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Marc A Vos

Publications and source records attributed to Marc A Vos.

36 records · Page 2Linked to original sources
PubMed2004

Tridimensional activation patterns of acquired torsade-de-pointes tachycardias in dogs with chronic AV-block.

BACKGROUND: Dogs with chronic AV block exposed to type-III antiarrhythmic agents develop polymorphic ventricular tachycardias (PVT). Controversy exists regarding PVT mechanism and underlying pathophysiology. METHODS AND RESULTS: In dogs with acute (n = 10, AAVB) or chronic AV block (n = 14, CAVB, 62 +/- 5 days after AV-node ablation) 60 pins (12 mm long, 4 bipolar electrodes) were inserted into both ventricles. QT intervals and effective refractory periods (ERP) at 56 +/- 22 randomly selected sites (extrastimulus technique, 800 ms basic cycle length) were determined before and after Almokalant (0.34 micromol/kg). A multiplexer mapping system was used to reconstruct 3D activation patterns. The heart-to-body-weight index (HBWI) was obtained after the experiments. CAVB led to a significant increase in HBWI (11.3 +/- 1.5 vs. 9 +/- 1.2 g/kg BW, p < 0.001), and a significant increase in ERP (280 +/- 28 ms vs. 260 +/- 37 ms, p < 0.05) and QT interval (339 +/- 16 vs. 288 +/-12 ms, p < 0.05). Dispersion (DISP) of ERP was similar for AAVB and CAVB dogs. No AAVB dog, but 9 of 14 CAVB dogs developed PVTs in response to Almokalant. All PVTs originated from an endocardial focus. Consecutive beats continued to reveal centrifugal activation patterns in 8 of 10 episodes. In only 2 episodes was reentrant activation evident. CONCLUSION: Myocardial hypertrophy associated with CAVB predisposes the canine heart to drug induced PVTs. This seems to be primarily linked to prolonged repolarization. PVTs in this model are not only initiated, but also perpetuated by a centrifugal spread of activation.

Animals↗
PubMed2004

Electrophysiological and proarrhythmic parameters in transmural canine left-ventricular needle biopsies.

This study was designed to validate the use of small, transmural, left-ventricular biopsies in the dog for investigations of electrophysiological and proarrhythmic properties of the heart. This technique could facilitate pharmacological in vitro testing in remodelled hearts of both man and animal. Small, transmural, semi-cylindrical, left-ventricular biopsies from dogs with normal sinus rhythm (SR) were characterized electrophysiologically and compared with biopsies from electrically remodelled hearts from dogs with chronic, complete AV-block (CAVB). In at least five biopsy segments recordings were made to determine the action potential duration (APD), the transmural gradient of repolarization, the maximal transmural dispersion (deltatM(max)) and presence of early after-depolarizations (EADs) at different pacing cycle lengths (PCLs) in the absence and presence of a class-III agent, ibutilide (10(-6) M). The biopsies showed stable and normal AP characteristics, a conduction velocity of 0.22 +/- 0.05 m/s and normal frequency dependence of the APD. The location of the longest APD varied, thus creating transmural repolarization gradients with differing morphology. Ibutilide prolonged the APD, accentuated repolarization gradients and induced EADs. CAVB biopsies had significantly longer APDs, a larger dispersion of repolarization and showed more EADs in the presence of ibutilide than SR biopsies. We conclude that this biopsy technique provides coherent and valid transmural electrophysiological data in dogs under various conditions.

Action Potentials↗
PubMed2004

Genetic basis of drug-induced arrhythmias.

Drug-induced torsade de pointes arrhythmia (TdP) is frequently seen in patients. This proarrhythmia is not restricted to anti-arrhythmics but includes a variety of drugs. A genetic predisposition is an attractive explanation for this clinical problem. In this review, we: 1) explain the arrhythmogenic mechanisms of TdP, 2) provide data for a genetic cause based upon mutations in the long QT or in cytochrome genes responsible for drug metabolism, and 3) present pathology-based electrical remodeling as an alternative explanation. It can be concluded that the current evidence for a genetic basis for drug-induced TdP is weak.

Animals↗
PubMed2003

Electrophysiological safety of sertindole in dogs with normal and remodeled hearts.

Inhibition of the potassium current IKr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 21 nM. Action potentials in these cells prolonged in a reverse rate- and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30-157 nM), QTc was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.

Action Potentials↗
PubMed2003

Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog.

