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1
National Heart and Lung
Institute, Imperial College
London, London, UK
2
Department of Cardiology,
Royal Brompton and Harefield
NHS Foundation Trust, London,
UK
Correspondence to
Professor Martin R Cowie,
National Heart and Lung
Institute, Imperial College
London, Dovehouse Street,
London, SW3 6LY, UK; ​m.​
cowie@​imperial.​ac.u​ k
Received 4 August 2017
Revised 2 November 2017
Accepted 4 November 2017
To cite: Zakeri R, Cowie MR.
Heart Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
heartjnl-2016-310790
Copyright Article author (or their employer) 2018. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Heart failure with preserved ejection fraction:
controversies, challenges and future directions
Rosita Zakeri,1,2 Martin R Cowie1,2
Abstract
Heart failure with preserved ejection fraction (HFpEF)
comprises almost half of the population burden of HF.
Because HFpEF likely includes a range of cardiac and
non-cardiac abnormalities, typically in elderly patients,
obtaining an accurate diagnosis may be challenging,
not least due to the existence of multiple HFpEF mimics
and a newly identified subset of patients with HFpEF
and normal plasma natriuretic peptide concentrations.
The lack of effective treatment for these patients
represents a major unmet clinical need. Heterogeneity
within the patient population has triggered debate over
the aetiology and pathophysiology of HFpEF, and the
neutrality of randomised clinical trials suggests that we
do not fully understand the syndrome(s). Dysregulated
nitric oxide–cyclic guanosine monophosphate–protein
kinase G signalling, driven by comorbidities and
ageing, may be the fundamental abnormality in
HFpEF, resulting in a systemic inflammatory state and
microvascular endothelial dysfunction. Novel informatics
platforms are also being used to classify HFpEF
into subphenotypes, based on statistically clustered
clinical and biological characteristics: whether such
subclassification will lead to more targeted therapies
remains to be seen. In this review, we summarise
current concepts and controversies, and highlight the
diagnostic and therapeutic challenges in clinical practice.
Novel treatments and disease management strategies
are discussed, and the large gaps in our knowledge
identified.
Introduction
Heart failure (HF) with preserved ejection fraction
(HFpEF) accounts for up to half of all HF in the
developed world.1 The reported population prev-
alence ranges from 1% to 3%, and is predicted
to rise further with lengthening life expectancy,
greater diagnostic awareness, and increasing rates
of obesity, diabetes, hypertension and atrial fibril-
lation (AF).1 Whether HFpEF constitutes a single
syndrome or a collection of syndromes is debated,
neverless the diagnostic label identifies patients
with a poor quality of life, high rates of hospitalisa-
tion and premature mortality.1–3 Clinical guidelines
offer few evidence-based treatment recommenda-
tions.2–4 Large randomised clinical trials of thera-
pies improving outcomes in HF with reduced EF
(HFrEF) have failed to demonstrate prognostic
benefit in patients with HFpEF, obliging us to
re-examine our understanding of the mechanisms
driving morbidity and mortality in this syndrome,
and the extent of their reversibility.
In this review, we summarise current ideas,
controversies and challenges in the diagnosis and
treatment of HFpEF; discuss our understanding
of its pathophysiology; and outline novel targeted
Zakeri R, Cowie MR. Heart 2018;0:1–8. doi:10.1136/heartjnl-2016-310790
Review
therapies and disease management strategies under
investigation. The large gaps in our knowledge are
clearly evident.
Diagnosis
How is HFpEF diagnosed?
