Functionally distinct sodium channels in ventricular epicardial and endocardial cells contribute to a greater sensitivity of the epicardium to electrical depression.

A greater depression of the action potential (AP) of the ventricular epicardium (Epi) versus endocardium (Endo) is readily observed in experimental models of acute ischemia and Brugada syndrome. Endo and Epi differences in transient outward K(+) current and/or ATP-sensitive K(+) channel current are believed to contribute to the differential response. The present study tested the hypothesis that the greater sensitivity of Epi is due in part to its functionally distinct early fast Na(+) current (I(Na)). APs were recorded from isolated Epi and Endo tissue slices and coronary-perfused wedge preparations before and after exposures to elevated extracellular K(+) concentration ([K(+)](o); 6-12 mM). I(Na) was recorded from Epi and Endo myocytes using whole cell patch-clamp techniques. In tissue slices, increasing [K(+)](o) to 12 mM reduced V(max) to 51.1 +/- 5.3% and 26.8 +/- 9.6% of control in Endo (n = 9) and Epi (n = 14), respectively (P < 0.05). In wedge preparations (n = 12), the increase in [K(+)](o) caused selective depression of Epi APs and transmural conduction slowing and block. I(Na) density was not significantly different between Epi (n = 14) and Endo (n = 15) cells, but Epi cells displayed a more negative half-inactivation voltage [-83.6 +/- 0.1 and -75.5 +/- 0.3 mV for Epi (n = 16) and Endo (n = 16), respectively, P < 0.05]. Our data suggest that reduced I(Na) availability in ventricular Epi may contribute to its greater sensitivity to electrical depression and thus may contribute to the R-ST segment changes observed under a variety of clinical conditions including acute myocardial ischemia, severe hyperkalemia, and Brugada syndrome.

Occurrence of "J waves" in 12-lead ECG as a marker of acute ischemia and their cellular basis.

The "J wave" (also referred to as "the Osborn wave,""the J deflection," or "the camel's hump") is a distinctive deflection occurring at the QRS-ST junction. In 1953, Dr. John Osborn described the "J wave" as an "injury current" resulting in ventricular fibrillation during experimental hypothermia. Although "J Wave" is supposed to be pathognomonic of hypothermia, it is seen in a host of other conditions such as hypercalcemia, brain injury, subarachnoid hemorrhage, cardiopulmonary arrest from over sedation, the Brugada syndrome, vasospastic angina, and idiopathic ventricular fibrillation. However, there is paucity of literature data as regards to ischemic etiology of "J Wave." In this article, we present a case where "J waves" were probably induced by ischemia. We also discuss the mechanism of ischemia-induced "J wave" accentuation and its prognostic implications.

Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry?

BACKGROUND: Pinacidil is known to augment a time-independent outward current in cardiac tissues by activating the ATP-regulated potassium channels. Activation of this current, IK-ATP, is thought to be responsible for increased potassium permeability in ischemia. The contribution of IK-ATP activation to arrhythmogenesis and the role of activation of this current in suppression of arrhythmias are areas of great interest and debate. Because electrical depression attending myocardial ischemia is more accentuated in ventricular epicardium than in endocardium, we endeavored to contrast the effects of pinacidil-induced IK-ATP activation on the electrophysiology of canine ventricular epicardium and endocardium. METHODS AND RESULTS: Standard microelectrode techniques were used. Pinacidil (1 to 5 mumol/L) produced a marked dispersion of repolarization and refractoriness in isolated canine ventricular epicardium as well as between epicardium and endocardium. In endocardium, pinacidil abbreviated action potential duration (APD90) and refractoriness by 8.0 +/- 2.3%. In epicardium, the effects of pinacidil were nonhomogeneous. At some sites, pinacidil induced an all-or-none repolarization at the end of phase 1 of the action potential, resulting in 55.5 +/- 8.7% abbreviation of APD90 and refractoriness. Adjacent to these were sites at which the dome was maintained with only minor changes in APD and refractoriness. Extrasystolic activity displaying features of reentry was observed in isolated sheets of epicardium (63.2%) after exposure to pinacidil (1 to 5 mumol/L) but never in its absence. Dispersion of repolarization and ectopic activity was most readily induced in epicardium by a slowing of the stimulation rate in the presence of pinacidil. Electrical homogeneity was restored and arrhythmias abolished after washout of pinacidil or addition of either a transient outward current blocker, 4-aminopyridine, or a blocker of the ATP-regulated potassium channels, glybenclamide. CONCLUSIONS: Our data suggest that the activation of IK-ATP can produce a marked dispersion of repolarization and refractoriness in epicardium as well as between epicardium and endocardium, leading to the development of extrasystolic activity via a mechanism that we have called phase 2 reentry. The available data also suggest that blockade of the transient outward current and/or the ATP-regulated potassium channels may be useful antiarrhythmic interventions under ischemic or "ATP depleted" conditions.

