Universal Definition and Classification of Heart Failure - SEC Enero 2021

European Journal of Heart Failure (2021) POSITION PAPER
doi:10.1002/ejhf.2115
Universal definition and classification of heart

failure:
A report of the Heart Failure Society of America, Heart
Failure Association of the European Society of Cardiology,
Japanese Heart Failure Society and Writing Committee of
the Universal Definition of Heart Failure
Endorsed by Canadian Heart Failure Society, Heart Failure
Association of India, the Cardiac Society of Australia and
New Zealand, and the Chinese Heart Failure Association.
Biykem Bozkurt* (Chair) (USA), Andrew J.S. Coats (Co-Chair) (UK and Australia),
Hiroyuki Tsutsui (Co-Chair) (Japan), Ca Magdy Abdelhamid (Egypt), Stamatis
Adamopoulos (Greece), Nancy Albert (USA), Stefan D. Anker (Germany), John
Atherton (Australia), Michael Böhm (Germany), Javed Butler (USA), Mark H.
Drazner (USA), G. Michael Felker (USA), Gerasimos Filippatos (Greece), Mona
Fiuzat (USA), Gregg C. Fonarow (USA), Juan-Esteban Gomez-Mesa (Colombia),
Paul Heidenreich (USA), Teruhiko Imamura (Japan), Ewa A. Jankowska (Poland),
James Januzzi (USA), Prateeti Khazanie (USA), Koichiro Kinugawa (Japan), Carolyn
S.P. Lam (Singapore), Yuya Matsue (Japan), Marco Metra (Italy), Tomohito Ohtani
(Japan), Massimo Francesco Piepoli (Italy), Piotr Ponikowski (Poland), Giuseppe
M.C. Rosano (Italy), Yasushi Sakata (Japan), Petar Seferović (Serbia), Randall C.
Starling (USA), John R. Teerlink (USA), Orly Vardeny (USA), Kazuhiro Yamamoto
(Japan), Clyde Yancy (USA), Jian Zhang (China), Shelley Zieroth (Canada)
Received 2 January 2021; revised 27 January 2021; accepted 27 January 2021
The Comprehensive RWI Data Supplement table is available in the Appendix. Affiliations are also listed in the Appendix
*Corresponding author. Biykem Bozkurt, The Mary and Gordon Cain Chair of Cardiology and Professor of Medicine, Medical Care Line Executive, DeBakey VA Medical Center,
Director, Winters Center for Heart Failure Research, Associate Director, Cardiovascular Research Institute, Associate Provost of Faculty Affairs and Senior Associate Dean of
Faculty Development, Baylor College of Medicine, 2002 Holcombe Blvd, Houston, TX 77030, USA. Tel: +1 713 794-7350, Fax: +1 713 794-07551,
Email: bbozkurt@bcm.edu
This article is co-published in Journal of Cardiac Failure and European Journal of Heart Failure.
© 2021 European Society of Cardiology and Elsevier, Inc.

2 Position Paper
In this document, we propose a universal definition of heart failure (HF) as a clinical syndrome with symptoms and/or signs caused by
a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of
pulmonary or systemic congestion. We also propose revised stages of HF as: At-risk for HF (Stage A), Pre-heart failure (Stage B), Symptomatic
HF (Stage C) and Advanced HF (Stage D). Finally, we propose a new and revised classification of HF according to left ventricular ejection
fraction (LVEF). These include HF with reduced ejection fraction (HFrEF): symptomatic HF with LVEF ≤40%; HF with mildly reduced ejection
fraction (HFmrEF): symptomatic HF with LVEF 41–49%; HF with preserved ejection fraction (HFpEF): symptomatic HF with LVEF ≥50%;
and HF with improved ejection fraction (HFimpEF): symptomatic HF with a baseline LVEF ≤40%, a ≥10 point increase from baseline LVEF,
and a second measurement of LVEF > 40%.
..........................................................................................................
Keywords Heart failure • Cardiomyopathy • HFrEF • HFpEF • HFmrEF • Stages of heart failure •
Definition of heart failure
Table of contents 7.5 Valvular heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
...........................................................................................................................
7.6 Congenital heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 7.7 High-output failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Summary of key points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 7.8 Other overlapping and competing diagnoses with heart
Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1 Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 8 Proposed revised stages of the heart failure continuum . . . . 15
1.1 Writing committee composition . . . . . . . . . . . . . . . . . . . . . . . . . 3 8.1 NYHA classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.2 Consensus development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 8.2 Recognition of clinical trajectory in heart failure . . . . . . 17
1.3 Peer review and approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 8.3 Acute versus decompensated heart failure . . . . . . . . . . . . . 17
2 Current definitions of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 9 Proposed new classifications of heart failure according to ejec-
2.1 Definitions of heart failure used in current clinical trials and tion fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
registries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 10 Approaches to specific aetiologies of heart failure . . . . . . . . 18
2.2 Gaps in current definitions of heart failure . . . . . . . . . . . . . . . 5 11 Perspective for the non-cardiologist . . . . . . . . . . . . . . . . . . . . . . . 18
2.2.1 Combined definition with haemodynamic characteri- 12 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
zation of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
2.2.2 Cardiomyopathy and heart failure . . . . . . . . . . . . . . . . . 5
2.2.3 Biomarkers in the definition of heart failure . . . . . . 6
2.2.4 Clinical and research aspects of defining heart failure Abbreviations and acronyms
................................................................ 7 ACC American College of Cardiology
2.2.5 Patient and clinician perspective . . . . . . . . . . . . . . . . . . . 7 AHA American Heart Association
2.2.6 Competing diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 ARVC arrhythmogenic right ventricular
3 Current classifications of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . 7 cardiomyopathy
3.1 Current subclassification of heart failure according to ejec- BNP B-type natriuretic peptide
tion fraction and its limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 CKD chronic kidney disease
3.2 Current classification according to stages of heart failure EF ejection fraction
and its limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 eGFR estimated glomerular filtration rate
4 Gaps in definitions according to trajectory of changes in heart EHR electronic health record
failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 ESC European Society of Cardiology
4.1 Trajectory changes in ejection fraction . . . . . . . . . . . . . . . . . 10 GDMT guideline-directed management and therapy
4.2 Trajectory changes in clinical status . . . . . . . . . . . . . . . . . . . . 10 HFA Heart Failure Association
5 Learning from other disease definitions . . . . . . . . . . . . . . . . . . . . . 11 HF heart failure
6 Proposed universal definition of heart failure . . . . . . . . . . . . . . . 11 HFimpEF heart failure with improved ejection fraction
6.1 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 HFpEF heart failure with preserved ejection fraction
6.2 Objective marker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 HFmrEF heart failure with mildly reduced ejection
6.3 Proposed new heart failure definition . . . . . . . . . . . . . . . . . . 12 fraction
7 Other syndromes related to heart failure . . . . . . . . . . . . . . . . . . . 14 HFrEF heart failure with reduced ejection fraction
7.1 Right heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 HFrecEF heart failure with recovered ejection fraction
7.2 Acute myocardial infarction/acute coronary syndrome 14 HFSA Heart Failure Society of America
7.3 Cardiogenic shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 JHFS Japanese Heart Failure Society
7.4 Hypertensive emergency and hypertensive heart disease LVEF left ventricular ejection fraction
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 MI myocardial infarction

Universal definition and classification of heart failure 3
NT-proBNP N-terminal pro-B-type natriuretic peptide HF with guideline-directed management and therapy (GDMT)
........................................................................................................................................................................
NYHA New York Heart Association strategies,13,14 all underline the necessity for a universally rec-
SGLT2 sodium–glucose co-transporter 2 ognizable definition of HF. Evolving evidence for new effective
WHO World Health Organization preventive and treatment strategies in HF will require clarity
in the different stages and/or ejection fraction (EF) subgroups
of HF,15,16 along with an increased emphasis on performance
measures with a need for accuracy in patient diagnoses and treat-
Summary of key points ment indications17–19 ; a need for improved communication and
understanding of the definition of HF with patients and for shared
• In this document, we propose a universal definition of heart decision-making and transitions of care between different levels of
failure (HF) as the following: HF is a clinical syndrome with care and health care professionals3 ; and an increased recognition
symptoms and/or signs caused by a structural and/or functional and emphasis of standard diagnoses and endpoints in the settings
cardiac abnormality and corroborated by elevated natriuretic of research, clinical trials and registries.20,21
peptide levels and/or objective evidence of pulmonary or The objectives of this document are to provide a universal def-
systemic congestion. inition of HF that is clinically relevant, simple but conceptually
• We propose revised stages of HF as: At risk for HF (Stage A), comprehensive, with the ability to sub-classify and to encompass
for patients at risk for HF but without current or prior symp- stages within, with universal applicability globally, and with prog-
toms or signs of HF and without structural or biomarker evi- nostic and therapeutic validity and acceptable sensitivity and speci-
dence of heart disease. Pre-heart failure (Stage B), for patients ficity. We envision the proposed universal definition and classifi-
without current or prior symptoms or signs of HF but evi- cations to be used in a standardized fashion across scientific soci-
dence of structural heart disease or abnormal cardiac func- eties and guidelines, employed by clinicians and used in research
tion, or elevated natriuretic peptide levels. HF (Stage C), for studies.
patients with current or prior symptoms and/or signs of HF
caused by a structural and/or functional cardiac abnormality.
Advanced HF (Stage D), for patients with severe symptoms 1 Methodology
and/or signs of HF at rest, recurrent hospitalizations despite
guideline-directed medical therapy (GDMT), refractory or 1.1 Writing committee composition
intolerant to GDMT, requiring advanced therapies such as con- The Heart Failure Society of America (HFSA), the Heart Failure Asso-
sideration for transplant, mechanical circulatory support, or ciation (HFA) of the European Society of Cardiology (ESC) and the
palliative care. Japanese Heart Failure Society (JHFS) selected the members of the
• Finally, we propose a new and revised classification of HF writing committee. The writing committee consisted of 38 individu-
according to left ventricular ejection fraction (LVEF). The clas- als with domain expertise in HF, cardiomyopathy and cardiovascular
sification includes HF with reduced ejection fraction (HFrEF): disease.
HF with LVEF ≤40%; HF with mildly reduced ejection fraction
(HFmrEF): HF with LVEF 41–49%; HF with preserved ejection
fraction (HFpEF): HF with LVEF ≥50%; and HF with improved 1.2 Consensus development
ejection fraction (HFimpEF): HF with a baseline LVEF ≤40%, a On 20 August 2020, in response to the necessity for consensus for
≥10 point increase from baseline LVEF, and a second measure- definition of HF, the HFSA, HFA/ESC and JHFS convened a virtual
ment of LVEF >40%. consensus conference to develop a universal definition of HF with par-
ticipation from 14 different countries and 6 continents. The work of
the writing committee was accomplished via a series of teleconference
and web conference meetings, along with extensive email correspon-
dence. The review work was distributed among subgroups of the writ-
Preamble ing committee based on interest and expertise. The proceedings of the
workgroups were then assembled, resulting in the proposed universal
Currently available definitions of heart failure (HF) are ambiguous definition. All members reviewed and approved the final vocabulary.
and lack standardization.1–8 Some definitions focus on the diagnos-
tic features of the clinical syndrome,3–5 whereas other definitions
approach the definition as a characterization of the haemodynamic 1.3 Peer review and approval
and physiological aspects.2,8 There is significant variation in differ-
The 2020 Universal Definition of HF was reviewed by official reviewers
ent platforms,1–5 and a growing need for standardization of the
nominated by the HFSA, HFA/ESC and JHFS. The writing committee
definition of HF.6,9 anticipates that the proposed definition and classification will require
A universal definition of HF is of critical importance to review and updating in the same manner as other published universal
clinicians, investigators, administrators, health care services, insti- definitions.22 The writing committee, therefore, plans to review the
tutions, legislators and payers alike. The increasing prevalence universal definition on a periodic basis, starting with the anniversary of
and burden of HF,10,11 an increased recognition of growing health publication of the definition, to ascertain whether modifications should
care disparities12 and deficiencies in the optimal treatment of be considered.

4 Position Paper
2 Current definitions of heart at a rate commensurate with the requirements of the metabo-
........................................................................................................................................................................
lizing tissues’,2 is a complex and impractical definition that often
failure cannot be verified in practice and apply to only a certain sub-
Heart failure is a clinical syndrome with different aetiologies and group of patients with HF. As such, in a study of patients with
pathophysiology rather than a specific disease. This makes defining advanced HF awaiting left ventricular assist device implantation,
HF more complex than diseases that have a pathologic gold stan- cardiac output was shown to be insufficient to meet the metabolic
dard for diagnosis such as cancer. Not surprisingly, definitions of needs of the body only in 25% of these patients with advanced
HF vary widely in the medical literature, in contemporary guide- HF at rest, demonstrating the inadequacy of such definitions in the
lines, and in medical practice. Differing definitions have been devel- majority of the HF population.24 In clinical care, other diagnostic
oped for different purposes, ranging from ‘textbook’ definitions of criteria such as measurement of plasma natriuretic peptides play
HF, which are typically focused on pathophysiology, to case defini- an important role in clarifying the diagnosis of HF.3–5 A summary
tions such as the Framingham criteria23 that are primarily used in of contemporary definitions of HF from the American College of
research. The traditional textbook definition of HF, which is usu- Cardiology/American Heart Association (ACC/AHA), HFA/ESC,
ally defined as a ‘condition in which the heart cannot pump enough and JHFS guidelines is provided in Table 1. Although the definitions
blood to meet the body’s needs’1 or ‘abnormality of cardiac struc- of HF used in current practice guidelines from the ACC/AHA,3
HFA/ESC,4 and JHFS5 differ in some details, they share the following
ture or function leading to failure of the heart to deliver oxygen
common elements: they identify HF as a clinical syndrome, i.e. a rec-
ognizable cluster of signs and symptoms; they require the presence
of at least some of the cardinal symptoms of HF including dyspnoea,
Table 1 Heart failure definitions in contemporary
fluid retention/oedema, fatigue, activity intolerance and exercise
clinical practice guidelines
limitation; and they require some form of structural or functional
ACCF/AHA (2013)3 HF is a complex clinical syndrome that heart disease. Some also specify a reduced cardiac output and/or
results from any structural or elevated intra-cardiac pressures at rest or during stress.4 Overall,
functional impairment of ventricular the existing definitions of HF comprise three elements: evidence of
filling or ejection of blood. The structural heart disease, a history of symptoms that are commonly
cardinal manifestations of HF are reported in HF and objective signs commonly seen in HF.
dyspnoea and fatigue, which may limit
exercise tolerance, and fluid
retention, which may lead to 2.1 Definitions of heart failure used
pulmonary and/or splanchnic in current clinical trials and registries
congestion and/or peripheral oedema.
Some patients have exercise
The definitions and inclusion criteria used in clinical trials and reg-
intolerance but little evidence of fluid istries in HF differ from those in clinical practice, guidelines and
retention, whereas others complain textbooks. Most trials in HF with reduced EF (HFrEF) (Table 2),25–29
primarily of oedema, dyspnoea, or and in HF with preserved EF (HFpEF) (Table 3)30–33 reflect inclusion
fatigue. criteria that usually include a left ventricular EF (LVEF) threshold, an
ESC (2016)4 HF is a clinical syndrome characterized established HF diagnosis with specific New York Heart Association
by typical symptoms (e.g. (NYHA) functional class categories, certain levels of natriuretic
breathlessness, ankle swelling and peptides and may sometimes include a requirement of past HF hos-
fatigue) that may be accompanied by pitalizations, depending on the severity of HF targeted for the trial.
signs (e.g. elevated jugular venous
HFpEF studies also may include corroborative evidence by imag-
pressure, pulmonary crackles and
ing reflecting structural and/or functional changes. Nonetheless, a
peripheral oedema) caused by a
number of gaps remain in standardizing the criteria for clinical tri-
structural and/or functional cardiac
abnormality, resulting in reduced als. These include sensitivity and specificity of diagnostic criteria
cardiac output and/or elevated for HF, establishing standardized natriuretic peptide criteria; the
intracardiac pressures at rest or complexity of additional requirements to ascertain the diagnosis
during stress. of HF; challenges with HFpEF including multiple comorbidities that
JCS/JHFS (2017)5 HF is a clinical syndrome consisting of are often excluded in clinical trials, how to handle patients with EF
dyspnoea, malaise, swelling and/or recovery or changes in clinical trajectory, competing diagnoses that
decreased exercise capacity due to may mimic findings of HF and the generalizability of the trial criteria
the loss of compensation for cardiac to the ultimately intended treatment population. It is also impor-
pumping function due to structural tant to distinguish between clinical trial inclusion criteria that aim
and/or functional abnormalities of the
to select target populations, from clinical trial endpoint definitions
heart.
that facilitate measurement of outcomes secondary to the disease
ACCF/AHA, American College of Cardiology Foundation/American Heart Asso- process. For example, natriuretic peptides, which are commonly
ciation; ESC, European Society of Cardiology; HF, heart failure; JCS, Japanese used in entry criteria in HF trials, are not commonly required for
Circulation Society; JHFS, Japanese Heart Failure Society.
clinical endpoint definitions.21

