Cycle Length Dependence Research Articles

136-01: Repolarization Changes From Remodelling Explain Why Persistent Atrial Fibrillation Responds Less Well To Pulmonary Vein Isolation

Introduction: It is not clear why persistent (AF) is less trigger dependent than paroxysmal AF and responds less well to pulmonary vein isolation (PVI). We hypothesized that structural remodelling may flatten left atrial APD restitution, reducing the ability of a trigger to cause APD oscillations in persistent AF patients. Methods: Monophasic action potentials (MAP) were recorded in 47 patients (61 ± 9 years, LA 44 ± 6mm, 52% persistent AF) near the PV antra during pacing. We plotted MAP duration restitution cycle length (CL) dependence of APD90, i.e. the time from monophasic action potential (MAP) upstroke to 90% repolarization, as a restitution curve, and calculated its maximum slope. ERP was defined routinely. Both factors were related to LA size to assess structural remodelling. Results: Dynamic ERP tracked APD in remodelled human LA (Fig A; p < 0.05). Fig B shows an AF trigger engaging steep APD restitution (C) to initiate AF. Fig D shows that APD restitution slope correlated negatively with LA diameter (p < 0.05). Compared to patients with paroxysmal AF, those with persistent AF (remodelled atria) had shorter APD90 (236 ± 35 vs 284 ± 46ms, p < 0.01), flatter APD restitution (0.67 ± 0.2 vs 1.5 ± 0.4, p < 0.001) and shorter ERP (204 ± 28 vs 241 ± 38ms, p = 0.01).

Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium

Cardiac experimental biology and translational research would benefit from an in vitro surrogate for human heart muscle. This study investigated structural and functional properties and interventional responses of human engineered cardiac tissues (hECTs) compared to human myocardium. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs, >90% troponin-positive) were mixed with collagen and cultured on force-sensing elastomer devices. hECTs resembled trabecular muscle and beat spontaneously (1.18 ± 0.48 Hz). Microstructural features and mRNA expression of cardiac-specific genes (α-MHC, SERCA2a, and ACTC1) were comparable to human myocardium. Optical mapping revealed cardiac refractoriness with loss of 1:1 capture above 3 Hz, and cycle length dependence of the action potential duration, recapitulating key features of cardiac electrophysiology. hECTs reconstituted the Frank-Starling mechanism, generating an average maximum twitch stress of 660 μN/mm(2) at Lmax, approaching values in newborn human myocardium. Dose-response curves followed exponential pharmacodynamics models for calcium chloride (EC50 1.8 mM) and verapamil (IC50 0.61 μM); isoproterenol elicited a positive chronotropic but negligible inotropic response, suggesting sarcoplasmic reticulum immaturity. hECTs were amenable to gene transfer, demonstrated by successful transduction with Ad.GFP. Such 3-D hECTs recapitulate an early developmental stage of human myocardium and promise to offer an alternative preclinical model for cardiology research.

Weakly divergent ray and diffraction beams in oceanic waveguides

Conditions that should be satisfied by the sound velocity profile of an oceanic waveguide for the dependence of the ray cycle length on the ray phase velocity to contain smooth extrema are formulated. The extrema correspond to weakly divergent ray beams forming “caustic” beams. It is found that diffraction effects cause a considerable smoothing of the sharp extrema that occur in the dependence of the interference period of neighboring modes on their phase velocity. As a result, in addition to the weakly divergent ray beams, weakly divergent diffraction beams and the corresponding “diffraction” caustics can be formed.

Action potential characterization in intact mouse heart: steady-state cycle length dependence and electrical restitution

