Advertisement

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

      Summary of Key Points

      In this document, we propose a universal definition of heart failure (HF) as the following: HF is 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 propose revised stages of HF as follows. At-risk for HF (Stage A), for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-HF (stage B), for patients without current or prior symptoms or signs of HF, but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C), for 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 and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT), refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). The classification includes HF with reduced EF (HFrEF): HF with an LVEF of ≤40%; HF with mildly reduced EF (HFmrEF): HF with an LVEF of 41% to 49%; HF with preserved EF (HFpEF): HF with an LVEF of ≥50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%.

      Key Words

      Abbreviations:

      ACC (American College of Cardiology), ACEI (angiotensin converting enzyme inhibitor), AHA (American Heart Association), ARB (angiotensin receptor blocker), ARNI (Angiotensin receptor-neprilysin inhibitor), BNP (brain natriuretic peptide), CKD (chronic kidney disease), CV (Cardiovascular), EF (ejection fraction), ESC (European Society of Cardiology), GDMT (guideline-directed management and therapy), HF (heart failure), HFA (Heart Failure Association of European Society of Cardiology), HFmrEF (heart failure with mildly reduced ejection fraction), HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejection fraction), JHFS (Japanese Heart Failure Association), LV (left ventricular), LVEF (left ventricular ejection fraction), LVF (left ventricular failure), MRA (mineralocorticoid receptor antagonist), NT-proBNP (N-terminal prohormone of brain natriuretic peptide), NYHA (New York Heart Association), RHF (right heart failure), RV (right ventricular), RVF (right ventricular failure), SGLT2i (sodium-glucose cotransporter-2 inhibitors)

      Preamble

      Currently available definitions of heart failure (HF) are ambiguous and lack standardization.
      • Braunwald E.
      Heart failure.
      • Wagner S
      • Cohn K.
      Heart failure. A proposed definition and classification.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      • Tan LB
      • Williams SG
      • Tan DK
      • Cohen-Solal A
      So many definitions of heart failure: are they all universally valid? A critical appraisal.
      • Harris P.
      The problem of defining heart failure.
      • Denolin H
      • Kuhn H
      • Krayenbuehl HP
      • Loogen F
      • Reale A.
      The definition of heart failure.
      Some definitions focus on the diagnostic features of the clinical syndrome,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      whereas other definitions approach the definition as a characterization of the hemodynamic and physiological aspects.
      • Wagner S
      • Cohn K.
      Heart failure. A proposed definition and classification.
      ,
      • Denolin H
      • Kuhn H
      • Krayenbuehl HP
      • Loogen F
      • Reale A.
      The definition of heart failure.
      There is significant variation in different platforms
      • Braunwald E.
      Heart failure.
      • Wagner S
      • Cohn K.
      Heart failure. A proposed definition and classification.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      and a growing need for standardization of the definition of HF.
      • Tan LB
      • Williams SG
      • Tan DK
      • Cohen-Solal A
      So many definitions of heart failure: are they all universally valid? A critical appraisal.
      ,
      • Cleland JGF
      • Pellicori P
      • Clark AL.
      Prevention or procrastination for heart failure?: why we need a universal definition of heart failure.
      A universal definition of HF is of critical importance to clinicians, investigators, administrators, health care services, institutions, legislators, and payers alike. The increasing prevalence and burden of HF,
      • Virani SS
      • Alonso A
      • Benjamin EJ
      • Bittencourt MS
      • Callaway C
      • Carson AP
      • et al.
      Heart disease and stroke statistics-2020 update: a report from the American Heart Association.
      ,
      • Heidenreich PA
      • Trogdon JG
      • Khavjou OA
      • Butler J
      • Dracup K
      • Ezekowitz MD
      • et al.
      Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association.
      an increased recognition of growing health care disparities,
      • Pinney SP.
      Disparities in heart failure care: now is the time to focus on health care delivery.
      and deficiencies in the optimal treatment in HF with guideline-directed management and therapy (GDMT) strategies
      • Bozkurt B.
      Reasons for lack of improvement in treatment with evidence-based therapies in heart failure.
      ,
      • Greene SJ
      • Fonarow GC
      • DeVore AD
      • Sharma PP
      • Vadugahathan M
      • Albert NM
      • et al.
      Titration of medical therapy for heart failure with reduced ejection fraction.
      all underline the necessity for a universally recognizable definition of HF. Evolving evidence for new effective preventive and treatment strategies in HF will require clarity in the different stages and/or ejection fraction (EF) subgroups of HF,
      • Bozkurt B
      • Ezekowitz J.
      Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
      ,
      • Vaduganathan M
      • Claggett BL
      • Jhund PS
      • Cunningham JW
      • Ferreira JP
      • Zannad F
      • et al.
      Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.
      along with an increased emphasis on performance measures with a need for accuracy in patient diagnoses and treatment indications,
      • Bonow RO
      • Ganiats TG
      • Beam CT
      • et al.
      ACCF/AHA/AMA-PCPI 2011 performance measures for adults with heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures and the American Medical Association-Physician Consortium for Performance Improvement.
      • Heidenreich PA
      • Fonarow GC
      • Breathett K
      • Jurgens CY
      • Pisani BA
      • Pozehl BJ
      • et al.
      2020 ACC/AHA clinical performance and quality measures for adults with heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures.
      • Bozkurt B
      • Hershberger RE
      • Butler J
      • Isler ML
      • Grady KL
      • Kirklin JK
      • et al.
      TEMPORARY NOTICE: 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Heart Failure) [e-pub ahead of print].
      a need for improved communication and understanding of the definition of HF with patients and for shared decision-making and transitions of care between different levels of care and health care professionals,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      and an increased recognition and emphasis of standard diagnoses and end points in the settings of research, and clinical trials and registries.
      • Fiuzat M
      • Lowy N
      • Stockbridge N
      • Sbolli M
      • Latta F
      • Lindenfeld J
      • et al.
      Endpoints in heart failure drug development: history and future.
      ,
      • Hicks KA
      • Mahaffey KW
      • Mehran R
      • Nissen SE
      • Wiviott SD
      • Dunn B
      • et al.
      2017 cardiovascular and stroke endpoint definitions for clinical trials.
      The objectives of this document are to provide a universal definition of HF that is clinically relevant, simple but conceptually comprehensive, with the ability to subclassify and to encompass stages within; with universal applicability globally, and with prognostic and therapeutic validity and acceptable sensitivity and specificity. We envision the proposed universal definition and classifications to be used in a standardized fashion across scientific societies and guidelines, used by clinicians, and used in research studies.

      Methodology

      Writing Committee Composition

      The Heart Failure Society of America (HFSA), Heart Failure Association of the European Society of Cardiology (HFA/ESC), and the Japanese Heart Failure Society (JHFS) selected the members of the writing committee. The writing committee consisted of 38 individuals with domain expertise in HF, cardiomyopathy, and cardiovascular disease.

      Consensus Development

      On August 20, 2020, in response to the necessity for consensus for definition of HF, the HFSA, HFA, and the JHFS convened a virtual consensus conference to develop a universal definition of HF with participation 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 correspondence. The review work was distributed among subgroups of the writing committee based on interest and expertise. The proceedings of the workgroups were then assembled, resulting in the proposed universal definition. All members reviewed and approved the final vocabulary.

      Peer Review and Approval

      The 2020 Universal Definition of HF was reviewed by official reviewers nominated by the HFSA, HFA, and JHFS. The writing committee anticipates that the proposed definition and classification will require review and updating in the same manner as other published universal definitions.
      • Thygesen K
      • Alpert JS
      • Jaffe AS
      • Chaitman BR
      • Bax JJ
      • Morrow DA
      • et al.
      Fourth universal definition of myocardial infarction (2018).
      The writing committee, therefore, plans to review the universal definition on a periodic basis, starting with the anniversary of publication of the definition, to ascertain whether modifications should be considered.

      Current Definitions of HF

      HF is a clinical syndrome with different etiologies and pathophysiology rather than a specific disease. This makes defining HF more complex than diseases that have a pathologic gold standard for diagnosis, such as cancer. Not surprisingly, definitions of HF vary widely in the medical literature, in contemporary guidelines, and in medical practice. Differing definitions have been developed for different purposes, ranging from “textbook” definitions of HF, which are typically focused on pathophysiology, to case definitions such as the Framingham criteria,
      • McKee PA
      • Castelli WP
      • McNamara PM
      • Kannel WB.
      The natural history of congestive heart failure: the Framingham study.
      which are primarily used in research. The traditional textbook definition of HF, which is usually defined as a “condition in which the heart cannot pump enough blood to meet the body's needs”
      • Braunwald E.
      Heart failure.
      or an “abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues,”
      • Wagner S
      • Cohn K.
      Heart failure. A proposed definition and classification.
      is a complex and impractical definition that often cannot be verified in practice and apply to only a certain subgroup of patients with HF. As such, in a study of patients with advanced HF awaiting left ventricular assist device implantation, cardiac output was shown to be insufficient to meet the metabolic needs of the body only in 25% of these patients with advanced HF at rest, demonstrating the inadequacy of such definitions in the majority of the HF population.
      • Adamo L
      • Nassif ME
      • Novak E
      • LaRue SJ
      • Mann DL.
      Prevalence of lactic acidaemia in patients with advanced heart failure and depressed cardiac output.
      In clinical care, other diagnostic criteria such as measurement of plasma natriuretic peptides play an important role in clarifying the diagnosis of HF.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      A summary of contemporary definitions of HF from the American College of Cardiology/American Heart Association (ACC/AHA), the HFA/ESC, and the JHFS guidelines is provided in Table 1. Although the definitions of HF used in current practice guidelines from the ACC/AHA,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      HFA/ESC,
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      and JHFS
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      differ in some details, they share the following common elements: they identify HF as a clinical syndrome, that is, a recognizable cluster of signs and symptoms; they require the presence of at least some of the cardinal symptoms of HF including dyspnea, fluid retention/edema, fatigue, activity intolerance, and exercise limitation; and they require some form of structural or functional heart disease. Some also specify a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      Overall, the existing definitions of HF comprise 3 elements: evidence of structural heart disease, a history of symptoms that are commonly reported in HF, and objective signs commonly seen in HF.
      Table 1HF Definitions in Contemporary Clinical Practice Guidelines.
      ACCF/AHA (2013)
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary and/or splanchnic congestion and/or peripheral edema. Some patients have exercise intolerance but little evidence of fluid retention, whereas others complain primarily of edema, dyspnea, or fatigue.
      ESC (2016)
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      HF is a clinical syndrome characterized by typical symptoms (eg, breathlessness, ankle swelling and fatigue) that may be accompanied by signs (eg, elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.
      JCS/JHFS (2017)
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      HF is a clinical syndrome consisting of dyspnea, malaise, swelling and/or decreased exercise capacity due to the loss of compensation for cardiac pumping function due to structural and/or functional abnormalities of the heart.

      Definitions of HF Used in Current Clinical Trials and Registries

      The definitions and inclusion criteria used in clinical trials and registries in HF differ from those in clinical practice, guidelines and textbooks. Most trials in HF with reduced EF (HFrEF) (Table 2), and in HF with preserved EF (HFpEF) (Table 3) reflect inclusion criteria that usually include a LVEF threshold, an established HF diagnosis with specific New York Heart Association (NYHA) functional class categories, certain levels of natriuretic peptides and may sometimes include a requirement of past HF hospitalizations, depending on the severity of HF targeted for the trial. HFpEF studies also may include corroborative evidence by imaging, reflecting structural and/or functional changes. Nonetheless, a number of gaps remain in standardizing the criteria for clinical trials. These gaps include the sensitivity and specificity of the diagnostic criteria for HF; establishing standardized natriuretic peptide criteria; the complexity of additional requirements to ascertain the diagnosis of HF; challenges with HFpEF, including multiple comorbidities that are often excluded in clinical trials; how to handle patients with EF recovery or changes in clinical trajectory; competing diagnoses that may mimic findings of HF; and the generalizability of the trial criteria to the ultimately intended treatment population. It is also important to distinguish between clinical trial inclusion criteria that aim to select target populations, from clinical trial end point definitions that facilitate measurement of outcomes secondary to the disease process. For example, natriuretic peptides, which are commonly used in entry criteria in HF trials, are not commonly required for clinical end point definitions.
      • Hicks KA
      • Mahaffey KW
      • Mehran R
      • Nissen SE
      • Wiviott SD
      • Dunn B
      • et al.
      2017 cardiovascular and stroke endpoint definitions for clinical trials.
      Table 2Summary of HF Inclusion Criteria for Recent Clinical Trials: HFrEF
      Trial NameAge, NYHA Functional ClassLVEF (%)Natriuretic PeptidesHF Hospitalization or other
      PARADIGM-HF
      • McMurray JJ
      • Packer M
      • Desai AS
      • Gong J
      • Lefkowitz MP
      • Rizkala AR
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      Age ≥18 years

      NYHA II-IV

      LVEF <35%If previous hospitalization, BNP ≥100 pg/mL or NTproBNP ≥400 pg/mL

      If no previous hospitalization, BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL
      Within previous 12 months
      VICTORIA
      • Armstrong PW
      • Pieske B
      • Anstrom KJ
      • Ezekowitz J
      • Hernandez AF
      • Butler J
      • et al.
      Vericiguat in patients with heart failure and reduced ejection fraction.
      Age ≥18 years

      NYHA functional class II-IV

      LVEF <45%Within past 30 days:

      NSR, BNP >300 pg/mL, NT-proBNP >1,000 pg/mL

      AF BNP >500 pg/mL; NT-proBNP >1,600 pg/mL
      Within 6 months or outpatient IV diuretics for HF within 3 months
      DAPA-HF
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      Age ≥18 years

      NYHA functional class II-IV
      LVEF ≤40%If HF hospitalization within 12 months:

      NT-proBNP ≥400 pg/mL

      If no hospitalization, NT-proBNP ≥600 pg/mL

      AF NT-proBNP ≥900 pg/mL
      Diagnosis of HF for ≥2 months
      EMPEROR-Reduced
      • Packer M
      • Anker SD
      • Butler J
      • Filippatos G
      • Pocock SJ
      • Carson P
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      Age ≥18 years

      NYHA functional class II-IV
      LVEF ≤40%LVEF ≤30%, NT-proBNP ≥ 600pg/mL (NSR) or ≥ 1200pg/mL in AF

      LVEF 31%–35%, NT-proBNP ≥1000 pg/mL (NSR) or ≥2000 pg/mL in AF

      LVEF 36%–40%, NT-proBNP ≥2500 pg/mL (NSR) or ≥5000 pg/mL in AF

      LVEF <40% but HF hospitalization within 12 months, NT-proBNP ≥600 pg/mL (NSR) or ≥1200 pg/mL in AF
      NYHA functional class II-IV ≥3 months
      GALACTIC-HF
      • Teerlink JR
      • Diaz R
      • Felker GM
      • McMurray JJV
      • Metra M
      • Solomon SD
      • et al.
      Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.
      Age ≥18 and <85 years, NYHA functional class II-IVLVEF ≤35%NT-proBNP ≥400pg/mL (NSR) or ≥1200 pg /mL in AF; or BNP ≥125 pg/mL (NSR) ≥375 pg/mLCurrently hospitalized for HF (inpatients) or had either made an urgent visit to the emergency department or been hospitalized for HF within 12 months (outpatients) =
      ACEI, angiotensin-converting enzyme inhibitor; AF, Atrial fibrillation; ARB, angiotensin receptor blocker; ARNI, Angiotensin receptor-neprilysin inhibitor; CV, cardiovascular ; MRA, Mineralocorticoid receptor antagonist; NSR, Normal sinus rhythm.
      Table. 3Summary of HF Inclusion Criteria for Recent Clinical Trials: HFpEF
      Trial NameAge, NYHA functional ClassLVEF (%)Natriuretic PeptidesHF Hospitalization
      TOPCAT
      • Pitt B
      • Pfeffer MA
      • Assmann SF
      • Boineau R
      • Anand IS
      • Claggett B
      • et al.
      Spironolactone for heart failure with preserved ejection fraction.
      Age ≥50 years

      NYHA functional class II-IV

      LVEF ≥45%BNP ≥100 pg/mL

      or NT-proBNP ≥360 pg/mL
      Within previous 12 months, with management of HF a major component
      PARAGON-HF
      • Solomon SD
      • McMurray JJV
      • Anand IS
      • Ge J
      • Lam CSP
      • Maggioni AP
      • et al.
      Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.
      Age≥50 years

      NYHA functional class II-IV
      LVEF ≥45% and LAE LVHIf NSR, NT-proBNP >200 pg/mL

      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
      Within previous 9 months
      EMPEROR-Preserved
      • Anker SD
      • Butler J
      • Filippatos GS
      • Jamal W
      • Salsali A
      • Schnee J
      • et al.
      Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial.
      Age≥18 years

      NYHA functional class II-IV (≥3 months)
      LVEF >40% (no prior history of LVEF ≤40%)NT-proBNP >300 pg/mL in NSR or >900 pg/mL in AFWithin 12 months OR evidence of structural changes (LAE or increased LVM) on echo
      DELIVER
      • Williams DM
      • Evans M.
      Dapagliflozin for heart failure with preserved ejection fraction will the DELIVER Study deliver?.
      Age≥40 years

      NYHA functional class II-IV
      (LVEF >40% and evidence of structural heart disease (ie, LAE or LVH)Elevated natriuretic peptidesMedical history of HF ≥6 weeks before enrolment with at least intermittent need for diuretic treatment
      AF, Atrial fibrillation; CV, cardiovascular; ECG, electrocardiogram; Echo, echocardiogram; LAE, left atrial enlargement; LBBB, Left bundle branch block; LVH, left ventricular hypertrophy; LVM, Left ventricular mass; NSR, Normal sinus rhythm.

