REVIEW

Therapy

The Therapy and Management of Heart Failure with Preserved

Ejection Fraction: New Insights on Treatment

Giulio Balestrieri,1 Raul Limonta,2 Enrico Ponti,3 Anna Merlo,2 Edoardo Sciatti,1
Salvatore D’Isa,1 Mauro Gori,1 Gavino Casu,3 Cristina Giannattasio,4
Michele Senni1,4 and Emilia D’Elia1

1. Cardiovascular Department, ASST Papa Giovanni XXIII, Bergamo, Italy; 2. School of Medicine and Surgery, Milano Bicocca University,
Milan, Italy; 3. Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 4. Department of Medicine
and Surgery, University of Milano Bicocca, Milan, Italy

Abstract
Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterised by the presence of diastolic dysfunction and elevated
left ventricular filling pressure, in the setting of a left ventricular ejection fraction of at least 50%. Despite the epidemiological prevalence of
HFpEF, a prompt diagnosis is challenging and many uncertainties exist. HFpEF is characterised by different phenotypes driven by various
cardiac and non-cardiac comorbidities. This is probably the reason why several HFpEF clinical trials in the past did not reach strong outcomes to
recommend a single therapy for this syndrome; however, this paradigm has recently changed, and the unmet clinical need for HFpEF treatment
found a proper response as a result of a new class of drug, the sodium–glucose cotransporter 2 inhibitors, which beneficially act through the
whole spectrum of left ventricular ejection fraction. The aim of this review was to focus on the therapeutic target of HFpEF, the role of new drugs
and the potential role of new devices to manage the syndrome.

Keywords
Heart failure with preserved ejection fraction, therapy, management, drugs

Received: 18 June 2023 Accepted: 28 October 2023 Citation: Cardiac Failure Review 2024;10:e05. DOI: https://doi.org/10.15420/cfr.2023.13
Disclosure: The authors have no conflicts of interest to declare.
Correspondence: Emilia D’Elia, Cardiovascular Department, Hospital Papa Giovanni XXIII, Piazza OMS 1, Bergamo, Italy. E: [email protected]

Copyright: © The Author(s) 2024. This work is open access and is licensed under CC BY-NC 4.0. Users may copy, redistribute and make derivative works for non-
commercial purposes, provided the original work is cited correctly.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical HFpEF is mainly characterised by different phenotypes driven by different
syndrome affecting approximately 3 million people in the US and up to cardiac and non-cardiac comorbidities. This is probably the reason why
32 million people worldwide. Patients with HFpEF are hospitalised several HFpEF clinical trials did not reach strong outcomes to recommend
approximately 1.4 times per year and have a mortality rate of approximately a single therapy for this syndrome, as happened in heart failure with
15% per year.1 reduced ejection fraction (HFrEF), where four pillars have been elected as
optimal medical therapy from international guidelines.6,7 Recently, the
HFpEF is mainly characterised by the presence of diastolic dysfunction paradigm has changed and the unmet clinical need for HFpEF treatment
(DD) and elevated left ventricular (LV) filling pressure, in the setting of a LV found a proper response as a result of a new class of drug, the sodium–
ejection fraction (LVEF) ≥50%.2 Despite epidemiological evidence of a glucose cotransporter 2 inhibitors (SGLT2i), which beneficially act through
steadily increasing prevalence, both in absolute terms and relative to the the whole spectrum of LVEF.8
entire HF population, a prompt diagnosis of HFpEF is still challenging. Two
scores have been created to better recognise this syndrome: the 2018 In this review, we focus on the HFpEF phenotypes according to the latest
H2FPEF score and the 2020 HFA-PEFF algorithm.3,4 Although they evidence, the role of the new drugs and the potential role of new devices
represent a remarkable step forward for a correct diagnosis, this approach to treat this complex syndrome.
still leaves many cases in the ‘uncertainty area’.
The Origin of HFpEF Phenotypes
From a haemodynamic perspective, a hallmark of this syndrome is a The term ‘preserved ejection fraction’ was first coined in the CHARM
pulmonary capillary wedge pressure of ≥15 mmHg (at rest) or ≥25 mmHg program to split the enrolled population into two subgroups on the basis
(after exercise), or LV end-diastolic pressure ≥16 mmHg (at rest). However, of the most validated and readily available tool to define LV squeezing
direct haemodynamic measurement during exercise is not widely function, which was LVEF measured by echocardiography.9 This ‘heart-
available; it is an invasive procedure and should be kept for very selected centred’ approach proved to be very effective in defining the subgroup of
cases. Right heart catheterisation at rest and during exercise is indeed the patients who could benefit from therapies targeting neurohormonal
diagnostic gold standard for an accurate HFpEF diagnosis.5 activation.

