Heart failure with preserved ejection fraction:

Controversies, challenges and future directions

Rosita Zakeri1,2, Martin R. Cowie1,2

1Royal Brompton and Harefield NHS Trust; 2Imperial College London, UK

Word count: 3000 (excluding figures, tables, references)

Correspondence to:

Professor Martin R. Cowie MD MSc FRCP FRCP (Ed) FESC

National Heart and Lung Institute

Imperial College London

Dovehouse Street

London, SW3 6LY

United Kingdom

Email: m.cowie@imperial.ac.uk

Tel: +442073518856

Fax: +442073518148

The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a

worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if

accepted) to be published in HEART editions and any other BMJPGL products to exploit all

subsidiary rights"

Abstract ( 206 words ).

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 HFpEF

patients with 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 co-morbidities 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 sub-phenotypes, based on

statistically clustered clinical and biological characteristics: whether such sub-classification 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.

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Introduction

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for up to half of all

HF in the developed world1. The reported population prevalence ranges from 1 to 3%, and is

predicted to rise with lengthening life expectancy, greater diagnostic awareness, and increasing

rates of obesity, diabetes, hypertension, and atrial fibrillation (AF)1. Whether HFpEF constitutes

a single syndrome or a collection of syndromes is debated, but the diagnostic label identifies

patients with a poor quality of life, high rates of hospitalisation, and premature mortality 1-3.

Clinical guidelines offer few evidence-based treatment recommendations2-4. Large randomised

clinical trials of therapies 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 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 bimodal6. 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 advocate using EF≥50% as one component of a diagnostic algorithm for HFpEF,2, 3

alongside detection of additional myocardial abnormalities to implicate a cardiac cause for

symptoms (Table 1)2, 3. A streamlined method for identifying LV diastolic dysfunction has been

proposed, based on expert opinion7. The gold standard to confirm (or refute) a diagnosis of

HFpEF is based on demonstration of elevated LV filling pressures during cardiac catheterisation,

at which time the presence or absence of concomitant pulmonary arterial hypertension can be

assessed2, 3. Non-invasive or invasive stress testing is recommended to unmask symptoms

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(which often occur exclusively on exertion) and diastolic dysfunction, in order to improve

diagnostic sensitivity, particularly in individuals with an intermediate pre-test probability of

HFpEF8. 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 clinical, echocardiographic, and invasive hemodynamic evidence of HFpEF9. 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 pericardial restraint10, and by AF, which is associated

with raised plasma BNP concentrations11. The phenotypic overlap between HFpEF versus ‘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 coronary artery disease (CAD) can be considered to have HFpEF. CAD is widely noted

in HFpEF cohorts and HF symptoms that are disproportionate to the severity of CAD or persist

after revascularisation may represent one of several proposed HFpEF patient phenotypes12.

Evidence of microvascular ischaemia (e.g. as demonstrated by cardiac stress MRI) would be

compatible with microvascular inflammation, which is hypothesised to be important in HFpEF13.

In practice, due to the lack of pathognomonic diagnostic criteria and complex

requirement for systematic exclusion of other pathologies in typically elderly patients with

multi-morbidity, many individuals with breathlessness or fluid retention may be labelled as

‘HFpEF’ without the phenotype being properly established. Cardiopulmonary exercise testing is

empirically used to differentiate HFpEF from exercise intolerance due to non-cardiac limitations

such as pulmonary disease or deconditioning, though feasibility may be limited in some elderly

or frail patients.

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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

HF14, even after adjusting for the cumulative burden of comorbidities15. Skeletal muscle mass is

reduced in HFpEF, beyond that which is observed with normal aging, and directly contributes to

exercise limitation16. 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 HFpEF17. These

observations suggest that HFpEF is not simply an ageing heart and vascular system. Indeed, the

majority of older adults with co-morbidities do not develop HFpEF.

