Cardiac Depolarization Research Articles

Epigenetic Changes Governing Scn5a Expression in Denervated Skeletal Muscle.

The SCN5A gene encodes the α-subunit of the voltage-gated cardiac sodium channel (NaV1.5), a key player in cardiac action potential depolarization. Genetic variants in protein-coding regions of the human SCN5A have been largely associated with inherited cardiac arrhythmias. Increasing evidence also suggests that aberrant expression of the SCN5A gene could increase susceptibility to arrhythmogenic diseases, but the mechanisms governing SCN5A expression are not yet well understood. To gain insights into the molecular basis of SCN5A gene regulation, we used rat gastrocnemius muscle four days following denervation, a process well known to stimulate Scn5a expression. Our results show that denervation of rat skeletal muscle induces the expression of the adult cardiac Scn5a isoform. RNA-seq experiments reveal that denervation leads to significant changes in the transcriptome, with Scn5a amongst the fifty top upregulated genes. Consistent with this increase in expression, ChIP-qPCR assays show enrichment of H3K27ac and H3K4me3 and binding of the transcription factor Gata4 near the Scn5a promoter region. Also, Gata4 mRNA levels are significantly induced upon denervation. Genome-wide analysis of H3K27ac by ChIP-seq suggest that a super enhancer recently described to regulate Scn5a in cardiac tissue is activated in response to denervation. Altogether, our experiments reveal that similar mechanisms regulate the expression of Scn5a in denervated muscle and cardiac tissue, suggesting a conserved pathway for SCN5A expression among striated muscles.

The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.

Wide QRS tachycardias: the rationale behind electrocardiographic diagnostic criteria

Wide QRS tachycardias represent one of the most challenging scenarios in the interpretation of the electrocardiogram, even among experienced professionals or specialists. The various existing diagnostic criteria are essential tools for the correct identification of the origin of tachycardia, however, the knowledge of the electrophysiological principles of cardiac depolarization is fundamental to understand them, thus allowing greater accuracy in the interpretation of the exam.

Abstract 346: Cardiac Expression of Fetal and Adult SCN5A Isoforms in Sudden Unexplained Infant Death (SUID)

Sodium Voltage-Gated Channel Alpha Subunit 5 (SNC5A) plays a vital role in cardiac depolarization and has been implicated in Long QT Syndrome and sudden cardiac death. SCN5A encodes fetal and adult isoforms, differing by splicing of exon 6A or 6B, respectively. Fetal SCN5A decreases peak sodium current, leading to slower channel activation and inactivation and providing a potential substrate for arrhythmia. Little is known about developmental expression of these isoforms. We investigated developmental expression of SCN5A isoforms in infants, toddlers, and adults, including expression ratios in SUID cases and controls (0-12 months). We extracted RNA from heart tissue collected at autopsy (fetus-24 months) with 80 SUID cases and 27 controls, and 5 adult donor hearts. RNA Integrity Numbers ranged from 4.8-9.5. Relative SCN5A isoform expression was quantified by qRT-PCR. Non-parametric t-test and ANOVA were used; P<0.05 was considered statistically significant. Our results show a significant stepwise increase in adult/fetal isoform expression with age. Relative expression of adult/fetal SCN5A increased significantly from fetal-4 months to 5-24 months (P<0.0001), and again in adulthood (P<0.0001). There was no significant difference between case and control groups at 0-4 or 0-12 months. Expression of adult/fetal SCN5A increases significantly from birth to 24 months of age and into adulthood. Relative adult/fetal SCN5A expression is lowest during the neonatal period through 4 months, corresponding with the peak incidence of SUID. Further investigation of protein expression of SCN5A isoforms may shed light onto the age-dependent incidence of sudden death.

Fetal Cardiac Cellular Damage Caused by Anemia in Utero in Hb Bart's Disease.

