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

• Published in: Journal of cardiac failure Vol. 25; no. 10; pp. 828 - 836
• Main Authors: Goldstein, Robert E., Klein, Michael G., Ouimet, Sean P., Shou, Matie, Hood, Maureen N., Flagg, Thomas P., Haigney, Mark C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2019
• Subjects: action potential; mexiletine; Ranolazine; systolic dysfunction; systolic dysfunction; action potential; Ranolazine; mexiletine
• ISSN: 1071-9164; 1532-8414
• DOI: 10.1016/j.cardfail.2019.08.015

•Ranolazine or mexiletine do not adversely affect swine with advanced heart failure.•In vivo drug levels shortened action potential duration prolonged by heart failure.•Bradycardia enhanced late Na+ current but did not affect in vivo hemodynamic results.•The swine model suggests drug inhibition of late Na+ current may be safe in patients wih heart failure.
To evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls.
Ranolazine and mexiletine potently inhibit depolarizing late Na+ current (INa,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.
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/dtmax) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dtmax, LVSP, heart rate, maximal LV pressure fall rate (–dP/dtmax), 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 INa,late. Patch-clamped HF cardiomyocytes confirmed drug-induced INa,late blockade.
Ranolazine or mexiletine blocking INa,late neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of INa,late by ranolazine or mexiletine may not exacerbate HF in patients.