Heart Failure with Preserved Ejection Fraction (HFpEF)

🎧 Heart Failure with Preserved Ejection Fraction (HFpEF) — deep-dive podcast

📋 Key Information Summary

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HFpEF is defined as heart failure with LVEF ≥50%, elevated natriuretic peptides, and evidence of structural/functional cardiac abnormalities — prevalence is rising and now accounts for approximately 50% of all heart failure cases in Australia.
The HFA-PEFF algorithm is the preferred diagnostic pathway: Step 1 (Pre-test assessment), Step 2 (Echocardiographic and natriuretic peptide scoring), Step 3 (Functional testing with diastolic stress echo or invasive haemodynamics), Step 4 (Aetiological work-up including phenotyping).
Elevated NT-proBNP ≥125 pg/mL or BNP ≥35 pg/mL is required as an entry criterion; however, obesity, atrial fibrillation, and renal impairment significantly affect interpretation — use age-adjusted cut-offs where applicable.
Diastolic assessment requires integrated evaluation: E/e' ratio ≥15, left atrial volume index ≥34 mL/m², tricuspid regurgitation velocity ≥2.8 m/s, and septal e' velocity <7 cm/s or lateral e' <10 cm/s.
Empagliflozin (Jardiance®) and dapagliflozin (Forxiga®) are first-line disease-modifying therapies in HFpEF regardless of diabetes status — EMPEROR-Preserved and DELIVER trials demonstrated significant reduction in HF hospitalisation (NNT ~31 over 2 years).
Loop diuretics (furosemide, bumetanide) remain the cornerstone of decongestive therapy; target the lowest effective dose maintaining euvolaemia with daily weight monitoring.
Comorbidity management is central: rate control for atrial fibrillation, target BP <130/80 mmHg for hypertension, GLP-1 receptor agonists for obesity-related HFpEF (STEP-HFpEF), and optimised glycaemic control in diabetes.
Exercise-based cardiac rehabilitation improves exercise capacity (peak VO₂), quality of life, and functional class (NYHA) — refer all eligible patients to supervised programmes.
HFpEF phenotyping (obesity/metabolic, atrial fibrillation-driven, vascular, right ventricular dysfunction, pulmonary, rare genetic/infiltrative) guides targeted management and is increasingly important in precision medicine.
Aboriginal and Torres Strait Islander peoples have a disproportionately higher burden of heart failure (2.7× age-adjusted prevalence), driven by earlier onset of cardiovascular risk factors — culturally safe, community-based models of care are essential.
Special populations require dose adjustments: SGLT2 inhibitors are not recommended in severe renal impairment (eGFR <20 mL/min/1.73 m²); caution with diuretics in elderly patients to avoid pre-renal injury; pregnancy requires multidisciplinary management.
Regular monitoring includes clinical review every 1–3 months, repeat echocardiography at 6–12 months or with clinical deterioration, serial NT-proBNP to guide therapy, and ongoing assessment for decompensation triggers.

🎬 Heart Failure with Preserved Ejection Fraction (HFpEF) — clinical explainer

Introduction & Australian Epidemiology

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome characterised by symptoms and signs of heart failure in the presence of a left ventricular ejection fraction (LVEF) ≥50%, alongside evidence of elevated left ventricular filling pressures and structural or functional cardiac abnormalities. HFpEF represents a heterogeneous group of disorders unified by a common final pathway of diastolic dysfunction, increased myocardial stiffness, and impaired ventricular-arterial coupling.

Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF has historically lacked robust evidence-based therapies, earning it the moniker of a "therapeutic desert." However, the landscape has shifted dramatically with the publication of landmark SGLT2 inhibitor trials and emerging data on GLP-1 receptor agonists, fundamentally changing the management paradigm.

Australian Burden of Disease

The Australian Institute of Health and Welfare (AIHW) estimates that approximately 480,000 Australians are living with heart failure, with HFpEF accounting for roughly half of all cases. The prevalence of HFpEF is increasing due to population ageing, rising rates of obesity, type 2 diabetes mellitus, hypertension, and atrial fibrillation. Key Australian epidemiological data include:

Heart failure prevalence increases from approximately 1–2% in those aged <55 years to >10% in those aged ≥75 years.
HFpEF accounts for approximately 50% of incident heart failure hospitalisations, with this proportion rising over the past two decades.
In-hospital mortality for HFpEF-related admissions is approximately 4–6%, with 30-day readmission rates of 20–25%.
Heart failure is the leading cause of preventable hospitalisation in Australians aged ≥65 years (AIHW National Hospital Morbidity Database).
The direct cost of heart failure management in Australia is estimated at $2.7 billion annually, with HFpEF patients contributing disproportionately due to comorbidity burden and recurrent admissions.
Women are disproportionately affected by HFpEF compared to HFrEF, representing approximately 60% of HFpEF cases.
Aboriginal and Torres Strait Islander Australians experience heart failure at 2.7 times the age-adjusted rate of non-Indigenous Australians, with earlier onset and more severe disease at presentation.

Classification and Terminology

The 2021 ESC and 2022 AHA/ACC/HFSA guidelines classify heart failure into categories based on LVEF:

Category	LVEF	Abbreviation	Description
Reduced	≤40%	HFrEF	Established evidence base for neurohormonal therapy
Mildly reduced	41–49%	HFmrEF	Intermediate phenotype; growing evidence base
Preserved	≥50%	HFpEF	Heterogeneous; SGLT2i and GLP-1 RA now evidence-based
Improved	Previously ≤40%, now >40%	HFimpEF	Treated HFrEF with recovered LVEF; continue GDMT

Heart Failure with Preserved Ejection Fraction (HFpEF) clinical infographic — pathophysiology, clinical clues, diagnosis, imaging, and management — Tap or click image to enlarge — Heart Failure with Preserved Ejection Fraction (HFpEF): pathophysiology, clinical clues, diagnosis, imaging, and management.

