Stratified Treatment to Ameliorate Diastolic Left Ventricular Stiffness in Heart Failure With Preserved Ejection Fraction

Inclusion Criteria:

1. Age ≥ 18 years at time of screening

2. Symptomatic chronic heart failure patients with diagnosis of heart failure and:

• NYHA class II-IV

• Preserved systolic Left Ventricular (LV) function, defined by: LV EjectionFraction (LVEF) ≥ 50% and LV end-diastolic volume index <97 ml/m2

• Evidence of diastolic LV dysfunction and at least 1 out of the 5 followingadditional criteria:

1. H2FPEF score ≥ 6;

2. HFA-PEFF score ≥ 5;

3. Pulmonary capillary wedge pressure > 15 mmHg at rest or > 25 mmHg withexercise assessed with right heart catheterization;

4. Cardiac MRI T1 derived extracellular volume <29% at screening

5. Oral diuretics, if prescribed to the patient according to local guidelines and at thediscretion of the investigator, should be stable for at least 1 week prior to baselinevisit

6. Signed and dated written informed consent in accordance with GCP and local legislationprior to admission to the trial

Exclusion Criteria:

1. Reduced systolic LV function (LVEF < 50%), measured at any time point in the historyof the patient

2. Obstructive coronary artery disease with evidence of ischemia

3. Myocardial infarction, coronary artery bypass graft surgery or other majorcardiovascular surgery, stroke or TIA in past 90 days prior to screening visit

4. More than mild valve stenosis

5. More than moderate aortic and/or mitral valve regurgitation

6. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulationdiseases (e.g. hemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathywith reversible causes (stress cardiomyopathy), hypertrophic (obstructive)cardiomyopathy or known pericardial constriction

7. History of mitral valve repair or replacement

8. Atrial fibrillation or atrial flutter with a resting heart rate > 110 bpm at screening

9. Acute decompensation that requires intravenous loop diuretics

10. Systolic blood pressure ≥ 180 mmHg. If SBP > 150 mmHg and < 180 mmHg, the patientshould be receiving at least 3 antihypertensive drugs at screening or baseline visit

11. Symptomatic hypotension and/or a SBP < 100 mmHg at screening or baseline visit

12. Impaired renal function, defined as eGFR < 30 ml/min/1.73 m2

13. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT),or alkaline phosphatase above 3x upper limit of normal or history of cirrhosis withevidence of portal hypertension

14. Hemoglobin < 9 g/dl at screening

15. Chronic obstructive pulmonary disease, more than GOLD class 2

16. Pulmonary function test with FEV1/FVC < 80%

17. Primary pulmonary arterial hypertension

18. Type 1 Diabetes Mellitus

19. History of ketoacidosis

20. Any documented active or suspected malignancy or history of malignancy within 2 yearsprior to screening, except appropriately treated basal cell carcinoma of the skin orin situ carcinoma of uterine cervix or low risk prostate cancer (biopsy Gleason scoreof ≤ 6 and clinical stage T1c or T2a)

21. Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitorwithin 3 months prior to screening visit. Discontinuation of a SGLT-2 inhibitor orcombined SGLT-1 and 2 inhibitor for the purposes of study enrolment is not permitted

22. Pregnancy or lactation

23. Any (clinical) condition that, in the investigator's opinion, would jeopardizepatients safety while participating in this trial, or may prevent the patient fromadhering to the trial protocol