      Gaps in Current Definitions of HF

      Combined Definition With Hemodynamic Characterization of HF

      The current definitions that include a hemodynamic characterization, such as the HFA/ESC definition, which defines HF as a “a clinical syndrome characterized by typical signs and symptoms, caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress,”
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      have the following limitations. Although accurate, this type of definition is hard to apply in public health or epidemiologic settings because of the subjectivity of the symptoms counterbalanced by the unfeasibility (invasive) or unreliability of measurements of cardiac output or filling pressures. For a definition to be also useful for the nonspecialist, it should be assessable easily and with relatively low interobserver variability. The Framingham criteria, which were developed for just such a purpose,
      • McKee PA
      • Castelli WP
      • McNamara PM
      • Kannel WB.
      The natural history of congestive heart failure: the Framingham study.
      are now considered insufficiently specific for adoption as a definition of HF in the contemporary setting.

      Cardiomyopathy and HF

      A key distinction that has led to persistent confusion in many discussions of the definition of HF is that between the concepts of “heart failure” and “cardiomyopathy.” As defined elsewhere in this document, HF is a clinical syndrome, that is, a recognizable pattern of signs and symptoms. “Cardiomyopathy” is a term, itself with widely differing definitions, that describes features of structural and functional heart muscle dysfunction. These different definitions may lead to potential confusion. In clinical practice, the term “cardiomyopathy” is often used as a more general term encompassing types of cardiac dysfunction, which may be further qualified with the underlying cause (eg, ischemic cardiomyopathy, nonischemic cardiomyopathy, etc). Alternatively, cardiomyopathy may be understood to be a specific form of myocardial disease that excludes forms of HF with a clearly established cause (such as ischemic heart disease). Even guideline statements from various scientific bodies have varied in their use of this term.
      • Bozkurt B
      • Colvin M
      • Cook J
      • Cooper LT
      • Deswal A
      • Fonarow GC
      • et al.
      Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
      ,
      • Maron BJ
      • Towbin JA
      • Thiene G
      • Antzelevitch C
      • Corrado D
      • Arnett D
      • et al.
      Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
      Furthermore, the maladaptive hemodynamic and compensatory mechanisms in HF may result in development of or worsening of cardiomyopathy.
      • Katz AM.
      Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure.
      Classification systems have been proposed that attempt to incorporate both the classification of HF and cardiomyopathy into a unified system, most notably the proposed MOGES criteria (Morpho-functional phenotype–M; organ[s] involvement–O; genetic inheritance pattern–G; etiological annotation–E–including genetic defect or underlying disease/substrate; and the functional status–S), but these systems have not been widely adopted owing to their complexity.
      • Arbustini E
      • Narula N
      • Tavazzi L
      • Serio A
      • Grasso M
      • Favalli V
      • et al.
      The MOGE(S) classification of cardiomyopathy for clinicians.
      HF encompasses a broader spectrum of cardiac disorders, not only cardiomyopathies that could be an underlying cause of the HF syndrome. In this statement, we do not provide specific classification strategies for cardiomyopathies, which we believe to be outside the scope of this document.
      • Bozkurt B
      • Colvin M
      • Cook J
      • Cooper LT
      • Deswal A
      • Fonarow GC
      • et al.
      Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.

      Biomarkers in the Definition of HF

      Natriuretic peptides such as brain natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are elevated in most forms of HF and are an integral component of making a diagnosis of HF in many clinical settings, especially when the diagnosis is uncertain.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      ,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      The use of these biomarkers has the highest class of recommendation to support a diagnosis or exclusion of HF
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      in contemporary practice guidelines, but are notably absent from most definitions of HF. This is in contrast with the universal definition of myocardial infarction (MI), where elevations of a circulating biomarker (troponin) are both central to the clinical diagnosis and fundamental to the universal definition itself.
      • Thygesen K
      • Alpert JS
      • Jaffe AS
      • Chaitman BR
      • Bax JJ
      • Morrow DA
      • et al.
      Fourth universal definition of myocardial infarction (2018).
      Although a biomarker based approach has incremental diagnostic value, especially in the context of clinical uncertainty, in some communities with limited resources, natriuretic peptide measurements currently may not be readily available, but their availability is rapidly increasing, and natriuretic peptide measurements are becoming part of standard care. Furthermore, certain clinical conditions other than HF, such as chronic kidney disease (CKD), atrial fibrillation, pericardial disease, pulmonary embolism, and even aging can also result in an increase in natriuretic peptide levels, and obesity is associated with lower natriuretic peptide levels, underlining the importance of an individualized interpretation of biomarker levels, particularly in special populations and in the setting of competing diagnoses and comorbidities. It is important to recognize that, although measuring natriuretic peptide levels may improve diagnostic accuracy and guide risk stratification in patients with HF, in certain patients with HF, such as patients with HFpEF or obesity, natriuretic peptide levels can be lower than those with HFrEF (although usually higher than those without HF); this circumstance may complicate their use for diagnosis and prognosis. Differences according to race/ethnicity, sex, and age will need to be taken into consideration in their interpretation and different thresholds are commonly used for patients with atrial fibrillation, a very common comorbidity in HF that can lead to increased natriuretic peptide levels. A potential influence of comorbidities is also relevant for troponin interpretation in patients with suspected acute MI; however, despite similar limitations, the introduction of a quantitative biomarker element to a disease definition has improved the accurate classification of disease states and proven to be of value in MI and other diseases.
      • Thygesen K
      • Alpert JS
      • Jaffe AS
      • Chaitman BR
      • Bax JJ
      • Morrow DA
      • et al.
      Fourth universal definition of myocardial infarction (2018).
      ,
      • Inker LA
      • Astor BC
      • Fox CH
      • Isakova T
      • Lash JP
      • Peralata CA
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      In general, both BNP and NT-proBNP values track similarly, and either can be used in patient care settings as long as their respective absolute values and cut points are not used interchangeably. Notably, BNP, but not NT-proBNP, is a substrate for neprilysin. Angiotensin receptor neprilysin inhibitor may result in an increase in BNP levels, but not NT-proBNP levels.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      Furthermore, patient-level changes need to be interpreted according to baseline levels; natriuretic peptides are higher during periods of decompensation compared with compensated periods, reflecting dynamic temporal changes.

      Clinical and Research Aspects of Defining HF

      Clinical research requires standardized definitions for identifying cases of HF and the collection of end points of interest, including especially HF-related hospitalizations.
      • Hicks KA
      • Mahaffey KW
      • Mehran R
      • Nissen SE
      • Wiviott SD
      • Dunn B
      • et al.
      2017 cardiovascular and stroke endpoint definitions for clinical trials.
      Given the increased use of electronic heath records as research tools, there is growing interest in the use of computer algorithms to identify cases of HF from electronic heath record data for research purposes. Although classical signs and symptoms are often included in electronic heath record data, they may not be codified as discrete data fields, leading to increased interest in the use of machine learning techniques to identify cases.
      • Blecker S
      • Katz SD
      • Horwitz LI
      • Kuperman G
      • Park H
      • Gold A
      • et al.
      Comparison of approaches for heart failure case identification from electronic health record data.
      Definitions of HF are important not only for clinical practice or research entry criteria, but also for the generalizability of research findings to the HF population, uniformity in end points of clinical trials; reliability and appropriateness of data captured in clinical, administrative, and billing registries; and performance measures.

      Patient and Clinician Perspective

      A syndrome that is based solely on symptoms can be confusing for clinicians and patients, both because they are often not specific to a single disease (eg, fatigue and dyspnea) and because they are highly subjective, for example, with the same objective limitation being considered disabling by 1 person and perceived as being normal for age by another. Once diagnosed, and with effective therapy, patients may become asymptomatic (NYHA functional class I) ; however, structural, cellular, and molecular abnormalities may continue to worsen silently.
      • Sabbah HN.
      Silent disease progression in clinically stable heart failure.
      Although Stage C HF uses the wording “current or previous symptoms” in the definition, patients may believe that lack of signs and symptoms equates to “being out of HF,” and be less likely to adhere to care.
      • Seid MA
      • Abdela OA
      • Zeleke EG.
      Adherence to self-care recommendations and associated factors among adult heart failure patients. From the patients' point of view.
      Health care professionals may be less likely to optimize GDMT when symptoms are mild or absent.
      • Gislason GH
      • Rasmussen JN
      • Abildstrom SZ
      • Schramm TK
      • Hansen ML
      • Buch P
      • et al.
      Persistent use of evidence-based pharmacotherapy in heart failure is associated with improved outcomes.
      Removing the word “congestive” in the term HF was an important reminder to providers that there is a range of signs and symptoms once diagnosed. Further, patients may not understand or recognize when HF worsens, until symptoms are severe enough to prompt emergency care.
      • Santos GC
      • Liljeroos M
      • Dwyer AA
      • Jaques C
      • Girard J
      • Strömbert
      • et al.
      Symptom perception in heart failure: a scoping review on definition, factors and instruments.
      In the era of shared decision-making and patient understanding of chronic conditions, it will be important to acknowledge and incorporate different stages that are understandable by patients after diagnosis.

      Competing diagnoses

      There are many conditions that may mimic HF, either in isolation (mimicry) or when coexisting with HF (co-causative). The combination of acute dyspnea, hypervolemia, and cardiorenal syndrome is often labeled as HF in an emergency care setting, although the problem could be confounded by, or even be predominantly due to, anemia and iron deficiency. Recognizing proportionate contributions of a clinical picture, to dissect out the element that is specifically HF-related, will be an important part of establishing a HF diagnosis, and it may not be an easy differentiation to make in all situations. It is HF only if the cardiac component is considered “important.” However, it is also important to recognize that HF can coexist with other diagnoses. For example, HF syndromes with lesser degrees of systolic impairment, such as HFpEF, frequently present with a wide range of cardiac and noncardiac abnormalities.
      • Zakeri R
      • Cowie MR.
      Heart failure with preserved ejection fraction: controversies, challenges and future directions.
      Newer, sometimes inconsistent terminology regarding mildly reduced EF has further complicated subcategorization of HF. It is important to promote greater clarity and specificity in the diagnosis of HF.

      Current Classifications of HF

      An important part of defining HF is that of creating a “usable” classification scheme. There are a variety of classification frameworks in current use that attempt to define distinct subsets of HF (Table 4). Some of these, such as NYHA functional class and EF categories, have been used subsequently as entry criteria for clinical trials, resulting in their incorporation into product labeling and guideline recommendations about which patients should receive a given therapy.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      Others, such as classifying patients by HF etiology, may have important implications for prognosis or differential response to therapy.
      • Felker GM
      • Thompson RE
      • Hare JM
      • Hruban RH
      • Clemetson DE
      • Howard DL
      • et al.
      Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.
      Table 4Selected Classification Frameworks Currently Used for HF
      ParameterExplanation
      NYHA functional class
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      I, II, III, IV based on symptoms severity
      EF
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      HFrEF, HFmrEF, or HFpEF based on LVEF
      Etiology
      • Bozkurt B
      • Colvin M
      • Cook J
      • Cooper LT
      • Deswal A
      • Fonarow GC
      • et al.
      Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
      Specific etiology of HF, for example, ischemic/nonischemic, valvular, hypertensive, infiltrative cardiomyopathy such as cardiac amyloidosis, peripartum cardiomyopathy, viral myocarditis chemotherapy-induced cardiomyopathy
      Disease progression (ACCF/AHA)
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      ,
      • Hunt SA
      • Baker DW
      • Chin MH
      • Cinquegrani MP
      • Feldman AM
      • Francis GS
      • et al.
      ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America.
      Stages A, B, C, or D according to presence of HF symptoms and signs and cardiac structural changes
      MOGES
      • Arbustini E
      • Narula N
      • Tavazzi L
      • Serio A
      • Grasso M
      • Favalli V
      • et al.
      The MOGE(S) classification of cardiomyopathy for clinicians.
      Morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S)
      INTERMACS Profiles for Advanced HF
      • Stevenson LW
      • Pagani FD
      • Young JB
      • Jessup M
      • Miller L
      • Kormos RL
      • et al.
      INTERMACS profiles of advanced heart failure: the current picture.
      Profiles 1–7 according to symptoms, functional capacity, hemodynamic stability for patients who are considered for advanced HF therapies
      INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support
      • Stevenson LW
      • Pagani FD
      • Young JB
      • Jessup M
      • Miller L
      • Kormos RL
      • et al.
      INTERMACS profiles of advanced heart failure: the current picture.
      ; MOGE(S) nosology system.
      • Arbustini E
      • Narula N
      • Tavazzi L
      • Serio A
      • Grasso M
      • Favalli V
      • et al.
      The MOGE(S) classification of cardiomyopathy for clinicians.

