Seminar

Heart failure with preserved ejection fraction: everything

the clinician needs to know
Patricia Campbell, Frans H Rutten, Matthew MY Lee, Nathaniel M Hawkins, Mark C Petrie

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognised and diagnosed in clinical practice, a Lancet 2024; 403: 1083–92
trend driven by an ageing population and a rise in contributing comorbidities, such as obesity and diabetes. Published Online
Representing at least half of all heart failure cases, HFpEF is recognised as a complex clinical syndrome. Its diagnosis February 14, 2024
https://doi.org/10.1016/
and management are challenging due to its diverse pathophysiology, varied epidemiological patterns, and evolving
S0140-6736(23)02756-3
diagnostic and treatment approaches. This Seminar synthesises the latest insights on HFpEF, integrating findings
This online publication has been
from recent clinical trials, epidemiological research, and the latest guideline recommendations. We delve into the corrected. The corrected version
definition, pathogenesis, epidemiology, diagnostic criteria, and management strategies (non-pharmacological and first appeared at thelancet.com
pharmacological) for HFpEF. We highlight ongoing clinical trials and future developments in the field. Specifically, on March 14, 2024
this Seminar offers practical guidance tailored for primary care practitioners, generalists, and cardiologists who do Department of Cardiology,
not specialise in heart failure, simplifying the complexities in the diagnosis and management of HFpEF. We provide Southern Trust, Craigavon Area
Hospital, Portadown, UK
practical, evidence-based recommendations, emphasising the importance of addressing comorbidities and integrating (P Campbell MD); Department
the latest pharmacological treatments, such as SGLT2 inhibitors. of General Practice and Nursing
Science, Julius Centre,
Introduction Epidemiology University Medical Centre,
Utrecht University, Utrecht,
Heart failure with preserved ejection fraction (HFpEF), Because of a growing and ageing population and Netherlands
simply put, is when a person has a diagnosis of heart increasing prevalence of conditions that contribute to the (Prof F H Rutten MD); School of
failure and their left ventricular ejection fraction (LVEF) patho­physiology of HFpEF, such as obesity, hypertension, Cardiovascular and Metabolic
Health, University of Glasgow,
is 50% or higher. The definition of HFpEF offered by the and diabetes, the total number of patients living with
British Heart Foundation
European Society of Cardiology (ESC) is more complex: HFpEF continues to rise.5 In high-income countries, the Glasgow Cardiovascular
“Those with symptoms and signs of HF [heart failure], prevalence of known heart failure is generally estimated Research Centre, Glasgow, UK
with evidence of structural and/or functional cardiac at 1–2% of the general adult population, with an estimated (M M Y Lee PhD,
Prof M C Petrie MD); Division of
abnormalities and/or raised natriuretic peptides (NPs), 50% of those having HFpEF. However, these estimates
Cardiology, University of
and with an LVEF ≥50%, have HFpEF”.1 This nuanced are largely based on administrative claims data or British Columbia, Faculty of
and lengthy definition makes it more difficult to electronic health records. There are no modern Medicine, Vancouver, BC,
diagnose HFpEF than heart failure with reduced ejection prospective, population-based studies using natriuretic Canada (N M Hawkins MD)
fraction (≤40%) or mildly reduced ejection fraction peptides and detailed echo­cardiography to assess the true Correspondence to:
Patricia Campbell, Department of
(41–49%). One example of the challenge of diagnosing prevalence of HFpEF. If such a study were to be
Cardiology, Southern Trust,
HFpEF is that approximately 20% of patients with conducted, especially with a liberal interpretation of the Craigavon Area Hospital,
HFpEF (mostly those living with obesity) have normal ESC’s definition of HFpEF, it is possible that the Portadown BT63 5QQ, UK
natriuretic peptide levels.2 Therefore, there is no prevalence of HFpEF would be much higher than patriciam.campbell@
southerntrust.hscni.net
one simple definition that specifies a combination of currently cited. A meta-analysis of echo­ cardiographic
imaging or natriuretic peptides that gives a binary rule- screening studies in the general population reported a
in or rule-out assessment of whether a person has prevalence of all-type heart failure in people aged 65 years
HFpEF.
Clinical trials of HFpEF have adopted a simple
definition of HFpEF (table). Typically, this definition Search strategy and selection criteria
includes a combination of LVEF more than 40% Searches for heart failure with preserved ejection fraction
(although HFpEF is technically defined as ≥50%) and were for material up to Sept 28, 2023 and were restricted to
elevated N-terminal pro-B type natriuretic peptide material published in English. Searches were run in PubMed,
(NT-proBNP) levels (usually above 300 pg/mL in ClinicalTrials.gov, and the Cochrane Library (Wiley). Search
sinus rhythm and 600 pg/mL in atrial fibrillation) terms included: “randomized controlled trial”, “meta-
in combination with a structural abnormality analysis”, “systematic reviews”, “epidemiological studies”,
(usually left ventricular hypertrophy or an enlarged “population studies”, “review article”, and “editorial”. Specific
left atrium) on echo­cardiography. Many clinicians use search terms included: “heart failure preserved ejection
this com­ bination to diagnose HFpEF in clinical fraction”, “epidemiology”, “prognosis”, “pathogenesis”,
practice; however, guidelines use LVEF greater than “inflammation”, “phenotypes”, “contributing co-morbidities”,
50% as the cut-point and also recommend functional “diagnosis”, “HFpEF mimics”, “congestion management”,
abnormality assessment with tissue Doppler imaging “SGLT2i”, “GLP-1 receptor agonist”, “sacubitril/valsartan”,
to define increased left ventricular stiffness with “mineralocorticoid receptor agonists”, “tirzepatide”,
impaired relaxation, and increased left ventricular “ziltivekimab”, “self-care”, and “rehabilitation”.
filling pressures.1

www.thelancet.com Vol 403 March 16, 2024 1083

 Seminar

Left ventricular Left ventricular Left atrium enlargement Elevated filling pressures Natriuretic peptide
ejection fraction hypertrophy level (pg/mL)
EMPEROR- >40% Septal or posterior wall Width ≥4·0 cm; length E:e’ (mean septal and NT-proBNP >300 (no
Preserved (2021)3 thickness ≥1·1 cm; left ≥5·0 cm; area ≥20·0 cm2; lateral) ≥13; e’ (mean septal atrial fibrillation) or
ventricular mass index volume ≥55 mL or volume and lateral) <9 cm/s >900 (with atrial
≥95 g/m2 (women) and index ≥34 mL/m2 fibrillation)
≥115 g/m2 (men)
DELIVER (2022)4 >40% Septal or posterior wall Width (diameter) ≥3·8 cm, NA NT-proBNP ≥300 (no
thickness ≥1·1 cm length ≥5·0 m; area atrial fibrillation or
≥20 cm2; volume ≥55 mL or flutter) or ≥600 (with
volume index ≥29 mL/m2 atrial fibrillation or
flutter)
e’=early diastolic mitral annulus velocity. E:e’=early diastolic mitral inflow velocity to early diastolic mitral annulus velocity. HFpEF=heart failure with preserved ejection
fraction. NA=not applicable. NT-proBNP=N-terminal pro-B type natriuretic peptide. SGLT2i=SGLT2 inhibitor.