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 New Insights on HFpEF Treatment

The mainstays of the reduced ‘LVEF paradigm’ consisted of: a single and obesity. This group of patients also includes those with HF with
organ involved, or at least responsible for the clinically relevant outcomes; improved ejection fraction (EF). Weight loss and blood pressure control
an easily recognisable dysfunction, with no need to deeply investigate the using renin–angiotensin–aldosterone system (RAAS) inhibitors (RAASi)
underlying aetiology, at least for what concerns the basic pharmacological are central to these patients.
treatment; and effective therapies approved by international guidelines to
treat the disease. The next four clusters include a population that is, on average, older
(aged between 60 and 90 years), with a higher burden of comorbidities,
Similarly, scientific communities tried to apply the same ‘paradigm’ to including arterial hypertension. The second cluster is the most represented
patients with a normal LVEF. Nonetheless, this model did not fit in this and consists of patients with an average age of 77 years who have AF, in
setting as: multiple organs and systems are involved, with the heart the absence of diabetes. These patients, even more than others, benefit
playing an important, but not exclusive, role due to cardiac and non- from a lenient heart rate control to avoid further reducing their already
cardiac comorbidities; a variety of morphological and functional compromised chronotropic reserve. The third cluster is the second most
abnormalities of uncertain significance, with rest echocardiography still represented and consists of the oldest patients, with an average age of
playing a key role as a gatekeeper, but with the need to implement it with 88 years, the highest burden of comorbidities and the highest
other techniques; and frequent inconsistency between phase II clinical concentration of natriuretic peptides. These patients present with frank
trials showing improvement in surrogate outcomes and neutral phase III congestion, which must be attenuated using diuretics, including anti-
clinical trials with neutral results on clinically relevant outcomes. aldosterone agents, which have shown remarkable clinical benefit in the
TOPCAT trial.22 These patients derive the highest prognostic benefit from
All of this evidence led us to consider the importance of phenotype in the intensive treatment of all comorbidities.
HFpEF, to address a tailored therapy rather than ‘one size fits all’.
The fourth cluster consists of patients with an average age of 71 years, AF
Phenotyping for Tailored Therapy and diabetes. In this group of patients, in addition to glycaemic control,
Complexity and multimorbidity are the hallmarks of HFpEF. This has been the introduction of an SGLT2 inhibitor appears to be fundamental, as the
graphically represented as overlapping circles, where every circle is a EMPEROR-Preserved and DELIVER trials have shown a reduction in
pathophysiological abnormality.10 According to this model, patients with cardiovascular (CV) mortality and hospitalisation for HF.
HFpEF could fall into one or another part of the circle and they could
develop the syndrome on the basis of a single mechanism or as the result Finally, the fifth cluster is the fusion of the second and fourth clusters
of multiple concurrent injuries. Addressing the single components of the because it includes elderly patients with an average age of 82 years,
picture seems to be the way for tailored treatment. diabetes and AF. The DECLARE-TIMI 58 trial found that diabetes patients
without AF may benefit from the use of SGLT2i because they have a
In contrast, the clinical phenotypic approach is a different and perhaps preventive effect on this arrhythmia.23–25
more ambitious way to classify patients.11,12 The underlying assumption is
that HFpEF is not a single disease, but a group of different disease Beyond the different clusters identified by Uijil et al. and by the countless
processes that share HF symptoms and signs as clinical manifestation. attempts of many other authors, obesity is a common comorbidity in many
The studies supporting this view divide HFpEF cohorts into mutually patients with HFpEF. Excess visceral adipose tissue promotes the
exclusive subgroups, the so-called phenotypes, on the basis of the clinical hyperactivation of neurohormonal systems that, together with the
and epidemiological characteristics of patients.13–20 The cluster of reduced plasma activity of neprilysin typical of these patients, make the
comorbidities characterising a specific phenotype is the result of a specific pro-inflammatory and fibrotic effect of aldosterone unopposed, favouring
pathological pathway that could be hopefully targeted by specific diastolic dysfunction that is responsible for the progressive increase in
treatments. filling pressures.21 Considering the typical pathophysiological changes of
the obese phenotype, RAASi, particularly aldosterone antagonists and
HFpEF Phenotypes: Pieces of a neprilysin inhibitors (ARNI), play a central role, in addition to the use of
Complex Clinical Puzzle SGLT2i. Furthermore, the STEP-HFpEF trial has recently demonstrated in
The physiopathological complexity and clinical heterogeneity of HFpEF obese HFpEF patients that semaglutide versus placebo significantly
have prompted cardiologists to use artificial intelligence and machine reduced body weight, improving symptoms, physical limitations and
learning techniques to analyse the complex relationships within this exercise function, with a positive impact on quality of life (QoL),
diverse population, and identify specific subgroups with the goal of inflammatory status and survival.26
greater internal homogeneity to treat them in the same way. The first
research group to attempt this ambitious goal was that of Shah et al., who Current Progress in ‘Phenomapping’:
identified patient subgroups based on their comorbidities, including those Insights From the Literature
related to obesity, metabolic syndrome and pulmonary hypertension.11,21 Recently, a review conducted by Peters et al. identified the three most
recurrent HFpEF phenotypes in studies that focused on specific
More recently, Uijil et al. proposed a model consisting of five clusters characteristics through statistical analysis of large datasets, known as
obtained from HFpEF patients recorded in the Swedish Heart Failure ‘phenomapping’.27 These three phenotypes were also observed in studies
Registry, and validated it externally with the Chronic Heart Failure where researchers did not employ this static strategy, demonstrating some
European Society of Cardiology guideline-based Cardiology Practice robustness in the results (Figure 1).28 The first two analysed phenotypes
Quality project registry.18 closely reflect everyday clinical practice, as they represent two patient
groups commonly encountered in outpatient settings. The most prevalent
The first cluster is that of young patients, with an average age <60 years phenotype is ‘older, vascular ageing’, which aligns with Shah et al.’s findings,
and a reduced burden of comorbidities, including arterial hypertension describing a group of elderly patients with arterial stiffness leading to