Severe fetal anemias can cause high output cardiac failure. Mitochondria are key regulators of cardiac function. However, the effects of an early phase of fetal anemia on the fetal heart and cardiac mitochondrial function are not known. The aim of this study is to compare mitochondrial function and cardiac biochemical alterations in the fetal cardiac tissue between anemic and non-anemic fetuses. A cross-sectional study was conducted in Fetuses affected by Hb Bart's disease (n=18) and non-anemic fetuses (n=10) at 17-20 weeks. Echocardiograms had been carried out in all cases to assess prenatal cardiac function. Cardiac tissues were collected after pregnancy termination for the determination of cardiac iron accumulation, mitochondrial function, including mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, mitochondrial dynamics, inflammation, and apoptosis. Prenatal cardiac function evaluated by ultrasound was comparable between the Hb Bart's and non-anemic groups. In Bart's group, the levels of cardiac mitochondrial depolarization and swelling, and the TNF-α level were significantly higher, compared to the non-anemic group. On the contrary, anti-inflammatory (IL-10) levels were significantly lower in the Hb Bart's group. Additionally, active caspase-3 and Bcl-2 expression were also significantly higher (P= 0.001, P=0.035) in Bart's group. The mitochondrial fission protein expression, including p-DRP1/total DRP1, was significantly higher in Bart's group. However, there was no difference in cardiac iron accumulation levels between these two groups. Despite equivalent prenatal cardiac function and comparable cardiac iron accumulation in the Bart's and non-anemic groups, fetal anemia is significantly associated with cardiac mitochondrial dysfunction, increased mitochondrial fission, and increased inflammation and apoptosis. These findings indicate that an early phase of fetal anemia without cardiac iron overload can lead to cardiac mitochondrial dysfunction in fetuses with Hb Bart's.

Dynamic changes in ventricular depolarization during exercise in patients with Brugada syndrome.

Brugada syndrome (BS) is a genetic pathological condition associated with a high risk for sudden cardiac death (SCD). Ventricular depolarization disorders have been suggested as a potential electrophysiological mechanism associated with high SCD risk on patients with BS. This paper aims to characterize the dynamic changes of ventricular depolarization observed during physical exercise in symptomatic and asymptomatic BS patients. To this end, cardiac ventricular depolarization features were automatically extracted from 12-lead ECG recordings acquired during standardized exercise stress test in 110 BS patients, of whom 25 were symptomatic. Conventional parameters were evaluated, including QRS duration, R and S wave amplitudes (, ), as well as QRS morphological features, such as up-stroke and down-stroke slopes of the R and S waves (, and ). The effects of physical exercise and recovery on the dynamics of these markers were assessed in both BS populations. Features showing significantly different dynamics between the studied groups were used alone and in combination with the clinical characteristics of the patients in a logistic regression analysis. Results show larger changes in the second half of the QRS complex through and measured in the right precordial leads for asymptomatic patients, especially during recovery, when the vagal tone is more pronounced. Multivariate analysis involving both types of features resulted in a reduced model of three relevant features ( in lead V2, Sex and heart rate recovery, HRR), which achieved a suitable discrimination performance between groups; sensitivity = 80% and specificity = 75% (AUC = 83%). However, after controlling the model for possible confounding factors, only one feature () remained meaningful. This adjusted model significantly improved the overall discrimination performance by up to: sensitivity = 84% and specificity = 100% (AUC = 94%). The study highlights the importance of physical exercise test to unmask differentiated behaviors between symptomatic and asymptomatic BS patients through depolarization dynamic analysis. This analysis together with the obtained model may help to identify asymptomatic patients at low or high risk of future cardiac events, but it should be confirmed by further prospective studies.

Precordial bipolar leads: A new method to study anterior acute myocardial infarction

IntroductionA new ECG method produces Precordial Bipolar Leads (PBL) generated by subtraction of measurements of Standard Precordial Unipolar Leads (SPUL). This procedure brings new information about time/amplitude mismatch among SPUL, presenting it as tracings and local VCG loops exploring the precordial left-to-right axis on the horizontal plane. In this study, results of V2-V1 bipolar precordial derivation V2-V1 (right to left) and its relationship with the anteroposterior axis are presented. Material and methodsRecords of 37 patients and 15 controls from Physionet database were used to create new PBL and compare between V1 and V2 SPUL. So, bipolar V2-V1 was obtained by subtracting V1 measurements from V2, always having as positive the V2 SPUL and as negative V1. The algorithm used was subtracting, in every millisecond, the voltage recorded by the right electrode from the simultaneously recorded left electrode. Combination of SPUL and PBL can be presented as tracings or local loops, showing detailed information of the electric horizontal plane of the heart at retrosternal location. PBL V2-V1 reflects right ventricle and septal electric activity. ResultsThe new method is able to detect changes in vectors and differences of milliseconds between SPUL and presents new and important information about the right-to-left electric axis. Right ventricle and interventricular septum electric activity can be differentiate in anterior AMI and LBBB. ConclusionTime/amplitude mismatch between SPUL could be the source of abundant and new information about cardiac depolarization and repolarization. As data to obtain PBL and new loops are already obtained in any ECG device that records simultaneously 12 leads, the system can be added to ECG software algorithms without any additional cable or recording work.

