*Bi-Hua Tan, MD, PhD, *Carmen R. Valdivia, MD and *Jonathan C. Makielski, MD. University of Wisconsin, Madison, WI. Mutations in SCN5A with decreased Na current underlie arrhythmia syn- dromes such as the Brugada syndrome (BS). Some BS mutations have been shown to have kinetic abnormalities, while others cause defects in traf- ficking. The mutation G1406R was previously reported in a large French family with BS and/or isolated cardiac conduction defect and showed no detectable Na + current after 8h of transfection, but it was studied in only one of the two splice variant backgrounds that exist in every human in a 2:1 mRNA transcript ratio. We made G1406R in the two common splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, and transfected them into HEK-293 cells, and voltage clamped them after 24 hours and 48 hours incubation with and without mexiletine (500 M). In the Q1077del variant, after 24 hours, the mutant channel had significantly increased expression levels to -229  50 pA/pF (n=15) compared to no treatment (-11  4 pA/pF, n=15, p 0.001). Interestingly, we also found that the current density of G1406R, even without drug, was increased after 48 hours of incubation to -11317 pA/pF (n=11), but this was still less than the wild-type levels (-321  81 pA/pF, n=9, p 0.02) after 24 hours incubation, suggesting that the expression defect of G1406R in Q1077del is only partial. Mexiletine further increased current density of G1406R after 48 hours incubation to normal levels of -315  64 pA/pF (n=13). In the Q1077 variant, mexil- etine increased the expression levels of mutant channel to -188  45 pA/pF (n=12) compared to no treatment (-23  7 pA/pF, n=17, p 0.001) after 24 hours incubation, and to -390  69 pA/pF (n=8) compared to no treatment (-37  9, n=13, p 0.001) after 48 hours incubation. Thus in the Q1077 background the defect was more severe and did not increase at 48 hours, but was still rescued by drug. These data show for the first time that the molecular phenotype of a BS mutation depends upon the splice variant background, and it is only the second report of drug rescue of a BS mutation. These findings may have implications for expression defect mechanisms and potential treatment in BS. P2-8 QUINOLONES AND PROARRHYTHMIA: DIFFERGENT TORSADOGENIC POTENTIAL DESPITE SIMILAR EFFECTS ON MYOCARDIAL REPOLARIZAITON Peter Milberg, MD, Wilhelm Haverkamp, Gerold Mo ¨nnig, MD, F. Talebpour, MD, Gu ¨nther Breithardt, MD, PhD and Lars Eckardt, MD. University Hospital of Mu ¨nster, Mu ¨nster, Germany, University Hospital Mu ¨nster, Mu ¨nster, Germany and Department for Medical Informatics and Biomathematics, Mu ¨nster, Germany. Background: Numerous non-cardiovascular drugs prolong repolarization and may thereby increase the risk for patients to develop life-threatening tachyar- rhythmias of the torsade de pointes- (TdP) type. As these drugs show different proarrhythmic potential despite similar QT-prolongation, we investigated the electrophysiologic characteristics of proarrhythmia in an intact heart model. As a group of drugs which are known for having a different proarrhythmic potential, we chose fluorquinolone-antibiotics. Methods and Results: In 46 Langendorff-perfused rabbit hearts, ciprofloxa- cin (C; n=10), ofloxacin (O, n=14), levofloxacin (L, n=10) in high concen- trations of 100 to 1000M and moxifloxacin (M; n=12) in a lower concen- tration of 50 to 250M led to a significant increase in QT-interval and monophasic action potential (MAP)-duration. Eight simultaneously recorded MAP demonstrated an increase in dispersion of repolarization in the presence of all antibiotics. The ratio of MAP90 and MAP50 showed a triangular pattern of MAP prolongation for all drugs at high concentrations. Moreover all drugs showed an increase in instability of consecutive action potential recordings in increasing concentrations. C (4 out of 10), O (3 out of 14), M (9 out of 12) and L (2 out of 10) led to early afterdepolarizations (EADs ) and TdP at high