Biological phenotypes of heart failure with preserved ejection fraction
Lewis. Biological phenotypes of HFpEF
Gavin A. Lewis, MBChB,1,2 Erik B. Schelbert, MD, MS,3-5 Simon G. Williams, MD,2 Colin Cunnington, MBChB, DPhil,1,6 Fozia Ahmed, MBChB, MD,1,6 Theresa McDonagh, MBChB, MD,7 Christopher A. Miller MBChB, PhD1,2,8
Total Word Count: (9,968)
Affiliations1. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL2. University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Wythenshawe, Manchester, M23 9LT3. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA4. UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA, USA5. Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA6. Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL7. King’s College Hospital, Denmark Hill, London, SE5 9RS.8. Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT
From University of Manchester, Manchester, UK (GAL, CC, FA, CAM); University Hospital of South Manchester, Manchester, UK (GAL, SGW, CAM); University of Pittsburgh, PA, USA (EBS); Central Manchester University Hospitals Manchester, UK (CC, FA); King’s College Hospital (TM).
Sources of fundingDr Lewis is funded by a fellowship grant from the National Institute for Health Research. Dr Miller is funded by a Clinician Scientist Award (CS-2015-15-003) from the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
DisclosuresNone declared.
Address for CorrespondenceDr. Christopher A. Miller, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PLTelephone: 0044 161 291 2034. Fax: 0044 161 291 2389
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AbstractHeart failure with preserved ejection fraction (HFpEF) involves multiple pathophysiological mechanisms, which result in the heterogeneous phenotypes that are evident clinically, and which have potentially confounded previous HFpEF trials. A greater understanding of the in vivo human processes involved, and in particular, which are the causes and which are the downstream effects, may allow the syndrome of HFpEF to be distilled into distinct diagnoses based on the underlying biology. From this, specific interventions can follow, targeting individuals identified on the basis of their biological phenotype. This review describes the biological phenotypes of HFpEF and therapeutic interventions aimed at targeting these phenotypes.
Condensed AbstractHeart failure with preserved ejection fraction (HFpEF) involves multiple pathophysiological mechanisms, resulting in clinically evident heterogeneous phenotypes. A greater understanding of the in vivo human process involved may allow the syndrome of HFpEF to be distilled into distinct diagnoses based on underlying biology, allowing targeted intervention based on their ‘biological phenotype’. This review describes the biological phenotypes of HFpEF and therapeutic interventions aimed at targeting these phenotypes.
Key WordsHeart failure with preserved ejection fraction, heart failure, diastolic dysfunction, myocardial fibrosis, titin, ejection fraction.
Abbreviations List
CMR = cardiovascular magnetic resonanceCVF = collagen volume fractionECM = extracellular matrixEF = ejection fractionHF = heart failureHFpEF = heart failure with preserved ejection fractionHFrEF = heart failure with reduced ejection fractionLV = left ventricularLVH = left ventricular hypertrophyLA = left atrial
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Introduction
Described as the “single largest unmet need in cardiovascular medicine”, heart failure with
preserved ejection fraction (HFpEF) potentially accounts for up to half of heart failure (HF),
indeed, as the population ages and its risk factors become more prevalent, the impact of
HFpEF is set to rise considerably.
However, reflecting the ongoing lack of understanding of HFpEF, its definition, even its
name, continues to change in clinical guidelines and randomised controlled trials (1,2). While
the use of natriuretic peptides has provided greater confidence in the diagnosis of HF, which
represents progress from some early HFpEF trials that appear to have included patients who
did not have HF, the heterogeneity of HFpEF continues to frustrate clinicians and be cited as
a reason for the failure of clinical effectiveness trials (2). Even after leaving aside specific
causes of HF in the context of a normal or near normal ejection fraction (EF) (e.g.
hypertrophic cardiomyopathy, cardiac amyloidosis, Fabry disease), it is true that HFpEF
represents a broad cohort of patients with a range of comorbid conditions (3). However, it is
precisely this heterogeneity that needs to be embraced and explored if management is to
advance. Defining the diverse pathophysiological mechanisms of HFpEF will provide the
basis for the development of therapies that target each of these mechanisms, which can then
be trialled in patients identified as displaying particular mechanisms. The ‘one-size fits all’
approach to HFpEF has proved unsuccessful.
An outline of therapy based on ‘clinical phenotypes’ of HFpEF has been recently proposed
(4). Whilst this acknowledges the heterogeneity and need for individualised management, it is
the ‘biological phenotypes’, i.e. the underlying disease mechanisms of HFpEF, that ultimately
need to be addressed, and which will be the focus of the current discussion (Figure 1). When
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interpreting the presented data, it is important to note that study findings reflect the population
studied, which often differs according to data source (clinical trials vs. registries vs.
mechanistic studies), and may itself contribute to the heterogeneity.
Morphological heterogeneity
Left ventricular hypertrophy (LVH) and left atrial (LA) dilatation are considered hallmarks of
HFpEF and are included in its definition in recent guidelines (1) and in the inclusion criteria
of current randomised controlled trials, however there is considerable morphologic
heterogeneity.
In clinical trials and contemporary registries, approximately one-third to two-thirds of patients
with HFpEF do not have LVH (Figure 2A) (5,6). A further proportion of patients (for
example, 12% and 9% in the studies by Katz et al (6) and Shah et al (7) respectively) have
eccentric LVH rather than the conventional concentric pattern. Hypertrophic remodelling is
more common in HFpEF patients with hypertension, although approximately half of patients
with HFpEF and normal left ventricular (LV) mass have hypertension (6). Furthermore, LVH
is not exclusive to HFpEF, indeed the prevalence of LVH is similar in patients with
hypertension and no history of HF as compared to patients with hypertension and HFpEF (8).