Table: HFpEF definitions in recent clinical trials of SGLT2 inhibitors

and over in high-income countries of 11·8%, with more heart failure, including HFpEF by 62%,11 possibly related
than three quarters of these cases being HFpEF. This to a higher prevalence of unfavourable behavioural risk
meta-analysis gives a calculated prevalence of all-type factors, including physical inactivity, poor diet, smoking,
heart failure in the general population of 4·2% (around and medication non-adherence.12
3% for HFpEF); twice as high as the typical reported
prevalence.6 Epidemiological data indicate that the Prognosis
prevalence of HFpEF relative to heart failure with reduced Although HFpEF is thought to be associated with better
ejection fraction (HFrEF) is increasing at a rate of 1% per survival than HFrEF based on findings from clinical trial
year, indicating that HFpEF is becoming the most data,13 most observational studies show that this difference
common type of heart failure.7 is negligible.1 Data from the Karolinska–Rennes (KaRen)
The three signatory epidemiological features of HFpEF study of patients with HFpEF revealed mortality rates at
are increasing prevalence with advancing age, female 1 (15%), 3 (31%), 5 (47%), and 10 (74%) years.14 Although
sex, and comorbidities that either contribute to the the dominant cause of death is cardiovascular in both
myocardial stiffness (eg, metabolic and inflammatory) HFrEF and HFpEF, non-cardiovascular death does assume
or exacerbate the functional abnormality (eg, atrial a greater proportion of deaths in HFpEF.15
fibrillation and valve disease). These three factors Previous studies have noted no difference between
interact, as women have greater life expectancy, and HFpEF and HFrEF in terms of hospitalisation rate,
advancing age accrues comorbidities. hospitalisation duration, and the effect on quality of life
There is considerable international variation in the (QoL).12 However, more recent data from the ESC Heart
prevalence of HFpEF and its contributing factors. For Failure Long-Term Registry shows percentages of
example, compared with high-income countries, low- patients hospitalised for heart failure and all-cause
income countries have a higher prevalence of hyper­ admission in the HFrEF (14·6% and 31·9%), heart
tension, which contributes to HFpEF populations being failure midrange ejection fraction (8·7% and 22·0%),
younger.8 and HFpEF (9·7% and 23·5%) groups.16 Atherosclerosis
Risk In Communities surveillance data indicated an
Sex and socioeconomic status increase in admissions for acute decompensated heart
HFpEF is more common in women, with one study failure, primarily driven by HFpEF.17
showing women with heart failure had HFpEF in 67% of
cases, compared with 42% of men with heart failure having Pathogenesis
HFpEF.9 These data support the notion that sex might play Originally, HFpEF was viewed as a disorder due solely to
a pathophysiological role in this condition.5 This higher abnormalities in left ventricular diastolic function. Our
prevalence of HFpEF in women than men might be partly understanding has evolved so that HFpEF is now
related to obesity and diabetes. Women have obesity more understood as a systemic syndrome, perhaps partly
often than men, and the relationship between obesity and triggered by inflammation and with important
incident HFpEF seems stronger in women.6 Diabetes contributions from ageing, lifestyle factors, genetic
confers a higher risk for heart failure, mainly driven by predisposition, and multiple comorbidities (some of
HFpEF, in women (relative risk 1·95, 95% CI 1·70–2·22) which might be disease drivers; figure 1).
compared with men (1·74, 95% CI 1·55–1·95).10
Low socioeconomic status assessed by all common Inflammation
measures (education, income, occupation, and region) is The inflammatory state induced by chronic obstructive
independently associated with greater risk of incident pulmonary disease, renal impairment, obesity, diabetes,

1084 www.thelancet.com Vol 403 March 16, 2024

 Seminar

Myocardial Congestion Heart muscle

fibrosis thickening

Abnormal cardiac Epicardial coronary

contraction vascular disease

Abnormal cardiac Microvascular coronary

relaxation artery disease

Hypertension Pulmonary vessel

HFpEF dysfunction

Kidney impairment Right heart dysfunction

Atrial fibrillation Chronotropic

incompetence

Inflammation Diabetes Obesity

Figure 1: Interacting causes, contributors, or drivers of HFpEF reflecting the complex and heterogeneous underlying pathophysiology
HFpEF=heart failure with preserved ejection fraction.

and other comorbidities is predictive of incident HFpEF, Pulmonary hypertension is very common in HFpEF,
but not of HFrEF.18,19 Inflammation has been proposed as seen in roughly 80% of patients, and mortality is
a central mechanism in the pathogenesis of HFpEF.20 increased in this cohort.26 Some patients will go on to
The Paulus theory states that a chronic proinflammatory develop pulmonary vascular disease, manifest by
state, caused by the plethora of comorbidities, results elevation in pulmonary vascular resistance and reduction
in coronary endothelial inflammation and cardiac in pulmonary arterial compliance,27 resulting in reduced
dysfunction. Reduced bioavailability of nitric oxide is exercise capacity and increased risk of adverse outcomes.28
linked to myocardial and vascular stiffness via the Pulmonary hypertension eventually leads to right
cyclic guanosine monophosphate (cGMP) pathway. This ventricular systolic dysfunction, which is common and
unifying hypothesis is supported by tissue studies of associated with adverse outcomes in HFpEF.29 However,
patients with HFpEF showing reduced levels of cGMP.21 right ventricular dysfunction can be noted in patients
Metabolic disorders and obesity also promote expansion with near normal pulmonary pressures in the setting of
of the epicardial adipose tissue and secretion of atrial fibrillation or tricuspid regurgitation, and can occur
adipocytokines, which causes further inflammation and during exercise, even when resting function appears
fibrosis of the myocardium. Based on proteomic normal.24
analyses, there is a strong relationship between inflam­ Left atrial remodelling is common in HFpEF and
matory biomarkers, HFpEF, and extracellular matrix occurs secondary to increased left ventricular filling
reorganisation.22 Inflammation affects not only the left pressures. Left atrial dysfunction is associated with worse
ventricle, but also the left atrium, and atrial fibrillation QoL, more pulmonary vascular disease, greater right
might often be the first sign of HFpEF, especially in ventricular dysfunction, reduced exercise capacity, and
patients with obesity or diabetes.23 an increased risk of adverse outcomes, suggesting that
patients with greater atrial myopathy might also
Structural and functional cardiac phenotypes constitute a different phenotype within the HFpEF
Although diastolic dysfunction plays a central role in the spectrum.30
development of HFpEF, with the impairment in
relaxation causing elevated filling pressures at rest or Comorbidities contributing to pathophysiology and
with exertion,24 multiple non-diastolic abnormalities inflammation
contribute to the syndrome. These abnormalities Comorbidity burden is associated with increased severity
include subtle left ventricular systolic dysfunction, of HFpEF symptoms and corresponds to a poorer QoL
left atrial impairment, relative pericardial restraint, and a worse prognosis.31 Hypertension, coronary artery
abnormal right ventricular-pulmonary artery coupling, disease, obesity, sleep apnoea, diabetes, chronic kidney
pul­monary vascular disease, systemic vascular stiffening, disease, and atrial fibrillation are risk factors for HFpEF,
coronary and peripheral microvascular dysfunction, and which are increasing over time.10,32 Diabetes is a potent
chronotropic incompetence.25 risk factor for HFpEF.33 Importantly, diabetes and obesity

