Asymptomatic sinus bradycardia following bariatric surgery.

Approximately 121,000 bariatric surgical procedures are performed annually, and salutary effects include a reduction in cardiovascular morbidity and mortality, risk factor modification, and improvement in sympathovagal tone. There are anecdotal accounts of unexplained sinus bradycardia (SB) after significant weight loss but no systematic studies have been conducted. The purpose of this study was to determine the frequency of incident SB, its timing, and association with weight loss, clinical characteristics, and predictors. We evaluated various clinical characteristics including resting heart rate, blood pressure, body mass index (BMI), heart rate reserve (HRR), basal metabolic rate, and exercise regimen in 151 consecutive patients who underwent bariatric surgery. Multiple logistic regression analysis was performed to determine predictors of SB. Twenty-five of 137 patients (18%) experienced postoperative SB. Patients with SB had significantly greater reduction in BMI than those without bradycardia (35 ± 9.6% and 25.7 ± 13%, respectively, p = 0.002). HRR was significantly greater in patients with SB (116 ± 14 beats/min) compared with those without bradycardia (105 ± 14 beats/min, p = 0.007). Multiple logistic regression analysis revealed that the odds of developing SB were 1.96 and 1.91 and associated with the percent decrease in BMI (95% confidence interval 1.3 to 3.0, p = 0.002) or increase in HRR (95% confidence interval 1.28 to 2.85, p = 0.002), respectively. In conclusion, SB occurred 14 ± 11 months postoperatively and its predictors were the percent reduction in BMI or increase in HRR.

Improved throughput of PatchXpress hERG assay using intracellular potassium fluoride.

Blockade of the human ether-a-go-go-related gene (hERG) potassium channel, with a consequent possibility of QT prolongation and increased susceptibility to a characteristic polymorphic ventricular arrhythmia, torsade de pointes, is an important cause of withdrawal of drugs from the market. In the aftermath of recent drug withdrawals, regulatory agencies now require in vitro hERG screening of all pharmaceutical compounds that are targeted for human use. To minimize the potential for failure in later-stage drug development, many pharmaceutical and biotechnology companies have begun to use automated patch clamp systems with higher throughput than conventional manual patch-clamp techniques to conduct routine functional hERG screening during drug discovery and early development. We have optimized an automated patch-clamp hERG screening method for the PatchXpress 7000A system (Molecular Devices, Sunnyvale, CA) using potassium fluoride (KF) in the internal recording solution. In this study we show that (1) the biophysical and pharmacological properties of hERG current recorded with KF are similar to those with standard potassium chloride solutions, (2) use of KF significantly improves the success rate of hERG screening using PatchXpress without compromising data quality, and (3) utilization of KF can significantly increase the throughput of hERG screening with PatchXpress.

Application of PatchXpress planar patch clamp technology to the screening of new drug candidates for cardiac KCNQ1/KCNE1 (I Ks) activity.

A cardiac safety concern for QT prolongation and potential for pro-arrhythmia exists due to inhibition of the cardiac slowly activating delayed rectifier potassium current, I(Ks). Selective inhibitors of I Ks have been shown to prolong the QT interval in animal models. On the other hand, I Ks has been considered as a target for anti-arrhythmic therapy due to certain biophysical and pharmacological properties and its expression pattern in the heart. Consequently, we have developed a method utilizing a human embryonic kidney (HEK)-293 cell line expressing KCNQ1/KCNE1 (genes that encode for the I Ks channel) as a model for screening of new compounds for I Ks activity. This study was designed (1) to establish and optimize the experimental conditions for measurement of I Ks using PatchXpress() 7000A (Molecular Devices Corporation, Sunnyvale, CA) and (2) to test the effects of I Ks inhibitors and compare the 50% inhibitory concentration (IC50) values determined with PatchXpress versus conventional patch clamp in order to validate the PatchXpress approach for higher-throughput I Ks screening. Biophysical properties of HEK/I Ks recorded with PatchXpress were similar to those recorded with conventional patch-clamp and reported in the literature. The IC50 values for I Ks block determined with PatchXpress correlated well with conventional patch-clamp values from HEK-293 cells as well as from native cardiac myocytes for the majority of compounds tested. Electrophysiological recording of I Ks expressed in HEK-293 cells with the PatchXpress is of acceptable quality for screening purposes. This approach can be utilized for functional prescreening of development compounds for I Ks inhibition either for optimizing lead anti-arrhythmic or other therapeutic candidates or to exclude compounds with the potential to prolong QT.