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W Haverkamp

Publications and source records attributed to W Haverkamp.

At least 37 records · Page 2Linked to original sources
PubMed2001

Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel.

Propafenone has been shown to affect the delayed-rectifier potassium currents in cardiomyocytes of different animal models. In this study we investigated effects and mechanisms of action of propafenone on HERG potassium channels in oocytes of Xenopus laevis with the two-electrode voltage-clamp technique. Propafenone decreased the currents during voltage steps and the tail currents. The block was voltage-dependent and increased with positive going potentials (from 18% block of tail current amplitude at -40 mV to 69% at +40 mV with 100 micromol/l propafenone). The voltage dependence of block could be fitted with the sum of a monoexponential and a linear function. The fractional electrical distance was estimated to be delta=0.20. The block of current during the voltage step increased with time starting from a level of 83% of the control current. Propafenone accelerated the increase of current during the voltage step as well as the decay of tail currents (time constants of monoexponential fits decreased by 65% for the currents during the voltage step and by 37% for the tail currents with 100 micromol/l propafenone). The threshold concentration of propafenone effect was around 1 micromol/l and the concentration of half-maximal block (IC50) ranged between 13 micromol/l and 15 micromol/l for both current components. With high extracellular potassium concentrations, the IC50 value rose to 80 degrees mol/l. Acidification of the extracellular solution to pH 6.0 increased the IC50 value to 123 micromol/l, alkalization to pH 8.0 reduced it to 10 micromol/l and coexpression of the beta-subunit minK had no statistically significant effect on the concentration dependence. In conclusion, propafenone has been found to block HERG potassium channels. The data suggest that propafenone affects the channels in the open state and give some hints for an intracellular site of action.

Animals↗
PubMed2001

Torsade de pointes induced by ajmaline.

Ajmaline, a reserpine derivative, is an effective class I antiarrhythmic agent. Herein we report two cases of ajmaline-induced abnormal QT prolongation accompanied by polymorphic ventricular tachycardia of the torsade de pointes type. Since ajmaline is increasingly used for the acute termination of wide complex tachycardia and as a diagnostic tool after syncope and in patients with idiopathic ventricular tachyarrhythmias, our observations suggest that caution should be exercised with regard to the effects of the drug on the QT interval and its potency to induce proarrhythmia of the torsade de pointes type.

Ajmaline↗
PubMed2001

Load-induced changes in repolarization: evidence from experimental and clinical data.

The high incidence of arrhythmias in patients with heart failure, hypertension, valvular heart disease, or mitral walve prolapse suggests a strong link between wall motion abnormalities and arrhythmias. A potential common mechanism underlying these observations may be that overload leads to electrophysiologic changes and facilitates arrhythmias. This article summarizes the interaction between changes in atrial and ventricular loading conditions and repolarization. Most experimental and clinical studies demonstrated 1) a reduction of action potential duration and refractoriness, 2) development of early afterdepolarizations, and 3) ectopic beats originating from these afterdepolarizations. Discrepancies between studies are related to different study designs, i.e., varying magnitude, velocity, and timing of increased load, the level of repolarization at which action potential duration is measured as well as different animal species. Direct effects of increased load on repolarization are most likely caused by activation of stretch-activated nonselective cation ion channels and changes in calcium handling. Current antiarrhythmic drug therapy is aimed at electrical disorders as the primary cause of arrhythmias. If mechanical disorders play a central role in the genesis of cardiac arrhythmias, future treatment should be directed at restoring a more normal mechanical function of the heart. Additional studies will further clarify the nature and clinical significance of load-related changes in repolarization and arrhythmogenesis.

Animals↗
PubMed2001

In vivo recording of monophasic action potentials in awake dogs--new applications for experimental electrophysiology.