LV mass, and the binary presence of LVH, are associated with adverse outcome in HFpEF on
multivariable analyses, primarily driven by an association with increased rates of
hospitalisation (5,6,9).
Similarly, a third to a half of patients in HFpEF studies have normal LA size (Figure 2B)
(5,7,10). In comparison, a third of patients with hypertension without HF have LA
enlargement (11). The relationship between LV mass and LA size is also not straightforward.
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For example, in the echocardiographic sub-study of the Treatment of Preserved Cardiac
Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT) (7,12), patients who
were enrolled on the basis of elevated natriuretic peptides had significantly larger LA volumes
than patients who were enrolled on the basis of previous hospitalisation, but had thinner LV
walls, lower mass and a lower prevalence of LVH. LA size has an inconsistent association
with adverse outcome in HFpEF; dichotomous LA enlargement was associated with adverse
outcome in the Irbesartan in Heart Failure With Preserved Ejection Fraction (I-PRESERVE)
trial on multivariable analysis (5,13), although LA area, as a continuous variable, was not. In
the echocardiographic sub-study of TOPCAT (9), LA width but not LA volume was
independently associated with outcome, and LA size was not associated with adverse outcome
in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-
Preserved Echocardiographic substudy (CHARMES) (10,14).
Thus, while measurements of LV mass and LA size may be prone to error and variability, it is
clear that these parameters are inadequate for identifying patients with HFpEF and guiding
management. Other features, ideally reflecting underlying pathophysiological mechanisms,
are required.
Functional heterogeneity
Diastolic dysfunction also forms part of the guideline definition of HFpEF (1). Using invasive
conductance pressure-volume assessments, Westermann et al (15) found mean LV relaxation
time constant, end-diastolic pressure, diastolic stiffness and stiffness constant to be higher in
HFpEF patients (EF > 50%) at rest, and mean end-diastolic volume, stroke volume and
cardiac output to be reduced during tachycardic atrial pacing, compared to mean values in
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age, gender and co-morbidity-matched controls, although there was a strong trend towards a
higher prevalence of hypertension in the HFpEF group (37% vs. 20%; p=0.05).
However, consistently, a third of patients in the echocardiographic substudies of HFpEF
RCTs have normal diastolic function, even in the context of elevated natriuretic peptides, and
a further 20-30% have only mild or grade 1 diastolic dysfunction (Figure 2C) (5,7,10). In
comparison, a recent study of older people (aged 67–90 years) without HF found 96% had
abnormal diastolic function according to guideline-based definitions (16).
Advanced diastolic dysfunction was associated with adverse outcome in CHARMES
(moderate and severe diastolic dysfunction) and TOPCAT (severe diastolic dysfunction), but
diastolic function was not associated with outcome in I-PRESERVE. Katz et al (6) found
diastolic function to be worse in patients with HFpEF and concentric LVH compared to
eccentric LVH, but outcome was equivalent.
The load-dependency and variability of echocardiographic diastolic assessment are well
documented (17). In a condition in which diastolic dysfunction has been considered a defining
pathophysiology (‘diastolic heart failure’), it is unclear whether the variation in presence, and
prognostic significance, of diastolic dysfunction in HFpEF reflects the inadequacy of its
assessment with echocardiography, or a pathophysiological mechanism independent of
diastolic function in a substantial proportion of patients.
Atrial function may be abnormal in approximately 25% to 50% of patients with HFpEF,
although it has not been assessed in large cohorts, reference ranges are not well defined for all
analysis techniques and atrial dysfunction is prevalent in patients with hypertension without
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HF (18). Nevertheless, Freed et al (18) found LA reservoir strain to be independently
associated with adverse outcome in HFpEF, even after adjusting for LA volume and after
excluding patients with atrial fibrillation.
Defining what represents a ‘preserved ejection fraction’ has also been inconsistent across
guidelines, clinical trials and mechanistic studies (1,2,15) Post-hoc analysis from the
TOPCAT study, where ejection fraction (EF) ranged from 44 to 85%, showed significantly
higher event rates occurring at the lower end of the EF spectrum, particularly when EF was
less than 50% (19).
Myocyte structure and function
Titin
Elevated cardiomyocyte resting tension or passive stiffness (FPassive) has been demonstrated in
both isolated cardiomyocytes and strips of myocardium from patients with HFpEF (20-22).
Resting tension in cardiomyocytes is highly dependent on titin, a large sarcomeric protein that
functions as a molecular spring, storing energy during contraction and releasing it during
relaxation. The compliance of titin itself is dependent on post-transcriptional and post-
translational modifications, including isoform expression and phosphorylation (23).
Differential splicing results in two adult myocardial titin isoforms; N2B and N2BA. Van
Heerebeek et al (22) demonstrated a significant shift towards expression of the shorter, stiffer
N2B-isoform in myocardium from patients with HFpEF, which was hypothesised as being
responsible for the observed higher cardiomyocyte passive stiffness. RNA binding motif-20 is
a major splicing factor of titin and inhibition of RNA binding motif-20 results in expression
of highly compliant titin isoforms. Recently, in a murine HFpEF-like model (transverse aortic
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constriction and deoxycorticosterone acetate pellet implantation), Methawasin et al (24) found
that inactivating RNA binding motif-20 resulted in upregulation of compliant titin isoforms
and a large reduction in cellular passive stiffness, which translated into attenuation of
concentric LVH and normalisation of diastolic function and exercise tolerance. The
improvements occurred despite persistent, and unchanged, myocardial fibrosis, suggesting
they were cardiomyocyte-specific.
