Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog.

An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and Tpeak-Tend, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating IKr inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na+ or Ca2+ channel inhibition in vivo. Peramivir prolonged Tpeak-Tend and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tpeakc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.

In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events.

Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.

Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.

We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization.

Transient cardiac electrophysiological changes in a rat model of subarachnoid haemorrhage: a brain-heart interaction.

AIMS: Subarachnoid haemorrhage (SAH) is one of the causes of sudden cardiac death (SCD). However, the time course of ventricular arrhythmias and potential mechanisms responsible for this effect after SAH remain unknown. OBJECTIVE: This study aims to investigate the effect of SAH on ventricular electrophysiological changes and its potential mechanisms in long-term phase. METHODS AND RESULTS: We examined the ventricular electrophysiological remodelling and potential mechanisms in a Sprague Dawley rat model of SAH at six time points (baseline, and Days 1, 3, 7, 14 and 28) and explored the potential mechanisms. We measured the ventricular effective refractory period (ERP), ventricular fibrillation threshold (VFT) and left stellate ganglion (LSG) activity at different time points before and after SAH. We also detected neuropeptide Y (NPY) levels in plasma and myocardial tissues by enzyme-linked immunosorbent assay, and quantified NPY 1 receptor (NPY1R) protein and mRNA expression levels by western blotting and quantitative real-time reverse transcription-polymerase chain reaction, respectively. Subarachnoid haemorrhage gradually prolonged QTc intervals, shortened ventricular ERP and reduced VFT during the acute phase, peaking at Day 3. However, no significant changes were observed from Days 14 to 28 compared to Day 0. Subarachnoid haemorrhage gradually increased LSG activity, increased NPY concentrations and up-regulated NPY1R expression in the acute phase of SAH, peaking at Day 3. However, no significant variations were found from Days 14 to 28 compared to Day 0. CONCLUSION: Subarachnoid haemorrhage increases the transient susceptibility of VAs in the acute phase, and the underlying mechanisms for this response included increased sympathetic activity and up-regulated NPY1R expression.

Incorrectly corrected? QT interval analysis in rats and mice.

QT interval, a surrogate measure for ventricular action potential duration (APD) in the surface ECG, is widely used to identify cardiac abnormalities and drug safety. In humans, cardiac APD and QT interval are prominently affected by heart rate (HR), leading to widely accepted formulas to correct the QT interval for HR changes (QT corrected - QTc). While QTc is widely used in the clinic, the proper way to correct the QT interval in small mammals such as rats and mice is not clear. Over the years, empiric correction formulas were developed for rats and mice, which are widely used in the literature. Recent experimental findings obtained from pharmacological and direct pacing experiments in unanesthetized rodents show that the rate-adaptation properties are markedly different from those in humans and the use of existing QTc formulae can lead to major errors in data interpretation. In the present review, these experimental findings are summarized and discussed.

Dual atrioventricular nodal non-reentrant tachycardia: Various atrioventricular conduction responses to atrioventricular simultaneous pacing.

BACKGROUND: Specific pacing methods to unmask the existence of the dual atrioventricular (AV) nodal pathway in patients with dual AV nodal non-reentrant tachycardia remain to be established. OBJECTIVE: This study aimed to determine the electrophysiological characteristics of dual AV nodal non-reentrant tachycardia by its responses to specific pacing methods. METHODS: Five patients diagnosed as having dual AV nodal non-reentrant tachycardia were retrospectively investigated. RESULTS: Atrial pacing could not induce the clinical tachycardia as continuous double firing in any of the 5 patients, but did induce sudden prolongation of the A-H interval as the linking phenomenon in 1 patient. A single atrial extrastimulation after sinus excitations was performed without interruption of double firing in 1 patient, and it induced the double ventricular response phenomenon within the limited range of the extrastimulus intervals. The pacing method of AV simultaneous basic pacing preceding atrial programmed extrastimulation did not allow interruptions of double firing during the basic drive trains and induced the double ventricular response phenomenon within the limited range of the extrastimulus intervals in all 5 patients, even in 1 patient without inducibility of the clinical tachycardia in the catheterization laboratory. The double ventricular response phenomenon within the limited range of the extrastimulus intervals may be based on the existence of the dual AV nodal pathway with concealed retrograde penetration. CONCLUSION: The AV simultaneous basic pacing preceding atrial programmed extrastimulation method consistently and reproducibly unmasked the existence of the dual AV nodal pathway as the double ventricular response phenomenon in patients with dual AV nodal non-reentrant tachycardia.

