analyzing-long-term-electrocardiography-recordings-to-detect

Analyzing Long-Term Electrocardiography Recordings to Detect Arrhythmias in Mice

Arrhythmias are common, affecting millions of patients worldwide. Current treatment strategies are associated with significant side effects and remain ...

real-time-electrocardiogram-monitoring-during-treadmill-training

Real-Time Electrocardiogram Monitoring During Treadmill Training in Mice

Regular physical exercise is a major contributor to cardiovascular health, influencing various metabolic as well as electrophysiological processes. ...

isolation-high-quality-murine-atrial-ventricular-myocytes-for

Isolation of High Quality Murine Atrial and Ventricular Myocytes for Simultaneous Measurements of Ca<sup>2+</sup> Transients and L-Type Calcium Current

Mouse models play a crucial role in arrhythmia research and allow studying key mechanisms of arrhythmogenesis including altered ion channel function and ...

microdissection-immunofluorescence-staining-myocardial-sleeves-murine

Microdissection and Immunofluorescence Staining of Myocardial Sleeves in Murine Pulmonary Veins

Pulmonary veins (PVs) are the major source of ectopic beats in atrial arrhythmias and play a crucial role in the development and progression of atrial ...

Ludwig-Maximilians University Munich (LMU)

DZHK (German Centre for Cardiovascular Research)

University Hospital Munich, Campus Großhadern, Ludwig-Maximilians University Munich (LMU)

DZHK (German Centre for Cardiovascular Research), Partner Site Munich, Munich Heart Alliance (MHA)

Ludwig-Maximilians-University Munich (LMU)

LMU Munich

German Center for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance (MHA)

The potential of microRNAs (miRNA) as non-invasive diagnostic, prognostic, and predictive biomarkers, as well as therapeutic targets, has recently been recognized. Previous studies have highlighted the importance of consistency in the methodology used, but to our knowledge, no study has described the methodology of sample preparation and storage systematically with respect to miRNAs as blood biomarkers. The aim of this study was to investigate the stability of miRNAs in blood under various relevant clinical and research conditions: different collection tubes, storage at different temperatures, physical disturbance, as well as serial freeze-thaw cycles.

Stability of Circulating Blood-Based MicroRNAs - Pre-Analytic Methodological Considerations.

Arrhythmias are common and contribute substantially to cardiovascular morbidity and mortality. The underlying pathophysiology of arrhythmias is complex and remains incompletely understood, which explains why mostly only symptomatic therapy is available. The evaluation of the complex interplay between various cell types in the heart, including cardiomyocytes from the conduction system and the working myocardium, fibroblasts and cardiac immune cells, remains a major challenge in arrhythmia research because it can be investigated only in vivo. Various animal species have been used, and several disease models have been developed to study arrhythmias. Although every species is useful and might be ideal to study a specific hypothesis, we suggest a practical trio of animal models for future use: mice for genetic investigations, mechanistic evaluations or early studies to identify potential drug targets; rabbits for studies on ion channel function, repolarization or re-entrant arrhythmias; and pigs for preclinical translational studies to validate previous findings. In this Review, we provide a comprehensive overview of different models and currently used species for arrhythmia research, discuss their advantages and disadvantages and provide guidance for researchers who are considering performing in vivo studies.

Animal models of arrhythmia: classic electrophysiology to genetically modified large animals.

Cardiac arrhythmias are common diseases affecting millions of people worldwide. A broad and diverse array of arrhythmias exists, ranging from harmless ones such as sinus arrhythmia to fatal disorders such as ventricular fibrillation. The underlying pathophysiology of arrhythmogenesis is complex and still not fully understood. Since their discovery, non-coding RNAs (ncRNAs) and especially microRNAs (miRNAs) came into the spotlight of arrhythmia research as it has been shown that they play an important role in regulating normal development of the cardiac conduction system and are involved in remodeling processes leading to arrhythmias. This chapter will give a brief overview on basic electrophysiologic concepts and will summarize the current knowledge on ncRNAs and their role in arrhythmogenesis.

Non-coding RNA and Cardiac Electrophysiological Disorders.

