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Publication Record


Hypogonadism as a Reversible Cause of Torsades de Pointes in Men.
Salem JE, Waintraub X, Courtillot C, Shaffer CM, Gandjbakhch E, Maupain C, Moslehi JJ, Badilini F, Haroche J, Gougis P, Fressart V, Glazer AM, Hidden-Lucet F, Touraine P, Lebrun-Vignes B, Roden DM, Bachelot A, Funck-Brentano C
(2018) Circulation 138: 110-113
MeSH Terms: Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Androgen Antagonists, Biomarkers, Cross-Sectional Studies, Databases, Factual, Electronic Health Records, Heart Rate, Hormone Replacement Therapy, Humans, Hypogonadism, Male, Middle Aged, Paris, Pharmacovigilance, Prospective Studies, Risk Assessment, Risk Factors, Testosterone, Torsades de Pointes
Added October 1, 2018
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21 MeSH Terms
Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors.
Grouthier V, Lebrun-Vignes B, Glazer AM, Touraine P, Funck-Brentano C, Pariente A, Courtillot C, Bachelot A, Roden DM, Moslehi JJ, Salem JE
(2018) Heart 104: 1859-1863
MeSH Terms: Action Potentials, Adolescent, Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Aromatase Inhibitors, Cardiotoxicity, Databases, Factual, Europe, Female, Heart Conduction System, Heart Rate, Humans, Long QT Syndrome, Middle Aged, Prognosis, Risk Assessment, Risk Factors, Selective Estrogen Receptor Modulators, Tamoxifen, Torsades de Pointes, Young Adult
Show Abstract · Added October 1, 2018
OBJECTIVE - A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.
METHODS - We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.
RESULTS - SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs.
CONCLUSIONS - SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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23 MeSH Terms
Azithromycin Causes a Novel Proarrhythmic Syndrome.
Yang Z, Prinsen JK, Bersell KR, Shen W, Yermalitskaya L, Sidorova T, Luis PB, Hall L, Zhang W, Du L, Milne G, Tucker P, George AL, Campbell CM, Pickett RA, Shaffer CM, Chopra N, Yang T, Knollmann BC, Roden DM, Murray KT
(2017) Circ Arrhythm Electrophysiol 10:
MeSH Terms: Action Potentials, Animals, Anti-Bacterial Agents, Arrhythmias, Cardiac, Azithromycin, CHO Cells, Calcium Channel Blockers, Calcium Channels, L-Type, Cricetulus, Dose-Response Relationship, Drug, Electrocardiography, Ambulatory, Female, HEK293 Cells, Heart Rate, Humans, KCNQ1 Potassium Channel, Mice, Inbred C57BL, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Potassium Channel Blockers, Potassium Channels, Inwardly Rectifying, Potassium Channels, Voltage-Gated, Rabbits, Sodium Channel Blockers, Telemetry, Time Factors, Transfection, Young Adult
Show Abstract · Added July 6, 2017
BACKGROUND - The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells.
METHODS AND RESULTS - In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC=110±3 μmol/L) and Na current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for I in cardiomyocytes. Mild block occurred for K currents representing I (CHO cells expressing hERG; IC=219±21 μmol/L) and I (CHO cells expressing KCNQ1+KCNE1; IC=184±12 μmol/L), whereas azithromycin suppressed L-type Ca currents (rabbit ventricular myocytes, IC=66.5±4 μmol/L) and I (HEK cells expressing Kir2.1, IC=44±3 μmol/L).
CONCLUSIONS - Chronic exposure to azithromycin increases cardiac Na current to promote intracellular Na loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.
© 2017 American Heart Association, Inc.
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28 MeSH Terms
Heart rate variability during sleep in children with autism spectrum disorder.
Harder R, Malow BA, Goodpaster RL, Iqbal F, Halbower A, Goldman SE, Fawkes DB, Wang L, Shi Y, Baudenbacher F, Diedrich A
(2016) Clin Auton Res 26: 423-432
MeSH Terms: Aging, Autism Spectrum Disorder, Autonomic Nervous System, Child, Child, Preschool, Female, Heart Rate, Humans, Male, Polysomnography, Sleep, Sleep Stages, Sleep, REM
Show Abstract · Added October 14, 2016
PURPOSE - Autonomic dysfunction has been reported in autism spectrum disorders (ASD). Less is known about autonomic function during sleep in ASD. The objective of this study is to provide insight into the autonomic cardiovascular control during different sleep stages in ASD. We hypothesized that patients with ASD have lower vagal and higher sympathetic modulation with elevated heart rate, as compared to typical developing children (TD).