The role of alcohol consumption on echocardiographic and electrophysiologic changes in atrial fibrillation.

BACKGROUND: A wealth of evidence suggests that alcohol consumption is a risk factor for atrial fibrillation (AF); however, the mechanisms underlying this association are unclear. This makes it challenging to develop therapeutic strategies in patients with AF attributed to alcohol consumption. PURPOSE: To investigate the echocardiographic and electrophysiologic changes caused by alcohol consumption in patients with AF. METHODS: The study was registered in Chinese Clinical Trial Registry (Registration number ChiCTR2000041575). Data on 134 consecutive non-valvular AF patients who underwent radiofrequency catheter ablation in our center was collected from April 1, 2019 to June 30, 2020. Patients were divided into no-alcohol (72) and alcohol groups [categorized into light (34), moderate (11) and heavy (17) alcohol consumption]. All patients underwent echocardiographic and electrophysiologic examinations for the assessment of left atrial (LA) strain, inter-atrial conduction, intra-atrial conduction, and atrial effective refractory period (ERP). RESULTS: Overall, the mean age was 61 ± 11 years and 87 (65%) were males. Compared with the no-alcohol group, impaired peak LA longitudinal strain, obvious inter-atrial conduction delay and increasing ERP dispersion were observed in the alcohol group. Intra-atrial conduction delay and ERP dispersion increased with increasing amounts of alcohol consumption. CONCLUSION: Alcohol consumption was associated with substantial abnormal echocardiographic and electrophysiologic changes in AF patients. These changes may contribute to the occurrence and progression of AF attributed to alcohol consumption, which may help in the development of new strategies for the prevention and management of AF. However further investigation is required.

Glucocorticoid Induces Atrial Arrhythmogenesis via Modification of Ion Channel Gene Expression in Rats.

Excess psychological stress is one of the precipitating factors for paroxysmal atrial fibrillation (AF), although the involved mechanisms are still uncertain. To test a hypothesis that one of the stress-induced hormones, glucocorticoid, is involved in the pathogenesis of stress-induced AF, we investigated whether the glucocorticoid could alter the temporal profile of cardiac ion channels gene expression, thereby leading to atrial arrhythmogenesis.Dexamethasone (DEX, 1.0 mg/kg) was injected subcutaneously in Sprague-Dawley rats. At predetermined times after DEX injection (0, 1, 3, 6, 12, and 24 hours), the mRNA levels of cardiac ion channel genes (erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2, SUR2A, Kir6.2, Kir3.4, Kir3.1 Kir2.2, Kir2.1, SCN5A, and α1C) were determined using RNase protection assay. DEX induced immediate and transient increase in the mRNA level of Kv1.5 and Kir2.2 with peaks at 6 (5.0 fold) and 3 hours (3.3 fold) after DEX injection, respectively. Patch-clamp studies revealed a significantly increased current density of the corresponding current, IKur and IK1 at 6 hours after DEX injection. Simultaneously, electrophysiological study in isolated perfused hearts showed significantly increased number of repetitive atrial responses induced by single atrial extrastimulus (3.2 ± 2.4 to 26.7 ± 16.4, P = 0.004) with shorting of the refractory period (36.4 ± 4.6 to 27.4 ± 5.5 ms, P = 0.049) after DEX injection.Glucocorticoid immediately modified Kv1.5 and Kir2.2 gene expression at pretranslational levels, thus leading to effective refractory period shortening that could be arrhythmogenic. These results implied that transient glucocorticoid-induced biochemical modification of cardiac ion channels might be one of the mechanisms underlying the stress-induced paroxysmal AF.

Location and coupling interval of an ectopic excitation determine the initiation of atrial fibrillation from the pulmonary veins.

