Introduction: Long-QT syndrome type 3 (LQT3) is caused by a gain-of-function mutation in the cardiac sodium channel that increases the late sodium current and prolongs repolarization. We previously suggested that narrowing the perinexus which is adjacent gap junction conceals the LQT3 phenotype by depleting extracellular sodium ([Na]) within this nanodomain and curtails the late current and repolarization. However, it is unknown if elevating bulk [Na] alone modulates action potential duration (APD) in widened perinexi to unmask LQT3. Hypothesis: Elevated [Na] and widened perinexi synergistically prolong APD in LQT3. Methods: The dependence of APD on [Na] and perinexal width was explored with a computational model and in Langendorff-perfused guinea pig hearts. The late sodium current was induced with ATXII (7nM). Perfusate [Na] changed from 145 (145Na) to 160 mM (160Na). Perinexal expansion was induced with βadp1 (1uM). APD was quantified from whole-heart optical maps. Perinexal width was quantified by transmission electron microscopy. Results: A computational model, including preferential sodium channel location at the intercalated disk, predicts that combination of elevated [Na] and widened perinexus prolongs APD greater than summing the effect of the individual interventions alone. Therefore, the combination is synergistic and not additive. Isolated heart experiments are consistent with the model. Specifically, ATXII+βadp1 significantly widens perinexal width from 27.8±4.1 to 49.7±9.3 nm and prolongs APD by 18.1±5.1ms with 600ms pacing relative to ATXII alone. In the presence of ATXII, 160Na significantly prolongs APD by 12.0±5.8ms relative to 145Na. Furthermore, the combination of both interventions is synergistic. Specifically, in the presence of ATXII, 160Na+βadp1 significantly prolongs APD more than the sum of the individual effects (49.9±7.5ms vs. 30.2±5.4ms). Conclusions: The data demonstrate that in LQT3, enhancing sodium and perinexal width concurrently prolong APD more than the individual effects alone. This synergistic effect suggests that maintaining reduced plasma sodium level can be a simple and effective method to conceal LQT3, even in the presence of perinexal expansion associated with osmotically induced stress.