History of Heart Failure Definition

Heart failure (HF) is a significant global public health issue, particularly among older patients, and is a primary cause of death and illness. Furthermore, HF is widely acknowledged as a common reason for hospitalisation, leading to substantial healthcare expenses and significantly impacting the quality of life for patients.

In the 2023 edition of The ESC Textbook of Heart Failure, Groenewegen et al. characterised HF as an epidemic; currently, it affects approximately 64 million individuals globally, and the prevalence of HF is increasing because of the ageing population. Quantifying the burden of HF is a difficult challenge because of the complex characteristics of this condition and the evolving definitions of HF over time.^1,2

With populations ageing and changing risk profiles worldwide, understanding the global epidemiology of HF is crucial for preventing and treating its underlying causes, and minimising its global implications.^3,4

The absence of a universally recognised definition of HF has presented challenges to the study of its epidemiology. Previously, researchers in this field simply diagnosed HF based on clinical findings, contributing to its complexity. Unfortunately, HF is difficult to diagnose clinically, with a wide range of nonspecific symptoms often overlapping with other pathologies, complicating prompt diagnosis. Consequently, interpreting data on mortality, post-mortem studies and hospitalisation rates in terms of prevalence and incidence has proven challenging, making national and international comparisons challenging. In this situation, extensive population studies have employed a variety of methodologies involving scores derived from an initial assessment of medical history and clinical examination, followed by the use of chest radiography to establish the presence of HF. Initiated in 1948, the Framingham Study serves as a classic example. This research study established the incidence and prevalence of HF using standardised clinical and radiological criteria.

The Framingham Study is a milestone in cardiovascular epidemiology. The large amount of new scientific data produced over a period of five decades has had a substantial impact on the current prevention of cardiovascular disease, and has indirectly affected worldwide prevention strategies. The Framingham Study initially provided excellent insights into the prevalence, incidence and prognosis of cardiovascular disease. This approach continues to provide significant data that improve our knowledge of the fundamental mechanisms. This study also aimed to determine the factors that contribute to cardiovascular disease, including modifiable factors, such as hypertension, hypercholesterolaemia, diabetes, unhealthy diets, smoking, physical inactivity and obesity, as well as non-modifiable factors, such as the patient’s sex or race.^2,5,6

The Framingham Study is the source of the now well-established concept of risk factors, which are essential for cardiovascular disease prevention. It guided the identification of fundamental principles, including the impact of obesity, hypercholesterolaemia, hypertension, diet, physical inactivity, tobacco use and diabetes on cardiovascular disease. These discoveries were initially published as novel cardiovascular risk factors, and are currently the primary focus of global prevention efforts intended to reduce the incidence of cardiovascular disease. The Framingham Study was also a pioneer in developing cardiovascular risk prediction equations for absolute risk assessment.^6–8

Heart Failure: A Historical Viewpoint

The definition and concept of HF have undergone an important evolution over time, reflecting continuous developments in medical knowledge and technology.

The oldest documented case of decompensated HF is the bones found in a tomb in the Valley of the Queens by the Italian Egyptologist, Ernesto Schiaparelli. The Egyptian Museum in Turin, Italy, currently preserves these objects, which date back more than 3,500 years. The remains originated with Nebiri, an Egyptian dignitary, who resided there during the reign of the 18th dynasty. After ruling out other diseases as the cause of ‘fluid in the air spaces of the lung’, pathologist Andreas Nerlich performed a histological examination of the lungs and identified the presence of pulmonary oedema, likely caused by HF. Several Egyptian mummies also show other signs of HF, such as heart hypertrophy or coronary atherosclerosis. On the opposite side of the world, The Yellow Emperor’s Classic of Internal Medicine, China, addressed dropsical swellings as early as 2600 BCE. Greek and Roman manuscripts describe what might have been HF, but the most prevalent symptoms mentioned in these books – dyspnoea and oedema – may have been caused by something other than HF.9,10

The Hippocratic Corpus discusses rales, stating that if one holds their ear against their chest and listens for a while, they may hear a sound akin to boiling vinegar. Additionally, he addressed a relatively contemporary method of removing this fluid by drilling a cavity in the rib cage, but there appeared to be a lack of comprehension regarding the reason for the fluid’s accumulation at that time.^11–13

Subsequently, the Romans applied Digitalis purpurea as a medicinal agent in ancient Egypt, Greece and India, which led to the earliest descriptions of HF.

