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Biomedical subjects

D M Roden

Publications and source records attributed to D M Roden.

At least 19 recordsLinked to original sources
PubMed2001

Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes.

BACKGROUND: Mutations in the cardiac sodium (Na) channel gene (SCN5A) give rise to the congenital long-QT syndrome (LQT3) and the Brugada syndrome. Na channel blockade by antiarrhythmic drugs improves the QT interval prolongation in LQT3 but worsens the Brugada syndrome ST-segment elevation. Although Na channel blockade has been proposed as a treatment for LQT3, flecainide also evokes "Brugada-like" ST-segment elevation in LQT3 patients. Here, we examine how Na channel inactivation gating defects in LQT3 and Brugada syndrome elicit proarrhythmic sensitivity to flecainide. METHODS AND RESULTS: We measured whole-cell Na current (I(Na)) from tsA-201 cells transfected with DeltaKPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and DeltaKPQ channels both exhibited modified inactivation gating (from the closed state), thus potentiating tonic I(Na) block. Flecainide (1 micromol/L) tonic block was only 16.8+/-3.0% for wild type but was 58.0+/-6.0% for 1795insD (P<0.01) and 39.4+/-8.0% (P<0.05) for DeltaKPQ. In addition, the 1795insD mutation delayed recovery from inactivation by enhancing intermediate inactivation, with a 4-fold delay in recovery from use-dependent flecainide block. CONCLUSIONS: We have linked 2 inactivation gating defects ("closed-state" fast inactivation and intermediate inactivation) to flecainide sensitivity in patients carrying LQT3 and Brugada syndrome mutations. These results provide a mechanistic rationale for predicting proarrhythmic sensitivity to flecainide based on the identification of specific SCN5A inactivation gating defects.

Anti-Arrhythmia Agents↗
PubMed2001

Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide: a placebo-controlled, implantable cardioverter-defibrillator-based evaluation.

OBJECTIVES: To compare the incidence of pause-dependent polymorphic ventricular tachycardia (PVT) in patients with implantable cardioverter-defibrillators (ICDs) randomly assigned to the QT-prolonging antiarrhythmic dofetilide or placebo. BACKGROUND: Drug-related torsade de pointes (TdP) is usually recognized within days of initiating therapy, but its incidence during long-term therapy is unknown. METHODS: We assessed the frequency of TdP and ICD electrograms compatible with TdP in a multicenter study that randomized ICD patients to placebo (n = 87) or dofetilide (n = 87). As reported elsewhere, the number of patients with a primary trial end point (ICD intervention for VT or ventricular fibrillation) was similar in the two groups. For this analysis, a qualifying event was TdP (on electrocardiogram) or an intracardiac electrogram showing pause-dependent PVT. RESULTS: A total of 620 electrograms obtained in 131 patients were analyzed blindly by prospectively defined criteria for episodes of pause-dependent polymorphic VT. These were identified in 15/87 (17%) patients receiving dofetilide and 5/87 (6%) patients on placebo (p < 0.05). Five of these episodes were early (<3 days), all of which were TdP on dofetilide. There were 15 late events, 10 on dofetilide and five on placebo (p = 0.29). The median time to a late event was 22 days (range 6 to 107 days) for dofetilide and 99 days (range 34 to 207 days) for placebo. CONCLUSIONS: Pause-dependent PVT was more common among patients receiving dofetilide, although total VT incidence was similar in the two groups. These data suggest that in ICD patients either long-term dofetilide therapy is associated with an increased risk of TdP or the drug alters VT morphology.

Anti-Arrhythmia Agents↗
PubMed2001

Pharmacogenetics and drug-induced arrhythmias.

Drugs are widely recognized to vary in the beneficial and undesirable effects they produce in human subjects. The understanding that variants (polymorphisms and mutations) in the human genome are common and may well modulate both disease and its response to drugs, is a critical new concept in understanding mechanisms of drug action and their variability in human subjects. Variability can arise because of variability in genes encoding molecules of drug disposition, in genes encoding molecules that drugs target, or in genes that modulate the overall activity of the complex biological systems within which drugs act. The evolving understanding of the genetic basis of variability in response to drugs used in the treatment of sudden cardiac death has important implications not only for the treatment of patients who have survived an episode, but also for helping formulate a framework for further understanding mechanisms of drug action at the genetic level.