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

ventricular-arterial stiffening in HFpEF, particularly among women18. Additionally, senile wild

type transthyretin deposition has been associated with HFpEF in predominantly elderly

patients19.

Comorbidities are universal in HFpEF cohorts and uniquely influence ventricular and

vascular remodelling and prognosis15. Recently it has been suggested that comorbidities are

integral to the development of HFpEF.13 Cardio-metabolic diseases including obesity, systemic

hypertension, and diabetes, are proposed to induce a systemic pro-inflammatory 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 (Figure 1). This hypothesis reconciles

phenotypic diversity in HFpEF cohorts, with findings at cellular and tissue level in human HFpEF

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biopsies20, in vivo endothelial dysfunction21 and autopsy evidence of coronary microvascular

rarefaction in HFpEF22.

Importantly, however, the heterogeneity of patient characteristics, organ-system

involvement, and number of pathophysiological abnormalities that have been associated with

established HFpEF (Figure 2), support a multi-factorial 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 sub-phenotypes of HFpEF have been described according to dominant co-

morbidities or grouped clinical characteristics23. For example, an HFpEF sub-phenotype with

pulmonary arterial hypertension and right ventricular dysfunction has been well characterised

and often signifies advanced stage HF23. Accumulating evidence suggests that patients with

HFpEF and concomitant obesity10, 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 sub-phenotypes extending

beyond individual comorbidity-defined subgroups23, 24. Large dataset-based clustering and

machine learning analyses are well suited to model the complex interactions that may

contribute to HFpEF pathophysiology (Figure 2). 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?

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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

(Supplemental table). Trials employing a low EF cut-off for HFpEF (e.g. >40% CHARM-

Preserved25, >45% I-PRESERVE26), or recruiting few patients with EF≥50% (SENIORS27),

insufficiently represented symptomatic HFpEF, as defined by current guidelines3. 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 Perindopril 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 study29.

Therapies targeting the renin-angiotensin system have uniformly failed to demonstrate

benefit in HFpEF trials25, 26, 28, 29. Evidently, neurohumoral stimulation does not exert a dominant

impact on the clinical course of unselected patients with HFpEF. RELAX30 tested an alternative

therapeutic hypothesis, that prevention of cGMP breakdown with PDE-5 inhibition would

enhance exercise capacity in patients with HFpEF, but was also neutral. Translational studies

have reported low myocardial cGMP content in human HFpEF biopsies20, 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 pre- and post-capillary pulmonary hypertension) may

produce a different result.

RCT evidence is generally regarded as the most robust evidence for regulatory

authorities 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

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hospitalisation had been selected as the primary endpoint in CHARM-Preserved25 or TOPCAT28

the study conclusions might have been different (Supplemental table).

What therapies for HFpEF are currently under investigation?

Several novel therapies are currently under investigation in randomised trials (Figure 3).

i) Therapies to modify cellular cGMP and structural adaptations

Pharmacological modulation of the NO-cGMP-PKG signalling pathway may increase

cGMP content and reduce myocardial stiffness in HFpEF (Figure 1). To date, neither direct

replenishment of cGMP, via soluble guanylate cylase stimulators (riociguat31, 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 in NEAT-

HFpEF, possibly due to excess hypotension or renal sodium retention33, and is therefore

contraindicated in HFpEF unless required for another indication e.g. angina4. 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 vasodilation during exercise and submaximal exercise endurance in

patients with HFpEF34. 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, sacubitril-valsartan, was associated

with lower NT-proBNP, reduced LA size and a trend towards improved functional class

compared with valsartan therapy alone35, implying a disease-modifying effect in HFpEF. A phase

III trial with the combined primary endpoint of cardiovascular death or first HF hospitalisation is

underway (PARAGON-HF, NCT01920711). The impact of sacubitril-valsartan, compared with

individualised medical management of comorbidities, on NT-proBNP, symptoms, exercise

capacity and safety in HFpEF is also being studied (NCT03066804).

