Investigating the role of the carotid body in human cardiovascular disease

Abstract

Cardiovascular diseases such as hypertension (HTN) and heart failure (with and without reduced ejection fraction; HFrEF and HFpEF) are leading causes of global disease burden. Underlying mechanisms are incompletely understood and for HFpEF particularly, effective treatment options limited. Common to these conditions is excessive activation of the sympathetic nervous system (SNS). The carotid bodies (CB); small glands whose primary role is oxygen sensing, also modulate SNS and can become aberrant in hypertension and HFrEF, contributing to excess sympathetic activity (SNA) and in HFrEF; exercise ventilatory inefficiency and increased mortality. The focus of this thesis was investigating the level of peripheral chemosensitivity further in these diseases and its contribution to ventilatory efficiency. Resting peripheral chemosensitivity (hypoxic ventilatory response; HVR) was elevated in HFpEF vs healthy controls (NTN), but similar to HFrEF. Possible underlying mechanisms are CB hypoperfusion from increased inflammation and SNA, however these were not elevated in HFpEF vs NTN in this thesis. The slope of linear regression of minute ventilation vs carbon dioxide production (exercise ventilatory efficiency; VE/VCO2) was increased in HTN vs NTN, signifying abnormalities in cardio-respiratory matching. HVR was elevated to the same degree by submaximal exercise in NTN and HTN; indicating similar sensitisation of the CB at rest and in submaximal exercise. CB inhibition with intravenous dopamine improved: VE/VCO2 ratio in NTN and HTN similarly in submaximal exercise; VE/VCO2 slope and ratio at peak in HFrEF; VE/VCO2 nadir and ratio at AT, in NTN, HFrEF and HFpEF; exercise systolic blood pressure (SBP) in HTN and HFpEF. Further work is needed to examine underlying mechanisms of increased peripheral chemosensitivity in HFpEF and ventilatory inefficiency in HTN; however this thesis added to our knowledge of CB activity and ventilatory efficiency in a range of cardiovascular diseases vs healthy controls, along with the potential benefits of targeting this pathway.

Date of Award	4 Feb 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Emma C J Hart (Supervisor) & Angus K Nightingale (Supervisor)