Transgenic mice have been increasingly utilized to investigate the molecular mechanisms of cardiac arrhythmias, yet the rate dependence of the murine action potential duration and the electrical restitution curve (ERC) remain undefined. In the present study, 21 isolated, Langendorff-perfused, and atrioventricular node-ablated mouse hearts were studied. Left ventricular and left atrial action potentials were recorded using a validated miniaturized monophasic action potential probe. Murine action potentials (AP) were measured at 30, 50, 70, and 90% repolarization (APD(30)-APD(90)) during steady-state pacing and varied coupling intervals to determine ERCs. Murine APD showed rate adaptation as well as restitution properties. The ERC time course differed dramatically between early and late repolarization: APD(30) shortened with increasing S1-S2 intervals, whereas APD(90) was prolonged. When fitted with a monoexponential function, APD(30) reached plateau values significantly faster than APD(90) (tau = 29 +/- 2 vs. 78 +/- 6 ms, P < 0.01, n = 12). The slope of early APD(90) restitution was significantly <1 (0.16 +/- 0.02). Atrial myocardium had shorter final repolarization and significantly faster ERCs that were shifted leftward compared with ventricular myocardium. Recovery kinetics of intracellular Ca(2+) transients recorded from isolated ventricular myocytes at 37 degrees C (tau = 93 +/- 4 ms, n = 18) resembled the APD(90) ERC kinetics. We conclude that mouse myocardium shows AP cycle length dependence and electrical restitution properties that are surprisingly similar to those of larger mammals and humans.

Predicting the Length of Magnetic Cycles in Late‐Type Stars

In this paper we present a modification of a local approximation of the so-called interface dynamo in an attempt to reproduce the length of the magnetic cycles for a sample of late-type stars. The sample consists of 25 stars, observed during the Mount Wilson and Las Campanas long-term monitoring campaigns, for which well-defined cycles have been detected. We have focused our efforts on reproducing general trends observed, namely, the dependence of the cycle length, Pcyc, on the stellar rotation period, Prot, rather than attempting to infer from the dynamo model individual cycle lengths for each star. In spite of the simplicity of the model, the results are promising. The trend of increasing cycle length with increasing rotation period is reproduced with a minimum of assumptions.

Cycle length sequence dependent repolarization dynamics

Cardiac repolarization, particularly its heterogeneity, is known to play a significant role in arrhythmogenesis. Steepness of cardiac restitution, or the cycle length dependency of repolarization, has also been implicated as a condition that favors occurrence of reentrant arrhythmias. However, most assessments of heterogeneity and restitution are based on static observations and do not directly account for the extent or heterogeneity of dynamic changes. The uncertainty and unpredictability of arrhythmias and the difficulty of identifying patients most at risk may possibly be explained by the lack of consideration of dynamic changes of repolarization, its heterogeneity and time varying restitution. In this brief article, we show the global changes in repolarization that occur in normal canine hearts in response to programmed cycle length sequences. Specifically, we show the beat-to-beat tracking of repolarization during rapid (step) changes in cycle length as well as linear up and down (sawtooth) changes, and random cycle length sequences. The measurement and robust characterization of the dynamic repolarization response to specific cycle length sequences may offer an opportunity to characterize the substrate for arrhythmias to a greater extent than has been possible to date. Although there is no guarantee that characterization of repolarization dynamics will provide definitive means to identify patients at risk, such assessment will, at a minimum, put into perspective the role that repolarization dynamics may play in detecting states of increased arrhythmia risk. Another potential use of these techniques is in the assessment of repolarization in patients undergoing EP testing, pharmacological therapies or during other provocative testing.

Irregularity of the ventricular rhythm during atrial fibrillation: effect of slow atrioventricular nodal pathway ablation.

The contribution of dual atrioventricular (AV) nodal pathway physiology to the irregularity of the ventricular rhythm during atrial fibrillation has not been clarified. This study was performed to assess the effects of slow AV nodal pathway ablation on the irregularity of the ventricular rhythm during atrial fibrillation. Irregularity of the ventricular rhythm was quantified using analysis of heart rate variability. In 20 patients with AV nodal reentrant tachycardia, absolute heart rate variability during atrial fibrillation was quantified before and after slow AV nodal pathway ablation by the standard deviation of all NN intervals (SDNN). Relative heart rate variability was determined by computing the coefficient of variation, SDNN normalized for the standard deviation of the mean ventricular cycle length (MVCL-AF). The slope of the regression between MVCL-AF and SDNN was significantly more gradual after slow pathway ablation (slope 0.39 vs. 0.23, p < 0.001). Coefficient of variation increased in 12 patients with heart rates > 120 beats/min at baseline (18.6 +/- 3.9 vs. 22.1 +/- 2.7% MVCL-AF, p < 0.05), but decreased in 8 patients with heart rates < 120 beats/min at baseline (25.6 +/- 3.1 vs. 22.2 +/- 2.2% MVCL-AF, p = 0.05). Furthermore, coefficient of variation correlated with MVCL-AF only at baseline (slope 0.034, r = 0.66), but no relation was found after slow pathway ablation (slope 0, r = 0). Slow AV nodal pathway ablation alters the relation between absolute heart rate variability and mean ventricular rate during atrial fibrillation and eliminates cycle length dependency of relative heart rate variability. These data indicate that dual AV nodal pathway physiology contributes to the irregularity of the ventricular rhythm during atrial fibrillation.

