Education in Heart

Management of patients with heart failure and

Heart: first published as 10.1136/heartjnl-2022-321097 on 22 March 2023. Downloaded from http://heart.bmj.com/ on June 19, 2023 by guest. Protected by copyright.
preserved ejection fraction
Alicja Jasinska-­Piadlo  ‍ ‍,1,2 Patricia Campbell  ‍ ‍1

1
Cardiology Department, INTRODUCTION
Southern Health and Social Care Heart failure (HF) is a clinical syndrome with
LEARNING OBJECTIVES
Trust, Portadown, UK ⇒ To understand the definition and simplified
2
School of Computing, Ulster typical symptoms of breathlessness, fatigue,
University, Belfast, UK reduced exercise tolerance, body swelling and pathophysiology of HFpEF.
signs of fluid retention such as increased jugular ⇒ To understand the appropriate diagnostic work-­
Correspondence to venous pressure (JVP), pulmonary congestion and up for those patients with suspected HFpEF.
Dr Patricia Campbell, Cardiology peripheral oedema. They are the consequences of ⇒ To understand contemporary pharmacological
Department, Southern impaired myocardial function, causing inability to and non-­pharmacological therapies for HFpEF.
Health and Social Care Trust, This paper covers part of the ESC Core Curriculum
Craigavon, UK; maintain cardiac output in response to metabolic
​PatriciaM.​Campbell@​ demand. HF affects 1%–3% of people world- for the General Cardiologist (2013)41 :
southerntrust.h​ scni.​net wide.1 HF prevalence in the USA is estimated at 2.17 Heart Failure Objectives:
2.5% with 6 million patients having a confirmed
Published Online First ⇒ To recognise the impact of heart failure on
22 March 2023 HF diagnosis.2 According to a study of 4 million
people in general practice in UK, 1.6% of popu- morbidity and mortality in the individual patient
lation have HF.3 There is, however, a cohort of and in the population at large
patients who are undiagnosed and the true prev- ⇒ To recognise heart failure and the different
alence of HF is likely higher.4 It is estimated that underlying causes
50% of patients with HF have heart failure with ⇒ To perform specialist assessment and treatment
preserved ejection fraction (HFpEF).5 HFpEF is of patients with heart failure
associated with multimorbidity, with as many as ⇒ To work with patients and their families’
50% of patients having five or more significant primary care physicians, sub-­specialists, nurses,
comorbidities.The hallmark of HFpEF is the and other healthcare professionals
presence of increased left ventricular (LV) stiff- ⇒ To organise structured follow-­up of patients
ness with impaired relaxation. This pathology after diagnosis
develops with older age; hence, the prevalence of
HFpEF is projected to increase as a consequence
of the ageing population.6 The European Society high, with an average one admission per year from
of Cardiology (ESC) estimates the prevalence initial HF diagnosis. Management of comorbidi-
of HFpEF in the population aged >60 years at ties and diuretic therapy have long been central in
4.9%.7 People with HFpEF have a higher prev- the treatment of HFpEF, with the aim of reducing
symptom burden and preventing hospitalisation.
alence of hypertension, diabetes mellitus (DM),
However, breakthrough RCT data on sodium–
chronic kidney disease (CKD), atrial fibrillation
glucose cotransporter-­ 2 inhibitors use in HFpEF
(AF) and non-­cardiovascular (CV) comorbidities
(EMPagliflozin outcomE tRial in Patients With
(such as obesity and chronic obstructive pulmo-
chrOnic heaRt Failure With Preserved Ejection
nary disease (COPD)) than those with heart
Fraction (EMPEROR-­ Preserved), Dapagliflozin
failure with reduced ejection fraction (HFrEF).
in PRESERVED Ejection Fraction Heart Failure
Women with HFpEF significantly outnumber
(PRESERVED-­ HF) and Dapagliflozin Evaluation
men, leading to a gender ratio of approximately
to Improve the LIVEs of Patients With PReserved
2:1, supporting the notion that gender plays a
Ejection Fraction Heart Failure (DELIVER)) show
crucial role in this condition.8
improved patient-­reported outcomes and reduced
Regardless of the type, HF is associated with
heart failure hospitalisations (class 2a recommen-
very high 5-­ year mortality reaching 50%–75%.1
dation 2022 American College of Cardiology HF
Outcomes in HFpEF are comparable with those in
guidelines).
heart failure with reduced ejection fraction; there-
In view of these data, HFpEF is recognised as a
fore, intervention should be implemented early
growing epidemiological issue7 due to high mortality,
to prevent mortality, morbidity and poor patient-­
increasing costs from high hospital admission rates,
reported outcomes. Mortality due to non-­ CV
© Author(s) (or their poor patient reported outcomes impacting QoL and
causes is increased in those with HFpEF.1 Although
employer(s)) 2023. Re-­use years lost in employment. As such, it is important
permitted under CC BY-­NC. No HFpEF is thought to have better survival than for clinicians to have a good understanding on how
commercial re-­use. See rights HFrEF based on findings from clinical trial data,9 to diagnose and treat HFpEF.
and permissions. Published most observational studies show that this differ-
by BMJ.
ence is ’negligible’.4 There is no difference between
To cite: Jasinska-­Piadlo A, HFpEF and HFrEF in terms of hospitalisation rate, DEFINITION
Campbell P. Heart hospitalisation duration and impact on quality Contemporary definitions of HF distinguish HF
2023;109:874–883. of life (QoL).9 The rate of hospital admissions is types based on differences in the left ventricular
874   Jasinska-­Piadlo A, Campbell P. Heart 2023;109:874–883. doi:10.1136/heartjnl-2022-321097
 Education in Heart
ejection fraction (LVEF).4 10 Current international vision for the treatment of HFpEF is a personalised
guidelines (ESC and American Heart Association approach including precise risk stratification, using

