Cinétiques de la fréquence cardiaque et de la repolarisation ventriculaire durant l’effort et la récupération

Lors des variations normales de la fréquence cardiaque, notamment durant l’effort et la récupération, l’intervalle QT s’adapte à la durée du cycle cardiaque (RR) selon deux processus : la dépendance QT/RR qui définit la relation entre le RR et le QT à l’état stable, et l’hystérésis QT/RR qui définit la cinétique de l’adaptation du QT entre deux états stables. Plusieurs approches ont été suggérées pour quantifier ces deux processus. Il apparaît que la dépendance QT/RR autant que l’hystérésis QT/RR sont hautement individuels et il a été avancé que certains profils de dépendance ou d’hystérésis QT/RR étaient associés à un mauvais pronostic chez des patients cardiaques. Ces descripteurs de la relation QT/RR varient également entre des sujets apparemment en santé, et bien qu’il semble plausible que ces différences s’expliquent par des variations de la modulation autonome, ce sujet a été pratiquement inexploré. Les travaux présentés dans le cadre de cette thèse visent à définir la réponse normale de l’intervalle QT lors de l’effort et de la récupération, et à caractériser l’adaptation de cette réponse chez des sujets entraînés. L’existence de nombreuses approches présentant de grandes disparités nous a conduits à réaliser une revue systématique de littérature portant sur les méthodes de quantification de l’hystérésis QT/RR et visant à spécifier les limites inhérentes aux méthodes documentées ainsi qu’à déterminer la méthode la plus appropriée pour comparer l’hystérésis entre des conditions où les registres de fréquences cardiaques observées diffèrent. Une deuxième revue systématique a identifié l’ensemble des conditions cliniques dans lesquelles l’hystérésis QT/RR a été mesurée. Il en ressort qu’une hystérésis exagérée pourrait être un prédicteur de mortalité arythmique dans certaines populations, un marqueur d’ischémie durant un test d’effort, et une manifestation du syndrome du QT long. Toutefois, ces preuves d’associations tiennent sur peu d’études et devront être confirmées par des études de plus grande ampleur utilisant des méthodes reproductibles permettant de distinguer l’hystérésis QT/RR de la dépendance QT/RR. Une étude a été conduite chez des hommes en santé afin de déterminer si la cinétique du RR et l’hystérésis QT/RR variaient chez un même sujet entre des protocoles d’effort impliquant des mécanismes de modulation autonome différents. Les résultats démontrent que la cinétique du RR et l’hystérésis QT/RR sont plus lents en récupération qu’à l’effort et que la cinétique du RR est plus lente lorsque l’exercice ou la récupération est amorcé depuis une fréquence cardiaque plus élevée. Cette étude suggère aussi que la présomption habituelle selon laquelle l’hystérésis QT/RR demeure constante chez un individu est inappropriée. Il apparaît que l’hystérésis est exagérée lors d’efforts de faible intensité initiés depuis le repos par rapport aux autres conditions étudiées. Également, l’étude indique que l’estimation de la cinétique individuelle du RR et du QT est plus fiable lorsqu’elle inclut des mesures obtenues à des intensités d’effort relativement élevées que lorsqu’elle se limite à des données de faible intensité. Une dernière étude a comparé la dépendance QT/RR, la cinétique du RR et l’hystérésis QT/RR entre des hommes entraînés en endurance et des hommes modérément actifs, évalués lors d’efforts d’une même intensité relative. Cette étude confirme les résultats antérieurs selon lesquels la cinétique du RR est accélérée chez les hommes entraînés, autant à l’effort qu’en récupération. De plus, les résultats indiquent une prolongation faible mais significative de l’intervalle QT chez les athlètes, indépendante de la fréquence cardiaque, et une augmentation de la pente QT/RR. Toutefois, aucune modification significative de l’hystérésis QT/RR n’a été identifiée chez ces sujets. Dans l’ensemble, les travaux réalisés démontrent que les cinétiques du RR et du QT varient chez un même sujet et témoignent vraisemblablement de mécanismes différents de la modulation autonome cardiaque selon les conditions d’effort et de récupération. Chez des individus entraînés en endurance, la cinétique de la fréquence cardiaque est accélérée et on observe également une faible prolongation de la repolarisation et un accroissement de sa dépendance à la fréquence cardiaque.During physiological heart rate variations in the course of exercise and recovery, the QT interval adapts to cardiac cycle length (RR) according to two distinct processes: QT/RR dependency which describes the steady-state relationship between QT and RR intervals, and QT/RR hysteresis which describes the time course of QT accommodation between steady-state conditions. Several approaches were suggested to quantify these two processes. It appears that both QT/RR dependency and QT/RR hysteresis are highly individual and it was put forward that certain profiles of QT/RR dependency and hysteresis could be useful risk predictors in cardiac patients. However, these descriptors of the QT/RR relationship remain largely variable among healthy subjects. While it is plausible that such inter-individual discrepancies are explained by variations of cardiac autonomic modulation, very few studies have addressed this question. The work conducted in this thesis aims to define the normal response of the QT interval during exercise and recovery and to characterize adaptations of this response in endurance-trained individuals. A systematic review of the literature addressing methods of QT/RR hysteresis estimation is reported. The review highlights the inherent limits of reported approaches and a theoretical comparison of methods suggests that one procedure, namely estimation of the memory in the modelled QT/RR relationship, is superior for comparison of QT/RR hysteresis between conditions where the range of observed RR intervals varies. A second systematic review was conducted with the aim of identifying clinical conditions in which QT/RR hysteresis was examined. It emerges from this review that an increased QT/RR hysteresis could be a predictor of severe arrhythmia, a marker of exercise-induced myocardial ischemia and a feature of the long QT syndrome. However, the proofs of such associations are rather weak and would need to be confirmed by larger studies using reliable methods that can differentiate QT/RR hysteresis from QT/RR dependency. A study was conducted in healthy men in order to determine if RR kinetics and QT/RR hysteresis varied in the same subject between exercise protocols implying different mechanisms of autonomic modulation. The results demonstrate that both RR kinetics and QT/RR hysteresis are slower during recovery compared to exercise, and that RR kinetics is slower when exercise or recovery is initiated from a higher baseline heart rate. This work also suggests that the usual assumption that QT/RR hysteresis remains invariant in a same individual is incorrect. It appears that hysteresis is larger in the transition from rest to low intensity exercise compared to other investigated conditions. In addition, our results show that quantification of individual RR and QT kinetics is more reliable when it is computed from recordings including exercise data at moderate intensities compared to estimations relying solely on data recorded during low intensity exercise. The last study aimed to compare QT/RR dependency, RR kinetics and QT/RR hysteresis between endurance-trained and moderately active young men, evaluated during exercise at identical relative work outputs. The study corroborates previous findings that RR kinetics is accelerated in endurance-trained men, both during exercise and recovery. In addition, the study reveals a small but significant rate-independent QT prolongation in athletes and an increased steady-state QT/RR slope. However, no significant modification of QT/RR hysteresis was observed in these subjects. Overall, this work identifies within-subject variations of RR and QT kinetics, likely explained by varying mechanisms of autonomic cardiac modulation across investigated conditions. In endurance-trained men, heart rate kinetics is accelerated while repolarisation is protracted and its heart rate dependency is increased

