Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability

Abstract

Background: Late Na + current (I NaL ) in human and dog hearts has been implicated in abnormal repolarization associated with heart failure (HF). HF slows inactivation gating of late Na + channels, which could contribute to these abnormalities. Aims: To test how altered gating affects I NaL time course, Na + influx, and action potential (AP) repolarization. Methods: I NaL and AP were measured by patch clamp in left ventricular cardiomyocytes from normal and failing hearts of humans and dogs. Canine HF was induced by coronary microembolization. Results: I NaL decay was slower and I NaL density was greater in failing hearts than in normal hearts at 24°C (human hearts: τ = 659 ± 16 vs. 529 ± 21 ms; n = 16 and 4 hearts, respectively; mean ± SEM; p b 0.002; dog hearts: 561 ± 13 vs. 420 ± 17 ms; and 0.307 ± 0.014 vs. 0.235 ± 0.019 pA/pF; n = 25 and 14 hearts, respectively; p b 0.005) and at 37°C this difference tended to increase. These I NaL changes resulted in much greater (53.6%) total Na + influx in failing cardiomyocytes. I NaL was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC 50 = 62 nM) or tetrodotoxin (IC 50 = 1.2 μM), tested in dogs. A 50% I NaL inhibition by toxins or passing current opposite to I NaL , decreased beat-to-beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes. Conclusions: Chronic HF leads to larger and slower I NaL generated mainly by the cardiac-type Na + channel isoform, contributing to larger Na + influx and AP duration variability. Interventions designed to reduce/normalize I NaL represent a potential cardioprotective mechanism in HF via reduction of related Na + and Ca 2+ overload and improvement of repolarization.

Influence of heart failure on nucleolar organization and protein expression in human hearts

“…In agreement with previous experimental observations, the upregulation of I NaL during HF [15] or its enhancement in situations of reduced repolarization reserve [21] prolongs APD, causes AP triangulation and increase the reverse rate-dependent prolongation of APD, which are important harbingers for cardiac arrhythmias. The contribution of I NaL in the reverse APD ratedependence was also previously simulated by our group [60] using a different human AP model [48] and conditions of reduced repolarization reserve.…”

“…On the basis of experimental observations [3,4,7,9,11,[13][14][15]67] and previous simulation studies [5,12,44,47], we hereby propose various changes in the formulation of several ionic currents of the GPB model to reproduce the reported experimental changes in AP and intracellular Ca 2+ and Na + handling in ventricular myocytes from failing human hearts [8,31,66]. Our model will be referred to as the basic HF model.…”

“…Major changes in intracellular and sarcoplasmic reticulum (SR) Ca 2+ homeostasis are also associated with HF in several animal species, included human [9,[11][12][13]. In myocytes from failing hearts [Na + ] i concentration and Ca 2+ handling are closely linked; [Na + ] i is increased in failing ventricular myocytes from human and other animal species [3,4,9,14] and a prominent increase of the human late Na + current (I NaL ) has also been documented [15,16], and has been proposed as a therapeutic target [17][18][19]. Experimental studies have shown that the I NaL is involved in the generation of EADs in myocytes [17,18] and life-threatening arrhythmias, such as torsade de pointes (TdP) [20], especially under conditions of reduced repolarization reserve in several animal species [21][22][23].…”

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

“…For example, [Na] i accumulates very slowly, causing a very slow increase in I NaK , which can also initiate the Hopf-homoclinic bifurcation, as shown in our previous simulations (57). Late I Na is another candidate because it may slowly inactivate (58). Finally, the gradual rise in [Ca] i may also activate other outward currents, such as the Ca-activated Cl current (I Cl(Ca) ) (59) or small conductance Ca-activated K current (60).…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…Block of I Na,late has been shown to completely suppress TdP in various models. 62,63 Furthermore, pharmacological inhibition of I Na,late reduces APD variability in myocytes from failing human hearts (where I Na,late density is increased) 64 and has also been observed to suppress reentry in a rat model of ventricular fibrillation. 65 Abnormalities in sodium and calcium handling play a crucial role in various cardiac pathologies.…”