INTRODUCTION: Ectopic beats originating from the pulmonary vein (PV) trigger atrial fibrillation (AF). The purpose of this study was to clarify the electrophysiological determinant of AF initiation from the PVs. METHODS: Pacing studies were performed with a single extra stimulus mimicking an ectopic beat in the left superior PVs (LSPVs) in 62 patients undergoing AF ablation. Inducibility of AF, effective refractory period (ERP), and conduction properties within the PVs were analyzed. RESULTS: A single extra stimulus in LSPV induced AF in 20 patients (32% of all patients) at the mean coupling interval (CI) of 172 ms. A CI-dependent anisotropic conduction at the AF onset was visualized in a three-dimensional mapping. Onset of AF was site-specific with reproducibility in each individual. Mean ERP in LSPV in the AF-inducible group was shorter than that in the AF-noninducible group (182 ± 55 vs. 254 ± 51 ms, p < .0001). LSPV ERP dispersion was greater in the AF-inducible group than in the AF-noninducible group (45 ± 28 vs. 27 ± 19 ms, p < .01). Circumferential intra-PV conduction time (IPVCT) exhibited decremental properties in response to shortening of CI and the prolongation of IPVCT in the AF-inducible site was greater than that in the AF-noninducible site (p < .05) in each individual. CONCLUSIONS: Location and CI of an ectopic excitation ultimately determine the initiation of AF from the PVs. ERP dispersion and circumferential conduction delay may lead to anisotropic conduction and reentry within the PVs that initiate AF.

Simultaneous analyses of hemodynamic and electrophysiological effects of oseltamivir along with its pharmacokinetic profile using the canine paroxysmal atrial fibrillation model.

Since information of antiviral drug oseltamivir on the anti-atrial fibrillation (AF) property is still limited, we assessed it using the canine paroxysmal AF model. Oseltamivir in doses of 3 and 30 mg/kg/10 min was intravenously infused to the isoflurane-anesthetized, chronic atrioventricular block dogs (n = 6) with monitoring hemodynamic and electrophysiological variables, in which AF was induced by 10 s of burst pacing on atrial septum. Oseltamivir decreased AF incidence and AF duration, and prolonged AF cycle length in a dose-dependent manner. The low and high doses attained the peak plasma drug concentrations of 9.7 and 96.5 µg/mL, which were approximately 100 and 1000 times greater than those observed in human clinical cases, respectively. The low dose of oseltamivir decreased mean blood pressure without altering sinoatrial or idioventricular rate, whereas its high dose reduced each of them. Oseltamivir delayed inter-atrial conduction in dose- and frequency-dependent manners, whereas it prolonged atrial effective refractory period in dose-dependent but frequency-independent manners. The high dose prolonged ventricular effective refractory period, which was not detected with the low dose. These findings can be used for repurposing oseltamivir as an anti-AF drug candidate.

Vagal response during circumferential pulmonary vein isolation decreases the recurrence of atrial fibrillation in the short-term in patients with paroxysmal atrial fibrillation: A prospective, observational study.

BACKGROUND: Vagal responses (VRs) are often seen in patients undergoing circumferential pulmonary vein isolation (CPVI). The possible mechanism of VR is that CPVI creates a coincidental modification of the cardiac ganglionated plexi (GP). AIM: To investigate whether the presence of VR during CPVI impacts post-ablation recurrence in patients with paroxysmal atrial fibrillation (AF). METHODS: A total of 112 consecutive patients with symptomatic paroxysmal AF who underwent CPVI for the first time from October 1, 2017 to April 30, 2019 were prospectively enrolled, of which two were lost the follow-up. Patients were divided into two groups based on whether VRs were experienced during CPVI. Electrophysiological parameters, including atrial effective refractory period (AERP) and mean heart rate (MHR), were measured before and post-ablation. The patients were then followed up for 12 months. RESULTS: The 71 patients who had experienced VRs during CPVI were assigned to group B, and the remaing 39 patients who did not experience VR during CPVI were assigned to group A. The MHR (79.6 ± 8.3 vs 70.4 ± 7.8 b/min; p ≤ 0.001) was significantly higher; and the AERP (244 ± 22 vs 215 ± 27 ms; p ≤ 0.001) was prolonged in group B compared to respective pre-ablation values. There were no significant changes in the MHR (69.5 ± 7.9 vs 69.7 ± 8.7 b/min; p = 0.541) and AERP (224 ± 28 vs 225 ± 33 ms; p = 0.542) in group A. During the first four months of follow-up after ablation, the MHR gradually slowed down to pre-procedural levels in group B. The recurrence of AF (6/71 vs 7/39; p = 0.023) significantly decreased in group B relative to group A during the first 6 months after ablation, but there was no significant difference (14/71 vs 9/39; p = 0.598) at the end of the 12-month follow-up period. CONCLUSION: Patients with paroxysmal AF who develop VRs during CPVI might have a decreased recurrence of AF and accelerated MHR in the short-term.