Among patients with a clinical diagnosis of HF,
the distribution of EF has been reported variably
as either unimodal5 or bimodal.6 The decision to
dichotomise HF into HFrEF or HFpEF according
to an EF of 50% was arbitrary, but has become
enshrined in the literature. Current guidelines advo-
cate using EF≥50% as one component of a diag-
nostic algorithm for HFpEF,2 3 alongside detection
of additional myocardial abnormalities to implicate
a cardiac cause for symptoms (table 1).2 3 A stream-
lined method for identifying left ventricular (LV)
diastolic dysfunction has been proposed, based on
expert opinion.7 The gold standard to confirm (or
refute) a diagnosis of HFpEF is based on demon-
stration of elevated LV filling pressures during
cardiac catheterisation, at which time the pres-
ence or absence of concomitant pulmonary arterial
hypertension can be assessed.2 3 Non-invasive or
invasive stress testing is recommended to unmask
symptoms (which often occur exclusively on exer-
tion) and diastolic dysfunction, in order to improve
diagnostic sensitivity, particularly in individuals
with an intermediate pretest probability of HFpEF.8
Other pathologies giving rise to similar symptoms,
such as myocardial ischaemia or anaemia, should be
actively excluded before a diagnosis of HFpEF is
accepted (table 2).
Areas of diagnostic uncertainty
‘Normal’ levels of B-type natriuretic peptide (BNP)
are reported in up to 30% of patients, despite clin-
ical, echocardiographic and invasive haemodynamic
evidence of HFpEF.9 The absence of LV dilatation
(and thus lower diastolic wall stress) in HFpEF
yields lower BNP concentrations and therefore less
sensitive discrimination between the normal and
HF state. Further ambiguity may be introduced
by obesity, which is associated with lower plasma
BNP concentrations and possible heightened peri-
cardial restraint,10 and by AF, which is associated
with raised plasma BNP concentrations.11 The
phenotypic overlap between HFpEF and ‘AF with
associated breathlessness and raised BNP’ may be
considerable, though prompt different management
strategies.
It is unclear whether patients with HF symptoms,
preserved EF and more than mild epicardial coro-
nary artery disease (CAD) can be considered to have
HFpEF. CAD is widely noted in HFpEF cohorts and
  1
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Review

Table 1  Diagnostic criteria for HFpEF

ESC guidelines 20162 AHA guidelines 20133
History and examination Symptoms and signs of HF Symptoms and signs of HF
Ejection fraction ≥50% ≥50%
Natriuretic peptides BNP>35 pg/mL and/or Elevated levels are supportive
NT-proBNP>125 pg/mL
Imaging Cardiac structural alterations Abnormal LV diastolic function
 LAVI>34  mL/m2
 LVMI≥115  g/m2 (Males) ≥95 g/m2 (Females)
And/or cardiac functional alterations
 E/e’ mean septal-lateral≥13
 Mean e’ septal/lateral wall<9  cm/s
Additional indirect measures
 Reduced global longitudinal strain
 Elevated PASP (from TR velocity)
ECG AF, LVH, repolarisation abnormalities No specifications
Exclusions Exclude other known causes of HF Exclude other known causes of HF
Further testing in case of uncertainty Diastolic stress test
 E/e’, PASP, strain, SV and CO
or invasive assessment of LV pressures
 Rest PCWP≥15 mm Hg or LVEDP≥16 mm Hg±change with exercise*
*Defined as increase in PCWP to ≥25 mm Hg with exercise by Obokata et al.8
AF, atrial fibrillation; BNP, b-type natriuretic peptide; CO, cardiac output; HF, heart failure; HFpEF, HF with preserved ejection fraction; LAVI, left atrial volume index; LV, left
ventricular; LVEDP, left ventricular end diastolic pressure; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; NT-proBNP, N-terminal pro B-type natriuretic peptide;
PASP, pulmonary artery systolic pressure; PCWP, pulmonary capillary wedge pressure; SV, stroke volume; TR, tricuspid regurgitation.

HF symptoms that are disproportionate to the severity of CAD
or persist after revascularisation may represent one of several
proposed HFpEF patient phenotypes.12 Evidence of microvas-
cular ischaemia (eg, as demonstrated by cardiac stress magnetic
resonance imaging [MRI]) would be compatible with microvas-
cular inflammation, which is hypothesised to be important in
HFpEF.13
In practice, due to the lack of pathognomonic diagnostic
criteria and complex requirement for systematic exclusion of
other pathologies, in typically elderly patients with multimor-
bidity, many individuals with breathlessness or fluid retention
may be labelled as ‘HFpEF’ without the phenotype being prop-
erly established. Cardiopulmonary exercise testing is empirically
used to differentiate HFpEF from exercise intolerance due to
non-cardiac limitations such as pulmonary disease or decon-
ditioning, though feasibility may be limited in some elderly or
frail patients.
