Evaluation of GeranylGeranylAcetone in Heart Failure With Preserved Ejection Fraction (GLADIATOR)

Inclusion Criteria: Age≥ 50 years 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: Current acute decompensated heart failure, requiring hospitalization or augmented therapy with intravenous diuretics, vasodilators, and/or inotropic drugs Acute coronary syndrome, transient ischemic attack/cerebrovascular accident, major surgery within the previous 3 months Hemoglobin <9 g/dl at screening LVEF <40% measured at any time point in the history of the patient History of mitral valve repair or replacement 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 Acute myocarditis within 3 months prior to randomization Infiltrative cardiomyopathy Genetic cardiomyopathy Severe pulmonary disease requiring home oxygen or chronic oral steroid therapy Precapillary pulmonary hypertension BMI >40 kg/m2 Estimated glomerular filtration rate (GFR) <20 ml/min or >90 ml/min History of solid organ transplantation including kidney transplantation Atrial fibrillation or atrial flutter with resting ventricular rate >110 bpm Not able to undergo the complete study protocol Doubt about compliance Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control Chronic absorption problems Proven allergy for lactose products or cow-milk. Proven allergy for Iodide-containing contrast, Iohexol or PAH. 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 Currently enrolled in another investigational device or drug trial Estimated life expectancy <1 year