Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction

The goal of this double-blind randomized, placebo-controlled cross-over trial is to evaluate the effectiveness of GerenylGeranylAcetone (GGA) in patients with Heart Failure with a preserved ejection fraction.

The main questions it aims to answer are:

* What is the effect of GGA on diastolic function?
* What is the effect of GGA on endothelial function?

Main study tasks:

* Participants will be treated with either GGA or placebo for 13 weeks. After this they will have a break (wash-out) period for 6 weeks and then cross over to the other study arm.
* Cardiac function will be measured using echocardiogram in all participants
* Renal measurements and endothelial measurements will be performed on the participants.
* Participants will perform a 5 minute walking distance test for functional capacity.
* Participants will fill out questionnaires to score signs \& symptoms.

Researchers will compare the patients to themselves to see if the drug improves diastolic- and endothelial function.


Eligibility Criteria:
Inclusion Criteria:

1. Age≥ 50 years
2. Patients with a diagnosis of symptomatic chronic heart failure (New York Heart Association class II or III) AND preserved systolic LV function (LV ejection fraction or LVEF ≥ 50%) documented within the last 6 months AND evidence of diastolic LV dysfunction with at least 1 out of the following 4 criteria:

   * HFA-PEFF score ≥5
   * H2FPEF score ≥6
   * HFpEF according to the 2021 ESC HF Guidelines (NT-proBNP\>125 pg/ml AND either LV mass indexed or LVMI \>95 g/m2 for women and \>115 g/m2 for men OR left atrial volume indexed or LAVI \>34 ml/m2 OR mean e; septal/lateral \< 9 cm/s) OR E/e' \>13 OR TR velocity at rest \>2,8m/s.
   * Pulmonary capillary wedge pressure (PCWP) \>15 mmHg and/or \>25 mmHg during exercise.

Exclusion Criteria:

1. Current acute decompensated heart failure, requiring hospitalization or augmented therapy with intravenous diuretics, vasodilators, and/or inotropic drugs
2. Acute coronary syndrome, transient ischemic attack/cerebrovascular accident, major surgery within the previous 3 months
3. Hemoglobin \<9 g/dl at screening
4. LVEF \<40% measured at any time point in the history of the patient
5. History of mitral valve repair or replacement
6. Presence of significant valvular disease defined as mitral valve regurgitation defined as grade ≥ 3+ MR; tricuspid valve regurgitation defined as grade ≥ 2+ TR; aortic valve disease defined as ≥ 2+ AR or \> moderate AS
7. Acute myocarditis within 3 months prior to randomization
8. Infiltrative cardiomyopathy
9. Genetic cardiomyopathy
10. Severe pulmonary disease requiring home oxygen or chronic oral steroid therapy
11. Precapillary pulmonary hypertension
12. BMI \>40 kg/m2
13. Estimated glomerular filtration rate (GFR) \<20 ml/min or \>90 ml/min
14. History of solid organ transplantation including kidney transplantation
15. Atrial fibrillation or atrial flutter with resting ventricular rate \>110 bpm
16. Not able to undergo the complete study protocol
17. Doubt about compliance
18. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control
19. Chronic absorption problems
20. Proven allergy for lactose products or cow-milk.
21. Proven allergy for Iodide-containing contrast, Iohexol or PAH.
22. Any documented or suspected malignancy or history of malignancy within 1 year prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix
23. Currently enrolled in another investigational device or drug trial
24. Estimated life expectancy \<1 year