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

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.

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 control 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.