Heart failure with preserved ejection fraction (HFpEF)

Heart failure with preserved ejection fraction (HFpEF) is defined as a clinical syndrome of symptomatic heart failure in the presence of a left ventricular ejection fraction (LVEF) ≥50%, with objective evidence of cardiac structural or functional abnormalities consistent with elevated left ventricular (LV) filling pressures or diastolic dysfunction. HFpEF now accounts for approximately 50% of all heart failure cases in Australia and worldwide, and its prevalence is rising as the population ages.

In Australia, heart failure affects approximately 480,000 people, with an annual incidence of around 30,000 new cases. HFpEF is the dominant heart failure phenotype in patients over 75 years, in women, and in those with hypertension, diabetes, obesity, atrial fibrillation, and chronic kidney disease. The Australian Institute of Health and Welfare (AIHW) reports that heart failure is responsible for over 1 million hospitalisation days annually, with HFpEF contributing increasingly to this burden. Five-year mortality for HFpEF exceeds 50%, comparable to many malignancies, yet disease-modifying therapies have historically been limited.

Recent landmark trials (EMPEROR-Preserved, DELIVER) have demonstrated that SGLT2 inhibitors significantly reduce hospitalisation for heart failure in HFpEF, marking a paradigm shift in management. Australian treatment is guided by the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand (NHFA/CSANZ) Heart Failure Guidelines.

HFpEF is a heterogeneous syndrome driven by a complex interplay of cardiac and systemic abnormalities. Unlike HFrEF, systolic function is preserved, but multiple mechanisms contribute to impaired exercise tolerance, elevated filling pressures, and symptoms.

Core Pathophysiological Mechanisms

• Diastolic dysfunction: Impaired LV relaxation (lusitropy) and increased LV stiffness are the hallmarks of HFpEF. Delayed isovolumetric relaxation and reduced early diastolic filling result in elevated LV end-diastolic pressure (LVEDP), transmitted as elevated left atrial pressure, pulmonary venous hypertension, and dyspnoea — particularly on exertion when heart rate rises and diastolic filling time shortens.
• Concentric LV remodelling and hypertrophy: Chronic pressure overload (hypertension, aortic stenosis) leads to myocardial hypertrophy, increased cardiomyocyte stiffness, and reduced compliance. Interstitial fibrosis — driven by TGF-β, aldosterone, and systemic inflammation — further reduces ventricular distensibility.
• Systemic inflammation and comorbidity-driven injury: Obesity, diabetes, hypertension, and CKD generate a chronic pro-inflammatory state (elevated TNF-α, IL-6, CRP) that causes microvascular endothelial dysfunction, reduces bioavailable nitric oxide, impairs cyclic GMP/PKG signalling in cardiomyocytes, increases titin phosphorylation, and promotes myocardial fibrosis. This "cardiometabolic" pathway is central to HFpEF pathogenesis.
• Chronotropic incompetence: Up to 50% of HFpEF patients fail to increase heart rate appropriately on exertion, limiting cardiac output augmentation and contributing to exercise intolerance independently of diastolic dysfunction.
• Pulmonary hypertension and right ventricular dysfunction: Chronically elevated left-sided filling pressures lead to post-capillary pulmonary hypertension. Over time, reactive pulmonary arteriolar vasoconstriction and remodelling cause pre-capillary component (combined post- and pre-capillary PH). RV dysfunction significantly worsens prognosis.
• Extracardiac contributions: Impaired peripheral vasodilatory reserve, skeletal muscle dysfunction, renal sodium retention (cardiorenal syndrome), and altered neurohormonal activation (RAAS, sympathetic nervous system) all contribute to symptoms and disease progression.

Key Phenotypes

Symptoms

• Dyspnoea: Exertional breathlessness is the cardinal symptom. Orthopnoea and paroxysmal nocturnal dyspnoea occur with more advanced disease. Unlike HFrEF, symptoms may be intermittent and disproportionate to resting examination findings.
• Exercise intolerance and fatigue: Often the predominant complaint. Patients describe inability to perform activities of daily living, with early fatigue on exertion. Skeletal muscle deconditioning compounds the cardiac limitation.
• Ankle oedema: Bilateral pitting oedema, exacerbated by prolonged standing, heat, medications (e.g., calcium channel blockers), or dietary indiscretion.
• Acute decompensation: Triggers include AF with rapid ventricular response, dietary sodium excess, medication non-adherence, hypertensive crisis, intercurrent illness (respiratory infection, anaemia), NSAIDs, or corticosteroids.