www.thelancet.com Vol 403 March 16, 2024 1085

 Seminar

affect left ventricle function even in the absence of comorbidities associated with HFpEF that have
coronary artery disease and hypertension.34 The rate of overlapping presentations is a frequent clinical scenario
obesity is fast on the rise globally, and excess adipose (including chronic obstructive pulmonary disease, obesity,
tissue is associated with an increased risk of HFpEF.35 In type 2 diabetes, ageing, frailty, or deconditioning).26,42
the general population, there is a direct relationship Collaboration with heart failure specialists can help
between body mass and the parameters of diastolic generalists learn how to diagnose HFpEF. Further
dysfunction.36 confusion can be caused by interpretation of spirometry.
Acute myocardial infarction is a driver for developing Spirometry might show an obstructive pattern due to
HFrEF, but chronic coronary artery disease is more related pulmonary congestion caused by unrecognised heart
to HFpEF.37 Both obstructive epicardial coronary artery failure, which further causes misclassification of HFpEF
disease and coronary microvascular dysfunction are very as chronic obstructive pulmonary disease.43
common in HFpEF and often remain undetected.22 Because both type 2 diabetes and heart failure can result
Another contributing comorbidity is anaemia with a in reduced exercise tolerance, and a sedentary lifestyle can
prevalence in HFpEF varying from 12% to 33%.33,38 Causes mask HFpEF symptoms, HFpEF can remain unrecognised.
of low haemoglobin in patients with HFpEF include iron In a Dutch study of 581 patients older than 60 years with
deficiency, chronic inflammation, and impaired renal type 2 diabetes not known to have HFpEF, opportunistic
function.39 In an analysis of the TOPCAT trial, patients screening revealed new heart failure in 27·7% of the
with HFpEF and anaemia had a higher mortality risk and participants, the majority of which (22·9%) was HFpEF.44
increased hospitalisations.40 Approximately 20% of patients with HFpEF have
normal natriuretic peptide levels.2 The reason for this
Diagnosis finding might relate to the mechanism of natriuretic
The diagnosis of HFpEF might be fairly straightforward peptide release. Natriuretic peptides are released in
in patients with overt physical examination signs of response to high left ventricular diastolic wall stress.
congestion on physical examination (eg, pitting leg oedema Bearing in mind that left ventricular diastolic wall stress
and pulmonary crackles), elevated natriuretic peptide levels is inversely proportional to wall thickness, in cases with
(ESC criteria of NT-proBNP >125 pg/mL sinus rhythm) mild left ventricular hypertrophy (common in HFpEF),
or atrial fibrillation (>365 pg/mL), brain natriuretic wall stress might be diminished, and pericardial adipose
peptide (>35 pg/mL sinus rhythm) or atrial fibrillation tissue could prevent cardiac stretch, and natriuretic
(> 105 pg/mL), or radiographic evidence of congestion or peptides not released as a result.
echocardiographic evidence of elevated filling pressures. Another reason for low natriuretic peptide levels is
Such cases are typically encountered in emergency care obesity.45 Patients with obesity and heart failure have
settings. However, it is worth noting that even in these lower natriuretic peptide concentrations due to increased
overtly congested patients, natriuretic peptide levels can expression of clearance receptors and augmented peptide
be normal or lower than expected for the given severity of degradation by the adipose tissue.46 If there is a suspicion
congestion.41 of HFpEF in a patient with obesity and low natriuretic
In the community, the diagnosis of HFpEF is much peptide levels, referral to a heart failure specialist for
more challenging. Patients are at risk of misdiagnosis or HFpEF diagnosis might be warranted.
under-diagnosis due to several factors, including (1) under- Therefore, in patients at risk with emerging symptoms,
reporting of symptoms by patients (eg, shortness of breath we propose a simple stepwise algorithm to allow for
on exertion, orthopnoea, or paroxysmal nocturnal accurate HFpEF diagnosis (figure 2). This algorithm is
dyspnoea), (2) non-specific heart failure symptoms (eg, based around the ESC Heart Failure Guidelines and
fatigue, reduced exercise tolerance, or ankle swelling), published HFpEF risk scores.
(3) absence of awareness of heart failure as a cause of
pulmonary symptoms, (4) the presence of mimicking Step 1: identify a defining feature of HFpEF
comorbidities, (5) the absence of ready access of natriuretic This algorithm (figure 2) allows for a diagnosis of HFpEF
peptides or echocardiography, and (6) uncertainty on how in most patients (approximately 80%) at step 1 whereby a
to diagnose HFpEF (due to uncertainty of how to interpret patient with symptoms, with or without signs, of heart
natriuretic peptide levels and echocardiographic reports). failure, or with an LVEF of 50% or higher has a defining
There is a long-standing perception among many feature (eg, detectable congestion or elevated natriuretic
clinicians that HFpEF is a condition that causes acute peptide levels), and meets at least one of the echo­
breathlessness with detectable pulmonary and peripheral cardiographic criteria. Therefore, the need to proceed to
oedema. There is less appreciation of heart failure as a step 2 and 3 is rare. For the generalist, moving to step 2
chronic condition that presents with exercise-related should prompt a referral onward for expert guidance.
breathlessness and reduced exercise tolerance in the Guidelines emphasise that the greater the number of
absence of signs of fluid overload. Fluid overload might be non-invasive indicators of raised left ventricular filling
absent, particularly in patients receiving diuretics pressures, the greater the likelihood of a diagnosis of
for hypertension. Confusion caused by common HFpEF.1