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(AHA)) divide HF into HFrEF with LVEF of <40%, targeted therapies and preventative intervention.
heart failure with mildly reduced ejection fraction In HFpEF, the myocardium displays a number of
(HFmrEF) with LVEF between 41% and 49%, and functional and structural abnormalities.7 Comorbid
HFpEF with LVEF of >50%.4 10 11 Figure 1 presents conditions initiate a systemic proinflammatory state
internationally accepted definition and diagnostic which leads to coronary microvascular endothelial
criteria distinguishing types of HF.4 10 11 Per this inflammation. This inflammation ignites a cascade
definition, HFpEF is a clinical syndrome consisting of changes at the molecular level that promotes
of symptoms and signs of HF, with evidence of myocyte hypertrophy and interstitial fibrosis. These
structural and/or functional cardiac abnormali- contribute to increased LV diastolic stiffness, which
ties and/or raised natriuretic peptides (NPs), and slows LV relaxation. LV diastolic filling pressures
with an LVEF of ≥to 50%.4 What is worth noting increase, leading to impaired cardiac output, which
though is that NP may not be raised in about 20% gives rise to symptoms of HF.7 12 Altered intramyo-
of patients presenting with true HFpEF. In the cardial signalling, energetic abnormalities and
Diagnostic process section, we provide further impaired density and autoregulation of the micro-
explanation of the underlying causes of normal NP circulation have also been noted. The remodelling
in patients with HFpEF. in HFpEF differs from that seen in HFrEF, driven
Prior to use of the term HFpEF, ’diastolic dysfunc- primarily by a loss of cardiomyocytes.
tion’ term was used to describe this complex clinical
syndrome; however, its use has been discouraged DIAGNOSTIC PROCESS
since it became clear that diastolic dysfunction is The most common symptom in HFpEF is breath-
not unique to HFpEF, but it coexists in HFrEF and lessness on exertion and reduced exercise capacity.
HFmrEF too.9 Originally, HFpEF was viewed as a Therefore, it is important to collect a detailed clin-
disorder due solely to abnormalities in LV diastolic ical history focusing on change in exercise capacity
function; however, the understanding has evolved over time and current exercise tolerance. Although
such that HFpEF is now understood as a systemic breathlessness on exertion is highly sensitive in
syndrome, involving multiple organ systems, likely diagnosing HF, it has only 50% specificity for
triggered by inflammation and with an important identifying a cardiac cause4; hence, clinical history
contribution of ageing, lifestyle factors, genetic should focus on all non-­cardiac causes of breathless-
predisposition and multiple comorbidities.12 ness, such as lung disease and deconditioning.
The assessment of a patient presenting with
PATHOPHYSIOLOGY symptoms and/or signs of HFpEF includes detailed
The pathophysiology of HFpEF is complex, and clinical history with consideration of current
systemic changes related to comorbid conditions comorbidities such as obesity, hypertension, DM,
drive myocardial dysfunction. Various mechanisms COPD, CKD, coronary artery disease (CAD),
have been suggested as causing the pathophysi- AF, metabolic syndrome, poor physical activity,
ology of HFpEF, either individually or in combi- deconditioning and all modifiable risk factors.
nation with LV diastolic dysfunction.13 Over the Importantly in women, it must focus on history
last decade, a new paradigm has been presented, of eclampsia, pre-­ eclampsia, therapies for breast
describing a sequence of events leading to HFpEF. A cancer.14 Medication history should focus on all
systemic proinflammatory state induced by concom- prescribed drugs potentially precipitating HFpEF
itant comorbidities is thought to be at the core the (chemotherapy and immune modulating drugs)
pathological process in HFpEF.12 As illustrated in and over-­the counter drugs such as non-­steroidal
figure 2, HFpEF is a caused by diverse underlying anti-­
inflammatory medication, supplements and
conditions and comorbidities, resulting in a popu- herbal remedies.15 Family history should focus on
lation of people with diverse characteristics. Future history of CAD, HF of all causes, cardiomyopathy,