Titin stiffness is acutely modulated by phosphorylation. Titin is phosphorylated by a number
of pathways including cyclic adenosine monophosphate (cAMP)-dependent protein kinase-A
(PKA), activated in response to β-adrenergic stimulation by catecholamines, cyclic guanosine
monophosphate (cGMP)-dependent protein kinase-G (PKG), activated by nitric oxide (NO)
or natriuretic peptides, and protein kinase Cα (PKCα), calcium/calmodulin-dependent protein
kinase II (CaMKII), and extracellular signal-regulated kinase-2 (ERK2), activated by
endothelin-1 and angiotensin-II (23,25). PKA, PKG, and ERK2 signalling appear to decrease
cardiomyocyte resting tension, whereas PKCα phosphorylation increases it (Figure 3).
Hypophosphorylation of the N2B-isoform of titin has been demonstrated in myocardial tissue
from patients with HFpEF and in preclinical models, and is associated with elevated passive
stiffness of cardiomyocytes (26-28). In contrast to work by Van Heerebeek, Zile et al (21)
found no difference in N2BA:N2B isoform ratio between patients with hypertension and
HFpEF, patients with hypertension but no evidence of HF and normotensive controls, but
they did find that the ratio of phosphorylated N2BA:N2B was significantly higher in the
HFpEF group compared to the other groups, which is in keeping with findings from
preclinical models (28,29). Specifically, increased phosphorylation was seen at a PKC site on
the N2BA isoform and reduced phosphorylation at the PKA/PKG site on the N2B-isoform.
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Low PKA and PKG activity and cGMP concentration have also been demonstrated in HFpEF,
indeed administration of PKA and PKG in vitro is associated with normalisation of
cardiomyocyte passive stiffness (22,26,30).
Bishu et al (28) found augmentation of cGMP levels via natriuretic peptide stimulation and
phosphodiesterase-5 inhibition resulted in a significant relative increase in the
phosphorylation of N2B, and hence a reduction in the ratio of phosphorylated N2BA:N2B,
which was associated with a lower cardiomyocyte resting tension and improved diastolic
function. The beneficial effects were seen without changes to the phosphorylation status of
other sarcolemmic proteins and after excluding potential effects of transmembrane calcium
currents and myocardial fibrosis. Fukada et al (29) showed that the extent of the reduction in
resting tension during protein kinase A-mediated phosphorylation of titin was greater in
myocardial tissue with higher N2B-isoform expression. Thus, manipulation of myocardial
titin isoform expression and the phosphorylation state of each isoform represent attractive
therapeutic targets.
The combined angiotensin-II receptor and neprilysin inhibitor, valsartan/sacubitril, the
neprilysin inhibitor component of which augments active natriuretic peptides resulting in an
increase in cGMP, was associated with a greater reduction in serum NT-proBNP levels than
valsartan alone in patients with HFpEF after 12 weeks of treatment in the PARAMOUNT trial
(31). The ongoing PARAGON-HF is investigating the clinical effectiveness of
valsartan/sacubitril. The SOCRATES-preserved trial (NCT01951638) is investigating the
effect of augmenting cGMP levels using an orally active soluble guanylyl-cyclase stimulator.
Calcium handling
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HFpEF is associated with abnormal cardiomyocyte calcium homeostasis and ion channel
remodelling (32). Selby et al (33) found ventricular myocardium from patients with LVH and
LA dilatation has increased resting (diastolic) tension due to a persistent increase in actin-
myosin cross-bridge activation as a result of elevated diastolic cytosolic calcium
concentration, itself due to reduced sarcolemmal calcium extrusion due to abnormalities in the
function of the sodium-calcium exchanger. Calcium leak from the sarcoplasmic reticulum and
reduced sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) expression have also been
shown to contribute to the elevated diastolic cytosolic calcium concentration in preclinical
HFpEF models, although the data suggests both may be consequences of diastolic dysfunction
rather than causes (32,34).
In the study by Selby et al, diastolic tension increased further as heart rate increased, as a
result of increasing amounts of calcium entering the cell, in ventricular myocardium from
patients with LVH and LA dilatation, whereas no significant change was seen in myocardium
from patients with normal LV mass and LA size, findings which are in keeping with those
from a single cell model of HFpEF (32,33). These findings are consistent with the
aforementioned tachycardia-induced reduction in LV end-diastolic volumes observed by
Westermann et al (15), and potentially provide a mechanism for the observed exercise
limitation and intolerance to tachycardia seen in HFpEF. Heart rate restriction may therefore
be a potential therapeutic strategy. Nevertheless, in the study by Selby et al, increased
diastolic tension was seen to prevent complete cardiomyocyte relaxation even at low normal
heart rates (e.g. 60 beats/min), hence while such interventions may be beneficial for
preventing excessive tachycardias, reducing heart rate to less than physiological rates is
unlikely to be of therapeutic value (35). Indeed, two small studies investigating the short-term
impact of ivabradine (If-inhibitor) on exercise capacity and diastolic function found opposing
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results, and more recently Komajda et al showed no improvement in diastolic function,
exercise capacity or NT-proBNP after 8 months of ivabradine therapy despite a mean heart
rate reduction of 13beats/min (36-38).
Increased intracellular sodium concentration is also observed in HFpEF and may contribute to
the increased diastolic cytosolic calcium concentration via sodium-calcium exchange (2).