METHODS - We studied 21 children with ASD and 23 TD children during overnight polysomnography. Heart rate and spectral parameters were calculated for each vigilance stage during sleep. Data from the first four sleep cycles were used to avoid possible effects of different individual sleep lengths and sleep cycle structures. Linear regression models were applied to study the effects of age and diagnosis (ASD and TD).
RESULTS - In both groups, HR decreased during non-REM sleep and increased during REM sleep. However, HR was significantly higher in stages N2, N3 and REM sleep in the ASD group. Children with ASD showed less high frequency (HF) modulation during N3 and REM sleep. LF/HF ratio was higher during REM. Heart rate decreases with age at the same level in ASD and in TD. We found an age effect in LF in REM different in ASD and TD.
CONCLUSION - Our findings suggest possible deficits in vagal influence to the heart during sleep, especially during REM sleep. Children with ASD may have higher sympathetic dominance during sleep but rather due to decreased vagal influence.
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13 MeSH Terms
ICU sedation with dexmedetomidine after severe traumatic brain injury.
Humble SS, Wilson LD, Leath TC, Marshall MD, Sun DZ, Pandharipande PP, Patel MB
(2016) Brain Inj 30: 1266-70
MeSH Terms: Adult, Analgesics, Non-Narcotic, Blood Pressure, Brain Injuries, Traumatic, Dexmedetomidine, Dose-Response Relationship, Drug, Female, Heart Rate, Humans, Intensive Care Units, Male, Middle Aged, Retrospective Studies, Young Adult
Show Abstract · Added June 26, 2018
OBJECTIVE - To comprehensively describe the use of dexmedetomidine in a single institutional series of adult ICU patients with severe TBI. This study describes the dexmedetomidine dosage and infusion times, as well as the physiological parameters, neurological status and daily narcotic requirements before, during and after dexmedetomidine infusion.
METHODS - This study identified 85 adult patients with severe TBI who received dexmedetomidine infusions in the Trauma ICU at Vanderbilt University Medical Center between 2006-2010. Demographic, haemodynamic, narcotic use and sedative use data were systematically obtained from the medical record and analysed for changes associated with dexmedetomidine infusion.
RESULTS - During infusion with dexmedetomidine, narcotic and sedative use decreased significantly (p < 0.001 and p < 0.05). Median MAP, SBP, DBP and HR also decreased significantly during infusion when compared to pre-infusion values (p < 0.001). Despite the use of dexmedetomidine, RASS and GCS scores improved from pre-infusion to infusion time periods.
CONCLUSIONS - The findings demonstrate that initiation of dexmedetomidine infusion is not associated with a decline in neurological functioning in adults with severe TBI. Although there was an observed decrease in haemodynamic parameters during infusion with dexmedetomidine, the change was not clinically significant and the requirements for narcotics and additional sedatives were minimized.
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MeSH Terms
Individual differences in timing of peak positive subjective responses to d-amphetamine: Relationship to pharmacokinetics and physiology.
Smith CT, Weafer J, Cowan RL, Kessler RM, Palmer AA, de Wit H, Zald DH
(2016) J Psychopharmacol 30: 330-43
MeSH Terms: Adult, Behavior, Addictive, Central Nervous System Stimulants, Dextroamphetamine, Dose-Response Relationship, Drug, Female, Heart Rate, Humans, Individuality, Male, Substance-Related Disorders, Surveys and Questionnaires, Young Adult
Show Abstract · Added February 9, 2017
Rate of delivery of psychostimulants has been associated with their positive euphoric effects and potential addiction liability. However, information on individual differences in onset of d-amphetamine's effects remains scarce. We examined individual differences in the time to peak subjective and physiological effects and the pharmacokinetics/pharmacodynamics of oral d-amphetamine. We considered two independent studies that used different dosing regimens where subjects completed the drug effects questionnaire at multiple time points post d-amphetamine. Based on the observation of distinct individual differences in time course of drug effects questionnaire "feel", "high", and "like" ratings (DEQH+L+F) in Study 1, subjects in both studies were categorized as early peak responders (peak within 60 minutes), late peak responders (peak > 60 minutes) or nonresponders; 20-25% of participants were categorized as early peak responders, 50-55% as late peak responders and 20-30% as nonresponders. Physiological (both studies) and plasma d-amphetamine (Study 1) were compared among these groups. Early peak responders exhibited an earlier rise in plasma d-amphetamine levels and more sustained elevation in heart rate compared to late peak responders. The present data illustrate the presence of significant individual differences in the temporal pattern of responses to oral d-amphetamine, which may contribute to heightened abuse potential.
