J Jacc 2023 01 049 PDF

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 81, NO.
18, 2023
ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
THE PRESENT AND FUTURE
JACC SCIENTIFIC STATEMENT
Heart Failure With Preserved

Ejection Fraction
JACC Scientific Statement
Barry A. Borlaug, MD,a Kavita Sharma, MD,b Sanjiv J. Shah, MD,c Jennifer E. Ho, MDd
ABSTRACT
The incidence and prevalence of heart failure with preserved ejection fraction (HFpEF) continue to rise in tandem with the
increasing age and burdens of obesity, sedentariness, and cardiometabolic disorders. Despite recent advances in the
understanding of its pathophysiological effects on the heart, lungs, and extracardiac tissues, and introduction of new,
easily implemented approaches to diagnosis, HFpEF remains under-recognized in everyday practice. This under-
recognition presents an even greater concern given the recent identification of highly effective pharmacologic-based and
lifestyle-based treatments that can improve clinical status and reduce morbidity and mortality. HFpEF is a heterogenous
syndrome and recent studies have suggested an important role for careful, pathophysiological-based phenotyping to
improve patient characterization and to better individualize treatment. In this JACC Scientific Statement, we provide an
in-depth and updated examination of the epidemiology, pathophysiology, diagnosis, and treatment of HFpEF.
(J Am Coll Cardiol 2023;81:1810–1834) © 2023 by the American College of Cardiology Foundation.
D uring the past 20 years, the diagnostic

approach to heart failure with preserved
ejection fraction (HFpEF) has markedly
evolved in parallel with our scientific understanding
peptide
congestion.4
(NP) levels or other
As we examine the global scope and secular trends

evidence
of this disease, it is important to recognize that this

of
of this complex clinical syndrome. 1 Indeed, with the clinical definition has varying degrees of overlap with
publication of recent pivotal sodium-glucose trans- data we rely on to define HFpEF epidemiology and
port protein-2 inhibitor (SGLT2i) trials and their outcomes (Table 1). For example, relying on hospi-
widespread therapeutic implications, 2,3 the absence talization or International Classification of Diseases
of noninvasive gold standard diagnostic tests for (ICD)-9 codes alone may reduce specificity, increase
HFpEF is more apparent than ever. Recent efforts associations with mortality, and reduce estimates of
have garnered consensus around a new universal prevalence. Relying on easily measured biomarkers of
definition, anchored clinically to the syndrome of congestion, such as the NPs, misses approximately
heart failure (HF) caused by structural and/or func- one-third of all affected patients and may dispropor-
tional cardiac abnormalities, with HFpEF defined as tionately affect patients with obesity or African
a left ventricular ejection fraction (LVEF) $50% ancestry.5,6 Indeed, HFpEF remains underdetected in
further corroborated by either elevated natriuretic many settings, particularly in patients with obesity,
Listen to this manuscript’s

audio summary by
Editor-in-Chief From the aDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; bDivision of Cardiology, Department
Dr Valentin Fuster on of Medicine, Johns Hopkins University, Baltimore, Maryland, USA; cNorthwestern University Feinberg School of Medicine,
www.jacc.org/journal/jacc. Chicago, Illinois, USA; and the d
CardioVascular Institute and Division of Cardiology, Department of Medicine, Beth Israel
Deaconess Medical Center, Boston, Massachusetts, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received December 20, 2022; revised manuscript received January 27, 2023, accepted January 30, 2023.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2023.01.049

JACC VOL. 81, NO. 18, 2023 Borlaug et al 1811
MAY 9, 2023:1810–1834 Heart Failure With Preserved Ejection Fraction
become the dominant HF subtype in the ABBREVIATIONS

HIGHLIGHTS AND ACRONYMS
future, affecting approximately 1 in 10
HFpEF is an increasingly common cause adults during their lifetime. Therefore, cli-
AF = atrial fibrillation
of exercise intolerance linked to obesity nicians should have a low threshold for
BMI = body mass index
and sedentary behavior. considering HFpEF as a potential (and
cGMP = cyclic guanosine
increasingly common) diagnosis in patients
Despite advances in understanding of monophosphate
with dyspnea or exercise intolerance.
pathophysiological mechanisms, diag- CMD = coronary microvascular
SEX AND RACE DIFFERENCES IN HFpEF dysfunction
nosis, and treatment, HFpEF remains
EPIDEMIOLOGY. Important sex differences in EF = ejection fraction
under-recognized.
HF subtypes have been described. Although HF = heart failure
Further research is needed to charac- the incidence of HFpEF is similar among HFpEF = heart failure with
terize HFpEF phenotypes to promote men and women, the prevalence of HFpEF preserved ejection fraction
individualized management and to is higher in women compared with men HFrEF = heart failure with
improve outcomes. (Figure 1). 15,16 In one study, women out- reduced ejection fraction
numbered men 2:1 with respect to HFpEF LA = left atrium

likely accounting for substantial underappreciation of hospitalizations. This is further reflected in LV = left ventricle
its actual scope. 7,8 lifetime risk estimates of HF: the lifetime LVEF = left ventricular
A number of specific diseases cause the clinical risk of HFpEF is nearly double that of ejection fraction
syndrome of HF in tandem with a normal LVEF, but HFrEF among women (10.7% vs 5.8%), ML = machine learning
have their own unique pathophysiology, natural his- whereas the lifetime risk of HFpEF and NO = nitric oxide
tory, and treatments (Table 2). These etiologies HFrEF are similar among men.14 NP = natriuretic peptide
should not be considered to represent true “garden Studies on race/ethnic differences in PCWP = pulmonary capillary
variety” HFpEF because of their distinct features and HFpEF burden are evolving. Data from the wedge pressure
treatments, and the present text does not apply to ARIC (Atherosclerosis Risk In Communities) PH = pulmonary hypertension
these “masqueraders.” In this JACC Scientific State- study of HF-related hospitalizations in 4 U.S. PVD = pulmonary vascular
ment, we examine the epidemiology, pathophysi- communities between 2005 and 2014 show disease
ology, diagnosis, and treatment of HFpEF in the that average event rates for first HFpEF hos- RV = right ventricle
context of these recognized limitations and the pitalization were highest among Black SGLT2i = sodium glucose
available evidence. women (7.4 per 1,000 person-years [95% CI: cotransporter-2 inhibitor
6.7-8.1 per 1,000 person-years]) when compared with