1086 www.thelancet.com Vol 403 March 16, 2024

 Seminar

Step 1 Symptoms of heart failure, ejection fraction ≥50% HFpEF

Most (80%) patients diagnosed at step 1 Plus a defining feature of:
• Congestion on examination or on radiology typically with:
• NT-proBNP (pg/mL) >125 SR, 365 AF or B type natriuretic
peptide >35 SR, or >105 AF
Plus one or more echocardiographic parameters:
• ↑ left ventricular mass index ≥95 g/m2 (women)
or ≥115 g/m2 (men)
• ↑ relative wall thickness >0·42
• ↑ left atrial volume index >34 ml/m2 SR or >40 ml/m2 AF
• ↑ E:e' >9 at rest
• ↑ tricuspid regurgitation velocity >2·8 m/sec at rest

If high index of suspicion, but NT-proBNP levels are normal

Step 2 Assess probability of HFpEF: Low score (0–1) then HFpEF unlikely
HFA-PEFF or H2FPEF score High score (≥5 or ≥6 respectively) then
HFpEF likely

If intermediate score

Step 3 Non-invasive or invasive exercise haemodynamics High filling pressures at rest or on exertion,
then HFpEF

Figure 2: HFpEF diagnostic algorithm

AF=atrial fibrillation. E:e’=early diastolic mitral inflow velocity to early diastolic mitral annulus velocity. H2FPEF=heart failure with preserved ejection fraction score.
HFA-PEFF=Heart Failure Association Pre-test assessment, Echocardiography and natriuretic peptide, Functional testing, Final aetiology. HFpEF=heart failure with
preserved ejection fraction. NT-proBNP=N-terminal pro-B type natriuretic peptide. SR=sinus rhythm.

The precise cutoffs for NT-proBNP and echo­ Step 3: elevated filling pressure
cardiographic parameters are much debated. For In the event of intermediate probability (where
example, recent publications have highlighted different HFA-PEFF score is 2–4 or H2FPEF 2–5), step 3 is required
cutoffs for NT-proBNP according to age and other to determine the presence of elevated filling pressures at
factors.47 Echocardiographic parameters and their rest or on exertion. The filling pressure can be established
cutoffs are often also confusing to generalists. Our with non-invasive (with exercise stress echocardiography)
recommendation is that patients with suspected heart or invasive haemodynamic exercise testing. In global
failure are referred from primary care to secondary care clinical practice, the availability of both non-invasive and
via heart failure diagnostic pathways. These pathways invasive haemodynamics is rare.
allow referral to a process where heart failure
diagnostic tests (NT-proBNP, electro­ cardiograms, and Mimics of HFpEF
echocardiograms) are performed, and the results The physician should, with clinical history and
reviewed by a heart failure team. Clear feedback with examination and investigation, rule out cardiac and non-
respect to both heart failure diagnosis (HFpEF or HFrEF) cardiac mimickers of HFpEF. Cardiac mimickers are
and management plan can be provided to the primary plentiful and include myocardial disease resulting in a
care team. thickened heart, including hypertrophic cardiomyopathy,
infiltrative disorders (eg, amyloidosis, haemochromatosis,
Step 2: HFpEF risk scores and sarcoidosis), and storage disorders (most notably
For approximately 20% of HFpEF cases where the Fabry disease); pericardial disease, such as constrictive
NT-proBNP is normal but a high index of suspicion pericarditis, primary valvular heart disease, pulmonary
remains, HFpEF risk scores might be helpful. The arterial hypertension (group 1 pulmonary hypertension)
two heart failure scores are the Heart Failure or lung disease-related pulmonary hypertension (group 3
Association Pre-test assessment, Echocardiography and pulmonary hypertension, which at first sight might be
natriuretic peptide, Functional testing, Final aetiology difficult to distinguish from pulmonary hypertension
(HFA-PEFF) score (range 0–6),48 and the heart failure related to HFpEF); and high-output heart failure, and
with preserved ejection fraction (H2FPEF) score primary right ventricular failure (arrhythmogenic
(range 0–9).49 Where the score is high (HFA-PEFF ≥5, ventricular cardiomyopathy and right ventricular
H2FPEF ≥6), then a diagnosis of HFpEF is likely, and infarction). The echocardiogram should be examined for
when low (HFA-PEFF 0–1, H2FPEF 0–1), HFpEF is evidence of these cardiac mimickers, and this list should
unlikely. be systematically considered in every patient, but

www.thelancet.com Vol 403 March 16, 2024 1087

 Seminar

SGLT2i Diuretics for fluid retention Screening for treatment of aetiologies or cardiovascular and non-cardiovascular
(class I) (class I) comorbidities
(class I)

Dapagliflozin Loop (furosemide, bumetanide, or torasemide) Cardiovascular

10 mg once daily with or without: thiazide (bendroflumethiazide, • Atrial fibrillation: anticoagulation; rate or rhythm control
or empagliflozin chlorthalidone, hydrochlorthiazide, indapamide, or • Coronary artery disease: antiplatelet; lipid-lowering; or revascularise valvular
10 mg once daily metolazone); or with or without: mineralocorticoid heart disease
receptor antagonist (spironolactone or eplerenone) • Hypertensive heart disease: ACE inhibitor or ARB; calcium channel blockers;
or diuretics
• Stroke
Non-cardiovascular
• Diabetes: SGLT2 inhibitor (avoid saxagliptin and thiazolidinediones)
• Obesity: GLP1 receptor agonist; exercise; or caloric restriction
• Chronic kidney disease: SGLT2 inhibitor; ACE inhibitor or ARB; or finerenone
• Lung disease or sleep disorder: obstructive sleep apnoea screening or treatment
• Other: thyroid disorders; frailty, cachexia, or sarcopenia; iron deficiency and
anaemia; electrolyte disorders; gout and arthritis; erectile dysfunction;
depression; cancer; or infection

Figure 3: The core strategies in HFpEF management

ACEi=angiotensin-converting enzyme inhibitor. ARB=angiotensin-receptor blocker. HFpEF=heart failure with preserved ejection fraction. SGLT2i=SGLT2 inhibitor.