Figure 1  Types of HF according to differences of LVEF based on internationally accepted universal definition of HF.4 10 11 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 ventricular; LVEF, left ventricular ejection fraction.
Jasinska-P­ iadlo A, Campbell P. Heart 2023;109:874–883. doi:10.1136/heartjnl-2022-321097 875
 Education in Heart

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Figure 2  Illustration of the many faces of the HFpEF phenotype reflecting heterogeneous and complex underlying pathophysiology in HFpEF
syndrome. In the future, HFpEF treatment should be based on personalised approach, precise risk stratification with targeted therapies and
preventative intervention. Graphic inspired by Professor C Miller, with permission. HFpEF, heart failure with preserved ejection fraction.

amyloidosis and genetic conditions (hypertrophic must be checked. Liver function tests, thyroid func-
cardiomyopathy and muscular dystrophies). tion tests and lipid profile are useful in assessing
Clinical examination should focus on examina- the risk of metabolic syndrome. Although NP levels
tion of radial pulse rhythm and rate and blood have been shown to have high negative predictive
pressure (BP). Signs of volume overload (raised value in excluding HF (when levels are <125 pg/
jugular venous pressure (JVP), peripheral oedema mL for N-­terminal pro B-­type natriuretic peptide
and pulmonary crepitations) may not be obvious (NT-­proBNP) and <35 pg/mL for brain natriuretic
in early stages of HFpEF. Cardiac auscultation peptide (BNP) as per ESC guidelines and for UK
may reveal systolic flow murmurs or murmurs practitioners NT-­proBNP level less than 400 pg/mL
from valvular abnormalities. Assessment of body as per National Institute for Health and Care Excel-
build with weight, body mass index and presence lence (NICE) guidelines), approximately 20% of
of central obesity is essential. While there are no patients with HFpEF will have normal NP levels.7
specific ECG findings to indicate HFpEF, ECG is The reason for normal NP levels in HFpEF is due to
recommended to detect AF and left ventricular the mechanism in which NPs are released. NPs are
hypertrophy (LVH). released due to high LV diastolic wall stress. Bearing
First-­line laboratory blood tests should include in mind that the LV diastolic wall stress is inversely
NP, full blood count, ferritin and transferrin satu- proportional to the wall thickness, in cases with
ration to exclude anaemia, which may precipi- mild LVH (which is common in HFpEF), the effect
tate symptoms of breathlessness. Renal function of diastolic LV wall stress may be diminished and
including urea, creatinine, electrolytes and esti- NP may not be released. In contrast to HFpEF, the
mated glomerular filtration rate (eGFR), and HbA1c LV diastolic wall stress in HFrEF more commonly
876 Jasinska-­Piadlo A, Campbell P. Heart 2023;109:874–883. doi:10.1136/heartjnl-2022-321097
 Education in Heart

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Figure 3  Cardiac and non-­cardiac causes of raised natriuretic peptides (serum levels >125 pg/mL for N-­terminal probrain natriuretic peptide
or >35 pg/mL for brain natriuretic peptide). *Denotes hypertrophic or restrictive cardiomyopathy. ACS, acute coronary syndrome; COPD, chronic
obstructive pulmonary disease; ICD, implantable cardioverter–defibrillator; LV, left ventricular; PE, pulmonary embolism.

triggers release of NP in patients with dilated LV with a physician with subspecialty training in HF, if
and thinned myocardial walls. Another reason for a clinical suspicion of HF persists in patients with
NP levels below the cut-­off thresholds is obesity.16 NT-­proBNP levels of <400 pg/mL.
It is worthwhile noting that NP levels can be raised Transthoracic echocardiogram (ECHO) should
due to a variety of cardiac and non-­CV causes other be offered to every patient presenting with symp-
than HF. Pathological processes leading to the toms suggestive of HF and elevated NP levels.
increased LV diastolic stress or myocardial injury, ECHO is useful in identifying other causes of
resulting from acute ischaemia, inflammation or breathlessness such as HFrEF, valvular heart disease
iatrogenic causes (eg, cardioversion), can cause high and right ventricle pathologies, such as primary
levels of NP. Non-­cardiac conditions can increase and secondary pulmonary hypertension. All ECHO
serum NP via indirect mechanisms such as impaired measurements should be performed in accordance
metabolism, low creatinine clearance, systemic with the most recent guidelines of the European
hypoxia, starvation and dehydration. Figure 3 high- Association of Cardiovascular Imaging or American
lights the cardiac and non-­cardiac causes of raised Society of Echocardiography.18 19 Of note, reduced
NP levels. longitudinal strain is a good predictor of HF,
We would like to point out that there is a discrep- and poor longitudinal strain is strongly linked to
ancy in the cut-­off points for NT-­proBNP and BNP worse outcomes in HFpEF.20 Diagnosis of HFpEF
levels between ESC and NICE HF guidelines.17 may pose a challenge for clinical centres with no
In figure 4, we present the differences between access to specialist tests and/or HF expertise. Thus,
the ESC and NICE diagnostic algorithm for HF, there has been a key change to the ESC 2021 HF
which would be of particular use to the UK-­based guidelines,4 which recommends a simple three-­step
practitioners. Despite higher cut-­ off points for diagnostic pathway to enable effective detection of
NT-­proBNP levels, NICE recommends a discussion HFpEF.