Despite centuries of extensive use of blood and leeches as treatments, the clinical condition of patients significantly improved following the publication of William Withering’s 1785 report on the benefits of using digitalis in the treatment of HF.^2,5 The centre of medical science returned to Egypt, specifically Alexandria, where Herophilus and Erasistratus performed the first dissections and experiments on humans. Despite acknowledging the heart’s contraction, they believed that air filled the arteries and restricted blood flow to the veins. Even Galen, a Greek physician of the Roman Empire in the 2nd century, failed to understand the heart’s function as a pump and believed it to be only a source of heat. People also believed that the arterial walls, not the blood flowing through the lumen, transmitted the pulse.

Ibn Sina, also known as Avicenna in the West, was a medieval Arab scholar with a wide reputation for his expertise in heart disease. His manuscript, translated into Latin in the 14th century as The Book on Drugs for Cardiac Diseases, includes remedies for breathing difficulties, palpitation and syncope, widely employed in the Galenic tradition of humour. There is no doubt that Avicenna did not know about hypertension or obesity. We must remember that The Canon of Avicenna was written in the early 1100s, and must be interpreted in light of current heart disease knowledge and treatments.^13,14

Until William Harvey’s description of circulation in 1628, the nature of the condition was not well understood. This description serves as the foundation for the subsequent development of haemodynamic abnormalities in HF. A few years later, a description of mitral stenosis and tamponade-induced HF became available.^3,5,15

In the mid-18th century, Giovanni Maria Lancisi observed that valve regurgitation results in ventricular dilatation; however, he recognised that the ventricular cavity does not expand with aortic stenosis. He also proposed that the dilatation compromises the heart’s strength. Later, other researchers explained the connection between acute and chronic HF, eccentric and concentric cardiac hypertrophy, and the importance of changes that are both ‘good’ (adaptative) and ‘bad’ (maladaptive) for the failing heart. All of this was assessed at the bedside using touch, percussion and auscultation, and ultimately corroborated by autopsy, as Wilhelm Röntgen did not discover X-rays until 1895. The 20th century distinguished between the various types of heart enlargement. A turning moment came in 1918, when Ernest Starling documented ‘Law of the Heart’. The surprising, sceptical and confusing discovery that increasing end-diastolic volume improves cardiac performance contradicts the 19th-century concept that dilatation compromised the heart.¹⁶

Röntgen’s discovery of X-rays and Einthoven’s development of electrocardiography towards the end of the 1800s facilitated the investigation of HF. The development of nuclear medicine, cardiac catheterisation and echocardiography was crucial in the comprehensive examination of patients with HF, and was particularly useful for the diagnosis of the underlying condition.^5,15,17

The introduction of cardiac catheterisation and cardiac surgery in the 1940s and 1960s significantly advanced comprehension of HF. This facilitated the characterisation of various kinds of structural heart disease, congenital or rheumatic. However, these changes did not solve the clinical and pathological problems connected with HF, so ischaemic heart disease, high blood pressure and dilated cardiomyopathies slowly became recognised as major causes. Despite the two decades of intense debate surrounding the challenges of quantifying contractility, it has become clear that patients with chronic HF have reduced contractility, making its improvement beneficial. The perspective that the main role of the heart was focused on revealing the cause of diminished contractility in HF. Consequently, the importance of energy deprivation and the chaotic movement of calcium quickly gained prominence, leading to initiatives to develop inotropic agents that surpass the efficacy of digitalis. The concept was objective, taking into account the association between the ejection fraction and outcomes.^13,18

People used Southey’s tubes to treat HF associated with fluid retention in the 19th and early 20th centuries. Patients used these tubes to drain peripheral oedema, thereby improving their quality of life.⁵

The 20th century saw the introduction of the first class of diuretics, the thiazides (hydrochlorothiazide), as a common treatment for HF. This was followed by the administration of loop diuretics (furosemide, torsemide), corticoid mineral receptor antagonists (spironolactone, eplerenone) and carbonic anhydrase inhibitors (acetazolamide). In 1970, the use of angiotensin-converting enzyme inhibitors was widespread.

The potential to reduce afterload and increase cardiac output in HF has been available since the mid-1970s due to the availability of vasodilators. Jay Cohn conducted the Vasodilator-Heart Failure Trial in 1986, the first significant randomised clinical trial on HF, demonstrating that vasodilators do not extend the survival of patients with HF, despite short-term haemodynamic improvement.¹⁵

The change in perspective occurred in the 1980s, when HF became recognised as a neuroendocrine disease rather than a cardiac disease. This led to a new way of understanding and treating HF. As a result, angiotensin-converting enzymes and, later, β-blockers were available as therapies for HF. Angiotensin-converting enzyme inhibitor medications minimise the risk of mortality and hospitalisation in patients with HF with reduced ejection fraction, no matter how severe their symptoms were. β-blockers act as ideal positive inotropes, since they raise ejection fraction without increasing oxygen demand, lowering symptoms, and the risk of mortality and hospitalisation. Both classes of pharmaceutical products reduce ventricular remodelling, and seem to be beneficial regardless of etiopathogenesis, race or sex. The improvement in the quality of life of these patients then continued with the advent of angiotensin receptor blockers. Research has shown that adding these medications to standard HF therapy further reduces hospitalisation.

