PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes.

Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support.

Evaluation of the F2R IVS-14A/T PAR1 polymorphism with subsequent cardiovascular events and bleeding in patients who have undergone percutaneous coronary intervention.

Abnormal platelet reactivity is associated with recurrent ischemia and bleeding following percutaneous coronary intervention (PCI). Protease-activated receptor-1 (PAR1), encoded by F2R, is a high affinity thrombin receptor on platelets and the target of the antiplatelet drug vorapaxar. The intronic single nucleotide polymorphism F2R IVS-14 A/T affects PAR1 receptor density and function.

Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy.

Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals.

Common genetic variants and response to atrial fibrillation ablation.

Background: Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation.

Integrating EMR-linked and in vivo functional genetic data to identify new genotype-phenotype associations.

The coupling of electronic medical records (EMR) with genetic data has created the potential for implementing reverse genetic approaches in humans, whereby the function of a gene is inferred from the shared pattern of morbidity among homozygotes of a genetic variant. We explored the feasibility of this approach to identify phenotypes associated with low frequency variants using Vanderbilt's EMR-based BioVU resource. We analyzed 1,658 low frequency non-synonymous SNPs (nsSNPs) with a minor allele frequency (MAF)<10% collected on 8,546 subjects.

Biobanks and electronic medical records: enabling cost-effective research.

The use of electronic medical record data linked to biological specimens in health care settings is expected to enable cost-effective and rapid genomic analyses. Here, we present a model that highlights potential advantages for genomic discovery and describe the operational infrastructure that facilitated multiple simultaneous discovery efforts.

Whole-exome sequencing in familial atrial fibrillation.

Aims: Positional cloning and candidate gene approaches have shown that atrial fibrillation (AF) is a complex disease with familial aggregation. Here, we employed whole-exome sequencing (WES) in AF kindreds to identify variants associated with familial AF.

Methods And Results: WES was performed on 18 individuals in six modestly sized familial AF kindreds.

Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome.

Objectives: The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes.

Background: diLQTS is associated with the potentially fatal arrhythmia torsades de pointes. The contribution of rare genetic variants to the underlying genetic framework predisposing to diLQTS has not been systematically examined.

Common SCN10A variants modulate PR interval and heart rate response during atrial fibrillation.

Aims: SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF.

QT variability during initial exposure to sotalol: experience based on a large electronic medical record.

Aims: A prolonged QT interval is associated with increased risk of Torsades de pointes (TdP) and may be fatal. We sought to investigate the extent to which clinical covariates affect the change in QT interval among 'real-world' patients treated with sotalol and followed in an electronic medical record (EMR) system.

Methods And Results: We used clinical alerts in our EMR system to identify all patients in whom a new prescription for sotalol was written (2001-11).

A KCNJ8 mutation associated with early repolarization and atrial fibrillation.

Aim: The Kir 6.1 K(atp) channel is believed to play an important role in ventricular repolarization as determined from both functional and genetic studies of the potassium inwardly-rectifying channel, subfamily J, member 8 (KCNJ8)-S422L missense mutation in patients with J-wave syndromes. Although Kir6.

Characterization of genome-wide association-identified variants for atrial fibrillation in African Americans.

Background: Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown.

Genetic determinants of response to cardiovascular drugs.

Purpose Of Review: To survey genetic variation contributing to variable responsiveness and toxicity to important cardiovascular drugs and highlight recent developments in the field of cardiovascular pharmacogenomics and personalized medicine.

Recent Findings: Previously recognized pharmacogenomic associations with drug efficacy have been further validated (e.g.

Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record.

Aim: Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European-Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose.

Patients & Methods: We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European-Americans (n = 1022) and African-Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose.

Value of the signal-averaged electrocardiogram in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited disease that causes structural and functional abnormalities of the right ventricle (RV). The presence of late potentials as assessed by the signal-averaged electrocardiogram (SAECG) is a minor task force criterion.

Objective: The purpose of this study was to examine the diagnostic and clinical value of the SAECG in a large population of genotyped ARVC/D probands.

Current perspectives on congenital long QT syndrome.

Congenital long QT syndrome is a genetic disorder characterized by prolonged QT interval on electrocardiogram and increased risk of sudden cardiac death from ventricular arrhythmias. In long QT syndrome, genes that encode for the various cardiac ion channels or regulatory proteins of these channels are mutated. The various mutations individually lead to a disruption of the normal cardiac myocyte action potential, and thus leading to a propensity for ventricular arrhythmias.

Intravenous sedation for cardiac procedures can be administered safely and cost-effectively by non-anesthesia personnel.

Aims: Primary: to determine the safety and efficacy of intravenous sedation for cardiac procedures administered by non-anesthesia personnel. Secondary: to assess cost effectiveness of such sedation.

Methods: Anesthesiologists trained non-anesthesia personnel, and established our sedation protocol, which was then used in 9,558 patients who had cardiac procedures with sedation by non-anesthesia personnel, recorded on a computerized database.

Clonidine-induced delirium.

Clonidine-induced delirium has rarely been reported. To the best of our knowledge, there are six related case reports in the literature. We describe one such case here and review the six previously published cases.