Jasinska-P­ iadlo A, Campbell P. Heart 2023;109:874–883. doi:10.1136/heartjnl-2022-321097 877

 Education in Heart

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Figure 4  Diagnostic algorithms for HF: European Society of Cardiology 2021 HF guidelines4 and NICE 2018 HF guidelines.17 Reproduced with
permission from Br J Cardiol 2022;29(suppl 2):S3–S6, doi: 10.5837/bjc.2022.s06. ECHO, echocardiogram; ESC, European Society of Cardiology; HF,
heart failure; NICE, National Institute for Health and Care Excellence; NT-­proBNP, N-­terminal probrain natriuretic peptide.

Simple three-­step diagnostic pathway: pressures, the greater the likelihood of a diagnosis
► Signs and symptoms of HF. of HFpEF.4
► An LVEF of ≥50%.
► Objective evidence of cardiac structural and/ THERAPY FOR HFPEF
or functional abnormalities consistent with LV The goals of therapy for patients with HFpEF are
diastolic dysfunction/raised LV filling pressures, to reduce symptoms, improve functional status and
including raised NPs (see table 1). lower the risk of hospital admission.
If resting ECHO and laboratory indicators are
inconclusive, a diastolic stress test can help. Invasive Diuretics: the cornerstone of therapy
haemodynamic exercise testing is used to confirm Patients with HFpEF and documented volume over-
the diagnosis of HFpEF. A pulmonary capillary load should be offered diuretic therapy.4 10 Therapy
wedge pressure (PCWP) of ≥15 mm Hg at rest or is initiated with loop diuretics, type and dose
≥25 mm Hg with exercise or LV end-­diastolic pres- depending on the severity of volume overload. For
sure of ≥16 mm Hg (at rest) is deemed diagnostic. those patients with diuretic resistance, sequential
Current guidelines do not require gold standard nephron blockade can be achieved using thiazide/
testing in every patient to make a diagnosis of thiazide-­like diuretics and/or mineralocorticoid
HFpEF. Because in majority of patients the diagnosis receptor antagonists (MRAs), the latter of these has
can be made based on the combination of symp- been included in the 2022 AHA HF guidelines with
toms, signs, ECHO findings and NT-­proBNP level, class 2b level of recommendation for treatment of
further testing is often not necessary. However, for HFpEF.10
those cases where patients present with persistent
symptoms but simple tests do not confirm a diag-
Treating underlying comorbidities
nosis of HFpEF, we can consider either exercise
Up until 2022, the core of therapeutic recommen-
stress ECHO or invasive haemodynamic exercise
dations in HFpEF was a focus on delivering therapy
testing.21 Unfortunately, there are no real-­ world for underlying comorbidity and treating modifiable
data suggesting how frequently the invasive haemo- HF risk factors. Hypertension, AF, CAD, hyper-
dynamic exercise testing is used in clinical practice. lipidaemia, obesity, anaemia, DM, CKD and sleep
Because many patients with HFpEF have only apnoea are conditions that are frequently associ-
symptoms during exertion, acquiring ECHO during ated with HFpEF. There is no evidence for HFpEF-­
exercise can unmask LV diastolic and systolic func- specific management of these conditions.
tions.7 Two most studied parameters indicative of Even though multiple randomised controlled
increase in PCWP and pulmonary artery systolic trials (RCTs) using ACE inhibitors (ACEis), angio-
pressure are early diastolic transmitral flow velocity tensin II receptor blockers (ARBs), MRAs, beta
to early diastolic mitral annular tissue velocity (E:e') blockers and angiotensin–neprilysin inhibitors
ratio and the tricuspid regurgitation peak velocity.21 (ARNI) in patients with HFpEF did not show
Guidelines emphasise that the larger the amount mortality benefit or reduction in hospitalisation,4
of non-­ invasive indicators of raised LV filling
their effects on the course of HFpEF were shown

