools. Distinguishing right-sided heart failure from hepatic failure is often clinically difficult.

Dyspnea, prominent in left ventricular failure, becomes less prominent in isolated right-sided heart failure because of the absence of pulmonary congestion. However, when cardiac output becomes markedly reduced in patients with terminal right-sided heart failure (as may occur in isolated right ventricular infarction and in the late stages of primary pulmonary hypertension and pulmonary thromboembolic disease), severe dyspnea may occur as a consequence of the reduced cardiac output, poor perfusion of respiratory muscles, hypoxemia, and metabolic acidosis.

In children, manifestations of heart failure vary with age. [ 61 ] Signs of pulmonary venous congestion in an infant generally include tachypnea, respiratory distress (retractions), grunting, and difficulty with feeding. Often, children with heart failure have diaphoresis during feedings, which is possibly related to a catecholamine surge that occurs when they are challenged with eating while in respiratory distress.

Right-sided venous congestion is characterized by hepatosplenomegaly and, less frequently, with edema or ascites . Jugular venous distention is not a reliable indicator of systemic venous congestion in infants, because the jugular veins are difficult to observe. Also, the distance from the right atrium to the angle of the jaw may be no more than 8-10 cm, even when the infant is sitting upright. Uncompensated heart failure in an infant primarily manifests as a failure to thrive. In severe cases, failure to thrive may be followed by signs of renal and hepatic failure.

In older children, left-sided venous congestion causes tachypnea, respiratory distress, and wheezing (cardiac asthma). Right-sided congestion may result in hepatosplenomegaly, jugular venous distention, edema, ascites, and/or pleural effusions. Uncompensated heart failure in older children may cause fatigue or lower-than-usual energy levels. Patients may complain of cool extremities, exercise intolerance, dizziness, or syncope.

For more information, see the Medscape Drugs & Diseases article Pediatric Congestive Heart Failure .

Framingham system for diagnosis of heart failure

In the Framingham system, the diagnosis of heart failure requires that either two major criteria or one major and two minor criteria be present concurrently, as shown in Table 1 below. [ 1 ] Minor criteria are accepted only if they cannot be attributed to another medical condition.

Table 1. Framingham Diagnostic Criteria for Heart Failure (Open Table in a new window)

American College of Cardiology/American Heart Association (ACC/AHA) stage A patients are at high risk for heart failure; thus, this stage is now also known as "at risk for heart failure." [ 4 , 5 , 6 , 7 ]  Patients in this stage do not have structural heart disease or symptoms of heart failure. Thus, management in these cases focuses on prevention, through reduction of risk factors. Measures include the following [ 3 ] :

• Treat hypertension (optimal blood pressure: < 130/80 mm Hg [ 62 ] )
• Encourage smoking cessation
• Treat lipid disorders
• Encourage regular exercise
• Discourage alcohol intake and illicit drug use

Patients who have a family history of dilated cardiomyopathy should be screened with a comprehensive history and physical examination together with echocardiography and transthoracic echocardiography every 2-5 years. [ 8 ]

ACC/AHA stage B patients are now also designated as "pre-heart failure.. [ 4 , 5 , 6 , 7 ]  These individuals are asymptomatic, with left ventricular (LV) dysfunction from previous myocardial infarction (MI), LV remodeling from LV hypertrophy (LVH), and asymptomatic valvular dysfunction, which includes patients with New York Heart Association (NYHA) class I heart failure (see Heart Failure Criteria, Classification, and Staging for a description of NYHA classes). [ 3 ] In addition to the heart failure education and aggressive risk factor modification used for stage A, treatment with an angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB) and/or beta-blockade is indicated.

Evaluation for coronary revascularization either percutaneously or surgically, as well as correction of valvular abnormalities, may be indicated. [ 3 ] Treatment with an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden death in patients with an LV ejection fraction (LVEF) below 30% that is more than 40 days post-MI is reasonable if the expected survival is more than 1 year.

There is less evidence for implantation of an ICD in patients with nonischemic cardiomyopathy, an LVEF less than 30%, and no heart failure symptoms. There is no evidence for use of digoxin in these populations. [ 63 ] Aldosterone receptor blockade with eplerenone is indicated for post-MI LV dysfunction.

ACC/AHA stage C patients have structural heart disease and current or previous symptoms of heart failure; they are therefore designated as having "symptomatic heart failure." [ 4 , 5 , 6 , 7 ]  ACC/AHA stage C corresponds with NYHA class I-IV heart failure. The preventive measures used for stage A disease are indicated, as is dietary sodium restriction.

Drugs routinely used in these patients include ACEI/ARBs, beta-blockers, or angiotensin receptor–neprilysin inhibitors (ARNIs), in conjunction with evidence-based beta-blockers, and loop diuretics for fluid retention. [ 3 , 62 , 64 ] For selected patients, therapeutic measures include aldosterone receptor blockers, hydralazine and nitrates in combination, and cardiac resynchronization with or without an ICD (see Electrophysiologic Intervention ). [ 3 , 62 , 64 ]

A meta-analysis performed by Badve et al suggested that the survival benefit of treatment with beta-blockers extends to patients with chronic kidney disease and systolic heart failure (risk ratio 0.72). [ 65 ]

The 2016 and 2017 ACC/AHA focused updates to the 2013 guidelines added a class IIa recommendation for ivabradine, a sinoatrial node modulator, in patients with stage C heart failure. [ 62 , 64 ]  They indicate that ivabradine may reduce hospitalization for patients with symptomatic (NYHA class II-III) stable chronic heart failure with reduced ejection fraction (LVEF ≤35%) who are receiving recommended therapy, including a beta blocker at the maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest. [ 62 , 64 ]

ACC/AHA stage D patients have refractory heart failure (NYHA class IV) that requires specialized interventions; they are in "advanced heart failure." [ 4 , 5 , 6 , 7 ] Therapy includes all the measures used in stages A, B, and C. Treatment considerations include heart transplantation or placement of an LV assist device in eligible patients; pulmonary catheterization; and options for end-of-life care. [ 3 ] For palliation of symptoms, continuous intravenous infusion of a positive inotrope may be considered.

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• Heart Failure. This chest radiograph shows an enlarged cardiac silhouette and edema at the lung bases, signs of acute heart failure.
• Heart Failure. Cardiac cirrhosis. Congestive hepatopathy with large renal vein.
• Heart Failure. Cardiac cirrhosis. Congestive hepatopathy with large inferior vena cava.
• Heart Failure. This electrocardiogram (ECG) is from a 32-year-old female with recent-onset congestive heart failure and syncope. The ECG demonstrates a tachycardia with a 1:1 atrial:ventricular relationship. It is not clear from this tracing whether the atria are driving the ventricles (sinus tachycardia) or the ventricles are driving the atria (ventricular tachycardia [VT]). At first glance, sinus tachycardia in this ECG might be considered with severe conduction disease manifesting as marked first-degree atrioventricular block with left bundle branch block. On closer examination, the ECG morphology gives clues to the actual diagnosis of VT. These clues include the absence of RS complexes in the precordial leads, a QS pattern in V6, and an R wave in aVR. The patient proved to have an incessant VT associated with dilated cardiomyopathy.
• Heart Failure. This is a posteroanterior view of a right ventricular endocardial activation map during ventricular tachycardia in a patient with a previous septal myocardial infarction. The earliest activation is recorded in red; late activation displays as blue to magenta. Fragmented low-amplitude diastolic local electrocardiograms were recorded adjacent to the earliest (red) breakout area, and local ablation in this scarred zone (red dots) resulted in termination and noninducibility of this previously incessant arrhythmia.
• Heart Failure. A 28-year-old woman presented with acute heart failure secondary to chronic hypertension. The enlarged cardiac silhouette on this anteroposterior (AP) radiograph is caused by acute heart failure due to the effects of chronic high blood pressure on the left ventricle. The heart then becomes enlarged, and fluid accumulates in the lungs (ie, pulmonary congestion).
• Heart Failure. Epsilon wave on an electrocardiogram in a patient with arrhythmogenic right ventricular dysplasia (ARVD). ARVD is a congenital cardiomyopathy that is characterized by infiltration of adipose and fibrous tissue into the RV wall and loss of myocardial cells. Primary injuries usually are at the free wall of the RV and right atria, resulting in ventricular and supraventricular arrhythmias. The most significant of all rhythms associated with heart failure are the life-threatening ventricular arrhythmias.
• Heart Failure. Electrocardiogram depicting ventricular fibrillation in a patient with a left ventricular assist device (LVAD). Ventricular fibrillation is often due to ischemic heart disease and can lead to myocardial infarction and/or sudden death.
• Heart Failure. The rhythm on this electrocardiogram (ECG) is sinus with borderline PR prolongation. There is evidence of an acute/evolving anterior ischemia/myocardial infarction (MI) superimposed on the left bundle branch block (LBBB)–like pattern. Note the primary T-wave inversions in leads V2-V4, rather than the expected discordant (upright) T waves in the leads with a negative QRS. Although this finding is not particularly sensitive for ischemia/MI with LBBB, such primary T-wave changes are relatively specific. The prominent voltage with left atrial abnormality and leftward axis in concert with the left ventricular intraventricular conduction delay (IVCD) are consistent with underlying left ventricular hypertrophy. This ECG is an example of "bundle branch block plus." Image courtesy of http://ecg.bidmc.harvard.edu.
• Heart Failure. This electrocardiogram (ECG) shows evidence of severe left ventricular hypertrophy (LVH) with prominent precordial voltage, left atrial abnormality, lateral ST-T abnormalities, and a somewhat leftward QRS axis (–15º). The patient had malignant hypertension with acute heart failure, accounting also for the sinus tachycardia (blood pressure initially 280/180 mmHg). The ST-T changes seen here are nonspecific and could be due to, for example, LVH alone or coronary artery disease. However, the ECG is not consistent with extensive inferolateral myocardial infarction. Image courtesy of http://ecg.bidmc.harvard.edu.
• Heart Failure. The rhythm on this electrocardiogram is atrial tachycardia (rate, 154 beats/min) with a 2:1 atrioventricular (AV) block. Note the partially hidden, nonconducted P waves on the ST segments (eg, leads I and aVL). The QRS is very wide with an atypical intraventricular conduction defect (IVCD) pattern. The rSR' type complex in the lateral leads (I, aVL) is not due to a right bundle branch block (RBBB) but to an atypical left ventricular conduction defect. These unexpected rSR' complexes in the lateral leads (El-Sherif sign) correlate with underlying extensive myocardial infarction (MI) and, occasionally, ventricular aneurysm. (El-Sherif. Br Heart J. 1970;32:440-8.) The notching on the upstroke of the S waves in lead V4 with a left bundle branch block-type pattern also suggests underlying MI (Cabrera sign). This patient had severe cardiomyopathy secondary to coronary artery disease, with extensive left ventricular wall motion abnormalities. Image courtesy of http://ecg.bidmc.harvard.edu.
• Heart Failure. On this electrocardiogram, baseline artifact is present, simulating atrial fibrillation. Such artifact may be caused by a variety of factors, including poor electrode contact, muscle tremor, and electrical interference. A single premature ventricular complex (PVC) is present with a compensatory pause such that the RR interval surrounding the PVC is twice as long as the preceding sinus RR interval. Evidence of a previous anterior myocardial infarction is present with pathologic Q waves in leads V1-V3. Borderline-low precordial voltage is a nonspecific finding. Cardiac catheterization showed a 90% stenosis in the patient's proximal portion the left anterior descending coronary artery, which was treated with angioplasty and stenting. Broad P waves in lead V1 with a prominent negative component is consistent with a left atrial abnormality. Image courtesy of http://ecg.bidmc.harvard.edu.
• Heart Failure. This electrocardiogram (ECG) is from a patient who underwent urgent cardiac catheterization, which revealed diffuse severe coronary spasm (most marked in the left circumflex system) without any fixed obstructive lesions. Severe left ventricular wall motion abnormalities were present, involving the anterior and inferior segments. A question of so-called takotsubo cardiomyopathy (left ventricular apical ballooning syndrome) is also raised (see Bybee et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Int Med 2004:141:858-65). The latter is most often reported in postmenopausal, middle-aged to elderly women in the context of acute emotional stress and may cause ST elevations acutely with subsequent T-wave inversions. A cocaine-induced cardiomyopathy (possibly related to coronary vasospasm) is a consideration but was excluded here. Myocarditis may also be associated with this type of ECG and the cardiomyopathic findings shown here. No fixed obstructive epicardial coronary lesions were detected by coronary arteriography. The findings in this ECG include low-amplitude QRS complexes in the limb leads (with an indeterminate QRS axis), loss of normal precordial R-wave progression (leads V1-V3), and prominent anterior/lateral T-wave inversions. Image courtesy of http://ecg.bidmc.harvard.edu.
• Heart Failure. This electrocardiogram shows an extensive acute/evolving anterolateral myocardial infarction pattern, with ST-T changes most apparent in leads V2-V6, I, and aVL. Slow R-wave progression is also present in leads V1-V3. The rhythm is borderline sinus tachycardia with a single premature atrial complex (PAC) (fourth beat). Note also the low limb-lead voltage and probable left atrial abnormality. Left ventriculography showed diffuse hypokinesis as well as akinesis of the anterolateral and apical walls, with an ejection fraction estimated at 33%. Image courtesy of http://ecg.bidmc.harvard.edu.
• Heart Failure. This electrocardiogram shows a patient is having an evolving anteroseptal myocardial infarction secondary to cocaine. There are Q waves in leads V2-V3 with ST-segment elevation in leads V2-V5 associated with T-wave inversion. Also noted are biphasic T waves in the inferior leads. These multiple abnormalities suggest occlusion of a large left anterior descending artery that wraps around the apex of the heart (or multivessel coronary artery disease). Image courtesy of http://ecg.bidmc.harvard.edu.
• Heart Failure. A color-enhanced angiogram of the left heart shows a plaque-induced obstruction (top center) in a major artery, which can lead to myocardial infarction (MI). MIs can precipitate heart failure.
• Heart Failure. Emphysema is included in the differential diagnosis of heart failure. In this radiograph, emphysema bubbles are noted in the left lung; these can severely impede breathing capacity.
• Heart Failure. Cervicocephalic fibromuscular dysplasia (FMD) can lead to complications such as hypertension and chronic kidney failure, which can lead to heart failure. In this color Doppler and spectral Doppler ultrasonographic examination of the left internal carotid artery (ICA) in a patient with cervicocephalic FMD, stenoses of about 70% is seen in the ICA.
• Heart Failure. Cervicocephalic fibromuscular dysplasia (FMD) can lead to complications such as hypertension and chronic kidney failure, which, in turn, can lead to heart failure. Nodularity in an artery is known as the "string-of-beads sign," and it can be seen this color Doppler ultrasonographic image from a 51-year-old patient with low-grade stenosing FMD of the internal carotid artery (ICA).
• Heart Failure. Electrocardiogram from a 46-year-old man with long-standing hypertension. Note the left atrial abnormality and left ventricular hypertrophy with strain.
• Heart Failure. Electrocardiogram from a 46-year-old man with long-standing hypertension. Left atrial abnormality and left ventricular hypertrophy with strain is revealed.
• Heart Failure. Apical four-chamber echocardiogram in a 37-year-old man with arrhythmogenic right ventricular dysplasia (ARVD), a congenital cardiomyopathy. Note the prominent trabeculae and abnormal wall motion of the dilated RV. ARVD can result in ventricular and supraventricular arrhythmias. The most significant of all rhythms associated with heart failure are the life-threatening ventricular arrhythmias.
• Heart Failure. Cardiac magnetic resonance image (CMRI), short-axis view. This image shows right ventricular (RV) dilatation, trabucular derangement, aneurysm formation, and dyskinetic free wall in a patient with arrhythmogenic RV dysplasia.
• Heart Failure. This transthoracic echocardiogram demonstrates severe mitral regurgitation with a heavily calcified mitral valve and prolapse of the posterior leaflet into the left atrium.
• Heart Failure. Echocardiogram of a patient with severe pulmonic stenosis. This image shows a parasternal short-axis view of a thickened pulmonary valve. Pulmonic stenosis can lead to pulmonary hypertension, which can result in hepatic congestion and in right-sided heart failure.
• Heart Failure. Echocardiogram of a patient with severe pulmonic stenosis. This image shows a Doppler scan of the peak velocity (5.2 m/s) and gradients (peak 109 mmHg, mean 65 mmHg) across the valve.
• Heart Failure. Echocardiogram of a patient with severe pulmonic stenosis. This image shows moderately severe pulmonary insufficiency (orange color flow) is also present.
• Heart Failure. This video is an echocardiogram of a patient with severe pulmonic stenosis. The first segment shows the parasternal short-axis view of the thickened pulmonary valve. The second segment shows the presence of moderate pulmonary insufficiency (orange color flow). AV = aortic valve, PA = pulmonary artery, PI = pulmonary insufficiency, PV = pulmonary valve.
• Heart Failure. Transesophageal echocardiogram with continuous wave Doppler interrogation across the mitral valve. An increased mean gradient of 16 mmHg is revealed, consistent with severe mitral stenosis.
• Table 1. Framingham Diagnostic Criteria for Heart Failure
• Table 2. Evidence-Based BNP and NT-proBNP Cutoff Values for Diagnosing HF
• Table 3. 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Heart Failure Staging System
• Table 4. 2022 ACC/AHA/Heart Failure Society of America (HFSA) Heart Failure Staging System
• Table 5. 2022 ACC/AHA/HFSA Classification of Heart Failure (HF) by Left Ventricular Ejection Fraction (LVEF)

Contributor Information and Disclosures

Ioana Dumitru, MD Associate Professor of Medicine, Division of Cardiology, Founder and Medical Director, Heart Failure and Cardiac Transplant Program, University of Nebraska Medical Center; Associate Professor of Medicine, Division of Cardiology, Veterans Affairs Medical Center Ioana Dumitru, MD is a member of the following medical societies: American College of Cardiology , Heart Failure Society of America , International Society for Heart and Lung Transplantation Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Nothing to disclose.

Yasmine S Ali, MD, MSCI, FACC, FACP Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine; President, LastSky Writing, LLC Yasmine S Ali, MD, MSCI, FACC, FACP is a member of the following medical societies: American College of Cardiology , American College of Physicians , American Heart Association , American Medical Association , American Medical Writers Association , National Lipid Association , Tennessee Medical Association Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: LastSky Writing;Philips Healthcare;M Health;Verywell Health; MedStudy;WellnessVerge;Prose Media; AKH, Inc.; LearnRoll, LLC; Eradigm; RxCe.com; M3 USA; M3 EU; Future US Inc.; Edanz Group; ChesterPA511<br/>Serve(d) as a speaker or a member of a speakers bureau for: RxCe.com.

