Research

JAMA Cardiology | Original Investigation

Diagnosis of Heart Failure With Preserved Ejection Fraction

Among Patients With Unexplained Dyspnea
Yogesh N. V. Reddy, MD, MSc; David M. Kaye, MBBS, PhD; M. Louis Handoko, MD, PhD;
Arno A. van de Bovenkamp, MD; Ryan J. Tedford, MD; Carson Keck, MD; Mads J. Andersen, MD, PhD;
Kavita Sharma, MD; Rishi K. Trivedi, MD, PhD; Rickey E. Carter, PhD; Masaru Obokata, MD, PhD;
Frederik H. Verbrugge, MD, PhD; Margaret M. Redfield, MD; Barry A. Borlaug, MD

Supplemental content
IMPORTANCE Diagnosis of heart failure with preserved ejection fraction (HFpEF) among
dyspneic patients without overt congestion is challenging. Multiple diagnostic approaches
have been proposed but are not well validated against the independent gold standard for
HFpEF diagnosis of an elevated pulmonary capillary wedge pressure (PCWP) during exercise.
OBJECTIVE To evaluate H2FPEF and HFA-PEFF scores and a PCWP/cardiac output (CO) slope
of more than 2 mm Hg/L/min to diagnose HFpEF.

DESIGN, SETTING, AND PARTICIPANTS This retrospective case-control study included patients
with unexplained dyspnea from 6 centers in the US, the Netherlands, Denmark, and Australia
from March 2016 to October 2020. Diagnosis of HFpEF (cases) was definitively ascertained
by the presence of elevated PCWP during exertion; control individuals were those with
normal rest and exercise hemodynamics.

MAIN OUTCOMES AND MEASURES Logistic regression was used to evaluate the accuracy of
HFA-PEFF and H2FPEF scores to discriminate patients with HFpEF from controls.

RESULTS Among 736 patients, 563 (76%) were diagnosed with HFpEF (mean [SD] age, 69 [11]
years; 334 [59%] female) and 173 (24%) represented controls (mean [SD] age, 60 [15] years;
109 [63%] female). H2FPEF and HFA-PEFF scores discriminated patients with HFpEF from
controls, but the H2FPEF score had greater area under the curve (0.845; 95% CI,
0.810-0.875) compared with the HFA-PEFF score (0.710; 95% CI, 0.659-0.756) (difference,
−0.134; 95% CI, –0.177 to −0.094; P < .001). Specificity was robust for both scores, but
sensitivity was poorer for HFA-PEFF, with a false-negative rate of 55% for low-probability
scores compared with 25% using the H2FPEF score. Use of the PCWP/CO slope to redefine
HFpEF rather than exercise PCWP reclassified 20% (117 of 583) of patients, but patients
reclassified from HFpEF to control by this metric had clinical, echocardiographic, and
hemodynamic features typical of HFpEF, including elevated resting PCWP in 66% (46 of 70)
of reclassified patients.

CONCLUSIONS AND RELEVANCE In this case-control study, despite requiring fewer data, the
H2FPEF score had superior diagnostic performance compared with the HFA-PEFF score and
PCWP/CO slope in the evaluation of unexplained dyspnea and HFpEF in the outpatient
setting.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Barry A.
Borlaug, MD, Department of
Cardiovascular Medicine, Mayo Clinic,
JAMA Cardiol. 2022;7(9):891-899. doi:10.1001/jamacardio.2022.1916 200 First St SW, Rochester, MN 55905
Published online July 13, 2022. (borlaug.barry@mayo.edu).

