HFA HFpEF Diagnosis Consensus 2019

European Heart Journal (2019) 40, 3297–3317 CLINICAL RESEARCH
doi:10.1093/eurheartj/ehz641 Heart failure/cardiomyopathy
How to diagnose heart failure with preserved

ejection fraction: the HFA–PEFF diagnostic
algorithm: a consensus recommendation from
the Heart Failure Association (HFA) of the
Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

European Society of Cardiology (ESC)
Burkert Pieske1,2,3,4*, Carsten Tschöpe1,2,5, Rudolf A. de Boer 6, Alan G. Fraser7,
Stefan D. Anker1,2,5,8, Erwan Donal9, Frank Edelmann1,2, Michael Fu10,
Marco Guazzi11,12, Carolyn S.P. Lam13,14, Patrizio Lancellotti15,
Vojtech Melenovsky16, Daniel A. Morris1, Eike Nagel 17,18,
Elisabeth Pieske-Kraigher1, Piotr Ponikowski19, Scott D. Solomon20,
Ramachandran S. Vasan21, Frans H. Rutten 22, Adriaan A. Voors6,
Frank Ruschitzka23, Walter J. Paulus24, Petar Seferovic25, and
Gerasimos Filippatos26,27
1
Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; 2German Center for Cardiovascular Research (DZHK),
Berlin, Partner Site, Germany; 3Department of Internal Medicine and Cardiology, German Heart Institute, Berlin, Germany; 4Berlin Institute of Health (BIH), Germany; 5Berlin
Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charite, Berlin, Germany; 6University Medical Centre Groningen, University of Groningen, Department of
Cardiology, Groningen, the Netherlands; 7School of Medicine, Cardiff University, Cardiff, UK; 8Department of Cardiology and Pneumology, University Medicine Göttingen
(UMG), Germany; 9Cardiology and CIC, IT1414, CHU de Rennes LTSI, Université Rennes-1, INSERM 1099, Rennes, France; 10Section of Cardiology, Department of Medicine,
Sahlgrenska University Hosptal/Ostra, Göteborg, Sweden; 11Department of Biomedical Sciences for Health, University of Milan, IRCCS, Milan, Italy; 12Department of Cardiology,
IRCCS Policlinico, San Donato Milanese, Milan, Italy, 13National Heart Centre, Singapore & Duke-National University of Singapore; 14University Medical Centre Groningen, The
Netherlands; 15Department of Cardiology, Heart Valve Clinic, University of Liège Hospital, GIGA Cardiovascular Sciences, CHU Sart Tilman, Liège, Belgium; 16Institute for
Clinical and Experimental Medicine - IKEM, Prague, Czech Republic; 17Institute for Experimental and Translational Cardiovascular Imaging, University Hospital Frankfurt;
18
German Centre for Cardiovascular Research (DZHK), Partner Site Frankfurt, Germany; 19Medical University, Clinical Military Hospital, Wroclaw, Poland; 20Cardiovascular
Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 21Section of Preventive Medicine and Epidemiology and Cardiovascular Medicine,
Department of Medicine, Boston University School of Medicine, Boston, MA, USA; 22Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht,
Utrecht University, Utrecht, The Netherlands; 23University Heart Centre, University Hospital Zurich, Switzerland; 24Department of Physiology and Amsterdam Cardiovascular
Sciences, Amsterdam University Medical Center, The Netherlands; 25University of Belgrade School of Medicine, Belgrade University Medical Center, Serbia; 26Department of
Cardiology, National and Kapodistrian University of Athens Medical School; University Hospital “Attikon”, Athens, Greece; and 27University of Cyprus, School of Medicine,
Nicosia, Cyprus
Received 16 May 2018; revised 30 October 2018; editorial decision 16 August 2019; accepted 26 August 2019; online publish-ahead-of-print 31 August 2019
Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new step-
wise diagnostic process, the ‘HFA–PEFF diagnostic algorithm’. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory set-
ting and includes assessment for HF symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly,
atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of
breathlessness, HFpEF can be suspected if there is a normal left ventricular ejection fraction, no significant heart valve disease or cardiac
ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of
HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically
performed by a cardiologist. Measures include mitral annular early diastolic velocity (e0 ), left ventricular (LV) filling pressure estimated
using E/e0 , left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic
* Corresponding author. Tel: þ49 30 450 553702, Fax: þ49 30 450 7 553702, Email: [email protected]
C The Author(s) 2019. For permissions, please email: [email protected].
Published on behalf of the European Society of Cardiology. All rights reserved. V
3298 B. Pieske et al.
strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score >_5
points implies definite HFpEF; <_1 point makes HFpEF unlikely. An intermediate score (2–4 points) implies diagnostic uncertainty, in which
case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2:
Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for
a better classification of HFpEF.
...................................................................................................................................................................................................
Keywords Heart failure • HFpEF • diagnosis • echocardiography • biomarkers • natriuretic peptides • exercise
echocardiography
..

Introduction .. Why new diagnostic
..
In the general population aged >_60 years, 4.9% were identified to
.. recommendations for heart
..
have heart failure with preserved ejection fraction (HFpEF),1 imply- .. failure with preserved ejection
ing several millions of affected individuals in Europe. This number
..
.. fraction?
is expected to increase further as people live longer and obesity ..
..
and diabetes become more common.1–3 Heart failure with pre- .. The key criteria in the previous HFA recommendations were: (i)
served ejection fraction already accounts for more than half of all .. symptoms and/or signs of HF, (ii) normal or only mildly abnormal LV
..
heart failure (HF) hospital admissions.1 Providing effective manage- .. systolic function, and (iii) LV diastolic dysfunction.4 Diagnostic param-
ment is a major unmet clinical need that will depend on a clear .. eters were invasive measurements, echocardiographic indices of LV
..
diagnosis. .. diastolic function and filling pressures, LV hypertrophy (LVH), left
The Heart Failure Association (HFA) of the European Society ..
.. atrial (LA) enlargement, serum natriuretic peptides (NP), and atrial
of Cardiology (ESC) published a consensus statement in 2007 .. fibrillation (AF).4 Over time, both advantages and disadvantages of
on ‘How to diagnose diastolic heart failure’.4 Since then, termin- ..
.. this approach have been reported.
ology has evolved through HF with normal ejection fraction .. Cut-offs for key non-invasive parameters are often based on lim-
(HFnEF) to the current definition as ‘HF with preserved ejec- ..
.. ited data, and may fall in a non-diagnostic intermediate range. The
tion fraction’.4 .. non-invasive diagnosis or exclusion of HFpEF will not depend on a
Additional diagnostic criteria for HFpEF have been published, ..
.. single parameter above or below a certain cut-off, but on a combin-
including one scoring system,5 but they differ in echocardiographic .. ation of parameters derived from clinical, laboratory, and imaging
cut-off values, the role of comorbidities, the inclusion of biomarkers,
..
.. tests that together will give a probability for the diagnosis. A recent
the role of invasive haemodynamic assessment, and the role of exer- .. example of such an approach was a composite HFpEF diagnostic
cise stress testing.3,4,6–8 Understanding of the pathophysiology of
..
.. score, derived retrospectively from clinical characteristics (age
HFpEF has advanced,9–13 diagnostic options have evolved,14–17 and .. >60 years, obesity, atrial fibrillation, treatment with >_2 antihyperten-
this novel information needs to be integrated into a new comprehen-
..
.. sive drugs) and echocardiographic measurements [E/e0 >9, pulmon-
sive diagnostic algorithm for suspected HFpEF. .. ary artery systolic pressure (PASP) >35 mmHg].5
A writing committee initiated by the HFA of the ESC has
..
..
therefore produced an updated consensus recommendation— ..
.. Echocardiographic criteria for diagnosing
the HFA–PEFF diagnostic algorithm (Figure 1). Its key elements ..
are (i) the concept that identification of HFpEF involves all lev- .. heart failure with preserved ejection
.. fraction
els of care, including general practitioners, internists, general ..
cardiologists, HF specialists, and invasive cardiologists; (ii) a .. Left ventricular ejection fraction (LVEF) estimates global function but
..
stepwise diagnostic approach from initial clinical assessment to .. does not indicate LV volume or stroke volume. Despite a preserved
more specialized tests will therefore be useful; (iii) the diagnosis .. LVEF, patients with HFpEF have impaired LV long-axis systolic func-
..
is not always straightforward, so the integration of distinct .. tion, which can be measured using mitral annular systolic excursion
parameters from complementary diagnostic domains into a new .. or systolic velocities or LV global longitudinal strain (GLS).19 As well
..
diagnostic score is recommended; (iv) for the subset of patients .. as global diastolic dysfunction, they have long-axis diastolic dysfunc-
with an inconclusive score, definitive diagnosis (or exclusion) .. tion which can be measured from the velocity of long-axis lengthen-
..
will require invasive haemodynamics and/or non-invasive or in- .. ing of the LV in early diastole (from mitral annular velocity, e0 ). These
vasive exercise stress tests; and (v) underlying pathophysiologic- .. were not considered in the previous HFA recommendations.4
..
al alterations (such as chronotropic incompetence, reduced LV .. A mean E/e0 index >_15 at rest has good diagnostic value for identi-
compliance) and specific aetiologies (such as amyloidosis18) .. fying a high mean pulmonary capillary wedge pressure (mPCWP),
..
have to be considered. A precise diagnosis is increasingly im- .. supporting the likelihood of HFpEF,20,21 but an E/e0 ratio within the
portant since new targeted therapies are becoming available for
.. intermediate range (9–14) is less sensitive.22 The E/e0 ratio has limita-
..
defined subsets of HFpEF patients. . tions that are relevant in routine clinical practice23–29 and its use as a
How to diagnose HFpEF 3299

Figure 1 HFA-PEFF diagnostic algorithm. Overview of the diagnostic heart failure with preserved ejection fraction steps 1–4 (P–F). CT, computed
tomography; PET, positron emission tomography.
..
single diagnostic index above all other non-invasive measures of filling ..
..
Defining aetiology and
pressures (such as retrograde pulmonary venous flow) cannot be
recommended. In consequence, HFpEF cannot be diagnosed from a
..
.. pathophysiology
single echocardiographic measure, and inclusion of recently validated ..
.. Heart failure with preserved ejection fraction typically evolves from a
functional and structural parameters into a diagnostic score may bet- .. combination of risk factors and comorbidities, including advanced
ter define this heterogeneous disorder. ..
.. age, female sex, obesity, systemic arterial hypertension, diabetes mel-
.. litus, renal dysfunction, anaemia, iron deficiency, sleep disorders, and
Usefulness of natriuretic peptides ..
.. chronic obstructive pulmonary disease.1,2,11,42–44 Heart failure with
In general, NP levels are higher in patients presenting with acute .. preserved ejection fraction ‘masqueraders’ such as heart valve dis-
shortness of breath for cardiac reason or in acute HF, than in
..
.. ease, arrhythmias, and pericardial constriction need to be excluded.
patients who have chronic HF.30,31 Of note, our recommendations .. Similarly, a patient with a normal LVEF and HF-like symptoms caused
target stable symptomatic HFpEF, and natriuretic peptide levels
..
.. by significant coronary artery disease (CAD) is also not considered
can be normal in these patients even with invasively confirmed .. to have HFpEF.
HFpEF. In consequence, normal NP levels do not exclude HFpEF,
..
.. Similar to current practice for heart failure with reduced ejection
especially in the presence of obesity.32,33 Interpretation depends .. fraction (HFrEF), we recommend applying the descriptive term
..
also on whether the patient is in sinus rhythm (SR) or has AF, .. HFpEF for both the classical form with typical risk factors and comor-
which itself is associated with increased NP levels even in the ab- .. bidities, and for rarer cases with a specific aetiology, provided that the
..
sence of HF.34,35 .. key diagnostic criteria are met. Specific aetiologies that may be treat-
Besides obesity, sex, age, and renal function affect NP levels,36,37 .. able include inherited or acquired infiltrative, restrictive, inflamma-
..
but using stratified cut-points only marginally improves diagnostic ac- .. tory, or genetic cardiomyopathies45–48 (Table 2). They should always
curacy (net reclassification index 3%),38 at the expense of less every- .. be considered once a diagnosis of HFpEF has been made (Table 2,
..
day utility. The variability of repeated measurements in individual .. Supplementary material online, S2–S4). It has been suggested that
patients is up to 100%, so a rise or fall of <_100% may not necessarily ..
.. patients with HFrEF share a common mechanism that responds to
indicate recovery or progression of disease.39,40 .. common treatment (inhibition of the renin-angiotensin system)3 but
..
.. there are other treatments for subsets of patients with HFrEF that
Diagnostic algorithms for heart failure .. are specific (such as treating ischaemia when there is hibernating myo-
..
with preserved ejection fraction .. cardium, using targeted antiviral therapy or immune modulation in in-
The concept of a diagnostic algorithm that incorporates imaging and .. flammatory HFrEF, and corticosteroid therapy in sarcoidosis-related
..
biomarkers (NPs) was recommended by the HFA in 2007,4 and .. HFrEF); in that respect, our proposed use of the generic term HFpEF
adapted by others.41 It allowed parallel diagnostic pathways starting .. is similar and should include specific myocardial aetiologies.
..
from haemodynamic measurements, echocardiography, or NPs,4 .. Basic mechanisms affecting the myocardium in HFpEF include
that could yield different results for the same patients. In addition, the .. myocyte hypertrophy, systolic and diastolic dysfunction, energetic
..
proportion of non-classifiable patients was substantial. Thus, our .. abnormalities, interstitial fibrosis, inflammation, increased oxidative
revised algorithm (see below) proposes a novel stepwise diagnostic
.. stress, endothelial dysfunction, and impaired density and autoregula-
..
approach that has only one entry point, and all patients will be .. tion of the microcirculation.9,10,12,45–48,154,155 Cardiovascular patho-
classifiable.
.. physiological processes include increased systemic vascular
resistance, increased conduit arterial stiffness, abnormal ventricular-

arterial coupling, reduced LV long-axis systolic function, slowed early
diastolic relaxation, reduced LV compliance with increased end-
diastolic stiffness, reduced LA reservoir and contractile function,
impaired right ventricular (RV) function, and chronotropic incompe-
tence.52,156–164 Patients often have reduced reserve of stroke vol-
ume, heart rate, and cardiac output (CO), and the increase in CO
relative to oxygen consumption is blunted.165 Heart failure with pre-
served ejection fraction patients typically have high LV filling pres-
sures, whether at rest and/or on exercise, and they may develop fluid
retention and an expanded plasma volume.28,159,164,166,167 All these
mechanisms might be targets for treatment.

In a meta-analysis, exercise capacity in HFpEF was related to chro-
notropic incompetence, high mPCWP, blunted augmentation of ar-
teriovenous oxygen-content difference (implying inadequate
perfusion of exercising skeletal muscles), reduced stroke volume re-
serve, and pulmonary hypertension.168 Changes in pulmonary artery
pressure (PAP) on exercise are determined by the interplay between
CO, PA compliance, pulmonary vascular resistance, and mPCWP.
The increase in PAP is flow-dependent so it is best reported in rela-
tion to the increase in CO; the upper limit of normal is þ3 mmHg/L/
min.169 There are haemodynamic differences between patients with
pre- and post-capillary pulmonary hypertension.164
We recommend that the pathophysiological phenotype(s) prevail-
ing in an individual HFpEF patient are determined, as that may allow
the selection of specific therapies (see diagnostic Step 4 below).
Figure 2 Flowchart of the HFA-PEFF diagnostic algorithm. Step P

The new Heart Failure is meant to identify patients with the potential diagnosis of heart fail-
ure with preserved ejection fraction, and exclude or identify other
Association diagnostic specific causes for their heart failure-like symptoms. Patients likely
to have heart failure with preserved ejection fraction are those with
recommendations typical demographics (e.g. elderly, female, and comorbidities), a pre-
The flowchart (Figure 2) provides an overview of the new diagnostic served left ventricular ejection fraction on a standard echocardiog-
raphy, and other easily detectable findings such as elevated
algorithm.
natriuretic peptides or atrial fibrillation. Alternative causes such as
coronary artery disease, significant valvular disease, pulmonary dis-
Step 1(P): Pre-test assessment ease, and anaemia should be excluded during this initial workup. If
Step 1(P) should be performed in any patient who presents with Step P is positive, the second Step E should be done, which includes
symptoms and/or signs compatible with a diagnosis of HF. It requires a comprehensive echocardiography and brain natriuretic peptide/
a detailed clinical and demographic history; an electrocardiogram N-terminal natriuretic peptide levels, if not already done on Step P.
(ECG); blood tests; standard echocardiography to exclude other Step F1 should be done, if Step E is inconclusive. Depended on clin-
causes such as HFrEF or heart valve disease; and investigations for is- ical facilities and patient conditions an invasive or non-invasive stress
chaemia, arrhythmias, anaemia, or pulmonary disease (Figure 2). NP test is recommended. However, the invasive stress test has a higher
validity and is an option, if the result of the non-invasive stress test is
levels can be obtained if the assay is available; elevated levels suggest
not conclusive. The fourth Step, Step F2 is designed to identify a spe-
heart disease but normal levels do not exclude HFpEF. Step 1(P) mir-
cific aetiology, if appropriate, when heart failure with preserved
rors the 2016 ESC HF guidelines concerning initial HF diagnostic ejection fraction has been diagnosed. For details of steps 2–4, see
workup.3 Figures 3–5.
Symptoms and signs

Breathlessness on exertion (New York Heart Association Class II or ..
III) is highly sensitive for a diagnosis of HF but only moderately specific .. Electrocardiographic abnormalities
(about 50%) for a cardiac cause.170 Orthopnoea is quite specific but .. Patients may have electrocardiographic features of LVH (such as a
..
relatively insensitive. Patients with HFpEF often report reduced exer- .. Sokolov-Lyon Index >_3.5 mV; abnormal repolarisation) and/or LA
cise capacity and fatigue, out of proportion to cardiac abnormalities .. enlargement, but there are no pathognomonic signs and the diagnos-
..
at rest. In elderly, overweight and deconditioned persons, poor exer- .. tic value of an ECG to identify HFpEF is poor.5 The most important
cise capacity, dyspnoea on exertion, and peripheral oedema may also
.. indication is to detect atrial fibrillation (AF), which is highly predictive
..
have a non-cardiac origin. . of underlying HFpEF.5,148
Laboratory tests
Table 1 Risk factors and findings consistent with
Several tests are recommended, including: sodium, potassium, urea, heart failure with preserved ejection fraction in a
and creatinine (with an estimated glomerular filtration rate); liver symptomatic patient
function tests; HbA1c (metabolic syndrome and type 2 diabetes are
common comorbidities); thyroid stimulating hormone; and full Early (age >_ 70 in men or >_ in women)
blood count, ferritin, transferrin saturation, and for anaemia. Anaemia Overweight/obesity
associated with HFpEF aggravates symptoms and exercise Metabolic syndrome/diabetes mellitus
intolerance.171,172 Physical inactivity/deconditioning
Arterial hypertension
Natriuretic peptides Atrial fibrillation
Multiple studies in primary care have shown that serum levels ECG abnormalities (beyond atrial fibrillation)
<125 pg/mL (or ng/L) for N-terminal pro-brain natriuretic peptide Elevated natriuretic peptide levels (if available, BNP >_ 35 pg/mL or

