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Biomedical subjects

Dan M Roden

Publications and source records attributed to Dan M Roden.

At least 37 records · Page 2Linked to original sources
PubMed2006

Common sodium channel promoter haplotype in asian subjects underlies variability in cardiac conduction.

BACKGROUND: Reduced cardiac sodium current slows conduction and renders the heart susceptible to ventricular fibrillation. Loss of function mutations in SCN5A, encoding the cardiac sodium channel, are one cause of the Brugada syndrome, associated with slow conduction and a high incidence of ventricular fibrillation, especially in Asians. In this study, we tested the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction. METHODS AND RESULTS: Resequencing 2.8 kb of SCN5A promoter identified a haplotype variant consisting of 6 polymorphisms in near-complete linkage disequilibrium that occurred at an allele frequency of 22% in Asian subjects and was absent in whites and blacks. Reporter activity of this variant haplotype, designated HapB, in cardiomyocytes was reduced 62% compared with wild-type haplotype (P=0.006). The relationship between SCN5A promoter haplotype and PR and QRS durations, indexes of conduction velocity, was then analyzed in a cohort of 71 Japanese Brugada syndrome subjects without SCN5A mutations and in 102 Japanese control subjects. In both groups, PR and QRS durations were significantly longer in HapB individuals (P< or =0.002) with a gene-dose effect. In addition, up to 28% and 48% of variability in PR and QRS durations, respectively, were attributable to this haplotype. The extent of QRS widening during challenge with sodium channel blockers, known to be arrhythmogenic in Brugada syndrome and other settings, was also genotype dependent (P=0.002). CONCLUSIONS: These data demonstrate that genetically determined variable sodium channel transcription occurs in the human heart and is associated with variable conduction velocity, an important contributor to arrhythmia susceptibility.

Adolescent↗
PubMed2006

Recombinase-mediated cassette exchange to rapidly and efficiently generate mice with human cardiac sodium channels.

SCN5A encodes the predominant voltage-gated sodium channel isoform in human heart and nearly 100 variants have now been described and studied in vitro. However, development of animal models to analyze function of such large numbers of human gene variants represents a continuing challenge in translational medicine. Here, we describe the implementation of a two stage procedure, recombinase-mediated cassette exchange (RMCE), to efficiently and rapidly generate mice in which a full-length human cDNA replaces expression of the murine ortholog. In the first step of RMCE, conventional homologous recombination in mouse ES cells was used to replace scn5a exon 2 (that contains the translation start site) with a cassette acceptor that includes the thymidine kinase gene, flanked by loxP/inverted loxP sites. In the second step, the cassette acceptor site was replaced by the full-length wild-type human SCN5A cDNA by Cre/loxP-mediated recombination. The exchange event occurred in 7/29 (24%) colonies, and the time from electroporation to first homozygotes was only 8 months. PCR-restriction fragment length polymorphism (RFLP) showed that the murine isoform was replaced by the human one, and functional studies indicated that mice with human cardiac sodium channels have wild-type sodium current density, action potential durations, heart rates, and QRS durations. These data demonstrate that RMCE can be used to generate mice in which a targeted allele can be rapidly and efficiently replaced by variants of choice, and thereby can serve as an enabling approach for the functional characterization of ion channel and other DNA variants.

Animals↗
PubMed2006

ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death--executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.

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Anti-Arrhythmia Agents↗
PubMed2006

Future of antiarrhythmic drugs.

