Frequency of CYP2D6 Alleles Including Structural Variants in the United States.

The CYP2D6 gene encodes an enzyme important in the metabolism of many commonly used medications. Variation in CYP2D6 is associated with inter-individual differences in medication response, and genetic testing is used to optimize medication therapy. This report describes a retrospective study of CYP2D6 allele frequencies in a large population of 104,509 de-identified patient samples across all regions of the United States (US). Thirty-seven unique CYP2D6 alleles including structural variants were identified. A majority of these alleles had frequencies which matched published frequency data from smaller studies, while eight had no previously published frequencies. Importantly, CYP2D6 structural variants were observed in 13.1% of individuals and accounted for 7% of the total variants observed. The majority of structural variants detected (73%) were decreased-function or no-function alleles. As such, structural variants were found in approximately one-third (30%) of CYP2D6 poor metabolizers in this study. This is the first CYP2D6 study to evaluate, with a consistent methodology, both structural variants and single copy alleles in a large US population, and the results suggest that structural variants have a substantial impact on CYP2D6 function.

Mechanism of loss of consciousness during vascular neck restraint.

Vascular neck restraint (VNR) is a technique that police officers may employ to control combative individuals. As the mechanism of unconsciousness is not completely understood, we tested the hypothesis that VNR simply compresses the carotid arteries, thereby decreasing middle cerebral artery blood flow. Twenty-four healthy police officers (age 35 ± 4 yr) were studied. Heart rate (HR), arterial pressure, rate of change of pressure (dP/dt), and stroke volume (SV) were measured using infrared finger photoplethysmography. Bilateral mean middle cerebral artery flow velocity (MCAVmean) was measured by using transcranial Doppler ultrasound. Neck pressure was measured using flat, fluid-filled balloon transducers positioned over both carotid bifurcations. To detect ocular fixation, subjects were asked to focus on a pen that was moved from side to side. VNR was released 1-2 s after ocular fixation. Ocular fixation occurred in 16 subjects [time 9.5 ± 0.4 (SE) s]. Pressures over the right (R) and left (L) carotid arteries were 257 ± 22 and 146 ± 18 mmHg, respectively. VNR decreased MCAVmean (R 45 ± 3 to 8 ± 4 cm/s; L 53 ± 2 to 10 ± 3 cm/s) and SV (92 ± 4 to 75 ± 4 ml; P < 0.001). Mean arterial pressure (MAP), dP/dt, and HR did not change significantly. We conclude that the most important mechanism in loss of consciousness was decreased cerebral blood flow caused by carotid artery compression. The small decrease in CO (9.6 to 7.5 l/min) observed would not seem to be important as there was no change in MAP. In addition, with no significant change in HR, ventricular contractility, or MAP, the carotid sinus baroreceptor reflex appears to contribute little to the response to VNR.

Randomized controlled trial of fixed rate versus rate responsive pacing after radiofrequency atrioventricular junction ablation: quality of life, ventricular refractoriness, and paced QT dispersion.

INTRODUCTION: Ablation of the AV junction is a widely accepted treatment of drug-refractory atrial fibrillation. Long-term pacing of the right ventricular (RV) apex following AV junction ablation can result in adverse cardiac remodeling. However, anecdotal studies report that pacing too slowly following AV junction ablation was associated with propensity to sudden cardiac death. The aim of this study was to provide information about the balance between measures of quality of life versus measures of electrical remodeling achieved by pacing with different rate modalities in a randomized pilot clinical trial. METHODS AND RESULTS: Patients with permanent atrial fibrillation were randomized to VVI (80 beats/min) versus VVIR (minimum rate 80 beats/min), whereas patients with paroxysmal atrial fibrillation were randomized to DDI versus DDDR pacing at discharge from hospital. Serially, measurements of exercise capacity, quality of life, cycle length dependence of QT dispersion (QTdisp), RV refractoriness, and the incidence of nonsustained ventricular tachycardia were made in 28 patients over a 6-month follow-up period. Time-dependent increases in QTdisp were observed in patients randomized to the rate responsive mode (RR-ON) but only when paced at 40 beats/min. This was paralleled by time-dependent increases in RV refractoriness (270 +/- 11 ms at baseline to 302 +/- 5 ms at 6 months) in patients with RR-ON. RR-ON also was associated with trends to an increasing incidence of episodes of nonsustained ventricular tachycardia and worsening of some measures of quality of life. Exercise capacity was not substantially different in the randomized groups. CONCLUSION: Rate responsive pacing results in electrical remodeling of the ventricle following AV junction ablation, but exercise capacity was similar in groups with RR-ON or RR-OFF.

Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia.

The ERG1 gene encodes a family of potassium channels. Mutations in human ERG1 lead to defects in cardiac repolarization, referred to as the long QT syndrome. Through homologous recombination in mouse embryonic stem cells the ERG1 B potassium channel transcript was eliminated while the ERG1 A transcript was maintained. Heterologous expression of ERG1 isoforms had previously indicated that the deactivation time course of ERG1 B is 10-fold more rapid than that of ERG1 A. In day-18 fetal +/+ myocytes, I(Kr) exhibited two time constants of deactivation (3,933 +/- 404 and 350 +/- 19 ms at -50 mV), whereas in age-matched ERG1 B(-/-) mice the rapid component was absent. Biexponential deactivation rates (2,039 +/- 268 and 163 +/- 43 ms at -50 mV) were also observed in adult +/+ myocytes. In adult ERG1 B(-/-) myocytes no I(Kr) was detected. Electrocardiogram intervals were similar in +/+ and -/- mice. However, adult -/- mice manifested abrupt spontaneous episodes of sinus bradycardia (>100 ms of slowing) in 6 out of 21 mice. This phenomenon was never observed in +/+ mice (0 out of 16). We conclude that ERG1 B is necessary for I(Kr) expression in the surface membrane of adult myocytes. Knockout of ERG1 B predisposes mice to episodic sinus bradycardia.

Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels.

BACKGROUND: Overexpression of calcineurin in transgenic (TG) mice results in cardiac hypertrophy and unexpected deaths. METHODS AND RESULTS: None of the TG survived beyond 24 weeks (n=38) whereas all of the wildtype (WT, n=47) survived. Prolongation of repolarization preceded the development of sustained pleomorphic ventricular tachycardia and high degree atrioventricular block, which occurred during spontaneous sudden deaths. Since depolarization-activated K(+) channels contribute dominantly to repolarization in mice, we hypothesized that the TG would decrease these K(+) currents and that the in vivo administration of cyclosporin A (CsA), a calcineurin inhibitor, would reduce this effect. CsA reversed cardiac hypertrophy: capacitance measurements of WT left ventricular myocytes (127+/-7 pF; n=45) and CsA-treated TG (129+/-14 pF; n=17) were significantly lower than in placebo-treated TG (220+/-11 pF; n=41; P<0.001 by ANOVA). Independent of whether the data fit a bi- or a tri-exponential model, the density of I(tof) was significantly reduced in TG versus WT and CsA reversed this effect. While I(tos) and I(Kslow) were also reduced in TG, CsA does not reverse this change because long-term in vivo CsA treatment of WT also reduces I(tos) and I(Kslow.) To assess whether the decreased 'repolarization reserve' contributed to arrhythmogenesis, the residual I(Kr) was blocked by dofetilide precipitating pleomorphic ventricular tachycardias. CONCLUSION: Since the downregulation of I(tof) was observed with overexpression of calcineurin and was also reversed by the calcineurin inhibitor CsA, we conclude that downregulation of I(tof) is a consequence of calcineurin overexpression.