particularly among those with atypical features, such as 95% CI 0·73–0·87; p<0·0001).52 The ESC 2023 Heart
younger age, relevant family history, or an absence of Failure Guideline update has given SGLT2 inhibitor use
typical risk factors (eg, hypertension, diabetes, and for HFpEF a class 1a recommendation.53
obesity). Where doubt lies, additional imaging (eg,
cardiac MRI or PET scanning) and laboratory work (eg, Treatment of congestion
alpha-galactosidase for Fabry or iron studies for Relief from congestion with diuretics remains a
haemochromatosis) might be necessary. cornerstone of HFpEF care for patients who are volume
overloaded.1 Therapy is initiated with loop diuretics with
HFpEF management the type and dose depending on the severity of volume
Non-pharmacological management overload. For patients who do not show a sufficient
Figure 3 outlines the core strategies in HFpEF diuresis with loop diuretics, either a thiazide or thiazide-
management. Management strategies for HFpEF include like diuretic or mineralocorticoid receptor antagonists
the identification and treatment of common comorbid (MRAs) can be added, individually or in combination.
conditions. This approach is often implemented in a The recommendation for MRAs (particularly spiro­
hospital setting by a multidisciplinary team including nolactone) comes from the signs of benefit from the
nurses, medicine for the older physicians, pharmacists, TOPCAT trial.54
and physiotherapists. Involvement of the general
practitioner is important for ensuring seamless transition Treatment of cardiovascular and non-cardiovascular
of care when the patient goes home, and for subsequent comorbidities
monitoring in an ambulatory clinic setting. Although The core of therapeutic recommendations in HFpEF are
clinical trials have shown the benefits of multidisciplinary focused on the treatment of underlying comorbidity and
care (especially by heart failure nurses)50 in HFrEF, treating modifiable heart failure risk factors. Multiple
similar trials for HFpEF are yet to be completed. Notably, cardiac and non-cardiac conditions, including hyper­
a trial that reported the benefits of cardiac rehabilitation tension, coronary artery disease, obesity, sleep apnoea,
in patients who were recently hospitalised with heart anaemia, diabetes, chronic kidney disease, atrial
failure included about 50% of participants with HFpEF.51 fibrillation, and chronotropic incompetence are all fre­
quently associated with HFpEF, and might accelerate
Pharmacological management disease progression or contribute to functional into­
A table of notable HFpEF drug trials is included in the lerance. However, there is no evidence for HFpEF-
See Online for appendix appendix. specific management of these conditions. Pragmatic
strategies for managing common comorbidities are
SGLT2 inhibitors addressed in the panel.
Recently (in 2021 and 2022), the first positive outcome
trials in HFpEF were published. In the EMPEROR- GLP-1 receptor agonists
Preserved3 and DELIVER trials,4 SGLT2 inhibitors The GLP-1 receptor agonist semaglutide was assessed for
reduced the composite of cardiovascular death and heart treatment of HFpEF in the STEP-HFpEF trial.55
failure hospitalisations by 20% (hazard ratio [HR] 0·80; Semaglutide markedly improved health status and

1088 www.thelancet.com Vol 403 March 16, 2024

 Seminar

reduced weight. Reduction in NT-proBNP levels was

approximately 15% greater with semaglutide than with Panel: Common concurrent conditions and the pragmatic
placebo, suggesting a reduction in left ventricular filling therapeutic strategies
pressures. Semaglutide reduced C-reactive protein. It • Hypertension: manage to guideline recommended
will be important to see how these findings translate to targets, typically <130/80 mm Hg
hard endpoints in determining the role of GLP-1 agonism • Coronary artery disease: antiplatelet therapy; intensify
for HFpEF care. statin therapy if elevated LDL levels; and revascularisation
for patients with angina or inducible ischaemia
Angiotensin receptor-neprilysin inhibitors and MRAs • Obesity: glucagon-like peptide-1 receptor agonist
Additional therapies might be considered for HFpEF, in semaglutide; aerobic exercise training and calorie
keeping with the 2022 American College of Cardiology/ restriction; obstructive sleep apnoea screening and
American Heart Association (AHA) treatment treatment; consider bariatric surgery
guidelines,56 although not included in the 2022 ESC • Diabetes: angiotensin-converting enzyme (ACE) inhibitor,
Heart Failure Guideline update.52 These agents include or angiotensin receptor blocker (ARB) for chronic kidney
angiotensin-receptor blockers (ARBs), angiotensin disease, or proteinuria; finerenone for proteinuria despite
receptor-neprilysin (ARN) inhibitors, and MRAs. ACE inhibitor or ARB therapy
Although none of these drugs reduced the primary • Chronic kidney disease: ACE inhibitor or ARB for
outcomes in pivotal randomised controlled trials in proteinuria; SGLT2 inhibitors; finerenone for diabetes and
HFpEF, subsequent analyses have suggested potential proteinuria despite ACE inhibitor or ARB therapy
benefit in some patients with HFpEF. For example, a • Atrial fibrillation: anticoagulated; consider rhythm control
possible sign of reduction in heart failure hospitalisations strategy initially if appropriate; aim for rate control to
was noted with the ARB candesartan in the CHARM- approximately 80–90 beats per min
Preserved trial of patients with symptomatic heart failure • Chronotropic incompetence: avoid β-blockers unless
and an ejection fraction greater than 40% (HR 0·84; there is a compelling indication
95% CI 0·70–1·00; p=0·047).57
In the PARAGON-HF trial, sacubitril with valsartan,
when compared with valsartan, was associated with a Serious adverse events relative to placebo in pivotal
modest (not statistically significant) reduction in the randomised control trials were uncommon. For example,
primary composite of total (first and recurrent) in TOPCAT the incidence of hyperkalaemia was
hospitalisations for heart failure and cardiovascular increased, but hypokalaemia decreased with no
death (rate ratio 0·87; 95% CI 0·75–1·01; p=0·06).54 significant difference in serious adverse events overall.
Improvements in secondary endpoints including QoL, Drug discontinuation relative to placebo was equally
New York Heart Association functional class, and a uncommon. For example, in DELIVER, 5·8% of patients
composite of renal events among patients assigned to discontinued both dapagliflozin and placebo.4 Both
sacubitril with valsartan, was seen. Subgroup analyses SGLT2 inhibtors and ARN inhibitors reduce adverse
suggested a greater benefit in women and in patients renal outcomes in patients with HFpEF.51,61,62 Finally,
with an LVEF at or lower than the median value of 57%.58 there is synergism between these therapies. The principal
ARN inhibitors have been included in the 2022 AHA side-effects of MRA are worsening renal function and
heart failure guidelines with a class 2b level of hyperkalaemia, both of which are counteracted by SGLT2
recommendation for the treatment of HFpEF.55 inhibitors and ARN inhibitors.
In the TOPCAT trial,59 the MRA spironolactone,
compared with placebo, did not reduce the primary Ongoing trials
outcome of time to cardiovascular death, aborted cardiac The ongoing SPIRIT-HF (Spironolactone in the
arrest, or heart failure hospitalisation in patients with heart Treatment of Heart Failure; NCT04727073) and SPIRRIT
failure and ejection fraction of 45% or more (HR 0·89; (Spironolactone Initiation Registry Randomized
95% CI: 0·77–1·04). Concerns were raised regarding Interventional Trial in Heart Failure with Preserved
patient selection and study conduct at some sites. A Ejection Fraction; NCT02901184) trials will shed more
favourable treatment effect was seen in patients enrolled light on the role of spironolactone in HFpEF. The non-
in the Americas, where recruitment criteria included steroidal MRA finerenone is being investigated in the
elevated natriuretic peptide level (HR for primary ongoing FINEARTS-HF trial (NCT04435626). Similarly,
composite: 0·82; 95% CI 0·69–0·98). This finding might the STEP-HFpEF DM (Semaglutide Treatment Effect in
be a better reflection of the effect of spironolactone in a People with obesity and HFpEF and type 2 diabetes;
true HFpEF population, with treatment benefits seemingly NCT04916470) trial is ongoing.
greatest in patients with an ejection fraction in the lower The SUMMIT (a study of tirzepatide [LY3298176] in
range.60 MRAs have been included in the 2022 AHA Heart participants with heart failure with preserved ejection
Failure guidelines with a class 2b level of recommendation fraction and obesity; NCT04847557) trial is assessing the
for the treatment of HFpEF.55 efficacy and safety of a dual glucose-dependent

