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Biomedical subjects

A A Wilde

Publications and source records attributed to A A Wilde.

At least 55 records · Page 3Linked to original sources
PubMed1998

Suppression of torsades de pointes by atropine.

A 67 year old woman with a history of chronic atrial fibrillation presented with asthma cardiale. She took no medication and there was no family history of long QT syndrome. She was treated with furosemide, nitroprusside, acenocoumarol, and digoxin. Two days later excessively prolonged RR intervals, which were terminated by escape beats with a right bundle branch block morphology, suggested impending total AV block. There was also severe QT (0.48 s) and QTc (0.56) interval prolongation with bizarre inverted TU waves and multifocal premature ventricular complexes within the U waves. The patient experienced angina pectoris followed by episodes of torsades de pointes, which were interpreted as the result of bradycardia, and the bradycardia as the result of high grade AV block induced by increased vagal tone caused by ischaemia in the presence of digoxin intoxication (serum digoxin was 2.5 micrograms/l). Subsequent atropine infusion sped up the ventricular rate and shortened the QT (0.39) and QTc (0.51) intervals. Digoxin was replaced by metoprolol to control ventricular rate and angina pectoris. Within days, QT and QTc intervals became normal and the U waves disappeared. Neither torsades de pointes nor angina pectoris recurred. Based on a review of the literature, it is suggested that the electrophysiological mechanism of this effect is not only an increase of the heart rate, but also a direct action of muscarinic receptor antagonism on Purkinje cells and ventricular refractoriness.

Aged↗
PubMed1998

T wave alternans after sotalol: evidence for increased sensitivity to sotalol after conversion from atrial fibrillation to sinus rhythm.

A 64 year old woman with an 11 year history of paroxysmal atrial fibrillation presented to the emergency room because of palpitations that had started two weeks previously. She had used sotalol 80 mg once daily for three years without any episodes of proarrhythmia or other adverse effects. However, she developed pronounced T wave alternans with giant inverted T waves and excessive QT prolongation following sotalol administration one day after conversion from atrial fibrillation to sinus rhythm. This case demonstrates bizarre T wave changes, T wave alternans, and extreme QT prolongation following sotalol administration shortly after conversion from atrial fibrillation to sinus rhythm. In this situation, sotalol administration may be proarrhythmic, because it enhances repolarisation inhomogeneities based on a spatially inhomogeneous distribution of repolarisation controlling ion channels to induce repolarisation abnormalities that may lead to torsade de pointes.

Adrenergic beta-Antagonists↗
PubMed1998

Molecular mechanisms of arrhythmias.

Most arrhythmias occur in patients with structural heart disease, where anatomical factors play an important role. Patients without structural heart disease may also suffer from arrhythmias, and recently the genetic basis for such so-called idiopathic arrhythmias has been elucidated. In the congenital long QT syndrome, characterized by a prolonged QT interval, torsade de pointes and sudden death, three aberrant ionic currents have been identified, resulting in a prolongation of the ventricular action potential, which in its turn may cause early afterdepolarization and torsade de pointes. In LQTS1, mutations in the KvLQT1 gene reduce the slow component of the delayed rectifier Iks; in LQTS, mutations in the Human Ether a-go-go Related Gene (HERG) reduce the rapid component of the delayed rectifier Iks. Both potassium currents are important determinants of repolarization: a reduction in outward currents carried by K+ ions prolongs the action potential. In LQTS3, there are mutation in the NA+ channel gene (SCN5A) which causes the channel to inactivate incompletely; the persistent inward current carried by Na+ ions also prolongs the action potential. In the Brugada syndrome, characterized by right bundle branch block, ST elevation in V1-V3 and sudden death, mutations have been observed in the Na+ channel gene, but it is as yet unclear which functional changes in the NA+ channel are responsible for the typical ECG changes and the arrhythmias. Various cardiac disorders may lead to changes in gene expression that modify channel function. In hypertrophy, the ventricular action potential is prolonged by a decrease in the inward rectifier and the transient outward current. After prolonged episodes of rapid electrical activity, the atrial action potential is shortened, because of a reduction in the Iks type calcium current. Finally, many carriers of mutated genes display no abnormalities on the ECG. It is conceivable that such individuals may show excessive QT prolongation when taking cardiac or noncardiac drugs (such as neuroleptics, antidepressants, antihistamines, antimicrobials, antimalarials) that block potassium currents.