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 Research Original Investigation Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea
E
xertional dyspnea is one of the most common symp-
toms reported in clinical practice, particularly among
older adults and adults with obesity.1 Heart failure (HF)
with preserved ejection fraction (HFpEF) is a common etiol-
ogy that is important to identify to guide proper treatment.2-4
Diagnosis of HFpEF is straightforward among patients with
overt congestion but is often challenging in ambulatory pa-
tients with exertional dyspnea, in whom symptoms and he-
modynamic abnormalities often manifest only during exer-
tional activities.5-11 Hemodynamic exercise testing has thus
emerged as the gold standard to definitively establish or re-
fute the diagnosis among these patients,7,9,12 but estimates from
community-based studies still show that many patients with
dyspnea due to HFpEF remain undiagnosed.13
Clinical scoring models are widely available in cardiovas-
cular medicine to enhance diagnosis, risk stratification, and
medical decision-making, but few are routinely used in clini-
cal practice because of complexity, time requirements for ap-
plication, and lack of external validation reducing confidence
in their veracity.14-16 Two scoring models were developed
to enhance diagnostic evaluation in HFpEF: the H2FPEF and
HFA-PEFF algorithms.7,10 These models have been validated
using the reference standards of diagnosis established by
clinical impression,17-20 trial eligibility,21-23 and previous HF
hospitalization,24,25 but to our knowledge, no multicenter study
has yet validated these approaches using the invasive gold
standard.7 In this study, we sought to validate HFA-PEFF and
H2FPEF scores in patients with unexplained dyspnea from a large,
multicenter, international cohort, with case-control status ascer-
tained definitively using the gold standard—an elevated pulmo-
nary capillary wedge pressure (PCWP) during exercise.
Methods
This international, multicenter, case-control study included
patients with unexplained dyspnea and normal EF (≥50%) who
underwent evaluation for possible HFpEF in 3 centers in the
US (Mayo Clinic, Rochester, Minnesota; Johns Hopkins Hos-
pital, Baltimore, Maryland; and Medical University of South
Carolina, Charleston) and 3 international centers (Amster-
dam University Medical Centre, Amsterdam, the Nether-
lands; Aarhus University Hospital, Aarhus, Denmark; and Al-
fred Hospital, Melbourne, Victoria, Australia) from March 2016
to October 2020. Because HFA-PEFF and H2FPEF scores re-
quire echocardiographic variables, only patients with echo-
cardiographic data available were included. The H2FPEF score
was originally derived and then validated from a cohort of pa-
tients who underwent invasive exercise testing for the evalu-
ation of unexplained dyspnea at 1 center between 2006 and
2016.10 Because of the potential for overinflation of diagnos-
tic performance, patients from this original derivation and vali-
dation cohort were not included. This study followed the
Strengthening the Reporting of Observational Studies in Epi-
demiology (STROBE) reporting guideline. The study was
approved by the Mayo Clinic institutional review board, which
waived informed consent because of the use of deidentified
patient data.
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Key Points
Question What is the performance of the H2FPEF and HFA-PEFF
algorithms to diagnose heart failure with preserved ejection
fraction (HFpEF) compared with the invasive gold standard of an
elevated pulmonary capillary wedge pressure (PCWP) during
exercise?
Findings In this case-control study of 736 patients, H2FPEF and
HFA-PEFF scores provided discriminatory information to identify
HFpEF, but there was superior discrimination for the H2FPEF
score. The use of an alternative criterion, the PCWP/cardiac output
slope, led to potential misclassification in 20% of patients.
Meaning The findings suggest that the H2FPEF and HFA-PEFF
algorithms can discriminate patients with HFpEF from control
individuals among ambulatory patients with dyspnea and that the
H2FPEF score provides superior diagnostic performance despite
fewer input variables.
Case Definitions and Ascertainment
Across all centers, patients were studied in the supine posi-
tion at rest and during supine cycle ergometry exercise to
exhaustion.9,10 For the primary analysis, positive diagnosis of
HFpEF (cases) was defined as elevated PCWP at rest (≥15 mm
Hg) or during exercise (≥25 mm Hg) at cardiac catheterization
based on current guidelines.7 Control individuals were de-
fined as those with normal rest and exercise hemodynamics
across all centers, with symptoms deemed primarily related
to deconditioning. More details of exclusion criteria and evalu-
ation are given in the eMethods in the Supplement.
H2FPEF and HFA-PEFF Scores
The European Society of Cardiology HFA-PEFF score is calcu-
lated from echocardiography and natriuretic peptide data (eFig-
ure 1 in the Supplement).7 Scores of 0 to 1 are considered to
represent low probability of HFpEF (rule out), and scores of 5
to 6 represent high probability (rule in).7 The H2FPEF score in-
cludes echocardiographic and clinical variables and ranges from
0 to 9 (Figure).10 H2FPEF scores of 0 to 1 are associated with a
low probability of HFpEF (<25%; rule out), and scores of 6 to
9 are associated with a high probability of HFpEF (>90%; rule
in).10 Patients with scores in the intermediate category for both
scores require additional exercise testing for diagnosis.
An additional sensitivity analysis was performed in which
HFpEF case status was defined using a recently proposed al-
ternative hemodynamic criterion: the slope of increase in PCWP
compared with the increase in cardiac output (CO) with exer-
cise of more than 2 mm Hg/L/min rather than the absolute
PCWP at rest and exercise.26
Statistical Analysis
Logistic regression with receiver operating characteristic curves
was used to assess the strength of association and discrimina-
tory performance of the variables included in the HFA-PEFF and
H2FPEF scores. Because these scores are used as both rule-
out and rule-in tests, sensitivity of the suggested low-
probability HFpEF cut points (≤1 for both scores) and speci-
ficity of the suggested high-probability cut points (≥6 for the
H2FPEF score and ≥5 for the HFA-PEFF score) were tested by
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 Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea Original Investigation Research

Figure. Comparison of H2FPEF and HFA-PEFF Scores for Diagnosis of Heart Failure With Preserved Ejection Fraction (HFpEF)

A Prevalence of HFpEF for H2FPEF score B Prevalence of HFpEF for HFA-PEFF score

100 100

80 80

60 60
HFpEF, %

HFpEF, %
40 40

20 20

0 0
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6
H2FPEF score HFA-PEFF score

C ROC curve for H2FPEF and HFA-PEFF score D Prevalence of HFpEF for each score category

1.0 100

H2FPEF score H2FPEF score

HFA-PEFF score
0.8 80

HFA-PEFF
score
0.6 60
Sensitivity

HFpEF, %

0.4 40

0.2 20

P <.0001

0 0
0 0.2 0.4 0.6 0.8 1.0 Low Intermediate High
1 – Specificity Score probability category