Cycle length statistics during human atrial fibrillation reveal refractory properties of the underlying substrate: a combined in silico and clinical test of concept study.

AIMS: The treatment of atrial fibrillation beyond pulmonary vein isolation has remained an unsolved challenge. Targeting regions identified by different substrate mapping approaches for ablation resulted in ambiguous outcomes. With the effective refractory period being a fundamental prerequisite for the maintenance of fibrillatory conduction, this study aims at estimating the effective refractory period with clinically available measurements. METHODS AND RESULTS: A set of 240 simulations in a spherical model of the left atrium with varying model initialization, combination of cellular refractory properties, and size of a region of lowered effective refractory period was implemented to analyse the capabilities and limitations of cycle length mapping. The minimum observed cycle length and the 25% quantile were compared to the underlying effective refractory period. The density of phase singularities was used as a measure for the complexity of the excitation pattern. Finally, we employed the method in a clinical test of concept including five patients. Areas of lowered effective refractory period could be distinguished from their surroundings in simulated scenarios with successfully induced multi-wavelet re-entry. Larger areas and higher gradients in effective refractory period as well as complex activation patterns favour the method. The 25% quantile of cycle lengths in patients with persistent atrial fibrillation was found to range from 85 to 190 ms. CONCLUSION: Cycle length mapping is capable of highlighting regions of pathologic refractory properties. In combination with complementary substrate mapping approaches, the method fosters confidence to enhance the treatment of atrial fibrillation beyond pulmonary vein isolation particularly in patients with complex activation patterns.

An exploratory analysis of effects of poyendarone, a deuterated analogue of dronedarone, on the canine model of paroxysmal atrial fibrillation.

Poyendarone, a deuterated analogue of dronedarone, is expected to reduce the onset of cardiovascular adverse events of dronedarone, including congestive heart failure and excessive QT-interval prolongation. Since information is still lacking on the anti-atrial fibrillatory property of poyendarone, we assessed it along with effects on the inter-atrial conduction time (IACT) and atrial effective refractory period (AERP) using the canine paroxysmal atrial fibrillation model. Poyendarone hydrochloride (n = 4) and dronedarone hydrochloride (n = 4) in intravenous doses of 0.3 and 3 mg/kg/30 s were cumulatively administered. Poyendarone hardly altered sinoatrial rate, but dronedarone decreased it in a dose-related manner, whereas both drugs slightly but significantly reduced idioventricular rate. Poyendarone shortened duration of burst pacing-induced atrial fibrillation, whereas such abbreviation was not observed by dronedarone. Poyendarone and dronedarone similarly prolonged IACT in a frequency-dependent manner, indicating that their INa inhibitory actions may be similar. The high dose of poyendarone prolonged AERP in a reverse frequency-dependent manner, extent of which at basic pacing cycle lengths of 300 and 400 ms was comparable to that of dronedarone. However, the extent at a basic pacing cycle length of 200 ms was tended to be greater in poyendarone than in dronedarone, suggesting greater IKs inhibitory action of poyendarone. The deuteration of dronedarone attenuated the inhibition of sinus automaticity and prolonged the AERP with keeping the blood pressure and ventricular rate stable. Thus, poyendarone may have both more potent anti-atrial fibrillatory action and wider cardiovascular safety margin than dronedarone.

Effects of genetic background, sex, and age on murine atrial electrophysiology.

AIMS: Genetically altered mice are powerful models to investigate mechanisms of atrial arrhythmias, but normal ranges for murine atrial electrophysiology have not been robustly characterized. METHODS AND RESULTS: We analyzed results from 221 electrophysiological (EP) studies in isolated, Langendorff-perfused hearts of wildtype mice (114 female, 107 male) from 2.5 to 17.7 months (mean 7 months) with different genetic backgrounds (C57BL/6, FVB/N, MF1, 129/Sv, Swiss agouti). Left atrial monophasic action potential duration (LA-APD), interatrial activation time (IA-AT), and atrial effective refractory period (ERP) were summarized at different pacing cycle lengths (PCLs). Factors influencing atrial electrophysiology including genetic background, sex, and age were determined. LA-APD70 was 18 ± 0.5 ms, atrial ERP was 27 ± 0.8 ms, and IA-AT was 17 ± 0.5 ms at 100 ms PCL. LA-APD was longer with longer PCL (+17% from 80 to 120 ms PCL for APD70), while IA-AT decreased (-7% from 80 to 120 ms PCL). Female sex was associated with longer ERP (+14% vs. males). Genetic background influenced atrial electrophysiology: LA-APD70 (-20% vs. average) and atrial ERP (-25% vs. average) were shorter in Swiss agouti background compared to others. LA-APD70 (+25% vs. average) and IA-AT (+44% vs. average) were longer in 129/Sv mice. Atrial ERP was longer in FVB/N (+34% vs. average) and in younger experimental groups below 6 months of age. CONCLUSION: This work defines normal ranges for murine atrial EP parameters. Genetic background has a profound effect on these parameters, at least of the magnitude as those of sex and age. These results can inform the experimental design and interpretation of murine atrial electrophysiology.