Diagnostic Criteria & Phenotyping

Diagnosis of HFpEF remains one of the most challenging tasks in clinical cardiology. Unlike HFrEF, where reduced LVEF provides a straightforward diagnostic anchor, HFpEF requires integration of clinical, biochemical, echocardiographic, and sometimes invasive haemodynamic data. The HFA-PEFF diagnostic algorithm, developed by the Heart Failure Association of the ESC, provides a structured, evidence-based approach.

HFA-PEFF Diagnostic Algorithm

The HFA-PEFF algorithm is a stepwise, standardised approach to HFpEF diagnosis comprising four steps:

Step 1

Pre-Test Assessment

Clinical evaluation of symptoms and signs of HF (dyspnoea on exertion, orthopnoea, peripheral oedema, elevated JVP) in the context of appropriate risk factors (age >60, hypertension, obesity, AF, diabetes, CKD, CAD). Exclude non-cardiac causes of dyspnoea. Measure BNP/NT-proBNP — if NT-proBNP >125 pg/mL or BNP >35 pg/mL, proceed to Step 2.

Step 2

Echocardiographic & NP Scoring (HFA-PEFF Score)

Comprehensive transthoracic echocardiography with diastolic function assessment. Apply the HFA-PEFF scoring system (maximum 6 points): 2 points for diastolic function (E/e', TR velocity, LA volume index), 2 points for structural abnormalities (LA volume index ≥34 mL/m², LV mass index ≥115 g/m² (men) / ≥95 g/m² (women), wall thickness ≥12 mm), 2 points for natriuretic peptides (NT-proBNP >220 pg/mL or BNP >80 pg/mL). A score ≥5 points is diagnostic; 2–4 points requires further testing.

Step 3

Functional Testing

For intermediate scores (2–4), perform diastolic stress echocardiography (exercise or dobutamine) with assessment of E/e' ratio during stress. Alternatively, right heart catheterisation with exercise to document elevated pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg during exercise. Cardiopulmonary exercise testing (CPET) demonstrating peak VO₂ <14 mL/kg/min or VE/VCO₂ slope ≥34 supports diagnosis.

Step 4

Aetiological Work-Up & Phenotyping

Once HFpEF is confirmed, pursue targeted investigations to identify underlying aetiology and phenotype: cardiac MRI for infiltrative disease (amyloidosis), genetic testing for HCM/sarcomeric mutations, coronary angiography for ischaemic aetiology, sleep studies for OSA, and comprehensive comorbidity assessment. Phenotyping enables precision management.

Diastolic Function Assessment

Echocardiographic evaluation of diastolic function is central to HFpEF diagnosis. The 2016 ASE/EACVI guidelines recommend an integrated approach using multiple parameters:

Parameter	Normal	Abnormal (supports HFpEF)	Grey Zone
Septal e' velocity	≥7 cm/s	<7 cm/s	7–10 cm/s
Lateral e' velocity	≥10 cm/s	<10 cm/s	10–12 cm/s
Average E/e' ratio	<10	>14	10–14
Left atrial volume index	<34 mL/m²	≥34 mL/m²	—
TR peak velocity	≤2.8 m/s	>2.8 m/s	—
LAVI/LAEF change with Valsalva	LAVI decreases	No decrease (loss of LA compliance reserve)	—

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Clinical pitfall: No single echocardiographic parameter is sufficient to diagnose or exclude HFpEF. Diastolic assessment must be integrated with clinical context, natriuretic peptides, and the HFA-PEFF scoring system. E/e' alone has limited sensitivity in obese patients and those with atrial fibrillation.

Invasive Haemodynamics

Right heart catheterisation (RHC) remains the gold standard for confirming elevated filling pressures when non-invasive assessment is inconclusive. Key haemodynamic criteria include:

Resting PCWP ≥15 mmHg (measured at end-expiration, mean) is diagnostic of elevated left-sided filling pressures.
Exercise PCWP ≥25 mmHg during supine or upright exercise is diagnostic of HFpEF when resting pressures are normal — this identifies "occult" or "exertional" HFpEF.
Exercise-induced elevation in pulmonary artery pressure (mPAP ≥30 mmHg) with normal resting haemodynamics is characteristic of early-stage HFpEF.
Left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg measured during left heart catheterisation supports diagnosis.

In Australia, RHC for HFpEF evaluation is performed at major tertiary centres with heart failure expertise. MBS item 38218 (right heart catheterisation) covers this procedure when clinically indicated. Exercise RHC requires specialised haemodynamic exercise equipment and is available at select centres including Royal Melbourne Hospital, Royal Prince Alfred Hospital, and the Alfred Hospital.

HFpEF Phenotyping

HFpEF is increasingly recognised as a syndrome with multiple distinct pathophysiological phenotypes, each with different treatment implications:

Phenotype 1

Obesity/Metabolic

BMI ≥30, metabolic syndrome, insulin resistance, epicardial fat, systemic inflammation. Most common phenotype (≥60% of HFpEF). Responds well to SGLT2i and GLP-1 RA.

Key target: Weight loss, SGLT2i, GLP-1 RA

Phenotype 2

Atrial Fibrillation-Driven

AF as primary driver of HF symptoms via loss of atrial kick, tachycardia-mediated cardiomyopathy, and atrial myopathy. Rhythm control may improve symptoms and outcomes.

Key target: Rate/rhythm control, LA ablation

Phenotype 3

Vascular/Hypertensive

Long-standing hypertension, arterial stiffness, concentric LVH, elevated afterload. Classic "diastolic heart failure." Responds to aggressive BP control and antihypertensive therapy.