Gyanendra K Sharma, MD, FACC, FASE Professor of Medicine and Radiology, Director, Adult Echocardiography Laboratory, Section of Cardiology, Medical College of Georgia at Augusta University Gyanendra K Sharma, MD, FACC, FASE is a member of the following medical societies: American Association of Cardiologists of Indian Origin, American Association of Physicians of Indian Origin , American College of Cardiology , American Society of Echocardiography , Society for Cardiovascular Magnetic Resonance , Society of Cardiovascular Computed Tomography Disclosure: Nothing to disclose.

Mathue M Baker, MD Cardiologist, BryanLGH Heart Institute and Saint Elizabeth Regional Medical Center Mathue M Baker, MD is a member of the following medical societies: American College of Cardiology Disclosure: Nothing to disclose.

Henry H Ooi, MD, MRCPI Director, Advanced Heart Failure and Cardiac Transplant Program, Nashville Veterans Affairs Medical Center; Assistant Professor of Medicine, Vanderbilt University School of Medicine Disclosure: Nothing to disclose.

Mariclaire Cloutier Freelance editor, Medscape Drugs & Diseases Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha , American Academy of Emergency Medicine , American College of Chest Physicians , American College of Emergency Physicians , American College of Physicians , American Heart Association , American Thoracic Society , Arkansas Medical Society , New York Academy of Medicine , New York AcademyofSciences ,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital

David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

William K Chiang, MD Associate Professor, Department of Emergency Medicine, New York University School of Medicine; Chief of Service, Department of Emergency Medicine, Bellevue Hospital Center

William K Chiang, MD is a member of the following medical societies: American Academy of Clinical Toxicology , American College of Medical Toxicology , and Society for Academic Emergency Medicine

Joseph Cornelius Cleveland Jr, MD Associate Professor, Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center

Joseph Cornelius Cleveland Jr, MD is a member of the following medical societies: Alpha Omega Alpha , American Association for the Advancement of Science , American College of Cardiology , American College of Chest Physicians , American College of Surgeons , American Geriatrics Society , American Physiological Society , American Society of Transplant Surgeons , Association for Academic Surgery , Heart Failure Society of America , International Society for Heart and Lung Transplantation , Phi Beta Kappa , Society of Critical Care Medicine , Society of Thoracic Surgeons , and Western Thoracic Surgical Association

Disclosure: Thoratec Heartmate II Pivotal Tria; Grant/research funds Principal Investigator - Colorado; Abbott Vascular E-Valve E-clip Honoraria Consulting; Baxter Healthcare Corp Consulting fee Board membership; Heartware Advance BTT Trial Grant/research funds Principal Investigator- Colorado; Heartware Endurance DT trial Grant/research funds Principal Investigator-Colorado

Shamai Grossman, MD, MS Assistant Professor, Department of Emergency Medicine, Harvard Medical School; Director, The Clinical Decision Unit and Cardiac Emergency Center, Beth Israel Deaconess Medical Center

Shamai Grossman, MD, MS is a member of the following medical societies: American College of Emergency Physicians

John D Newell Jr, MD Professor of Radiology, Head, Division of Radiology, National Jewish Health; Professor, Department of Radiology, University of Colorado School of Medicine

John D Newell Jr, MD is a member of the following medical societies: American College of Chest Physicians , American College of Radiology , American Roentgen Ray Society , American Thoracic Society , Association of University Radiologists , Radiological Society of North America , and Society of Thoracic Radiology

Disclosure: Siemens Medical Grant/research funds Consulting; Vida Corporation Ownership interest Board membership; TeraRecon Grant/research funds Consulting; Medscape Reference Honoraria Consulting; Humana Press Honoraria Other

Craig H Selzman, MD, FACS Associate Professor of Surgery, Surgical Director, Cardiac Mechanical Support and Heart Transplant, Division of Cardiothoracic Surgery, University of Utah School of Medicine

Craig H Selzman, MD, FACS is a member of the following medical societies: Alpha Omega Alpha , American Association for Thoracic Surgery , American College of Surgeons , American Physiological Society , Association for Academic Surgery , International Society for Heart and Lung Transplantation , Society of Thoracic Surgeons , Southern Thoracic Surgical Association , and Western Thoracic Surgical Association

Gary Setnik, MD Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School

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• Published: 05 March 2020

Acute heart failure

• Mattia Arrigo 1 ,
• Mariell Jessup 2 ,
• Wilfried Mullens 3 , 4 ,
• Nosheen Reza 2 ,
• Ajay M. Shah 5 ,
• Karen Sliwa 6 &
• Alexandre Mebazaa 7 , 8  

Nature Reviews Disease Primers volume  6 , Article number:  16 ( 2020 ) Cite this article

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• Cardiovascular diseases
• Heart failure

Acute heart failure (AHF) is a syndrome defined as the new onset (de novo heart failure (HF)) or worsening (acutely decompensated heart failure (ADHF)) of symptoms and signs of HF, mostly related to systemic congestion. In the presence of an underlying structural or functional cardiac dysfunction (whether chronic in ADHF or undiagnosed in de novo HF), one or more precipitating factors can induce AHF, although sometimes de novo HF can result directly from the onset of a new cardiac dysfunction, most frequently an acute coronary syndrome. Despite leading to similar clinical presentations, the underlying cardiac disease and precipitating factors may vary greatly and, therefore, the pathophysiology of AHF is highly heterogeneous. Left ventricular diastolic or systolic dysfunction results in increased preload and afterload, which in turn lead to pulmonary congestion. Fluid retention and redistribution result in systemic congestion, eventually causing organ dysfunction due to hypoperfusion. Current treatment of AHF is mostly symptomatic, centred on decongestive drugs, at best tailored according to the initial haemodynamic status with little regard to the underlying pathophysiological particularities. As a consequence, AHF is still associated with high mortality and hospital readmission rates. There is an unmet need for increased individualization of in-hospital management, including treatments targeting the causative factors, and continuation of treatment after hospital discharge to improve long-term outcomes.

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Introduction

Heart failure (HF) is a chronic and progressive clinical syndrome induced by structural or functional cardiac abnormalities displaying either reduced (in HF with reduced ejection fraction (HFrEF)) or preserved (in HF with preserved ejection fraction (HFpEF)) left ventricular ejection fraction (LVEF) 1 . Cardiac dysfunction leads to elevated cardiac filling pressures at rest and during stress 1 . HF symptoms include dyspnoea (shortness of breath) and fatigue, often accompanied by typical physical signs, such as pulmonary rales (abnormal crackling sounds), peripheral oedema or distended jugular veins 1 . The substantial reduction in short-term mortality in patients with several cardiac conditions (particularly acute coronary syndromes and congenital heart disease) and the relevant improvement in long-term survival in patients with HFrEF (as a result of widespread use of effective disease-modifying oral therapies and devices), combined with several demographic changes, such as extended life expectancy, have sharply increased the number of patients living with HF 2 . In developed countries, HF has become a substantial public health problem, affecting 2% of the adult population, and the number of hospital admissions related to HF has tripled since the 1990s 2 .

Acute HF (AHF) is defined as new or worsening of symptoms and signs of HF and is the most frequent cause of unplanned hospital admission in patients of >65 years of age 3 . From a clinical perspective, we distinguish de novo HF — in which symptoms occur in patients without a previous history of HF — from acutely decompensated HF (ADHF) — in which symptoms increase in patients with previously diagnosed chronic HF. This classification provides little additional information in regard to the pathophysiology of AHF but has mainly clinical implications (de novo HF requires a more extensive diagnostic process to investigate the underlying cardiac pathology than ADHF). As HF is a chronic and progressive disease, the majority of hospitalizations are related to ADHF rather than de novo AHF 4 , 5 . The clinical presentation of AHF is characterized mostly by symptoms and signs related to systemic congestion (that is, extracellular fluid accumulation, initiated by increased biventricular cardiac filling pressures) 6 , 7 . Accordingly, the initial treatment in most patients with AHF consists of non-invasive ventilation and intravenous diuretics, which are administered alone or, especially in Europe and Asia, in combination with short-acting vasodilators 8 . Only a minority of patients with AHF present with cardiogenic shock, a critical condition characterized by the presence of clinical signs of peripheral tissue hypoperfusion; cardiogenic shock has a tenfold higher in-hospital mortality than AHF without shock and requires specific treatments 9 , 10 .

In contrast to the substantial improvements in the treatment of chronic HFrEF, AHF is still associated with poor outcomes, with 90-day readmission rates and 1-year mortality reaching 10–30% 11 , 12 . Although AHF is not a specific disease but the shared clinical presentation of different, heterogeneous cardiac abnormalities, most patients still receive decongestive drugs only, at best tailored according to the initial haemodynamic status with little regard to the underlying pathophysiological particularities. This approach might have contributed to the multitude of neutral or negative clinical trials assessing the effect of decongestive treatments on survival and to the persistence of poor outcomes in AHF. Thus, there is an unmet need for increased individualization and continuation of treatment after hospital discharge to improve long-term outcomes. This Primer reviews current concepts of epidemiology, pathophysiology, diagnosis and management of AHF to stimulate advances in research and clinical practice to improve patient outcomes. As cardiogenic shock is a separate entity with specific features, it is not discussed in this Primer.

Epidemiology

There are several reasons why global data on AHF are very limited. Differential coding of the syndrome, coupled with nuanced differences in case definitions, defies simple regional comparison. The International Classification of Disease (ICD) system classifies AHF and chronic HF as intermediate conditions and not underlying causes of death. The ICD also does not distinguish between de novo HF and ADHF as reasons for hospital admission. No global data on the proportion of HFrEF and HFpEF as underlying causes of AHF are available. The Global Burden of Disease (GBD) collaborators reported on global, regional and national age-specific and sex-specific mortality of 282 causes of death in 195 countries for the period 1980–2017, including cardiovascular diseases such as rheumatic heart disease, ischaemic heart disease and cardiomyopathy, but they did not list AHF 13 . The latest estimate by the GBD team in 2010 was 37.7 million cases of prevalent HF worldwide, leading to an average of 4.2 years lived with this disability for each patient, but data on the global incidence of AHF were not reported 14 . Data on annual hospitalizations for HF are only available for the USA and Europe and exceed 1 million in both regions 4 , 5 . Among these hospitalizations, >90% were due to symptoms and signs of fluid accumulation (indicating AHF). In addition, up to one in four patients (24%) are readmitted within 30 days, readmission rates in the first 3 months after hospitalization for AHF may reach 30% in the USA and in other countries 4 and one in two patients (50%) are readmitted within 6 months 4 , 5 . Recurrent fluid accumulation in patients with HF has uniformly been associated with worse outcomes independent of age and renal function 15 . In multiple studies of the 30-day to 90-day post-discharge period, ~25–30% of patients with AHF are readmitted during this time frame 16 , 17 , 18 , 19 , 20 . However, a substantial proportion of these patients are readmitted for a non-HF-related cause 21 , 22 . Medical comorbidities precipitate rehospitalization and, when poorly managed, contribute to worsening HF over time 22 . Psychosocial factors such as anxiety, depression, cognitive impairment and social isolation also confer increased risk of unplanned recurrent readmission or death of patients following hospitalization for AHF 23 .

There are no national data on the prevalence of AHF or chronic HF in low-income and middle-income countries. All registries of HF for these regions are based on hospital registries that included only patients admitted for AHF, without separating de novo HF from ADHF. Data from some of the key registries have recently been summarized 24 but focus on aetiology, risk factors, sociodemographic profile and mortality. The INTER-CHF study, one of the largest registries, reported on 5,823 patients with HF from 108 centres in six geographical regions 25 . The overall 1-year mortality was 16.5%, with the highest mortality in Africa (34%) and India (23%), about average mortality in southeast Asia (15%) and the lowest mortality in China (7%), South America (9%) and the Middle East (9%) 25 .

Risk factors

A systematic review of worldwide risk factors for HF found that ischaemic heart disease was the major underlying contributor to AHF admissions in >50% of patients in high-income regions, as well as eastern and central European regions 26 . In Asia Pacific high-income regions and Latin America, ischaemic heart disease contributed to 30–40% of admissions 26 , whereas in sub-Saharan Africa it contributed to <10% 27 . Hypertension was a consistent contributor to HF globally (17%) 26 . Of the other commonly reported risk factors, rheumatic heart disease was particularly prevalent in East Asia (34%) and sub-Saharan Africa (14%) 26 . The heterogeneous group of cardiomyopathies (which can include familial, peripartum, infective (for example, due to HIV infection), autoimmune, post-myocarditis and idiopathic cardiomyopathy, amongst others) were particularly prevalent in Africa (25.7%), with Chagas disease-associated cardiomyopathy being a specific cause in Latin America 26 . Chagas disease-associated acute myocarditis is commonly (>50% cases) associated with a substantial pericardial effusion, but it usually leads to AHF in only 1–5 of every 10,000 infected people 28 . However, Chagas disease remains common in Latin America and is the cause of HF in 10% of patients in the RAMADHF study and 28% in the GESICA study 29 , 30 .

In high-income regions with associated high scores in the human development index (a statistical tool that takes into account life expectancy, education and income), patients with AHF typically have a median age of >75 years at presentation, whereas in other areas, such as Latin America and sub-Saharan Africa, the median age of patients with AHF is up to two decades lower 25 . This difference could be due to poorly treated hypertension, ischaemic heart disease and late diagnosed rheumatic heart disease leading to HF presentation in younger age groups. In addition, there are differences between regions in the sex distribution; for example, rheumatic heart disease commonly affects women more than men 31 , 32 , and peripartum cardiomyopathy is particularly common in Africa 33 . As the obesity epidemic also affects women disproportionately, hypertensive heart disease leading to HF is commonly more prevalent in women than men 25 .

Morbidity and mortality

Globally, in-hospital AHF mortality hovers at ~4%, rises to ~10% within 60 to 90 days after discharge and increases further to 25–30% at 1 year 16 , 17 , 18 , 34 , 35 . The INTER-CHF prospective cohort study showed striking global variations in HF-associated mortality, with the highest 1-year overall and HF-related mortality in the countries with the youngest populations, such as India and African countries 25 . However, there was no analysis of HFpEF versus HFrEF as the underlying condition in the HF group.

Data from the THESUS-HF registry (a prospective study of AHF in nine sub-Saharan countries) were analysed to determine the predictors of readmission and outcome (including death) after an AHF event 35 . Similar to results in high-income countries, the predictors of 180-day mortality included malignancy, severe lung disease, smoking history, systolic blood pressure and heart rate either below or above their physiological ranges and symptoms and signs of congestion (orthopnoea (dyspnoea when lying flat), peripheral oedema and rales) at admission, kidney dysfunction, anaemia and HIV positivity. The risks predicted by calibration plots, comparing observed event rates with those predicted by the models, were generally low for all risk factors considered, suggesting that the main factors contributing to adverse outcomes in patients with AHF are still largely unknown 35 .

Mechanisms/pathophysiology

Pathophysiological mechanisms of ahf.

An underlying structural or functional cardiac condition is a prerequisite for AHF and includes a multitude of different acute (for example, myocardial infarction) or chronic (for example, dilated cardiomyopathy and ischaemic heart disease) cardiac pathologies. The underlying cardiac disease leads to the activation of several pathophysiological pathways (at first adaptive responses, which with time become maladaptive) that counter the negative effects of HF on oxygen delivery to the peripheral tissues, but such pathways can also eventually cause systemic congestion, ventricular remodelling and organ dysfunction 36 . Furthermore, some acute diseases can act as precipitating factors and trigger AHF either by directly impairing cardiac diastolic and/or systolic function or by further promoting systemic congestion 36 . Systemic congestion has a major effect on the clinical presentation in the majority of patients with AHF and is a relevant determinant of multi-organ dysfunction occurring in AHF (Fig.  1 ). The pathophysiology of AHF is heterogeneous, as it is greatly affected by the nature of the underlying cardiac disease. It is perhaps not surprising, therefore, that the responses to treatment may vary and that different patients may respond best to distinct treatment strategies that depend on the underlying pathophysiology.

Acute heart failure (HF) results from the combination of an underlying but newly diagnosed cardiac dysfunction and precipitating factors or the onset of a new cardiac dysfunction (de novo HF) or the combination of an underlying chronic cardiac dysfunction and one or more precipitating factors (acutely decompensated HF (ADHF), that is, decompensation of chronic HF). Precipitating factors may directly affect left ventricular (LV) or right ventricular (RV) function (for example, myocardial ischaemia and arrhythmias) or may contribute to the development of congestion (for example, infection, hypertension and non-compliance with treatment recommendations). LV dysfunction (diastolic dysfunction in HF with preserved ejection fraction (HFpEF) or diastolic and systolic dysfunction in HF with reduced ejection fraction (HFrEF)) leads to pulmonary congestion, which in turn contributes to RV dysfunction and systemic congestion. Systemic congestion, neurohumoral activation and inflammation negatively affect ventricular function and further contribute to self-perpetuating congestion.

LV systolic and diastolic dysfunction

An acute change in cardiac function, mostly a worsening of left ventricular (LV) diastolic function, which in turn leads to an increase in LV filling pressures and pulmonary congestion, can result in AHF 37 ; an example of such sudden changes is acute myocardial ischaemia. Several pathophysiological mechanisms underlie the link between ischaemia, LV systolic and diastolic dysfunction and pulmonary congestion. LV contraction is highly dependent on oxidative energy generation and, therefore, ischaemia triggers systolic impairment, which leads to an increased residual LV end-diastolic volume and filling pressure. LV filling normally occurs in two phases, an early rapid phase that is highly dependent upon fast myocardial relaxation and a later phase that is dependent on left atrial contraction and the atrial-to-ventricular pressure gradient, which in turn is affected by the physical properties of the LV (for example, stiffness). Myocardial relaxation is also an active energy-requiring process that involves removing cytoplasmic calcium, mostly via re-uptake into the sarcoplasmic reticulum by the sarcoplasmic reticulum Ca 2+ ATPase (SERCA) pump and in part via extrusion across the cardiomyocyte plasma membrane. The end-diastolic properties of the LV are affected by the residual LV end-diastolic volume, structural changes (for example, fibrosis) and also by extremely delayed relaxation. The reduction in oxidative ATP generation in cardiomyocytes with the onset of severe acute ischaemia rapidly impairs myocardial relaxation, thereby affecting early LV filling and further increasing filling pressures. The presence of any coexisting conditions in which relaxation is already impaired or end-diastolic LV stiffness is increased will increase the likelihood of AHF. Conditions in which end-diastolic LV stiffness may be increased (and, therefore, also conditions with an increased risk of AHF precipitated by ischaemia) include chronic LV systolic dysfunction with raised LV end-diastolic volume and structural fibrosis and/or hypertrophy, both of which could result from diabetes mellitus, chronic hypertension, chronic kidney disease, chronic aortic stenosis and ageing 38 . LV filling may also be impaired by the sudden development of atrial fibrillation with the accompanying loss of atrial contraction, which may substantially increase filling pressures when there is already pre-existing diastolic dysfunction. For example, severe mitral stenosis (which is a common manifestation of rheumatic heart disease) is a type of diastolic dysfunction due to the valve abnormality rather than LV structural disease, and it can also induce atrial fibrillation, thereby increasing the risk of triggering AHF.

