Aim: Left ventricular (LV) hypertrophy is an independent risk factor for the development of heart failure (HF). However, the mechanisms involved in the progression from LV hypertrophy to HF are not well understood. Adrenergic activation in HF contributes to the progression of cardiac dysfunction. Thus, we aimed to investigate the role of β-adrenoceptor-G-protein-adenylate cyclase (AC) signalling in the pathogenesis of hypertrophy in human right (RV) and LV myocytes.

Methods and Results: Myocytes were isolated from RV and LV samples of 11 patients with normal systolic LV function but diastolic dysfunction due to compensatory LV hypertrophy. Föster-resonance energy transfer was used to measure cAMP in 114 myocytes. LV myocytes showed no signs of desensitization to β-AR stimulation, but significantly attenuated AC activation as compared to RV myocytes. β₂-AR stimulation induced smaller increase of cAMP in LV myocytes which was similar to RV myocytes after phosphodiesterase (PDE) inhibition. Only PDE4 inhibition revealed differences in cAMP regulation between both ventricles, alone and upon β-AR stimulation.

Conclusion: Concentric hypertrophy does not affect global β-AR sensitivity of LV myocytes. However, LV myocytes are not able to produce the same amount of cAMP due to differential cAMP hydrolytic activity of PDE4 in the β₂-AR compartment. These results suggest a different PDE4 compartmentation, promoting unique downstream feedback mechanisms within ventricles. Targeting this binding might be a potential treatment option of LV hypertrophy before it deteriorates to HF.