Key target: BP <130/80, afterload reduction

Phenotype 4

Right Ventricular Dysfunction

RV–pulmonary arterial uncoupling, elevated PVR, RV dilatation. Associated with worse prognosis. Monitor with serial echocardiography and consider PA pressure monitoring.

Key target: Diuretics, PAH-specific Rx if appropriate

Phenotype 5

Rare/Infiltrative/Genetic

Cardiac amyloidosis (ATTR and AL), HCM, Fabry disease, radiation heart disease, constrictive pericarditis. Requires disease-specific therapy (tafamidis for ATTR, chemotherapy for AL).

Key target: Disease-specific therapy (tafamidis, chemotherapy)

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Do not miss cardiac amyloidosis: Cardiac ATTR amyloidosis is underdiagnosed in elderly Australians (especially men >75 years with aortic stenosis or bilateral carpal tunnel syndrome). Technetium-99m pyrophosphate scintigraphy (PYP scan) — available at major Australian nuclear medicine centres — is the key screening tool. Tafamidis (Vyndaqel®) is now PBS-listed (Authority Required) for ATTR cardiomyopathy and significantly reduces mortality.

Investigations

Essential BNP / NT-proBNP Age-adjusted cut-offs recommended. NP levels are lower in obese patients (BMI >30) — use lower thresholds (NT-proBNP >50 pg/mL for screening in obesity). Available at all Australian pathology providers (MBS item 66524).

Essential Transthoracic Echocardiography Comprehensive study including 2D, M-mode, spectral and tissue Doppler, LA volume indexed to BSA, LV mass index, GLS (global longitudinal strain). MBS item 55114. Perform within 2 weeks of suspected diagnosis.

Available ECG (12-lead) Assess for AF, LVH, conduction disease, Q waves (amyloidosis: pseudo-infarct pattern, low voltage). Available universally.

Available FBC, UEC, LFTs, HbA1c, Lipids, Iron Studies, TFTs Comprehensive metabolic and comorbidity screening. Iron deficiency (ferritin <100 or 100–299 with transferrin saturation <20%) is common and treatable — IV iron (ferric carboxymaltose) is recommended. MBS items 66512, 66514.

Available Cardiac MRI Gold standard for LV mass quantification, tissue characterisation (LGE for fibrosis, T1 mapping for diffuse fibrosis/infiltration, ECV). Essential for suspected amyloidosis, HCM, or myocarditis. MBS item 63400. Available at major metropolitan centres.

Specialist Right Heart Catheterisation ± Exercise Gold standard for invasive haemodynamic confirmation. Rest and exercise PCWP measurement. MBS item 38218. Available at tertiary centres.

Specialist Cardiopulmonary Exercise Testing (CPET) Peak VO₂, VE/VCO₂ slope, exercise oscillatory ventilation. Objectively quantifies functional capacity and aids prognosis. MBS item 13200 (where applicable). Available at specialist heart failure centres.

Referral Tc-99m Pyrophosphate Scintigraphy (PYP Scan) Screening for transthyretin cardiac amyloidosis (ATTR). Sensitivity and specificity >95% for ATTR (with concurrent serum/urine immunofixation to exclude AL). Available at Royal Melbourne, RPAH, Royal Adelaide, Fiona Stanley.

Referral Genetic Testing For suspected hereditary ATTR, HCM, Fabry disease, or other genetic cardiomyopathies. Available via genetic services at major tertiary centres and through commercial laboratories (e.g., Invitae, Australian Genomics).

Treatment Strategies

Management of HFpEF has evolved from a comorbidity-focused, symptom-driven approach to one incorporating disease-modifying therapies. The cornerstone of treatment is now SGLT2 inhibitors, supported by diuretic therapy, comorbidity management, and exercise-based rehabilitation.

SGLT2 Inhibitors — First-Line Disease-Modifying Therapy

SGLT2 inhibitors represent the most significant therapeutic advance in HFpEF management. Two landmark trials have established their efficacy:

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Practice-changing evidence: The EMPEROR-Preserved trial (empagliflozin) and DELIVER trial (dapagliflozin) both demonstrated significant reduction in the composite of cardiovascular death and heart failure hospitalisation in HFpEF patients with LVEF >40%. The benefit was consistent across subgroups including those without diabetes. These trials fundamentally changed the management of HFpEF.

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Empagliflozin

Jardiance® · SGLT2 inhibitor

Adult dose 10 mg PO once daily

Paediatric dose Not indicated for HFpEF in paediatrics

Renal adjustment Initiate if eGFR ≥20 mL/min/1.73 m². Can continue below this threshold once initiated. No dose adjustment required.

Hepatic adjustment No dose adjustment. Avoid in severe hepatic impairment (Child-Pugh C).

Key trial EMPEROR-Preserved: HR 0.79 (95% CI 0.69–0.90) for primary endpoint. NNT ~31 over 2 years.

PBS status ✔ PBS General Benefit (for type 2 DM) ⚠ Authority Required (for HF without DM)

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Dapagliflozin

Forxiga® · SGLT2 inhibitor

Adult dose 10 mg PO once daily

Paediatric dose Not indicated for HFpEF in paediatrics

Renal adjustment Initiate if eGFR ≥20 mL/min/1.73 m². No dose adjustment required. May continue below threshold.

Hepatic adjustment No dose adjustment. Use with caution in severe hepatic impairment.

Key trial DELIVER: HR 0.82 (95% CI 0.73–0.92) for primary endpoint. Benefit seen across LVEF spectrum up to ≥70%.