Cycle Length Dependence of Action Potential Duration and Dispersion in the Human Atrium

Cycle Length Dependence of Action Potential Duration and Dispersion in the Human Atrium

Cycle length dependence of action potential duration and dispersion in the human atrium

Cycle length dependence of action potential duration and dispersion in the human atrium

Muscarinic effects on action potential duration and its rate dependence in canine Purkinje fibers.

Studies of the autonomic influence on action potential duration (APD) in the ventricles show direct effects of muscarinic stimulation on epicardial, but not endocardial, APD and conflicting results regarding direct vagal effects on the conduction system. In canine Purkinje fibers, we analyzed the action of the M2 agonist oxotremorine (OXO, 0.1 microM) on APD and on its cycle length (CL) dependence. Fibers were impaled with glass microelectrodes and superfused with Tyrode's solution. APD90 was measured after 3 minutes of drive at CL between 0.3 and 5 seconds. The best fit for the APD/CL relationship at steady state was a hyperbole: APD = APDmax*CL/(CL+CL50), where APDmax (APD at infinite CL) is a rate independent measure of APD, and CL50 (CL at which 50% APDmax is reached) is an index of the rate dependence of APD. In five fibers, OXO reduced APD at all CL (P < 0.05), APDmax was also reduced to 377 +/- 41 ms from 447 +/- 34 ms (P < 0.05), while CL50 was unchanged (405 +/- 46 ms from 437 +/- 28 ms). No effects of OXO on APD and APDmax were seen in two fibers obtained from dogs pretreated with pertussis toxin (PTX). In conclusion, stimulation of M2 receptors in intact, and not PTX treated, Purkinje fibers affects APD but not its CL dependence. This may reflect the activation of a rate independent, background current through a GTP binding protein-linked pathway, such as, IK,ACh. These data differ from those obtained in endocardial and epicardial muscle, stressing the regional differences in vagal modulation of ventricular electrophysiological properties.

Cycle length dependence of the electrophysiological effects of increased load on the myocardium.

Mechanoelectric feedback, the process by which changes in mechanical activity change the electrophysiology of the myocardium, has been linked to the genesis of arrhythmias. We investigated possible arrhythmogenic mechanisms by measuring changes in steady-state action potential duration and, more particularly, electrical restitution on a transiently applied load change, because action potential recovery may provide clues to arrhythmogenesis. Pigs were anesthetized and their hearts exposed. A snare was placed around the aorta, and the right atrium was paced. Ventricular pressure, monophasic action potential, and segment motion were recorded from the left ventricle. The action potential duration was measured before and during transient aortic occlusion. Electrical restitution curves were constructed from the records obtained during normal loading or during transient aortic occlusion. The degree of shortening of action potential duration on aortic occlusion decreased with decreases in the steady-state beat-to-beat interval (P = .0008). Control restitution curves had the typical configuration, with a rapid initial, usually monotonic, rise toward a plateau. Some curves showed a marginal "supernormal" section. Increased load reduced the action potential duration at the plateau of the restitution curve (9.4 ms, P < .0001) but increased the action potential duration at the start of the restitution curve (8.7 ms, P = .03). Increased loading increased the maximum slope of the electrical restitution curve by 32 ms/100 ms (P = .04). Increased load also increased the supernormal period of the electrical restitution curves. Mechanoelectric feedback produces changes in rate-dependent electrophysiology, which could favor a matrix conducive to arrhythmogenesis.

