|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
|
|
|
|||||||||
|
|||||||||||
|
J Am Coll Cardiol, 2000; 35:778-786 © 2000 by the American College of Cardiology Foundation |
a Masonic Medical Research Laboratory, Utica, New York, USA
Manuscript received July 30, 1999; revised manuscript received September 21, 1999, accepted November 3, 1999.
Reprint requests and correspondence: Dr. Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, New York 13501-1787
ca{at}mmrl.edu
 |
Abstract |
|---|
 Top Abstract MethodsResultsDiscussionReferences |
|---|
To define the cellular mechanisms responsible for the development of life-threatening arrhythmias in response to sympathetic activity in the congenital and acquired long QT syndromes (LQTS).
METHODS
Transmembrane action potentials (AP) from epicardial (EPI), M and endocardial (ENDO) cells and a transmural electrocardiogram were simultaneously recorded from an arterially perfused wedge of canine left ventricle. We examined the effect of beta-adrenergic agonists and antagonists on action potential duration (APD90), transmural dispersion of repolarization (TDR) and the development of Torsade de Pointes (TdP) in models of LQT1, LQT2 and LQT3 forms of LQTS.
RESULTS
IKs block with chromanol 293B (LQT1) homogeneously prolonged APD90 of the three cell types without increasing TDR. Addition of isoproterenol prolonged QT and APD90 of M but abbreviated that of EPI and ENDO, causing a persistent increase in TDR; Torsade de Pointes developed or could be induced only in the presence of isoproterenol. IKr block with d-sotalol (LQT2) and augmentation of late INa with ATX-II (LQT3) prolonged APD90 of M more than EPI and ENDO, causing increases in QT and TDR. TdP developed in the absence of isoproterenol. In LQT2 isoproterenol initially prolonged, then abbreviated, the APD90 of M but always abbreviated EPI, thus transiently increasing TDR and the incidence of TdP. In LQT3, isoproterenol always abbreviated APD90 of the three cell types, causing a persistent decrease in TDR and suppression of TdP. The arrhythmogenic as well as protective actions of isoproterenol were reversed by propranolol.
CONCLUSIONS
Our data suggest that beta-adrenergic stimulation induces TdP by increasing transmural dispersion of repolarization in LQT1 and LQT2 but suppresses TdP by decreasing dispersion in LQT3. The data indicate that beta-blockers are protective in LQT1 and LQT2 but may facilitate TdP in LQT3.
| ||||||||||||||||||||||||||||||||||||
Preliminary clinical reports suggest differences in the sensitivity of LQT1, LQT2 and LQT3 to beta-adrenergic stimuli (11). Experimental studies employing isolated guinea pig myocytes also suggest differences in the effect of isoproterenol on action potential duration (APD) in pharmacologic models that mimic LQT2 (dofetilide) and LQT3 (anthopleurin A) (12).
Recent studies from our laboratory examined the electrophysiologic, electrocardiographic and pharmacologic characteristics of the LQT1, LQT2 and LQT3 syndromes using arterially-perfused canine left ventricular wedge preparations, in which we are able to simultaneously record transmembrane activity from epicardial, M and endocardial or Purkinje sites together with a pseudo-ECG along the same axis, permitting correlation of transmembrane and ECG activity (13–18). The wedge preparation is capable of developing and sustaining a variety of arrhythmias, including TdP. The pharmacologic models mimicked the clinical congenital syndromes with respect to prolongation of the QT interval, T wave morphology, rate dependence of repolarization and response to antiarrhythmic drugs (14–18). Using this model, we recently demonstrated the determining role of beta-adrenergic stimuli in the development of transmural dispersion of repolarization (TDR) and TdP in a model of LQT1 (15). This study uses the wedge preparation to define the role of beta-adrenergic stimuli and elucidate their cellular mechanisms under conditions mimicking the LQT1, LQT2 and LQT3 forms of the congenital LQTS.
