The ICVP model (Integrative CardioVascular Pharmacology model) is a hypothesis model designed for cardiovascular safety pharmacology studies by telemetry. This model includes basic cardiovascular parameters derived from blood pressure (abdominal systolic and diastolic aortic pressures, abdominal aortic pulse pressure, heart rate) and ECG (PQ, PR, QT intervals and QRS complex duration). QT interval is corrected using the probabilistic method and the one step QTc model. This latter highly sensitive method is also used to model the risk of QTc prolongation using the same statistical criteria as clinical thorough QT (TQT) studies. In addition, it includes key hemodynamic parameters obtained from in silico modelling of stroke volume by pulse contour analysis such as cardiac output and systemic vascular resistance. It includes also results of in silico modelling of the autonomic control obtained with the HFAM model (high frequency autonomic modulation). This latter model is used to assess drug induced changes on the autonomic nervous: sympathovagal balance, parasympathetic predominance or withdrawal, sympathetic activation, sympathovagal coactivation. The combination of all these measured and in silico parameters enables two reflex pathways to be integrated into the model: the baroreflex pathway and the cardioinhibitory reflexes pathway. The model follows a classical scheme including pre-established relationships between cardiovascular parameters and compensatory reflex mechanisms. The ICVP model is used to depict the preferred hypothesis that can be proposed to support drug effects and underlying mechanisms of action.In this study, the ICVP model was applied to a set of pharmacological safety studies involving more than 20 reference drugs tested in beagle dogs by telemetry and covering various pharmacological mechanisms of action. All studies were retrospectively reanalysed from raw blood pressure and ECG signals. The results show that the model and the underlying in silico models are highly robust. No anomalies were detected in relation to the expected pharmacological effects of the reference drugs tested, whatever the mechanism of action and known off-targets. In many cases, it was possible to establish functional links with off-targets. This study demonstrate that the ICVP model can improve the safety assessment of new drug candidates and is a valuable decision-support tool.

Jacket telemetry technology enables the collection of both qualitative and quantitative ECG interval data in routine repeat-dose toxicology studies. The ICH M3(R2) guideline Q&As emphasize that integrated safety pharmacology assessments should maintain a level of rigor comparable to stand-alone safety pharmacology studies. However, unlike implanted telemetry, jacket-based ECG electrodes are more prone to displacement or disconnection, especially in socially housed animals such as monkeys and dogs, which can compromise data quality.To address these challenges, the Decro jacket—previously validated as a reliable platform for integrating safety pharmacology endpoints in dog toxicology studies—was completely redesigned and upgraded to include integrated 3D ECG electrodes embedded within the jacket. The new design features an adjustable, single-layer soft and stretchable jacket with integrated 3D ECG electrode patches, eliminating the need to shave or trim the animals' fur.Our study aimed to evaluate the performance of this new system by comparing its signal quality to that of invasive telemetry in six group-housed Beagle dogs.Dogs received vehicle control, quinidine (30 mg/kg), or ivabradine (2 mg/kg) orally according to a Latin square design. To ensure objective comparison, data from both systems were analyzed using a specialized software developed in RPL (RS/1 programming language). Ventricular repolarization was assessed with QT intervals corrected by the probabilistic method and the one-step QTc model. Drug effects on autonomic control were quantified using the High Frequency Autonomic Modulation (HFAM) model known to be highly sensitive to ECG quality signal. Beat-to-beat analysis was fully automated.Across four 8-h recording sessions per dog, the jacket showed no damage or adverse interactions, indicating robust design and excellent animal acceptance. High-quality lead II ECG signals were consistently obtained despite intact hair. Mean predose heart rate, PQ, PR, QRS, and QT intervals showed no or minimal differences between jacketed and implanted telemetry. Pharmacological responses to quinidine and ivabradine were reliably detected by both systems, with identical results.This upgraded jacket telemetry system overcomes traditional limitations by providing sensitive, high-quality ECG data with improved animal welfare, making it a valuable tool for safety pharmacology assessment in toxicology studies involving conscious dogs.