Amino Acids↗
PubMed1997

[Congenital long QT syndrome].

The long QT syndrome (LQTS) combines a prolonged QT interval with an enhanced risk of polymorphous ventricular arrhythmias that may lead to syncope and sudden cardiac death. It may be congenital or acquired (the latter sometimes caused by drugs). Congenital LQTS is a rare disease, usually discovered during the clinical evaluation of understood syncopes or at cardiological examination after an unexpected sudden cardiac death of a close relative. The syncope frequently occurs during physical exercise, fear or sudden loud noises. In patients with symptomatic LQTS, the mortality 10 years after the first syncope amounts to approximately 50%. A prolonged QT interval indicates abnormal repolarization or deceleration of the depolarization. An increase of the sympathetic tone, e.g. during physical exercise and emotions, causes prolongation of the QT interval. Congenital LQTS has been associated with genetic mutations, for instance on chromosomes 3 and 7. Treatment consists af administration of beta-blockers, sympathectomy and, if necessary, implantation of an automatic cardioverter/defibrillator.

Adrenergic beta-Antagonists↗
PubMed1997

Evolution of cardiac abnormalities in Becker muscular dystrophy over a 13-year period.

We evaluated the course of cardiac involvement in 27 previously reported patients with Becker muscular dystrophy (BMD) originating from nine kindreds. Since almost all affected individuals of each kindred were included, intrafamilial variability could be studied. We also attempted to identify associations between cardiac involvement, functional ability and mutations at DNA level. The mean follow-up period was 12.5 years. The number of patients with electrocardiographic abnormalities progressed from 44% to 71%. Dilated cardiomyopathy (DCM) with or without congestive heart failure was now present in 33% as compared with 15% in the previous study. In addition, 22% developed borderline echocardiographic abnormalities. Six patients (22%) became symptomatic and four patients died of congestive heart failure. In all families cardiac abnormalities were found. There was no association between DCM and mutation type. Despite equal functional motor ability, there was a considerable intrafamilial variation in cardiac involvement, even in brother pairs. We conclude that cardiac abnormalities are the rule and not the exception in BMD and are progressive over time. Left ventricular dilatation may begin at any moment in the course of BMD and the rate of progression is unpredictable. A substantial proportion of patients will develop an incapacitating and life-threatening DCM.

Adolescent↗
PubMed1997

The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene.

The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance. Patients suffer from syncopal attacks often resulting in sudden cardiac death. The main diagnostic parameter is a prolonged QT(c) interval as judged by electro-cardiographic investigation. LQTS is a genetically heterogeneous disease with four loci having been identified to date: chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3) and 4q25-26 (LQT4). The corresponding genes code for potassium channels KVLQT1 (LQT1) and HERG (LQT2) and the sodium channel SCN5A (LQT3). The KVLQT1 gene is characterized by six transmembrane domains (S1-S6), a pore region situated between the S5 and S6 domains and a C-terminal domain accounting for approximately 60% of the channel. This domain is thought to be co-associated with another protein, viz. minK (minimal potassium channel). We have studied a Romano Ward family with several affected individuals showing a severe LQTS phenotype (syncopes and occurrence of sudden death). Most affected individuals had considerable prolongations of QT(c). By using haplotyping with a set of markers covering the four LQT loci, strong linkage was established to the LQT1 locus, whereas the other loci (LQT2, LQT3 and LQT4) could be excluded. Single-strand conformation polymorphism analysis and direct sequencing were used to screen the KVLQT1 gene for mutations in the S1-S6 region, including the pore domain. We identified a Gly-216-Arg substitution in the S6 transmembrane domain of KVLQT1. The mutation was present in all affected family members but absent in normal control individuals, providing evidence that the mutated KVLQT1-gene product indeed caused LQTS in this family. The mutated KVLQT1-gene product thus probably results in a dominant negative suppression of channel activity.

DNA Mutational Analysis↗
PubMed1997

Sulfonylurea derivatives in cardiovascular research and in cardiovascular patients.

Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). In the beta-cell sulfonylureas act by blocking ATP-sensitive potassium channels (K.ATP channels). In several organ systems, including the cardiovascular system, sulfonylurea receptors and functional K.ATP channels have been identified. In the heart their role is not clear: an endogenous cardioprotective effect has been suggested. There is no doubt that K.ATP channels are effectively blocked by sulfonylureas. In the last decade sulfonylureas have been widely used as a pharmacological tool in experimental (cardiac) research. Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. However, other membrane currents are affected as well. In addition, myocardial metabolism is modified by sulfonylurea pretreatment. Hence, it should seriously be questioned whether these drugs are suitable in assessing involvement of cardiac K.ATP channels in, for example, ischemia-related events. The detrimental effects of sulfonylureas in experimental studies on myocardial ischemia have led to speculation whether the widespread use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease, should be reconsidered. However, a review of the clinical literature reveals that the most consistent finding is a lower incidence of ventricular arrhythmias associated with the use of glibenclamide, while no excess mortality has been shown for this agent in NIDDM with ischemic heart disease. Despite some direct effects on systemic and coronary vasculature, there are, at present, no firm clinical data on the basis of which sulfonylurea derivatives should be withheld from the cardiac patient.

Animals↗
PubMed1997

Ion channels, the QT interval, and arrhythmias.

Aberrations in genes encoding for ion channels have been shown to underlie a number of cardiac arrhythmia syndromes, hitherto classified as idiopathic. These aberrations, inherited and congenital, may lead to dysfunction of channels with resultant abnormal current characteristics. In addition, a variety of stimuli may cause altered expression of these genes. Because prolongation of the action potential (and the QT-interval) is often the result, patients are at risk for the occurrence of arrhythmias based on reentry and the development of abnormal impulse initiation. Molecular dissection of the inherited syndromes has led to rapid progress in our understanding of basic knowledge about ion channel function and its relation to channel structure. This progress is undoubtedly of benefit for the understanding of the repolarization changes in more common conditions and will become of benefit to many more patients who suffer from therapy resistant arrhythmias.

Action Potentials↗
PubMed1997

Mitral valve prolapse and ventricular arrhythmias: observations in a patient with a 20-year history.

INTRODUCTION: Ventricular arrhythmias are a common feature in patients with mitral valve prolapse. In an attempt to determine the origin and underlying electrophysiologic mechanism, we describe a patient with ventricular fibrillation, exercise-induced ventricular tachycardia (VT), and, at the time of diagnosis, prolapse of the posterior mitral valve leaflet without mitral regurgitation. METHODS AND RESULTS: Treatment with beta-blockade and diphenylhydantoin prevented the occurrence of malignant ventricular arrhythmias for more than 17 years. Discontinuation of the therapy resulted in an immediate reappearance of the VT, which, despite the marked enlargement of the left ventricle (secondary to development of severe mitral valve regurgitation), had a strikingly similar morphology. For hemodynamic reasons, the patient was finally selected for valve replacement. Detailed pre-, peri-, and postoperative studies were performed, including administration of flunarizine, body surface mapping, construction of perioperative epicardial and endocardial maps, and studies of the excised muscles in vitro. CONCLUSIONS: Delayed afterdepolarization-induced triggered activity is the mechanism of VT in this mitral valve prolapse patient. The trigger is provided by isolated ventricular premature complexes elicited by a different electrophysiologic mechanism, possibly reentry, which is related to stretch and presumably to fibrosis of the papillary muscles.

Adult↗
PubMed1994

Phentolamine blocks ATP sensitive potassium channels in cardiac ventricular cells.