PBS status ✔ PBS General Benefit (for type 2 DM) ⚠ Authority Required (for HF without DM)

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SGLT2 inhibitor monitoring: Check renal function and volume status before initiation. Anticipate an initial eGFR dip of 3–5 mL/min (haemodynamic effect, not injury) — this is expected and typically recovers. Monitor for genital mycotic infections (most common adverse effect, ~5% incidence), euglycaemic diabetic ketoacidosis (rare), and volume depletion especially in patients on high-dose diuretics. Counsel patients on sick-day management rules.

Diuretic Management

Loop diuretics remain the mainstay of symptomatic management in HFpEF, addressing congestion through natriuresis and diuresis. They provide no mortality benefit but are essential for symptom control.

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Furosemide

Lasix® · Frusemide · Loop diuretic

Adult dose (oral) 20–80 mg PO daily or BD; titrate to maintain euvolaemia

Adult dose (IV) 20–80 mg IV bolus or infusion (2–10 mg/hr) for acute decompensation

Bioavailability (oral) Approximately 50% (10–100% variable). IV preferred in acute decompensation.

Renal adjustment In CKD (eGFR <30), higher doses may be required (up to 250–500 mg) due to reduced tubular secretion. Consider IV administration.

PBS status ✔ PBS General Benefit

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Bumetanide

Burinex® · Loop diuretic

Adult dose 0.5–2 mg PO daily or BD; bioavailability ~80% (more predictable than furosemide)

Renal adjustment Dose increase required in renal impairment. Maximum 10 mg/day.

PBS status ✔ PBS General Benefit

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Metolazone

Zaroxolyn® · Thiazide-like diuretic

Adult dose 2.5–5 mg PO daily; used as sequential nephron blockade with loop diuretics for diuretic resistance

Key note Synergistic with loop diuretics — monitor closely for electrolyte depletion and acute kidney injury. Start low, use for 3–5 days only.

PBS status ⚠ Authority Required

Comorbidity Treatment — Integrated Approach

HFpEF is rarely an isolated cardiac condition. Most patients have ≥3 comorbidities, and addressing these comprehensively is fundamental to improving outcomes. Key principles include:

Aggressive blood pressure control — target <130/80 mmHg. ACE inhibitors, ARBs, and calcium channel blockers are all appropriate. ARNI (sacubitril/valsartan) showed numerical but non-significant benefit in PARAGON-HF (LVEF ≥57% subgroups and women showed possible benefit).
Rate and rhythm control for atrial fibrillation — beta-blockers, digoxin, or calcium channel blockers for rate control. Catheter ablation may be superior to pharmacological rhythm control in HFpEF with AF (CASTLE-HFpEF subgroup analyses ongoing).
Weight management — GLP-1 receptor agonists (semaglutide) for BMI ≥30 (see Emerging Therapies section). Multidisciplinary weight management programmes.
Diabetes optimisation — SGLT2 inhibitors as first-line. GLP-1 RA for additional benefit. Avoid pioglitazone and saxagliptin (worsen HF). Metformin safe if eGFR >30.
Iron replacement — IV ferric carboxymaltose (Ferinject®) if ferritin <100 or 100–299 µg/L with transferrin saturation <20%. Improves exercise capacity and quality of life (AFFIRM-AHF, IRONMAN data applicable).
Sleep-disordered breathing — screening and treatment of obstructive sleep apnoea with CPAP. OSA is present in 50–75% of HFpEF patients.

Exercise Training

Exercise-based cardiac rehabilitation is a Class I recommendation (Level A evidence) for HFpEF and provides some of the most meaningful improvements in functional capacity and quality of life:

Supervised aerobic exercise training (3–5 sessions per week, 30–60 minutes per session, moderate intensity 60–80% peak HR) improves peak VO₂ by approximately 1.5–2.0 mL/kg/min — a clinically meaningful improvement.
Resistance training (2–3 sessions per week) is complementary and improves peripheral muscle strength and exercise tolerance.
The Ex-DHF trial and subsequent meta-analyses confirmed improvements in NYHA class, 6-minute walk distance, and quality of life scores (Minnesota Living with Heart Failure Questionnaire).
Cardiac Rehabilitation programme referral should occur for all HFpEF patients who are medically stable — MBS items 13550, 13560, and 13565 support cardiac rehabilitation in Australia.
For those unable to access supervised programmes, structured home-based exercise with telehealth monitoring is a reasonable alternative.

Quick Reference — HFpEF Pharmacotherapy

Treatment Target

First-Line Agent

Duration

Key Notes

Disease modification (all HFpEF)

SGLT2 inhibitor (empagliflozin or dapagliflozin)

Ongoing/lifelong

Regardless of diabetes status. Start early.

Congestion/volume overload

Furosemide 20–80 mg PO daily

Ongoing; titrate to symptoms

Target lowest effective dose. Add metolazone if resistant.

Hypertension (BP ≥130/80)

ACEi/ARB or CCB ± thiazide

Ongoing

Consider ARNI if LVEF close to 50% or female.

Atrial fibrillation (rate control)

Beta-blocker or diltiazem or digoxin

Ongoing

Target resting HR <80 bpm. CA ablation if symptomatic.

Iron deficiency

Ferric carboxymaltose IV (Ferinject®)

Single course; replete at 6/12

1000 mg if weight ≥70 kg; 500 mg if <70 kg.

Obesity (BMI ≥30)

Semaglutide (Ozempic® / Wegovy®)

Ongoing

STEP-HFpEF data. Weight loss 10–15%. PBS authority for T2DM.

Comorbidity Management

HFpEF is fundamentally a disease of comorbidity. The majority of patients present with ≥5 comorbid conditions, and the interaction between these conditions drives disease progression, symptom burden, and adverse outcomes. An integrated, multidisciplinary approach to comorbidity management is essential.