(NT-proBNP) or <35 pg/mL for BNP, have high negative predictive NT-proBNP >_ 125 pg/mL)
values (NPV; 95–99%) for excluding any heart failure.39,40,121,173–177
The main trigger for release of NPs is high LV end-diastolic wall
stress, which is inversely proportional to wall thickness. It is therefore
..
understandable that the excellent NPV of NPs is true particularly for .. (CMR) imaging, or myocardial scintigraphy, or an anatomical ap-
HFrEF with a dilated LV, but not necessarily for HFpEF where LVH .. proach using coronary computed tomography (CT) angiography or
..
tends to normalize wall stress. In consequence, it has become clear .. invasive angiography, should be considered if CAD is suspected.187
that up to 20% of patients with invasively proven HFpEF have NPs .. A stress test provides information about exercise capacity, the
..
below these diagnostic thresholds,28,178–180 which represents a limi- .. blood pressure response to exercise (which may be hypertensive),
tation to the use of NPs. Therefore, it is important to understand .. and the heart rate response. Chronotropic incompetence is present
..
that with our SCORE approach HFpEF can still be diagnosed even, if .. in 33–77% of HFpEF patients,188,189 and defined as the failure to reach
NP cut-offs (stratified by SR vs. AF) are below the given thresh- .. 70–80%188–190 of the predicted maximal heart rate. Reduced heart
..
olds’.28,178–180 .. rate recovery after exercise has prognostic value.191–193 Reduced ex-
.. ercise capacity can be defined as a peak workload <_75% of the value
..
Echocardiography .. predicted for age. In elderly patients with suspected HFpEF a 6-
.. minute walk test (6MWT) distance <_300 m can be considered abnor-
Standard echocardiography should be performed in every breathless ..
patient in whom there is clinical suspicion of HF, unless all the factors .. mal193 but 6MWT performance is affected by non-cardiac as well as
.. cardiopulmonary conditions.193,194
listed in Table 1 are absent or negative. Echocardiography may ex- ..
clude alternative causes of dyspnoea such as HFrEF, valve disease, pri- .. In selected cases, advanced cardiopulmonary exercise testing
..
mary pulmonary hypertension, or pericardial effusion.181,182 .. (CPET) with spiro-ergometry may be performed. Reduced exercise
Left ventricular ejection fraction should be measured, not esti- .. capacity is defined as a peak oxygen consumption (VO2 max)
..
mated, ideally from biplane or three-dimensional images. Only small .. <_20 mL/kg/min, and ventilatory inefficiency as a VE/VCO2 slope
variations in normal ranges for EF by age, gender, and ethnic group .. >_30.166,195 Cardiopulmonary exercise testing provides objective evi-
..
have been reported, so it is recommended that a single cut-point of .. dence of exercise capacity and may differentiate between cardiac and
>_50% is applied to define a ‘preserved’ EF. Left ventricular diameters .. non-cardiac causes (pulmonary, peripheral) for dyspnoea,157,166,196–200
..
and volumes should also be recorded. A diagnosis of HFpEF is sug- .. but its value to distinguish between HFpEF and non-cardiac causes
gested if there is a non-dilated LV with a normal EF, concentric .. may be limited.166 Cardiopulmonary exercise testing is not a typical
..
remodelling or LVH, and left atrial enlargement. Echocardiographic .. element in the initial HFpEF workup (see below).
findings at rest compatible with this HFpEF phenotype are often .. If HFpEF is suspected after Step 1(P), a more specific assessment
..
found in asymptomatic patients, who are at risk of progressing to .. may confirm or exclude the diagnosis (Step 2(E)).
overt HFpEF.183,184 Of note, the presence of structural alterations on
..
..
echocardiography supports, but its absence does not exclude HFpEF. ..
A more detailed or advanced echocardiographic study (see Step
.. Step 2(E): Echocardiographic and
..
2(E); Supplementary material online, S1) is not necessary at this step, .. natriuretic peptide heart failure with
but if it can be performed then only one examination will be needed.
.. preserved ejection fraction diagnostic
..
.. score
..
Exercise tests .. There is no single non-invasive diagnostic criterion for HFpEF so we
Coexisting epicardial stenotic coronary artery disease in patients ... recommend a combination of echocardiographic measurements of
with HFpEF impacts on mortality and should be detected and .. cardiac structure and function, and NP levels. Some may already be
..
treated.133 Coronary microvascular dysfunction is part of the HFpEF .. available from Step 1(P).
pathophysiology134 so non-invasive stress testing can give false- .. Many of these measurements are continuously distributed within a
..
positive results.134,186 Nonetheless, a bicycle or treadmill exercise .. population, from normal to possibly abnormal and to overtly abnor-
test, or tests with higher sensitivity to detect ischaemia such as
.. mal values. Diagnostic cut-points may vary according to age, gender,
..
dobutamine stress echocardiography, cardiac magnetic resonance . body weight, renal function, and the presence of atrial fibrillation.
Table 2 Potential specific aetiologies underlying heart failure with preserved ejection fraction-like syndromes in
Step 4 (F2)
Abnormalities of the myocardium

....................................................................................................................................................................................................................
lschaemic Myocardial post-infarction/scar49
Myocardial stunning50
Epicardial coronary artery disease51
Microvascular and endothelial dysfunction52,53–55
Toxic Recreational substance abuse Such as alcohol,56 cocaine,57 and anabolic steroids58
Heavy metals Such as iron,59 lead,60 cadmium,60 cobalt,61 copper (M. Wilson)62
Medications Such as chloroquine,63 ergotamine,64 cytostatic drugs (e.g. anthracy-
clines),64 immunomodulating drugs (e.g. interferons monoclonal

antibodies such as trastuzumab, cetuximab)64
Radiation Mean cardiac radiation doses > 3 Gy65,66
Immune and inflammatory Related to infection Such as cardiotropic viruses,67,68 HIV,69–71 hepatitis,72 helminths,73
parasites (e.g. Chagas’ disease74)
Not related to infection Lymphocytic myocarditis,75–79 autoimmune diseases (e.g. rheumatoid
arthritis,80 connective tissue disorders like scleroderma,81
M. Raynaud,55 systemic lupus erythematosus,82 dermato/polymyosi-
tis,83 and hypersensitivity and eosinophilic myocarditis73,84–87
Infiltrative Related to malignancy Direct infiltrations and metastases88–90
Not related to malignancy Amyloidosis,19,91 sarcoidosis,92,93 primarily and secondary haemo-
chromatosis,94–96 storage diseases97 (e.g. Fabry disease,98,99 Danon
disease,100–102 Pompe disease,99,102 PRKAG2 deficiency,99
Gaucher’s disease99)103,104,105,106
Metabolic Hormonal Such as thyroid diseases,107,108 parathyroid diseases,109 acromegaly,110
GH deficiency,111 Cushing disease,112 Conn’s disease,113 Addison
disease,114 phaeochromocytoma,115 pathologies related to preg-
nancy and peripartum116,117
Nutritional Such as deficiencies in thiamine,118 L-carnitine,119 selenium,120 (func-
tional) iron,121,122 complex malnutrition (e.g. AIDS, infections,73
anorexia nervosa73,123,124)
Genetic Diverse forms Such as HCM,97,125,126 restrictive cardiomyopathies,103,104,106 hyper-
trophic form of non-compaction cardiomyopathy,127,128
early forms of muscu-
lar dystrophies (Duchenne/Becker disease129).
Endomyocardial HES,84 EMF,71,127 endocardial fibroelastosis,128 carcinoid,130,131 endo-
cardial calcification (Paget’s disease132)
....................................................................................................................................................................................................................
Abnormalities of loading conditions
....................................................................................................................................................................................................................
Hypertension Primary and secondary forms of hypertension112,113,115,130,131
Valvular and structural defects Acquired Heart valve diseases133,134
Valvular and structural defects Congenital Septal defects132,135,136
Pericardial and endomyocardial pathologies Pericardial Constrictive pericarditis and pericardial effusion137,138
Endomyocardial HES,86 EMF,73,139 endocardial fibroelastosis,140 carcinoid,141,142 endo-
cardial calcification (Paget’s disease143)
High output states Severe anaemia,144 sepsis,145 thyrotoxicosis,105 arteriovenous fis-
tula,146 and pregnancy147
Volume overload Renal failure and fluid overload148,149,150
Abnormalities of the cardiac rhythm
Rhythm disorders Atrial/ventricular arrhythmias, pacing, conduction disorders38,151–153
EMF, endomyocardial fibrosis; GH, growth hormone; HCM, hypertrophic cardiomyopathy; HES, hypereosinophilic syndrome (formerly known as Löffler’s endocarditis); HIV/
AIDS, human immunodeficiency virus/acquired immune deficiency; LV, left ventricular; PRKAG2, protein kinase AMP-activated non-catalytic subunit gamma 2.
..
To take account of these factors, we recommend the use of major .. Average septal-lateral E/e0 ratio
and minor diagnostic criteria according to the severity of an abnor- ..
mality and the presence of modifiers. Major criteria (and cut-points)
.. Major criterion: average septal–lateral E=e0 ratio >_15
..
have been selected for their high specificity, while minor criteria ..
.. Minor criterion: average septal–lateral E=e0 ratio 9 -14
should be more sensitive. Cut-points were derived particularly from ..
studies that compared echocardiographic parameters against invasive .. The ratio of the peak velocity of mitral inflow during early diastole
..
haemodynamic data.5,28,166 .. (E), recorded by pulsed Doppler between the tips of the mitral leaf-
In one cohort with 64% prevalence of HFpEF determined by inva- .. lets, over the average of septal and lateral mitral annular early diastol-
..
sive measurements, the univariable sensitivity of septal e0 velocity .. ic peak velocities (e0 ) recorded by pulsed tissue Doppler, reflects the
<7 cm/s to diagnose HFpEF, without adjusting for age or other varia- .. mPCWP.41 The mitral E/e0 index correlates with LV stiffness and fi-
..
bles, was 46%, while its specificity was 76%.5 The sensitivity and speci- .. brosis20,21 and is less age-dependent than e0 .206 It also has diagnostic
ficity of an E/e0 ratio >9 were 78% and 59%, compared with 46% and .. value during exercise.28,158 The E/e0 index is little influenced by
..

86% for E/e0 >13. The sensitivity and specificity of LA volume index .. changes in volume but it is influenced by the severity of LVH.23,24
>30 mL/m2 were about 70%. Measurements of LV mass had low sen- ..
..
sitivity (26%) for HFpEF but high specificity (86%) if LVH was present. .. Tricuspid regurgitation peak velocity or
PAP >35 mmHg [derived from tricuspid regurgitation (TR) velocity] .. pulmonary arterial systolic pressure
..
was 46% sensitive and 86% specific for HFpEF,5 which makes it an im- ..
portant diagnostic criterion. The utility of GLS <16% was moderate
.. Major criterion: TR peak velocity >2:8 m=s
..
(sensitivity 62% and specificity 56%5).201 .. Major criterion: Pulmonary artery systolic pressure >35 mmHg
The utility of NP levels varies according to several factors including
..
..
cardiac rhythm. For NT-proBNP >275 pg/mL, a sensitivity of 59% .. Pulmonary arterial systolic pressure is calculated from the modified
and a specificity of 77% were reported (accuracy 68%).5 Sensitivity
.. Bernoulli equation as 4 peak TR velocity plus estimated right atrial
..
decreased to 46% while specificity increased to 85% if the cut-off was .. pressure. Elevated PASP and reduced RV function are important pre-
increased to >450 pg/mL (accuracy 66%). At our lowest recom-
.. dictors of mortality in HFpEF.207–211 Even a moderate increase in
..
mended cut-off of 125 pg/mL (minor criterion, if the patient is in sinus .. PASP can lead to increased ventricular interaction since a leftward
.. shift of the ventricular septum impedes LV filling.212 A PASP
rhythm), the sensitivity reported in that study was 77% and the speci-
... >35 mmHg discriminates HFpEF from hypertensives and controls.207
ficity 53% (accuracy 65%). Of note, 39% of patients in that study ..
were in AF or had a history of paroxysmal AF.5 Combining the results .. A TR peak velocity >2.8 m/s indicates increased PASP41,213 and is an
.. indirect marker of LV diastolic dysfunction.41
of E/e0 and NT-proBNP can increase their predictive value, notably ..
their sensitivity to diagnose HFpEF.202 ..
.. Left ventricular global longitudinal
..
Echocardiographic measurements of function and .. systolic strain
..
morphology ..
.. Minor criterion: GLS < 16%
In Step 1(P) we recommend standard echocardiography, at least to ..
assess LVEF and LV diameter. In Step 2(E) we recommend more .. Left ventricular peak systolic GLS is not angle-dependent, unlike
detailed echocardiographic measurements (Supplementary material
.. myocardial velocities recorded by tissue Doppler.186 It is measured
..
online, S1). These could all be obtained during a single study. The .. using speckle-tracking echocardiography as the average of systolic
echocardiographic criteria in the HFA–PEFF score, listed below, mir-
..
.. strain obtained from all LV segments in the apical 4-chamber, apical
ror consensus recommendations for the diagnosis of LV diastolic .. 2-chamber, and apical long-axis views.214
function.41
..
.. Reduced LV longitudinal systolic strain and LV early diastolic strain
.. rate have both been identified in HFpEF.19,215,216 Impaired GLS pre-
..
Septal and lateral mitral annular peak early diastolic velocity (e0 ) .. dicts HF hospitalization, cardiovascular death, or cardiac arrest.216,217
.. It correlates with invasive measurements of LV stiffness and with NP
Major criterion: septal e0 <7 cm=s; or lateral e0 <10 cm=s
..
.. levels.19,204,218 All strain values are dimensionless and are expressed
.. as percentages. For ease of use in these recommendations, we sug-
½subjects aged <75 years ..
.. gest a cut-point of 16% in absolute values;219–222 and a value below
Major criterion: septal e0 <5 cm=s; or lateral e0 <7 cm=s .. 16% (e.g. 14%) is recommended as a minor criterion.
..
½subjects aged >_75 years ...
.. Left atrial volume index
The main determinant of e0 , the early diastolic velocity of mitral annu- ..
lar motion, is LV relaxation. It reflects LV lengthening and is influ- .. Major criterion: >34 mL=m2 ½in sinus rhythm
..
enced by preload.203,204 Left ventricular longitudinal e0 velocity ..
.. Major criterion: >40 mL=m2 ½in atrial fibrillation
declines with age;205 normative ranges reported from elderly partici- ..
pants were found to be lower than those given in the 2007 HFA con- .. Minor criterion: 29-34 mL=m2 ½in sinus rhythm
sensus.206 We include age-specific e0 criteria in the HFA–PEFF score,
..
.. Minor criterion: 34–40 mL=m2 ½in atrial fibrillation
measured as recommended.41 .
The maximal volume of the LA, measured at end-systole from bi- .. Minor criterion: NT-proBNP 125–220 pg=mL; or
plane or three-dimensional images and indexed to body surface area .. BNP 35–80 pg=mL ½in sinus rhythm
[left atrial volume index (LAVI)] is an indirect correlate of LV filling
..
..
pressures.41 It is more accurate as a marker of chronic LA remodel- .. Minor criterion: NT-proBNP 375–660 pg=mL; or
..
ling than either LA area or diameter223–225 and it correlates with ..
BNP 105–240 pg=mL ½in atrial fibrillation
other echocardiographic indices of LV diastolic function.226 A LAVI ...
of 29–34 mL/m2 is considered as a minor criterion since it represents .. In Step 1(P), a single low cut-point was recommended in order to
..
the upper limit in healthy subjects.227,228 .. have a sensitive marker for cardiac abnormalities. In this step, in order
In patients without AF or heart valve disease, LAVI >34 mL/m2 in- ..
.. to increase specificity, a higher cut-off value is recommended as a
dependently predicts death, heart failure, AF, and ischaemic .. major criterion, in agreement with ESC guidelines.3 Cut-offs are also
stroke.229–231 In patients with HFpEF and permanent AF, LAVI was ..
.. stratified for the presence of SR or AF.
35% more enlarged than it was in HFpEF patients in SR.34 Patients .. Natriuretic peptide levels should always be interpreted in con-
..

with permanent AF may have a large LAVI even if they have no LV .. text.180 Definitive cut-offs to diagnose HFpEF in patients with SR or
diastolic dysfunction.34,41 We therefore recommend separate cut- .. in AF are not well established, and trials have used different val-
offs for LAVI in SR vs. AF. ..
.. ues.237,238 In the setting of screening, average NPs have been
.. reported to be 3–3.5 fold higher in patients with AF than in patients
Left ventricular mass index and relative ..
.. in SR.239 Average NPs were found to be threefold higher in patients
wall thickness .. with AF than in patients in SR.34,35,240 In prevalent symptomatic
..
.. HFpEF with AF, levels tend to be even higher.241 For diagnosing
Major criterion: LVMI >_149 g=m2 in men or >_122 g=m2 ..
.. HFpEF, we hence recommend values in patients with AF that are
in women and RWT >0:42 .. three times higher than used for patients in SR.
..
Minor criterion: LVMI >_115 g=m2 in men or >_95 g=m2 in women ..
..
or RWT >0:42 or LV end-diastolic wall thickness >_12 mm ..
.. Calculating and interpreting the
..
Increased LV diastolic wall thickness in a non-dilated heart implies .. HFA–PEFF score
that the patient has LVH. It develops first in the basal segments of the ..
.. The score has functional, morphological, and biomarker domains.
ventricular septum,232 and a wall thickness >_12 mm at that site is ..
common in elderly people. Localized septal hypertrophy may be a .. Within each domain, a major criterion scores 2 points or a minor cri-
.. terion 1 point (Figure 3; Supplementary material online, Table S1).
consequence of abnormal ventricular–arterial coupling but it is not ..
sufficient to indicate that there is significant global LV remodelling or .. Each domain can contribute maximally 2 points, if any major criterion
.. from this domain is positive, or 1 point if no major but any minor cri-
hypertrophy. ..
Left ventricular geometry is often classified using relative wall .. terion is positive. If several major criteria within a single domain are
.. positive, this domain still contributes 2 points; and if no major but sev-
thickness (RWT), calculated as twice the LV posterior wall thickness ..
divided by the LV internal diameter at end-diastole (LVPW 2/ .. eral minor criteria are positive the contribution still is 1 point. Major
.. and minor criteria are not additive in a single domain. Points are
LVIDD), and using left ventricular mass index (LVMI) normalized to ..
body surface area or height. Four patterns are described: normal
.. added only when they come from different domains.
.. For example, 2 major (E/e0 >15, and TR >2.8 m/s) and 1 minor
(normal LVMI, RWT <_0.42), concentric remodelling (normal LVMI, ..
RWT >0.42), concentric hypertrophy (increased LVMI, RWT
.. (GLS <16) criteria, all in the functional domain, will lead to a total
..
>0.42), and eccentric hypertrophy (increased LVMI, RWT .. score from that domain of 2 points. The total score would be 5, if at
<_0.42).41,233,234 In patients with HFpEF, both concentric LVH and
.. least one minor criterion (LAVI <34 mL/m2; LV wall thickness
..
concentric remodelling can be observed.235 .. >12 mm) and one major criterion (BNP in SR >80 pg/mL) would be
The absence of LVH on echocardiography does not exclude
.. present coming from the morphological and biomarker domains, re-
..
HFpEF.5 We therefore recommend the finding of concentric hyper- .. spectively. It is important to understand that not all parameters from
.. each domain need to be recordable (which is typically the case). The
trophy (increased LVMI and increased RWT) as a major criterion, or ..
any one of a lesser degree of LVH, RWT, and LV end-diastolic wall .. HFA-PEFF score can be calculated even if not all parameters are
.. obtained, which adds to the practical utility of the score.
thickness as a minor criterion.227,234,236 ..
.. A total score >_5 points is considered to be diagnostic of HFpEF,
.. while a score of <_1 point is considered to make a diagnosis of HFpEF
Natriuretic peptides ..
.. very unlikely and to mandate investigations for alternative causes.
Major criterion: NT-proBNP >220 pg=mL; .. Patients with an intermediate score (2–4 points, Figures 2 and 3) need
..
or BNP >80 pg=mL ½in sinus rhythm .. further evaluation (Step 3(F1); Figures 4A,B).
.. If LAVI, LVMI, or wall thickness cannot be assessed by echocardi-
..
Major criterion: NT-proBNP >660 pg=mL or .. ography, we recommend using measurements obtained from CMR
.. imaging instead. Of note, there are some systematic differences in
BNP >240 pg=mL ½in atrial fibrillation ..
. measurements of LV volumes and LVEF between imaging