Ranolazine inhibits the late sodium current, minimising intracellular sodium accumulation
and hence reducing calcium concentration, and is associated with reduced diastolic tension
and improved diastolic function in human myocardium in vitro (39). In an in vivo proof of
concept study in patients with HFpEF, ranolazine was associated with an acute improvement
in LV end-diastolic pressure and pulmonary capillary wedge pressure (PCWP) but it had no
effect on invasive relaxation parameters, and it also had no effect on diastolic function,
exercise parameters or NT-pro-BNP levels after 14 days of treatment (40).
In a preclinical HFpEF model, Primessnig et al (41) demonstrated that an inhibitor of the
calcium leak from the sarcoplasmic reticulum reversed maladaptive LV remodelling (reversed
the increase in LV mass and LA size seen with placebo), improved diastolic function, and
reduced NT-proBNP levels, independent of blood pressure effects. The same inhibitor has
previously been shown to improve mortality in models of hypertensive heart disease (42).
Such work requires translation into human tissue, but nevertheless, abnormal calcium
handling is a potential therapeutic target in HFpEF.
Myocardial energetics
Ventricular diastole is an active process that utilises ATP, and excessive energy is consumed
maintaining the abnormally increased diastolic tension in HFpEF (33). In addition,
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microvascular dysfunction (see below) and myocardial extracellular matrix expansion (see
below), which increases the oxygen diffusion distance between the capillary and collagen-
encircled cardiomyocyte, potentially render the cardiomyocyte prone to hypoxia (43). In
keeping with the resultant lower resting energy reserve, myocardial phosphocreatine
(PCr)/ATP ratio, measured using phosphorus-31 magnetic resonance spectroscopy (31P-
MRS), is significantly lower in patients with hypertensive heart disease compared to healthy
controls, and in patients with HFpEF compared to controls, and is associated with diastolic
dysfunction (44,45). Furthermore, Lamb et al (45) demonstrated that PCr/ATP ratio declined
more severely in patients with hypertensive heart disease than in healthy controls during
exercise, suggesting the energy reserve equilibrium declines further during exercise, which is
consistent with the findings of Selby et al (33) and Westermann et al (15) described earlier.
Recently, distinct alterations in fatty acid beta-oxidation (FAO) have also been demonstrated
in patients with HFpEF using quantitative metabolomic profiling (46). Interventions that shift
energy substrate utilisation have led to significant improvements in PCr/ATP ratio and
diastolic function in other conditions, but have not been investigated in HFpEF (47-49).
Myocardial extracellular matrix
Changes in extracellular matrix (ECM) composition and structure appear to be important
pathophysiological mechanisms in HFpEF.
ECM expansion secondary to collagen accumulation is consistently demonstrated on a group
level in myocardial tissue from patients with HFpEF (20-22,30), the magnitude of which is
similar to that seen in HF with reduced EF (22). Zile et al (21) found myocardial collagen
volume fraction (CVF) was significantly higher in patients with hypertension and HFpEF
compared to patients with hypertension and no history of HF, suggesting a potentially crucial
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pathophysiological discriminator, although CVF in the group of patients with hypertension
and no history of HF was no different to that in non-hypertensive controls, which is contrary
to other studies (50). Nevertheless, asymptomatic patients with LVH and patients with HFpEF
have been found to display distinct fibrotic cytokine profiles, with a shift in collagen
homeostasis to a more profibrotic state seen in HFpEF (21,51).
Borbely et al found collagen volume fraction (CVF) was normal in a third of patients with
HFpEF despite evidence of diastolic dysfunction. This is in keeping with the proportion (14%
to 56% depending on the cut off used) of HFpEF patients with a normal myocardial ECM
volume measured using cardiovascular magnetic resonance (CMR) imaging in a recent large
cohort, and demonstrates the pathophysiological variation.
Collagen content in myocardial tissue from patients with HFpEF, and CMR-derived
myocardial ECM volume in patients with HFpEF, are associated with echocardiographic
parameters of diastolic function and LA size (21,52,53). In an important study, Rommel et al
(54) found CMR-derived myocardial ECM volume was the only independent predictor of
load-independent intrinsic LV stiffness, as measured using invasive pressure-volume
assessment, in patients with HFpEF. Furthermore, when patients were dichotomised
according to median ECM volume, both groups showed a pathological upward shift of the
end-diastolic pressure volume relationship during exercise, but in patients with elevated ECM
volume, the dominant pathophysiology was an increase in myocardial passive stiffness,
whereas in patients with a below median ECM volume the dominant mechanisms were
arterial stiffness and impaired active relaxation. Interestingly, both groups demonstrated
similar echocardiographic diastolic parameters. As such, this study serves to demonstrate the
variations in biological phenotypes that exist between individuals that are broadly classified
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as having HFpEF, the inadequacy of echocardiographic diastolic parameters for detecting
these phenotypic variations, and, more broadly, the inadequacy of echocardiography for
determining intrinsic LV stiffness.