|
Methods |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
100 µm) native branch of left descending coronary artery and perfused with cardioplegic solution. Unperfused tissue, readily identified by its maintained red appearance (erythrocytes not washed away) was carefully removed using a razor blade. The preparation was then placed in a small tissue bath and arterially perfused with Tyrode’s solution of the following composition (mmol/L): 129 NaCl, 4 KCl, 0.9 NaH2PO4, 20 NaHCO3, 1.8 CaCl2, 0.5 MgSO4, 5.5 glucose, buffered with 95% O2 and 5% CO2 (37 ± 1°C). The perfusate was delivered to the artery by a roller pump (Cole Parmer Instrument Co., Niles, Illinois). Perfusion pressure was monitored with a pressure transducer (World Precision Instruments, Inc., Sarasota, Florida) and maintained between 40 and 50 mm Hg by adjustment of the perfusion flow rate. The preparations remained immersed in the arterial perfusate, which was allowed to rise to a level 2 to 3 mm above the tissue surface when possible. To facilitate impalement with the floating microelectrodes, in some experiments the bath solution was brought to a level just shy of the top of the wedge and the chamber was covered to the extent possible so as to avoid a temperature gradient between the top and lower segments of the wedge. Preparations displaying significant ST segment elevation or depression, or in which temperature gradients were evident along the length of the preparation, were excluded from the study. Recordings of a transmural ECG and transmembrane action potentials. The ventricular wedges were allowed to equilibrate in the tissue bath until electrically stable, usually 1 h, and stimulated using bipolar silver electrodes insulated except at the tips and applied to the endocardial surface (S1).
A transmural ECG was recorded using 3 M KCL-Agar electrodes (1.1 mm, internal diameter). The electrodes were placed in the Tyrode’s solution bathing the preparation, 1.0 to 1.5 cm from the epicardial and endocardial surfaces of the preparation, along the same vector as the transmembrane recordings (Epicardium: "positive" pole). The electrical field of the preparation as a whole was measured using this technique. Thus, the electrocardiographic registration represents a pseudo-ECG of that part of the left ventricle. To differentiate it from local electrogram activity, we refer to it as an ECG in the remainder of the text.
Transmembrane action potentials were simultaneously recorded from the epicardial, M and endocardial sites using three to four separate intracellular floating microelectrodes (direct current resistance: 10 to 20 M_; 2.7 mol/L KCl). Epicardial and endocardial action potentials were recorded from the epicardial and the endocardial surfaces of the preparations at positions approximating the transmural axis of the ECG recording. M cell action potentials were recorded at the site along the same axis at which APD was longest.
All amplified signals were digitized, stored on magnetic media and CD and analyzed using Spike 2 (Cambridge Electronic Design, Cambridge, United Kingdom).
Study protocols. The IKs blocker, chromanol 293B (30 µmol/L), was used to create a model of LQT1 (15), the IKr blocker, d-sotalol (100 µmol/L), was used to mimic the LQT2 syndrome (14) and ATX-II (20 nmol/L), an agent that augments late INa, was used to generate a model of LQT3 (14,18). The validity of these pharmacologic models as surrogates for the congenital syndromes was previously demonstrated in myocyte (12), perfused wedge (14–18) and in vivo studies (19,20).
We routinely examined:
Control measurements were obtained after approximately 1 h of equilibration. The chromanol 293B, d-sotalol and ATX-II data were collected for a period of up to 1 h starting 1 h after addition of the respective drug. The effect of isoproterenol was recorded at 2 and 10 min, approximating the maximal and steady state influence of the catecholamine, respectively. A steady-state was achieved within 5–7 min. Propranolol data were recorded after 20 min of exposure to each concentration of drug.
Action potential duration was measured at 90% repolarization (APD90). Transmural dispersion of repolarization (TDR) was defined as the difference between the longest and the shortest repolarization time (activation time + APD90) of transmembrane action potentials recorded across the wall (M cell – epicardial cell). The QT interval was defined as the time between QRS onset and the point at which the final downslope of the T wave crossed the baseline. In all figures, graphic correlation of transmembrane and electrocardiographic activity was achieved by dropping a dotted line from the point of full repolarization of each action potential (APD100-approximated by eye) to the ECG trace.
The development of spontaneous as well as programmed electrical stimulation (PES)-induced TdP was assessed in the absence of any drugs (control), in the presence of chromanol 293B, d-sotalol or ATX-II alone and after further addition of isoproterenol (2 min and 10 min), propranolol or a combination of the two agents. Programmed electrical stimulation-induced arrhythmias were evaluated using single extrastimuli (S2) applied to the epicardial surface of the wedge.
Statistics. Statistical analysis of the data was performed using a Student t test for paired data or Analysis of Variance coupled with Scheffe’s test, as appropriate. Data are expressed as mean ± SD values, except for those shown in the figures, which are expressed as mean ± SEM values. Significance was defined as a p < 0.05.
|
Results |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
|
|
|
|
|
Figure 2 illustrates the influence of isoproterenol in the LQT2 model. After a preferential prolongation of the M cell action potential and an increase in TDR by 100 µmol/L d-sotalol, isoproterenol (100 nmol/L) initially prolonged (2 min) and then abbreviated the QT interval and the APD of the M cell to the control level (10 min), whereas the APD of the epicardial cell was always abbreviated, resulting in a transient increase in TDR. Composite data of the influence of isoproterenol in the LQT2 model is shown in Figure 4, C and D.