Fluid retention

In HF, an increase in the volume of extracellular fluid (referred to as fluid retention or fluid accumulation) and/or a change in the compliance of venous beds (which results in fluid redistribution without an increase in the overall volume) can lead to an increase in filling pressures. In fact, in the majority of patients, AHF occurs without acute changes in cardiac function but is induced by fluid accumulation and/or redistribution, which results in systemic congestion, especially in the presence of an underlying diastolic dysfunction 39 . The interactions between intravascular and interstitial fluid volumes are complex, and there is no linear correlation between central haemodynamics and volume changes 40 . Animal studies have shown that marked intravascular volume expansion does not lead to increased cardiac filling pressures if sympathetic activity is low 41 , 42 , and in patients with HF intravascular volume is only marginally reduced after diuretic therapy despite large reductions in body weight 40 . By contrast, only half of the patients exhibit a weight gain of >0.9 kg over the month preceding hospital presentation for ADHF, indicating that changes in the compliance state of the venous beds are also important drivers of congestion 43 . The majority of the retained sodium is stored in the extracellular compartment, which consists of both the intravascular compartment and the interstitium 44 . In healthy individuals, increased total body sodium is usually not accompanied by oedema formation, as a large quantity of sodium may be buffered by the interstitial glycosaminoglycan networks without compensatory water retention 45 . Moreover, the interstitial glycosaminoglycan networks display low compliance (limited elastic properties), which prevents fluid accumulation in the interstitium 46 . In patients with HF, when sodium accumulation persists, the glycosaminoglycan networks may become dysfunctional, resulting in reduced buffering capacity, increased interstitial compliance and oedema formation even in the presence of mildly elevated hydrostatic pressures 44 .

Fluid retention is frequently related to increased neurohumoral activation (that is, activation of the renin–angiotensin–aldosterone system and the vasopressin system) leading to renal salt and water retention, although it can also be iatrogenic (for example, caused by the administration of inappropriately large amounts of intravenous fluids). The neurohumoral pathway is already activated above the physiological baseline level early during disease progression in patients with chronic HF (even before the development of symptoms) or kidney disease, and, therefore, these patients are particularly prone to fluid accumulation. Mechanisms and consequences of neurohumoral activation have been extensively reviewed elsewhere 47 . Importantly, the resulting organ dysfunction contributes to self-perpetuation of congestion.

In HF, alterations in both proximal and distal nephron segments increase kidney sodium avidity 48 , which is already increased even before clinical symptoms of HF occur 49 , 50 . Furthermore, in several studies increased central venous pressure has been associated with worsening of renal function (WRF), often resulting in a further drop in natriuresis 51 , 52 , 53 . However, changes in renal function during AHF need to be interpreted within the specific clinical context, as this approach helps to correctly assess risk and determine further treatment strategies. In fact, it is possible that changes in renal function parameters occurring during AHF that would typically indicate WRF do not correspond to ‘true’ WRF, when accompanied by simultaneous favourable ongoing diuresis and improvement in HF status. Currently, misinterpretation of WRF in the AHF setting is a leading cause of decongestion not being achieved in AHF. To distinguish between ‘true’ WRF and ‘pseudo’ WRF during AHF, renal evaluation should include the assessment not only of changes in glomerular function (indicating the development of WRF), but also of the tubular response to diuretic therapy (diuretic response and/or efficiency), that is, the ability to eliminate residual congestion and the administered therapy.

Fluid redistribution

Sympathetic stimulation can induce a transient vasoconstriction leading to a sudden displacement of volume from the splanchnic and peripheral venous system to the pulmonary circulation, without exogenous fluid retention — that is, fluid redistribution 54 . Large veins physiologically contain one-quarter of the total blood volume and stabilize cardiac preload, buffering fluid retention 55 . Preload indicates the degree of stretch of cardiomyocytes at the end of diastole and correlates with the end-diastolic volume and pressure. By contrast, afterload indicates the pressure that the heart has to overcome to eject blood during ventricular contraction and correlates with systolic arterial pressure. A mismatch in the ventricular–vascular coupling relationship with increased afterload and decreased venous capacitance (leading to increased preload and end-diastolic volume) may excessively increase cardiac workload and exacerbate pulmonary and systemic congestion 56 . Finally, acute mechanical factors may also increase ventricular preload and cause AHF; for example, the sudden occurrence of mitral valve regurgitation due to ruptured papillary muscle chords or the sudden development of a ventricular septal defect.

Fluid accumulation and fluid redistribution both produce systemic congestion in AHF, but their relative contributions probably vary according to different clinical scenarios, and the decongestive therapy should be tailored accordingly (see Management) 36 .

Precipitating factors of AHF

The onset and increase in systemic congestion that precede AHF may develop over hours up to days, and can be triggered by several factors, either directly through stimulation of pathophysiological mechanisms leading to fluid accumulation or redistribution or indirectly through a worsening of cardiac diastolic or systolic function. The understanding of the pathophysiology involved in the development of AHF is important for providing the appropriate treatment. Although in many patients a progressive increase in body weight and pulmonary pressures may be observed as early as several days before hospital admission, in a relevant proportion of patients AHF is associated with only a minimal increase in body weight 39 , 43 . Several registries, including the North American OPTIMIZE-HF registry and the Euro-Asian registry of the GREAT network, have investigated the presence of precipitants in patients with AHF 57 , 58 . Acute coronary syndromes, arrhythmias (in particular atrial fibrillation), infections (in particular airway infections), uncontrolled hypertension and non-compliance with dietary recommendations and drug prescriptions are the most common identified precipitants 57 , 58 . Of note, in a relevant proportion of patients (~40–50%), no precipitants could be identified, whereas a combination of multiple factors were present in ~5–20% of patients 57 , 58 .

The identification of precipitants provides prognostic information, as highlighted by several studies showing an association between precipitating factors and both mortality and readmission rates 57 , 58 , 59 , 60 . AHF precipitated by acute coronary syndromes or infection is associated with higher short-term mortality than AHF precipitated by atrial fibrillation or uncontrolled hypertension 57 , 58 . Notably, although patients with AHF precipitated by acute coronary syndromes and those with AHF precipitated by infection have similar unfavourable prognoses, the risk of death changes with time differently in the two patient groups: it is the highest during the first days after admission in the first group and peaks ~3 weeks after admission in the second 58 , 61 . The explanation for this phenomenon is speculative; we might suggest a complex interaction between infection and a combination of endothelial dysfunction, atherosclerotic plaque instability, activated coagulation, fluid retention, inflammatory and ischaemic myocardial injury, arrhythmias and the risk of other precipitating non-cardiac illnesses that may lead to death 58 . Finally, and most importantly, the identification of precipitating factors enables the delivery of specific treatments directed towards the underlying causes of AHF, in addition to decongestive therapy.

Congestion and organ dysfunction

In the heart, elevated ventricular filling pressures lead to increased ventricular wall tension, myocardial stretch and remodelling, contributing to a progressive worsening in cardiac contractility, valvular regurgitation and systemic congestion 62 . In response to the increased wall tension, circulating natriuretic peptides (which stimulate diuresis and vasodilation) are physiologically released by atrial and ventricular cardiomyocytes as a compensatory mechanism, and often high-sensitivity cardiac troponins are detectable in a large proportion of patients with AHF, revealing nonischaemic myocyte injury or necrosis 63 . Increases in left atrial pressure and mitral valve regurgitation will increase the hydrostatic pressure in the pulmonary capillaries, thereby increasing fluid filtration rate from the capillaries to the pulmonary interstitium, causing lung stiffness and dyspnoea 64 . Notably, the relationship between hydrostatic pressure and interstitial fluid content is rather complex, as other mechanisms are involved in fluid homeostasis. For example, the lymphangiogenic factor VEGF-D has been found to regulate and mitigate pulmonary and systemic congestion in patients with HF or renal failure 65 , 66 , 67 . Indeed, in the early stage of lung congestion, the lymphatic system can cope with the large volume of interstitial fluid, but eventually, the drainage capacity is exceeded. Hence, fluid moves to pleural and intra-alveolar spaces causing pleural effusion and pulmonary oedema 68 .

Systemic congestion is a central feature in most patients with AHF 6 . In addition to poor cardiac function, numerous organs play a part in the development and propagation of congestion 69 . Congestion is the essential pathophysiological mechanism of impaired organ function in AHF, and hypoperfusion — if present — might cause further deterioration in organ function and is associated with increased mortality risk 6 . Improvement in organ function with decongestive therapies has been associated with a reduced risk of death, and, therefore, prevention and treatment of organ dysfunction is a key therapeutic target in patients with AHF.

AHF is associated with WRF. Elevated central venous pressure leads to renal venous hypertension, which in turn increases renal interstitial pressure. Ultimately, the hydrostatic pressure in the renal interstitium exceeds the intratubular hydrostatic pressure, resulting in the collapse of tubules and, therefore, reduced glomerular filtration rate 70 . In addition, renal venous hypertension induces a reduction in renal blood flow, renal hypoxia and ultimately interstitial fibrosis 51 , 52 , 71 . Other contributors to AHF-induced renal dysfunction include inflammatory processes, iatrogenic factors (for example, contrast media and nephrotoxic medications), impaired cardiac output and elevated intra-abdominal pressure 7 , 72 . Of note, an increase in plasma creatinine is often interpreted by clinicians as a sign of hypovolaemia, prompting a reduction in decongestive therapy, on the basis that excessive decongestion might result in renal tubular damage; however, this is not always the case, as discussed above (see Fluid retention) 73 , 74 . In patients with an increase in creatinine during decongestive therapy, it is recommended that decongestive therapy is pursued until euvolaemia is achieved 75 , as clinical outcomes are extremely poor if patients are discharged with ongoing congestion in the presence of WRF 76 . By contrast, relying exclusively on serial measurements of levels of biomarkers (such as circulating natriuretic peptides) to assess changes in volume might lead to inappropriate dose escalation of loop diuretics in patients without substantial residual congestion. This dose escalation may lead to adverse effects such as hypotension and/or further WRF. A multiparameter-based evaluation of congestion before discharge would be of benefit in patients with HF. In addition to biomarkers, clinical assessment at rest and during dynamic manoeuvres, supplemented with technical assessments (such as echocardiography or measurement of pulmonary pressures), is probably the best strategy, although it needs prospective evaluation 75 .

In patients with liver congestion, elevations in alkaline phosphatase, bilirubin and/or γ-glutamyl transferase (also known as glutathione hydrolase 1 proenzyme) are often observed 77 , 78 , 79 . Centrilobular necrosis and markedly elevated transaminases (alanine aminotransferase and aspartate aminotransferase) owing to hypoperfusion in the setting of hypoxic hepatitis are observed in severe hypoperfusion states such as cardiogenic shock 78 .

Splanchnic congestion results in increased intra-abdominal pressure and ischaemia of villi, which modify intestinal morphology, and alters intestinal permeability, nutrient absorption and the bacterial biolayer, possibly contributing to chronic inflammation and malnutrition 80 , 81 , 82 . Additionally, venous congestion and/or hypoperfusion impairs the splanchnic microcirculation and increases the risk of bowel ischaemia, enabling lipopolysaccharide or endotoxin produced by Gram-negative gut bacteria to enter the circulatory system and increase the pro-inflammatory environment of AHF 56 . Finally, congestion per se also results in endothelial activation, which further promotes a pro-inflammatory environment 83 , 84 .

Diagnosis, screening and prevention

The management of patients with HF is strikingly heterogeneous across the world according to sociocultural disparities and differences in health-care systems. Many cardiology societies have endeavoured to increase awareness of HF among the population in different countries and to educate health-care professionals to improve the management of patients with HF. The following sections about diagnosis and treatment of AHF reflect current recommendations in high-income countries and may be substantially different from management standards in low-income or developing countries depending on local availability of resources. The modern management of patients with AHF also includes an optimal interplay between accurate diagnosis, rapid implementation of disease-modifying drugs and devices, specific treatment of the underlying cardiac disease and frequent outpatient follow-up visits. Whereas loop diuretics to relieve congestion are inexpensive and widely available, disease-modifying drugs (particularly sacubitril (a neprilysin inhibitor)–valsartan (an angiotensin receptor blocker) 85 , which promotes vasodilation and natriuresis, and sodium-glucose cotransporter 2 inhibitors, which reduce blood glucose levels in patients with diabetes mellitus and have also been shown to have beneficial effects in patients with HF) 86 and cardiac devices are usually available only in high-income areas. Furthermore, accurate diagnosis of the underlying cardiac diseases and specific treatments often require multimodal imaging techniques, as well as interventional and surgical procedures, which are mostly available in high-volume centres in developed countries. Finally, frequent follow-up visits to reduce the need for hospital readmissions are only feasible in countries with an established network of health-care providers with sufficient expertise in the treatment of patients with HF.

Initial diagnosis

Clinical presentation.

Symptoms and signs related to systemic congestion characterize the clinical picture of patients presenting with AHF, to a similar extent regardless of LVEF 87 . The most common symptoms include dyspnoea during exercise or at rest, orthopnoea, fatigue and reduced exercise tolerance; symptoms are often accompanied by clinical signs such as peripheral oedema, jugular vein distension, the presence of a third heart sound (known as “S3 gallop”, an early diastolic low-frequency sound that may be present under different haemodynamic conditions and might represent termination of the rapid filling of the left ventricle), and pulmonary rales 88 . In patients presenting with chest discomfort, the differentiation between AHF and acute coronary syndrome may be challenging. Symptoms and signs related to peripheral hypoperfusion, such as cold and clammy skin, altered mental status and oliguria, characterize cardiogenic shock. Cardiogenic shock, as well as respiratory failure, myocardial infarction and arrhythmia, should be rapidly excluded during the initial triage of patients admitted for suspected AHF because these conditions require an appropriate level of monitoring and specific treatments 9 , 89 . Commonly accepted criteria for hospitalization in an intensive care unit or a cardiac care unit include haemodynamic instability (heart rate <40 beats per minute or >130 beats per minute, systolic blood pressure <90 mmHg or evidence of hypoperfusion) and respiratory distress (respiratory rate >25 breaths per minute, peripheral oxygen saturation <90% despite supplemental oxygen, use of accessory muscles for breathing or need for mechanical ventilatory support) 90 .

Several algorithms and scores, most of which include clinical variables and biomarkers, have been developed to predict in-hospital death, but most of these tools have not been adequately prospectively tested for triage or resources allocation purposes. The ADHERE risk tree is used to classify patients on the basis of whether three parameters collected at admission (that is, blood urea nitrogen, systolic blood pressure and serum creatinine) are above or below specific cut-off values; this tool enables patient stratification into five groups with substantially different in-hospital mortality ranging from 2% to 22% 91 . The GWTG-HF score is computed by adding the points derived from seven variables (age, systolic blood pressure, heart rate, blood urea nitrogen, plasma sodium, history of chronic obstructive pulmonary disease and black ethnicity) and enables stratification into nine categories with in-hospital risk of death ranging from <1% to >50% 92 . The MEESSI-AHF score includes 13 independent risk factors and may be used to estimate the 30-day mortality in patients with AHF 93 .

Diagnostic work-up

The clinical picture of AHF is neither sensitive nor specific enough for confirming or ruling out the diagnosis; thus, additional tests are required 94 . Cardiovascular biomarkers play a crucial part in the diagnostic process of AHF. Patients presenting with suspected AHF should undergo measurement of plasma natriuretic peptides (for example, brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP) or mid-regional pro-atrial natriuretic peptide (MR-proANP)). Although no diagnostic test can on its own reliably differentiate AHF from chronic HF, as all cardiovascular biomarkers are impaired in both patient groups, natriuretic peptides display high sensitivity for detecting underlying cardiac disease in patients presenting with acute dyspnoea. In patients with AHF, levels of circulating natriuretic peptides are elevated compared with levels in patients with shortness of breath of non-cardiac origin 95 , 96 , 97 ; thus the measurement of natriuretic peptides provides higher diagnostic accuracy than clinical evaluation alone 98 . By contrast, dyspnoea in patients with normal (or unchanged) circulating natriuretic peptides is very likely to be of non-cardiac origin. The measurement of natriuretic peptides is recommended in patients with suspected AHF upon admission 1 , 89 . In patients with chronically elevated natriuretic peptides owing to chronic HF, a relevant increase in circulating natriuretic peptides may indicate AHF. Additional tests, such as echocardiography or other imaging procedures, are required to confirm the diagnosis of AHF in patients with elevated natriuretic peptides. Several new biomarkers reflecting different pathophysiological aspects of AHF (for example, myocardial injury, systemic congestion, inflammation and fibrosis) may be useful for diagnostic or prognostic purposes, but their role in routine clinical practice is still not well established.

The initial diagnostic process should include a comprehensive evaluation not only of the clinical phenotype but also of the underlying cardiac disorders, precipitating factors and comorbidities. Our (M.A.) group has proposed a ‘7-P’ protocol for guiding evaluation and personalization of treatment. The seven elements are phenotype, pathophysiology, precipitants, pathology, polymorbidity, potential iatrogenic harms and patient preferences 99 (Box  1 ). The diagnosis of AHF is frequently made clinically based on history and clinical signs assisted by measuring circulating natriuretic peptides. The role of imaging for the initial assessment of AHF is limited to patients in whom the underlying cardiac condition is unknown (for example, patients with de novo HF, who require a more extensive diagnostic process than patients with ADHF) or the detection of congestion is uncertain. In these patients, echocardiography and lung ultrasonography may add valuable information. Transthoracic echocardiography should be performed in all patients with de novo HF or in patients with ADHF when a relevant change in cardiac pathology is suspected, to estimate LV and RV function and exclude severe valve disease or pericardial tamponade. Lung ultrasonography has emerged as a valuable modality to detect and monitor pulmonary congestion in patients with AHF. This bedside technique enables the detection of interstitial fluid in the pulmonary parenchyma in a rapid, inexpensive and reliable manner 100 , 101 . An ischaemic trigger of AHF, such as acute coronary syndromes, should be ruled out by electrocardiography and (serial) measurement of cardiac troponins; arrhythmias can be evaluated by electrocardiography, continuous electrocardiographic monitoring or interrogation of implantable cardioverter–defibrillator interrogation in selected patients; and infections by measurement of inflammatory markers (for example, C-reactive protein and procalcitonin) and additional investigations according to the clinical presentation (for example, analysis of microbiological specimens and imaging). Additional imaging modalities (for example, MRI) are rarely needed during the initial work-up but may be helpful during further investigations. The initial laboratory evaluation should also include a basic assessment of the function of other organ systems (for example, kidney, liver and blood).

