Short-term rapid atrial pacing alters the gene expression profile of rat liver: Cardiohepatic interaction in atrial fibrillation

Yaegashi, Takanori; Kato, Takeshi; Usui, Soichiro; Kanamori, Naomi; Furusho, Hiroshi; Takashima, Shinya; Murai, Hisayoshi; Kaneko, Shuichi; Takamura, Masayuki

doi:10.1016/j.hrthm.2016.08.036

Cited by 8 publications

(10 citation statements)

References 30 publications

(22 reference statements)

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“…In order to utilize rodents appropriately in pacing and arrhythmia research, understanding of their native cardiac electrophysiology is necessary. However, up to now such studies were mainly performed ex vivo or in anesthetized open-chest or closed-chest preparations ( Choy et al, 2016 ; Yaegashi et al, 2016 ; Huang, 2017 ). Cardiac electrophysiology in such preparations may not represent the normal properties as in the freely moving state.…”

Section: Discussionmentioning

confidence: 99%

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length

et al. 2018

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Aim: The cardiac electrophysiology of mice and rats has been analyzed extensively, often in the context of pathological manipulations. However, the effects of beating rate on the basic electrical properties of the rodent heart remain unclear. Due to technical challenges, reported electrophysiological studies in rodents are mainly from ex vivo preparations or under deep anesthesia, conditions that might be quite far from the normal physiological state. The aim of the current study was to characterize the ventricular rate-adaptation properties of unanesthetized rats and mice.Methods: An implanted device was chronically implanted in rodents for atrial or ventricular pacing studies. Following recovery from surgery, QT interval was evaluated in rodents exposed to atrial pacing at various frequencies. In addition, the frequency dependence of ventricular refractoriness was tested by conventional ventricular programmed stimulation protocols.Results: Our findings indicate total absence of conventional rate-adaptation properties for both QT interval and ventricular refractoriness. Using monophasic action potential recordings in isolated mice hearts we could confirm the previously reported shortening of the action potential duration at fast pacing rates. However, we found that this mild shortening did not result in similar decrease of ventricular refractory period.Conclusion: Our findings indicate that unanesthetized rodents exhibit flat QT interval and ventricular refractory period rate-dependence. This data argue against empirical use of QT interval correction methods in rodent studies. Our new methodology allowing atrial and ventricular pacing of unanesthetized freely moving rodents may facilitate more appropriate utility of these important animal models in the context of cardiac electrophysiology studies.

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Section: Discussionmentioning

confidence: 99%

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length

et al. 2018

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“…Atrial fibrillation (AF) is the most common among the severe cardiac arrhythmias, which is associated with a high risk of thromboembolism and stroke [107]. AF activates the coagulation system, leading to prothrombotic or hypercoagulable state [107,108]. e liver is an essential organ synthesizing many coagulation factors and other prothrombic molecules [108].…”

Section: E Heart-liver Axis In Modern Medicinementioning

confidence: 99%

“…AF activates the coagulation system, leading to prothrombotic or hypercoagulable state [107,108]. e liver is an essential organ synthesizing many coagulation factors and other prothrombic molecules [108]. Using rapid atrial pacing (RAP) rat model, Yaegashi et al found that shortterm RAP mimicking paroxysmal AF markedly altered the hepatic gene expression profile, and hepatic mRNA levels of prothrombic molecules, including fibrinogen chains, prothrombin, coagulation factor X, and antithrombin III, were augmented by short-term RAP [108].…”

Section: E Heart-liver Axis In Modern Medicinementioning

confidence: 99%

“…e liver is an essential organ synthesizing many coagulation factors and other prothrombic molecules [108]. Using rapid atrial pacing (RAP) rat model, Yaegashi et al found that shortterm RAP mimicking paroxysmal AF markedly altered the hepatic gene expression profile, and hepatic mRNA levels of prothrombic molecules, including fibrinogen chains, prothrombin, coagulation factor X, and antithrombin III, were augmented by short-term RAP [108]. e activation of the IL-6/STAT3 signaling pathway is responsible for the augmented fibrinogen and coagulation factor X production by RAP [108].…”

Section: E Heart-liver Axis In Modern Medicinementioning

confidence: 99%

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Hepatocardiac or Cardiohepatic Interaction: From Traditional Chinese Medicine to Western Medicine