PH-dependent actions of 4-aminopyridine on atrial repolarization: effects on the transient outward current

Effects of extracellular pH (pHo) were examined on the changes in atrial repolarization induced by 4-aminopyridine (4AP), which is a selective blocker of the transient outward potassium channel, I(to). Action potential parameters were measured, using the conventional microelectrode technique, in the absence and presence of 4AP (0.1-3.0 mM) at pHo 6.5, 7.25, and 8.0. Phase 1 amplitude served as an index of I(to). The onset and recovery kinetics of phase 1 amplitude were assessed at a basic cycle length of 0.5 s, and time constants (tau on and tau r) were computed. Both onset and recovery kinetics had monoexponential functions. Tonic blockade was influenced by external pH, and Kd for half block was 0.19, 0.44, and 2.43 mM for pHo 8.0, 7.25, and 6.5, respectively. Phasic block was defined and exhibited cycle length dependence. Phasic block was also modified by external pH with the greatest effect at pHo 8.0. 4AP (0.3 mM) accelerated tau on, 0.62 +/- 0.2, 0.55 +/- 0.1, and 2.0 +/- 0.8 beats for pHo 8.0, 7.25, and 6.5 compared with control 6.8 +/- 1.9, 6.3 +/- 1.9, and 5.1 +/- 1.4 beats. In contrast, 4AP slowed tau r by about 1 s from control value to 1.5 +/- 0.5 s at pHo 6.5, 4.8 +/- 1.5 s at pHo 7.25 (p < 0.05), and 5.7 +/- 2.0 s at pHo 8.0. We conclude that an increase in extracellular pH enhances block of Ito induced by 4AP, whereas low pHo attenuates the block.

PH-dependent actions of 4-aminopyridine on atrial repolarization: effects on the transient outward current

Effects of extracellular pH (pHo) were examined on the changes in atrial repolarization induced by 4-aminopyridine (4AP), which is a selective blocker of the transient outward potassium channel, I(to). Action potential parameters were measured, using the conventional microelectrode technique, in the absence and presence of 4AP (0.1-3.0 mM) at pHo 6.5, 7.25, and 8.0. Phase 1 amplitude served as an index of I(to). The onset and recovery kinetics of phase 1 amplitude were assessed at a basic cycle length of 0.5 s, and time constants (tau on and tau r) were computed. Both onset and recovery kinetics had monoexponential functions. Tonic blockade was influenced by external pH, and Kd for half block was 0.19, 0.44, and 2.43 mM for pHo 8.0, 7.25, and 6.5, respectively. Phasic block was defined and exhibited cycle length dependence. Phasic block was also modified by external pH with the greatest effect at pHo 8.0. 4AP (0.3 mM) accelerated tau on, 0.62 +/- 0.2, 0.55 +/- 0.1, and 2.0 +/- 0.8 beats for pHo 8.0, 7.25, and 6.5 compared with control 6.8 +/- 1.9, 6.3 +/- 1.9, and 5.1 +/- 1.4 beats. In contrast, 4AP slowed tau r by about 1 s from control value to 1.5 +/- 0.5 s at pHo 6.5, 4.8 +/- 1.5 s at pHo 7.25 (p < 0.05), and 5.7 +/- 2.0 s at pHo 8.0. We conclude that an increase in extracellular pH enhances block of Ito induced by 4AP, whereas low pHo attenuates the block.

Mechanism of Repetitive Monomorphic Ventricular Tachycardia

The most common form of idiopathic ventricular tachycardia (VT) is repetitive monomorphic VT (RMVT), which is characterized by frequent ventricular ectopy and salvos of nonsustained VT with intervening sinus rhythm. Unlike most other forms of idiopathic VT, this tachycardia typically occurs at rest and is nonsustained. The mechanism of RMVT is undefined. Because of a common site of origin, the right ventricular outflow tract (RVOT), we hypothesized that RMVT is mechanistically related to paroxysmal sustained, exercise-induced VT, which has been shown to be consistent with cAMP-mediated triggered activity. Therefore, in this study, we sought to identify (1) the mechanism of RMVT at the cellular level by using electropharmacological probes known to activate either stimulatory or inhibitory G proteins and thereby modify intracellular cAMP levels, (2) potential autonomic triggers of RMVT through analysis of heart rate variability, and (3) whether well-characterized somatic activating mutations in the stimulatory G protein, G alpha s, underlie RMVT. Twelve patients with RMVT underwent electrophysiological study. Sustained monomorphic VT was reproducibly initiated and terminated with programmed stimulation and/or isoproterenol infusion in 11 of the 12 patients (the other patient had incessant RMVT). Induction of VT demonstrated cycle length dependence and was facilitated by rapid atrial or ventricular pacing. Termination of VT occurred in response to interventions that either lowered stimulated levels of intracellular cAMP (and thus decreased intracellular Ca2+)--ie, adenosine (12 of 12), vagal maneuvers or edrophonium (8 of 9), and beta-blockade (3 of 5)--or directly decreased the slow-inward calcium current--ie, verapamil (10 of 12). Analysis of heart rate variability during 24-hour ambulatory monitoring in 7 patients showed that the sinus heart rate is increased and accelerates before nonsustained VT (P < .05), whereas high-frequency heart rate variability is unchanged. These findings are consistent with transient increases in sympathetic tone preceding nonsustained VT. Finally, myocardial biopsy samples were obtained from the site of origin of the VT (typically the RVOT) and from the right ventricular apex from 9 patients. Genomic DNA was extracted from each biopsy sample, and three exons of G alpha s in which activating mutations have previously been described were amplified by polymerase chain reaction. All sequences from these regions were found to be identical to that of control. Although the arrhythmia occurs at rest, the constellation of findings in idiopathic VT that is characterized by RMVT is consistent with the mechanism of cAMP-mediated triggered activity. Therefore, the spectrum of VT resulting from this mechanism includes not only paroxysmal exercise-induced VT but also RMVT.