OBJECTIVE: Left ventricular hypertrophy has been associated with the prolongation of QT-time, and an increased risk of ventricular arrhythmias. The renin angiotensin system has been implicated in the development of ventricular hypertrophy. At 5 weeks complete AV block (CAVB) in the dog, there is: (1) biventricular hypertrophy associated with a transient activation of components of the renin angiotensin system, (2) increased APD, more pronounced in the left than in the right ventricle leading to spatial dispersion of repolarization, and (3) enhanced susceptibility to drug-induced torsade de pointes arrhythmias. To investigate whether these remodeling processes develop in parallel, time dependency was assessed in absence or presence of the AT1 receptor-blocker Irbesartan. METHODS AND RESULTS: Dogs in sinus rhythm, 2 and 5 weeks CAVB were compared to dogs chronically treated with Irbesartan (30 mg/kg BID). Endocardial monophasic APD of left and right ventricle was measured and susceptibility to torsade de pointes was tested by infusing Dofetilide (0.025 mg/kg/5'). Hypertrophy was determined by relating heart-to-body weight at sacrifice. Left ventricular APD had increased more than right ventricular APD at 2 and 5 weeks CAVB, leading to an increase in spatial dispersion. At that time torsade de pointes were evocable in the majority of the dogs. Hypertrophy had only developed completely at 5 weeks CAVB. Irbesartan had no effect on electrical and structural parameters or on arrhythmogenicity. CONCLUSIONS: In the CAVB dog ventricular hypertrophy is not a prerequisite for electrical remodeling or drug-induced torsade de pointes, and the AT1-receptor has no dominant role in the completion of these remodeling processes.

Angiotensin II↗
PubMed2003

Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes.

In guinea-pig ventricular myocytes, in which the deactivation of slowly activating delayed rectifier potassium current (IKs) is slow, IKs can be increased by rapid pacing as a result of incomplete deactivation and subsequent current accumulation. Whether accumulation of IKs occurs in dogs, in which the deactivation is much faster, is still unclear. In this study the conditions under which accumulation occurs in canine ventricular myocytes were studied with regard to its physiological relevance in controlling action potential duration (APD). At baseline, square pulse voltage clamp experiments revealed that the accumulation of canine IKs could occur, but only at rather short interpulse intervals (< 100 ms). With action potential (AP) clamp commands of constant duration (originally recorded at rate of 2 Hz), an accumulation was only found at interpulse intervals close to 0 ms. Transmembrane potential recordings with high-resistance microelectrodes revealed, however, that at the fastest stimulation rates with normally captured APs (5 Hz) the interpulse interval exceeded 50 ms. This suggested that no IKs accumulation occurs, which was supported by the lack of effect of an IKs blocker, HMR 1556 (500 nM), on APD. In the presence of the beta-adrenergic receptor agonist isoproterenol (isoprenaline, 100 nM) the accumulation with AP clamp commands of constant duration was much more pronounced and a significant accumulating current was found at a relevant interpulse interval of 100 ms. HMR 1556 prolonged APD, but this lengthening was reverse rate dependent. AP clamp experiments in a physiologically relevant setting (short, high rate APs delivered at a corresponding rate) revealed a limited accumulation of IKs in the presence of isoproterenol. In conclusion, a physiologically relevant accumulation of IKs was only observed in the presence of isoproterenol. Block of IKs, however, led to a reverse rate-dependent prolongation of APD indicating that IKs does not have a dominant role at short cycle lengths.

Action Potentials↗
PubMed2003

Absence of reverse electrical remodeling during regression of volume overload hypertrophy in canine ventricles.

OBJECTIVE: Ventricular hypertrophy predisposes for cardiac arrhythmias, presumably due to prolongation of repolarization (electrical remodeling). The temporal relation between the development of hypertrophy and electrical remodeling, as well as their reversibility upon restoration of normal load, however, are poorly understood. This was investigated in the present study using volume overload hypertrophy induced by atrio-ventricular (AV) block and normalization of load by pacing. METHODS: Dogs were subjected to either 16 weeks of AV-block (CAVB group, n=9) or 8 weeks of AV-block followed by 8 weeks of right ventricular (RV) pacing at physiological heart rate (CAVB+PACE group, n=9). RESULTS: Left ventricular (LV) mass (2D-echocardiography) increased after 8 weeks of AV-block to approximately 30% above baseline and returned to 10+/-14% after 8 weeks of pacing. QT-time (surface ECG) also increased after AV-block. However, 8 weeks of pacing did not decrease QT and QTc-time (c=corrected for heart rate), neither during physiological pacing nor during temporary pacing at 100 beats/min. Lack of reverse electrical remodeling was confirmed by the absence of changes in LV and RV action potential duration (monophasic action potentials) at week 8 and 16. CONCLUSIONS: In volume overload hypertrophy due to AV-block, structural and electrical remodeling develop in parallel but restoration of physiological heart rate causes dissociation between reverse structural remodeling and reverse electrical remodeling.