Figure 3 Step 2 (E): Echocardiographic and natriuretic peptide heart failure with preserved ejection fraction workup and scoring system (diagnos-
tic workup).
..
modalities.242 In one comparative study, LV volumes were larger and .. Many patients with HFpEF have symptoms mainly on exertion that
LVEF was lower but not statistically different with CMR compared .. are usually attributed to the increase in LV filling pressures which is
..
with other imaging modalities.243 .. needed to maintain adequate filling and stroke volume.159,249
.. Acquiring echocardiographic data during exercise can unmask LV dia-
..
Step 3 (F1): Functional testing .. stolic and systolic dysfunction. The parameters that have been
.. studied most often, during or immediately after exercise, are the mi-
Symptoms compatible with HF can be confirmed to originate from ..
.. tral E/e0 ratio and the TR peak velocity, which indicate increases in
the heart if haemodynamic abnormalities such as reduced stroke vol- .. mPCWP and PASP, respectively.28,41,244–248,250
ume, reduced CO, and elevated LV filling pressures are detected ei- ..
.. Ideally a semi-supine bicycle test with imaging during exercise, or
ther at rest or during exercise. In a typical elderly patient with .. else a treadmill or upright bicycle exercise protocol with imaging
multiple comorbidities, the presence or absence of isolated cardiac ..
.. at or immediately after peak stress, is recommended41,244 but
structural and/or functional abnormalities at rest does not always es- .. there are no universally adopted protocols. The European
tablish or exclude the diagnosis of HFpEF. If invasive testing demon- ..
.. Association of Cardiovascular Imaging and the American Society of
strates a high LV filling pressure [left ventricular end-diastolic ..
.. Echocardiography recommend a stepped protocol, starting at
pressure (LVEDP) >_16 mmHg, PCWP >_15 mmHg] at rest, then the .. 25 W at 60 r.p.m. with the load increasing by 25 W every 3 min
diagnosis may be confirmed; otherwise, assessment during exercise is ..
recommended, either by non-invasive exercise stress echocardiog- .. until the patient has reached his maximal predicted workload and/
.. or maximal predicted heart rate (220—age in years) and/or devel-
raphy or by invasive haemodynamics (Figures 2 and 4A,B). ..
.. oped limiting symptoms.244 Some patients cannot perform that
.. protocol, and a ramped exercise test on a semi-supine bicycle at
..
Exercise stress echocardiography: the diastolic stress test .. 60 r.p.m. starting at 15 W and with increments of 5 W every mi-
During exercise in healthy people, enhanced LV untwisting and early .. nute has also been proposed, to a submaximal target heart rate of
..
diastolic suction maintain or increase stroke volume despite shorten- .. 100–110/min or until the patient develops limiting symptoms.245
ing of the filling time and without increasing LV filling pressures. In .. None of these protocols have been shown to be superior to
..
patients with HFpEF, impaired early diastolic relaxation, reduced .. others.
increments in suction, and poor LV compliance lead to inadequate .. The mitral E/e0 ratio and peak TR velocity should be acquired at
..
increases in stroke volume and CO on exercise, increased LV filling .. baseline, during each stage including peak exercise, and during a
pressures, and increased PASP.28,41,244–248 High LV filling pressures
.. submaximal stage before fusion of the mitral E and A velocities213
..
and inadequate CO responses during exercise can also impair RV .. or during the first 2 min of the recovery phase when mitral E and A
reserve.52
.. velocities are no longer fused and LV filling pressures remain

Figure 4 Step 3 (F): Functional tests in cases of diagnostic uncertainty. (A, upper panel) It shows the diastolic stress test workup with exercise
echocardiography is shown. If key haemodynamic abnormalities are identified, a definite heart failure with preserved ejection fraction diagnosis can
be made. (B, lower panel) It shows the invasive haemodynamic measurements at rest (left) or during exercise (right) that may complement stress
echocardiography and are recommended in cases with remaining diagnostic uncertainty.
elevated.41,244 Changes in CO can be assessed by measuring

.. during submaximal exercise (20 W) and in about 20% of HFpEF
..
the velocity integral of flow in the LV outflow tract, multiplied .. patients during peak exercise, and that TR velocity was measurable in
by the HR.
.. only 50%; about 20% of controls were considered to have false-posi-
..
Exercise echocardiography should be considered abnormal if .. tive tests.28 Data from stress echocardiography are not sufficient to
..
average E/e0 ratio at peak stress increases to >_15, with or without .. substitute for invasive haemodynamic data under all circumstances. If
a peak TR velocity >3.4 m/s.28,41,244 An increase only in TR velocity .. the score remains <5 points or if exercise echocardiography cannot
..
should not be used to diagnose HFpEF because it might be caused .. be performed, we recommend an invasive haemodynamic stress test
simply by a normal hyperdynamic response to exercise (with .. in any case of doubt, especially if a therapeutic decision depends on
..
increased pulmonary blood flow) in the absence of LV diastolic .. the results.
dysfunction.251 ..
..
An average E/e0 ratio during exercise >_15 adds 2 points to the ..
HFA–PEFF score. An average E/e0 ratio >_15 with a peak TR velocity .. Invasive haemodynamic tests at rest and with exercise
..
>3.4 m/s adds 3 points to the previous score from Step 2(E). If the .. Left ventricular end-diastolic pressure LVEDP in the resting supine
combined score from Step 2(E) and Step 3(F1) is >_5 points, then the .. position is typically obtained in the context of left heart catheteriza-
..
diagnosis of HFpEF can be confirmed. .. tion and bears important diagnostic information in the workup of un-
However, echocardiographic stress tests also have limitations. It .. explained dyspnoea. In selected patients, LV compliance and stiffness
..
was reported that E/e0 was not measurable in about 10% of subjects . can be determined directly by using a multiple-loop conductance
..
catheter to record the end-diastolic pressure–volume relationship .. Step 4(F2): Final aetiology
(EDPVR) during preload reduction, giving a volume-independent par- .. Most cases of HFpEF are related to common risk factors and comor-
..
ameter for LV stiffness (constant of chamber stiffness, b, normal .. bidities, but the possibility of a specific underlying aetiology should al-
<0.27252).21,159,253–255 Invasive demonstration of impaired LV relax- ..
.. ways be considered (Table 2, Supplementary material online, Tables
ation at rest, measured by high-fidelity pressure catheters as the time .. S2–S4; Figure 5A,B). We postulate that identification of specific HFpEF
constant of LV relaxation (tau, s > 48 ms4) or of elevated LV filling ..
.. aetiologies will advance the field of targeted therapies.
pressures at rest (LVEDP >_16 mmHg) confirms definite evidence of .. Specific heart muscle diseases that may present with
HFpEF. ..
.. the HFpEF phenotype include hypertrophic cardiomyopa-
Right heart catheterization should be considered for the struc- .. thies,125,264–266 myocarditis and chronic inflammatory cardiomyop-
tured workup of suspected HFpEF, especially when left heart pres- ..
.. athy,67,75–77,97,137,267,268 autoimmune diseases,78,79 non-infiltrative
sures are not available. When resting mPCWP, measured using a .. and infiltrative cardiomyopathies,83,125 idiopathic or acquired endo-
Swan-Ganz catheter, is elevated in the presence of a normal LV end- ..
.. myocardial fibrosis,269 storage diseases,125,269 and other genetic dis-

diastolic volume index, then usually LV end-diastolic distensibility is .. orders including early stages of cardiomyopathies associated with
reduced. A resting mPCWP >_15 mmHg3 confirms definite evidence ..
.. muscular dystrophy.103 Rare causes such as toxicity from drugs or
of HFpEF. .. heavy metals, radiation, and metabolic causes related to hormonal or
However, normal LVEDP or mPCWP levels at rest do not exclude
..
.. nutritional disease, should also be considered (Table 2). The trigger
HFpEF. In compensated HFpEF, haemodynamic alterations may be .. may occur long before the onset of symptoms. For instance
detected only during exercise or when the patient deterio-
..
.. radiation-induced HFpEF develops after 10–15 years, even when low
rates.28,179,230,256,257 Also, volume depletion or intensified diuretic .. mean cardiac radiation doses of 3.3 Gy are used.104,129
treatment may shift the diastolic pressure–volume relationship to the
..
.. Aetiological workup may include a standard exercise stress test
left, without changing LV compliance (dV/dP; the inverse of LV stiff- .. that may identify myocardial ischaemia, an abnormal blood pressure
..
ness252) If resting filling pressures are normal, exercise right heart .. response to exercise, chronotropic incompetence, or supraventricu-
catheterization is recommended for the definite workup of unex- .. lar and ventricular arrhythmias (Figure 5A; Supplementary material
..
plained exertional dyspnoea,179 especially if the patient has an inter- .. online, S2). These findings can immediately translate into manage-
mediate Score in Step 2(E) or if exercise echocardiography is .. ment strategies, such as anti-ischaemic therapy, improved blood
..
inconclusive or not feasible (Figures 2 and 4B). Specialized centres .. pressure control, removal of bradycardic agents (such as beta-
may perform exercise right heart catheterization upfront in the ab- ..
.. blockers often prescribed for hypertension), and control of exercise-
sence of exercise echocardiography, depending on the individual ex- .. induced cardiac arrhythmias.
perience of the site. ..
.. More sophisticated tools for aetiological workup include CMR
During supine exercise in healthy control subjects, cut-offs for .. which is most accurate for determining LA and LV volumes and
peak PCWP and LVEDP are <20–23 mmHg258,259 and <25 ..
.. mass,270 detects scar and myocardial ischaemia due to epicardial cor-
mmHg,260,261 respectively. Patients with values <25 mmHg during .. onary disease or microvascular dysfunction,65 and stress perfusion
peak exercise are classified as having non-cardiac dyspnoea. A ..
.. imaging to reveal diffuse subendocardial defects. Regional and diffuse
steep increase in PCWP during exercise is a typical haemodynamic .. myocardial oedema (T2-imaging) and infiltration or fibrosis are quan-
response in HFpEF,256,262 indicating that the dyspnoea on exertion ..
.. tified using late gadolinium enhancement [LGE; for extracellular vol-
is mainly of cardiac origin. Patients with peak exercise PCWP .. ume fraction (ECV)] or T1-mapping137,267,271–274 (Supplementary
>_25 mmHg are classified as having HFpEF (Supplementary material
..
.. material online, Table S3). Right or left ventricular myocardial biopsy,
online, S2). An increase in LV filling pressure during exercise that is .. (99m)Tc-DPD scintigraphy to identify cardiac amyloidosis, positron
not accompanied by increases in end-diastolic volume, indicates
..
.. emission tomography (PET)-CT, as well as specific genetic and la-
limitation to LV filling or the development of pericardial .. boratory tests (Figure 5B) should be considered in selected cases
constraint.256
..
.. where a specific aetiology is suspected.
A high resting mPCWP and a pathological increase in mPCWP .. Of note, we do not intend to lump together all causes of the clinic-
during exercise predict poor outcomes from HFpEF.168,249,263
..
.. al syndrome of heart failure with a normal ejection fraction under the
Patients with a normal mPCWP at rest (<12 mmHg) but a steep in- .. term ‘HFpEF’, but instead to stress the importance to always consider
..
crease during exercise (to >_25 mmHg) have a two-fold increase in .. specific aetiologies if the clinical diagnosis of HFpEF is made. It is also
mortality.263 Ten-year mortality was 6.6% if resting mPCWP was .. important to understand that non-myocardial aetiologies (Table 2)
..
<_12 mmHg and peak exercise mPCWP was <25 mmHg; 28.2% in .. that may mimic HFpEF, such as constrictive pericarditis, primary
patients with low mPCWP at rest and high exercise mPCWP; and ..
.. valvular heart disease, or high output failure should not be considered
35.2% in those with high resting mPCWP and high peak exercise .. part of the HFpEF syndrome.
mPCWP (>_25 mmHg).263 ..
..
Exercise mPCWP reclassifies patients with a normal resting ..
mPCWP and stratifies risk. If other investigations have been inconclu- .. Limitations, gaps in evidence, and
..
sive, invasive measurement of mPCWP or LVEDP is considered as .. unanswered questions
the clinical reference investigation for diagnosing HFpEF28 (see .. Heart failure with preserved ejection fraction is a clinical syndrome
..
Supplementary material online, S7 about how to perform an invasive .. with multiple contributing factors, aetiologies, and pathophysiological
stress test). Other causes such as significant CAD, mitral stenosis, or .. expressions.168,275 It is a limitation that we suggest an algorithm that
..
pericardial constriction must be excluded. . reduces it to a single clinical diagnosis. Future studies should evaluate

Figure 5 Step 4 (F2): Final aetiological workup. (A) It shows the role of ergometry to detect underlying causes such as inadequate blood pressure
response, chronotropic incompetence, or myocardial ischaemia during exercise. (B) It shows the aetiological workup using cardiac magnetic reson-
ance (CMR). CT, computed tomography; PET, positron emission tomography.
and refine the recommended diagnostic algorithm and classify HFpEF

.. real-time non-invasive assessments of chamber volumes, stroke vol-
..
patients into specific subgroups. Ideally, a large and unselected sample .. umes, and CO, as well as filling pressures, in combination with in-
of breathless patients, and age-matched controls, would undergo all
.. novative markers of systolic and diastolic function, will markedly
..
tests including echocardiography and the ‘gold standard’ invasive .. reduce the significance of LVEF in characterizing HF.
haemodynamic assessment.
.. We have recommended exercise testing as a component of the
..
The stage and severity of HFpEF may impact on the accuracy of a .. diagnostic workflow in cases of uncertainty, but there is no consensus
..
specific diagnostic parameter. In a recent trial 45% of patients had .. yet about which stress protocol should be used or which measure-
‘early’ HFpEF with normal filling pressures at rest, and elevated filling .. ments are most important. It is uncertain if a simple parameter such
..
pressures only during invasive haemodynamic exercise testing.5 .. as the 6MWT distance could be as useful as detailed cardiopulmon-
Because of the intermittent diastolic pressure overload in early .. ary stress testing, which can be difficult to perform in breathless eld-
..
HFpEF, LAVI may be smaller (and less diagnostic), and functional indi- .. erly subjects.193
ces such as global LA strain or LA conduit strain might be more ap- .. Besides increases in filling pressures, HFpEF patients may be
..
propriate diagnostic parameters.276 In consequence, the patient mix .. haemodynamically limited by their inability to adequately enhance
under investigation may affect the test results. Prospective testing .. stroke volume during exercise,165,278,279,283 but no cut-points
..
and retesting in distinct HFpEF patients populations is needed to sort .. have been published to diagnose the resulting impaired reserve of
this out. .. CO. Unfortunately, reliable data on LV diastolic properties,
..
The diagnosis of HF is still based on LVEF, partly for historical rea- .. stroke volume, and CO can currently only be obtained invasively,
sons and despite its limitations277 for predicting cardiac functional re- .. ideally by conductance catheterization. 3D echocardiography
..
serve and symptoms. Exercise capacity correlates better with long- .. and CMR is now reaching a state where pressure–volume loops
axis functional reserve of the LV52,278–281 and with peripheral blood .. and stroke volumes can be obtained non-invasively,20,284 but
..
flow282 than with LVEF. In fact, a preserved LVEF has no diagnostic .. these measurements still await validation in broader HFpEF
role for HFpEF except to exclude HF with reduced LVEF. In future,
.. cohorts.
..
It will be important not just to confirm the diagnosis using the scor- .. reviewing panels provided declaration of interest forms for all rela-
ing system that we propose, but to document which specific abnor- .. tionships that might be perceived as real or potential sources of con-
..
malities correlate with individual responses to treatment, in order to .. flicts of interest. Figures were drawn by Medical Visuals, Maartje
dissect out specific pathophysiological mechanisms that need differ- .. Kunen.
..
ent treatments.285,286 We recommend that future HFpEF studies and .. Conflict of interest: Dr B.P. has received research funds from
registries should collect, record, and analyse the detailed compo- ..
.. Bayer Healthcare, Servier, and Astra-Zeneca, as well as speakers hon-
nents that are included in the HF–PEFF Score. .. oraria/committee membership fees from Novartis, Bayer Healthcare,
There is a close relationship between HFpEF and AF. There is ..
.. Daiichi-Sankyo, MSD, Stealth Peptides, Astra-Zeneca, Sanofi, Vifor,
overlap in symptoms, signs, echocardiographic findings, and NP levels .. and Servier. Dr R.A.d.B. is supported by the Netherlands Heart
between the two conditions, and a substantial proportion of patients ..
.. Foundation (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-
in HFpEF registries and trials have AF. We have provided distinct ..
diagnostic thresholds for NP and LAVI in SR vs. AF, based on existing .. HF, grant 2017-21, and CVON RED-CVD, grant 2017-11); and the
.. Innovational Research Incentives Scheme program of the

