To further characterize arrhythmic mechanisms in German shepherd dogs (GSDs) affected with inherited ventricular arrhythmias by evaluating intracellular calcium cycling and expression of calcium ...handling genes.
Twenty five GSDs, 9 backcross dogs, and 6 normal mongrel dogs (controls) were studied. The GSDs and backcross dogs were from a research colony of inherited ventricular arrhythmias. The control research dogs were purchased.
Action potentials (APs) and pseudo-electrocardiograms (ECG) were recorded from left ventricular (LV) wedge preparations of GSDs and normal dogs. Midmyocardial (Mid) LV cells from GSDs and normal mongrels were isolated by enzymatic digestion. Cells were either field stimulated or voltage clamped and calcium transients were measured by confocal microscopy using the indicator Fluo-3AM. Expression of calcium handling genes was measured by quantitative RT-PCR.
Mean calcium transient decay (tau) was not different between affected GSDs and control dogs, but striking cell-to-cell variability for tau was observed within affected GSDs and between affected GSDs and controls (P < 0.0001 each); within-dog variability accounted for 75% of total variability. Calcium sparks and afterdepolarizations occurred in GSD but not control cells. ATP2A2/SERCA2a expression was significantly reduced (P = 0.0063) in affected GSDs and inversely correlated (P = 0.0006) with severity of ventricular arrhythmias.
German shepherd dogs with inherited ventricular arrhythmias have electrophysiologic abnormalities in calcium cycling associated with reduced ATP2A2/SERCA2a expression. These animals provide a unique opportunity to study calcium remodeling at the genetic and molecular level in familial ventricular arrhythmias.
When U Say "U Waves," What Do U Mean? VISKIN, SAMI; ZELTSER, DAVID; ANTZELEVITCH, CHARLES
Pacing and clinical electrophysiology,
02/2004, Letnik:
27, Številka:
2
Journal Article
'Electrical Diseases of the Heart: Genetics, Mechanisms, Treatment, Prevention' provides a unique contemporary and succinct distillation of the current status of recently delineated electrical ...diseases of the heart, emphasizing their common and diverse clinical features. The latest developments in the field of experimental and clinical cardiac electrophysiology, genetics, pharmacology and interventional therapies of various clinical arrhythmogenic entities are featured and discussed in terms of recent advances in basic and clinical science. The book is divided into 7 major parts. Each part consists of chapters (total of 64) dealing with related topics. Each chapter is outlined with objectives, key points, current perspectives, and recommendations for future investigations and includes established and evidence-based knowledge, the authors' personal opinions, areas of controversy, and future trends.
The Brugada syndrome is a congenital syndrome displaying an autosomal dominant mode of transmission in patients with a structurally normal heart. The disease has been linked to mutations in
SCN5A, a ...gene located on the short arm of chromosome 3 (p21-24) that encodes for the
α subunit of the sodium channel. The syndrome is characterized by a dynamic ST-segment elevation (accentuated J wave) in leads V
1 to V
3 of the ECG followed by negative T wave. Right bundle-branch block of varying degrees is observed in some patients. The syndrome is associated with syncope and a relatively high incidence of sudden cardiac death secondary to the development of polymorphic ventricular tachycardia that may degenerate into ventricular fibrillation. An acquired form of the Brugada syndrome is also recognized, caused by a wide variety of drugs and conditions that alter the balance of currents active during the early phases of the action potential. Among patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia, there is a subpopulation with a clinical and electrocardiographic pattern similar to that of the Brugada syndrome. These cases of arrhythmogenic right ventricular cardiomyopathy/dysplasia are thought to represent an early or concealed form of the disease. This review examines the overlap between these 2 syndromes.
A prolongation of the ventricular effective refractory period in response to cholinergic agonists or vagal stimulation has been demonstrated in a number of in vivo animal models. However, exposure of ...isolated myocardial tissues obtained from these hearts to as much as 10 M acetylcholine has been shown to produce essentially no change in action potential duration or effective refractory period. The discrepancy between the in vivo and in vitro findings generally has been explained on the basis of accentuated antagonism, whereby parasympathetic agonists exert their influence through antagonism of the effects of β-adrenergic tone in vivo. The fact that acetylcholine exerts little if any direct effect on the electrical activity of ventricular myocardium, although well accepted, is based exclusively on studies performed using endocardial preparations. Our recent demonstration of major electrophysiological differences between canine ventricular endocardium and epicardium prompted us to examine the effects of acetylcholine and the role of accentuated antagonism in these two tissue types. Using standard microelectrode techniques, we show that acetylcholine (10-10 M) has little if any effect in canine ventricular endocardium but a pronounced effect to either prolong or markedly abbreviate action potential duration and effective refractory period in epicardium. These effects of acetylcholine on epicardium are attended by an accentuation of the spike and dome morphology of the action potential, are readily reversed with atropine, fail to appear when epicardium is pretreated with the transient outward current blocker 4-aminopyridine, are accentuated in the presence of isoproterenol (10 to 5×10 M), and persist in the presence of propranolol. Isoproterenol-induced abbreviation of action potential duration and effective refractory period is also shown to be more pronounced in epicardium than in endocardium; equimolar concentrations of acetylcholine completely antagonize the effects of isoproterenol in endocardium and epicardium. We conclude that acetylcholine exerts important direct effects on the electrical response of canine ventricular myocardium, which are accentuated in the presence of β-adrenergic agonists. Our findings suggest the differential response of epicardium and endocardium to acetylcholine is due to the presence of a transient outward current-mediated spike and dome morphology in the epicardial action potential. Finally, the data suggest that acetylcholine may exert antiarrhythmic as well as arrhythmogenic effects through its actions to alter conduction and refractoriness.
BACKGROUND: This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced ...by beta-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome. METHODS AND RESULTS: A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific IKs blocker, dose-dependently (1 to 100 micromol/L) prolonged the QT interval and action potential duration (APD90) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 micromol/L abbreviated the APD90 of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the IKs blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 micromol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 micromol/L abbreviated the APD90 of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP. CONCLUSIONS: This experimental model of LQT1 indicates that a deficiency of IKs alone does not induce TdP but that the addition of beta-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual IKs in epicardial and endocardial cells but not in M cells, in which IKs is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of beta-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome.
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