Table 2 Summary of heart failure inclusion criteria for recent clinical trials – heart failure with reduced ejection
fraction
Trial Age, NYHA class LVEF (%) Natriuretic peptides HF hospitalization or other
...................................................................................................................................................................
PARADIGM-HF25 Age ≥18 years LVEF <35% If previous hospitalization, BNP Within previous 12 months
NYHA II–IV ≥100 pg/mL or NT-proBNP
≥400 pg/mL
If no previous hospitalization, BNP
≥150 pg/mL or NT-proBNP
≥600 pg/mL
VICTORIA26 Age ≥18 years LVEF <45% Within past 30 days: Within 6 months or outpatient
NYHA II–IV NSR, BNP >300 pg/mL, NT-proBNP IV diuretics for HF within
>1000 pg/mL 3 months
AF, BNP >500 pg/mL, NT-proBNP
>1600 pg/mL
DAPA-HF27 Age ≥18 years LVEF ≤40% If HF hospitalization within 12 months: Diagnosis of HF for at least
NYHA II–IV NT-proBNP ≥400 pg/mL 2 months
If no hospitalization, NT-proBNP
≥600 pg/mL
AF, NT-proBNP ≥900 pg/mL
EMPEROR-Reduced28 Age ≥18 years LVEF≤40% LVEF ≤30%, NT-proBNP ≥600 pg/mL NYHA class II–IV for at least
NYHA II–IV (NSR) or ≥1200 pg/mL in AF 3 months
LVEF 31–35%, NT-proBNP ≥1000 pg/mL
(NSR) or ≥2000 pg/mL in AF
LVEF 36–40%, NT-proBNP ≥2500 pg/mL
LVEF <40% but HF hospitalization within
12 months, NT-proBNP ≥600 pg/mL
GALACTIC-HF29 Age ≥18 and LVEF≤35% NT-proBNP ≥400 pg/mL (NSR) or Currently hospitalized for HF
<85 years ≥1200 pg/mL in AF; or BNP (inpatients) or had either
NYHA II–IV ≥125 pg/mL (NSR) ≥375 pg/mL made an urgent visit to the
emergency department or
been hospitalized for HF
within 12 months (outpatients)
AF, atrial fibrillation; BNP, B-type natriuretic peptide; HF, heart failure; IV, intravenous; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic
peptide; NYHA, New York Heart Association; NSR, normal sinus rhythm.
2.2 Gaps in current definitions of heart purpose,23 are now considered insufficiently specific for adoption
......................................................
failure as a definition of HF in the contemporary setting.
2.2.1 Combined definition with haemodynamic

characterization of heart failure 2.2.2 Cardiomyopathy and heart failure
The current definitions that include a haemodynamic character- A key distinction that has led to persistent confusion in many
ization such as the HFA/ESC definition which defines HF as ‘a discussions of the definition of HF is that between the concepts
clinical syndrome characterized by typical signs and symptoms, of ‘heart failure’ and ‘cardiomyopathy.’ As defined elsewhere in
caused by a structural and/or functional cardiac abnormality, this document, HF is a clinical syndrome, that is, a recogniz-
resulting in a reduced cardiac output and/or elevated intra-cardiac able pattern of signs and symptoms. ‘Cardiomyopathy’ is a term,
pressures at rest or during stress’,4 have the following limitations: itself with widely differing definitions, that describes features of
while accurate, this type of definition is hard to apply in public structural and functional heart muscle dysfunction. These differ-
health or epidemiological settings, because of the subjectivity of ent definitions may lead to potential confusion. In clinical practice,
the symptoms counterbalanced by the unfeasibility (invasive) or the term ‘cardiomyopathy’ is often used as a more general term
unreliability of measurements of cardiac output or filling pressures. encompassing types of cardiac dysfunction, which may be further
For a definition to be also useful for the non-specialist, it should be qualified with the underlying cause (e.g. ischaemic cardiomyopathy,
assessable easily and with relatively low inter-observer variability. non-ischaemic cardiomyopathy, etc.). Alternatively, cardiomyopa-
The Framingham criteria, which were developed for just such a thy may be understood to be a specific form of myocardial disease

6 Position Paper
Table 3 Summary of heart failure inclusion criteria for recent clinical trials – heart failure with preserved ejection
fraction
Trial Age, NYHA class LVEF (%) Natriuretic peptides HF hospitalization

...................................................................................................................................................................
TOPCAT30 Age ≥50 years LVEF ≥45% BNP ≥100 pg/mL Within previous 12 months, w/
NYHA II–IV or NT-proBNP ≥360 pg/mL management of HF a major
component
PARAGON-HF31 Age ≥50 years LVEF ≥45% and LAE If NSR, NT-proBNP >200 pg/mL Within previous 9 months
NYHA II–IV LVH If AF: >600 pg/mL
or If no previous hospitalization
and
If NSR: NT-proBNP >300 pg/mL
If AF: NT-proBNP >900 pg/mL
EMPEROR-Preserved32 Age ≥18 years LVEF >40% (no prior NT-proBNP >300 pg/mL in NSR Within 12 months OR
NYHA II–IV (at history of LVEF or >900 pg/mL in AF evidence of structural
least 3 months) ≤40%) changes (LAE or increased
LVM) on echo
DELIVER33 Age ≥40 years (LVEF >40% and Elevated natriuretic peptides Medical history HF ≥6 weeks
NYHA II–IV evidence of structural before enrolment with at
heart disease (i.e. least intermittent need for
LAE or LVH) diuretic treatment
AF, atrial fibrillation; BNP, B-type natriuretic peptide; HF, heart failure; LAE, left atrial enlargement; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy;
LVM, left ventricular mass; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; NSR, normal sinus rhythm.
that excludes forms of HF with a clearly established cause (such diagnostic value, especially in the context of clinical uncertainty,
.............................................................................................
as ischaemic heart disease). Even guideline statements from varin some communities with limited resources, natriuretic peptide
ious scientific bodies have varied in their use of this term.34,35 measurements currently may not be readily available, but their
Furthermore, the maladaptive haemodynamic and compensatory availability is rapidly increasing, and natriuretic peptide measure-
mechanisms in HF may result in development of or worsening of ments are becoming part of standard care. Furthermore, certain
cardiomyopathy.36 Classification systems have been proposed that clinical conditions other than HF, such as chronic kidney disease
attempt to incorporate both the classification of HF and cardiomy- (CKD), atrial fibrillation, pericardial disease, pulmonary embolism,
opathy into a unified system, most notably the proposed MOGES and even aging can also result in an increase in natriuretic pep-
criteria (Morpho-functional phenotype-M, organ(s) involvement-O,
tide levels, and obesity is associated with lower natriuretic peptide
genetic inheritance pattern-G, etiological annotation-E including
levels, underlining the importance of an individualized interpreta-
genetic defect or underlying disease/substrate, and the functional
tion of biomarker levels, particularly in special populations and in
status-S), but these have not been widely adopted due to their
the setting of competing diagnoses and comorbidities. It is impor-
complexity.37 HF encompasses a broader spectrum of cardiac dis-
tant to recognize that though measuring natriuretic peptide levels
orders, not only cardiomyopathies that could be an underlying
may improve diagnostic accuracy and guide risk stratification in
cause of the HF syndrome. In this statement, we do not pro-
vide specific classification strategies for cardiomyopathies, which patients with HF, in certain patients with HF, such as patients with
we believe to be outside the scope of this document.34 HFpEF or obesity, natriuretic peptide levels can be lower than those
with HFrEF (though usually higher than those without HF); this
2.2.3 Biomarkers in the definition of heart failure may complicate their use for diagnosis and prognosis. Differences
according to race/ethnicity, sex and age will need to be taken into
Natriuretic peptides such as B-type natriuretic peptide (BNP) and
consideration in their interpretation and different thresholds are
N-terminal pro-B-type natriuretic peptide (NT-proBNP) are ele-
commonly used for patients with atrial fibrillation, a very common
vated in most forms of HF and are an integral component of
comorbidity in HF that can lead to increased natriuretic peptide
making a diagnosis of HF in many clinical settings, especially when
the diagnosis is uncertain.3–5,38 The use of these biomarkers has levels. A potential influence of comorbidities is also relevant for
the highest class of recommendation to support a diagnosis or troponin interpretation in patients with suspected acute MI; how-
exclusion of HF4,38 in contemporary practice guidelines, but are ever, despite similar limitations, the introduction of a quantitative
notably absent from most definitions of HF. This is in contrast biomarker element to a disease definition has improved the accu-
with the universal definition of myocardial infarction (MI), where rate classification of disease states and proven to be of value in
elevations of a circulating biomarker (troponin) are both central MI and other diseases.22,39 In general, both BNP and NT-proBNP
to the clinical diagnosis and fundamental to the universal defini- values track similarly, and either can be used in patient care settings
tion itself.22 Although a biomarker-based approach has incremental as long as their respective absolute values and cut-points are not

used interchangeably. Notably, BNP, but not NT-proBNP, is a sub- although the problem could be confounded by, or even be pre-
........................................................................................................................................................................
strate for neprilysin. Angiotensin receptor–neprilysin inhibitor may dominantly due to, anaemia and iron deficiency. Recognizing pro-
result in an increase in BNP levels, but not NT-proBNP levels.38 portionate contributions of a clinical picture, to dissect out the
Furthermore, patient-level changes need to be interpreted accord- element that is specifically HF-related, will be an important part
ing to baseline levels; natriuretic peptides are higher during periods of establishing a HF diagnosis, and it may not be an easy differ-
of decompensation compared with compensated periods, reflect- entiation to make in all situations. It is HF only if the cardiac
ing dynamic temporal changes. component is considered ‘important’. However, it is also impor-
tant to recognize that HF can co-exist with other diagnoses. For
example, HF syndromes with lesser degrees of systolic impairment
2.2.4 Clinical and research aspects of defining heart such as HFpEF frequently present with a wide range of cardiac
failure and non-cardiac abnormalities.45 Newer, sometimes inconsistent
Clinical research requires standardized definitions for identifying terminology regarding mildly reduced EF has further complicated
cases of HF and the collection of endpoints of interest, including subcategorization of HF. It is important to promote greater clarity
especially HF-related hospitalizations.21 Given the increased use of and specificity in the diagnosis of HF.
electronic health records (EHR) as research tools, there is growing
interest in the use of computer algorithms to identify cases of
HF from EHR data for research purposes. Although classical signs 3 Current classifications of heart
and symptoms are often included in EHR data, they may not be failure
codified as discrete data fields, leading to increased interest in the
use of machine learning techniques to identify cases.40 Definitions An important part of defining HF is that of creating a ‘usable’
of HF are important not only for clinical practice or research entry classification scheme. There are a variety of classification frame-
criteria, but also for the generalizability of research findings to the works in current use that attempt to define distinct subsets of HF
HF population, uniformity in endpoints of clinical trials; reliability (Table 4).3,4,37,46,47 Some of these, such as NYHA class and EF cate-
and appropriateness of data captured in clinical, administrative and gories, have been subsequently used as entry criteria for clinical
billing registries and performance measures. trials, resulting in their incorporation into product labelling and
guideline recommendations about which patients should receive
a given therapy.3–5 Others, such as classifying patients by HF aetiol-
2.2.5 Patient and clinician perspective ogy, may have important implications for prognosis or differential
A syndrome that is based solely on symptoms can be confusing for response to therapy.48
clinicians and patients, both because they are often not specific to
a single disease (e.g. fatigue and dyspnoea) and because they are
3.1 Current subclassification of heart
highly subjective, for example with the same objective limitation
being considered disabling by one person and perceived as being
failure according to ejection fraction
normal for age by another. Once diagnosed, and with effective ther- and its limitations
apy, patients may become asymptomatic (NYHA class I); however, Because clinical trial inclusion criteria, and hence evidence of ben-
structural, cellular and molecular abnormalities may continue to efit, have often been restricted to patients with a reduced EF, HF
worsen silently.41 Although Stage C HF uses the wording ‘current has traditionally been subcategorized according to EF when defin-
or previous symptoms’ in the definition, patients may believe that ing recommended treatments in clinical practice guidelines.3–5 All
lack of signs and symptoms equates to ‘being out of HF’, and be guidelines use the terminology of HFrEF and HFpEF (Table 5) but
less likely to adhere to care.42 Health care professionals may be differ in the terminology used in patients with EFs between 40%
less likely to optimize GDMT when symptoms are mild or absent.43 and 49%. The 2013 ACC/AHA guidelines have used the terminol-
Removing the word ‘congestive’ in the term HF was an important ogy of HFpEF-borderline for patients with EF between 41–49%,
reminder to providers that there is a range of signs and symp- and HFpEF-improved for those whose EF improved from a lower
toms once diagnosed. Further, patients may not understand or level to an EF of >40% under the subgrouping of patients with
recognize when HF worsens, until symptoms are severe enough to HFpEF.3 The HFA/ESC and JHFS guidelines have defined a third cat-
prompt emergency care.44 In the era of shared decision-making and egory of HF with mid-range EF (HFmrEF) or mildly reduced EF for
patient understanding of chronic conditions, it will be important to those with an EF of 41% to 49%.4,5 The concept of HFmrEF is not
acknowledge and incorporate different stages that are understand- necessarily accepted by all guidelines.49
able by patients after diagnosis. In an effort, through a public-private partnership with the US
Food and Drug Administration (FDA) and with an intent to
standardize terminology and LVEF cut-points used in US clinical
2.2.6 Competing diagnoses trials, the Heart Failure Collaboratory and Academic Research
There are many conditions that may mimic HF, either in isola- Consortium proposed the following definitions and EF ranges as
tion (mimicry) or when co-existing with HF (co-causative). The their most recent recommendations: (i) HFrEF: HF with LVEF
combination of acute dyspnoea, hypervolaemia and cardiorenal ≤40%; (ii) HFpEF: HF with LVEF ≥50%; (iii) HFmrEF: HF with LVEF
syndrome is often labelled as HF in an emergency care setting, >40% and LVEF <50%.50