      Current Subclassification of HF According to EF and Its Limitations

      Because clinical trial inclusion criteria, and hence evidence of benefit, have often been restricted to patients with a reduced EF, HF has traditionally been subcategorized according to EF when defining recommended treatments in clinical practice guidelines.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      All guidelines use the terminology of HFrEF, and HFpEF (Table 5), but differ in the terminology used in patients with EFs between 40% and 49%. The 2013 ACC/AHA guidelines have used the terminology of HFpEF–borderline for patients with EF between 41% and 49%, and HFpEF–improved for those whose EF improved from a lower level to an EF of >40% under the subgrouping of patients with HFpEF.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      The HFA/ESC and JHFS guidelines have defined a third category of HF with mid-range EF (HFmrEF) or mildly reduced EF for those with an EF of 41% to 49%.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      The concept of HFmrEF is not necessarily accepted by all guidelines.
      • Atherton JJ
      • Sindone A
      • De Pasquale CG
      • Driscoll A
      • MacDonald PS
      • Hopper I
      • et al.
      National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: guidelines for the prevention, detection, and management of heart failure in Australia 2018.
      Table 5Current HF Classifications According to LVEF in Contemporary Clinical Practice Guidelines
      Society NameHF Classification According to LVEFLVEFAdditional requirements
      ACCF/AHA (2013)
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      Heart failure with reduced ejection fraction (HFrEF)≤40%Symptoms and signs
      Heart failure with preserved ejection fraction (HFpEF)≥50%Symptoms and signs
       HFpEF, borderline41%–49%Symptoms and signs
       HFpEF, improved>40%Symptoms and signs
      ESC (2016)
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      Heart failure with reduced ejection fraction (HFrEF)<40 %Symptoms and signs
      Heart failure with mid-range ejection fraction (HFmrEF)40-49%Symptoms and signs, elevated levels of natriuretic peptides and ≥1 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 ≥1 additional criterion of relevant structural heart disease (LVH or LAE) or diastolic dysfunction
      JCS/JHFS (2017)
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      Heart failure with reduced ejection fraction (HFrEF)<40%
      Heart failure with mid-range ejection fraction (HFmrEF)40% to <50%
      Heart failure with preserved ejection fraction (HFpEF)≥50%
      Heart failure with preserved ejection fraction, improved (HFpEF improved) or heart failure with recovered EF (HFrecEF)≥40%
      JCS, Japanese Cardiology Society; LAE, left atrial enlargement; LVH, left ventricular hypertrophy.
      In an effort, through a public–private partnership with the US Food and Drug Administration and with an intent to standardize terminology and LVEF cut-points used in US clinical trials, the Heart Failure Collaboratory, and Academic Research Consortium proposed the following definitions and EF ranges as their most recent recommendations: HFrEF, HF with left ventricular EF (LVEF) of ≤40%; HFpEF, HF with a LVEF of ≥50%; and HFmrEF, HF with a LVEF of >40% and a LVEF of <50%.
      • Abraham WT
      • Ptoska MA
      • Fiuzat M
      • Filippatos G
      • Lindenfeld J
      • Mehran R
      • et al.
      Standardized definitions for heart failure: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium (HF-ARC).
      The dichotomization of LVEF of above or below, for example, 40% has been helpful to apply therapies that have been shown to work in patients with reduced EF. Further classification into HFmrEF has potential usefulness, as well as challenges owing to its ambiguity, uncertainty, and dynamic trajectory.
      • Bozkurt B
      • Ezekowitz J.
      Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
      ,
      • Bohm M
      • Bewarder Y
      • Kindermann I.
      Ejection fraction in heart failure revisited- where does the evidence start?.
      Post hoc analyses of certain HF trials have suggested that standard therapy for HFrEF may be effective and extended to patients with HFmrEF,
      • Solomon SD
      • Claggett B
      • Lewis EF
      • Desai A
      • Anand I
      • Sweitzer NK
      • et al.
      Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
      • Solomon SD
      • Vaduganathan M
      • Claggett BL
      • Packer M
      • Zile M
      • Swedberg K
      • et al.
      Sacubitril/Valsartan across the spectrum of ejection fraction in heart failure.
      • Lund LH
      • Claggett B
      • Liu J
      • lam CS
      • Jhund PS
      • Rosano GM
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      • Cleland JGF
      • Bunting KV
      • Flather MD
      • Altman DG
      • Holmes J
      • Coats AJS
      • et al.
      Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
      but meta-analyses report diverse findings with neurohormonal antagonism in patients with HFmrEF, specifying benefit in certain subgroups and underlining heterogeneity of this category.
      • Bozkurt B
      • Ezekowitz J.
      Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
      ,
      • Cleland JGF
      • Bunting KV
      • Flather MD
      • Altman DG
      • Holmes J
      • Coats AJS
      • et al.
      Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
      • Zheng SL
      • Chan FT
      • Nabeebaccus AA
      • Shah AM
      • McDonagh T
      • Okonko DO
      • et al.
      Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis.
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • Miura M
      • Yamauchi TT
      • Onose T
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      The characteristics of HFmrEF overlap with HFrEF and HFpEF, straddling either category, sometimes one more than the other, depending on the clinical circumstance or patients studied.
      • Bozkurt B
      • Ezekowitz J.
      Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
      In population-based studies, usually without exclusions of specific etiologies, HFmrEF comprises 10% to 20% of the HF population,
      • Lund LH
      • Claggett B
      • Liu J
      • lam CS
      • Jhund PS
      • Rosano GM
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      ,
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • Anker SD
      • Crespo-leiro MG
      • Harjola VP
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      resembles the HFrEF group, but with similar
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • Miura M
      • Yamauchi TT
      • Onose T
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      or better survival than HFrEF patients.
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • Anker SD
      • Crespo-leiro MG
      • Harjola VP
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Bozkurt B
      • Ezekowitz J.
      Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
      Although some patients’ characteristics of HFmrEF are just between those of HFrEF and HFpEF, the prognosis of patients is not necessarily related to EF,
      • van Veldhuisen DJ
      • Linssen GC
      • Jaarsma T
      • van Gilst WH
      • Hoes AW
      • Tijssen JGP
      • et al.
      B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.
      and the relation between mortality and BNP is not affected by the EF.
      • van Veldhuisen DJ
      • Linssen GC
      • Jaarsma T
      • van Gilst WH
      • Hoes AW
      • Tijssen JGP
      • et al.
      B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.
      ,
      • Lam CSP
      • Gamble GD
      • Ling LH
      • Sim D
      • Leong KTG
      • Yeo PSD
      • et al.
      Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.
      In many patients, HFmrEF reflects a transitional trajectory for a dynamic temporal change, either to improvement or recovery from HFrEF
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • Miura M
      • Yamauchi TT
      • Onose T
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Rastogi A
      • Novak E
      • Platts AE
      • Mann DL.
      Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction.
      or to deterioration to HFrEF.
      • Bozkurt B
      • Ezekowitz J.
      Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
      ,
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • Miura M
      • Yamauchi TT
      • Onose T
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Rastogi A
      • Novak E
      • Platts AE
      • Mann DL.
      Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction.
      ,
      • Vedin O
      • Lam CSP
      • Koh AS
      • Benson L
      • Teng THK
      • Tay WT
      • et al.
      Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study.
      Although HFrEF and HFpEF have different clinical spectrums and proposed pathophysiological mechanisms, there is no clear defining syndrome recognized or postulated for HFmrEF. It is likely that patients in this range may have etiologies that are similar to those in lower or higher LVEF groups and may be in transition from higher to lower LVEF or vice versa. Persistent HFmrEF can be seen in some patients, including heterogeneous etiologies such as those with ischemic, infiltrative, restrictive, or hypertrophic cardiomyopathies.
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • Miura M
      • Yamauchi TT
      • Onose T
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Rastogi A
      • Novak E
      • Platts AE
      • Mann DL.
      Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction.
      ,
      • Vedin O
      • Lam CSP
      • Koh AS
      • Benson L
      • Teng THK
      • Tay WT
      • et al.
      Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study.
      Therefore, a lower than normal EF does not necessarily represent 1 phenotype and does not always entail the maladaptive deleterious mechanisms seen in patients with HFrEF. Furthermore, patients with restrictive, infiltrative, and hypertrophic cardiomyopathies, who may have HFmrEF, have traditionally been excluded from some clinical trials, emphasizing the necessity to focus on etiology rather than LVEF. The prevalence of HFmrEF, without overlap of other categories, has posed a major challenge for recruitment in trials, resulting in termination due to enrolment futility
      • Linde C
      • Curtis AB
      • Fonarow GC
      • Lee K
      • Little W
      • Tang A
      • et al.
      Cardiac resynchronization therapy in chronic heart failure with moderately reduced left ventricular ejection fraction: lessons from the Multicenter InSync Randomized Clinical Evaluation MIRACLE EF study.
      and in some clinical trials and epidemiologic studies, patients with an LVEF of 40% to 49% due have been categorized as HFpEF.
      Another criticism is the accuracy of the measurement of EF in clinical practice. Echocardiography is widely used to assess EF in patients with cardiovascular diseases, but the interobserver and intraobserver variability are not small enough to allow precise quantification of differences in 1 integer place values such as 39% versus 41%. Although other cardiovascular imaging modalities can be used to assess EF, there is substantial variation between modalities as well.
      • Pellikka PA
      • She L
      • Holly TA
      • Lin G
      • Varadarajan P
      • Pai RG
      • Bonow RO
      • et al.
      Variability in ejection fraction measured By echocardiography, gated single-photon emission computed tomography, and cardiac magnetic resonance in patients with coronary artery disease and left ventricular dysfunction.
      Furthermore, EF is not a reliable measure of contractile performance, is load dependent, and can vary according to hemodynamic status and loading conditions. Other imaging modalities such as global longitudinal strain are evolving to better characterize the ventricle, structural abnormalities, contractile performance, reverse remodeling, and response to therapy, and will likely expand the structural phenotyping beyond EF.
      Finally, the trajectory of EF over time in addition to a single absolute value of EF, and severity of LV dysfunction even among HFrEF may need to be taken into account to further classify patients with HF. Despite all these reservations, classification by EF has proven to be clinically and epidemiologically useful.

      Current Classification According to Stages of HF and Its Limitations

      The ACC/AHA stages are categorized as Stage A, patients at high risk for HF but without structural heart disease or symptoms of HF; Stage B, structural heart disease but without signs or symptoms of HF; Stage C, structural heart disease with prior or current symptoms of HF; and Stage D, refractory HF requiring specialized interventions.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      ,
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Hunt SA
      • Baker DW
      • Chin MH
      • Cinquegrani MP
      • Feldman AM
      • Francis GS
      • et al.
      ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America.
      The original ACC/AHA definition of stages of HF
      • Hunt SA
      • Baker DW
      • Chin MH
      • Cinquegrani MP
      • Feldman AM
      • Francis GS
      • et al.
      ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America.
      has been ubiquitously adapted throughout other HF guidelines globally.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      • Tsutsui H
      • Isobe M
      • Ito H
      • Okumura K
      • Ono M
      • Kitakaze M
      • et al.
      JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
      Although these stages of HF are well-recognized among health care professionals, they are not standard nomenclature for general practitioners, patients, or payers, or in the literature or education platforms provided by patient advocacy groups. Patients living with HF are less likely to identify with stages of HF in comparison with the familiarity with EF and subjective symptom burden. Contemporary clinical trials have not enrolled or randomized based on stages of HF, and most treatment strategies are not guided by the stages in HF.
      The ACC/AHA stages are based on symptoms and the presence or absence of structural heart disease and are applicable to both HFrEF and HFpEF. Certainly, there are prognostic nuances that are missed in such a broad staging classification, and opinions also vary as to whether those individuals solely identified with risk factors should be labeled as having a disease state, especially given that they are risk factors for many different diseases (not just HF risk factors). In comparison classification schemas such as the Society for Cardiovascular Angiography and Interventions cardiogenic shock stages
      • Baran DA
      • Grines CL
      • Bailey S
      • Burkhoff D
      • Hall SA
      • Henry TD
      • et al.
      SCAI clinical expert consensus statement on the classification of cardiogenic shock: this document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019.
      classified their stages based on detailed parameters of laboratory values and hemodynamics, as well as physical examination findings, and exemplifies a more detailed approach to staging. Furthermore, the definitional progression along the ACC/AHA stages A through D is a unidirectional path with little appreciation of a possibility to revert to a lower stage with appropriate GDMT.
      If the HF process were to be defined as a continuum from Stage A through D, the greatest number of patients would be in Stage A or Stage B.
      • Ammar KA
      • Jacobsen SJ
      • Mahoney DW
      • Kors JA
      • Redfield MM
      • Burnett Jr., JC
      • et al.
      Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community.
      • Wagner M
      • Tiffe T
      • Morbach C
      • Gelbrich G
      • Stork S
      • Heuschmann PU.
      Characteristics and course of heart failure stages A-B and determinants of progression - design and rationale of the STAAB cohort study.
      • Morbach C
      • Gelbrich G
      • Tiffe T
      • Eichner FA
      • Christa M
      • Mattern R
      • et al.
      Prevalence and determinants of the precursor stages of heart failure: results from the population-based STAAB cohort study [e-pub ahead of print].
      • Young K
      • Scott C
      • Rodeheffer RJ
      • Chen CH.
      Preclinical heart failure: evaluation of long-term outcomes in patients with stage A and stage B heart failure in the general population.
      This is due to the fact that the prevalence of hypertension, diabetes, coronary artery disease, obesity/metabolic syndrome—the risk factors with significant relative risk and population attributable risk for development of HF—are present in approximately one-third of the US population.
      • Virani SS
      • Alonso A
      • Benjamin EJ
      • Bittencourt MS
      • Callaway C
      • Carson AP
      • et al.
      Heart disease and stroke statistics-2020 update: a report from the American Heart Association.
      By population based registries, >40% to 50% of the adult population have been categorized to be in Stages A or B.
      • Ammar KA
      • Jacobsen SJ
      • Mahoney DW
      • Kors JA
      • Redfield MM
      • Burnett Jr., JC
      • et al.
      Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community.
      • Wagner M
      • Tiffe T
      • Morbach C
      • Gelbrich G
      • Stork S
      • Heuschmann PU.
      Characteristics and course of heart failure stages A-B and determinants of progression - design and rationale of the STAAB cohort study.
      • Morbach C
      • Gelbrich G
      • Tiffe T
      • Eichner FA
      • Christa M
      • Mattern R
      • et al.
      Prevalence and determinants of the precursor stages of heart failure: results from the population-based STAAB cohort study [e-pub ahead of print].
      The high prevalence of HF risk in the general population raises the question of whether Stage A patients should really be defined to have HF. From a public health and health care perspective, being called HF, regardless of such an early status as stage A, raises important concerns, because HF is usually perceived as an advanced chronic disease with symptoms and very adverse outcomes and may have implications for health and life insurance. Of course, it is critical to focus on prevention, with recognition, prevention, and treatment of these risk factors, but it is also important to differentiate those who have HF from those at risk for HF. Similarly, clinicians in general or HF practice have not adopted the terminology of Stage A HF beyond academic circles, partly due to the lack of actionable specific treatment recommendations according to stages, and most of their assessment and management focuses on management of left ventricular dysfunction (Stage B) or symptomatic HF (stages C/D). When clinicians address risk factors such as hypertension, diabetes, obesity, or coronary artery disease, they do not refer to those as Stage A HF or pre-HF, but rather independent diagnoses. Furthermore, despite recognized increased adverse outcome risk and possibility of progress to symptomatic HF in some patients,
      • Ammar KA
      • Jacobsen SJ
      • Mahoney DW
      • Kors JA
      • Redfield MM
      • Burnett Jr., JC
      • et al.
      Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community.
      ,
      • Young K
      • Scott C
      • Rodeheffer RJ
      • Chen CH.
      Preclinical heart failure: evaluation of long-term outcomes in patients with stage A and stage B heart failure in the general population.
      ,
      • Correa de Sa DD
      • Hodge DO
      • Slusser JP
      • Redfield MM
      • Simari RD
      • Burnett JC
      • et al.
      Progression of preclinical diastolic dysfunction to the development of symptoms.
      the data on the likelihood of progression from Stages A/B to C/D are limited.
      • Wagner M
      • Tiffe T
      • Morbach C
      • Gelbrich G
      • Stork S
      • Heuschmann PU.
      Characteristics and course of heart failure stages A-B and determinants of progression - design and rationale of the STAAB cohort study.
      ,
      • Young K
      • Scott C
      • Rodeheffer RJ
      • Chen CH.
      Preclinical heart failure: evaluation of long-term outcomes in patients with stage A and stage B heart failure in the general population.
      ,
      • Correa de Sa DD
      • Hodge DO
      • Slusser JP
      • Redfield MM
      • Simari RD
      • Burnett JC
      • et al.
      Progression of preclinical diastolic dysfunction to the development of symptoms.
      Thus most clinicians do not commonly use the HF terminology for Stage A patients, and do not commonly educate patients regarding the risk of progression from Stages A/B to C.
      Another important development that needs to be taken in consideration of stages in HF is the advances in the prevention of future risk of HF by specific therapies. Although in the past, prevention and holistic treatment of risk factors by standard treatment strategies were felt to prevent HF,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      there is growing evidence that certain treatment strategies are better for the prevention of HF and not all treatment strategies of hypertension and diabetes prevent HF equally or at all. For example, in the treatment of hypertension, diuretic-based antihypertensive therapies, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have been shown to prevent HF in a wide range of target populations, whereas calcium channel blockers have not.
      • Bozkurt B
      • Aguilar D
      • Deswal A
      • Dunbar SB
      • Francis GS
      • Horwich T
      • et al.
      Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association.
      There is growing evidence that treatment with sodium–glucose cotransporter 2 inhibitors prevents HF hospitalizations among patients with type II diabetes
      • Zinman B
      • Wanner C
      • Lachin JM
      • Fitchett D
      • Bluhmki E
      • Hantel S
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes.
      • Neal B
      • Perkovic V
      • Mahaffey KW
      • de Zeeuw D
      • Fulcher G
      • Erondu N
      • et al.
      Canagliflozin and cardiovascular and renal events in Type 2 diabetes.
      • Wiviott SD
      • Raz I
      • Bonaca MP
      • Mosenzon O
      • Kato ET
      • Cahn A
      • et al.
      Dapagliflozin and cardiovascular outcomes in Type 2 diabetes.
      or in patients with HFrEF, regardless of diabetes,
      • Packer M
      • Anker SD
      • Butler J
      • Filippatos G
      • Pocock SJ
      • Carson P
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ,
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      whereas other glucose treatment strategies do not. It is also interesting to note that patients with a higher future HF risk identified by risk scores that include biomarkers such as albuminuria, seem to derive greater benefit from sodium–glucose cotransporter inhibitor therapy among patients with type 2 diabetes.
      • Berg DD
      • Wiviott SD
      • Scirica BM
      • Gurmu Y
      • Mosenzon O
      • Murphy SA
      • et al.
      Heart failure risk stratification and efficacy of sodium-glucose cotransporter-2 inhibitors in patients with Type 2 diabetes mellitus.
      The biomarker profile may identify patients with cardiometabolic, cardiovascular, and cardiac structural changes in patients predestined to develop HF or, in other words, pre-HF. Supporting this concept was the STOP-HF trial, which provided evidence that screening with natriuretic peptides among individuals with cardiovascular disease or with cardiovascular risk factors, such as diabetes and hypertension, can be helpful to prevent development of HF or left ventricular systolic or diastolic dysfunction.
      • Ledwidge M
      • Gallagher J
      • Conlon C
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      Accordingly, the 2017 ACC/AHA/HFSA focused update for the management of HF guidelines incorporated recommendations for natriuretic peptides–based screening in the prevention of HF as a Class IIa recommendation.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      Similarly, high sensitivity cardiac troponin levels are associated with future development of incident HF in the general population
      • Saunders JT
      • Nambi V
      • de Lemos JA
      • Chambless LE
      • Virani SS
      • Boerwinkle E
      • et al.
      Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
      ,
      • deFilippi CR
      • de Lemos JA
      • Christenson RH
      • Gottdiener JS
      • Kop WJ
      • Zhan M
      • et al.
      Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
      and in those with evidence of cardiotoxicity or cardiac injury in high-risk populations,
      • Avila MS
      • Ayub-Ferreira SM
      • de Barros Wanderley Jr, MR
      • das Dores Cruz F
      • Gonçalves Brandão SM
      • Carvalho Rigaud VO
      • et al.
      Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: the CECCY Trial.
      allowing for treatment strategies to prevent development of HF. Thus, biomarker elaboration can further identify risk and presence of ultrastructural abnormalities in HF among asymptomatic patients and could be a marker for Stage B HF without the development of macroscopic structural changes detectable by imaging or electrocardiogram.