EPIDEMIOLOGY OF HFpEF
Black men (6.2 per 1,000 person-years [95% CI: 5.5-
7.0 per 1,000 person-years]), White women (5.9 per
HFpEF INCIDENCE, PREVALENCE, AND LIFETIME
1,000 person-years [95% CI: 5.5-6.2 per 1,000 person-
RISK. Although the overall incidence of HF in the
years]), and White men (4.9 per 1,000 person-years
United States appears to be stable or even
[95% CI: 4.5-5.3 per 1,000 person-years]). During
decreasing, the incidence of HFpEF specifically
this time period, annual percent change for first
continues to rise (Figure 1).9,10 Across 4 community-
HFpEF hospitalization increased for all 4 race-sex
based cohorts, the incidence rate of HFpEF is esti-
groups and was particularly pronounced among
mated at w27 cases per 10,000 person-years.11 Over
Black women.17 These racial disparities in HFpEF
the span of 2 decades, secular trends in the Fra-
prevalence may actually be underestimated given
mingham Heart Study suggest a >50% higher inci-
lower NP levels in Black individuals compared with
dence rate in 2000-2009 vs 1990-1999. Similarly, the
other race/ethnic groups, which likely leads to
prevalence of HFpEF is increasing and is expected
underdiagnosis.6
to exceed that of heart failure with reduced ejection
fraction (HFrEF) in the near future. 12 Specifically, HFpEF ACROSS THE HF STAGES:
data from the national inpatient sample demon- FROM RISK FACTORS TO DISEASE
strate that the number of HFpEF hospitalizations
more than doubled from 189,260 in 2008 to 495,095 HFpEF RISK FACTORS (STAGE A). Most traditional
in 2018. 13 Using pooled data from the CHS (Cardio- HF risk factors are shared and increase susceptibility
vascular Health Study) and MESA (Multi-Ethnic for both HFpEF and HFrEF, including older age, hy-
Study of Atherosclerosis), the estimated lifetime pertension, and ischemic heart disease. 18 However, it
risk of HFpEF at age 45 years is >10% in both men is important to note that obesity, metabolic
and women. 14 Taken together, these data suggest dysfunction, and physical inactivity appear to spe-
that the total burden of HFpEF is projected to cifically predispose to HFpEF more so than HFrEF
1812 Borlaug et al JACC VOL. 81, NO. 18, 2023
Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834
T A B L E 1 HFpEF Definitions and Considerations Across Different Studies
HFpEF Definition Criteria Use Cases Considerations
Universal definition4 Clinical HF with structural and/or functional Clinical practice Developed in 2021–data evolving on stage A, B,
cardiac abnormality, corroborated by and C reclassifications (especially stage B)
[natriuretic peptide levels and/or
objective evidence of pulmonary or
systemic congestion
Hemodynamic Elevated PCWPs at rest ($15 mm Hg) CPET, physiology-based “Gold standard” physiological evidence of HF
definition1,112,119 or with exercise (PCWP $25 mm Hg studies but relies on tertiary referral centers with
supine or PCWP/CO slope >2 upright) greater expertise
Epidemiologic Combination of signs, symptoms, and Prospective longitudinal Robust for overtly congested patients with
studies1,112 objective evidence, eg, Framingham cohorts advanced HF, “specific but not sensitive,”
Heart Study criteria may miss outpatient diagnoses
HF hospitalization Combination of signs, symptoms, and objective Clinical trials Expert clinical endpoint adjudication,
criteria151 evidence, eg, Cardiovascular Trials Initiative “specific but not sensitive,” relies on chart
and U.S. Food and Drug Administration documentation, may miss outpatient
diagnoses
ICD billing codes1,23 Variable ICD codes used: AHA Get With the Outcomes research, Misclassification has been described,
Guidelines and others claims-based datasets especially with complex medical
conditions including HFpEF, “sensitive
but not as specific,” missed most
outpatient diagnoses, many non-HF
diagnoses included152
AHA ¼ American Heart Association; CO ¼ cardiac output; CPET ¼ cardiopulmonary exercise testing; HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction;
ICD ¼ International Classification of Diseases; PCWP ¼ pulmonary capillary wedge pressure.
(Figure 2). Among 4 community-based cohorts, higher Evolving studies will need to more clearly define
body mass index (BMI) and insulin resistance were how to apply these criteria to preclinical HFpEF. The
differentially associated with future HFpEF, particu- diagnosis of stage B HF requires establishing the
larly among women vs men. 19 In addition, physical absence of HF symptoms; however, clinicians may be
inactivity was associated with higher risk of HFpEF less likely to rigorously test for symptoms such as ex-
compared with HFrEF in a dose-dependent manner. 20 ercise intolerance in patients with abnormal cardiac
Excess body fat leads to development of HFpEF structure/function associated with HFpEF (eg, LV hy-
through a variety of mechanisms (Figure 2), and, with pertrophy, left atrial enlargement, diastolic dysfunc-
continued increases in the obesity and physical tion) compared with patients with asymptomatic LV
inactivity epidemics and associated cardiometabolic systolic dysfunction. If exercise intolerance is present,
consequences, current trends in increasing HFpEF determining whether it is due to cardiac vs extrac-
incidence and prevalence will continue to compound ardiac abnormalities can also be challenging.
in the future. 8 Further study is required to better Furthermore, it is known that NP concentrations are
understand the mechanisms linking adiposity and lower among individuals with overt HFpEF vs HFrEF.1
deconditioning with HFpEF. Whether the same cutpoints in preclinical HFpEF vs
CARDIOVASCULAR REMODELING IN PRECLINICAL preclinical HFrEF adequately capture risk remains to
HFpEF (STAGE B). How individuals progress from be seen, but seems unlikely as roughly one-third of
risk factors (stage A) to cardiac remodeling and patients with stage C HFpEF have NP levels below
preclinical HFpEF (stage B) and eventual HFpEF typical thresholds used for HF diagnosis.5 A recent
(stages C and D) remains incompletely understood. In study has shown that even among patients where
contrast to stage B HFrEF, which is easily recognized HFpEF has been excluded, an increasing burden of
as asymptomatic left ventricular (LV) systolic HFpEF risk factors and functional abnormalities based
dysfunction, readily prompting a change in clinical on echocardiography are strongly correlated with he-
management, stage B HFpEF remains nebulous. The modynamic and aerobic limitations typical of (but less
most recent consensus document defined patients severe than) those observed in patients with overt,
with stage B HF as individuals free of HF symptoms, stage C HFpEF. 21 As we consider the role of potential
with evidence of structural heart disease (eg, LV preventive therapies for HFpEF, clearly defining
hypertrophy, chamber enlargement), abnormal preclinical HFpEF will be paramount.
cardiac function (eg, elevated filling pressures or UNDER-RECOGNITION OF HFpEF (STAGE C).
diastolic dysfunction), or elevated NP or cardiac Recently developed scoring systems (discussed later in
troponin levels.4 this paper) now provide a means to screen larger
patient populations and estimate the potential scope cardiovascular mortality.27 As compared with women,
of undiagnosed HFpEF in the community. Among in- men with HFpEF consistently display greater risk for
dividuals with unexplained dyspnea but without mortality as well as HF hospitalization, and this also
diagnosis of HFpEF in ARIC, the H2FPEF score was contributes to the greater prevalence of HFpEF in
high risk ($5) in 35%, indicating that a substantial women as compared with men (Figure 1). 28
proportion of older adults with HFpEF in the commu-
nity are likely undiagnosed (Figure 3).22 This underdi- PATHOPHYSIOLOGY OF HFpEF
agnosis may be even more problematic among Black
patients, who are known to have lower NP levels than COMMON DISEASE MECHANISM HYPOTHESES.
White individuals, 6 and who made up a larger pro- HFpEF was first considered to be caused by diastolic
portion of patients with undiagnosed dyspnea as dysfunction caused by hypertensive LV remodeling in
H 2FPEF scores increased in the analysis from isolation, exacerbated by abnormal ventricular-
ARIC (20.7% Black in the lowest score category and arterial coupling and chronotropic incompetence.
38.3% in the highest risk category; P < 0.001).22 The These mechanisms were initially observed in HFpEF
problem of HFpEF under-recognition is even greater patients with predominantly hypertensive heart dis-
now given the emergence of SGLT2is as highly effec- ease, where the primary mechanistic hypotheses
tive treatments. centered around hypertension leading to LV hyper-
CLINICAL OUTCOMES AMONG PATIENTS trophy with stiff and relatively small LVs and, even-
WITH HFpEF tually, overt HF.29-32 Over the past 2 decades the
predominant clinical phenotype in HFpEF has shifted
SURVIVAL AND HF READMISSIONS. Patients with from older adults with isolated hypertensive heart
HFpEF have similarly poor survival when compared disease to multimorbid patients with obesity, dia-
with HFrEF (Figure 1). In community-based cohorts, betes, and metabolic syndrome,8,33 focusing greater
the incidence rate of all-cause mortality among in- attention toward systemic inflammation, endothelial
dividuals with newly diagnosed HFpEF vs HFrEF was dysfunction, altered myocardial energetics, and
394 vs 459 events per 10,000 person-years, respec- abnormalities in skeletal muscle. 34-37
tively. 11 Among individuals in the Get With The HYPERTENSIVE VENTRICULAR STIFFENING. Passive
Guidelines-HF registry with linked Medicare data myocardial stiffness is often increased in HFpEF and
through 2014, the 5-year mortality rate was 75.3% has been considered an important contributor to
among those with HFpEF, and 75.7% among those pathophysiology.31,32 The causes for myocardial
23
with HFrEF. Despite similarly poor outcomes, the stiffening include factors influencing the extracel-
mode of death differs by HF subtype, with a lesser lular matrix and those intrinsic to the cardiomyocyte
proportion of cardiovascular compared with non- itself. 37 Myocardial fibrosis is a well-established
24
cardiovascular deaths in HFpEF vs HFrEF. Among a feature of HFrEF, and total collagen volume is
nationwide study of patients admitted with HFpEF in similarly increased in HFpEF endomyocardial biopsy
2017, the 30-day all-cause readmission rate was 21%, tissue.38-41 Both collagen type I and type III expres-
but only a minority (9.2%) of these readmissions was sion and tissue staining are elevated in HFpEF and
due to acute HFpEF.25 Similar to mode of death, the are coupled to reduced collagenase,
proportion of cardiovascular and HF-specific read- metalloproteinase-1, but increased tissue inhibitor of
missions appears lower in HFpEF vs HF with metalloproteinase expression, which may further
mid-range ejection fraction (EF), underscoring the enhance fibrosis. In addition to altering matrix
importance of management of noncardiac comorbid- turnover, cross-linking of collagen including the
ities in HFpEF. 26 formation of advanced glycation end products con-
RACE AND SEX DIFFERENCES IN HFpEF OUTCOMES. tributes to fibrosis and stiffening. Potential mecha-
In the ARIC study, age-adjusted 28-day and 1-year nisms for the altered matrix structure include
case fatality rates after HFpEF hospitalization were inflammation, diabetes, and neurohumoral activa-
higher among White vs Black individuals. Specif- tion. Although increases in passive stiffness are
ically, 28-day age-adjusted case fatality was 11.7% commonly attributed exclusively to myocardial
(White males), 10.1% (White females), 7.2% (Black fibrosis, in the largest endomyocardial biopsy study
females), and 7.6% (Black males). 17 However, within a of HFpEF to date, moderate or greater myocardial
clinical trial sample, Black patients with HFpEF had fibrosis was only present in the minority (27%) of
worse outcomes including HF hospitalization patients. 38 Alterations in isotype expression and
compared with White patients, with no difference in phosphorylation of sarcomeric proteins such as titin
T A B L E 2 Clues, Evaluation, and Treatment Options for HFpEF Masqueraders
Clues to the Possible Presence of an HFpEF Masquerader
Definite HFpEF (high natriuretic peptides, high PCWP, and/or HF hospitalization) with low H2FPEF score
Kussmaul’s sign: [JVP with inspiration
YVoltage ECG relative to [LV wall thickness LVH without a history of hypertension or progression withdrawal of antihypertensives due to
progressively low BP
Inability to up-titrate or initiate neurohormonal therapy; history of recently coming off all antihypertensive therapy
Known risk factor for infiltrative/restrictive cardiomyopathy HFpEF in a young patient (age <55 y, unless obese or diabetic)
Prominent musculoskeletal or neurologic features: eg, bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, significant
peripheral neuropathy
Etiology Clinical Clues Diagnostic Evaluation Treatment Options
Cardiac amyloidosis Progressively lower BP, recent BP Serum immunofixation, free light chains, Chemotherapy (for light chain
medication withdrawal, or orthostatic urine protein electrophoresis, amyloidosis), tafamidis (for
hypotension; bilateral carpal tunnel prealbumin, strain echocardiography transthyretin amyloidosis),
syndrome, lumbar spinal stenosis, (relative apical sparing ratio >0.87, consider anticoagulation (high risk
biceps tendon rupture; peripheral LVEF/GLS ratio >4.1), cardiac MRI with for cardioembolic complications),
neuropathy; persistent low-level [ T1 mapping (high ECV, difficulty nulling avoid nondihydropyridine CCBs,
troponin, low tissue Doppler velocities the myocardium), nuclear scintigraphy, ACE inhibitor, ARB, ARNIs.
(e’, a’, s’ <5 cm/s), low-voltage ECG biopsy.
with [ LV wall thickness.
Hypertrophic Family history; symptoms due to LV Echocardiography with strain imaging Mavacamten (for LV outflow tract
cardiomyopathy obstruction; ECG with increased voltage (asymmetric septal hypertrophy, LV obstruction); weigh risk/benefit of
out of proportion to hypertension outflow tract or intracavitary septal reduction surgery/ablation;
history; ECG with deep T-wave obstruction, SAM, apical hypertrophy, beta-blockers, nondihydropyridine
inversions in precordial leads (apical specific bullseye patterns such as focal CCBs; avoid vasodilators.
HCM). anteroseptal or apical abnormalities);
cardiac MRI.
Cardiac sarcoidosis History of extracardiac sarcoidosis; Echocardiography (septal thinning); cardiac Immunosuppression.
prominent ventricular arrhythmias MRI (septal thinning, midmyocardial or
despite preserved LVEF; high-grade AV subepicardial scar); FDG-PET; biopsy.
block (especially if age <60 y).
Hemochromatosis Family history; history of frequent Ferritin, HFE genetic testing, cardiac MRI Chelation therapy; therapeutic
transfusions; presence of liver with T2* imaging; cardiac biopsy. phlebotomy.
disease þ diabetes.
Fabry disease Echocardiogram with infiltrative Alpha-galactosidase level, genetic testing, Enzyme replacement therapy.
appearance but ECG shows increased cardiac biopsy (with electron
voltage; rash in bathing suit microscopy).
distribution; significant proteinuria.
High-output HF Echocardiography with 4-chamber Evaluate for underlying cause of high Treat underlying cause (eg, correction
enlargement and/or increased LV output state (eg, anemia, thiamine of anemia, thiamine replacement,
outflow tract VTI. deficiency, fistula, cirrhosis, AVMs). fistula ligation for shunts, liver
transplantation for cirrhosis,
embolization for AVMs).
Myocarditis History of flu-like illness (or diagnosed Cardiac MRI (epicardial or subepicardial late Immunosuppression for specific types
COVID or influenza) prior to onset of gadolinium enhancement), cardiac (eg, giant cell, eosinophilic
symptoms; troponin elevation. biopsy. myocarditis).
Congenital heart History of other congenital anomalies, Echocardiography, cardiac MRI, cardiac CT, Percutaneous or surgical correction of
disease elevated hemoglobin (suggests invasive hemodynamics with saturations. congenital anomaly.
secondary polycythemia due to chronic ASD will cause RA/RV enlargement;
hypoxemia). Common forms of PAPVR will cause RV/PA enlargement
congenital heart disease that can and diastolic septal flattening (volume
present late in life include ASD, PAPVR, overload); small VSDs typically affect the
VSD (perimembranous, supracristal), left side of the heart > right side of the
PDA. heart, will cause LA/LV enlargement; PDA
will cause LA/LV enlargement.
Valvular heart Differentiate primary from secondary Echocardiography, invasive hemodynamics, Surgical or percutaneous valve
disease causes of valve disease (patients with CT (for calcific valve disease). interventions.
HFpEF can develop significant MR due
to LA enlargement and TR due to RA
enlargement [or RV failure], particularly
in the setting of atrial fibrillation/
flutter).
Coronary artery All patients with signs and symptoms of Stress testing; coronary CT angiography; Revascularization, aspirin, statin,
disease HFpEF should be evaluated for CAD. invasive coronary angiography. beta-blockers, nitrates.
Continued on the next page
modify cardiomyocyte stiffness leading to increased obese HFpEF) can also effectively increase LV stiff-
passive LV chamber stiffness in patients with ness (Figure 4).44,45
34,37,42,43
HFpEF. Heightened pericardial constraint OBESITY-CARDIOMETABOLIC STRESS. Myocardial
(eg, due to increased epicardial and pericardial fat in stiffness estimated based on echocardiography is
T A B L E 2 Continued
Etiology Clinical Clues Diagnostic Evaluation Treatment Options
Toxins History of toxin exposure (eg, Clinical history, blood testing, Removal of offending toxin; evaluate
chemotherapy or radiation [even if endomyocardial biopsy. and treat for coronary, valvular,
remote], illicit drug use, and pericardial disease in patients
hydroxychloroquine, heavy metals). with history of XRT.
Pulmonary arterial Risk factor for PAH (eg, autoimmune Echocardiography (elevated PA systolic Pulmonary vasodilators; treatment of
hypertension disease, anorexigen exposure, HIV, liver pressure [>50 mm Hg] with E/A underlying cause of PAH if
disease, congenital heart disease, ratio <1 or lateral E/e’ ratio <8; systolic secondary (eg, lung disease, OSA,
chronic lung disease, OSA, pulmonary interventricular septal flattening; RA chronic thromboembolic
embolism); exertional lightheadedness. > LA size and/or interatrial septum pulmonary hypertension).
bows right-to-left); right heart
catheterization.
Predominant lung Patients with risk factors for severe lung Right heart catheterization to define whether Inhaled therapies for COPD/reactive
disease with disease including long smoking history, hemodynamic congestion is present, airways disease, nocturnal oxygen
cor pulmonale environmental exposures, severe sleep spirometry, lung mechanics and alveolar or continuous positive airway
apnea, oxygen dependence, severe diffusion capacity, high-resolution chest pressure, interstitial lung disease
abnormalities on spirometry. CT. Note that mild to moderate treatments.
abnormalities in spirometry and lung
diffusion are also common in HFpEF.
Pericardial disease History of pericarditis, pericardial effusion, Echocardiography (constriction: diastolic Constrictive pericarditis: immuno-
(constrictive radiation therapy, cardiac surgery, septal bounce; respiratory variation in suppression for active pericardial
pericarditis, autoimmune disease; low BP; exertional mitral inflow; septal e’ $ lateral e’; inflammation ([ CRP, [ ESR,
chronic lightheadedness/dizziness; prominent diastolic flow reversal in hepatic vein pericardial edema on cardiac MRI
pericardial right-sided heart failure (eg, hepatic flow during expiration), CT, MRI with T2 T2 imaging); pericardiectomy for
effusion) congestion, ascites); low output state. imaging and LGE, invasive advanced disease without evidence
hemodynamics (discordance in LV/RV of inflammation.
pressure tracings during inspiration in Pericardiocentesis, drain, or window
patients with constrictive physiology). for pericardial effusion.
Anatomic causes Significant symptoms and/or diuretic use CT or MRI; other diagnostic imaging based Correction of anatomic cause of cardiac
(extrinsic cardiac despite relatively normal cardiac on cause of extracardiac compression. compression (eg, hiatal hernia,
compression) structure/function; obscured dilated esophagus, tumor).
echocardiography images.
[ ¼ increased; Y ¼ decreased; ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; ARNI ¼ angiotensin receptor/neprilysin inhibitor; ASD ¼ atrial septal
defect; AV ¼ atrioventricular; AVM ¼ arteriovenous malformation; BP ¼ blood pressure; CAD ¼ coronary artery disease; CCB ¼ calcium-channel blocker; COPD ¼ chronic
obstructive pulmonary disease; CRP ¼ c-reactive protein; CT ¼ computed tomography; ECG ¼ electrocardiogram; ESR ¼ erythrocyte sedimentation rate;
FDG-PET ¼ fluorodeoxyglucose-positron emission tomography; HCM ¼ hypertrophic cardiomyopathy; JVP ¼ jugular venous pressure; GLS ¼ global longitudinal strain;
LA ¼ left atrial; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; LVH ¼ left ventricular hypertrophy; MRI ¼ magnetic
resonance imaging; OSA ¼ obstructive sleep apnea; PA ¼ pulmonary artery; PAH ¼ pulmonary arterial hypertension; PAPVR ¼ partial anomalous pulmonary venous return;
PDA ¼ patent ductus arteriosus; RA ¼ right atrial; RV ¼ right ventricular; SAM ¼ systolic anterior motion; TR ¼ tricuspid regurgitation; VSD ¼ ventricular septal defect;
VTI ¼ velocity time integral; XRT ¼ radiation therapy; other abbreviation as in Table 1.
F I G U R E 1 Epidemiology of HFpEF
HFpEF Incidence HFpEF Prevalence HFpEF Clinical Outcomes
• 27 cases per 10,000 • 1.0%-1.5% of population • 5-year mortality: 75.3%

