Differential β-Adrenergic Signaling and Camp Dynamics in Left and Right Ventricles from Patients with Valve Disease

Objectives: Left ventricular hypertrophy is an independent risk factor for the development of heart failure. However, the fundamental mechanisms involved in contributing to the progression from hypertrophy to heart failure are still not well understood. It is well accepted that adrenergic activation in heart failure contributes to cardiac dysfunction progression. Thus, we aimed to investigate the role of β-adrenoceptor-G protein adenylate cyclase signaling in the pathogenesis of cardiac hypertrophy in the human heart.

Methods: Human myocytes were isolated from RV and LV samples of 11 patients submitted to Ross procedure. The patients showed normal systolic left ventricular function without signs of pulmonary hypertension. However diastolic dysfunction was present due to compensatory left ventricular hypertrophy caused by the underlying valvular disease. Föster-resonance energy transfer (FRET) was used to measure cAMP in 114 myocytes. We were able to successfully establish for the first-time isolation, culture and real-time cAMP imaging in human ventricular myocytes.

Result: LV myocytes showed no desensitization to β-AR stimulation, but a significant attenuated adenylyl cyclase activation compared with the RV. However, β2-AR stimulation also elicited smaller increases on cAMP in LV which disappear after adenylyl cyclase activation plus phosphodiesterase (PDE) inhibition. Only PDE4 inhibition revealed differences in cAMP regulation within ventricles, alone or upon β-AR stimulation.

Conclusion: Compensatory hypertrophy does not affect global β-AR sensitivity in human ventricles. However, LV myocytes are not able to produce the same amount of cAMP due to differential cAMP hydrolytic activity of PDE4 in the β2-ARs compartment. These results suggest a different PDE4 compartmentation associated to different dynamic binding of AC/AKAP/PDE4/β2-ARs macromolecular complex, promoting unique downstream feedback mechanisms within ventricles. Targeting this binding might be a potential option to treat compensatory LV hypertrophy at the beginning before it deteriorates to heart failure.

Publication History

Article published online:
19 February 2021