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Introduction: Compared to concordant T wave alternans (CA), discordant T wave alternans (DA) may be associated with an increased dispersion of repolarization (DR) and a greater propensity to develop reentrant ventricular tachyarrhythmias. The electrophysiologic mechanisms of DA in the in vivo heart are not well understood. Methods and Results: The mechanisms of DA were investigated in the canine anthopleurin-A surrogate model of long QT3 syndrome using tridimensional analysis of activation and repolarization patterns from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. Two mechanisms for the development of DA were observed. (1) Stepwise shortening of cycle length (CL) superimposed on preexisting DR resulted in different diastolic intervals (DI) at midmyocardial sites compared to epicardial and endocardial sites. The dispersion of DI coupled with different restitution kinetics at those sites induced DA. (2) The dependence of conduction velocity on DI as the CL is abruptly shortened could result in differential conduction delays at mid sites. This enhanced the dispersion of DI between sites and, coupled with the different restitution kinetics, induced DA. The critical step for the development of DA in both mechanisms was the occurrence of short ARI in two consecutive beats either at epicardial sites in the first mechanism or at mid sites in the second mechanism. Sites with DA had significantly more DR compared to sites with concordant T wave alternans, and ventricular tachyarrhythmias developed mainly in the presence of DA. Conclusion: In the in vivo heart, DA developed due to critical interaction between dispersion of DI and differences in restitution kinetics at different myocardial sites. The dispersion of DI could result from preexisting DR or differential conduction delay at a critical short CL. DA is critically linked to the development of malignant tachyarrhythmias. (J... [ABSTRACT FROM AUTHOR]

Introduction: Down-regulation of key K+ channel subunit gene expression and K+ currents is a universal response to cardiac hypertrophy, whatever the cause, Including the postmyocardial Infarction (post-MI) remodeled heart. Methods and Results: We investigated the hypothesis that down-regulation of K+ channel genes and currents post-MI occurs early and before significant remodeled hypertrophy of the noninfarcted myocardium could be detected. We investigated (1) the Incidence of induced ventricular tachyarrhythmias (VT) in 3-day post-MI rat heart; (2) action potential (AP) characteristics of isolated left ventricular (LV) myocytes from sham-operated and 3-day post-MI head; (3) time course of changes in outward K+ currents Ito-fast(f) and IK in isolated myocytes from 3-day and 4-week post-MI noninfarcted LV and compared the changes with sham-operated animals; and (4) changes in the messenger and protein levels of Kv2.1, Kv4.2, and Kv4.3 In the LV and right ventricle of 3-day post-MI heart. Sustained VT was Induced in 6 of 10 3-day post-MI rats and in none of 8 sham rats. The membrane capacitance of myocytes isolated from 3-day post-MI noninfarcted LV was not significantly different from control, whereas membrane capacitance 4-week post-MI was significantly higher, reflecting the development of hypertrophy. At duration was increased and the density of Ito-f and IK were significantly decreased In 3-day post-MI LV myocytes compared with sham The reduced density of IK, did not significantly differ in 4-week post-MI LV myocytes, whereas the density of IK was decreased further at 4 weeks post-MI. The changes in Ito-f and IK correlated with decreased messenger and protein levels of Kv4.2/Kv4.3 and Kv2.1, respectively. Conclusion: These results support the hypothesis that down-regulation of K+ channel gene expression and current In the post-MI LV occurs early and may be dissociated from the slower time course of post-MI remodeled hypertrophy. These changes may contribute to early arrhythmogenesis of the post-MI head. [ABSTRACT FROM AUTHOR]

Introduction: L-type calcium channels were studied in cell-attached patches from ventricular cell membranes of human fetal heart. Methods and Results: Experiments were performed in the presence of 70 mM Ba2+ as the charge carrier at 22°C to 24°C. Unitary current sweeps were evoked by 300-msec depolarizing pulses to 0 mV from a holding potential of -50 mV at 0.5 Hz. Recorded currents were blocked by nisoldipine (1 μM) and stimulated by (-)Bay K 8644 (1 μM). During control, channel activity was seen in 13.9% ± 4.2% of the total 200 sweeps. Ensemble average current amplitude was 0.03 ± 0.01 pA (n = 6) and average conductance was 20.4 ± 0.2 pS (n = 5). Analysis of single channel kinetics showed open time and closed time histograms were best fit by one and two exponentials, respectively. Mean open time was To = 0.99 ± 0.05 msec (n = 6). Mean closed time fast (Tcf) and slow (Tcs) component values were Tcf = 0.85 ± 0.09 msec and Tcs = 8.0 ± 0.94 msec (n = 6), respectively. With intrapipette (-)Bay K 8644 (1 μM), mean open time was best fit by two exponentials, Tcf = 0.9 ± 0.2 msec (n = 10) and Tos = 134 ± 2.6 msec (n = 10); mean close time values were Tcf = 0.6 ± 0.1 msec (n = 10) and Tcs = 9.8 ± 1.9 msec (n = 10), respectively. With (-)Bay K 8644, channel activity was 66.5% ± 7.4%, the ensemble average current was 0.52 ± 0.04 pA (n = 10) and the conductance 20.7 ± 0.5 pS (n = 5). conclusion: (1) the data establishes the characteristics of L-type Ca channels of human fetal hearts and their modulation by dihydropyridines; (2) the open time kinetics differ from those of avian embryonic and rat fetal hearts; and (3) the findings provide new and relevant information for understanding the physiologic behavior of unitary Ca2+ channels in the developing human heart and the baseline comparison for diseases that implicate Ca2+ channels in their etiology, such as autoimmune-associated congenital heart block. [ABSTRACT FROM AUTHOR]

Introduction: The effects of a Class III agent, azimilide dihydrochloride, on atrial flutter circuits were studied in a functional model of single loop reentrant atrial flutter using dogs, 3 to 5 days after production of sterile pericarditis. Methods and Results: A computerized mapping system was used to construct activation maps from 138 to 222 epicardial sites in the right atrium. Doses of 3, 10, and 30 mg/kg IV azimilide dihydrochloride were analyzed in 8 dogs in which sustained atrial flutter lasting more than 30 minutes was induced by burst pacing. Atrial flutter was always due to a single loop circus movement reentry in the lower right atrium. At 3 mg/kg, azimilide dihydrochloride terminated atrial flutter in 2 dogs; however, atrial flutter was reinduced. At 10 mg/kg, atrial flutter was terminated in all 8 dogs but was reinduced in 4 dogs with slower rate. At 30 mg/kg. atrial flutter was terminated in the remaining 4 dogs and could not be reinduced. Atrial flutter cycle length always increased prior to termination. Isochronal activation maps showed that the increase in cycle length was due to additional conduction delays in the slow zone of the reentrant circuit. The site of termination was always located within the slow conduction zone situated in the lower right atrium between the line of functional conduction block and the AV ring. Reflective refractory periods (ERPs) were measured at selected sites in the slow zone and normal zone at twice diastolic threshold for the 10 mg/kg dose. Azimilide preferentially prolonged ERP in the slow zone (42.4 ± 20.1 msec, mean ± SD) compared with the normal zone (23.3 ± 15.4 msec, P < 0.0001). The increase in cycle length corresponded with the increase in ERP in the slow zone. Conclusions: In a functional model of circus movement atrial flutter, azimilide dihydrochloride terminates and prevents reinduction of atrial flutter by a preferential increase in refractoriness leading to further conduction delay and conduction block in the slow zone of the functional reentrant circuit. [ABSTRACT FROM AUTHOR]