H2FPEF and HFA-PEFF scores of 0 to 1 indicated a low probability of HFpEF; exercise testing for diagnosis. C, The P value is for the difference in area under
H2FPEF scores of 6 to 9 and HFA-PEFF scores of 5 to 6 indicated a high the curve between scores. ROC indicates receiver operating characteristic.
probability of HFpEF. Intermediate probability of HFpEF required additional

logistic regression compared with the gold standard diagno-
sis from invasive exercise testing. Positive predictive value
(PPV) and negative predictive value (NPV) were plotted as a
function of disease prevalence based on sensitivity and speci-
ficity, according to formulas derived from Bayes theorem. Full
details are included in the eMethods in the Supplement. Two-
sided P < .05 was considered significant. We analyzed data
using JMP, version 14.1.0 (JMP Statistical Discovery LLC) and
BlueSky Statistics, version 7.40 (BlueSky Statistics LLC).
Results
Among 736 patients with unexplained dyspnea who had data
necessary to calculate the HFA-PEFF or H2FPEF score across
all centers, 563 (76%) were diagnosed with HFpEF (mean [SD]
age, 69 [11] years; 334 [59%] female) and 173 (24%) repre-
sented controls (mean [SD] age, 60 [15] years; 109 [63%] fe-
male). The distribution of scores, patients from participating
centers, and the clinical characteristics of patients are pre-
sented in eTables 1 to 3 and eFigure 2 in the Supplement. Over-
all, compared with controls, patients with HFpEF were older,
were more likely to have obesity, and had a higher prevalence
of hypertension, atrial fibrillation (AF), and kidney dysfunc-
tion with higher natriuretic peptide levels (Table 1).
On echocardiography, patients with HFpEF were more
likely to have diastolic dysfunction, with higher noninvasive
estimates of filling pressure (higher early diastolic mitral in-
flow velocity to septal mitral annulus tissue relaxation veloc-
ity [E/e′] ratio), lower e′, and greater estimated right ventricu-

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 Research Original Investigation Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea

Table 1. Baseline Characteristics of Study Patientsa

Control individuals Patients with HFpEF
Characteristic (n = 173) (n = 563) P value
Age, y 60 (15) 69 (11) <.001
Sex, No. (%)
Female 109 (63) 334 (59)
.42
Male 64 (37) 229 (41)
Body mass indexb 27.9 (5.8) 32.4 (7.2) <.001
Comorbidities, No. (%)
Hypertension 111 (64) 463 (82) <.001
Diabetes 25 (14) 108 (19) .15
Atrial fibrillation
Any 14 (8) 212 (38) <.001
Paroxysmal 10 (6) 126 (22) <.001
Permanent 4 (2) 86 (15) <.001
Hemoglobin level, g/dL 13.1 (1.6) 13.0 (1.6) .20
NTproBNP level, mean (95% CI), pg/mL 83 (50-198) 273 (99-868) <.001
Abbreviations: CO, cardiac output;
Creatinine level, mg/dL 0.98 (0.32) 1.12 (0.62) .007
e′, septal mitral annulus tissue
Echocardiography relaxation velocity in early diastole;
LV end diastolic dimension, mm 47 (5) 48 (7) .09 E/e′, ratio of early diastolic mitral
LV mass index, g/m2 78 (25) 86 (27) <.001 inflow velocity to e′; HFpEF, heart
Relative wall thickness 0.39 (0.10) 0.41 (0.10) .001 failure with preserved ejection
fraction; LA, left atrium; LV, left
Septal wall thickness, mm 9.4 (2.3) 10.3 (2.3) <.001
ventricle; NA, not applicable;
LV ejection fraction, % 62 (6) 61 (6) .03 NTproBNP, N-terminal pro brain
LA volume index, mL/m2 32 (12) 37 (14) <.001 natriuretic peptide; PAP, pulmonary
Septal E/e′ ratio 9.3 (3.8) 12.9 (6.5) <.001 artery pressure; PASP, pulmonary
artery systolic pressure;
Septal e′, cm/s 8 (3) 7 (2) <.001
PCWP, pulmonary capillary wedge
TR velocity, m/s 2.45 (0.45) 2.79 (0.58) <.001 pressure; TR, tricuspid regurgitation.
PASP, mm Hg 30 (11) 39 (15) <.001 SI conversion factors: To convert BNP
Invasive hemodynamics to ng/L, multiply by 1.0; creatinine to
Rest PCWP, mm Hg 10 (3) 16 (6) <.001 μmol/L, multiply by 88.4;
Rest mean PAP, mm Hg 18 (5) 28 (10) <.001 hemoglobin to g/L, multiply by 10.0.
a
Rest CO, L/minc 5.5 (1.6) 5.3 (1.9) .36 Data are presented as mean (SD)
values unless otherwise indicated.
Peak PCWP, mm Hg 18 (5) 32 (6) <.001
b
Calculated as weight in kilograms
Peak mean PAP, mm Hg 31 (8) 45 (11) <.001
c
divided by height in meters
Peak CO, L/min 10.6 (3.3) 9.1 (3.4) <.001 squared.
PCWP/CO slope, mean (95% CI), mm 1.6 (1.0-2.7) 4.2 (2.6-7.5) <.001 c
Hg/L/minc PCWP/CO slope was available for
146 controls and 437 patients with
PCWP/CO slope >2 mm Hg/L/min, No. (%)c 47 (32) 367 (84) <.001
HFpEF.