In a substudy of the I-PRESERVE trial (55), circulating markers of collagen deposition
(procollagen type I amino-terminal peptide and osteopontin) were associated with adverse
outcome (death and hospitalisation for pre-specified cardiovascular causes) on univariable
analysis, but not on multivariable analysis, although circulating collagen markers are not
specific to the heart and confounded by numerous factors such as renal function (56). In a
study of HFpEF patients by Duca et al (53), CMR-derived ECM volume was associated with
adverse outcome (hospitalisation for HF or cardiovascular death) during median 24 month
follow-up on univariable analysis, but not on multivariable analysis, although the study was
relatively small given the heterogeneity of the condition (n=117). Recently Schelbert et al
(57), in a considerably large cohort of patients (n=410) with HFpEF or at risk for HFpEF
(BNP>100pg/mL but no clinical HF), found CMR-derived myocardial ECM volume was
strongly associated with adverse outcome on univariable and multivariable analyses (Figure
4). Indeed, myocardial ECM volume was more strongly associated with outcome than factors
such as age, LV mass, atrial fibrillation or previous myocardial infarction, and a clear ‘dose-
response’ relationship was observed between ECM volume and outcome. Considerable data
demonstrate both the potential for myocardial ECM to have a primary aetiological role in
HFpEF, and the adverse impact that ECM expansion has on myocardial mechanical, electrical
and microvascular function, which is in keeping the adverse impact in other organs
(21,54,58,59).
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Importantly, myocardial ECM expansion is reversible. Brilla et al (60) and Diez et al (50)
demonstrated regression of myocardial fibrosis in patients with hypertensive heart disease,
which was associated with improvement in diastolic function, after 6 months of lisinopril and
12 months of losartan respectively. Izawa et al (61) demonstrated regression of myocardial
fibrosis after 12 months of spironolactone, albeit in a different population (dilated
cardiomyopathy). In patients with HFpEF, Deswal et al (62) found 6 months of treatment with
eplerenone was associated with a significant reduction in circulating markers of collagen
deposition, compared to placebo. Interestingly, in the studies by Diez et al (50) and Izawa et
al (61), myocardial fibrosis regression was most prominent in patients with a greater burden
of myocardial fibrosis at baseline. This demonstration that antifibrotic agents may be more
effective in patients exhibiting a fibrotic phenotype may explain why angiotensin converting
enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists have not proven
beneficial in phase III trials in which recruitment has not targeted phenotypic variations
(12,63,64). The on-going PIROUETTE trial (NCT02932566) is investigating the effect of a
pure antifibrotic agent in patients with HFpEF with evidence of ECM expansion at baseline.
The angiotensin-II receptor blocker component of valsartan/sacubitril is associated with
myocardial fibrosis regression (65), and thus, given the effect of the neprilysin inhibitor
component described earlier, two HFpEF biological phenotypes are being targeted in the
PARAGON-HF trial (NCT01920711).
Lopez et al (66) found it was the degree of collagen cross-linking, rather than total collagen
volume, which was associated with LV filling pressures in patients with HFpEF and
hypertension. The same group also found torasemide reduced overexpression of lysyl oxidase
(which catalyses collagen cross-linking), collagen cross-linking and CVF, although in
hypertensive patients with HF and a preserved mean EF (54%), torasemide was not associated
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with a reduction in circulating collagen markers (67). Recently, lysyl oxidase-like 2 inhibition
was found to essentially eliminate the interstitial fibrosis, LV remodelling and HF associated
with transaortic constriction, although lysyl oxidase-like 2 inhibition has not proven beneficial
in phase II trials of pulmonary and hepatic fibrosis, possibly because once formed, collagen
crosslinks, particularly hydroxyallysine crosslinks, are much less susceptible to degradation,
thus lysyl oxidase-like 2 inhibition may need to be given earlier in the disease process
(68,69).
Zile et al (21) found myocardial fibrosis and abnormal titin function may co-exist in HFpEF,
synergistically leading to increased myocardial stiffness, although there is little evidence for
common pathophysiological pathways. Manipulation of titin isoform compliance by
Methawasin et al (24) did not alter collagen volume fraction. It is not known whether anti-
fibrotic agents influence titin compliance.
Vascular function
Paulus et al have proposed a central role for endothelial dysfunction, driven by co-morbidity
induced-systemic inflammation, in the pathophysiology of HFpEF (70). Circulating levels of
interleukin-6 and tumor necrosis factor-α are strongly and independently associated with
incident HFpEF (71), and cross sectional studies have consistently demonstrated elevated
circulating inflammatory markers in patients with established HFpEF, although this latter
finding may represent a manifestation of HFpEF rather than a cause (21). Paulus et al (70)
postulate that systemic inflammation leads to coronary microvascular endothelial
inflammation, as evidenced by abundant expression of vascular cell adhesion molecules,
which stimulates endothelial production of reactive oxygen species and impairment of
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endothelial-myocyte nitric oxide signalling, which in turn results in reduced myocyte PKG,
pro-hypertrophic signalling and increased myocyte stiffness (30,72,73).
Myocardial vascular function
Microvascular endothelial inflammation is known to be associated with endothelial
dysfunction and microvascular rarefaction (74), and, in an autopsy study that included 124
HFpEF patients (defined as HF hospitalisation and or outpatient HF diagnosis between
approximately 1980 and 2010, and a LV EF >40% within a median of 1 day of HF event),
HFpEF was associated with reduced microvascular density, which itself was associated with
myocardial fibrosis, in comparison to a control group who had died of non-cardiovascular
causes (59). However, whilst statistical adjustments were made for the between group
differences, the HFpEF group had substantially higher rates of confounders such as
hypertension (79 vs. 31%), diabetes (42 vs. 11%), epicardial coronary disease (65 vs. 0%) and
renal dysfunction. Srivaratharajah et al (75) found HFpEF was associated with a significant
reduction in myocardial flow reserve, as assessed using 82Rubidium positron emission
tomography, compared to hypertensive and normotensive controls, although natriuretic
peptides were not included in HF diagnosis, patients with infiltrative cardiomyopathies and
significant valvular heart disease were not excluded, and there were important baseline
differences between groups. Interestingly, HFpEF patients had higher resting myocardial
blood flow than normotensive controls and a trend towards higher resting myocardial blood
flow than hypertensive controls, which appears discordant with the reduced microvascular
density observed by Mohammed et al (59). Kato et al (76) found coronary flow reserve,
measured using phase-contrast CMR of the coronary sinus at rest and during adenosine stress,
showed a significant inverse correlation with serum natriuretic peptide levels in patients with
HFpEF and without significant epicardial coronary disease. Using paired arterial and coronary
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sinus blood gas sampling at rest and during supine cycle ergometry, van Empel et al (77)
found myocardial oxygen delivery, and potentially oxygen extraction, were reduced in
HFpEF and correlated with PCWP. Nevertheless, therapies that reduce inflammation and/or
improve endothelial function, (e.g. statins, angiotensin receptor blockers, phosphodiesterase-5
inhibitors), have proved ineffective in improving patient outcomes in HFpEF (63,78-80). It
may be that such therapies need to be given earlier in the disease process, before
microvascular rarefaction has occurred. A phase 2 trial of the antioxidant coenzyme-Q in
HFpEF is planned (NCT02779634).
