Browsing by Author "Kovacs, Richard J."

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Ondansetron blocks wild-type and p.F503L variant small conductance C2+-activated K+ channels
(2018-08-01)
Ko, Jum-Suk
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Guo, Shuai
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Hassel, Jonathan
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Celestino-Soper, Patricia
;
Lynnes, Ty C.
Apamin-sensitive small-conductance Ca2+ activated K+ (SK) current (I-KAS) is encoded by Ca2+ -activated K+ channel subfamily N (KCNN) genes. I-KAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I-KAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WI) and variant KCNN channels. and determined if the 5-HT3 receptor antagonist ondansetron blocks I-KAS. We searched 2,306.335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNEI and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 valiant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing I KAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WI and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced I-KAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F5031. KCNN2 variant increases Ca2+ sensitivity and I-KAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent I-KAS blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT3 receptor antagonist, blocks small-conductance Ca2+-activated K+ (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of druginduced long QT syndrome.
Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram
(2017-01)
Doytchinova, Anisiia
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Hassel, Jonathan L.
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Yuan, Yuan
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Lin, Hongbo
;
Yin, Dechun
BACKGROUND Sympathetic nerve activity is important to cardiac arrhythmogenesis. OBJECTIVE The purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone. METHODS We recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 +/- 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection. RESULTS In patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V1V6) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P <.001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 +/- 0.14, P <.05) and shortening of QT interval (P <.001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA. CONCLUSION SKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone.
Simultaneous recordings of intrinsic cardiac nerve activity and skin sympathetic nerve activity from human patients during the postoperative period
(2017-11-01)
Shen, Mark J.
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Coffey, Arthur C.
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Straka, Susan
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Adams, David E.
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Wagner, David B.
BACKGROUND Intrinsic cardiac nerve activity (ICNA) and skin nerve activity (SKNA) are both associated with cardiac arrhythmias in dogs. OBJECTIVE The purpose of this study was to test the hypothesis that ICNA and SKNA correlate with postoperative cardiac arrhythmias in humans. METHODS Eleven patients (mean age 60 6 13 years; 4 women) were enrolled in this study. Electrical signals were simultaneously recorded from electrocardiogram (ECG) patch electrodes on the chest wall and from 2 temporary pacing wires placed during open heart surgery on the left atrial epicardial fat pad. The signals were filtered to display SKNA and ICNA. Premature atrial contractions (PACs) and premature ventricular contractions were determined manually. The SKNA and ICNA of the first 300 minutes of each patient were calculated minute by minute to determine baseline average amplitudes of nerve activities and to determine their correlation with arrhythmia RESULTS We processed 1365 6 973 minutes of recording per patient. Low-amplitude SKNA and ICNA were present at all time, while the burst discharges were observed much less frequently. Both SKNA and burst ICNA were significantly associated with the onset of PACs and premature ventricular contractions. Baseline average ICNA (aICNA), but not average SKNA, had a significant association with PAC burden. The correlation coefficient (r) between aICNA and PAC burden was 0.78 (P<.01). A patient with the greatest aICNA developed postoperative atrial fibrillation. CONCLUSION ICNA and SKNA can be recorded from human patients in the postoperative period. The baseline magnitude of ICNA correlates with PAC burden and development of postoperative atrial fibrillation.