person-years • Highly age dependent (GWTG registry)
• Lifetime risk: 1 in 10 at • 30-day all-cause
age 45 years readmission rate: 21%
Secular trends ↑ incidence over time ↑ prevalence over time ?
↔
Sex differences > <
HFpEF incidence rising HFpEF prevalence rising Similarly poor survival
HFpEF vs HFrEF
relative to HFrEF relative to HFrEF ↓ CV death in HFpEF vs HFrEF
Summary of current understanding of HF incidence, prevalence, and outcomes and influence of sex drawn from references 10-17 and 24-27.
CV ¼ cardiovascular; HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction;
GWTG ¼ AHA Get With The Guidelines.
F I G U R E 2 Pathophysiology of Obesity-Related HFpEF
Men
8 β = 0.024,
r = 0.774
Cumulative Incidence of HFpEF
10%
Total Blood Volume (L)

7 Women
2 β = 0.033,
8% r = 0.876
HFpEF 6
6%
5
4%
4
2%
3
0% 0.2
0 2 4 6 8 10 12 14 50 100 150
0
0
Mitral valve level Mid-cavity level
50
00
50
00
50
00
1,
2,
1,
2,
3,
Years Body Mass (kg)
Nonobese Men Nonobese Women Leisure Time Physical Activity
(MET/min/Week)
Obese Men Obese Women
Pericardial restraint &

Increased blood
Sex Differences Physical Inactivity ventricular
volume
interdependence
Obesity Worse RV Decreased myocardial Greater senescent Increased stressed HFpEF

contractility efficiency myocardial stiffening blood volume
ΔLV Diastolic Elastance (mm Hg/mL)
0.020
100
† 35 P for linear
20 † r = 0.40, P < 0.05 trend < 0.001
30 0.015 80
Peak SBV/TBV (%)
Tension (mN/mm2)
†
Efficiency (%)
15 25
* 60
§ * 20 0.010
10 ‡
¶ 15 40
10 0.005
5 # 20
5
r = 0.56, P < 0.0001
0 0 0.000 0
0.01 0.1 1 10 100 0 20 40 60 10 20 30 40 50
6%
%
.6
+4
>4
2.
+0
Ca2+ Concentration (μM) BMI (kg/m2) BMI (kg/m2)

to
<−
to
%
.6
%
Nonfasting (n = 9) HFpEF: Ob/DM (n = 14) HFpEF NCD

+0
.6
−2
HFpEF: Ht/Hp (n = 13) HFpEF: Mixed (n = 15)

4-Year Weight Change (%)
Obesity is a major risk factor for HFpEF, particularly in women, in addition to reductions in physical activity. TBV is strongly related to body mass, with a stronger
relationship in women. Cardiomegaly due to chamber remodeling and increases in epicardial fat in obesity to enhance pericardial restraint and ventricular interaction.
As compared with nonobese patients, those with increasing BMI display impaired RV sarcomere function, reduced myocardial efficiency, and more severe increases in
SBV and ratio of SBV to TBV, reflected in reduced venous capacitance in obese patients with HFpEF. Age-related diastolic LV stiffening is exaggerated in patients with
greater weight gain. Figure adapted with permission.19,20,44,46,47,49-51,150 BMI ¼ body mass index; LV ¼ left ventricular; RV ¼ right ventricular; SBV ¼ stressed blood
volume; TBV ¼ total blood volume; other abbreviations as in Figure 1.
increased in patients with obesity, and the increases Direct tissue analyses are shedding new light as
in LV chamber stiffness with aging are amplified well. In human myocardial tissue biopsy samples
among patients with greater weight gain (Figure 2).46 from a contemporary obese HFpEF cohort, car-
Blood and plasma volumes increase with greater body diomyocyte hypertrophy and fibrosis were common
weight,47 a relationship that is steeper in women than in HFpEF, although the severity of each was mild to
men, 47 and patients with obesity-related HFpEF moderate.38 In a follow-up study from the same
display higher blood volume and greater sensitivity of group, patients with Class II or greater obesity
filling pressures on plasma volume. 44,48 Even in the exhibited substantially reduced right ventricular (RV)
absence of frank volume overload, abnormal distri- systolic sarcomere function, but less passive car-
bution of blood volume (increased stressed blood diomyocyte stiffness compared with cardiomyocytes
volume) due to impaired venous capacitance is pre- from patients with a primarily hypertensive pheno-
sent in HFpEF, and notably is associated with type of HFpEF (Figure 2).50 However, there are major
increasing BMI (Figure 2), resulting in even greater and fundamental differences between the RV and LV
elevations in cardiac filling pressures. 49 at the chamber, matrix, and cardiomyocyte levels,
F I G U R E 3 Scope of Undiagnosed HFpEF in the Community
Estimated
H2FPEF Undiagnosed
Dyspnea, Score HFpEF,
HF Hospitalization or CV Death n Probability n
Diagnosed HFpEF 502 1.00 N/A

Dyspnea, n = 641
H2FPEF ≥6 69 0.95 65
Unexplained
H2FPEF ≥5 227 0.85 193 410/641

(64%)
H2FPEF 3-4 264 0.65 172
H2FPEF 1-2 150 0.30 45

Asymptomatic
(Reference)
0 2 4 6 8
HR (95% CI)
Among 4,892 community-dwelling older adults participating in the ARIC study, 76.6% had no dyspnea, 10.3% had been diagnosed with HFpEF, and 13.1%
had moderate or greater dyspnea, but no diagnosis of HFpEF. Among those with unexplained dyspnea, 35% had high-risk H2FPEF scores. If we extrapolate
HFpEF risk from prior work117 to this sample from ARIC22 it becomes clear that a substantial proportion of older adults with HFpEF in the community
potentially remain undiagnosed and, therefore, untreated. ARIC ¼ Atherosclerosis Risk in Communities; other abbreviations as in Figure 1.
and it remains unknown whether such differences women without HF, 51 which may relate to greater
would be observed in LV specimens. myocardial reliance on fat vs carbohydrate oxida-
Myocardial work increases and efficiency de- tion. 8,51 Recent studies have demonstrated that
creases with increasing BMI and insulin resistance in myocardial energetics are abnormal in HFpEF52 and
F I G U R E 4 Mechanisms of Hemodynamic Congestion in HFpEF
50
Pressure (mm Hg)
40
Intrinsic Atrial and 30
↑Afterload-Mediated
Ventricular Myocardial
20 Cardiac Dysfunction
Dysfunction
10
0
Hypervolemia ↑Ventricular Interaction