878 Jasinska-­Piadlo A, Campbell P. Heart 2023;109:874–883. doi:10.1136/heartjnl-2022-321097

 Education in Heart

Table 1  Objective evidence used in the diagnosis of HFpEF

Parameter Threshold Comments

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LV mass index >95 g/m2 (female)
>115 g/m2 (male)
Relative wall thickness >0.42 Although the presence of concentric LV hypertrophy is supportive, its absence does not exclude HFpEF diagnosis.
LA volume index >34 mL/m2 (SR) In the absence of AF or valvular disease, LA enlargement reflects chronically elevated LV filling pressure.
>40 mL/m2 (AF)
E:e′ ratio at rest >9 Sensitivity 78% and specificity 59% for HFpEF by invasive exercise testing; cut-­off of 13 has lower sensitivity (46%) but
higher specificity (86%)
NT-­proBNP >125 (SR), >365 (AF) pg/mL Up to 20% of patients with invasively proven HFpEF have NPs below diagnostic thresholds, particularly in the presence
of obesity.
PA systolic pressure/TR >35 mm Hg/>2.8 m/s Sensitivity 54% and specificity 85% for the presence of HFpEF by invasive exercise testing
velocity at rest
Reference values as per European Society of Cardiology, reproduced with permission from Br J Cardiol 2022;29(suppl 2):S3–S6, doi: 10.5837/bjc.2022.s06. British Society of
Echocardiography42 value references are as follows: LV mass index >99 g/m2 (female), LV mass index >110 g/m2 (male), relative wall thickness >0.42, LA volume index >38 mL/
m2, E:e′ ratio at rest >13.
AF, atrial fibrillation; E:e′, early diastolic transmitral flow velocity: early diastolic mitral annular tissue velocity; HFpEF, heart failure preserved ejection fraction; IVSd,
interventricular septal thickness end diastole; LA, left atrial; LV, left ventricular; NP, natriuretic peptide; NT-­proBNP, N-­terminal pro-­B-­type natriuretic peptide; PA, pulmonary
artery; SR, sinus rhythm; TR, tricuspid regurgitation.

in subgroup analyses.22 23 Therefore, in selected inhibitor in patients on insulin or on sulfonylureas,

patients with HFpEF, MRAs, ARBs and ARNIs may the dose of these may need to be reduced. SGLT2
be considered to decrease hospitalisations, particu- inhibitor should be avoided in all patients with type
larly among patients with LVEF on the lower end 1 DM and type 2 DM and prior diabetic ketoac-
of this spectrum, and their use is given a class 2b idosis (DKA) or a condition predisposing to DKA
recommendation in 2022 HF guidelines from AHA/ (including pancreatic insufficiency, drug or alcohol
American College of Cardiology (ACC)/Heart addiction, and prolonged fasting). Use is not recom-
Failure Society of America(HFSA).10 mended if eGFR is <15–20 mL/min/1.73 m2.

Hypertension Chronic kidney disease

Hypertension is the leading cause of HFpEF, with Patients with HFpEF and CKD should be treated
a prevalence ranging from 60% to 89%,4 and BP with evidence-­ based therapies that reduce the
control is well established for preventing HF. Effec- progression of CKD by renin–angiotensin–aldo-
tive treatment leads to regression of LVH, with sterone system inhibitors and SGLT2 inhibitor
ARB, ACEi and calcium channel blockers, causing therapy. There is an expected initial decline in
more effective LVH regression than beta blockers eGFR on initiation of SGLT2 inhibitor of approxi-
or diuretics. Poorly controlled hypertension may mately 4 mL/min/1.73 m2; however, in longer term,
precipitate episodes of decompensation.4 Patients the rate of eGFR decline is slowed compared with
with HFpEF frequently have an exaggerated BP patients not on SGLT2 inhibitor. In the Dapagli-
response to exercise and may present with hyper- flozin and Prevention of Adverse Outcomes in
tensive acute pulmonary oedema. Exact BP targets Chronic Kidney Disease (DAPA-­CKD) trial, patients
are uncertain in HFpEF, and typically the goal is with CKD, with or without diabetes, had a lower
similar as for the general population. Evaluation risk of a decline in estimated GFR of at least 50%,
of the patient’s age and comorbidities (ie, diabetes, end-­stage kidney disease, or death from renal or
CKD, CAD, valvular heart disease and stroke) CV causes when treated with dapagliflozin versus
should guide personalised choice of antihyperten- placebo.25 We invite readers to a position paper
sive agents. In the case of uncontrolled HF symp- from the ESC ad hoc task force on SGLT2 inhibitor
toms or repeated hospitalisations despite reasonable on cardiac, renal and metabolic effects of SGLT2
BP control, the target should be reduced. When inhibitor.26
treating to a lower BP goal, carefully monitor dose
adjustments as patients with HFpEF can have an Chronic coronary syndrome
exaggerated hypotensive response to vasodilator Despite CAD and ischaemic heart disease being
therapy. more strongly associated with HFrEF, CAD is also
common in HFpEF, with prevalence in epidemio-
Diabetes logical and registry studies of 35%–60%.9 Due to
Despite favourable benefits of sodium–glucose exercise intolerance and the impact of increasing
cotransporter-­2 (SGLT2) inhibitor in individ- end-­diastolic LV pressures, it can be challenging
uals with HFpEF (see the SGLT2 inhibitor use to document ischaemia using non-­ invasive and
in HFpEF section), these medicines are recom- invasive testing in patients with HF. To determine
mended as primary type 2 diabetes treatment only the existence and degree of CAD and to assess the
for patients at highest CV risk or if metformin is need for revascularisation, CT coronary angiog-
contraindicated or not tolerated.24 To reduce the raphy should be considered in patients with a low
risk of hypoglycaemia when treating with SGLT2 to intermediate pretest probability of CAD or those

