Heart failure classification, 2021 ESC/HFA

Traditionally, HF has been divided into distinct phenotypes based on the measurement of left ventricular ejection fraction (LVEF) (table). The rationale behind this relates to the original treatment trials in HF that demonstrated substantially improved outcomes in patients with LVEF ≤40%. However, HF spans the entire range of LVEF (a normally distributed variable), and measurement by echocardiography is subject to substantial variability. According to the 2021 ESC/HFA guidelines the following classification of HF is available (Table):

Reduced LVEF is defined as ≤40%, i.e. those with a significant reduction in LV systolic function. This is designated as HFrEF.
Patients with a LVEF between 41% and 49% have mildly reduced LV systolic function, i.e. HFmrEF. Retrospective analyses from RCTs in HFrEF or HF with preserved ejection fraction (HFpEF) that have included patients with ejection fractions in the 40-50% range suggest that they may benefit from similar therapies to those with LVEF ≤40%.^1-6 This supports the renaming of HFmrEF from ‘heart failure with mid-range ejection fraction’ to ‘heart failure with mildly reduced ejection fraction’.⁷
Those with symptoms and signs of HF, with evidence of structural and/or functional cardiac abnormalities and/or raised natriuretic peptides (NPs), and with an LVEF ≥50%, have HFpEF.

These definitions are consistent with a recent report on the Universal Definition of Heart Failure.⁸

Patients with non-CV disease, e.g. anaemia, pulmonary, renal, thyroid, or hepatic disease may have symptoms and signs very similar to those of HF, but in the absence of cardiac dysfunction, they do not fulfil the criteria for HF. However, these pathologies can coexist with HF and exacerbate the HF syndrome.

Table Definition of heart failure with reduced ejection fraction, mildly reduced ejection fraction and preserved ejection fraction

	Type of HF	HFrEF	HFmrEF	HFpEF
CRITERIA	1	Symptoms ± Signs*	Symptoms ± Signs*	Symptoms ± Signs*
	2	LVEF ≤40%	LVEF 41-49%**	LVEF ≥50%
	3	–	–	Objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/raised LV filling pressures, including raised natriuretic peptides***

HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricle; LVEF = left ventricular ejection fraction.
* Signs may not be present in the early stages of HF (especially in HFpEF) and in optimally treated patients.
** For the diagnosis of HFmrEF, the presence of other evidence of structural heart disease (e.g. increased left atrial size, LV hypertrophy or echocardiographic measures of impaired LV filling) makes the diagnosis more likely.
*** For the diagnosis of HFpEF, the greater the number of abnormalities present, the higher the likelihood of HFpEF.

Literature:
1. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP, PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609_1620.
2. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, O’Meara E, Shah SJ, McKinlay S, Fleg JL, Sopko G, Pitt B, Pfeffer MA, TOPCAT Investigators. 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.
3. Abdul-Rahim AH, Shen L, Rush CJ, Jhund PS, Lees KR, McMurray JJV, VICCTAHeart Failure Collaborators. Effect of digoxin in patients with heart failure and mid-range (borderline) left ventricular ejection fraction. Eur J Heart Fail 2018;20:1139_1145.
4. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEPCHF) study. Eur Heart J 2006;27:2338_2345.
5. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ, von Lueder TG, Bohm M, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H, Hjalmarson A, Wikstrand J, Kotecha D, Beta-blockers in Heart Failure Collaborative Group. Beta-blockers for heart failure with reduced, mid-range,and preserved ejection fraction: an individual patient-level analysis of doubleblind randomized trials. Eur Heart J 2018;39:26_35.
6. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP, PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609_1620.
7. Lam CSP, Voors AA, Piotr P, McMurray JJV, Solomon SD. Time to rename the middle child of heart failure: heart failure with mildly reduced ejection fraction. Eur Heart J 2020;41:2353_2355.
8. Bozkurt B, Coats AJS, Tsutsui H, Abdelhamid CM, Adamopoulos S, Albert N, Anker SD, Atherton J, Bohm M, Butler J, Drazner MH, Michael Felker G, Filippatos G, Fiuzat M, Fonarow GC, Gomez-Mesa JE, Heidenreich P, Imamura T, Jankowska EA, Januzzi J, Khazanie P, Kinugawa K, Lam CSP, Matsue Y, Metra M, Ohtani T, Francesco Piepoli M, Ponikowski P, Rosano GMC, Sakata Y, Seferovic P, Starling RC, Teerlink JR, Vardeny O, Yamamoto K, Yancy C, Zhang J, Zieroth S. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail 2021;23:352_380.

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