Examination Findings

• Elevated JVP: Raised jugular venous pressure at rest or provoked by hepatojugular reflux. May be absent at rest in compensated patients.
• Third or fourth heart sound: S4 gallop is characteristic of diastolic dysfunction (atrial kick into non-compliant ventricle). S3 may occur in decompensated HFpEF.
• Bibasal crackles: Pulmonary oedema in acute decompensation; may be absent in chronic compensated disease.
• Peripheral oedema: Pitting oedema of ankles and legs; ascites and pleural effusions in advanced disease.
• Obesity, hypertension: Highly prevalent; assist in establishing the cardiometabolic HFpEF phenotype.

Diagnostic Criteria (ESC/NHFA Framework)

Diagnosis of HFpEF requires ALL of the following:

• Essential
  NT-proBNP / BNP

  First-line biomarker for diagnosis and monitoring. NT-proBNP preferred in obese patients (less adipose tissue suppression). Elevated values support diagnosis; normal values in a non-obese, non-AF patient effectively exclude HF. Also guides prognosis and treatment titration. Available at all Australian public and private pathology laboratories. Medicare rebatable (MBS 66101).
• Essential
  Transthoracic Echocardiogram (TTE)

  Cornerstone of HFpEF diagnosis. Assess: LVEF (biplane Simpson method), LV dimensions and wall thickness, LV diastolic function (ASE/EACVI 2016 algorithm — E/A ratio, e' velocity, E/e' ratio, LA volume index, TR velocity), LA size, valvular pathology, RVSP, RV function. Every patient with suspected HFpEF requires a TTE. Available Australia-wide; Medicare rebatable.
• Essential
  12-lead ECG

  Assess for LVH (Sokolow-Lyon, Cornell voltage criteria), atrial fibrillation/flutter, conduction abnormalities, and low voltages with increased LV wall thickness (raises concern for cardiac amyloidosis — voltage/mass discordance). QRS morphology relevant to device therapy eligibility.
• Essential
  Full Blood Count, UEC, eGFR, LFTs

  Anaemia (worsens symptoms, targets Hb >10 g/dL), electrolytes (hypokalaemia, hyponatraemia as prognostic markers), creatinine/eGFR (dose adjustment for SGLT2i, diuretics; cardiorenal syndrome monitoring), liver function (hepatic congestion in advanced HF). Essential at baseline and at each medication change.
• Essential
  HbA1c, Fasting Glucose / OGTT

  Diabetes is present in 30–40% of HFpEF patients and is a key therapeutic target. HbA1c guides SGLT2 inhibitor prescribing. Screen all HFpEF patients for type 2 diabetes if not already diagnosed.
• Essential
  Chest X-Ray

  Assess for cardiomegaly, pulmonary vascular congestion, pleural effusions, interstitial oedema (Kerley B lines), and alternative pulmonary diagnoses (COPD, fibrosis). Less sensitive than NT-proBNP and echo; used as adjunct in acute presentation.
• Available
  Serum Iron Studies, Ferritin, Transferrin Saturation

  Iron deficiency (ferritin <100 µg/L or ferritin 100–299 µg/L + transferrin saturation <20%) is present in up to 50% of HF patients and worsens outcomes independent of haemoglobin. IV iron (ferric carboxymaltose) improves QoL and 6-minute walk distance. Recommend routine testing at diagnosis and annually.
• Available
  Thyroid Function Tests (TSH)

  Hypothyroidism and hyperthyroidism both cause or exacerbate heart failure. Screen at baseline, particularly in elderly women and patients with AF. Amiodarone causes both hypo- and hyperthyroidism.
• Available
  Exercise Stress Echocardiogram / Diastolic Stress Test

  Gold standard functional test when resting echo is borderline. Exercise provokes elevation of E/e' ratio (>15), rise in RVSP, and symptoms — unmasking exertional diastolic dysfunction. Performed at major cardiac centres. Recommended when resting echo is inconclusive and symptoms persist.
• Referral
  Cardiac MRI

  Reference standard for myocardial characterisation. T1 mapping and extracellular volume (ECV) quantify myocardial fibrosis. Late gadolinium enhancement (LGE) identifies infiltrative disease (amyloidosis), hypertrophic cardiomyopathy, myocarditis. Recommended when echo quality is poor, aetiology uncertain, or amyloidosis/HCM suspected. Available at major Australian tertiary centres.
• Referral
  Serum Protein Electrophoresis + Free Light Chains (SPEP/FLC)

  Screen for AL amyloidosis in patients with LVH, low ECG voltages, and HFpEF — particularly in those aged >65 years with unexplained LVH or "sparkling" myocardium on echo. Urgent referral to haematology/amyloid service if positive. ATTR amyloidosis screening: Tc-99m pyrophosphate scintigraphy (nuclear scan).
• Specialist
  Right Heart Catheterisation (RHC)

  Invasive haemodynamic measurement of PCWP (≥15 mmHg at rest or ≥25 mmHg on exercise confirms elevated LV filling pressure). Required when diagnosis uncertain, pulmonary hypertension requires phenotyping, or prior to advanced therapy (transplant, device). Performed at specialist centres.