The effect of isoproterenol in the LQT3 model is illustrated in Figure 3. ATX-II 20 nmol/L alone produced a dramatic prolongation of the M cell action potential and a more modest prolongation of the APD of epicardium, resulting in a dramatic increase in TDR. Isoproterenol (100 nmol/L) produced a persistent abbreviation of the QT interval and the APD of both cells, resulting in a persistent decrease of TDR. Composite data of the influence of isoproterenol in the LQT3 model is shown in Figure 4, E and F.
In four preparations, we examined the influence of isoproterenol (100 nmol/L) alone on transmembrane and ECG activity. Isoproterenol always abbreviated the APD90 of the three cell types, thus abbreviating the QT interval without any major changes in TDR or the development of TdP.
Effect of propranolol on the QT interval, APD and dispersion of repolarization. In all three models, therapeutic concentrations of propranolol (0.1 to 1 µmol/L) had little or no effect on the QT interval, APD90 of the three cell types or TDR. Higher concentrations (3 µmol/L) preferentially abbreviated the QT interval and APD90 of the M cell, resulting in a significant decrease of TDR, most likely due to the effect of this concentration of propranolol to block the late INa, which is intrinsically larger in the M cell than in the other cell types (21).
Effect of propranolol to suppress the influence of isoproterenol. Figure 5 illustrates composite data of the effects of propranolol (1 µmol/L) to suppress the influence of isoproterenol in the three models. Once again, 1 µmol/L propranolol had little to no effect on the QT interval, APD90 or TDR in the three models. In LQT1 (Fig. 5, A and B) and LQT2 (Fig. 5, C and D), propranolol completely suppressed the effect of isoproterenol (at both 2 and 10 min) to persistently or transiently prolong the M cell APD90 and thus to increase TDR. In LQT3 (Fig. 5, E and F), propranolol completely suppressed the protective effect of isoproterenol (at both 2 and 10 min) to abbreviate the M cell APD90 and to decrease TDR.
|
|
|
|
Discussion |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
Beta-adrenergic stimulation with isoproterenol is known to augment a number of currents, including Ca2+-activated IKs, Ca2+-activated chloride current (ICl[Ca]) (24) and Na+/Ca2+ exchange current (INa-Ca). The response of APD and of the QT interval to beta-adrenergic stimulation largely depends on the shift in net outward current. An increase in net outward repolarizing current, due to a relatively large increase of IKs and ICl(Ca) vs. INa-Ca is thought to be responsible for the abbreviation of APD and QT interval in response to beta-adrenergic stimulation under normal conditions and for abbreviation of epicardial and endocardial cell APD under long QT conditions. A defect in IKs (especially in the M region) could offset this balance and account for failure of beta-adrenergic stimulation to abbreviate APD and QT interval in patients with the LQT1 genotype (5–7,25–27). Among the three transmural cell types, the M cell has been reported to have an intrinsically smaller IKs (28).
In the LQT1 model (reduced IKs), isoproterenol prolongs the APD of the M cell because IKs (outward current) is reduced to levels at which INa-Ca (inward current) predominates. The presence of higher levels of IKs in epicardial and endocardial cells (even in the presence of chromanol 293B) accounts for the effect of the beta-agonist to abbreviate APD in these cells. The disparate effects of isoproterenol on the three cell types results in a persistent increase of TDR and in the development of spontaneous as well as stimulation-induced TdP. Our findings in the LQT1 model are concordant with a high sensitivity of patients with the LQT1 syndrome to beta-adrenergic stimulation. Cardiac events in this syndrome often occur during exercise, when catecholamine levels are maximally elevated.