It is remarkable that atrial natriuretic peptide was considered potentially beneficial for HF due to its vasodilator properties, even at this early stage of neuroendocrine research. However, research shows that it has a limited effect on modulating the pathophysiology of HF, and does not alter cardiac structure, function or survival. Thus, the history of neuroendocrine disease has led to significant changes in the treatment of HF patients, shifting from vasodilators to anti-renin–angiotensin system drugs, and from positive to negative inotropes. These developments have resulted in improvements in quality of life and a decrease in hospitalisation rates.¹⁵

A Starting Point for Heart Failure Definition

In 1933, Sir Thomas Lewis underlined in his textbook, Diseases of the Heart, that “the very essence of cardiovascular medicine is the recognition of early heart failure”.¹⁹ Starting with this point of view, initially, HF was defined simply as “a condition in which the heart is unable to discharge its contents adequately” (Thomas Lewis, 1933). Although fundamentally correct, this essentially accurate primary definition fails to capture the complexity and diversity of the condition’s clinical manifestations. In 1950, Paul Wood proposed a more comprehensive definition of the syndrome, describing it as a condition in which the heart is unable to adequately circulate blood to meet the body’s needs, even when the filling pressure is proper: “a condition in which the heart fails to maintain adequate circulation for the body’s needs despite satisfactory filling pressure”. In the meantime, the ways of assessing these patients have advanced considerably, especially in terms of paraclinical investigations. In 1954, Inge Edler and Hellmuth Hertz pioneered the use of ultrasonography to examine cardiac structures. Therefore, advancements in medical imaging facilitate the understanding of cardiac pathophysiology. In 1980, Eugene Braunwald expanded the definition of HF to define it as “a pathophysiologic state in which an abnormality of cardiac function is responsible for the heart’s inability to pump blood at a rate that is commensurate with the demands of the metabolic tissues”.

Although medical progress was in full swing at the time, the definition of HF remained largely unchanged until 3 years later, when Denolin et al. proposed a new terminology for HF in Definition of Heart Failure in 1983. They explained that HF is “the condition of any heart disease in which, despite adequate ventricular filling, the cardiac output is low or the heart is unable to pump blood at a rate adequate to meet the demands of the tissues, with functional parameters remaining within normal limits”.^5,15,17,20

In 1985, shortly after the term ‘syndrome’ was first used in the concept of this pathology, Philip Poole-Wilson defined HF as “a clinical syndrome caused by an abnormality of the heart and recognized by a characteristic pattern of haemodynamic, renal, neural, and hormonal responses”. In 1987, 2 years later, Peter Harris proposed a universal definition of HF: “[a] syndrome… that occurs when the heart is chronically unable to maintain adequate blood pressure without support”. Jay Cohn devised his own definition of HF in 1988 to emphasise the link between the disease’s pathophysiological mechanisms and its effects. He called it “a syndrome in which cardiac dysfunction is associated with reduced exercise tolerance, a high incidence of ventricular arrhythmias, and a reduced life expectancy”.⁵

The specialised literature employed a variety of definitions of HF during this period. Some of these definitions were among those previously mentioned, while others were widely used, despite being generated anonymously and pragmatically, such as ‘abnormal function of the heart causing a limitation of exercise capacity’ or ‘ventricular dysfunction with symptoms’. The evolution of methods for the investigation and diagnosis of HF highlights a dynamic, constantly adapting pathway with each new proposed definition, enhancing our understanding of the underlying pathophysiological mechanisms and their correlation with clinical manifestations.

This has allowed the transition from the ‘inability of the heart to pump enough blood’ to an understanding of the mechanisms of ventricular dysfunction and neurohormonal changes, and it is now one of the elements that guide medical decision-making on the choice of optimal therapy in HF. The periodic refinement of the definition, coupled with the continuous development of new diagnostic and treatment criteria, marks important milestones in the medical evolution towards improved clinical outcomes. Recent improvements have emphasised the importance of early recognition of HF, as the current drug treatment has the potential to improve the quality of life and symptoms, reduce hospitalisation rates, and delay the progression of the disease and the patient’s survival.⁵