NYHA Functional Classification

Prognostic Risk Markers

MAGGIC Risk Score

The MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score estimates 1- and 3-year mortality in heart failure, applicable to both HFpEF and HFrEF. Incorporates age, LVEF, NYHA class, BMI, creatinine, smoking, diabetes, COPD, HF duration, diuretic use, and systolic BP. Available as an online calculator for clinical use.

SGLT2 Inhibitors — First-Line Disease-Modifying Therapy

Loop Diuretics — Symptom Relief

Mineralocorticoid Receptor Antagonists (MRA)

Hypertension Management

• Target BP: <130/80 mmHg per Australian hypertension guidelines. Aggressive BP control reduces LV hypertrophy, diastolic dysfunction, and AF burden.
• ACE inhibitors / ARBs: No mortality benefit demonstrated specifically in HFpEF (PEP-CHF, CHARM-Preserved, I-PRESERVE trials). However, indicated for concurrent hypertension (perindopril 5–10 mg daily, ramipril 5–10 mg daily, candesartan 8–32 mg daily, irbesartan 150–300 mg daily). PBS listed for hypertension.
• ARNi (sacubitril/valsartan — Entresto®): PARAGON-HF trial showed borderline non-significant benefit overall; post-hoc analyses suggest benefit in patients with LVEF just above 45% (HFmrEF borderline), women, and those with below-median LVEF. May be considered (Class IIb) in selected patients, particularly women or LVEF 45–55%. PBS listed for HFrEF; authority script required for HFpEF/HFmrEF.
• Calcium channel blockers: Amlodipine (5–10 mg daily) provides BP lowering with neutral HF effect. Felodipine similarly safe. Non-dihydropyridine CCBs (diltiazem, verapamil) useful for rate control in AF but negative inotropes — use with caution.
• Beta-blockers: No mortality benefit in HFpEF (unlike HFrEF). Use for rate control in AF (bisoprolol 2.5–10 mg daily, carvedilol 3.125–25 mg BD, metoprolol succinate 25–200 mg daily) and for angina or post-MI indications. Avoid in decompensated HF.

Atrial Fibrillation Management

• Rate control vs rhythm control: Rate control target HR 60–100 bpm at rest. Beta-blockers and non-dihydropyridine CCBs (diltiazem, verapamil) first-line. Digoxin as add-on for refractory rate control (target digoxin level 0.5–0.9 ng/mL). Early rhythm control (EAST-AFNET 4 trial) reduces cardiovascular outcomes — consider early electrical cardioversion + antiarrhythmic therapy in newly diagnosed AF + HFpEF.
• Anticoagulation: AF with HFpEF — high CHA₂DS₂-VASc score in virtually all patients (age ≥75 alone = score 2). Anticoagulate with DOAC (rivaroxaban, apixaban, edoxaban, dabigatran) — superior to warfarin. PBS listed. Assess bleeding risk (HAS-BLED score) before prescribing.
• Catheter ablation: AF ablation in HFpEF patients improves exercise capacity, QoL, and NT-proBNP. Consider referral to electrophysiology for paroxysmal/persistent AF in symptomatic NYHA II–III HFpEF patients.

Obesity and Metabolic Management

• Weight loss: OPTIMA trial and observational data demonstrate significant improvement in symptoms, exercise capacity, and echocardiographic parameters with >10% weight loss. Target BMI <30; structured caloric restriction + supervised exercise most effective. GLP-1 receptor agonists (semaglutide, liraglutide) show emerging benefit in obese HFpEF (STEP-HFpEF trial — semaglutide 2.4 mg/week subcutaneous improved symptoms, weight, and 6MWT).
• Sleep apnoea treatment: Screen all obese HFpEF patients with Epworth Sleepiness Scale and overnight oximetry/polysomnography. CPAP therapy for obstructive sleep apnoea (OSA) improves BP, diastolic function, and symptoms. Not yet shown to reduce mortality in HF.
• Diabetes management: SGLT2 inhibitors are preferred antidiabetic agents in HFpEF (dual cardiac and glycaemic benefit). GLP-1 agonists (semaglutide) have HF-agnostic benefit in obese HFpEF. Avoid thiazolidinediones (pioglitazone) — cause sodium/water retention and worsen HF. Saxagliptin (and possibly other DPP-4 inhibitors) associated with increased HF hospitalisation — avoid.

