The struggle towards a Universal Definition of Heart Failure—how to proceed?

Abstract

Johann Bauersachs Definitions and classifications are crucial in medicine and provide the basis for proper and timely diagnosis to enable prompt, precise, and efficient therapies. The diagnosis of heart failure (HF) currently relies on signs (pulmonary crackles, peripheral oedema) and symptoms (dyspnoea on exertion, fatigue) that are not always objective, and neither sensitive nor specific.1 , 2 Many patients are not diagnosed with HF before they get hospitalized for a decompensation. Although there are several evidence-based treatments for HF with reduced ejection fraction (HFrEF) and even for asymptomatic left ventricular (LV) dysfunction (ejection fraction <40%), the diagnosis is often made late, and valuable time has passed before effective treatments are initiated. Even in patients with symptoms, frequently it takes many months or even years until the diagnosis is made. Especially HF without significant reduction in LV ejection fraction may be mistaken even by cardiologists. Against this background, the current debate articles, one of the first of this newly introduced format in the European Heart Journal, appraise the value of a universal definition of HF based on the determination of circulating natriuretic peptide (NP) levels.3 The enormous theoretical advantage of NPs as central diagnostic markers for HF is that they would allow an objective diagnostic standard and that NPs are generally elevated before symptoms or signs of HF develop. Production of NPs—exclusively synthesized in myocardial tissue—depends on intra-cardiac volumes and filling pressures, which determine wall stress. Increased NP levels do not only reflect LV systolic function but may be secondary to other cardiac abnormalities such as diastolic dysfunction, valvular heart disease, right HF or atrial fibrillation.3 Nevertheless, almost all of these culminate in elevations of plasma volume and dilatation of the left atrium, early events in HF development that precede clinical signs/symptoms. Thus, it is tempting to use NPs instead of non-specific signs/symptoms to set a new universal definition of HF. Despite concerns about sensitivity and specificity in some patients, NPs are already a crucial component for the diagnosis or exclusion of both acute HF and HF with preserved ejection fraction (HFpEF).2 , 4 Given the difficulties in diagnosing and treating HFpEF, the endeavours of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) to better define this complex entity have led to the definition of a new subcategory of HFpEF in the 2016 ESC guidelines, i.e. HF with mid-range ejection fraction (HFmrEF), the diagnosis of which requires an ejection fraction of 40–49%, elevated NP levels and either relevant structural heart disease or diastolic dysfunction on echocardiography.2 Albeit criticized by some, the introduction of this new subcategory has stimulated considerable research efforts, e.g. showing that neurohormonal modulators such as beta-blockers, candesartan, and spironolactone, are almost equally effective in reducing hard clinical outcomes in HFmrEF compared to HFrEF, which prompted respective HFA recommendations for the treatment of HFmrEF.5 , 6 This example reiterates the importance of setting better definitions for complex diseases to stimulate research and pave the way to better diagnosis, treatment, and ultimately patient outcomes. The concept for a universal definition of HF proposed by Cleland et al. provides an excellent basis for the current efforts of different HF societies and associations, including the HFA of the ESC, to develop a universal definition of HF that is accepted worldwide with the goal of improving diagnosis and treatment of (early stages of) HF globally. The authors compare their suggestion with the universal definition of myocardial infarction based on troponin levels. While troponins clearly have revolutionized diagnostic and treatment strategies for acute coronary syndromes (ACS), in most cases HF is undoubtedly a chronic disease with subtle onset lacking the acute symptom of chest pain that triggers troponin determination in suspected ACS. However, also in ACS, it took decades until the current 1-h rule-in/rule-out algorithm using high-sensitivity troponin was firmly established.7 In their counterstatement, Pfeffer and Teerlink point out several important caveats precluding the simple introduction of NP elevation for HF diagnosis. More evidence is necessary before NPs can be used as the central diagnostic tool for HF in the broad, mostly asymptomatic population. These two excellent articles will clearly stimulate further discussion regarding a universal definition of HF that hopefully will lead to improved patient outcomes. Note added in proof: The debate is indeed timely at the light of the recent publication of an alternative “Universal Definition and Classification of Heart Failure” jointly developed by the HFA, the Heart Failure Society of America, and the Japanese Heart Failure Society.8 Conflict of interest: J.B. received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Servier, Abiomed, Boehringer Ingelheim, Daiichi-Sankyo, AstraZeneca, CVRx, Orion, BMS, Cardior, Pfizer, MSD, and Medtronic and research support from Zoll, CVRx, Vifor, and Abiomed, all not related to this editorial. John G F Cleland, Pierpaolo Pellicori, James L Januzzi, Faiez Zannad, Andrew L Clark, Mark Richards, John J V McMurray, Christian Mueller *Corresponding authors. Tel: +1 617 732 5681, Email: [email protected] Recently, the 4th Universal Definition of Myocardial Infarction was published.1 Perhaps it is time to consider a First Universal Definition of Heart Failure. Objective, clinically verifiable, diagnostic criteria are desirable not only for the scientific classification of disease but also for describing its epidemiology, for informing patients on the nature and prognosis of their disease, for choosing and implementing treatment in a timely fashion, for strategic planning of clinical services, and for selection and risk stratification of those invited to participate in research.2 , 3 Diagnostic uncertainty has far-reaching consequences but insisting on diagnostic certainty may also be detrimental if it delays intervention until the disease is severe, or inappropriately excludes patients from treatment, or underestimates the size of the problem. Diagnostic criteria that are sensitive might lack specificity, but this can be resolved by further investigation, creating the opportunity for an early, accurate diagnosis and timely intervention. Currently, the diagnosis of heart failure is based mainly on subjective criteria and mostly made by clinicians who have little training in cardiology and even less in heart failure. Those who are trained have widely varying experience, opinions, motivations, and access to diagnostic investigations. Currently, for many patients, a diagnosis is made only when symptoms and signs are severe enough to require hospitalisation.4–7 However, cardiac dysfunction often exists and progresses for years before a final insult causes the onset, often sudden and catastrophic, of symptoms and signs of heart failure. Many people have exertional breathlessness long before they receive a diagnosis of heart failure, which they attribute to being old or unfit, and manage by adopting a sedentary lifestyle. Waiting for diagnostic certainty, only once symptoms and signs are obvious, may miss the best opportunity to modify the natural history of heart failure. Guidelines define heart failure as the presence of typical symptoms and signs due to cardiac dysfunction.8 However, there are many causes of fatigue, breathlessness, and ankle swelling; symptoms and signs are neither sensitive nor specific for heart failure. 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This was first to the European Heart on and a on to the being to a debate Conflict of interest: from and from and from Bayer, and support from and from Novartis, and from and from Vifor, and from BMS, and and from Servier, the is a of the of is a of has received support from and has received from Novartis, and and in clinical for Bayer, CVRx, and from Bayer, Novartis, and CVRx, has received from AstraZeneca, Cardior, and and at and is the of and honoraria and research support from and has received research support from Bayer, AstraZeneca, and and has for Bayer, Novartis, AstraZeneca, and that the of has received for in and for AstraZeneca, Bayer, Novartis, and has received research support from and and honoraria from AstraZeneca, Boehringer Ingelheim, Novartis, and John Teerlink authors. 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