INTRODUCTION: Despite enormous developments in the field of clinical and experimental electrophysiology there is still a gap in evaluating repolarization in the awake animal. Numerous previous studies have used monophasic action potentials (MAP) to assess repolarization in vitro and in vivo in anesthetized animal models. However, an approach for recording MAP in awake dogs without interference of anesthesia has not yet been developed. METHODS AND RESULTS: We developed an experimental technique to record MAP in conscious dogs by means of conventional rubber introducers which were implanted into the internal jugular vein. In seven awake dogs, atrial as well as ventricular MAP were simultaneously measured without complications. Pacing thresholds were low and stable over time ranging from 0.2 to 4.0 mA. The MAP amplitudes ranged from 10 to 30 mV for ventricular and from 5 to 15 mV for atrial MAP. Continuous MAP recordings of stable amplitude could be made from the same endocardial site for periods of up to one hour. Antegrade and retrograde AV-nodal conduction properties could be assessed. Programmed stimulation was performed to simultaneously determine local refractory periods and MAP duration at cycle lengths from 500 to 200 ms. CONCLUSION: In awake, unsedated dogs the measurement of MAP via rubber introducers permits safe, long-term recording of MAP. Such recordings may be useful for safety pharmacological studies in evaluating cardiovascular and non-cardiovascular drugs with regard to their effects on repolarization. In various canine in vivo models including in vivo models of long QT syndrome, heart failure or sudden cardiac death, the present technique permits electrophysiological measurements without interference of anesthesia.

Action Potentials↗
PubMed2001

Clinical value of electrocardiographic parameters in genotyped individuals with familial long QT syndrome.

Rate corrected QT interval (QTc) and QT dispersion (QTd) have been suggested as markers of an increased propensity to arrhythmic events and efficacy of therapy in patients with long QT syndrome (LQTS). To evaluate whether QTc and QTd correlate to genetic status and clinical symptoms in LQTS patients and their relatives, ECGs of 116 genotyped individuals were analyzed. JTc and QTc were longest in symptomatic patients (n = 28). Both QTd and JTd were significantly higher in symptomatic patients than in asymptomatic (n = 29) or unaffected family members (n = 59). The product of QTd/JTd and QTc/JTc was significantly different among all three groups. Both dispersion and product put additional and independent power on identification of mutation carriers when adjusted for sex and age in a logistic regression analysis. Thus, symptomatic patients with LQTS show marked inhomogenity of repolarization in the surface ECG. QT dispersion and QT product might be helpful in finding LQTS mutation carriers and might serve as additional ECG tools to identify asymptomatic LQTS patients.

Adult↗
PubMed2001

Prolonged QRS duration increases QT dispersion but does not relate to arrhythmias in survivors of acute myocardial infarction.

QT dispersion has been suggested and disputed as a risk marker for ventricular arrhythmias after myocardial infarction. Delayed ventricular activation after myocardial infarction may affect arrhythmic risk and QT intervals. This study determined if delayed activation as assessed by (1) QRS duration in the 12-lead ECG and by (2) late potentials in the signal-averaged ECG affects QT dispersion and its ability to assess arrhythmic risk after myocardial infarction. QT duration, JT duration, QT dispersion, and JT dispersion were compared to QRS duration in the 12-lead ECG and to late potentials in the signal-averaged ECG recorded in 724 patients 2-3 weeks after myocardial infarction. Prolonged QRS duration (> 110 ms) and high QRS dispersion increased QT and JT dispersion by 12%-15% (P < 0.05). Presence of late potentials, in contrast, did not change QT dispersion. Only the presence of late potentials (n = 113) was related to arrhythmic events during 6-month follow-up. QT dispersion, JT dispersion, QRS duration, and QRS dispersion were equal in patients with (n = 29) and without arrhythmic events (QT disp 80 +/- 7 vs 78 +/- 1 ms, JT disp 80 +/- 6 vs 79 +/- 2 ms, mean +/- SEM, P > 0.2). In conclusion, prolonged QRS duration increases QT dispersion irrespective of arrhythmic events in survivors of myocardial infarction. Presence of late potentials, in contrast, relates to arrhythmic events but does not affect QT dispersion. Therefore, QT dispersion may not be an adequate parameter to assess arrhythmic risk in survivors of myocardial infarction.

Aged↗
PubMed2001

Brugada syndrome and supraventricular tachyarrhythmias: a novel association?

