CardiologyTier 1Disease (DEADMAN)

Heart failure - preserved ejection fraction

Description

Heart failure symptoms and signs with EF >=50%, raised filling pressures, and objective evidence of structural or functional cardiac abnormality
*A syndrome of stiff ventricle + systemic comorbidity, not a milder form of HFrEF*

Nomenclature - 2026

2026 Second Universal Definition retired HFmrEF as a category -> HFrEF / HFimpEF / HFpEF
ESC 2026 moved to two phenotypes with a single treatment framework, and made MRA Class I across the EF spectrum
EF ~>=50% remains the practical threshold; the documents deliberately move away from rigid cutoffs

Phenotypes worth separating - because they have specific treatments

Phenotype	Clue	Specific therapy
Obesity-related / metabolic	High BMI, plasma volume expansion, low NT-proBNP for the degree of congestion	Semaglutide or tirzepatide
Hypertensive / ageing	LVH, AF, elderly F	BP control, MRA, SGLT2i
Cardiac amyloidosis (ATTR)	Wall thickness >12-14 mm, low voltage, apical sparing strain, carpal tunnel, neuropathy	Tafamidis/acoramidis
HCM	Asymmetric septal hypertrophy, outflow gradient	Mavacamten, myectomy
Constrictive pericarditis	Prior TB/RT/surgery, respirophasic septal shift, pericardial calcification	Pericardiectomy
High output	AV fistula, thyrotoxicosis, anaemia, Paget's	Treat the cause

*Chasing an "unexplained thick ventricle" is the single highest-yield diagnostic exercise in HFpEF*

Epidemiology

~50% of all heart failure, and the proportion is rising
Driven by population ageing, obesity, diabetes, hypertension and AF
F>M (the reverse of HFrEF); median age ~75
Incidence of HFrEF is falling; HFpEF incidence is not
Mortality approaches HFrEF, but a larger share of deaths is non-cardiovascular

Aetiopathogenesis

Diastole has two phases - and they fail differently

Early: active, energy-requiring relaxation (SERCA2a-mediated calcium reuptake)
- Impaired by ageing, ischaemia, LVH
Late: passive stretch/compliance
- Impaired by restrictive infiltration (amyloid), fibrosis, and constriction (pericardium)

Mechanism

Comorbidity (obesity, diabetes, hypertension, CKD) -> systemic microvascular inflammation
- -> coronary microvascular endothelial dysfunction -> dec NO -> dec cGMP/PKG
- -> titin hypophosphorylation (stiff titin) + interstitial fibrosis
- -> inc LV stiffness and inc LVEDP
Consequences
- -> inc LA pressure -> LA myopathy -> AF (AF and HFpEF each cause the other)
- -> pulmonary venous hypertension -> post-capillary PH -> RV failure
- -> chronotropic incompetence, impaired vasodilator and diastolic reserve
Exercise physiology is the key: at rest filling pressures may be normal; on exertion the stiff ventricle cannot accommodate increased venous return -> steep rise in LVEDP -> exertional dyspnoea
- This is why resting echo is often normal and why exercise testing/invasive haemodynamics resolve the doubtful case
Sodium/water retention: plasma volume expansion, especially in obesity

Diagnosis

The problem

The symptoms are non-specific and the ventricle looks normal - HFpEF is a diagnosis of positive evidence, not of exclusion

Requirements

A. Symptoms and signs of heart failure
B. EF >=50%
C. Objective evidence of raised filling pressures or structural change

Echocardiography

LA volume index >34 mL/m2 (the "haemoglobin A1c of diastolic function" - integrates chronic pressure elevation)
E/e' >=15 (average); septal e' <7 cm/s, lateral e' <10
TR velocity >2.8 m/s (raised PASP)
LV mass index raised; relative wall thickness >0.42
Global longitudinal strain reduced despite normal EF; *apical sparing suggests amyloid*

Diastolic dysfunction grading

Grade	Pattern	Physiology	Typical setting
1	Impaired relaxation (E/A <0.8)	Abnormal but complete relaxation, normal filling pressure	Normal ageing, hypertension; often asymptomatic
2	Pseudonormal (E/A 0.8-2)	Slow, incomplete relaxation; raised LVEDP and LA pressure, LA enlargement	Hypertensive/diabetic cardiomyopathy; symptoms on mild exertion
3	Restrictive (E/A >2, short deceleration time)	Very high LVEDP and LA pressure	Severe HF, cardiac amyloidosis; marked symptoms

Grade 2 is the trap - the mitral inflow pattern looks normal; tissue Doppler and LA size unmask it

Natriuretic peptides

NT-proBNP >125 ng/L (non-acute) / >300 ng/L (acute) supports the diagnosis
*A normal NT-proBNP does NOT exclude HFpEF, particularly in obesity* - BNP is lower for any given filling pressure with high BMI
Raised by age, AF, renal impairment