Alteration in the Cycle Length Dependence of Action Potential Duration by Ischaemia in the Human Heart - Relevance to Arrhythmogenesis by a Premature Beat

Conference Abstract| July 01 1995 Alteration in the Cycle Length Dependence of Action Potential Duration by Ischaemia in the Human Heart - Relevance to Arrhythmogenesis by a Premature Beat P Taggart; P Taggart 1Departments of Academic and Clinical Cardiology, UCL Hospitals, Departments of Physiology, Charing Cross Hospital, London and University of Leeds Search for other works by this author on: This Site PubMed Google Scholar PMI Sutton; PMI Sutton 1Departments of Academic and Clinical Cardiology, UCL Hospitals, Departments of Physiology, Charing Cross Hospital, London and University of Leeds Search for other works by this author on: This Site PubMed Google Scholar MR Boyett; MR Boyett 1Departments of Academic and Clinical Cardiology, UCL Hospitals, Departments of Physiology, Charing Cross Hospital, London and University of Leeds Search for other works by this author on: This Site PubMed Google Scholar MJ Lab; MJ Lab 1Departments of Academic and Clinical Cardiology, UCL Hospitals, Departments of Physiology, Charing Cross Hospital, London and University of Leeds Search for other works by this author on: This Site PubMed Google Scholar RH Swanton RH Swanton 1Departments of Academic and Clinical Cardiology, UCL Hospitals, Departments of Physiology, Charing Cross Hospital, London and University of Leeds Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1995) 89 (s33): 19P. https://doi.org/10.1042/cs089019P Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation P Taggart, PMI Sutton, MR Boyett, MJ Lab, RH Swanton; Alteration in the Cycle Length Dependence of Action Potential Duration by Ischaemia in the Human Heart - Relevance to Arrhythmogenesis by a Premature Beat. Clin Sci (Lond) 1 July 1995; 89 (s33): 19P. doi: https://doi.org/10.1042/cs089019P Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu nav search search input Search input auto suggest search filter All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1995 The Biochemical Society and the Medical Research Society1995 Article PDF first page preview Close Modal You do not currently have access to this content.

Regional differences in rabbit atrial repolarization: importance of transient outward current

Regional differences in rabbit atrial repolarization were investigated using a conventional microelectrode technique. A more rapid phase 1 repolarization (lower phase 1 amplitude) was seen in the left atrial (LA) roof area compared with the right atrial (RA) roof area: 54 +/- 10 vs. 82 +/- 6 mV at 1,000 ms (P < 0.001). In addition, action potential duration at 40 mV above the resting potential (APD40) was shorter in LA and was associated with a slower phase 3 repolarization rate. Furthermore, the recovery time constant of phase 1 amplitude at 500 ms was 0.9 +/- 0.2 s in LA and 3.5 +/- 1.5 s in RA (P < 0.001). Pacing cycle lengths (2,000, 1,500, 1,000, 800, and 500 ms) modulated phase 1 amplitude, APD40, and phase 3 rate in both regions. 4-Aminopyridine (4-AP; 1 mM), a selective transient outward current (I(to)) blocker, abolished cycle length dependence of the above action potential parameters and diminished the differences in electrophysiological properties between the two regions. 4-AP also flattened the restitution curve of phase 1 amplitude in both regions. In conclusion, the findings suggest that the different kinetics of I(to) play an important role in regional differences of atrial repolarization.