www.thelancet.com Vol 403 March 16, 2024 1089

 Seminar

insulinotropic polypeptide and GLP-1 receptor agonists Conclusion

in patients with HFpEF and obesity. The HERMES trial HFpEF represents at least 50% of all heart failure cases,
(a research study to investigate how ziltivekimab works and the poor QoL and high rates of hospitalisation and
compared with placebo in people with heart failure and death represent a large unmet need. Due to an ageing
inflammation; NCT05636176) is assessing the effect of population and increasing prevalence of comorbidities or
this novel therapeutic monoclonal antibody targeting the disease drivers, such as obesity and diabetes, HFpEF
IL-6 ligand, in people living with HFpEF and who have prevalence is rising. The diagnosis of HFpEF can seem
concomitant inflammation. complex for the generalist, but by using natriuretic
In addition to pharmacological treatment, patients with peptides and rest echocardiography (step 1 in our
HFpEF should be offered comprehensive guidance and algorithm), a diagnosis can be made in most patients.
support for implementing and maintaining lifestyle Referral to heart failure specialists can be necessary for
changes and self-care strategies. Programmes for those where uncertainty persists. Current HFpEF manage­
managing chronic diseases and instruction in self- ment includes addressing comorbidities and consideration
management might lower the probability of hospital of pharmacological therapies, such as SGLT2 inhibitors.
admission for people with HFpEF.1 Exercise training in Contributors
patients with HFpEF improves outcomes, with benefits MCP conceptualised this seminar. All authors contributed to the design
noted in exercise performance and QoL for patients and content. PC, FHR, MMYL, and NMH wrote the paper and all
authors helped with revisions. PC, FHR, MMYL, and NMH directly
living with HFpEF. These benefits are observed even in accessed and verified the underlying data. All authors had full access to
frail, older hospitalised patients with HFpEF.63,64 Caloric the data in the study and accept responsibility to submit for publication.
restriction and exercise training had additive beneficial Declaration of interests
effects on exercise capacity and QoL in a randomised trial PC reports research grants from AstraZeneca; consulting fees from
of 100 patients with obesity and HFpEF (SECRET trial).65 Vifor, Pharmacosmos, and Boehringer Ingelheim; and speaker
The ongoing REHAB-HFpEF (physical rehabili­tation for honoraria from Novartis, Boehringer Ingelheim, AstraZeneca, Pfizer,
Vifor, and Pharmacosmos. FHR reports a speaker honorary from
older patients with acute heart failure and preserved Novartis. MMYL’s employer, the University of Glasgow, receives grant
ejection fraction; NCT05525663) and REACH-HFpEF (a support from AstraZeneca and Boehringer Ingelheim; and he serves
randomised controlled trial of a facilitated home-based on clinical endpoint committees for Bayer, and steering committees for
rehabilitation intervention in patients with heart failure Cytokinetics. NMH reports research grants from AstraZeneca;
consulting fees from AstraZeneca; and honoraria from AstraZeneca,
with preserved ejection fraction) trials will examine the Boehringer Ingelheim, Novartis, Novo Nordisk, and Servier.
effect of lifestyle changes on HFpEF outcomes. MCP reports research grants from Boehringer Ingelheim, Roche,
The management of HFpEF also requires careful SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic,
consideration of which therapies should be avoided or Boston Scientific, and Pharmacosmos; consulting fees from
Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, AbbVie,
withdrawn. Loop diuretic doses should be minimised Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens,
once patients are euvolaemic and guideline directed and Vifor; and honoraria from Boehringer Ingelheim, Novartis,
medical therapy has been initiated (combinations of AstraZeneca, Novo Nordisk, AbbVie, Bayer, Takeda, Corvia,
Cardiorentis, Pharmacosmos, Siemens, and Vifor. MCP is a Director of
SGLT2 inhibitors, MRA, and ARN inhibitors). All these
Global Clinical Trial Partners.
therapies have some diuretic effect. When low
Acknowledgments
potassium is observed in HFpEF, the prescriber should
We thank Liz Coyle of the University of Glasgow, for her excellent
(as a first step) consider starting or up titrating an MRA assistance in the preparation of this Seminar.
instead of prescribing potassium supplements if there
References
is no contraindication to MRA (eg, estimated 1 McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for
glomerular filtration rate <30 mL/min per 1·73m2). the diagnosis and treatment of acute and chronic heart failure.
Eur Heart J 2021; 42: 3599–726.
Nitrates should be discontinued unless indicated for
2 Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart
concurrent angina. In the NEAT-HFpEF (Nitrate’s failure with preserved ejection fraction: the HFA-PEFF diagnostic
Effect on Activity Tolerance in Heart Failure with algorithm: a consensus recommendation from the Heart Failure
Association (HFA) of the European Society of Cardiology (ESC).
Preserved Ejection Fraction) trial,66 activity levels Eur Heart J 2019; 40: 3297–317.
decreased progressively and significantly with increased 3 Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart
doses of isosorbide mononitrate compared with failure with a preserved ejection fraction. N Engl J Med 2021;
385: 1451–61.
placebo, and there was no benefit in terms of QoL or
4 Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart
submaximal exercise capacity. There is no evidence for failure with mildly reduced or preserved ejection fraction.
the efficacy of β-blockers in patients with HFpEF and N Engl J Med 2022; 387: 1089–98.
LVEF over 50%. There does appear to be some benefit 5 Borlaug BA, Redfield MM. Diastolic and systolic heart failure are
distinct phenotypes within the heart failure spectrum. Circulation
in patients with LVEF 41–49%.67 β-blockers are used in 2011; 123: 2006–14.
HFpEF where there is a non-HFpEF indication, such as 6 Savji N, Meijers WC, Bartz TM, et al. The association of obesity and
atrial fibrillation rate control, myocardial infarction, or cardiometabolic traits with incident HFpEF and HFrEF.
JACC Heart Fail 2018; 6: 701–09.
angina. In one study, β-blocker withdrawal improved
7 Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL,
maximal functional capacity in patients with HFpEF Redfield MM. Trends in prevalence and outcome of heart failure
and chronotropic incompetence.68 with preserved ejection fraction. N Engl J Med 2006; 355: 251–59.