In the LQT2 model (reduced IKr), isoproterenol transiently prolongs the APD of the M cell, possibly due to a more rapid increase of INa-Ca than of IKs. The constant abbreviation of epicardial and endocardial action potentials is most likely due to higher levels of IKs in these cell types. As a consequence, TDR and the incidence of TdP are only transiently increased. The persistent effect of isoproterenol to abbreviate epicardial and endocardial APD and its transient effect to prolong the APD of the M cells is also observed in strips of tissues isolated from the three regions of the wall following pretreatment with the IKr blocker, E-4031 (29). Effects similar to those of isoproterenol are observed in the M cell preparations in response to acceleration of the stimulation rate. These effects are eliminated after addition of ryanodine or in the presence of low [Ca2+]o, suggesting that the effects are secondary to intracellular Ca2+ loading. In isolated M cell, but not endocardial or epicardial, preparations pretreated with E-4031, acceleration of rate or addition of isoproterenol also transiently induce early afterdepolarization (EAD) activity (29). Our data are concordant with those of Priori et al. (12) who demonstrated an effect of isoproterenol to transiently prolong APD and induce EADs in guinea pig myocytes pretreated with the IKr blocker, dofetilide. Taken together, these findings suggest that beta-adrenergic stimulation contributes to precipitation of TdP in LQT2 by producing a transient but dramatic increase in TDR and causing induction of EAD-mediated extrasystoles. The transient nature of these changes following an increase in sympathetic activity may explain why cardiac events in LQT2 generally occur following a startle, especially from a sleep state (alarm clock, telephone bell or ambulance siren, etc.). Delays in APD adaptation during sudden arousal reaction is reported to occur not only in LQTS patients, but also in normal subjects (30). The presumption is that if TdP does not occur soon after the surge in sympathetic activity in LQT2 patients, it is unlikely to occur later (22).
In the LQT3 model (increased late INa), isoproterenol produces a persistent abbreviation of the APD of all three ventricular cell types. Preferential abbreviation of the M cell APD results in a persistent decrease of TDR and a decrease in the incidence of both spontaneous and stimulation-induced TdP. These effects of isoproterenol are likely due to an increase of IKs as well as a reduction of the electrogenic INa-Ca due to a more positive M cell action potential plateau voltage. Our data suggest that beta-adrenergic stimulation may protect against cardiac events in patients with the LQT3 genotype. These findings are consonant with the observation that patients with the LQT3 syndrome, unlike those with LQT1 or LQT2, often have cardiac events at rest or during sleep when sympathetic tone is expected to be low (11,23).
Differential effect of beta-adrenergic blockade in the LQT1, LQT2 and LQT3 genotype. Our data indicate that beta-blockade with propranolol totally suppresses the development of TdP in the LQT1 model, largely suppresses it in LQT2 and can induce the arrhythmia in LQT3. These distinctions are due to the fact that the substrate for reentry (augmented TDR) appears only after beta-adrenergic stimulation in LQT1, may be present in the absence of sympathetic stimulation, but is greatly amplified by beta-adrenergic stimulation in LQT2 and is importantly reduced following sympathetic stimulation in LQT3.
These experimental findings appear to closely mirror the clinical experience. Beta-blockade has long been considered as a first-line therapy in patients with congenital LQTS (1–7). Patients with the LQT1 genotype are highly responsive to beta-adrenergic blocking agents (31). Beta-blockers are also effective in suppressing cardiac events in patients with the LQT2 genotype (22). The effectiveness of beta-blockers in patients with the LQT3 genotype is not well defined because of the rarity of the syndrome, although events generally occur at rest or during sleep, when heart rate is relatively slow (11). Both clinical (23) and experimental (12,14) studies have demonstrated that LQT3 displays a much steeper QT- and APD-rate relation than either LQT1 or LQT2. Thus, the substrate for reentry rapidly dissipates as heart rate is accelerated in LQT3 and reappears as heart rate is slowed. Our data of a protective effect of isoproterenol in LQT3, when coupled with the rate-slowing effect of the beta-blockers, suggest that beta-blockade might be contraindicated in LQT3. A test of this hypothesis clearly must await appropriate clinical trials.
Study limitations. Our interpretations of the data are based on the assumption that the activity recorded from the cut surface of the perfused wedge preparation is representative of cells within the respective layers of the wall throughout the wedge. Such validation was provided in three previous studies employing the perfused wedge preparation (14,17,18).
The extent to which our pharmacologic models mimic the three forms of congenital long QT syndrome is also important. We believe that these pharmacologic models provide reasonable surrogates for the respective clinical syndromes because the behavior of the models mimics the clinical observations with respect to the electrocardiographic changes in the morphology and appearance of the T wave (32,33), rate dependence of the QT interval (23) and response to pharmacologic agents (23,31).