PURPOSE OF REVIEW: This article briefly summarizes the principal mechanisms of action of contemporary antiarrhythmic agents, delineates their limitations in the treatment of cardiac arrhythmias, and discusses why there is a need for new cardiac antiarrhythmic drugs. RECENT FINDINGS: In recent years, the limited efficacy and proarrhythmic potential of classic antiarrhythmic drugs have focused attention on nonpharmacologic approaches to treatment of cardiac arrhythmias. Despite the current success of ablative therapy and implantable defibrillators, the need is still pressing for new antiarrhythmic drugs. Evolving knowledge about the molecular mechanisms of cardiac arrhythmias provides innovative strategies for discovering new cardiac antiarrhythmic drugs. Some of these have already led to the development of new compounds on the verge of clinical use, and others hold great promise for future drug development. SUMMARY: Cardiac arrhythmias are associated with significant morbidity and mortality in developed countries. Antiarrhythmic drug therapy was traditionally the mainstay of arrhythmia treatment; however, the inefficacy of drug treatment and the potential that antiarrhythmic drugs can provoke life-threatening arrhythmias have generated interest in new approaches to antiarrhythmic drug development. Improved understanding of the cellular and molecular basis of cardiac arrhythmias holds the promise of identifying novel approaches for the treatment of cardiac arrhythmias. These approaches may target traditional and newly discovered cardiac ion channels, as well as new molecular and signaling pathways that modulate arrhythmic substrates.

Anti-Arrhythmia Agents↗
PubMed2006

Pharmacogenetics of antiarrhythmic therapy.

Individuals vary widely in their responses to therapy with most drugs. Indeed, responses to antiarrhythmic drugs are so highly variable that study of the underlying mechanisms has elucidated important lessons for understanding variable responses to drug therapy in general. Variability in drug response may reflect variability in the relationship between a drug dose and the concentrations of the drug and metabolite(s) at relevant target sites; this is termed pharmacokinetic variability. Another mechanism is that individuals vary in their response to identical exposures to a drug (pharmacodynamic variability). In this case, there may be variability in the target molecule(s) with which a drug interacts or, more generally, in the broad biological context in which the drug-target interaction occurs. Variants (polymorphisms and mutations) in the genes that encode proteins that are important for pharmacokinetics or for pharmacodynamics have now been described as important contributors to variable drug actions, including proarrhythmia, and these are described in this review. However, the translation of pharmacogenetics into clinical practice has been slow. To this end, the creation of large, well-characterised DNA databases and appropriate control groups, as well as large prospective trials to evaluate the impact of genetic variation on drug therapy, may hasten the impact of pharmacogenetics and pharmacogenomics in terms of delivering personalised drug therapy and to avoid therapeutic failure and serious side effects.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Risk factor interactions and genetic effects associated with post-operative atrial fibrillation.

Postoperative Atrial Fibrillation (PoAF) is the most common arrhythmia after heart surgery, and continues to be a major cause of morbidity. Due to the complexity of this condition, many genes and/or environmental factors may play a role in susceptibility. Previous findings have shown several clinical and genetic risk factors for the development of PoAF. The goal of this study was to determine whether interactions among candidate genes and a variety of clinical factors are associated with PoAF. We applied the Multifactor Dimensionality Reduction (MDR) method to detect interactions in a sample of 940 adult subjects undergoing elective procedures of the heart or great vessels, requiring general anesthesia and sternotomy or thoracotomy, where 255 developed PoAF. We took a random sample of controls matched to the 255 AF cases for a total sample size of 510 individuals. MDR is a powerful statistical approach used to detect gene-gene or gene-environment interactions in the presence or absence of statistically detectable main effects in pharmacogenomics studies. We chose polymorphisms in three (IL-6, ACE, and ApoE) candidate genes, all previously implicated in PoAF risk, and a variety of environmental factors for analysis. We detected a single locus effect of IL-6 which is able to correctly predict disease status with 58.8% (p<0.001) accuracy. We also detected an interaction between history of AF and length of hospital stay that predicted disease status with 68.34% (p<0.001) accuracy. These findings demonstrate the utility of novel computational approaches for the detection of disease susceptibility genes. While each of these results looks interesting, they only explain part of PoAF susceptibility. It will be important to collect a larger set of candidate genes and environmental factors to better characterize the development of PoAF. Applying this approach, we were able to elucidate potential associations with postoperative atrial fibrillation.

Adult↗
PubMed2005

New mechanism contributing to drug-induced arrhythmia: rescue of a misprocessed LQT3 mutant.