      Gaps in Definitions According to Trajectory of Changes in HF

      The HF syndrome is dynamic, with changing clinical trajectories based on signs, symptoms, and disease progression, driven by underlying pathophysiologic processes. Changes in HF may be captured in several ways, including alterations in cardiac structure and function and by clinical status.

      Trajectory Changes in EF

      GDMT can result in improvement in LVEF and reverse remodeling in patients with HFrEF.
      • Wilcox JE
      • Fang JC
      • Margulies KB
      • Mann DL.
      Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
      The phenomenon of improvement and recovery of LVEF has led to a growing interest in the long-term outcomes and management of these patients and how they differ from “nonresponders,” or individuals whose LVEF does not improve with treatment. Currently, there is no consensus definition for patients with HFrEF whose LVEF improves, which has led to a variety of terms describing this phenotype, including patients with “improved” LVEF, HFpEF (borderline), HFpEF, and HF with recovered EF (HFrecEF). The magnitude of change that defines “recovery” of LVEF is not standardized, but it is recognized that distinguishing HFrecEF from HFmrEF requires serial measurements of the LVEF to appropriately capture change over time because this group might represent HFrecEF or deteriorated HFpEF. Moreover, because the measurement of the LVEF is subject to significant intrareader or inter-reader variability, small changes in the LVEF need to be interpreted cautiously. Thus, a recent scientific panel put forth a working definition of HFrecEF that includes a baseline LVEF of ≤40%, a ≥10% increase from baseline LVEF, and a second measurement in the LVEF of >40%.
      • Wilcox JE
      • Fang JC
      • Margulies KB
      • Mann DL.
      Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
      In this formulation, recovered EF signifies improvement of LVEF to >40%, but not necessarily totally normalized. There have been other attempts to characterize improvement in EF as an increase in LVEF of >10%.
      • Wilcox JE
      • Fang JC
      • Margulies KB
      • Mann DL.
      Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
      It is also important to recognize that the trajectory might not be linear and unidirectional and a patient may have improvement followed by a decline in EF or vice versa, depending on the underlying etiology, duration of disease, adherence to the GDMT, comorbidities, or re-exposure to cardiotoxins.

      Trajectory Changes in Clinical Status

      Another method that captures the HF trajectory relies on an assessment of the patient's clinical status, which can inform the risk for hospitalization for HF or for mortality. A de novo diagnosis of HF, also referred to as new-onset HF, carries an increased risk for adverse clinical outcomes because the patient is not likely to be treated with optimal GDMT at the time of diagnosis.
      Most patients with HF have episodes of clinical worsening of HF, which has been defined previously as worsening signs or symptoms in concert with a hospitalization.
      • Butler J
      • Braunwald E
      • Gheorghiade M.
      Recognizing worsening chronic heart failure as an entity and an end point in clinical trials.
      Data from more contemporary studies resulted in expansion of worsening HF to also include patients who require escalation of outpatient therapies, such as diuretics, even without a hospitalization.
      • Greene SJ
      • Mentz RJ
      • Felker GM.
      Outpatient worsening heart failure as a target for therapy: a review.
      This is because the need for intensifying diuretic therapy, regardless of location (inpatient or outpatient), portends a worse prognosis than a patient who does not require intensification of therapy. Worsening HF implies a period of stability preceding a deterioration of signs and symptoms. However, the phrase “stable” HF may be a misnomer, because patients with HF always carry a residual risk for hospitalization or sudden cardiac death, even when minimally symptomatic or asymptomatic receiving optimal treatment. For such patients, remission may be a more suitable term.
      • Solomon SD
      • Claggett B
      • Packer M
      • Desai A
      • Zile MR
      • Swedberg K
      • et al.
      Efficacy of Sacubitril/Valsartan relative to a prior decompensation: the PARADIGM-HF trial.
      When a patient with worsening HF does 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 circulatory support or cardiac transplantation or, if they do not qualify for advanced therapies, clinicians can consider referral for palliative care.
      Patients may have improvement in HF symptoms, functional capacity, quality of life, and exercise performance with GDMT. Some patients with reversible or treatable causes of HF, such as cardiomyopathy due to hypertensive heart disease, alcoholic cardiomyopathy, peripartum cardiomyopathy, or tachycardia-induced cardiomyopathy, may even recover from HF with treatment and manifest resolution of HF symptoms, as well as normalization of the EF and cardiac structure. These patients require close follow-up and require continuation of treatment to ascertain that HF symptoms or LV dysfunction do not reoccur in the future.
      • Halliday BP
      • Wassall R
      • Lota AS
      • Khalique Z
      • Gregson J
      • Newsome S
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF) : an open-label, pilot, randomised trial.

      Learning From Other Disease Definitions

      Disease definitions are not all the same. Some are categorical, where the disease is present or it is not. In some, there may be a single pathognomonic feature that defines the disease state, such as many cancers and infectious diseases. In others, where numerical thresholds are used, a disease may be defined against a quantitative threshold of abnormality in an anatomical and/or functional feature. Examples of these include hypertension, osteoporosis, sarcopenia, and CKD. In some (eg, CKD, hypertension) the presence of this numerical abnormality alone is sufficient to define the disease, whereas in others (eg, HF, sarcopenia) the loss of function must be symptomatic or functionally evident for the disease to be defined. In the current universal definition of MI, elevation of cardiac troponin is central to the clinical diagnosis and fundamental to the universal definition.
      • Thygesen K
      • Alpert JS
      • Jaffe AS
      • Chaitman BR
      • Bax JJ
      • Morrow DA
      • et al.
      Fourth universal definition of myocardial infarction (2018).
      There are many other corollaries and lessons to learn from other areas of cardiology and medicine in regard to disease definition and classifications. The current ACC/AHA classification of valvular heart disease is very similar to the current ACC/AHA HF categorization into Stages A through D.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      ,
      • Nishimura RA
      • Otto CM
      • Bonow RO
      • Carabello BA
      • Erwin III, JP
      • Fleisher LA
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
      Such categorization is an 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 patients are categorized as paroxysmal (≤48 hours), persistent (>7 days or cardioverted), long standing (>1 year), and permanent.
      • January CT
      • Wann LS
      • Calkins H
      • Chen LY
      • Cigarroa JE
      • Cleveland Jr., JC
      • et al.
      2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons.
      However, in atrial fibrillation, clinicians also use the CHA2DS2-VASc risk score to determine potential stroke risk and thereby guide management.
      • January CT
      • Wann LS
      • Calkins H
      • Chen LY
      • Cigarroa JE
      • Cleveland Jr., JC
      • et al.
      2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons.
      A similar parallel in HF is the MAGGIC model for the 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.
      • Pocock SJ
      • Ariti CA
      • McMurray JJ
      • Maggioni A
      • Køber L
      • Squire IB
      • et al.
      Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies.
      In regard to noncardiovascular strategies for disease definition, there are quite a few examples. CKD is classified based on albuminuria and the estimated glomerular filtration rate.
      • Inker LA
      • Astor BC
      • Fox CH
      • Isakova T
      • Lash JP
      • Peralata CA
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      Albuminuria states are similar to numeric categorization of disease, like LVEF in HF, whereas an estimated glomerular filtration rate ranging from normal to end-stage renal disease provides prognostic information and guides management decisions, such as drug dosing and the need for dialysis. Liver disease is categorized based on pathology using imaging and tissue sampling to define levels of steatosis, hepatitis, fibrosis, and cirrhosis.
      • Martin P
      • DiMartini A
      • Feng S
      • Brown Jr., R
      • Fallon M
      Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
      Much like CKD, liver disease also supplements disease categorization with risk scores like the Model for End-stage Liver Disease score.
      • Kartoun U
      • Corey KE
      • Simon TG
      • Zheng H
      • Aggarwal R
      • Ng K
      • et al.
      The MELD-Plus: a generalizable prediction risk score in cirrhosis.
      Lung disease is assessed using pulmonary function tests which helps clinicians stratify patients based on air-flow limitation and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) system.
      • Vestbo J
      • Hurd SS
      • Agusti AG
      • Jones PW
      • Vogelmeier C
      • Anzueto A
      • et al.
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
      Chronic obstructive lung disease also stratifies patients based on symptoms and risk of exacerbations similar to congestion-perfusion
      • Nohria A
      • Lewis E
      • Stevenson LW.
      Medical management of advanced heart failure.
      categorization in HF. Pulmonary hypertension classification (World Health Organization Groups 1–5)
      • Simonneau G
      • Gatzoulis MA
      • Adatia I
      • Celemajer D
      • Denton C
      • Ghofrani A
      • et al.
      Updated clinical classification of pulmonary hypertension.
      is similar to the etiology-based groupings for cardiomyopathies
      • Bozkurt B
      • Colvin M
      • Cook J
      • Cooper LT
      • Deswal A
      • Fonarow GC
      • et al.
      Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
      ,
      • Maron BJ
      • Towbin JA
      • Thiene G
      • Antzelevitch C
      • Corrado D
      • Arnett D
      • et al.
      Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
      with genetic, acquired, and mixed categories and is a potential model for future HFpEF
      • Shah SJ
      • Katz DH
      • Selvaraj S
      • Burke MA
      • Yancy CW
      • Gheorghiade M
      • et al.
      Phenomapping for novel classification of heart failure with preserved ejection fraction.
      disease stratification. Finally, the field of cancer groups disease using a combination of epidemiology-based staging (ie, at risk for cancer, precancer, carcinoma in situ, localized, early/late locally advanced, and metastasized) coupled with disease-specific markers that determine treatment course and targeted therapies. Cancer, which is a chronic disease similar to HF, reflects one of the most comprehensive combined approaches of classification using epidemiology, biomarker thresholds, and trajectory.
      Future attempts at defining HF will need to draw on principles of categorization used in other disease states. Each organ system has a unique pathophysiology that helps to determine its disease categorization, and, ultimately, all organ systems are interconnected. Indeed, HF represents an end-stage phenotype for most (if not all) cardiovascular diseases. In the terminal stages of disease, the universal element is disseminated disease and multiorgan failure. However, unlike other organ systems, the heart is unique in that hemodynamics play a central role in the disease state. Many disease states are moving toward a combination of epidemiology-based, numeric, and targeted marker-based therapies. Disease definitions are critical to patients’ and clinicians’ understanding of their pathology, informs clinical decision-making, categorization for financial billing, and the creation of future health policies.

      Proposed Universal Definition of HF

      In this section, we provide a consensus opinion on a new proposed universal definition of HF.

      Symptoms

      HF, like many noncategorical diseases, is widely held to be a clinical syndrome, devoid of any single pathognomonic histological or biochemical signal, and being the possible end result of many quite distinct and varied clinical disease states. Common symptoms and signs of HF are listed in Table 6.
      Table 6Symptoms and Signs of HF
      Symptoms of HF
       Typical
        Breathlessness
        Orthopnea
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Paroxysmal nocturnal dyspnea
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Reduced exercise tolerance
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Fatigue, tiredness
      Common in low perfusion, low cardiac output states.
        Ankle swelling
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Inability to exercise
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Swelling of parts of the body other than ankles
        Bendopnea
       Less typical
        Nocturnal cough
        Wheezing
        Bloated feeling
      Can be typical in the setting of right HF or biventricular failure.
        Postprandial satiety
      Can be typical in the setting of right HF or biventricular failure.
        Loss of appetite
        Decline in cognitive function, confusion (especially in the elderly)
      Common in low perfusion, low cardiac output states.
        Depression
        Dizziness, syncope
      Common in low perfusion, low cardiac output states.
      Signs of HF
       More specific
        Elevated jugular venous pressure
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Third heart sound
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Summation gallop with third and fourth heart sounds
        Cardiomegaly, laterally displaced apical impulse
        Hepatojugular reflux
        Cheyne Stokes respiration in advanced HF
      Common in low perfusion, low cardiac output states.
       Less specific
        Peripheral edema (ankle, sacral, scrotal)
        Pulmonary rales
      Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
        Unintentional weight gain (>2 kg/week)
        Weight loss (in advanced HF) with muscle wasting and cachexia
        Cardiac murmur
        Reduced air entry and dullness to percussion at lung bases suggestive of pleural effusion
        Tachycardia, irregular pulse
        Tachypnea
        Hepatomegaly/ascites
        Cold extremities
      Common in low perfusion, low cardiac output states.
        Oliguria
        Narrow pulse pressure
      low asterisk Commonly used in clinical trials, registries, risk scoring, and have been tested for sensitivity and specificity.
      Common in low perfusion, low cardiac output states.
      Can be typical in the setting of right HF or biventricular failure.
      The current ACCF/AHA Classification of HF
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      includes 2 presymptomatic stages, A and B. Although we restrict the definition of the syndrome of HF to being a symptomatic clinical condition, our proposed revised stages still straddle the presymptomatic stages. To not lose the advantage that the A/B/C/D staging system offered, to incorporate the asymptomatic phases under the HF umbrella, and to enhance understandability of these asymptomatic phases we propose a new categorization of Stages A and B into “at risk” and “pre-HF” in Section Proposed New Classifications of HF According to Ejection Fraction.

      Objective Marker

      In learning from other disease states that incorporated a core and frequently measured variables in their definition, such as acute MI, estimated glomerular filtration rate in CKD, hemoglobin A1c in diabetes, bone mineral density in osteoporosis, or forced expiratory volume in 1 second in chronic obstructive pulmonary disease, making the diagnosis more accessible to nonspecialists and more reliable and consistent between observers, hospitals and health care systems, we propose the incorporation of an objective measurement in addition to the symptoms in the HF definition.
      In HF, possible candidates for such a measurement might theoretically be hemodynamic measures such as an elevated pulmonary capillary wedge pressure and right atrial pressure by right heart catheterization, biomarkers associated with congestion such as natriuretic peptides, measures of neurohormonal overactivity or measures of exercise limitation, such as maximal oxygen consumption. None of these measures are commonly or reliably associated with the disease states of HF; for example, the LVEF can vary from low through normal to high and still be part of an HF syndrome; no single hemodynamic measure is adequate to serve as a practical, noninvasive, and reliable measurement; measurement of exercise limitation with cardiopulmonary exercise testing with expired gas exchange is not practical or universally available; and to date, neurohormone levels have not universally been considered reliable measures of the disease state. The closest have been the natriuretic peptides, which are recommended in modern guidelines as both diagnostic tests of reasonable clinical usefulness with prognostic usefulness and as good tests to rule out HF as a cause of breathlessness in certain settings.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      Contemporary guidelines already state that natriuretic peptides can be used as an initial diagnostic test and that patients with normal plasma natriuretic peptide concentrations are unlikely to have HF.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      A detailed diagnostic algorithm will require specific operational thresholds based on individual natriuretic peptides and assay systems, as well as detailing other clinical features that can affect natriuretic peptide levels (Table 7), but for common clinical purposes, simple thresholds can be established that have sufficient operational accuracy to be incorporated usefully into a universal definition of HF.
      Table 7Causes of Elevated Natriuretic Peptide Levels Other than Primary Diagnosis of HF
      Cardiovascular causes
       Acute coronary syndrome, MI
       Pulmonary embolism
       Myocarditis
       Hypertrophic cardiomyopathy
       Valvular heart disease
       Congenital heart disease
       Atrial or ventricular arrhythmias
      Heart contusion, cardiac infiltration or malignancy
       Cardioversion, ICD shock
       Pericardial disease
       Invasive or surgical procedures involving the heart
       Pulmonary hypertension, right ventricular failure
       Infiltrative cardiomyopathies
      Noncardiovascular causes
       Advanced age
       Kidney disease
       Critical illnesses including Sepsis syndrome, cytokine syndrome
       Ischemic or hemorrhagic stroke
       Pulmonary disease (pneumonia, chronic obstructive pulmonary disease)
       Liver disease
       Severe anemia
       Severe metabolic and hormone abnormalities (eg, thyrotoxicosis, diabetic ketoacidosis, severe burns)
      Causes of lower natriuretic peptide levels
       Obesity or increased BMI
       Pericardial disease
      In certain patients with pericardial disease and effusion, natriuretic peptides may be lower and increase after pericardiocentesis.
      low asterisk In certain patients with pericardial disease and effusion, natriuretic peptides may be lower and increase after pericardiocentesis.