1090 www.thelancet.com Vol 403 March 16, 2024

 Seminar

8 Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, 28 Vanderpool RR, Saul M, Nouraie M, Gladwin MT, Simon MA.
Coats AJS. Global burden of heart failure: a comprehensive and Association between hemodynamic markers of pulmonary
updated review of epidemiology. Cardiovasc Res 2023; 118: 3272–87. hypertension and outcomes in heart failure with preserved ejection
9 Kitzman DW, Gardin JM, Gottdiener JS, et al. Importance of heart fraction. JAMA Cardiol 2018; 3: 298–306.
failure with preserved systolic function in patients > or = 65 years of 29 Mohammed SF, Hussain I, AbouEzzeddine OF, et al. Right
age. CHS Research Group. Cardiovascular Health Study. ventricular function in heart failure with preserved ejection
Am J Cardiol 2001; 87: 413–19. fraction: a community-based study. Circulation 2014; 130: 2310–20.
10 Ohkuma T, Komorita Y, Peters SAE, Woodward M. Diabetes as a 30 Melenovsky V, Hwang S-J, Redfield MM, Zakeri R, Lin G,
risk factor for heart failure in women and men: a systematic review Borlaug BA. Left atrial remodeling and function in advanced heart
and meta-analysis of 47 cohorts including 12 million individuals. failure with preserved or reduced ejection fraction. Circ Heart Fail
Diabetologia 2019; 62: 1550–60. 2015; 8: 295–303.
11 Potter EL, Hopper I, Sen J, Salim A, Marwick TH. Impact of 31 van Deursen VM, Urso R, Laroche C, et al. Co-morbidities in
socioeconomic status on incident heart failure and left ventricular patients with heart failure: an analysis of the European Heart
dysfunction: systematic review and meta-analysis. Failure Pilot Survey. Eur J Heart Fail 2014; 16: 103–11.
Eur Heart J Qual Care Clin Outcomes 2019; 5: 169–79. 32 Christiansen MN, Køber L, Weeke P, et al. Age-specific trends in
12 Havranek EP, Mujahid MS, Barr DA, et al. Social determinants of incidence, mortality, and comorbidities of heart failure in Denmark,
risk and outcomes for cardiovascular disease: a scientific statement 1995 to 2012. Circulation 2017; 135: 1214–23.
from the American Heart Association. Circulation 2015; 33 Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac
132: 873–98. comorbidities on morbidity and mortality in a predominantly male
13 Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved population with heart failure and preserved versus reduced ejection
ejection fraction in perspective. Circ Res 2019; 124: 1598–617. fraction. J Am Coll Cardiol 2012; 59: 998–1005.
14 Shahim A, Hourqueig M, Donal E, et al. Predictors of long-term 34 Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure
outcome in heart failure with preserved ejection fraction: among adult patients with diabetes. Circulation 2001; 103: 2668–73.
a follow-up from the KaRen study. ESC Heart Fail 2021; 8: 4243–54. 35 Rush CJ, Berry C, Oldroyd KG, et al. Prevalence of coronary artery
15 Kapłon-Cieślicka A, Benson L, Chioncel O, et al. A comprehensive disease and coronary microvascular dysfunction in patients with
characterization of acute heart failure with preserved versus mildly heart failure with preserved ejection fraction. JAMA Cardiol 2021;
reduced versus reduced ejection fraction – insights from the 6: 1130–43.
ESC-HFA EORP Heart Failure Long-Term Registry. Eur J Heart Fail 36 Seo J-S, Jin H-Y, Jang J-S, Yang T-H, Kim D-K, Kim D-S. The
2022; 24: 335–50. relationships between body mass index and left ventricular diastolic
16 Chioncel O, Lainscak M, Seferovic PM, et al. Epidemiology and one- function in a structurally normal heart with normal ejection
year outcomes in patients with chronic heart failure and preserved, fraction. J Cardiovasc Ultrasound 2017; 25: 5–11.
mid-range and reduced ejection fraction: an analysis of the ESC 37 Hollenberg SM, Warner Stevenson L, Ahmad T, et al. 2019 ACC
Heart Failure Long-Term Registry. Eur J Heart Fail 2017; 19: 1574–85. expert consensus decision pathway on risk assessment,
17 Chang PP, Wruck LM, Shahar E, et al. Trends in hospitalizations management, and clinical trajectory of patients hospitalized with
and survival of acute decompensated heart failure in four US heart failure: a report of the American College of Cardiology Solution
communities (2005–2014): ARIC Study community surveillance. Set Oversight Committee. J Am Coll Cardiol 2019; 74: 1966–2011.
Circulation 2018; 138: 12–24. 38 Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients
18 Paulus WJ, Tschöpe C. A novel paradigm for heart failure with with heart failure and preserved ejection fraction. N Engl J Med
preserved ejection fraction: comorbidities drive myocardial 2008; 359: 2456–67.
dysfunction and remodeling through coronary microvascular 39 Kleijn L, Belonje AMS, Voors AA, et al. Inflammation and anaemia
endothelial inflammation. J Am Coll Cardiol 2013; 62: 263–71. in a broad spectrum of patients with heart failure. Heart 2012;
19 Lam CSP, Voors AA, de Boer RA, Solomon SD, van Veldhuisen DJ. 98: 1237–41.
Heart failure with preserved ejection fraction: from mechanisms to 40 Gupta K, Kalra R, Rajapreyar I, et al. Anemia, mortality, and
therapies. Eur Heart J 2018; 39: 2780–92. hospitalizations in heart failure with a preserved ejection fraction
20 Lourenço AP, Leite-Moreira AF, Balligand J-L, et al. An integrative (from the TOPCAT Trial). Am J Cardiol 2020; 125: 1347–54.
translational approach to study heart failure with preserved ejection 41 Bachmann KN, Gupta DK, Xu M, et al. Unexpectedly low
fraction: a position paper from the Working Group on Myocardial natriuretic peptide levels in patients with heart failure.
Function of the European Society of Cardiology. Eur J Heart Fail JACC Heart Fail 2021; 9: 192–200.
2018; 20: 216–27. 42 Rutten FH, Moons KGM, Cramer M-JM, et al. Recognising heart
21 van Heerebeek L, Hamdani N, Falcão-Pires I, et al. Low myocardial failure in elderly patients with stable chronic obstructive pulmonary
protein kinase G activity in heart failure with preserved ejection disease in primary care: cross sectional diagnostic study. BMJ 2005;
fraction. Circulation 2012; 126: 830–39. 331: 1379.
22 Tromp J, Westenbrink BD, Ouwerkerk W, et al. Identifying 43 Rutten FH, Broekhuizen BDL. Misclassification of both chronic
pathophysiological mechanisms in heart failure with reduced obstructive pulmonary disease and heart failure. JAMA Netw Open
versus preserved ejection fraction. J Am Coll Cardiol 2018; 2018; 1: e185486.
72: 1081–90. 44 Boonman-de Winter LJM, Rutten FH, Cramer MJM, et al. High
23 Packer M. Do most patients with obesity or type 2 diabetes, and prevalence of previously unknown heart failure and left ventricular
atrial fibrillation, also have undiagnosed heart failure? A critical dysfunction in patients with type 2 diabetes. Diabetologia 2012;
conceptual framework for understanding mechanisms and 55: 2154–62.
improving diagnosis and treatment. Eur J Heart Fail 2020; 45 Madamanchi C, Alhosaini H, Sumida A, Runge MS. Obesity and
22: 214–27. natriuretic peptides, BNP and NT-proBNP: mechanisms and
24 Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right diagnostic implications for heart failure. Int J Cardiol 2014; 176: 611–17.
ventricular-pulmonary artery coupling with exercise in heart failure 46 Mueller C, McDonald K, de Boer RA, et al. Heart Failure Association
with preserved ejection fraction. Eur Heart J 2016; 37: 3293–302. of the European Society of Cardiology practical guidance on the use of
25 Borlaug BA. The pathophysiology of heart failure with preserved natriuretic peptide concentrations. Eur J Heart Fail 2019; 21: 715–31.
ejection fraction. Nat Rev Cardiol 2014; 11: 507–15. 47 Hildebrandt P, Collinson PO, Doughty RN, et al. Age-dependent
26 Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, values of N-terminal pro-B-type natriuretic peptide are superior to a
Redfield MM. Pulmonary hypertension in heart failure with single cut-point for ruling out suspected systolic dysfunction in
preserved ejection fraction: a community-based study. primary care. Eur Heart J 2010; 31: 1881–89.
J Am Coll Cardiol 2009; 53: 1119–26. 48 Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart
27 Gorter TM, Obokata M, Reddy YNV, Melenovsky V, Borlaug BA. failure with preserved ejection fraction: the HFA-PEFF diagnostic
Exercise unmasks distinct pathophysiologic features in heart failure algorithm: a consensus recommendation from the Heart Failure
with preserved ejection fraction and pulmonary vascular disease. Association (HFA) of the European Society of Cardiology (ESC).
Eur Heart J 2018; 39: 2825–35. Eur J Heart Fail 2020; 22: 391–412.