© The Author(s) 2016.
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13 MeSH Terms
Valsalva Maneuver in Pulmonary Arterial Hypertension: Susceptibility to Syncope and Autonomic Dysfunction.
Mar PL, Nwazue V, Black BK, Biaggioni I, Diedrich A, Paranjape SY, Loyd JE, Hemnes AR, Robbins IM, Robertson D, Raj SR, Austin ED
(2016) Chest 149: 1252-60
MeSH Terms: Adult, Autonomic Nervous System Diseases, Baroreflex, Blood Pressure, Case-Control Studies, Familial Primary Pulmonary Hypertension, Female, Heart Rate, Hemodynamics, Humans, Hypertension, Pulmonary, Male, Syncope, Valsalva Maneuver
Show Abstract · Added February 21, 2017
BACKGROUND - Patients with pulmonary arterial hypertension (PAH) are routinely instructed to avoid performing the Valsalva maneuver for fear of syncope or sudden cardiac death. The mechanism of this action has not been elucidated. We conducted a case-control trial of nine patients with PAH and 15 healthy control subjects to determine if systemic hemodynamic changes during the Valsalva maneuver in these patients invoke greater susceptibility to syncope than healthy control subjects. Metrics commonly employed in autonomic testing were used to assess the degree of autonomic failure.
METHODS - Common Valsalva parameters, including adrenergic baroreflex sensitivity, pressure recovery time, systolic BP (SBP) recovery, diastolic BP (DBP) recovery, mean arterial pressure recovery, and the Valsalva ratio, were calculated. Mann-Whitney U tests were used to compare continuous variables. The primary end point was adrenergic baroreflex sensitivity.
RESULTS - Patients with PAH had lower adrenergic baroreflex sensitivity (9.7 ± 4.6 mm Hg/s vs 18.8 ± 9.2 mm Hg/s; P = .005), longer pressure recovery time (3.6 ± 2.5 s vs 1.7 ± 0.8 s; P = .008), similar SBP recovery (-13 ± 11 mm Hg vs -12 ± 23 mm Hg; P = .640), less DBP recovery (-1 ± 12 mm Hg vs 13 ± 14 mmHg; P = .025), less mean arterial pressure recovery (-5 ± 11 mm Hg vs 5 ± 17 mm Hg; P = .048), and a decreased Valsalva ratio (1.25 ± 0.11 vs 1.60 ± 0.22; P < .001) compared with healthy control subjects.
CONCLUSIONS - Compared with healthy control subjects, patients with PAH are more susceptible to syncope during the Valsalva maneuver because of autonomic dysfunction causing cerebral hypoperfusion. These study patients with PAH exhibited a degree of susceptibility to syncope similar to a spectrum of patients with intermediate autonomic failure who typically experience a SBP drop of 10 to 30 mm Hg with standing.
Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Heart rate characteristic index monitoring for bloodstream infection in an NICU: a 3-year experience.
Coggins SA, Weitkamp JH, Grunwald L, Stark AR, Reese J, Walsh W, Wynn JL
(2016) Arch Dis Child Fetal Neonatal Ed 101: F329-32
MeSH Terms: Bacteremia, Blood Culture, Cohort Studies, Electronic Health Records, Female, Heart Rate, Humans, Infant, Newborn, Infant, Premature, Intensive Care Units, Neonatal, Male, Monitoring, Physiologic, Neonatal Sepsis, Retrospective Studies, Statistics as Topic, United States
Show Abstract · Added February 21, 2016
BACKGROUND - Bloodstream infection (BSI) among neonatal intensive care unit (NICU) infants is a frequent problem associated with poor outcomes. Monitoring for abnormal heart rate characteristics (HRCs) may decrease infant mortality by alerting clinicians to sepsis before it becomes clinically apparent.
METHODS - HRC scores were acquired using the HRC (HeRO) monitor system from Medical Predictive Science Corporation and entered into the electronic medical record by bedside staff. We retrospectively analysed HRC scores recorded twice daily in the medical record during a 30-month period (1 January 2010 through 30 June 2012) for infants in the NICU at the Monroe Carell Jr. Children's Hospital at Vanderbilt. We identified infants that met Centers for Disease Control criteria for late-onset BSI (>3 days of life) during the study period.