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Education in Heart
with equivocal non-­invasive stress tests, while inva- symptoms, physical limitations and exercise func-
sive coronary angiography may be considered in tion on 6 min walking distance in patients with
HFpEF with and without type 2 diabetes.30 The

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patients with an intermediate to high pretest prob-
ability of CAD.4 There are no prospective trials of results have implication on clinical practice, and
revascularisation in patients with HFpEF. Medical they were reflected in the new 2022 HF guidelines
therapy with beta blockers, long-­ acting nitrates, from AHA/ACC/HFSA,10 stating that SGLT2 inhib-
calcium channel blockers, ivabradine, ranolazine, itor can be beneficial in decreasing HF hospitalisa-
trimetazidine, nicorandil and their combinations tions and CV mortality (class 2a).
should be considered in HFpEF for angina relief.4 Dapagliflozin reduced the combined risk of
worsening HF or CV death in patients with HF
and mildly reduced or preserved ejection fraction,31
Atrial fibrillation
with a relative risk reduction of 18%. The results
There is a lack of large RCT evidence to guide
of this trial will have impact on future clinical HF
specific therapy for individuals with HFpEF and AF.
guidelines on pharmacotherapy in HFpEF.
It is recommended that patients with HFpEF and
The benefit of SGLT2 inhibitor on mortality and
chronic AF have adequate rate control, with beta
hospitalisation has been shown in patients with
blockers and non-­ dihydropyridine calcium channel
HFrEF in the DAPA-­HF trial. Patients who received
blockers frequently used as first-­line agents. Recently,
dapagliflozin had a 26% reduction in the primary
Rate Control Therapy Evaluation in Permanent
endpoint (CV death, hospitalisation or urgent HF
Atrial Fibrillation (RATE-­AF), an open-­label trial in
visit) compared with patients who obtained stan-
elderly patients with AF and symptoms of HF (most
dard treatment alone, with significant reduction in
with HFpEF), compared the use of bisoprolol to
both worsening HF and CV death components of
digoxin.27 The primary outcome of QoL was compa-
the primary endpoint. In both diabetics and non-­
rable between the two groups at 6 months. However,
diabetics, identical outcomes were seen.32
numerous secondary QoL objectives, including func-
SGLT2 inhibitors are not currently included in
tional ability and NT-­ proBNP decrease, preferred
most recent European guidelines on treatment of
digoxin at 12 months, with both groups having a
HF, as the results of the trials were available after
comparable decrease in heart rate. Beta blockers
the guidelines were published. However, there are
caused more adverse effects, such as dizziness, drowsi-
two guidelines currently in development by NICE
ness and hypotension, than digoxin.
in the UK: ‘Empagliflozin for treating chronic heart
RCTs comparing rate control to rhythm control with
failure with preserved or mildly reduced ejection
antiarrhythmic medications have not demonstrated an
fraction [ID3945]’33 and ‘Dapagliflozin for treating
advantage of rhythm control. Recent RCTs involving
chronic heart failure with preserved or mildly
ablation indicate that ablation may be better to anti-
reduced ejection fraction [ID1648]’.34 The expected
arrhythmic medicines for rhythm control strategies. If
date of publication of aforementioned guidelines is
rate and rhythm control strategies fail, patients with
yet to be confirmed. As mentioned earlier, SGLT2
HFpEF and difficult-­to-­control heart rates may benefit
inhibitors are recommended though in patients
from atrioventricular node ablation and placement of
with type 2 DM who do not tolerate metformin.24
a permanent pacemaker; when LVEF is >50%, there
is no evidence that cardiac resynchronisation therapy
(CRT) is superior to right ventricular pacing.10 This Follow-up for patients with HFpEF
paper does not cover the entire care of AF, and we The frequency of clinical evaluation in ambulatory
refer readers to ESC practise guidelines on AF-­specific patients with HFpEF is determined by the severity
care.28 of HF symptoms and comorbid conditions (eg,
CKD), but it is recommended that patients with
HFpEF have a clinical review every 6 months.
SGLT2 inhibitor use in HFpEF Patients should be reviewed quickly with deteriora-
The landmark trials EMPEROR-­ Preserved,29 tion of clinical status, within 2 weeks of medication
PRESERVED-­HF30 and DELIVER31 showed the change, and within 7–14 days of hospital discharge
positive impact of SGLT2 inhibitor on outcomes after HF decompensation29 to significantly reduce
in patients with HFpEF. The EMPEROR-­Preserved the chance of readmission. It is important to eval-
trial showed 21% reduction in the primary uate patients with worsening HF signs or symptoms
composite endpoint of time to HF hospitalisation for cardiac (eg, rhythm disorders and ischaemia)
or CV death in the empagliflozin arm. The benefit and non-­cardiac (eg, worsening diabetes and hypo-
of empagliflozin first reached statistical significance thyroidism) causes of HFpEF exacerbation. NP
at 18 days after randomisation and maintained level may be useful during symptom re-­evaluation.
significance thereafter. While there was no benefit However, low levels of NP can be present even in
on all-­cause mortality, empagliflozin resulted in a very symptomatic patients; hence, testing should
significant reduction in total HF hospitalisations, a not be guided by NP levels alone.
decrease in the slope of the eGFR decline, and a
modest improvement in QoL at 52 weeks. Impor- Patient education
tantly, the benefit was similar, irrespective of the The management of a patient with HFpEF requires
presence or absence of diabetes at baseline. a multidisciplinary approach and good patient
PRESERVED-­ HF demonstrated that treat- education. In addition to pharmacological treat-
ment with dapagliflozin significantly improved ment, patients with HFpEF should be offered a