Pathophysiology
Does HFpEF simply represent advanced age?
Observational studies report abnormalities in cardiovascular
structure and function in HFpEF which exceed those observed
in age, sex and body size matched individuals without HF,14 even
after adjusting for the cumulative burden of comorbidities.15
Skeletal muscle mass is reduced in HFpEF, beyond that which is
observed with normal ageing, and directly contributes to exer-
cise limitation.16 Furthermore, mortality rates among patients
with HFpEF exceed those for patients with similar age, sex
and comorbidity distribution in trials of hypertension, diabetes
and CAD, with a higher proportion of cardiovascular deaths
observed in HFpEF.17 These observations suggest that HFpEF
is not simply an ageing heart and vascular system. Indeed, the
majority of older adults with comorbidities do not develop
HFpEF.
2 Zakeri R, Cowie MR. Heart 2018;0:1–8. doi:10.1136/heartjnl-2016-310790
Do advancing age and comorbidities contribute to HFpEF
pathophysiology?
Late-onset HFpEF may have a different pathophysiology to
HFpEF presenting at a younger age. Observational studies
suggest that ‘accelerated’ ageing may be a mechanism for ventric-
ular–arterial stiffening in HFpEF, particularly among women.18
Additionally, senile wild-type transthyretin deposition has been
associated with HFpEF in predominantly elderly patients.19
Comorbidities are universal in HFpEF cohorts and uniquely
influence ventricular and vascular remodelling and prognosis.15
Recently, it has been suggested that comorbidities are integral
to the development of HFpEF.13 Cardiometabolic diseases,
including obesity, systemic hypertension and diabetes, are
proposed to induce a systemic proinflammatory state which in
turn triggers systemic and coronary microvascular inflammation.
Nitric oxide (NO) bioavailability is reduced and downstream
second messenger signalling at the level of the endothelium
and cardiomyocyte (reduced cyclic guanosine monophosphate
(cGMP) content and protein kinase G (PKG) activity) promotes
myocyte and myocardial hypertrophy, cardiomyocyte stiffness
and interstitial fibrosis13. This hypothesis reconciles phenotypic
diversity in HFpEF cohorts, with findings at cellular and tissue
level in human HFpEF biopsies,20 in vivo endothelial dysfunc-
tion21 and autopsy evidence of coronary microvascular rarefac-
tion in HFpEF.22
Importantly, however, the heterogeneity of patient character-
istics, organ-system involvement and number of pathophysio-
logical abnormalities that have been associated with established
HFpEF (Figure 1) support a multifactorial aetiology in most
patients. Therefore, identification of vulnerable individuals
and specific genetic or environmental aetiological factors is still
needed. 
Do distinct pathophysiological subtypes of HFpEF exist?