Anti-Arrhythmia Agents↗
PubMed2001

Sympathetic activation enhances QT prolongation by quinidine.

INTRODUCTION: Salt restriction results in endogenous sympathetic activation, and we previously showed that plasma concentrations of quinidine measured after oral drug administration are increased during a low-salt diet. However, it is not known whether, independent of effects on plasma concentration, the extent to which quinidine prolongs the QT interval also is modulated by changes in endogenous sympathetic activity. METHODS AND RESULTS: In these studies, we evaluated quinidine concentration-QT relations during low-salt (10 mEq/day for 8 days) and high-salt (400 mEq/day for 8 days) diets, with or without beta blockade in normal volunteers. In the absence of beta blockade, the concentration producing a fixed (15%) increase in QTc was significantly lower with salt restriction: 1.2 +/- 0.4 microg/mL (low salt) versus 2.2 +/- 0.4 microg/mL (high salt) (P < 0.01). With beta blockade, this difference was abolished: 1.9 +/- 0.3 microg/mL (low salt + beta blockade) versus 2.1 +/- 0.3 microg/mL (high salt + beta blockade). QT morphologic abnormalities including bifid T waves and U waves were abolished with beta-adrenergic blockade. CONCLUSION: Sympathetic activation by a low-salt diet not only modulates drug disposition but also increases sensitivity to drug-induced QT prolongation.

Adrenergic alpha-Antagonists↗
PubMed2001

Drug block of I(kr): model systems and relevance to human arrhythmias.

The long QT-related arrhythmia torsades de pointes (TdP) can arise with mutations in HERG and during treatment with drugs that block cardiac I Kr, the current encoded by HERG. Multiple test systems have been used to assess drug block of I Kr. This study evaluated the I Kr blocking potency of a series of antiarrhythmics associated with a range of clinical risks of TdP in two such systems: mouse AT-1 cells (in which I Kr is the major repolarizing current) and Ltk cells transiently transfected with HERG (n = 4-10 cells per drug). For each compound, the concentration required to produce 50% block of I Kr or HERG tail currents (IC 50 ) was determined. There was an excellent correlation ( r = 0.98, p < 10 -5 ) between values obtained in the two systems. However, the relation between the liability of a drug to cause TdP appeared dissociated from I Kr blocking potency. Quinidine, dofetilide, ibutilide, procainamide, and disopyramide are all associated with TdP, but only the first three were potent blockers (IC 50 < or = 1 microM ), whereas procainamide and disopyramide were not (IC 50 > 50 microM ). Conversely, verapamil and amiodarone, drugs not associated with TdP, were also blockers (IC 50 < or = 1 microM ). We conclude that I Kr blocking potency can be readily assessed in either AT-1 cells or systems in which HERG is heterologously expressed. However, not all drugs causing TdP are potent I Kr blockers, and I Kr block is not necessarily associated with TdP. Other properties of these drugs, therefore, contribute to their propensity to cause TdP.

Animals↗
PubMed2001

Potassium current antagonist properties and proarrhythmic consequences of quinolone antibiotics.

Quinolones are clinically important antibiotic drugs. One quinolone antibiotic, sparfloxacin (SPX), has been recently reported to increase the QT interval, and another quinolone, grepafloxacin (GRX), was withdrawn because it induced torsade de pointes (TdP), a polymorphic ventricular tachycardia (VT) linked to excessive QT interval prolongation. To determine whether SPX, GRX, and other recently developed quinolones, gatifloxacin (GAT) and moxifloxacin (MOX), have similar, potentially deleterious, properties we compared these agents in two ways. First, we measured their relative antagonist potency against the rapid component of the delayed rectifier K(+) current (I(Kr)), and second we determined the QT interval prolongation and inducibility of VT and TdP using a well established in vivo rabbit arrhythmia model. All of these agents are I(Kr) antagonists with the following IC(50) values (mean +/- S.E.) for I(Kr) block: SPX, 0.23 +/- 0.07 microM; MOX, 0.75 +/- 0.31 microM; GAT, 26.5 +/- 13.4 microM; and GRX, 27.2 +/- 11.6 microM. All agents also increased the maximum QT interval (mean +/- S.E.) from baseline (241 +/- 10 ms): SPX, 370 +/- 30 ms; MOX, 270 +/- 30 ms; GRX, 280 +/- 25 ms; and GAT, 255 +/- 23 ms. No agents caused TdP during a standard 30-min observation period, but SPX-treated animals developed nonsustained VT (three of six) and TdP (one of six) during an extended 60-min observation period. These findings show that I(Kr) block may be a common feature of many quinolone antibiotics, and that the proarrhythmic consequences vary according to I(Kr) antagonist potency, but are also influenced by additional, unidentified factors.