8 Position Paper
recognized or postulated for HFmrEF. It is likely that patients
........................................................................................................................................................................
Table 4 Selected classification frameworks currently
in this range may have aetiologies that are similar to those in
used for heart failure
lower or higher LVEF groups, and may be in transition from
higher to lower LVEF or vice versa. Persistent HFmrEF can be
NYHA class3 I, II, III, IV based on symptom severity
Ejection fraction4 HFrEF, HFmrEF, HFpEF based on left seen in some patients, including heterogeneous aetiologies such
ventricular ejection fraction as those with ischaemic, infiltrative, restrictive or hypertrophic
Aetiology34 Specific aetiology of HF, e.g. cardiomyopathies.57,61,62 Therefore, lower than a normal EF does
ischaemic/non-ischaemic, valvular, not necessarily represent one phenotype and does not always
hypertensive, infiltrative cardiomyopathy entail the maladaptive deleterious mechanisms seen in patients
such as cardiac amyloidosis, peripartum with HFrEF. Furthermore, patients with restrictive, infiltrative and
cardiomyopathy, viral myocarditis, hypertrophic cardiomyopathies, who may have HFmrEF, have tra-
chemotherapy-induced cardiomyopathy ditionally been excluded from some clinical trials, emphasizing the
Disease progression Stages A, B, C, D according to presence of necessity to focus on aetiology rather than LVEF. The prevalence
(ACCF/AHA)3,46 HF symptoms and signs and cardiac
of HFmrEF, without overlap of other categories, has posed a major
structural changes
challenge for recruitment in trials, resulting in termination due to
MOGES37a Morpho-functional phenotype (M), organ(s)
enrolment futility63 and in some clinical trials and epidemiologi-
involvement (O), genetic inheritance
pattern (G), etiological annotation (E) cal studies, patients with LVEF 40–49% have been categorized as
including genetic defect or underlying HFpEF.
disease/substrate, and the functional Another criticism is the accuracy of the measurement of EF in
status (S) clinical practice. Echocardiography is widely used to assess EF in
INTERMACS Profiles 1 through 7 according to symptoms, patients with cardiovascular diseases, but the inter-observer and
profiles of functional capacity, haemodynamic intra-observer variability are not small enough to allow precise
advanced HF47 stability for patients who are considered quantification of differences in one integer place values such as
for advanced HF therapies 39% vs. 41%. Although other cardiovascular imaging modalities
ACCF/AHA, American College of Cardiology Foundation/American Heart Asso- can be used to assess EF, there is substantial variation between
ciation; HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; modalities as well.64 Furthermore, EF is not a reliable measure of
HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with contractile performance, is load-dependent, and can vary according
reduced ejection fraction; INTERMACS, Interagency Registry for Mechanically
Assisted Circulatory Support; NYHA, New York Heart Association.
to haemodynamic status and loading conditions. Other imaging
a MOGE(S) nosology system. modalities such as global longitudinal strain are evolving to better
characterize the ventricle, structural abnormalities, contractile
performance, reverse remodelling, response to therapy, and will
The dichotomization of LVEF of above or below, for example, likely expand the structural phenotyping beyond EF.
40% has been helpful to apply therapies that have been shown Finally, the trajectory of EF over time in addition to a single
to work in patients with reduced EF. Further classification into absolute value of EF, and severity of left ventricular dysfunction even
HFmrEF has potential utility as well as challenges due to its ambi- among HFrEF may need to be taken into account to further classify
guity, uncertainty and dynamic trajectory.15,51 Post-hoc analyses patients with HF. Despite all these reservations, classification by EF
of certain HF trials have suggested that standard therapy for has proven to be clinically and epidemiologically useful.
HFrEF may be effective and extended to patients with HFmrEF,52–55
but meta-analyses report diverse findings with neurohormonal
3.2 Current classification according
antagonism in patients with HFmrEF, specifying benefit in certain
subgroups and underlining heterogeneity of this category15,55–57
to stages of heart failure and its
The characteristics of HFmrEF overlap with HFrEF and HFpEF, limitations
straddling either category, sometimes one more than the other The ACC/AHA stages are categorized as Stage A, patients at high
depending on the clinical circumstance or patients studied.15 In risk for HF but without structural heart disease or symptoms of
population-based studies, usually without exclusions of specific HF; Stage B, structural heart disease but without signs or symp-
aetiologies, HFmrEF comprises 10–20% of the HF population,54,58 toms of HF; Stage C, structural heart disease with prior or cur-
resembles the HFrEF group, but with similar57 or better sur- rent symptoms of HF; Stage D, refractory HF requiring specialized
vival than HFrEF patients.15,58 Although some patient character- interventions..3,4,46 The original ACC/AHA definition of stages of
istics of HFmrEF are just between those of HFrEF and HFpEF, HF46 has been ubiquitously adapted throughout other HF guide-
the prognosis of patients is not necessarily related to EF,59 and lines globally.3–5 Although these stages of HF are well recognized
the relation between mortality and BNP is not affected by EF.59,60 amongst health care professionals, they are not standard nomencla-
In many patients, HFmrEF reflects a transitional trajectory for a ture for general practitioners, patients, payers, or among the liter-
dynamic temporal change; either to improvement or recovery from ature or education platforms provided by patient advocacy groups.
HFrEF,57,61 or to deterioration to HFrEF.15,57,61,62 Although HFrEF Patients living with HF are less likely to identify with stages of HF in
and HFpEF have different clinical spectrums and proposed patho- comparison to the familiarity with EF and subjective symptom bur-
physiological mechanisms, there is no clear defining syndrome den. Contemporary clinical trials have not enrolled or randomized

Table 5 Current heart failure classifications according to left ventricular ejection fraction in contemporary clinical
practice guidelines
Society HF classification according to LVEF LVEF Additional requirements

...................................................................................................................................................................
ACCF/AHA3 • Heart failure with reduced ejection fraction (HFrEF) ≤40% Symptoms and signs
• Heart failure with preserved ejection fraction (HFpEF) ≥50% Symptoms and signs
a) HFpEF, borderline 41–49% Symptoms and signs
b) HFpEF, improved >40% Symptoms and signs
ESC4 • Heart failure with reduced ejection fraction (HFrEF) <40% Symptoms and signs
• Heart failure with mid-range ejection fraction 40–49% Symptoms and signs, elevated levels of natriuretic
(HFmrEF) peptides and at least one additional criterion of
relevant structural heart disease (LVH or LAE) or
diastolic dysfunction
• Heart failure with preserved ejection fraction (HFpEF) ≥50% Symptoms and signs, elevated levels of natriuretic
peptides and at least one additional criterion of
relevant structural heart disease (LVH or LAE) or
diastolic dysfunction
JCS/JHFS5 • Heart failure with reduced ejection fraction (HFrEF) <40%
• Heart failure with mid-range ejection fraction 40% to <50%
(HFmrEF)
• Heart failure with preserved ejection fraction (HFpEF) ≥50%
• Heart failure with preserved ejection fraction, ≥40%
improved (HFpEF improved) or heart failure with
recovered ejection fraction (HFrecEF)
ACCF/AHA, American College of Cardiology Foundation/American Heart Association; ESC, European Society of Cardiology; HF, heart failure; JCS, Japanese Cardiology
Society; JHFS, Japanese Heart Failure Society; LAE, left atrial enlargement; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy.
based on stages of HF and most treatment strategies are not guided have HF. From the public and health care perspective, being called
.....................................................................................
by the stages in HF. HF, regardless of such an early status as Stage A, raises important
The ACC/AHA stages are based on symptoms and the presence concerns, since HF is usually perceived as an advanced chronic
or absence of structural heart disease and are applicable to both disease with symptoms and very adverse outcomes, and may have
HFrEF and HFpEF. Certainly, there are prognostic nuances that are implications for health and life insurance. Of course, it is critical to
missed in such a broad staging classification, and opinions also vary focus on prevention, with recognition, prevention and treatment
as to whether those individuals solely identified with risk factors of these risk factors, but it is also important to differentiate those
should be labelled as having a disease state, especially given that who have HF from those at risk for HF. Similarly, clinicians in
they have risk factors for many different diseases (not just HF general or HF practice have not adopted the terminology of Stage
risk factors). In comparison, classification schemas such as the A HF beyond academic circles, partly due to lack of actionable spe-
Society for Cardiovascular Angiography and Interventions (SCAI) cific treatment recommendations according to stages, and most of
cardiogenic shock stages65 classified their stages based on detailed their assessment and management focuses on management of left
parameters of laboratory values, and haemodynamics as well as ventricular dysfunction (Stage B) or symptomatic HF (Stages C/D).
physical examination findings and exemplifies a more detailed When clinicians address risk factors such as hypertension, diabetes,
approach to staging. Furthermore, the definitional progression obesity or coronary artery disease, they do not refer to those
along the ACC/AHA stages A through D is a unidirectional path as Stage A HF or pre-HF but rather independent diagnoses. Fur-
with little appreciation of a possibility to revert to a lower stage thermore, despite recognized increased adverse outcome risk and
with appropriate GDMT. possibility of progress to symptomatic HF in some patients,66,69,70
If the HF process were to be defined as a continuum from Stage the data on the likelihood of progression from Stages A/B to C/D
A through D, the highest number of patients would be in Stage A or are limited.67,69,70 Thus most clinicians do not commonly use the HF
Stage B.66–69 This is due to the fact that the prevalence of hyper- terminology for Stage A patients, and do not commonly educate
tension, diabetes, coronary artery disease, obesity/metabolic patients regarding risk of progression from Stages A/B to C.
syndrome – the risk factors with significant relative risk and Another important development that needs to be taken into
population attributable risk for development of HF – are consideration of stages in HF is the advances in prevention of
present in approximately one-third of the US population.10 future risk of HF by specific therapies. Although in the past,
By population-based registries, more than 40 to 50% of the adult prevention and holistic treatment of risk factors by standard
population has been categorized to be in Stages A or B.66–68 The treatment strategies were felt to prevent HF,3 there is growing
high prevalence of HF risk in the general population raises the evidence that certain treatment strategies are better for the
question of whether Stage A patients should really be defined to prevention of HF, and not all treatment strategies of hypertension

10 Position Paper
and diabetes prevent HF equally or at all. For example, in the treat- LVEF, HFpEF (borderline), HFpEF, and HF with recovered EF (HFre-
........................................................................................................................................................................
ment of hypertension, diuretic-based antihypertensive therapies, cEF). The magnitude of change that defines ‘recovery’ of LVEF is not
angiotensin-converting enzyme inhibitors or angiotensin receptor standardized, but it is recognized that distinguishing HFrecEF from
blockers have been shown to prevent HF in a wide range of HFmrEF requires serial measurements of the LVEF to appropriately
target populations, whereas calcium channel blockers have not.71 capture change over time as this group might represent HFrecEF
There is growing evidence that treatment with sodium–glucose or deteriorated HFpEF. Moreover, because the measurement of
co-transporter 2 (SGLT2) inhibitors prevent HF hospitalizations the LVEF is subject to significant intra- or inter-reader variability,
among patients with type 2 diabetes72–74 or in patients with HFrEF small changes in the LVEF need to be interpreted cautiously. Thus,
regardless of diabetes27,28 whereas other glucose treatment strate- a recent scientific panel put forth a working definition of HFre-
gies do not. It is also interesting to note that patients with a higher cEF that includes: a baseline LVEF of ≤40%, a ≥10% increase from
future HF risk identified by risk scores that include biomarkers baseline LVEF, and a second measurement of LVEF of >40%.80 In
such as albuminuria, seem to derive greater benefit from SGLT2 this formulation, recovered EF signifies improvement of LVEF to
inhibitor therapy among patients with type 2 diabetes.75 The over 40% but not necessarily totally normalized. There have been
biomarker profile may identify patients with cardiometabolic, car- other attempts to characterize improvement in EF as an increase in
diovascular and cardiac structural changes in patients predestined LVEF by more than 10%.80 It is also important to recognize that the
to develop HF or in other words pre-HF. Supporting this concept trajectory might not be linear and unidirectional, and a patient may
was the STOP-HF trial which provided evidence that screening have improvement followed by a decline in EF or vice versa depend-
with natriuretic peptides among individuals with cardiovascular ing on the underlying aetiology, duration of disease, adherence to
disease or with cardiovascular risk factors such as diabetes and GDMT, comorbidities or re-exposure to cardiotoxins.
hypertension, can be helpful to prevent development of HF or
left ventricular systolic or diastolic dysfunction.76 Accordingly, the
2017 ACC/AHA/HFSA focused update of the guidelines for the 4.2 Trajectory changes in clinical status
management of HF incorporated recommendations for natriuretic Another method that captures the HF trajectory relies on an
peptide-based screening in the prevention of HF as a Class IIa assessment of the patient’s clinical status, which can inform the
recommendation.38 Similarly, high-sensitivity cardiac troponin risk for hospitalization for HF or for mortality. A de novo diagnosis
levels are associated with future development of incident HF in the of HF, also referred to as ‘new-onset HF’, carries an increased risk
general population77,78 and in those with evidence of cardiotoxicity for adverse clinical outcomes since the patient is not likely to be
or cardiac injury in high-risk populations79 allowing for treatment treated with optimal GDMT at the time of diagnosis.
strategies to prevent development of HF. Thus, biomarker elab- Most patients with HF have episodes of clinical worsening of HF,
oration can further identify risk and presence of ultrastructural which has been previously defined as worsening signs or symptoms
abnormalities in HF among asymptomatic patients and could be in concert with a hospitalization.81 Data from more contemporary
a marker for Stage B HF without development of macroscopic studies resulted in expansion of worsening HF to also include
structural changes detectable by imaging or electrocardiography. patients who require escalation of outpatient therapies, such as
diuretics, even without a hospitalization.82 This is because the need
for intensifying diuretic therapy, regardless of location (inpatient or
4 Gaps in definitions according outpatient), portends a worse prognosis than a patient who does
to trajectory of changes in heart not require intensification of therapy. Worsening HF implies a
period of stability preceding a deterioration of signs and symptoms.
failure However, the phrase ‘stable’ HF may be a misnomer, as patients
The HF syndrome is dynamic, with changing clinical trajectories with HF always carry a residual risk for hospitalization or sudden
based on signs, symptoms, and disease progression, driven by cardiac death, even when minimally symptomatic or asymptomatic
underlying pathophysiologic processes. Changes in HF may be receiving optimal treatment. For such patients remission may be
captured in several ways, including alterations in cardiac structure a more suitable term.83 When a patient with worsening HF does
and function and by clinical status. not improve with therapy escalation and continues to decline, she
or he can be referred to as refractory to treatment. These patients
are often assessed for advanced therapies such as mechanical
4.1 Trajectory changes in ejection
circulatory support or cardiac transplant, or if they do not qualify
fraction for advanced therapies, clinicians can consider referral for palliative
GDMT can result in improvement in LVEF and reverse remodelling care.
in patients with HFrEF.80 The phenomenon of improvement and Patients may have improvement in HF symptoms, functional
recovery of LVEF has led to a growing interest in the long-term out- capacity, quality of life and exercise performance with GDMT.
comes and management of these patients and how they differ from Some patients with reversible or treatable causes of HF
‘non-responders’, or individuals whose LVEF does not improve with such as cardiomyopathy due to hypertensive heart disease,
treatment. Currently, there is no consensus definition for patients alcoholic cardiomyopathy, peripartum cardiomyopathy, or
with HFrEF whose LVEF improves, which has led to a variety of tachycardia-induced cardiomyopathy may even recover from
terms describing this phenotype, including patients with ‘improved’ HF with treatment and manifest resolution of HF symptoms,

as well as normalization of the EF and cardiac structure. These also stratifies patients based on symptoms and risk of exacerba-
........................................................................................................................................................................
patients require close follow-up and continuation of treatment to tions similar to congestion–perfusion91 categorization in HF. Pul-
ascertain that HF symptoms or left ventricular dysfunction do not monary hypertension classification [World Health Organization
re-occur in the future.84 (WHO) groups 1–5]92 is similar to the aetiology-based groupings
for cardiomyopathies34,35 with genetic, acquired, and mixed cate-
gories and is a potential model for future HFpEF93 disease stratifica-
tion. Finally, the field of cancer groups disease using a combination
5 Learning from other disease of epidemiology-based staging (i.e. at risk for cancer, pre-cancer,
carcinoma in situ, localized, early/late locally advanced, and metasta-
definitions sized) coupled with disease-specific markers that determine treat-
Disease definitions are not all the same. Some are categorical, ment course and targeted therapies. Cancer, which is a chronic
where the disease is present or it is not. In some there may be disease similar to HF, reflects one of the most comprehensive com-
a single pathognomonic feature that defines the disease state, such bined approaches of classification using epidemiology, biomarker
as many cancers and infectious diseases. In others, where numerical thresholds and trajectory.
thresholds are used, a disease may be defined against a quantitative Future attempts at defining HF will need to draw on princi-
threshold of abnormality in an anatomical and/or functional feature. ples of categorization used in other disease states. Each organ
Examples of these include hypertension, osteoporosis, sarcopenia system has a unique pathophysiology that helps to determine its
and CKD. In some (e.g. CKD, hypertension) the presence of this disease categorization, and ultimately, all organ systems are inter-
numerical abnormality alone is sufficient to define the disease, connected. Indeed, HF represents an end-stage phenotype for
whereas in others (e.g. HF, sarcopenia) the loss of function must be most (if not all) cardiovascular diseases. In the terminal stages of
symptomatic or functionally evident for the disease to be defined. disease, the universal element is disseminated disease and mul-
In the current universal definition of MI, elevation of cardiac tiorgan failure. However, unlike other organ systems, the heart
troponin is central to the clinical diagnosis and fundamental to the is unique in that haemodynamics play a central role in the dis-
universal definition.22 ease state. Many disease states are moving towards a combination
There are many other corollaries and lessons to learn from of epidemiology-based, numeric, and targeted marker-based ther-
other areas of cardiology and medicine in regard to disease apies. Disease definitions are critical to patients’ and clinicians’
definition and classifications. Current ACC/AHA classification of understanding of their pathology, inform clinical decision-making,
valvular heart disease is very similar to the current ACC/AHA categorization for financial billing, and creation of future health
HF categorization into Stages A–D.3,85 Such categorization is an policies.
epidemiology-based system where the disease stage is defined
based on stages of susceptibility from ‘at risk’ to subclinical disease
to clinical disease, and finally, recovery, disability, or death. Atrial
fibrillation is also based on an epidemiology-based system where 6 Proposed universal definition
patients are categorized as paroxysmal (≤48 h), persistent (>7 days
or cardioverted), long-standing (>1 year), and permanent.86 How-
of heart failure
ever, in atrial fibrillation, clinicians also use the CHA2 DS2 -VASc In this section, we provide a consensus opinion on a new proposed
risk score to determine potential stroke risk and thereby guide universal definition of HF.
management.86 A similar parallel in HF is the MAGGIC model for
prediction of mortality and other attempts at scoring to help risk
stratify patients who may have worsening HF, rehospitalization, or
a greater chance of dying.87 6.1 Symptoms
In regard to non-cardiovascular strategies for disease definition, Heart failure, like many non-categorical diseases, is widely held
there are quite a few examples. CKD is classified based on albu- to be a clinical syndrome, devoid of any single pathognomonic
minuria and estimated glomerular filtration rate (eGFR).39 Albu- histological or biochemical signal, and being the possible end result
minuria states are similar to numeric categorization of disease, of many quite distinct and varied clinical disease states. Common
like LVEF in HF, whereas eGFR ranging from normal to end-stage symptoms and signs of HF are listed in Table 6.
renal disease provides prognostic information and guides man- The current ACCF/AHA classification of HF3 includes two
agement decisions, such as drug dosing and the need for dialy- pre-symptomatic stages, A and B. Although we restrict the definition
sis. Liver disease is categorized based on pathology using imag- of the syndrome of HF to being a symptomatic clinical condition,
ing and tissue sampling to define levels of steatosis, hepatitis, our proposed revised stages still straddle the pre-symptomatic
fibrosis, and cirrhosis.88 Much like CKD, liver disease also sup- stages. To not lose the advantage that the A/B/C/D staging system
plements disease categorization with risk scores like the MELD offered, to incorporate the asymptomatic phases under the HF
score.89 Lung disease is assessed using pulmonary function tests umbrella, and to enhance understandability of these asymptomatic
which help clinicians stratify patients based on air-flow limitation phases, we propose a new categorization of Stages A and B into ‘at
and the GOLD system.90 Chronic obstructive pulmonary disease risk’ and ‘pre-HF’ in Section 9 below.