Parasympathetic control of cycle length dependence of endocardial ventricular repolarisation in the intact feline heart during steady state conditions

Parasympathetic modulation of the rate dependence of ventricular repolarisation in vivo during steady state conditions was investigated by analysing the effects of removing vagal activity in three groups of anaesthetised cats. Bilateral vagotomy was performed while different levels of background sympathetic tone were present in the control periods of each group: in group 1 (n = 6), cardiac sympathetic nerves were intact; in group 2 (n = 7), bilateral stellate ganglionectomy was performed; and in group 3 (n = 7), beta adrenergic blockade (propranolol, 0.5 mg.kg-1) was performed after stellate ganglionectomy. The duration of a left ventricular endocardial monophasic action potential (APD) was measured during atrial pacing at 7-10 cycle lengths (CL). The APD/CL relation was fitted to a hyperbolic function: APD = CL/[(axCL)+b]. Two parameters were considered: APDmax (1/a, ie, APD extrapolated at infinite cycle length, a rate-independent measure of APD) and CL50 (bxAPDmax, ie, the cycle length at which 50% of APDmax is reached). In control conditions, APDmax and CL50 were longer in groups 2 and 3, when cardiac sympathetic effects were reduced or absent. Vagotomy reduced APDmax and CL50 similarly in groups 1 and 2 (APDmax, -24% and -18%; CL50, -36% and -27%) (p < 0.05 v control). In group 3, vagotomy did not affect APDmax and CL50. No direct parasympathetic influence on the rate dependence of endocardial ventricular repolarisation was observed. The vagal modulation of sympathetic effects may take place either through vago-sympathetic reflexes or via the antagonism of circulating catecholamines distal to the beta receptor.

Response of nonreentrant catecholamine-mediated ventricular tachycardia to endogenous adenosine and acetylcholine. Evidence for myocardial receptor-mediated effects.

Reentrant ventricular tachycardia (VT) is known to be insensitive to the nucleoside adenosine. However, we have previously identified a form of nonreentrant, catecholamine-mediated VT that can be initiated with rapid pacing, demonstrates cycle length dependence, and is sensitive to exogenous adenosine as well as to the Valsalva maneuver. The mechanism of this tachycardia is thought to be due to a catecholamine-induced, cAMP-mediated increase in intracellular calcium, resulting in delayed afterdepolarizations and triggered activity. The antiarrhythmic effects of exogenous adenosine and Valsalva on this form of VT may be due to receptor-mediated inhibition of adenylate cyclase or to noncardiac receptor-mediated effects, i.e., exogenous adenosine may modulate VT through alterations in autonomic tone by activation of arterial chemoreceptors, and Valsalva has been shown to decrease venous return, resulting in a reduction in cardiac dimensions and myocardial stretch. To clarify this issue and circumvent both autonomic and noncardiac receptor effects, the response of nonreentrant catecholamine-mediated VT to endogenous adenosine and acetylcholine was evaluated. Group 1 (n = 8): Dipyridamole (0.56 mg/kg i.v.), a nucleoside transport blocker that potentiates the effects of endogenous adenosine, reproducibly abolished sustained nonreentrant, nonautomatic, catecholamine-mediated VT in the five patients in whom it was evaluated. VT recurred with the addition of aminophylline, a competitive adenosine A1-receptor antagonist. Edrophonium (10 mg i.v.), a cholinesterase inhibitor that potentiates the effects of acetylcholine at the muscarinic cholinergic receptor, terminated VT in four of four patients, an effect that was reversed by atropine. Group 2 (n = 6): In patients with reentrant VT, dipyridamole and edrophonium had no effect on VT cycle length or duration. Group 3 (n = 4): Adenosine and vagal maneuvers had no effect on catecholamine-mediated VT caused by automaticity in three of four patients tested. In one patient, adenosine transiently suppressed VT (< 5 seconds), after which it spontaneously resumed. The results of this study further delineate the mechanism of a newly recognized form of clinical VT. It can be identified by termination of the tachycardia in response to activation of the adenosine A1 or muscarinic cholinergic receptor, which results in inhibition of adenylate cyclase. These receptor-mediated effects appear to be specific for identifying nonreentrant, nonautomatic, catecholamine-mediated VT.