↑Stressed and Pericardial Restraint
Blood Volume
Increases in pulmonary capillary wedge pressure (blue) and left ventricular end diastolic pressure (red) develop through a variety of pathophysiological
perturbations in HFpEF, many of which coexist within the same patient, but some that do not, and may require different treatments. Abbreviation as in
Figure 1.
notably reverse with weight loss among patients with coronary microvascular dysfunction in heart failure
obesity but no HF.53 Myocardial gene expression with preserved ejection fraction) study investigated
signatures differ in obese HFpEF compared with the prevalence of coronary microvascular dysfunction
HFrEF and controls, with uniquely up-regulated (CMD) and its association with endothelial dysfunc-
genes in HFpEF enriched for mitochondrial adeno- tion, myocardial dysfunction, and HF severity in pa-
sine triphosphate synthesis/electron transport, path- tients with HFpEF. 65 Nearly 75% of patients in the
ways that are down-regulated in HFrEF, further study had evidence of CMD, similar to other invasive
evidencing fundamental differences in the HF sub- studies,66,67 and patients with worse coronary flow
54
types. HFpEF down-regulated genes included reserve were associated with higher N-terminal pro
endoplasmic reticulum stress, autophagy, and brain natriuretic peptide, markers of endothelial
angiogenesis pathways. dysfunction such as higher urinary albumin-to-
In a hemodynamic study of obese HFpEF compared creatinine ratio, and worse RV function.65 In a sub-
with nonobese HFpEF and controls, those with study analysis of proteomics from the PROMIS-HFpEF
obesity demonstrated worse exercise capacity (lower study, comorbidity burden was associated with worse
peak oxygen consumption), higher biventricular structural and functional parameters by echocardiog-
filling pressures, and depressed pulmonary artery raphy and with inflammatory proteins; proteins
vasodilatory reserve.44 Furthermore, obese patients involved in inflammation mediated the relationship
with HFpEF were more likely to have RV dysfunction between comorbidity burden and markers of hemo-
as well as cardiomegaly due to increased epicardial dynamics and RV function.68 Chronically, CMD may
fat, leading to enhanced pericardial restraint and promote vascular rarefaction, which has been
ventricular interaction (Figure 2). 44,55 Similar findings demonstrated in autopsy studies in HFpEF, showing
were noted in a post hoc analysis of the RELAX associations with fibrosis.69 Population-based studies
(PhosphdiesteRasE-5 Inhibition to Improve CLinical have also supported the role of endothelial adhesion
Status and EXercise Capacity in Diastolic Heart Fail- molecules (eg, intercellular adhesion molecule-1
ure) trial, in which obese patients with HFpEF had [ICAM-1] and vascular cell adhesion molecule-1
worse peak oxygen consumption and 6-minute walk [VCAM-1], key drivers of leukocyte infiltration across
distance compared with nonobese patients with the vascular endothelium and into the heart and other
HFpEF, with greater evidence of systemic inflamma- organs) in HFpEF pathogenesis by relating elevated
tion (higher c-reactive protein levels). 56 circulating levels of these proteins to both the echo-
cardiographic substrate for HFpEF and incident
MICROVASCULAR INFLAMMATION. In 2013, Paulus HFpEF.70,71
and Tschope34 proposed a new model wherein More recent studies have expanded and reshaped
comorbidities, such as obesity, diabetes, chronic lung the Paulus hypothesis to include metabo-
disease and hypertension, induce a proinflammatory inflammation, wherein obesity and nutrient over-
state in which coronary microvascular endothelial load leads to chronic microvascular inflammation,
dysfunction develops, leading to downstream reduc- enhanced activation of inducible NO synthase,
tion in nitric oxide (NO) bioavailability, cyclic gua- nitrosative stress, metabolic inflexibility, disrupted
nosine monophosphate (cGMP), and eventual protein NO/cGMP signaling, and altered protein folding and
kinase G activity in cardiomyocytes. Studies of LV cellular quality control. 35,72 The primary origin of
endomyocardial biopsy and analyses of inflammatory metabo-inflammation in HFpEF remains unclear.
cell markers suggested increased oxidative stress and Adipocytes and adipose macrophages may secrete
depressed NO signaling resulting in inflammation inflammatory adipokines, such as interleukin-6, and
play a key role in this syndrome.34,37,42 This cascade increases in visceral fat are independently associated
was proposed to explain maladaptive changes with risk of HFpEF 73 and hemodynamic disease
including myocyte hypertrophy, increased myocyte severity, especially in women. 74,75 Myocardial tissue
tension, and interstitial fibrosis. However, therapies may also be a source, as evidenced by increased
targeting this pathway have not shown efficacy in monocyte infiltration38 and inducible NO synthase
57-60
clinical trials, although it is difficult to discern expression in RV tissue.72 Emerging data suggest that
whether these therapies effectively improved intra- SGLT2is work at least in part by enhancing nutrient
cellular cGMP– protein kinase G signaling. deprivation signaling in multiple cell types, resulting
Several studies have reported associations between in improved cell quality control and reduced inflam-
elevated inflammatory biomarkers and incident mation and oxidative stress.76 Further study is
HFpEF, prevalent HFpEF severity, and outcomes.61-64 required to better understand the primary source(s)
The PROMIS-HFpEF (Prevalence and correlates of of inflammation, preferably from human tissue, and
examining cardiomyocytes from the left and right microvasculature, as indicated earlier in this
sides of the heart. paper.65,66,94 Thus, in some patients RV dysfunction
CARDIAC PATHOPHYSIOLOGY. Impairments in car- can occur in concert with LV dysfunction due to cor-
diac structure and function are the most conspicuous onary microvascular dysfunction and/or metabolic
abnormalities in HFpEF and span all 4 chambers.1 Al- abnormalities in both ventricles simultaneously.
terations in LV relaxation and increases in chamber Indeed, the RV in patients with HFpEF exhibits
stiffness are present and importantly contribute to heightened afterload sensitivity in response to pul-
elevation in filling pressures.31,32,77 Over time, chronic, monary artery pressure elevation compared with pa-
sustained or intermittent elevation in LV filling pres- tients without HF. 90
sures in HFpEF cause remodeling and dysfunction of Although there is evidence to support sequential
the left atrium (LA), frequently culminating in the causal linkages in disease progression, such as atrial
development of atrial fibrillation (AF), which may be myopathy leading to PVD and RV dysfunction,91
considered as a “biomarker” of underlying LA myop- recent studies have also shown that atrial and
athy and an indicator of more advanced HFpEF biventricular dysfunction can progress across both
(Central Illustration).78-80 Indeed, abnormalities in LA sides of the heart in parallel, not just in series as
function are more predictive of adverse outcome than shown in the Central Illustration, 95 suggesting a
80
those of the LV, and impairments in LA strain have common response to shared inflammatory, metabolic,
been shown to be the most robust imaging markers or ischemic insults. It is likely that such insults
distinguishing HFpEF from noncardiac causes of dys- also affect extracardiac organ function in parallel
pnea.81-83 Although LV dysfunction precedes LA (as mentioned later in this paper).
dysfunction in the majority of patients with HFpEF, a NONCARDIAC MECHANISMS. Numerous extrac-
subset of patients with HFpEF may develop a primary ardiac mechanisms importantly contribute to the
LA myopathy as the cause of elevated LA pressure and pathophysiology of HFpEF, 36 some with differing
reduced LV filling (resulting in insufficient cardiac impacts in women and men. 74,75,96 These include
output augmentation during exertion). abnormalities in conduit arterial vessels, 96,97 the
Regardless of the cause, sustained elevation in endothelium and microvasculature,65,66,94 skeletal
LA pressures leads to worsening pulmonary hyper- muscle,98,99 lung, 89,100 kidney,84 and adipose tissue,
tension (PH), especially in patients with more severe especially among patients with excess visceral
LA myopathy. 84 Roughly 80% of patients with HFpEF fat.8,74,75 According to the Fick principle, peak O 2
have PH,85,86 which starts as a passive result of consumption during exercise is determined by the
downstream LA pressure elevation, but in many pa- product of cardiac output and arterial-venous O2
tients ultimately leads to pulmonary vascular disease content difference, and, in patients with HFpEF, each
(PVD), characterized by a combination of vascular component contributes w50% to deficits in peak
remodeling and vasoconstriction that affects the VO 2.99,101 Autonomic dysfunction is also common in
pulmonary veins, capillaries, and small arteries, HFpEF because many patients display chronotropic
leading to worsening exercise capacity, lung incompetence, 30,102 blunted arterial baroreflex sensi-
congestion, pulmonary diffusion abnormalities, and tivity,30 and abnormalities in venous capacitance that
increased mortality (Central Illustration). 87-89 importantly contribute to elevation of filling pres-
Development of PVD is then associated with sures. 49,103 In patients with diagnosed HFpEF, it is
increased risk of RV dysfunction, secondary tricuspid important to consider alternative, noncardiac
regurgitation, and systemic venous congestion,90,91 contributors to each identified pathophysiological
which are also markers of advanced or “Stage D” abnormality given the potential to treat these con-
HFpEF (Central Illustration). However, recent studies tributors. For example, in patients with evidence
have extended the importance of earlier stages of of HFpEF and PVD, noncardiac contributors to PVD
PVD progression in HFpEF as well. For example, PVD (eg, chronic lung disease) should be identified
that is “latent,” or apparent only during exercise, is and treated.
associated with increased risk for adverse events, and MULTIPLE PHENOTYPE HYPOTHESIS. Hemodynamic
significantly modifies the response to novel therapies abnormalities that cause tissue congestion are
such as shunt devices,92 leading to an excessive in- consistent across all patients with HFpEF (by defini-
crease in pulmonary artery pressure as lung perfusion tion),4 but this does not mean that all patients reach
93
increases during exercise. this characteristic signature of hemodynamic abnor-
Patients with HFpEF have systemic endothelial malities through a common mechanism. In contrast to
dysfunction, which may also affect the coronary the hypothesis that HFpEF is predominantly a single
C E NT R AL IL L U STR AT IO N Temporal Disease Progression in Heart Failure With Preserved Ejection Fraction
Borlaug BA, et al. J Am Coll Cardiol. 2023;81(18):1810–1834.
Initially HFpEF is characterized by relatively little cardiac remodeling and mild impairment in LV mechanics, with elevation in LV filling pressures exclusively during
exercise. With time, there is progressive deterioration in LA function and remodeling leading to secondary atrial functional MR and development of paroxysmal AF.
Mild elevation in LV filling pressures at rest may develop at this stage. With further progression, LA remodeling/dysfunction progress further, with transition to
permanent AF, worsening PH, pulmonary vascular remodeling and vasoconstriction, RV and RA dysfunction, more severely impaired cardiac output, and increased
pericardial restraint, findings of advanced HFpEF. Patients present at any time during this progression, and treatments may differ depending on presentation.
Progression through these stages is not inevitable and may follow distinct tempos. Comorbidities, inflammation, and endothelial dysfunction can manifest differently
among individuals, further increasing heterogeneity. AF ¼ atrial fibrillation; HFpEF ¼ heart failure with preserved ejection fraction; LA ¼ left atrial; LV ¼ left
ventricular; MR ¼ mitral regurgitation; PH ¼ pulmonary hypertension; RA ¼ right atrial; RV ¼ right ventricular.
disorder caused by singular inciting mechanisms, even as the individual causes differ from a cellular,
multiple lines of evidence now suggest that HFpEF is organ, and tissue basis, and, in most patients
more accurately conceptualized as a combination of with HFpEF, multiple mechanisms interact in a
pathophysiological phenotypes that converges to complex fashion to cause hemodynamic abnormal-
produce this common hemodynamic signature of ities (Figure 5, Table 3).104,105 A key unanswered
elevated LV filling pressures at rest or with exercise, question is to what extent the different phenogroups
F I G U R E 5 Phenotypic Spectrum of HF With Normal EF
HFpEF
Obese,
Cardiometabolic
Ischemic
Arterial
Stiffening
All
Clinical
HF,
EF ≥50%
Pulmonary
Vascular
Disease LA
Myopathy
The area of the outer circle represents all patients with the clinical syndrome of HF and an EF $50%. Even after excluding non-HFpEF
“masqueraders” (Table 2), shown here by the shaded blue area, multiple pathophysiologically distinct phenogroups exist within the broader
spectrum of HFpEF (yellow circle). These individual phenogroups are sometimes singular but typically display considerable overlap with one
another, complicating schemes to separate them into discrete cohorts. The area of each ellipsoid is not based on direct data but included for
illustrative purposes. EF ¼ ejection fraction; LA ¼ left atrial; other abbreviation as in Figure 1.
represent distinct disorders or merely different categorize patients into phenotypes, using combina-
stages in the spectrum of disease progression tions of comorbidities, measures of cardiac and
(Central Illustration).106,107 extracardiac structure/function, and multilayered
There is abundant data to support the concept of omics.109,110 This characterization is one of the key
different phenotypes, but the optimal phenotypic goals of the National Heart, Lung, and Blood Insti-
nosology is not yet resolved and represents an tute–funded HeartShare clinical research network,
important knowledge gap in the field.108 Phenotypes which is part of the Accelerating Medicines Partner-
may be categorized based on the severity or pattern of ship HF project.111 Although ML studies of HFpEF
organ dysfunction or hemodynamics, as suggested by continue to proliferate in the literature, they are
the cardiac and noncardiac mechanisms described merely the starting point for deeper investigation into
earlier in this paper (Table 3), or phenotypes may be the pathobiology of identified HFpEF subtypes. Ulti-
separated based on the presence or absence of co- mately, any nosologic phenotype system must be tied
morbid conditions such as obesity 8,44 or coronary to both pathophysiology and, most importantly,
disease.65,67 Recent work has further explored treatment response, and this will require further
whether machine learning (ML) techniques can better study in appropriately powered prospective trials.
helpful to exclude HFpEF. 116,117 This is partly related

