BACKGROUND: Response to catecholamines is blunted in terminal heart failure due to β-receptor downregulation and uncoupling from adenylyl cyclase (AC). Improved myocardial responsiveness to catecholamines after ventricular assist device (VAD) support is associated with upregulation of β1-adrenergic receptors (β1-ARs). Little is known about the regulation of AC and β2-AR coupling after VAD; moreover β2-AR stimulation during VAD was claimed to induce myocardial recovery. METHODS: We analyzed in VAD-supported human myocardium the regulation of AC activity upon β1-AR and selective β2-AR stimulation in 8 non-failing hearts (NF) and 17 paired samples of VAD patients. AC messenger RNA was measured by TaqMan. AC was stimulated via β2-AR using clenbuterol (β2-AR agonist) and bisoprolol (β1-AR blocker). Organ bath experiments were done with trabeculae from both ventricles. Samples were stratified according to chronic or acute heart failure history. RESULTS: Isoprenaline-induced AC activity was downregulated (p < 0.001) pre-VAD and increased significantly (p < 0.05) after unloading (mean ± standard deviation pmole/mg/min) in NF (47.9 ± 14.9), pre-VAD (24.35 ± 13.3), and post-VAD (50.04 ± 50.25). Forskolin stimulation revealed significant (p < 0.05) upregulation of AC activity during VAD, especially in acutely failing hearts (NF, 192.1 ± 68.7; pre-VAD, 191.1 ± 60.4; post-VAD, 281.5 ± 133). However, forskolin stimulation relative to isoprenaline-induced inotropy remained reduced before and after VAD compared with NF. The selective stimulation of β2-AR did not reveal influence of VAD support on β2-AR-AC coupling. Stimulation of ventricular trabeculae by > 100 μmole/liter clenbuterol revealed negative inotropic responses. CONCLUSIONS: VAD does not influence β2-AR coupling to AC stimulation. Elevated response to catecholamines after VAD support is influenced by β1-AR upregulation and modulation of AC activity. Restoration of β-adrenergic responsiveness was restricted to acutely failing hearts.
BACKGROUND: Response to catecholamines is blunted in terminal heart failure due to β-receptor downregulation and uncoupling from adenylyl cyclase (AC). Improved myocardial responsiveness to catecholamines after ventricular assist device (VAD) support is associated with upregulation of β1-adrenergic receptors (β1-ARs). Little is known about the regulation of AC and β2-AR coupling after VAD; moreover β2-AR stimulation during VAD was claimed to induce myocardial recovery. METHODS: We analyzed in VAD-supported human myocardium the regulation of AC activity upon β1-AR and selective β2-AR stimulation in 8 non-failing hearts (NF) and 17 paired samples of VAD patients. AC messenger RNA was measured by TaqMan. AC was stimulated via β2-AR using clenbuterol (β2-AR agonist) and bisoprolol (β1-AR blocker). Organ bath experiments were done with trabeculae from both ventricles. Samples were stratified according to chronic or acute heart failure history. RESULTS:Isoprenaline-induced AC activity was downregulated (p < 0.001) pre-VAD and increased significantly (p < 0.05) after unloading (mean ± standard deviation pmole/mg/min) in NF (47.9 ± 14.9), pre-VAD (24.35 ± 13.3), and post-VAD (50.04 ± 50.25). Forskolin stimulation revealed significant (p < 0.05) upregulation of AC activity during VAD, especially in acutely failing hearts (NF, 192.1 ± 68.7; pre-VAD, 191.1 ± 60.4; post-VAD, 281.5 ± 133). However, forskolin stimulation relative to isoprenaline-induced inotropy remained reduced before and after VAD compared with NF. The selective stimulation of β2-AR did not reveal influence of VAD support on β2-AR-AC coupling. Stimulation of ventricular trabeculae by > 100 μmole/liter clenbuterol revealed negative inotropic responses. CONCLUSIONS: VAD does not influence β2-AR coupling to AC stimulation. Elevated response to catecholamines after VAD support is influenced by β1-AR upregulation and modulation of AC activity. Restoration of β-adrenergic responsiveness was restricted to acutely failing hearts.
Authors: Stephanie J Nakano; Juliana Sucharov; Robert van Dusen; Mackenzie Cecil; Karin Nunley; Sean Wickers; Anis Karimpur-Fard; Brian L Stauffer; Shelley D Miyamoto; Carmen C Sucharov Journal: J Card Fail Date: 2016-07-15 Impact factor: 5.712