www.thelancet.com Vol 403 March 16, 2024 1091

 Seminar

49 Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BAA. 59 Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart
A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. N Engl J Med 2014;
failure with preserved ejection fraction. Circulation 2018; 370: 1383–92.
138: 861–70. 60 Solomon SD, Claggett B, Lewis EF, et al. Influence of ejection
50 Blue L, Lang E, McMurray JJV, et al. Randomised controlled trial fraction on outcomes and efficacy of spironolactone in patients with
of specialist nurse intervention in heart failure. BMJ 2001; heart failure with preserved ejection fraction. Eur Heart J 2016;
323: 715–18. 37: 455–62.
51 Mc Causland FR, Claggett BL, Vaduganathan M, et al. Dapagliflozin 61 Packer M, Butler J, Zannad F, et al. Empagliflozin and major renal
and kidney outcomes in patients with heart failure with mildly outcomes in heart failure. N Engl J Med 2021; 385: 1531–33.
reduced or preserved ejection fraction: a prespecified analysis of the 62 Vaduganathan M, Mentz RJ, Claggett BL, et al. Sacubitril/valsartan
DELIVER randomized clinical Trial. JAMA Cardiol 2023; 8: 56–65. in heart failure with mildly reduced or preserved ejection fraction:
52 Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors a pre-specified participant-level pooled analysis of PARAGLIDE-HF
in patients with heart failure: a comprehensive meta-analysis of five and PARAGON-HF. Eur Heart J 2023; 44: 2982–93.
randomised controlled trials. Lancet 2022; 400: 757–67. 63 Kitzman DW, Whellan DJ, Duncan P, et al. Physical rehabilitation
53 McDonagh TA, Metra M, Adamo M, et al. 2023 focused update of for older patients hospitalized for heart failure. N Engl J Med 2021;
the 2021 ESC Guidelines for the diagnosis and treatment of acute 385: 203–16.
and chronic heart failure. Eur Heart J 2023; 44: 3627–39. 64 Mentz RJ, Whellan DJ, Reeves GR, et al. Rehabilitation intervention
54 Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin- in older patients with acute heart failure with preserved versus
neprilysin inhibition in heart failure with preserved ejection reduced ejection fraction. JACC Heart Fail 2021; 9: 747–57.
fraction. N Engl J Med 2019; 381: 1609–20. 65 Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric restriction
55 Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in or aerobic exercise training on peak oxygen consumption and quality
patients with heart failure with preserved ejection fraction and of life in obese older patients with heart failure with preserved
obesity. N Engl J Med 2023; 389: 1069–84. ejection fraction: a randomized clinical trial. JAMA 2016; 315: 36–46.
56 Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/ 66 Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate
HFSA Guideline for the management of heart failure: a report of in heart failure with preserved ejection fraction. N Engl J Med 2015;
the American College of Cardiology/American Heart Association 373: 2314–24.
Joint Committee on Clinical Practice Guidelines. Circulation 2022; 67 Cleland JGF, Bunting KV, Flather MD, et al. Beta-blockers for heart
145: e895–1032. failure with reduced, mid-range, and preserved ejection fraction:
57 Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in an individual patient-level analysis of double-blind randomized
patients with chronic heart failure and preserved left-ventricular trials. Eur Heart J 2018; 39: 26–35.
ejection fraction: the CHARM-Preserved trial. Lancet 2003; 68 Palau P, Seller J, Domínguez E, et al. Effect of β-blocker withdrawal
362: 777–81. on functional capacity in heart failure and preserved ejection
58 Vaduganathan M, Claggett BL, Desai AS, et al. Prior heart failure fraction. J Am Coll Cardiol 2021; 78: 2042–56.
hospitalization, clinical outcomes, and response to sacubitril/
valsartan compared with valsartan in HFpEF. J Am Coll Cardiol Crown Copyright © 2024 Published by Elsevier Ltd. All rights reserved.
2020; 75: 245–54.

1092 www.thelancet.com Vol 403 March 16, 2024