A ventricular AP model is altered by NaV1.5+β1 proton modulation. Overlay of simulated epicardial (Epi) and mid-myocardial (M) ventricular APs incorporating NaV1.5+β1 data recorded with the extracellular solution titrated to pH 7.4 (A) or pH 6.0 (B). NaV1.5+β1 currents recorded at pH 6.0 preferentially prolonged mid-myocardial APs over epicardial and endocardial APs. At pH 6.0, the APD90 was increased from 348 ms to 353 ms (epicardial), 361 ms to 378 ms (mid-myocardial), and 348 ms to 354 ms (endocardial). APs obtained using pH 6.0 data also displayed an 11 mV reduction in their peak depolarization (40 mV to 29 mV) and a 5 mV increase in the threshold for AP firing (−51 mV to −46 mV), and reduced the maximum rate of the AP upstroke by 60% (197 mV/ms to 81 mV/ms) (inset). The inset displays an expanded view of the initial rise of a mid-myocardial cell AP at pH 7.4 and 6.0. (C) Epicardial, mid-myocardial, and endocardial ventricular APs display the preferential increase of mid-myocardial APs with pH 6.0 data.