The widespread existence of widely differing definitions of HF has made it impossible to develop clinical trials to help standardise data on therapeutic approaches and improve clinical outcomes. In 1995, the European Society of Cardiology published its first HF guideline, titled ‘Symptoms of heart failure, objective evidence of cardiac dysfunction, and response to treatment for heart failure’. This guideline provides accurate information on how to diagnose HF based on a thorough clinical evaluation, paraclinical and imaging investigations, and treatment. This guideline provides the first standardised framework for diagnosis and treatment that facilitates the comparability and reproducibility of clinical trials.⁵

However, at that time, there were no accurate cut-off values for cardiac dysfunction, or changes in flow, pressure, size or volume that could reliably identify patients with HF, making an objective definition of HF impossible. The diagnosis of HF was based on the identification of the three essential components of HF: symptoms or signs of HF (dyspnoea either at rest or during exertion, fatigability, peripheral oedema, jugular swelling, ascites), objective evidence of major cardiac dysfunction at rest and clinical response to treatment for HF.

Although fulfilment of only the first two criteria was mandatory for diagnosis, the patient often had an improvement in symptoms and/or signs in response to treatment with diuretics, digitalis glycosides or angiotensin-converting enzyme inhibitors. One argument for not including the clinical response to treatment in the mandatory diagnostic criteria for patients with HF could be that it will obscure a diagnosis of HF by improving the patient’s symptoms and/or signs, particularly since these are not specific and could overlap with other pathologies. Thus, by masking the clinical picture that could indicate HF, we may delay or even miss the diagnosis. The symptoms of this clinical syndrome are also complicated because they can be caused by a number of different things. To improve the clinical state of HF, the aetiologic treatment must be different from the symptomatic treatment.^21,22

For instance, myocardial ischaemia frequently causes exercise-induced ventricular dysfunction, which manifests as an increase in ventricular filling pressure and a decrease in cardiac output, leading to symptoms of HF (dyspnoea). In this regard, the gold standard for confirming the diagnosis of coronary artery disease and deciding on revascularisation is a thorough assessment of the coronary ischaemic lesion by coronary CT angiography or coronary angiography. Thus, symptomatic treatment would delay optimal therapeutic management for this category of patients.

The 1995 guidelines from the European Society of Cardiology stress how important it is to find the cause of the clinical syndrome (high blood pressure, arrhythmias, valvular heart disease, coronary ischaemic lesions) and the factors that make it worse (anaemia, renal dysfunction, thyroid dysfunction, cardiotoxic drugs). These factors are very important in understanding how HF develops and how it can be treated. It also emphasises that HF should never be the final diagnosis with only symptomatic treatment.^21,22

Once the diagnosis of HF has been established, it is recommended to use systems to describe the severity of HF symptoms and their impact on the patient’s daily activity.

In 1928, American cardiologist, Harold Brunn, in collaboration with the New York Heart Association, proposed the New York Heart Association (NYHA) classification for HF as a standardised framework for assessing and communicating the severity of HF, which has now become a standard in the symptomatic monitoring of these patients. The NYHA functional classification provides a simple way to characterise the degree of HF. It places patients into one of four categories according to symptom severity and limitations during physical activity. Limitations, or symptoms, refer to varying degrees of dyspnoea and/or angina.

The following classes make up this widely used classification:

• NYHA class I: No limitation: regular exercise does not cause excessive fatigue, dyspnoea or palpitations.
• NYHA class II: Mild limitation of physical activity: comfortable at rest, but usual activity causes fatigue, palpitations, dyspnoea or angina.
• NYHA class III: Marked limitation of physical activity: comfortable at rest, but less than usual activity causes symptoms.
• NYHA class IV: Inability to perform any physical activity without discomfort: symptoms of HF are present even at rest, with increased discomfort with any physical activity.²²

The NYHA classification remains a valuable tool in HF assessment, although it also presents some difficulties and limitations in clinical applicability related to:

• Subjectivity of assessment: the classification relies on patients’ subjective perceptions of their symptoms, resulting in variability in the classification.
• Symptom overlap: patients with comorbidities (pulmonary disease, anaemia, musculoskeletal disorders) complicate the assessment of HF severity, resulting in over- or underestimation of symptoms;
• Limited specificity: the absence of specific factors, such as left ventricular ejection fraction (LVEF) or objective functional test results, limits the NYHA classification’s ability to provide a comprehensive and accurate picture.
• The inability to assess symptom variability arises from the fact that HF symptoms can vary depending on treatment, the patient’s activity level, and their emotional and psychological state, which can lead to an exacerbation or diminution of symptoms. The NYHA classification fails to account for these dynamic variations, resulting in an inaccurate assessment of long-term clinical status.
• Physical activity dependence: since the classification relies on how symptoms affect physical activities, patients with low activity levels or those who modify their activities to avoid symptoms may find it challenging to apply.