12 Position Paper
In HF, possible candidates for such a measurement might theo-
........................................................................................................................................................................
Table 6 Symptoms and signs of heart failure
retically be haemodynamic measures such as elevated pulmonary
Symptoms of heart failure capillary wedge pressure and right atrial pressure by right heart
Typical Breathlessness catheterization, biomarkers associated with congestion such as
Orthopnoeaa natriuretic peptides, measures of neurohormonal overactivity or
Paroxysmal nocturnal dyspnoeaa measures of exercise limitation such as maximal oxygen consump-
Reduced exercise tolerancea tion. None of these are commonly or reliably associated with the
Fatigue, tirednessb disease states of HF; for example, the LVEF can vary from low
Ankle swellinga
through normal to high and still be part of an HF syndrome; no
Inability to exercisea
Swelling of parts of the body other than ankles single haemodynamic measure is adequate to serve as a practical,
Bendopnoea non-invasive and reliable measurement; measurement of exercise
Less typical Nocturnal cough limitation with cardiopulmonary exercise testing with expired gas
Wheezing exchange is not practical or universally available; and to date, neu-
Bloated feelingc rohormone levels have not universally been considered reliable
Postprandial satietyc measures of the disease state. The closest have been the natriuretic
Loss of appetite
peptides, which are recommended in modern guidelines as both
Decline in cognitive function, confusion
(especially in the elderly)b
diagnostic tests of reasonable clinical usefulness with prognostic
Depression utility and as good tests to rule out HF as a cause of breathlessness
Dizziness, syncopeb in certain settings.4,38 Contemporary guidelines already state that
Signs of heart failure natriuretic peptides can be used as an initial diagnostic test, and that
More specific Elevated jugular venous pressurea patients with normal plasma natriuretic peptide concentrations are
Third heart sounda unlikely to have HF.4,38 A detailed diagnostic algorithm will require
Summation gallop with third and fourth heart
specific operational thresholds based on individual natriuretic pep-
sounds
Cardiomegaly, laterally displaced apical impulse
tides and assay systems, as well as detailing other clinical features
Hepatojugular reflux which can affect natriuretic peptide levels, but for common clinical
Cheyne–Stokes respiration in advanced heart purposes simple thresholds can be established that have sufficient
failureb operational accuracy to be incorporated usefully into a universal
Less specific Peripheral oedema (ankle, sacral, scrotal) definition of HF.
Pulmonary ralesa
Unintentional weight gain (>2 kg/week)
Weight loss (in advanced heart failure) with 6.3 Proposed new heart failure definition
muscle wasting and cachexia We propose a contemporary universal definition of HF (Figure 1)
Cardiac murmur that is simple but conceptually comprehensive, with near universal
Reduced air entry and dullness to percussion at
applicability, prognostic and therapeutic validity, and acceptable
lung bases suggestive of pleural effusion
Tachycardia, irregular pulse
sensitivity and specificity.
Tachypnoea
Hepatomegaly/ascites • UNIVERSAL DEFINITION OF HF
Cold extremitiesb HF is a clinical syndrome with current or prior
Oliguria
Narrow pulse pressure
• Symptoms and or signs (Table 6) caused by a
a Commonly used in clinical trials, registries, risk scoring and have been tested structural and/or functional cardiac abnormality (as
for sensitivity and specificity.
b Common in low perfusion, low cardiac output states.
determined by EF <50%, abnormal cardiac cham-
c Can be typical in the setting of right heart failure or biventricular failure. ber enlargement, E/E′ >15, moderate/severe ven-
tricular hypertrophy or moderate/severe valvular
obstructive or regurgitant lesion)
• and corroborated by at least one of the following:
6.2 Objective marker
In learning from other disease states that incorporated a core • Elevated natriuretic peptide levels (for values refer to
and frequently measured variables in their definition, such as Table 7)
acute MI, eGFR in CKD, glycated haemoglobin in diabetes, bone • Objective evidence of cardiogenic pulmonary or sys-
mineral density in osteoporosis or forced expiratory volume in temic congestion by diagnostic modalities such as imag-
the first second in COPD, making the diagnosis more accessi- ing (e.g. by chest X-ray or elevated filling pressures
ble to non-specialists and more reliable and consistent between by echocardiography) or haemodynamic measurement
observers, hospitals and health care systems, we propose the (e.g. right heart catheterization, pulmonary artery
incorporation of an objective measurement in addition to the catheter) at rest or with provocation (e.g. exercise).
symptoms in the HF definition.

........................................................................................................................................................................
Table 7 Natriuretic peptide levels supporting
definition of heart failure
Ambulatory Hospitalized/
decompensated
...........................................................................
BNP pg/ml ≥35 ≥ 100
NT-proBNP pg/ml ≥ 125 ≥ 300
BNP, Brain natriuretic peptide; NT, proBNP=N-terminal pro-b-type

natriuretic peptide.
Causes of elevated natriuretic peptide levels other than

primary diagnosis of heart failure
Cardiovascular Acute coronary syndrome, myocardial
Causes infarction
Pulmonary embolism
Myocarditis
Hypertrophic cardiomyopathy
Valvular heart disease
Congenital heart disease
Atrial or ventricular arrhythmias
Heart contusion, cardiac infiltration or
Figure 1 Universal definition of heart failure (HF).
malignancy
Cardioversion, ICD shock
Pericardial disease
Such a definition is comprehensive and practical enough to form
Invasive or surgical procedures involving the
the base which allows further subclassifications and which can
heart
encompass formal disease stages, both with universal applicability, Pulmonary hypertension, right ventricular
prognostic and therapeutic validity, and an acceptable sensitivity failure
and specificity. Please note that the definition of HF requires not Infiltrative cardiomyopathies
only symptoms or signs (Table 6) but also presence of either Noncardiovascular Advanced age
elevated natriuretic peptides or objective evidence of pulmonary causes Kidney disease
or systemic congestion by diagnostic modalities. For example, it Critical illnesses including Sepsis
would be important for peripheral oedema or ascites (Table 6) to syndrome, cytokine syndrome
be corroborated by presence of elevated right-sided cardiac filling Ischemic or hemorrhagic stroke
pressures or rales by presence of elevated left-sided cardiac filling Pulmonary disease (pneumonia, chronic
pressures; or elevated natriuretic peptides. It is also important obstructive pulmonary disease)
Liver disease
to note that elevated jugular venous pressure estimated by an
Severe anemia
experienced clinician could be accepted as an objective evidence.
Severe metabolic and hormone
Please also note that in certain patients, congestion and haemo- abnormalities (e.g. thyrotoxicosis, diabetic
dynamic abnormalities may become manifest with provocation such ketoacidosis, severe burns)
as exercise, especially in patients with HFpEF. This can support the Causes of lower natriuretic peptide levels
diagnosis of HF. It is also critical to note that in patients with low Obesity, or increased BMI
perfusion and hypovolaemic state, there may not be any evidence Pericardial diseasea
of congestion or elevated filling pressures, but rather decreased a Incertain patients with pericardial disease and effusion natriuretic peptides may
cardiac output accompanied with low or normal ventricular filling be lower and rise after pericardiocenthesis.
pressures94 (e.g. in the setting of over-diuresis in patients with HF).
Once the hypovolaemic state is corrected, patients with HF usually
have elevated filling pressures. We recognize that asymptomatic stages with patients at risk
In the definition above, we did not specify left or right HF. (former Stage A HF), or patients with structural heart disease or
Though left heart HF, and in advanced stages, biventricular HF are cardiomyopathies (former Stage B HF) would not be covered under
common, right HF can also be recognized as part of the above the above definition as having HF, which emphasizes symptoms and
definition when patients present with symptoms or signs (Table 6) signs of HF, but we conceptualize the HF syndrome as a continuum
caused by a cardiac abnormality and have elevated natriuretic pep- of disease with certain stages, such as pre-HF. This is similar to the
tide levels or objective evidence of cardiogenic pulmonary or approach with other disease states such as cancer, which defines
systemic congestion. Right HF primarily due to cardiac abnor- those at risk and pre-cancer. The stages preceding the symptomatic
malities such as arrhythmogenic right ventricular cardiomyopathy phases as those at risk and pre-HF will be discussed in the following
(ARVC) would be part of this definition. section.

14 Position Paper
We also realize certain patients with competing diagnoses such usually excluded from clinical trials in HF. These patients may
........................................................................................................................................................................
as CKD with marked volume overload, can present with symptoms present with asymptomatic left ventricular dysfunction or pre-HF
and signs of HF, have elevated natriuretic peptides, and may even or symptoms and signs of HF due to a cardiac abnormality and may
have evidence of congestion by imaging or elevated filling pressures. have elevated natriuretic peptides or evidence of congestion by
Although some of these patients may have concomitant HF, these imaging or haemodynamics. During the acute phase, these patients
patients have a primary abnormality that may require a specific are diagnosed as having an MI complicated by HF rather than with
treatment beyond that for HF. In the following section, we will HF alone. This does not mean acute MI should be replaced by HF
address such other syndromes. alone, but it does mean the setting and specific aetiology of HF
can be an important feature that determines specific therapeutic
approaches. This setting has also been subject to specific clinical
7 Other syndromes related trial evaluation.95–97 In addition to specific therapies for acute
to heart failure MI, these patients have indications for specific treatment for
asymptomatic left ventricular dysfunction (pre-HF or Stage B HF)
As noted above, the definition of HF comprises a combination or symptomatic HF complicating acute MI during the acute phase,
of symptoms and/or signs of HF caused by a structural and/or or as primary diagnoses in the chronic phase post-MI.
functional cardiac abnormality, and evidence of elevated filling
pressures by natriuretic peptides or by imaging/haemodynamic
assessment. Although many clinicians will initially envision patients 7.3 Cardiogenic shock
with left HF as embodying this definition, it is important to note Another important form of HF is cardiogenic shock, which is the
that there are other syndromes that may fulfil this definition of clinical state of organ hypoperfusion due to severe cardiac dys-
HF, addressed below. These aetiologies require specific treatment function. In cardiogenic shock, the symptoms and signs reflect-
and management strategies targeting the underlying or proximate ing HF include hypotension unresponsive to volume repletion,
cause, as well as treating the HF itself. altered mental status, cool extremities, and laboratory evidence
of end-organ dysfunction such as elevated lactate levels due to
hypoperfusion.65 Cardiogenic shock is an extreme form of HF
7.1 Right heart failure which requires some form of definitive therapy such as intravenous
The most common cause of right HF is left HF. However, right HF inotropes, vasopressors, or mechanical circulatory support. Car-
is characterized not only by signs and symptoms of right-sided HF diogenic shock is a type of HF, but due to its specific haemo-
but also by right atrial enlargement or right ventricular dysfunction. dynamic and clinical characterization requiring specific therapies
The presence of right HF in the setting of left HF is typically due such as vasoactive agents, circulatory support and/or revasculariza-
to post-capillary, WHO group 2 pulmonary hypertension and may tion depending on the aetiology, we believe keeping the descriptor
require modified treatment approaches and portends a poor prog- ‘cardiogenic shock’ will help to identify a patient cohort with spe-
nosis; therefore, recognition of biventricular HF is important.92 cific and urgent treatment needs. Cardiogenic shock may occur
Given the importance of these distinctions, the classification of as an acute de novo presentation (e.g. large acute MI, fulminant
types of ventricular failure in HF commonly includes three cate- myocarditis) or with progressive deterioration in a patient with
gories: left ventricular failure, right ventricular failure and combined chronic HF. Subacute cardiogenic shock may be in continuum of the
left and right ventricular failure usually termed as biventricular wet and cold advanced HF patient with low cardiac output state.
failure. We believe isolated right HF due to primary pulmonary Such patients may meet the criteria for cardiogenic shock espe-
hypertension aetiologies (WHO groups 1, 3, 4), though may have cially when they have evidence of end-organ dysfunction. A system
symptoms or signs which may mimic HF and may have elevated describing stages of cardiogenic shock has been proposed by SCAI
natriuretic peptide levels, would not be categorized under HF, as and other societies and characterizes the patients as Stage A ‘at
the signs and/or symptoms are not caused primarily by a structural risk’ for cardiogenic shock, stage B ‘beginning’ shock, stage C ‘clas-
and/or functional cardiac abnormality. On the other hand, right HF sic’ cardiogenic shock, stage D ‘deteriorating’, and E ‘extremis’.65
due to primary right ventricular conditions such as ARVC would Such classification is important to characterize the severity and
be categorized under HF. stage of shock, but it is also important to acknowledge the presence
of HF as the preceding cause of shock in such patients, and identify
advanced HF complicated with cardiogenic shock as the diagnosis.
7.2 Acute myocardial infarction/acute
coronary syndrome
7.4 Hypertensive emergency
Acute MI may be complicated by HF. Given its acuity, specific
pathophysiology and specific treatment strategies, we believe acute and hypertensive heart disease
MI would be the overarching definition for the episode in proximity Hypertensive emergencies encompass a spectrum of clinical
to acute MI. It is also possible that these patients may recover with presentations of uncontrolled blood pressure associated with
timely treatment strategies and not progress to chronic HF, but end-organ damage that can include acute left ventricular dysfunc-
also many may progress to chronic HF. In clinical trials, patients tion, pulmonary oedema, MI/ischemia and/or aortic dissection.
with acute MI or acute coronary syndrome within 6 weeks are All of these complications may result in or be complicated with