Current recommendations on the management of AHF are mainly based on expert opinion rather than robust evidence, as randomized controlled trials are either lacking or their results are neutral or negative 1 , 3 , 9 . Recent data have shown that timely initiation of therapy may be a crucial factor in the treatment of AHF, with a positive association between short time from admission to diuretic administration and improved in-hospital survival. For this reason, the initial treatment should be delivered as soon as possible, ideally as early as during the diagnostic work-up 102 . However, because short-term intravenous therapy with diuretics or vasodilators is unlikely to change the mid-term and long-term clinical course in patients with AHF, the choice of initial treatment should take into account not only the clinical phenotype but also the underlying cardiac disorders, precipitating factors and comorbidities.

Box 1 The ‘7-P’ protocol

The assessment of the clinical phenotype based on peripheral perfusion (whereby normal perfusion is considered ‘warm’ and symptoms or signs of hypoperfusion are considered ‘cold’) and/or systemic congestion (whereby no congestion is considered ‘dry’ and the presence of congestion is considered ‘wet’) enables the classification of patients into one of four profiles. The vast majority of patients with AHF are well perfused but congested (‘warm–wet‘).

The initial treatment tackling haemodynamic disorders (for example, vasodilators and/or diuretics to reduce systemic congestion and positive inotropic drugs to improve peripheral perfusion) should be personalized according to the clinical phenotype and the leading pathophysiology (for example, fluid accumulation, fluid redistribution or peripheral hypoperfusion).

Identification of the precipitants of AHF is essential for providing optimal specific (medical and/or surgical) therapy and for estimating both prognosis and recovery potential.

Similarly, identification of the underlying cardiac pathology can contribute to tailoring the treatment.

The assessment of polymorbidity (for example, renal and hepatic dysfunction) or other relevant conditions (such as pregnancy, bleeding risk and allergies) should be integrated into the management plan.

Potential iatrogenic harms associated with diagnostic procedures and treatment should also be considered.

Patient preferences and ethical considerations should be integrated into the personalization of the treatment. Discussion with the patient or with relatives about resuscitation directives and treatment options are crucial and need to be evaluated early rather than late, particularly in patients with AHF who might show rapid deterioration. In the absence of long-term therapeutic options, palliation and supportive care should be offered to patients and relatives.

Screening and prevention

As mentioned above, AHF can arise de novo or in patients with previously diagnosed HF (ADHF). The prospective STOP-HF study investigated the efficacy of a natriuretic peptide-based screening programme and collaborative care in reducing newly diagnosed HF in an at-risk population 103 . However, although this study showed a significant reduction in the rate of emergency hospitalization for major cardiovascular events in the screening group, the reduction in the incidence of HF did not reach statistical significance. Thus, the role of screening in preventing HF — and more specifically AHF — has yet to be determined, and screening is not recommended by current guidelines 1 .

By contrast, prevention of decompensation in patients with previously diagnosed HF is of major importance. Hospital readmissions are frequent — in particular during the first months after hospital discharge for AHF — and are associated with adverse outcomes and relevant health-care expenditure 12 . The optimal strategy for reducing hospital readmission has not been prospectively validated in clinical trials. Residual congestion and lack of disease-modifying treatment implementation before hospital discharge have been associated with worse post-discharge outcomes 104 , 105 . Patient education and empowerment may play a crucial part: patients should understand the importance of compliance with medical treatment, be able to recognize symptoms or signs of worsening HF, have a plan about when and how to start or increase diuretic treatment, and know when to contact their cardiologist or the medical emergency system to avoid unnecessary delay. Furthermore, particular attention should be given to avoid self-medication or initiation of contraindicated drugs (for example, NSAIDs) by other physicians who are unaware of the HF diagnosis. Finally, a continuation of the chronic treatment of HF (diuretics and disease-modifying drugs) without interruption should be ensured, although this goal may be challenging, in particular in low-income countries and in the absence of insurance coverage for medical treatments.

Pre-hospital early management

There is a growing body of evidence that delayed treatment delivery is associated with poor outcomes in AHF 102 . For this reason, current guidelines advocate a ‘time-to-treatment’ concept, similar to those for acute myocardial infarctions or cerebrovascular accidents, and recommend early initiation of treatment in patients with AHF, optimally before hospital admission 1 , 9 , 89 . In the pre-hospital setting, patients with AHF should benefit from adequate non-invasive monitoring (that is, continuous electrocardiography and measurement of blood pressure and peripheral oxygen saturation (SpO 2 )), oxygen supplementation in case of hypoxia (SpO 2 <90%) or non-invasive ventilation in case of respiratory distress. Preclinical non-invasive ventilation treatment can reduce intubation rates and improve short-term outcome in patients with cardiogenic pulmonary oedema 106 . When the clinical diagnosis of AHF is straightforward, intravenous treatment (mostly vasodilators and/or diuretics) based on the clinical phenotype and involved pathophysiology should be delivered without waiting for additional testing. Diuretics are mainly used in the presence of fluid retention, whereas vasodilators are administered to reduce filling pressures and modulate ventricular–vascular coupling in the presence of fluid redistribution and preserved systolic blood pressure (>110 mmHg; caution should be used if the systolic blood pressure is 90–110 mmHg) 1 , 3 . The use of vasodilators is recommended by current guidelines 1 , 3 . However, in light of the new results of randomized clinical trials (such as RELAX-AHF-2, TRUE-AHF and GALACTIC) showing no prognostic benefit of vasodilatory agents in AHF, these recommendations may change. The use of inotropes should be restricted to patients in cardiogenic shock due to impaired myocardial contractility, as their inappropriate use is associated with arrhythmias, increased morbidity and mortality 107 . Notably, pre-hospital treatment should not delay rapid transfer to hospital, preferably to a site with a cardiology and cardiac care unit and/or an intensive care unit. Upon arrival at the hospital, patients should be triaged to exclude cardiopulmonary instability (that is, cardiogenic shock and respiratory failure) and undergo a detailed clinical evaluation.

In-hospital management

Individuals with AHF are at risk of death not only from cardiovascular failure but also from the consequences of organ dysfunction due to congestion and hypoperfusion; thus, it is imperative that the treatment strategy addresses both these issues. Despite the fact that there is little evidence from randomized controlled trials that tackling congestion improves survival, the effect of diuretics on symptoms and organ congestion are evident. Once oxygen saturation has been restored (with oxygen supplementation, non-invasive ventilation or mechanical ventilation), the initial treatment goals in patients presenting with AHF consist of achieving decongestion without residual fluid retention, optimizing perfusion pressures to preserve organ perfusion and maintaining or initiating disease-modifying oral therapies directed towards neurohumoral activation, as these medications also increase diuretic response and improve long-term survival 108 , 109 (Fig.  2 )

Congestion is assessed on the basis of the presence of compatible clinical signs (for example, pulmonary rales, distended jugular veins and peripheral oedema), evidence of organ congestion on chest X-ray radiography or lung ultrasonography and elevated filling pressures on invasive monitoring. Abnormal peripheral perfusion is assessed on the basis of the presence of compatible clinical signs (for example, cold and clammy skin, oliguria and altered mental status) and other evidence of altered oxygen transport (for example, increased blood lactate and low central venous or mixed venous oxygen saturation). The response to fluid challenge (that is, change in cardiac output after administration of 250–500 ml of fluids), positive inotropic agents (that is, intravenous drugs that increase cardiac contractility) and vasopressors (that is, intravenous drugs that increase arterial blood pressure by causing peripheral vasoconstriction) should be closely assessed by measuring changes in stroke volume, either by echocardiography or by other invasive monitoring systems. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MCS, mechanical circulatory support; SBP, systolic blood pressure.

Decongestive therapy

As patients with AHF present with a similar congestion profile irrespective of their LVEF 87 , the decongestive therapy is similar in patients with HFrEF or HFpEF 1 . The decongestive treatment should be tailored according to the haemodynamic phenotype and the underlying pathophysiology and administered (intravenously, to overcome reduced enteral absorption owing to gastrointestinal congestion) as soon as possible after presentation to increase its success. The practical approach to diuretic treatment has been extensively described in a consensus statement of the Heart Failure Association of the European Society of Cardiology 75 . Because loop diuretics are >90% protein-bound by albumin in the blood and need to be secreted into the proximal convoluted tubule through several organic anion transporters, when renal blood flow is reduced (such as in AHF), diuretic dosing needs to be adjusted to achieve a plasma concentration sufficient to obtain the desired effect. Furthermore, the peak effect of intravenous loop diuretics occurs within the first hours, with sodium excretion returning to baseline by 6–8 hours; however, to maintain the decongestive effect, the administration of diuretics should continue until euvolaemia is achieved, with three or four daily doses or continuous infusion.

The diuretic response may be evaluated by measuring the urinary volume output and spot urinary sodium content within the first hours after loop diuretic administration 75 . The measurement of spot urinary sodium content is particularly useful in patients with low to medium urine output. Whereas in patients producing high urinary volumes natriuresis is almost universally high, more-recent data indicate that in patients with a low to medium urine output, spot urinary sodium content offers independent prognostic information in addition to urinary volume output 110 . In patients with congestion, an hourly urine output of <100–150 ml during the first 6 hours and/or a spot urinary sodium content of <50–70 mmol 2 hours after loop diuretic administration generally indicates an inadequate response to diuretics 75 . Early evaluation of the diuretic response is recommended to identify patients with diuretic resistance, enabling rapid intensification (such as doubling) of the loop diuretic dose to attain the ceiling (maximum) dose quickly. As increasing the loop diuretic dose any further than the ceiling dose does not induce incremental diuresis and/or natriuresis, the addition of another diuretic agent with a different mode of action should be considered (sequential nephron blockade). In refractory forms, renal replacement therapy may be considered, although these technologies — despite being very effective in volume removal — have not been shown to improve outcomes 111 , 112 , 113 . Mechanisms and treatment approaches to diuretic resistance have been extensively reviewed elsewhere 114 .

Decongestive treatments should be continued until euvolaemia has been achieved and the medications are switched to an oral form. Loop diuretic therapy should then be reduced to the lowest dose that can maintain euvolaemia 1 , 115 . The quantification of fluid excess and the determination of euvolaemia may be challenging in clinical practice and may require a multimodal approach including symptoms, clinical signs, imaging (such as echocardiography, chest X-ray radiography and lung ultrasonography) and biomarkers 75 . Other techniques, such as data from implanted cardiac devices, pulmonary artery pressure sensors, bioelectrical impedance analysis and indicator dilution techniques, may provide additional valuable information, but their widespread use is limited by technical reasons and cost.

Comprehensive therapy

Specific treatments for the underlying cardiac disease and the precipitating factors should be implemented during hospitalization. For example, myocardial revascularization and optimal antimicrobial treatment should not be delayed when AHF is precipitated by myocardial ischaemia or infection, respectively. On the basis of the comorbidities identified during the initial evaluation and treatment, clinicians should be able to anticipate the need for particular drugs for some specific forms of HF (for example, HF associated with amyloidosis), surgical procedures (for example, for valvular heart disease), mechanical circulatory support (such as LV assist device) or cardiac transplantation. Finally, enrolment of patients in a comprehensive multidisciplinary HF care management programme, promoting medication adherence, up-titration of disease-modifying therapy, cardiac rehabilitation, treatment of underlying comorbidities and timely follow-up with the health-care team, is essential 1 .

Long-term management

Management goals and pre-discharge management.

Individuals who survive the first episode of AHF are at increased risk of experiencing another episode 12 . Thus, the management goals include improving survival and reducing the risk of hospital readmission due to subsequent episodes of AHF. Ensuring that the individual’s condition is sufficiently stabilized for a safe hospital discharge is the central element of pre-discharge management. Patients with AHF are considered ready for discharge after achieving adequate decongestion and stable renal function on guideline-directed oral therapy 1 . Congestion is the most common cause of AHF readmission, and persistent congestion and renal dysfunction are known markers of a poor post-discharge prognosis 69 . A variety of clinical markers (such as weight and fluid loss) and biochemical markers (such as natriuretic peptides) are used as proxies of congestion, but because HF decompensation can occur owing to both fluid accumulation and redistribution, these biomarkers cannot be applied uniformly across patients with AHF. Several studies have demonstrated the usefulness of natriuretic peptides and cardiac troponins in predicting the risk of death and readmission for HF 116 , 117 , 118 . Patients with AHF who have markedly elevated pre-discharge natriuretic peptide levels have worse clinical outcomes, including all-cause and cardiovascular mortality and morbidity, than patients with lower levels. However, the benefits of achieving specific natriuretic peptide target values prior to discharge have not been demonstrated. Abnormally elevated cardiac troponins are often detected in patients with AHF in the absence of overt myocardial ischaemia and are similarly associated with poor outcomes 116 , 117 . Another biomarker of myocardial fibrosis, soluble ST2 receptor (also known as IL-1 receptor-like 1, a protein involved in the process of myocardial fibrosis and hypertrophy) has been correlated with disease severity and a poor prognosis in patients with AHF 119 . ST2, along with other biomarkers of oxidative stress, inflammation and remodelling, requires further study and remains in preclinical exploration 120 . Overall, defining and achieving satisfactory decongestion remains the major hurdle in AHF management.

In addition to achieving adequate decongestion, implementation of the medical treatment of precipitating factors is recommended to improve post-discharge outcome. In patients with HFrEF, disease-modifying oral HF therapy according to HF guidelines (consisting of β-adrenergic receptor blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor–neprilysin inhibitors, and mineralocorticoid receptor antagonists) should be continued or started during hospitalization and gradually titrated thereafter 1 , as it is associated with improved outcomes 105 . In patients with HFpEF, optimal control of comorbidities and precipitating factors is recommended 1 . Additional treatments, including appropriate drugs for some specific forms of HF or surgical procedures, should be evaluated during hospitalization.

Finally, pillars of pre-discharge management include ensuring a deliberate transition to outpatient care and creating a plan to assess and improve post-discharge prognosis. Care coordination for patients with HF is highly complex as clinicians, patients, care-givers and ancillary services must collaborate to titrate pharmacological therapy, monitor fluid volume status and electrolytes, treat comorbidities, initiate lifestyle changes and establish plans for adherence to treatment and emergency care 1 , 120 . Conversations regarding illness severity, barriers to self-care and advance care planning should be introduced before discharge.

Post-discharge management

In addition to continued supervised medical therapy, post-discharge management should incorporate efforts to improve symptoms and quality of life (QOL), delay disease progression and attempt to triage and prognosticate using a risk assessment framework to prevent hospital readmission and death. Generally, post-discharge prognostic tools are prediction models that take several patient clinical variables (for example, age, vital signs during hospitalization, laboratory data and comorbidities) into account and relate them to 30-day and 1-year mortality. Regardless of the time period considered, patients with AHF remain at persistently high risk of rehospitalization and death 121 . Thus, the American College of Cardiology Foundation–American Heart Association guideline for the management of HF recommends the first post-discharge telephone contact within 3 days and a follow-up visit 7–14 days after discharge, and the European Society of Cardiology guidelines recommend the first follow-up outpatient visit within 7 days of discharge 1 , 120 . Despite the complexity of factors associated with rehospitalization for HF, the readmission rate is a ubiquitous metric used to elucidate patient factors (as mentioned above) and health-care system factors that contribute to HF-related morbidity and mortality. Such health-care system factors include, for example, the quality of care provided, patient education, transitional support and medication reconciliation (that is, ensuring that the list of all medications a patient is taking is always as accurate and up-to-date as possible, to facilitate adjustments to the therapy whenever the patient is admitted to, or transferred or discharged from, a hospital). The public health and financial burdens of HF readmissions continue to grow, and evidence is surfacing that some national health policies, for example the Hospital Readmissions Reduction Program in the USA, which were intended to reduce these readmissions, may have had the unintended consequence of increasing post-discharge mortality 122 .

Clinicians should attempt to identify patients with AHF at high risk of readmission by incorporating clinical, laboratory, imaging and haemodynamic data into a comprehensive assessment. Concerning clinical characteristics in the post-discharge phase include multiple comorbidities (for example, chronic obstructive pulmonary disease, anaemia and chronic renal disease), low systolic blood pressure, high heart rate, progressive orthopnoea and jugular vein distension; laboratory parameters that should raise concerns include low serum sodium, elevated blood urea nitrogen and serum creatinine, low serum albumin and elevated natriuretic peptides 123 , 124 , 125 . In addition to traditional echocardiographic parameters used to evaluate biventricular filling pressures, other imaging techniques, such as lung ultrasonography and point-of-care ultrasonographic assessment of right internal jugular vein compliance, have shown promise in prediction of AHF rehospitalization in patients admitted with AHF 126 , 127 . Clinicians should prioritize a comprehensive clinical assessment of patients with AHF with close surveillance for these hallmarks of decompensation and perform targeted interventions focused on decongestion and patient education in the vulnerable early post-discharge phase 128 .

Implantable pulmonary artery pressure sensors to monitor the haemodynamic status and guide therapy can reduce the risk HF-related hospitalization in patients with HFrEF and HFpEF, but questions regarding true device efficacy remain, owing to concerns about potential bias and misconduct during trial execution 129 , 130 , 131 , 132 , 133 . Remote care using intrathoracic impedance monitoring has been associated with an increased risk of HF-related hospitalization 134 . Thus, the 2016 European Society of Cardiology guidelines provide a weak recommendation for the use of wireless implantable haemodynamic monitoring systems in patients with HF to reduce the risk of recurrent HF hospitalization 1 . Ultimately, prevention of readmission after an AHF hospitalization remains a challenge. Reliable identification of high-risk patients and of effective interventions to reduce the risk of rehospitalization has been elusive, as high-quality studies in representative patient cohorts are still needed.

Innovative care delivery models are being increasingly investigated as tools to improve post-discharge outcomes in patients with HF; however, results thus far have been disappointing. Telemonitoring alone did not reduce HF readmission in large multicentre and multinational trials 135 , 136 , 137 , 138 . Patient-centred transitional care approaches that include structured education, communication, clinical care and close surveillance did not improve outcomes compared with usual care models 139 . Questions remain regarding whether the use of these techniques alone can benefit certain subpopulations of patients and whether proving their efficacy will require a combination of patient-centred strategies.