To compensate for these limitations, clinicians use the NYHA classification in conjunction with objective assessments, such as echocardiography, exercise testing and biomarkers, so that, despite the difficulties in its application, it remains the most important prognostic marker in routine clinical use in HF.^17,20

The development of pharmacological and non-pharmacological approaches to treating this common and often fatal condition has advanced significantly since the first European Society of Cardiology guidelines for the evaluation and management of HF in 1995. As a result, the 1997 Heart Failure Guidelines for the Evaluation and Management of Heart Failure, published by the American College of Cardiology (ACC) and the American Heart Association (AHA), adopted a new approach to HF classification that emphasises both the course and progression of the disease. This guideline was an important landmark in the treatment and management of HF, providing the best available evidence at the time.

The ACC/AHA classification divides HF into four stages, based on the structural and functional progression of the disease:

• Stage A identifies patients at high risk of developing HF (hypertension, diabetes, obesity, coronary artery disease), but without structural abnormalities or HF symptoms. Their management requires risk factor control and lifestyle modification.
• Stage B refers to patients with cardiac structural abnormalities (left ventricular hypertrophy, ventricular systolic dysfunction, history of myocardial infarction), but without symptoms of HF. Their management requires pharmacological treatment (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or b-blockers) or surgery if necessary.
• Stage C highlights patients with cardiac structural abnormalities and current or previous symptoms of HF (dyspnoea, asthenia, exercise limitation). Their management requires pharmacological treatment, medical devices, such as an implantable cardiac defibrillator or cardiac resynchronisation, and surgery.
• Stage D identifies patients with HF who are refractory to standard treatments and have severe symptoms at rest. Their management requires advanced treatment options, including cardiac transplantation, ventricular assist devices or palliative therapy.

The NYHA functional classification and the ACC/AHA classification system complement each other in clinical practice, offering a comprehensive picture of the patient’s condition, and enhancing clinical and therapeutic decision-making for the patient. Therefore, the ACC/AHA 1997 guidelines provide a staging system that reliably and objectively identifies patients during the course of disease progression, and assigns therapeutic options appropriate to the stage of disease.²³

Arguments on the Need for a Universal Definition

The traditional 2013 ACC/AHA definition of HF found in the literature stated that “heart failure is a complex clinical syndrome resulting from any structural or functional impairment of ventricular filling or blood ejection. The cardinal manifestations of HF (dyspnoea and fatigue) may limit exercise tolerance and fluid retention with pulmonary congestion, splanchnic congestion, and peripheral edema”.²⁴

Later, in 2016, the European Society of Cardiology (ESC) proposed a definition of HF as a “clinical syndrome characterized by typical symptoms (dyspnoea, fatigue) that may be accompanied by signs (increased jugular venous pressure, pulmonary congestion, and peripheral oedema) caused by a structural or functional cardiac abnormality, resulting in reduced cardiac output and increased intracardiac pressures.”²⁵

In 2017, the Japanese Circulation Society and the Japanese Heart Failure Society defined HF as a ‘clinical syndrome’ that includes dyspnoea, impaired general condition, congestion and decreased exercise capacity. This is due to the loss of cardiac pumping function as a result of structural and functional abnormalities of the heart.²⁶

Developed by prestigious global societies, the aforementioned definitions are not fully testable in practice, and only apply to a specific subgroup of HF patients. This is because they do not have a clear and unified definition based on precise, objective criteria that reduce variability and errors in diagnosis. Although the above definitions developed by the ACC/AHA, Heart Failure Association of the ESC (HFA/ESC) and Japanese Heart Failure Society differ in some details, they share the following common elements: they say that HF is a clinical syndrome, which means that at least some of the main symptoms must be present, such as shortness of breath, fluid retention or oedema, tiredness and limited ability to do physical activities. They also say that HF must be caused by either structural or functional heart disease.^2,5 However, the lack of concrete, objective data has reduced their clinical applicability, preventing global standardisation of diagnostic and treatment criteria, and facilitating clinical trials to improve medical practice.

As definitions are mostly based on the clinical picture, the comorbidities of these groups of patients have often led to mistakes in diagnosing HF. This can happen when the signs and symptoms are mistakenly attributed to other diseases with similar clinical presentations or when symptoms are confused with those of other conditions that hide the clinical picture of HF syndrome.

In a study of patients with advanced HF who were candidates for left ventricular assist device implantation, researchers found that cardiac output measured by determining LVEF was an essential parameter to quantify. Until that point, this aspect was not present in existing definitions. Despite patients meeting the diagnostic criteria for HF, the lack of individualised stage-specific therapeutic recommendations for the clinical stages of HF highlights the inadequacy of the existing HF definitions.