INTRODUCTION: The Brugada syndrome is a distinct form of idiopathic ventricular fibrillation characterized by a unique ECG pattern consisting of a right bundle branch block-like aspect and ST segment elevation in leads V1 to V3. As a high induction rate of ventricular tachyarrhythmias has been reported in Brugada syndrome, we hypothesized that this also may be true for supraventricular tachycardias in these patients. METHODS AND RESULTS: Between January 1995 and December 2000, we identified 35 consecutive patients with Brugada syndrome; 26 had a history of cardiac arrest or syncope and 9 were asymptomatic. All patients underwent electrophysiologic study, including an atrial and ventricular stimulation protocol. Ten patients (29%) were found to have supraventricular tachyarrhythmias (SVT) in addition to the Brugada syndrome. These 10 patients presented with aborted sudden cardiac death (n = 3) and/or a family history of sudden cardiac death (n = 4), syncope (n = 4), or primarily with a Brugada typical ECG, a positive family history, and palpitations (n = 2). Eight of them underwent genetic testing, but only 1 had a mutation in the SCN5A gene. In 6 patients, an AV nodal reentrant tachycardia was easily and reproducibly inducible. Two patients had clinical documented and inducible episodes of an atrial tachycardia (1 in addition to an AV nodal reentrant tachycardia). One patient had paroxysmal atrial fibrillation alternating with sinus rhythm, and 2 patients with accessory pathways were identified. CONCLUSION: This is the first description of an association of the Brugada syndrome with SVT. Thus, the arrhythmogenic substrate in Brugada syndrome may not be restricted to the ventricular level. Palpitations in this syndrome should raise the possibility of SVT. Conversely, in patients with SVT and aborted sudden cardiac death or syncope not related to SVT, the Brugada syndrome should be considered a possible additional electrophysiologic abnormality.

Adult↗
PubMed2001

Effects of thoracic epidural anesthesia with and without autonomic nervous system blockade on cardiac monophasic action potentials and effective refractoriness in awake dogs.

BACKGROUND: The effects of thoracic epidural anesthesia (TEA) on myocardial repolarization and arrhythmogenicity are only incompletely understood. This is primarily because of the lack of appropriate experimental models. In most of the studies performed thus far, TEA was used in anesthetized animals. Baseline anesthesia itself may have modified the effects of TEA. This study investigates right atrial and ventricular repolarization by recording monophasic action potentials after TEA in awake dogs. The authors hypothesized that an antiarrhythmic role of TEA exists, which may be related to a direct effect of TEA on myocardial repolarization. METHODS: The hypothesis was tested in an in vivo canine model, in which atrial and ventricular myocardial action potential duration and refractoriness are recorded by means of monophasic action potential catheters. RESULTS: Thoracic epidural anesthesia significantly increased ventricular monophasic action potential duration for cycle lengths shorter than 350 ms. Changes in monophasic action potential duration were paralleled by a concomitant prolongation of effective refractory period (ERP) at higher rates so that the ratio of ERP to action potential duration was unaffected. CONCLUSIONS: This model helps to study the role of TEA on ventricular repolarization and arrhythmogenicity. Because lengthening of repolarization and prolongation of refractoriness may, in some circumstances, be antiarrhythmic, TEA may be protective against generation of ventricular arrhythmias mediated, e.g., by increased sympathetic tone. The results also imply that the beneficial role of TEA might be stronger at the ventricular site as compared with the atrium. At atrial sites there was only a trend toward prolongation of repolarization even at short cycle lengths.

Action Potentials↗
PubMed2000

Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes.

The effects of 17 commonly used antiarrhythmic drugs on the rapidly activating cardiac voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1 and Kv4.2) were studied in the expression system of the Xenopus oocyte. A systematic overview on basic properties was obtained using a simple and restricted experimental protocol (command potentials 10 mV and 50 mV positive to the threshold potential; concentration of 100 micromol/l each). The study revealed that 8 of 17 drugs yielded significant effects (changes >10% of control) on at least one type of potassium channel in the oocyte expression system. These drugs were ajmaline, diltiazem, flecainide, phenytoin, propafenone, propranolol, quinidine and verapamil, whereas the effects of adenosine, amiodarone, bretylium, disopyramide, lidocaine, mexiletine, procainamide, sotalol and tocainide were negligible. The drug effects were characterized by reductions of the potassium currents (except for quinidine and ajmaline). A voltage-dependence of drug effect was found for quinidine, verapamil and diltiazem. The different effect of the drugs was not related to the fast or slow current inactivation of the potassium channels (except for verapamil). Profiles of the individual drug effects at the different potassium channel types were identical for propafenone and flecainide and differed for all other substances. The study demonstrates marked differences in sensitivity to antiarrhythmic drugs within the group of voltage-operated cardiac potassium channel types. Taking the restrictions of the oocyte system into consideration, the findings suggest that several antiarrhythmic drugs exert significant effects at rapidly activating cardiac potassium channels.

