Cardiac L-type Ca²⁺-currents show distinct alterations in chronic heart failure, including increased single-channel activity and blunted adrenergic stimulation, but minor changes of whole-cell currents. Expression of L-type Ca²⁺-channel β₂-subunits is enhanced in human failing hearts. In order to determine whether prolonged alteration of Ca²⁺-channel gating by β₂-subunits contributes to heart failure pathogenesis, we generated and characterized transgenic mice with cardiac overexpression of a β_2a-subunit or the pore Ca_v1.2 or both, respectively.

Four weeks induction of cardiac-specific overexpression of rat β_2a-subunits shifted steady-state activation and inactivation of whole-cell currents towards more negative potentials, leading to increased Ca²⁺-current density at more negative test potentials. Activity of single Ca²⁺-channels was increased in myocytes isolated from β_2a-transgenic mice. Ca²⁺-current stimulation by 8-Br-cAMP and okadaic acid was blunted in β_2a-transgenic myocytes. In vivo investigation revealed hypotension and bradycardia upon Ca_v1.2-transgene expression but not in mice only overexpressing β_2a. Double-transgenics showed cardiac arrhythmia. Interstitial fibrosis was aggravated by the β_2a-transgene compared with Ca_v1.2-transgene expression alone. Overt cardiac hypertrophy was not observed in any model.

Cardiac overexpression of a Ca²⁺-channel β_2a-subunit alone is sufficient to induce Ca²⁺-channel properties characteristic of chronic human heart failure. β_2a-overexpression by itself did not induce cardiac hypertrophy or contractile dysfunction, but aggravated the development of arrhythmia and fibrosis in Ca_v1.2-transgenic mice.