Comparison of Activation Times Estimation for Potential-Based ECG Imaging.

Activation times (AT) describe the sequence of cardiac depolarization and represent one of the most important parameters for analysis of cardiac electrical activity. However, estimation of ATs can be challenging due to multiple sources of noise such as fractionation or baseline wander. If ATs are estimated from signals reconstructed using electrocardiographic imaging (ECGI), additional problems can arise from over-smoothing or due to ambiguities in the inverse problem. Often, resulting AT maps show falsely homogeneous regions or artificial lines of block. As ATs are not only important clinically, but are also commonly used for evaluation of ECGI methods, it is important to understand where these errors come from. We present results from a community effort to compare methods for AT estimation on a common dataset of simulated ventricular pacings. ECGI reconstructions were performed using three different surface source models: transmembrane voltages, epi-endo potentials and pericardial potentials, all using 2nd-order Tikhonov and 6 different regularization parameters. ATs were then estimated by the community participants and compared to the ground truth. While the pacing site had the largest effect on AT correlation coefficients (CC larger for lateral than for septal pacings), there were also differences between methods and source models that were poorly reflected in CCs. Results indicate that artificial lines of block are most severe for purely temporal methods. Compared to the other source models, ATs estimated from transmembrane voltages are more precise and less prone to artifacts.

The desire for physiological pacing: Are we there yet?

Pacing is a well established therapy for bradycardia support and certain types of heart failure. Despite technological advances the optimal pacing lead position remains controversial. Right ventricular pacing, particularly apical has been the site of choice but the induction of abnormal cardiac depolarization and the recognition of an increased risk of impairment of left ventricular systolic function, heart failure and mortality has driven a desire for a true physiological pacing system. A number of different lead positions have been determined and of these His bundle pacing appears to most closely mimic normal ventricular conduction. This article reviews the background to the development of physiological pacing, evaluates historical data for right ventricular pacing and the basis for change and new lead positions.

P1604Validating previously reported Brugada syndrome-associated common variants identified in caucasian population in the Han Chinese BrS cohort in Taiwan: SADS-BrS registry

Abstract Background Brugada syndrome (BrS) is a sudden arrhythmic death. The prevalence of BrS is higher in the Southeast Asian populations than that in Caucasian patients. A previous genome-wide association study (GWAS) has reported 13 SNPs significantly associated with BrS. However, no study was performed to validate whether these SNPs are enriched in BrS patients in Han Chinese (HC). Purpose Evaluating the common variants previously reported in Caucasian BrS patients could be generalized to HC BrS patients in Taiwan Methods We genotyped 200 unrelated BrS patients using Affymetrix TWB Array (N=653,291 SNPs, a customized array for HC in Taiwan). The controls are obtained from the Taiwan Biobank (N ≈ 16,000) using the same array. An imputation workflow was shown in Figure 1. To confirm the accuracy of the imputed genotype of each variant, Sanger sequencing was performed in 10% of randomly selected cases. Results Among the 3 most important common variants (rs11708996 in SCN5A, rs10428132 in SCN10A and rs9388451 in HEY2/NCOA7) reported in the previous GWAS mainly conducted in Caucasian BrS patients, 2 of them (rs10428132 and rs9388451) were successfully replicated in the HC population in Taiwan (P<0.01). We also found that the differences of minor allele frequency (dMAF: the MAF of cases minus the MAF of controls) of the two variants were relatively smaller between the BrS cases and healthy controls in HC population compared with that in Caucasian populations (dMAF, rs9388451: 0.15 (Caucasian) vs −0.07 (HC); rs10428132: 0.28 (Caucasian) vs 0.11 (HC)). For the remaining 10 common variants reaching genome-wide significance (P=5×10–8) in Caucasian BrS patients, 9 of them were also significantly enriched in the HC BrS patients after the Bonferroni correction (P<0.05/12=0.0042). We next analyzed the variants identified in the previous GWAS on ECG traits (PR interval, QRS duration, QTc interval, and heart rate) in the Caucasian population. Among the reported 75 variants associated with ECG traits, 5 common variants (rs6798015 (PR), rs1760876 (QRS), rs6795970 (PR/QRS), rs2074238 (QTc) and rs314370 (heart rate)) were significant after Bonferroni correction (P<0.05/75=0.00066). Figure 1 Conclusions The preliminary results indicated that 85% of common variants of SCN10A and HEY2/NCOA7 previously reported in Caucasian BrS patients are replicated in BrS patients in the HC population but not the common variant of SCN5A (rs11708996). Furthermore, the common variants of SCN10A and HEY2/NCOA7 related to cardiac depolarization or repolarization may also contribute to the development of BrS. Acknowledgement/Funding NTUH 106-S3469, NTUH106-S3458 and NTUH 106-018

