This protocol is a component of the CarDia project under the National Institute for Metabolic and Cardiovascular Disease Research (EXCELES Program, ID: LX22NPO5104), which is financed by the European Union - Next Generation EU. It falls under Work Package 5 (WP5), focusing on metabolic disorders in heart failure. The aim of this observational protocol is to track the biochemical and metabolomic reactions to the commencement of standard heart failure medications (SGLT2i, soluble guanylate cyclase-sGC stimulators, sacubitril/valsartan-ARNI) and to assess if the initial response (within the first three months) can predict the disease's progression. The protocol will investigate the temporal changes in parameters that indicate neurohumoral activation, hypoxia response, systemic energy substrate metabolism, iron metabolism, and HIF1A activation in peripheral blood following the initiation of standard heart failure therapy (baseline, 1 day, 1 week, 1 month, 3 months). This study could yield crucial insights into identifying individuals who exhibit a poorer response to the new treatment and are at a higher risk of an unfavorable disease trajectory. Patients will be compared with a control group, who are those without any therapy alteration during the initial observation period (3 months). As an observational study, the decision to initiate therapy will be based solely on medical indications. Heart failure patients at the Cardiocenter of the Institute for Clinical and Experimental Medicine - IKEM in Prague, CZ will undergo blood sampling at specific intervals before and after the initiation of clinically indicated treatment. A subset of patients will also receive genetic DNA testing to explore gene variability that influences the metabolic neurohumoral response to heart failure.

Patients will be followed up at 1 and 2-year intervals to monitor the occurrence of clinical events. The study's observational nature ensures that participation does not influence the standard of care or pharmacotherapy selection.

Inclusion Criteria:

• ability to give written informed consent
• Heart failure New York Functional class (NYHA) II-IV with duration more than 3 months (regardless ejection fraction, universal definition of HF)
• NTproBNP more than 125 pg/ml at screening (Universal definition of HF)
• O2 sat more than 90%

Exclusion Criteria:

• Previous SGLT2 inhibitor therapy or i.v., iron therapy in past 3 months (for SGLT2i arm)
• Previous sGC stimulator (for sGC arm), or previous ARNI (for ARNI arm), or previous SGLT2i, sGC or ARNI for control group.
• Coronary artery bypass grafting (CABG), cardiac resynchronisation therapy (CRT), STEMI, valve replacement, in past 3 months, or planned within next 3 months
• Blood loss needing transfusion in past 3 months
• Clinical instability (including HF hospitalization) in the past 1 month
• Myelodysplasia, chronic hemolysis, erythropoetin therapy
• Systemic inflammatory condition (lupus, rheumatoid arthritis...) or infection
• Uncontrolled cancer
• Chronic kidney disease (CKD) grade 4-5
• Severe anemia with Hgb less than 90 g/L
• No chronic exposure to hypoxia (severe chronic obstructive pulmonary disease, obstructive sleep apnoea, long-term oxygen therapy)
• History of SGLT2i allergy or intolerance
• Repeated genitourinary infection

Stable HF patients with HFrEF, HFmrEF or HFpEF