Impact of Combined Clenbuterol and Metoprolol Therapy on Reverse Remodelling during Mechanical Unloading

Background

Clenbuterol (Cl), a β₂ agonist, is associated with enhanced myocardial recovery during left ventricular assist device (LVAD) support, and exerts beneficial remodelling effects during mechanical unloading (MU) in rodent heart failure (HF). However, the specific effects of combined Cl+β₁ blockade during MU are unknown.

Methods and Results

We studied the chronic effects (4 weeks) of β₂-adrenoceptor (AR) stimulation via Cl (2 mg/kg/day) alone, and in combination with β₁-AR blockade using metoprolol ((Met), 250 mg/kg/day), on whole heart/cell structure, function and excitation-contraction (EC) coupling in failing (induced by left coronary artery (LCA) ligation), and unloaded (induced by heterotopic abdominal heart transplantation (HATx)) failing rat hearts. Combined Cl+Met therapy displayed favourable effects in HF: Met enhanced Cl''s improvement in ejection fraction (EF) whilst preventing Cl-induced hypertrophy and tachycardia. During MU combined therapy was less beneficial than either mono-therapy. Met, not Cl, prevented MU-induced myocardial atrophy, with increased atrophy occurring during combined therapy. MU-induced recovery of Ca²⁺ transient amplitude, speed of Ca²⁺ release and sarcoplasmic reticulum Ca²⁺ content was enhanced equally by Cl or Met mono-therapy, but these benefits, together with Cl''s enhancement of sarcomeric contraction speed, and MU-induced recovery of Ca²⁺ spark frequency, disappeared during combined therapy.

Conclusions

Combined Cl+Met therapy shows superior functional effects to mono-therapy in rodent HF, but appears inferior to either mono-therapy in enhancing MU-induced recovery of EC coupling. These results suggest that combined β₂-AR simulation +β₁-AR blockade therapy is likely to be a safe and beneficial therapeutic HF strategy, but is not as effective as mono-therapy in enhancing myocardial recovery during LVAD support.