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ii) 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 reserve36. Theoretically, greater LV filling occurs

at lower heart rates, although excess rate lowering may exacerbate chronotropic incompetence

in HFpEF. The If current blocker, ivabradine, variably demonstrated improved37, 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 adaptive pacing can improve

exercise capacity in HFpEF patients in sinus rhythm who display chronotropic incompetence

(NCT02145351).

Pulmonary vasodilation may improve pulmonary hypertension 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.

iii) 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

patients40. 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).

iv) Monitoring strategies to prevent adverse outcomes

Outcomes from disease management programmes have not been reported stratified by

HF type41, though feasibility of implementing a specialised HFpEF programme has been

described in a single centre42.

Following the favourable results of the CHAMPION trial43, which included patients with a

spectrum of EFs, additional prospective studies of remote pulmonary artery pressure

monitoring are underway in the US and Europe/Australia.

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v) Treatment of comorbidities and exercise training

OPTIMIZE-HFpEF will determine whether systematic screening and targeted

management of comorbidities in HFpEF patients (>60 years) will improve a composite outcome

comprising symptoms, NT-proBNP, diuretic use, HF hospitalisation and death (NCT02425371)

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 is 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

peripheral (arterial and skeletal muscle) targets44. 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 Telerehabilitation 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 comparison 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 multi-parametric biomarkers and new imaging techniques, may

help to identify unique biological signature(s) for HFpEF (e.g. circulating galectin-3 and magnetic

resonance imaging-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 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 (e.g. diabetes,

hypertension, AF), as well as better description of the trajectory/ies of HFpEF, including mode

10

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 sub-phenotypes

Characterisation of HFpEF sub-phenotypes 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 pulmonary 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 HFpEF patients hinders

translational research in this field. More broadly representative animal models (beyond

hypertension-related remodelling) may identify novel disease mechanisms. 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

generalisability of trial findings and their relevance to clinical practice. Validation of simplified

diagnostic algorithms are urgently required, as are 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

11

interim analysis, and thus may improve the value and efficiency of clinical trials. Such a strategy

may have altered the outcome of the TOPCAT trial28. Flexible trial protocols may also accelerate

incorporation of emerging science: for example enrolment criteria for PARAGON stipulated BNP

elevation, though recent data suggest that neprilysin inhibition may preferentially benefit

patients with a low BNP45. Patient reported outcome measures ([PROMs] symptom burden,

quality of life) and non-cardiovascular sequelae associated with HFpEF (e.g. 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-HFpEF33 and there

are signs that regulators are more willing to consider such endpoints in areas of unmet need46.

Ultimately, a single therapy or therapeutic approach may not be effective for all patients

with HFpEF. Complex (combined) interventions or therapeutic programmes incorporating

exercise and lifestyle modification, including weight loss, should be evaluated and have been

beneficial in small trials44, 47. The 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 HFpEF prevention48.

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,

our current knowledge base is inadequate to the task of managing this increasing clinical

problem.

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13

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32. Pieske B, Maggioni AP, Lam CSP, Pieske-Kraigher E, Filippatos G, Butler J, Ponikowski P, Shah SJ, Solomon SD, Scalise AV, Mueller K, Roessig L and Gheorghiade M. Vericiguat in patients with worsening

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33. Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, LeWinter MM, Joseph SM, Shah SJ, Semigran MJ, Felker GM, Cole RT, Reeves GR, Tedford RJ, Tang WH, McNulty SE, Velazquez EJ, Shah MR, Braunwald E and Network NHFCR. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015;373:2314-24.

34. Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC and Chirinos JA. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015;131:371-80; discussion 380.

35. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ and Prospective comparison of AwARBoMOhfwpefI. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387-95.

36. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J and Kitzman DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol. 2012;60:120-8.

37. Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M and Marwick TH. Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. Journal of the American College of Cardiology. 2013;62:1330-8.