an acute presentation of HF. Hypertension increases HF risk by syndrome, hypertensive emergency as mentioned above, and also
........................................................................................................................................................................
two to threefold98 and accounts for almost half of the HF cases other cardiovascular primary diagnoses such as atrial fibrillation
in the US population as a population attributable risk.99 Thus, with rapid ventricular response, prolonged ventricular arrhythmias,
both acutely hypertensive emergency and chronically, hypertensive pulmonary embolus, pericardial diseases, and acute valvular dys-
heart disease can be complicated with HF. Treatment of hyperten- function. In these cardiovascular diagnoses, complication with HF
sion is of utmost importance in the prevention and treatment of is associated with worse prognosis and outcomes and underlines
HF, underlined as a Class I recommendation with strong level of the urgency of addressing the underlying problem as well as the HF.
evidence in guidelines.4,38 Other non-cardiovascular entities such as renal failure, liver fail-
ure, morbid obesity with peripheral oedema and chronic respira-
tory failure hypoventilation syndrome may present with symptoms
7.5 Valvular heart disease and signs that mimic HF. Due to volume overload and neurohor-
Aortic stenosis and mitral regurgitation can result in HF. Valvular monal compensatory mechanisms involved in some of these dis-
heart disease is acknowledged as a specific disease, as it results ease states, symptoms, signs and even haemodynamic characteriza-
in specific haemodynamic and ventricular alterations and requires tion and biomarker profile can overlap with HF, and these patients
specific treatment strategies targeting valvular abnormality. Most may indeed also have concomitant HF. In these cases, the proximate
HF clinical trials exclude significant valvular heart disease for these cause of the signs and symptoms of volume overload is a distinct
reasons. entity to which treatment is often primarily directed, in addition to
HF. These events are often of significant interest to clinical events
committees of clinical trials, where they may be considered as an
7.6 Congenital heart disease event ‘with HF’ rather than a primary HF event. Another important
Some types of congenital heart disease can result in HF. Incom- concept that supports the principality of these competing diag-
plete or palliative correction of a congenital lesion leading to a noses are that the symptoms and signs of HF may disappear once
chronic state of haemodynamic stress may result in subsequent the underlying primary cause is treated, for example symptoms and
HF, especially in complex congenital heart diseases such as tetral- signs that mimic HF may resolve with haemodialysis in a patient
ogy of Fallot, single ventricle defects and transposition of the great with end-stage CKD who may have missed a dialysis appointment.
arteries. Additional myocardial, coronary or conduction system Thus, it is important not to catalogue every presentation with
injury can occur due to complications of corrective surgery and shortness of breath and oedema that requires treatment with fluid
can lead to progressive contractile dysfunction in some patients. management strategies or diuretics as HF. It is, however, also impor-
The treatment should target the underlying anomaly and specific tant to not miss the complication with HF which requires timely
haemodynamic conditions. management of HF as well as the proximate cause. Many of these
factors can contribute to worsening outcomes in a complementary
fashion in patients with HF. For example, patients with HF associ-
7.7 High-output failure ated with CKD or diabetes are at much higher risk than those with-
out. Rather than ‘competing’, these diagnoses can become comple-
High-output HF presents with similar symptoms and signs of
mentary comorbidity risk factors to HF for worse outcomes.
systemic or pulmonary congestion, frequently associated with
rapid heart rate and signs of peripheral vasodilatation. Cardiac
dysfunction may be represented by pathologically elevated cardiac
output, echocardiographic signs of right ventricular dilatation
8 Proposed revised stages of the
or dysfunction, and elevated natriuretic peptide concentrations. heart failure continuum
High-output HF is a response to extracardiac causes including liver
To enhance clinician, patient and public understanding and adop-
disease, arteriovenous shunt, lung disease, thiamine deficiency,
tion, to avoid the stigma of HF before the symptoms are manifest,
anaemia, thyroid disease or myeloproliferative disorders. Treat-
to address the evolving role of biomarkers to define patients with
ment is generally directed to the underlying causes. Given the
structural and subclinical heart disease who are at higher risk of
unique nature of high-output failure, it is appropriate that it has a
developing HF and are potential candidates for targeted treatment
separate classification.
strategies for the prevention of HF, and to address some of the
gaps identified in Section 3.2 in the current approach to staging HF,
7.8 Other overlapping and competing we propose the following stages (Figure 2):
diagnoses with heart failure • At risk for HF (Stage A): patients at risk for HF but
Patients can experience clinical deterioration as specific events that without current or prior symptoms or signs of HF and
may not necessarily meet the universal definition of a diagnosis of without structural cardiac changes or elevated biomarkers
HF. Such occurrences consist of events of a primary disease process of heart disease. Patients with hypertension, atherosclerotic
that may be associated with signs and symptoms of HF as a result cardiovascular disease, diabetes, obesity, known exposure to
of the primary cause that is not HF at that encounter. These can cardiotoxins, positive family history of cardiomyopathy or
include cardiovascular causes such as acute MI or acute coronary genetic cardiomyopathy would be in this category. Not all of

16 Position Paper
Figure 2 Stages in the development and progression of heart failure (HF). CVD, cardiovascular disease; DM, diabetes mellitus; GDMT,
guideline-directed medical therapy; HTN, hypertension; LV, left ventricular; LVH, left ventricular hypertrophy; RV, right ventricular.
these patients will develop HF, but risk factor intervention may Although certain genetic markers may be associated with struc-
..................................................................................................
be warranted. tural cardiac changes and future HF, we did not specifically include
• Pre-HF (Stage B): patients without current or prior symp- genetic markers in the definition of pre-HF or Stage B HF as the
toms or signs of HF but evidence of one of the following: penetrance, expressivity, phenotypic characterization and progno-
sis with genetic markers vary significantly. Because the evidence for
• Structural heart disease: e.g. left ventricular hypertro-
precision for risk evolves with biomarkers, genetics, omics and/or
phy, cardiac chamber enlargement, ventricular wall motion
risk calculators, alternative approaches can be developed in the
abnormality, myocardial tissue abnormality (e.g. evidence
future to identify risk categories beyond traditional risk factors, and
of myocardial oedema, scar/fibrosis abnormality by cardiac
pre-HF beyond cardiac structure and biomarkers alone, and sup-
magnetic resonance T2 or late gadolinium enhancement
port expansion of indications for preventive treatment strategies
imaging), valvular heart disease.
for patients at risk or with pre-HF.
• Abnormal cardiac function: e.g. reduced left or right ven-
Please note that the cut-offs provided for natriuretic peptide
tricular systolic function, evidence of increased filling pres-
levels in Table 7 represent thresholds lower than inclusion crite-
sures (by invasive or non-invasive measures), abnormal
ria used in some clinical trials for symptomatic HF,27,28 but sim-
diastolic dysfunction.
ilar to those used in former guidelines.4 Thresholds proposed
• Elevated natriuretic peptide levels (for levels, refer to
in the table have higher sensitivity and may have lower speci-
Table 7) or elevated cardiac troponin levels (over 99th
ficity especially in older patients, or patients with atrial fibrilla-
percentile in a normal reference population) especially in
tion or CKD. Usually, higher cut-off values are recommended for
the setting of exposure to cardiotoxins.
the diagnosis of HF in these patients.100 For example, for ages
• HF (Stage C): patients with current or prior symptoms 50–75 years, NT-proBNP threshold value of 900 pg/mL; for ages
and/or signs of HF caused by a structural and/or functional >75 years, NT-proBNP value of 1800 pg/mL provide reliable sen-
cardiac abnormality. sitivity and specificity for the diagnosis of HF, compared with
• Advanced HF (Stage D): severe symptoms and/or signs of an NT-proBNP value of 450 pg/mL for ages <50 among patients
HF at rest, recurrent hospitalizations despite GDMT, refrac- requiring hospitalization.100 Similarly, in patients with atrial fibrilla-
tory or intolerant to GDMT, requiring advanced therapies tion, an increase by 20–30% have been suggested in natriuretic pep-
such as consideration for transplantation, mechanical circula- tide level thresholds for trial enrolment in HF,100 since atrial fibril-
tory support, or palliative care. lation is known to result in increased concentrations of natriuretic
peptides even in the absence of HF. Furthermore, it is important
• Abnormal cardiac function: e.g. reduced left or right ven- to note that natriuretic peptide cut-offs selected for population
tricular systolic function, can be characterized by reduced screening for pre-HF (Stage B HF) may be lower than 99% reference
EF, abnormal ventricular strain, or other non-invasive or limits76 and will need to be defined according to the population
invasive modalities. at risk.

8.1 NYHA classification from dilated cardiomyopathy will relapse following treatment with-
........................................................................................................................................................................
drawal suggesting remission rather than recovery84 (Figure 2). Full
The NYHA funtional classification is important to characterize
and persistent recovery is rare, and even in the setting of reversible
symptoms and functional capacity of patients with symptomatic
causes, patients may have recurrence of symptoms and or develop
(Stage C) HF or advanced HF (Stage D). The NYHA classification
left ventricular dysfunction in the future.
system categorizes HF on a scale of I to IV; Class I: no limitation of
physical activity, Class II: slight limitation of physical activity, Class III:
marked limitation of physical activity, and Class IV: symptoms occur 8.3 Acute versus decompensated heart
even at rest; discomfort with any physical activity. We believe it is failure
important to specify NYHA class at baseline after the initial diagno- In this document, we do not use the terms ‘acute new-onset HF’ or
sis, and after treatment through the continuum of care of a patient ‘acute decompensated HF’, which are the terminologies commonly
with HF. A patient with symptomatic HF (Stage C) may become used to describe patients requiring hospitalization or urgent care.
asymptomatic with treatment. Since that patient will still be cat- The indications for hospitalization and/or urgent care utilization
egorized as HF Stage C, NYHA class I can further specify his/her vary, and most patients who require hospitalization for HF may
absence of current symptoms. Worsening NYHA class is associ- have chronic progressively worsening HF, rather than an acute sin-
ated with worse prognosis and any symptomatic patient with HF gular event. We realize these patients may present with rapid onset
(NYHA class II–IV HF) should have further optimization of GDMT. or progressively escalating symptoms and/or signs of HF which are
associated with adverse outcomes, requiring urgent evaluation and
8.2 Recognition of clinical trajectory treatment. We have elected to characterize these patients as having
in heart failure ‘decompensated HF’ which may represent acutely decompensated
It is well-recognized that the natural history of HF encompasses patients due to an inciting event (e.g. atrial fibrillation with rapid
changes in the clinical risk of hospitalization and death over time, ventricular response) or chronically and progressively worsening
with risk increasing from ‘pre-HF’ to ‘new onset/de novo HF’, and patients with marked deterioration of HF signs and symptoms
further increasing with each episode of ‘worsening HF’ where there despite ongoing therapy requiring urgent intervention, hospitaliza-
is deterioration of HF signs and symptoms despite ongoing therapy, tion, or rapid escalation of therapies including advanced therapies.
requiring hospitalization or outpatient escalation of therapy.101 It We recognize that there are a variety of acute presentations of
is crucial to identify both the stage of the patient’s natural history, HF (e.g. myocarditis, peripartum, cardiotoxicity, stress cardiomy-
as well as recognize the patient’s clinical trajectory (improving vs. opathy, etc.) and other entities associated with acute presentations
stalled or persistent vs. worsening)102 for optimal treatment, risk of HF such as hypertensive emergency and acute MI, that will
mitigation strategies, and patient-centred discussions. Gaining per- require specialized treatment strategies targeting the underlying
spective of not only where the patient stands at the point in time, aetiology. These have been addressed by other investigators103–105
but in which direction the patient is headed, is a critical element and are beyond the scope of this document.
of determining whether to continue along the current therapeu-
tic course or to change direction. Thus, a patient with ‘worsen-
ing chronic HF’ following initial stabilization of ‘new onset/de novo
9 Proposed new classifications
HF’ would alert a physician of the immediate high risk for recur- of heart failure according
rent hospitalization or death, particularly in the period of close
proximity to the worsening HF event, and trigger escalation of
to ejection fraction
disease-modifying therapies rather than a focus on decongestion The strongest argument to use LVEF to categorize HF is that LVEF
with diuretics alone. Of note, we caution against a terminology of defines a group known to respond to life-prolonging therapy from
‘stable HF’, as patients are expected to improve with GDMT. These randomized controlled trials.3,4,25,30,31,38,52,53,83,95,97,106 While LVEF
patients should have further optimization of therapies despite per- also provides prognostic information, this reason alone does not
ceived stability or improvement, as there is evidence for signifi- justify using LVEF to define HF. Accordingly, LVEF categories were
cant improvement in outcomes with additional therapies in these created that define groups where treatment differs.
patients. Lack of improvement is a marker of worse prognosis and To be able to differentiate patients who benefit from GDMT
should be termed as ‘persistent’ rather than ‘stable’, and prompt according to clinical trial entry criteria of patients with HFrEF, cap-
clinicians to further optimize therapy. For those patients who have ture evolving recognition of the need to identify effective treatment
resolution of symptoms and signs of HF along with resolution of strategies in patients with HF associated with a mildly reduced or
previously present structural and functional heart disease after a mid-range LVEF, as well as preserved LVEF, and harmonize with
phase of symptomatic HF, we recommend ‘HF in remission’ or existing practice guidelines, we propose the following four clas-
NYHA class I HF status rather than ‘recovered HF’, which should sifications of EF (Figure 3):
be reserved for patients who have persistent resolution of HF
symptoms and signs, normalization of cardiac structure, function • HF with reduced EF (HFrEF): HF with LVEF ≤40%
and biomarker profile following resolution and treatment of a fully • HF with mildly reduced EF (HFmrEF): HF with LVEF
reversible cause, especially in view of the TRED-HF trial results 41–49%
which demonstrated that many patient deemed to have ‘recovered’ • HF with preserved EF (HFpEF): HF with LVEF ≥50%.

18 Position Paper
in patients with HFimpEF regardless of whether it has improved
........................................................................................................................................................................
to normal range (LVEF ≥50%), especially in view of the TRED-HF
trial results.84 We also recognize that patients with baseline LVEF
of 41-49% who have improved LVEF to ≥50% may be categorized
as HFimpEF.
10 Approaches to specific
aetiologies of heart failure
In addition to the recognition of the syndrome of HF and its
classifications, it is critical that every effort should be made to
diagnose and define the specific aetiology/aetiologies of HF. Under-
standing the underlying aetiological processes of HF can provide
important information in selecting the most appropriate therapy
Figure 3 New classification of heart failure (HF) according to
beyond standard approaches guided by EF phenotypic charac-
left ventricular ejection fraction (LVEF). EF, ejection fraction.
terization, especially when specific targeted treatment strategies
• HF with improved EF (HFimpEF): HF with a baseline LVEF are indicated,34 provided the diagnostic and/or specific treatment
≤40%, a ≥10 point increase from baseline LVEF, and a second strategies are cost-effective, with favourable benefit risk ratios and
measurement of LVEF >40%. are in line with patient goals. For example, a patient with cardiac
amyloidosis requires different treatment strategies than standard
We acknowledge the growing body of evidence that standard ther- HF therapies. The diagnosis of such a patient solely as HFpEF
apy for HFrEF may be effective and extended to select patients or HFrEF without further work-up to confirm the diagnosis of
with HFmrEF.52–55 It is however important to recognize the het- cardiac amyloidosis may deprive the patient potentially life-saving
erogeneity of this category, underlined by diverse findings from therapies for amyloidosis.
meta-analyses with neurohormonal antagonism, specifying benefit In clinical practice, the aetiology of HF has often been placed
in certain subgroups.15,55–57 into two categories: ischaemic and non-ischaemic cardiomyopa-
Evidently, LVEF is not a singular measurement by which left thy. However, further diagnostic work-up for aetiology should
ventricular function is assessed in isolation. Chamber volumes and be carried out beyond the first step of defining ischaemic or
other cardiac structural and functional parameters are important non-ischaemic aetiology, especially for dilated, infiltrative, hyper-
and other diagnostic modalities can be complementary. Though trophic and idiopathic cardiomyopathies.34 Many attempts have
the above classification is provided for targeting GDMT according been made for morpho-functional classifications of cardiomy-
to LVEF indications, other cardiac features are also important for opathies in the past.34,35,37,107 In this statement, we do not provide
phenotypic characterization, aetiology or prognosis. Development recommendations for classifications of specific cardiomyopathies,
of left ventricular dilatation in a patient with HFpEF or HFmrEF as we feel those remain outside the scope of this document.
may imply impending HFrEF. It is important to recognize that
cardiac structural and functional information in addition to LVEF
is important to guide management of the patient. 11 Perspective for the
Since GDMT can result in improvement in LVEF and reverse
remodelling in patients with HFrEF, the trajectory of improvement
non-cardiologist
and recovery of EF has been of interest to determine the types The majority of the HF care is provided by non-cardiologists,
(e.g. device, medical, advanced) and duration of treatment.80 In including general practitioners, internal medicine or family
cases where longitudinal surveillance of LVEF is available, clinicians medicine clinicians, hospitalists, emergency room providers,
should also consider the trajectory of LVEF, in addition to the and other specialists. We believe the universal definition will be
LVEF at the point in time, recognizing that a significant decrease useful to these clinicians for the timely diagnosis and management
in LVEF over time is a poor prognostic factor calling for considera- of patients with HF. Important points for the non-cardiologists are
tion of intensification of therapy and advanced management strate- as follows. it is critical to optimally identify and treat patients at
gies according to patient goals. Importantly, EF can decline after risk for HF to prevent or delay the development of HF; recognize
withdrawal of pharmacological treatment in many patients who that pre-HF patients, such as asymptomatic patients with elevated
had improved EF to normal range with GDMT.84 This implies that natriuretic peptide levels likely will require referral to a cardiol-
there is not full recovery in cardiac structure and function in most ogist for further diagnostic and treatment strategies to prevent
patients despite improvement in EF. Therefore, we recommend use progression of HF,76,108 that the diagnosis and timely treatment of
of the improved terminology rather than recovered EF. We believe HF should not be missed or delayed in patients with symptoms
‘improved EF’ deserves a separate classification and should not be and signs of HF, and elevated natriuretic peptide levels or patients
classified as HFmrEF or HFpEF even after improvement in LVEF to with evidence of systemic or pulmonary congestion/elevated filling
41–49% or ≥50% respectively, as discontinuing HFrEF therapy in pressures, and patients with advanced HF would be considered
this group leads to poor outcome.84 GDMT should be continued for referral to HF specialists according to their goals.