880 Jasinska-­Piadlo A, Campbell P. Heart 2023;109:874–883. doi:10.1136/heartjnl-2022-321097

 Education in Heart
comprehensive guide and support in implementing see an update of the ESC guidelines to reflect the
and maintaining lifestyle changes and self-­care strat- use of SGLT2 inhibitor for patients with HFpEF.

Heart: first published as 10.1136/heartjnl-2022-321097 on 22 March 2023. Downloaded from http://heart.bmj.com/ on June 19, 2023 by guest. Protected by copyright.
egies. Programmes for managing chronic diseases Due to variations in coexisting comorbid condi-
and instruction in self-­management may lower the tions driving the condition, multiple clinical
probability of hospital admission for people with phenotypes and underlying pathophysiologies
HFpEF.35 are responsible for the manifestation of HFpEF.
Participation in structured exercise-­ based Despite this, current clinical practice lacks
programmes, cardiac rehabilitation, weight loss personalised and targeted treatment options for
programmes and dietary interventions not only can patients with this complex clinical syndrome.
lead to improved exercise tolerance36 but also is Future clinical practice should strive to deliver
associated with lower odds of all-­cause mortality, personalised therapy for this highly prevalent
hospitalisations, incident stroke and incident AF in and growing cohort of patients.
patients with HFrEF and HFpEF.37 Meta-­analyses
of multidisciplinary team (MDT) care demonstrate SUMMARY
a reduction in death as well as hospital admissions The pathophysiology of HFpEF is complex, and
in favour of MDT care.38–40 The studies included in systemic changes related to various comorbid
the analyses rarely excluded patients with HFpEF; conditions drive myocardial dysfunction in myriad
therefore, MDT therapy may also improve survival differing ways. The diagnosis of HFpEF can seem
as well as reduce hospital admissions. Until recently, complex, but recent guidelines recommend use of
many HF MDT services intentionally exclude a simple three-­step diagnostic pathway to enable
patients with HFpEF due to a perceived lack of effective diagnosis in the majority of cases. For
effective treatments. Given the restricted avail- patients whose initial testing is inconclusive,
ability of high-­quality structured programmes for referral to specialist centres for additional exer-
patients with HF, it is extremely difficult to deter- cise testing should be considered. Regardless of
mine which individuals with HFpEF are most likely LVEF, a diagnosis of HF has significant negative
to benefit or should be given priority access, as well effects on both the quality and quantity of life.
as how to deliver suitable services. However, it is HFpEF represents 50% of all HF cases, and these
worth stressing that HF experts agree that patients patients are currently recognised as having the
with HF, of any type, ideally should have access to greatest unmet need in cardiology, with many HF
rehabilitation programmes. Figure 5 summarises services not offering care to this patient group.
important aspects of the patient education. Each Due to an ageing population and increasing prev-
contact with the patient should be seen as an oppor- alence of comorbidities, HFpEF incidence is
tunity to ensure that patients understand their rising. Outcomes in HFpEF are comparable with
condition and know how to manage it to achieve those in HFrEF; therefore, intervention should be
and maintain a high QoL. implemented early to prevent mortality, morbidity
and poor patient reported outcomes. HFpEF is
EXPERT’S GLIMPSE OF WHAT THE FUTURE associated with multimorbidity, with as many as
SHOULD HOLD 50% of patients having five or more significant
With the recent publication of the DELIVER trial comorbidities. Management of the comorbidities
results in combination with those of EMPEROR-­ and diuretic therapy have long been central in
Preserved and PRESERVED-­ HF, we expect to the treatment of HFpEF with the aim of reducing