      Proposed New HF Definition

      We propose a contemporary universal definition of HF (Figure 1) that is simple but conceptually comprehensive, with near universal applicability, prognostic and therapeutic validity, and acceptable sensitivity and specificity.
      • Universal HF Definition
      HF is a clinical syndrome with current or prior
      • Symptoms and or signs (Table 6) caused by a structural and/or functional cardiac abnormality (as determined by an EF of <50%, abnormal cardiac chamber enlargement, E/E’ of >15, moderate/severe ventricular hypertrophy or moderate/severe valvular obstructive or regurgitant lesion)
      • and corroborated by at least one of the following:
        • Elevated natriuretic peptide levels (for values refer toTable 8)
          Table 8Natriuretic Peptide Levels Supporting Definition of HF
          AmbulatoryHospitalized/Decompensated
          BNP, pg/mL≥35≥ 100
          NT-proBNP, pg/mL≥ 125≥ 300
        • Objective evidence of cardiogenic pulmonary or systemic congestion by diagnostic modalities, such as imaging (eg, by chest radiograph or elevated filling pressures by echocardiography) or hemodynamic measurement (eg, right heart catheterization, pulmonary artery catheter) at rest or with provocation (eg, exercise)
      Such a definition is comprehensive and practical enough to form the base that allows further subclassifications and that can encompass formal disease stages, with universal applicability, prognostic and therapeutic validity, and an acceptable sensitivity and specificity. Please note that the definition of HF requires not only symptoms or signs (Table 6). but also presence of either elevated natriuretic peptides or objective evidence of pulmonary or systemic congestion by diagnostic modalities. For example, it would be important for peripheral edema or ascites (Table 6) to be corroborated by presence of elevated right-sided cardiac filling pressures or rales by presence of elevated left-sided cardiac filling pressures; or elevated natriuretic peptides. It is also important to note that elevated jugular venous pressure estimate by an experienced clinician could be accepted as an objective evidence.
      Please also note that, in certain patients, congestion and hemodynamic abnormalities may become manifest with provocation such as exercise, especially in patients with HFpEF. This can support the diagnosis of HF. It is also critical to note that, in patients with low perfusion and a hypovolemic state, there may not be any evidence of congestion or elevated filling pressures, but rather decreased cardiac output accompanied with low or normal ventricular filling pressures
      • Stevenson LW.
      Design of therapy for advanced heart failure.
      (eg, in the setting of overdiuresis in patients with HF). Once the hypovolemic state is corrected, patients with HF usually have elevated filling pressures.
      In this definition, we did not specify left or right HF. Although left heart HF, and in advanced stages, biventricular HF, are common, right HF can also be recognized as part of the above definition when patients present with symptoms or signs (Table 6) caused by a cardiac abnormality and have elevated natriuretic peptide levels or objective evidence of cardiogenic pulmonary or systemic congestion. Right HF primarily owing to cardiac abnormalities such as arrhythmogenic right ventricular cardiomyopathy would be part of this definition.
      We recognize that asymptomatic stages with patients at risk (former Stage A HF) or patients with structural heart disease or cardiomyopathies (former Stage B HF) would not be covered under this definition as having HF, which emphasizes symptoms and signs of HF, but we conceptualize the HF syndrome as a continuum of disease with certain stages, such as pre-HF. This is similar to the approach with other disease states such as cancer, which defines those at risk and pre-cancer. The stages preceding the symptomatic phases as those at risk and in pre-HF will be discussed in Section Proposed Revised Stages of the HF Continuum.
      We also realize certain patients with competing diagnoses such as CKD with marked volume overload, can present with symptoms and signs of HF, have elevated natriuretic peptides, and may even have evidence of congestion by imaging or elevated filling pressures. Although some of these patients may have concomitant HF, these patients have a primary abnormality that may require a specific treatment beyond that for HF. In Section Proposed Revised Stages of the HF Continuum, we address such other syndromes.

      Other Syndromes Related to HF

      As noted in Section Other Syndromes Related to HF, the definition of HF comprises a combination of symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality, and evidence of elevated filling pressures by natriuretic peptides or by imaging or hemodynamic assessment. Although many clinicians will initially envision patients with left HF as embodying this definition, it is important to note that there are other syndromes that may fulfill this definition of HF, as addressed here. These etiologies require specific treatment and management strategies targeting the underlying or proximate cause, as well as treating the HF itself.

      Right HF

      The most common cause of right HF is left HF. However, right HF is characterized not only by signs and symptoms of right-sided HF, but also by right atrial enlargement or right ventricular dysfunction. The presence of right HF in the setting of left HF is typically due to postcapillary, World Health Organization group 2 pulmonary hypertension and may require modified treatment approaches and portends a poor prognosis; therefore, recognition of biventricular HF is important.
      • Simonneau G
      • Gatzoulis MA
      • Adatia I
      • Celemajer D
      • Denton C
      • Ghofrani A
      • et al.
      Updated clinical classification of pulmonary hypertension.
      Given the importance of these distinctions, the classification of types of ventricular failure in HF commonly includes 3 categories; left ventricular failure, right ventricular failure, and combined left and right ventricular failure usually termed as biventricular failure. We believe that isolated right HF owing to primary pulmonary hypertension etiologies (World Health Organization Groups 1, 3, and 4), although they may have symptoms or signs that may mimic HF and may have elevated natriuretic peptide levels, would not be categorized under HF, because the signs and/or symptoms are not caused primarily by a structural and/or functional cardiac abnormality. In contrast, right HF due to primary right ventricular conditions such as arrhythmogenic right ventricular cardiomyopathy would be categorized under HF.

      Acute MI/Acute Coronary Syndrome

      Acute MI may be complicated by HF. Given its acuity, specific pathophysiology, and specific treatment strategies, we believe acute MI would be the overarching definition for the episode in proximity to acute MI. It is also possible that these patients may recover with timely treatment strategies and not progress to chronic HF, but also many may progress to chronic HF. In clinical trials, patients with acute MI or acute coronary syndrome within 6 weeks are usually excluded from clinical trials in HF. These patients may present with asymptomatic left ventricular dysfunction, or pre-HF, or symptoms and signs of HF due to a cardiac abnormality and may have elevated natriuretic peptides or evidence of congestion by imaging or hemodynamics. During the acute phase, these patients are diagnosed as having an MI complicated by HF, rather than with HF alone. This does not mean acute MI should be replaced by HF alone, but it does mean the setting and specific etiology of HF can be an important feature that determines specific therapeutic approaches. This setting has also been subject to specific clinical trial evaluation.
      • Pitt B
      • Remme W
      • Zannad F
      • Neaton J
      • Martinez F
      • Roniker B
      • et al.
      Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
      Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      • Pfeffer MA
      • Braunwald E
      • Moye LA
      • Brown Jr., EJ
      • Cuddy TE
      • Davis BR
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.
      In addition to specific therapies for acute MI, these patients have indications for specific treatment for asymptomatic LV dysfunction (pre-HF or Stage B HF) or symptomatic HF complicating acute MI during the acute phase, or as primary diagnoses in the chronic phase post MI.

      Cardiogenic Shock

      Another important form of HF is cardiogenic shock, which is the clinical state of organ hypoperfusion due to severe cardiac dysfunction. In cardiogenic shock, the symptoms and signs reflecting HF include hypotension unresponsive to volume repletion, altered mental status, cool extremities, and laboratory evidence of end organ dysfunction such as elevated lactate levels due to hypoperfusion.
      • Baran DA
      • Grines CL
      • Bailey S
      • Burkhoff D
      • Hall SA
      • Henry TD
      • et al.
      SCAI clinical expert consensus statement on the classification of cardiogenic shock: this document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019.
      Cardiogenic shock is an extreme form of HF that requires some form of definitive therapy, such as intravenous inotropes, vasopressors, or mechanical circulatory support. Cardiogenic shock is a type of HF, but due to its specific hemodynamic and clinical characterization requiring specific therapies such as vasoactive agents, circulatory support, and/or revascularization depending on the etiology, we believe keeping the descriptor “cardiogenic shock” will help to identify a patient cohort with specific and urgent treatment needs. Cardiogenic shock may occur as an acute de novo presentation (eg, large acute myocardial infarct, fulminant myocarditis) or with progressive deterioration in a patient with chronic HF. Subacute cardiogenic shock may be in continuum of the wet and cold advanced HF patient with a low cardiac output state. Such patients may meet the criteria for cardiogenic shock, especially when they have evidence of end-organ dysfunction. A system describing the stages of cardiogenic shock has been proposed by the Society for Cardiovascular Angiography and Interventions and other societies and characterizes the patients as Stage A “at risk” for cardiogenic shock, stage B “beginning” shock, stage C “classic” cardiogenic shock, stage D “deteriorating,” and E “extremis.”
      • Baran DA
      • Grines CL
      • Bailey S
      • Burkhoff D
      • Hall SA
      • Henry TD
      • et al.
      SCAI clinical expert consensus statement on the classification of cardiogenic shock: this document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019.
      Such classification is important to characterize the severity and stage of shock, but it is also important to acknowledge the presence of HF as the preceding cause of shock in such patients, and to identify advanced HF complicated with cardiogenic shock as the diagnosis.

      Hypertensive Emergency and Hypertensive Heart Disease

      Hypertensive emergencies encompass a spectrum of clinical presentations of uncontrolled blood pressure associated with end-organ damage that can include acute left ventricular dysfunction, pulmonary edema, MI/ischemia, and/or aortic dissection. All of these complications may result in or be complicated by an acute presentation of HF. Hypertension increases HF risk by 2- to 3-fold
      • Levy D
      • Larson MG
      • Vasan RS
      • Kannel WB
      • Ho KK.
      The progression from hypertension to congestive heart failure.
      and accounts for almost one-half of the HF cases in the US population as a population attributable risk.
      • Cheng S
      • Claggett B
      • Correia AW
      • Shah AM
      • Gupta DK
      • Skali H
      • et al.
      Temporal trends in the population attributable risk for cardiovascular disease: the Atherosclerosis Risk in Communities study.
      Thus, both acutely hypertensive emergency and chronically, hypertensive heart disease can be complicated with HF. The treatment of hypertension is upmost importance in prevention and treatment of HF, underlined as a Class I recommendation with strong level of evidence in guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.

      Valvular Heart Disease

      Aortic stenosis and mitral regurgitation can result in HF. Valvular heart disease is acknowledged as a specific disease, because it results in specific hemodynamic and ventricular alterations and requires specific treatment strategies targeting valvular abnormality. Most HF clinical trials exclude significant valvular heart disease for these reasons.

      Congenital Heart Disease

      Some types of congenital heart disease can result in HF. Incomplete or palliative correction of a congenital lesion leading to a chronic state of hemodynamic stress may result in subsequent HF, especially in complex congenital heart diseases such as tetralogy of Fallot, single ventricle defects, and transposition of the great arteries. Additional myocardial, coronary, or conduction system injury can occur due to complications of corrective surgery and can lead to progressive contractile dysfunction in some patients. The treatment should target the underlying anomaly and specific hemodynamic conditions.

      High-output HF

      High-output HF presents with similar symptoms and signs of systemic or pulmonary congestion, frequently associated with rapid heart rate and signs of peripheral vasodilation. Cardiac dysfunction may be represented by pathologically elevated cardiac output, echocardiographic signs of right ventricular dilation or dysfunction, and elevated natriuretic peptide concentrations. High-output HF is a response to extracardiac causes including liver disease, arteriovenous shunt, lung disease, thiamine deficiency, anemia, thyroid disease, or myeloproliferative disorders. The treatment is generally directed to the underlying causes. Given the unique nature of high-output failure, it is appropriate that it have a separate classification.

      Other Overlapping and Competing Diagnoses With HF

      Patients can experience clinical deterioration as specific events that may not necessarily meet the universal definition of a diagnosis of HF. Such occurrences consist of events of a primary disease process that may be associated with signs and symptoms of HF as a result of the primary cause that is not HF at that encounter. These can include cardiovascular causes such as acute MI or acute coronary syndrome, hypertensive emergency as mentioned above, and also other cardiovascular primary diagnoses, such as atrial fibrillation with rapid ventricular response, prolonged ventricular arrhythmias, pulmonary embolus, pericardial diseases, and acute valvular dysfunction. In these cardiovascular diagnoses, complication with HF is associated with worse prognosis and outcomes and underlines the urgency of addressing the underlining problem as well as the HF.
      Other noncardiovascular entities such as renal failure, liver failure, morbid obesity with peripheral edema, and chronic respiratory failure hypoventilation syndrome may present with symptoms and signs that mimic HF. Due to the volume overload and neurohormonal compensatory mechanisms involved in some of these disease states, symptoms, signs, and even hemodynamic characterization and the biomarker profile can overlap with HF, and these patients may indeed also have concomitant HF. In these cases, the proximate cause of the signs and symptoms of volume overload is a distinct 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 event “with HF” rather than a primary HF event. Another important concept that supports the principality of these competing diagnoses are that the symptoms and signs of HF may disappear once the underlying primary cause is treated; for example, symptoms and signs that mimic HF may resolve with hemodialysis in a patient with end-stage CKD who may have missed a dialysis appointment. Thus, it is important not to catalog every presentation with shortness of breath and edema that requires treatment with fluid management strategies or diuretics as HF. It is, however, also important to not miss the complication with HF, which requires timely 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 associated with CKD or diabetes mellitus are at much higher risk than those without. Rather than “competing,” these diagnoses can become complementary comorbidity risk factors to HF for worse outcomes.

      Proposed Revised Stages of the HF Continuum

      To enhance clinician, patient, and public understanding and adoption; to avoid the stigma of HF before the symptoms are manifest; to address the evolving role of biomarkers to define patients with structural and subclinical heart disease who are at higher risk of developing HF and are potential candidates for targeted treatment strategies for the prevention of HF; and to address some of the gaps identified in Section Current Classification According to Stages of HF and Its Limitations in the current approach to staging HF, we propose the following stages (Figure 2).
      • AT RISK FOR HF (STAGE A): Patients at risk for HF, but without current or prior symptoms or signs of HF and without structural cardiac changes or elevated biomarkers of heart disease. Patients with hypertension, atherosclerotic cardiovascular disease, diabetes, obesity, known exposure to cardiotoxins, a positive family history of cardiomyopathy, or genetic cardiomyopathy would be in this category. Not all of these patients will develop HF, but risk factor intervention may be warranted.
      • PRE-HF (STAGE B): Patients without current or prior symptoms or signs of HF with evidence of one of the following:
      • Structural Heart Disease: for example, left ventricular hypertrophy, cardiac chamber enlargement, ventricular wall motion abnormality, myocardial tissue abnormality (eg, evidence of myocardial edema, scar/fibrosis abnormality by T2-weighted cardiac magnetic resonance imaging or late gadolinium enhancement imaging), valvular heart disease.
      • Abnormal cardiac function: for example, reduced left or right ventricular systolic function, evidence of increased filling pressures (by invasive or noninvasive measures), abnormal diastolic dysfunction.
      • Elevated natriuretic peptide levels (for levels, refer to Table 8) or elevated cardiac troponin levels (>99th percentile in a normal reference population), especially in the setting of exposure to cardiotoxins.
      • HF (STAGE C): Patients with current or prior symptoms and/or signs of hf caused by a structural and/or functional cardiac abnormality.
      • ADVANCED HF (STAGE D): Severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite GDMT, refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplantation, mechanical circulatory support, or palliative care.
      Figure 2
      Figure 2Stages in the development and progression of HF. CVD, cardiovascular disease; DM, diabetes mellitus; HTN, hypertension;
      Abnormal cardiac function: for example, reduced left or right ventricular systolic function, can be characterized by reduced EF, abnormal ventricular strain, or other noninvasive or invasive modalities.
      Although certain genetic markers may be associated with structural cardiac changes and future HF, we did not specifically include genetic markers in the definition of pre-HF or Stage B HF, because the penetrance, expressivity, phenotypic characterization, and prognosis with genetic markers vary significantly. Because the evidence for precision for risk evolves with biomarkers, genetics, omics and/,or risk calculators, alternative approaches can be developed in the future to identify risk categories beyond traditional risk factors, and pre-HF beyond cardiac structure and biomarkers alone; and support expansion of indications for preventive treatment strategies for patients at risk or with pre-HF.
      Please note that the cutoffs provided for natriuretic peptide levels in Table 8 represent thresholds lower than inclusion criteria used in some clinical trials for symptomatic HF,
      • Packer M
      • Anker SD
      • Butler J
      • Filippatos G
      • Pocock SJ
      • Carson P
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ,
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      but similar to those used in former guidelines.
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      Thresholds proposed in the table have higher sensitivity and may have lower specificity especially in older patients, or patients with atrial fibrillation or CKD Table 7. Usually, higher cutoff values are recommended for the diagnosis of HF in these patients.
      • Ibrahim NE
      • Burnett Jr., JC
      • Butler J
      • Camacho A
      • Felker GM
      • Fiuzat M
      • et al.
      Natriuretic peptides as inclusion criteria in clinical trials: a JACC: heart failure position paper.
      For example, for ages 50 to 75, an NT-proBNP threshold value of 900 pg/mL and for ages >75 years, an NT-proBNP value of 1800 pg/mL provide reliable sensitivity and specificity for the diagnosis of HF, compared with an NT-proBNP value of 450 pg/mL for ages <50 among patients requiring hospitalization.
      • Ibrahim NE
      • Burnett Jr., JC
      • Butler J
      • Camacho A
      • Felker GM
      • Fiuzat M
      • et al.
      Natriuretic peptides as inclusion criteria in clinical trials: a JACC: heart failure position paper.
      Similarly, in patients with atrial fibrillation, an increase by 20% to 30% have been suggested in natriuretic peptide level thresholds for trial enrollment in HF,
      • Ibrahim NE
      • Burnett Jr., JC
      • Butler J
      • Camacho A
      • Felker GM
      • Fiuzat M
      • et al.
      Natriuretic peptides as inclusion criteria in clinical trials: a JACC: heart failure position paper.
      because atrial fibrillation is known to result in increased concentrations of natriuretic peptides even in the absence of HF. Furthermore, it is important to note that natriuretic peptide cut-offs selected for population screening for pre-HF (Stage B HF) may be <99% of the reference limits
      • Ledwidge M
      • Gallagher J
      • Conlon C
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      and will need to be defined according to the population at risk.

