Multifaceted remodelling of cAMP microdomains driven by different aetiologies of heart failure

Heart failure with preserved ejection fraction (HFpEF) will soon take over as the predominant form of heart failure. This is largely driven by the continuing increased incidences of obesity and type 2 diabetes (T2D), which promote HFpEF in the absence of pressure overload stresses. With beta-blockers showing little effectiveness in treating obesity/T2D HFpEF and with no HFpEF-targeted drugs currently available, we are in urgent need of a better understanding of how obesity/T2D HFpEF develops and how we may treat this condition. An exciting emerging field aiming to do this focuses on the investigation of 3',5'-cyclic adenosine monophosphate (cAMP) microdomains in the heart. The previous work has largely focused on the investigation of cAMP microdomain remodelling in heart failure with reduced ejection fraction (HFrEF), with this work uncovering potential new targets for intervention strategies that otherwise would have been overlooked when studying changes in cAMP dynamics at the whole-cell level. In this review, we aimed to discuss current advancements in our understanding of cAMP microdomain remodelling in HFrEF vs that in obesity/T2D-associated HFpEF, with particular focus on the unresolved questions and limitations we face in being able to translate this knowledge.