High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry.

BACKGROUND: Elevated intracellular calcium activity is thought to play an important role in arrhythmia induction, particularly during ischemia and reperfusion. Delayed after-depolarization-induced triggered activity and intracellular communication problems are thought to be responsible. METHODS AND RESULTS: Increased extracellular calcium levels and rapid pacing are interventions known to elevate intracellular calcium activity. The present study, conducted using standard microelectrode techniques, was designed to compare the effects of increased [Ca2+]o (1.8 to 5.4 mmol/L) in isolated canine ventricular epicardial and endocardial tissues and to test the hypothesis that elevated intracellular calcium activity contributes to arrhythmogenesis in working ventricular myocardial tissues by promoting electrical heterogeneity. High [Ca2+]o caused a slight abbreviation of action potential duration (APD90) in endocardium but more dramatic rate-dependent and dynamic changes in epicardium. Under steady-state conditions, epicardium displayed a marked abbreviation of APD90 at fast rates but no significant changes at slow rates. A significant augmentation of phase 1 was evident at the faster stimulation rates. Vmax and conduction velocity were only slightly reduced. The marked abbreviation of the epicardial response at the factor rates was due to loss of the action potential dome. Recovery of the dome after deceleration was not synchronous throughout the preparation. As a consequence, a sudden slowing of rate caused marked dispersion of repolarization among neighboring epicardial sites, giving rise to ectopic activity via a phase 2 reentry mechanism. These effects of high [Ca2+]o were mimicked by exposure of the preparations to low [Na+]o. Electrical homogeneity was restored and arrhythmias were abolished after addition of the Ito blocker 4-aminopyridine 1 mmol/L. 4-Aminopyridine also eliminated the differential response of epicardium and endocardium to high [Ca2+]o. CONCLUSIONS: Our data demonstrate the induction of marked electrical heterogeneity and reentrant activity by high [Ca2+]o and rapid stimulation, conditions known to elevate [Ca2+]i. The results suggest that increased intracellular calcium activity, as occurs during ischemia and reperfusion, may contribute to the development of electrical inhomogeneity in the ventricle and thus to the genesis of ventricular arrhythmias through a mechanism other than triggered activity, namely, phase 2 reentry. Our data point to an increase in net outward current as the underlying mechanism for the calcium-induced changes. Our results also suggest that the presence of a prominent transient outward current (Ito) in epicardium sensitizes that tissue to the effects of high calcium. Finally, the results suggest that Ito blockers can reverse high calcium-induced electrical heterogeneity and thus can exert antiarrhythmic actions.

I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium.

Transmural heterogeneities of repolarizing currents underlie prominent differences in the electrophysiology and pharmacology of ventricular epicardial, endocardial, and M cells in a number of species. The degree to which heterogeneities exist between the right and left ventricles is not well appreciated. The present study uses standard microelectrode and whole cell patch-clamp techniques to contrast the electrophysiological characteristics and pharmacological responsiveness of tissues and myocytes isolated from right (RVE) and left canine ventricular epicardium (LVE). RVE and LVE studied under nearly identical conditions displayed major differences in the early repolarizing phases of the action potential. The magnitude of phase 1 in RVE was nearly threefold that in LVE: 28.7 +/- 6.2 vs. 10.6 +/- 4.1 mV (basic cycle length = 2,000 ms). Phase 1 in RVE was also more sensitive to alterations of the stimulation rate and to 4-aminopyridine (4-AP), suggesting a much greater contribution of the transient outward current (I(to) 1) in RVE than in LVE. The combination of 4-AP plus ryanodine, low chloride, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (chloride channel blocker) completely eliminated the notch and all rate dependence of the early phases of the action potential, making RVE and LVE indistinguishable. At +70 mV, RVE myocytes displayed peak I(to) 1 densities between 28 and 37 pA/pF. LVE myocytes included cells with similar I(to) 1 densities (thought to represent subsurface cells) but also cells with much smaller current levels (thought to represent surface cells). Average peak I(to) 1 density was significantly smaller in LVE than in RVE at voltages more than or equal to +10 mV. Our data point to prominent differences in the magnitude of the I(to) 1-mediated action potential notch in cells at the surface of RVE compared with the LVE and suggest that important distinctions may exist in the response of these two tissues to pharmacological agents and pathophysiological states, as previously demonstrated for epicardium and endocardium. Our findings also suggest that a calcium-activated outward current contributes to the early repolarization phase in RVE and LVE and that the influence of this current, although small, is more important in the left ventricle.