Pragmatic subphenotypes of HFpEF have been described
according to dominant comorbidities or grouped clinical
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Table 2  Differential diagnosis of HFpEF
Classical HFpEF
Heart failure (high left ventricular
filling pressures) associated with:
Differential diagnosis—cardiac
Specific cardiomyopathy
Congenital heart disease
Coronary artery disease
Heart failure with recovered EF
High cardiac output heart failure
Malignancy
Pericardial disease
Pulmonary vein stenosis
Right heart failure due to:
Rhythm disturbance
Zakeri R, Cowie MR. Heart 2018;0:1–8. doi:10.1136/heartjnl-2016-310790
Atrial fibrillation
Chronic kidney disease
Coronary artery disease
 Mild-to-moderate obstructive epicardial
disease
 Abnormal coronary microcirculation
Diabetes
Hypertension
Obesity
Sleep disordered breathing
Hypertrophic cardiomyopathy
Sarcomeric (and other) gene mutations
Glycogen storage disease
Lysosomal storage disease (including Fabry’s
disease)
Amyloidosis
Restrictive cardiomyopathy
 Familial
  Sarcomeric (and other) gene mutations
  Amyloidosis
  (familial TTR or apolipoprotein
mutation)
  Hereditary haemochromatosis (iron
overload)
  Fabry’s disease
  Glycogen storage disease
  Laminopathy/desminopathy
  Pseudoxanthoma elasticum
 Non-familial
  Amyloidosis (or wild-type TTR)
  Systemic sclerosis
  Sarcoidosis
  Endomyocardial fibrosis
  Carcinoid heart disease
  Radiation
  Drug toxicity (eg, anthracyclines)
  Heavy metals (copper, iron, cobalt, lead)
Arrhythmogenic right or left ventricular
cardiomyopathy
Non-compaction cardiomyopathy
Atrial and ventricular septal defects
Moderate-to-severe (obstructive) epicardial
disease
Anaemia, hyperthyroidism, sepsis, skeletal
disorders, systemic arteriovenous fistulas,
vitamin B1 deficiency
Direct infiltration and masses (primary or
secondary)
Radiation-induced cardiomyopathy
Atrial myxoma
Constrictive pericarditis
Pericardial effusion and cardiac tamponade
Effusive-constrictive pericarditis
Primary pulmonary arterial hypertension
Right ventricular infarction
Atrial or ventricular arrhythmias
Complete atrioventricular dissociation
Continued
Review
Table 2  Continued 
Valvular heart disease Acquired or congenital severe stenosis or
regurgitation
Differential diagnosis—extracardiac
Anaemia
Pulmonary disease Chronic obstructive pulmonary disease
Interstitial lung disease
Renal failure (acute or chronic)
EF, ejection fraction; HFpEF, heart failure with preserved ejection fraction; TTR,
transthyretin.
characteristics.23 For example, an HFpEF subphenotype with
pulmonary arterial hypertension and right ventricular dysfunc-
tion has been well characterised and often signifies advanced
stage HF.23 Accumulating evidence suggests that patients with
HFpEF and concomitant obesity,10 diabetes15 or AF11 exhibit
unique characteristics and a poorer prognosis than patients
without these comorbidities. As yet, however, it remains
unproven whether these clinical subtypes reflect a spectrum of
the same disease or mutually exclusive mechanisms that may
respond to different therapies
‘Deep’ phenotyping of individuals with HFpEF, using
advanced bioinformatics, is an evolving area of investigation.
Initial studies have proposed novel subphenotypes extending
beyond individual comorbidity-defined subgroups.23 24 Large
dataset-based clustering and machine learning analyses are well
suited to model the complex interactions that may contribute to
HFpEF pathophysiology . Importantly, however, generalisability
and reliability of the output depend on patient selection and the
quality and completeness of data entry. Furthermore, ‘omics'
methodologies have not yet been applied to HFpEF patient
cohorts without elevated BNP or diastolic dysfunction.
Treatment
What is the evidence for current treatment recommendations
in HFpEF?
No therapy has yet been shown to improve survival in randomised
controlled trials of patients with HFpEF and EF≥50%. Existing
treatment recommendations focus on judicious use of diuretics
to relieve congestion (when present), and optimal management
of comorbidities (table 3).
What has been learnt from previous trials in HFpEF?
No single reason underlies the neutral or negative outcomes
of previous trials (online supplementary table S1). Trials
employing a low EF cut-off for HFpEF (eg >40% CHARM-Pre-
served,25>45% I-PRESERVE26) or recruiting few patients with
EF ≥50% (SENIORS27) insufficiently represented symptomatic
HFpEF, as defined by current guidelines.3 In TOPCAT, regional
differences in placebo group adverse event rates correlated with
apparent differences in benefit with spironolactone therapy,28
suggesting possible inappropriate patient inclusion at some sites.
