Late sodium current is a new therapeutic target to improve contractility and rhythm in failing heart

Abstract

Most cardiac Na+ channels open transiently within milliseconds upon membrane depolarization and are responsible for the excitation propagation. However, some channels remain active during hundreds of milliseconds, carrying the so-called persistent or late Na+ current (I(NaL)) throughout the action potential plateau. I(NaL) is produced by special gating modes of the cardiac-specific Na+ channel isoform. Experimental data accumulated over the past decade show the emerging importance of this late current component for the function of both normal and especially failing myocardium, where I(NaL) is reportedly increased. Na+ channels represent a multi-protein complex and its activity is determined not only by the pore-forming alpha subunit but also by its auxiliary beta subunits, cytoskeleton, and by Ca2+ signaling and trafficking proteins. Remodeling of this protein complex and intracellular signaling pathways may lead to alterations of I(NaL) in pathological conditions. Increased I(NaL) and the corresponding Na+ influx in failing myocardium contribute to abnormal repolarization and an increased cell Ca2+ load. Interventions designed to correct I(NaL) rescue normal repolarization and improve Ca2+ handling and contractility of the failing cardiomyocytes. New therapeutic strategies to target both arrhythmias and deficient contractility in HF may not be limited to the selective inhibition of I(NaL) but also include multiple indirect, modulatory (e.g. Ca(2+)- or cytoskeleton- dependent) mechanisms of I(NaL) function.

Figure (1)

Biophysical properties of the slowly inactivating, late Na⁺ current (I_NaL) evaluated by whole cell patch clamp in human ventricular cardiomyocytes (A-E) and human cloned Na_v1.5 expressed in tsA201 cells (F). A-B: I_NaL can be carried either by Na⁺ or Li⁺. B: I-V relation for I_NaL. C: examples of steady-state activation and availability curves, G(V_m) and A(V_p), respectively. D: Examples of original traces illustrating voltage-independent I_NaL decay. E: slow reactivation of I_NaL. F: I_NaL produced by Na_v1.5 was assessed as difference current before application of a selective Na⁺ channel blocker tetrodotoxin (TTX, 30 μM) and after TTX. Voltage protocols are shown at the traces. Recording was performed at 24°C. Modified from [11] (A-E) and [65](F), used with permission.

Figure (2)

A: Chronic heart failure slows and increases I_NaL. A: examples of whole cell I_NaL recordings in human and dog ventricular cardiomyocytes. B: Idealized I_NaL and their integrals in normal and failing dog cardiomyocytes of same size (200 pF) calculated using Q₁₀ factors (37°C) and average parameters of I_NaL density and decay time constant measured in normal and HF canine VCs. Larger and slower I_NaL in failing cardiomyocytes results in substantial increase in total charge (or Na⁺ influx) transfer by I_NaL. Gray areas illustrate difference between failing and normal cells. Adapted from [13], used with permission.

Figure (3)

Inactivation of both late scattered mode (A) or burst mode (B) of the late openings of Na⁺ channel was slowest in failing human cardiomyocytes compared with those from normal human hearts or heterologously expressed Na_v1.5. *P<0.05, heart failure vs. normal heart or clone (Mean±SEM). Cell-attached patches, 24°C. (Adapted from [12]). C: recordings of action potentials in failing human cardiomyocytes are shown along with the late scattered mode and burst mode openings occurring at -10 mV, i.e. within the voltages of the action potential plateau. Adapted from [12, 40], used with permission.

Figure (4)

Schematic illustration of Na⁺ channel macromolecular complex. A: The pore forming α subunit of the channel interacts with β-subunits, cytoskeleton and the extracellular matrix (Modified after [50], used with permission). B: schematic presentation of the α subunit of the cardiac Na⁺ channel isoform (Na_v1.5) with reported sites of interaction with β subunits (restricted only to β1 and β2) and other regulatory proteins. Reprinted from [17], used with permission.

Figure (5)

A: Frequency-dependence of action potential duration in ventricular cardiomyocytes of normal dogs and dogs with chronic heart failure. Note that largest difference occurs at low pacing rates. B: at the low (0.2 Hz) and the physiologic (1 Hz) pacing rates, AP duration in failing myocytes exhibits significant beat-to beat variability (see respective SD values in the APD₉₀ distribution histograms) Adapted from [10] with permission.

Figure (6)

A: Examples of effects of a specific Na⁺ channel blocker saxitoxin (STX) on AP duration, contraction and Ca²⁺ transient in ventricular cardiomyocytes of dogs with chronic heart failure at a low pacing rate of 0.2 Hz STX reduces AP duration, abolishes “dome” phase of contraction and of Ca²⁺ transient in failing cells. B: At higher pacing rates a specific I_NaL blockers ranolazine reduces diastolic tension, and a specific Na⁺ channel blocker tetrodotoxin (TTX) reduces Ca²⁺ accumulation (Fluo-4 signals). Adapted from [14, 15, 17], used with permission.

Figure (7)

Simplified hypothetical diagram of the intracellular Ca²⁺ signaling pathways modulating late sodium current in normal and failing ventricular cardiac myocytes. Pathways 1, 2 and 3 (marked by black digits) represent Ca²⁺ binding to: the E-F domain, CaM-binding site (IQ motif) on C-terminus of NaCh as well as CaM/CaMKII complex, respectively. In addition, shown are the inhibitory sites of the CaM antagonist peptide P290-309 and KN93 - inhibitor of CaMKII, which were used in our original study [110] to discover the I_NaL modulation depicted in the diagram. Dashed line arrows indicate the regulation pathways which are operational only in heart failure. Reprinted from [110], used with permission.

Figure (8)

Simplified diagram of the modulatory mechanisms that lead to the I_NaL increase in HF. These mechanisms may serve as a road map to develop new strategies for HF treatment (see text for detail).