Therapeutic Targeting of PDEs and PI3K in Heart Failure with Preserved Ejection Fraction (HFpEF).
PURPOSE OF REVIEW
Heart Failure with preserved Ejection Fraction (HFpEF) is a prevalent disease with considerable individual and societal burden. HFpEF patients often suffer from multiple pathological conditions thatcomplicate management and adversely affect outcome, including pulmonary hypertension and chronic obstructive pulmonary disease (COPD). To date, no treatment proved to be fully effective in reducing morbidity and mortality in HFpEF, possibly due to an incomplete understanding of the underlying molecular mechanisms.


RECENT FINDINGS
The emerging view proposes chronic systemic inflammation, leading to endothelial dysfunction and interstitial fibrosis, as a prominent cause of HFpEF, rather than a mere co-existent disease. In the last decade, efforts from pharmaceutical companies attempted to target pharmacologically enzymes which play key roles in systemic and lung inflammation, such as the cyclic nucleotide-degrading enzymes phosphodiesterases (PDEs) and phosphoinositide-3 phosphate kinases (PI3Ks), especially to limit COPD. In this review, we will summarize major successes and drawbacks of hitting these enzymes to tackle inflammation in HFpEF-associated co-morbidities, with a major focus on the results of completed and ongoing clinical trials. Finally, we will discuss the potential of repurposing and/or developing new PDE and PI3K inhibitors for HFpEF therapy.
['Sala|Valentina|V|', 'Margaria|Jean Piero|JP|', 'Murabito|Alessandra|A|', 'Morello|Fulvio|F|', 'Ghigo|Alessandra|A|', 'Hirsch|Emilio|E|']
D004730:Endothelium, Vascular D006333:Heart Failure D006801:Humans D006976:Hypertension, Pulmonary D007249:Inflammation D010726:Phosphodiesterase Inhibitors D000081082:Phosphoinositide-3 Kinase Inhibitors D029424:Pulmonary Disease, Chronic Obstructive D013318:Stroke Volume
Chronic obstructive pulmonary disease PDE inhibitors Phosphodieserases Phosphoinositide-3 kinase inhibitors