A new implantable tool for repeated assessment of supraventricular electrophysiology and atrial fibrillation susceptibility in freely moving rats.

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties, including atrial effective refractory period (AERP) and conduction velocity, are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles, and stainless-steel fixating pins. Initial quality validation was performed ex vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4, and 8 wk postimplantation. Capture threshold was stable. Baseline AERP values (38.1 ± 2.3 and 39.5 ± 2.0 using 70-ms and 120-ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are nonphysiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research.NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, technical challenges restrict long-term supraventricular electrophysiology studies in these species. Here, we developed an implantable electrode adapted for such studies in the rat. Our findings indicate that this new tool is effective for long-term follow-up of critical parameters such as atrial refractoriness. Obtained data shed light on the normal electrophysiology and on the increased AF susceptibility that develops in rats with implanted atrial electrodes over time.

A simple and practical criterion for determining a failed His-bundle pacing.

AIMS: To establish a simple criterion for determining a failed His-bundle pacing (HBP). This criterion states that if stimulus to QRS end interval is longer than His-bundle potential to QRS end interval ('S-QRSend > H-QRSend') then a failed HBP can be determined. METHODS AND RESULTS: We performed retrospective analysis on 737 pacing tests around His-bundle in 241 patients and prospective analysis on 400 tests in 123 patients. A successful HBP is defined as that whole His-bundle is captured with or without capture of adjacent ventricular myocardium, otherwise, a failed HBP was considered. The output criteria and effective refractory period criteria were used as the gold standards for determining a successful HBP. The gold standards are that if decreasing the pacing output or pacing cycle length to a certain level results in duration or morphology changes of QRS, then a successful HBP is ascertained. In retrospective analysis of patients with normal His-Purkinje conduction, a failed HBP was determined in 31% (154/492) of pacing tests according to 'S-QRSend > H-QRSend'; all of them were validated by the gold standards (specificity = 100%). In prospective study, a failed HBP was confirmed according to the simple criterion with 100% accuracy in 33% (79/241) pacing tests. This simple criterion was also suitable for patients with His-Purkinje conduction disease although cases with 'S-QRSend > H-QRSend' rarely occurred. CONCLUSION: A failed HBP can be easily and reliably determined solely by 'S-QRSend > H-QRSend' in more than 30% pacing tests.

Novel Assessment of Accessory Pathway Function in Patients with Wolff-Parkinson-White Syndrome.

Surrogates for the shortest pre-excited R-R interval in atrial fibrillation (SPERRI) such as the accessory pathway effective refractory period (APERP) and shortest pre-excited paced cycle length (SPPCL) are flawed assessments of accessory pathway function in patients with WPW. Multi-extrastimulus pacing may have the theoretical advantage of more accurately mimicking the clinical reality of atrial fibrillation and thus may serve to better assess accessory pathway function. This cross-sectional study included 25 consecutive patients, aged ≤ 18 years, undergoing electrophysiology study for WPW. The longest S1S2, S2S3, S3S4 coupling intervals at which the antegrade AP refractoriness occurred, SPERRI, and SPPCL were recorded. Induction of atrial fibrillation was attempted in all patients and induced in 8 (32%, 4 SPERRIbaseline (265 ms ± 61 ms), 4 SPERRIIsuprel (258 ms ± 41 ms)). At baseline, the lower value of the S3ERP or S4ERP (274 ms ± 52 ms) was lower than the SPPCL (296 ms ± 54 ms, p < 0.0001) and APERP (296 ms ± 41 ms, p < 0.0001). More patients had S3ERP or S4ERP ≤ 250 ms (12/25, 48%) compared to those with APERP ≤ 250 ms (2/25 8%), p = 0.0016), SPPCL 5/24, 20%), p = 0.008 or either (6/25, 24%), p = 0.0143). With Isuprel, the lower value of the S3ERP or S4ERP (221 ms ± 36 ms) trended to be lower than the APERP (252 ms ± 36 ms, p = 0.0001) and the SPPCL (266 ms ± 57 ms, p = 0.001). With Isuprel, there was no statistical difference in the proportion of patients with S3ERP or S4ERP < 250 ms (12/16, 75%) compared to those with APERP ≤ 250 ms ((9/16, 56%), p = 0.08), SPPCL ≤ 250 ms ((9/16, 56%), p = 0.08), or either ((10/16, 63%), p = 0.16). Multi-extrastimulus pacing protocols demonstrate that accessory pathways are less refractory than as defined by single extrastimulus pacing and straight decremental pacing.

