anthopleurin-a and Tachycardia--Ventricular

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions of adrenergic activation. Recently, the genes for the LQTS inked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQT1) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQT1 potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na+ channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest that LQT3 patients are more likely to benefit from Na+ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however

Topics: Action Potentials; Adrenergic Antagonists; Animals; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Cardiotonic Agents; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 7; Disease Models, Animal; Electrocardiography; Genetic Therapy; Guinea Pigs; Heart Rate; Humans; Intercellular Signaling Peptides and Proteins; Long QT Syndrome; Mexiletine; Molecular Biology; Myocardium; Peptides; Phenethylamines; Potassium; Potassium Channel Blockers; Potassium Channels; Receptors, Adrenergic; Risk Factors; Sodium Channel Blockers; Sodium Channels; Sulfonamides; Syncope; Tachycardia, Ventricular

T wave alternans (TWA) is characterized by cycle-to-cycle changes in the QT interval and/or T wave morphology. It is believed to amplify the underlying dispersion of ventricular repolarization. The aim of this study was to examine the mechanisms and arrhythmogenesis of TWA accompanied by QRS complex and/or blood pressure (BP) waveform alternans, using transmural ventricular electrogram recordings in an anthopleurin-A model of long QT syndrome.. The cardiac cycle length was gradually shortened by interruption of vagal stimulation, and TWA was induced in six canine hearts. Transmural unipolar electrograms were recorded with plunge needle electrodes from endocardial (Endo), mid-myocardial (Mid), and epicardial (Epi) sites, along with the surface ECG and BP. The activation-recovery interval (ARI) was measured to estimate local refractoriness. During TWA, ARI alternans was greater at the Mid than the Epi/Endo sites, and it was associated with the development of marked spatial dispersion of ventricular repolarization. As TWA increased, ventricular activation of the cycles associated with shorter QT intervals displayed delayed conduction at the Mid sites as a result of a critically longer ARI of the preceding cycle and longer QT interval, while normal conduction was preserved at the Epi site. Delayed conduction at the Mid sites manifested as surface ECG QRS and BP waveform alternans, and spontaneous ventricular tachyarrhythmias developed in absence of ventricular prematurity. In other instances, in absence of delayed conduction during TWA, ventricular premature complexes infringed on a prominent spatial dispersion of ventricular repolarization of cycles with long QT intervals and initiated ventricular tachyarrhythmia.. TWA accompanied by QRS alternans may signal a greater ventricular electrical instability, since it is associated with intramural delayed conduction, which can initiate ventricular tachyarrhythmia without ventricular premature complexes.

Topics: Animals; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Dogs; Electrocardiography; Heart Conduction System; Intercellular Signaling Peptides and Proteins; Long QT Syndrome; Models, Cardiovascular; Peptides; Systole; Tachycardia, Ventricular; Ventricular Function, Left; Ventricular Premature Complexes

The purpose of this study was to investigate the electrophysiologic mechanism(s) that underlie the transition of one or more short-long (S-L) cardiac sequences to ventricular tachyarrhythmias (VTs) in the long QT syndrome.. One or more S-L cardiac cycles, usually the result of a ventricular bigeminal rhythm, frequently precedes the onset of VT in patients with either normal or prolonged QT interval. Electrophysiologic mechanisms that underlie this relationship have not been fully explained.. We investigated electrophysiologic changes associated with the transition of a S-L cardiac sequence to VT in the canine anthopleurin-A model, a surrogate of LQT3. Experiments were performed on 12 mongrel puppies after administration of anthopleurin-A. Correlation of tridimensional activation and repolarization patterns was obtained from up to 384 electrograms. Activation-recovery intervals were measured from unipolar electrograms and were considered to represent local repolarization.. We analyzed 24 different episodes of a S-L sequence that preceded VT obtained from 12 experiments. The VT followed one S-L sequence (five episodes), two to five S-L sequences (12 episodes) and more than five S-L sequences (seven episodes). The single premature ventricular beats coupled to the basic beats were consistently due to a subendocardial focal activity (SFA). There were two basic mechanisms for the development of VT after one or more S-L sequences: 1) in 10 examples of a S-L sequence due to a stable unifocal bigeminal rhythm, the occurrence of a second SFA, which arose consistently from a different site, infringed on the pattern of dispersion of repolarization (DR) of the first SFA to initiate reentrant excitation; 2) in the remaining 14 episodes of a S-L sequence, a slight lengthening (50 to 150 ms) in one or more preceding cycle lengths (CLs) resulted in alterations of the spatial pattern of DR at key sites to promote reentry. The lengthening of the preceding CL produced differentially a greater degree of prolongation of repolarization at midmyocardial and endocardial sites compared with epicardial sites with consequent increase of DR. The increased DR at key adjacent sites resulted in the development of de novo zones of functional conduction block and/or slowed conduction to create the necessary prerequisites for successful reentry.. The occurrence of VT after one or more S-L cardiac sequences was due to well defined electrophysiologic changes with predictable consequences that promoted reentrant excitation.

Topics: Animals; Disease Models, Animal; Dogs; Electrocardiography; Follow-Up Studies; Heart Conduction System; Image Processing, Computer-Assisted; Intercellular Signaling Peptides and Proteins; Long QT Syndrome; Peptides; Tachycardia, Ventricular

We have previously developed a canine in vivo model of the long QT syndrome (LQTS) using the neurotoxin anthopleurin A (AP-A), which acts by slowing sodium channel inactivation. The recent discovery of a genetic mutation in the cardiac sodium channel in some patients with the congenital LQTS, resulting in abnormal gating behavior similar to sodium channels exposed to AP-A, provides a strong endorsement of this animal model as a valid surrogate to the clinical syndrome of LQTS. In the present study, we conducted high-resolution tridimensional isochronal mapping of both activation and repolarization patterns in puppies exposed to AP-A that developed LQTS and polymorphic ventricular tachyarrhythmias (VTs). To map repolarization, we measured activation-recovery intervals (ARIs) using multiple unipolar extracellular electrograms. We demonstrated, for the first time in vivo, the existence of spatial dispersion of repolarization in the ventricular wall and differences in regional recovery in response to cycle-length changes that were markedly exaggerated after AP-A administration. Analysis of tridimensional activation patterns showed that the initial beat of polymorphic VT consistently arose as focal activity from a subendocardial site, whereas subsequent beats were due to successive subendocardial focal activity, reentrant excitation, or a combination of both mechanisms. Reentrant excitation was due to infringement of a focal activity on the spatial dispersion of repolarization, resulting in functional conduction block and circulating wave fronts. The polymorphic QRS configuration of VT in the LQTS was due to either changing the site of origin of focal activity, resulting in varying activation patterns, or varying orientations of circulating wave fronts.

Topics: Animals; Cardiotonic Agents; Dogs; Electrocardiography; Electrophysiology; Heart; Intercellular Signaling Peptides and Proteins; Long QT Syndrome; Peptides; Tachycardia, Ventricular