Zhang

Xian-ming

2021

Evidence-Based Complementary and Alternative Medicine

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There is a close relationship between the liver and heart based on “zang-xiang theory,” “five-element theory,” and “five-zang/five-viscus/five-organ correlation theory” in the theoretical system of Traditional Chinese Medicine (TCM). Moreover, with the development of molecular biology, genetics, immunology, and others, the Modern Medicine indicates the existence of the essential interorgan communication between the liver and heart (the heart and liver). Anatomically and physiologically, the liver and heart are connected with each other primarily via “blood circulation.” Pathologically, liver diseases can affect the heart; for example, patients with end-stage liver disease (liver failure/cirrhosis) may develop into “cirrhotic cardiomyopathy,” and nonalcoholic fatty liver disease (NAFLD) may promote the development of cardiovascular diseases via multiple molecular mechanisms. In contrast, heart diseases can affect the liver, heart failure may lead to cardiogenic hypoxic hepatitis and cardiac cirrhosis, and atrial fibrillation (AF) markedly alters the hepatic gene expression profile and induces AF-related hypercoagulation. The heart can also influence liver metabolism via certain nonsecretory cardiac gene-mediated multiple signals. Moreover, organokines are essential mediators of organ crosstalk, e.g., cardiomyokines link the heart to the liver, while hepatokines link the liver to the heart. Therefore, both TCM and Western Medicine, and both the basic research studies and the clinical practices, all indicate that there exist essential “heart-liver axes” and “liver-heart axes.” To investigate the organ interactions between the liver and heart (the heart and liver) will help us broaden and deepen our understanding of the pathogenesis of both liver and heart diseases, thus improving the strategies of prevention and treatment in the future.

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“…Very little is known regarding the effects of RAP on the rodent atria. Until recently, only short-term RAP studies of several hours have been reported, mostly focusing on various molecular effects without actual data on AF substrate formation (Yamashita et al, 2000, 2003, 2005; Beharier et al, 2007; Yaegashi et al, 2016). Using a bi-atrial implantable device developed in our group, we previously managed to apply continuous RAP in unanesthetized rats under online confirmation of 1:1 atrial capture and serial measurements of AERP for up to 24 h (Etzion et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Rapid Atrial Pacing Promotes Atrial Fibrillation Substrate in Unanesthetized Instrumented Rats

et al. 2019

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AimThe self-perpetuating nature of atrial fibrillation (AF) has been a subject of intense research in large mammalian models exposed to rapid atrial pacing (RAP). Recently, rodents are increasingly used to gain insight into the pathophysiology of AF. However, little is known regarding the effects of RAP on the atria of rats and mice. Using an implantable device for electrophysiological studies in rodents, we examined on a daily basis, the effects of continuous RAP on the developed AF substrate of unanesthetized rats and mice.Methods and ResultsAggressive burst pacing did not induce AF at baseline in the large majority of rodents, but repeatedly induced AF episodes in rats exposed to RAP for more than 2 days. A microarray study of left atrial tissue from rats exposed to RAP for 2 days vs. control pacing identified 304 differentially expressed genes. Enrichment analysis and comparison with a dataset of atrial tissue from AF patients revealed indications of increased carbohydrate metabolism and changes in pathways that are thought to play critical roles in human AF, including TGF-beta and IL-6 signaling. Among 19 commonly affected genes in comparison with human AF, downregulation of FOXP1 and upregulation of the KCNK2 gene encoding the Kir2.1 potassium channel were conspicuous findings, suggesting NFAT activation. Further results included reduced expression of MIR-26 and MIR-101, which is in line with NFAT activation.ConclusionOur results demonstrate electrophysiological evidence for AF promoting effects of RAP in rats and several molecular similarities between the effects of RAP in large and small mammalian models.

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Short-term rapid atrial pacing alters the gene expression profile of rat liver: Cardiohepatic interaction in atrial fibrillation

Abstract: Background: Atrial fibrillation (AF) activates the coagulation system,

Cited by 8 publications

References 30 publications

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length

Hepatocardiac or Cardiohepatic Interaction: From Traditional Chinese Medicine to Western Medicine

Rapid Atrial Pacing Promotes Atrial Fibrillation Substrate in Unanesthetized Instrumented Rats

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