Cardiovascular safety pharmacology arose from the need to assess certain forms of drug induced functional cardiotoxicity in toxicology within a regulatory framework. Cardiotoxic effects resulting from direct or indirect pharmacological effects are difficult to apprehend in conventional toxicology studies, whether electrophysiological and/or hemodynamic. The reflex regulatory systems of the cardiovascular system, and in particular the autonomic nervous system, interfere with and very often minimize the functional impact of these pharmacological effects, which are sometimes only visible over a very short time window. Modeling approaches now make it possible to assess key hemodynamic parameters, going beyond blood pressure alone. Non-clinical cardiovascular safety pharmacology must continue to evolve toward a comprehensive framework for arrhythmic risk, in order to improve its translational relevance to humans and better bridge non-clinical QT prolongation data with clinical risk assessment. It also needs to integrate concepts from clinical research, such as Coumel's triangle, autonomic conflict or hidden cardiotoxicity. The ultimate goal of cardiovascular safety pharmacology should extend beyond protecting participants in clinical trials. It should broaden its scope to include patient subpopulations with underlying cardiovascular disease, who are often the most vulnerable to functional cardiotoxic effects. Twenty-five years after their initial publication, the safety pharmacology guidelines are currently undergoing revision. This review aims to foster a more balanced and comprehensive approach to cardiovascular safety pharmacology, beyond arrhythmic risk.

Dogs, one of the two main non-rodent species used in safety assessments for new chemical entities (NCEs), commonly integrate safety pharmacology endpoints such as ECG and respiratory recordings via jacket telemetry in toxicology studies. The Decro system, a miniaturized telemetry system previously validated in rats, offers several advantages, including the integration of respiratory, activity, and ECG recordings into a single setup, thereby reducing equipment handling time. This study aimed to develop and validate an adjustable, one-size-fits-all jacket with integrated respiratory belts designed for dogs. Four Beagle dogs, each implanted with an invasive DSI telemetry system and housed in pairs, were outfitted with Decro jackets during two separate three-hour sessions. The dogs demonstrated good tolerance to the jackets with no observed clinical signs or changes in behavior. The Decro jackets successfully recorded ECG and respiratory signals, consistently achieving high-quality cardiac signal scores (>95 %) and respiratory signal scores (>80 %) throughout the recording periods. ECG signals acquired in Lead II configuration with the jackets were compared to those obtained with DSI. Statistical bias between both methods for heart rate was assessed using Bland-Altman analysis, which plots the difference against their mean values. The analysis revealed a bias of 0.6 beat per minute and an agreement limits of [−3.7, 4.9] beats per min (95 % confidence interval). In conclusion, the Decro jacket proves to be a reliable setup for integrating safety pharmacology endpoints into toxicology studies. Beyond its technical benefits, this solution holds significant promise for addressing hemodynamic parameters currently under investigation.

The recently published ICH E14/S7B Q&As incorporated an additional thorough QT (TQT) substitution path for compounds that are double negative in nonclinical studies (hERG and in vivo QT). To increase regulatory confidence in such an approach, general requirements for nonclinical telemetry studies were detailed in the Q&As that focus on model sensitivity, data analysis techniques, and clinical translation. Briefly, criteria for the integrated risk assessment include prescriptive in vitro hERG requirements, and an in vivo evaluation at sufficient multiples over the highest clinical exposure with demonstrated adequate sensitivity to detect an effect of a similar magnitude as a dedicated clinical QT study. Harmonization of best practices for a Latin square crossover study design were recently published by industry subject matter experts (SMEs) to ensure high quality QTc data to support an ICH E14/S7B Q&A 5.1 scenario that meets regulatory expectations. However, there is no industry consensus on best practices for alternate study designs (ascending dose, parallel groups, etc.) routinely utilized for oncology small molecule, large molecule, oligonucleotide, and peptide modalities. To increase industry consistency and ensure data quality, SMEs are collaborating to review current methodologies for alternative study designs where continuous data collection is required in implanted and jacketed telemetry studies. A survey was generated by members of the working group to gather information on alternative study designs employed, data analysis processes, QT interval correction and statistical methods, individual study and test facility sensitivity, and use of pharmacokinetic sampling. The most common current alternative designs included escalating dose (vehicle plus 3 doses levels, N = 4) and parallel (2–3 treatment groups plus concurrent vehicle, N = 4–8/group) which have been submitted to satisfy the ICH S7B, S6, S9, and to a limited extent, the S7B 5.1/6.1 Q&As. Escalating dose designs were typically applied to small molecules, whereas parallel designs were used to test oligonucleotides, large and small molecules. Data from this survey will be used as a starting point for the working group to recommend best practices for alternate study designs in the context of supporting the ICH E14/S7B Q&A 5.1 and 6.1 scenarios and build regulatory confidence in nonclinical QTc data.