Thus, numerous aspects have been found to be gaps in the definitions of HF, including:

• variability in terminology and diagnostic criteria;
• concurrent diagnoses: failure to highlight comorbidities that may increase, diminish or mask the signs and symptoms required for diagnosis;
• lack of a personalised approach based on individual patient phenotypes;
• insufficient use of biomarkers in diagnosis; the importance of natriuretic peptides in diagnostic accuracy not being found in all existing definitions;
• the lack of a unified framework for staging HF, with no widely used staging system (stages A–D), which has led to confounding in the assessment of disease severity and progression;
• lack of a clear classification of ejection fraction for individualised therapies for each category. Previous definitions did not clearly distinguish between patients with a moderately reduced ejection fraction (HFmrEF) and other patients; and
• insufficient focus on prevention by identifying and managing risk factors.

An important aspect worth mentioning is the need for individualised interpretation of biomarker levels, especially in the context of clinical uncertainty. Many conditions lead to changes in natriuretic peptide levels, thus complicating medical decisions in establishing competing diagnoses and comorbidities. Chronic kidney disease, AF, pericardial disease, pulmonary embolism, acute coronary syndrome, old age and severe anaemia are all associated with increased natriuretic peptide levels, while obesity and mitral stenosis are associated with low values. In some patients with pericardial disease and pericardial effusion, natriuretic peptides may be lower, with increased values after pericardiocentesis. Measurement of natriuretic peptide levels improves diagnostic accuracy and guides risk stratification, so threshold values have been developed to support the diagnosis of HF (outpatient: B-type natriuretic peptide ≥35 pg/ml; N-terminal pro B-type natriuretic peptide ≥125 pg/ml; and in hospitalised or decompensated patients: B-type natriuretic peptide ≥100 pg/ml; N-terminal pro B-type natriuretic peptide ≥300 pg/ml), and other threshold values according to comorbidities (AF commonly seen with elevated values).^2,5

Some definitions focused on the diagnostic components of the clinical syndrome, while other concepts approached the definition as a characterisation of haemodynamic and physiological aspects. The presence of these discrepancies in definition, the increasing prevalence and the difficulties in achieving optimal treatment for patients with HF have highlighted the growing need for standardisation of the definition of HF towards a universal definition, which is imperative for both clinicians and investigators. The new strategies, therefore, require greater clarity in the wording of the different stages or classifications, the accuracy of diagnostic steps and treatment indications. Improved doctor–patient communication seems to be equally necessary for making the best decisions on individualised therapy, but also for raising awareness of the pathology they are facing and the importance of their compliance with treatment.

The Universal Definition of Heart Failure: From Failure to Functionality

Recognising the need for consensus on the definition of HF, the Journal of Heart Failure and the European Journal of Heart Failure published ‘Universal Definition and Classification of Heart Failure’ in 2021.^2,27 Representatives from organisations, such as the Heart Failure Society of America, the Heart Failure Association of the ESC and the Japanese Heart Failure Society developed this international consensus, with endorsements from the Canadian Heart Failure Society, the Heart Failure Association of India, the Cardiac Society of Australia and New Zealand, and the Chinese Heart Failure Association.

They convened a conference to develop a contemporary universal definition of HF that adds valuable information to current medical practice in response to the ambiguity of the definitions available up to that time. Consequently, they propose a simple yet conceptually comprehensive contemporary universal definition of HF that offers a broad spectrum of applicability and clarity in description.^2,25,28,29

To appreciate this new definition, it is important to recall the traditional pathophysiological definition that it replaces: a condition in which the heart cannot pump enough blood to meet the body’s needs. The new definition includes cardiac mechanical heterogeneity, which is defined as the presence of structural or functional cardiac disturbances, regardless of ejection fraction.

Natriuretic peptides play an important role in confirming or excluding HF. Changes in intraventricular pressure and elevations in parietal stress cause elevations in these biomarkers. Although not included in most definitions of HF to date, the universal definition of HF establishes the presence of natriuretic peptides as a mandatory biological condition, fundamental for diagnosis.

The revision of the ACC/AHA classification of the four stages of HF, which emphasises the symptomatic nature of HF and focuses on the clinical status of patients, is another important aspect of the universal definition of HF. As a result, we classify patients at risk of developing HF (stage A), patients in the pre- HF stage (stage B), patients with symptoms of HF (stage C) and patients with end-stage disease, advanced HF (stage D). This new classification goes beyond the American College of Cardiology and AHA stages A and B, which mean at risk of developing HF and pre-HF, respectively. It stresses how important it is to control risk factors, make changes to your lifestyle and use preventive therapies to stop the progression from pre- HF to overt HF. It aims to clearly differentiate these precursor stages of HF from HF proper, now limited to the symptomatic state, and encourages the control of risk factors and the discovery of new preventive approaches to HF.