Assessment of the effect of erdafitinib on cardiac safety: analysis of ECGs and exposure–QTc in patients with advanced or refractory solid tumors

To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors. Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12mg. Triplicate ECG monitoring continued in Parts 2-4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration-QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data. Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration-QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as - 0.00269ms/(ng/mL) and - 1.138ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9mg daily) was < 10ms at the upper bound of the two-sided 90% confidence interval. ECG data and the concentration-QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters. Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34.

Toward a novel semi-invasive activation mapping tool for the diagnosis of supraventricular arrhythmias from the esophagus.

Supraventricular arrhythmia diagnosis using the surface electrocardiogram (sECG) is often cumbersome due to limited atrial signal quality. In some instances, use of esophageal electrocardiography (eECG) may facilitate the diagnosis. Here, we present a novel approach to reconstruct cardiac activation maps from eECG recordings. eECGs and sECGs were recorded from 19 individuals using standard acquisition tools. From the recordings, algorithms were developed to estimate the esophageal ECG catheter's position and to reconstruct high-resolution mappings of the cardiac electric activity projected in the esophagus over time. Esophageal two-dimensional activation maps were created for five healthy individuals and 14 patients suffering from different arrhythmias. The maps are displayed as time-dependent contour plots, which not only show voltage over time as conventional ECGs, but also the location, direction, and projected propagation speed of the cardiac depolarization wavefront in the esophagus. Representative examples of sinus rhythm, atrial flutter, and ventricular pre-excitation are shown. The methodology presented in this report provides a high-resolution view of the cardiac electric field in the esophagus. It is the first step toward a three-dimensional mapping system, which shall be able to reconstruct a three-dimensional view of the cardiac activation from recordings within the esophagus.

On-chip spatiotemporal electrophysiological analysis of human stem cell derived cardiomyocytes enables quantitative assessment of proarrhythmia in drug development

We examined a simultaneous combined spatiotemporal field potential duration (FPD) and cell-to-cell conduction time (CT) in lined-up shaped human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using an on-chip multielectrode array (MEA) system to evaluate two origins of lethal arrhythmia, repolarization and depolarization. The repolarization index, FPD, was prolonged by E-4031 and astemizole, and shortened by verapamil, flecainide and terfenadine at 10 times higher than therapeutic plasma concentrations of each drug, but it did not change after lidocaine treatment up to 100 μM. CT was increased by astemizol, flecainide, terfenadine, and lidocaine at equivalent concentrations of Nav1.5 IC50, suggesting that CT may be an index of cardiac depolarization because the increase in CT (i.e., decrease in cell-to-cell conduction speed) was relevant to Nav1.5 inhibition. Fluctuations (short-term variability; STV) of FPD and CT, STVFPD and STVCT also discriminated between torsadogenic and non-torsadogenic compounds with significant increases in their fluctuation values, enabling precise prediction of arrhythmogenic risk as potential new indices.

Cardiac repolarization and depolarization in people with Type 1 diabetes with normal ejection fraction and without known heart disease: a case-control study.