IntroductionRetrospective translational analyses have shown a high rate of false negatives between clinical thorough QT studies (TQT) and preclinical cardiovascular safety pharmacology studies. The aim of this work was to model the results of clinical TQT studies from cardiovascular safety pharmacology studies conducted on a large set of reference drugs in beagle dogs by implanted telemetry.MethodsAll preclinical studies were based on a standard four-animal crossover design comparing the vehicle to the reference drug. The model used was based on the one-step QTc correction model. This model was adapted in order to apply the same statistical method in preclinical studies as in clinical trials.ResultsThe sensitivity of the model made it possible to detect QTc prolongation of at least 5 ms with all reference hERG blockers known to cause QT prolongation in humans. Modelling of moxifloxacin (10 mg/kg, po) effects was in agreement with data published from clinical TQT studies with moxifloxacin 400 mg showing a QTc prolongation greater than 5 ms between 1 and 4 hours post-dose. This study shows a noticeable reduction in the risk of false negatives with several references drugs associated with a phenomenon of concealed QTc prolongation. Moreover, several reference drugs did change the slope of the QT/HR slope justifying the principles of the one-step QTc model.ConclusionModelling results of TQT studies with the one-step QTc model for applying the same statistical approach as in the clinic can improve the translational value of preclinical cardiovascular safety pharmacology studies and reduce the risk of false negatives.

Hemodynamic and autonomic effects of a selective α2-adrenoceptor agonist was modelled using two in silico models from abdominal aortic pressure measured by telemetry in young adult beagle dogs. First, central aortic pressure was modelled from the abdominal aortic pressure waveform using the N-point moving average (NPMA) method for beat-to-beat estimation of SV. The principle of SV modeling is based on the proportionality of the systolic area of the central aortic pressure waveform to SV. Secondly, effects on the autonomic nervous system was modelled using the High Frequency Autonomic Modulation (HFAM) model. The principle of the HFAM model is based on a beat-by-beat analysis of the amplitude of high-frequency oscillations in the RR interval and heart rate. The compound was administered at low, mid and high doses orally following a cross-over design. At the high dose, central systolic and diastolic aortic pressure increased. Behind this effect on BP, in silico modeling of hemodynamic effects showed a marked increase in systemic vascular resistance. In parallel, heart rate was markedly reduced. In silico modeling of autonomic changes with the HFAM model showed marked parasympathetic activation associated with a strong reduction in sympathetic activity. SV remained unchanged but cardiac output was markedly reduced. All these results of in silico modeling are perfectly consistent with peripheral vasoconstrictor and central effects resulting from stimulation of vascular and central α2-adrenoceptors. This work nicely illustrates the valuable additional information provided by in silico modeling of hemodynamic and autonomic parameters in telemetry safety pharmacology studies to decipher complex cardiovascular profiles.

Introduction: This study delves into the mechanisms through which severe hypernatremia may precipitate ventricular tachycardia, drawing from a clinical case involving a 14-year-old patient presenting with ventricular tachycardia in the context of hypernatremia. By using in silico modelling, we aim to decipher whether and how hypernatremia could favour such an event. We hypothesized that hypernatremia could increase late sodium current in a context of adrenergic stimulation, both being already known to favour early-after-depolarizations. Main symptoms: After a thorough investigation ruling out secondary causes, including clinical, electrocardiogram, and biological anomalies, as well as genetic factors, the focus turned to assessing whether hypernatremia alone could account for the ventricular tachycardia episode. Main diagnoses: Leveraging a numerical model of human ventricular action potential (TNNP model) integrated with late sodium current (INaLate), we demonstrated that severe hypernatremia, coupled with β-adrenergic stimulation indicative of sympathetic tone, could indeed trigger ventricular tachycardia. Conclusion: In silico modelling can help to predict arrhythmia risk and to select the best strategies. This case suggests a re-evaluation of cardiopulmonary resuscitation algorithms, favouring the preferential use of lidocaine over epinephrine and amiodarone in cases of critical hypernatremia-related cardiac arrest.