Peripheral vascular function
HFpEF is associated with increased central arterial stiffness and increased magnitude of
arterial wave reflections in comparison to age-matched controls, although these parameters
have not been assessed in comparison to age and blood pressure-matched controls (80-82).
Increased afterload, particularly late systolic load, is associated with LVH and impaired
systolic and diastolic function in people without cardiovascular disease and in patients
undergoing invasive assessment for coronary disease with a LV EF >50%, and is strongly and
independently associated with incident HF (84,85). Arterial stiffness is associated with
decreased exercise capacity in HFpEF (83,86), and in preclinical models increased afterload is
associated with LV hypertrophy, fibrosis and HF (87). Organic nitrates have been shown to
reduce arterial wave reflections acutely (88), but in a recent randomised controlled trial in
patients with HFpEF, 6 months of isosorbide dinitrate, with or without hydralazine, did not
reduce wave reflections or improve remodelling or exercise tolerance, and were poorly
tolerated (89). Similarly in the NEAT-HFpEF trial (90), 6 weeks of isosorbide mononitrate
therapy did not improve quality of life or exercise capacity compared to placebo, indeed dose-
dependent decreases in physical activity levels were seen in patients receiving isosorbide
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mononitrate, possibly due to orthostatic hypotension. Inorganic nitrate, converted to nitric
oxide via the nitrate-nitrite-nitric oxide pathway in a process enhanced by tissue hypoxia and
acidosis, appears to be better tolerated with less risk of resting hypotension (91). Borlaug et al
(92) found sodium nitrite infusion acutely improved exercise PCWP and ventricular
performance in patients with HFpEF. Zamani et al (93) found a single dose of inorganic
nitrate-rich beetroot juice and subsequently 2 weeks of an oral preparation of inorganic nitrate
(potassium nitrate) improved exercise duration and quality of life in patients with HFpEF, and
was well tolerated. In addition to a beneficial effect on arterial wave reflections, the authors
suggested the positive findings were mediated by replacement of myocardial nitric oxide
deficiency and peripheral vasodilation. Further trials of inorganic nitrates are underway
(NCT02256345). Angiotensin-converting enzyme and phosphodiesterase-5 inhibition are not
associated with improvements in aortic distensibility in HFpEF (94) (78).
HFpEF is also associated with impaired skeletal muscle vasodilatory reserve during exercise
that results in a blunted exercise-induced reduction in systemic vascular resistance and
presumed abnormal skeletal muscle oxygen delivery, which, together with changes in skeletal
muscle fibre type and reduced capillary density, may contribute to the observed exercise
intolerance (95-97).
Pulmonary vascular function
In a population-based study of 244 patients with HFpEF, Lam et al (98) found 83% had
pulmonary hypertension, defined as a pulmonary artery systolic pressure (PASP) of over
35mmHg, derived from tricuspid regurgitation velocities on echocardiography, with a median
PASP of 48 (IQR 37-56mmHg), which is consistent with a prior invasive catheter based study
(99). PASP was significantly higher in patients with HFpEF than with hypertension without
20
HF, and was strongly associated with symptoms and mortality (hazard ratio 1.2 per 10 mmHg
increase on multivariable analysis). As expected, PASP was associated with pulmonary
venous pressure, estimated using E/e’ ratio, but interestingly, after accounting for pulmonary
venous pressure, PASP in HFpEF still exceeded that of hypertensive controls without HF,
suggesting abnormal pulmonary arterial function. Whether this pulmonary arterial
hypertension is due to pulmonary vascular remodeling secondary to sustained pulmonary
venous pressure elevation, primary abnormalities in pulmonary arterial function, abnormal
RV-PA coupling, or a combination of these factors remains unclear, but nevertheless PA
pressure is a potential therapeutic target.
However, in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise
Capacity in HFpEF (RELAX) trial (79), phosphodiesterase-5 inhibition with sildenafil for 24
weeks had no effect on exercise capacity, clinical status, quality of life, LV mass, diastolic
function or PASP compared to placebo. Similarly, despite an earlier trial suggesting sildenafil
may be beneficial in patients with HFpEF and pulmonary hypertension (100), Hoendermis et
al (101) recently found sildenafil for 12 weeks did not reduce PA pressures or improve other
invasive haemodynamic or clinical parameters in patients with HFpEF and pulmonary
hypertension. In the RELAX trial, plasma cGMP levels did not differ significantly between
groups, leading the authors to suggest that the negative results may have been because
sildenafil was unable to enhance cGMP sufficiently. Bonderman et al (102) found no
significant changes in mean PA pressure or other haemodynamic parameters 6 hours after
treatment with a soluble guanylate cyclase stimulator (riociguat) in patients with HFpEF and
pulmonary hypertension.