38. Pal N, Sivaswamy N, Mahmod M, Yavari A, Rudd A, Singh S, Dawson DK, Francis JM, Dwight JS, Watkins H, Neubauer S, Frenneaux M and Ashrafian H. Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction. Circulation. 2015;132:1719-25.

39. Komajda M, Isnard R, Cohen-Solal A, Metra M, Pieske B, Ponikowski P, Voors AA, Dominjon F, Henon-Goburdhun C, Pannaux M, Bohm M and prEserve DlvefchFwisI. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur J Heart Fail. 2017.

40. Kaye DM, Hasenfuss G, Neuzil P, Post MC, Doughty R, Trochu JN, Kolodziej A, Westenfeld R, Penicka M, Rosenberg M, Walton A, Muller D, Walters D, Hausleiter J, Raake P, Petrie MC, Bergmann M, Jondeau G, Feldman T, Veldhuisen DJ, Ponikowski P, Silvestry FE, Burkhoff D and Hayward C. One-Year Outcomes After Transcatheter Insertion of an Interatrial Shunt Device for the Management of Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2016;9.

41. McAlister FA, Stewart S, Ferrua S and McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol. 2004;44:810-9.

42. Shah SJ, Cogswell R, Ryan JJ and Sharma K. How to Develop and Implement a Specialized Heart Failure with Preserved Ejection Fraction Clinical Program. Curr Cardiol Rep. 2016;18:122.

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44. Edelmann F, Gelbrich G, Dungen HD, Frohling S, Wachter R, Stahrenberg R, Binder L, Topper A, Lashki DJ, Schwarz S, Herrmann-Lingen C, Loffler M, Hasenfuss G, Halle M and Pieske B. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol. 2011;58:1780-91.

45. Anand IS, Claggett B, Liu J, Shah AM, Rector TS, Shah SJ, Desai AS, O'Meara E, Fleg JL, Pfeffer MA, Pitt B and Solomon SD. Interaction Between Spironolactone and Natriuretic Peptides in Patients With Heart Failure and Preserved Ejection Fraction: From the TOPCAT Trial. JACC Heart Fail. 2017;5:241-252.

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Figure legends

Figure 1. Pathphysiological abnormalities associated with the HFpEF syndrome

Figure 2. Therapeutic targets under investigation in HFpEF. LA denotes left atrial; sGC, soluble

guanylate cyclase.

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 (sGC). sGC 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.

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Table 1. Diagnostic criteria for HFpEF

ESC guidelines20162

AHA guidelines20133

History & examination

Symptoms and signs of HF Symptoms and signs of HF

Ejection fraction

≥ 50% ≥ 50%

Natriuretic peptides

BNP>35pg/mLNT-proBNP>125pg/mL

Elevated levels are supportive

Imaging Cardiac structural alterations:LAVI>34mL/m2

LVMI ≥115g/m2 (M) ≥95g/m2 (F)

And/or cardiac functional alterations:

E/e’ mean septal-lateral ≥13

Mean e’ septal/lateral wall <9cm/s

Additional indirect measures:

Reduced global longitudinal strain

Elevated PASP (from TR velocity)

Abnormal LV diastolic function

Electrocardiogram

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≥15mmHg or

LVEDP≥16mmHg ± change with

exercise*

20

*Defined as increase in PCWP to ≥25mmHg with exercise by Obokata et al.8

AF denotes atrial fibrillation; BNP, b-type natriuretic peptide; CO, cardiac output; HF, heart failure; 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.

