Hemodynamic Effects of Late Sodium Current Inhibitors in a Swine Model of Heart Failure

Objectives: To evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls. Background: Ranolazine and mexiletine potently inhibit depolarizing late Na⁺ current (I_Na,late) and Na⁺ entry into cardiomyocytes. Blocking Na⁺ entry may increase forward-mode Na/Ca exchange and reduce cellular Ca⁺² load, further compromising systolic contraction during HF. Methods and Results: Anesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls. The swine with HF had characteristic elevated left ventricular end-diastolic pressure (LVEDP) and reduced maximal left ventricular pressure rise (+dP/dt_max) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dt_max, LVSP, heart rate, maximal LV pressure fall rate (–dP/dt_max), or time constant for isovolumic relaxation. Similar results seen in additional swine with HF: 7 were given mexiletine, and 7 others were given ranolazine after a 27% rate decrement to maximize I_Na,late. Patch-clamped HF cardiomyocytes confirmed drug-induced I_Na,late blockade. Conclusions: Ranolazine or mexiletine blocking I_Na,late neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of I_Na,late by ranolazine or mexiletine may not exacerbate HF in patients.