      NYHA Functional Classification

      The NYHA functional classification is important to characterize symptoms and functional capacity of patients with symptomatic (Stage C) HF or advanced HF (Stage D). The NYHA functional classification 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 even at rest and discomfort with any physical activity. We believe it is important to specify NYHA functional class at baseline after the initial diagnosis, and after treatment through the continuum of care of a patient with HF. A patient with symptomatic HF (Stage C) may become asymptomatic with treatment. Because that patient will still be categorized as HF/Stage C, NYHA functional class I can further specify his or her absence of current symptoms. Worsening NYHA functional class is associated with a worse prognosis and any symptomatic patient with HF (NYHA functional class II–IV HF) should have further optimization of GDMT.

      Recognition of Clinical Trajectory in HF

      It is well-recognized that the natural history of HF encompasses changes in the clinical risk of hospitalization and death over time, with risk increasing from “pre-HF” to “new onset/de novo HF,” and further increasing with each episode of “worsening HF” where there is deterioration of HF signs and symptoms despite ongoing therapy, requiring hospitalization or outpatient escalation of therapy.
      • Greene SJ
      • Fonarow GC
      • Butler J.
      Risk profiles in heart failure: baseline, residual, worsening, and advanced heart failure risk.
      It is crucial to identify both the stage of the patient's natural history, as well as recognize the patient's clinical trajectory (improving vs stalled or persistent vs worsening),
      • Hollenberg SM
      • Warner SL
      • Ahmad T
      • Amin VJ
      • Bozkurt B
      • Butler J
      • et al.
      2019 ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patients hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee.
      for optimal treatment, risk mitigation strategies, and patient-centered discussions. Gaining perspective of not only where the patient stands at the point in time, but in which direction the patient is headed, is a critical element of determining whether to continue along the current therapeutic course or to change direction. Thus, a patient with worsening chronic HF after initial stabilization of new onset/de novo HF would alert a physician of the immediate high risk for recurrent hospitalization or death, particularly in the period of close proximity to the worsening HF event, and trigger an escalation of disease-modifying therapies, rather than a focus on decongestion with diuretics alone. Of note, we caution against a terminology of stable HF, because patients are expected to improve with GDMT. These patients should have further optimization of therapies despite perceived stability or improvement, because there is evidence for significant improvement in outcomes with additional therapies in these patients. Lack of improvement is a marker of worse prognosis and should be termed as persistent rather than stable, and prompt clinicians to further optimize therapy. For those patients who have resolution of symptoms and signs of HF along with resolution of previously present structural and functional heart disease after a phase of symptomatic HF, we recommend HF in remission or NYHA functional class I HF status rather than recovered HF, which should be reserved for patients who have persistent resolution of HF symptoms and signs, normalization of cardiac structure, function, and biomarker profile after resolution and treatment of a fully reversible cause, especially in view of the TRED-HF trial results, which demonstrated that many patient deemed to have recovered from dilated cardiomyopathy will relapse after treatment withdrawal, suggesting remission rather than recovery
      • Halliday BP
      • Wassall R
      • Lota AS
      • Khalique Z
      • Gregson J
      • Newsome S
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF) : an open-label, pilot, randomised trial.
      (Figure 2). Full and persistent recovery is rare, and even in the setting of reversible causes, patients may have recurrence of symptoms and or develop LV dysfunction in the future.

      Acute versus Decompensated HF

      In this document, we do not use the terms acute new-onset HF or acute decompensated HF, which are the terminologies commonly used to describe patients requiring hospitalization or urgent care. The indications for hospitalization and or urgent care use vary, and most patients who require hospitalization for HF may have chronic progressively worsening HF, rather than an acute singular event. We realize these patients may present with rapid onset or progressively escalating symptoms and/or signs of HF that are associated with adverse outcomes, requiring urgent evaluation and treatment. We have elected to characterize these patients as having decompensated HF, which may represent acutely decompensated patients due to an inciting event (eg, atrial fibrillation with rapid ventricular response) or chronically and progressively worsening patients with marked deterioration of HF signs and symptoms despite ongoing therapy requiring urgent intervention, hospitalization, or rapid escalation of therapies, including advanced therapies.
      We recognize that there are a variety of acute presentations of HF (eg, myocarditis, peripartum, cardiotoxicity, stress cardiomyopathy) and other entities associated with acute presentations of HF, such as hypertensive emergency and acute MI, that will require specialized treatment strategies targeting the underlying etiology. These have been addressed by other investigators
      • Chioncel O
      • Mebazaa A
      • Harjola VP
      • Coats AJ
      • Piepoli MF
      • Crespo-Leiro MG
      • et al.
      Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC Heart Failure Long-Term Registry.
      • Gheorghiade M
      • Zannad F
      • Sopko G
      • Klein L
      • Piña IL
      • Konstam MA
      • et al.
      Acute heart failure syndromes: current state and framework for future research.
      • Mebazaa A
      • Yilmaz MB
      • Levy P
      • Ponikowski P
      • Peacock WF
      • Laribi S
      • et al.
      Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine.
      and are beyond the scope of this document.

      Proposed New Classifications of HF According to EF

      The strongest argument to use LVEF to categorize HF is that LVEF defines a group known to respond to life-prolonging therapy from randomized controlled trials.
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Drazner MH
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      ,
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ,
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • Butler J
      • Casey Jr., DE
      • Colvin MM
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      ,
      • Solomon SD
      • Claggett B
      • Lewis EF
      • Desai A
      • Anand I
      • Sweitzer NK
      • et al.
      Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
      ,
      • Solomon SD
      • Vaduganathan M
      • Claggett BL
      • Packer M
      • Zile M
      • Swedberg K
      • et al.
      Sacubitril/Valsartan across the spectrum of ejection fraction in heart failure.
      ,
      • Solomon SD
      • Claggett B
      • Packer M
      • Desai A
      • Zile MR
      • Swedberg K
      • et al.
      Efficacy of Sacubitril/Valsartan relative to a prior decompensation: the PARADIGM-HF trial.
      ,
      • Pitt B
      • Remme W
      • Zannad F
      • Neaton J
      • Martinez F
      • Roniker B
      • et al.
      Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
      ,
      • Pfeffer MA
      • Braunwald E
      • Moye LA
      • Brown Jr., EJ
      • Cuddy TE
      • Davis BR
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.
      ,
      • Pfeffer MA
      • Swedberg K
      • Granger CB
      • Held P
      • McMurray JJV
      • Michelson EL
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      • Pitt B
      • Pfeffer MA
      • Assmann SF
      • Boineau R
      • Anand IS
      • Claggett B
      • et al.
      Spironolactone for heart failure with preserved ejection fraction.
      • Solomon SD
      • McMurray JJV
      • Anand IS
      • Ge J
      • Lam CSP
      • Maggioni AP
      • et al.
      Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.
      • McMurray JJ
      • Packer M
      • Desai AS
      • Gong J
      • Lefkowitz MP
      • Rizkala AR
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      Although the LVEF also provides prognostic information, this reason alone does not justify using LVEF to define HF. Accordingly, LVEF categories were created that define groups where treatment differs.
      To be able to differentiate patients who benefit from GDMT according to clinical trial entry criteria of patients with HFrEF, capture evolving recognition of the need to identify effective treatment strategies in patients with HF associated with a mildly reduced or mid-range LVEF, as well as preserved LVEF, and harmonize with existing practice guidelines, we propose the following four classifications of EF (Figure 3):
      • HF with reduced EF (HFrEF): HF with LVEF ≤40%.
      • HF with mildly reduced EF (HFmrEF): HF with LVEF 41-49%
      • HF with preserved EF (HFpEF):HF with LVEF ≥50%.
      • HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%.
      Figure 3
      Figure 3New classification of HF according to LVEF.
      We acknowledge the growing body of evidence that standard therapy for HFrEF may be effective in and extended to select patients with HFmrEF.
      • Solomon SD
      • Claggett B
      • Lewis EF
      • Desai A
      • Anand I
      • Sweitzer NK
      • et al.
      Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
      • Solomon SD
      • Vaduganathan M
      • Claggett BL
      • Packer M
      • Zile M
      • Swedberg K
      • et al.
      Sacubitril/Valsartan across the spectrum of ejection fraction in heart failure.
      • Lund LH
      • Claggett B
      • Liu J
      • lam CS
      • Jhund PS
      • Rosano GM
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      • Cleland JGF
      • Bunting KV
      • Flather MD
      • Altman DG
      • Holmes J
      • Coats AJS
      • et al.
      Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
      It is, however, important to recognize the heterogeneity of this category, underlined by diverse findings from meta-analyses with neurohormonal antagonism, specifying benefit in certain subgroups.
      • Bozkurt B
      • Ezekowitz J.
      Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
      ,
      • Cleland JGF
      • Bunting KV
      • Flather MD
      • Altman DG
      • Holmes J
      • Coats AJS
      • et al.
      Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
      • Zheng SL
      • Chan FT
      • Nabeebaccus AA
      • Shah AM
      • McDonagh T
      • Okonko DO
      • et al.
      Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis.
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • Miura M
      • Yamauchi TT
      • Onose T
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      Evidently, LVEF is not a singular measurement by which LV function is assessed in isolation. Chamber volumes and other cardiac structural and functional parameters are important and other diagnostic modalities can be complementary. Although this classification is provided for targeting GDMT according to LVEF indications, other cardiac features are also important for phenotypic characterization, etiology, or prognosis. The development of LV dilation in a patient with HFpEF or HFmrEF 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.
      Because GDMT can result in improvement in the LVEF and reverse remodeling in patients with HFrEF, the trajectory of improvement and recovery of EF has been of interest to determine the types (eg, device, medical, advanced) and duration of treatment.
      • Wilcox JE
      • Fang JC
      • Margulies KB
      • Mann DL.
      Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
      In cases where longitudinal surveillance of LVEF is available, clinicians should also consider the trajectory of the LVEF, in addition to the LVEF at the point in time, recognizing that a significant decrease in the LVEF over time is a poor prognostic factor calling for consideration of intensification of therapy and advanced management strategies according to patient goals. Importantly, the EF can decrease after withdrawal of pharmacological treatment in many patients who had improved EF to normal range with GDMT.
      • Halliday BP
      • Wassall R
      • Lota AS
      • Khalique Z
      • Gregson J
      • Newsome S
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF) : an open-label, pilot, randomised trial.
      This result implies that there is not full recovery in cardiac structure and function in most patients despite improvement in EF. Therefore, we recommend use of the improved terminology rather than recovered EF. We believe improved EF deserves a separate classification and should not be classified as HFmrEF or HFpEF, even after an improvement in the LVEF to 41% to 49% or to ≥50%, respectively, because discontinuing HFrEF therapy in this group leads to a poor outcome.
      • Halliday BP
      • Wassall R
      • Lota AS
      • Khalique Z
      • Gregson J
      • Newsome S
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF) : an open-label, pilot, randomised trial.
      GDMT should be continued in patients with HF with improved EF regardless of whether it has improved to normal range, a LVEF of ≥50%, especially in view of the TRED-HF trial results.
      • Halliday BP
      • Wassall R
      • Lota AS
      • Khalique Z
      • Gregson J
      • Newsome S
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF) : an open-label, pilot, randomised trial.
      We also recognize that patients with a baseline LVEF of 41% to 49% who have an improved LVEF to ≥50% may be categorized as HF with improved EF.

      Approaches to Specific Etiologies of HF

      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 etiology/etiologies of HF. Understanding the underlying etiological processes of HF can provide important information in selecting the most appropriate therapy beyond standard approaches guided by EF phenotypic characterization, especially when specific targeted treatment strategies are indicated,
      • Bozkurt B
      • Colvin M
      • Cook J
      • Cooper LT
      • Deswal A
      • Fonarow GC
      • et al.
      Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
      provided the diagnostic and/or specific treatment strategies are cost effective, with favorable benefit risk ratios and are in line with patient goals. For example, a patient with cardiac amyloidosis requires different treatment strategies than standard HF therapies. The diagnosis of such a patient solely as HFpEF or HFrEF without further workup to confirm the diagnosis of cardiac amyloidosis may deprive the patient potentially life-saving therapies for amyloidosis.
      In clinical practice, the etiology of HF has often been placed into 2 categories: ischemic and nonischemic cardiomyopathy. However, a further diagnostic workup for etiology should be carried out beyond the first step of defining ischemic or nonischemic etiology, especially for dilated, infiltrative, hypertrophic, and idiopathic cardiomyopathies.
      • Bozkurt B
      • Colvin M
      • Cook J
      • Cooper LT
      • Deswal A
      • Fonarow GC
      • et al.
      Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
      Many attempts have been made for morphofunctional classifications of cardiomyopathies in the past.
      • Bozkurt B
      • Colvin M
      • Cook J
      • Cooper LT
      • Deswal A
      • Fonarow GC
      • et al.
      Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
      ,
      • Maron BJ
      • Towbin JA
      • Thiene G
      • Antzelevitch C
      • Corrado D
      • Arnett D
      • et al.
      Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
      ,
      • Arbustini E
      • Narula N
      • Tavazzi L
      • Serio A
      • Grasso M
      • Favalli V
      • et al.
      The MOGE(S) classification of cardiomyopathy for clinicians.
      ,
      • Elliott P
      • Andersson B
      • Arbustini E
      • Bilinska Z
      • Cecchi F
      • Charron P
      • et al.
      Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases.
      In this statement, we do not provide recommendations for classifications of specific cardiomyopathies, because we feel those remain outside the scope of this document.

      Perspective for the Noncardiologist

      The majority of the HF care is provided by noncardiologists, including general practitioners, internal medicine or family medicine clinicians, hospitalists, emergency room providers, and other specialists. We believe the universal definition will be useful to these clinicians for the timely diagnosis and management of patients with HF. Important points for the noncardiologists are as follows. It is critical to optimally identify and treat patients at risk for HF to prevent or delay the development of HF; recognize that pre-HF patients, such as asymptomatic patients with elevated natriuretic peptide levels likely will require referral to a cardiologist for further diagnostic and treatment strategies to prevent progression of HF
      • Ledwidge M
      • Gallagher J
      • Conlon C
      • et al.
      Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
      ,
      • Mueller C
      • McDonald K
      • de Boer RA
      • Maisel A
      • Cleland JGF
      • Kozhuharov N
      • et al.
      Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations.
      ; that the diagnosis and timely treatment of HF should not be missed or delayed in patients with symptoms and signs of HF; and that elevated natriuretic peptide levels or patients with evidence of systemic or pulmonary congestion/elevated filling pressures, and patients with advanced HF would be considered for referral to HF specialists according to their goals.