The universal definition’s new nomenclature, another notable advance, offers opportunities to accurately and concretely describe the clinical variability present in the evolving course of HF. These new terms describe the clinical trajectory of the HF patient, and are important steps towards a precise and standardised nomenclature. Furthermore, the following terms have been defined:

• New-onset/de novo HF has recently progressed from pre-HF to HF.
• Worsening HF indicates a decline in HF signs and symptoms despite current treatment, necessitating either hospitalisation or an increase in outpatient therapy.
• Persistent HF describes a lack of improvement and is a negative prognostic marker that requires optimisation of therapy;
• HF in remission emphasises the improvement of HF symptoms and signs with remission of the structural or functional heart disease that gave rise to symptomatic HF.^17,20,24,30

This new universal definition, however, would have remained imperfect without adjusting the classification of HF according to LVEF. Therefore, the universal definition modifies the classification scheme and establishes the following categories:

• HF with reduced ejection fraction: symptomatic HF with LVEF ≤40%;
• HF with moderate-low ejection fraction: symptomatic HF with LVEF 41–49%;
• HF with preserved ejection fraction (HFpEF): symptomatic HF with LVEF ≥50%;
• HF with improved ejection fraction: symptomatic HF with a baseline LVEF ≤40%, an increase ≥10 points from baseline LVEF, and a second LVEF measurement >40%.

The universal definition suggests changes in the nomenclature of HF according to LVEF, replacing the previously used term ‘mid-range’ with ‘mildly reduced’ for symptomatic HF with LVEF 41–49%. In this way, neurohormonal blocking therapy works better for a certain group of patients than for those with HF with reduced ejection fraction or HFpEF. This means that therapy should be tailored to each patient’s LVEF.

Recently, speculation and attention have focused on a novel category of HF known as HF with supra-normal ejection fraction (HFsnEF), defined when the LVEF is >65%. Wehner et al. found that the relationship between LVEF and prognosis may be U-shaped. They found that deviations in LVEF from 60 to 65% were linked to lower survival rates, regardless of age, sex or other health problems. Nevertheless, the definition, diagnostic methods and pathophysiological approach to supranormal LVEF remain limitedly studied. However, it seems that women are more likely to have the clinical characteristics of HFsnEF, including a higher prevalence of non-ischaemic HF, higher blood urea nitrogen plasma levels and lower levels of natriuretic peptides. The precise pathogenesis of HFsnEF, which is associated with microvascular dysfunction and a low stroke volume index, requires further research. A higher risk of long-term adverse events tends to correlate with the poorly established prognosis of HFsnEF.^31,32

This represents an important marker for the management and individualisation of therapy in patients with HF, in whom adapting guideline-directed medical therapy according to ejection fraction leads to favourable outcomes. A significant decrease in ejection fraction, for example, is a negative prognostic factor that requires intensive therapy to improve. By using the correct clinical classifications for cardiac ultrasound to put patients into the groups suggested by the universal definition of HF, more people can get the best treatment for their specific phenotype.

The physiological differences of HF by ejection fraction are depicted in the following, pointing out distinctions in ventricular remodelling, neurohormonal activation, and systolic and diastolic function (Figure 1).

This new definition appears to be a cornerstone in HF, providing better patient stratification by emphasising the phenotyping of HF patients. It is universal, widely applicable, comprehensive and practical enough to form the basis that allows further subclassifications. Refining the stages of HF has demonstrated the importance of identifying individualised therapy with promising results. Scientific societies, guidelines, clinicians and research studies intend to use the universal definition of HF in a standardised manner due to its prognostic and therapeutic validity, acceptable sensitivity and specificity.^5,24,30

HF has undergone decades of evolving definitions. From past insights to the universal definition, this timeline (Figure 2) captures key milestones in the journey of understanding HF.

