Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure.

Pathophysiological remodeling of cardiac function occurs at multiple levels, spanning the spectrum from molecular and sub-cellular changes to those occurring at the organ-system levels. Of key importance to arrhythmias are changes in the electrophysiological substrate at the tissue level. In this manuscript, we provide an overview of mechanisms by which heterogeneous remodeling of ion channels, calcium handling proteins, gap junctions, and stretch-activated pathways produce functionally significant repolarization gradients across regions (anterior vs lateral) and muscle layers (epicardial vs midmyocardial vs endocardial) of the left ventricule. These repolarization gradients form an electrophysiological substrate that predisposes to arrhythmias and sudden cardiac death in heart failure.

From mitochondrial dynamics to arrhythmias.

The reactive oxygen species (ROS)-dependent mitochondrial oscillator described in cardiac cells exhibits at least two modes of function under physiological conditions or in response to metabolic and oxidative stress. Both modes depend upon network behavior of mitochondria. Under physiological conditions cardiac mitochondria behave as a network of coupled oscillators with a broad range of frequencies. ROS weakly couples mitochondria under normal conditions but becomes a strong coupling messenger when, under oxidative stress, the mitochondrial network attains criticality. Mitochondrial criticality is achieved when a threshold of ROS is overcome and a certain density of mitochondria forms a cluster that spans the whole cell. Under these conditions, the slightest perturbation triggers a cell-wide collapse of the mitochondrial membrane potential, Delta psi(m), visualized as a depolarization wave throughout the cell which is followed by whole cell synchronized oscillations in Delta psi(m), NADH, ROS, and GSH. This dynamic behavior scales from the mitochondrion to the cell by driving cellular excitability and the whole heart into catastrophic arrhythmias. A network collapse of Delta psi(m) under criticality leads to: (i) energetic failure, (ii) temporal and regional alterations in action potential (AP), (iii) development of zones of impaired conduction in the myocardium, and, ultimately, (iv) a fatal ventricular arrhythmia.

Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation.

Electrical coupling between myocytes plays a critical role in propagation, repolarization, and arrhythmias. On the basis of predictions from cable theory, we hypothesized that the cardiac space constant (lambda) measured from the decay of subthreshold transmembrane potential (ST-Vm) in space would provide an index of regional cell-to-cell coupling in the intact heart. With the use of voltage-sensitive dyes, the distribution of ST-Vm was measured from hundreds of sites in close proximity to the site of subthreshold stimulation. lambda was calculated from the exponential decay of ST-Vm in space. Consistent with known directional differences in axial resistance, the spatial distribution of ST-Vm was strongly dependent on fiber orientation, because lambda was significantly (P < 0.001) longer along (1.5 +/- 0.1 mm) compared with across (0.8 +/- 0.1 mm) fibers. There was a close linear relationship (P < 0.001) between conduction velocity (CV) and lambda along all fiber angles tested. Reducing gap junctional conductance by heptanol reversibly decreased CV and lambda in parallel by approximately 50%. In contrast, sodium channel blockade by flecainide slowed CV by 40% but had no effect on lambda, reaffirming that lambda was an index of passive but not active membrane properties. These data establish the feasibility of measuring lambda as an index of cell-to-cell coupling in the intact heart, and indicate strong dependency of lambda on fiber orientation and pharmacological alterations of gap junction conductance.

Cellular basis for dispersion of repolarization underlying reentrant arrhythmias.

Substantial heterogeneity in ion channel density and expression exists in cells isolated from various regions of the heart. Cell-to-cell coupling in the intact heart, however, is expected to attenuate the functional expression of the ion channel heterogeneities. Due to limitations of conventional electrophysiological recording techniques, the extent to which cellular electrical heterogeneities are functionally present in intact myocardium remains unknown. High-resolution optical mapping with voltage-sensitive dyes was used to measure transepicardial and transmural repolarization gradients in the Langendorff perfused guinea pig ventricle and the canine wedge preperation, respectively. Diversity of repolarization kinetics in the transepicardial direction modulated dispersion of repolarization in a biphasic fashion as premature coupling interval was shortened. Moreover, modulation of repolarization paralleled arrhythmia vulnerability in a predictable fashion. Transmural optical mapping revealed significant gradients of repolarization across the ventricular wall that were markedly increased in a surrogate model of LQTS. Transmural gradients of repolarization in LQTS were associated with an enhanced susceptibility to TdP. Therefore, despite strong cell-to-cell coupling in the normal heart, heterogeneities in the ionic make-up of cells across the epicardial and transmural surfaces result in functional heterogeneities of repolarization leading to arrhythmias.

Mechanism linking T-wave alternans to the genesis of cardiac fibrillation.

BACKGROUND: Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. METHODS AND RESULTS: -T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209+/-46 bpm) that was significantly lower (by 57+/-36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation. CONCLUSIONS: Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.

Modulated dispersion explains changes in arrhythmia vulnerability during premature stimulation of the heart.

BACKGROUND: Previously, we have shown that a premature stimulus can significantly modulate spatial gradients of ventricular repolarization (ie, modulated dispersion), which result from heterogeneous electrophysiological properties between cells. The role modulated dispersion may play in determining electrical instability in the heart is unknown. METHODS AND RESULTS: To determine if premature stimulus-induced changes in repolarization are a mechanism that governs susceptibility to cardiac arrhythmias, optical action potentials were recorded simultaneously from 128 ventricular sites (1 cm2) in 8 Langendorff-perfused guinea pig hearts. After baseline pacing (S1), a single premature stimulus (S2) was introduced over a range of S1S2 coupling intervals. Arrhythmia vulnerability after each premature stimulus was determined by measurement of a modified ventricular fibrillation threshold (VFT) during the T wave of each S2 beat (ie, S2-VFT). As the S1S2 interval was shortened to an intermediate value, spatial gradients of repolarization and vulnerability to fibrillation decreased by 51+/-9% (mean+/-SEM) and 73+/-45%, respectively, compared with baseline levels. As the S1S2 interval was further shortened, repolarization gradients increased above baseline levels by 54+/-30%, which was paralleled by a corresponding increase (37+/-8%) in vulnerability. CONCLUSIONS: These data demonstrate that modulation of repolarization gradients by a single premature stimulus significantly influences vulnerability to ventricular fibrillation. This may represent a novel mechanism for the formation of arrhythmogenic substrates during premature stimulation of the heart.