      Appendix 1

      Appendix A.1.
      Appendix A.1Author Relationships With Industry and Other Entities
      Writing Committee MemberEmployment/AffiliationConsultantSpeakers BureauOwnership/Partnership/PrincipalPersonal ResearchInstitutional, Organizational, or Other Financial BenefitExpert Witness
      Magdy AbdelhamidProfessor of Cardiovascular Medicine Faculty of Medicine, Kasr Al Ainy, Cairo University, EgyptNoneNoneNoneNoneNoneNone
      Stamatis AdampoulosDirector, Heart Failure and Transplant Units, Onassis Cardiac Surgery Centre, Athens-GreeceNoneNoneNoneNoneNoneNone
      Nancy AlbertAssociate Chief Nursing Officer, Research and Innovation- Nursing Institute and Clinical Nurse Specialist, Kaufman Center for Heart Failure- Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OHAmgen, AstraZeneca, Boston Scientific, Merck, NovartisNoneNoneNoneNoneNone
      Stefan AnkerDepartment of Cardiology (CVK), Charité - Universitätsmedizin Berlin; Berlin Institute of Health Center for Regenerative Therapies (BCRT) ; German Centre for Cardiovascular Research (DZHK), Berlin, GermanyVifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Abbott, Actimed, Cardiac Dimensions, Impulse DynamicsNoneNoneVifor Int and Abbott,NoneNone
      John AthertonDirector of Cardiology, Royal Brisbane and Women's Hospital, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia 4006Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Impedimed, Novartis, Otsuka, Vifor Pharma.Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, NovartisNoneNoneNoneNone
      Michael BöhmKlinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Saarland University

      Kirrberger Str. 1, 66421 Homburg/Saar, Germany
      NoneAbott, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Medtronic, Novartis, Servier, ViforNoneNoneDeutsche Forschungsgemein-schaft (DFG, SFB-TTR 219, S-01None
      Biykem BozkurtBaylor College of Medicine, Winters Center for Heart Failure Research, Cardiovascular Research Institute and Michael E. DeBakey VA Medical Center Houston, TX USAAbbott

      Amgen

      Baxter

      Bristol Myers Squibb

      Liva Nova

      RELYPSA/Vifor Pharma

      Respicardia Registry Steering Committee

      Sanofi-aventis

      Pharmaceuticals, Inc
      NoneNoneNoneNoneNone
      Javed ButlerUniversity of Mississippi Medical CenterAbbott, Adrenomed, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Sequana Medical, V-Wave Limited, and ViforNovartis, BI-Lilly, Astra Zeneca, JanssenNoneNoneNoneNone
      Andrew CoatsUniversity of Warwick, UK and Monash University, AustraliaAstra Zeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Gore, Impulse Dynamics, RespicardiaNoneNoneNoneNoneNone
      Mark DraznerClinical Chief of Cardiology, University of Texas Southwestern Medical Center, Department of Internal Medicine/Division of CardiologyNoneNoneNoneNoneNoneNone
      G. Michael FelkerDuke University School of Medicine, Durham, NCNovartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Innolife, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, 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 PharmaNoneNoneNoneNoneNone
      Gerasimos FilippatosNational and Kapodistrian University of Athens; Department of Cardiology, Athens University Hospital Attikon, Athens, GreeceMedtronic, Vifor, Servier, Novartis, Boehringer Ingelheim, Bayer, Amgen.NoneNoneNoneEuropean UnionNone
      Mona FiuzatDuke UniversityNoneNoneNoneNoneNoneNone
      Gregg FonarowDivision of Cardiology, University of California, Los Angeles, CA, USAbbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, Merck, NovartisNoneNoneNIHNoneNone
      Juan Esteban Gomez-MesaHead of the Cardiology Service of the 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.NoneNoneNoneNoneNoneNone
      Paul HeidenreichVA Palo Alto Health Care System, Stanford University School of MedicineNoneNoneNoneNoneNoneNone
      Teruhiko ImamuraSecond Department of Internal Medicine, University of ToyamaNoneNoneNoneNoneNoneNone
      James JanuzziMassachusetts General HospitalRoche Diagnostics, Siemens, Quidel, Abbott, Novartis, Merck, Jana Care, ImbriaNoneNoneNovartis, RocheEndpoint committees: AbbVie, Amgen, Bayer, CVRx, InterceptNone
      Ewa JankowskaDepartment of Heart Diseases, Wroclaw Medical University, Poland and Centre for Heart Diseases, University Hospital, Wroclaw, PolandBayer, Abbott, Vifor Pharma, Pfizer, Servier, AstraZeneca, Boehringer

      Ingelheim, Berlin Chemie, Novartis, Cardiac Dimensions
      Bayer, Vifor Pharma, Pfizer, Servier, AstraZeneca, Boehringer Ingelheim, Fresenius, Berlin Chemie, Gedeon Richter, NovartisNoneNoneUnrestricted research grant for Wroclaw Medical University Co-PI role in the AFFIRM-AHF trial sponsored by Vifor PharmaNone
      Prateeti KhazanieThe University of Colorado School of Medicine, Division of Cardiology, Department of Medicine, Aurora, Colorado, USNoneNoneNoneNoneNoneNone
      Koichiro KinugawaUniversity of ToyamaNoneNoneNoneNoneNoneNone
      Carolyn S.P. LamNational Heart Centre, Singapore & Duke-National University of SingaporeAbbott Diagnostics, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Biofourmis, Boehringer Ingelheim, Boston Scientific, Corvia Medical, 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 LLCNoneco-founder & non-executive director of EKo.ai Pte LtdBoston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor PharmaNoneNone
      Yuya MatsueDepartment of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine and Cardiovascular Respiratory Sleep Medicine Juntendo University, Graduate School of MedicineOtsuka Pharmaceutical Co., Ltd. and Novartis JapanOtsuka Pharmaceutical Co. and Pfizer, Inc.Philips Respironics, ResMed, and Fukuda Denshi
      Marco MetraUniversity of BresciaActelion, Amgen, Astra-Zeneca, Bayer, Livanova, Servier, Vifor pharma, WindTree Therapeutics, as member of Committees for clinical trials or advisory boardsAbbott vascular, Amgen, Edwards Therapeutics, ServiernonenoneNonenone
      Tomohito OhtaniDepartment of Cardiovascular Medicine, Osaka University Graduate School of MedicineNoneBristol-Myers Squibb Company, Daiichi-Sankyo Co. Ltd, Nippon Boehringer Ingelheim Co. Ltd, Otsuka Pharmaceutical Co. Ltd.NoneNoneNoneNone
      Massimo Francesco PiepoliCardiac Unit, Guglielmo da Saliceto Hospital, Piacenza and University of Parma, ItalyAstra Zeneca, Novartis, Servier, Vifor, TRX ItalyNoneNoneNoneNoneNone
      Piotr PonikowskiDepartment of Heart Diseases, Wroclaw Medical University, Poland;

      Centre for Heart Diseases, University Hospital, Wroclaw, Poland
      Vifor Pharma, Amgen, Servier, Novartis, Bayer, Pfizer, Cibiem, Coridea, Impulse Dynamics, Renal Guard Solutions, Boehringer Ingelheim, AstraZeneca, Corvia, BMS, V-wave LimitedVifor Pharma, Amgen, Servier, Novartis, Pfizer, Impulse Dynamics, Renal Guard Solutions, Boehringer Ingelheim, AstraZeneca, Berlin Chemie, Radcliffe Group; Ono PharmaceuticalNoneNoneAbbott Vascular – co-PI of the RESHAPE-2 trial

      Vifor Pharma – PI of the AFFIRM-AHF trial

      Vifor Pharma - research grant for the institution

      Medical Research Agency – Poland: grant for IIT
      None
      Giuseppe RosanoCentre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, ItalyNoneNoneNoneNoneNoneNone
      Yasushi SakataDepartment of Cardiovascular Medicine, Osaka University Graduate School of MedicineNoneOtsuka Pharmaceutical Co., Ltd.

      DAIICHI SANKYO COMPANY, LIMITED

      Novartis Pharma K.K.

      Nippon Boehringer Ingelheim Co., Ltd.
      NoneNoneAstellas Pharma Inc.

      Otsuka Pharmaceutical Co., Ltd.

      DAIICHI SANKYO COMPANY, LIMITED

      Medtronic Japan Co., Ltd.

      Nippon Boehringer Ingelheim Co., Ltd.

      Bristol-Myers Squibb K.K.
      None
      Petar SeferovicVice-president, European Society of Cardiology

      President, Heart failure Association of the ESC (2018-2020)

      Academician, Serbian Academy of 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
      Boehringer Ingelheim, Novartis, Vifor PharmaBoehringer Ingelheim, Novartis, Medtronic, Abbott, Servier, Astra Zeneca, RespicardiaNoneNoneNoneNone
      Randy C StarlingEmployee Cleveland Clinic

      Heart, Vascular and Thoracic Institute

      Cleveland Ohio USA

      Member FDA Circulatory System Devices Panel
      Novartis PARAGLIDE steering committee. No honoraria.

      Cardiac Dimensions Steering Committee Carillon Trial
      NoneNoneNoneNoneNone
      John R TeerlinkSection of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California San FranciscoAbbott, Amgen, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cytokinetics, Daxor, EBR Systems, Lilly, LivaNova, Medtronic, Merck, Novartis, Relypsa, Servier, Windtree Therapeutics, ZS PharmaNoneNoneNoneNoneNone
      Hiroyuki TsutsuiDepartment of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu UniversityNippon Boehringer Ingelheim Co., Ltd.

      Bayer Yakuhin, Ltd.

      Novartis Pharma K.K.

      Ono Pharmaceutical Co., Ltd.
      MSD K.K.

      Astellas Pharma Inc.

      Pfizer Japan Inc.

      Bristol-Myers Squibb Company

      Otsuka Pharmaceutical Co., Ltd.

      Daiichi Sankyo Co., Ltd.

      Mitsubishi Tanabe Pharma Corporation

      Nippon Boehringer Ingelheim Co., Ltd.

      Takeda Pharmaceutical Company Limited

      Bayer Yakuhin, Ltd.

      Novartis Pharma K.K.

      Kowa Pharmaceutical Co. Ltd.

      Teijin Pharma Ltd.
      NoneActelion Pharmaceuticals Japan Ltd.

      Japan Tobacco Inc.

      Mitsubishi Tanabe Pharma Corporation

      Nippon Boehringer Ingelheim Co., Ltd.

      Daiichi Sankyo Co., Ltd.

      IQVIA Services Japan

      Omron Healthcare
      Astellas Pharma Inc.

      Novartis Pharma K.K.

      Daiichi Sankyo Co., Ltd.

      Takeda Pharmaceutical Company Limited

      Mitsubishi Tanabe Pharma Corporation

      Teijin Pharma Ltd.

      MSD K.K.
      None
      Orly VardenyMinneapolis Veterans Administration Health Care Center and University of MinnesotaSanofi-Pasteur, NovartisNoneNoneNIH, FDA, AstraZeneca, BayerAmerican Heart AssociationNone
      Kazuhiro YamamotoDepartment of Cardiovascular Medicine, and Endocrinology and Metabolism

      Faculty of Medicine

      Tottori University
      NoneOtsuka Pharmaceutical Co. Ltd, Daiichi-Sankyo Co. Ltd., Novartis,NoneNoneAbbott, Otsuka Pharmaceutical Co. Ltd., Medtronic Japan Co., Ltd., Daiichi-Sankyo Co. Ltd., Biotronik Japan Inc., Japan Lifeline Co. Ltd., Mitsubishi Tanabe Pharma Co. Ltd., Fukuda Denshi, Takeda Pharmaceutical Co. Ltd., Novartis, Ono Pharmaceutical Co. Ltd., Boston Scientific Co. Ltd.

      None
      Clyde YancyNorthwestern University, Feinberg School of MedicineSpousal Employment, Abbott, Inc.NoneNoneNoneDeputy Editor, JAMA NetworkNone
      Shelley ZierothCardiac Sciences Program, University of ManitobaAbbott, Akcea, Astra Zeneca, Amgen, Alnylam, Boehringer Ingelheim, Eli-Lilly, Merck, Novartis, Otsuka, Pfizer, Servier, ViforAmgen, Astra Zeneca, Boehringer Ingelheim, Eli-Lilly, Novartis, Servier, ViforNoneNovartisNoneNone
      Jian ZhangFuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeNoNoNoNoNoNo
      FDA, US Food and Drug Administration.
      Appendix 2.