T A B L E 3 Mechanisms of Abnormal Hemodynamics in HFpEF
to insensitivity of these estimations and partly
Mechanism Specific Causes Relevant Phenogroups related to the fact that in approximately one-third of
Intrinsic myocardial Pressure-overload Stiff vasculature/hypertensive patients with HFpEF, LV filling pressures are normal
dysfunctiona hypertrophy/remodeling Ischemic (epicardial or
Vascular rarefaction microvascular) at rest and only increase during exercise. 86 Exercise
Interstitial fibrosis Obese testing is required in these patients to diagnose
Ischemia LA myopathy
Cardiomyocyte energy deprivation or exclude HFpEF. The gold standard diagnostic
Oxidative/nitrosative stress test involves rest and exercise hemodynamic assess-
Insulin resistance
ment during right heart catheterization (Table 1),
Hypervolemia Obesity Obese
Renin-angiotensin-aldosterone Chronic kidney disease which is consistent with the new universal
activation
definition that requires objective evidence of
Chronic kidney disease
[Stressed blood volume Obesity Obese congestion.1,4,118,119 An increase in pulmonary capil-
Excessive sympathoexcitation Autonomic dysfunction lary wedge pressure (PCWP) at rest ($15 mm Hg) or
[Ventricular interaction & Obesity Pulmonary vascular disease exercise ($25 mm Hg) made at end expiration con-
pericardial restraint Right-sided heart Obesity
remodeling & dysfunction Atrial tricuspid regurgitation firms the diagnosis during supine exercise. 118 An in-
Tricuspid regurgitation crease in PCWP relative to the increase in cardiac
Afterload-mediated Systolic hypertension Stiff vasculature/hypertensive
myocardial dysfunction Aortic stiffening Chronic kidney disease
output during exercise >2 mm Hg/L/min has also
been used to establish the diagnosis of HFpEF, 120 but
a
May affect myocardium in atria, ventricles, or both this metric may only apply to upright exercise as
Abbreviations as in Tables 1 and 2.
pressures are much higher in the supine position, and
application to supine exercise may reclassify a sig-
nificant minority of patients into the wrong diag-
nostic category.121
DIAGNOSIS OF HFpEF Although invasive exercise testing provides
definitive diagnosis, it is not universally available
Diagnosis of HFpEF relies on history revealing and carries greater cost and requirement for
symptoms of dyspnea and fatigue coupled with expertise compared with noninvasive imaging mo-
objective evidence of congestion and an dalities. Alternative provocative maneuvers have
EF $50%.1,4,112 Evidence of congestion may be been tested, including saline infusion and passive
apparent based on physical examination findings, but leg raise. An increase in PCWP $18 mm Hg with
these findings are often absent among ambulatory saline or $19 mm Hg with leg raise may also help to
patients (Figure 6).113 Plasma NPs may be elevated identify patients with HFpEF. 122,123 Although these
reflecting congestion, but as reviewed earlier in this alternative tests are superior to resting assessment
paper, roughly one-third of patients with HFpEF alone, they do not replicate the patient’s experience
display NP values below typically used clinical of dyspnea during exertion, are less physiologically
thresholds for HF diagnosis despite elevated LV relevant, and do not challenge the cardiovascular
filling pressures at rest or with exercise, 5,114 particu- system to the extent observed with exercise,
larly among patients with obesity-related HFpEF. 9,44 where increases in heart rate, contractility, loading
Several other causes of NP deficiency have been conditions, and autonomic signaling to a much
identified, including lower LV diastolic wall stress for greater magnitude.124 Exercise stress echocardiog-
any given elevation in LV diastolic pressure,7 African raphy is also used as an alternative to invasive he-
ancestry, NPPB polymorphisms, insulin resistance, modynamic exercise testing and offers incremental
and increased androgenicity in women.6 Thus, value to resting echocardiography in isolation, but
normal NP levels cannot be used to rule out HFpEF. is often limited by the ability to acquire diagnostic
Imaging may be useful to evaluate for ambient or quality imaging during stress and false-negative
chronic markers of congestion, such as increases in results as a number of patients with HFpEF may
the E/e’ ratio, left atrial enlargement, reduced left not display elevation in E/e’ or other surrogate
atrial reservoir strain, increases in estimated pulmo- markers with exertion.116,125
nary artery pressures, and distention of the inferior Diagnostic scoring systems have been developed to
vena cava (Figure 6).115 aid medical decision making regarding the need for
The presence of echocardiographic and NP in- invasive exercise testing in the evaluation of patients
dicators of congestion is useful to increase the like- with possible HFpEF, including the H 2FPEF and HFA-
lihood that HFpEF is present, but their absence is not PEFF (Heart Failure Association Pre-test assessment,
F I G U R E 6 Clinical Presentation of HFpEF
Exercise
50
PA Wedge Pressure (mm Hg)
40
S1 S2 S1
S3 S4
30
20
10
Rest
0
Number of
Patients
Clinical
Presentation Ambulatory, External Dyspnea Hospitalization
Patients with earlier stage HFpEF display elevation in PA wedge pressures only during exercise (red tracing), despite normal values at rest (blue tracing). With more
dramatic elevation in cardiac filling pressures at rest, evidence of congestion becomes apparent at rest, with elevation in the E/e’ ratio and dilation/loss of collapsibility
of the inferior cava. Patients with the most overt congestion fulfilling the Framingham criteria (Table 1) present with jugular distention, S3 gallops, and radiographic
edema. These patients typically require hospitalization and represent only a small fraction of the broader HFpEF spectrum. PA ¼ pulmonary artery; other abbreviation
as in Figure 1.
Echocardiography & natriuretic peptide, Functional Once the diagnosis of clinical HF has been made
testing, Final aetiology) scores (Figure 7). 117,118 Low or in a patient with normal EF, it is essential to rule
high scores with either scheme are used to exclude or out HFpEF “masqueraders,” disorders with their
diagnose HFpEF, respectively, and patients with in- own specific etiologies, natural histories, and
termediate scores are best referred for exercise treatments, which differ from “garden variety”
testing. In a large multicenter comparative study with HFpEF and have specific treatments that differ from
invasive hemodynamic confirmation of diagnoses, HFpEF (Table 2).
both scores were validated as accurate tools to
TREATMENT OF HFpEF
discriminate HFpEF from noncardiac causes of dys-
pnea, but the H2FPEF score was shown to be more
Once HFpEF has been diagnosed and alternate
sensitive, with greater overall accuracy and discrim-
diagnoses have been excluded, systematic treatment
ination than the HFA-PEFF score, despite require-
of HFpEF, which includes management of comorbid-
ment for fewer input variables.121 It is important to
ities and pharmacologic and nonpharmacologic ther-
note that the H2 FPEF score was derived and validated
apies, should be instituted (Figure 8). Systematic
in patients with unexplained dyspnea. In patients
laboratory investigation of patients with HFpEF is
with overt signs and symptoms of HF (Figure 6)
also critical for optimal management of these patients
and elevated NPs, a low H2FPEF score does not
(Table 4).
exclude HFpEF, but may point to atypical causes
of the HFpEF syndrome such as infiltrative COMORBIDITY MANAGEMENT. Blood pressure con-
cardiomyopathies. trol in accordance with clinical practice guidelines
F I G U R E 7 Diagnostic Evaluation of HFpEF
Patient With Unexplained

Exertional Dyspnea
and No Clear Alternative Cause
H2FPEF Score HFA-PEFF Score

Major Criteria Minor Criteria
Definition Points Domain
(2 Points Max Per Category) (1 Point Max Per Category)
Heavy BMI >30 kg/m2 2 Functional • Average E/e' ratio ≥15 • Average E/e' ratio 9-14
• Septal e' <7 cm/s • Global longitudinal strain <16%
Hypertension 2 or more 1 • Lateral e' <10 cm/s
antihypertensive • Tricuspid regurgitation velocity >2.8 m/s
medicines • Left atrial volume index 29-34 mL/m2
Morphological • Left atrial volume index >34 mL/m2
Atrial • Left ventricular mass index >149/122 g/m2 • Left ventricular mass index >115/95 g/m2
Any history 3
Fibrillation (men/women) and relative wall (men/women)
Pulmonary artery 1 thickness >0.42 • Relative wall thickness >0.42
Pulmonary
• Left ventricular wall thickness ≥12 mm
Hypertension systolic pressure
>35 mm Hg (echo) Biomarker NTproBNP >220 pg/mL NTproBNP 125-220 pg/mL
Elder >60 years 1 (sinus) BNP >80 pg/mL BNP 35-80 pg/mL
Filling E/e' ratio >9 1 Biomarker NTproBNP >660 pg/mL NTproBNP 365-660 pg/mL
pressures (echo) (atrial BNP >240 pg/mL BNP 105-240 pg/mL
fibrillation)
Low probability score Intermediate probability score High probability score