4-Quinolones↗
PubMed2000

A common polymorphism associated with antibiotic-induced cardiac arrhythmia.

Drug-induced long QT syndrome (LQTS) is a prevalent disorder of uncertain etiology that predisposes to sudden death. KCNE2 encodes MinK-related peptide 1 (MiRP1), a subunit of the cardiac potassium channel I(Kr) that has been associated previously with inherited LQTS. Here, we examine KCNE2 in 98 patients with drug-induced LQTS, identifying three individuals with sporadic mutations and a patient with sulfamethoxazole-associated LQTS who carried a single-nucleotide polymorphism (SNP) found in approximately 1.6% of the general population. While mutant channels showed diminished potassium flux at baseline and wild-type drug sensitivity, channels with the SNP were normal at baseline but inhibited by sulfamethoxazole at therapeutic levels that did not affect wild-type channels. We conclude that allelic variants of MiRP1 contribute to a significant fraction of cases of drug-induced LQTS through multiple mechanisms and that common sequence variations that increase the risk of life-threatening drug reactions can be clinically silent before drug exposure.

Amino Acid Sequence↗
PubMed2000

Novel KCNQ1 mutations associated with recessive and dominant congenital long QT syndromes: evidence for variable hearing phenotype associated with R518X.

Congenital long QT syndrome may be transmitted as either an autosomal dominant or recessive trait. Two families with the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS), and one family with the autosomal dominant Romano-Ward syndrome (RWS) were evaluated for mutations in KCNQ1. Two different novel frameshift mutations were discovered in one of the JLNS families (1188delC) and in the RWS family (504delG). A third allele (R518X) was observed in the second JLNS family. The R518X allele was previously associated with recessive long QT syndrome without deafness, but was present in a congenitally deaf proband in our study. These data extend the range of known KCNQ1 mutations associated with both recessive and dominant forms of congenital long QT syndrome, and demonstrate that the R518X allele may be associated with or without congenital deafness.

Adolescent↗
PubMed2000

The long QT syndromes: genetic basis and clinical implications.

It is becoming clear that mutations in the KVLQT1, human "ether-a-go-go" related gene, cardiac voltage-dependent sodium channel gene, minK and MiRP1 genes, respectively, are responsible for the LQT1, LQT2, LQT3, LQT5 and LQT6 variants of the Romano-Ward syndrome, characterized by autosomal dominant transmission and no deafness. The much rarer Jervell-Lange-Nielsen syndrome (with marked QT prolongation and sensorineural deafness) arises when a child inherits mutant KVLQT1 or minK alleles from both parents. In addition, some families are not linked to the known genetic loci. Cardiac voltage-dependent sodium channel gene encodes the cardiac sodium channel, and long QT syndrome (LQTS) mutations prolong action potentials by increasing inward plateau sodium current. The other mutations cause a decrease in net repolarizing current by reducing potassium currents through "dominant negative" or "loss of function" mechanisms. Polymorphic ventricular tachycardia (torsade de pointes) is thought to be initiated by early after-depolarizations in the Purkinje system and maintained by reentry in the myocardium. Clinical presentations vary with the specific gene affected and the specific mutation. Nevertheless, patients with identical mutations can also present differently, and some patients with LQTS mutations may have no manifest baseline phenotype. The question of whether the latter situation is one of high risk for administration of QT prolonging drugs or during myocardial ischemia is under active investigation. More generally, the identification of LQTS genes has provided tremendous new insights for our understanding of normal cardiac electrophysiology and its perturbation in a wide range of conditions associated with sudden death. It seems likely that the approach of applying information from the genetics of uncommon congenital syndromes to the study of common acquired diseases will be an increasingly important one in the next millennium.

Cardiac Pacing, Artificial↗