Atrial Fibrillation

AF and HFpEF share bidirectional pathophysiology — AF promotes atrial myopathy and impaired filling, while the stiff, hypertrophied left ventricle of HFpEF promotes atrial dilation and AF substrate. Approximately 40–60% of HFpEF patients have AF, and its presence worsens symptoms, exercise capacity, and prognosis.

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Rate vs. Rhythm Control: For HFpEF patients with AF, rate control (target resting HR <80 bpm) is the default first strategy. Rhythm control with catheter ablation is increasingly favoured for symptomatic patients, with emerging data from EARLY-AF and CASTLE-AF subgroup analyses suggesting benefit. Consider early rhythm control especially if AF is suspected as the primary driver of HF symptoms (AF-dominant phenotype).

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Bisoprolol

Cardicor® · Beta-1 selective blocker

Adult dose (AF rate control) 2.5–10 mg PO once daily; titrate to HR target

Renal adjustment Start 1.25 mg in severe renal impairment (eGFR <20). Max 10 mg.

PBS status ✔ PBS General Benefit

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Digoxin

Lanoxin® · Cardiac glycoside

Adult dose 62.5–125 µg PO once daily (aim for serum level 0.5–0.9 ng/mL)

Renal adjustment 62.5 µg daily if eGFR <30 mL/min/1.73 m². Monitor levels closely.

PBS status ✔ PBS General Benefit

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Diltiazem SR

Dilzem SR® · Non-dihydropyridine CCB

Adult dose 180–360 mg PO once daily (modified release)

Caution Avoid in decompensated HF. Use only in stable HFpEF with preserved blood pressure. Do not combine with beta-blockers without specialist supervision.

PBS status ✔ PBS General Benefit

Anticoagulation in HFpEF with AF: Direct oral anticoagulants (DOACs) are preferred over warfarin. Assess bleeding risk using HAS-BLED score. Use CHA₂DS₂-VASc score for stroke risk stratification — most HFpEF patients with AF have a score ≥2 and require anticoagulation. Apixaban (Eliquis® 5 mg BD, reduce to 2.5 mg BD if ≥2 of: age ≥80, weight ≤60 kg, Cr ≥133 µmol/L) or rivaroxaban (Xarelto® 20 mg daily with food, reduce to 15 mg if eGFR 15–49) are the preferred agents.

Hypertension

Hypertension is the most prevalent comorbidity in HFpEF (present in 60–90% of patients) and is a major driver of LVH, diastolic dysfunction, and disease progression. Aggressive blood pressure management is critical:

Target: <130/80 mmHg (consistent with 2023 ESH and AHA/ACC guidelines). In elderly patients (>80 years), target SBP 130–139 mmHg to avoid excessive hypotension.
First-line agents: ACE inhibitors (perindopril, ramipril) or ARBs (candesartan, valsartan). ARBs showed benefit in the TOPCAT trial (spironolactone subgroup analysis for Americas region).
Second-line: Calcium channel blockers (amlodipine for additional afterload reduction). Thiazide-like diuretics (indapamide) for volume/pressure management.
ARNI (sacubitril/valsartan): The PARAGON-HF trial narrowly missed its primary endpoint but demonstrated benefit in subgroups with LVEF <57% and in women (RR 0.73, 95% CI 0.59–0.90). Consider ARNI for patients with HFpEF and LVEF close to the lower end of normal, particularly women. PBS-listed for HFrEF; use for HFpEF requires private prescription or authority application.
Mineralocorticoid receptor antagonists (MRAs): Spironolactone 25–50 mg daily — the TOPCAT trial showed reduction in HF hospitalisation in the Americas cohort (HR 0.82) but not the Russian/Georgian cohort. Consider for patients with persistent congestion despite SGLT2i and diuretics, monitoring potassium closely.

Obesity

Obesity (BMI ≥30) is present in 60–80% of HFpEF patients and is increasingly recognised as a central pathophysiological driver rather than merely a comorbidity. The "obesity-HFpEF" phenotype is characterised by epicardial adiposity, systemic inflammation, expanded plasma volume, and impaired cardiopulmonary reserve.

Target weight reduction of ≥10% of body weight through lifestyle modification, pharmacotherapy, and consideration of bariatric surgery.
Semaglutide 2.4 mg SC weekly (Wegovy®): The STEP-HFpEF trial demonstrated significant improvements in HF symptoms (Kansas City Cardiomyopathy Questionnaire), exercise capacity (6MWD), body weight (mean −13.3%), and CRP. The STEP-HFpEF DM trial confirmed similar benefits in patients with type 2 diabetes.
Bariatric surgery: Consider for BMI ≥40 or BMI ≥35 with significant comorbidities. Associated with reversal of LVH, improvement in diastolic function, and reduction in HF hospitalisation.
Structured dietary counselling (Mediterranean diet, sodium restriction <2 g/day) as adjunctive therapy.

Diabetes Mellitus

Type 2 diabetes is present in 40–45% of HFpEF patients and accelerates myocardial fibrosis, microvascular dysfunction, and cardiomyocyte hypertrophy through advanced glycation end-products (AGEs), oxidative stress, and insulin resistance.

SGLT2 inhibitors are first-line — provide both glucose-lowering and HF-specific benefit. Empagliflozin and dapagliflozin are PBS-listed for type 2 diabetes (General Benefit).
GLP-1 receptor agonists (semaglutide, liraglutide) provide weight reduction and cardiovascular benefit. Semaglutide 0.5–1 mg SC weekly (Ozempic®) is PBS-listed (Authority Required) for type 2 diabetes.
Avoid saxagliptin — associated with increased HF hospitalisation (SAVOR-TIMI 53). Other DPP-4 inhibitors (linagliptin, sitagliptin) appear neutral.
Metformin remains safe in HFpEF if eGFR >30 mL/min/1.73 m². Reduce dose if eGFR 30–45.
HbA1c target: individualised, generally <53 mmol/mol (7%) for most patients; less stringent (<64 mmol/mol / 8%) in elderly or frail patients.