To investigate depolarization and repolarization durations in people with Type 1 diabetes, including the relationship to age. 855 persons with Type 1 diabetes without known heart disease were included and matched with 1710 participants from a general population study. Clinical examinations, questionnaires and biochemistry were assessed. A 10-second 12-lead ECG was performed and analysed digitally. QTc was longer in people with Type 1 diabetes compared to controls (414±16 vs. 411±19 ms, P <0.001), and particularly so in young people with Type 1 diabetes. The fully adjusted increase was 13.8 ms (95% confidence interval (CI): 8.6-19.0 ms, P <0.001) at age 20 years and 3.4 ms (CI: 1.5-5.3 ms, P<0.001) at age 40 years. The rate-corrected QRSc was increased in people with Type 1 diabetes (97±11 vs. 95±11 ms, P <0.001) and was age-independent (P =0.5). JTc was increased in the young people with Type 1 diabetes (10.7 ms (CI: 5.4-16.0 ms, P <0.001) at age 20 years), but not in older people with Type 1 diabetes (interaction age-diabetes, P <0.01). For people with Type 1 diabetes, cardiac depolarization is increased at all ages, whereas repolarization is increased only relatively in young people with Type 1 diabetes. Hence, young people with Type 1 diabetes may be more prone to ventricular arrhythmias. The findings contribute to the understanding of sudden cardiac death in young people with Type 1 diabetes.

Maturation of the QT Variability Index is Impaired in Preterm Infants

Reduced heart rate (HR) variability in preterm infants compared with full-term infants suggests that autonomic cardiac control is developmentally delayed. However, the association between developmental changes in myocardial repolarization and gestational age remains unknown. This study investigated the association between the myocardial repolarization lability index, namely the QT variability index (QTVI) = log10 [(QTv/QTm2)/(HRv/HRm2)], and the perinatal profile of healthy 1-month-old infants. We included 209 infants (143 boys and 87 girls; mean gestational weeks at birth, 38.6 ± 1.7) who were born in university hospitals between 2014 and 2015 without apparent cardiac disease. We compared the ECG variability indices in 28 infants born before 37 gestational weeks (mean gestational weeks at birth, 35.6 ± 1.1 as preterm) and 181 infants born at the average number of gestational weeks (mean gestational weeks at birth, 38.8 ± 1.1 as controls). There was a negative correlation between the QTVI and gestational weeks (r = − 0.460, p = 0.035). QTVI values in preterm infants were larger than those in the controls (0.01 ± 0.50 vs. −0.26 ± 0.48, p = 0.023). In conclusion, the QTVI is negatively correlated with gestational age. The QTVI can serve as an index of the maturity of the cardiac autonomic nervous system and myocardial depolarization.

CaMKII-dependent endoplasmic reticulum fission by whisker stimulation and during cortical spreading depolarization.

Cortical spreading depolarization waves, the cause underlying migraine aura, are also the markers and mechanism of pathology in the acutely injured human brain. Propagation of spreading depolarization wave uniquely depends on the interaction between presynaptic and postsynaptic glutamate N-methyl-d-aspartate receptors (NMDARs). In the normally perfused brain, even a single wave causes a massive depolarization of neurons and glia, which results in transient loss of neuronal function and depression of the ongoing electrocorticographic activity. Endoplasmic reticulum is the cellular organelle of particular importance for modulation of neurotransmission. Neuronal endoplasmic reticulum structure is assumed to be persistently continuous in neurons, but is rapidly lost within 1 to 2 min of global cerebral ischaemia, i.e. the organelle disintegrates by fission. This phenomenon appears to be timed with the cardiac arrest-induced cortical spreading depolarizations, rather than ensuing cell death. To what extent NMDAR-dependent processes may trigger neuronal endoplasmic reticulum fission and whether fission is reversible in the normally perfused brain is unknown. We used two-photon microscopy to examine neuronal endoplasmic reticulum structural dynamics during whisker stimulation and cortical spreading depolarizations in vivo. Somatosensory stimulation triggered loss of endoplasmic reticulum continuity, a likely outcome of constriction and fission, in dendritic spines within less than 10 s of stimulation, which was spontaneously reversible and recovery to normal took 5 min. The endoplasmic reticulum fission was inhibited by blockade of NMDAR and Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated downstream of the NMDARs, whereas inhibition of guanosine triphosphate hydrolases hindered regain of endoplasmic reticulum continuity, i.e. fusion. In contrast to somatosensory stimulation, endoplasmic reticulum fission during spreading depolarization was widespread and present in dendrites and spines, and was preceded by dramatic rise in intracellular Ca2+. The endoplasmic reticulum fission during spreading depolarization was more persistent, as 1 h after the depolarization cortical neurons still exhibited loss of endoplasmic reticulum continuity. Notably, endoplasmic reticulum fission was accompanied with loss of electrocorticographic activity, whereas subsequent regain of synaptic function paralleled the organelle fusion. Furthermore, blocking CaMKII activity partly rescued endoplasmic reticulum fission and markedly shortened the recovery time of brain spontaneous activity. Thus, prevention of endoplasmic reticulum fission with CaMKII inhibitors may be a novel strategy to rescue brain function in patients with migraine and a promising therapeutic avenue in the acutely injured brain.