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 New Insights on HFpEF Treatment

Figure 1: Three Heart Failure with Preserved Ejection Fraction Phenotypes

1 2 3

eGFR

Systemic
inflammation
Spironolactone

NYHA
class II–III NT-proBNP

Older, vascular ageing phenotype Metabolic, obese phenotype Relatively younger,

low BNP phenotype

The first phenotype is the 'older, vascular ageing', characterised by arterial stiffness, leading to arterial hypertension, and left ventricular hypertrophy. It is associated with significant systemic
inflammation and often coexists with chronic kidney disease, which is also observed in the second phenotype, the 'metabolic, obese', where type 2 diabetes is the prevalent comorbidity and patients
often report dyspnoea and reduced tolerance to physical activity, which can also be attributed to deconditioning. The last phenotype is the 'younger, low BNP', which overlaps with the previous one due
to the frequent presence of excess body weight and, notably, responsiveness to spironolactone. BNP = B-type natriuretic peptide; eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal
pro-B-type natriuretic peptide; NYHA = New York Heart Association. Source: Partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported
licence.

hypertension and chronic kidney disease.11 These patients exhibit concentric biomarkers, such as B-type natriuretic peptide (BNP)/N-terminal fraction of
LV hypertrophy on echocardiograms, a higher incidence of chronic kidney pro-BNP (NT-proBNP) and soluble ST2. Identifying these patients solely
disease and elevated levels of inflammatory molecules in the blood, through peptide assays and resting echocardiography is challenging;
contributing to the pathophysiology of this phenotype and partially justifying thus, prompt additional investigations are necessary, including
its partial overlap with the ‘metabolic, obese’ group. measurements of telediastolic filling pressures and non-invasive or
invasive assessment of pulmonary artery pressures during exercise.
Additionally, inflammation is responsible for remodelling the left atrial Uncertainty remains regarding this third phenotype, which seems to
muscle and conduction tissue, promoting the progression of these benefit from spironolactone treatment (based on post hoc analysis from
patients towards ‘left atrial myopathy’, associated with increased the TOPCAT trial in both the full and the Americas cohort) and exhibits
pulmonary pressures and right ventricular dysfunction, defining a subtype some degree of overlap with the ‘metabolic, obese’ phenotype, partially
of this first phenotype. Given that arterial stiffness and kidney disease justifying the responsiveness to mineralocorticoid receptor antagonists
play a role in the already poor prognosis of these patients, it is evident and lower atrial natriuretic peptide concentrations.29
that blood pressure control with drugs targeting the RAAS plays a central
role. Moreover, these elderly hypertensive patients are at a higher risk of While older HFpEF patients often experience classic symptoms, such as
AF, which is deleterious in HFpEF patients. dyspnoea and fatigue, younger patients with low BNP levels may present
with other symptoms, such as exercise intolerance, unexplained dyspnoea
The second most frequent phenotype is the ‘metabolic, obese’, on exertion or other non-specific complaints. Medications, lifestyle
represented by patients with high body weight and type 2 diabetes, modifications and interventions that have been shown to benefit older
predisposing them to widespread atherosclerotic vascular disease, HFpEF patients may need to be tailored for this group. Moreover,
particularly affecting the renal vessels, which accounts for the high traditional hard endpoints, such as mortality, may not be suitable for
prevalence of chronic kidney disease in this group. Obesity leads to assessing the efficacy of treatments in younger HFpEF patients. Alternative
increased renin–angiotensin activity and aldosterone levels, explaining outcome measures, including QoL, exercise capacity and early markers of
why patients with characteristics related to this phenotype showed better HFpEF progression should be considered in clinical trials.
responsiveness to spironolactone in the TOPCAT trial.29
Based upon these considerations, it appears clear that the scarcity of
While the patients in the first phenotype are older, those belonging to the dedicated research focused on ‘young-low BNP populations’ in HFpEF
third phenotype are ‘relatively younger’, with lower levels of stress highlights a significant research gap. Indeed, more studies are needed to