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Key interaction warning: Concurrent use of SGLT2 inhibitors and loop diuretics increases the risk of volume depletion and hypotension. When initiating an SGLT2 inhibitor in a patient on high-dose loop diuretics, consider reducing the diuretic dose by 25–50% and monitoring renal function and blood pressure at 1–2 weeks.

Heart Failure with Preserved Ejection Fraction (HFpEF) visual summary infographic — 🖼️ Heart Failure with Preserved Ejection Fraction (HFpEF) — visual summary

Emerging Therapies

HFpEF remains an area of intense research activity. After decades of negative trials, the SGLT2 inhibitor breakthrough has catalysed a new era of therapeutic development. Several novel agents and approaches are in advanced clinical testing.

GLP-1 Receptor Agonists for Obesity-Related HFpEF

The STEP-HFpEF programme represents a paradigm shift in recognising obesity as a treatable cause of HFpEF:

STEP-HFpEF (semaglutide 2.4 mg weekly): Mean weight loss of 13.3% vs. 2.6% placebo. Significantly improved KCCQ clinical summary score (+7.8 points difference, p<0.001), 6MWD (+20.3 m, p=0.008), and CRP (−38.5% relative reduction). These are clinically meaningful improvements.
STEP-HFpEF DM: Confirmed consistent benefits in the diabetes subgroup with similar magnitude of improvement.
Cardiovascular outcome data (MACE, HF hospitalisation) from larger, longer trials are pending.
In Australia, semaglutide (Wegovy® 2.4 mg) is approved by the TGA for weight management; Ozempic® (0.5–1 mg) is PBS-listed for type 2 diabetes. PBS listing for obesity without diabetes is not currently available.

Soluble Guanylate Cyclase (sGC) Stimulators

Vericiguat (Verquvo®), an sGC stimulator, addresses the nitric oxide–sGC–cGMP pathway that is impaired in HFpEF. The VITALITY-HFpEF trial (vericiguat vs. placebo) did not meet its primary endpoint (change in KCCQ physical limitation score or 6MWD). However, post-hoc analyses suggest potential benefit in specific subgroups. Vericiguat is currently PBS-listed only for HFrEF (after recent worsening HF event) and is not recommended for routine HFpEF management.

Novel Therapeutic Targets

Therapy	Mechanism	Trial	Status
Finerenone	Non-steroidal MRA (more selective for MR, less hyperkalaemia)	FINEARTS-HF (2024) — met primary endpoint (HF events + CV death)	Positive. HR 0.84 (95% CI 0.74–0.95). Regulatory submission expected. Not yet TGA-approved for HFpEF.
Tirzepatide	Dual GIP/GLP-1 receptor agonist	SUMMIT trial (obesity + HFpEF) — results expected 2025	Phase III. Anticipated to combine weight loss and metabolic benefits. Mounjaro® TGA-approved for T2DM.
Ziltivekimab	IL-6 monoclonal antibody (anti-inflammatory)	RESHAPE-HF2 (2024) — met primary endpoint	Positive. Targets the inflammatory phenotype. Not yet approved.
Tafamidis	TTR stabiliser (for ATTR cardiac amyloidosis)	ATTR-ACT — 30% reduction in all-cause mortality	PBS-listed (Authority Required) for ATTR cardiomyopathy. Vyndaqel® 80 mg daily. Paradigm-changing for this under-recognised HFpEF phenotype.
Sotatercept	Activin signalling inhibitor (TGF-β superfamily)	STELLAR (pulmonary arterial hypertension). Studied for HFpEF with elevated PAP.	FDA-approved for PAH. Potential HFpEF application under investigation.
Inclisiran	siRNA targeting PCSK9 (LDL-C reduction)	VICTORION-HEART — CV outcome data in broader population	PBS-listed for familial hypercholesterolaemia. Potential role in atherosclerotic HFpEF phenotype.

Precision Medicine Approaches

The future of HFpEF management is moving towards phenotype-directed therapy. Key precision medicine approaches include:

Machine learning–derived phenogroups: Cluster analyses from TOPCAT, RELAX, and NEAT-HFpEF datasets have identified 3–5 distinct phenogroups with differential treatment responses. These are not yet ready for clinical use but inform trial design.
Multi-omics profiling: Proteomic (including high-sensitivity troponin, GDF-15, galectin-3), metabolomic, and genomic biomarker panels may enable risk stratification and treatment selection.
Cardiac MRI-based tissue characterisation: T1 mapping, extracellular volume fraction (ECV), and late gadolinium enhancement patterns can identify specific myocardial pathologies (fibrosis, infiltration, inflammation) guiding targeted therapy.
Wearable technology and remote monitoring: Pulmonary artery pressure monitoring (CardioMEMS — not yet widely available in Australia), implantable cardiac monitors, and consumer-grade wearables for activity, HR, and weight trending.
Phenotype-specific trial design: Future trials are increasingly enrolling specific HFpEF phenotypes (e.g., obesity-predominant, AF-predominant) rather than the all-comer HFpEF population, which may have diluted treatment effects in earlier negative trials.

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Australian research context: Australian sites contribute to several international HFpEF trials through the NHMRC Clinical Trials Centre and major academic centres. The Australian Cardiac Amyloidosis Registry (led by the Baker Heart and Diabetes Institute) is advancing ATTR diagnosis and treatment pathways nationally. Patients with suspected rare HFpEF aetiologies should be referred to centres with active research programmes.

Special Populations

HFpEF management must be tailored to account for physiological differences, comorbidity patterns, and drug safety profiles in specific populations.