Figure 5  Education and self-­care topics to be covered by the multidisciplinary team caring for patients with HF. HF, heart failure.
Jasinska-P­ iadlo A, Campbell P. Heart 2023;109:874–883. doi:10.1136/heartjnl-2022-321097 881
Education in Heart
Contributors  There was equal contribution from both authors.
Key messages The final document reviewed and edited by PC.

Heart: first published as 10.1136/heartjnl-2022-321097 on 22 March 2023. Downloaded from http://heart.bmj.com/ on June 19, 2023 by guest. Protected by copyright.
Funding  This work was supported by the Public Health Agenacy
⇒ Approximately 50% of patients with heart failure (HF) have preserved and Health and Social Care Research and Development Department
ejection fraction. in Northern Ireland [grant number EAT/5495/18, 2018]; Southern
⇒ The incidence of heart failure with preserved ejection fraction (HFpEF) Health and Social Care Trust, Research and Development
increases with age; other risk factors include female gender, hypertension, Department .
obesity, metabolic syndrome and coronary artery disease. Competing interests  AJ-­P was a recipient of a Doctoral
⇒ HFpEF is associated with multimorbidity, with as many as 50% of patients Fellowship Award from the Research and Development department
of the Public Health Agency, Health and Social Care in Northern
having five or more significant comorbidities (including hypertension, Ireland and received speaker honorarium from Vifor-­Pharma. PC
diabetes mellitus, chronic kidney disease, atrial fibrillation and anaemia). received speaker honoraria from Novartis, Boehringer Ingelheim,
⇒ Elevated natriuretic peptide (NP) levels are a feature for most patients; Vifor-­Pharma, Pfizer and AstraZeneca and institutional research
however, an estimated 20% have normal NP levels. funding from AstraZeneca and is a member of the advisory board
for EMPEROR-­Preserved.
⇒ Outcomes in HFpEF are comparable to those for HF with reduced ejection
fraction; hence, early intervention should be implemented to prevent Patient consent for publication  Not applicable.
mortality, morbidity and poor patient-­reported outcomes. Ethics approval  Not applicable.
⇒ Therefore, accurate and prompt diagnosis is critical. Provenance and peer review  Commissioned; externally peer
⇒ Use of a simple three-­step diagnostic pathway can enable an HFpEF reviewed.
diagnosis for the majority of patients. Author note  References which include a * are considered to be
⇒ For those with inconclusive results, referral to specialist centres for exercise key references.
testing should be considered. Open access  This is an open access article distributed in
⇒ Treatment of fluid overload and targeted therapy for associated comorbid accordance with the Creative Commons Attribution Non
conditions is recommended. Commercial (CC BY-­NC 4.0) license, which permits others to
distribute, remix, adapt, build upon this work non-­commercially,
⇒ The results of EMPEROR-­Preserved and PRESERVED-­HF clinical trials support
and license their derivative works on different terms, provided
the use of sodium–glucose cotransporter-­2 inhibitors as a new treatment the original work is properly cited, appropriate credit is given, any
option in patients with HFpEF, with class 2a recommendation for use in the changes made indicated, and the use is non-­commercial. See: http://​
2022 American Heart Association/American College of Cardiology/HFSA HF creativecommons.org/licenses/by-nc/4.0/.
guidelines. ORCID iDs
⇒ The results of DELIVER trial show that use of SGLT2 inhibitors in patients Alicja Jasinska-­Piadlo http://orcid.org/0000-0002-3603-5999
with HFpEF showed reduction of the combined risk of worsening HF or Patricia Campbell http://orcid.org/0000-0002-5371-2242
cardiovascular death.

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