Quality of life

Patients with AHF and chronic HF cope with numerous physical and psychological symptoms that adversely affect their QOL. Dyspnoea, fatigue, dry mouth, orthopnoea, sleep disturbance and difficulty concentrating are highly prevalent, distressing and burdensome and are predictive of reduced QOL in this population 140 (Fig.  3 ). Depression is more common among patients with HF than in the general population, with at least 20% of patients with HF meeting criteria for major depression 141 . Prevalence estimates of depression in the HF population vary widely, ranging from 9% to 60%, and such variation is thought to be largely due to differences in outcome ascertainment methods (that is, interviews versus self-reported questionnaires) and in HF severity at the time of assessment 141 , 142 . Patients with HF with more severe depression have increased health-care utilization, rehospitalization rates and mortality 141 , 143 , 144 , 145 . For clinicians, differentiating between symptoms due to HF and those due to depression can be challenging, highlighting a crucial need for a pragmatic and standardized approach to QOL assessment in routine clinical care.

Physical and psychological symptoms that contribute to impaired quality of life in patients with acute heart failure (AHF).

In addition to the physiological alterations in patients with AHF, the stressors of the acute care environment can exacerbate physical and psychological impairments and lead to further declines in QOL 146 . Elderly hospitalized patients with AHF have a markedly higher symptom burden and worse QOL than age-matched cohorts with stable HFpEF and stable HFrEF 146 , 147 . For example, in a prospective, comprehensive, multicentre and multidimensional assessment of 27 patients of ≥60 years of age hospitalized with ADHF compared with three age-matched ambulatory cohorts with stable HF, 78% of the ADHF cohort had cognitive impairment and 30% had depressed mood, but only 11% had a previous diagnosis of depression, suggesting substantial under-recognition of depression in this population. In a sex-stratified analysis of several large international studies on chronic HF, disproportionately worse disease-specific and general QOL was observed in women than in men 148 . This sex-related difference was unexplained — possible hypotheses included differences in the perception of the effect of the disease between women and men and sex-related confounders that were not measured in this study (for example, access to health care, socioeconomic and educational factors, level of care-giver support, living alone or with other people and proactive help-seeking behaviour). In a global study of patients with LVEF <40% hospitalized with AHF, 13% of patients reported persistently unfavourable QOL, defined by Kansas City Cardiomyopathy Questionnaire (KCCQ) scores of <45, at 1 and 24 weeks after hospital discharge 149 . QOL issues also affect patient adherence to pharmacological and non-pharmacological treatment and place extraordinary stress on care-givers. Although many studies examining the QOL of patients with chronic stable HF have been published, there is a notable dearth of evidence regarding QOL in patients with AHF.

Similarly, interventions aimed at improving QOL in patients with AHF are not well studied. Guideline-directed medical therapy decreases symptoms and improves QOL in patients with HFrEF. Non-pharmacological and non-device-based or surgical strategies, such as multidisciplinary team management, exercise training, self-care education and lifestyle modifications, have been examined more rigorously in ambulatory patients with chronic HF, but have not been effective in improving QOL independently 1 . In a small single-centre study of hospitalized patients with HF, inpatient palliative care consultation was associated with improved symptom burden, depressive symptoms and QOL for up to 3 months after hospitalization 150 . Patient-centred outcomes such as QOL are increasingly incorporated into HF trials and recognized as predictors of clinical events. Further research into tools to assess and strategies to improve QOL in the AHF population should be prioritized as the global population of patients with HF continues to grow.

The development of new, effective interventions for the treatment of AHF has been unsuccessful since the 1990s. In contrast to substantial progress achieved in other fields of cardiology and oncology, for example, no new medication or device has been approved for AHF treatment. Many therapies have been tested in the setting of AHF, including inotropic agents (for example, levosimendan and omecamtiv mecarbil), vasodilators (for example, nesiritide, ularitide and serelaxin) and diuretics (for example, tolvaptan) 151 , 152 , 153 , 154 , but the results of these studies were neutral, and it is still unclear whether this neutrality was due to the inactivity of the tested drugs or inadequacy of the study designs. For instance, determining the best time to administer a tested drug is still a challenge. Few studies have assessed early end points and seem to indicate the use of effective agents as early as possible. On the one hand, if drugs that improve cardiac function are given as early as possible (for example, within 6 hours of presentation to the emergency department), they might prevent worsening of organ dysfunction and death. On the other hand, mortality in the first hours and days is related to severe and irreversible alteration in organ function, that is, excess congestion, hypoxia and/or hypoperfusion, and drugs that aim to improve heart function might not prevent death. Hence, studies have suggested that tested HF drugs should be administered within 48 hours of presentation. Furthermore, choosing the most appropriate primary end point also remains a challenge. For years, regulatory agencies sought ‘improvement in survival rate’ as the primary efficacy end point in both patients with AHF and patients with chronic HF, although intravenous drugs tested in patients with AHF were usually administered for 48 hours only, whereas oral therapy was given every day for years in patients with chronic HF. Because no drug has been shown to improve the survival rate in patients with AHF, experts and patient associations are asking to designate improvements in morbidity as the primary efficacy end point and mortality as a safety end point rather than a primary one.

Several new medications are being tested in AHF. These drugs act by modulating endothelial cell function via the adrenomedullin pathway (adrenomedullin is involved in the maintenance of the endothelial barrier function and in the regulation of the renin–angiotensin–aldosterone system and may have protective properties against fluid retention in AHF) 155 or improving cardiovascular function via the modulation of intracellular enzymes, such as dipeptidyl-peptidase 3 (a cytosolic enzyme involved in angiotensin II and enkephalin cleavage that has myocardial depressant properties and whose inhibition may improve haemodynamics) 156 , 157 , that are released into the circulation during cell necrosis. While these studies are ongoing, two challenges remain in the management of AHF. First, the implementation of disease-modifying oral HF therapy in patients with HFrEF is still a major challenge worldwide. Only a minority of patients receive the right classes and the right doses of angiotensin-converting enzyme inhibitors, β-adrenergic receptor blockers and mineralocorticoid receptor antagonists. Achieving this goal will certainly minimize episodes of AHF. The second challenge is the post-discharge medication for patients with AHF with HFpEF. Except for treating cardiovascular and metabolic comorbidities that are very frequent in these patients, no drug is recommended after discharge to prevent readmission for a new episode of acute dyspnoea.

Circulating biomarkers, such as natriuretic peptides, are increasingly used in the treatment of patients with AHF. However, during the acute episode, they indicate myocardial stretch but neither venous nor whole-body congestion. Furthermore, although observational studies have shown that a rapid decrease in natriuretic peptides levels is associated with improved outcomes, a recent trial showed no benefit from intensifying therapy to achieve low levels of natriuretic peptides 158 . Thus, a multimarker strategy based on serially evaluated biomarkers, such as natriuretic peptides, high-sensitivity cardiac troponins, soluble ST2, growth differentiation factor 15, cystatin-C, galectin-3 and high-sensitivity C-reactive protein, may provide increased prognostic accuracy and risk prediction but requires further investigation in different cohorts of patients with HF 159 . This multimarker strategy might identify high-risk patients who may benefit from novel therapies.

QOL is the main issue for individuals who survive an episode of AHF. Readmissions for dyspnoea are frequent in the months and years following an AHF episode, in particular if the patient does not have optimal doses of disease-modifying HF therapies and does not receive the appropriate devices when needed. Thus, patients seem to favour a rapid improvement in QOL, measured as the number of days out of hospital after discharge, rather than an improvement in survival rate with a bad QOL.

Basic and translational research is also needed to decipher mechanisms of decompensation in chronic HFrEF and HFpEF. AHF is associated with stimulation of the neuroendocrine system and worsening in congestion that harms many organs, including the lungs, kidney and liver. Studies need to elucidate the mechanisms that lead to organ dysfunctions in AHF to prevent worsening in organ function during AHF episodes.

In summary, AHF is a very frequent event that affects the QOL and survival in patients with chronic HFrEF or HFpEF. Signs and symptoms are often related to congestion and in a few patients to hypoperfusion. Mechanisms of decompensation are still unknown. The administration of symptomatic and causal treatments is recommended. Optimizing disease-modifying HF therapies as early as possible is probably the most effective way to prevent AHF episodes. Further research to decipher mechanisms of cardiac and neuroendocrine decompensation and to identify new treatments is needed.

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Acknowledgements

N.R. is supported by the National Institutes of Health, National Human Genome Research Institute, Ruth L. Kirschstein Institutional National Research Service T32 Award in Genomic Medicine (T32 HG009495).

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Department of Cardiology, University Hospital Zurich, Zurich, Switzerland

Mattia Arrigo

Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Mariell Jessup & Nosheen Reza

Ziekenhuis Oost Limburg, Genk, Belgium

Wilfried Mullens

University of Hasselt, Hasselt, Belgium

School of Cardiovascular Medicine & Sciences, King’s College London British Heart Foundation Centre, London, UK

Ajay M. Shah

Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences, Department of Medicine and Cardiology, University of Cape Town, Cape Town, South Africa

Karen Sliwa

Université de Paris, MASCOT, Inserm, Paris, France

Alexandre Mebazaa

Department of Anesthesia, Burn and Critical Care Medicine, AP-HP, Hôpital Lariboisière, Paris, France

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Introduction (A.M. and M.A.); Epidemiology (K.S.); Mechanisms/pathophysiology (M.A., W.M. and A.M.S.); Diagnosis, screening and prevention (A.M. and M.A.); Management (M.J., W.M. and N.R.); Quality of life (M.J. and N.R.); Outlook (A.M.); Overview of Primer (A.M.).

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Arrigo, M., Jessup, M., Mullens, W. et al. Acute heart failure. Nat Rev Dis Primers 6 , 16 (2020). https://doi.org/10.1038/s41572-020-0151-7

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MICHAEL KING, MD, JOE KINGERY, DO, AND BARETTA CASEY, MD, MPH

Am Fam Physician. 2012;85(12):1161-1168

More recent articles on heart failure and cardiomyopathy are available.

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Heart failure is a common clinical syndrome characterized by dyspnea, fatigue, and signs of volume overload, which may include peripheral edema and pulmonary rales. Heart failure has high morbidity and mortality rates, especially in older persons. Many conditions, such as coronary artery disease, hypertension, valvular heart disease, and diabetes mellitus, can cause or lead to decompensation of chronic heart failure. Up to 40 to 50 percent of patients with heart failure have diastolic heart failure with preserved left ventricular function, and the overall mortality is similar to that of systolic heart failure. The initial evaluation includes a history and physical examination, chest radiography, electrocardiography, and laboratory assessment to identify causes or precipitating factors. A displaced cardiac apex, a third heart sound, and chest radiography findings of venous congestion or interstitial edema are useful in identifying heart failure. Systolic heart failure is unlikely when the Framingham criteria are not met or when B-type natriuretic peptide level is normal. Echocardiography is the diagnostic standard to confirm systolic or diastolic heart failure through assessment of left ventricular ejection fraction. Evaluation for ischemic heart disease is warranted in patients with heart failure, especially if angina is present, given that coronary artery disease is the most common cause of heart failure.

Heart failure is a common clinical syndrome characterized by dyspnea, fatigue, and signs of volume overload, which may include peripheral edema and pulmonary rales. There is no single diagnostic test for heart failure; therefore, it remains a clinical diagnosis requiring a history, physical examination, and laboratory testing. Symptoms of heart failure can be caused by systolic or diastolic dysfunction. Appropriate diagnosis and therapy for heart failure are important given the poor prognosis. Survival is 89.6 percent at one month from diagnosis, 78 percent at one year, and only 57.7 percent at five years. 1

Heart failure has an estimated overall prevalence of 2.6 percent. 2 It is becoming more common in adults older than 65 years because of increased survival after acute myocardial infarction and improved treatment of coronary artery disease (CAD), valvular disease, and hypertension.

Heart failure is defined by the American Heart Association and American College of Cardiology as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.” 3 As cardiac output decreases because of stresses placed on the myocardium, activation of the sympathetic nervous and renin-angiotensin-aldosterone systems increases blood pressure (for tissue perfusion) and blood volume (enhancing preload, stroke volume, and cardiac output by the Frank-Starling mechanism). These compensatory mechanisms can also lead to further myocardial deterioration and worsening myocardial contractility. In systolic heart failure, cardiac output is decreased directly through reduced left ventricular function. In diastolic heart failure, cardiac output is compromised by poor ventricular compliance, impaired relaxation, and worsened end-diastolic pressure. 3 , 4

CAD is the underlying etiology in up to 60 to 70 percent of patients with systolic heart failure, 5 , 6 and a predictor for progression from asymptomatic to symptomatic left ventricular systolic dysfunction. Hypertension and valvular heart disease are significant risk factors for heart failure, with relative risks of 1.4 and 1.46, respectively. 6 Diabetes mellitus increases the risk of heart failure twofold by directly leading to cardiomyopathy and significantly contributing to CAD. Diabetes is one of the strongest risk factors for heart failure in women with CAD. 7 Smoking, physical inactivity, obesity, and lower socioeconomic status are often overlooked risk factors. 6 Numerous conditions can cause heart failure, either acutely without an underlying cardiac disorder or through decompensation of chronic heart failure ( Table 1 ) . 3 , 4 , 8 As a result, alternative causes should be promptly recognized, treated, and monitored to determine if the heart failure is reversible. 8

Classification

The most important consideration when categorizing heart failure is whether left ventricular ejection fraction (LVEF) is preserved or reduced (less than 50 percent). 3 , 8 A reduced LVEF in systolic heart failure is a powerful predictor of mortality. 9 As many as 40 to 50 percent of patients with heart failure have diastolic heart failure with preserved left ventricular function. 2 , 10 – 16 Overall, there is no difference in survival between diastolic and systolic heart failure that cannot be attributed to ejection fraction. 2 , 10 – 16 Patients with diastolic heart failure are more likely to be women, to be older, and to have hypertension, atrial fibrillation, and left ventricular hypertrophy, but no history of CAD. 11 – 14 , 17 , 18 Compared with systolic heart failure, which has well-validated therapies, diastolic heart failure lacks evidence-based treatment recommendations. 3 , 8 , 13

Heart failure symptoms can occur with preserved or reduced ejection fraction, (systolic or diastolic heart failure). The New York Heart Association classification system is the simplest and most widely used method to gauge symptom severity ( Table 2 ) . 19 The classification system is a well-established predictor of mortality and can be used at diagnosis and to monitor treatment response.

Initial Clinical Evaluation

Although no single item on clinical history, sign, or symptom has been proven to be diagnostic, many are helpful in assessing the probability of heart failure. The initial clinical evaluation, detailed in Tables 1 , 3 , 4 , 8 3 , 3 , 8 , 20 and 4 , 3 , 8 , 20 is directed at confirming heart failure, determining potential causes, and identifying comorbid illnesses. Table 5 lists findings for the initial evaluation of suspected heart failure, including history, physical examination, chest radiography, electrocardiography, and B-type natriuretic peptide (BNP) testing. 17 , 21 – 23 Evaluation for ischemic heart disease is warranted in patients with heart failure, especially if angina is present, given that CAD is the most common cause of heart failure.

History and Physical Examination

Patients with heart failure can have decreased exercise tolerance with dyspnea, fatigue, generalized weakness, and fluid retention, with peripheral or abdominal swelling and possibly orthopnea. 3 Patient history and physical examination are useful to evaluate for alternative or reversible causes ( Table 1 ) . 3 , 4 , 8 Nearly all patients with heart failure have dyspnea on exertion. However, heart failure accounts for only 30 percent of the causes of dyspnea in the primary care setting. 24 The absence of dyspnea on exertion only slightly decreases the probability of systolic heart failure, and the presence of orthopnea or paroxysmal nocturnal dyspnea has a small effect in increasing the probability of heart failure (positive likelihood ratio [LR+] = 2.2 and 2.6). 21 , 23

The presence of a third heart sound (ventricular filling gallop) is an indication of increased left ventricular end-diastolic pressure and a decreased LVEF. Despite being relatively uncommon findings, a third heart sound and displaced cardiac apex are good predictors of left ventricular dysfunction and effectively rule in the diagnosis of systolic heart failure (LR+ = 11 and 16). 21 , 23

The presence of jugular venous distention, hepatojugular reflux, pulmonary rales, and pitting peripheral edema is indicative of volume overload and enhances the probability of a heart failure diagnosis. Jugular venous distention and hepatojugular reflex have a moderate effect (LR+ = 5.1 and 6.4), whereas the others, along with cardiac murmurs, have only a small effect on the diagnostic probability (LR+ = 2.3 to 2.8). The absence of any of these findings is of little help in ruling out heart failure. 21

Laboratory Tests

Laboratory testing can help identify alternative and potentially reversible causes of heart failure. Table 4 lists laboratory tests appropriate for the initial evaluation of heart failure and other potential causes. 3 , 8 , 20 Other laboratory tests should be performed based on physician discretion to evaluate further causes or identify comorbid conditions that require enhanced control.