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Pregnancy

SGLT2 inhibitors Contraindicated in pregnancy. Discontinue at least 3 months before conception (teratogenicity concerns based on animal data). Switch to diuretic-based management.

ACE inhibitors / ARBs Absolutely contraindicated in pregnancy (teratogenic — renal agenesis, oligohydramnios). Switch to methyldopa, labetalol, or nifedipine for blood pressure control.

Diuretics Use with caution — may reduce placental perfusion. Furosemide may be continued if clinically necessary. Monitor amniotic fluid volume.

Anticoagulation Warfarin is teratogenic in first trimester. Use LMWH throughout pregnancy if anticoagulation required (AF, mechanical valve). DOACs are contraindicated in pregnancy.

Peripartum cardiomyopathy should be considered in any pregnant or postpartum woman presenting with HF symptoms. LVEF may be reduced or preserved. Multidisciplinary management with obstetrics and cardiology is essential.

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Paediatrics

HFpEF in children Rare but recognised, particularly in restrictive cardiomyopathy, post-chemotherapy, muscular dystrophies, and after Fontan palliation. Diagnosis relies on similar integrated criteria adapted for age-specific NP ranges.

SGLT2 inhibitors Not approved for paediatric heart failure. Clinical trials in paediatric populations are limited. Use is off-label and should only be considered under specialist supervision.

Diuretics Furosemide 1–2 mg/kg/dose PO/IV every 6–12 hours. Monitor closely for electrolyte disturbance. Growth monitoring is essential.

Refer all paediatric HF patients to a paediatric cardiologist. Transplantation assessment should be considered early for progressive disease. Restrictive cardiomyopathy in children carries a particularly poor prognosis (5-year transplant-free survival ~50%).

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Elderly (≥75 years)

SGLT2 inhibitors Safe and effective. May need to reduce concurrent diuretic dose. Monitor for volume depletion and falls risk. Geriatric assessment for frailty recommended.

Diuretics Start low (furosemide 20 mg daily). Over-diuresis is the most common cause of acute kidney injury in elderly HFpEF patients. Daily weight monitoring and electrolyte checks at initiation.

Anticoagulation (AF) DOACs preferred. Apixaban 2.5 mg BD if ≥2 criteria (age ≥80, weight ≤60 kg, Cr ≥133 µmol/L). Falls risk alone is not a contraindication to anticoagulation.

BP targets SBP 130–139 mmHg in those ≥80 years. Avoid excessive lowering — risk of orthostatic hypotension, syncope, and falls. Home BP monitoring recommended.

Polypharmacy is common — perform regular medication reviews. Deprescribe where possible. Cardiac amyloidosis (ATTR) should be actively screened for in men ≥75 with HFpEF + aortic stenosis or bilateral carpal tunnel syndrome.

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Renal Impairment

SGLT2 inhibitors Can initiate if eGFR ≥20 mL/min/1.73 m². Can continue below 20 once started. The cardio-renal protective effects extend into CKD stages 3b–4. Anticipate initial eGFR dip.

Loop diuretics Higher doses required in advanced CKD. Furosemide up to 250–500 mg orally or IV. Consider bumetanide (more predictable oral absorption). Sequential nephron blockade with metolazone for diuretic resistance.

MRAs Spironolactone — avoid if eGFR <30 or K⁺ >5.0 mmol/L. Monitor K⁺ at 1, 4, and 8 weeks after initiation. Finerenone has a more favourable potassium profile.

Cardiorenal syndrome is common in HFpEF. Avoid nephrotoxic agents (NSAIDs, iodinated contrast where possible). Coordinate management between cardiology and nephrology for complex cases.

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Hepatic Impairment

SGLT2 inhibitors No dose adjustment for mild–moderate impairment. Avoid in severe hepatic impairment (Child-Pugh C) due to limited data and altered drug metabolism.

Diuretics Use cautiously — hepatic congestion may impair drug metabolism. Monitor electrolytes closely as hypokalaemia can precipitate hepatic encephalopathy in cirrhotic patients. Spironolactone may be preferred for its K⁺-sparing properties in hepatorenal considerations.

Anticoagulants DOACs are contraindicated in Child-Pugh B/C (apixaban, rivaroxaban) or C (dabigatran). Use warfarin with INR monitoring in severe hepatic impairment if anticoagulation required.

Cardiac hepatopathy (congestive hepatopathy) occurs in advanced right-sided HF. Monitor LFTs (typically ALT/AST <3× ULN, elevated ALP/GGT, elevated bilirubin). Treat the underlying congestion.

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Immunocompromised

General considerations HFpEF in immunocompromised patients (transplant recipients, HIV, chemotherapy-induced, autoimmune disease) requires assessment of specific aetiologies: infiltrative disease, myocarditis, drug cardiotoxicity, and constrictive pericarditis.

Drug interactions Calcineurin inhibitors (cyclosporin, tacrolimus) promote hypertension and renal impairment — synergistic with HFpEF pathophysiology. mTOR inhibitors (sirolimus, everolimus) may cause peripheral oedema mimicking HF decompensation. Review immunosuppressive regimen with transplant team.

SGLT2 inhibitors Generally safe in immunocompromised patients, but genital mycotic infection risk may be higher — counsel on hygiene and early treatment. Avoid in severe immunosuppression (neutrophil count <0.5 × 10⁹/L) due to infection risk.

HIV-associated cardiomyopathy can present with preserved or reduced EF. Immune reconstitution inflammatory syndrome (IRIS) may precipitate cardiac decompensation. Coordinate management with infectious diseases specialists.