The interpretation of PEP-CHF, examining the value of perindo-
pril in the treatment of HFpEF, was hindered by a high drop-out
rate (40% treatment arm, 36% placebo arm), and one-third of
patients received open-label treatment during the study.29
Therapies targeting the renin–angiotensin system have
uniformly failed to demonstrate benefit in HFpEF trials.25 26 28 29
Evidently, neurohumoral stimulation does not exert a domi-
nant impact on the clinical course of unselected patients with
HFpEF. RELAX30 tested an alternative therapeutic hypoth-
esis that prevention of cGMP breakdown with phosphodies-
terase 5 (PDE-5) inhibition would enhance exercise capacity
3
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Figure 1  Pathphysiological abnormalities associated with the heart failure with preserved ejection fraction syndrome. AF, atrial fibrillation, LA, left
atria; LV, left ventricular; RV, right ventricular.

in patients with HFpEF, but was also neutral. Translational
studies have reported low myocardial cGMP content in human
HFpEF biopsies;20 hence, low cGMP production may be the key
perturbation in HFpEF, rather than excess cGMP breakdown,
explaining the neutral result. Since PDE-5 inhibitors improve
outcomes in patients with pulmonary arterial hypertension,
theoretically targeting patients with HFpEF who have severe
pulmonary vascular disease (combined precapillary and postcap-
illary pulmonary hypertension) may produce a different result.
Randomised controlled trials (RCT) evidence is generally
regarded as the most robust evidence for regulatory authori-
ties and guideline writers. Such studies are expensive, often of
limited duration, and typically focus on a few ‘hard’ endpoints,
such as cardiovascular mortality. However, if HF hospitalisation
had been selected as the primary endpoint in CHARM-Pre-
served25 or TOPCAT,28 the study conclusions might have been
different (supplementary table S1).
What therapies for HFpEF are currently under investigation?
Several novel therapies are currently under investigation in
randomised trials  (Figure 2)  underway (PARAGON-HF, NCT01920711). The impact of sacubi-
Therapies to modify cellular cGMP and structural adaptations
Pharmacological modulation of the NO-cGMP-PKG signalling
pathway may increase cGMP content and reduce myocardial stiff-
ness in HFpEF (Figure 3). To date, neither direct replenishment
of cGMP, via soluble guanylate cylase stimulators (riociguat,31
vericiguat32), nor indirect cGMP replenishment via the organic NO
donor, isosorbide mononitrate33 (ISMN), have met their primary
endpoints in HFpEF trials. ISMN reduced patient activity levels
4 Zakeri R, Cowie MR. Heart 2018;0:1–8. doi:10.1136/heartjnl-2016-310790
in the Nitrate’s Effect on Activity Tolerance in Heart Failure with
Preserved Ejection Fraction (NEAT-HFpEF) trial, possibly due to
excess hypotension or renal sodium retention,33 and is therefore
contraindicated in HFpEF unless required for another indication,
for example, angina.4 Inorganic nitrate preferentially delivers NO
during hypoxia and acidosis, as occur during stress and exercise,
potentially avoiding hypotensive sequelae. In a phase II study,
beetroot juice (dietary inorganic nitrate) improved systemic vaso-
dilation during exercise and submaximal exercise endurance in
patients with HFpEF.34 Further studies using an inhaled nitrite
preparation are in progress (NCT02742129).
Natriuretic peptides increase intracellular cGMP (Figure 3).
Neprilysin inhibitors prevent the breakdown of biologically active
natriuretic peptides. In the phase II PARAMOUNT trial, the
combined neprilysin inhibitor/angiotensin receptor blocker, sacu-
bitril–valsartan, was associated with lower NT-proBNP, reduced
left atrial size and a trend towards improved functional class
compared with valsartan therapy alone,35 implying a disease-modi-
fying effect in HFpEF. A phase III trial with the combined primary
endpoint of cardiovascular death or first HF hospitalisation is
tril–valsartan, compared with individualised medical management
of comorbidities, on NT-proBNP, symptoms, exercise capacity and
safety in HFpEF is also being studied (NCT03066804). 