BNP and N-terminal pro-BNP (the cleaved inactive N-terminal fragment of the BNP precursor) levels can be used to evaluate patients with dyspnea for heart failure. BNP is secreted by the atria and ventricles in response to stretching or increased wall tension. 25 BNP levels increase with age, are higher in women and blacks, and can be elevated in patients with renal failure. 21 , 26 BNP appears to have better reliability than N-terminal pro-BNP, especially in older populations. 25 , 26 Multiple systematic reviews have concluded that BNP and N-terminal pro-BNP levels can effectively rule out a diagnosis of heart failure 22 , 25 , 27 , 28 because of their negative predictive value (negative likelihood ratio [LR–] = 0.1 and 0.14). 22 The average cutoff levels for heart failure were a BNP level of 95 pg per mL (95 ng per L) or a N-terminal pro-BNP level of 642 pg per mL (642 ng per L). 22

As BNP levels increase, the specificity increases and thus the likelihood of a heart failure diagnosis. 25 BNP levels are strong predictors of mortality at two to three months and cardiovascular events in acute heart failure, specifically when BNP level is greater than 200 pg per mL (200 ng per L) or N-terminal pro-BNP level is greater than 5,180 pg per mL (5,180 ng per L). 22 , 25 Limited evidence supports monitoring reduction of BNP levels in the acute and outpatient settings. A 30 to 50 percent reduction in BNP level at hospital discharge showed improved survival and reduced rehospitalization rates. Optimizing management for outpatient targets of a BNP level less than 100 pg per mL (100 ng per L) and an N-terminal pro-BNP level less than 1,700 pg per mL (1,700 ng per L) showed improvement in decompensations, hospitalizations, and mortality events. 22 , 25

Chest Radiography

Chest radiography should be performed initially to evaluate for heart failure because it can identify pulmonary causes of dyspnea (e.g., pneumonia, pneumothorax, mass). Pulmonary venous congestion and interstitial edema on chest radiography in a patient with dyspnea make the diagnosis of heart failure more likely (LR+ = 12). Other findings, such as pleural effusion or cardiomegaly, may slightly increase the likelihood of heart failure (LR+ = 3.2 and 3.3), but their absence is only slightly useful in decreasing the probability of heart failure (LR– = 0.33 to 0.48). 21

Electrocardiography

Electrocardiography (ECG) is useful for identifying other causes in patients with suspected heart failure. Changes such as left bundle branch block, left ventricular hypertrophy, acute or previous myocardial infarction, or atrial fibrillation can be identified and may warrant further investigation by echocardiography, stress testing, or cardiology consultation. Normal findings (or minor abnormalities) on ECG make systolic heart failure only slightly less likely (LR– = 0.27). 23 The presence of other findings such as atrial fibrillation, new T-wave changes, or any abnormality has a small effect on the diagnostic probability of heart failure (LR+ = 2.2 to 3.8). 21

Clinical Decision Making

The definition of heart failure continues to be debated, but it remains a clinical diagnosis. Several groups have published diagnostic criteria, but the Framingham criteria are widely accepted and include the components of the initial evaluation, which enhances their accuracy ( Table 6 ) . 17 A previous study validated the Framingham criteria for diagnosing systolic heart failure, 29 and a more recent study analyzed them for systolic and diastolic heart failure. 17 Both studies reported high sensitivity for systolic heart failure (97 percent compared with 89 percent for diastolic heart failure), which effectively rules out heart failure when the Framingham criteria are not met (LR– = 0.04). 17 , 29 The Framingham criteria only have a small effect on confirming a diagnosis of heart failure (LR+ = 4.21 to 4.57), but have a moderate effect on ruling out heart failure in general and diastolic heart failure (LR– = 0.1 and 0.13). 17

Echocardiography is the most widely accepted and available method for identifying systolic dysfunction and should be performed after the initial evaluation to confirm the presence of heart failure. 3 Two-dimensional echocardiography with Doppler flow studies can assess LVEF, left ventricular size, wall thickness, valve function, and the pericardium. Echocardiography can assist in diagnosing diastolic heart failure if elevated left atrial pressure, impaired left ventricular relaxation, and decreased compliance are present. 2 , 3 Often, the diagnosis of diastolic heart failure is clinical without conclusive echocardiographic evidence. If echocardiography results are equivocal or inadequate, transesophageal echocardiography, radionuclide angiography, or cineangiography with contrast media (at catheterization) can be used to assess cardiac function. 30

If angina or chest pain is present with heart failure, the American Heart Association and the American College of Cardiology recommend that the patient undergo coronary angiography, unless there is a contraindication to potential revascularization. 3 Coronary angiography has been shown to improve symptoms and survival in patients with angina and reduced ejection fraction. 3 It is important to evaluate for CAD because it is the cause of heart failure and low ejection fraction in approximately two-thirds of patients. 4 , 5 Because wall motion abnormalities are common in nonischemic cardiomyopathy, noninvasive testing may not be adequate for assessing the presence of CAD, and cardiology consultation may be warranted.

Figure 1 is an algorithm for the evaluation and diagnosis of heart failure. When a patient presents with symptoms of heart failure, the initial evaluation is performed to identify alternative or reversible causes of heart failure and to confirm its presence. If the Framingham criteria are not met, or if the BNP level is normal, systolic heart failure is essentially ruled out. Echocardiography should be performed to assess LVEF when heart failure is suspected or if diastolic heart failure is still suspected when systolic heart failure is ruled out. Treatment options are guided by the final diagnosis and echocardiography results, with a consideration to evaluate for CAD.

Data Sources: A PubMed search was completed in Clinical Queries using the following key words in various combinations under the search by clinical study category: heart failure, symptoms, causes, diagnosis, diagnostic criteria, diastolic, systolic, brain natriuretic peptide. The categories searched included etiology, diagnosis, clinical prediction rules, and systematic reviews. The articles consisted of meta-analyses, systematic reviews, randomized controlled trials, and cohort studies. The related citations feature was used to locate similar research once appropriate articles had been discovered. We also searched the Agency for Healthcare Research and Quality Evidence Reports, Bandolier, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Institute for Clinical Systems Improvement, and the National Guideline Clearinghouse database. Search dates: April 5 through 16, 2010; May 24 through 28, 2010; selected newer articles January 1 and April 20, 2011.

Loehr LR, Rosamond WD, Chang PP, Folsom AR, Chambless LE. Heart failure incidence and survival (from the Atherosclerosis Risk in Communities study). Am J Cardiol. 2008;101(7):1016-1022.

Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289(2):194-202.

Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation [published correction appears in Circulation . 2010;121(12):e258]. Circulation. 2009;119(14):e391-e479.

Dosh SA. Diagnosis of heart failure in adults. Am Fam Physician. 2004;70(11):2145-2152.

Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation. 1998;97(3):282-289.

He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161(7):996-1002.

Bibbins-Domingo K, Lin F, Vittinghoff E, et al. Predictors of heart failure among women with coronary disease. Circulation. 2004;110(11):1424-1430.

Institute for Clinical Systems Improvement (ICSI). Heart failure in adults. Bloomington, Minn.: Institute for Clinical Systems Improvement (ICSI); 2009:95.

Solomon SD, Anavekar N, Skali H, et al.; Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation. 2005;112(24):3738-3744.

Aurigemma GP. Diastolic heart failure—a common and lethal condition by any name. N Engl J Med. 2006;355(3):308-310.

Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham heart study of the National Heart, Lung, and Blood Institute. Circulation. 2009;119(24):3070-3077.

Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic heart failure in the community. JAMA. 2006;296(18):2209-2216.

Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251-259.

Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355(3):260-269.

Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol. 1995;26(7):1565-1574.

Persson H, Lonn E, Edner M, et al. Diastolic dysfunction in heart failure with preserved systolic function: need for objective evidence: results from the CHARM Echocardiographic Substudy-CHARMES. J Am Coll Cardiol. 2007;49(6):687-694.

Maestre A, Gil V, Gallego J, Aznar J, Mora A, Martín-Hidalgo A. Diagnostic accuracy of clinical criteria for identifying systolic and diastolic heart failure: cross-sectional study. J Eval Clin Pract. 2009;15(1):55-61.

Masoudi FA, Havranek EP, Smith G, et al. Gender, age, and heart failure with preserved left ventricular systolic function. J Am Coll Cardiol. 2003;41(2):217-223.

New York Heart Association Criteria Committee. Disease of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis . 6th ed. Boston, Mass.: Little, Brown; 1964.

Remme WJ, Swedberg K Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure [published correction appears in Eur Heart J . 2001;22(23):2217–2218]. Eur Heart J. 2001;22(17):1527-1560.

Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency department have congestive heart failure?. JAMA. 2005;294(15):1944-1956.

Balion C, Santaguida PL, Hill S, et al. Testing for BNP and NT-proBNP in the diagnosis and prognosis of heart failure. Evid Rep Technol Assess (Full Rep). 2006;142:1-147.

Madhok V, Falk G, Rogers A, Struthers AD, Sullivan FM, Fahey T. The accuracy of symptoms, signs and diagnostic tests in the diagnosis of left ventricular dysfunction in primary care: a diagnostic accuracy systematic review. BMC Fam Pract. 2008;9:56.

Mulrow CD, Lucey CR, Farnett LE. Discriminating causes of dyspnea through clinical examination. J Gen Intern Med. 1993;8(7):383-392.

Chen WC, Tran KD, Maisel AS. Biomarkers in heart failure. Heart. 2010;96(4):314-320.

Ewald B, Ewald D, Thakkinstian A, Attia J. Meta-analysis of B type natriuretic peptide and N-terminal pro B natriuretic peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction. Intern Med J. 2008;38(2):101-113.

Battaglia M, Pewsner D, Jüni P, Egger M, Bucher HC, Bachmann LM. Accuracy of B-type natriuretic peptide tests to exclude congestive heart failure: systematic review of test accuracy studies. Arch Intern Med. 2006;166(10):1073-1080.

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ABC of heart failure

Clinical features and complications, clinical features.

Patients with heart failure present with a variety of symptoms, most of which are non-specific. The common symptoms of congestive heart failure include fatigue, dyspnoea, swollen ankles, and exercise intolerance, or symptoms that relate to the underlying cause. The accuracy of diagnosis by presenting clinical features alone, however, is often inadequate, particularly in women and elderly or obese patients.

Symptoms and signs in heart failure

• Paroxysmal nocturnal dyspnoea
• Reduced exercise tolerance, lethargy, fatigue
• Nocturnal cough
• Ankle swelling
• Cachexia and muscle wasting
• Tachycardia
• Pulsus alternans
• Elevated jugular venous pressure
• Displaced apex beat
• Right ventricular heave
• Crepitations or wheeze
• Third heart sound
• Hepatomegaly (tender)

Exertional breathlessness is a frequent presenting symptom in heart failure, although it is a common symptom in the general population, particularly in patients with pulmonary disease. Dyspnoea is therefore moderately sensitive, but poorly specific, for the presence of heart failure. Orthopnoea is a more specific symptom, although it has a low sensitivity and therefore has little predictive value. Paroxysmal nocturnal dyspnoea results from increased left ventricular filling pressures (due to nocturnal fluid redistribution and enhanced renal reabsorption) and therefore has a greater sensitivity and predictive value. Nocturnal ischaemic chest pain may also be a manifestation of heart failure, so left ventricular systolic dysfunction should be excluded in patients with recurrent nocturnal angina.

Common causes of lower limb oedema

• Gravitational disorder—for example, immobility
• Congestive heart failure
• Venous thrombosis or obstruction, varicose veins
• Hypoproteinaemia—for example, nephrotic syndrome, liver disease
• Lymphatic obstruction

Fatigue and lethargy

Fatigue and lethargy in chronic heart failure are, in part, related to abnormalities in skeletal muscle, with premature muscle lactate release, impaired muscle blood flow, deficient endothelial function, and abnormalities in skeletal muscle structure and function. Reduced cerebral blood flow, when accompanied by abnormal sleep patterns, may occasionally lead to somnolence and confusion in severe chronic heart failure.

Sensitivity, specificity, and predictive value of symptoms, signs, and chest x ray findings for presence of heart failure (ejection fraction <40%) in 1306 patients with coronary artery disease undergoing cardiac catheterisation

Swelling of ankles and feet is another common presenting feature, although there are numerous non-cardiac causes of this symptom. Right heart failure may manifest as oedema, right hypochondrial pain (liver distension), abdominal swelling (ascites), loss of appetite, and, rarely, malabsorption (bowel oedema). An increase in weight may be associated with fluid retention, although cardiac cachexia and weight loss are important markers of disease severity in some patients.

Physical signs

Physical examination has serious limitations as many patients, particularly those with less severe heart failure, have few abnormal signs. In addition, some physical signs are difficult to interpret and, if present, may occasionally be related to causes other than heart failure.

Oedema and a tachycardia, for example, are too insensitive to have any useful predictive value, and although pulmonary crepitations may have a high diagnostic specificity they have a low sensitivity and predictive value. Indeed, the commonest cause of lower limb oedema in elderly people is immobility, and pulmonary crepitations may reflect poor ventilation with infection, or pulmonary fibrosis, rather than heart failure. Jugular venous distension has a high specificity in diagnosing heart failure in patients who are known to have cardiac disease, although some patients, even with documented heart failure, do not have an elevated venous pressure. The presence of a displaced apex beat in a patient with a history of myocardial infarction has a high positive predictive value. A third heart sound has a relatively high specificity, although its universal value is limited by a high interobserver variability, with interobserver agreement of less than 50% in non-specialists.

In patients with pre-existing chronic heart failure, other clinical features may be evident that point towards precipitating causes of acute heart failure or deteriorating heart failure. Common factors that may be obvious on clinical assessment and are associated with relapses in congestive heart failure include infections, arrhythmias, continued or recurrent myocardial ischaemia, and anaemia.

Clinical diagnosis and clinical scoring systems

Several epidemiological studies, including the Framingham heart study, have used clinical scoring systems to define heart failure, although the use of these systems is not recommended for routine clinical practice.

Precipitating causes of heart failure

• Arrhythmias, especially atrial fibrillation
• Infections (especially pneumonia)
• Acute myocardial infarction
• Angina pectoris or recurrent myocardial ischaemia
• Alcohol excess
• Iatrogenic cause—for example, postoperative fluid replacement or administration of steroids or non-steroidal anti-inflammatory drugs
• Poor drug compliance, especially in antihypertensive treatment
• Thyroid disorders—for example, thyrotoxicosis
• Pulmonary embolism

In a patient with appropriate symptoms and a number of physical signs, including a displaced apex beat, elevated venous pressure, oedema, and a third heart sound, the clinical diagnosis of heart failure may be made with some confidence. However, the clinical suspicion of heart failure should also be confirmed with objective investigations and the demonstration of cardiac dysfunction at rest. It is important to note that, in some patients, exercise-induced myocardial ischaemia may lead to a rise in ventricular filling pressures and a fall in cardiac output, leading to symptoms of heart failure during exertion.

Classification

Symptoms and exercise capacity are used to classify the severity of heart failure and monitor the response to treatment. The classification of the New York Heart Association (NYHA) is used widely, although outcome in heart failure is best determined not only by symptoms (NYHA class) but also by echocardiographic criteria. As the disease is progressive, the importance of early treatment, in an attempt to prevent progression to more severe disease, cannot be overemphasised.

European Society of Cardiology's guidelines for diagnosis of heart failure

Essential features.

• Symptoms of heart failure (for example, breathlessness, fatigue, ankle swelling)
• Objective evidence of cardiac dysfunction (at rest)

Non-essential features

• Response to treatment directed towards heart failure (in cases where the diagnosis is in doubt)

Complications

Arrhythmias, atrial fibrillation.

Atrial fibrillation is present in about a third (range 10-50%) of patients with chronic heart failure and may represent either a cause or a consequence of heart failure. The onset of atrial fibrillation with a rapid ventricular response may precipitate overt heart failure, particularly in patients with pre-existing ventricular dysfunction. Predisposing causes should be considered, including mitral valve disease, thyrotoxicosis, and sinus node disease. Importantly, sinus node disease may be associated with bradycardias, which might be exacerbated by antiarrhythmic treatment.

NYHA classification of heart failure

Class i: asymptomatic.

No limitation in physical activity despite presence of heart disease. This can be suspected only if there is a history of heart disease which is confirmed by investigations—for example, echocardiography

Class II: mild

Slight limitation in physical activity. More strenuous activity causes shortness of breath—for example, walking on steep inclines and several flights of steps. Patients in this group can continue to have an almost normal lifestyle and employment

Class III: moderate

More marked limitation of activity which interferes with work. Walking on the flat produces symptoms

Class IV: severe

Unable to carry out any physical activity without symptoms. Patients are breathless at rest and mostly housebound

Atrial fibrillation that occurs with severe left ventricular dysfunction following myocardial infarction is associated with a poor prognosis. In addition, patients with heart failure and atrial fibrillation are at particularly high risk of stroke and other thromboembolic complications.

Ventricular arrhythmias

Malignant ventricular arrhythmias are common in end stage heart failure. For example, sustained monomorphic ventricular tachycardia occurs in up to 10% of patients with advanced heart failure who are referred for cardiac transplantation. In patients with ischaemic heart disease these arrhythmias often have re-entrant mechanisms in scarred myocardial tissue. An episode of sustained ventricular tachycardia indicates a high risk for recurrent ventricular arrhythmias and sudden cardiac death.

Predisposing factors for ventricular arrhythmias

• Recurrent or continued coronary ischaemia
• Recurrent myocardial infarction
• Hypokalaemia and hyperkalaemia
• Hypomagnesaemia
• Psychotropic drugs—for example, tricyclic antidepressants
• Digoxin (leading to toxicity)
• Antiarrhythmic drugs that may be cardiodepressant (negative inotropism) and proarrhythmic

Sustained polymorphic ventricular tachycardia and torsades de pointes are more likely to occur in the presence of precipitating or aggravating factors, including electrolyte disturbance (for example, hypokalaemia or hyperkalaemia, hypomagnesaemia), prolonged QT interval, digoxin toxicity, drugs causing electrical instability (for example, antiarrhythmic drugs, antidepressants), and continued or recurrent myocardial ischaemia. β Blockers are useful for treating arrhythmias, and these agents (for example, bisoprolol, metoprolol, carvedilol) are likely to be increasingly used as a treatment option in patients with heart failure.

Stroke and thromboembolism

Congestive heart failure predisposes to stroke and thromboembolism, with an overall estimated annual incidence of approximately 2%. Factors contributing to the increased thromboembolic risk in patients with heart failure include low cardiac output (with relative stasis of blood in dilated cardiac chambers), regional wall motion abnormalities (including formation of a left ventricular aneurysm), and associated atrial fibrillation. Although the prevalence of atrial fibrillation in some of the earlier observational studies was between 12% and 36%—which may have accounted for some of the thromboembolic events—patients with chronic heart failure who remain in sinus rhythm are also at an increased risk of stroke and venous thromboembolism. Patients with heart failure and chronic venous insufficiency may also be immobile, and this contributes to their increased risk of thrombosis, including deep venous thrombosis and pulmonary embolism.

Complications of heart failure

• Arrhythmias —Atrial fibrillation; ventricular arrhythmias (ventricular  tachycardia, ventricular fibrillation); bradyarrhythmias
• Thromboembolism —Stroke; peripheral embolism; deep venous  thrombosis; pulmonary embolism
• Gastrointestinal —Hepatic congestion and hepatic dysfunction;  malabsorption
• Musculoskeletal —Muscle wasting
• Respiratory —Pulmonary congestion; respiratory muscle weakness;  pulmonary hypertension (rare)

Recent observational data from the studies of left ventricular dysfunction (SOLVD) and vasodilator heart failure trials (V-HeFT) indicate that mild to moderate heart failure is associated with an annual risk of stroke of about 1.5% (compared with a risk of less than 0.5% in those without heart failure), rising to 4% in patients with severe heart failure. In addition, the survival and ventricular enlargement (SAVE) study recently reported an inverse relation between risk of stroke and left ventricular ejection fraction, with an 18% increase in risk for every 5% reduction in left ventricular ejection fraction; this clearly relates thromboembolism to severe cardiac impairment and the severity of heart failure. As thromboembolic risk seems to be related to left atrial and left ventricular dilatation, echocardiography may have some role in the risk stratification of thromboembolism in patients with chronic heart failure.

