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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: [email protected]
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.
2
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
3
(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.
4
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
5
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?
6
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
7
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).
8
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.
9
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.
12
13
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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.
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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.
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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.
19
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