Comorbidities
21
Obesity
Multiple studies have demonstrated an association between obesity and HF, with a ‘dose-
response’ relationship observed between BMI and HF incidence in people with a BMI in the
overweight range or higher (103,104). (105). Whilst obesity is associated with a number of
HF risk factors, obesity is independently associated with HF, with a relative risk of 1.41 (95%
confidence interval 1.34–1.47) per 5-unit increment in BMI in a recent meta-analysis (106).
More than 80% of patients with HFpEF are overweight or obese and in the TOPCAT and
RELAX trials, median/mean BMI was 31kg/m2 and over 35kg/m2 respectively (107). Obokata
et al (108) recently described a distinct obese HFpEF phenotype, characterised by greater
concentric LV remodelling, higher LV filling pressures at rest and with exercise, greater
plasma volume overload (yet lower NT-pro BNP levels), a larger increase in pulmonary
arterial pressures with exercise, larger right ventricular size and more significant exercise
intolerance compared to non-obese HFpEF. Weight loss following bariatric surgery is
associated with reduced LV mass and mass-volume ratio, and improved diastolic function
(109).
Lung disease
Approximately 30-40% of patients with HFpEF have COPD (110). Whilst COPD and HF
share a number of risk factors, multiple studies have demonstrated a strong and independent
relationship between the severity of airflow limitation and incident HF (adjusted odds ratio of
up to 3.9) (111). Indeed in a large, community-based sample, Lam et al (112) found airflow
obstruction was the most prominent noncardiac predictor of incident HFpEF, and Barr et al
(113) showed emphysema and airflow limitation are linear related to impaired LV filling.
Obstructive sleep apnoea (OSA) is also common, with a prevalence of approximately 25-50%
22
in HFpEF, although in a study by Stahrenberg et al (114) OSA was not independently
associated with exercise tolerance, and its impact on outcome in HFpEF is not clear (115).
Kidney disease
Approximately 25-50% of patients with HFpEF have chronic kidney disease (CKD; defined
as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2), the prevalence of
which increases with age (116). CKD is consistently associated with adverse outcome in HF,
and appears to be of greater prognostic importance in HFpEF than HFrEF (odds ratio for all-
cause mortality 2.40 (95% CI 2.18, 2.63) with LVEF > 40% vs. 2.0 (1.81, 2.21) with LVEF
<30%) (117).
Comorbidity pathophysiology and potential interventions
The pathophysiological mechanisms underlying the associations between these comorbidities
and HFpEF remain unclear. Obesity, lung disease and kidney disease are associated with
systemic inflammation and, as described earlier, Paulus et al (70) hypothesise that chronic
inflammation leads to endothelial dysfunction, myocardial hypertrophy, fibrosis and diastolic
dysfunction.
Circulating inflammatory markers are associated with incident HFpEF, natriuetric peptide
levels and diastolic dysfunction (118). However the relationship between comorbidities,
inflammation, and HFpEF is not consistent, and therapies that reduce inflammation or
improve endothelial function have not proved effective to date (63,78,79). Other proposed
pathophysiological mechanisms include abnormal haemodynamics, metabolic dysregulation
and neurohumoral activation (119).
23
In a large cohort of obese patients without previous HF, Sundström et al (105) recently
demonstrated a graded association between increasing weight loss and decreasing risk of
incident HF, suggesting that comorbid intervention before HFPEF ensues may be beneficial.
Empagliflozin, an inhibitor of sodium-glucose transporter-2 (SGLT-2), which is located
almost exclusively in the kidney, was associated with a 35% reduction in the risk of HF
hospitalization and a 39% reduction in the risk of HF death or hospitalization compared to
placebo in patients with type II diabetes mellitus and cardiovascular disease in the EMPA-
REG trial, with benefits seen in patients with and without HF at baseline (120,121). HF
outcomes relative to EF were not assessed, although HF outcome rates in those with baseline
HF were similar to those in HFpEF trials, leading to suggestions that empagliflozin may have
been beneficial in patients with HFpEF (122). The mechanisms by which empagliflozin may
positively impact HF are unclear, but the improvement in HF outcomes was independent of
glycaemic control. Hypotheses include a blood pressure lowering effect, sodium and fluid
loss, beneficial effects on the renin-angiotensin system, weight loss, maintenance of renal
function, decreased atrial stiffness and decreased inflammation. A phase-III trial of
empagliflozin in HFpEF is currently in progress, including patients without type II diabetes
(NCT03057951).
Discussion
It is clear that HFpEF involves multiple pathophysiological mechanisms, which, to a variable
extent, likely co-exist and combine to result in the heterogeneous phenotypes that are evident
clinically (123).
24
In an eloquent study, Shah et al (124) applied machine learning techniques to a well
characterised HFpEF cohort in order to identify groups of patients based on their clinical
phenotypes (“phenomapping”). Patients were recruited following hospitalisation for HF
although elevated natriuretic peptides were not required for diagnosis. Three markedly
differing phenogroups were identified: (1) younger patients with moderate diastolic
dysfunction who had relatively normal BNP (mean 72pg/mL); (2) obese, diabetic patients
with a high prevalence of obstructive sleep apnea who had the worst LV relaxation; and (3)
older patients with significant chronic kidney disease, electric and myocardial remodeling,
pulmonary hypertension, and RV dysfunction. Outcomes (including hospitalisation and death)
varied significantly by phenogroup, with a stepwise increase in risk profile from group 1,
which had the lowest risk to group 3, which had the highest. The phenogrouping provided
more discriminatory risk profiling than BNP and results were confirmed in a validatory
cohort. The work by Shah et al demonstrates that the heterogeneity of HFpEF can, at least to
some extent, be resolved, and provides the opportunity for future trials to recruit, and
determine effect, according to phenotypic characterisation.