Therapies to improve exercise intolerance and functional
adaptations
It is debatable whether exercise intolerance in HFpEF is
predominantly due to impaired cardiac, chronotropic21 or
peripheral vascular reserve.36 Theoretically, greater LV filling
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Table 3  Current evidence for treatment of HFpEF

Level of
Target Therapy Evidence evidence
Survival ACEI/ARB No RCT evidence of benefit (possible benefit in subgroup with low BNP)49 –
Beta blockers Possible benefit on pooled analysis in patients with EF≥40%50 –
Mineralocorticoid receptor antagonist No RCT evidence of benefit –
Hospitalisation for HF ACEI/ARB No RCT evidence of benefit (possible benefit in subgroup with low BNP)49 –
Beta blockers No RCT evidence of benefit –
Mineralocorticoid receptor antagonist Benefit of spironolactone in TOPCAT (as secondary outcome)28 IIA4
Loop diuretics Benefit of diuretic therapy combined with vasodilators in CHAMPION43 IB2 or C3
Symptoms IB or C
 Congestion Loop diuretics CHAMPION trial (diuretic therapy combined with vasodilators)43
 Exercise capacity Isosorbide mononitrate Associated with reduced activity levels in NEAT-HFpEF33 III
Management of comorbidities in IB3 or C3
HFpEF
 Hypertension Antihypertensive therapy Management of acute hypertensive oedema –
BP targets extrapolated from hypertension guidelines
 Atrial fibrillation
 Stroke prevention Oral anticoagulation Risk scores extrapolated from AF guidelines IA (AF)
 Rhythm control Ablation No RCT evidence of benefit (Observational single-centre data)51 –
 Rate control Beta blockers, CCB, digoxin No RCT evidence for rate targets –
 CAD Pharmacotherapy (including statins) No RCT evidence of benefit –
Revascularisation No RCT evidence of benefit (Observational single centre data12) –
 Diabetes Empagliflozin Reduction in (incident) HF hospitalisation among patients with diabetes and high CV risk (HF –
phenotype not reported)48
 Kidney disease ACEI/ARB (for hypertension) –
 Obesity Weight loss programme (behavioural) Improvement in peak VO2 in patients≥60 years47 –
Pharmacotherapy/bariatric surgery No RCT evidence of benefit –
 Pulmonary disease No RCT evidence of benefit –
 Sleep disordered breathing No RCT evidence of benefit –
ACEI, ACE inhibitors; AF, atrial fibrillation; ARB, angiotensin receptor blockers; BNP, B-type natriuretic peptide; BP, blood pressure; CAD, coronary artery disease; CCB, calcium channel blockers;
CV, cardiovascular; HF, heart failure; HFpEF, heart failure with preserved ejection fraction.

Figure 2  Therapeutic targets under investigation in HFpEF. HFpEF, heart failure with preserved ejection fraction; LA, left atrial; sCG, soluble
guanylate cyclase.
Zakeri R, Cowie MR. Heart 2018;0:1–8. doi:10.1136/heartjnl-2016-310790 5
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Figure 3  Myocardial cyclic guanosine monophosphate (cGMP) signalling in HFpEF (potential therapeutic targets are highlighted in red). Natriuretic
peptides bind to the natriuretic peptide receptors A and B (NPRA/B) and stimulate cGMP via particulate guanylate cyclase (pGC). Neprilysin inhibitors
act through this pathway. Nitric oxide synthases produce nitric oxide which stimulates cGMP via soluble guanylate cyclase (sCG). sCG stimulators
and nitrates/nitrites target this pathway. cGMP activates protein kinase G (PKG) which has a number of beneficial effects (as demonstrated).
Phosphodiesterase-5a inhibitors (PDE5a) act directly on this pathway by preventing the breakdown of cGMP.

occurs at lower heart rates, although excess rate lowering
may exacerbate chronotropic incompetence in HFpEF. The If
current blocker, ivabradine, variably demonstrated improved,37
worsened38 or no effect39 on exercise capacity, quality of life
and BNP in phase II HFpEF trials. RAPID-HF will assess
whether restoring chronotropic competence using rate adap-
tive pacing can improve exercise capacity in patients with
HFpEF in sinus rhythm who display chronotropic incompe-
tence (NCT02145351).
