The central nervous control of the heart by inhibitory heterotrimeric G-proteins

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Disorders of the rhythm of the heart are an important cause of death and morbidity in clinical medicine. For example, sudden death due to ventricular arrhythmia (atypical beating patterns of the heart), may account for up to 11% of unexpected deaths. It is known that the brain can significantly influence the observed pathology. For example, the initiation of the fear and flight response during exercise or under physiological stress can destabilise heart rhythm in a number of cardiac pathologies and result in lethal cardiac arrhythmia. Our proposal focuses on the role that certain signalling proteins in the brain might have in controlling the activity of the cardiovascular system. Our idea is that abnormalities of central nervous control of the heart by themselves might lead to significant cardiac pathology and the development of cardiovascular disease. This better understanding of heart rhythm control by the brain would hopefully lead to better treatment for disorders of heart rhythm in the future.

Technical Summary

Professor Tinker‘s laboratory have evidence that the in-vivo control of heart rate and ventricular excitability are impaired in mice with global genetic deletion of the heterotrimeric G-protein alpha subunit, Go. Furthermore, Go is predominantly expressed in the central nervous system (CNS) and conditional deletion in the heart does not affect heart rate control. Thus we hypothesise that Galphao-mediated signalling in the CNS, specifically in inhibitory circuits in the brainstem, determines autonomic control of the heart. Deficiency of Galphao leads to increased sympathetic discharge and sympathovagal imbalance. In turn this is reflected in abnormal heart rate variability, promoting cardiac remodelling leading to a long QT syndrome and predisposition to ventricular arrhythmias.

Our goals are:
- To characterise cardiovascular function and central cardiovascular control in mice with
conditional genetic deletion of Galphao in the CNS.
- To investigate the physiological basis for this by measuring sympathetic and vagal nerve
outflows and associated cardiovascular reflexes.
- To identify the area of the CNS in which Galphao-mediated signalling is responsible for autonomic control of the heart

We plan to generate mice with conditional deletion of Galphao in the CNS using a cre-loxP approach either by (i) crossing mice with floxed Galphao alleles with mice expressing a pan neuronal cre recombinase or (ii) injecting a virus expressing cre into specific central and peripheral neurones in mice with floxed Galphao alleles. These mice would then be studied with in-vivo techniques including telemetry monitoring and formal electrophysiological studies. Autonomic function can be studied in detail with the working heart brainstem preparation.

This a novel programme of work that revisits the role of the central autonomic control on cardiac pathophysiology using modern genetic interventions. This work is important. It expands our current knowledge of the autonomic conol of the heart: cardiac and respiratory physiological function is integrated by a number of reflexes and understanding the mechanisms by which this arises is fundamentally important. However it also forms the basis for understanding the potential ‘nervous origins‘ of cardiac arrhythmia and therefore providing novel therapeutic opportunities in the future. In addition, changes in these reflexes, such as the loss of heart rate variability, are associated with a variety of pathological outcomes. It is also not clear if these are markers of worsening prognosis or are involved additionally in actually driving the pathology. Our proposal aims to explore aspects of both questions.

Publications

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Ang R (2018) Modulation of Cardiac Ventricular Excitability by GLP-1 (Glucagon-Like Peptide-1). in Circulation. Arrhythmia and electrophysiology

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Calmont A (2018) Defective Vagal Innervation in Murine Mutant Hearts. in Journal of cardiovascular development and disease

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Hosford PS (2018) A critical role for the ATP-sensitive potassium channel subunit K6.1 in the control of cerebral blood flow. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Description Capability building Research Fund (CRF)
Amount £41,777 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 04/2017
 
Description Clinical Research Network Fellowship
Amount £41,777 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2018
 
Description Autonomic modulation and cardiac electrophysiology in humans 
Organisation University College London
Department Institute of Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution To translate the findings from my doctoral research into the clinical arena, I am interested in exploring the effects of vagal modulation on cardiac ventricular electrophysiology. I am collaborating with Professor Pier Lambiase to conduct studies in humans to explore the effects of vagal stimulation on human cardiac electrophysiology. I am contributing to the research partnership by conducting parallel studies in animal models to study the cellular and molecular mechanisms underlying the effects seen in humans.
Collaborator Contribution Professor Pier Lambiase leads a research programme studying conduction-repolarisation properties in the normal and inherited heart rhythm disorder patients using a variety of invasive and non-invasive techniques. He has an interest in studying the effects of autonomic tone on cardiac electrophysiological properties. For example, the group has recently demonstrated significant conduction and repolarisation gradients exist in the normal heart during invasive electrophysiological studies which are modulated by mental stress. Professor Lambiase also has access to the ECGi body surface ECG mapping system developed by Professor Yoram Rudy to study arrhythmogenic cardiomyopathies facilitating early diagnosis and risk stratification.
Impact This is the first year of the collaboration and an intermediate fellowship application as a result of this collaboration is currently being submitted. 2016 update-> we are currently studying the effects of baroreflex modulation on cardiac ventricular excitability in humans.
Start Year 2015
 
Description Study of autonomic modulation on cardiac excitability in large animal models 
Organisation University of California, Los Angeles (UCLA)
Department Electrical and Computer Engineering Department
Country United States 
Sector Academic/University 
PI Contribution I am interested to study central mechanisms important in autonomic regulation of cardiac excitability and will be looking to employ opto- and pharmaco- genetic tools in the larger animal models available at the Shivkumar lab.
Collaborator Contribution Professor Shivkumar is the director of the UCLA Cardiac Arrhythmia Center at the David Geffen School of Medicine at UCLA. His field of specialization is interventional cardiac electrophysiology, and he heads a group at UCLA conducting mechanistic studies of autonomic interventions in the treatment of cardiac arrhythmias.
Impact We will be collaborating with Professor Shivkumar in the study of autonomic modulation of arrhytmogenic substrates of the heart.
Start Year 2017
 
Description Vagal stimulation in humans 
Organisation San Paolo Hospital
Country Brazil 
Sector Hospitals 
PI Contribution I am interested to study the effects of vagal nerve stimulation on cardiac excitability in humans. I visited the lab of Dr JC Pachon in Sao Paolo and we conducted pilot studies stimulating the cervical vagus nerve in humans and recording electrical signals from the heart during cardiac electrophysiological studies.
Collaborator Contribution Dr Pachon Mateos is a Cardiac Electrophysiologist based in Sao Paolo Heart Hospital, Brazil. His research interest includes ablation of ganglionic plexi in the treatment of cardioinhibitory vasovagal syncope and atrial fibrillation. He has developed a technique of vagal nerve stimulation by catheters placed in the internal jugular vein.
Impact Pilot data used for fellowship application.
Start Year 2016
 
Description "Let's Talk Heart" public seminar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Let's Talk Hearts is part of a series of talks, open to all, providing a forum to learn about heart conditions. The intended audience is the general public and the purpose is to inform how and why we should keep our heart healthy, and the latest research on cardiovascular health. My talk explores the idea of how the brain regulates heart function and how meditation, for example, can potentially lead to improved health by recruiting vagal activity.
Year(s) Of Engagement Activity 2016
URL http://www.letstalkhearts.info