When the diagnosis is uncertain

H2FPEF or HFA-PEFF score to estimate probability
- H2FPEF: Heavy (BMI>30), Hypertensive (>=2 drugs), AF, Pulmonary hypertension, Elder (>60), Filling pressure (E/e'>9)
Diastolic stress echocardiography or invasive exercise haemodynamics (PCWP >=15 at rest or >=25 on exercise) - the reference standard

Always look for the specific cause

CMR - LV mass, fibrosis pattern, infiltration
*Bone scintigraphy (DPD/PYP) + serum free light chains + serum/urine immunofixation if wall thickness is increased* - ATTR is far commoner than previously thought and is now treatable
Genetic testing for HCM; ischaemia assessment; iron studies, TFT, HbA1c

Management

A. Treat the congestion

Loop diuretic to euvolaemia - symptomatic only, no mortality benefit
- The therapeutic window is narrow: the stiff ventricle is preload-dependent, so over-diuresis causes hypotension and AKI

B. Disease-modifying therapy

Agent	Status
SGLT2 inhibitor (dapagliflozin, empagliflozin)	Class I - the strongest evidence (EMPEROR-Preserved, DELIVER). Reduces HF hospitalisation; benefit independent of diabetes and across the EF spectrum
MRA	Now Class I across the EF spectrum (ESC 2026). *Finerenone is the MRA of choice in HFpEF* (FINEARTS-HF)
Semaglutide or tirzepatide	Class IIa if LVEF >=45% and BMI >=30, regardless of diabetes (STEP-HFpEF, SUMMIT). Improves symptoms, exercise capacity and weight
ARNI / ARB	May be considered, particularly at the lower end of the EF range (PARAGON-HF)
Beta blocker	*No proven benefit in HFpEF; may worsen chronotropic incompetence* - use only for another indication (AF rate control, angina)
Digoxin, nitrates	No benefit; nitrates worsen exercise capacity (NEAT-HFpEF)

C. Treat the comorbidities - this is the majority of the work

Hypertension - the single most important; target <130/80
Atrial fibrillation - rhythm control (early ablation is increasingly favoured) improves symptoms; anticoagulate by CHA2DS2-VA
Obesity - weight loss (GLP-1 RA, bariatric surgery in selected patients) - the closest thing to disease modification in this phenotype
CKD - SGLT2i, finerenone
Diabetes - SGLT2i, GLP-1 RA
Iron deficiency - IV iron improves symptoms with or without anaemia
Obstructive sleep apnoea, COPD, anaemia, thyroid disease
Cardiac rehabilitation and supervised exercise training - improves peak VO2 and quality of life; one of the better-evidenced interventions here

D. Phenotype-specific therapy

ATTR cardiac amyloidosis -> tafamidis (or acoramidis, vutrisiran)
AL amyloidosis -> urgent haematology referral for anti-plasma-cell therapy
HCM with obstruction -> beta blocker/verapamil, disopyramide, mavacamten, septal reduction
Constrictive pericarditis -> pericardiectomy (the one surgically curable cause)
Severe AS or MR -> intervene

E. Avoid

Over-diuresis (preload dependence), NSAIDs, thiazolidinediones, non-dihydropyridine CCBs in decompensation
Do not assume "diastolic heart failure" and stop looking - the specific diagnoses carry the specific treatments

Associations

Hypertension and LVH - the commonest substrate
Obesity and metabolic syndrome; T2DM
Atrial fibrillation - present in 60-70%; bidirectional causation
CKD - cardiorenal syndrome
Ageing and female sex
Cardiac amyloidosis (ATTR-wt and AL), HCM, Fabry disease, haemochromatosis, sarcoidosis
Constrictive pericarditis, restrictive cardiomyopathy
Obstructive sleep apnoea, COPD, pulmonary hypertension
Anaemia and iron deficiency, sarcopenia and frailty
Carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture - the ATTR red flags that precede the cardiac diagnosis by years

Natural history & complications

Mortality approaches HFrEF: ~50-70% at 5 years in hospitalised cohorts
A higher proportion of deaths is non-cardiovascular (~30-50%) - reflects comorbidity burden
High hospitalisation and readmission rates; frequent decompensation triggered by AF, hypertension, non-adherence, NSAIDs, infection
Progression to reduced EF is uncommon - HFpEF usually stays HFpEF
Prognostic markers: NT-proBNP, renal function, pulmonary hypertension and RV dysfunction, frailty, hospitalisation frequency
*AF onset is often the inflection point* - loss of atrial contribution to filling in a stiff ventricle causes abrupt decompensation
Untreated AL amyloidosis with cardiac involvement has a median survival of months - the reason to exclude it early
Frailty, polypharmacy and multimorbidity dominate the later course; begin advance care planning early

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