Nevertheless, it is the biology underlying these clinical phenotypes that ultimately needs to be
determined; in particular, which biological mechanisms are root causes and which are
downstream effects. Studies are required that simultaneously investigate multiple biological
mechanisms, in order to understand the relative contribution of each mechanism, how
different mechanisms interact and whether apparently distinct mechanisms share common
drivers. For example, in order to more fully understand myocardial stiffness, concurrent
assessments of titin, calcium handling, energetics and extracellular matrix, their interaction
and molecular drivers, are required.
25
Machine learning techniques, such as those used by Shah et al, applied to large, deeply
phenotyped (biological and clinical) datasets in conjunction with well-defined outcomes may
help to further resolve the heterogeneity of HFpEF, improve our understanding of how
biological mechanisms integrate (‘biological phenogroups’) and how biological phenotypes
integrate with clinical phenotypes. From this, specific interventions can follow, targeting
individuals identified on the basis of their biological phenotypes. Biological heterogeneity has
potentially compromised HFpEF trials previously (12-14); HFpEF now needs ‘to get
personal’.
This involves multiple challenges, not least the translation of cardiovascular molecular
biology into clinical diagnostics that are acceptable and scalable. CMR ECM volume
quantification has its limitations, but is an example of a technique that non-invasively
interrogates a pathophysiological mechanism, which can be used to identify patients and
measure the effect of interventions. A specific preclinical HFpEF model is lacking, although
this reflects the heterogeneity of the condition and our lack of understanding of the integrated
pathophysiology. Nevertheless, the ‘epidemic’ status of HF means the potential gains are
large.
Understanding the relationship between HFpEF and aging may help with understanding the
biology of HFpEF more generally. In the study by Shah et al, older patients had more severe
electrical and myocardial remodelling, more abnormal ventricular-arterial coupling, worse RV
function and higher PA pressures in comparison to younger patients, despite a similar
duration of HF. The mechanisms responsible for these age-related phenotypic differences are
not clear, but it does not appear to simply reflect accumulation of comorbidities; whilst CKD
was more common in older patients, obesity, diabetes and obstructive sleep apnea were not.
26
Diastolic dysfunction is common in older patients without HF and is generally considered a
benign manifestation of aging. However, it may reflect changes in myocardial and vascular
structure that confer vulnerability (16). Indeed, preclinical studies have demonstrated that the
myocardial response to injury is directly influenced by age (125).
Finally, natriuretic peptides increase the diagnostic confidence of HFpEF and are associated
with adverse outcomes, and therefore contemporary clinical trials often require elevated
natriuretic peptide levels for entry. However, elevation of natriuretic peptide levels potentially
reflects an advanced stage in the pathophysiological process, when decompensation has
occurred. Indeed, post hoc analyses of data from the I-PRESERVE and TOPCAT trials found
patients with low levels of natriuretic peptides derived benefit from irbesartan and
spironolactone respectively, but patients with higher levels were unresponsive to intervention
(126,127). Characterisation of the biological phenotypes, understanding the biological
differences between patients with typical co-morbidities but without HF and those with
clinically similar profiles but with HF, and identification of interventions that disrupt or
reverse this pathobiology, may pave the way for patients to targeted before the HFpEF
syndrome ensues.
27
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Legends
CENTRAL ILLUSTRATION (Figure 1). Biological phenotypes in heart failure with
preserved ejection fraction (HFpEF). HFpEF is a systemic disease with multiple biological
phenotypes contributing to a heterogeneous clinical syndrome, including cardiomyocyte,
extracellular matrix, vascular and co-morbidity-related pathophysiological mechanisms.
Figure 2. Morphological and functional heterogeneity in HFpEF clinical trials. The
prevalence of left ventricular hypertrophy (A), left atrial dilatation (B) and diastolic
dysfunction (C) is highly variable, demonstrated in major HFpEF randomised trials (I-
PRESERVE, CHARM-Preserve, and TOPCAT).
Figure 3. Cardiomyocyte-specific biological phenotypes in HFpEF. Titin phosphorylation
and isoform expression (N2B/N2BA) alter cardiomyocyte stiffness. Mitochondrial
dysfunction leads to abnormal phosphocreatinine (PCr) to adenosine triphosphate (ATP) ratio.
Abnormal calcium handling may result from calcium leak and reduced expression of the
sarcoendoplasmic reticulum calcium-transport ATPase (SERCA) pump. ADP, adenosine
triphosphate; CaMKII, Ca2+/calmodulin-dependent protein kinase-II; cAMP, cyclic adenosine
monophosphate; Cr, creatinine; ERK2, extracellular signal-regulated kinase-2; GMP,
guanosine monophosphate; GTP, guanosine triphosphase; pGC, particulate guanylyl cyclase;
PKA, protein kinase A; PKCα, protein kinase Cα; PKG, protein kinase G; sGC, soluble-
guanylyl cyclase.
Figure 4. Outcomes in patients with HFpEF or at risk of HFpEF according to
extracellular volume (ECV). ECV measurement of myocardial fibrosis provides robust risk
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