literature and consensus. These thresholds need more prospective ..
research for their validation. In addition, other functional measures .. Netherlands Organization for Scientific Research (NWO VIDI, grant
.. 917.13.350). The UMCG, which employs Dr De Boer has received
are also likely to be affected by concomitant AF. Of note, we did not ..
adopt the alternative view that AF per se could be used as a stand-
.. research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers
.. Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. Dr
alone indicator of HFpEF, but we again emphasize the close associ- ..
ation between AF and HFpEF.
.. R.A.d.B. received personal fees from MandalMed Inc., Novartis, and
.. Servier. Dr A.A.V. has received consultancy fees and/or research
There is controversy about the best non-invasive indicators of ele- ..
vated LV filling pressures and mPCWP.287 The E/e0 index has gained a
.. grants from Amgen, Bayer, Boehringer Ingelheim, Merck/Merck Sharp
.. & Dohme, Novartis, Roche Diagnostics, Sanofi Aventis, Servier,
supremacy in clinical practice that is not fully supported by all clinical ..
.. Stealth Peptides, Singulex, Sphingotec, Trevena, and Vifor. Dr C.T.
investigations.288,289 The diagnostic utility of alternative indices such .. received research grants from Novartis and speaker fees from Astra
as retrograde pulmonary venous flow,290,291 estimated LV stiffness ..
.. Zeneca, Berlin Chemie, Akcea, Impulse Dynamics, Servier, Bayer,
(diastolic pressure–volume quotient),284 and left atrial strain rate dur- .. Pfizer, Abbott, Boston Scientific. Dr S.D.A. has received consultancy
ing atrial contraction74,161,276,292 in patients in sinus rhythm, and the L ..
.. fees and/or research grants from Abbott Vascular, Bayer, Boehringer
wave of mitral inflow293 and left atrial strain during reservoir func- .. Ingelheim, Brahms, Novartis, Servier, Stealth Peptides, and Vifor. Dr
tion160,294 in patients in AF, merit further investigation. ..
.. C.S.L. is supported by a Clinician Scientist Award from the National
Modern imaging methods generate a huge quantity of digital data .. Medical Research Council of Singapore; has received research sup-
about global and regional left ventricular morphology and function ..
.. port from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca,
throughout the cardiac cycle, and about arterial and endothelial func- .. Medtronic, and Vifor Pharma; has served as consultant or on the
tion and myocardial perfusion, which can be coupled with compre- ..
.. Advisory Board/ Steering Committee/ Executive Committee for
hensive demographic data including traditional risk factors and new .. Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic,
biomarkers and with proteomic, metabolomic, and genomic data. ..
.. Vifor Pharma, Novartis, Amgen, Merck, Janssen Research &
Making sense of all this information is a challenge that can likely be ..
met by machine learning. Recent studies suggest that it may be useful .. Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk,
.. Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare,
for diagnosis and for defining pathophysiology,15,295,296 but long-term ..
studies in large populations are needed to unravel which features
.. Biofourmis, Darma, Applied Therapeutics, MyoKardia, WebMD
.. Global LLC, Radcliffe Group Ltd and Corpus. Patent pending: PCT/
best predict clinical outcomes and responses to treatment. ..
Molecular phenotyping for a better identification of distinct HFpEF
.. SG2016/050217. Co-founder & non-executive director: eKo.a; Dr
.. W.J.P. is supported by grants from CardioVasculair Onderzoek
phenotypes is emerging and may also help to develop targeted ..
therapies.
.. Nederland (CVON), Dutch Heart Foundation, The Hague, The
.. Netherlands (RECONNECT, EARLY-HFPEF). Dr E.N. has received
..
.. research grants from Bayer AG and fees/speaker honoraria from
.. Bayer AG and Siemens Healthiness. Dr F.E. reports personal fees
Supplementary material ..
.. from Novartis, grants and personal fees from Boehringer Ingelheim,
.. personal fees from CVRx, Pfizer, Medtronic, Resmed, grants and per-
Supplementary material is available at European Heart Journal online. ..
.. sonal fees from Servier, from MSD, Bayer, Vifor, Berlin Chemie. Dr
.. E.P.-K. reports research grants and consulting fees from Bayer
Acknowledgements ..
.. Healthcare and MSD. Dr G.F. received research grants from the
We acknowledge the continuous support of the Heart Failure .. European Union and is Committee member of trials and registries
Association (HFA) for this manuscript. Members of this Task Force ..
.. sponsored by Novartis, Medtronic, BI, Vifor, Servier, Bayer. The
were selected by the HFA Board and HFA HFpEF Committee to .. remaining authors have no conflicts of interest to declare.
represent professionals involved with the medical care of patients ..
..
with HFpEF. Selected experts in the field undertook a comprehensive ..
review of the published evidence for diagnosis of HFpEF according to .. References
.. 1. van Riet EE, Hoes AW, Wagenaar KP, Limburg A, Landman MA, Rutten FH.
the ESC Committee for Practice Guidelines (CPG) and HFA policy. ..
A critical evaluation of suggested procedures was done by all authors
.. Epidemiology of heart failure: the prevalence of heart failure and ventricular
.. dysfunction in older adults over time. A systematic review. Eur J Heart Fail 2016;
and accepted after consensus. The experts of the writing and . 18:242–252.
2. Seferovic PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, .. Investigators P. Impaired systolic function by strain imaging in heart failure with
Paulus WJ, Komajda M, Cosentino F, de Boer RA, Farmakis D, Doehner W,
.. preserved ejection fraction. J Am Coll Cardiol 2014;63:447–456.
..
Lambrinou E, Lopatin Y, Piepoli MF, Theodorakis MJ, Wiggers H, Lekakis J, .. 20. Kasner M, Westermann D, Steendijk P, Gaub R, Wilkenshoff U, Weitmann K,
Mebazaa A, Mamas MA, Tschope C, Hoes AW, Seferovic JP, Logue J, .. Hoffmann W, Poller W, Schultheiss HP, Pauschinger M, Tschope C. Utility of
McDonagh T, Riley JP, Milinkovic I, Polovina M, van Veldhuisen DJ, Lainscak M, .. Doppler echocardiography and tissue Doppler imaging in the estimation of dia-
Maggioni AP, Ruschitzka F, McMurray J. Type 2 diabetes mellitus and heart fail- .. stolic function in heart failure with normal ejection fraction: a comparative
ure: a position statement from the Heart Failure Association of the European .. Doppler-conductance catheterization study. Circulation 2007;116:637–647.
Society of Cardiology. Eur J Heart Fail 2018;20:853–872. .. 21. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kuhl U, Schultheiss HP,
3. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, .. Tschope C. Diastolic tissue Doppler indexes correlate with the degree of colla-
Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C,
.. gen expression and cross-linking in heart failure and normal ejection fraction.
..
Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, .. J Am Coll Cardiol 2011;57:977–985.
Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M, Document R. .. 22. Sharifov OF, Schiros CG, Aban I, Denney TS, Gupta H. Diagnostic accuracy of
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic .. tissue Doppler index E/e’ for evaluating left ventricular filling pressure and dia-
heart failure: the Task Force for the diagnosis and treatment of acute and .. stolic dysfunction/heart failure with preserved ejection fraction: a systematic re-
chronic heart failure of the European Society of Cardiology (ESC). Developed .. view and meta-analysis. J Am Heart Assoc 2016;5:e002530.
with the special contribution of the Heart Failure Association (HFA) of the .. 23. Donal E, Galli E, Fraser AG. Non-invasive estimation of left heart filling pres-
..

ESC. Eur J Heart Fail 2016;18:891–975. sures: another nail in the coffin for E/e’? Eur J Heart Fail 2017;19:1661–1663.
..
4. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers .. 24. Mitter SS, Shah SJ, Thomas JD. A test in context: E/A and E/e’ to assess diastolic
FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbely A, Edes .. dysfunction and LV filling pressure. J Am Coll Cardiol 2017;69:1451–1464.
I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, .. 25. Lancellotti P, Galderisi M, Edvardsen T, Donal E, Goliasch G, Cardim N, Magne
Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement .. J, Laginha S, Hagendorff A, Haland TF, Aaberge L, Martinez C, Rapacciuolo A,
on the diagnosis of heart failure with normal left ventricular ejection fraction by .. Santoro C, Ilardi F, Postolache A, Dulgheru R, Mateescu AD, Beladan CC,
the Heart Failure and Echocardiography Associations of the European Society .. Deleanu D, Marchetta S, Auffret V, Schwammenthal E, Habib G, Popescu BA.
of Cardiology. Eur Heart J 2007;28:2539–2550.
.. Echo-Doppler estimation of left ventricular filling pressure: results of the multi-
..
5. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, .. centre EACVI Euro-Filling study. Eur Heart J Cardiovasc Imaging 2017;18:
evidence-based approach to help guide diagnosis of heart failure with preserved .. 961–968.
ejection fraction. Circulation 2018;138:861. .. 26. Andersen OS, Smiseth OA, Dokainish H, Abudiab MM, Schutt RC, Kumar A,
6. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of .. Sato K, Harb S, Gude E, Remme EW, Andreassen AK, Ha JW, Xu J, Klein AL,
congestive heart failure: the Framingham study. N Engl J Med 1971;285: .. Nagueh SF. Estimating left ventricular filling pressure by echocardiography. J Am
1441–1446. .. Coll Cardiol 2017;69:1937–1948.
7. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diag-
.. 27. Sharifov OF, Schiros CG, Aban I, Perry GJ, Dell’italia LJ, Lloyd SG, Denney TS,
..
nostic criteria. Circulation 2000;101:2118–2121. .. Jr, Gupta H. Left ventricular torsion shear angle volume approach for noninva-
8. Yturralde RF, Gaasch WH. Diagnostic criteria for diastolic heart failure. Prog .. sive evaluation of diastolic dysfunction in preserved ejection fraction. J Am
Cardiovasc Dis 2005;47:314–319. .. Heart Assoc 2017;7:e007039.
9. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejec- .. 28. Obokata M, Kane GC, Reddy YN, Olson TP, Melenovsky V, Borlaug BA. Role
tion fraction: comorbidities drive myocardial dysfunction and remodeling .. of diastolic stress testing in the evaluation for heart failure with preserved ejec-
through coronary microvascular endothelial inflammation. J Am Coll Cardiol .. tion fraction: a simultaneous invasive-echocardiographic study. Circulation 2017;
2013;62:263–271.
.. 135:825–838.
10. Tschope C, Van Linthout S. New insights in (inter)cellular mechanisms by heart
.. 29. Obokata M, Borlaug BA. The strengths and limitations of E/e’ in heart failure
..
failure with preserved ejection fraction. Curr Heart Fail Rep 2014;11:436–444. .. with preserved ejection fraction. Eur J Heart Fail 2018;20:1312–1314.
11. Little WC, Zile MR. HFpEF: cardiovascular abnormalities not just comorbidities. .. 30. Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P, Omland T,
Circ Heart Fail 2012;5:669–671. .. Storrow AB, Krishnaswamy P, Abraham WT, Clopton P, Steg G, Aumont MC,
12. Franssen C, Chen S, Hamdani N, Paulus WJ. From comorbidities to heart failure .. Westheim A, Knudsen CW, Perez A, Kamin R, Kazanegra R, Herrmann HC,
with preserved ejection fraction: a story of oxidative stress. Heart 2016;102: .. McCullough PA; Breathing Not Properly Multinational Study Investigators.
320–330. .. Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure
13. Tromp J, Westenbrink BD, Ouwerkerk W, van Veldhuisen DJ, Samani NJ,
.. with reduced or preserved ejection fraction. Results from the Breathing Not
..
Ponikowski P, Metra M, Anker SD, Cleland JG, Dickstein K, Filippatos G, van .. Properly Multinational Study. J Am Coll Cardiol 2003;41:2010–2017.
der Harst P, Lang CC, Ng LL, Zannad F, Zwinderman AH, Hillege HL, van der .. 31. McCullough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE,
Meer P, Voors AA. Identifying pathophysiological mechanisms in heart failure .. Herrmann HC, Steg PG, Westheim A, Knudsen CW, Storrow AB, Abraham
with reduced versus preserved ejection fraction. J Am Coll Cardiol 2018;72: .. WT, Lamba S, Wu AH, Perez A, Clopton P, Krishnaswamy P, Kazanegra R,
1081–1090. .. Maisel AS; Breathing Not Properly Multinational Study Investigators. B-type
14. Sengupta PP, Kramer CM, Narula J, Dilsizian V. The potential of clinical pheno- .. natriuretic peptide and renal function in the diagnosis of heart failure: an ana-
typing of heart failure with imaging biomarkers for guiding therapies: a focused
.. lysis from the Breathing Not Properly Multinational Study. Am J Kidney Dis 2003;
..
update. JACC Cardiovasc Imaging 2017;10:1056–1071. .. 41:571–579.
15. Omar AMS, Narula S, Abdel Rahman MA, Pedrizzetti G, Raslan H, Rifaie O, .. 32. Buckley LF, Canada JM, Del Buono MG, Carbone S, Trankle CR, Billingsley H,
Narula J, Sengupta PP. Precision phenotyping in heart failure and pattern clus- .. Kadariya D, Arena R, Van Tassell BW, Abbate A. Low NT-proBNP levels in
tering of ultrasound data for the assessment of diastolic dysfunction. JACC .. overweight and obese patients do not rule out a diagnosis of heart failure with
Cardiovasc Imaging 2017;10:1291–1303. .. preserved ejection fraction. ESC Heart Fail 2018;5:372–378.
16. Tabassian M, Sunderji I, Erdei T, Sanchez-Martinez S, Degiovanni A, Marino P, .. 33. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence sup-
Fraser AG, D’Hooge J. Diagnosis of heart failure with preserved ejection frac-
.. porting the existence of a distinct obese phenotype of heart failure with pre-
..
tion: machine learning of spatiotemporal variations in left ventricular deform- .. served ejection fraction. Circulation 2017;136:6–19.
ation. J Am Soc Echocardiogr 2018;31:1272–1284. .. 34. Lam CS, Rienstra M, Tay WT, Liu LC, Hummel YM, van der Meer P, de Boer
17. Trippel TD, Van Linthout S, Westermann D, Lindhorst R, Sandek A, Ernst S, .. RA, Van Gelder IC, van Veldhuisen DJ, Voors AA, Hoendermis ES. Atrial fibril-
Bobenko A, Kasner M, Spillmann F, González A, López B, Ravassa S, Pieske B, .. lation in heart failure with preserved ejection fraction: association with exercise
Paulus WJ, Dı́ez J, Edelmann F, Tschöpe C. Investigating a biomarker-driven ap- .. capacity, left ventricular filling pressures, natriuretic peptides, and left atrial vol-
proach to target collagen turnover in diabetic heart failure with preserved ejec- .. ume. JACC Heart Fail 2017;5:92–98.
tion fraction patients. Effect of torasemide versus furosemide on serum C-
.. 35. McKelvie RS, Komajda M, McMurray J, Zile M, Ptaszynska A, Donovan M,
terminal propeptide of procollagen type I (DROP-PIP trial). Eur J Heart Fail
.. Carson P, Massie BM, Investigators IP. Baseline plasma NT-proBNP and clinical
..
2018;20:460–470. .. characteristics: results from the irbesartan in heart failure with preserved ejec-
18. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral .. tion fraction trial. J Card Fail 2010;16:128–134.
FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso- .. 36. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC.
Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of .. Jr., Plasma brain natriuretic peptide concentration: impact of age and gender.
heart failure with preserved ejection fraction. Eur Heart J 2015;36:2585–2594. .. J Am Coll Cardiol 2002;40:976–982.
19. Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, Zile .. 37. Suthahar N, Meijers WC, Ho JE, Gansevoort RT, Voors AA, van der Meer P,
MR, Voors AA, Lefkowitz MP, Packer M, McMurray JJ, Solomon SD,
.. Bakker SJL, Heymans S, van Empel V, Schroen B, van der Harst P, van
Veldhuisen DJ, de Boer RA. Sex-specific associations of obesity and N-terminal

.. 55. Tschope C, Westermann D, Steendijk P, Kasner M, Rudwaleit M,
..
pro-B-type natriuretic peptide levels in the general population. Eur J Heart Fail .. Schwimmbeck PL, Poller WC, Schultheiss HP. Coronary vasospasm-induced
2018;20:1205–1214. .. acute diastolic dysfunction in a patient with Raynaud’s phenomenon. Clin Res
38. Rogers RK, Stoddard GJ, Greene T, Michaels AD, Fernandez G, Freeman A, .. Cardiol 2006;95:344–348.
Nord J, Stehlik J. Usefulness of adjusting for clinical covariates to improve the .. 56. Catena C, Colussi G, Verheyen ND, Novello M, Fagotto V, Soardo G, Sechi
ability of B-type natriuretic peptide to distinguish cardiac from noncardiac dys- .. LA. Moderate alcohol consumption is associated with left ventricular diastolic
pnea. Am J Cardiol 2009;104:689–694. .. dysfunction in nonalcoholic hypertensive patients. Hypertension 2016;68:
39. Zaphiriou A, Robb S, Murray-Thomas T, Mendez G, Fox K, McDonagh T,
.. 1208–1216.
..
Hardman SM, Dargie HJ, Cowie MR. The diagnostic accuracy of plasma BNP .. 57. Tong W, Lima JA, Meng Q, Flynn E, Lai S. Long-term cocaine use is related to
and NTproBNP in patients referred from primary care with suspected heart .. cardiac diastolic dysfunction in an African-American population in Baltimore,
failure: results of the UK natriuretic peptide study. Eur J Heart Fail 2005;7: .. Maryland. Int J Cardiol 2004; 97:25–28.
537–541. .. 58. Baggish AL, Weiner RB, Kanayama G, Hudson JI, Picard MH, Hutter AM Jr,
40. Fuat A, Murphy JJ, Hungin AP, Curry J, Mehrzad AA, Hetherington A, Johnston .. Pope HG Jr. Long-term anabolic-androgenic steroid use is associated with left
JI, Smellie WS, Duffy V, Cawley P. The diagnostic accuracy and utility of a B- .. ventricular dysfunction. Circ Heart Fail 2010;3:472–476.
type natriuretic peptide test in a community population of patients with sus-
.. 59. Seldrum S, Pierard S, Moniotte S, Vermeylen C, Vancraeynest D, Pasquet A,
..
pected heart failure. Br J Gen Pract 2006;56:327–333. .. Vanoverschelde JL, Gerber BL. Iron overload in polytransfused patients without

41. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, .. heart failure is associated with subclinical alterations of systolic left ventricular
Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, .. function using cardiovascular magnetic resonance tagging. J Cardiovasc Magn
Alexandru Popescu B, Waggoner AD, Houston T, Oslo N, Phoenix A, .. Reson 2011;13:23.
Nashville T, Hamilton OC, Uppsala S, Ghent Liege B, Cleveland O, Novara I, .. 60. Yang WY, Zhang ZY, Thijs L, Cauwenberghs N, Wei FF, Jacobs L, Luttun A,
Rochester M, Bucharest R, St. Louis M. Recommendations for the evaluation of .. Verhamme P, Kuznetsova T, Nawrot TS, Staessen JA. Left ventricular structure
left ventricular diastolic function by echocardiography: an update from the
.. and function in relation to environmental exposure to lead and cadmium. J Am
..
American Society of Echocardiography and the European Association of .. Heart Assoc 2017;6.
Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2016;17:1321–1360. .. 61. Linna A, Oksa P, Groundstroem K, Halkosaari M, Palmroos P, Huikko S, Uitti J.
42. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola .. Exposure to cobalt in the production of cobalt and cobalt compounds and its
VP, Parissis J, Laroche C, Piepoli MF, Fonseca C, Mebazaa A, Lund L, Ambrosio .. effect on the heart. Occup Environ Med 2004;61:877–885.
GA, Coats AJ, Ferrari R, Ruschitzka F, Maggioni AP, Filippatos G. Epidemiology .. 62. Grandis DJ, Nah G, Whitman IR, Vittinghoff E, Dewland TA, Olgin JE, Marcus
and one-year outcomes in patients with chronic heart failure and preserved, .. GM. Wilson’s disease and cardiac myopathy. Am J Cardiol 2017;120:2056–2060.
mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure
.. 63. Tonnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy—a review
..
Long-Term Registry. Eur J Heart Fail 2017;19:1574–1585. .. of the literature. Immunopharmacol Immunotoxicol 2013;35:434–442.
43. Triposkiadis F, Giamouzis G, Parissis J, Starling RC, Boudoulas H, Skoularigis J, .. 64. Slordal L, Spigset O. Heart failure induced by non-cardiac drugs. Drug Safety
Butler J, Filippatos G. Reframing the association and significance of co- .. 2006;29:567–586.
morbidities in heart failure. Eur J Heart Fail 2016;18:744–758. .. 65. Hendel RC, Friedrich MG, Schulz-Menger J, Zemmrich C, Bengel F, Berman DS,
44. Beale AL, Meyer P, Marwick TH, Lam CSP, Kaye DM. Sex differences in cardio- .. Camici PG, Flamm SD, Le Guludec D, Kim R, Lombardi M, Mahmarian J,
vascular pathophysiology: why women are overrepresented in heart failure .. Sechtem U, Nagel E. CMR first-pass perfusion for suspected inducible myocar-
with preserved ejection fraction. Circulation 2018;138:198–205. .. dial ischemia. JACC Cardiovasc Imaging 2016;9:1338–1348.
45. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield
.. 66. Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bogaert J, Davin L, Cosyns
..
MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure .. B, Coucke P, Dulgheru R, Edvardsen T, Gaemperli O, Galderisi M, Griffin B,
with preserved ejection fraction. Circulation 2015;131:550–559. .. Heidenreich PA, Nieman K, Plana JC, Port SC, Scherrer-Crosbie M, Schwartz
46. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von .. RG, Sebag IA, Voigt JU, Wann S, Yang PC; European Society of Cardiology
Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss H-P, .. Working Groups on Nuclear Cardiology and Cardiac Computed Tomography
Tschöpe C. Cardiac inflammation contributes to changes in the extracellular .. and Cardiovascular Magnetic Resonance, American Society of Nuclear
matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail .. Cardiology, Society for Cardiovascular Magnetic Resonance, Society of
2011;4:44–52.
.. Cardiovascular Computed Tomography. Expert consensus for multi-modality
..
47. Wang C, Fan F, Cao Q, Shen C, Zhu H, Wang P, Zhao X, Sun X, Dong Z, Ma .. imaging evaluation of cardiovascular complications of radiotherapy in adults: a
X, Liu X, Han S, Wu C, Zou Y, Hu K, Ge J, Sun A. Mitochondrial aldehyde de- .. report from the European Association of Cardiovascular Imaging and the
hydrogenase 2 deficiency aggravates energy metabolism disturbance and dia- .. American Society of Echocardiography. Eur Heart J Cardiovasc Imaging 2013;14:
stolic dysfunction in diabetic mice. J Mol Med (Berl) 2016;94:1229–1240. .. 721–740.
48. Perseghin G, Ntali G, De Cobelli F, Lattuada G, Esposito A, Belloni E, Canu T, .. 67. Escher F, Kasner M, Kuhl U, Heymer J, Wilkenshoff U, Tschope C, Schultheiss
Costantino F, Ragogna F, Scifo P, Del Maschio A, Luzi L. Abnormal left ventricu- .. HP. New echocardiographic findings correlate with intramyocardial inflamma-
lar energy metabolism in obese men with preserved systolic and diastolic func-
.. tion in endomyocardial biopsies of patients with acute myocarditis and inflam-
..
tions is associated with insulin resistance. Diabetes Care 2007;30:1520–1526. .. matory cardiomyopathy. Mediators Inflamm 2013;2013:1.
49. Ho JE, Enserro D, Brouwers FP, Kizer JR, Shah SJ, Psaty BM, Bartz TM, .. 68. Wessely R, Vorpahl M, Schomig A, Klingel K. Late constrictive involvement of
Santhanakrishnan R, Lee DS, Chan C, Liu K, Blaha MJ, Hillege HL, van der Harst .. the pericardium in a case of previous myocarditis. Cardiovasc Pathol 2004;13:
P, van Gilst WH, Kop WJ, Gansevoort RT, Vasan RS, Gardin JM, Levy D, .. 327–329.
Gottdiener JS, de Boer RA, Larson MG. Predicting heart failure with preserved .. 69. Fontes-Carvalho R, Mancio J, Marcos A, Sampaio F, Mota M, Rocha Gonçalves
and reduced ejection fraction: the international collaboration on heart failure .. F, Gama V, Azevedo A, Leite-Moreira A. HIV patients have impaired diastolic
subtypes. Circ Heart Fail 2016;9:e003116.
.. function that is not aggravated by anti-retroviral treatment. Cardiovasc Drugs
..
50. Pernot M, Lee WN, Bel A, Mateo P, Couade M, Tanter M, Crozatier B, Messas .. Ther 2015;29:31–39.
E. Shear wave imaging of passive diastolic myocardial stiffness: stunned versus .. 70. Ntusi N, O’Dwyer E, Dorrell L, Wainwright E, Piechnik S, Clutton G, Hancock
infarcted myocardium. JACC Cardiovasc Imaging 2016;9:1023–1030. .. G, Ferreira V, Cox P, Badri M, Karamitsos T, Emmanuel S, Clarke K, Neubauer
51. Konerman MC, Greenberg JC, Kolias TJ, Corbett JR, Shah RV, Murthy VL, .. S, Holloway C. HIV-1-related cardiovascular disease is associated with chronic
Hummel SL. Reduced myocardial flow reserve is associated with diastolic dys- .. inflammation, frequent pericardial effusions, and probable myocardial edema.
function and decreased left atrial strain in patients with normal ejection fraction .. Circ Cardiovasc Imaging 2016;9:e004430.
and epicardial perfusion. J Card Fail 2018;24:90–100. .. 71. Freiberg MS, Chang CH, Skanderson M, Patterson OV, DuVall SL, Brandt CA,
52. Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-
.. So-Armah KA, Vasan RS, Oursler KA, Gottdiener J, Gottlieb S, Leaf D,
..
pulmonary artery coupling with exercise in heart failure with preserved ejection .. Rodriguez-Barradas M, Tracy RP, Gibert CL, Rimland D, Bedimo RJ, Brown ST,
fraction. Eur Heart J 2016;37:3293–3302. .. Goetz MB, Warner A, Crothers K, Tindle HA, Alcorn C, Bachmann JM, Justice
53. Taqueti VR, Solomon SD, Shah AM, Desai AS, Groarke JD, Osborne MT, .. AC, Butt AA. Association between HIV infection and the risk of heart failure
Hainer J, Bibbo CF, Dorbala S, Blankstein R, Di Carli MF. Coronary microvascu- .. with reduced ejection fraction and preserved ejection fraction in the antiretro-
lar dysfunction and future risk of heart failure with preserved ejection fraction. .. viral therapy era: results from the Veterans Aging Cohort Study. JAMA Cardiol
Eur Heart J 2018;39:840–849. .. 2017;2:536–546.
54. Elesber AA, Redfield MM, Rihal CS, Prasad A, Lavi S, Lennon R, Mathew V,
.. 72. Che W, Liu W, Wei Y, Xu Y, Hou L, Matsumori A, Hu D. Increased serum
..
Lerman LO, Lerman A. Coronary endothelial dysfunction and hyperlipidemia .. N-terminal pro-B-type natriuretic peptide and left ventricle diastolic dysfunc-
are independently associated with diastolic dysfunction in humans. Am Heart J .. tion in patients with hepatitis C virus infection. J Viral Hepat 2012;19:
2007;153:1081–1087. . 327–331.
73. Andy JJ, Ogunowo PO, Akpan NA, Odigwe CO, Ekanem IA, Esin RA. Helminth
.. 97. Tschope C, Bock CT, Kasner M, Noutsias M, Westermann D, Schwimmbeck
..
associated hypereosinophilia and tropical endomyocardial fibrosis (EMF) in .. PL, Pauschinger M, Poller WC, Kuhl U, Kandolf R, Schultheiss HP. High preva-
Nigeria. Acta Trop 1998;69:127–140. .. lence of cardiac parvovirus B19 infection in patients with isolated left ventricu-
74. Barros MV, Machado FS, Ribeiro AL, Rocha MO. Diastolic function in Chagas’ .. lar diastolic dysfunction. Circulation 2005;111:879–886.
disease: an echo and tissue Doppler imaging study. Eur J Echocardiogr 2004;5: .. 98. Pieroni M, Chimenti C, Ricci R, Sale P, Russo MA, Frustaci A. Early detection of
182–188. .. Fabry cardiomyopathy by tissue Doppler imaging. Circulation 2003;107:
75. Lurz P, Luecke C, Eitel I, Fohrenbach F, Frank C, Grothoff M, de Waha S, .. 1978–1984.
Rommel KP, Lurz JA, Klingel K, Kandolf R, Schuler G, Thiele H, Gutberlet M.
.. 99. Nagueh SF. Anderson-Fabry disease and other lysosomal storage disorders.
..
Comprehensive cardiac magnetic resonance imaging in patients with suspected .. Circulation 2014;130:1081–1090.
myocarditis: the MyoRacer-trial. J Am Coll Cardiol 2016;67:1800–1811. .. 100. Cheng Z, Cui Q, Tian Z, Xie H, Chen L, Fang L, Zhu K, Fang Q. Danon disease
76. Kasner M, Sinning D, Escher F, Lassner D, Kuhl U, Schultheiss HP, Tschope C. .. as a cause of concentric left ventricular hypertrophy in patients who underwent
The utility of speckle tracking imaging in the diagnostic of acute myocarditis, as .. endomyocardial biopsy. Eur Heart J 2012;33:649–656.
proven by endomyocardial biopsy. Int J Cardiol 2013;168:3023–3024. .. 101. Cheng Z, Fang Q. Danon disease: focusing on heart. J Hum Genet 2012; 57:
77. Tschope C, Cooper LT, Torre-Amione G, Van Linthout S. Management of .. 407–410.
myocarditis-related cardiomyopathy in adults. Circ Res 2019;124:1568–1583.
.. 102. Chen CA, Chien YH, Hwu WL, Lee NC, Wang JK, Chen LR, Lu CW, Lin MT,
..
78. Plazak W, Kopec G, Tomkiewicz-Pajak L, Rubis P, Dziedzic H, Suchon E, .. Chiu SN, Chiu HH, Wu MH. Left ventricular geometry, global function, and

Kostkiewicz M, Olszowska M, Musial J, Podolec P. Heart structure and function .. dyssynchrony in infants and children with pompe cardiomyopathy undergoing
in patients with generalized autoimmune diseases: echocardiography with tissue .. enzyme replacement therapy. J Card Fail 2011;17:930–936.
Doppler study. Acta Cardiol 2011;66:159–165. .. 103. Kamdar F, Garry DJ. Dystrophin-deficient cardiomyopathy. J Am Coll Cardiol
79. Puntmann VO, D’Cruz D, Smith Z, Pastor A, Choong P, Voigt T, Carr-White .. 2016;67:2533–2546.
G, Sangle S, Schaeffter T, Nagel E. Native myocardial T1 mapping by cardiovas- .. 104. Andratschke N, Maurer J, Molls M, Trott KR. Late radiation-induced heart dis-
cular magnetic resonance imaging in subclinical cardiomyopathy in patients with .. ease after radiotherapy. Clinical importance, radiobiological mechanisms and
systemic lupus erythematosus. Circ Cardiovasc Imaging 2013;6:295–301.
.. strategies of prevention. Radiother Oncol 2011;100:160–166.
..
80. Aslam F, Bandeali SJ, Khan NA, Alam M. Diastolic dysfunction in rheumatoid .. 105. Linhart A, Cecchi F. Common presentation of rare diseases: left ventricular
arthritis: a meta-analysis and systematic review. Arthritis Care Res (Hoboken) .. hypertrophy and diastolic dysfunction. Int J Cardiol 2018;257:344–350.
2013;65:534–543. .. 106. Muchtar E, Blauwet LA, Gertz MA. Restrictive cardiomyopathy: genetics, patho-
81. Vemulapalli S, Cohen L, Hsu V. Prevalence and risk factors for left ventricular .. genesis, clinical manifestations, diagnosis, and therapy. Circ Res 2017;121:
diastolic dysfunction in a scleroderma cohort. Scand J Rheumatol 2017;46: .. 819–837.
281–287. .. 107. Selvaraj S, Klein I, Danzi S, Akhter N, Bonow RO, Shah SJ. Association of serum
82. Chen JZ, Tang Y, Zhu MS, Xu AP. Heart involvement in systemic lupus erythe-
.. triiodothyronine with B-type natriuretic peptide and severe left ventricular dia-
..
matosus: a systemic review and meta-analysis. Clin Rheumatol 2016;35: .. stolic dysfunction in heart failure with preserved ejection fraction. Am J Cardiol
2437–2448. .. 2012;110:234–239.
83. Pereira NL, Grogan M, Dec GW. Spectrum of Restrictive and infiltrative cardio- .. 108. Thomas MR, McGregor AM, Jewitt DE. Left ventricle filling abnormalities prior
myopathies: part 1 of a 2-part series. J Am Coll Cardiol 2018;71:1130–1148. .. to and following treatment of thyrotoxicosis—is diastolic dysfunction impli-
84. Seguela PE, Iriart X, Acar P, Montaudon M, Roudaut R, Thambo JB. Eosinophilic .. cated in thyrotoxic cardiomyopathy? Eur Heart J 1993;14:662–668.
cardiac disease: molecular, clinical and imaging aspects. Arch Cardiovasc Dis 2015; .. 109. Altay H, Colkesen Y. Parathyroid hormone and heart failure: novel biomarker
108:258–268.
.. strategy. Endocr Metab Immune Disord Drug Targets 2013;13:100–104.
..
85. Crane MM, Chang CM, Kobayashi MG, Weller PF. Incidence of myeloprolifera- .. 110. Akdeniz B, Gedik A, Turan O, Ozpelit E, Ikiz AO, Itil O, Badak O, Baris N,
tive hypereosinophilic syndrome in the United States and an estimate of all .. Comlekci A. Evaluation of left ventricular diastolic function according to new
hypereosinophilic syndrome incidence. J Allergy Clin Immunol 2010;126:179–181. .. criteria and determinants in acromegaly. Int Heart J 2012;53:299–305.
86. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994; .. 111. Arcopinto M, Salzano A, Giallauria F, Bossone E, Isgaard J, Marra AM, Bobbio E,
83:2759–2779. .. Vriz O, Aberg DN, Masarone D, De Paulis A, Saldamarco L, Vigorito C,
87. Ommen SR, Seward JB, Tajik AJ. Clinical and echocardiographic features of .. Formisano P, Niola M, Perticone F, Bonaduce D, Sacca L, Colao A, Cittadini A,
hypereosinophilic syndromes. Am J Cardiol 2000;86:110–113.
.. Investigators T. Growth hormone deficiency is associated with worse cardiac
..
88. Tunçkale A, Ilerigelen B, Aktuglu G. Evaluation of the left ventricular systolic .. function, physical performance, and outcome in chronic heart failure: insights
and diastolic functions by echocardiography in patients with acute leukemia. .. from the T.O.S.CA. GHD Study. PLoS One 2017;12:e0170058.
Acta Haematol 1999;102:38–41. .. 112. Kamenicky P, Redheuil A, Roux C, Salenave S, Kachenoura N, Raissouni Z,
89. Palaskas N, Thompson K, Gladish G, Agha AM, Hassan S, Iliescu C, Kim P, .. Macron L, Guignat L, Jublanc C, Azarine A, Brailly S, Young J, Mousseaux E,
Durand JB, Lopez-Mattei JC. Evaluation and management of cardiac tumors. .. Chanson P. Cardiac structure and function in Cushing’s syndrome: a cardiac
Curr Treat Options Cardiovasc Med 2018;20:29. .. magnetic resonance imaging study. J Clin Endocrinol Metab 2014;99:E2144–53.
90. Pazos-Lopez P, Pozo E, Siqueira ME, Garcia-Lunar I, Cham M, Jacobi A,
.. 113. Kurisu S, Iwasaki T, Mitsuba N, Ishibashi K, Dohi Y, Nishioka K, Utsunomiya H,
Macaluso F, Fuster V, Narula J, Sanz J. Value of CMR for the differential diagno-
.. Hidaka T, Kihara Y. Effects of serum potassium level on left ventricular
..
sis of cardiac masses. JACC Cardiovasc Imaging 2014;7:896–905. .. diastolic function in patients with primary aldosteronism. Int J Cardiol 2012;160:
91. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, .. 68–70.
Roger VL, Gertz MA, Dispenzieri A, Zeldenrust SR, Redfield MM. Left ventricu- .. 114. Schumaecker MM, Larsen TR, Sane DC. Cardiac manifestations of adrenal insuf-
lar amyloid deposition in patients with heart failure and preserved ejection frac- .. ficiency. Rev Cardiovasc Med 2016;17:131–136.
tion. JACC Heart Fail 2014;2:113–122. .. 115. Ferreira VM, Marcelino M, Piechnik SK, Marini C, Karamitsos TD, Ntusi NAB,
92. Murtagh G, Laffin LJ, Beshai JF, Maffessanti F, Bonham CA, Patel AV, Yu Z, .. Francis JM, Robson MD, Arnold JR, Mihai R, Thomas JDJ, Herincs M, Hassan-
Addetia K, Mor-Avi V, Moss JD, Hogarth DK, Sweiss NJ, Lang RM, Patel AR.
.. Smith ZK, Greiser A, Arlt W, Korbonits M, Karavitaki N, Grossman AB, Wass
..
Prognosis of myocardial damage in sarcoidosis patients with preserved left ven- .. JAH, Neubauer S. Pheochromocytoma is characterized by catecholamine-
tricular ejection fraction: risk stratification using cardiovascular magnetic reson- .. mediated myocarditis, focal and diffuse myocardial fibrosis, and myocardial dys-
ance. Circ Cardiovasc Imaging 2016;9:e003738. .. function. J Am Coll Cardiol 2016;67:2364–2374.
93. Murtagh G, Laffin LJ, Patel KV, Patel AV, Bonham CA, Yu Z, Addetia K, El- .. 116. Wells GL, Little WC. Peripartum cardiomyopathy presenting as diastolic heart
Hangouche N, Maffesanti F, Mor-Avi V, Hogarth DK, Sweiss NJ, Beshai JF, Lang .. failure. Congest Heart Fail 2008;14:52–54.
RM, Patel AR. Improved detection of myocardial damage in sarcoidosis using .. 117. Alma LJ, Bokslag A, Maas A, Franx A, Paulus WJ, de Groot C. Shared bio-
longitudinal strain in patients with preserved left ventricular ejection fraction.
.. markers between female diastolic heart failure and pre-eclampsia: a systematic
..
Echocardiography 2016;33:1344–1352. .. review and meta-analysis. ESC Heart Fail 2017;4:88–98.
94. Liu P, Olivieri N. Iron overload cardiomyopathies: new insights into an old dis- .. 118. Al-Daghri NM, Al-Attas OS, Alkharfy KM, Alokail MS, Abd-Alrahman SH,
ease. Cardiovasc Drugs Ther 1994;8:101–110. .. Sabico S. Thiamine and its phosphate esters in relation to cardiometabolic risk
95. Spirito P, Lupi G, Melevendi C, Vecchio C. Restrictive diastolic abnormalities .. factors in Saudi Arabs. Eur J Med Res 2013;18:32.
identified by Doppler echocardiography in patients with thalassemia major. .. 119. Yoshihisa A, Watanabe S, Yokokawa T, Misaka T, Sato T, Suzuki S, Oikawa M,
Circulation 1990;82:88–94. .. Kobayashi A, Takeishi Y. Associations between acylcarnitine to free carnitine
96. Murphy CJ, Oudit GY. Iron-overload cardiomyopathy: pathophysiology, diagno-
.. ratio and adverse prognosis in heart failure patients with reduced or preserved
sis, and treatment. J Card Fail 2010;16:888–900.
.. ejection fraction. ESC Heart Fail 2017;4:360–364.
120. Saito Y, Hashimoto T, Sasaki M, Hanaoka S, Sugai K. Effect of selenium defi-

.. Sousa-Uva M, Uwe Voigt J, Luis Zamorano J; European Society of Cardiology.
..
ciency on cardiac function of individuals with severe disabilities under long-term .. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases:
tube feeding. Dev Med Child Neurol 2008;40:743–748. .. the Task Force for the Diagnosis and Management of Pericardial Diseases of the
121. Doust JA, Glasziou PP, Pietrzak E, Dobson AJ. A systematic review of the diag- .. European Society of Cardiology (ESC) Endorsed by: The European Association
nostic accuracy of natriuretic peptides for heart failure. Arch Intern Med 2004; .. for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015;36:2921–2964.
164:1978–1984. .. 139. Grimaldi A, Mocumbi AO, Freers J, Lachaud M, Mirabel M, Ferreira B,
122. Martens P, Nijst P, Verbrugge FH, Smeets K, Dupont M, Mullens W. Impact of .. Narayanan K, Celermajer DS, Sidi D, Jouven X, Marijon E. tropical endomyocar-
iron deficiency on exercise capacity and outcome in heart failure with reduced,
.. dial fibrosis: natural history, challenges, and perspectives. Circulation 2016;133:
..
mid-range and preserved ejection fraction. Acta Cardiol 2018;73:115–123. .. 2503–2515.
123. Hammer S, van der Meer RW, Lamb HJ, SchäR M, de Roos A, Smit JWA, .. 140. Ino T, Benson LN, Freedom RM, Rowe RD. Natural history and prognostic risk
Romijn JA. Progressive caloric restriction induces dose-dependent changes in .. factors in endocardial fibroelastosis. Am J Cardiol 1988;62:431–434.
myocardial triglyceride content and diastolic function in healthy men. J Clin .. 141. Mansencal N, McKenna WJ, Mitry E, Beauchet A, Pellerin D, Rougier P,
Endocrinol Metab 2008;93:497–503. .. Dubourg O. Comparison of prognostic value of tissue Doppler imaging in car-
124. Escudero CA, Potts JE, Lam PY, De Souza AM, Mugford GJ, Sandor GG. An .. cinoid heart disease versus the value in patients with the carcinoid syndrome
echocardiographic study of left ventricular size and cardiac function in adoles-
.. but without carcinoid heart disease. Am J Cardiol 2010;105:527–531.
..
cent females with anorexia nervosa. Eur Eat Disord Rev 2016;24:26–33. .. 142. Hassan SA, Banchs J, Iliescu C, Dasari A, Lopez-Mattei J, Yusuf SW. Carcinoid