lar systolic pressure than controls (Table 1). Ejection fraction
was slightly lower in the group with HFpEF. Left atrial vol-
ume, left ventricular mass, relative wall thickness, and septal
hypertrophy were greater in the group with HFpEF.
Individual Components of the Scores
All components of the H2FPEF score and nearly all compo-
nents of the HFA-PEFF score demonstrated greater preva-
lence or severity in patients with HFpEF compared with con-
trols (Table 2). All components of the H 2 FPEF score
discriminated patients with HFpEF from controls individu-
ally, and most of the HFA-PEFF score components were also
predictive (Table 3 and eFigure 3 in the Supplement).
Validation of Diagnostic Utility
The H2FPEF and HFA-PEFF scores discriminated cases from
controls overall among the 627 patients for whom the H2FPEF
score could be calculated and the 594 patients for whom the
HFA-PEFF score could be calculated. Among the 485 patients
with all necessary data available to calculate both scores, the
H2FPEF score had a higher area under the curve (AUC) (0.845;
95% CI, 0.810-0.875; P < .001) compared with the HFA-PEFF
score (0.710; 95% CI, 0.659-0.756; P < .001) (difference, −0.134;
95% CI, –0.177 to −0.094; P < .001) (Table 4 and Figure). The
false-negative rate was higher with the HFA-PEFF score than
with the H2FPEF score; a total of 47% (20 of 43) of patients with
a HFA-PEFF score of 0 and 61% (33 of 54) of patients with a
HFA-PEFF score of 1 were found to have HFpEF based on inva-
sive testing (Figure). Overall, there was a 55% false-negative rate
with HFA-PEFF estimation of low probability compared with 25%
using the H2FPEF score. In contrast, for the H2FPEF score, 7%
(2 of 27) of patients with a score of 0 and 36% (15 of 42) of pa-
tients with a score of 1 were found to have HFpEF. False-
positive rates were low for both algorithms in the rule-in range.
A total of 279 of 298 patients (94%) with either an HFA-PEFF or
H2FPEF score in the rule-in range had HFpEF, whereas 98% (117
of 120) of patients with both scores in the rule-in range had
HFpEF (eFigure 4 and eTable 4 in the Supplement).

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 Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea Original Investigation Research

Table 2. Prevalence of Components of H2FPEF and HFA-PEFF Scores

No. (%)
Control individuals Patients with HFpEF
Score component (n = 173) (n = 563) P value
H2FPEF score
Age >60 y 97 (56) 461 (82) <.001
Obesitya 50 (29) 335 (59) <.001
Treated with ≥2 antihypertensives 64 (37) 375 (67) <.001
Any AF 14 (8) 212 (38) <.001
E/e′>9 66 (39) 381 (71) <.001 Abbreviations: AF, atrial fibrillation;
PASP>35 mm Hg 25 (17) 249 (49) <.001 e′, septal mitral annulus tissue
relaxation velocity in early diastole;
HFA-PEFF score
E/e′, ratio of early diastolic mitral
Functional domain inflow velocity to e′; HFpEF, heart
Septal e′<7 (age <75 y) or <5 (age >75 y) 45 (27) 187 (35) .05 failure with preserved ejection
Septal e′<7 58 (34) 258 (48) .002 fraction; LAVI, left atrial volume
index; LV, left ventricle;
E/e′≥15 16 (10) 152 (28) <.001
LVMI, LV mass index;
TR velocity >2.8 15 (13) 171 (40) <.001 NTproBNP, N-terminal pro brain
E/e′ of 9-14 50 (30) 221 (41) .006 natriuretic peptide; PASP, pulmonary
Functional domain scoreb artery systolic pressure; RWT, relative
2 63 (36) 373 (66) wall thickness; TR, tricuspid
regurgitation.
1 19 (11) 80 (14) <.001 a
Defined as a body mass index
0 91 (53) 110 (20)
greater than 30 (calculated as
Morphological domain weight in kilograms divided by
LAVI>34 (sinus) or >40 (AF) 58 (36) 237 (48) .008 height in meters squared).
LAVI of 29-34 (sinus) or 34-40 (AF) 34 (21) 90 (18) .42 b
Scores range from 0 to 2, with
RWT>0.42 and LVMI≥149 (male) or ≥122 2 (1) 17 (3) .27 higher scores indicating higher
(female) functional domain score component
RWT>0.42 45 (26) 233 (43) <.001 of HFA-PEFF score.
LV wall thickness ≥12 18 (11) 151 (28) <.001 c
Scores range from 0 to 2, with
LVMI≥115 (male) or ≥95 (female) 21 (13) 113 (21) .01 higher scores indicating higher
Morphological domain scorec morphological domain score
component of HFA-PEFF score.
2 60 (35) 243 (43) d
Includes 37 patients with BNP
1 49 (28) 198 (35) .003 measurements from 1 center who
0 64 (37) 118 (21) had BNP greater than 80 (sinus) or
Natriuretic peptide domain greater than 240 (AF).
NTproBNP level >220 (sinus) or >660 (AF)d 31 (24) 243 (52) <.001 e
Includes 37 patients with BNP
NTproBNP level of 125-220 (sinus) or 24 (18) 75 (16) .54 measurements from 1 center who
375-660 (AF)e had BNP of 35 to 80 (sinus) or 105
Natriuretic peptide scoref to 240 (AF).
f
2 31 (24) 243 (52) Scores range from 0 to 2, with
1 24 (18) 75 (16) <.001 higher scores indicating higher
natriuretic peptide domain score
0 76 (58) 148 (32)
component of HFA-PEFF score.