The principle of proportionality of the systolic area of the central aortic pressure to stroke volume (SV) has been long known. The aim of the present work was to evaluate an in silico solution derived from this principle for modeling effects of pimobendan on SV, cardiac output and systemic vascular resistance in dogs by telemetry. Blood pressure was measured in the abdominal aorta in accordance with standard practice. Central aortic pressure was modelled from the abdominal aortic pressure waveform using the N-point moving average (NPMA) method for beat-to-beat estimation of SV. Left ventricular (LV) pressure was also recorded by telemetry. Pimobendan was administered by the oral route at doses of 0.2, 0.6, and 1.2 mg/kg orally (API in capsule) following a cross-over design. Pimobendan induced an increase in LV dP/dt max consistent with its positive inotropic properties due to its phosphodiesterease III (PDE) inhibitory properties. In parallel, in silico modeling of hemodynamic effects showed a dose dependent increase in cardiac output reflecting an overall improvement in cardiac performance. Pimobendan also induced a decrease in systemic vascular resistance consistent with its vasodilatory properties. This work perfectly illustrates the valuable additional information provided by in silico modeling of hemodynamic parameters in telemetry safety pharmacology studies to decipher complex cardiovascular profiles such as that of an inodilator like pimobendan. This in silico modeling solution can be considered as a New Approach Methodology (NAM) which reinforces 3Rs and animal welfare by offering an alternative solution to left ventricular catheter implantation.

The principle of proportionality of the systolic area of the central aortic pressure to stroke volume (SV) has been long known. The aim of the present work was to evaluate an in silico solution derived from this principle for modelling SV (iSV model) in cardiovascular safety pharmacology studies by telemetry. Blood pressure was measured in the abdominal aorta in accordance with standard practice. Central aortic pressure was modelled from the abdominal aortic pressure waveform using the N-point moving average (NPMA) method for beat-to-beat estimation of SV. First, the iSV was compared to the SV measured by ultrasonic flowmetry in the ascending aorta (uSV) after various pharmacological challenges in beagle dogs anaesthetised with etomidate/fentanyl. The iSV showed minimal bias (0.2 mL i.e. 2%) and excellent agreement with uSV. Then, previous telemetry studies including reference vasoactive and inotropic compounds were retrospectively reanalysed to model drug effects on stroke volume (iSV), cardiac output (iCO) and systemic vascular resistance (iSVR). Among them, the examples of nicardipine and isoprenaline highlight risks of erroneous or biased estimation of drug effects from the abdominal aortic pressure due to pulse pressure amplification. Furthermore, the examples of verapamil, quinidine and moxifloxacin show that iSV, iCO and iSVR are earlier biomarkers than blood pressure itself for predicting drug effect on blood pressure. This in silico modelling approach included in vivo telemetry safety pharmacology studies can be considered as a New Approach Methodology (NAM) that provides valuable additional information and contribute to improving non-clinical translational research to the clinic.

Abstract Background Current therapy for Heart Failure (HF) includes neurohormonal antagonist and modulator drugs that improve remodelling, symptoms and clinical outcomes. However, these drugs do not target the underlying problem of reduced contractility. Improving cardiac contractility without harmful consequences is an unmet need in heart failure therapy. The human peptide hormone ghrelin increases cardiac output in HF patients and increases contractility in murine cardiomyocytes. Purpose We aim to study the cardiovascular effects of a novel oral small molecule ghrelin receptor agonist, AC01, in in vivo and ex vivo mouse models and in non-human primates. Methods HF mice (N=11) underwent pressure-volume loops analysis of cardiac functional and hemodynamic to assess the effects of intravenous AC01 (N=7) or placebo (N=4). Primary cardiomyocytes isolated from HF (N=3) and SHAM (N=5) mice, were treated with combinations of vehicle, AC01, ghrelin receptor antagonist (D-Lys-3-GHRP-6) and pertussis toxin (PTX, a Gαi signalling inhibitor). Live cell imaging was performed to assess cardiomyocyte fractional shortening and Ca2+ signalling, while biochemistry assays were employed to measure PKA activity, and phosphorylation of cardiac Troponin I (cTnI). Cynomolgus monkeys (N=6) were instrumented with devices to measure pulse contour, central aortic blood pressure and ECG devices. Cardiovascular effects of AC01 following single oral dosing were assessed through pulse contour hemodynamic modelling and analysis of autonomic system activation. Results In HF mice, AC01 significantly improved cardiac output (p< 0.01), stroke volume (p< 0.001), and ejection fraction (p< 0.001), and increased nominally the end-systolic pressure-volume curve relationship. In cardiomyocytes, AC01 dose-dependently improved fractional shortening (p< 0.01) without increasing Ca2+ transient amplitudes. AC01 reduced PKA activity (p< 0.05) and reduced phosphorylation of cTnI at Serine 23-24 (p< 0.01). These effects were blocked by pre-treatment with either D-Lys-3-GHRP-6 or PTX. In monkeys, oral AC01 sustainably increased cardiac output (p< 0.05) and stroke volume (p< 0.05) and reduced heart rate without altering central systolic blood pressure or causing tachycardia or arrhythmia. Conclusions AC01 improved CO, SV, and EF in HF mice by increasing contractility in a load-independent fashion. AC01 increased cardiomyocyte contractility without affecting Ca2+ transient amplitudes, through ghrelin receptor Gαi signalling, leading to reduced phosphorylation of cTnI. AC01 improved left ventricle systolic function in monkeys. AC01 is a first in class novel inotrope, which improves contractility in different species without harmful mobilization of Ca2+. AC01 should be explored for the treatment of patients with heart failure.graphical abstract