Animals↗
PubMed2000

[New knowledge in arrhythmogenesis--role of ion channels and genetic aspects].

Recent advances in molecular biology have had a major impact on our understanding of the mechanisms of human diseases. Electrophysiology is one of the areas which, besides others, has substantially benefited from this development. Our understanding of the structure, function and mechanisms of the regulation of ion channels as well as their contribution to the pathogenesis of cardiac arrhythmias has substantially increased. The results of these studies are not only of special interest from the scientific point of view. It is likely to assume that, in the future, they will increasingly influence the diagnosis and treatment of arrhythmias.

Arrhythmias, Cardiac↗
PubMed2000

Molecular genetics of arrhythmias--a new paradigm.

The molecular genetic background of inherited cardiac arrhythmias has only recently been uncovered. This late development in comparison to other inherited cardiac disorders has partly been due to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus families. Thus, traditional genetic linkage studies, which are based on the genetic information obtained from large multi-generation families, were made difficult. Inherited arrhythmogenic disorders can be divided into 'primary electrical disorders' (e.g., long-QT [LQT] syndrome) in which a detectable, organic heart disease is not evident, and into inherited diseases of the myocardial structure (e.g., hypertrophic cardiomyopathies) in which the arrhythmias occur combined with the structural alterations. To date, all inherited arrhythmogenic disorders in which the causative genes have been identified turned out to be channelopathies, since the genes encode channel subunits that regulate important ion currents that tune the cardiac action potential. The discovery of the genetic bases of the LQT syndrome became a new methodologic paradigm; because with the use of 'classical' genetic linkage strategies (named [positional] candidate strategies) not only the causative genes have been found, but moreover, functional components with a previously unknown but fundamental role for a normal repolarization process were discovered. Disease mutations turned out to be not only a family-specific event with a distinct phenotype and the potential of an additional diagnostic tool, but also, when expressed in heterologous expression systems, characterize the defective ion channel in a topological way and lead to a more specific understanding of ion channel function. Most, if not all, primary electrical cardiac disorders show a high genetic diversity. For the LQT syndromes, sixth disease loci and the responsible gene have been recently discovered (so-called locus or genetic heterogeneity). Within all disease genes, the mutations are spread over the entire gene (allelic heterogeneity); in addition, more than one disease mutation may be present. This complexity requires, at least, complete mutation analysis of all LQT genes before medical advice should be given. Meanwhile, genotype-phenotype correlations in large families are being used to evaluate intergene, interfamilial and intrafamilial differences in the clinical phenotype, reflecting gene specific, gene-site specific and individual consequences of a given mutation. A widespread phenotypic heterogeneity even within mutation carriers in the same family raises the importance of modifying factors and genes that are mostly unknown to date. The reduced penetrance and variable expressivity associated with the LQT mutations remain still to be explained. First insights into the complex actions of mutations are being extracted, from expression data; these preliminary results may lead to potential implications for a specific (gene-site directed) therapy. This paper discusses the current data on molecular genetics and genotype-phenotype correlations in LQT syndrome and related disorders and the potential implications for diagnosis and treatment.

Arrhythmias, Cardiac↗
PubMed2000

Detection of missense mutations in the genes for lipoprotein lipase and hepatic triglyceride lipase in patients with dyslipidemia undergoing coronary angiography.

Coronary events have a close association with a low HDL/hypertriglyceridemia (LHDL/HTG) phenotype. As enzymes that hydrolyze triglyceride-rich lipoproteins are associated with a modulation of both HDL cholesterol and triglycerides, we have tested the hypothesis that mutations in the genes encoding lipoprotein lipase (LPL) or hepatic lipase (HTGL) may contribute to the formation of coronary atherosclerosis and, thus, of coronary heart disease (CHD). The entire coding and boundary regions of LPL and HTGL genes were analyzed by direct sequencing in 20 patients with both LHDL/HTG and diagnosed CHD. In the LPL gene six different polymorphisms were identified with same frequencies observed in the general population. In the HTGL gene, besides several polymorphisms, we identified three missense mutations: Asn37His, Val73Met, and Ser267Phe. Population screening using allele specific PCR identified Val73Met as a polymorphism while the two others were absent from 100 control individuals. One of the mutations (Ser267Phe) is known to cause HTGL deficiency and is associated with type III hyperlipoproteinemia. Since this dyslipoproteinemia meets the criteria of LHDL/HTG, it is intriguing to speculate that missense mutations in HTGL may play a role in the pathogenesis of this atherogenic phenotype.