125. Seferovic PM, Polovina M, Bauersachs J, Arad M, Gal TB, Lund LH, Felix SB, .. heart disease. Heart 2017;103:1488–1495.
Arbustini E, Caforio ALP, Farmakis D, Filippatos GS, Gialafos E, Kanjuh V, .. 143. Shaker JL. Paget’s disease of bone: a review of epidemiology, pathophysiology
Krljanac G, Limongelli G, Linhart A, Lyon AR, Maksimovic R, Milicic D, .. and management. Ther Adv Musculoskelet Dis 2009;1:107–125.
Milinkovic I, Noutsias M, Oto A, Oto O, Pavlovic SU, Piepoli MF, Ristic AD, .. 144. Caughey MC, Avery CL, Ni H, Solomon SD, Matsushita K, Wruck LM,
Rosano GMC, Seggewiss H, Asanin M, Seferovic JP, Ruschitzka F, Celutkiene J, .. Rosamond WD, Loehr LR. Outcomes of patients with anemia and acute de-
Jaarsma T, Mueller C, Moura B, Hill L, Volterrani M, Lopatin Y, Metra M, Backs
.. compensated heart failure with preserved versus reduced ejection fraction
..
J, Mullens W, Chioncel O, de Boer RA, Anker S, Rapezzi C, Coats AJS, .. (from the ARIC study community surveillance). Am J Cardiol 2014;114:
Tschope C. Heart failure in cardiomyopathies: a position paper from the Heart .. 1850–1854.
Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019; .. 145. Vallabhajosyula S, Pruthi S, Shah S, Wiley BM, Mankad SV, Jentzer JC. Basic and
21:553–576. .. advanced echocardiographic evaluation of myocardial dysfunction in sepsis and
126. Westphal JG, Rigopoulos AG, Bakogiannis C, Ludwig SE, Mavrogeni S, Bigalke B, .. septic shock. Anaesth Intensive Care 2018;46:13–24.
Doenst T, Pauschinger M, Tschope C, Schulze PC, Noutsias M. The MOGE(S) .. 146. Zamboli P, Luca S, Borrelli S, Garofalo C, Liberti ME, Pacilio M, Luca S,
classification for cardiomyopathies: current status and future outlook. Heart Fail
.. Palladino G, Punzi M. High-flow arteriovenous fistula and heart failure: could
..
Rev 2017;22:743–752. .. the indexation of blood flow rate and echocardiography have a role in the iden-
127. Brescia ST, Rossano JW, Pignatelli R, Jefferies JL, Price JF, Decker JA, Denfield .. tification of patients at higher risk? J Nephrol 2018;31:975.
SW, Dreyer WJ, Smith O, Towbin JA, Kim JJ. Mortality and sudden death in .. 147. Aggarwal SR, Herrington DM, Vladutiu CJ, Newman JC, Swett K, Gonzalez F,
pediatric left ventricular noncompaction in a tertiary referral center. Circulation .. Kizer JR, Kominiarek MA, Tabb KM, Gallo LC, Talavera GA, Hurwitz BE,
2013;127:2202–2208. .. Rodriguez CJ. Higher number of live births is associated with left ventricular
128. Towbin JA, Lorts A, Jefferies JL. Left ventricular non-compaction cardiomyop- .. diastolic dysfunction and adverse cardiac remodelling among US Hispanic/Latina
athy. Lancet 2015;386:813–825. .. women: results from the Echocardiographic Study of Latinos. Open Heart 2017;
129. Saiki H, Petersen IA, Scott CG, Bailey KR, Dunlay SM, Finley RR, Ruddy KJ, Yan
.. 4:e000530.
..
E, Redfield MM. Risk of heart failure with preserved ejection fraction in older .. 148. Reddy YNV, Obokata M, Gersh BJ, Borlaug BA. High prevalence of occult heart
women after contemporary radiotherapy for breast cancer. Circulation 2017; .. failure with preserved ejection fraction among patients with atrial fibrillation
135:1388–1396. .. and dyspnea. Circulation 2018;137:534–535.
130. Messerli FH, Rimoldi SF, Bangalore S. The transition from hypertension to heart .. 149. Nijst P, Martens P, Dupont M, Tang WHW, Mullens W. Intrarenal flow altera-
failure: contemporary update. JACC Heart Fail 2017;5:543–551. .. tions during transition from euvolemia to intravascular volume expansion in
131. Herrscher TE, Akre H, Overland B, Sandvik L, Westheim AS. High prevalence .. heart failure patients. JACC Heart Fail 2017;5:672–681.
of sleep apnea in heart failure outpatients: even in patients with preserved sys-
.. 150. Koell B, Zotter-Tufaro C, Duca F, Kammerlander AA, Aschauer S, Dalos D,
..
tolic function. J Card Fail 2011;17:420–425. .. Antlanger M, Hecking M, Saemann M, Mascherbauer J, Bonderman D. Fluid sta-
132. Cossio-Aranda J, Zamora KD, Nanda NC, Uzendu A, Keirns C, Verdejo-Paris J, .. tus and outcome in patients with heart failure and preserved ejection fraction.
Martinez-Rios MA, Espinola-Zavaleta N. Echocardiographic correlates of severe .. Int J Cardiol 2017;230:476–481.
pulmonary hypertension in adult patients with ostium secundum atrial septal .. 151. Vaduganathan M, Patel RB, Shah SJ, Butler J. Sudden cardiac death in heart fail-
defect. Echocardiography 2016;33:1891–1896. .. ure with preserved ejection fraction: a target for therapy? Heart Fail Rev 2016;
133. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in .. 21:455–462.
heart failure with preserved ejection fraction. J Am Coll Cardiol 2014;63(25 Pt
.. 152. Fang F, Zhang Q, Chan JY, Xie JM, Fung JW, Yip GW, Lam YY, Chan A, Yu CM.
..
A):2817–2827. .. Deleterious effect of right ventricular apical pacing on left ventricular diastolic
134. Shah SJ, Lam CSP, Svedlund S, Saraste A, Hage C, Tan R-S, Beussink-Nelson L, .. function and the impact of pre-existing diastolic disease. Eur Heart J 2011;32:
Ljung Faxén U, Fermer ML, Broberg MA, Gan L-M, Lund LH. Prevalence and .. 1891–1899.
correlates of coronary microvascular dysfunction in heart failure with preserved .. 153. Joseph J, Claggett BC, Anand IS, Fleg JL, Huynh T, Desai AS, Solomon SD,
ejection fraction: PROMIS-HFpEF. Eur Heart J 2018;39:3439–3450. .. O’Meara E, Mckinlay S, Pitt B, Pfeffer MA, Lewis EF. QRS duration is a predictor
135. Gorter TM, Willems TP, van Melle JP. Ventricular interdependence in pulmon- .. of adverse outcomes in heart failure with preserved ejection fraction. JACC
ary arterial hypertension: providing small pieces of a complex puzzle. Eur J
.. Heart Fail 2016;4:477–486.
..
Heart Fail 2015;17:1–2. .. 154. Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschope C,
136. Abdelkarim A, Levi DS, Tran B, Ghobrial J, Aboulhosn J. Fenestrated transcath- .. Leite-Moreira AF, Musters R, Niessen HW, Linke WA, Paulus WJ, Hamdani N.
eter ASD closure in adults with diastolic dysfunction and/or pulmonary hyper- .. Myocardial microvascular inflammatory endothelial activation in heart failure
tension: case series and review of the literature. Congenit Heart Dis 2016;11: .. with preserved ejection fraction. JACC Heart Fail 2016;4:312–324.
663–671. .. 155. Hamdani N, Paulus WJ. Myocardial titin and collagen in cardiac diastolic dys-
137. Aquaro GD, Perfetti M, Camastra G, Monti L, Dellegrottaglie S, Moro C, Pepe .. function: partners in crime. Circulation 2013;128:5–8.
A, Todiere G, Lanzillo C, Scatteia A, Di Roma M, Pontone G, Perazzolo Marra .. 156. Borlaug BA. The pathophysiology of heart failure with preserved ejection frac-
M, Barison A, Di Bella G; Cardiac Magnetic Resonance Working Group of the
.. tion. Nat Rev Cardiol 2014;11:507–515.
..
Italian Society of Cardiology. Cardiac MR with late gadolinium enhancement in .. 157. Sinning D, Kasner M, Westermann D, Schulze K, Schultheiss HP, Tschope C.
acute myocarditis with preserved systolic function: ITAMY study. J Am Coll .. Increased left ventricular stiffness impairs exercise capacity in patients with
Cardiol 2017;70:1977–1987. .. heart failure symptoms despite normal left ventricular ejection fraction. Cardiol
138. Adler Y, Charron P, Imazio M, Badano L, Baron-Esquivias G, Bogaert J, Brucato .. Res Pract 2011;2011:1.
A, Gueret P, Klingel K, Lionis C, Maisch B, Mayosi B, Pavie A, Ristic AD, Sabate .. 158. Kasner M, Sinning D, Lober J, Post H, Fraser AG, Pieske B, Burkhoff D, Tschope
Tenas M, Seferovic P, Swedberg K, Tomkowski W, Achenbach S, Agewall S, Al- .. C. Heterogeneous responses of systolic and diastolic left ventricular function to
Attar N, Angel Ferrer J, Arad M, Asteggiano R, Bueno H, Caforio AL, Carerj S,
.. exercise in patients with heart failure and preserved ejection fraction. ESC
..
Ceconi C, Evangelista A, Flachskampf F, Giannakoulas G, Gielen S, Habib G, .. Heart Fail 2015;2:121–132.
Kolh P, Lambrinou E, Lancellotti P, Lazaros G, Linhart A, Meurin P, Nieman K, .. 159. Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K,
Piepoli MF, Price S, Roos-Hesselink J, Roubille F, Ruschitzka F, Sagrista Sauleda J, . Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschope C. Role of left
ventricular stiffness in heart failure with normal ejection fraction. Circulation

.. B-type natriuretic peptide levels in heart failure with preserved ejection frac-
..
2008;117:2051–2060. .. tion. Am J Cardiol 2012;110:870–876.
160. Singh A, Addetia K, Maffessanti F, Mor-Avi V, Lang RM. LA strain for categoriza- .. 179. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemo-
tion of LV diastolic dysfunction. JACC Cardiovasc Imaging 2017;10:735–743. .. dynamics enhance diagnosis of early heart failure with preserved ejection frac-
161. Sanchis L, Andrea R, Falces C, Lopez-Sobrino T, Montserrat S, Perez-Villa F, .. tion. Circ Heart Fail 2010;3:588–595.
Bijnens B, Sitges M. Prognostic value of left atrial strain in outpatients with de .. 180. Meijers WC, Hoekstra T, Jaarsma T, van Veldhuisen DJ, de Boer RA. Patients
novo heart failure. J Am Soc Echocardiogr 2016;29:1035–1042 e1. .. with heart failure with preserved ejection fraction and low levels of natriuretic
162. Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA. Differential
.. peptides. Neth Heart J 2016;24:287–295.
..
hemodynamic effects of exercise and volume expansion in people with and .. 181. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B,
without heart failure. Circ Heart Fail 2015;8:41–48. .. Lancellotti P, Lansac E, Rodriguez Mu~ noz D, Rosenhek R, Sjögren J, Tornos Mas
163. Reddy YNV, Andersen MJ, Obokata M, Koepp KE, Kane GC, Melenovsky V, .. P, Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL, Roffi M,
Olson TP, Borlaug BA. Arterial stiffening with exercise in patients .. Alfieri O, Agewall S, Ahlsson A, Barbato E, Bueno H, Collet J-P, Coman IM,
with heart failure and preserved ejection fraction. J Am Coll Cardiol 2017;70: .. Czerny M, Delgado V, Fitzsimons D, Folliguet T, Gaemperli O, Habib G,
136–148. .. Harringer W, Haude M, Hindricks G, Katus HA, Knuuti J, Kolh P, Leclercq C,
164. Gorter TM, Obokata M, Reddy YNV, Melenovsky V, Borlaug BA. Exercise
.. McDonagh TA, Piepoli MF, Pierard LA, Ponikowski P, Rosano GMC, Ruschitzka
..
unmasks distinct pathophysiologic features in heart failure with preserved ejec- .. F, Shlyakhto E, Simpson IA, Sousa-Uva M, Stepinska J, Tarantini G, Tchétché D,

tion fraction and pulmonary vascular disease. Eur Heart J 2018;39:2825–2835. .. Aboyans V, Windecker S, Aboyans V, Agewall S, Barbato E, Bueno H, Coca A,
165. Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD, .. Collet J-P, Coman IM, Dean V, Delgado V, Fitzsimons D, Gaemperli O,
Borlaug BA. Cardiac output response to exercise in relation to metabolic de- .. Hindricks G, Iung B, Jüni P, Katus HA, Knuuti J, Lancellotti P, Leclercq C,
mand in heart failure with preserved ejection fraction. Eur J Heart Fail 2013;15: .. McDonagh T, Piepoli MF, Ponikowski P, Richter DJ, Roffi M, Shlyakhto E,
776–785. .. Simpson IA, Zamorano JL, Kzhdryan HK, Mascherbauer J, Samadov F,
166. Reddy YNV, Olson TP, Obokata M, Melenovsky V, Borlaug BA. Hemodynamic
.. Shumavets V, Camp GV, Loncar D, Lovric D, Georgiou GM, Linhartova K,
..
correlates and diagnostic role of cardiopulmonary exercise testing in heart fail- .. Ihlemann N, Abdelhamid M, Pern T, Turpeinen A, Srbinovska-Kostovska E,
ure with preserved ejection fraction. JACC Heart Fail 2018;6:665–675. .. Cohen A, Bakhutashvili Z, Ince H, Vavuranakis M, Temesvári A, Gudnason T,
167. Miller WL, Mullan BP. Volume overload profiles in patients with preserved and .. Mylotte D, Kuperstein R, Indolfi C, Pya Y, Bajraktari G, Kerimkulova A, Rudzitis
reduced ejection fraction chronic heart failure: are there differences? A pilot .. A, Mizariene V, Lebrun F, Demarco DC, Oukerraj L, Bouma BJ, Steigen TK,
study. JACC Heart Fail 2016;4:453–459. .. Komar M, De Moura Branco LM, Popescu BA, Uspenskiy V, Foscoli M, Jovovic
168. Pandey A, Khera R, Park B, Haykowsky M, Borlaug BA, Lewis GD, Kitzman .. L, Simkova I, Bunc M, de Prada JAV, Stagmo M, Kaufmann BA, Mahdhaoui A,
DW, Butler J, Berry JD. Relative impairments in hemodynamic exercise reserve
.. Bozkurt E, Nesukay E, Brecker SJD; ESC Scientific Document Group. 2017
..
parameters in heart failure with preserved ejection fraction: a study-level .. ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart
pooled analysis. JACC Heart Fail 2018;6:117–126. .. J 2017;38:2739–2791.
169. Naeije R, Vanderpool R, Dhakal BP, Saggar R, Saggar R, Vachiery JL, Lewis GD. .. 182. Hwang JW, Park SJ, Cho EJ, Kim EK, Lee GY, Chang SA, Choi JO, Lee SC, Park
Exercise-induced pulmonary hypertension: physiological basis and methodo- .. SW. Relation of N-terminal Pro-B-type natriuretic peptide and left ventricular
logical concerns. Am J Respir Crit Care Med 2013;187:576–583. .. diastolic function to exercise tolerance in patients with significant valvular heart
170. Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, Mant D, McManus .. disease and normal left ventricular systolic function. Am J Cardiol 2017;119:
RJ, Holder R, Deeks J, Fletcher K, Qume M, Sohanpal S, Sanders S, Hobbs FD. .. 1846–1853.
Systematic review and individual patient data meta-analysis of diagnosis of heart
.. 183. Wan SH, Vogel MW, Chen HH. Pre-clinical diastolic dysfunction. J Am Coll
..
failure, with modelling of implications of different diagnostic strategies in pri- .. Cardiol 2014;63:407–416.
mary care. Health Technol Assess 2009;13:1-207. .. 184. From AM, Scott CG, Chen HH. The development of heart failure in patients
171. Kasner M, Aleksandrov AS, Westermann D, Lassner D, Gross M, von Haehling .. with diabetes mellitus and pre-clinical diastolic dysfunction a population-based
S, Anker SD, Schultheiss H-P, Tschöpe C. Functional iron deficiency and diastol- .. study. J Am Coll Cardiol 2010;55:300–305.
ic function in heart failure with preserved ejection fraction. Int J Cardiol 2013; .. 185. Obokata M, Borlaug BA. Stress imaging in heart failure: physiologic, diagnostic,
168:4652–4657. .. and therapeutic insights. Circ Cardiovasc Imaging 2018;11:e007785.
172. Bekfani T, Pellicori P, Morris D, Ebner N, Valentova M, Sandek A, Doehner W,
.. 186. Task Force Members, Montalescot G, Sechtem U, Achenbach S, Andreotti F,
..
Cleland JG, Lainscak M, Schulze PC, Anker SD, von Haehling S. Iron deficiency .. Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR,
in patients with heart failure with preserved ejection fraction and its association .. Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E,
with reduced exercise capacity, muscle strength and quality of life. Clin Res .. Ruschitzka F, Sabate M, Senior R, Taggart DP, van der Wall EE, Vrints CJ,
Cardiol 2018. .. Guidelines E, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H,
173. Cowie MR, Struthers AD, Wood DA, Coats AJ, Thompson SG, Poole-Wilson .. Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof
PA, Sutton GC. Value of natriuretic peptides in assessment of patients with .. P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF,
possible new heart failure in primary care. Lancet 1997;350:1349–1353.
.. Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W,
..
174. Krishnaswamy P, Lubien E, Clopton P, Koon J, Kazanegra R, Wanner E, .. Windecker S, Document R, Knuuti J, Valgimigli M, Bueno H, Claeys MJ,
Gardetto N, Garcia A, DeMaria A, Maisel AS. Utility of B-natriuretic peptide .. Donner-Banzhoff N, Erol C, Frank H, Funck-Brentano C, Gaemperli O,
levels in identifying patients with left ventricular systolic or diastolic dysfunction. .. Gonzalez-Juanatey JR, Hamilos M, Hasdai D, Husted S, James SK, Kervinen K,
Am J Med 2001;111:274–279. .. Kolh P, Kristensen SD, Lancellotti P, Maggioni AP, Piepoli MF, Pries AR, Romeo
175. Gustafsson F, Steensgaard-Hansen F, Badskjaer J, Poulsen AH, Corell P, .. F, Ryden L, Simoons ML, Sirnes PA, Steg PG, Timmis A, Wijns W, Windecker S,
Hildebrandt P. Diagnostic and prognostic performance of N-terminal ProBNP .. Yildirir A, Zamorano JL. 2013 ESC guidelines on the management of stable cor-
in primary care patients with suspected heart failure. J Card Fail 2005;11(5
.. onary artery disease: the Task Force on the management of stable coronary ar-
..
Suppl):S15–20. .. tery disease of the European Society of Cardiology. Eur Heart J 2013;34:
176. Chow SL, Maisel AS, Anand I, Bozkurt B, de Boer RA, Felker GM, Fonarow GC, .. 2949–3003.
Greenberg B, Januzzi JL Jr, Kiernan MS, Liu PP, Wang TJ, Yancy CW, Zile MR; .. 187. Phan TT, Shivu GN, Abozguia K, Davies C, Nassimizadeh M, Jimenez D,
American Heart Association Clinical Pharmacology Committee of the Council .. Weaver R, Ahmed I, Frenneaux M. Impaired heart rate recovery and chrono-
on Clinical Cardiology, Council on Basic Cardiovascular Sciences, Council on .. tropic incompetence in patients with heart failure with preserved ejection frac-
Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke .. tion. Circ Heart Fail 2010;3:29–34.
Nursing, Council on Cardiopulmonary Critical Care, Perioperative and .. 188. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter
Resuscitation, Council on Epidemiology and Prevention, Council on Functional
.. MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM,
..
Genomics and Translational Biology, Council on Quality of Care and .. Ofili EO, O’Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE,
Outcomes Research. Role of biomarkers for the prevention, assessment, and .. Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ,
management of heart failure: a scientific statement from the American Heart .. Hernandez AF, Mascette AM, Braunwald E, Relax Trial FT. Effect of
Association. Circulation 2017;135:e1054–e1091. .. phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart
177. Tschope C, Kasner M, Westermann D, Gaub R, Poller WC, Schultheiss HP. .. failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;
The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: cor- .. 309:1268–1277.
relation with echocardiographic and invasive measurements. Eur Heart J 2005;
.. 189. Bangalore S, Yao SS, Chaudhry FA. Comparison of heart rate reserve versus
..
26:2277–2284. .. 85% of age-predicted maximum heart rate as a measure of chronotropic re-
178. Anjan VY, Loftus TM, Burke MA, Akhter N, Fonarow GC, Gheorghiade M, .. sponse in patients undergoing dobutamine stress echocardiography. Am J
Shah SJ. Prevalence, clinical phenotype, and outcomes associated with normal . Cardiol 2006;97:742–747.
..
190. Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. .. 210. Aschauer S, Zotter-Tufaro C, Duca F, Kammerlander A, Dalos D,
J Am Coll Cardiol 2001;37:153–156. .. Mascherbauer J, Bonderman D. Modes of death in patients with heart failure
191. Cahalin LP, Arena R, Labate V, Bandera F, Lavie CJ, Guazzi M. Heart rate recov- .. and preserved ejection fraction. Int J Cardiol 2017;228:422–426.
ery after the 6 min walk test rather than distance ambulated is a powerful prog- .. 211. Gorter TM, van Veldhuisen DJ, Bauersachs J, Borlaug BA, Celutkiene J, Coats
nostic indicator in heart failure with reduced and preserved ejection fraction: a .. AJS, Crespo-Leiro MG, Guazzi M, Harjola VP, Heymans S, Hill L, Lainscak M,
comparison with cardiopulmonary exercise testing. Eur J Heart Fail 2013;15: .. Lam CSP, Lund LH, Lyon AR, Mebazaa A, Mueller C, Paulus WJ, Pieske B,
519–527.
.. Piepoli MF, Ruschitzka F, Rutten FH, Seferovic PM, Solomon SD, Shah SJ,
..
192. Ahmeti A, Henein MY, Ibrahimi P, Elezi S, Haliti E, Poniku A, Batalli A, Bajraktari .. Triposkiadis F, Wachter R, Tschope C, de Boer RA. Right heart dysfunction and
G. Quality of life questionnaire predicts poor exercise capacity only in HFpEF .. failure in heart failure with preserved ejection fraction: mechanisms and man-
and not in HFrEF. BMC Cardiovasc Disord 2017;17:268. .. agement. Position statement on behalf of the Heart Failure Association of the
193. Wolsk E, Kaye D, Borlaug BA, Burkhoff D, Kitzman DW, Komtebedde J, Lam .. European Society of Cardiology. Eur J Heart Fail 2018;20:16–37.
CSP, Ponikowski P, Shah SJ, Gustafsson F. Resting and exercise haemodynamics .. 212. Kasner M, Westermann D, Steendijk P, Drose S, Poller W, Schultheiss HP,
in relation to six-minute walk test in patients with heart failure and preserved .. Tschope C. Left ventricular dysfunction induced by nonsevere idiopathic pul-
ejection fraction. Eur J Heart Fail 2018;20:715–722.
.. monary arterial hypertension: a pressure-volume relationship study. Am J Respir
..
194. Gary RA, Sueta CA, Rosenberg B, Cheek D. Use of the 6-minute walk test for .. Crit Care Med 2012;186:181–189.
women with diastolic heart failure. J Cardiopulm Rehabil 2004;24:264–268. .. 213. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K,