Iron Deficiency Treatment

Acute decompensation in HFpEF is typically characterised by rapid fluid accumulation, elevated filling pressures, and severe dyspnoea — often precipitated by AF with rapid ventricular rate, dietary sodium excess, or intercurrent illness. HFpEF patients are highly preload-dependent; both over-diuresis and under-diuresis are harmful.

Acute Management Steps

Discharge Criteria

• Clinically euvolaemic (no JVP elevation, no basal crackles, minimal/no oedema)
• Stable oral diuretic regimen maintaining dry weight
• Resting HR <100 bpm (if AF)
• Stable renal function (creatinine within 20% of baseline)
• SGLT2 inhibitor initiated or planned at post-discharge review
• Cardiology outpatient follow-up arranged within 7–14 days
• Patient education completed: fluid restriction (1.5–2 L/day), daily weights, sodium restriction (<2 g/day), when to seek emergency review

🤰 Pregnancy and HFpEF

HFpEF in pregnancy is uncommon but can occur in women with pre-existing hypertensive cardiomyopathy, hypertrophic cardiomyopathy, or inherited connective tissue disorders. Management requires multidisciplinary cardio-obstetric input.

• ACE inhibitors/ARBs/ARNi: Contraindicated in all trimesters — teratogenic (renal agenesis, oligohydramnios, skeletal malformations). Must be ceased prior to conception or immediately upon diagnosis of pregnancy.
• SGLT2 inhibitors: Not recommended in pregnancy — insufficient safety data; animal studies suggest embryotoxicity. Cease at conception.
• Frusemide: May be used cautiously for symptomatic relief of severe congestion in pregnancy. Avoid high doses — risk of placental hypoperfusion and fetal growth restriction.
• Beta-blockers: Metoprolol and labetalol considered relatively safe in pregnancy for rate control and BP. Neonatal monitoring for bradycardia and hypoglycaemia required.
• Anticoagulation in AF: LMWH (enoxaparin) in first trimester and near term; DOAC use in pregnancy contraindicated.

👴 Elderly Patients (≥75 years)

HFpEF is predominantly a disease of the elderly. Polypharmacy, frailty, cognitive impairment, falls risk, and reduced renal reserve require individualised management.

• Diuretic caution: Elderly patients at high risk of over-diuresis, orthostatic hypotension, and falls. Use minimum effective diuretic dose. Daily home weight monitoring essential.
• SGLT2 inhibitors: Evidence from EMPEROR-Preserved and DELIVER includes patients up to 90 years. eGFR ≥20 allows initiation. Volume depletion risk — review concomitant diuretics at initiation. Genital hygiene instruction important.
• Amyloid screening: Cardiac amyloidosis (ATTR and AL) peaks in those aged >70 years. Low ECG voltages with LVH on echo, carpal tunnel syndrome, spinal stenosis, or spontaneous biceps tendon rupture are red flags. Screen with SPEP/FLC and pyrophosphate scan — tafamidis (Vyndamax®) is PBS-listed for ATTR amyloid cardiomyopathy.
• Cognitive assessment: Heart failure is associated with cognitive impairment. Use validated tools (MMSE, MoCA). Ensure reliable medication support (blister packs, carer involvement).

🫘 Chronic Kidney Disease (CKD)

Cardiorenal syndrome is common — CKD and HFpEF coexist in up to 50% of patients. Managing both conditions simultaneously requires careful diuretic titration and medication adjustment.

• SGLT2 inhibitors: Reno-protective class effect (CREDENCE, DAPA-CKD). Can be initiated at eGFR ≥20 for HF indication. Expected initial eGFR dip of 3–5 mL/min — benign and reversible. Do not discontinue for this reason alone.
• MRA (spironolactone): Avoid with eGFR <30 or K+ >5.0 — significant hyperkalaemia risk. Patiromer or sodium zirconium cyclosilicate can enable MRA use in CKD by binding dietary potassium.
• ACEi/ARBs: Use with caution in CKD stage 4–5. Accept up to 20–30% rise in creatinine after initiation if K+ and BP stable — reflects reduced intra-glomerular pressure (beneficial mechanism). Dose reduce — perindopril 2.5–5 mg daily, ramipril 2.5 mg daily.

🛡️ Cardiac Amyloidosis (ATTR/AL)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of HFpEF in the elderly, particularly men >65 years of African ancestry (wild-type ATTR) or those with TTR gene mutations (hereditary ATTR).