Unlikely HFpEF (H2FPEF 2-5 or HFA-PEFF 2-4) Likely HFpEF
(H2FPEF 0-1 or HFA-PEFF 0-1) Further evaluation needed (H2FPEF 6-9 or HFA-PEFF 5-6)
Hemodynamic
Stress Test
In patients with unexplained dyspnea and normal EF, the probability of underlying HFpEF can be estimated by the H2FPEF score or HFA-PEFF score. Patients with
intermediate probability scores should undergo additional hemodynamic exercise stress testing to establish the diagnosis. HFA-PEFF ¼ Heart Failure Association
Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final aetiology; other abbreviations as in Figures 1, 3, and 5.
(target <130/80 mm Hg) is important in the man- Obesity is highly prevalent in HFpEF and weight
agement of HFpEF, with selection of antihyperten- loss through lifestyle-based interventions is indi-
sive agents driven by the presence of other cated. Kitzman et al 129 showed in a randomized trial
126
comorbidities and other indications. AF is highly that weight loss through caloric restriction improves
prevalent in HFpEF and is associated with more exercise capacity, health status, and markers of
advanced disease, poorer exercise capacity, and inflammation in patients with obesity-related
increased mortality (Central Illustration).79,127 Goals HFpEF. Weight loss through bariatric surgery and
of therapy include prevention of thromboembolism, other interventions may also improve cardiac func-
modification of contributing risk factors, and control tion,130 as well as hemodynamic abnormalities, 131
126
of symptoms. Emerging data suggest a greater but further prospective study is required. Epicar-
role for more aggressive rhythm control, including dial coronary disease is observed in two-thirds of
catheter ablation, although prospective trial data is patients with HFpEF and is often challenging to
required.128 Notably, aggressive rate control may be diagnose. 69,132 When CMD is included, coronary
deleterious in HFpEF patients with AF due to sig- disease is observed in an even greater proportion of
nificant LA dysfunction resulting in low stroke patients (Figure 5).65-67 Although prospective data
volume and inability to increase stroke volume are lacking, observational studies have shown that
during exertion. complete revascularization in patients with HFpEF
F I G U R E 8 Treatment of HFpEF
Diagnosis of HFpEF Rule out alternate etiologies (”masqueraders”) of HFpEF (see Table 2)
confirmed
• Hypertension: Diuresis first (SGLT2i*/MRA**), ARNI*** or ACE inhibitor, or ARB, other
medications according to comorbidities. Goal BP <130/80 mm Hg.
• Iron deficiency: Treat with IV iron if anemic and transferrin saturation <20%.
Start SGLT2i* • Diabetes: Preferential use of SGLT2i followed by GLP1 receptor agonist.
• CAD: Statins, aspirin, consider revascularization.
• AF: Anticoagulation, consider rhythm control, rate control to HR ~80 beats/min.†
• Obesity: Caloric restriction,‡ weight loss drugs/surgery.
Volume overload • CKD: ACE inhibitor/ARB and/or SGLT2i, especially if +microalbuminuria; avoid nephrotoxins.
present? • Lung disease and OSA: Treat per guidelines but also make sure euvolemic.
Yes No
Still symptomatic + EF <55%-60% or multiple HF hospitalizations and SBP >110-120 mm Hg?
Diuretics • Start ARNI and uptitrate to maximum dose as tolerated.
Preferential up-front
use of use of MRA**
± loop diuretic Ask 6 questions in all patients:
1. Is the patient on an SGLT2i? If not, why not?
2. Is the patient on an MRA? If not, why not?
Rx comorbidities 3. Is the patient on an ARNI? If not, why not?
4. Is the patient on potassium supplementation? If yes, replace with MRA if possible.
5. Is the patient on nitrates or a PDE5 inhibitor (or other pulmonary vasodilator)? If possible,
discontinue these drugs to see if symptoms improve
6. Is the patient on a beta-blocker? Unless using for AF, angina, or history of MI, try discontinuing
*SGLT2i should be considered in all patients to see if symptoms improve. For HTN, vasodilating beta-blocker (eg, carvedilol) preferred.
except those with type 1 diabetes, orthostatic
hypotension, eGFR <20-25 mL/min/1.73 m2, or very
frequent yeast infections (or history of severe
genitourinary infections, including Fournier's Implement in all patients:
gangrene). Yeast infections on therapy are readily
treatable (eg, fluconazole 150 mg PO x 1, unless • HF education: record daily weights, BP, HR; establish "dry weight" for volume-
contraindicated). Instruct patients to hold SGLT2i overloaded patients to guide diuretic dosing (especially loop diuretics).
therapy for a few days during active yeast infection • Exercise training regimen: aerobic training + resistance training preferred‡;
and on "sick days" (GI illness, dehydrated, active
infections that predispose to dehydration). High consider cardiac rehabilitation referral.
HgbA1c levels are not a contraindication to
SGLT2i. Slight elevation in serum creatinine (and
slight reduction in eGFR) is normal and expected
on SGLT2i therapy.
**MRA should be considered in all patients except
Persistent symptoms and/or
those with K+ >5.0 or eGFR <30 mL/min/1.73 m2.
Replace potassium supplementation with MRA
HF hospitalizations?
whenever possible. Use eplerenone in patients
with gynecomastia due to spironolactone.
Eplerenone is ½ as potent as spironolactone. Re-
check K+ and renal function 1 week and 1 month • Refer to HF clinic (or HFpEF clinic, if available).
after initiation, and q3-6 months thereafter.
***ARNI most effective if EF <55%-60% or frequent
• Reevaluate for "masqueraders" (atypical etiologies, eg, cardiac amyloidosis).
HF hospitalizations (congested phenotype); avoid • Evaluate for worsening comorbidities (eg, worsening renal function, CAD
in patients with history of angioedema, low BP, progression, poor control of diabetes).
orthostatic hypotension, restrictive cardiomyopathy,
pulmonary arterial hypertension, constrictive • If persistent fluid overload: Start HCTZ, even if eGFR is low. Sequential nephron
pericarditis, cardiac amyloidosis. blockade can augment diuresis, and low-potency thiazide often sufficient.
†AF patients often have low stroke volume and
• Implantable hemodynamic-guided management (especially if frequently
inability to augment stroke volume during exertion
due to LA dysfunction. Avoid excessive rate
hospitalized for HF or cardiorenal syndrome).
control in these patients. • Evaluate for chronotropic incompetence: If present, stop rate-controlling agents,
‡Caloric restriction, aerobic training, and
such as beta-blockers, if possible.
resistance training protocols per Brubaker PH, et
al. Circ Heart Fail 2022. • ENROLL IN AN HFpEF CLINICAL TRIAL
Summary of key points for treatment of HFpEF, with emphasis on evaluation and treatment of congestion with diuretics and SGLT2 inhibitors, treatment of
comorbidities, lifestyle interventions, and vigilant consideration for HFpEF masqueraders that are treated differently. For caloric restriction, aerobic
training, and resistance training protocols, see Brubaker et al.153 SGLT2 ¼ sodium glucose cotransporter-2; other abbreviation as in Figure 1.
and coronary disease is associated with improved related death in patients with and without
outcomes. 132 Further study is required to determine diabetes.2,3
the optimal treatment for CMD in HFpEF. Approxi- PHARMACOLOGIC TREATMENTS. The EMPEROR-
mately 50% of patients with HFpEF in clinical trial Preserved (EMPagliflozin outcomE tRial in Patients
cohorts have diabetes mellitus.133 SGLT2i should be With chrOnic heaRt Failure With Preserved Ejection
considered first-line therapy for glucose control in Fraction) and DELIVER (Dapagliflozin Evaluation
patients with HFpEF and diabetes given their to Improve the LIVEs of Patients With PReserved
reduction in HF hospitalizations and cardiovascular- Ejection Fraction Heart Failure) trials demonstrated
T A B L E 4 Laboratory Evaluation of Patients With Suspected or Diagnosed HFpEF
Test Interpretation/notes
Complete blood cell count with Elevated neutrophil-to-lymphocyte ratio is associated with worse prognosis. If anemia is present, evaluate
differential further for the etiology and potential treatment options. Hematocrit can be followed to evaluate for
hemoconcentration. Elevated hemoglobin is uncommon in HFpEF and should prompt evaluation for causes
of polycythemia, particularly congenital heart disease or chronic hypoxia.
Basic chemistry panel Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine (with eGFR). Hypokalemia: consider
hyperaldosteronism, if on loop diuretics, add MRA. Hyponatremia and elevated BUN are poor prognostic
signs. If creatinine is normal and the patient has evidence of fluid overload, consider hemodilution or
sarcopenia. Most patients with overt HFpEF will have abnormal renal function.
Liver function tests Total bilirubin, AST, ALT, alkaline phosphatase, albumin, total protein. Elevated total bilirubin and/or alkaline
phosphatase can be a sign of hepatic congestion due to right-sided heart failure.
BNP/NTproBNP Clinical thresholds for the diagnosis of HF in current use (eg, BNP >100 pg/mL), should not be used to rule out
the diagnosis of HFpEF given the high prevalence (w30%) of natriuretic peptide deficiency in HFpEF. MRA
use results in lower natriuretic peptide levels. NTproBNP should be used in patients on sacubitril/valsartan.
Factors associated with natriuretic peptide deficiency include obesity, African ancestry, insulin resistance,
NPPB polymorphisms, increased androgenicity in women, corticosteroid use, and factors associated with
lower diastolic wall stress (eg, small LV cavity, LV hypertrophy). Levels can be elevated in the presence of
atrial fibrillation, pulmonary arterial hypertension, primary RV dysfunction, and pulmonary embolism.
High-sensitivity troponin Persistent low-level elevations can be a clue to the presence of cardiac amyloidosis, hypertrophic
cardiomyopathy, other atypical etiologies (eg, cardiotoxicity or other causes of infiltrative
cardiomyopathy), or reduced subendocardial perfusion due to coronary microvascular dysfunction.
Low-level troponin elevation also points to a more “myocardial” phenotype of HFpEF.
Uric acid Indirect sign of abnormal renal function and/or endothelial dysfunction. Uric acid can be elevated in patients
on loop diuretics; if gout is present, consider lowering loop diuretic dose in favor of other diuretics
(eg, SGLT2i or MRA).
Prealbumin Low-normal or reduced levels can be indicative of ATTR cardiomyopathy (prealbumin ¼ transthyretin, and the
assay only detects TTR in its tetrameric form).
Serum free light chains, serum Serum protein electrophoresis is neither sensitive nor specific, so serum immunofixation should be used for the
immunofixation, UPEP evaluation of a plasma cell dyscrasia. Abnormal free light chains (especially elevated kappa/lambda ratio)
can occur in the setting of chronic kidney disease.
Iron studies, ferritin Low ferritin or transferrin saturation <20% indicate iron deficiency, which should be evaluated and treated if
indicated.
TSH Hyperthyroidism and hypothyroidism can mimic HFpEF and are treatable.
Autoimmune panel Consider ANA testing in patients with signs and symptoms of connective tissue disease. Reflex testing can be
performed if ANA is abnormal.
Intact PTH, 25-OH vitamin D, Indirect measures of abnormal renal function. Secondary hyperparathyroidism in a patient with normal
calcium, phosphorous creatinine and eGFR can be a clue to the presence of chronic kidney disease.
Urine albumin-to-creatinine ratio Alternate measure of abnormal renal function, which is helpful when eGFR is normal due to hemodilution.
Consider addition of renoprotective medications (eg, SGLT2i, ARNI, ACE inhibitor, or ARB) if present.
Hemoglobin A1c Evaluate for and treat diabetes.
Lipid profile Besides work-up for potential untreated hypercholesterolemia or hypertriglyceridemia, low levels of total
cholesterol, HDL, and LDL can be seen in the setting of hepatic congestion due to advanced HFpEF, in
which case ApoB may be more helpful.
ALT ¼ alanine aminotransferase; ANA ¼ antinuclear antibody; ApoB ¼ apolipoprotein B; AST ¼ aspartate aminotransferase; ATTR ¼ transthyretin amyloid
cardiomyopathy; BNP ¼ B-type natriuretic peptide; eGFR ¼ estimated glomerular filtration rate; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein;
MRA ¼ mineralocorticoid receptor antagonists; NTproBNP ¼ N-terminal pro brain natriuretic peptide; PTH ¼ parathyroid hormone; SGLT2i ¼ sodium glucose cotransporter-2
inhibitor; TSH ¼ thyroid-stimulating hormone; TTR ¼ transthyretin; UPEP ¼ urine protein electrophoresis; other abbreviations as in Tables 1 and 2.
that treatment with the SGLT2is empagliflozin and Cardiac function heart failure with an Aldosterone
dapagliflozin, respectively, was associated with an antagonist Trial) trial of spironolactone in HFpEF
18% to 21% reduction in the primary endpoints of HF failed to show a reduction in the primary composite
hospitalization or cardiovascular death among pa- endpoint of HF hospitalization or cardiovascular
tients with HF and EF >40%.2,3 Dapagliflozin has also death, 136 but there was substantial geographic
been shown to improve quality of life and exercise heterogeneity, and, in the Americas, spironolactone
capacity measured using 6-minute walk distance.134 use was associated with improved outcomes
Benefits from SGLT2i apply similarly to patients including the primary composite endpoint and HF
with and without diabetes, and across the spectrum hospitalizations. 137 The combined angiotensin
135
of EF. receptor/neprilysin inhibitor sacubitril/valsartan did
Diuretics are indicated to relieve the congestive not significantly reduce the risk of HF hospitaliza-
symptoms in patients with HFpEF. 126 Mineralocor- tion or cardiovascular death in the PARAGON-HF
ticoid receptor antagonists may decrease risk of HF (Prospective Comparison of ARNI with ARB
hospitalizations, particularly in those with lower Global Outcomes in HF With Preserved Ejection
range LVEF. The TOPCAT (Treatment Of Preserved Fraction) trial (P ¼ 0.06).138 Benefit was greater in
women and among patients with lower EF, but, in frequently offered to patients with HFpEF as po-
the subsequently published PARALLAX (Prospective tential additive treatment options given the high
Comparison of ARNI vs Comorbidity-Associated morbidity and mortality of HFpEF (which rivals
Conventional Therapy on Quality of Life and Exer- most cancers).
cise Capacity) trial, there was no salutary effect of
sacubitril/valsartan on health status or submaximal KNOWLEDGE GAPS AND
exercise capacity, 139 in contrast to the favorable FUTURE DIRECTIONS
effects observed with SGLT2i. 134
NONPHARMACOLOGIC THERAPIES. Exercise training The past 20 years have witnessed major strides in
improves aerobic capacity and quality of life in improved understanding of HFpEF epidemiology,
HFpEF and moderate intensity training appears pathophysiology, molecular mechanisms, diagnosis,
equivalent to higher intensities.140,141 Pulmonary ar- and treatment. After decades of neutral trials in
tery pressure monitoring has demonstrated benefit in HFpEF, a proven therapy (SGLT2i) now exists. Never-
the treatment of HFpEF, as seen in the CHAMPION theless, major unmet needs and knowledge gaps are
(CardioMEMS Heart Sensor Allows Monitoring of still present (Table 6). As outlined earlier in this paper,
Pressure to Improve Outcomes in NYHA Class III HFpEF prevalence is increasing, too often remains
Heart Failure Patients) trial with a 50% reduction in undetected, and, even when diagnosed, is associated
HF hospitalization compared with standard care with high rates of hospitalization and rehospitaliza-
during the follow-up period of 18 months with an tion. Despite the success of SGLT2i, both the DELIVER
overall number needed to treat of 2 to prevent 1 HF and EMPEROR-Preserved trials only showed a 3% ab-
hospitalization.142 Implantation of a rate-adaptive solute risk reduction in the primary outcome, which
atrial pacemaker to enhance heart rate responses to was driven by HF hospitalization and not cardiovas-
exercise in patients with HFpEF and chronotropic cular mortality. 2,3 Thus, improved diagnosis and
incompetence was not shown to improve exercise treatment of HFpEF is essential.
performance or quality of life in the RAPID-HF (Rate- We now understand that HFpEF is a systemic,
Adaptive Atrial Pacing in Diastolic Heart Fail- “reserve dysfunction” syndrome that involves multi-
ure) trial. 143 ple organs, not just the heart, and one that often re-
Treatment with an atrial shunt device in REDUCE quires perturbational testing to assist with diagnosis
LAP-HF II (Randomized trial to REDUCE Elevated and treatment selection. Improved understanding of
Left Atrial Pressure in Patients with Heart Failure II) HFpEF in this manner has expanded the potential
had no significant effect on the primary composite treatment landscape beyond conventional HF thera-
outcome of cardiovascular death, stroke, HF events, pies to those that have beneficial effects in multiple
and change in health status.144 However, a post hoc organs. Indeed, a likely reason for the broad success of
analysis showed that patients with latent pulmo- SGLT2i is the ability to improve the metabolic health
nary vascular disease (elevated exercise pulmonary of multiple organs while also promoting renopro-
vascular resistance >1.74 WU, which is the upper tective diuresis. Successful future therapeutics will
limit of normal in healthy older individuals) were likely fall into 1 of 2 categories: 1) broadly applicable
harmed by shunt therapy, whereas those with therapeutics such as SGLT2i that ameliorate abnor-
normal pulmonary vascular resistance with exercise malities in multiple organs; and 2) tailored therapies
appeared to improve.92 Pericardiotomy to reduce that are directed toward specific subtypes of HFpEF
external constraint on the LV has been shown to (ie, a precision medicine approach to HFpEF).
improve hemodynamics in animal models and in Despite numerous major differences between
pilot human studies,145,146 but further study is HFpEF and HFrEF indicating that these are 2 distinct
required. Preliminary analyses from the open-label syndromes,148 both of the aforementioned categories
roll-in phase of the REBALANCE-HF (Endovascular of therapeutics also open up the possibility of EF-
Ablation of the Right Greater Splanchnic Nerve in agnostic HF therapeutics. Like SGLT2i, some thera-
Subjects Having HFpEF) trial testing endovascular pies developed for HFpEF may be beneficial to all HF
splanchnic nerve ablation revealed improvements in patients, especially as we understand that the
LV filling pressures during exercise and patient- comorbidity-inflammation-endothelial dysfunction
reported health status, although the results of the paradigm may extend to many patients with HFrEF as
blinded, sham-controlled trial are not yet avail- well. On the other hand, precision therapeutics
able. 147 A large number of clinical trials are under developed for HFpEF subtypes may be beneficial
way for the identification of promising HFpEF across the HF spectrum. For example, novel therapies
therapies (Table 5), which should be more for HFpEF that reduce interstitial fibrosis, targeted to
T A B L E 5 Ongoing and Upcoming Clinical Trials in HFpEF
Trial Name (NCT #) Therapy Population/Key Enrollment Criteria Primary Outcome
Cardiometabolic drug trials