Idiopathic Long QT Syndrome Exacerbated by Beta‐Adrenergic Blockade and Responsive to Left Cardiac Sympathetic Denervation: Implications Regarding Electrophysiologic Substrate and Adrenergic Modulation

Electrophysiologic Substrate of Long QT Syndrome. Introduction: The mechanisms of T wave abnormalities and arrhythmias in patients affected by the long QT syndrome (LQTS) are unclear, as are the reasons why a high‐risk subgroup (20%) continues to have syncope during therapy with beta blockers but is protected after left cardiac sympathetic denervation (LCSD). Afterdepolarizations, both early (EAD) or delayed (DAD), have been implicated as likely electrophysiologic substrates for the ECG abnormalities and arrhythmias in LQTS. To test this hypothesis, we analyzed nine Hotter recordings of a LQTS patient typical of the high‐risk subgroup. Methods and Results: We applied to the ECG rules derived from previous in vitro and in vivo studies, which relate the coupling intervals of the dysrhythmic beats to the preceding cycle lengths, to discriminate among arrhythmia mechanisms. In the absence of therapy, the patient's ECG showed peaked T waves, with a notched second component accentuated by sinus pauses. The amplitude of the notches increased directly with the preceding RR interval (r = 0.58, P &lt; 0.05), as it is observed with EAD. Therapy with the beta blocker propranolol did not modify the notches, which maintained their amplitude and their relationship with the preceding RR (r = 0.62, P &lt; 0.05). Moreover, during beta‐blocker therapy, ventricular premature beats, couplets, and runs of ventricular tachycardia (VT) occurred. The coupling intervals of ventricular premature beats and couplets were not influenced by the preceding RR intervals. By contrast, the coupling interval of the first beat of VT decreased as the preceding RR shortened, as it occurs with DAD‐induced triggered activity. After LCSD, T wave notch amplitude was reduced (P &lt; 0.05) and was no longer influenced by the preceding RR (r = 0.31, P = 0.22). The same was true when the calcium entry blocker verapamil was administered. Conclusion: In this patient, T wave abnormalities and some ventricular arrhythmias had the behavior observed in vitro for EAD and the consequent triggered activity. However, the cycle length dependence of VT manifested the behavior observed in vitro for DAD and the related triggered activity. The fact that these phenomena were accentuated by beta blockade and disappeared after LCSD suggests that the alpha‐adrenergic receptor‐effector system may be a modulator of T wave abnormalities and arrhythmias in some patients unresponsive to beta blockade and protected by LCSD. (J Cardiovasc Electrophysiol, Vol. 3, pp. 295–305, August 1992)

Relation between repolarization and refractoriness in the human ventricle: Cycle length dependence and effect of procainamide

The cycle length dependence of the action potential duration and the effective refractory period of the right ventricular endocardium were investigated in 24 patients undergoing electrophysiologic studies for suspected ventricular tachycardia. The action potential duration at 90% repolarization and the effective refractory period at twice diastolic threshold strength were measured at the same catheter site at steady state cycle lengths of 350 to 600 ms. Both measurements decreased linearly with decreasing cycle length, maintaining a parallel relation. When the relation between action potential duration and effective refractory period was expressed as the effective refractory period-action potential duration difference, nearly constant values (range -12 to -15 ms) were obtained at all cycle lengths. To determine whether sodium channel blocking drugs influence the effective refractory period-action potential duration relation in humans, measurements of these two variables were obtained in 15 patients before and during the infusion of procainamide. Procainamide prolonged the action potential duration at each cycle length by a near constant amount over baseline values (p less than 0.001). Procainamide also increased the effective refractory period at each cycle length but with a greater incremental increase at the shorter cycle lengths. The rate-dependent increase in the effective refractory period-action potential duration difference became significant at cycle lengths less than or equal to 400 ms; at these high rates, the effective refractory period-action potential duration difference became positive (1.6 ms, p less than 0.01 compared with baseline). Thus, in the human ventricle, the action potential duration and the effective refractory period have a close relation that remains fixed over a wide range of cycle lengths.(ABSTRACT TRUNCATED AT 250 WORDS)