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 New Insights on HFpEF Treatment

better understand the unique aspects of HFpEF in this population, and to administration. Simultaneously, a transient mild reduction in the
identify effective diagnostic and treatment approaches to solve this glomerular filtration rate and, equally slightly, an increase in creatinine
unmet clinical need. levels can be observed. SGLT2i reduce insulin resistance and contribute
to weight loss, both for their diuretic effect and, over time, for the loss of
In summary, among the three clinical phenotypes, there is a gradient of calories in the urine, which induces a fasting-like state promoting lipolysis
age, inflammation, diagnostic tools and poor prognosis, which is highest and ketogenesis.43
in the ‘older, vascular ageing’ phenotype and gradually decreases from
the ‘metabolic, obese’ to the ‘younger, low BNP’ phenotype. Ketone bodies are an alternative source of energy to glucose and fatty
acids, improving metabolic efficiency. This is even more evident in
A New Drug for HFpEF: SGLT2i patients with HFpEF, whose cardiac cells become less efficient in terms
In recent years, cardiologists have added SGLT2i to their pharmacological of oxidative metabolism and become increasingly dependent on
arsenal.6,7 Initially, these molecules were shown to reduce the incidence glycolysis.44 Therefore, ketone bodies provide the cardiomyocyte with
of CV events, including HF, in patients with type 2 diabetes who were at an ‘extra’ energy supply without interfering with glucose oxidation,
high or very high CV risk.25,30–32 Subsequently, two randomised controlled causing improved cardiac performance, regardless of the presence of
clinical trials, DAPA-HF and EMPEROR-Reduced, were conducted with diabetes.45
patients with HFrEF.33,34 In these trials, dapagliflozin and empagliflozin,
respectively, significantly reduced the incidence of fatal CV events and SGLT2i: Practical Implications
hospitalisation for HF, leading to their inclusion as the ‘fourth pillar’ of The introduction of SGLT2i has transformed the paradigm of HFpEF
HFrEF pharmacological therapy. The efficacy of these molecules was also treatment.46,47 Rather than solely targeting neurohormonal activation, this
studied in HFpEF and heart failure with moderately reduced EF (HFmrEF) class of drugs addresses comorbidities, which is a peculiar feature of
in the EMPEROR-Preserved and DELIVER clinical trials.23,24 HFpEF, and offers a valuable opportunity for cross-sectional intervention
on the cardio–renal–metabolic continuum, which is profoundly altered in
Both of these trials had positive results, with a significant reduction in the these patients.
primary outcome (a composite of CV death and hospitalisation for HF).
The magnitude of the effect was similar in EMPEROR-Preserved (HR 0.79; According to new evidence, SGLT2i should be introduced during
95% CI [0.69–0.90]; p<0.001) and in DELIVER (HR 0.82; 95% CI [0.73– hospitalisation for acute HF.48 Clinical studies have shown that their use is
0.92]; p<0.001). The positive result was mainly driven by a lower risk of safe, well-tolerated and effective in achieving faster decongestion.
hospitalisation for HF and worsening HF events. The effect on CV deaths Furthermore, their use in combination with ARNI and mineralocorticoid
was almost significant in both trials (HR 0.88; 95% CI [0.74–1.05] in receptor antagonists (MRA) has an additive effect, facilitating faster
DELIVER; HR 0.91; 95% CI [0.76–1.09] in EMPEROR-Preserved). Given the titration of the latter due to improved potassium control.49,50
large number of patients needed to reach a significant result, a
prespecified meta-analysis of DELIVER and EMPEROR-Preserved was Neurohormonal Antagonism
planned, and it proved a significant reduction in CV mortality (HR 0.88; Patterns of neurohormonal activation are different in HF cohorts according
95% CI [0.77–1.00]).35 SGLT2i also improved health status and QoL, as to LVEF.51,52 Sympathetic and RAAS activation, resulting in elevated levels
measured by the Kansas City Cardiomyopathy Questionnaire.36,37 of plasma renin activity, aldosterone, catecholamines and NT-proBNP, is a
key feature of HFrEF. Just a small proportion of HFpEF patients display the
In summary, empagliflozin and dapagliflozin significantly reduced the same cascade of activation, and the prognostic impact of elevated plasma
incidence of CV events and worsening HF in HFpEF, demonstrating that level of neurohormones (well established in HFrEF patients) is uncertain in
SGLT2i improved the prognosis of HF patients across the entire LVEF the HFpEF subgroup.53
spectrum.
The heterogeneity of the HFpEF population is at least in part responsible
SGLT2i: Pharmacology and Mechanism of Action for the puzzling results of the several neutral trials that tried to replicate
The introduction of SGLT2i has opened up a new avenue for HF treatment the success achieved in the HFrEF trials.54,55
beyond neurohormonal activation control. The mechanism of action of
this drug class is complex and not yet fully understood. However, it is Angiotensin-converting Enzyme Inhibitors
known that inhibiting SGLT2 at the proximal convoluted tubule level and Angiotensin Receptor Blockers
causes glucose and sodium to be excreted in the urine, which, due to Three large-scale randomised clinical trials tested the safety and
osmotic effects, promotes diuresis.38 This diuresis, however, is different efficacy of angiotensin-converting enzyme inhibitors in HFpEF.56–58 Two
from that caused by loop diuretics, as it appears to have a selective effect of them, the CHARM-Preserved and the I-PRESERVE used an angiotensin
on interstitial volume, with minimal impact on vascular volume. This leads receptor blocker (ARB), the PEP-CHF trial used an angiotensin-
to a reduction in preload and, albeit modestly, blood pressure without converting enzyme inhibitor.56–58 CHARM-Preserved inclusion criteria
triggering compensatory activation of the RAAS.39 were: LVEF >40%, New York Heart Association (NYHA) class II–IV and
previous hospital admission for HF. The primary outcome of composite
Additionally, the increase in sodium concentration in the ultrafiltrate CV death and HF admission was not met (HR 0.89; [95% CI 0.77–1.03];
promotes the restoration of a normal tubule-glomerular feedback, which, p=0.118). The echocardiographic CHARM substudy proved that only half
through the macula densa, induces vasoconstriction of the afferent of patients enrolled had a moderate or severe DD, given that a worse
arteriole. This leads to a reduction in intraglomerular pressure, which, due DD was a strong prognostic predictor.59 Based on these observations,
to haemodynamic effects, reduces the extent and rate of the glomerular the clinical trials that followed tried to target a more selected cohort,
filtration rate and proteinuria reduction.40–42 The beneficial effect on the adding in the inclusion criteria both echocardiographic evidence of DD
kidneys is purely haemodynamic and visible from the beginning of drug and congestion. The results were fairly similar, confirming no effects on