STEP HFpEF Semaglutide vs placebo EF $45% and NYHA functional class II-IV Change in KCCQ and change in body weight at
& STEP HFpEF-DM (NCT04788511, BMI $30 kg/m2 without or with T2DM 12 mo
NCT04916470)
SUMMIT (NCT04847557) Tirzepatide vs placebo EF $50% and NYHA functional class II-IV Composite: all-cause mortality, HF events,
Elevated NT-proBNP 6-min walk distance, KCCQ
BMI $30 kg/m2
CAMEO-SEMA (NCT05371496) Semaglutide vs placebo EF $50% and NYHA functional class II-IV Change in PCWP incorporating rest and exercise
BMI $30 kg/m2 measurements at 1 y
Exercise PCWP $25 mm Hg
CAMEO-DAPA (NCT04730947) Dapagliflozin vs placebo EF $50% and NYHA functional class II-IV Change in PCWP incorporating rest and exercise
Exercise PCWP $25 mm Hg measurements at 6 mo
HuMAIN (NCT05284617) HU6 vs placebo EF $50% and NYHA functional class II-IV Change in body weight at 6 mo
BMI $30 kg/m2 and T2DM
Neurohormonal drug trials
FINEARTS-HF (NCT04435626) Finerenone vs placebo EF >40% and NYHA functional class II-IV Total number of CV deaths and HHF
Structural heart disease
Elevated NT-proBNP
SPIRRIT (NCT02901184) Spironolactone vs standard EF $40% and NYHA functional class II-IV Time to CV death or first HHF
of care NT-proBNP >300 ng/L or >750 ng/L in AF
SPIRIT-HF (NCT04727073) Spironolactone vs placebo EF $40% and NYHA functional class II-IV Total number of CV deaths and HHF
NT-proBNP >300 ng/L or >900 ng/L in AF
PARAGLIDE-HF (NCT03988634) Sacubitril/Valsartan vs EF >40% Change in NT-proBNP from baseline to the
Valsartan Hospitalized with acute decompensated HFpEF average of wk 4 and 8
Elevated NT-proBNP or BNP during hospitalization
Pulmonary hypertension due to
HFpEF trials
CADENCE (NCT04945460) Sotatercept vs placebo EF $50% with combined pre- and postcapillary PH Pulmonary vascular resistance
PVR $4 WU, PCWP >15 but <30 mm Hg
PH-HFpEF (NCT03015402) Sodium nitrite vs placebo PH-HFpEF confirmed diagnosis by RHC PAP during submaximal exercise
oral capsule
Metformin for PH-HFpEF Metformin vs placebo PH-HFpEF confirmed within the past 6 mo Mean PAP during submaximal exercise at 12 wk
(NCT03629340) $3 features of metabolic syndrome
Open-Label Rollover Study of Open label levosimendan Completed double-blind therapy in a PH-HFpEF Clinical safety measured by number of adverse
Levosimendan in PH-HFpEF clinical study of levosimendan sponsored by events at 2 y
(NCT03624010) Tenax Therapeutics, Inc.
Nitric oxide/cGMP/PKG-activating
drug trials
INABLE-Training (NCT02713126) Sodium nitrite vs placebo EF $50% and NYHA functional class II-IV Change in peak VO2 at 12 wk
solution Previous HHF, elevated PCWP (rest or exercise) or
NT-proBNP >400 pg/mL or BNP >200 pg/mL
KNO3CK OUT HFpEF Potassium nitrate vs EF >50% and NYHA functional class II-III Change in peak VO2 and change in total work
(NCT02840799) potassium chloride Elevated filling pressures performed during a maximal-effort exercise
test
Continued on the next page
patients with HFpEF with high extracellular volume CONCLUSIONS

content on cardiac magnetic resonance imaging, 149
could be expanded to all patients with HF (regard- HFpEF is one of the most pressing diagnostic and
less of EF) who have evidence of substantial inter- therapeutic challenges in clinical medicine today
stitial myocardial fibrosis. given its increasing prevalence, underdiagnosis, poor
Therefore, future therapeutic strategies will prognosis, limited therapeutic options, and substan-
benefit from deep, multimodal, and multiorgan tial burden on the health care system worldwide.
phenotyping coupled with hypothesis-driven and Despite these challenges, the success of recent
ML-guided approaches to uncover novel HFpEF SGLT2i trials has shown that HFpEF is treatable.
mechanisms, subtypes, and therapeutic targets. Ongoing large-scale studies of HFpEF pathobiology,
Given the heterogeneity of the HFpEF syndrome, an increasing number of translational studies span-
development of automated techniques to enhance ning the gap between the bedside and the bench, and
the diagnosis, subtyping, and therapeutic decision- numerous clinical trials of novel therapeutics in
making in patients with HFpEF may also be of HFpEF offer a glimpse of hope toward a future of
significant utility. reduced prevalence, morbidity, and mortality
T A B L E 5 Continued
Trial Name (NCT #) Therapy Population/Key Enrollment Criteria Primary Outcome
Trials targeting left atrial myopathy