12 Appendix
Author relationships with industry and other entities
Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

Member Bureau Partnership/ research organizational, or witness
Principal other financial
benefit
..............................................................................................................................................................................................................................................
Magdy Abdelhamid Professor of Cardiovascular Medicine None None None None None None
Faculty of Medicine, Kasr Al Ainy,
Universal definition and classification of heart failure
Cairo University, Egypt

Stamatis Adampoulos Director, Heart Failure and Transplant None None None None None None

Units, Onassis Cardiac Surgery
Centre,
Athens, Greece
Nancy Albert Associate Chief Nursing Officer, Amgen, AstraZeneca, None None None None None
Research and Innovation- Nursing Boston Scientific,
Institute and Clinical Nurse Merck, Novartis
Specialist, Kaufman Center for
Heart Failure- Heart, Vascular and
Thoracic Institute, Cleveland Clinic,
Cleveland, OH, USA
Stefan Anker Department of Cardiology (CVK), Vifor, Bayer, Boehringer None None Vifor Int and None None
Charité - Universitätsmedizin Ingelheim, Novartis, Abbott
Berlin; Berlin Institute of Health Servier, Abbott,
Center for Regenerative Therapies Actimed, Cardiac
(BCRT); German Centre for Dimensions, Impulse
Cardiovascular Research (DZHK), Dynamics
Berlin, Germany
John Atherton Director of Cardiology, Royal Amgen, AstraZeneca, Amgen, AstraZeneca, None None None None
Brisbane and Women’s Hospital, Bayer, Boehringer Boehringer Ingelheim,
Faculty of Medicine, University of Ingelheim, Eli Lilly, Eli Lilly, Novartis
Queensland, Brisbane, QLD, Impedimed, Novartis,
Australia Otsuka, Vifor Pharma.
Michael Böhm Klinik für Innere Medizin III, None Abbott, Amgen, None None Deutsche None
Universitätsklinikum des AstraZeneca, Bayer, Forschungsgemein-
Saarlandes, Saarland University, Boehringer Ingelheim, schaft (DFG, SFB-TTR
Homburg/Saar, Germany Bristol-Myers Squibb, 219, S-01)
Medtronic, Novartis,
Servier, Vifor
19
20
Continued

benefit
..............................................................................................................................................................................................................................................
Biykem Bozkurt Baylor College of Medicine, Winters Abbott, Amgen, Baxter, None None None None None
Center for Heart Failure Research, Bristol-Myers Squibb,
Cardiovascular Research Institute Liva Nova,
and Michael E. DeBakey VA Medical RELYPSA/Vifor
Center Houston, TX, USA Pharma, Respicardia
Registry Steering
Committee,
Sanofi-Aventis,
scPharmaceuticals, Inc
Javed Butler University of Mississippi Medical Abbott, Adrenomed, Novartis, BI-Lilly, Astra None None None None
Center Amgen, Applied Zeneca, Janssen
Therapeutics, Array,
AstraZeneca, Bayer,
Boehringer Ingelheim,
CVRx, G3 Pharma,
Impulse Dynamics,
Innolife, Janssen,
LivaNova, Luitpold,
Medtronic, Merck,
Novartis,
NovoNordisk,
Relypsa, Sequana
Medical, V-Wave
Limited, and Vifor
Andrew Coats University of Warwick, UK and AstraZeneca, Bayer, None None None None None
Monash University, Australia Boehringer Ingelheim,
Menarini, Novartis,
Nutricia, Servier, Vifor,
Abbott, Actimed,
Arena, Cardiac
Dimensions, Corvia,
CVRx, Enopace, ESN
Cleer, Faraday, Gore,
Impulse Dynamics,
Respicardia
Mark Drazner Clinical Chief of Cardiology, None None None None None None
University of Texas Southwestern
Medical Center, Department of
Internal Medicine/Division of
Cardiology

Position Paper
Continued

benefit
..............................................................................................................................................................................................................................................
G. Michael Felker Duke University School of Medicine, Novartis, Amgen, BMS, None None None None None
Durham, NC, USA Cytokinetics,
Medtronic,
Cardionomic, Innolife,
Boehringer Ingelheim,
American Regent,
Abbott, AstraZeneca,
Eidos Therapeutics,
Reprieve, and Sequana,
and has served on
clinical endpoint
committees/data

safety monitoring
boards for Amgen,
Merck, Medtronic,
EBR Systems, V-Wave,
LivaNova, Siemens,
and Rocket Pharma
Gerasimos Filippatos National and Kapodistrian University Medtronic, Vifor, Servier, None None None European Union None
of Athens; Department of Novartis, Boehringer
Cardiology, Athens University Ingelheim, Bayer,
Hospital Attikon, Athens, Greece Amgen.
Mona Fiuzat Duke University None None None None None None
Gregg Fonarow Division of Cardiology, University of Abbott, Amgen, None None NIH None None
California, Los Angeles, CA, USA AstraZeneca, Bayer,
CHF Solutions,
Edwards, Janssen,
Medtronic, Merck,
Novartis
Juan Esteban Head of the Cardiology Service of the None None None None None None
Gomez-Mesa Fundación Valle del Lili. Cali,
Colombia; Facultad de Medicina of
the Universidad Icesi. Cali,
Colombia; Coordinator of the
Interamerican Council of Heart
Failure & Pulmonary Hypertension
of the Interamerican Society of
Cardiology.
Paul Heidenreich VA Palo Alto Health Care System, None None None None None None
Stanford University School of
Medicine
Teruhiko Imamura Second Department of Internal None None None None None None
Medicine, University of Toyama
21
22
Continued

benefit
..............................................................................................................................................................................................................................................
Ewa Jankowska Department of Heart Diseases, Bayer, Abbott, Vifor Bayer, Vifor Pharma, None None Unrestricted research None
Wroclaw Medical University, Pharma, Pfizer, Servier, Pfizer, Servier, grant for Wroclaw
Poland AstraZeneca, AstraZeneca, Medical University
and Centre for Heart Diseases, Boehringer Ingelheim, Boehringer Ingelheim, Co-PI role in the
University Hospital, Wroclaw, Berlin Chemie, Fresenius, Berlin AFFIRM-AHF trial
Poland Novartis, Cardiac Chemie, Gedeon sponsored by Vifor
Dimensions Richter, Novartis Pharma
James Januzzi Massachusetts General Hospital Roche Diagnostics, None None Novartis, Roche Endpoint committees: None
Siemens, Quidel, AbbVie, Amgen, Bayer,
Abbott, Novartis, CVRx, Intercept
Merck, Jana Care,
Imbria
Prateeti Khazanie The University of Colorado School of None None None None None None
Medicine, Division of Cardiology,
Department of Medicine, Aurora,
Colorado, US
Koichiro Kinugawa University of Toyama None None None None None None
Carolyn S.P. Lam National Heart Centre, Singapore & Abbott Diagnostics, None co-founder & Boston None None
Duke-National University of Amgen, Applied non-executive Scientific,
Singapore Therapeutics, director of EKo.ai Bayer, Roche
AstraZeneca, Bayer, Pte Ltd Diagnostics,
Biofourmis, AstraZeneca,
Boehringer Ingelheim, Medtronic,
Boston Scientific, and Vifor
Corvia Medical, Pharma
Cytokinetics, Darma
Inc., Eko.ai Pte Ltd,
JanaCare, Janssen
Research &
Development LLC,
Medtronic, Menarini
Group, Merck,
MyoKardia, Novartis,
Novo Nordisk,
Radcliffe Group Ltd.,
Roche Diagnostics,
Sanofi, Stealth
BioTherapeutics, The
Corpus, Vifor Pharma
and WebMD Global
LLC

Position Paper
Continued

benefit
..............................................................................................................................................................................................................................................
Yuya Matsue Department of Cardiovascular Otsuka Pharmaceutical Otsuka Pharma- Philips Respironics,
Biology and Medicine, Juntendo Co., Ltd. and Novartis ceutical Co. ResMed, and Fukuda
University Graduate School of Japan and Pfizer, Inc. Denshi
Medicine and Cardiovascular
Respiratory Sleep Medicine
Juntendo University, Graduate
School of Medicine
Marco Metra University of Brescia, Brescia, Italy Actelion, Amgen, Abbott Vascular, Amgen, none none None none
AstraZeneca, Bayer, Edwards Therapeutics,
Livanova, Servier, Vifor Servier
pharma, WindTree
Therapeutics, as

member of
Committees for
clinical trials or
advisory boards
Tomohito Ohtani Department of Cardiovascular None Bristol-Myers Squibb None None None None
Medicine, Osaka University Company,
Graduate School of Medicine Daiichi-Sankyo,
Nippon Boehringer
Ingelheim, Otsuka
Pharmaceutical
Massimo Francesco Cardiac Unit, Guglielmo da Saliceto AstraZeneca, Novartis, None None None None None
Piepoli Hospital, Piacenza and University of Servier, Vifor, TRX
Parma, Italy Italy
Piotr Ponikowski Department of Heart Diseases, Vifor Pharma, Amgen, Vifor Pharma, Amgen, None None Abbott Vascular – co-PI None
Wroclaw Medical University, Servier, Novartis, Servier, Novartis, of the RESHAPE-2 trial
Poland; Centre for Heart Diseases, Bayer, Pfizer, Cibiem, Pfizer, Impulse Vifor Pharma – PI of the
University Hospital, Wroclaw, Coridea, Impulse Dynamics, Renal AFFIRM-AHF trial
Poland Dynamics, Renal Guard Solutions, Vifor Pharma - research
Guard Solutions, Boehringer Ingelheim, grant for the
Boehringer Ingelheim, AstraZeneca, Berlin institution
AstraZeneca, Corvia, Chemie, Radcliffe Medical Research
BMS, V-wave Limited Group; Ono Agency – Poland:
Pharmeceutical grant for IIT
Giuseppe Rosano IRCCS San Raffaele, Rome, Italy None None None None None None
Yasushi Sakata Department of Cardiovascular None Otsuka Pharmaceutical, None None Astellas Pharma Inc. None
Medicine, Osaka University Daiichi-Sankyo, Otsuka Pharmaceutical,
Graduate School of Medicine Novartis Pharma K.K., Daiichi Sankyo,
Nippon Boehringer Medtronic Japan,
Ingelheim Nippon Boehringer
Ingelheim,
Bristol-Myers Squibb
K.K.
23
24
Continued

benefit
..............................................................................................................................................................................................................................................
Petar Seferovic Vice-president, European Society of Boehringer Ingelheim, Boehringer Ingelheim, None None None None
Cardiology Novartis, Vifor Novartis, Medtronic,
President, Heart Failure Association Pharma Abbott, Servier,
of the ESC (2018–2020) AstraZeneca,
Academician, Serbian Academy of Respicardia
Sciences and Arts
Professor of Cardiology, University of
Belgrade Faculty of Medicine and
Heart Failure Center, Belgrade
University Medical Center
President, Heart Failure Society of
Serbia
Randy C. Starling Employee Cleveland Clinic Novartis PARAGLIDE None None None None None
Heart, Vascular and Thoracic Institute steering committee.
Cleveland, OH, USA No honoraria.
Member FDA Circulatory System Cardiac Dimensions
Devices Panel Steering Committee
Carillon Trial
John R. Teerlink Section of Cardiology, San Francisco Abbott, Amgen, None None None None None
Veterans Affairs Medical Center AstraZeneca, Bayer,
and School of Medicine, University Boehringer Ingelheim,
of California San Francisco Bristol-Myers Squibb,
Cytokinetics, Daxor,
EBR Systems, Lilly,
LivaNova, Medtronic,
Merck, Novartis,
Relypsa, Servier,
Windtree
Therapeutics, ZS
Pharma
Hiroyuki Tsutsui Department of Cardiovascular Nippon Boehringer MSD K.K, Astellas None Actelion Phar- Astellas Pharma Inc. None
Medicine, Ingelheim, Bayer Pharma, Pfizer Japan, maceuticals Novartis Pharma K.K.,
Faculty of Medical Sciences, Yakuhin, Novartis Bristol-Myers Squibb, Japan, Japan Daiichi-Sankyo, Takeda
Kyushu University Pharma K.K., Ono Otsuka Tobacco Inc., Pharmaceutical,
Pharmaceutical Pharmaceutical, Mitsubishi Mitsubishi Tanabe
Daiichi-Sankyo, Tanabe Pharma Corporation,
Mitsubishi Tanabe Pharma Corp., Teijin Pharma, MSD
Pharma, Nippon Nippon K.K.
Boehringer Ingelheim, Boehringer
Takeda Ingelheim,
Pharmaceutical, Bayer Daiichi-Sankyo,
Yakuhin, Novartis IQVIA
Pharma K.K., Kowa Services
Pharmaceutical, Teijin Japan, Omron
Pharma Ltd. Healthcare

Position Paper
Continued

benefit
..............................................................................................................................................................................................................................................
Orly Vardeny Minneapolis Veterans Administration Sanofi-Pasteur, Novartis None None NIH, FDA, American Heart None
Health Care Center and University AstraZeneca, Association
of Minnesota Bayer
Kazuhiro Yamamoto Department of Cardiovascular None Otsuka Pharmaceutical, None None Abbott, Otsuka None
Medicine, and Endocrinology and Daiichi-Sankyo, Pharmaceutical Co.