Positive predictive values and NPVs varied with disease
prevalence. eFigure 5 in the Supplement shows the PPV and
NPV for the rule-in and rule-out thresholds for the H2FPEF and
HFA-PEFF scores plotted as a function of disease prevalence.
In cohorts in which disease prevalence was high, differences
in PPV between scores were not clinically significant, but the
2 scores differed more by NPV, which was greater for the rule-
out H2FPEF score. Conversely, in populations with low dis-
ease prevalence, modeling predicted greater discrimination
with the H2FPEF compared with the HFA-PEFF, with higher
PPV for rule-in values (eFigure 5 in the Supplement).
Concordance and Discordant Group Differences
Most patients had concordant estimations of probability using
H2FPEF and HFA-PEFF scores (62.5% [303 of 485]), with the
remaining patients (37.5% [182 of 485]) having discordant
estimations of probability (eFigure 4 in the Supplement). Dis-
crepancies in HFpEF probability using H2FPEF and HFA-PEFF
scores ranging between 28% and 41% have been reported by
other researchers,13,18 similar to the 38% discordant result
observed in the present study. For patients with a low H2FPEF
score but an intermediate or a high HFA-PEFF score, the
prevalence of true HFpEF was 30% (6 of 20). Among patients
with a low HFA-PEFF score but an intermediate or a high
H2FPEF probability, the prevalence of true HFpEF was 78%
(31 of 40).
Among the discrepantly categorized groups, body mass in-
dex, hypertension history, invasively verified HFpEF, and ex-
ertional pulmonary vascular pressures were higher in the
H2FPEF high-probability and HFA-PEFF low- and intermediate-
probability groups, whereas left atrial volume and N-terminal
pro brain natriuretic peptide (NTproBNP) levels were higher
in the HFA-PEFF high-probability and H2FPEF low- and inter-
mediate-probability groups (eTable 5 in the Supplement).

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 Research Original Investigation Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea

Table 3. Operating Characteristics of Individual Score Components in Isolation

Sensi- Speci-
Score component OR (95% CI) AUC (95% CI) tivity ficity P value
H2FPEF score
Age >60 y 3.55 (2.45-5.13) 0.629 (0.589-0.669) 82 44 <.001
Obesitya 3.60 (2.49-5.21) 0.652 (0.614-0.693) 59 71 <.001
≥2 Antihypertensives 3.38 (2.37-4.82) 0.648 (0.606-0.688) 67 63 <.001
Any AF 6.84 (3.86-12.12) 0.648 (0.619-0.676) 38 92 <.001
E/e′>9 3.91 (2.72-5.62) 0.662 (0.621-0.704) 72 61 <.001
PASP>35 mm Hg 4.69 (2.95-7.46) 0.660 (0.622-0.697) 49 83 <.001
HFA-PEFF score
Functional domain
Septal e′<7 (age <75 y) or <5 1.47 (1.00-2.16) 0.541 (0.502-0.580) 35 73 .048
(age >75 y) Abbreviations: AF, atrial fibrillation;
Septal e′<7 1.77 (1.23-2.53) 0.568 (0.527-0.610) 48 66 .002 AUC, area under the curve; e′, septal
E/e′>15 3.82 (2.21-6.60) 0.595 (0.566-0.625) 29 90 <.001 mitral annulus tissue relaxation
velocity in early diastole; E/e′, ratio of
TR velocity >2.8 m/s 4.53 (2.54-8.05) 0.637 (0.598-0.676) 40 87 <.001
early diastolic mitral inflow velocity to
E/e′>9 3.91 (2.72-5.62) 0.662 (0.621-0.704) 72 61 <.001 e′; LAVI, left atrial volume index;
Functional domain score 4.88 (3.30-7.21) 0.676 (0.634-0.720) NA NA <.001 LV, left ventricle; LVMI, LV mass
Morphological domain index; NA, not applicable;
NTproBNP, N-terminal pro brain
LAVI>34 mL/m2 (SR) or >40 1.65 (1.14-2.38) 0.561 (0.517-0.604) 48 64 .008
mL/m2 (AF) natriuretic peptide; OR, odds ratio;
PASP, pulmonary artery systolic
LAVI>29 mL/m2 (SR) or >34 0.83 (0.54-1.30) 0.514 (0.478-0.551) NA NA .42
mL/m2 (AF) pressure; RWT, relative wall
thickness; SR, sinus rhythm;
RWT>0.42 g/m2 and LVMI≥149 2.75 (0.63-12.0) 0.510 (0.499-0.521) NA NA .18
(male) or ≥122 g/m2 (female) TR, tricuspid regurgitation.
a
RWT>0.42 2.11 (1.44-3.09) 0.583 (0.544-0.623) 43 74 <.001 Defined as a body mass index
LV wall thickness ≥12 mm 3.23 (1.91-5.45) 0.585 (0.556-0.615) 28 89 <.001 greater than 30 (calculated as
weight in kilograms divided by
LVMI≥115 (male) or ≥95 g/m2 1.86 (1.12-3.07) 0.542 (0.512-0.573) 21 87 .02 height in meters squared).
(female)
b
Morphological domain score 1.47 (1.19-1.82) 0.580 (0.532-0.627) 79 37 <.001 Includes 37 patients with BNP
measurements from 1 center who
Natriuretic peptide domain
had BNP greater than 80 (sinus) or
NTproBNP level >220 (SR) or 3.52 (2.26-5.47) 0.642 (0.600-0.685) 52 76 <.001 greater than 240 (AF).
>660 (AF)b c
Includes 37 patients with BNP
NTproBNP level >125 (SR) or 0.86 (0.52-1.42) 0.511 (0.474-0.548) NA NA .55
>375 (AF)c measurements from 1 center who
had BNP of 35 to 80 (sinus) or 105
Natriuretic peptide score 1.98 (1.58-2.49) 0.660 (0.612-0.708) NA NA <.001
to 240 (AF).