Action Potentials↗
PubMed2003

Probing the contribution of IKs to canine ventricular repolarization: key role for beta-adrenergic receptor stimulation.

BACKGROUND: In large mammals and humans, the contribution of IKs to ventricular repolarization is still incompletely understood. METHODS AND RESULTS: In vivo and cellular electrophysiological experiments were conducted to study IKs in canine ventricular repolarization. In conscious dogs, administration of the selective IKs blocker HMR 1556 (3, 10, or 30 mg/kg PO) caused substantial dose-dependent QT prolongations with broad-based T waves. In isolated ventricular myocytes under baseline conditions, however, IKs block (chromanols HMR 1556 and 293B) did not significantly prolong action potential duration (APD) at fast or slow steady-state pacing rates. This was because of the limited activation of IKs in the voltage and time domains of the AP, although at seconds-long depolarizations, the current was substantial. Isoproterenol increased and accelerated IKs activation to promote APD95 shortening. This shortening was importantly reversed by HMR 1556 and 293B. Quantitatively similar effects were obtained in ventricular-tissue preparations. Finally, when cellular repolarization was impaired by IKr block, IKs block exaggerated repolarization instability with further prolongation of APD. CONCLUSIONS: Ventricular repolarization in conscious dogs is importantly dependent on IKs. IKs function becomes prominent during beta-adrenergic receptor stimulation, when it promotes AP shortening by increased activation, and during IKr block, when it limits repolarization instability by time-dependent activation. Unstimulated IKs does not contribute to cellular APD at baseline. These data highlight the importance of the synergism between an intact basal IKs and the sympathetic nervous system in vivo.

Adrenergic beta-Agonists↗
PubMed2003

Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells.

OBJECTIVE: To investigate whether hypertrophy in the dog with chronic atrioventricular block (CAVB) alters [Na+]i and Na/K-pump function of ventricular myocytes. METHODS: We measured the [Na+]i dependence of the Na/K pump current, I(p). This relation was used as a calibration curve for [Na+]i based on I(p). We measured I(p) at the time of access and extrapolated [Na+] at the pump sites, i.e. subsarcolemmal [Na+], [Na+](subs), from the calibration curve. RESULTS: The extrapolated [Na+](subs) was significantly higher in CAVB (7.9 vs. 3.2 mM in control). The [Na+]i dependence of I(p) in CAVB myocytes was shifted to the right (range of [Na+](i): 0-20 mM). In resting cells, the I(p), i.e. steady state Na+ efflux, which matches Na+ influx, was higher in CAVB (0.25+/-0.02 vs. 0.47+/-0.06 pA/pF, P<0.05). Maximal I(p) density was not different, and DHO sensitivity was not altered. CONCLUSIONS: Hypertrophy in CAVB cells is associated with increased [Na+](subs). This results from an increase in Na+ influx, and a decreased sensitivity of I(p) for Na+ in the range of [Na+]i studied. There is no evidence for a decrease in total pump capacity or for a functional Na/K-ATPase isoform shift. The rise in Na+ contributes to the contractile adaptation and preservation of sarcoplasmic reticulum Ca2+ content at the low heart rates of the dog with CAVB.

Animals↗
PubMed2003

A novel mutation L619F in the cardiac Na+ channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating.

Congenital long QT syndrome type 3 (LQT3) is caused by mutations in the gene SCN5A encoding the alpha-subunit of the cardiac Na(+) channel (Nav1.5). Functional studies of SCN5A mutations in the linker between domains III and IV, and more recently the C-terminus, have been shown to alter inactivation gating. Here we report a novel LQT3 mutation, L619F (LF), located in the domain I-II linker. In an infant with prolonged QTc intervals, mutational analysis identified a heterozygous missense mutation (L619F) in the domain I-II linker of the cardiac Na(+) channel. Wild-type (WT) and mutant channels were studied by whole-cell patch-clamp analysis in transiently expressed HEK cells. LF channels increase maintained Na(+) current (0.79 pA/pF for LF; 0.26 pA/pF for WT) during prolonged depolarization. We found a +5.8mV shift in steady state inactivation in LF channels compared to WT (WT, V(1/2)=-64.0 mV; LF, V(1/2)=-58.2 mV). The positive shift of inactivation, without a corresponding shift in activation, increases the overlap window current in LF relative to WT (1.09 vs. 0.58 pA/pF), as measured using a positive voltage ramp protocol (-100 to +50 mV in 2s). The increase in window current, combined with an increase in non-inactivating Na(+) current, may act to prolong the AP plateau and is consistent with the disease phenotype observed in patients. Moreover, the defective inactivation imposed by the L619F mutation implies a role for the I-II linker in the Na(+) channel inactivation process.