Impact of the Norepinephrine Prodrug Droxidopa on the QTc Interval in Healthy Individuals.

A double‐blind, 4‐period crossover study (NCT01327066) was conducted to assess the effect of the novel norepinephrine prodrug droxidopa on the QT interval in in healthy subjects. Subjects were randomized to receive a single dose of droxidopa 600 mg (maximal dose) and 2000 mg (supratherapeutic dose) compared with the positive control, moxifloxacin 400 mg, and placebo, each separated by a 3‐day washout period. Patients were monitored by continuous Holter monitoring, and electrocardiograms (ECGs) were extracted 0.5–23 hours after dosing. Blood samples for pharmacokinetic analysis were collected before dosing and after ECG data collection. The primary end point was the time‐matched placebo‐adjusted change from baseline in the individually corrected QT (QTcI). The time‐averaged QTcI mean placebo‐corrected changes from baseline for droxidopa 600 and 2000 mg were 0.1 milliseconds (90%CI, ‐0.9 to 1.0 milliseconds) and 0.3 milliseconds (90%CI, ‐0.6 to 1.3 milliseconds), respectively, and 9 milliseconds (90%CI, 8.4–10.3 milliseconds) for moxifloxacin. This study found no effect of either dose of droxidopa on cardiac repolarization using QTcI. Analysis of the pharmacokinetic/pharmacodynamic relationship and cardiac repolarization showed no association with droxidopa exposure. There were no clinically relevant effects of droxidopa on heart rate, atrioventricular conduction, or cardiac depolarization identified. No morphologic ECG changes were observed.

073_16774-Q1 Automatic Sensitivity in Patients With Dual Chamber Pacemaker: Is it Always Necessary to Program it?

Sensitivity defines the ability of cardiac pacemaker and implanted cardiac defibrillator (ICD) to correctly detect spontaneous cardiac events. The amplitude of the spontaneous cardiac depolarization signals is variable and when the amplitude of signals is associated with atrial or ventricular

High resolution 3-Dimensional imaging of the human cardiac conduction system from microanatomy to mathematical modeling

Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the specialised cardiomyocytes known collectively as the cardiac conduction system. Here, using contrast enhanced micro-computed tomography, we present, in attitudinally appropriate fashion, the first 3-dimensional representations of the cardiac conduction system within the intact human heart. We show that cardiomyocyte orientation can be extracted from these datasets at spatial resolutions approaching the single cell. These data show that commonly accepted anatomical representations are oversimplified. We have incorporated the high-resolution anatomical data into mathematical simulations of cardiac electrical depolarisation. The data presented should have multidisciplinary impact. Since the rate of depolarisation is dictated by cardiac microstructure, and the precise orientation of the cardiomyocytes, our data should improve the fidelity of mathematical models. By showing the precise 3-dimensional relationships between the cardiac conduction system and surrounding structures, we provide new insights relevant to valvar replacement surgery and ablation therapies. We also offer a practical method for investigation of remodelling in disease, and thus, virtual pathology and archiving. Such data presented as 3D images or 3D printed models, will inform discussions between medical teams and their patients, and aid the education of medical and surgical trainees.

P1080Hypothermia-induced differential effects on cardiac depolarisation and repolarisation in vivo

P1080Hypothermia-induced differential effects on cardiac depolarisation and repolarisation in vivo