Abstract
Cystic fibrosis (CF), the most common autosomal recessive disorder in the Caucasian population, is increasingly recognised as a multisystem disorder. Beyond its hallmark pulmonary manifestations, CF is associated with malnutrition, cardiovascular dysfunction, peripheral muscle impairments, and potential susceptibility to exertional heat-illness – all of which can influence health status and exercise tolerance. The introduction of CF transmembrane conductance regulator (CFTR) modulator therapies, particularly Elexacaftor/Tezacaftor/Ivacaftor (ETI), has transformed prognosis for many people with CF (pwCF), necessitating a deeper understanding of evolving extrapulmonary manifestations in this new treatment era. This thesis provides the first integrated assessment of cardiovascular function, peripheral muscle capacity, body composition, and thermoregulatory responses during exercise in pwCF established on ETI. Across four experimental studies, key findings reshape our current physiological understanding and reveal persistent vulnerabilities that warrant clinical and further research.Study one demonstrates that pwCF on ETI display no difference in body composition and peripheral muscle function — including strength, power, endurance, and fatigability, compared to matched healthy controls. This suggests meaningful improvements in musculoskeletal health, likely attributable to enhanced nutritional status and increased physical activity, and warrants further investigation across the broader spectrum of CF disease, including individuals with more severe disease or those who are sedentary.
However, study two reveals persistent micro- and macrovascular endothelial dysfunction in pwCF despite ETI therapy, evidenced by attenuated acetylcholine-mediated microvascular endothelial function and reduced flow-mediated dilation. These findings indicate a residual cardiovascular phenotype with potential implications for long-term vascular ageing and cardiometabolic risk, highlighting the need for targeted vascular interventions.
Study three shows that although absolute aerobic capacity (V̇O2peak) is preserved in some pwCF on ETI, when normalised to body mass or fat-free mass, pwCF showed lower values approaching significance. Moreover, they exhibit lower cardiac output and stroke volume during maximal exercise, further supporting persistent cardiac limitations. These findings support the development of strategies aimed at improving cardiac function and central haemodynamics.
In study four, thermoregulatory and perceptual responses to exercise in the heat were studied for the first time in pwCF on CFTR modulator therapy. These were largely comparable between pwCF and controls, including core and skin temperature, sweat rate, heart rate, and subjective thermal responses. However, pwCF reported increased thirst at baseline and after 30 minutes of cycling in the heat. Survey data revealed a lack of adaptation in salt supplementation behaviours since initiating CFTR modulator therapy. This underscores the need for updated hydration guidelines and further study into individualised electrolyte strategies in this population.
Together, these findings advance our understanding of the residual extrapulmonary burden in CF despite ETI, particularly in the context of ageing and increasing physical independence. While ETI marks a step-change in CF care, optimising cardiovascular, muscular, and thermoregulatory health remains critical. Future work should focus on precision exercise interventions and adjunct therapies targeting, in particular, endothelial function and cardiac output to enhance health span and quality of life as this population ages.
| Date of Award | 1 Jul 2025 |
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| Original language | English |
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| Supervisor | Ant Shepherd (Supervisor), Jo Corbett (Supervisor) & Zoe Louise Saynor (Supervisor) |