Pulmonary vasodilation may improve pulmonary hyperten-
sion in HFpEF. A number of agents are currently being tested,
including oral trepostinil (NCT03037580, NCT03043651),
riociguat (NCT02744339) and nitrate therapy (NCT02980068).
BEAT-HFpEF (NCT02885636) is investigating whether
albuterol improves pulmonary vascular tone in HFpEF.
Therapies to ameliorate advanced symptoms
Creation of a controlled left-to-right interatrial shunt in patients
with advanced HFpEF, improved functional capacity and quality
of life after 12 months in an open-label study of 64 patients.40
Open-label phase 1 studies are underway for similar devices
(CORolla, NCT02499601; Occlutech atrial flow regulator,
NCT03030274). A small sham-controlled RCT is due to report
shortly (REDUCE LAP-HF I; NCT 02600234). 
Monitoring strategies to prevent adverse outcomes
Outcomes from disease management programmes have not been
reported stratified by HF type,41 though feasibility of imple-
menting a specialised HFpEF programme has been described in
a single centre.42
Following the favourable results of the CHAMPION trial,43
which included patients with a spectrum of EFs, additional
prospective studies of remote pulmonary artery pressure moni-
toring are underway in the USA and Europe/Australia.
6 Zakeri R, Cowie MR. Heart 2018;0:1–8. doi:10.1136/heartjnl-2016-310790
Treatment of comorbidities and exercise training
OPTIMIZE-HFpEF (NCT02425371) will determine whether
systematic screening and targeted management of comorbidities
in HFpEF patients (>60 years of age) will improve a composite
outcome comprising symptoms, NT-proBNP, diuretic use, HF
hospitalisation and death compared with usual care. The safety,
tolerability and efficacy of iron repletion, in the presence or
absence of anaemia, on walking distance after 1 year are being
investigated in FAIR-HFpEF (NCT03074591).
To date, exercise training represents the only intervention
that has demonstrated symptomatic benefit in relatively young
patients with HFpEF, likely through beneficial effects on periph-
eral (arterial and skeletal muscle) targets.44 The exercise protocol
employed in early studies may not be feasible in all elderly or
frail patients with HFpEF; thus, further studies to refine the
content of exercise programmes (Exercise Intolerance in Elderly
Patients With HFpEF, NCT02636439), define the mechanism
of benefit (Resistance training in HFpEF, NCT02435667) and
optimal location of exercise (Implementation of Telerehabili-
tation In Support of HOme-based Physical Exercise for Heart
Failure, NCT02435667) are underway.
Future directions
Definition of HFpEF and its fundamental mechanisms
The lack of consistent diagnostic criteria for HFpEF makes compar-
ison across randomised trials difficult. There is a pressing need
to improve the specificity of an HFpEF diagnosis from other HF
syndromes and comorbid disease states, such as symptomatic CAD
and AF. Novel diagnostics, including multiparametric biomarkers
and new imaging techniques, may help to identify unique biolog-
ical signature(s) for HFpEF (eg, circulating galectin-3 and MRI-T1
mapping techniques may be used to quantify myocardial fibrosis).
Fundamental and specific changes in myocardial structure and
function in patients with HFpEF support the ongoing search for
 Downloaded from http://heart.bmj.com/ on January 5, 2018 - Published by group.bmj.com
mechanistically targeted therapies.15 Few insights are available from
the extreme ends of the HFpEF spectrum; thus, identification of
key predictors and drivers of HFpEF from at-risk populations with
comorbid disease (eg, diabetes, hypertension, AF), as well as better
description of the trajectory/ies of HFpEF, including mode of death
and cardiovascular events, may lead to identification of pivotal
mechanisms and new therapeutic targets. Albeit in the context of
a typically elderly population where non-cardiovascular events may
also critically determine clinical outcomes.