RESULTS - During the study period, we recorded 127 673 HRC scores from 2384 infants. We identified 46 infants with BSI. Although 8% (9701/127 673) of the HRC scores were ≥2 and 1% (1387/127 673) were ≥5, BSI (at any time) was observed in just 5% of patients with HRC scores ≥2, and 9% of patients with HRC scores ≥5. Of infants with BSI, 5/46 (11%) had at least one HRC score ≥5 and 17/46 (37%) had at least one score ≥2 recorded in the 48 h period prior to the evaluation that resulted in the first positive blood culture of the episode.
CONCLUSIONS - In our single-centre retrospective study, elevated HRC scores had limited ability to detect BSI. BSI was infrequent at any time during hospitalisation in infants with significantly elevated HRC scores.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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16 MeSH Terms
The neurotransmitters serotonin and glutamate accelerate the heart rate of the mosquito Anopheles gambiae.
Hillyer JF, Estévez-Lao TY, Mirzai HE
(2015) Comp Biochem Physiol A Mol Integr Physiol 188: 49-57
MeSH Terms: Animals, Anopheles, Dose-Response Relationship, Drug, Female, Glutamic Acid, Heart Rate, Myocardial Contraction, Serotonin, Serotonin Receptor Agonists
Show Abstract · Added February 5, 2016
Serotonin and glutamate are neurotransmitters that in insects are involved in diverse physiological processes. Both serotonin and glutamate have been shown to modulate the physiology of the dorsal vessel of some insects, yet until the present study, their activity in mosquitoes remained unknown. To test whether serotonin or glutamate regulate dorsal vessel physiology in the African malaria mosquito, Anopheles gambiae, live mosquitoes were restrained, and a video of the contracting heart (the abdominal portion of the dorsal vessel) was acquired. These adult female mosquitoes were then injected with various amounts of serotonin, glutamate, or a control vehicle solution, and additional videos were acquired at 2 and 10 min post-treatment. Comparison of the videos taken before and after treatment revealed that serotonin accelerates the frequency of heart contractions, with the cardioacceleration being significantly more pronounced when the wave-like contractions of cardiac muscle propagate in the anterograde direction (toward the head). Comparison of the videos taken before and after treatment with glutamate revealed that this molecule is also cardioacceleratory. However, unlike serotonin, the activity of glutamate does not depend on whether the contractions propagate in the anterograde or the retrograde (toward the posterior of the abdomen) directions. Serotonin or glutamate induces a minor change or no change in the percentage of contractions and the percentage of the time that the heart contracts in the anterograde or the retrograde directions. In summary, this study shows that the neurotransmitters serotonin and glutamate increase the heart contraction rate of mosquitoes.
Copyright © 2015 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Genetic variation in alpha2-adrenoreceptors and heart rate recovery after exercise.
Kohli U, Diedrich A, Kannankeril PJ, Muszkat M, Sofowora GG, Hahn MK, English BA, Blakely RD, Stein CM, Kurnik D
(2015) Physiol Genomics 47: 400-6
MeSH Terms: Adult, Catecholamines, Exercise, Female, Heart Rate, Humans, Linear Models, Male, Polymorphism, Single Nucleotide, Receptors, Adrenergic, alpha-2, Receptors, Adrenergic, beta-1
Show Abstract · Added September 28, 2015
Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular outcomes. HRR is mediated by both parasympathetic reactivation and sympathetic withdrawal and is highly heritable. We examined whether common genetic variants in adrenergic and cholinergic receptors and transporters affect HRR. In our study 126 healthy subjects (66 Caucasians, 56 African Americans) performed an 8 min step-wise bicycle exercise test with continuous computerized ECG recordings. We fitted an exponential curve to the postexercise R-R intervals for each subject to calculate the recovery constant (kr) as primary outcome. Secondary outcome was the root mean square residuals averaged over 1 min (RMS1min), a marker of parasympathetic tone. We used multiple linear regressions to determine the effect of functional candidate genetic variants in autonomic pathways (6 ADRA2A, 1 ADRA2B, 4 ADRA2C, 2 ADRB1, 3 ADRB2, 2 NET, 2 CHT, and 1 GRK5) on the outcomes before and after adjustment for potential confounders. Recovery constant was lower (indicating slower HRR) in ADRA2B 301-303 deletion carriers (n = 54, P = 0.01), explaining 3.6% of the interindividual variability in HRR. ADRA2A Asn251Lys, ADRA2C rs13118771, and ADRB1 Ser49Gly genotypes were associated with RMS1min. Genetic variability in adrenergic receptors may be associated with HRR after exercise. However, most of the interindividual variability in HRR remained unexplained by the variants examined. Noncandidate gene-driven approaches to study genetic contributions to HRR in larger cohorts will be of interest.
Copyright © 2015 the American Physiological Society.
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11 MeSH Terms