Abstract 11953: Nanoscale Movement of L-Type Calcium Channels in the Cardiomyocyte Membrane Can Contribute to Arrhythmia During Heart Failure
Cardiac L-Type calcium channels (LTCCs) are crucial for normal excitation-contraction coupling and are located predominantly in T-tubules. In heart failure T-tubules lose their organisation, however less is known about the spatial redistribution of LTCCs. We hypothesised that LTCCs may move from T-tubules to locations where they are usually not present in control cardiomyocytes, e.g. the crest. We examined the subcellular location of LTCCs in isolated adult rat cardiomyocytes using a combination of high resolution scanning ion conductance microscopy and patch-clamp called “smart” patch-clamp. Cells were isolated from control rats and from rats 16 weeks after induction of myocardial infarction (MI) by permanent coronary arterial ligation. “Smart” patch-clamp allowed us to record single-channel currents from functional LTCCs with nanoscale resolution on the surface of cardiomyocytes. In control cardiomyocytes a majority of channels were found in T-tubules (T-tubules: 21 channels in 76 patches; crest: 2 channels in 21 patches). However, after 16 weeks of MI the channel occurrence was similar in both T-tubules and the crest (T-tubules: 4 channels in 19 patches; crest: 4 channels in 18 patches). In addition, the open probability of LTCCs (Po) found in the crest after MI was significantly increased as compared to that of channels in T-tubules (T-tubules, Po=0.10 ± 0.02, n=22 vs. Crest, Po=0.25 ± 0.09, n=4, P=0.007). Using the O'Hara-Rudy model, we simulated the consequence of LTCC movement from T-tubules to the crest on the ventricular action potential, applying the 50/50 channel distribution in T-tubules and the crest (as in experiments after 16 weeks of MI). Increased Po of channels in the crest was a natural consequence of crest re-location: calcium dependent inactivation was weakened due to reduced intracellular calcium at the crest vs. T-tubular space. This resulted in development of arrhythmogenic early afterdepolarizations (EADs, 1Hz pacing). We conclude that nanoscale changes in the spatial location of LTCCs occur during heart failure that impact on their function. LTCC redistribution from T-tubule to crest in heart failure may contribute to arrhythmia risk by introducing a source of focal ectopy.
- © 2012 by American Heart Association, Inc.