Atrial fibrillation (AF) is a major healthcare challenge contributing to high morbidity and mortality. Treatment options are still limited, mainly due to insufficient understanding of the underlying pathophysiology. Further research and the development of reliable animal models resembling the human disease phenotype is therefore necessary to develop novel, innovative and ideally causal therapies. Since ischaemic heart failure (IHF) is a major cause for AF in patients we investigated AF in the context of IHF in a close-to-human porcine ischaemia-reperfusion model. Myocardial infarction (AMI) was induced in propofol/fentanyl/midazolam-anaesthetized pigs by occluding the left anterior descending artery for 90 minutes to model ischaemia with reperfusion. After 30 days ejection fraction (EF) was significantly reduced and haemodynamic parameters (pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), left ventricular enddiastolic pressure (LVEDP)) were significantly elevated compared to age/weight matched control pigs without AMI, demonstrating an IHF phenotype. Electrophysiological properties (sinus node recovery time (SNRT), atrial/AV nodal refractory periods (AERP, AVERP)) did not differ between groups. Atrial burst pacing at 1200 bpm, however, revealed a significantly higher inducibility of atrial arrhythmia episodes including AF in IHF pigs (3/15 vs. 10/16, p = 0.029). Histological analysis showed pronounced left atrial and left ventricular fibrosis demonstrating a structural substrate underlying the increased arrhythmogenicity. Consequently, selective ventricular infarction via LAD occlusion causes haemodynamic alterations inducing structural atrial remodeling which results in increased atrial fibrosis as the arrhythmogenic atrial substrate in pigs with IHF.

Characterization of a porcine model of atrial arrhythmogenicity in the context of ischaemic heart failure.

Genetic Burden of Birthweight on Atrial Fibrillation: Translational Challenges in Genetic Atrial Fibrillation Studies.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although "natural" AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a "perfect" animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.

Animal Models of Atrial Fibrillation.

Connexin hemichannels in atrial fibrillation: orphaned and irrelevant?

Genetic insight into sick sinus syndrome. Is there a pill for it or how far are we on the translational road to personalized medicine?

Cardiac electrophysiology is a complex system established by a plethora of inward and outward ion currents in cardiomyocytes generating and conducting electrical signals in the heart. However, not only cardiomyocytes but also other cell types can modulate the heart rhythm. Recently, cardiac macrophages were demonstrated as important players in both electrophysiology and arrhythmogenesis. Cardiac macrophages are a heterogeneous group of immune cells including resident macrophages derived from embryonic and fetal precursors and recruited macrophages derived from circulating monocytes from the bone marrow. Recent studies suggest antiarrhythmic as well as proarrhythmic effects of cardiac macrophages. The proposed mechanisms of how cardiac macrophages affect electrophysiology vary and include both direct and indirect interactions with other cardiac cells. In this review, we provide an overview of the different subsets of macrophages in the heart and their possible interactions with cardiomyocytes under both physiologic conditions and heart disease. Furthermore, we elucidate similarities and differences between human, murine and porcine cardiac macrophages, thus providing detailed information for researchers investigating cardiac macrophages in important animal species for electrophysiologic research. Finally, we discuss the pros and cons of mice and pigs to investigate the role of cardiac macrophages in arrhythmogenesis from a translational perspective.

Cardiac Macrophages and Their Effects on Arrhythmogenesis.

