Molecular and electrophysiological evidence for "remodeling" of the L-type Ca2+ channel in persistent atrial fibrillation in humans.

Persistent atrial fibrillation (AF) is associated with shortened action potential duration (APD) and reduced atrial refractoriness. Remodeling of ion currents responsible for AP morphology has been proposed as a major mechanism in persistent AF. In the present study we investigated the activity of the cardiac L-type Ca2+ channel and the mRNA transcription of the cardiac L-type Ca2+ channel subunits in patients with persistent AF compared to patients in sinus rhythm (SR). Right atrial appendages of 10 patients in SR and of 5 patients with AF were used for myocyte isolations to record L-type Ca2+ currents (ICa,L) by the patch-clamp technique. Right atrial appendages of 16 patients in Sr and of 5 patients with AF served as sources for determining the mRNA expression of the L-type Ca2+ channel alpha 1c-, alpha 2/delta-, beta a-, and beta b/beta c-subunits by semiquantitative RT-PCR. ICa,L density was reduced by 70% (p < 0.001) in AF patients compared to the sinus rhythm group. Cell sizes, expressed as cell capacitance, were identical in both groups. mRNA expressions of the alpha 1c-subunit and the beta b/beta c-subunits were reduced in AF patients by 18.9% (p < 0.05) and 77.7% (p < 0.005), respectively, while mRNA transcriptions of the alpha 2/delta- and the beta a-subunits were not significantly different between SR and AF patients. A decrease in the availability of functional L-type Ca2+ channels in AF patients, due to reduced alpha 1c-subunit and substantial lack of beta b/beta c-subunit transcription seems to contribute to the shortening of APD and refractory periods in AF, thereby favoring increased atrial excitation rate and perpetuation of AF.