Most long term (more than 10 years of follow up) longitudinal studies of heart failure, including the Framingham heart study (1971), were performed before the widespread use of angiotensin converting enzyme inhibitors. In the Framingham study the overall survival at eight years for all NYHA classes was 30%, compared with a one year mortality in classes III and IV of 34% and a one year mortality in class IV of over 60%. The prognosis in patients whose left ventricular dysfunction is asymptomatic is better than that in those whose left ventricular dysfunction is symptomatic. The prognosis in patients with congestive heart failure is dependent on severity, age, and sex, with a poorer prognosis in male patients. In addition, numerous prognostic indices are associated with an adverse prognosis, including NYHA class, left ventricular ejection fraction, and neurohormonal status.

Morbidity and mortality for all grades of symptomatic chronic heart failure are high, with a 20-30% one year mortality in mild to moderate heart failure and a greater than 50% one year mortality in severe heart failure. These prognostic data refer to patients with systolic heart failure, as the natural course of diastolic dysfunction is less well defined

Some predictors of poor outcome in chronic heart failure

• High NYHA functional class
• Reduced left ventricular ejection fraction
• Low peak oxygen consumption with maximal exercise (% predicted value)
• Increased pulmonary artery capillary wedge pressure
• Reduced cardiac index
• Diabetes mellitus
• Reduced sodium concentration
• Raised plasma catecholamine and natriuretic peptide concentrations

Survival can be prolonged in chronic heart failure that results from systolic dysfunction if angiotensin converting enzyme inhibitors are given. Longitudinal data from the Framingham study and the Mayo Clinic suggest, however, that there is still only a limited improvement in the one year survival rate of patients with newly diagnosed symptomatic chronic heart failure, which remains at 60-70%. In these studies only a minority of patients with congestive heart failure were appropriately treated, with less than 25% of them receiving angiotensin converting enzyme inhibitors, and even among treated patients the dose used was much lower than doses used in the clinical trials.  

Cardiac mortality in placebo controlled heart failure trials

EF ejection fraction. SOLVD-P, SOLVD-T=studies of left ventricular dysfunction prevention arm (P) and treatment arm (T).

H-ISDN=hydralazine and isosorbide dinitrate.

*Treatment with H-ISDN.

Treatment with angiotensin converting enzyme inhibitors prevents or delays the onset of symptomatic heart failure in patients with asymptomatic, or minimally symptomatic, left ventricular systolic dysfunction. The increase in mortality with the development of symptoms suggests that the optimal time for intervention with these agents is well before the onset of substantial left ventricular dysfunction, even in the absence of overt clinical symptoms of heart failure. This benefit has been confirmed in several large, well conducted, postmyocardial infarction studies.

Key references

• Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R, et al. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994;334:493-8.
• Gradman A, Deedwania P, Cody R, Massie B, Packer M, Pitt B, et al. Predictors of total mortality and sudden death in mild to moderate heart failure. J Am Coll Cardiol 1989;14:564-70.
• Guidelines for the diagnosis of heart failure. The Task Force on Heart Failure of the European Society of Cardiology. Eur Heart J 1995;16:741-51.
• Rodeheffer RJ, Jacobsen SJ, Gersh BJ, Kottke TE, McCann HA, Bailey KR, et al. The incidence and prevalence of congestive heart failure in Rochester, Minnesota. Mayo Clin Proc 1993;68:1143-50.
• The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91.
• The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the cooperative north Scandinavian enalapril survival study (CONSENSUS). N Engl J Med 1987;316:1429-35.

Sudden death

The mode of death in heart failure has been extensively investigated, and progressive heart failure and sudden death seem to occur with equal frequency. Some outstanding questions still remain, however. Although arrhythmias are common in patients with heart failure and are indicators of disease severity, they are not powerful independent predictors of prognosis. Sudden death may be related to ventricular arrhythmias, although asystole is a common terminal event in severe heart failure. It has not been firmly established whether these arrhythmias are primary arrhythmias or whether some are secondary to acute coronary ischaemia or indicate in situ coronary thrombosis. The cause of death is often uncertain, especially as the patient may die of a cardiac arrest outside hospital or while asleep.

Gross oedema of ankles, including bullae with serous exudate

24 Hour Holter tracing showing frequent ventricular extrasystoles

Acknowledgments

The table on the sensitivity, specificity, and predictive value of symptoms, signs, and chest x ray findings is adapted with permission from Harlan et al ( Ann Intern Med 1977;86:133-8).

R D S Watson is consultant cardiologist in the university department of medicine and the department of cardiology, City Hospital, Birmingham.

The ABC of heart failure is edited by C R Gibbs, M K Davies, and G Y H Lip. CRG is research fellow and GYHL is consultant cardiologist and reader in medicine in the university department of medicine and the department of cardiology, City Hospital, Birmingham; MKD is consultant cardiologist in the department of cardiology, Selly Oak Hospital, Birmingham. The series will be published as a book in the spring.

• Introduction
• Conclusions
• Article Information

a Information was obtained via screening logs, reporting the single criterion that did not meet eligibility.

ICU indicates intensive care unit; SGLT-2, sodium-glucose cotransporter 2.

Distribution of wins, ties, and losses for the dapagliflozin group among the 64 232 paired comparisons, stratified by each level of the hierarchical primary composite outcome. Every possible pair of participants between groups was compared in a hierarchical fashion with a win, a loss, or a tie determined by the outcome evaluated at each level of the hierarchy. Early ties were determined when both participants in the pair died during hospitalization. Percentages are calculated for each level of the hierarchy. The win ratio equals the total wins for the dapagliflozin group divided by the total losses for the dapagliflozin group: 27 143/26 929 = 1.01 (95% CI, 0.90-1.13; P  = .89). ICU indicates intensive care unit.

a Determined by physician’s assessment.

b Baseline serum creatinine levels. To convert creatinine from mg/dL to μmol/L, multiply by 88.4.

c According to the Simplified Acute Physiology Score 3 subgroup.

Shown is the win ratio for the composite hierarchical primary outcome of hospital mortality, initiation of kidney replacement therapy, and intensive care unit (ICU) length of stay stratified for prespecified subgroups. A win ratio greater than 1.0 indicates a favorable effect for the dapagliflozin group. The width of point estimates are scaled according to the number of participants in each subgroup. The 95% CIs were not adjusted for multiple comparisons and should not be used to infer treatment effects.

Trial Protocol

Statistical Analysis Plan

eTable 1. Inclusion criteria

eTable 2. Exclusion criteria

eTable 3. Key study dates and milestones

eTable 4. Protocol deviations

eTable 5. Results for the secondary outcomes from the frequentist analysis

eTable 6. Results for the exploratory post-hoc outcome

eTable 7. Hazard ratios from subdistribution and cause-specific hazard models for initiation of kidney replacement therapy

eTable 8. All investigator-reported serious adverse events

eFigure 1. Intersection between the organ dysfunction eligibility criteria for randomized participants

eFigure 2. Utilization of dapagliflozin during study follow-up

eFigure 3. Posterior predictive distributions by study group and posterior distributions of average marginal effects on hospital mortality

eFigure 4. Posterior predictive distributions by study group and posterior distributions of average marginal effects on initiation of kidney replacement therapy

eFigure 5. Posterior predictive distributions by study group and posterior distributions of average marginal effects on ICU-free days

eFigure 6. Posterior predictive distributions by study group and posterior distributions of average marginal effects on hospital-free days

eFigure 7. Posterior predictive distributions by study group and posterior distributions of average marginal effects on mechanical ventilation-free days

eFigure 8. Posterior predictive distributions by study group and posterior distributions of average marginal effects on kidney replacement therapy-free days

eFigure 9. Posterior predictive distributions by study group and posterior distributions of average marginal effects on vasopressor-free days

eFigure 10. Distribution of ICU-, hospital-, KRT-, mechanical ventilation-, and vasopressor-free days

eFigure 11. Boxplot of serum creatinine and pH Levels

eFigure 12. Posterior predictive distributions by study group and posterior distributions of average marginal effects on modified major adverse kidney events

eFigure 13. Cumulative incidence functions for hospital mortality and use of kidney replacement therapy

Nonauthor Collaborators. The DEFENDER study Investigators

Data Sharing Statement

• Fluid Therapy for Critically Ill Adults With Sepsis: A Review JAMA Review June 13, 2023 This review summarizes the 4 phases of fluid therapy used for critically ill patients with sepsis: resuscitation, optimization, stabilization, and evacuation. Fernando G. Zampieri, MD, PhD; Sean M. Bagshaw, MD, MSc; Matthew W. Semler, MD, MSc
• SGL-2 Therapy for Acute Organ Dysfunction JAMA Editorial June 14, 2024 Hernando Gómez, MD, MPH; Lennie P. G. Derde, MD, PhD

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Tavares CAM , Azevedo LCP , Rea-Neto Á, et al. Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction : The DEFENDER Randomized Clinical Trial . JAMA. Published online June 14, 2024. doi:10.1001/jama.2024.10510

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Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction : The DEFENDER Randomized Clinical Trial

• 1 Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil
• 2 Geriatric Cardiology Unit, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
• 3 Center for Studies and Research in Intensive Care Medicine, Curitiba, Brazil
• 4 Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil
• 5 Hospital Santa Casa Curitiba, Curitiba, Brazil
• 6 Hospital M´Boi Mirim, São Paulo, Brazil
• 7 Hospital de Câncer de Barretos, Barretos, Brazil
• 8 Intensive Care Division, Hospital de Base, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, Brazil
• 9 Hospital Universitário São Francisco de Assis na Providência de Deus, Bragança Paulista, Brazil
• 10 Hospital de Emergência Dr Daniel Houly, Arapiraca, Brazil
• 11 Hospital Santa Lucia, Poços de Caldas, Brazil
• 12 Santa Casa de Misericórdia de Barretos, Barretos, Brazil
• 13 Hospital Maternidade São José, Colatina, Brazil
• 14 Hospital Municipal de Aparecida de Goiânia, Aparecida de Goiânia, Brazil
• 15 Hospital Nossa Senhora de Oliveira, Vacaria, Brazil
• 16 Centro Hospitalar Unimed, Joinville, Brazil
• 17 Department of Cardiovascular Disease, Saint Luke’s Mid America Heart Institute, University of Missouri–Kansas City School of Medicine, Kansas City
• 18 Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
• 19 Department of Intensive Care, Austin Hospital, Melbourne, Australia
• 20 George Institute for Global Health, London, United Kingdom
• 21 Imperial College London, London, United Kingdom
• 22 Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, Canada
• Editorial SGL-2 Therapy for Acute Organ Dysfunction Hernando Gómez, MD, MPH; Lennie P. G. Derde, MD, PhD JAMA
• Review Fluid Therapy for Critically Ill Adults With Sepsis: A Review Fernando G. Zampieri, MD, PhD; Sean M. Bagshaw, MD, MSc; Matthew W. Semler, MD, MSc JAMA

Question   Does the addition of dapagliflozin to standard of care improve the hierarchical outcome of hospital mortality, initiation of kidney replacement therapy, and the length of stay in the intensive care unit (ICU) among critically ill patients with acute organ dysfunction?

Findings   In this multicenter, open-label, randomized clinical trial that included 507 participants with at least 1 acute organ dysfunction (hypotension, kidney injury, or respiratory), the use of 10 mg of dapagliflozin for up to 14 days did not significantly reduce the combined outcome of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay, assessed by the win ratio method (win ratio, 1.01, not significant) through 28 days after randomization.

Meaning   The addition of dapagliflozin to standard care for individuals with critical illness and acute organ dysfunction did not improve clinical outcomes.

Importance   Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown.

Objective   To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction.

Design, Setting, and Participants   Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023.

Intervention   Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first.

Main Outcomes and Measures   The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support–free days, ICU, and hospital stay, assessed using bayesian regression models.

Results   Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P  = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group.

Conclusion and Relevance   The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin.

Trial Registration   ClinicalTrials.gov Identifier: NCT05558098

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are effective at improving clinical outcomes in several randomized clinical trials across the spectrum of cardiovascular, metabolic, and kidney diseases. 1 - 3 Their use in acute illness, including patients with COVID-19 4 , 5 or acute heart failure 6 , 7 and immediately after experiencing myocardial infarction, 8 , 9 have been recently tested with promising but nondefinitive results. Although the exact mechanism underlying their benefits is debated, 10 various potential beneficial mechanisms are proposed, several of which could be useful for patients with critical illness. These include improvements in endothelial dysfunction, adrenergic tone modulation, oxidative stress, and cardiorenal effects, lending biological plausibility to their use in treating acute organ dysfunction. Experimental models that simulate acute intensive care unit (ICU) conditions reveal that SGLT-2 inhibitors attenuate inflammation and provide protection against organ injury. 11 , 12 In particular, nephroprotective effects of SGLT-2 inhibitors may be of interest to those treating critically ill populations, given the high incidence of acute kidney injury in this population. 13

There is no trial that assessed safety and effectiveness of SLGT-2 inhibitors in a broad population of critically ill patients with organ failure. Therefore, we conducted a randomized clinical trial to assess the effects of dapagliflozin when added to standard care of critically ill patients with acute organ dysfunction. We hypothesized that dapagliflozin could reduce the composite outcome of hospital mortality, initiation of kidney replacement therapy (KRT), and the duration of ICU stay.

The trial protocol (available in Supplement 1 ) was approved by the institutional review board from each site, and all patients or legal representatives provided written informed consent. The trial design and statistical analysis plan ( Supplement 2 ) were previously published. 14 This was an investigator-initiated, multicenter, open-label, randomized clinical trial conducted across 22 ICUs in Brazil. The trial operations were coordinated by the Academic Research Organization of the Hospital Israelita Albert Einstein. An independent data and safety monitoring board (DSMB) reviewed unblinded study data for safety. The trial was conducted in accordance with the Good Clinical Practice guidelines and is reported following the Consolidated Standards of Reporting Trials (CONSORT) 2010 reporting guideline statement for parallel-group randomized trials. 15

Eligible participants were aged 18 years or older, admitted to the ICU with an expected length of stay of 48 hours or longer, with at least 1 organ dysfunction criterion, (1) hypotension (mean arterial pressure <65 mm Hg, systolic blood pressure <90 mm Hg, or use of vasopressors), (2) signs of acute kidney injury (increase in 0.3 mg/dL [22.88 μmol/L] in serum creatinine or decrease in urine output <0.5 mL/kg/h for ≥6 hours), or (3) need of new use of high-flow nasal catheter, noninvasive, or invasive ventilation ( Table 1 ). Key exclusion criteria were the presence of organ dysfunction criteria for more than 24 hours, end-stage kidney disease undergoing maintenance dialysis, prior use of dapagliflozin or other SGLT-2 inhibitor, known type 1 diabetes, a history of diabetic ketoacidosis, and planned ICU admission following elective surgery ( Figure 1 ). Further details are found in eTables 1 and 2 in Supplement 3 .

Eligible patients were randomized in a 1:1 ratio to receive either 10 mg of open-label dapagliflozin in addition to standard care (dapagliflozin intervention group) or standard care alone (control group). Randomization was performed by a central, concealed, web-based automated system (Research Electronic Data Capture [REDCap]), stratified by study site with variable block sizes of 4, 8, and 12. There was no blinding.

Dapagliflozin, 10 mg/d, was given orally within 24 hours of randomization, preferably in the morning without fasting, for a duration of 14 days or until ICU discharge, whichever occurred first. For participants who were unable to swallow pills, dapagliflozin was administered enterally after macerating the medication and diluting it in water before administration. 4 , 5 Study protocol mandated that dapagliflozin administration was discontinued in the following situations: (1) absolute fasting or the inability to access the enteral route for drug administration, (2) occurrence of euglycemic diabetic ketoacidosis (blood glucose ≤250 mg/dL [13.88 mmol/L], metabolic acidosis, and moderate ketonuria [≥2 on urine stick] or ketonemia [blood ketones ≥1.5 mmol/L]), (3) more than 1 episode of severe hypoglycemia (blood glucose ≤50 mg/dL [2.77 mmol/L]), (4) withdrawal of consent, (5) suspected allergic reaction, and (6) initiation of KRT. Adherence was assessed daily for 14 days. Each study site was expected to provide standard of care treatment for critical illness for all trial participants, which was determined solely by the local site health care team and aligned with institutional protocols and international guidelines. This included various aspects of care, such as ventilation strategies, management of sepsis, delirium prevention and management, prophylaxis for deep venous thrombosis, sedation practices, pain management, and other relevant components of critical care. A minimum daily carbohydrate intake of 100 g of glucose was suggested for all study participants.

Baseline demographic information, comorbidities, concomitant medications, reasons for ICU admission, and illness severity were collected at enrollment. From days 1 to 5, monitoring included laboratory parameters such as blood gas analysis and serum creatinine levels. Participants were followed up for 28 days or until discharged home from the hospital. Adverse events were observed until trial follow-up was complete. Hospital outcomes were documented either at the time of hospital discharge or after 28 days of follow-up, whichever occurred earlier. All data collection was performed by trained site personnel using a dedicated electronic data capture system, and comprehensive data monitoring was conducted across all sites, either through remote means or on-site evaluations. Records of screening failures were documented in the form of weekly screening logs for each enrolling and active site. To ensure trial representativeness and diversity, self-reported race and ethnicity information was collected by site personnel, using available data from electronic medical records or directly from participants when feasible.

The primary outcome was a hierarchical composite of hospital mortality, initiation of KRT, and ICU length of stay through 28 days after randomization. For ICU length of stay, the cumulative number of calendar days (without fractions) spent in the ICU was calculated from randomization until hospital discharge.

The 7 prespecified secondary outcomes included hospital mortality, KRT use, ICU-free days, hospital-free days, vasopressor-free days, mechanical ventilation–free days, and KRT-free days. All secondary outcomes were evaluated within 28 days after randomization. To be considered free of vasopressor and mechanical ventilation, a cutoff of 6 hours or less within a calendar day was used. The ICU-free days, hospital-free days, and KRT-free days were defined as the count of full calendar days (without fractions) in which participants were alive and free from each respective component. These outcomes were measured on an ordinal scale ranging from 0 to 29, with higher values signifying more favorable outcomes. Participants who did not survive until hospital discharge were assigned a value of 0. For those discharged to home before day 28, it was assumed that they remained alive and free from the specified outcome beyond their discharge date.