Adult↗
PubMed2000

Modification of stretch-induced shortening of repolarization by streptomycin in the isolated rabbit heart.

The exact mechanism of mechano-electrical feedback and stretch-induced arrhythmias is unknown, but the role of stretch-activated ion channels and specific calcium channels has been proposed. The aim of the present study was to test the hypothesis that stretch-activated ion channels and not calcium channels contribute to stretch-related alterations of repolarization and that these effects can be neutralized by stretch-activated channel block. We studied the interaction of acute ventricular dilatation and the stretch-activated channel blocker streptomycin and the specific calcium channel blocker verapamil in an isolated retrogradely perfused rabbit heart model in which the left ventricular size is modified by abruptly changing the volume of a fluid-filled balloon placed in the left ventricle. Acute ventricular dilatation led to a rate-dependent decrease in repolarization. The mean effective refractory period (ERP) and monophasic action potential duration (MAP90) for cycle lengths between 300 and 1,000 ms decreased from 174.2+/-9 ms and 178.9+/-7 ms to 161.6+/-11 ms and 169.7+/-5 ms, respectively. Streptomycin (80 microM) inhibited this stretch-related shortening of repolarization (ERP: 175.4+/-8 ms; MAP90: 179.7+/-8 ms, p < 0.05) but had almost no effect on already dilated ventricles. Counteraction of the observed electrophysiologic changes could only be achieved by increasing the streptomycin concentration to 200 microM. Streptomycin nearly completely suppressed stretch-related ectopic ventricular complexes. In contrast, verapamil (1 microM) had no effect on stretch-related changes in repolarization and stretch-induced arrhythmias. The present study indirectly implicates stretch-activated ion channels in the genesis of stretch-related changes in repolarization and arrhythmias. The electrophysiologic changes after ventricular dilatation to a degree that increases left ventricular pressure in a clinically relevant range can be influenced by the stretch-activated channel blocker streptomycin but not by specific calcium channel block. This may have clinically important implications for the development of new antiarrhythmic drugs.

Animals↗
PubMed2000

Infarct related artery patency: relation to serial electropharmacological studies and outcome in patients with previous myocardial infarction and ventricular tachyarrhythmias.

Evidence suggests that infarct related artery (IRA) patency may improve survival after acute myocardial infarction, which is thought to be partially due to a lower incidence of malignant ventricular tachyarrhythmias. However, little is known about the effect of IRA patency on antiarrhythmic drug response and long-term outcome in patients with previous infarction who already experienced sustained ventricular tachyarrhythmias. A total of 152 patients with remote myocardial infarction and documented ventricular tachycardia (VT) or ventricular fibrillation (VF) underwent coronary angiography and programmed ventricular stimulation before and after oral administration of d,l-sotalol (240-640 mg/day). D,l-sotalol suppressed inducibility of VT/VF in 37 (25.2%) patients. The IRA was patent in 38.1% of all patients. There was no significant difference in the frequency of drug response between patients with patent or occluded IRAs (26.8% vs 24.2%, P = 0.87). In patients with a patent IRA, d,l-sotalol tended to be more effective in the absence of a left ventricular aneurysm, although this difference did not reach statistical significance (P = 0.38). Ejection fraction and collateral blood flow had no effect on drug response in the presence or absence of IRA patency. During follow-up (13.0 +/- 19.9 months) of 29 patients discharged on oral d,l-sotalol, 3 patients experienced symptomatic VT and 4 sudden death. Arrhythmia recurrence and death of all cause (n = 6) and cardiac death (n = 4) were independent of IRA patency status. IRA patency had no effect on short-term drug response to d,l-sotalol in patients with remote myocardial infarction and documented VT/VF. Long-term outcome of patients with sustained ventricular tachyarrhythmias is independent of IRA patency status. In contrast to a previous report, outcome of electropharmacological testing was not predicted by the patency of the IRA.

Aged↗