Table 2. Differential diagnosis of HFpEF

Classical HFpEFHeart failure (high left ventricular filling pressures) associated with:-

Atrial fibrillationChronic kidney diseaseCoronary artery disease

Mild to moderate obstructive epicardial disease, Abnormal coronary microcirculation

DiabetesHypertensionObesitySleep disordered breathing

Differential diagnosis - cardiacSpecific cardiomyopathy Hypertrophic cardiomyopathy

Sarcomeric (and other) gene mutationsGlycogen storage diseaseLysosomal storage disease (including Fabry’s disease)Amyloidosis Restrictive cardiomyopathy

FamilialSarcomeric (and other) gene mutationsAmyloidosis (familial TTR or apolipoprotein mutation)Hereditary haemochromatosis (iron overload)Fabry’s diseaseGlycogen storage diseaseLaminopathy/desminopathyPseudoxanthoma elasticum

Non-familialAmyloidosis (AL or wild-type TTR)Systemic sclerosisSarcoidosis

21

Endomyocardial fibrosisCarcinoid heart diseaseRadiationDrug toxicity (e.g. anthracyclines)Heavy metals (copper, iron, cobalt, lead)

Arrhythmogenic right or left ventricular cardiomyopathyNon-compaction cardiomyopathy

Congenital heart disease Atrial and ventricular septal defectsCoronary artery disease Moderate to severe (obstructive) epicardial diseaseHeart failure with recovered EFHigh cardiac output heart failure Anaemia, hyperthyroidism, sepsis, skeletal disorders,

systemic arteriovenous fistulas, vitamin B1 deficiencyMalignancy Direct infiltration and masses (primary or secondary)

Radiation-induced cardiomyopathyAtrial myxoma

Pericardial disease Constrictive pericarditisPericardial effusion and cardiac tamponadeEffusive-constrictive pericarditis

Pulmonary vein stenosisRight heart failure due to:- Primary pulmonary arterial hypertension

Right ventricular infarctionRhythm disturbance Atrial or ventricular arrhythmias

Complete atrioventricular dissociationValvular heart disease Acquired or congenital severe stenosis or regurgitationDifferential diagnosis – extra-cardiacAnaemiaPulmonary disease Chronic obstructive pulmonary disease

Interstitial lung diseaseRenal failure (acute or chronic)

EF, ejection fraction; TTR, transthyretin

22

Table 3. Current evidence for treatment of HFpEF

Target Therapy Evidence Level of evidence

Survival ACEI/ARBBeta-blockers Mineralocorticoid receptor antagonist

No RCT evidence of benefit (possible benefit in subgroup with low BNP49)Possible benefit on pooled analysis in patients with EF≥40%50

No RCT evidence of benefit

---

Hospitalisation for HF ACEI/ARBBeta-blockers Mineralocorticoid receptor antagonist Loop diuretics

No RCT evidence of benefit (possible benefit in subgroup with low BNP49)No RCT evidence of benefitBenefit of spironolactone in TOPCAT (as secondary outcome)28

Benefit of diuretic therapy combined with vasodilators in CHAMPION43

--IIA4

IB2 or C3

Symptoms:Congestion Loop diuretics CHAMPION trial (diuretic therapy combined with vasodilators)43 IB or CExercise capacity Isosorbide mononitrate Associated with reduced activity levels in NEAT-HFpEF33 III

Management of comorbidities IB3 or C3

Hypertension Antihypertensive therapy Management of acute hypertensive oedemaBP targets extrapolated from hypertension guidelines.

-

Atrial fibrillationi. Stroke preventionii. Rhythm controliii. Rate control

Oral anticoagulationAblationBeta-blockers, CCB, digoxin

Risk scores extrapolated from AF guidelines.No RCT evidence of benefit. (Observational single-centre data51). No RCT evidence for rate targets

IA (AF)--

CAD Pharmacotherapy (including statins)Revascularisation

No RCT evidence of benefit.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 program (behavioural)

Pharmacotherapy/bariatric surgeryImprovement in peak VO2 in patients ≥60 years47

No RCT evidence of benefit--

Pulmonary disease No RCT evidence of benefit -Sleep disordered breathing No RCT evidence of benefit -

ACEI, angiotensin converting enzyme 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; peak

24

VO2, peak oxygen consumption.

25

26

27

28

29