• Diagnosis: TTE with "sparkling" myocardium, restrictive filling pattern, and voltage/mass discordance on ECG → Tc-99m pyrophosphate scan (grade 2–3 uptake confirms ATTR-CM with high specificity when AL amyloid excluded by SPEP/FLC). Cardiac MRI with ECV mapping confirms diagnosis.
• Tafamidis (Vyndamax® 61 mg daily): PBS listed for ATTR cardiomyopathy (wild-type or variant) — reduces all-cause mortality and CV hospitalisation (ATTR-ACT trial, 30% mortality reduction). Avoid frusemide monotherapy without addressing amyloid — loop diuretics alone are insufficient.
• Contraindications in amyloid: Digoxin (toxic — binds amyloid fibrils, high risk of digoxin toxicity). Non-dihydropyridine CCBs (verapamil, diltiazem) can precipitate acute decompensation in amyloid CM — avoid.

Medicines to Avoid or Use with Caution in HFpEF

• NSAIDs (ibuprofen, naproxen, diclofenac, celecoxib): Cause sodium and water retention, reduce renal diuretic response, and worsen renal function. Absolutely avoid in HFpEF. Paracetamol preferred for analgesia. If essential, use lowest dose for shortest duration with daily weight and renal function monitoring.
• Thiazolidinediones (pioglitazone, rosiglitazone): Cause fluid retention and peripheral oedema — contraindicated in symptomatic HF (NYHA II–IV). Avoid in HFpEF regardless of NYHA class if already fluid-overloaded.
• Saxagliptin (and possibly other DPP-4 inhibitors): SAVOR-TIMI trial showed increased HF hospitalisation with saxagliptin. Use with caution in HFpEF — if DPP-4 inhibitor required, sitagliptin preferred (neutral in TECOS trial).
• Verapamil and diltiazem in amyloid CM: Non-dihydropyridine CCBs are contraindicated in cardiac amyloidosis — risk of profound haemodynamic compromise due to amyloid fibril binding.
• Digoxin: Limited role in HFpEF (not mortality-modifying). If used for AF rate control, target serum level 0.5–0.9 ng/mL. High risk of toxicity with renal impairment and in amyloid CM — avoid in those settings.
• High-dose loop diuretics: Excessive diuresis in HFpEF causes preload reduction, reflex tachycardia, and haemodynamic compromise. Use minimum effective dose. Worsening creatinine + worsening symptoms despite diuresis suggests inadequate cardiac output (refer urgently).
• Corticosteroids: Cause sodium/fluid retention and worsen HF. Minimise use; if essential (e.g., COPD exacerbation, inflammatory conditions), intensify diuretic monitoring during steroid course.

NHFA/CSANZ Quality Indicators for HFpEF

• Echocardiogram performed and LVEF documented at diagnosis
• NT-proBNP measured at diagnosis and at clinical deterioration
• SGLT2 inhibitor prescribed or contraindication documented in eligible patients (eGFR ≥20, no type 1 DM)
• Anticoagulation prescribed or contraindication documented for AF + HFpEF
• Iron deficiency screened and treated with IV iron if present
• Post-discharge follow-up within 7–14 days arranged before hospital discharge
• Patient enrolled in heart failure disease management programme or HF clinic

Heart Failure Disease Management Programmes

Structured heart failure disease management programmes (HFDMPs) reduce 30-day readmissions, improve medication adherence, and enhance quality of life. All HFpEF patients admitted with decompensation should be enrolled on discharge. Programmes include nurse-led HF clinics, telephone monitoring, telemonitoring (remote weight and BP monitoring), and cardiac rehabilitation.

Cardiac Rehabilitation

• Exercise training: HF-ACTION trial (HFrEF) and multiple smaller HFpEF studies demonstrate exercise training improves peak VO₂, 6-minute walk distance, and NYHA class in HFpEF. Recommend supervised cardiac rehabilitation with aerobic and resistance training, 3–5 sessions per week. Medicare-rebatable in Australia (MBS item 11700–11717 via cardiac rehabilitation programmes).
• Interval training vs continuous moderate exercise: High-intensity interval training (HIIT) shows greater improvement in peak VO₂ than continuous moderate exercise in some HFpEF studies — consider HIIT in motivated, stable NYHA II patients.

Prevention of Progression

Advance Care Planning

HFpEF carries a prognosis comparable to many cancers. Advance care planning (ACP) discussions should occur at diagnosis, at NYHA class III–IV, post-hospitalisation, and annually thereafter. Discuss resuscitation preferences, implantable defibrillator (no role in HFpEF), goals of care, and palliative care integration. Refer to specialist palliative care for refractory NYHA IV symptoms. Ensure advance care directive documented in patient's medical record.

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