Binding Sites↗
PubMed2003

Assessing predictors of drug-induced torsade de pointes.

Torsades de pointes (TdP) is a malignant polymorphic ventricular tachyarrhythmia that can be caused by drugs that induce electrophysiological changes. Although the number of drugs known to cause TdP has increased in recent years, there is no cell-based assay, in vitro heart preparation or animal model that predicts the potential of a drug to induce TdP in humans. Nevertheless, certain electrophysiological events are known to be associated with the development of TdP. For example, a drug that prolongs action potential duration, induces early afterdepolarizations and ectopic beats, and increases dispersion of ventricular repolarization is likely to cause TdP. By contrast, a drug that does not induce these changes is unlikely to cause TdP. The exact relationship between these electrophysiological events and the development of TdP has not been defined, but the potential of a drug to elicit these events might predict its pro-arrhythmic risk.

Animals↗
PubMed2003

Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and failure.

Altered intracellular Na(+) ([Na(+)](i)) is a potentially important factor in the functional adaptation of the hypertrophied and failing heart. We review the currently reported changes in [Na(+)](i) and Na(+) transport in different models of cardiac hypertrophy and heart failure. Direct measurements are limited, but most of these indicate that there is a rise in [Na(+)](i), in particular in hypertrophy. In addition to these direct measurements, several studies report a rise in Na(+) influx or an upregulation of Na(+) influx transporters. The most extensive literature on Na(+) regulating pathways concerns the Na/K-ATPase. Total Na/K-ATPase activity decreases in most models of cardiac hypertrophy and failure, though few measurements were actually performed in intact cells. This decrease can been related to a selective reduction of high-affinity (for cardiac glycosides) Na/K pump alpha-isoforms, across many species and models, including human heart failure. We have used these data to predict changes of [Na(+)](i) in a simulation model, varying the contribution of total Na/K pump capacity and expression of isoforms with different Na(+)(i) affinities, and varying Na(+) influx. A rise in Na(+) in cardiac hypertrophy and failure may improve systolic contractile function, though at the cost of worsening of diastolic function and increased risk of ventricular arrhythmias. The benefit of further increasing [Na(+)](i,) e.g. with cardiac glycosides, is thus compromised. Future therapies may include selective isoform blockers, which could raise [Na(+)](i) in restricted subcellular compartments, drug associations that reduce the arrhythmic risk, or even drugs that lower [Na(+)](i) and thus interfere with the remodelling pathways.

Animals↗
PubMed2002

Novel insights in the congenital long QT syndrome.

BACKGROUND: The congenital long QT syndrome is a potentially fatal, inherited cardiac syndrome. Early diagnosis and preventive treatment are instrumental to prevent sudden cardiac death in patients with the congenital long QT syndrome. PURPOSE: To review new insights in genetics and cellular electrophysiology, as well as the current understanding of the clinical diagnosis and treatment of the congenital long QT syndrome. DATA SOURCES: Authors' personal databases and search of PubMed database from 1966 to 2001. STUDY SELECTION: Experimental and clinical studies on the congenital long QT syndrome. DATA EXTRACTION: Data from peer-reviewed studies were manually extracted, classified, and summarized. DATA SYNTHESIS: The congenital long QT syndrome is characterized by abnormally prolonged ventricular repolarization, which predisposes patients to syncope, ventricular arrhythmias, and sudden cardiac death. The recent discovery of mutations in genes encoding ion channels has improved our understanding of the cellular origin of this condition. The congenital long QT syndrome may result from inherited defects in cardiac K+ and Na+ channels, which both result in prolongation of the ventricular action potential. The diagnosis is based on electrocardiographic and clinical criteria. Genetic screening of symptomatic patients or asymptomatic family members may identify patients at risk for life-threatening ventricular arrhythmias. beta-Blocking agents are the mainstay of treatment. Certain patients may also benefit from a pacemaker or implantable cardioverter defibrillator. Recent studies suggest that genotype-specific treatment of the congenital long QT syndrome will be feasible in the near future. CONCLUSIONS: The congenital long QT syndrome is a potentially life-threatening condition caused by mutations in genes encoding cardiac ion channels. Better understanding of the mechanisms responsible for this condition will guide genotype-specific therapy in the near future.

Electrocardiography↗
PubMed2002

Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy?