Adverse events of special interest were collected during the trial: (1) elevation of elevated serum liver transaminases (exceeding 3 times the reference range), (2) skin lesions, (3) hypoglycemia (blood glucose ≤50 mg/dL), (4) urinary tract infections, (5) bloodstream infections, and (6) occurrence of diabetic ketoacidosis (metabolic acidosis and moderate ketonuria [≥2 on urine stick] or ketonemia [blood ketones ≥1.5 mmol/L]). These events were reported without regard to their severity or causality assessment. All serious adverse events occurring during study follow-up were recorded, regardless of presumed causality.

The sample size was calculated under the hypothesis that dapagliflozin would lead to reductions in all the individual components of the hierarchical composite primary outcome, anticipating a 2% absolute reduction in hospital mortality (from 30% to 28%), a 3% absolute reduction in the initiation KRT (from 10% to 7%), and a mean reduction in ICU length of stay by 0.5 days (with an assumed variance of 1.1 days). In simulations, enrolling 500 participants would provide the study with at least 85% statistical power to detect an intervention effect, with a 95% CI for the win ratio exceeding 1.0 and a resulting median simulated value for the win ratio of 1.40. Ten thousand simulations with samples of 500 participants each were conducted, with 95% CIs calculated using bootstrapping. Additional information is shown in Supplements 1 and 2 .

The hierarchical composite primary outcome was analyzed using the generalized pairwise comparison method 16 and the treatment effect quantified using the win ratio method. This approach involved comparing each participant in the dapagliflozin group with every participant in the control group, generating all conceivable participant pairs across trial groups. In each pairwise comparison, a win, loss, or tie was defined based on the comparative assessment of participant outcomes in hierarchical fashion. The primary composite outcome hierarchy consisted of 3 hierarchical levels, (1) hospital mortality, (2) initiation of KRT, and (3) ICU length of stay. For the first level of comparison, if both participants in a pair died before discharge, it was classified as an early tie . This signifies that the pair is not subjected to further comparison for the second or third hierarchical levels, thus emphasizing the higher importance of hospital mortality. 17 If both participants survived, the pair was subsequently evaluated for the initiation of KRT. In the event of a tie, the participants were then compared with respect to ICU length of stay. The win ratio was calculated by dividing the total number of wins in the dapagliflozin group by the total number of losses. A detailed win ratio hierarchy flowchart is shown in the eMethods section in Supplement 3 , and review of the generalized pairwise method is found elsewhere. 18

The secondary binary outcomes were assessed with a bayesian hierarchical logistic regression (multilevel) model, adjusted for study site (random intercept), participant age, clinical suspicion of sepsis, and the use of vasopressors and mechanical ventilation at randomization using a normally distributed neutral prior, centered at an odds ratio (OR) of 1.0 (corresponding to a 95% credible interval [CrI] ranging between 0.5 and 2.0). 19 Days-free secondary outcomes were analyzed with a hierarchical ordinal bayesian model adjusted for the same covariates. Treatment effects were quantified using adjusted OR, bayesian 95% CrIs, and probability of benefit for the dapagliflozin group. Further details regarding secondary models’ assumptions are provided in Supplement 2 and in the eMethods section in Supplement 3 .

To complement the bayesian analysis, additional prespecified frequentist analyses were conducted for the secondary outcomes. For hospital mortality and initiation of KRT, a logistic regression model was used, adjusting for the same covariates used in the bayesian models. For the ordinal secondary outcomes, differences between the groups were computed using the Hodges-Lehmann estimator, with results presented as differences in days between groups along with their corresponding 95% CIs. Comparisons of trends in serum creatinine and pH levels between study groups were conducted from days 1 to 5 using a linear mixed-effects model for repeated measures.

The efficacy and safety analyses included all the participants who underwent randomization (intention-to-treat principle). An additional sensitivity analysis for safety outcomes was conducted in the safety analysis population, comprising participants who received at least 1 dose of dapagliflozin.

Prespecified subgroup analyses for the primary outcome were conducted using the stratified win ratio method 20 for the following subgroups, (1) presence of clinical suspicion of sepsis at randomization, (2) prior diabetes, (3) serum creatinine levels at enrollment (<1.5 mg/dL, 1.5-3.0 mg/dL, and >3.0 mg/dL [to convert creatinine from mg/dL to μmol/L, multiply by 88.4]), (4) reason for ICU admission due to cardiovascular causes (from the table of reasons for ICU admission of Simplified Acute Physiology Score 3 [SAPS 3]), 21 and (5) age (<65 years and ≥65 years).

The DSMB led all planned safety analyses after the enrollment of 100, 250, and 375 participants. These analyses included the absolute and relative frequencies of all serious adverse events, adverse events of special interest, hospital mortality, and initiation of KRT, according to study groups. An interim analysis was performed when half of the intended trial population (250 participants) was enrolled. At this analysis, the DSMB would recommend halting the trial for safety reasons if the posterior probability of harm associated with dapagliflozin for the composite outcome of hospital mortality or KRT exceeded 80%. No interim analyses were conducted for efficacy or futility (see Supplement 3 ).

Post hoc exploratory analyses were conducted to assess the effect of dapagliflozin on (1) modified major adverse kidney events (MAKEs), defined as the composite outcome of death, initiation of KRT, or doubling the serum creatinine level during the first 5 days after enrollment, and (2) the use of KRT while accounting for the competing risk of death (see the eMethods section in Supplement 3 ).

For the primary outcome, a 2-sided P value of less than .05 was considered to indicate statistical significance and 95% CIs were calculated using the bootstrap method. 16  P values are presented exclusively for the primary outcome and subgroup analyses. The analyses of secondary outcomes were not adjusted for multiple comparisons. All analyses were conducted using R software version 4.2.1 or higher (R Foundation for Statistical Computing). 22

From November 22, 2022, to August 30, 2023, 4434 participants were screened, and 507 participants from 22 sites in Brazil were randomized: 248 to receive dapagliflozin plus standard care and 259 to receive standard care ( Figure 1 ; eTable 3 in Supplement 3 ). All 507 participants (mean age, 63.9 (SD, 15) years; 46.9% women) were included in the analysis, with no loss to follow-up. The database lock was performed on October 20, 2023. Two hundred four (39.6%) had ICU admission due to suspected infection, and the median time from ICU admission to randomization was 1 day (IQR, 0-1 day, Table 1 ). At randomization, 235 participants (46.4%) required respiratory support with mechanical ventilation and 253 (49.9%) received norepinephrine. Furthermore, and the number of trial participants who met the organ dysfunction eligibility criteria were 249 (49.5%) for respiratory, 227 (44.2%) for hypotension, and 212 (42.2%) for kidney injury. The most common inclusion criterion was kidney injury in isolation (140 patients [27.6%]), followed by respiratory dysfunction in isolation (120 patients [23.6%]), and hypotension in isolation (96 patients [18.9%]); remaining possible combinations and their frequencies are shown in eFigure 1 in Supplement 3 .

All 248 participants randomized to receive dapagliflozin received at least 1 dose of the study medication. None of the control group participants received dapagliflozin or any other SGLT-2 inhibitor during study follow-up (eFigure 2 and eTable 4 in Supplement 3 ).

Dapagliflozin treatment did not result in a higher number of wins than the standard care alone group for the primary hierarchical composite outcome. The total number of wins was 27 143 (42.3%) in the dapagliflozin group and 26 929 (41.9%) in the standard care alone group, a win ratio of 1.01 (95% CI, 0.90 to 1.13; P  = .89; Table 2 ). Among all pairwise comparisons, there were 10 160 ties (15.8%), with 7832 (12.2%) occurring in the hospital mortality comparison and classified as early ties ( Figure 2 ).

Within 28 days, hospital mortality occurred in 88 of 248 participants (35.5%) in the dapagliflozin group compared with 89 of 259 participants (34.4%) in the standard care alone group. The adjusted OR for the bayesian model, accounting for study site, age, sepsis at randomization, use of vasopressors at randomization, and use of mechanical ventilation, was 1.06 (95% CrI, 0.76-1.52; Table 2 ). Initiation of KRT occurred in 27 participants (10.9%) in the dapagliflozin group compared with 39 participants (15.1%) in the standard care alone group (adjusted OR, 0.76; 95% CrI, 0.50-1.18). The posterior probabilities indicating that the use of dapagliflozin reduced the risk of hospital mortality and initiation of KRT compared with standard of care alone, were .36 and .90, respectively ( Table 2 and eFigures 3 and 4 in Supplement 3 ).

For the secondary ordinal outcomes of ICU-free days, hospital-free days, mechanical ventilation-free days, KRT-free days, and vasopressor-free days, the results from the bayesian hierarchical logistic regression models were inconclusive about treatment effect on these outcomes, yielding posterior probabilities of benefit for dapagliflozin between 0.39 to 0.63 ( Table 2 and eFigures 5-10 in Supplement 3 ). The complementary frequentist analyses of the secondary outcomes yielded results that were consistent with bayesian analysis, with an adjusted OR of 1.08 (95% CI, 0.73-1.60) for hospital mortality and 0.67 (95%CI, 0.39-1.13) for use of KRT (eTable 5 in Supplement 3 ). No significant differences between study groups were observed for serum creatinine and pH levels during the initial 5 days of trial follow-up (eFigure 11 in Supplement 3 ).

No evidence of heterogeneity of treatment effect was detected in predefined subgroups ( Figure 3 ), as assessed in a one-at-a-time subgroup analysis. Among patients receiving dapagliflozin compared with standard care, there was a posterior probability of benefit of .60 for modified MAKEs (eTable 6 and eFigure 12 in Supplement 3 ). When considering the competing risk of death, the cause-specific adjusted hazard ratio for the dapagliflozin group for the use of KRT was 0.72 (95% CI, 0.44-1.18), a similar result was obtained from the Fine and Gray model (adjusted HR, 0.71; 95% CI, 0.45-1.13; eTable 7 and eFigure 13 in Supplement 3 ).

Investigator-reported serious adverse events were documented in 115 participants (46.4%) in the dapagliflozin group and in 123 participants (47.5%) in the control group ( Table 3 and eTable 8 in Supplement 3 ). Adverse events of special interest, including urinary tract infections (4 [1.6%] vs 3 [1.2%]), hypoglycemia (2 [0.8%] vs 0), and bloodstream infections (1 [0.4%] vs 4 [1.5%]) were reported in the dapagliflozin group vs the control group, respectively. There were no reported cases of ketoacidosis.

In this randomized, open-label, controlled clinical trial involving 507 participants, the addition of dapagliflozin to standard care was not associated with an increase in the win ratio for a hierarchical end point of hospital mortality, use of KRT, and ICU length of stay. Of the 7 secondary end points, a suggestion of benefit was found for only 1 (the use of KRT, 0.90 probability of benefit). As expected in critically ill patients, a substantial number of serious adverse events were reported in both trial groups. However, dapagliflozin use was well tolerated, with numerically fewer serious adverse events reported in this group than the standard care alone group.

There is increasing interest in SGLT-2 inhibitors for treating acutely ill patients. There is high-quality evidence to support their use in outpatients with diabetes, 1 heart failure, 2 and chronic kidney disease, 3 and there is some potential benefit for patients with myocardial infarction. 8 , 9 The benefits of SGLT-2 inhibitors may derive from their nephroprotective effects. 3 , 23 Experimental evidence suggests that this may be evident in models of sepsis, 12 and the biological rational may also involve different pathways (including inflammation, energy metabolism, and endothelial function), 24 - 26 which are mediators for organ dysfunction among acutely illness patients. 27 - 29 This trial was designed to extend the prior evidence and assess the effects of dapagliflozin in an unselected population of critically ill patients in a randomized trial.

These results have several implications. First, despite a neutral result for the primary end point, dapagliflozin use appeared safe in a population of critically ill patients with a hospital mortality rate of 35%. More specifically, adverse events of interest that have been suggested to occur with dapagliflozin use, including bloodstream or urinary infections, were uncommon and occurred at similar rates in both groups, and no ketoacidosis event was reported during the trial. Second, although the results were also inconclusive for all secondary end points, they do not exclude the potential benefits or harms from this therapy. Third, the probability of benefit for the prespecified secondary outcome of reducing KRT use was 0.90. This was not confirmed in a post hoc analysis that considered composite kidney end points or competing risks. Although the finding may be due to chance, it is aligned with several trials in the outpatient setting that suggested a nephroprotective effect of SGLT-2 inhibitors. For example, the DARE-19 trial 4 found that kidney events were numerically lower in patients with COVID-19 who were treated with dapagliflozin. Taken together, these trial results suggest that further study of SGLT-2 inhibitors on critically ill patients should continue and that renal outcomes could be favored as a potential target.

This trial has several limitations. First, the unblinded nature of the trial may introduce bias. Second, the trial enrolled an unselected and heterogeneous population of critically ill patients across various stages of acute illness. It is conceivable, for example, that participants with specific features (diabetes, chronic kidney disease, etc) may have differential treatment effects, but these were not observed. As a first trial of its kind, broad inclusion criteria were used to assess safety and the drug effects on clinical outcomes. 30 Third, no data were available on the biological response to dapagliflozin, and it is possible that inadequate absorption of the oral drug may have influenced the findings. Fourth, the analysis of secondary outcomes used models adjusted for clinical suspicion of sepsis based on physicians’ assessment rather than confirmed through objective criteria.

The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin.

Accepted for Publication: May 17, 2024.

Published Online: June 14, 2024. doi:10.1001/jama.2024.10510

Corresponding Author: Fernando G. Zampieri, MD, PhD, Rua Comendador Elias Jafet, 755, São Paulo, SP, Brazil, 05653-000 ( [email protected] ).

Author Contributions: Drs Tavares, Schuler, Monfardini, Nieri, Damiani, and Zampieri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tavares, Almeida, Figueiredo, Monfardini, Silva, Kosiborod, Pereira, Damiani, Corrêa, Serpa-Neto, Berwanger, Zampieri.

Acquisition, analysis, or interpretation of data: Tavares, Azevedo, Rea-Neto, Campos, Amendola, Kozesinski-Nakatani, David-João, Lobo, Filiponi, Almeida, Bergo, Guimarães, Castro, Schuler, Westphal, Carioca, Monfardini, Nieri, Neves, Paulo, Albuquerque, Silva, Pereira, Corrêa, Serpa-Neto, Berwanger.

Drafting of the manuscript: Tavares, Azevedo, Filiponi, Almeida, Carioca, Monfardini, Corrêa, Serpa-Neto, Zampieri.

Critical review of the manuscript for important intellectual content: Tavares, Rea-Neto, Campos, Amendola, Kozesinski-Nakatani, David-João, Lobo, Almeida, Bergo, Guimarães, Figueiredo, Castro, Schuler, Westphal, Nieri, Neves, Paulo, Albuquerque, Silva, Kosiborod, Pereira, Damiani, Corrêa, Serpa-Neto, Berwanger.

Statistical analysis: Tavares, Schuler, Monfardini, Nieri, Damiani, Zampieri.

Obtained funding: Berwanger, Zampieri.

Administrative, technical, or material support: Tavares, Azevedo, Campos, Filiponi, Almeida, Monfardini, Neves, Paulo, Albuquerque, Silva, Pereira, Serpa-Neto.

Supervision: Tavares, Azevedo, David-João, Figueiredo, Kosiborod, Pereira, Corrêa, Berwanger.

Other: Guimarães.

Other - Database Quality Review: Carioca.

Other - Patient recruitment: Westphal.

Conflict of Interest Disclosures: Dr Tavares reported receiving grants from Novo Nordisk outside the submitted work. Dr Azevedo reported receiving lecture fees from Baxter, MSD, Biolab, and Nestle; nonfinancial support from MSD; and a grant for congress participations outside the submitted work. Dr Lobo reported receiving personal fees from Edwards, Pfizer, and Roche outside the submitted work. Dr Kosiborod reported receiving to his institution personal fees from 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, Bayer, Boehringer Ingelheim, Cytokinetics, Dexom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceutcials, Merck, NovoNordisk, Pfizer, Pharmacosmos, Regeneron, Sanofi, scPharmaceutical, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; grants to his institution from AstraZeneca and Boehringer Ingelheim; and having stock options from Artera Health and Saghmos Therapeutics. Dr Pereira reported receiving grants from the Brazilian Ministry of Health during the conduct of the study and outside the submitted work. Dr Serpa-Neto reported receiving personal fees from Drager outside the submitted work. Dr Berwanger reported receiving grants to his previous institution from Amgen, AstraZeneca, Bayer, Novartis, Servier, and Pfizer outside the submitted work. Dr Zampieri reported receiving consulting fees from Baxter International and Bactiguard and receiving grants to his institution from Ionis Pharmaceuticals outside the submitted work. No other disclosures were reported.

Funding/Support: This trial is funded by Brazilian Ministry of Health through the Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde—PROADI-SUS.

Role of the Funder/Sponsor: The Brazilian Ministry of Health approved the study but had no role in the design and conduct of the study; collection, management, analysis, interpretation of the data; manuscript preparation, review, or approval; nor in the decision to submit the manuscript for publication.

Group Information: A complete list of the DEFENDER study investigators appears in Supplement 4 .

Meeting Presentation: This paper was presented at the Critical Care Reviews Meeting; June 14, 2024; Belfast, United Kingdom.

Data Sharing Statement: See Supplement 5 .

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Acute heart failure: clinical presentation, one-year mortality and prognostic factors

Affiliation.

• 1 Department of Medicine, University Hospital Zürich, Switzerland. [email protected]
• PMID: 15921809
• DOI: 10.1016/j.ejheart.2005.01.014

Aims: Acute heart failure (HF) is a common but ill-defined clinical entity. We describe patients hospitalised with acute HF in regard of clinical presentation, mortality, and risk factors for an unfavourable outcome.

Methods and results: We conducted a prospective study including 312 consecutive patients from two European centers hospitalised with acute HF, defined as new onset or worsening of symptoms and signs of HF within 7 days. The mean age was 73 years and 56% were men. Twenty-eight percent had de-novo acute HF and 72% a decompensation of chronic HF. Coronary heart disease (CHD) was the most frequent underlying heart disease, elevated blood pressure >150 mmHg and acute ischemia being the most important triggers. Four percent of the patients had cardiogenic shock, 13% presented with pulmonary edema. LV-EF was <35%, 35-50% and >50% in 35%, 32% and 33% of the patients, respectively. ICU-treatment was necessary in 39% of the patients. Thirty-day mortality (11%) was increased in the presence of shock or elevated troponin T levels. Twelve-month all-cause mortality (29%) increased in the presence of shock, left ventricular dysfunction, renal insufficiency, CHD, and age.

Conclusions: This prospective study shows that despite modern treatment, morbidity and mortality of patients hospitalised with acute HF remain high.

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