Table 4. Diagnostic Performance of the H2FPEF and HFA-PEFF Algorithms

OR per unit change
Overall score (95% CI) AUC (95% CI) P value AUC comparisona P value
H2FPEF (n = 627) 2.18 (1.89 to 2.52) 0.845 (0.810 to 0.875) <.001 1 [Reference] NA Abbreviations: AUC, area under the
curve; NA, not applicable; OR, odds
HFA-PEFF (n = 594) 1.53 (1.37 to 1.72) 0.710 (0.659 to 0.756) <.001 –0.134 (–0.177 to –0.094) <.001
ratio.

Subgroup and Sensitivity Analyses
Discrimination for the H2FPEF and HFA-PEFF scores across
multiple subgroups of interest is given in eTable 6 in the Supple-
ment. Among patients with a low NTproBNP level and HFpEF,
an incorrect low-probability score among patients with true
HFpEF was more common with the HFA-PEFF score (31.3% [46
of 147]) compared with the H2FPEF score (4.2% [5 of 120])
(P < .001) (eFigure 6 in the Supplement). Patients with HFpEF
and elevated NTproBNP levels were more likely to be classi-
fied as having high probability of HFpEF using the HFA-PEFF
score (75.1% [181 of 241]) compared with the H2FPEF score
(57.4% [120 of 209]), but the H2FPEF score remained robust
even in the subset of patients with high NTproBNP levels and
among patients with AF (eTable 6 in the Supplement).
Use of a PCWP/CO slope more than 2 mm Hg/L/min rather
than peak exercise PCWP of 25 mm Hg or higher to define
HFpEF case status led to reclassification of 20% (117 of 583)
of patients, with 70 HFpEF cases reclassified from case to con-
trol and 47 controls reclassified as cases (eTable 7 in the Supple-
ment). The H2FPEF and HFA-PEFF scores poorly discrimi-
nated patients with HFpEF from controls using this alternative
hemodynamic definition to define HFpEF case status (AUC,
0.673-0.690) (eTable 8 in the Supplement), but reclassified pa-
tients had clinical, echocardiographic, and hemodynamic find-
ings that challenged the accuracy of reclassification.
Patients reclassified from controls to cases by PCWP/CO
slope had findings less typical of HFpEF, including lower body
mass index, left ventricular mass, E/e′ ratio, and prevalence
of AF. In contrast, patients reclassified from cases to controls
by PCWP/CO slope retained features typical of HFpEF in the
community, with a high prevalence of obesity and AF and el-
evated pulmonary vascular pressures that predispose to lung
congestion at rest and during exercise. Two-thirds (66% [46
of 70]) of patients reclassified from cases to controls by the