Introduction the autonomic nervous system (ANS) is both a recognized trigger and modulator of arrhythmogenesis [1]. Thanks to a new method of electrocardiogram analysis, we can accurately model in vivo the effect of a compound on the ANS. This model, called HFAM (High Frequency Autonomous Modulation), is based on the study of high-frequency oscillations (>0.1Hz) of RR intervals and heart rate, and enables us to identify different states of the ANS over very short periods of 10seconds: sympathetic predominance (S3 oscillations), parasympathetic predominance (S1 oscillations) or co-activation (S2 oscillations) [2]. The latter state could not be estimated using the methods available to date. Objective Develop an in silico approach to understand some arrhythmias. Method based on this work, we are developing an in silico prediction model, integrating the effects of the tested compounds on ANS, rhythm variability and ventricular repolarization. We have modified the M-cell model described by Ten Tusscher et al. (2006) [3] by integrating the effects on HF oscillations produced by different compounds, as well as the known effects of alpha1-, beta1-adrenergic and muscarinic stimulation on the different ionic conductances of the model. Results with this bioinformatics model, we succeeded in identifying all pro-arrhythmic molecules, without any false negatives (11/11). Applied to a clinical case of recovered cardiac arrest, the model also enabled us to propose the mechanism of the cardiac arrhythmia. Conclusion This model therefore represents a breakthrough in the early prediction of iatrogenic arrhythmias and could lead to a better understanding of the mechanisms of certain clinically observed arrhythmias, in order to better prevent or treat them effectively.

Central nervous (CNS) and respiratory systems are routinely investigated in safety pharmacology core battery studies. For small molecules, the assessment of both vital organ systems is frequently done in rats in two distinct studies. With the advent of a miniaturized technology of jacketed external telemetry for rats (DECRO system), the simultaneous assessment of modified Irwin's or functional observational battery (FOB) test and respiratory (Resp) studies has become possible within a single study. Therefore, the objectives of this study were to perform the FOB and the Resp studies simultaneously in pair-housed rats fitted with jacketed telemetry, and to assess the feasibility and the outcome of this combination in control, baclofen, caffeine, and clonidine treated groups, i.e., with three agents having both respiratory and CNS effects. Our results provided evidence that performing both Resp and FOB assessment simultaneously in the same rat was feasible and the outcome was successful. The expected CNS and respiratory effects of the 3 reference compounds were accurately captured in each assay confirming the results' relevance. In addition, heart rate and activity level were recorded as additional parameters making this design as an enhanced approach for nonclinical safety assessment in rats. This work provides clear evidence that the "3Rs" principles can be effectively applied in core battery safety pharmacology studies while remaining in compliance with worldwide regulatory guidelines. Both reduction in animal use and refinements in procedures are demonstrated with this model.

The common marmoset (Callithrix jacchus) is a nonhuman primate species that is already used in biomedical research. Due to the constrained supply of Cynomolgus monkey and the acute shortage of sexually mature animals arisen during the COVID-19 Pandemic, the marmoset has been increasingly used for toxicity testing of biotherapeutic proteins. However, incorporating safety pharmacology endpoints in marmoset toxicology studies was not as optimal as in Cynomolgus. Therefore, the purpose of this study was to test a jacketed telemetry system (DECRO system) which enables the simultaneous recordings of respiratory, ECG and activity parameters in freely moving marmosets. Ten animals (5 females and 5 males) were fitted with the Decro system and recorded for 14 h. Respiratory rate (RespR), expiratory and inspiratory times, tidal volume, minute ventilation, ECG analysis and intervals calculation, heart rate (HR), and activity level (AL) were assessed in all animals. During the light phase, the mean values ± SEM of HR and RespR varied from 271 ± 12 beat per min (bpm) to 318 ± 14 bpm, and from 63 ± 3 breath per min (brpm) to 73 ± 2 brpm, respectively based on the AL. During the dark cycle where AL was nearly null, the HR and RespR decreased to 247 ± 12 bpm and 53 ± 4 bpm, respectively. All the remaining parameters were successfully assessed using the different algorithms provided by the software. Overall, our results provided evidence that there were no clinical findings caused by the jacket. This preliminary study yielded promising results to support the use of the GLP software version of this jacketed telemetry system, in line with the 3Rs principles, in regulatory toxicology studies. With this development, the use of marmosets as an alternative to Cynomolgus in drug development is reinforced especially if considering that marmosets are one of the very few species capable of showing drug-induced torsades de pointes in healthy animals.

