Abstract 15055: Ranolazine Blocks the Enhanced Late Na+ Current and Shortens the Action Potential Duration in Ventricular Myocytes From Lamin A/C Mutant (LmnaN195K) Mice
Lamin A/C proteins, encoded by LMNA gene, are nuclear lamina filament proteins predominantly expressed in differentiated cells including cardiomyocytes. A missense mutation in LMNA gene (N195K) in patients affecting the A-type lamins causes dilated cardiomyopathy (DCM), and is associated with an increased incidence of arrhythmia and sudden death. The mechanism of arrhythmia and sudden death associated with Lmna-N195K gene mutation is unknown. To investigate this we used a homozygous mouse line expressing the Lmna-N195K mutation (LmnaN195K/N195K) that died at early age (6-7 weeks) due to underlying arrhythmia and/or left ventricular failure, which is consistent with human DCM. Using whole cell patch clamp technique, we measured peak and late Na+ current (INa) and action potential duration (APD), in ventricular myocytes isolated from LmnaN195K/N195K and wild type (WT) mice. The APD to 50% (APD50) (47±12 msec) and APD to 90% repolarization (APD90) (73±13 msec) were significantly prolonged in myocytes from LmnaN195K/N195K compared to 9±2 msec (APD50) and 18±6 msec (APD90) in myocytes from WT (n=5, p<0.001). The late INa (calculated as % ratio of late INa/peak INa) was 6-times greater in myocytes from LmnaN195K/N195K (1.8±0.5%) compared to myocytes from WT (0.3±0.5%, n=5). Therefore, a possible mechanism underlying the arrhythmias in patients with N195K mutation could be due to an enhanced late INa leading to a decrease in repolarization reserve and an increase in [Na+]i-induced [Ca2+]i overload. We tested whether ranolazine, an inhibitor of late INa could reduce this current and shorten the APD in myocytes from LmnaN195K/N195K. Ranolazine (10 μM) completely blocked the enhanced late INa (n=5) in myocytes from LmnaN195K/N195Kmice. Tetrodotoxin (1 μM) similarly blocked late INa in myocytes from LmnaN195K/N195K. Furthermore, in myocytes from LmnaN195K/N195K, ranolazine (10 μM) significantly shortened both APD50 and APD90 to 17±7 and 46±7 msec, respectively (p<0.05 compared to LmnaN195K/N195K). Taken together, these data show that inhibition of late INa by ranolazine normalizes both enhanced late INa and prolonged APD in LmnaN195K/N195K myocytes. We conclude that ranolazine may suppress arrhythmias in patients with LMNA-related DCM.
- © 2013 by American Heart Association, Inc.