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 Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea
PCWP/CO slope had an elevated resting PCWP, even without
exercise testing.
Discussion
In this multicenter, international, case-control study, we evalu-
ated a large series of patients with unexplained exertional dys-
pnea for suspected HFpEF. Case status was ascertained defini-
tively using directly measured PCWP during invasive exercise
testing. This study’s data validated both scoring systems against
the reference standard defined by the Heart Failure Associa-
tion of the European Society of Cardiology for diagnosis of
HFpEF as an elevation in PCWP during exercise,7 and greater
sensitivity and overall diagnostic accuracy was found for
the H2FPEF score. The use of an elevated PCWP/CO slope
as an alternative diagnostic criteria for HFpEF, as recently
proposed,26,27 reclassified 20% of patients and was associ-
ated with poorer accuracy for the HFA-PEFF and H2FPEF
scores, with clinical, echocardiographic, and hemodynamic
features of reclassified patients being less typical of HFpEF seen
in the community.
Dyspnea is a commonly encountered patient concern in
clinical practice. Diagnosis of HFpEF is often challenging in this
setting9 but is important to provide insight into symptom
causality, guide treatment decisions, and preclude unneces-
sary testing for pulmonary, neuromuscular, and other disor-
ders. Despite increasing awareness in general practice, recent
data suggest that HFpEF remains underrecognized. Selvaraj and
colleagues13 found that patients with self-reported dyspnea, no
documented HFpEF, and an elevated H2FPEF or HFA-PEFF score
had HF event rates that were similar to those among patients
with clinically diagnosed HFpEF. This finding suggests that
many of the patients had undiagnosed HFpEF, and this cohort
constituted one-third of the total population with HFpEF in that
community-based study, underlining the potential magnitude
of the problem. Although it is not feasible or warranted to per-
form invasive exercise testing for all patients at risk of HFpEF,
underdiagnosis may deprive afflicted patients of effective
treatments.2-4
Clinical risk scores offer a solution that may boost aware-
ness and help inform medical decision-making regarding
further evaluation, particularly when instruments are exter-
nally validated and not overly complex.14-16 The H2FPEF score
is an evidence-based algorithm that combines echocardio-
graphic and clinical variables and was previously derived and
validated in populations other than those in the present study.10
Discrimination of patients with HFpEF from controls in this
study was similar to that in the previous derivation study; the
AUC to distinguish patients with HFpEF from controls with the
H2FPEF score was 0.845 in this study and was 0.841 in the pre-
vious study,10 indicating robust reproducibility and external
validation.
The HFA-PEFF score is a somewhat more complex algo-
rithm using data from echocardiography and natriuretic pep-
tide testing.7 The reasons for the greater diagnostic accuracy
observed in the present study with the H2FPEF score com-
pared with the HFA-PEFF score may be associated with the pri-
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Original Investigation Research
mary differences among score components, including obe-
sity, AF, and natriuretic peptides (eFigure 1 in the Supplement).
Echocardiographic and natriuretic peptide abnormalities are
informative when present but have been shown to have poor
sensitivity for HFpEF.9,28 HFpEF is known to be associated with
comorbidities, including obesity, hypertension, and AF,5,6,8 and
the inclusion of clinical factors provides orthogonal informa-
tion to echocardiography to estimate pretest probability, po-
tentially explaining the superior diagnostic performance of the
H2FPEF score.
A history of AF is associated with HFpEF.29-32 The HFA-
PEFF score requires higher NTproBNP levels and left atrial sizes
to support the diagnosis of HFpEF in AF, essentially raising the
diagnostic threshold for HFpEF in the presence of AF rather
than using the presence of AF as a biomarker of potential
HFpEF. Obesity is one of the most common factors associ-
ated with HFpEF, and natriuretic peptide levels are known to
be lower (or even normal) in individuals with HFpEF and obe-
sity despite equal or high filling pressures,28,33,34 which may
conceal the presence of HFpEF in patients with obesity.
In a sensitivity analysis comparing the discrepantly cat-
egorized patients (eTable 5 in the Supplement), those with a
low-probability HFA-PEFF score and higher H2FPEF score were
more likely to have hemodynamic evidence of HFpEF and other
characteristics typical of HFpEF. Both scores include exercise
testing among patients with intermediate probability, and in
these cases, the true diagnosis would be ascertained defini-
tively through exercise evaluation regardless of which score
was applied.7,8,10 Therefore, for clinical purposes, the impor-
tant differences reside in the rule-in and rule-out perfor-
mances. Of note, 54 of 97 patients (56%) with low HFA-PEFF
scores of 0 or 1 (deemed exclusionary for HFpEF)7 were found
to have HFpEF, and the diagnosis would have been missed in
these patients. The validation of both scores with the use of
the invasive standard across multiple centers in our study sug-
gests that the scoring systems may be useful to enrich clinical
trials for genuine HFpEF, particularly because both scores have
been shown to also predict high event rates.22,25
Previous studies17-24 validated these scores using less ro-
bust reference standards and were variably limited by a lack
of appropriate dyspneic controls, use of variable case defini-
tions, and of note, the absence of definitive case or control as-
certainment. These previous validation studies used HFpEF
case status defined by previous HF hospitalization, clinical
impressions, or trial criteria and controls who were asymp-
tomatic or had no cardiovascular history.
Previous HF hospitalization is pathognomonic for HFpEF,
and the diagnosis of HFpEF is not considered to be challeng-
ing in this cohort.5 Other studies have used asymptomatic
controls, but a control group that also seeks care for dyspnea
and in whom disease is definitively excluded should be in-
cluded to accurately evaluate diagnostic accuracy.
To our knowledge, only 1 other study has used an inva-
sive approach to evaluate discrimination using HFA-PEFF and
H2FPEF scores. Churchill et al26 reported similar accuracy for
the 2 scores (AUC of 0.73 for HFA-PEFF and 0.74 for H2FPEF).
Accuracy for the HFA-PEFF score in the present study was simi-
lar to the accuracy in that study, but discrimination using the
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 Research Original Investigation Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea

H2FPEF score was greater in the present study. There are sev-
eral potential reasons for this difference. One explanation may
be patient selection. The study by Churchill et al26 included
data from a younger (mean age, 59 years) and selective co-
hort of 156 patients identified over 12 years at a single center
(approximately 13 patients per year),26 limiting external va-
lidity, compared with the present, multicenter study, which
included 736 patients.
An important difference may be the definition of HFpEF used
as the gold standard. Churchill et al.26 used a lower cutoff value
for exercise PCWP to define case status (≥15 mm Hg) if there was
an increased PCWP/CO slope, whereas the present study used
a more restrictive reference standard of a higher exercise PCWP
(≥25 mm Hg) without adjustment for CO.7 These definitions
agreed for most patients (80%), but there were differences in the
remaining 20%.26 Patients reclassified from controls to cases
based on the PCWP/CO slope in the present study had features
that are not typical of HFpEF, including young age, low comor-
bidity burden, and normal PCWP and pulmonary artery pres-
sures, raising questions of whether these patients should be di-
agnosed with HFpEF. Conversely, patients reclassified from cases
to controls based on the PCWP/CO slope had features typical of
HFpEF, including high comorbidity burden, obesity, diastolic dys-
function, and elevated pulmonary vascular pressures that cause
dyspnea (eTable 6 in the Supplement). Therefore, the lower di-
agnostic performance of the 2 scores in the study by Churchill
et al26 may be associated with limitations of the PCWP/CO slope
in defining HFpEF case status, and these limitations may ex-
plain the poorer discrimination observed using the PCWP/CO
slope with both scores in the present study.
Limitations
The study has limitations. All patients were referred to cath-
eterization for diagnosis, but invasive assessment has be-
come routine practice at many centers and is necessary to de-
finitively ascertain case or control status. Referral patterns for
invasive cardiopulmonary exercise testing likely differed across
the institutions studied, introducing bias. Although our mod-
eling estimates suggested similar test characteristics at lower
disease prevalence, the overall high prevalence of HFpEF in
the study sample may impact generalizability, and further
study in a broader population is needed. Pressure waveforms
were interpreted individually at each center rather than
through a central core laboratory. Although individual inter-
pretations may introduce greater variability, this is reflective
of real-world clinical practice, enhancing generalizability.
Whereas this multicenter study included patients evaluated
across 3 continents, there was no representation from Africa,
South America, or Asia,20 where prevalence of obesity and
other comorbidities differ; thus, this study’s results may not
apply to these regions.
Conclusions
In this case-control study, both the H2FPEF and the HFA-PEFF
algorithms discriminated patients with HFpEF from controls
with high specificity among patients presenting with unex-
plained dyspnea, but the H2FPEF score provided superior sen-
sitivity and overall diagnostic accuracy despite the require-
ment of fewer input variables.