Finally, extrapolation of the experimental data to the clinic must be approached with great caution for obvious reasons. It is our hope that these findings will prove helpful in the design of clinical trials to test the hypotheses suggested by the study.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  E. LEVINE, S. Z. ROSERO, A. S. BUDZIKOWSKI, A. J. MOSS, W. ZAREBA, and J. P. DAUBERT Congenital long QT syndrome: Considerations for primary care physicians Cleveland Clinic Journal of Medicine, August 1, 2008; 75(8): 591 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chinushi, D. Izumi, K. Iijima, S. Ahara, S. Komura, H. Furushima, Y. Hosaka, and Y. Aizawa Antiarrhythmic vs. pro-arrhythmic effects depending on the intensity of adrenergic stimulation in a canine anthopleurin-A model of type-3 long QT syndrome Europace, February 1, 2008; 10(2): 249 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2024 - H2038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes Europace, September 1, 2007; 9(suppl_4): iv4 - iv15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Morita, D. P. Zipes, H. Morita, and J. Wu Analysis of action potentials in the canine ventricular septum: No phenotypic expression of M cells Cardiovasc Res, April 1, 2007; 74(1): 96 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Whyte, S. Sanatani, J. Lim, and P. D. Booker A Comparison of the Effect on Dispersion of Repolarization of Age-Adjusted MAC Values of Sevoflurane in Children Anesth. Analg., February 1, 2007; 104(2): 277 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Topilski, O. Rogowski, R. Rosso, D. Justo, Y. Copperman, M. Glikson, B. Belhassen, M. Hochenberg, and S. Viskin The Morphology of the QT Interval Predicts Torsade de Pointes During Acquired Bradyarrhythmias J. Am. Coll. Cardiol., January 23, 2007; 49(3): 320 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Thomas, I. S. Gurung, M. J. Killeen, P. Hakim, C. A. Goddard, M. P. Mahaut-Smith, W. H. Colledge, A. A. Grace, and C. L.-H. Huang Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3 J. Physiol., January 1, 2007; 578(1): 85 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. Tan, A. Bardai, W. Shimizu, A. J. Moss, E. Schulze-Bahr, T. Noda, and A. A. M. Wilde Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome: Possible Therapy Implications Circulation, November 14, 2006; 114(20): 2096 - 2103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stengl, C. Ramakers, D. W. Donker, A. Nabar, A. V. Rybin, R. L.H.M.G. Spatjens, T. van der Nagel, W. K.W.H. Wodzig, K. R. Sipido, G. Antoons, et al. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted {beta}-adrenergic activation Cardiovasc Res, October 1, 2006; 72(1): 90 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Viitasalo, L. Oikarinen, H. Swan, H. Vaananen, J. Jarvenpaa, H. Hietanen, J. Karjalainen, and L. Toivonen Effects of Beta-Blocker Therapy on Ventricular Repolarization Documented by 24-h Electrocardiography in Patients With Type 1 Long-QT Syndrome J. Am. Coll. Cardiol., August 15, 2006; 48(4): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shimizu The long QT syndrome: Therapeutic implications of a genetic diagnosis Cardiovasc Res, August 15, 2005; 67(3): 347 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-B. Nam, A. Burashnikov, and C. Antzelevitch Cellular Mechanisms Underlying the Development of Catecholaminergic Ventricular Tachycardia Circulation, May 31, 2005; 111(21): 2727 - 2733. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Katra and K. R. Laurita Cellular Mechanism of Calcium-Mediated Triggered Activity in the Heart Circ. Res., March 18, 2005; 96(5): 535 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D.J. Ten Harkel, M. Witsenburg, P. L. de Jong, L. Jordaens, M. Wijman, and A. A.M. Wilde Efficacy of an implantable cardioverter-defibrillator in a neonate with LQT3 associated arrhythmias Europace, January 1, 2005; 7(1): 77 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Cardiac repolarization. The long and short of it Europace, January 1, 2005; 7(s2): S3 - S9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Whyte, P. D. Booker, and D. G. Buckley The Effects of Propofol and Sevoflurane on the QT Interval and Transmural Dispersion of Repolarization in Children Anesth. Analg., January 1, 2005; 100(1): 71 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Oginosawa, T. Nagatomo, H. Abe, N. Makita, J. C. Makielski, and Y. Nakashima Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome Cardiovasc Res, January 1, 2005; 65(1): 138 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Chang, S. Acharfi, M.-H. Wu, F.-T. Chiang, J.-K. Wang, T.-C. Sung, and M. Chahine A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia Cardiovasc Res, November 1, 2004; 64(2): 268 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ueda, D. P Zipes, and J. Wu Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT 3 Cardiovasc Res, July 1, 2004; 63(1): 69 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Fish, J. M. Di Diego, V. Nesterenko, and C. Antzelevitch Epicardial Activation of Left Ventricular Wall Prolongs QT Interval and Transmural Dispersion of Repolarization: Implications for Biventricular Pacing Circulation, May 4, 2004; 109(17): 2136 - 2142. [Abstract] [Full Text] [PDF]
|
|
|
|
p < 0.0005; 