Metabolism Novartis Ltd., Medtronic Japan
Faculty of Medicine Co., Ltd.,
Tottori University Daiichi-Sankyo,
Biotronik Japan Inc.,
Japan Lifeline,
Mitsubishi Tanabe
Pharma, Fukuda
Denshi, Takeda
Pharmaceutical,
Novartis, Ono
Pharmaceutical,
Boston Scientific
Clyde Yancy Northwestern University, Feinberg Spousal Employment, None None None Deputy Editor, JAMA None
School of Medicine Abbott, Inc. Network
Jian Zhang Fuwai Hospital, Chinese Academy of No No No No No No
Medical Science and Peking Union
Medical College
Shelley Zieroth Cardiac Sciences Program, University Abbott, Akcea, Amgen, AstraZeneca, None Novartis None None
of Manitoba AstraZeneca, Amgen, Boehringer Ingelheim,
Alnylam, Boehringer Eli-Lilly, Novartis,
Ingelheim, Eli-Lilly, Servier, Vifor
Merck, Novartis,
Otsuka, Pfizer, Servier,
Vifor
25
26 Position Paper
15. Bozkurt B, Ezekowitz J. Substance and substrate: LVEF and sex subgroup analy-
........................................................................................................................................................................
13 References ses of PARAGON-HF and PARADIGM-HF trials. Circulation 2020;141:362–366.
16. Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, Pedro Ferreira J,
1. Braunwald E. Heart failure. JACC Heart Fail 2013;1:1–20. Zannad F, Packer M, Fonarow GC, McMurray JJ, Solomon SD. Estimating
2. Wagner S, Cohn K. Heart failure. A proposed definition and classification. Arch lifetime benefits of comprehensive disease-modifying pharmacological therapies
Intern Med 1977;137:675–678. in patients with heart failure with reduced ejection fraction: a comparative
3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow analysis of three randomised controlled trials. Lancet 2020;396:121–128.
GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, 17. Bonow RO, Ganiats TG, Beam CT, Blake K, Casey DE Jr, Goodlin SJ,
Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Grady KL, Hundley RF, Jessup M, Lynn TE, Masoudi FA, Nilasena D, Piña IL,
Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Rockswold PD, Sadwin LB, Sikkema JD, Sincak CA, Spertus J, Torcson PJ, Tor-
Foundation/American Heart Association Task Force on Practice Guidelines. res E, Williams MV, Wong JB; American College of Cardiology Foundation;
2013 ACCF/AHA guideline for the management of heart failure: a report of American Heart Association Task Force on Performance Measures; Ameri-
the American College of Cardiology Foundation/American Heart Association can Medical Association-Physician Consortium for Performance Improvement.
Task Force on Practice Guidelines. Circulation 2013;128:e240–e327. ACCF/AHA/AMA-PCPI 2011 performance measures for adults with heart fail-
4. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, ure: a report of the American College of Cardiology Foundation/American
González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoy- Heart Association Task Force on Performance Measures and the American
annopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Rus- Medical Association-Physician Consortium for Performance Improvement. Cir-
chitzka F, Rutten FH, van der Meer P; ESC Scientific Document Group. 2016 culation 2012;125:2382–2401.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart fail- 18. Heidenreich PA, Fonarow GC, Breathett K, Jurgens CY, Pisani BA, Pozehl BJ,
ure: The Task Force for the diagnosis and treatment of acute and chronic heart Spertus JA, Taylor KG, Thibodeau JT, Yancy CW, Ziaeian B. 2020 ACC/AHA
failure of the European Society of Cardiology (ESC). Developed with the special Clinical performance and quality measures for adults with heart failure: a report
contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail of the American College of Cardiology/American Heart Association Task Force
2016;18:891–975. on Performance Measures. Circ Cardiovasc Qual Outcomes 2020;13:e000099.
5. Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, Kitakaze M, Kinugawa K, 19. Bozkurt B, Hershberger RE, Butler J, Isler ML, Grady KL, Kirklin JK, Heidenreich
Kihara Y, Goto Y, Komuro I, Saiki Y, Saito Y, Sakata Y, Sato N, Sawa Y, Shiose A, PA, Weintraub W. TEMPORARY NOTICE: 2021 ACC/AHA Key data elements
Shimizu W, Shimokawa H, Seino Y, Node K, Higo T, Hirayama A, Makaya M, and definitions for heart failure: a report of the American College of Cardiol-
Masuyama T, Murohara T, Momomura SI, Yano M, Yamazaki K, Yamamoto K, ogy/American Heart Association Task Force on Clinical Data Standards (Writing
Yoshikawa T, Yoshimura M, Akiyama M, Anzai T, Ishihara S, Inomata T, Committee to Develop Clinical Data Standards for Heart Failure). J Am Coll
Imamura T, Iwasaki YK, Ohtani T, Onishi K, Kasai T, Kato M, Kawai M, Cardiol 2020 Nov 26. https://doi.org/10.1016/j.jacc.2020.11.012 [Epub ahead of
Kinugasa Y, Kinugawa S, Kuratani T, Kobayashi S, Sakata Y, Tanaka A, Toda K, print].
Noda T, Nochioka K, Hatano M, Hidaka T, Fujino T, Makita S, Yamaguchi O, 20. Fiuzat M, Lowy N, Stockbridge N, Sbolli M, Latta F, Lindenfeld JA, Lewis EF,
Ikeda U, Kimura T, Kohsaka S, Kosuge M, Yamagishi M, Yamashina A; Japanese Abraham WT, Teerlink J, Walsh M, Heidenreich P, Bozkurt B, Starling RC,
Circulation Society and the Japanese Heart Failure Society Joint Working Group. Solomon S, Felker GM, Butler J, Yancy C, Stevenson LW, O’Connor C, Unger E,
JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic Temple R, McMurray J. Endpoints in heart failure drug development: history and
heart failure – digest version. Circ J 2019;83:2084–2184.
future. JACC Heart Fail 2020;8:429–440.
6. Tan LB, Williams SG, Tan DK, Cohen-Solal A. So many definitions of heart
21. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon
failure: are they all universally valid? A critical appraisal. Expert Rev Cardiovasc
SD, Marler JR, Teerlink JR, Farb A, Morrow DA, Targum SL, Sila CA, Hai MT, Jaff
Ther 2010;8:217–228.
MR, Joffe HV, Cutlip DE, Desai AS, Lewis EF, Gibson CM, Landray MJ, Lincoff
7. Harris P. The problem of defining heart failure. Cardiovasc Drugs Ther
AM, White CJ, Brooks SS, Rosenfield K, Domanski MJ, Lansky AJ, McMurray J,
1994;8:447–452.
Tcheng JE, Steinhubl SR, Burton P, Mauri L, O’Connor CM, Pfeffer MA, Hung
8. Denolin H, Kuhn H, Krayenbuehl HP, Loogen F, Reale A. The definition of heart
HM, Stockbridge NL, Chaitman BR, Temple RJ; Standardized Data Collection for
failure. Eur Heart J 1983;4:445–448.
Cardiovascular Trials Initiative (SCTI). 2017 Cardiovascular and stroke endpoint
9. Cleland JGF, Pellicori P, Clark AL. Prevention or procrastination for heart
definitions for clinical trials. Circulation 2018;137:961–972.
failure?: why we need a universal definition of heart failure. J Am Coll Cardiol
22. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White
2019;73:2398–2400.
HD; Executive Group on behalf of the Joint European Society of Cardiology
10. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP,
(ESC)/American College of Cardiology (ACC)/American Heart Association
Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV,
(AHA)/World Heart Federation (WHF) Task Force for the Universal Definition
Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland
of Myocardial Infarction. Fourth universal definition of myocardial infarction
DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS,
Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, (2018). Circulation 2018;138:e618–e651.
Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, 23. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of con-
Stokes A, Tirschwell DL, VanWagner L, Tsao CW; American Heart Association gestive heart failure: the Framingham study. N Engl J Med 1971;285:1441–1446.
Council on Epidemiology and Prevention Statistics Committee and Stroke 24. Adamo L, Nassif ME, Novak E, LaRue SJ, Mann DL. Prevalence of lactic acidaemia
Statistics Subcommittee. Heart disease and stroke statistics – 2020 update: a in patients with advanced heart failure and depressed cardiac output. Eur J Heart
report from the American Heart Association. Circulation 2020;141:e139–e596. Fail 2017;19:1027–1033.
11. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, 25. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL,
Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and
Nichol G, Orenstein D, Wilson PW, Woo YJ; American Heart Association Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure.
Advocacy Coordinating Committee; Stroke Council; Council on Cardiovas- N Engl J Med 2014;371:993–1004.
cular Radiology and Intervention; Council on Clinical Cardiology; Council on 26. Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam
Epidemiology and Prevention; Council on Arteriosclerosis; Thrombosis and Vas- CS, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J,
cular Biology; Council on Cardiopulmonary; Critical Care; Perioperative and O’Connor CM; VICTORIA Study Group. Vericiguat in patients with heart failure
Resuscitation; Council on Cardiovascular Nursing; Council on the Kidney in and reduced ejection fraction. N Engl J Med 2020;382:1883–1893.
Cardiovascular Disease; Council on Cardiovascular Surgery and Anesthesia, and 27. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez
Interdisciplinary Council on Quality of Care and Outcomes Research. Forecast- FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE,
ing the future of cardiovascular disease in the United States: a policy statement Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett
from the American Heart Association. Circulation 2011;123:933–944. JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E,
12. Pinney SP. Disparities in heart failure care: now is the time to focus on health Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL,
care delivery. J Am Coll Cardiol 2014;64:808–810. Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF
13. Bozkurt B. Reasons for lack of improvement in treatment with evidence-based Trial Committees and Investigators. Dapagliflozin in patients with heart failure
therapies in heart failure. J Am Coll Cardiol 2019;73:2384–2387. and reduced ejection fraction. N Engl J Med 2019;381:1995–2008.
14. Greene SJ, Fonarow GC, DeVore AD, Sharma PP, Vaduganathan M, Albert NM, 28. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J,
Duffy CI, Hill CL, McCague K, Patterson JH, Spertus JA, Thomas L, Williams Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C,
FB, Hernandez AF, Butler J. Titration of medical therapy for heart failure with Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Gian-
reduced ejection fraction. J Am Coll Cardiol 2019;73:2365–2383. netti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca

HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, 41. Sabbah HN. Silent disease progression in clinically stable heart failure. Eur J Heart
........................................................................................................................................................................
Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; Fail 2017;19:469–478.
EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with 42. Seid MA, Abdela OA, Zeleke EG. Adherence to self-care recommendations and
empagliflozin in heart failure. N Engl J Med 2020;383:1413–1424. associated factors among adult heart failure patients. From the patients’ point
29. Teerlink JR, Diaz R, Felker GM, McMurray JJ, Metra M, Solomon SD, Adams of view. PLoS One 2019;14:e0211768.
KF, Anand I, Arias-Mendoza A, Biering-Sørensen T, Böhm M, Bonderman D, 43. Gislason GH, Rasmussen JN, Abildstrom SZ, Schramm TK, Hansen ML,
Cleland JG, Corbalan R, Crespo-Leiro MG, Dahlström U, Echeverria LE, Buch P, Sørensen R, Folke F, Gadsbøll N, Rasmussen S, Køber L, Madsen M,
Fang JC, Filippatos G, Fonseca C, Goncalvesova E, Goudev AR, Howlett JG, Torp-Pedersen C. Persistent use of evidence-based pharmacotherapy in heart
Lanfear DE, Li J, Lund M, Macdonald P, Mareev V, Momomura SI, O’Meara E, failure is associated with improved outcomes. Circulation 2007;116:737–744.
Parkhomenko A, Ponikowski P, Ramires FJA, Serpytis P, Sliwa K, Spinar J, 44. Santos GC, Liljeroos M, Dwyer AA, Jaques C, Girard J, Strömberg A, Hullin R,
Suter TM, Tomcsanyi J, Vandekerckhove H, Vinereanu D, Voors AA, Yilmaz Schäfer-Keller P. Symptom perception in heart failure: a scoping review on
MB, Zannad F, Sharpsten L, Legg JC, Varin C, Honarpour N, Abbasi SA, Malik definition, factors and instruments. Eur J Cardiovasc Nurs 2020;19:100–117.
FI, Kurtz CE; GALACTIC-HF Investigators. Cardiac myosin activation with 45. Zakeri R, Cowie MR. Heart failure with preserved ejection fraction: controver-
omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105–116. sies, challenges and future directions. Heart 2018;104:377–384.
30. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, 46. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Gani-
Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, ats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA,
O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gre-
Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure goratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith CR Jr; American College
with preserved ejection fraction. N Engl J Med 2014;370:1383–1392. of Cardiology/American Heart Association Task Force on Practice Guidelines
31. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CS, Maggioni AP, Mar- (Committee to Revise the 1995 Guidelines for the Evaluation and Management
tinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veld- of Heart Failure); International Society for Heart and Lung Transplantation;
huisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov Heart Failure Society of America. ACC/AHA Guidelines for the evaluation and
SA, Comin-Colet J, Cleland J, Düngen HD, Goncalvesova E, Katova T, Kerr management of chronic heart failure in the adult: executive summary: a report
Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, of the American College of Cardiology/American Heart Association Task Force
Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Eval-
Angiotensin-neprilysin inhibition in heart failure with preserved ejection frac- uation and Management of Heart Failure): developed in collaboration with the
tion. N Engl J Med 2019;381:1609–1620. International Society for Heart and Lung Transplantation; endorsed by the Heart
32. Anker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K, Failure Society of America. Circulation 2001;104:2996–3007.
Zeller C, George J, Brueckmann M, Zannad F, Packer M; EMPEROR-Preserved 47. Stevenson LW, Pagani FD, Young JB, Jessup M, Miller L, Kormos RL, Naftel DC,
Trial Committees and Investigators. Evaluation of the effects of sodium-glucose Ulisney K, Desvigne-Nickens P, Kirklin JK. INTERMACS profiles of advanced
co-transporter 2 inhibition with empagliflozin on morbidity and mortality heart failure: the current picture. J Heart Lung Transplant 2009;28:535–541.
in patients with chronic heart failure and a preserved ejection fraction: 48. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL,
rationale for and design of the EMPEROR-Preserved trial. Eur J Heart Fail Baughman KL, Kasper EK. Underlying causes and long-term survival in patients
2019;21:1279–1287. with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077–1084.
33. Williams DM, Evans M. Dapagliflozin for heart failure with preserved ejection 49. Atherton JJ, Sindone A, De Pasquale CG, Driscoll A, MacDonald PS, Hopper I,
fraction: will the DELIVER study deliver? Diabetes Ther 2020;11:2207–2219. Kistler PM, Briffa T, Wong J, Abhayaratna W, Thomas L, Audehm R, Newton P,
34. Bozkurt B, Colvin M, Cook J, Cooper LT, Deswal A, Fonarow GC, Francis O’Loughlin J, Branagan M, Connell C. National Heart Foundation of Australia
GS, Lenihan D, Lewis EF, McNamara D, Pahl E, Vasan RS, Ramasubbu K, and Cardiac Society of Australia and New Zealand: guidelines for the prevention,
Rasmusson K, Towbin JA, Yancy C; American Heart Association Committee detection, and management of heart failure in Australia 2018. Heart Lung Circ
on Heart Failure and Transplantation of the Council on Clinical Cardiology; 2018;27:1123–1208.
Council on Cardiovascular Disease in the Young; Council on Cardiovascular 50. Abraham WT, Ptoska MA, Fiuzat M. Standardized definitions for heart failure:
and Stroke Nursing; Council on Epidemiology and Prevention; and Council on scientific expert panel from the Heart Failure Collaboratory and Academic
Quality of Care and Outcomes Research. Current diagnostic and treatment Research Consortium (HF-ARC). JACC Heart Fail 2020;8:961–972.
strategies for specific dilated cardiomyopathies: a scientific statement from the 51. Bohm M, Bewarder Y, Kindermann I. Ejection fraction in heart failure revis-
American Heart Association. Circulation 2016;134:e579–e646. ited – where does the evidence start? Eur Heart J 2020;41:2363–2365.
35. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss 52. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, O’Meara E,
AJ, Seidman CE, Young JB; American Heart Association; Council on Clinical Shah SJ, McKinlay S, Fleg JL, Sopko G, Pitt B, Pfeffer MA; TOPCAT Investigators.
Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Influence of ejection fraction on outcomes and efficacy of spironolactone
Outcomes Research and Functional Genomics and Translational Biology Inter- in patients with heart failure with preserved ejection fraction. Eur Heart J
disciplinary Working Groups; Council on Epidemiology and Prevention. Con- 2016;37:455–462.
temporary definitions and classification of the cardiomyopathies: an American 53. Solomon SD, Vaduganathan M, Claggett BL, Packer M, Zile M, Swedberg K,
Heart Association scientific statement from the Council on Clinical Cardiology, Rouleau JA, Pfeffer M, Desai A, Lund LH, Kober L, Anand I, Sweitzer N,
Heart Failure and Transplantation Committee; Quality of Care and Outcomes Linssen G, Merkely B, Luis Arango J, Vinereanu D, Chen CH, Senni M, Sibulo A,
Research and Functional Genomics and Translational Biology Interdisciplinary Boytsov S, Shi V, Rizkala A, Lefkowitz M, McMurray JJ. Sacubitril/valsartan across
Working Groups; and Council on Epidemiology and Prevention. Circulation the spectrum of ejection fraction in heart failure. Circulation 2020;141:352–361.
2006;113:1807–1816. 54. Lund LH, Claggett B, Liu J, Lam CS, Jhund PS, Rosano GM, Swedberg K,
36. Katz AM. Cardiomyopathy of overload. A major determinant of prognosis in Yusuf S, Granger CB, Pfeffer MA, McMurray JJ, Solomon SD. Heart failure with
congestive heart failure. N Engl J Med 1990;322:100–110. mid-range ejection fraction in CHARM: characteristics, outcomes and effect
37. Arbustini E, Narula N, Tavazzi L, Serio A, Grasso M, Favalli V, Bellazzi R, Tajik JA, of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail
Bonow RO, Fuster V, Narula J. The MOGE(S) classification of cardiomyopathy 2018;20:1230–1239.
for clinicians. J Am Coll Cardiol 2014;64:304–318. 55. Cleland JG, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJ, Man-
38. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey de Jr, Colvin MM, Drazner zano L, McMurray JJ, Ruschitzka F, van Veldhuisen DJ, von Lueder TG, Böhm M,
MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H, Hjalmarson
Masoudi FA, McBride P, Peterson PN, Stevenson LW, Westlake C. 2017 Å, Wikstrand J, Kotecha D; Beta-blockers in Heart Failure Collaborative Group.
ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the Beta-blockers for heart failure with reduced, mid-range, and preserved ejection
management of heart failure: a report of the American College of Cardiol- fraction: an individual patient-level analysis of double-blind randomized trials.
ogy/American Heart Association Task Force on Clinical Practice Guidelines and Eur Heart J 2018;39:26–35.
the Heart Failure Society of America. Circulation 2017;136:e137–e161. 56. Zheng SL, Chan FT, Nabeebaccus AA, Shah AM, McDonagh T, Okonko DO,
39. Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura M, Ayis S. Drug treatment effects on outcomes in heart failure with preserved ejec-
Feldman HI. KDOQI US commentary on the 2012 KDIGO clinical prac- tion fraction: a systematic review and meta-analysis. Heart 2018;104:407–415.
tice guideline for the evaluation and management of CKD. Am J Kidney Dis 57. Tsuji K, Sakata Y, Nochioka K, Miura M, Yamauchi T, Onose T, Abe R, Oikawa T,
2014;63:713–735. Kasahara S, Sato M, Shiroto T, Takahashi J, Miyata S, Shimokawa H; CHART-2
40. Blecker S, Katz SD, Horwitz LI, Kuperman G, Park H, Gold A, Sontag D. Investigators. Characterization of heart failure patients with mid-range left
Comparison of approaches for heart failure case identification from electronic ventricular ejection fraction – a report from the CHART-2 study. Eur J Heart
health record data. JAMA Cardiol 2016;1:1014–1020. Fail 2017;19:1258–1269.