Increased Na/Ca exchange (NCX) expression may be part of the genetic reprogramming in cardiac remodeling. In this review we address the following questions: (1) Is increased NCX activity a general feature of cardiac remodeling in hypertrophy and heart failure? (2) How does this contribute to the contractile and electrical phenotype of hypertrophy and heart failure? (3) Should be consider NCX a potential therapeutic target? From a review of the literature we found that NCX activity can be increased, unchanged, or even downregulated during cardiac remodeling. When NCX activity is increased, it can be considered compensatory for contractile function, but with negative side-effects, including an increased risk of arrhythmias. Changes in activity do not necessarily reflect changes in gene expression. Altered NCX activity can also be a consequence of changes in other Ca(2+) fluxes or in [Na(+)](i) homeostasis. The role of NCX in contractile alterations and arrhythmogenesis varies with the different stimuli or stages of cardiac remodeling. Pharmacological block of NCX in heart failure or hypertrophy may thus be useful, but most likely only in specific conditions, perhaps as part of a combined approach. Development of drugs that target only a specific mode of the exchanger may offer a further advantage.

Animals↗
PubMed2002

The JT-area indicates dispersion of repolarization in dogs with atrioventricular block.

UNLABELLED: Heterogeneity in cardiac repolarization (Delta APD) is known to be arrhythmic. In the dog model of chronic complete AV-block and acquired long QT syndrome, an increase in Delta MAPD (defined as left ventricular monophasic action potential duration (MAPD) minus right ventricular MAPD) is often associated with changes in T-wave morphology. The purpose of this study was to correlate known changes in Delta MAPD with the planimetric total area of the T-wave on the surface ECG (integral of J-T, mVx ms). METHODS: The relationship between Delta MAPD and total area of the T-wave (i.e., JT-area) was assessed in four different protocols with different types of dispersion: (1) class III drugs followed by levcromakalim (n= 7), (2) LAD coronary artery occlusion and reperfusion (n = 6), (3) dronedarone i.v., an amiodarone like agent (n = 5) and (4) steady state pacing at cycle lengths of 1000 ms and 500 ms (n = 5). RESULTS: Class III drugs increased Delta MAPD (55 +/- 40 ms to 120 +/- 50 ms(#), P<0.05), which was correlated (r = 0.74, P < 0.001) with JT-area (50 +/- 40 mV. ms to 95 +/- 35 mV x ms(#)). Ischemia increased both Delta MAPD (30 +/- 25 ms to 90 +/- 40 ms(#)) and JT-area (60 +/- 55 mV x ms to 75 +/- 50 mV x ms(#)). Both levcromakalim and reperfusion reversed these conditions. Dronedarone had no effect on Delta MAPD or on JT-area while a faster frequency reduced both Delta MAPD and JT-area. CONCLUSION: Changes in dispersion of ventricular repolarization are reflected by alterations in JT-area. This non-invasive parameter may therefore be used to indicate changes in heterogeneity in ventricular repolarization.

Action Potentials↗
PubMed2002

Role of the Na/Ca exchanger in arrhythmias in compensated hypertrophy.

Sudden, presumably arrhythmic, death is common in heart failure patients. Although total mortality is highest in end-stage failure, the fraction of sudden death in total mortality is higher in the early stages. In each of these stages various, not necessarily identical, ionic mechanisms may contribute to arrhythmogenesis. Dogs with chronic complete atrioventricular block (6-8 weeks) have an increased risk for arrhythmias and sudden death and have compensated biventricular hypertrophy. In this animal model, Ca(2+) release from the sarcoplasmic reticulum (SR) is not reduced. For low frequencies of stimulation, the SR Ca(2+) content is increased, related to a higher activity of the Na/Ca exchanger. Spontaneous Ca(2+) release induces inward Na/Ca exchange current, which can lead to delayed afterdepolarizations (DADs) triggering a new action potential. Such arrhythmogenic DADs and ectopic beats also can be observed in vivo during monophasic action potential recording. They appear after pacing protocols, and/or administration of ouabain, which result in contractile potentiation, suggestive of a enhanced sarcoplasmic reticulum Ca(2+) content. Other arrhythmogenic mechanisms related to increased dispersion of repolarization also can be identified in vivo. Downregulation of delayed K(+) currents is an important factor in prolongation of action potentials. In conclusion, in this animal model of compensated hypertrophy, Ca(2+) handling is different from end-stage heart failure. It is possible that arrhythmogenic mechanisms related to a higher Ca(2+) load contribute to the high incidence of sudden death in stages of compensated hypertrophy before overt heart failure. However, more than one ionic remodeling process is likely to be present, and different cellular mechanisms of arrhythmias can coexist.

Animals↗