Programmed deep septal stimulation: A novel maneuver for the diagnosis of left bundle branch capture during permanent pacing.

INTRODUCTION: Permanent deep septal stimulation with capture of the left bundle branch (LBB) enables maintenance/restoration of the physiological activation of the left ventricle. However, it is almost always accompanied by the simultaneous engagement of the local septal myocardium, resulting in a fused (nonselective) QRS complex, therefore, confirmation of LBB capture remains difficult. METHODS: We hypothesized that programmed extrastimulus technique can differentiate nonselective LBB capture from myocardial-only capture as the effective refractory period (ERP) of the myocardium is different from the ERP of the LBB. Consecutive patients undergoing pacemaker implantation underwent programmed stimulation delivered from the lead implanted in a deep septal position. Responses to programmed stimulation were categorized on the basis of sudden change in the QRS morphology of the extrastimuli, observed when ERP of LBB or myocardium was encroached upon, as: "myocardial," "selective LBB," or nondiagnostic (unequivocal change of QRS morphology). RESULTS: Programmed deep septal stimulation was performed 269 times in 143 patients; in every patient with the use of a basic drive train of 600 milliseconds and in 126 patients also during intrinsic rhythm. The average septal-myocardial refractory period was shorter than the LBB refractory period: 263.0 ± 34.4 vs 318.0 ± 37.4 milliseconds. Responses diagnostic for LBB capture ("myocardial" or "selective LBB") were observed in 114 (79.7%) of patients. CONCLUSIONS: A novel maneuver for the confirmation of LBB capture during deep septal stimulation was developed and found to enable definitive diagnosis by visualization of both components of the paced QRS complex: selective paced LBB QRS and myocardial-only paced QRS.

Cold-inducible RNA-binding protein modulates atrial fibrillation onset by targeting multiple ion channels.

BACKGROUND: Atrial fibrillation (AF), the most common sustained arrhythmia, significantly increases cardiovascular and cerebrovascular morbidity and mortality. The pathogenesis and treatment of AF remain a major challenge in the field of cardiology. We previously found that cold-inducible RNA-binding protein (CIRP) regulated ventricular repolarization by posttranscriptionally regulating Kv4.2/4.3 ion channels in rats, but the role of CIRP in AF is not clear. OBJECTIVE: The purpose of this study was to confirm that CIRP participates in atrial electrophysiological remodeling and AF occurrence by regulating atrial channels posttranscriptionally. METHODS: Programmed intra-atrial stimulation was used to induce AF in wild-type or transcription activator-like effector nucleases-based CIRP knockout (KO) rats. Atrial optical mapping, patch clamp, Western blotting, RNA immunoprecipitation, and luciferase reporter assays were performed to evaluate the underlying mechanism of atrial electrical remodeling. RESULTS: First, we observed a shortened atrial effective refractory period and increased susceptibility to AF in CIRP KO rats. Second, atria-specific CIRP delivery through an adeno-associated viral vector serotype 9 prolonged the atrial effective refractory period and attenuated AF development in CIRP KO rats. Third, we observed the shortened action potential duration and enhanced expression of Kv1.5 and Kv4.2/4.3 in KO rats. The transient outward current blocker 4-Aminopyridine and ultrarapid component of the delayed rectifier current blocker Diphenyl phosphine oxide-1 restored the shortened action potential duration in KO atria. Finally, we demonstrated that CIRP suppressed Kv1.5 and Kv4.2/4.3 expression by directly targeting their 3'-untranslated regions. CONCLUSION: CIRP plays a protective role in preventing AF onset through the posttranscriptional regulation of Kv1.5 and Kv4.2/4.3.