and atrial fibrillation
RESPONDER (NCT05425459) Atrial shunt device vs sham LVEF $40% and NYHA functional class II-IV Composite of HF event rates and KCCQ at 12 mo
Elevated PCWP during exercise, without high PVR
or pacemaker device
RELIEVE-HF (NCT03499236) Atrial shunt device vs sham HFpEF and HFpEF, NYHA functional class II-IV Composite of death, transplant or LVAD, HHF,
HHF and/or elevated NP levels worsening outpatient HF events, and change
in KCCQ
FROST-HF (NCT03751748) Atrial shunt device vs sham LVEF >45%, NYHA functional class II-IV, and Change in 6-min walk distance at 12 mo
LA enlargement
6MWT distance <80% predicted.
PCWP $25 mm Hg during supine exercise test
RELAXIN-LA (NCT05592275) Relaxin analogue vs placebo EF $50% and NYHA functional class II-IV Change in LA reservoir strain at 26 wk
Recent HF hospitalization or urgent outpatient
treatment for congestion with NTproBNP
>300 or >900 in AF
CABA-HFPEF (NCT05508256) Catheter ablation vs usual LVEF $40% and NYHA functional class II-IV Time free of CV death and total (first and
care Paroxysmal or persistent AF recurrent) unplanned cardiovascular
NT-proBNP >300 ng/L or >900 ng/L (AF) or HF hospitalizations
hospitalization
Trials targeting inflammation
Myeloperoxidase (MPO) inhibitor MPO inhibitor vs placebo EF $50% and NYHA functional class II-IV Exercise PCWP
with exercise in HFpEF PCWP $15 at rest or PCWP $25 with exercise
(NCT03611153)
ENDEAVOR (NCT04986202) MPO inhibitor vs placebo EF $40% and NYHA functional class II-IV Change in KCCQ and change in 6-min walk
NT-proBNP >200-250 ng/L or >400-500 ng/L in distance
AF (based on BMI)
HERMES (NCT05636176) Ziltivekumab vs placebo EF $40% and NYHA functional class II-IV Time to HF hospitalization, cardiovascular death,
NT-proBNP >300 or >600 in AF or urgent outpatient HF visit
C-reactive protein >2 mg/L
ColPET (NCT04857931) Colchicine vs placebo EF $45% and NYHA functional class II-IV Change in C-reactive protein at 6 mo
NT-proBNP >300 ng/L or >900 ng/L in AF
BMI >30 kg/m2, T2DM, or CRP >2 mg/L
Colchicine in patients with HFpEF Colchicine vs usual care EF $50% and NYHA functional class II-IV Change in sST2 at 12 wk
(NCT05637398) NT-proBNP >300 or >600 in AF, structural
heart disease
BMI >30 kg/m2 or T2DM
Device-based trials
Rebalance-HF (NCT04592445) Right greater splanchnic LVEF $50% and NYHA functional class II-IV Change in PCWP incorporating rest and exercise
nerve ablation vs sham Elevated NP, prior HHF, or increased diuretic measurements at 1 mo
requirement
Elevated PCWP during exercise
AIM HIGHer (NCT05064709) Cardiac contractility LVEF $40% and #60% and NYHA functional Change in 6-min walk distance and KCCQ at 6 mo
modulation vs sham class II-IV
Elevated NP levels
HERACLES-HFpEF (NCT04782908) Transvascular tricuspid LVEF $50% and NYHA functional class II-IV Change in LV end diastolic pressure volume
valve repair Severe tricuspid regurgitation relationship
Other trials
IRONMET-HFpEF (NCT04945707) Ferric Derisomaltose vs EF $50% and NYHA functional class II-IV Change in peak VO2
placebo Iron deficiency
REHAB-HFpEF (NCT05525663) Rehabilitation intervention Age $60 y Combined all-cause rehospitalization and death
vs attention control EF $45% at 6 mo
Hospitalization for acute decompensated HF
AMETHYST (NCT04327024) Verinurad and allopurinol EF $45% and HF symptoms Change in peak VO2
vs placebo Hyperuricemia
AF ¼ atrial fibrillation; BMI ¼ body mass index; cGMP ¼ cyclic guanosine monophosphate; CV ¼ cardiovascular; EF ¼ ejection fraction; HHF ¼ hypertensive heart failure; KCCQ ¼ Kansas City Cardiomyopathy
Questionnaire; LVAD ¼ left ventricular assist device; MPO ¼ myeloperoxidase; NP ¼ natriuretic peptide; NYHA ¼ New York Heart Association; PAP ¼ pulmonary artery pressure; PH ¼ pulmonary hypertension;
PVR ¼ pulmonary vascular resistance; RHC ¼ right heart catheterization; sST2 ¼ soluble suppression of tumorigenicity-2; T2DM ¼ type 2 diabetes mellitus; other abbreviations as in Tables 1, 2, and 4.
T A B L E 6 Key Knowledge Gaps and Unmet Needs in HFpEF
Category Knowledge Gap or Unmet Need
Diagnosis 1. Noninvasive tests with similar accuracy to invasive gold standard

2. Accurate markers of congestion (improvement over natriuretic peptides)
3. Improved detection of HFpEF given the high frequency of underdiagnosis
4. Valid, reproducible, easily applied definitions for preclinical HFpEF
Mechanism 5. Unraveling mechanisms linking adiposity and physical inactivity with HFpEF
6. Determinants of progression from stage A to stage B to stage C/D HFpEF
7. Repositories of cardiac and extracardiac tissue from HFpEF patients, including atrial tissue as well as biopsy or
necropsy material from both ventricles
8. Preclinical models that recapitulate human HFpEF
9. Unraveling effects of HF on the lungs and pulmonary vasculature in HFpEF
10. Improved understanding of the interactions and directionality between extracardiac organ dysfunction and the
heart in HFpEF
Phenotyping and natural 11. Understanding natural history and disease trajectory across HFpEF phenogroups or in the context of
history multimorbidity
12. Creation of an optimal phenotypic classification system for HFpEF
13. Identify and test in novel therapies targeting specific phenogroups in prospective trials
Therapy 14. Therapies that prevent the development of HFpEF
15. Investigations focused on obesity and physical inactivity and the role in HFpEF, including weight loss and
increasing activity levels/training
16. Phenotype-guided vs general strategies to treat HFpEF
17. Therapies targeting cardiometabolic perturbations in HFpEF
18. Novel therapies targeting peripheral determinants of exercise intolerance
19. Therapies that improve ventricular compliance, relaxation, and cardiac reserve
20. Therapies that target pulmonary vascular disease in HFpEF
21. Therapies targeting outside the cardiovascular system such as adipose tissue, inflammation, and skeletal muscle
22. Treatment of epicardial coronary artery disease
23. Treatment of coronary microvascular disease
24. Optimal treatment of atrial fibrillation and role of catheter ablation
Abbreviations as in Table 1.
associated with HFpEF, which would be a major to treat HF. Dr Sharma has received research grants from Amgen and
the American Heart Association; and has served as a consultant for
advance for population health.
Alleviant, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim,
FUNDING SUPPORT AND AUTHOR DISCLOSURES Novartis, NovoNordisk, and Rivus. Dr Shah has received research
grants from the NIH, Actelion, AstraZeneca, Corvia, Novartis, and
Pfizer; and has received consulting fees from Abbott, Actelion,
Supported in part by National Institutes of Health (NIH) grants
AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer
R01 HL128526 and U01 HL160226 (Dr Borlaug), U54 HL160273, R01
Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea,
HL107577, R01 HL127028, R01 HL140731, R01 HL149423 (Dr Shah), R01
CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai,
HL134893, R01 HL140224, R01 HL160003, K24 HL153669 (Dr Ho); and
Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck,
by the U.S. Department of Defense: W81XWH2210245 (Dr Borlaug). Dr
MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron,
Borlaug has received research support from the NIH and the United
Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr
States Department of Defense; and has received research grant
Ho has received research grants from the NIH and Bayer, AG.
funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mes-
oblast, Novo Nordisk, Rivus, and Tenax Therapeutics. Dr Borlaug has
served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, ADDRESS FOR CORRESPONDENCE: Dr Barry A.
Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Borlaug, Mayo Clinic and Foundation, 200 First Street
Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations;
SW, Rochester, Minnesota 55905, USA. E-mail:
and is named inventor (U.S. Patent no. 10,307,179) for the tools and
approach for a minimally invasive pericardial modification procedure [email protected].
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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 81, NO.

ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

THE PRESENT AND FUTURE

JACC SCIENTIFIC STATEMENT

Heart Failure With Preserved

D uring the past 20 years, the diagnostic

As we examine the global scope and secular trends

of this disease, it is important to recognize that this

Listen to this manuscript’s

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2023.01.049

become the dominant HF subtype in the ABBREVIATIONS

numbered men 2:1 with respect to HFpEF LA = left atrium

6.7-8.1 per 1,000 person-years]) when compared with

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

T A B L E 1 HFpEF Deﬁnitions and Considerations Across Different Studies

HFpEF Deﬁnition Criteria Use Cases Considerations

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

T A B L E 2 Clues, Evaluation, and Treatment Options for HFpEF Masqueraders

Clues to the Possible Presence of an HFpEF Masquerader

Etiology Clinical Clues Diagnostic Evaluation Treatment Options

Etiology Clinical Clues Diagnostic Evaluation Treatment Options

HFpEF Incidence HFpEF Prevalence HFpEF Clinical Outcomes

• 27 cases per 10,000 • 1.0%-1.5% of population • 5-year mortality: 75.3%

Secular trends ↑ incidence over time ↑ prevalence over time ?

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

F I G U R E 2 Pathophysiology of Obesity-Related HFpEF

Total Blood Volume (L)

Pericardial restraint &

Obesity Worse RV Decreased myocardial Greater senescent Increased stressed HFpEF

Ca2+ Concentration (μM) BMI (kg/m2) BMI (kg/m2)

Nonfasting (n = 9) HFpEF: Ob/DM (n = 14) HFpEF NCD

HFpEF: Ht/Hp (n = 13) HFpEF: Mixed (n = 15)

F I G U R E 3 Scope of Undiagnosed HFpEF in the Community

Diagnosed HFpEF 502 1.00 N/A

H2FPEF ≥5 227 0.85 193 410/641

H2FPEF 1-2 150 0.30 45

F I G U R E 4 Mechanisms of Hemodynamic Congestion in HFpEF

Hypervolemia ↑Ventricular Interaction

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

Borlaug BA, et al. J Am Coll Cardiol. 2023;81(18):1810–1834.

F I G U R E 5 Phenotypic Spectrum of HF With Normal EF

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

helpful to exclude HFpEF. 116,117 This is partly related

F I G U R E 6 Clinical Presentation of HFpEF

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

F I G U R E 7 Diagnostic Evaluation of HFpEF

Patient With Unexplained

H2FPEF Score HFA-PEFF Score

Low probability score Intermediate probability score High probability score

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

T A B L E 4 Laboratory Evaluation of Patients With Suspected or Diagnosed HFpEF

Heart Failure With Preserved Ejection Fraction MAY 9, 2023:1810–1834

T A B L E 5 Ongoing and Upcoming Clinical Trials in HFpEF

Trial Name (NCT #) Therapy Population/Key Enrollment Criteria Primary Outcome

Cardiometabolic drug trials

patients with HFpEF with high extracellular volume CONCLUSIONS

Trial Name (NCT #) Therapy Population/Key Enrollment Criteria Primary Outcome

Trials targeting left atrial myopathy