OBJECTIVE: The alpha adrenoceptor antagonist phentolamine prevents ischaemia related arrhythmias in rat, guinea pig, and cat heart. This effect has been related to the attenuation of ischaemia induced shortening of the action potential and has been ascribed to its alpha adrenoceptor antagonist properties. The aim of this study was to examine the effect of phentolamine on the ATP sensitive potassium channel (KATP), because this channel seems to be involved in action potential shortening during ischaemia. METHODS: Single channel experiments were performed on inside-out and outside-out patches of isolated rabbit ventricular cells at room temperature. Cells were isolated with conventional isolation techniques. Pipette and bath solution contained (in mmol.litre-1): K-gluconate 140, KCl 10, and HEPES-KOH 10 (pH 7.4). RESULTS: Excision of the patch always resulted in KATP channel activity [single channel conductance 60(SD 2.8) pS n = 4], which could be completely blocked by 5 mM ATP. In 22 of 26 patches the addition of 5 microM phentolamine to the intracellular side of the membrane reduced KATP channel activity. In 17 of these patches the effect was reversible. In four patches no effect was observed. Open probability decreased by 94% (n = 12). Addition of 50 microM phentolamine resulted in the disappearance of channel activity in six of eight patches which was reversible in four patches. In outside-out patches 5 microM phentolamine was only effective in 50% of the patches, reducing open probability by 98 to 100%. CONCLUSIONS: Phentolamine blocks ATP sensitive potassium channels in rabbit ventricular cells independently of the alpha adrenoceptor. This blocking effect probably occurs at the intracellular side of the membrane. The antiarrhythmic effect of phentolamine may at least partially be explained by blockade of KATP channels and may thus partly be independent of its effects on the alpha adrenoceptor.

Action Potentials↗
PubMed1994

K+ ATP-channel opening and arrhythmogenesis.

The role of adenosine triphosphate (ATP)-sensitive potassium channels (K+ ATP channels) under physiologic and pathophysiologic conditions has been debated in recent years. Moreover, because of the reported pro-arrhythmic effects of potassium-channel openers in the setting of acute myocardial ischemia, the potential benefit of K+ ATP-channel modulation in clinical practice has been questioned. Such pro-arrhythmic potential, based on the ability of potassium-channel openers to exacerbate the ischemia-induced shortening of the action potential, is also disputed. Both pro- and antiarrhythmic effects of K+ ATP-channel openers (and blockers) have been described. These apparently conflicting results can (to a great extent) be explained by taking into account the electrophysiologic mechanism of a particular arrhythmia. In addition, under ischemic conditions other factors of importance for the development of arrhythmias may, when they are not controlled, determine the outcome. It is concluded that both in normoxia and in ischemia, pharmacologic opening of K+ ATP channels might facilitate ventricular arrhythmias when it leads to serious electrophysiologic inhomogeneity. Because such favorable conditions are created only by relatively high doses, the problem of pro-arrhythmogeneity may be overestimated. On the other hand, before widescale application in the treatment of ischemic heart disease is established, well designed clinical and experimental studies should be performed to determine the risk for pro-arrhythmogeneity.

Adenosine Triphosphate↗
PubMed1993

Role of ATP-sensitive K+ channel current in ischemic arrhythmias.

In acute myocardial ischemia slow conduction and short refractoriness both predispose to cardiac arrhythmias. Moreover, spatial dispersion in these parameters, in part determined by inhomogeneity in extracellular potassium concentration ([K+]0), which develops within minutes, is considered highly arrhythmogenic. The incidence and time distribution of ventricular arrhythmias is determined by these electrophysiological changes and by factors pertinent to the experimental model. In the initial phase of ischemia, glibenclamide, a potent blocker of ATP-sensitive K+ channels (K+ATP channels), reduces the rate of increase in [K+]0 and therefore, presumably, also the inhomogeneity in [K+]0. During this phase of ischemia glibenclamide has an antiarrhythmic effect, which may be based on a reduction in inhomogeneity in [K+]0. In addition, glibenclamide prolongs the action potential of ischemic myocardium. Although under ischemic conditions action potential duration is no longer a reliable parameter or refractoriness, glibenclamide-induced prolongation or refractoriness may play a role in the prevention of arrhythmias. In contrast, openers of K+ATP channels increase the incidence of ventricular arrhythmias or, in other models, the time course of onset is accelerated. They shorten the duration of the action potential in ischemic tissue. In the globally ischemic rabbit heart, initial changes in [K+]0 are not influenced by cromakalim. It is concluded that activation of the K+ATP channel current during early myocardial ischemia potentially contributes to the development of ventricular arrhythmias. Particularly, the direct electrophysiological effect of increased K+ current is considered arrhythmogenic.

Adenosine Triphosphate↗