Abstract 2731: SERCA2a/NCX Ratio Determines Regional Propensity for Triggered Activity During Calcium Overload
Andersen-Tawil syndrome Type 1 (ATS1)-associated ventricular arrhythmias are initiated by frequent, hypokalemia-exacerbated, triggered activity (TA). We previously demonstrated that a guinea pig model of ATS1 (partial IK1 inhibition by 10μM BaCl2 and 2mM [K+]o) evidenced increased arrhythmia propensity and was marked by TA with different temporal and cytosolic Ca2+ characteristics. Differences in TA characteristics have been linked with heterogeneous regional sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and Na+-Ca2+ exchanger (NCX) protein expression; however, their specific roles in determining TA incidence and timing remain unclear. We hypothesize that lower functional SERCA2a/NCX ratio during intracellular Ca2+ accumulation underlies increased TA. Ca2+ transients were optically mapped from Langendorff-perfused ventricles. Under control conditions, cytosolic Ca2+ in the LV base (LVB) decayed slower (13.8±2.6%, p < 0.05) relative to LV apex (LVA). This is consistent with lower SERCA2a protein density in LVB vs. LVA (80.2±25.7%, p < 0.05). LVB NCX expression was significantly greater than LVA (81.2±30.9%, p < 0.05), i.e., LVB has a lower SERCA2a/NCX ratio. During ATS1 (n = 4), TA was more frequent in LVB (37 observed) vs. LVA (17) and occurred earlier in the cycle (73.9±2.2% vs. 80.0±2.1% respectively, p < 0.05). Furthermore, ATS1 increased diastolic Ca2+ (CaD) more in LVB (22.033.3%) than in LVA (15.5±4.0%, p < 0.05) relative to control. Therefore, a lower SERCA2a/NCX ratio in LVB spatially correlates with sites of earliest and most frequent TA. Importantly, decreasing the functional SERCA2a/NCX ratio via SERCA2a inhibition (5μM cyclopiazonic acid) during ATS1 increased the incidence of LVB and LVA TA (59 & 66, n = 3) and decreased their coupling intervals (57.2±2.5% & 53.4±3.5%). These data suggest that inhibiting SERCA2a in ATS1 increases CaD and decreases the rate of sarcoplasmic reticular Ca2+ loading, yet paradoxically increases TA. During cytosolic Ca2+ accumulation, the functional SERCA2a/NCX ratio may determine TA incidence and timing. Therefore, inhibiting NCX, rather than SERCA2a may offer a potential therapeutic target to alleviate arrhythmia burden during cytosolic Ca2+ elevation secondary to loss of IK1 function.