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 New Insights on HFpEF Treatment

mortality and some effect on HF hospitalisation. A large metanalysis number of events (just seven events). Splitting the components of the
that included the aforementioned clinical trials and other smaller size outcomes, a truly neutral effect on CV mortality (HR 0.95; 95% CI [0.79–
studies concluded that both ARB and angiotensin-converting enzyme 1.16]) and a modest positive effect on HF hospitalisations (rate ratio 0.85;
inhibitors have no effect on all-cause mortality (HR 1.01; 95% CI [0.92– 95% CI [0.72–1.00]) were evident. Other important secondary outcomes
1.11]), CV death (HR 1.02; 95% [0.90–1.14]) and HF hospitalisation (HR (NYHA class improvement, change in QoL assessed by the Kansas City
0.92; 95% CI [0.83–1.02]).60 Cardiomyopathy Questionnaire and renal function preservation) showed
benefit from ARNI treatment compared with valsartan.
A subanalysis of the CHARM study examined LVEF as a continuous
variable and found a significant effect on HF hospitalisation for values Prespecified subgroups analysis highlighted a different response to
<50%.22,61 Based on this evidence, the 2022 American Heart Association/ treatment in women (who benefitted most) compared with men and, as
American College of Cardiology/Heart Failure Society of America seen in the CHARM Preserved and TOPCAT trials, in the lower end of the
guidelines give a class 2b recommendation for ARB use with the aim of EF spectrum, with an efficacy of the treatment up to an EF of 57%.68
reducing HF hospitalisation, especially in the lower end of the LVEF.7
Recently, the PARAGLIDE study randomised 466 patients with LVEF >40 %
Mineralocorticoid Receptor Antagonists and a recent event of worsening heart failure to sacubitril/valsartan versus
One large, multicentre, randomised, double-blind, placebo-controlled valsartan. The primary endpoint of N-terminal fraction of pro-BNP
clinical trial and other smaller studies have tested the efficacy and safety reduction was greater in the sacubitril/valsartan group (p=0.0049), and
of MRA in HFpEF. The TOPCAT trial enrolled patients aged >50 years with was associated with clinical benefit as reduced worsening renal failure
at least one sign or symptom of HF and VEF >45%, history of HF compared with valsartan alone, despite a more symptomatic
hospitalisation in the previous 12 months or natriuretic peptide (NP) hypotension.69
level.22
A recent pool analysis of PARAGLIDE and PARAGON showed that in a
The overall result on the primary outcome of a composite CV death and population of 5,262 patients, sacubitril/valsartan versus valsartan alone
HF hospitalisation was neutral (HR 0.89; 95% CI [0.77–1.04]; p=0.14), as significantly reduced CV death and total worsening heart failure events
only HF hospitalisations were significantly reduced in the treatment arm (p=0.027). These data encourage the use of ARNI in HF with mildly
(HR 0.83; 95% CI [0.69–0.99], p=0.04). Two clearly diverging trajectories reduced or preserved LVEF, particularly in those with a LVEF below
in the occurrence of the primary outcome emerged since the first normal.70
publication of the results.62 Patients enrolled with the HF hospitalisation
criterion recorded a far lower rate of events than those enrolled with the β-blockers
NP criterion. Regional differences were also striking, with patients β-blockers have been studied less intensively and in smaller clinical trials
enrolled in Russia and Georgia (mostly with the hospitalisation criterion) compared with the RAASi agents. As a consequence, their use in this
showing a lower risk profile, few events and younger age. A post hoc population is still subject to clinical judgement and tailored care. The