28 Position Paper
58. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola 73. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W,
........................................................................................................................................................................
VP, Parissis J, Laroche C, Piepoli MF, Fonseca C, Mebazaa A, Lund L, Ambrosio Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group.
GA, Coats AJ, Ferrari R, Ruschitzka F, Maggioni AP, Filippatos G. Epidemiology Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med
and one-year outcomes in patients with chronic heart failure and preserved, 2017;377:644–657.
mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure 74. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG,
Long-Term Registry. Eur J Heart Fail 2017;19:1574–1585. Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding
59. van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JPH, Ruff CT, Gause-Nilsson IA, Fredriksson M, Johansson PA, Langkilde AM,
JG, Paulus WJ, Voors AA, Hillege HL. B-type natriuretic peptide and prognosis Sabatine MS; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular
in heart failure patients with preserved and reduced ejection fraction. J Am Coll outcomes in type 2 diabetes. N Engl J Med 2019;380:347–357.
Cardiol 2013;61:1498–1506. 75. Berg DD, Wiviott SD, Scirica BM, Gurmu Y, Mosenzon O, Murphy SA, Bhatt
60. Lam CSP, Gamble GD, Ling LH, Sim D, Leong KTG, Yeo PS, Ong HY, Jaufeer- DL, Leiter LA, McGuire D, Wilding JP, Johanson P, Johansson PA, Langkilde AM,
ally F, Ng TP, Cameron VA, Poppe K, Lund M, Devlin G, Troughton R, Richards Raz I, Braunwald E, Sabatine MS. Heart failure risk stratification and efficacy
AM, Doughty RN. Mortality associated with heart failure with preserved vs. of sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes
reduced ejection fraction in a prospective international multi-ethnic cohort mellitus. Circulation 2019;140:1569–1577.
study. Eur Heart J 2018;39:1770–1780. 76. Ledwidge M, Gallagher J, Conlon C, Tallon E, O’Connell E, Dawkins I, Wat-
61. Rastogi A, Novak E, Platts AE, Mann DL. Epidemiology, pathophysiology and son C, O’Hanlon R, Bermingham M, Patle A, Badabhagni MR, Murtagh G,
clinical outcomes for heart failure patients with a mid-range ejection fraction. Voon V, Tilson L, Barry M, McDonald L, Maurer B, McDonald K. Natriuretic
Eur J Heart Fail 2017;19:1597–1605. peptide-based screening and collaborative care for heart failure: the STOP-HF
62. Vedin O, Lam CS, Koh AS, Benson L, Teng THK, Tay WT, Braun OÖ, Savarese G, randomized trial. JAMA 2013;310:66–74.
Dahlström U, Lund LH. Significance of ischemic heart disease in patients 77. Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E,
with heart failure and preserved, midrange, and reduced ejection fraction: a Hoogeveen RC, Liu X, Astor BC, Mosley TH, Folsom AR, Heiss G, Coresh J,
nationwide cohort study. Circ Heart Fail 2017;10:e003875. Ballantyne CM. Cardiac troponin T measured by a highly sensitive assay predicts
63. Linde C, Curtis AB, Fonarow GC, Lee K, Little W, Tang A, Levya F, Momomura coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk
SI, Manrodt C, Bergemann T, Cowie MR. Cardiac resynchronization therapy in in Communities study. Circulation 2011;123:1367–1376.
chronic heart failure with moderately reduced left ventricular ejection fraction: 78. DeFilippi CR, de Lemos JA, Christenson RH, Gottdiener JS, Kop WJ, Zhan M,
lessons from the multicenter InSync randomized clinical evaluation MIRACLE Seliger SL. Association of serial measures of cardiac troponin T using a sensitive
EF study. Int J Cardiol 2016;202:349–355. assay with incident heart failure and cardiovascular mortality in older adults.
64. Pellikka PA, She L, Holly TA, Lin G, Varadarajan P, Pai RG, Bonow RO, Pohost JAMA 2010;304:2494–2502.
GM, Panza JA, Berman DS, Prior DL, Asch FM, Borges-Neto S, Grayburn P, 79. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, das Dores Cruz F,
Al-Khalidi HR, Miszalski-Jamka K, Desvigne-Nickens P, Lee KL, Velazquez EJ, Gonçalves Brandão SM, Rigaud VO, Higuchi-dos-Santos MH, Hajjar LA, Kalil
Oh JK. Variability in ejection fraction measured by echocardiography, gated Filho R, Hoff PM, Sahade M, Ferrari MS, de Paula Costa RL, Mano MS, Bitten-
single-photon emission computed tomography, and cardiac magnetic resonance court Viana Cruz CB, Abduch MC, Lofrano Alves MS, Guimaraes GV, Issa VS,
in patients with coronary artery disease and left ventricular dysfunction. JAMA Bittencourt MS, Bocchi EA. Carvedilol for prevention of chemotherapy-related
Netw Open 2018;1:e181456. cardiotoxicity: the CECCY trial. J Am Coll Cardiol 2018;71:2281–2290.
65. Baran DA, Grines CL, Bailey S, Burkhoff D, Hall SA, Henry TD, Hollenberg SM, 80. Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart failure with recovered left
Kapur NK, O’Neill W, Ornato JP, Stelling K, Thiele H, van Diepen S, Naidu SS. ventricular ejection fraction: JACC scientific expert panel. J Am Coll Cardiol
SCAI clinical expert consensus statement on the classification of cardiogenic 2020;76:719–734.
shock: this document was endorsed by the American College of Cardiology 81. Butler J, Braunwald E, Gheorghiade M. Recognizing worsening chronic heart
(ACC), the American Heart Association (AHA), the Society of Critical Care failure as an entity and an end point in clinical trials. JAMA 2014;312:789–790.
Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019. 82. Greene SJ, Mentz RJ, Felker GM. Outpatient worsening heart failure as a target
Catheter Cardiovasc Interv 2019;94:29–37. for therapy: a review. JAMA Cardiol 2018;3:252–259.
66. Ammar KA, Jacobsen SJ, Mahoney DW, Kors JA, Redfield MM, Burnett JC Jr, 83. Solomon SD, Claggett B, Packer M, Desai A, Zile MR, Swedberg K, Rouleau J,
Rodeheffer RJ. Prevalence and prognostic significance of heart failure stages: Shi V, Lefkowitz M, McMurray JJ. Efficacy of sacubitril/valsartan relative to a prior
application of the American College of Cardiology/American Heart Associ- decompensation: the PARADIGM-HF trial. JACC Heart Fail 2016;4:816–822.
ation heart failure staging criteria in the community. Circulation 2007;115: 84. Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R,
1563–1570. Rahneva T, Wage R, Smith G, Venneri L, Tayal U, Auger D, Midwinter W, Whif-
67. Wagner M, Tiffe T, Morbach C, Gelbrich G, Stork S, Heuschmann PU. Char- fin N, Rajani R, Dungu JN, Pantazis A, Cook SA, Ware JS, Baksi AJ, Pennell DJ,
acteristics and course of heart failure stages A-B and determinants of pro- Rosen SD, Cowie MR, Cleland JG, Prasad SK. Withdrawal of pharmacological
gression – design and rationale of the STAAB cohort study. Eur J Prev Cardiol treatment for heart failure in patients with recovered dilated cardiomyopathy
2017;24:468–479. (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019;393:61–73.
68. Morbach C, Gelbrich G, Tiffe T, Eichner FA, Christa M, Mattern R, Breunig M, 85. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Fleisher
Cejka V, Wagner M, Heuschmann PU, Störk S. Prevalence and determinants LA, Jneid H, Mack MJ, McLeod C, O’Gara PT, Rigolin VH, Sundt TM 3rd,
of the precursor stages of heart failure: results from the population-based Thompson A. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline
STAAB cohort study. Eur J Prev Cardiol 2020 May 6. https://doi.org/10.1177/ for the management of patients with valvular heart disease: a report of the
2047487320922636 [Epub ahead of print]. American College of Cardiology/American Heart Association Task Force on
69. Young K, Scott C, Rodeheffer RJ, Chen CH. Preclinical heart failure: evaluation Clinical Practice Guidelines. Circulation 2017;135:e1159–e1195.
of long-term outcomes in patients with stage A and stage B heart failure in the 86. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr,
general population. Circulation 2018;134[Suppl 1]:A15193 (abstr). Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT,
70. Correa de Sa DD, Hodge DO, Slusser JP, Redfield MM, Simari RD, Burnett JC, Shea JB, Tracy CM, Yancy CW. 2019 AHA/ACC/HRS focused update of the
Chen HH. Progression of preclinical diastolic dysfunction to the development 2014 AHA/ACC/HRS guideline for the management of patients with atrial
of symptoms. Heart 2010;96:528–532. fibrillation: a report of the American College of Cardiology/American Heart
71. Bozkurt B, Aguilar D, Deswal A, Dunbar SB, Francis GS, Horwich T, Jes- Association Task Force on Clinical Practice Guidelines and the Heart Rhythm
sup M, Kosiborod M, Pritchett AM, Ramasubbu K, Rosendorff C, Yancy C; Society in collaboration with the Society of Thoracic Surgeons. Circulation
American Heart Association Heart Failure and Transplantation Committee 2019;140:e125–e151.
of the Council on Clinical Cardiology; Council on Cardiovascular Surgery 87. Pocock SJ, Ariti CA, McMurray JJ, Maggioni A, Køber L, Squire IB, Swedberg K,
and Anesthesia; Council on Cardiovascular and Stroke Nursing; Council on Dobson J, Poppe KK, Whalley GA, Doughty RN; Meta-Analysis Global Group
Hypertension; and Council on Quality and Outcomes Research. Contribu- in Chronic Heart Failure. Predicting survival in heart failure: a risk score based
tory risk and management of comorbidities of hypertension, obesity, dia- on 39 372 patients from 30 studies. Eur Heart J 2013;34:1404–1413.
betes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart fail- 88. Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver
ure: a scientific statement from the American Heart Association. Circulation transplantation in adults: 2013 practice guideline by the American Association
2016;134:e535–e578. for the Study of Liver Diseases and the American Society of Transplantation.
72. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Hepatology 2014;59:1144–1165.
Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUT- 89. Kartoun U, Corey KE, Simon TG, Zheng H, Aggarwal R, Ng K, Shaw SY.
COME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in The MELD-Plus: a generalizable prediction risk score in cirrhosis. PLoS One
type 2 diabetes. N Engl J Med 2015;373:2117–2128. 2017;12:e0186301.

90. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, 102. Hollenberg SM, Warner Stevenson L, Ahmad T, Amin VJ, Bozkurt B, Butler J,
..............................................................................................
Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Davis LL, Drazner MH, Kirkpatrick JN, Peterson PN, Reed BN, Roy CL,
Global strategy for the diagnosis, management, and prevention of chronic Storrow AB. 2019 ACC expert consensus decision pathway on risk assessment,
obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care management, and clinical trajectory of patients hospitalized with heart failure:
Med 2013;187:347–365. a report of the American College of Cardiology Solution Set Oversight
91. Nohria A, Lewis E, Stevenson LW. Medical management of advanced heart Committee. J Am Coll Cardiol 2019;74:1966–2011.
failure. JAMA 2002;287:628–640. 103. Chioncel O, Mebazaa A, Harjola VP, Coats AJ, Piepoli MF, Crespo-Leiro MG,
92. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Laroche C, Seferovic PM, Anker SD, Ferrari R, Ruschitzka F, Lopez-Fernandez S,
Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Miani D, Filippatos G, Maggioni AP; ESC Heart Failure Long-Term Registry
Olschewski H, Robbins IM, Souza R. Updated clinical classification of Investigators. Clinical phenotypes and outcome of patients hospitalized for
pulmonary hypertension. J Am Coll Cardiol 2013;62(25 Suppl):D34–D41. acute heart failure: the ESC Heart Failure Long-Term Registry. Eur J Heart Fail
93. Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow 2017;19:1242–1254.
RO, Huang CC, Deo RC. Phenomapping for novel classification of heart failure 104. Gheorghiade M, Zannad F, Sopko G, Klein L, Piña IL, Konstam MA, Massie
with preserved ejection fraction. Circulation 2015;131:269–279. BM, Roland E, Targum S, Collins SP, Filippatos G, Tavazzi L; International
94. Stevenson LW. Design of therapy for advanced heart failure. Eur J Heart Fail Working Group on Acute Heart Failure Syndromes. Acute heart failure syn-
2005;7:323–331. dromes: current state and framework for future research. Circulation 2005;112:
95. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, 3958–3968.
Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction 105. Mebazaa A, Yilmaz MB, Levy P, Ponikowski P, Peacock WF, Laribi S, Ristic AD,
Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective Lambrinou E, Masip J, Riley JP, McDonagh T, Mueller C, DeFilippi C, Harjola
aldosterone blocker, in patients with left ventricular dysfunction after myocardial VP, Thiele H, Piepoli MF, Metra M, Maggioni A, McMurray J, Dickstein K,
infarction. N Engl J Med 2003;348:1309–1321. Damman K, Seferovic PM, Ruschitzka F, Leite-Moreira AF, Bellou A, Anker SD,
96. Effect of ramipril on mortality and morbidity of survivors of acute myocardial Filippatos G. Recommendations on pre-hospital & early hospital management of
infarction with clinical evidence of heart failure. The Acute Infarction Ramipril acute heart failure: a consensus paper from the Heart Failure Association of the
Efficacy (AIRE) Study Investigators. Lancet 1993;342:821–828. European Society of Cardiology, the European Society of Emergency Medicine
97. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, and the Society of Academic Emergency Medicine. Eur J Heart Fail 2015;17:
Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, 544–558.
Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM. Effect of captopril 106. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL,
on mortality and morbidity in patients with left ventricular dysfunction after Olofsson B, Östergren J, Yusuf S; CHARM Investigators and Committees. Effects
myocardial infarction. Results of the Survival and Ventricular Enlargement trial. of candesartan on mortality and morbidity in patients with chronic heart failure:
The SAVE Investigators. N Engl J Med 1992;327:669–677. the CHARM-Overall programme. Lancet 2003;362:759–766.
98. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from 107. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O,
hypertension to congestive heart failure. JAMA 1996;275:1557–1562. Kühl U, Maisch B, McKenna W, Monserrat L, Pankuweit S, Rapezzi C, Sefer-
99. Cheng S, Claggett B, Correia AW, Shah AM, Gupta DK, Skali H, Ni H, Rosamond ovic P, Tavazzi L, Keren A. Classification of the cardiomyopathies: a position
WD, Heiss G, Folsom AR, Coresh J, Solomon SD. Temporal trends in the statement from the European Society of Cardiology Working Group on Myocar-
population attributable risk for cardiovascular disease: the Atherosclerosis Risk dial and Pericardial Diseases. Eur Heart J 2008;29:270–276.
in Communities study. Circulation 2014;130:820–828. 108. Mueller C, McDonald K, de Boer RA, Maisel A, Cleland JG, Kozhuharov N,
100. Ibrahim NE, Burnett JC Jr, Butler J, Camacho A, Felker GM, Fiuzat M, Coats AJ, Metra M, Mebazaa A, Ruschitzka F, Lainscak M, Filippatos G,
O’Connor C, Solomon SD, Vaduganathan M, Zile MR, Januzzi JL Jr. Natriuretic Seferovic PM, Meijers WC, Bayes-Genis A, Mueller T, Richards M, Januzzi JL
peptides as inclusion criteria in clinical trials: a JACC: heart failure position Jr; Heart Failure Association of the European Society of Cardiology. Heart
paper. JACC Heart Fail 2020;8:347–358. Failure Association of the European Society of Cardiology practical guidance
101. Greene SJ, Fonarow GC, Butler J. Risk profiles in heart failure: baseline, residual, on the use of natriuretic peptide concentrations. Eur J Heart Fail 2019;21:
worsening, and advanced heart failure risk. Circ Heart Fail 2020;13:e007132. 715–731.

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European Journal of Heart Failure (2021) POSITION PAPER

Universal definition and classification of heart

© 2021 European Society of Cardiology and Elsevier, Inc.

Table of contents 7.5 Valvular heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

failure as a definition of HF in the contemporary setting.

2.2.1 Combined definition with haemodynamic

© 2021 European Society of Cardiology and Elsevier, Inc.

Trial Age, NYHA class LVEF (%) Natriuretic peptides HF hospitalization

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

recognized or postulated for HFmrEF. It is likely that patients

© 2021 European Society of Cardiology and Elsevier, Inc.

Society HF classification according to LVEF LVEF Additional requirements

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

In HF, possible candidates for such a measurement might theo-

© 2021 European Society of Cardiology and Elsevier, Inc.

BNP, Brain natriuretic peptide; NT, proBNP=N-terminal pro-b-type

Causes of elevated natriuretic peptide levels other than

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

in patients with HFimpEF regardless of whether it has improved

© 2021 European Society of Cardiology and Elsevier, Inc.

Author relationships with industry and other entities

Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

Cairo University, Egypt

© 2021 European Society of Cardiology and Elsevier, Inc.

Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

© 2021 European Society of Cardiology and Elsevier, Inc.

Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

© 2021 European Society of Cardiology and Elsevier, Inc.

Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

© 2021 European Society of Cardiology and Elsevier, Inc.

Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

© 2021 European Society of Cardiology and Elsevier, Inc.

Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

© 2021 European Society of Cardiology and Elsevier, Inc.

Writing Committee Employment/affiliation Consultant Speakers Ownership/ Personal Institutional, Expert

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

© 2021 European Society of Cardiology and Elsevier, Inc.

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