      References

        • Braunwald E.
        Heart failure.
        JACC Heart Fail. 2013; 1: 1-20
        • Wagner S
        • Cohn K.
        Heart failure. A proposed definition and classification.
        Arch Intern Med. 1977; 137: 675-678
        • Yancy CW
        • Jessup M
        • Bozkurt B
        • Butler J
        • Casey Jr., DE
        • Drazner MH
        • et al.
        2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
        Circulation. 2013; 128: e240-e327
        • Ponikowski P
        • Voors AA
        • Anker SD
        • Bueno H
        • Cleland JGF
        • Coats AJS
        • et al.
        2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
        Eur Heart J. 2016; 37: 2129-2200
        • Tsutsui H
        • Isobe M
        • Ito H
        • Okumura K
        • Ono M
        • Kitakaze M
        • et al.
        JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version.
        Circ J. 2019; 83: 2084-2184
        • Tan LB
        • Williams SG
        • Tan DK
        • Cohen-Solal A
        So many definitions of heart failure: are they all universally valid? A critical appraisal.
        Expert Rev Cardiovasc Ther. 2010; 8: 217-228
        • Harris P.
        The problem of defining heart failure.
        Cardiovasc Drugs Ther. 1994; 8: 447-452
        • Denolin H
        • Kuhn H
        • Krayenbuehl HP
        • Loogen F
        • Reale A.
        The definition of heart failure.
        Eur Heart J. 1983; 4: 445-448
        • Cleland JGF
        • Pellicori P
        • Clark AL.
        Prevention or procrastination for heart failure?: why we need a universal definition of heart failure.
        J Am Coll Cardiol. 2019; 73: 2398-2400
        • Virani SS
        • Alonso A
        • Benjamin EJ
        • Bittencourt MS
        • Callaway C
        • Carson AP
        • et al.
        Heart disease and stroke statistics-2020 update: a report from the American Heart Association.
        Circulation. 2020; 141: e139-e596
        • Heidenreich PA
        • Trogdon JG
        • Khavjou OA
        • Butler J
        • Dracup K
        • Ezekowitz MD
        • et al.
        Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association.
        Circulation. 2011; 123: 933-944
        • Pinney SP.
        Disparities in heart failure care: now is the time to focus on health care delivery.
        J Am Coll Cardiol. 2014; 64: 808-810
        • Bozkurt B.
        Reasons for lack of improvement in treatment with evidence-based therapies in heart failure.
        J Am Coll Cardiol. 2019; 73: 2384-2387
        • Greene SJ
        • Fonarow GC
        • DeVore AD
        • Sharma PP
        • Vadugahathan M
        • Albert NM
        • et al.
        Titration of medical therapy for heart failure with reduced ejection fraction.
        J Am Coll Cardiol. 2019; 73: 2365-2383
        • Bozkurt B
        • Ezekowitz J.
        Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials.
        Circulation. 2020; 141: 362-366
        • Vaduganathan M
        • Claggett BL
        • Jhund PS
        • Cunningham JW
        • Ferreira JP
        • Zannad F
        • et al.
        Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.
        Lancet. 2020; 396: 121-128
        • Bonow RO
        • Ganiats TG
        • Beam CT
        • et al.
        ACCF/AHA/AMA-PCPI 2011 performance measures for adults with heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures and the American Medical Association-Physician Consortium for Performance Improvement.
        Circulation. 2012; 125: 2382-2401
        • Heidenreich PA
        • Fonarow GC
        • Breathett K
        • Jurgens CY
        • Pisani BA
        • Pozehl BJ
        • et al.
        2020 ACC/AHA clinical performance and quality measures for adults with heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures.
        Circ Cardiovasc Qual Outcomes. 2020; 13 (e000099)
        • Bozkurt B
        • Hershberger RE
        • Butler J
        • Isler ML
        • Grady KL
        • Kirklin JK
        • et al.
        TEMPORARY NOTICE: 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Heart Failure) [e-pub ahead of print].
        J Am Coll Cardiol. 2021; (Accessed February 13, 2021)https://doi.org/10.1016/j.jacc.2020.11.012
        • Fiuzat M
        • Lowy N
        • Stockbridge N
        • Sbolli M
        • Latta F
        • Lindenfeld J
        • et al.
        Endpoints in heart failure drug development: history and future.
        JACC Heart Fail. 2020; 8: 429-440
        • Hicks KA
        • Mahaffey KW
        • Mehran R
        • Nissen SE
        • Wiviott SD
        • Dunn B
        • et al.
        2017 cardiovascular and stroke endpoint definitions for clinical trials.
        Circulation. 2018; 137: 961-972
        • Thygesen K
        • Alpert JS
        • Jaffe AS
        • Chaitman BR
        • Bax JJ
        • Morrow DA
        • et al.
        Fourth universal definition of myocardial infarction (2018).
        Circulation. 2018; 138: e618-e651
        • McKee PA
        • Castelli WP
        • McNamara PM
        • Kannel WB.
        The natural history of congestive heart failure: the Framingham study.
        N Engl J Med. 1971; 285: 1441-1446
        • Adamo L
        • Nassif ME
        • Novak E
        • LaRue SJ
        • Mann DL.
        Prevalence of lactic acidaemia in patients with advanced heart failure and depressed cardiac output.
        Eur J Heart Fail. 2017; 19: 1027-1033
        • Bozkurt B
        • Colvin M
        • Cook J
        • Cooper LT
        • Deswal A
        • Fonarow GC
        • et al.
        Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
        Circulation. 2016; 134: e579-e646
        • Maron BJ
        • Towbin JA
        • Thiene G
        • Antzelevitch C
        • Corrado D
        • Arnett D
        • et al.
        Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
        Circulation. 2006; 113: 1807-1816
        • Katz AM.
        Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure.
        N Engl J Med. 1990; 322: 100-110
        • Arbustini E
        • Narula N
        • Tavazzi L
        • Serio A
        • Grasso M
        • Favalli V
        • et al.
        The MOGE(S) classification of cardiomyopathy for clinicians.
        J Am Coll Cardiol. 2014; 64: 304-318
        • Yancy CW
        • Jessup M
        • Bozkurt B
        • Butler J
        • Casey Jr., DE
        • Colvin MM
        • et al.
        2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
        Circulation. 2017; 136: e137-e161
        • Inker LA
        • Astor BC
        • Fox CH
        • Isakova T
        • Lash JP
        • Peralata CA
        • et al.
        KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
        Am J Kidney Dis. 2014; 63: 713-735
        • Blecker S
        • Katz SD
        • Horwitz LI
        • Kuperman G
        • Park H
        • Gold A
        • et al.
        Comparison of approaches for heart failure case identification from electronic health record data.
        JAMA Cardiol. 2016; 1: 1014-1020
        • Sabbah HN.
        Silent disease progression in clinically stable heart failure.
        Eur J Heart Fail. 2017; 19: 469-478
        • Seid MA
        • Abdela OA
        • Zeleke EG.
        Adherence to self-care recommendations and associated factors among adult heart failure patients. From the patients' point of view.
        PLoS One. 2019; 14e0211768
        • Gislason GH
        • Rasmussen JN
        • Abildstrom SZ
        • Schramm TK
        • Hansen ML
        • Buch P
        • et al.
        Persistent use of evidence-based pharmacotherapy in heart failure is associated with improved outcomes.
        Circulation. 2007; 116: 737-744
        • Santos GC
        • Liljeroos M
        • Dwyer AA
        • Jaques C
        • Girard J
        • Strömbert
        • et al.
        Symptom perception in heart failure: a scoping review on definition, factors and instruments.
        Eur J Cardiovasc Nurs. 2020; 19: 100-117
        • Zakeri R
        • Cowie MR.
        Heart failure with preserved ejection fraction: controversies, challenges and future directions.
        Heart. 2018; 104: 377-384
        • Felker GM
        • Thompson RE
        • Hare JM
        • Hruban RH
        • Clemetson DE
        • Howard DL
        • et al.
        Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.
        N Engl J Med. 2000; 342: 1077-1084
        • Atherton JJ
        • Sindone A
        • De Pasquale CG
        • Driscoll A
        • MacDonald PS
        • Hopper I
        • et al.
        National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: guidelines for the prevention, detection, and management of heart failure in Australia 2018.
        Heart Lung Circ. 2018; 27: 1123-1208
        • Abraham WT
        • Ptoska MA
        • Fiuzat M
        • Filippatos G
        • Lindenfeld J
        • Mehran R
        • et al.
        Standardized definitions for heart failure: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium (HF-ARC).
        JACC Heart Fail. 2020;
        • Bohm M
        • Bewarder Y
        • Kindermann I.
        Ejection fraction in heart failure revisited- where does the evidence start?.
        Eur Heart J. 2020; 41: 2363-2365
        • Solomon SD
        • Claggett B
        • Lewis EF
        • Desai A
        • Anand I
        • Sweitzer NK
        • et al.
        Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
        Eur Heart J. 2016; 37: 455-462
        • Solomon SD
        • Vaduganathan M
        • Claggett BL
        • Packer M
        • Zile M
        • Swedberg K
        • et al.
        Sacubitril/Valsartan across the spectrum of ejection fraction in heart failure.
        Circulation. 2020; 141: 352-361
        • Lund LH
        • Claggett B
        • Liu J
        • lam CS
        • Jhund PS
        • Rosano GM
        • et al.
        Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
        Eur J Heart Fail. 2018; 20: 1230-1239
        • Cleland JGF
        • Bunting KV
        • Flather MD
        • Altman DG
        • Holmes J
        • Coats AJS
        • et al.
        Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
        Eur Heart J. 2018; 39: 26-35
        • Zheng SL
        • Chan FT
        • Nabeebaccus AA
        • Shah AM
        • McDonagh T
        • Okonko DO
        • et al.
        Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis.
        Heart. 2018; 104: 407-415
        • Tsuji K
        • Sakata Y
        • Nochioka K
        • Miura M
        • Yamauchi TT
        • Onose T
        • et al.
        Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
        Eur J Heart Fail. 2017; 19: 1258-1269
        • Chioncel O
        • Lainscak M
        • Seferovic PM
        • Anker SD
        • Crespo-leiro MG
        • Harjola VP
        • et al.
        Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
        Eur J Heart Fail. 2017; 19: 1574-1585
        • van Veldhuisen DJ
        • Linssen GC
        • Jaarsma T
        • van Gilst WH
        • Hoes AW
        • Tijssen JGP
        • et al.
        B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.
        J Am Coll Cardiol. 2013; 61: 1498-1506
        • Lam CSP
        • Gamble GD
        • Ling LH
        • Sim D
        • Leong KTG
        • Yeo PSD
        • et al.
        Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.
        Eur Heart J. 2018; 39: 1770-1780
        • Rastogi A
        • Novak E
        • Platts AE
        • Mann DL.
        Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction.
        Eur J Heart Fail. 2017; 19: 1597-1605
        • Vedin O
        • Lam CSP
        • Koh AS
        • Benson L
        • Teng THK
        • Tay WT
        • et al.
        Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study.
        Circ Heart Fail. 2017; 10e003875
        • Linde C
        • Curtis AB
        • Fonarow GC
        • Lee K
        • Little W
        • Tang A
        • et al.
        Cardiac resynchronization therapy in chronic heart failure with moderately reduced left ventricular ejection fraction: lessons from the Multicenter InSync Randomized Clinical Evaluation MIRACLE EF study.
        Int J Cardiol. 2016; 202: 349-355
        • Pellikka PA
        • She L
        • Holly TA
        • Lin G
        • Varadarajan P
        • Pai RG
        • Bonow RO
        • et al.
        Variability in ejection fraction measured By echocardiography, gated single-photon emission computed tomography, and cardiac magnetic resonance in patients with coronary artery disease and left ventricular dysfunction.
        JAMA Netw Open. 2018; 1 (e181456)
        • Hunt SA
        • Baker DW
        • Chin MH
        • Cinquegrani MP
        • Feldman AM
        • Francis GS
        • et al.
        ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America.
        Circulation. 2001; 104: 2996-3007
        • Baran DA
        • Grines CL
        • Bailey S
        • Burkhoff D
        • Hall SA
        • Henry TD
        • et al.
        SCAI clinical expert consensus statement on the classification of cardiogenic shock: this document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019.
        Catheter Cardiovasc Interv. 2019; 94: 29-37
        • Ammar KA
        • Jacobsen SJ
        • Mahoney DW
        • Kors JA
        • Redfield MM
        • Burnett Jr., JC
        • et al.
        Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community.
        Circulation. 2007; 115: 1563-1570
        • Wagner M
        • Tiffe T
        • Morbach C
        • Gelbrich G
        • Stork S
        • Heuschmann PU.
        Characteristics and course of heart failure stages A-B and determinants of progression - design and rationale of the STAAB cohort study.
        Eur J Prev Cardiol. 2017; 24: 468-479
        • Morbach C
        • Gelbrich G
        • Tiffe T
        • Eichner FA
        • Christa M
        • Mattern R
        • et al.
        Prevalence and determinants of the precursor stages of heart failure: results from the population-based STAAB cohort study [e-pub ahead of print].
        Eur J Prev Cardiol. 2021; (Accessed February 13, 2021)https://doi.org/10.1177/2047487320922636
        • Young K
        • Scott C
        • Rodeheffer RJ
        • Chen CH.
        Preclinical heart failure: evaluation of long-term outcomes in patients with stage A and stage B heart failure in the general population.
        Circulation. 2018;; 134 (A15103-A15193. Ref Type: Abstract)
        • Correa de Sa DD
        • Hodge DO
        • Slusser JP
        • Redfield MM
        • Simari RD
        • Burnett JC
        • et al.
        Progression of preclinical diastolic dysfunction to the development of symptoms.
        Heart. 2010; 96: 528-532
        • Bozkurt B
        • Aguilar D
        • Deswal A
        • Dunbar SB
        • Francis GS
        • Horwich T
        • et al.
        Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association.
        Circulation. 2016; 134: e535-e578
        • Zinman B
        • Wanner C
        • Lachin JM
        • Fitchett D
        • Bluhmki E
        • Hantel S
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Neal B
        • Perkovic V
        • Mahaffey KW
        • de Zeeuw D
        • Fulcher G
        • Erondu N
        • et al.
        Canagliflozin and cardiovascular and renal events in Type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Wiviott SD
        • Raz I
        • Bonaca MP
        • Mosenzon O
        • Kato ET
        • Cahn A
        • et al.
        Dapagliflozin and cardiovascular outcomes in Type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357
        • Packer M
        • Anker SD
        • Butler J
        • Filippatos G
        • Pocock SJ
        • Carson P
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • McMurray JJV
        • Solomon SD
        • Inzucchi SE
        • Køber L
        • Kosiborod MN
        • Martinez FA
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Berg DD
        • Wiviott SD
        • Scirica BM
        • Gurmu Y
        • Mosenzon O
        • Murphy SA
        • et al.
        Heart failure risk stratification and efficacy of sodium-glucose cotransporter-2 inhibitors in patients with Type 2 diabetes mellitus.
        Circulation. 2019; 140: 1569-1577
        • Ledwidge M
        • Gallagher J
        • Conlon C
        • et al.
        Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
        JAMA. 2013 July 3; 310: 66-74
        • Saunders JT
        • Nambi V
        • de Lemos JA
        • Chambless LE
        • Virani SS
        • Boerwinkle E
        • et al.
        Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
        Circulation. 2011; 123: 1367-1376
        • deFilippi CR
        • de Lemos JA
        • Christenson RH
        • Gottdiener JS
        • Kop WJ
        • Zhan M
        • et al.
        Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.
        JAMA. 2010; 304: 2494-2502
        • Avila MS
        • Ayub-Ferreira SM
        • de Barros Wanderley Jr, MR
        • das Dores Cruz F
        • Gonçalves Brandão SM
        • Carvalho Rigaud VO
        • et al.
        Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: the CECCY Trial.
        J Am Coll Cardiol. 2018; 71: 2281-2290
        • Wilcox JE
        • Fang JC
        • Margulies KB
        • Mann DL.
        Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
        J Am Coll Cardiol. 2020; 76: 719-734
        • Butler J
        • Braunwald E
        • Gheorghiade M.
        Recognizing worsening chronic heart failure as an entity and an end point in clinical trials.
        JAMA. 2014; 312: 789-790
        • Greene SJ
        • Mentz RJ
        • Felker GM.
        Outpatient worsening heart failure as a target for therapy: a review.
        JAMA Cardiol. 2018; 3: 252-259
        • Solomon SD
        • Claggett B
        • Packer M
        • Desai A
        • Zile MR
        • Swedberg K
        • et al.
        Efficacy of Sacubitril/Valsartan relative to a prior decompensation: the PARADIGM-HF trial.
        JACC Heart Fail. 2016; 4: 816-822
        • Halliday BP
        • Wassall R
        • Lota AS
        • Khalique Z
        • Gregson J
        • Newsome S
        • et al.
        Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF) : an open-label, pilot, randomised trial.
        Lancet. 2019; 393: 61-73
        • Nishimura RA
        • Otto CM
        • Bonow RO
        • Carabello BA
        • Erwin III, JP
        • Fleisher LA
        • et al.
        2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.
        Circulation. 2017; 135: e1159-e1195
        • January CT
        • Wann LS
        • Calkins H
        • Chen LY
        • Cigarroa JE
        • Cleveland Jr., JC
        • et al.
        2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society in Collaboration with the Society of Thoracic Surgeons.
        Circulation. 2019; 140: e125-e151
        • Pocock SJ
        • Ariti CA
        • McMurray JJ
        • Maggioni A
        • Køber L
        • Squire IB
        • et al.
        Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies.
        Eur Heart J. 2013; 34: 1404-1413
        • Martin P
        • DiMartini A
        • Feng S
        • Brown Jr., R
        • Fallon M
        Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
        Hepatology. 2014; 59: 1144-1165
        • Kartoun U
        • Corey KE
        • Simon TG
        • Zheng H
        • Aggarwal R
        • Ng K
        • et al.
        The MELD-Plus: a generalizable prediction risk score in cirrhosis.
        PLoS One. 2017; 12e0186301
        • Vestbo J
        • Hurd SS
        • Agusti AG
        • Jones PW
        • Vogelmeier C
        • Anzueto A
        • et al.
        Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
        Am J Respir Crit Care Med. 2013; 187: 347-365
        • Nohria A
        • Lewis E
        • Stevenson LW.
        Medical management of advanced heart failure.
        JAMA. 2002; 287: 628-640
        • Simonneau G
        • Gatzoulis MA
        • Adatia I
        • Celemajer D
        • Denton C
        • Ghofrani A
        • et al.
        Updated clinical classification of pulmonary hypertension.
        J Am Coll Cardiol. 2013; 62: D34-D41
        • Shah SJ
        • Katz DH
        • Selvaraj S
        • Burke MA
        • Yancy CW
        • Gheorghiade M
        • et al.
        Phenomapping for novel classification of heart failure with preserved ejection fraction.
        Circulation. 2015; 131: 269-279
        • Stevenson LW.
        Design of therapy for advanced heart failure.
        Eur J Heart Fail. 2005; 7: 323-331
        • Pitt B
        • Remme W
        • Zannad F
        • Neaton J
        • Martinez F
        • Roniker B
        • et al.
        Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
        N Engl J Med. 2003; 348: 1309-1321
      1. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
        Lancet. 1993; 342: 821-828
        • Pfeffer MA
        • Braunwald E
        • Moye LA
        • Brown Jr., EJ
        • Cuddy TE
        • Davis BR
        • et al.
        Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.
        N Engl J Med. 1992; 327: 669-677
        • Levy D
        • Larson MG
        • Vasan RS
        • Kannel WB
        • Ho KK.
        The progression from hypertension to congestive heart failure.
        JAMA. 1996; 275: 1557-1562
        • Cheng S
        • Claggett B
        • Correia AW
        • Shah AM
        • Gupta DK
        • Skali H
        • et al.
        Temporal trends in the population attributable risk for cardiovascular disease: the Atherosclerosis Risk in Communities study.
        Circulation. 2014; 130: 820-828
        • Ibrahim NE
        • Burnett Jr., JC
        • Butler J
        • Camacho A
        • Felker GM
        • Fiuzat M
        • et al.
        Natriuretic peptides as inclusion criteria in clinical trials: a JACC: heart failure position paper.
        JACC Heart Fail. 2020; 8: 347-358
        • Greene SJ
        • Fonarow GC
        • Butler J.
        Risk profiles in heart failure: baseline, residual, worsening, and advanced heart failure risk.
        Circ Heart Fail. 2020; 13e007132
        • Hollenberg SM
        • Warner SL
        • Ahmad T
        • Amin VJ
        • Bozkurt B
        • Butler J
        • et al.
        2019 ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patients hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee.
        J Am Coll Cardiol. 2019; 74: 1966-2011
        • Chioncel O
        • Mebazaa A
        • Harjola VP
        • Coats AJ
        • Piepoli MF
        • Crespo-Leiro MG
        • et al.
        Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC Heart Failure Long-Term Registry.
        Eur J Heart Fail. 2017; 19: 1242-1254
        • Gheorghiade M
        • Zannad F
        • Sopko G
        • Klein L
        • Piña IL
        • Konstam MA
        • et al.
        Acute heart failure syndromes: current state and framework for future research.
        Circulation. 2005; 112: 3958-3968
        • Mebazaa A
        • Yilmaz MB
        • Levy P
        • Ponikowski P
        • Peacock WF
        • Laribi S
        • et al.
        Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine.
        Eur J Heart Fail. 2015; 17: 544-558
        • Pfeffer MA
        • Swedberg K
        • Granger CB
        • Held P
        • McMurray JJV
        • Michelson EL
        • et al.
        Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
        Lancet. 2003; 362: 759-766
        • Pitt B
        • Pfeffer MA
        • Assmann SF
        • Boineau R
        • Anand IS
        • Claggett B
        • et al.
        Spironolactone for heart failure with preserved ejection fraction.
        N Engl J Med. 2014; 370: 1383-1392
        • Solomon SD
        • McMurray JJV
        • Anand IS
        • Ge J
        • Lam CSP
        • Maggioni AP
        • et al.
        Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.
        N Engl J Med. 2019; 381: 1609-1620
        • McMurray JJ
        • Packer M
        • Desai AS
        • Gong J
        • Lefkowitz MP
        • Rizkala AR
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • Elliott P
        • Andersson B
        • Arbustini E
        • Bilinska Z
        • Cecchi F
        • Charron P
        • et al.
        Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases.
        Eur Heart J. 2008; 29: 270-276
        • Mueller C
        • McDonald K
        • de Boer RA
        • Maisel A
        • Cleland JGF
        • Kozhuharov N
        • et al.
        Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations.
        Eur J Heart Fail. 2019; 21: 715-731
        • Armstrong PW
        • Pieske B
        • Anstrom KJ
        • Ezekowitz J
        • Hernandez AF
        • Butler J
        • et al.
        Vericiguat in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2020; 382: 1883-1893
        • Teerlink JR
        • Diaz R
        • Felker GM
        • McMurray JJV
        • Metra M
        • Solomon SD
        • et al.
        Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.
        N Engl J Med. 2021; 384: 105-116
        • Anker SD
        • Butler J
        • Filippatos GS
        • Jamal W
        • Salsali A
        • Schnee J
        • et al.
        Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial.
        Eur J Heart Fail. 2019; 21: 1279-1287
        • Williams DM
        • Evans M.
        Dapagliflozin for heart failure with preserved ejection fraction will the DELIVER Study deliver?.
        Diabetes Ther. 2020; 11: 2207-2219
        • Stevenson LW
        • Pagani FD
        • Young JB
        • Jessup M
        • Miller L
        • Kormos RL
        • et al.
        INTERMACS profiles of advanced heart failure: the current picture.
        J Heart Lung Transplant. 2009; 28: 535-541

      Linked Article