analysis proved that the outcome was met in patients enrolled in countries heterogeneity of the HFpEF population, and the various underlying
other than Russia and Georgia. To make things worse, the significantly mechanisms and aetiologies make the design of clinical trials even more
lower level of patients from Eastern Europe compared with the rest of the difficult than with other agents.
trial countries raises the legitimate suspicion that many participants were
not taking the drug at all.63 The SENIORS trial enrolled HF patients across the entire spectrum of the
LVEF and randomised them to nebivolol or a placebo.71 The subgroup
The TOPCAT trial shaped much of our knowledge around the use of MRA analysis of 752 patients with LVEF >35% is the largest cohort randomised
in HFpEF, being the only large-scale clinical trial on clinically relevant to a placebo we have to date. A smaller study, the J-DHF, tested carvedilol
outcomes. Smaller studies found beneficial effects of MRA on surrogate compared with a placebo in a smaller cohort of patients; several
outcomes (mainly echocardiographically assessed DD parameters, metanalyses put together data from randomised clinical trials and
reverse remodelling and NP decrease), but not on QoL, symptoms and observational cohorts with or without propensity score analysis, but the
exercise capacity.64,65 overall quality of the data was low, and the results are inconsistent
throughout the studies. Nonetheless, metanalyses suggest that β-blockers
New trials are ongoing to better define the role of MRA in HFpEF. SPIRRIT- could reduce CV mortality or all-cause mortality without significant effect
HFpEF and FINEARTS-HF (NCT04435626) will hopefully shed light on on HF hospitalisation.72–75
this.66
In all these clinical trials, β-blocker withdrawal was high due to drug
The 2022 American Heart Association/American College of Cardiology/ intolerance. Chronotropic incompetence related to β-blockers is a well-
Heart Failure Society of America guidelines give a class 2b recommendation recognised contributor to exercise intolerance commonly observed in
for MRA use, with the aim of reducing HF hospitalisation, especially in the HFpEF.76 One study reported significant improvement in functional
lower LVEF range.7 However, the European guidelines do not mention capacity measured by peak oxygen consumption after β-blocker
MRA for HFpEF.6 withdrawal in patients with HFpEF and chronotropic incompetence.77

Antagonist Receptor Neprilysin Inhibitors Treating Cardiac Comorbidities in HFpEF

The PARAGON-HF trial randomised 4,822 patients with NYHA class II–IV, HFpEF is a complex syndrome characterised by non-cardiac and cardiac
EF >45%, elevated NP and structural heart disease to valsartan alone or comorbidities, conditioning phenotypes and affecting prognosis. In this
sacubitril/valsartan.67 The primary endpoint was a composite of total HF review, we focus on the latter, underlying the potential therapeutic options
hospitalisation or CV death. The primary endpoint was missed for a small to improve symptoms, QoL and outcomes (Figure 2).78

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 New Insights on HFpEF Treatment

Figure 2: Heart Failure with Preserved Ejection Fraction Pathophysiology,

Clinical Manifestations and Possible Sites of Intervention

Burden of metabolic respiratory and renal comorbidities

Caloric restriction and

aerobic physical activity
COPD CKD
and/or and/or
Smoking cessation
HIG
H
Specific treatments

Ischaemic heart disease

CAD, AF

HFpEF

Extracellular fibrous
Systemic inflammation tissue deposition
Diuretics

SGLT2i

β-blockers and RAASi

(ACEi/ARB, ARNI, MRA)