195. Malhotra R, Bakken K, D’Elia E, Lewis GD. Cardiopulmonary exercise testing in .. Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic as-
heart failure. JACC Heart Fail 2016;4:607–616. .. sessment of the right heart in adults: a report from the American Society of
196. Guazzi M, Arena R, Halle M, Piepoli MF, Myers J, Lavie CJ. 2016 focused update: .. Echocardiography endorsed by the European Association of Echocardiography,
clinical recommendations for cardiopulmonary exercise testing data assessment .. a registered branch of the European Society of Cardiology, and the Canadian
in specific patient populations. Eur Heart J 2018;39:1144–1161. .. Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–713; quiz
197. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke
.. 786–768.
..
W, Duvinage A, Stahrenberg R, Durstewitz K, Loffler M, Dungen HD, Tschope .. 214. Voigt JU, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, Pedri
C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B, Aldo D. .. S, Ito Y, Abe Y, Metz S, Song JH, Hamilton J, Sengupta PP, Kolias TJ, d’Hooge J,
Effect of spironolactone on diastolic function and exercise capacity in patients .. Aurigemma GP, Thomas JD, Badano LP. Definitions for a common standard for
with heart failure with preserved ejection fraction: the Aldo-DHF randomized ... 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/
controlled trial. JAMA 2013;309:781–791. .. Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc
198. Edelmann F, Gelbrich G, Dungen HD, Frohling S, Wachter R, Stahrenberg R, .. Imaging 2015;16:1–11.
Binder L, Topper A, Lashki DJ, Schwarz S, Herrmann-Lingen C, Loffler M, .. 215. Morris DA, Boldt LH, Eichstadt H, Ozcelik C, Haverkamp W. Myocardial systol-
Hasenfuss G, Halle M, Pieske B. Exercise training improves exercise capacity .. ic and diastolic performance derived by 2-dimensional speckle tracking echocar-
and diastolic function in patients with heart failure with preserved ejection frac- .. diography in heart failure with normal left ventricular ejection fraction. Circ
tion: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot
.. Heart Fail 2012;5:610–620.
..
study. J Am Coll Cardiol 2011;58:1780–1791. .. 216. Morris DA, Ma XX, Belyavskiy B, Aravind Kumar R, Kropf M, Kraft R, Frydas A,
199. Guazzi M, Bandera F, Ozemek C, Systrom D, Arena R. Cardiopulmonary exer- .. Osmanoglou E, Marquez E, Donal E, Edelmann F, Tschöpe C, Pieske B, Pieske-
cise testing: what is its value? J Am Coll Cardiol 2017;70:1618–1636. .. Kraigher E. Left ventricular longitudinal systolic function analyzed by 2d
200. Corra U, Agostoni PG, Anker SD, Coats AJS, Crespo Leiro MG, de Boer RA, .. speckle-tracking echocardiography in heart failure with preserved ejection frac-
Hairola VP, Hill L, Lainscak M, Lund LH, Metra M, Ponikowski P, Riley J, .. tion: a meta-analysis. Open Heart 2017;4:e000630.
Seferovic PM, Piepoli MF. Role of cardiopulmonary exercise testing in clinical .. 217. Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, Liu L, Pitt B, Pfeffer MA,
stratification in heart failure. A position paper from the Committee on Exercise .. Solomon SD. Prognostic importance of impaired systolic function in heart fail-
Physiology and Training of the Heart Failure Association of the European
.. ure with preserved ejection fraction and the impact of spironolactone.
..
Society of Cardiology. Eur J Heart Fail 2018;20:3–15. .. Circulation 2015;132:402–414.
201. Kasner M, Gaub R, Sinning D, Westermann D, Steendijk P, Hoffmann W, .. 218. Carluccio E, Biagioli P, Alunni G, Murrone A, Leonelli V, Pantano P, Biscottini E,
Schultheiss HP, Tschope C. Global strain rate imaging for the estimation of dia- .. Paulus WJ, Ambrosio G. Advantages of deformation indices over systolic veloc-
stolic function in HFNEF compared with pressure-volume loop analysis. Eur J .. ities in assessment of longitudinal systolic function in patients with heart failure
Echocardiogr 2010;11:743–751. .. and normal ejection fraction. Eur J Heart Fail 2011;13:292–302.
202. Kasner M, Gaub R, Westermann D, Kaplan H, Akpulat S, Steendijk P, .. 219. Morris DA, Otani K, Bekfani T, Takigiku K, Izumi C, Yuda S, Sakata K, Ohte N,
Schultheiss HP, Tschope C. Simultaneous estimation of NT-proBNP on top to
.. Tanabe K, Friedrich K, Kuhnle Y, Nakatani S, Otsuji Y, Haverkamp W, Boldt
..
mitral flow Doppler echocardiography as an accurate strategy to diagnose dia- .. LH, Takeuchi M. Multidirectional global left ventricular systolic function in nor-
stolic dysfunction in HFNEF. Int J Cardiol 2011;149:23–29. .. mal subjects and patients with hypertension: multicenter evaluation. J Am Soc
203. Opdahl A, Remme EW, Helle-Valle T, Lyseggen E, Vartdal T, Pettersen E, .. Echocardiogr 2014;27:493–500.
Edvardsen T, Smiseth OA. Determinants of left ventricular early-diastolic .. 220. Menting ME, McGhie JS, Koopman LP, Vletter WB, Helbing WA, van den Bosch
lengthening velocity: independent contributions from left ventricular relax- .. AE, Roos-Hesselink JW. Normal myocardial strain values using 2D speckle
ation, restoring forces, and lengthening load. Circulation 2009;119: .. tracking echocardiography in healthy adults aged 20 to 72 years.
2578–2586.
.. Echocardiography 2016;33:1665–1675.
..
204. Graham RJ, Gelman JS, Donelan L, Mottram PM, Peverill RE. Effect of preload .. 221. Sugimoto T, Dulgheru R, Bernard A, Ilardi F, Contu L, Addetia K, Caballero L,
reduction by haemodialysis on new indices of diastolic function. Clin Sci (Lond) .. Akhaladze N, Athanassopoulos GD, Barone D, Baroni M, Cardim N,
2003;105:499–506. .. Hagendorff A, Hristova K, Lopez T, de la Morena G, Popescu BA, Moonen M,
205. von Bibra H, Paulus WJ, St John Sutton M, Leclerque C, Schuster T, Schumm- .. Penicka M, Ozyigit T, Rodrigo Carbonero JD, van de Veire N, von Bardeleben
Draeger PM. Quantification of diastolic dysfunction via the age dependence of .. RS, Vinereanu D, Zamorano JL, Go YY, Rosca M, Calin A, Magne J, Cosyns B,
diastolic function—impact of insulin resistance with and without type 2 dia- .. Marchetta S, Donal E, Habib G, Galderisi M, Badano LP, Lang RM, Lancellotti P.
betes. Int J Cardiol 2015;182:368–374.
.. Echocardiographic reference ranges for normal left ventricular 2D strain: results
..
206. Shah AM, Claggett B, Kitzman D, Biering-Sorensen T, Jensen JS, Cheng S, .. from the EACVI NORRE study. Eur Heart J Cardiovasc Imaging 2017;18:833–840.
Matsushita K, Konety S, Folsom AR, Mosley TH, Wright JD, Heiss G, Solomon .. 222. Kocabay G, Muraru D, Peluso D, Cucchini U, Mihaila S, Padayattil-Jose S,
SD. Contemporary assessment of left ventricular diastolic function in older .. Gentian D, Iliceto S, Vinereanu D, Badano LP. Normal left ventricular mechan-
adults: the atherosclerosis risk in communities study. Circulation 2017;135: .. ics by two-dimensional speckle-tracking echocardiography. Reference values in
426–439. .. healthy adults. Rev Esp Cardiol (Engl Ed) 2014;67:651–658.
207. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. .. 223. Stefano GT, Zhao H, Schluchter M, Hoit BD. Assessment of echocardiographic
Pulmonary hypertension in heart failure with preserved ejection fraction: a .. left atrial size: accuracy of M-mode and two-dimensional methods and predic-
community-based study. J Am Coll Cardiol 2009;53:1119–1126.
.. tion of diastolic dysfunction. Echocardiography 2012;29:379–384.
..
208. Al-Naamani N, Preston IR, Paulus JK, Hill NS, Roberts KE. Pulmonary arterial .. 224. Moya-Mur J-L, Garcı́a-Martı́n A, Garcı́a-Lledó A, Ruiz-Leria S, Jiménez-Nacher
capacitance is an important predictor of mortality in heart failure with a pre- .. JJ, Megias-Sanz A, Taboada D, Muriel A. Indexed left atrial volume is a more
served ejection fraction. JACC Heart Fail 2015;3:467–474. .. sensitive indicator of filling pressures and left heart function than is anteropos-
209. Rosenkranz S, Gibbs JSR, Wachter R, De Marco T, Vonk-Noordegraaf A, .. terior left atrial diameter. Echocardiography 2010;27:1049–1055.
Vachiéry J-L. Left ventricular heart failure and pulmonary hypertension. Eur .. 225. Marchese P, Malavasi V, Rossi L, Nikolskaya N, Donne GD, Becirovic M,
Heart J 2016;37:942–954. .. Colantoni A, Luciani A, Modena MG. Indexed left atrial volume is superior to
left atrial diameter in predicting nonvalvular atrial fibrillation recurrence after

.. 241. Kristensen SL, Mogensen UM, Jhund PS, Rorth R, Anand IS, Carson PE, Desai
..
successful cardioversion: a prospective study. Echocardiography 2012;29: .. AS, Pitt B, Pfeffer MA, Solomon SD, Zile MR, Kober L, McMurray J. N-terminal
276–284. .. Pro-B-type natriuretic peptide levels for risk prediction in patients with heart
226. Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield .. failure and preserved ejection fraction according to atrial fibrillation status. Circ
MM. Diastolic dysfunction and left atrial volume: a population-based study. J Am .. Heart Fail 2019;12:e005766.
Coll Cardiol 2005;45:87–92. .. 242. Wood PW, Choy JB, Nanda NC, Becher H. Left ventricular ejection fraction
227. Lang RM, Nanda N, Franke A, Collins KA. Live three-dimensional transthoracic .. and volumes: it depends on the imaging method. Echocardiography 2014;31:
echocardiography: case study world atlas. Echocardiography 2005;22:95–98.
.. 87–100.
..
228. Kou S, Caballero L, Dulgheru R, Voilliot D, De Sousa C, Kacharava G, .. 243. Hoffmann R, Barletta G, von Bardeleben S, Vanoverschelde JL, Kasprzak J, Greis
Athanassopoulos GD, Barone D, Baroni M, Cardim N, Gomez De Diego JJ, .. C, Becher H. Analysis of left ventricular volumes and function: a multicenter
Hagendorff A, Henri C, Hristova K, Lopez T, Magne J, De La Morena G, .. comparison of cardiac magnetic resonance imaging, cine ventriculography, and
Popescu BA, Penicka M, Ozyigit T, Rodrigo Carbonero JD, Salustri A, Van De .. unenhanced and contrast-enhanced two-dimensional and three-dimensional
Veire N, Von Bardeleben RS, Vinereanu D, Voigt JU, Zamorano JL, Donal E, .. echocardiography. J Am Soc Echocardiogr 2014;27:292–301.
Lang RM, Badano LP, Lancellotti P. Echocardiographic reference ranges for nor- .. 244. Lancellotti P, Pellikka PA, Budts W, Chaudhry FA, Donal E, Dulgheru R,
mal cardiac chamber size: results from the NORRE study. Eur Heart J Cardiovasc
.. Edvardsen T, Garbi M, Ha JW, Kane GC, Kreeger J, Mertens L, Pibarot P,
..
Imaging 2014;15:680–690. .. Picano E, Ryan T, Tsutsui JM, Varga A. The clinical use of stress echocardiog-