Case Report of a Remote Ischemic Preconditioning Intervention during Aerobic Exercise in a 44-year-old Amateur Triathlete Male with a History of Acute Myocardial Infarction

International Journal of Exercise Science 13(3): 924-937, 2020. Over the years, exercise has become increasingly important in patients with acute myocardial infarction (AMI). However, AMI patients need to be closely monitored since they maintain cardiovascular disease risks, such as ventricular repolarization abnormalities in electrocardiograms during exercise and rest. A recent study showed the need to focus on the different potential mechanisms and the applicability of remote ischemic preconditioning (RIPC) for cardiac patients engaged in exercise rehabilitation. This is the first case report that explores the effectiveness of an RIPC intervention in a 44-year-old amateur triathlete male with a history of AMI during a moderate (75% of gas exchange threshold) and high (115% of gas exchange threshold) intensity steady-state cycling aerobic exercise. Prior to aerobic exercise, the participant was allocated to either RIPC intervention or CTL (control) with four cycles of five minutes of ischemia followed by five minutes of reperfusion. ECG was continuously recorded during the protocol. These findings showed that RIPC improved participant’s oxygen uptake response and shortened his ventricular repolarization during steady-state aerobic exercises. By measuring the physiological and electrophysical parameters, this case report adds new evidence for the benefits of RIPC. This study also demonstrates the safety of the intervention for cardiac patients in addition to showing that the intervention is not dangerous or harmful. This provides a new approach to cardiac rehabilitation programs. Future studies with cardiac patients are needed to provide a safe, standardized exercise intervention in cardiac rehabilitation

Efficient ancestry and mutation simulation with msprime 1.0

Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this, a large number of specialized simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and the tskit library. We summarize msprime’s many features, and show that its performance is excellent, often many times faster and more memory efficient than specialized alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement

A global biodiversity observing system to unite monitoring and guide action

The rate and extent of global biodiversity change is surpassing our ability to measure, monitor and forecast trends. We propose an interconnected worldwide system of observation networks — a global biodiversity observing system (GBiOS) — to coordinate monitoring worldwide and inform action to reach international biodiversity targets.acceptedVersio

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Seven days of hot water heat acclimation does not modulate the change in heart rate variability during passive heat exposure

We examined if the change in heart rate variability during passive heat exposure is modified by hot water heat acclimation (HA). Sixteen healthy adults (28 ± 5 years, 5 females/11 males) underwent heat exposure in a water-perfused suit, before and after 7 days of HA (60 min at rectal temperature ≥38.6 °C). During passive heat exposure, heart rate, the standard deviation of NN intervals (SDNN), the square root of the mean squared differences of successive NN intervals (RMSSD), and the power in the high-frequency range (HF) were measured. No difference in heart rate (P = 0.22), SDNN (P = 0.87), RMSSD (P = 0.79), and HF (P = 0.23) was observed at baseline. The increase in HR (pre-HA, 43 ± 10; post-HA, 42 ± 9 bpm; P = 0.57) and the decrease of SDNN (pre-HA, −54.1 ± 41.0; post-HA, −52.2 ± 36.8 ms; P = 0.85), RMSSD (pre-HA, −70.8 ± 49.5; post-HA, −72.7 ± 50.4 ms; P = 0.91) and HF (pre-HA, −28.0% ± 14.5; post-HA, −23.2% ± 17.1%; P = 0.27) were not different between experimental visits at fixed increases in esophageal temperature. These results suggest that 7 consecutive days of hot water HA does not modify the change in heart rate variability indices during passive heat exposure. Novelty: • It remains unclear if HA alters the change in heart rate variability that occurs during passive heat exposure. • At matched levels of thermal strain, 7 consecutive days of hot water immersion did not modulate the change in indices of heart rate variability during passive heat exposure.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author