PAT Abstract, 2003

Pharmacogenomics of Arrhythmia Therapy

Goals

Arrhythmias, notably atrial and ventricular fibrillation, represent major public health burdens for which available therapies are incompletely effective. Remarkable progress has been made in identifying disease genes in rare monogenic arrhythmia syndromes and in identifying clinical markers of arrhythmia risk (including family history) in large populations. The goal of studies in the Pharmacology of Antiarrhythmic Therapy Center is to exploit these advances to further our understanding of genetic predictors of variability in arrhythmia phenotypes, and their variable responses to drug therapy. In this center, we have adopted an association study paradigm, and our major goals are therefore

• polymorphism discovery and characterization;
• patient accrual; and
• implementation of conventional and new genetic epidemiology tools.

Progress

Polymorphism discovery is currently performed by resequencing exons and flanking introns in ethnically defined panels obtained from the Coriell resource: Caucasians, African-Americans, Han Chinese in the Los Angeles area, and Mexican-Americans in the Los Angeles area. When promoter regions have been identified, screening extends to these. The priority in this center are genes encoding cardiac ion channels or their functional subunits expressed in heart, although we recognize that polymorphisms in other genes, notably those in the adrenergic and the renin-angiotensin-aldosterone signaling systems, are excellent candidate modulators of arrhythmia phenotypes and their response to drugs.

A major effort is currently devoted to generation of clinical databases that include well-defined patient phenotypes, along with DNA samples. Each database contains common information, including patient history, family history, medication history, and arrhythmia history, along with database-specific phenotypes. All databases are accumulated de novo, i.e. from patients starting a drug or newly identified with an arrhythmia rather than those followed for these conditions; thus, patient recruitment has been underway since late 2001/early 2002. A major effort since initiation of the grant has been construction of web-based data entry systems, and an Oracle database to house the accumulating phenotypic and genotypic information. Databases currently being accumulated, and their recruitment to August 15, 2003, include:

• Patients at high risk for ventricular fibrillation: All patients receiving implantable cardioverter/defibrillator (ICD) devices, by definition a high risk group, are approached for enrollment. Phenotypes include time to ICD discharges. As of August 15, this database contained 133 patients, 54 of whom had received ICDs for primary prevention and the remainder for a secondary prevention (i.e., prevention of recurrent ventricular tachycardia or ventricular fibrillation).
• Patients undergoing cardiac surgery: Phenotypes include the complications of hemorrhage/thrombosis and atrial fibrillation. This collection was ongoing at the initiation of this award, and currently includes 731 patients, 14.8% of whom had post-operative atrial fibrillation.
• All patients in whom therapy with a QT prolonging antiarrhythmic drug is initiated: Clinical practice suggests that these drugs should be initiated on an inpatient basis with few exceptions. We have implemented an interface with the electronic inpatient ordering system in the Vanderbilt University pharmacy that allows identification of each patient in whom therapy with these drugs is initiated. Phenotypic information includes baseline QT interval, maximum QT interval after drug challenge, and whether drug was continued at three days and at three months. This database includes 200 subjects.
• All patients starting the anticoagulant coumadin: This is a prospective evaluation of the effect of CYP2C9 genotype on the rates of bleeding and of thrombosis, and on steady state dose during coumadin. The data will be required to mount a prospective study in which patients will be randomized to standard vs genotype-guided therapy. This database currently includes 251 subjects.
• All patients with atrial fibrillation (AF) referred to the arrhythmia clinics at Vanderbilt University Hospital for management: This database currently includes 195 subjects, 26 of whom have at least one family member with atrial fibrillation, and 35 unaffected family members. Intensive efforts in a number of centers will identify genes causing or modulating the AF phenotype within the next 1-2 years. Accumulation of this database will allow us to test the hypothesis that variants in these genes determine common AF phenotypes and/or response to specific classes of drugs.
• Normal volunteers challenged with a QT-prolonging agent, ibutilide, and a beta-blocker, atenolol: Normal volunteers are studied on the general clinical research center, after being brought into salt balance. Ibutilide is used because the maximum extent of QT prolongation is immediately evident after intravenous challenge, thereby maximizing patient safety, streamlining the conduct of the study, and eliminating the factors related to variable drug elimination as a contributor to QT response. The outcome variables include measures of autonomic function (catecholamines, upright and supine blood pressure and heart rate), baseline electrocardiographic data, electrocardiographic data obtained during and following supine exercise in the presence and absence of ibutilide and, on a second study day, in the presence and absence of atenolol challenge. 136 subjects have completed this study.

Power calculations suggest that minimal databases for association studies between common polymorphisms and arrhythmia or drug response phenotypes will require several hundred subjects. Thus, our efforts to date have focused on polymorphism identification and on database building. As common polymorphisms are identified, genotyping assays are developed, either on the Taqman or the luminex platforms. The center also includes a genetic epidemiology effort that will focus not only on the role of single polymorphisms in mediating the phenotypes of interest, but also on gene-gene interactions using techniques such as Multifactor Dimensionality Reduction (MDR) developed at Vanderbilt.