229. Abhayaratna WP, Seward JB, Appleton CP, Douglas PS, Oh JK, Tajik AJ, Tsang .. raphy in non-ischaemic heart disease: recommendations from the European
TS. Left atrial size: physiologic determinants and clinical applications. J Am Coll .. Association of Cardiovascular Imaging and the American Society of
Cardiol 2006;47:2357–2363. .. Echocardiography. Eur Heart J Cardiovasc Imaging 2016;17:1191–1229.
230. Melenovsky V, Hwang SJ, Redfield MM, Zakeri R, Lin G, Borlaug BA. Left atrial .. 245. Erdei T, Smiseth OA, Marino P, Fraser AG. A systematic review of diastolic
remodeling and function in advanced heart failure with preserved or reduced .. stress tests in heart failure with preserved ejection fraction, with proposals
ejection fraction. Circ Heart Fail 2015;8:295–303.
.. from the EU-FP7 MEDIA study group. Eur J Heart Fail 2014;16:1345–1361.
..
231. Almeida P, Rodrigues J, Lourenco P, Maciel MJ, Bettencourt P. Left atrial volume .. 246. Burgess MI, Jenkins C, Sharman JE, Marwick TH. Diastolic stress echocardiog-
index is critical for the diagnosis of heart failure with preserved ejection frac- .. raphy: hemodynamic validation and clinical significance of estimation of ven-
tion. J Cardiovasc Med (Hagerstown) 2018. .. tricular filling pressure with exercise. J Am Coll Cardiol 2006;47:1891–1900.
232. Baltabaeva A, Marciniak M, Bijnens B, Moggridge J, He FJ, Antonios TF, .. 247. Holland DJ, Prasad SB, Marwick TH. Contribution of exercise echocardiography
MacGregor GA, Sutherland GR. Regional left ventricular deformation and .. to the diagnosis of heart failure with preserved ejection fraction (HFpEF). Heart
geometry analysis provides insights in myocardial remodelling in mild to moder- .. 2010;96:1024–1028.
ate hypertension. Eur J Echocardiogr 2008;9:501–508.
.. 248. van Riel AC, Opotowsky AR, Santos M, Rivero JM, Dhimitri A, Mulder BJ, Bouma
..
233. D’Andrea A, Radmilovic J, Ballo P, Mele D, Agricola E, Cameli M, Rossi A, .. BJ, Landzberg MJ, Waxman AB, Systrom DM, Shah AM. Accuracy of echocardiog-
Esposito R, Novo G, Mondillo S, Montisci R, Gallina S, Bossone E, Galderisi M; .. raphy to estimate pulmonary artery pressures with exercise: a simultaneous
Working Group on Echocardiography of the Italian Society of Cardiology. Left .. invasive-noninvasive comparison. Circ Cardiovasc Imaging 2017;10:e005711.
ventricular hypertrophy or storage disease? The incremental value of speckle .. 249. Obokata M, Olson TP, Reddy YNV, Melenovsky V, Kane GC, Borlaug BA.
tracking strain bull’s-eye. Echocardiography 2017;34:746–759. .. Haemodynamics, dyspnoea, and pulmonary reserve in heart failure with pre-
234. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard .. served ejection fraction. Eur Heart J 2018;39:2810–2821.
MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, .. 250. Belyavskiy E, Morris DA, Url-Michitsch M, Verheyen N, Meinitzer A,
Stewart W; American Society of Echocardiography’s Nomenclature and
.. Radhakrishnan AK, Kropf M, Frydas A, Ovchinnikov AG, Schmidt A, Tadic M,
..
Standards Committee, Task Force on Chamber Quantification, American College .. Genger M, Lindhorst R, Bobenko A, Tschope C, Edelmann F, Pieske-Kraigher E,
of Cardiology Echocardiography Committee, American Heart Association, .. Pieske B. Diastolic stress test echocardiography in patients with suspected heart
European Association of Echocardiography, European Society of Cardiology. .. failure with preserved ejection fraction: a pilot study. ESC Heart Fail 2019;6:
Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108. .. 146–153.
235. Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, O’Meara E, Desai AS, .. 251. Nagueh SF, Chang SM, Nabi F, Shah DJ, Estep JD. Cardiac imaging in patients
Heitner JF, Li G, Fang J, Rouleau J, Zile MR, Markov V, Ryabov V, Reis G, .. with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging 2017;
Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD. Cardiac structure
.. 10:e006547.
..
and function and prognosis in heart failure with preserved ejection fraction: .. 252. Krayenbuehl HH, Ritter M, Schneider J, Monrad ES, Grimm J. Influence of
findings from the echocardiographic study of the Treatment of Preserved .. Pressure and Volume Overload on Diastolic Compliance. Boston: Martinus
Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) .. Nijhoff;1987. p143–150.
Trial. Circ Heart Fail 2014;7:740–751. .. 253. Perez Del Villar C, Savvatis K, Lopez B, Kasner M, Martinez-Legazpi P, Yotti R,
236. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf .. Gonzalez A, Diez J, Fernandez-Aviles F, Tschope C, Bermejo J. Impact of acute
FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, .. hypertension transients on diastolic function in patients with heart failure with
Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for
.. preserved ejection fraction. Cardiovasc Res 2017;113:906–914.
..
cardiac chamber quantification by echocardiography in adults: an update from .. 254. Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Heart
the American Society of Echocardiography and the European Association of .. Fail Clin 2009;5:217–228.
Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–270. .. 255. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure–abnormalities in active
237. Pieske B, Butler J, Filippatos G, Lam C, Maggioni AP, Ponikowski P, Shah S, .. relaxation and passive stiffness of the left ventricle. N Engl J Med 2004;350:
Solomon S, Kraigher-Krainer E, Samano ET, Scalise AV, Muller K, Roessig L, .. 1953–1959.
Gheorghiade M; SOCRATES Investigators and Coordinators. Rationale and de- .. 256. Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH, Sullivan MJ. Exercise in-
sign of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies
.. tolerance in patients with heart failure and preserved left ventricular systolic
..
(SOCRATES). Eur J Heart Fail 2014;16:1026–1038. .. function: failure of the Frank-Starling mechanism. J Am Coll Cardiol 1991;17:
238. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, .. 1065–1072.
Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ; .. 257. Paulus WJ. H2FPEF score. At last, a properly validated diagnostic algorithm for
Prospective comparison of ARNI with ARB on Management Of heart failUre .. heart failure with preserved ejection fraction. Circulation 2018;138:871–873.
with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angioten- .. 258. Thadani U, Parker JO. Hemodynamics at rest and during supine and sitting bi-
sin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection .. cycle exercise in normal subjects. Am J Cardiol 1978;41:52–59.
fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380: .. 259. Yoshida A, Kadota K, Kambara H, Tamaki S, Suzuki Y, Kawai C, Tamaki N,
1387–1395.
.. Torizuka K. Left ventricular responses to supine bicycle exercise assessed by
..
239. van Doorn S, Geersing GJ, Kievit RF, van Mourik Y, Bertens LC, van Riet EES, .. radionuclide angiocardiography and a Swan-Ganz catheter. Jpn Circ J 1985;49:
Boonman-de Winter LJ, Moons KGM, Hoes AW, Rutten FH. Opportunistic .. 661–671.
screening for heart failure with natriuretic peptides in patients with atrial fibrilla- .. 260. Parker JO, Thadani U. Cardiac performance at rest and during exercise in nor-
tion: a meta-analysis of individual participant data of four screening studies. .. mal subjects. Bull Eur Physiopathol Respir 1979;15:935–949.
Heart 2018;104:1236–1237. .. 261. McCallister BD, Yipintsoi T, Hallermann FJ, Wallace RB, Frye RL. Left ventricu-
240. Filippatos G, Maggioni AP, Lam CSP, Pieske-Kraigher E, Butler J, Spertus J, .. lar performance during mild supine leg exercise in coronary artery disease.
Ponikowski P, Shah SJ, Solomon SD, Scalise AV, Mueller K, Roessig L, Bamber L,
.. Circulation 1968;37:922–931.
..
Gheorghiade M, Pieske B. Patient-reported outcomes in the SOluble guanylate .. 262. Maeder MT, Thompson BR, Brunner-La Rocca HP, Kaye DM. Hemodynamic
Cyclase stimulatoR in heArT failurE patientS with PRESERVED ejection fraction .. basis of exercise limitation in patients with heart failure and normal ejection
(SOCRATES-PRESERVED) study. Eur J Heart Fail 2017;19:782–791. . fraction. J Am Coll Cardiol 2010;56:855–863.
263. Dorfs S, Zeh W, Hochholzer W, Jander N, Kienzle RP, Pieske B, Neumann FJ. .. and diastolic ventricular function involving torsion, untwist, and longitudinal mo-
Pulmonary capillary wedge pressure during exercise and long-term mortality in
.. tion. J Am Coll Cardiol 2009;54:36–46.
..
patients with suspected heart failure with preserved ejection fraction. Eur Heart .. 280. Wenzelburger FW, Tan YT, Choudhary FJ, Lee ES, Leyva F, Sanderson JE. Mitral
J 2014;35:3103–3112. .. annular plane systolic excursion on exercise: a simple diagnostic tool for heart
264. Charron P, Elliott PM, Gimeno JR, Caforio ALP, Kaski JP, Tavazzi L, Tendera M, .. failure with preserved ejection fraction. Eur J Heart Fail 2011;13:953–960.
Maupain C, Laroche C, Rubis P, Jurcut R, Calo L, Helio TM, Sinagra G, .. 281. Mordi IR, Singh S, Rudd A, Srinivasan J, Frenneaux M, Tzemos N, Dawson DK.
Zdravkovic M, Kavoliuniene A, Felix SB, Grzybowski J, Losi MA, Asselbergs FW, .. Comprehensive echocardiographic and cardiac magnetic resonance evaluation
Garcia-Pinilla JM, Salazar-Mendiguchia J, Mizia-Stec K, Maggioni AP, Investigators .. differentiates among heart failure with preserved ejection fraction patients,
E. The Cardiomyopathy Registry of the EURObservational Research
.. hypertensive patients, and healthy control subjects. JACC Cardiovasc Imaging
..
Programme of the European Society of Cardiology: baseline data and contem- .. 2018;11:577–585.
porary management of adult patients with cardiomyopathies. Eur Heart J 2018. .. 282. Dhakal BP, Malhotra R, Murphy RM, Pappagianopoulos PP, Baggish AL, Weiner
265. Chan RH, Maron BJ, Olivotto I, Pencina MJ, Assenza GE, Haas T, Lesser JR,
Gruner C, Crean AM, Rakowski H, Udelson JE, Rowin E, Lombardi M, Cecchi F,
... RB, Houstis NE, Eisman AS, Hough SS, Lewis GD. Mechanisms of exercise in-
tolerance in heart failure with preserved ejection fraction: the role of abnormal
..
Tomberli B, Spirito P, Formisano F, Biagini E, Rapezzi C, De Cecco CN, Autore .. peripheral oxygen extraction. Circ Heart Fail 2015;8:286–294.
C, Cook EF, Hong SN, Gibson CM, Manning WJ, Appelbaum E, Maron MS. .. 283. Phan TT, Abozguia K, Nallur Shivu G, Mahadevan G, Ahmed I, Williams L,
Prognostic value of quantitative contrast-enhanced cardiovascular magnetic res- .. Dwivedi G, Patel K, Steendijk P, Ashrafian H, Henning A, Frenneaux M. Heart
..

onance for the evaluation of sudden death risk in patients with hypertrophic failure with preserved ejection fraction is characterized by dynamic impairment
cardiomyopathy. Circulation 2014;130:484–495. .. of active relaxation and contraction of the left ventricle on exercise and associ-
266. Hinojar R, Varma N, Child N, Goodman B, Jabbour A, Yu CY, Gebker R, .. ated with myocardial energy deficiency. J Am Coll Cardiol 2009;54:402–409.
Doltra A, Kelle S, Khan S, Rogers T, Arroyo Ucar E, Cummins C, Carr-White
.. 284. Kasner M, Sinning D, Burkhoff D, Tschope C. Diastolic pressure-volume quo-
..
G, Nagel E, Puntmann VO. T1 Mapping in discrimination of hypertrophic phe- .. tient (DPVQ) as a novel echocardiographic index for estimation of LV stiffness
notypes: hypertensive heart disease and hypertrophic cardiomyopathy: findings .. in HFpEF. Clin Res Cardiol 2015;104:955–963.
from the international T1 multicenter cardiovascular magnetic resonance study. .. 285. Lourenco AP, Leite-Moreira AF, Balligand JL, Bauersachs J, Dawson D, de Boer
Circ Cardiovasc Imaging 2015;8:e003285. .. RA, de Windt LJ, Falcao-Pires I, Fontes-Carvalho R, Franz S, Giacca M, Hilfiker-
267. Kasner M, Aleksandrov A, Escher F, Al-Saadi N, Makowski M, Spillmann F, .. Kleiner D, Hirsch E, Maack C, Mayr M, Pieske B, Thum T, Tocchetti CG,
Genger M, Schultheiss H-P, Kühl U, Pieske B, Morris DA, Noutsias M, Tschöpe .. Brutsaert DL, Heymans S. An integrative translational approach to study heart
C. Multimodality imaging approach in the diagnosis of chronic myocarditis with
.. failure with preserved ejection fraction: a position paper from the Working
..
preserved left ventricular ejection fraction (MCpEF): the role of 2D speckle- .. Group on Myocardial Function of the European Society of Cardiology. Eur J
tracking echocardiography. Int J Cardiol 2017;243:374–378. .. Heart Fail 2018;20:216–227.
268. Escher F, Westermann D, Gaub R, Pronk J, Bock T, Al-Saadi N, Kuhl U, .. 286. Tschope C, Birner C, Bohm M, Bruder O, Frantz S, Luchner A, Maier L, Stork
Schultheiss HP, Tschope C. Development of diastolic heart failure in a 6-year .. S, Kherad B, Laufs U. Heart failure with preserved ejection fraction: current
follow-up study in patients after acute myocarditis. Heart 2011;97:709–714. .. management and future strategies: expert opinion on the behalf of the nucleus
269. Pereira NL, Grogan M, Dec GW. Spectrum of restrictive and infiltrative cardio- .. of the “Heart Failure Working Group” of the German Society of Cardiology
myopathies: part 2 of a 2-part series. J Am Coll Cardiol 2018;71:1149–1166.
.. (DKG). Clin Res Cardiol 2018;107:1–19.
270. Grothues F, Smith GC, Moon JC, Bellenger NG, Collins P, Klein HU, Pennell
.. 287. Sharifov OF, Gupta H. What is the evidence that the tissue Doppler index E/e’
..
DJ. Comparison of interstudy reproducibility of cardiovascular magnetic reson- .. reflects left ventricular filling pressure changes after exercise or pharmacologic-
ance with two-dimensional echocardiography in normal subjects and in patients .. al intervention for evaluating diastolic function? A systematic review. J Am Heart
with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29–34. .. Assoc 2017;6:e004766.
271. Leong DP, De Pasquale CG, Selvanayagam JB. Heart failure with normal ejec- .. 288. Santos M, Rivero J, McCullough SD, West E, Opotowsky AR, Waxman AB,
tion fraction: the complementary roles of echocardiography and CMR imaging. .. Systrom DM, Shah AM. E/e’ ratio in patients with unexplained dyspnea: lack of
JACC Cardiovasc Imaging 2010;3:409–420. .. accuracy in estimating left ventricular filling pressure. Circ Heart Fail 2015;8:
272. Rommel KP, von Roeder M, Latuscynski K, Oberueck C, Blazek S, Fengler K,
.. 749–756.
..
Besler C, Sandri M, Lucke C, Gutberlet M, Linke A, Schuler G, Lurz P. .. 289. Hummel YM, Liu LCY, Lam CSP, Fonseca-Munoz DF, Damman K, Rienstra M,
Extracellular volume fraction for characterization of patients with heart failure .. van der Meer P, Rosenkranz S, van Veldhuisen DJ, Voors AA, Hoendermis ES.
and preserved ejection fraction. J Am Coll Cardiol 2016;67:1815–1825. .. Echocardiographic estimation of left ventricular and pulmonary pressures in
273. Puntmann VO, Peker E, Chandrashekhar Y, Nagel E. T1 mapping in characteriz- .. patients with heart failure and preserved ejection fraction: a study utilizing sim-
ing myocardial disease: a comprehensive review. Circ Res 2016;119:277–299. .. ultaneous echocardiography and invasive measurements. Eur J Heart Fail 2017;
274. Ferreira VM, Schulz-Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem .. 19:1651–1660.
U, Kindermann I, Gutberlet M, Cooper LT, Liu P, Friedrich MG. Cardiovascular
.. 290. Rossvoll O, Hatle LK. Pulmonary venous flow velocities recorded by trans-
..
magnetic resonance in nonischemic myocardial inflammation: expert recom- .. thoracic Doppler ultrasound: relation to left ventricular diastolic pressures. J
mendations. J Am Coll Cardiol 2018;72:3158–3176. .. Am Coll Cardiol 1993;21:1687–1696.
275. Fraser AG. What limits functional capacity in heart failure with preserved ejec- .. 291. Hadano Y, Murata K, Liu J, Oyama R, Harada N, Okuda S, Hamada Y, Tanaka
tion fraction? Unravelling the knots of an enigma. JACC Heart Fail 2018;6: .. N, Matsuzaki M. Can transthoracic Doppler echocardiography predict the dis-
127–129. .. crepancy between left ventricular end-diastolic pressure and mean pulmonary
276. Morris DA, Belyavskiy E, Aravind-Kumar R, Kropf M, Frydas A, Braunauer K, .. capillary wedge pressure in patients with heart failure? Circ J 2005;69:432–438.
Marquez E, Krisper M, Lindhorst R, Osmanoglou E, Boldt LH, Blaschke F,
.. 292. Braunauer K, Pieske-Kraigher E, Belyavskiy E, Aravind-Kumar R, Kropf M, Kraft
..
Haverkamp W, Tschope C, Edelmann F, Pieske B, Pieske-Kraigher E. Potential .. R, Frydas A, Marquez E, Osmanoglou E, Tschöpe C, Edelmann F, Pieske B,
usefulness and clinical relevance of adding left atrial strain to left atrial volume .. Düngen H-D, Morris DA. Early detection of cardiac alterations by left atrial
index in the detection of left ventricular diastolic dysfunction. JACC Cardiovasc .. strain in patients with risk for cardiac abnormalities with preserved left ven-
Imaging 2018;11:1405–1415. .. tricular systolic and diastolic function. Int J Cardiovasc Imaging 2018;34:701–711.
277. Triposkiadis F, Butler J, Abboud FM, Armstrong PW, Adamopoulos S, Atherton .. 293. Nakai H, Takeuchi M, Nishikage T, Nagakura T, Otani S. The mitral L wave: a
JJ, Backs J, Bauersachs J, Burkhoff D, Bonow RO, Chopra VK, de Boer RA, de .. marker of advanced diastolic dysfunction in patients with atrial fibrillation. Circ J
Windt L, Hamdani N, Hasenfuss G, Heymans S, Hulot JS, Konstam M, Lee RT,
.. 2007;71:1244–1249.
..
Linke WA, Lunde IG, Lyon AR, Maack C, Mann DL, Mebazaa A, Mentz RJ, .. 294. Cameli M, Sparla S, Losito M, Righini FM, Menci D, Lisi M, D’Ascenzi F, Focardi
Nihoyannopoulos P, Papp Z, Parissis J, Pedrazzini T, Rosano G, Rouleau J, .. M, Favilli R, Pierli C, Fineschi M, Mondillo S. Correlation of left atrial strain and
Seferovic PM, Shah AM, Starling RC, Tocchetti CG, Trochu JN, Thum T, .. Doppler measurements with invasive measurement of left ventricular end-
Zannad F, Brutsaert DL, Segers VF, De Keulenaer GW. The continuous heart .. diastolic pressure in patients stratified for different values of ejection fraction.
failure spectrum: moving beyond an ejection fraction classification. Eur Heart J .. Echocardiography 2016;33:398–405.
2019. .. 295. Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow
278. Tan YT, Wenzelburger F, Lee E, Heatlie G, Frenneaux M, Sanderson JE. .. RO, Huang CC, Deo RC. Phenomapping for novel classification of heart failure
Abnormal left ventricular function occurs on exercise in well-treated hyperten-
.. with preserved ejection fraction. Circulation 2015;131:269–279.
..
sive subjects with normal resting echocardiography. Heart 2010;96:948–955. .. 296. Sanchez-Martinez S, Duchateau N, Erdei T, Kunszt G, Aakhus S, Degiovanni A,
279. Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, Frenneaux M, .. Marino P, Carluccio E, Piella G, Fraser AG, Bijnens BH. Machine learning ana-
Sanderson JE. The pathophysiology of heart failure with normal ejection frac- .. lysis of left ventricular function to characterize heart failure with preserved
tion: exercise echocardiography reveals complex abnormalities of both systolic . ejection fraction. Circ Cardiovasc Imaging 2018;11:e007138.

HFA HFpEF Diagnosis Consensus 2019

Uploaded by

Copyright:

Available Formats

HFA HFpEF Diagnosis Consensus 2019

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

HFA HFpEF Diagnosis Consensus 2019

Uploaded by

Copyright:

Available Formats

European Heart Journal (2019) 40, 3297–3317 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehz641 Heart failure/cardiomyopathy

How to diagnose heart failure with preserved

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

resistance, increased conduit arterial stiffness, abnormal ventricular-

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Figure 2 Flowchart of the HFA-PEFF diagnostic algorithm. Step P

Symptoms and signs

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Abnormalities of the myocardium

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

elevated.41,244 Changes in CO can be assessed by measuring

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

and refine the recommended diagnostic algorithm and classify HFpEF

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Veldhuisen DJ, de Boer RA. Sex-specific associations of obesity and N-terminal

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

120. Saito Y, Hashimoto T, Sasaki M, Hanaoka S, Sugai K. Effect of selenium defi-

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

ventricular stiffness in heart failure with normal ejection fraction. Circulation

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

left atrial diameter in predicting nonvalvular atrial fibrillation recurrence after

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

Downloaded from https://academic.oup.com/eurheartj/article/40/40/3297/5557740 by guest on 30 October 2024

You might also like