Summary Communication is a keystone of animal behavior. However, the physiological states underlying natural vocal signaling are still largely unknown. In this study, we investigated the correlation of affective vocal utterances with concomitant cardiorespiratory mechanisms. We telemetrically recorded electrocardiography, blood pressure, and physical activity in six freely moving and interacting cynomolgus monkeys (Macaca fascicularis). Our results demonstrate that vocal onsets are strengthened during states of sympathetic activation, and are phase locked to a slower Mayer wave and a faster heart rate signal at ∼2.5 Hz. Vocalizations are coupled with a distinct peri-vocal physiological signature based on which we were able to predict the onset of vocal output using three machine learning classification models. These findings emphasize the role of cardiorespiratory mechanisms correlated with vocal onsets to optimize arousal levels and minimize energy expenditure during natural vocal production.

Background and Purpose HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes. Experimental Approach Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model. Key Results Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under beta-adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide-induced ventricular arrhythmias. Conclusion and Implications This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.

Background and Purposes: Several hERG blocking molecules known for their propensity in triggering Torsades de Pointes (TdP) were reported as increasing High Frequency QT oscillations (HFQT). This effect was found as reflecting a sympatho-vagal coactivation. The present work aims to characterise the mechanism(s) leading to this particular state of the autonomic nervous system. Experimental approach: Effects of 20 hERG blockers including 15 torsadogenic molecules were assessed by telemetry in beagle dogs. Electrocardiogram and stroke volume modelled from the pulse contour method were analysed at the first dose level causing either QTc prolongation and/or HFQT increase. Cardiac autonomic control was analysed using the High Frequency Autonomic Modulation (HFAM) model in dogs and in untreated genotyped LQT1 and LQT2 individuals, for comparison. Key results: The sympatho-vagal coactivation induced by torsadogenic molecules is elicited by reflex compensatory mechanisms in response to changes in stroke volume or cardiac output related to hemodynamic off-targets and/or QT prolongation. QTc prolongation was concealed or markedly blunted by the sympathetic component activation in a large proportion of tested torsadogenic drugs. Sympathetic reflex mechanisms in LQT patients similar to that found for dofetilide was also revealed in both patients exhibiting QTc prolongation and concealed QTc prolongation, irrespective to LQT type. Conclusions and implications: QTc prolongation and/or drug-induced hemodynamic side effects enhance beat to beat ventricular repolarisation variability via sympatho-vagal reflex compensatory mechanisms. Considering the sympathetic reflex component via analysis of HFQT oscillations dramatically improves prediction, sensitivity and specificity of drug induced Torsades de pointes risk assessment.

In order to contribute to a better knowledge on the relationship between amyloid and tau pathology, and electroencephalography (EEG) disturbances, the aim of this study was to evaluate the effects of injection of beta amyloid Abeta(1-42) peptide, tau (a recombinant AAV (Aden-Associated Virus) containing the human transgene tau with the P301 L mutation on rats and the combination of both, on the power of brain's rhythm (delta, theta, alpha, beta and gamma waves) during the different sleep/wake states of animals by EEG recording. Currently, no preclinical studies explore the effect of the tau pathology on EEG. The experimentations were performed 3 weeks and 3 months post injections. Beta amyloid deposits and hyperphosphorylated Tau are observed by immunohistofluorescence, only in the hippocampus. Furthermore, using a radial arm water maze, the main effect was observed on working memory which was significantly impaired in Abeta-Tau group only 3 months post injections. However, on EEG, as early as the 3(r)(d) week, an overall decrease of the EEG bands power was observed in the treated groups, particularly the theta waves during the rapid eye movement (REM) sleep. Beta amyloid was mainly involved in these perturbations. Obviously, EEG seems to be an interesting tool in the early diagnostic of amyloid and tau pathologies, with a good sensitivity and the possibility to perform a follow up during a large period.