Validation of HFpEF subphenotypes
Characterisation of HFpEF subphenotypes will provide greatest
value if categories can be replicated across populations, clearly
distinguished from ‘non-HFpEF’ and linked to unique mechanisms
of disease. This will be a starting point for prospective comparative
studies. Collection of high-dimensional data from large numbers
of patients, with and without HFpEF, should facilitate these aims,
provided this is matched to accurate coding practices. Integration of
data collection into routine clinical workflow may minimise missing
variables and enable correlation with nuanced clinical assessment.
One such initiative is being conducted in patients with pulmo-
nary vascular disease, including left-sided heart disease-related
pulmonary hypertension, in the multicentre NHLBI-sponsored
PVDOMICS network (NCT02980887).
Unfortunately, low availability of myocardial tissue from
patients with HFpEF hinders translational research in this field.
More broadly representative animal models (beyond hyperten-
sion-related remodelling) may identify novel disease mecha-
nisms. The extent to which ‘deep’ phenotyping of HFpEF will
advance the field will depend on the demonstration of biological
relevance and incremental therapeutic or prognostic value.
Clinical trial design considerations and novel therapeutic
strategies
Enrolment in HFpEF treatment trials is challenging. Patients
who are very elderly, frail, obese or have a high comorbidity
burden are often underrepresented, which limits the gener-
alisability of trial findings and their relevance to clinical prac-
tice. Validation of simplified diagnostic algorithms is urgently
required, as well as identification of the key clinical or biological
characteristics that influence outcome. Invasive stress testing can
be very useful but may not be feasible for all centres.
New trial designs may be useful in HFpEF, and this requires
discussion between trialists, regulators and reimbursement
authorities. Adaptive design features allow flexibility based on
interim analysis, and thus may improve the value and efficiency
of clinical trials. Such a strategy may have altered the outcome
of the TOPCAT trial.28 Flexible trial protocols may also accel-
erate incorporation of emerging science: for example, enrol-
ment criteria for PARAGON stipulated BNP elevation, though
recent data suggest that neprilysin inhibition may preferentially
benefit patients with a low BNP.45 Patient-reported outcome
measures (symptom burden, quality of life) and non-cardiovas-
cular sequelae associated with HFpEF (eg, sarcopaenia, renal
failure) should also feature more prominently among primary
or secondary endpoints of clinical trials. The feasibility of a
patient-centric endpoint was demonstrated in NEAT-HFpEF,33
and there are signs that regulators are more willing to consider
such endpoints in areas of unmet need.46
Ultimately, a single therapy or therapeutic approach may not
be effective for all patients with HFpEF. Complex (combined)
interventions or therapeutic programmes incorporating exer-
cise and lifestyle modification, including weight loss, should
be evaluated and have been beneficial in small trials.44 47 The
Zakeri R, Cowie MR. Heart 2018;0:1–8. doi:10.1136/heartjnl-2016-310790
Review
current focus on cardiovascular-targeted therapies is also
unlikely to reduce the burden of non-cardiovascular deaths in
HFpEF. Therefore, evidence from randomised trials to guide the
management of comorbidities in HFpEF remains vital, and may
provide relevant information for primary prevention.48
Conclusion
HFpEF is an evolving concept that, as yet, has failed to translate
into meaningful improvement in the outcome of individuals with
HF symptoms but no overt reduction in LV systolic function or
primary valve disease. The syndrome(s) is/are multifaceted and
debilitating, and the prevalence is likely to increase steeply in
the coming decades. Several emerging diagnostic and treatment
strategies appear promising but require validation. Currently,
those writing clinical guidelines have little high-quality evidence
on which to base advice for clinicians and their patients. In the
future, it is likely that the syndrome will be disaggregated into
different phenotypes, where different therapeutic approaches
may be appropriate. Certainly however our current knowledge
base is inadequate to the task of managing this increasing clinical
problem.49–51
Contributors  RZ and MRC drafted and revised the manuscript.
Competing interests  None declared.
Provenance and peer review  Commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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Heart failure with preserved ejection fraction:

controversies, challenges and future
directions
Rosita Zakeri and Martin R Cowie

Heart published online January 5, 2018

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