The global burden of renal-metabolic and respiratory comorbidities increases systemic inflammation, which in turn promotes endothelial dysfunction, atherosclerosis, and fibro-collagen deposition in the
myocardial interstitium following fibroblast activation. Weight control, achieved through both calorie restriction and regular aerobic physical activity (which also improves conditioning and reduces
exercise intolerance), smoking cessation, and treatment of individual non-cardiac comorbidities, play a central role. At the cardiac level, early identification, and equally intensive treatment of
comorbidities, such as ischaemic heart disease (coronary artery disease) and AF, are mandatory. Furthermore, all patients should be offered a loop diuretic to reduce congestive symptoms and a SGLT2i
to improve cardiovascular and renal prognosis in patients with HFpEF. ACEi = angiotensin-converting enzyme inhibitors; ARB = angiontensin receptor blockers; ARNI = antagonist receptor neprilysin
inhibitors; CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; HFpEF: heart failure with preserved ejection fraction; MRA = mineralocorticoid
receptor antagonists; RAASi = renin–angiotensin–aldosterone system inhibitors; SGLT2i = sodium–glucose cotransporter type 2 inhibitors.

Ischaemic Heart Disease: A General Term ongoing on the obese HFpEF phenotype, and they could also have a role
for Several Conditions Related to HFpEF in chronic inflammation and MVD.26
Ischaemic heart disease and HF are strongly and tightly connected
conditions.79–83 Ischaemic heart disease is a common cardiac comorbidity Atrial Fibrillation
in HFpEF, even though prevalence varies across studies, also depending AF is a highly prevalent cardiac comorbidity in HFpEF, ranging from 32%
on the imaging modalities used to ascertain it and on the general arterial to 65% in epidemiological studies.92,93 Despite this difference in absolute
involvement. Ischaemic heart disease includes microvascular dysfunction prevalence, AF is consistently reported to be more common in HFpEF
(MVD), coronary artery disease or previous ‘silent’ MI.84,85 than in HFrEF, and to be associated with older age. An interesting analysis
of the HF Long-Term Registry of the European Society of Cardiology,
MVD contributes to the pathophysiological mechanisms of HFpEF in evaluating both ambulatory and hospitalised HF patients, showed that
several ways. The pro-inflammatory state, exacerbated by the multiple after multivariable adjustment, AF significantly increased long-term
comorbidities present in HFpEF, promotes oxidative stress and endothelial mortality and hospitalisation just in the HFpEF and HFmrEF population,
dysfunction. The most important mechanisms leading to MVD in HFpEF but not in the HFrEF population.94.
consist of microvascular inflammation, capillary rarefaction and cardiac
fibrosis.86–89 The involvement of MVD in the pathophysiology of HFpEF is Patients with AF and HFpEF should be anticoagulated according to
crucial to identify possible therapeutic targets. SGLT2s have shown guidelines, keeping in mind the high incremental thromboembolic risk
beneficial effects of cardiac microvascular endothelial cells on added by HF.95 Based on the available evidence, no firm recommendation
cardiomyocyte function, and demonstrate an improvement in myocardial can be drawn on rhythm versus rate control strategy preference.
flow reserve in a single-centre prospective randomised clinical trial.90
Rate control is still a very popular choice among clinicians, and convincing
Ranolazine inhibits the late sodium current and reducing intracellular evidence to support a routine rhythm control strategy is still missing. The
calcium in cardiomyocytes and promotes ventricular relaxation by two major trials on this subject and subsequent metanalysis suggest no
decreasing diastolic tone and microcirculatory resistance, thus improving benefit of one strategy over the other.96–98 Three drug classes are valuable
coronary blood flow. It also acts on cardiac fibrosis; thus, it could improve options for rate control in HFpE: β-blockers, non-dihydropyridine calcium
the most important physiological mechanisms of MVD in this syndrome.91 channel blockers and digoxin. Few studies have directly compared these
New studies on antidiabetic agents, glucagon-like peptide-1 agonists, are drugs. The RATE-AF trial compared low-dose digoxin and bisoprolol in HF