Acute HF is characterised by the sudden onset or progressive exacerbation of chronic HF signs (S3 gallop, rales, variable weight) and symptoms (orthopnoea, nocturnal cough, dyspnoea) necessitating immediate intervention. Higher ventricular filling pressures, with or without a decrease in cardiac output, often cause pulmonary and systemic congestion in acute HF syndrome. This may occur due to an underlying cause (for example, an ischaemic event) or a precipitant cause (for example, severe hypertension), characterised by heterogeneity in the mode of presentation, pathophysiology and prognosis. Cardiac conditions, such as coronary artery disease, high blood pressure, valvular heart disease and AF, can be a worsening factor. Other noncardiac conditions, such as kidney failure, diabetes and anaemia, may also play a role. After the initial therapy that results in stabilisation, the majority of acute HF syndrome patients should be classified as chronic HF, rather than acute. It is known that approximately 80% of patients admitted for worsening HF have a past diagnosis of chronic HF. Individuals who stabilise following initial management should be classified as having chronic HF and treated in accordance with established guidelines. Clinically stable chronic HF occurs when compensatory mechanisms restore the left ventricle’s function mostly or fully.^33,34

Congestive HF, as defined by the ACC/AHA, is ‘a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood’. It results from any disorder that impairs ventricular filling or ejection of blood to the systemic circulation, being a common disorder worldwide with a high morbidity and mortality rate. Hospitalisations for acute cardiac failure typically arise from congestion or fluid overload, rather than poor cardiac output. Elevated left ventricular filling pressure, which causes congestion, often results in jugular venous distention, peripheral oedema, acute pulmonary oedema, paroxysmal nocturnal dyspnoea, cardiomegaly, hepatomegaly, pleural effusion, an increase in body weight, reduced exercise tolerance – a condition known as clinical congestion. To prevent recurrent hospitalisations, reduce morbidity and mortality, and improve patient outcomes, it is essential to diagnose and effectively treat the disease. A multifaceted approach to the treatment of HF is necessary, which includes the optimal administration of medication, patient education and the reduction of acute exacerbations. Patients require close clinical follow-up for assessing volume status, effects of drug therapy and escalation of care, as indicated.^34,35

Heart Failure with Preserved Ejection Fraction: A Subset of Diastolic Heart Failure or a Distinct Entity?

Diastolic HF describes a condition that impairs the heart’s capacity to relax and fill with blood, leading to HF symptoms without a decrease in the ejection fraction. In the absence of substantial systolic dysfunction, the heart is unable to properly fill with blood, resulting in HF symptoms, despite a normal or nearly normal ejection fraction. Upon closer examination for a complex definition, it is revealed that the pathophysiological mechanisms primarily contribute to diastolic HF. The primary conditions associated with increased myocardial stiffness and decreased compliance are hypertrophy, fibrosis and ischaemia. This leads to increased filling pressures, pulmonary congestion and systemic symptoms.

HFpEF refers to patients who meet the diagnostic criteria for HF, such as signs and symptoms of HF and elevated natriuretic peptide levels, but still have a normal ejection fraction (LVEF ≥50%).

The main point of overlap is the compromised diastolic function, seen in both diastolic HF and HFpEF, with elevated filling pressure that promotes symptoms, such as dyspnoea, fluid retention and impaired exercise capacity. The term diastolic HF encompasses any state of HF marked primarily by diastolic dysfunction, regardless of whether the ejection fraction remains intact. Patients with HFpEF reflect complex impairments in cardiac, vascular and peripheral function, rather than an isolated anomaly in left ventricular diastolic function. HFpEF requires specific evidence of increased filling pressures, and the need to identify the set of conditions (hypertension, diabetes, obesity and ageing) and mechanisms (myocardial fibrosis, endothelial dysfunction and inflammation) underlying HF. Echocardiography is an important tool for both finding different phenotypes within the HFpEF range and ruling out diseases that mimic HFpEF. These encompass hypertrophic cardiomyopathy, primary valvular heart disease, cardiac amyloidosis, pericardial disease and high-output failure. After excluding patients with low ejection fraction, it is important to look at these ‘masqueraders’, because each one has its own treatments that are different from standard HFpEF management.

The H2FPEF and Heart Failure Association Pretest Assessment, Echocardiography and Natriuretic Peptide, Functional Testing and Final Aetiology scores also provide support in diagnostic decision-making, with cut-off values indicating diagnostic probability. Additionally, ESC guidelines suggest using a combination of various indices of diastolic dysfunction along with natriuretic peptide testing. This approach is particularly beneficial in challenging diagnostic cases, such as in euvolemic patients presenting with exertional dyspnoea, when it is required to have objective documentation of elevated LV filling pressure either noninvasively or invasively.

Conclusion

HFpEF has many different mechanisms that make it hard to use ‘one size fits all’ approaches. Classifying patients according to their clinical and pathophysiological phenotypes is a key next step to ensure the proper treatment allocation. It is important to remember that LV relaxation and compliance decrease with normal ageing or with cardiometabolic comorbidities, such as obesity, insulin resistance and high blood pressure. Also, diastolic dysfunction is at the heart of HFpEF, but not all patients with it have or will develop clinical HFpEF.^36–39