BACKGROUND: The cardiac sodium channel (SCN5A) mutation L1825P has been identified in a patient with drug-induced torsade de pointes precipitated by the IKr blocker cisapride. Although L1825P generates late sodium current typical of SCN5A-linked long-QT syndrome (LQT3) in vitro, the patient reported had a normal QT interval before administration of the drug. To address this discrepancy, we tested the hypothesis that this mutant channel is not processed normally. METHODS AND RESULTS: CHO cells transfected with L1825P displayed significantly reduced peak INa (209+/-36 versus 23+/-3 pA/pF, P<0.05). Confocal imaging and cell-counting studies using epitope-tagged constructs demonstrated that cell surface expression of the mutant was only approximately 9% of wild-type. Incubating transfected cells with cisapride partially rescued misprocessing to 30% of wild-type. As a result, "late" sodium current increased with cisapride from 1.2+/-0.11 to 5.04+/-0.77 pA/pF (P<0.05). CONCLUSIONS: L1825P fails to generate QT prolongation because it does not reach the cell surface. Moreover, the data suggest that cisapride caused torsade de pointes not only by blocking IKr but also by rescuing cell surface expression of the mutant channel, further exaggerating the LQT3 phenotype. This not only represents a new mechanism in the drug-induced long-QT syndrome but also strongly supports the concept that variable cell surface expression contributes to clinical variability in the LQT3 phenotype.

Action Potentials↗
PubMed2005

Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.

BACKGROUND: In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). METHODS AND RESULTS: The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (< or =440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7+/-4 versus 13+/-9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. CONCLUSIONS: KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

Cohort Studies↗
PubMed2005

Unmasking of brugada syndrome by lithium.

BACKGROUND: The characteristic ECG pattern of ST-segment elevation in V1 and V2 in the Brugada syndrome is dynamic; it is often intermittently present in affected individuals and can be unmasked by sodium channel blockers, including antiarrhythmic drugs and tricyclic antidepressants. We report here 2 patients who developed the Brugada ECG pattern after administration of lithium, a commonly used drug not previously reported to block cardiac sodium channels. METHODS AND RESULTS: Lithium induced transient ST-segment elevation (type 1 Brugada pattern) in right precordial leads at therapeutic concentrations in 2 patients with bipolar disorder. Lithium withdrawal in the patients resulted in reversion to type 2 or 3 Brugada patterns or resolution of ST-T abnormalities. In Chinese hamster ovary cells transfected with SCN5A, which encodes the cardiac sodium channel, lithium chloride caused concentration-dependent block of peak INa at levels well below the therapeutic range (IC50 of 6.8+/-0.4 micromol/L). CONCLUSIONS: The widely used drug lithium is a potent blocker of cardiac sodium channels and may unmask patients with the Brugada syndrome.

Adult↗
PubMed2005

KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome.

BACKGROUND: Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant KCNH2 mutation along with a common single nucleotide polymorphism in the same gene. METHODS AND RESULTS: The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense KCNH2 mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common KCNH2 polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles. CONCLUSIONS: We have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases.

Adult↗
PubMed2005

Proarrhythmia as a pharmacogenomic entity: a critical review and formulation of a unifying hypothesis.

Proarrhythmia represents an extreme example of the phenomenon that drug effects vary widely among individuals. Studies of mechanisms leading to proarrhythmia have had important implications for understanding arrhythmogenesis, rational use of antiarrhythmic therapies, selection of patients for specific therapies, and drug development. In addition, because proarrhythmia often seems to develop in the absence of clear risk predictors, a role for genetics in predisposing to this adverse drug reaction has been postulated. This review presents mechanisms whereby genetic factors may contribute to variable drug responses and describes our current understanding of how these mechanisms play a role in proarrhythmia. A unifying hypothesis is presented: physiologic processes (such as drug elimination or cardiac repolarization) include multiple redundancies, and congenital or acquired absence of such redundancies--due to disease, interacting drugs, or genetic makeup--may confer no baseline phenotype, but nevertheless enhance susceptibility to unusual drug responses.

Anti-Arrhythmia Agents↗