Study to Evaluate the Efficacy and Safety of AZD4831 in Participants With Heart Failure With Left Ventricular Ejection Fraction > 40%

Inclusion Criteria

Part A

• ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.
• Documented stable symptomatic HF (New York Heart Association Class II-IV) for at least 1 month at Screening (Visit 1) (transient HF in the setting of an MI does not qualify), with a medical history of typical symptoms of HF and receiving optimal therapy for HF as determined by the health-care physician.
• LVEF > 40% at Screening (Visit 1). All participants will undergo a local echocardiogram at the Screening (Visit 1) with central reading to confirm the LVEF > 40% eligibility criteria before randomisation.
• 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 3). Difference in 6MWD between Screening and Randomisation must be 30 kg/m2.

The ECG performed at Screening should be used for heart rhythm evaluation.

7.At least one of the following:

• Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or LVMI > 95 g/m2 in women and > 115 g/m2 in men.
• Spectral tissue Doppler echocardiography - E/e' ratio (average of septal and lateral) ≥ 13 at rest at the echocardiogram performed at Screening (Visit 1).
• Indirectly estimated elevation of PASP by TRmax velocity > 2.8 m/s (280 cm/s) (PASP > 35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR directly measured pulmonary capillary wedge pressure > 15 mmHg at rest within the past 12 months or > 25 mmHg at exercise documented by right heart catheterisation within 12 months prior to Screening (Visit 1).
• HF decompensation within 6 months before Randomisation (Visit 3), defined as hospitalisation for HF or IV diuretic treatment for HF during an urgent, unscheduled visit without hospitalisation.

8.Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2

9.Male or female of non-childbearing potential.

Part B

• Participant must be ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent.
• Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit 1), and a medical history of typical symptoms/signs of heart failure ≥ 6 weeks before Screening (Visit 1), and receiving optimal therapy for HF as determined by the health-care physician, with at least intermittent need for diuretic treatment.
• LVEF >40% and evidence of structural heart disease (ie, left ventricular hypertrophy or

left atrial enlargement [defined by at least one of the following:LA enlargement and/or left ventricular hypertrophy at the echocardiogram

performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width

(diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34

mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or

LVMI > 95 g/m2 in women and > 115 g/m2 in men.]) documented by the most recent echocardiogram, or cardiac

magnetic resonance imaging within the last 12 months prior to Screening (Visit 1). If no

echocardiogram is available, it can be performed at Screening (Visit 1).

• 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 2). Difference in 6MWD between Screening and Randomisation must be 30 kg/m2. The ECG performed at Screening should be used for heart rhythm evaluation
• Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2
• Male or female of non-childbearing potential.

Exclusion Criteria

Part A

1 eGFR 110 bpm or 5000 pg/mL at Screening (Visit 1)

• Documented history of ejection fraction ≤ 40%.i.e. HF with recovered ejection fraction. Transient ejection fraction decrease e.g. in the setting of an MI