Monitoring

HFpEF requires longitudinal, structured monitoring to detect early decompensation, optimise therapy, and prevent hospitalisation. A multidisciplinary heart failure team approach (cardiologist, GP, heart failure nurse specialist, pharmacist, dietitian, exercise physiologist) is recommended.

Monitoring Schedule

At Diagnosis

Comprehensive baseline assessment: symptoms (NYHA class, KCCQ score), vital signs (BP, HR, weight, SpO₂), ECG, transthoracic echocardiography with diastolic function assessment, BNP/NT-proBNP, FBC, UEC, LFTs, HbA1c, fasting lipids, iron studies (ferritin, transferrin saturation), TFTs. Establish patient-specific self-management plan with daily weight monitoring.

2–4 Weeks

Follow-up after initiating SGLT2 inhibitor or diuretic: renal function (eGFR, K⁺), volume status assessment, BP, weight, symptom review. Adjust diuretic dose based on clinical congestion. Ensure sick-day rules understood for SGLT2i.

1–3 Monthly (Stable)

Clinical review: symptom assessment (NYHA, KCCQ), weight, BP, HR, medication adherence, side-effect assessment. UEC, BNP/NT-proBNP every 3 months. Referral to cardiac rehabilitation if not already enrolled. Dietitian review for sodium restriction and weight management.

6–12 Monthly

Repeat echocardiography to assess LV function, LA size, diastolic parameters, and RV function. Review and optimise comorbidity management (HbA1c, lipids, BP). Iron studies recheck if previously deficient. Functional capacity assessment (6MWT or CPET if available). Screen for AF (Holter monitor if palpitations or new symptoms).

Clinical Deterioration

Urgent review for: weight gain >2 kg in 3 days, worsening dyspnoea (NYHA class increase), new-onset orthopnoea or paroxysmal nocturnal dysnoea, peripheral oedema worsening, syncope or presyncope. Assess for precipitants (AF, infection, dietary indiscretion, medication non-adherence, ischaemia). Consider hospital admission if congestion not responsive to outpatient diuretic adjustment within 48 hours.

Self-Management Education

Patient self-management is a cornerstone of HFpEF care. Key elements include:

Daily weight monitoring at the same time each morning (before breakfast, after voiding). Report gain of >1.5 kg in 24 hours or >2 kg in 3 days.
Sodium restriction: target <2 g/day. Education on reading food labels, avoiding processed foods, and low-sodium cooking techniques.
Fluid management: typically 1.5–2 L/day fluid intake unless severe hyponatraemia or diuretic resistance.
Sick-day management rules for SGLT2 inhibitors — temporarily withhold if unable to maintain oral intake, vomiting, diarrhoea, or acutely unwell. Seek medical review within 24–48 hours.
Medication adherence tools — medication blister packs (Webster packs), smartphone reminders, carer support.
Recognition of decompensation symptoms and when to seek emergency care.

Aboriginal and Torres Strait Islander Health

Epidemiology

Aboriginal and Torres Strait Islander Australians experience heart failure at 2.7 times the age-adjusted prevalence of non-Indigenous Australians. Onset is approximately 10–15 years earlier. HFpEF prevalence is increasing alongside rising rates of obesity, type 2 diabetes (prevalence 3–4× higher than non-Indigenous Australians), hypertension, and rheumatic heart disease. Cardiovascular disease remains the leading cause of the health gap between Indigenous and non-Indigenous Australians (AIHW, 2023).

Remote and Rural Access

Approximately 38% of Aboriginal and Torres Strait Islander peoples live in remote or very remote areas where access to echocardiography, specialist cardiology, cardiac rehabilitation, and advanced diagnostics (cardiac MRI, RHC, CPET) is extremely limited. Telehealth-enabled echocardiography (store-and-forward) and point-of-care NP testing are being expanded through the Royal Flying Doctor Service and Aboriginal Community Controlled Health Organisations (ACCHOs). Portable echocardiography equipment is increasingly deployed in remote communities.

Cultural Safety

Heart failure management must be delivered in a culturally safe environment. Respect for cultural obligations, family structures, sorry business, and connection to Country is essential. ACCHOs such as the Central Australian Aboriginal Congress (NT), Winnunga Nimmityjah (ACT), and Aboriginal Medical Service Western Sydney provide culturally integrated chronic disease management. Acknowledge the social determinants of health: housing, food security, education, employment, and intergenerational trauma.

Rheumatic Heart Disease

RHD remains a significant cause of cardiac disease in Indigenous Australians, particularly in NT, WA, and QLD. RHD can lead to valvular heart disease with secondary HFpEF through mitral stenosis or regurgitation with preserved LVEF. The RHD Endgame Strategy (2020–2031) aims to eliminate ARF and RHD. Benzathine penicillin G (BPG) secondary prophylaxis every 28 days is critical — adherence support through ACCHO-based delivery models improves outcomes.

Medication Access and PBS

SGLT2 inhibitors and other HFpEF medications are available under the PBS. For Aboriginal and Torres Strait Islander patients with a current Centrelink concession card, PBS co-payment is reduced. Closing the Gap PBS co-payment (CTG-PBS) provides medicines at no or reduced cost for eligible Indigenous Australians. Ensure patients are registered for CTG-PBS through their pharmacy. Remote area medication supply through remote area Aboriginal health workers and community pharmacies.

Models of Care

Integrated chronic disease management through ACCHOs with embedded heart failure nurse specialists, Aboriginal health practitioners, and community-based cardiac rehabilitation programmes. The "Heart Failure in the Bush" programme (NT) and similar initiatives demonstrate that community-based, culturally tailored programmes improve medication adherence, reduce hospitalisation, and improve quality of life. Self-management education adapted for low health literacy using visual and verbal communication strategies.

📊 Heart Failure with Preserved Ejection Fraction (HFpEF) — slide deck

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📚 References

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