ARTICLE INFORMATION
Accepted for Publication: May 13, 2022.
Published Online: July 13, 2022.
doi:10.1001/jamacardio.2022.1916
Author Affiliations: Department of Cardiovascular
Medicine, Mayo Clinic, Rochester, Minnesota
(Reddy, Verbrugge, Redfield, Borlaug); Department
of Cardiology, Alfred Hospital, Melbourne, Victoria,
Australia (Kaye); Department of Cardiology,
Amsterdam University Medical Centers, Vrije
Universiteit Amsterdam, Amsterdam
Cardiovascular Sciences, Amsterdam, the
Netherlands (Handoko, van de Bovenkamp);
Division of Cardiology, Department of Medicine,
Medical University of South Carolina, Charleston
(Tedford, Keck); Department of Cardiology, Aarhus
University Hospital, Aarhus, Denmark (Andersen);
Division of Cardiology, Department of Medicine,
Johns Hopkins University, Baltimore, Maryland
(Sharma, Trivedi); Department of Health Sciences
Research, Mayo Clinic, Jacksonville, Florida
(Carter); Department of Cardiovascular Medicine,
Gunma University Graduate School of Medicine,
Maebashi, Gunma, Japan (Obokata); Biomedical
Research Institute, Faculty of Medicine and Life
Sciences, Hasselt University, Hasselt, Belgium
(Verbrugge); Centre for Cardiovascular Diseases,
University Hospital Brussels, Jette, Belgium
(Verbrugge).
Author Contributions: Dr Reddy had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Reddy, Carter, Redfield,
Borlaug.
Acquisition, analysis, or interpretation of data:
Reddy, Kaye, Handoko, van de Bovenkamp,
Tedford, Keck, Andersen, Sharma, Trivedi, Obokata,
Verbrugge, Borlaug.
Drafting of the manuscript: Reddy, Sharma, Carter,
Borlaug.
Critical revision of the manuscript for important
intellectual content: Reddy, Kaye, Handoko, van de
Bovenkamp, Tedford, Keck, Andersen, Trivedi,
Carter, Obokata, Verbrugge, Redfield, Borlaug.
Statistical analysis: Reddy, Keck, Borlaug.
Obtained funding: Tedford, Borlaug.
Administrative, technical, or material support:
Handoko, van de Bovenkamp, Tedford, Keck,
Trivedi, Borlaug.
Supervision: Tedford, Obokata, Borlaug.
Conflict of Interest Disclosures: Dr Reddy
reported receiving grants from Bayer and Sleep
Number and an internal competitive grant program
from Mayo Clinic Cardiovascular Division.
Dr Handoko reported receiving grants from The
Dutch Heart Foundation and educational, speaker,
and consultancy fees from Novartis, Boehringer
Ingelheim, AstraZeneca, Vifor Pharma, Bayer, Merck
Sharp & Dohme, Abbott, Daiichi Sankyo, and Quin
outside the submitted work. Dr Tedford reported
consulting and serving on the steering committee
for Abbott, Medtronic, Acceleron Pharma, and Aria
CV; consulting for Edwards Gradient, Itamar,
CareDx Lexicon Pharmaceuticals, Alleviant Eidos
Therapeutics, and United Therapeutics; serving on
a research advisory board for Abiomed; and
performing hemodynamic core laboratory work for
Merck and Actelion. Dr Sharma reported receiving
personal fees from Novartis, Bayer, Novo Nordisk,
Boehringer Ingelheim, Janssen, and AstraZeneca
and grants from Amgen outside the submitted
work. Dr Carter reported receiving grants from the
National Heart, Lung, and Blood Institute (NHLBI)
and the National Center for Advancing Translational
Sciences (NCATS), National Institutes of Health
(NIH), and serving on the scientific advisory board
for Anumana, Inc outside the submitted work.
Dr Obokata reported receiving research grants from
the Fukuda Foundation for Medical Technology,
Mochida Memorial Foundation for Medical and
Pharmaceutical Research, Nippon Shinyaku,
Japanese Circulation Society, and Takeda Science
Foundation. Dr Verbrugge reported receiving a
fellowship from the Belgian American Educational
Foundation and Special Research Fund (Bijzonder
Onderzoeksfonds) of Hasselt University. Dr Borlaug
reported receiving grants from the NHLBI, NIH, and
the US Department of Defense; research funding
from Axon, AstraZeneca, Corvia, Medtronic,
GlaxoSmithKline, Mesoblast, Novartis, and Tenax
Therapeutics; and serving on steering committee
and consulting for Actelion, Amgen, Aria,
Boehringer Ingelheim, Edwards Lifesciences,
Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk,
NGMBio, ShouTi, and VADovations. No other
disclosures were reported.

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 Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea
Additional Contributions: The authors thank the
patients who participated in this research across all
centers.
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