Arrhythmias are critical contributors to cardiovascular morbidity and mortality. Therapies are mainly symptomatic and often insufficient, emphasizing the need for basic research to unveil the mechanisms underlying arrhythmias and to enable better and ideally causal therapies. In translational approaches, mice are commonly used to study arrhythmia mechanisms in vivo. Experimental electrophysiology studies in mice are performed under anesthesia with medetomidine/midazolam/fentanyl (MMF) and isoflurane/fentanyl (IF) as commonly used regimens. Despite evidence of adverse effects of individual components on cardiac function, few data are available regarding the specific effects of these regimens on cardiac electrophysiology in mice. Here we present a study investigating the effects of MMF and IF narcosis on cardiac electrophysiology in vivo in C57BL/6N wild-type mice. Telemetry transmitters were implanted in a group of mice, which served as controls for baseline parameters without narcosis. In two other groups of mice, electrocardiogram and invasive electrophysiology studies were performed under narcosis (with either MMF or IF). Basic electrocardiogram parameters, heart rate variability parameters, sinus node and atrioventricular node function, and susceptibility to arrhythmias were assessed. Experimental data suggest a remarkable influence of MMF on cardiac electrophysiology compared with IF and awake animals. While IF only moderately reduced heart rate, MMF led to significant bradycardia, spontaneous arrhythmias, heart rate variability alterations as well as sinus and AV node dysfunction, and increased inducibility of ventricular arrhythmias. On the basis of these observed effects, we suggest avoiding MMF in mice, specifically when studying cardiac electrophysiology, but also whenever a regular heartbeat is required for reliable results, such as in heart failure or imaging research.

Medetomidine/midazolam/fentanyl narcosis alters cardiac autonomic tone leading to conduction disorders and arrhythmias in mice.

Atrial fibrillation (AF) is the most prevalent arrhythmia, often caused by myocardial ischemia/infarction (MI). Men have a 1.5× higher prevalence of AF, whereas women show a higher risk for new onset AF after MI. However, the underlying mechanisms of how sex affects AF pathophysiology are largely unknown. In 72 pigs with/without ischemic heart failure (IHF) we investigated the impact of sex on ischemia-induced proarrhythmic atrial remodeling and the susceptibility for AF. Electrocardiogram (ECG) and electrophysiological studies were conducted to assess electrical remodeling; histological analyses were performed to assess atrial fibrosis in male and female pigs. IHF pigs of both sexes showed a significantly increased vulnerability for AF, but in male pigs more and longer episodes were observed. Unchanged conduction properties but enhanced left atrial fibrosis indicated structural rather than electrical remodeling underlying AF susceptibility. Sex differences were only observed in controls with female pigs showing an increased intrinsic heart rate, a prolonged QRS interval and a prolonged sinus node recovery time. In sum, susceptibility for AF is significantly increased both in male and female pigs with ischemic heart failure. Differences between males and females are moderate, including more and longer AF episodes in male pigs and sinus node dysfunction in female pigs.

ArticleTotal : 4	Year
Publication title	2021
Publication title	2022
Publication title	2020
Publication title	2023

Article	Year
Stability of Circulating Blood-Based MicroRNAs - Pre-Analytic Methodological Considerations. PloS one\| PubMed ID: 28151938	2017
Animal models of arrhythmia: classic electrophysiology to genetically modified large animals. Nature reviews. Cardiology\| PubMed ID: 30894679	2019
Non-coding RNA and Cardiac Electrophysiological Disorders. Advances in experimental medicine and biology\| PubMed ID: 32285420	2020
Characterization of a porcine model of atrial arrhythmogenicity in the context of ischaemic heart failure. PloS one\| PubMed ID: 32365085	2020
Genetic Burden of Birthweight on Atrial Fibrillation: Translational Challenges in Genetic Atrial Fibrillation Studies. Circulation. Genomic and precision medicine\| PubMed ID: 32543993	2020
Animal Models of Atrial Fibrillation. Circulation research\| PubMed ID: 32716814	2020
Connexin hemichannels in atrial fibrillation: orphaned and irrelevant? Cardiovascular research\| PubMed ID: 33112373	2021
Genetic insight into sick sinus syndrome. Is there a pill for it or how far are we on the translational road to personalized medicine? European heart journal\| PubMed ID: 33860310	2021
Cardiac Macrophages and Their Effects on Arrhythmogenesis. Frontiers in physiology\| PubMed ID: 35812333	2022
Medetomidine/midazolam/fentanyl narcosis alters cardiac autonomic tone leading to conduction disorders and arrhythmias in mice. Lab animal\| PubMed ID: 36959339	2023
Effects of Sex on the Susceptibility for Atrial Fibrillation in Pigs with Ischemic Heart Failure. Cells\| PubMed ID: 37048048	2023

Philipp Tomsits

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