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patients with permanent AF.99 The vast majority of the trial cohort (81%) could translate into CV death, non-fatal ischaemic stroke and HF events
had HFpEF. The primary endpoint (QoL at 6 months from randomisation) reduction, or change in QoL measured by the Kansas City Cardiomyopathy
was not different in the two groups, and fewer adverse events were Questionnaire overall summary score.104 The trial enrolled 1,072 patients,
recorded in the digoxin group (p<0.001). of which 314 underwent an atrial shunt device procedure and 312 a sham
procedure. The overall population results were neutral both for the
Diabetes and Metabolism Disorders composite primary endpoint (win ratio 1.0; [95% CI 0.8–1.2]; p=0.85) and
Diabetes, excess weight and obesity, typical features of HFpEF patients, for the single components of the outcome. The analysis of prespecified
as already documented in the above-mentioned phenotypes, cause subgroups showed that in the highest tertiles of exercise pulmonary
inactivity and deconditioning, justifying the high prevalence of dyspnoea artery pressure (pulmonary pressure >70 mmHg) and right atrial volume
and exercise intolerance in this population. Weight loss, through caloric (>29.7 ml/m2), the HF events rate was higher in the device-treated patients
restriction or increased physical activity, and glycaemic control have a compared with those in the sham procedure arm, suggesting a detrimental
positive effect on prognosis and CV events. Notably, visceral and effect of the implanted interatrial shunt device. Several clinical trials are
pericardial adipose tissues play a negative, pro-inflammatory role ongoing or still have to start on the role of inter-atrial devices, and they
compared with subcutaneous adipose tissue, emphasising that ‘not all fat hopefully will be able to shed light on the net clinical benefit of this kind
is equal’.100 Metabolically active fat, responsible for releasing inflammatory of strategy in HFpEF (FROST-HF study, NCT05136820).105
adipokines into circulation, exerts a detrimental impact on the heart and
other organs, particularly the kidneys, where fibrotic degeneration leads Cardiac Contractility Modulation
to diastolic dysfunction and chronic kidney disease. Additionally, obesity Abnormal myocardial contractility, and pathological atrial and ventricular
is associated with obstructive sleep apnoea, contributing to increased remodelling is a key feature of HFpEF. Nowadays, a new therapeutic
right ventricular afterload, promoting functional deterioration, and option could be counted in this contest, cardiac contractility modulation
eventually its failure.101 (CCM). CCM is a new device acting through myocytes stimulation during
the absolute refractory period of the action potential, leading to an
From the therapeutic perspective, glucagon-like peptide-1 agonists may increase in peak calcium concentration and inducing positive inotropism.106
represent a future therapeutic target for patients with HFpEF, acting on CCM has been shown to improve tolerance to exercise and outcome in
several pathways involved in the pathophysiology of HFpEF, including HFrEF patients, and growing data exist on the benefits of HFmrEf in terms
diabetes and obesity. of functional status and QoL.107,108 A prospective, multicentre, single-arm
study (CCM-HFpEF) was designed to assess the impact of CCM in a bigger
It has been demonstrated that the use of liraglutide is associated with HFpEF cohort. Over a 24-week follow-up period, in a population of 47
reduced body weight and improved metabolic control. The LEADER study patients in NYHA II and III with LVEF >50%, CCM caused an improvement
demonstrated that the rate of the first occurrence of death from CV in health status and the Kansas City Cardiomyopathy Questionnaire with
causes, non-fatal MI or non-fatal stroke among patients with type 2 no impact on safety outcomes.109 Further randomised clinical trials are
diabetes was lower with liraglutide than with a placebo.102 needed to better define the potential impact on outcome and prognosis
of this innovative device in HFmrEF and HFpEF.
Moreover, in the STEP-HFpEF trial, semaglutide significantly reduced body
weight, improving symptoms with a positive impact on QoL in obese Conclusion
HFpEF patients.26 HFpEF is a complex syndrome characterised by profound clinical and
pathophysiological heterogeneity that accounts for the difficulty in
Supplementary Table 1 shows the most important trials on RAASi, SGLT2i identifying a unique pharmacological treatment. The identification of
and glucagon-like peptide-1 agonists in HFpEF described in this review. specific clinical phenotypes could play a role in choosing specific
strategies aimed at treating specific pathophysiological alterations and
Devices for HFpEF comorbidities, both cardiac and non-cardiac, with the aim of improving
Transcatheter Interatrial Shunt Device the quantity and, above all, the quality of life of the patient as quickly as
One of the key haemodynamic features of HFpEF is elevated left atrial and possible. Currently, SGLT2 inhibitors represent the only class of drugs with
pulmonary venous pressure at rest or on exertion, resulting in dyspnoea a beneficial role in the treatment of HFpEF, likely due to their ability to act
and reduced exercise capacity. A transcatheter-implanted interatrial shunt across multiple common pathophysiological aspects of different disease
device has been developed with the aim of opening an 8 mm large left-to- phenotypes.
right atrial shunt and unloading left atrium. The REDUCE LAP-HF I trial, a
phase II clinical trial, demonstrated a greater reduction of exercise Ultimately, the goal of phenotyping is not only to better understand the
pulmonary capillary wedge pressure in patients on active treatment complex pathophysiological mechanisms underlying HFpEF, but also to
compared with patients treated with a sham procedure.103 A phase III provide cardiologists with as many tools as possible to improve the
clinical trial, REDUCE LAP-HF II, was then conducted to test if the results quantity and, above all, the quality of life of their patients.

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