concentrations after lowering of potassium concentration. Conclusion: (1) All investigated fluorquinolones led presumably via IKr- blockade to a comparable increase of QT-interval, MAP-duration, disper- sion of repolarization and in high concentrations to triangularization of the MAP configuration and an increase in instability. (2) All tested quinolones are able to induce TdP, but C, O and L demonstrate a weak proarrhythmic potential as compared to M. Differences in the concentration-effect rela- tionship result in differences in the torsadogenic potential. P2-9 THE SLOW ACTIVATING, DELAYED RECTIFIER K  CURRENT IS A MAJOR COMPONENT OF REPOLARIZATION RESERVE *Yejia Song, MD, *John C. Shryock, PhD, *Lin Wu, MD and *Luiz Belardinelli, MD. University of Florida, Gainesville, FL and CV Therapeutics, Palo Alto, CA. The concept of repolarization reserve has been proposed to explain individual susceptibility to drug-induced action potential and Q-T pro- longation and torsades de pointes. However, the specific ion currents contributing to repolarization reserve remain to be elucidated. We examined the hypothesis that the slow activating, delayed rectifier K + current (I Ks ) is a major component of repolarization reserve that coun- teracts prolongation of action potential duration caused by 1) blockers of the rapid activating, delayed rectifier K + current (I Kr ), and 2) reduc- tion of extracellular K + ([K + ] o ). Action potential duration at 50% repolarization (APD 50 ) and the amplitudes of I Ks and I Kr of guinea pig isolated ventricular myocytes were determined using the whole-cell patch-clamp technique. To study the role of I Ks on action potential prolongations caused by the I Kr blockers E-4031 (1 mol/L) and moxi- floxacin (100 mol/L) and by the late Na + current enhancer ATX-II (5 nmol/L), APD 50 was measured in the absence and presence of the I Ks blocker chromanol 293B (30 mol/L). E-4031 and moxifloxacin each increased APD 50 by 122% (n=6) and 112% (n=4), respectively, and did not induce early afterdepolarizations (EADs). When applied with chromanol 293B (which itself increased the APD 50 by 372%, n=15), E-4031 and moxifloxacin caused a significantly greater prolon- gation of the APD 50 , by 10516% (n=7, p0.001 vs. E-4031 alone) and 968% (n=5, p=0.002 vs. moxifloxacin alone), respectively. EADs were induced in the presence of both chromanol 293B and E-4031. EADs were also induced by ATX-II. Reduction of [K + ] o from 4.6 to 3, 1.5, and 0 mmol/L decreased I Kr , but increased I Ks by 122, 324, and 549%, respectively (n=12, p0.01). Consequently, re- ducing [K + ] o from 4.6 to 3 mmol/L caused not a prolongation, but rather a shortening of the APD 50 by 101% (n=8), and attenuated ATX-II-induced EADs (n=3). These effects of low [K + ] o were re- versed by chromanol 293B. The present results confirm the hypothesis that I Ks is a major component of repolarization reserve, and suggest that cardiac myocytes with weak I Ks may be susceptible to drug-induced APD prolongation. P2-10 MULTIPLE PATHWAYS FOR CALCIUM HANDLING ABNORMALITIES LINKING A NOVEL CASQ2 MUTATION TO VENTRICULAR ARRHYTMIAS AND SUDDEN DEATH Marina Raffaele Di Barletta, PhD, Serge Viatchenko- Karpinski, PhD, Alessandra Nori, PhD, Dmitry Terentyev, PhD, Barbara Colombi, PhD, Mirella Memmi, PhD, Massimo Santoro, PhD, Raffaella Bloise, MD, Carlo Napolitano, MD, PhD, Pompeo Volpe, MD, PhD, Sandor Gyorke, MD, PhD and Silvia G. Priori, MD, PhD. Fondazione Salvatore Maugeri, Pavia, Italy, Texas Tech University HSC, Lubbock, TX, Universita ` di Padova, Padova, Italy and Fondazione Salvatore Maugeri-Universita ` di Pavia, Pavia, Italy. Four distinct mutations in the human cardiac calsequestrin gene ( CASQ2) have been linked to Catecolaminergic Polimorphic Ventricular Tachycar- dia (CPVT) and sudden death. Here we report a novel CASQ2 mutation consisting in a 16bp deletion at position 339-354 leading to a frameshift and a stop codon after 5aa (G112+5X), identified in a young patient with S137 Poster 2