HIF-mediated hierarchical hypoxic adaptation, a novel paradigm in heart failure pathogenesis: is there a role for targeted therapies?

Heart failure (HF) is a terminal cardiovascular syndrome related to systemic hypoxia. Hypoxia is considered a fundamental pathophysiological process, and the resulting tissue response depends on the severity and duration of exposure. Hypoxia-inducible factors (HIFs) promote adaptation to hypoxic conditions by regulating the expression of multiple hypoxia-responsive genes. Its short-term activation during acute hypoxia exerts cardioprotective effects, whereas chronic activation induces pathological hypertrophy, depending on the disease context. Therefore, HIF-mediated hypoxic responses in HF may involve hierarchical adaptations to hypoxia. This review discusses the role of HIFs in the physiology and pathology of HF, focusing on metabolic remodeling, angiogenesis, cardiac inflammation, and circadian influences, as well as their potential effects on myocardial performance. Furthermore, the therapeutic potential of HIF-targeting compounds in HF treatment will be reviewed. Overall, whether targeting HIF-induced changes in HF is an effective strategy remains to be established; thus, research in this field is urgently needed.