Exercise tolerance in ageing and hypertrophic cardiomyopathy : from pathophysiology to a lifestyle intervention

Abstract

Ageing and hypertrophic cardiomyopathy (HCM) are characterised by reduced functional capacity and quality of life (QoL); predictors of long-term outcomes. Chronic inflammation is a driver of pathophysiological cardiovascular hallmarks in ageing and HCM, including left ventricular (LV) hypertrophy and diastolic dysfunction. Exercise intolerance in ageing and HCM is suggested to be aetiological of central and/or peripheral factors. Excess decline in functional capacity with age can be potentially attenuated with physical activity and exercise. In addition, lifestyle interventions including exercise training and dietary nitrate (NO3 - ) supplementation can safely improve exercise tolerance in individuals with heart failure, but few studies report effects in HCM. The mitochondria play a central role in the initiation and development of inflammation and may be a driver of pathological cardiac alterations in ageing and HCM. The present thesis firstly, investigated the effect of age and sex on mechanisms of exercise tolerance in healthy individuals, with physical activity level (low, medium, or high) as a confounding factor. Secondly, it explored determinants of exercise tolerance in HCM compared to healthy controls. Thirdly, it evaluated the effects of a novel 16-week lifestyle intervention incorporating increased physical activity (step count) and NO3 - supplementation on cardiovascular function and QoL in HCM. Finally, in an animal model of cardiac hypertrophy and inflammageing, the thesis assessed the association between mitochondrial function and pathological phenotype in an ageing and HCM. The major findings of the present thesis suggest that i, Part A), the ability of skeletal muscles to extract delivered oxygen (represented by reduced arteriovenous O2 difference) at peak oxygen consumption (V̇ O2peak) is the key determinant of exercise tolerance in healthy older individuals when physical activity level is controlled for. However, no interaction between age and sex was found for V̇ O2peak and determinants (i.e., cardiac output and arteriovenous O2 difference). In contrast, females present with accelerated age-related vascular change in comparison to males. i, Part B), in comparison to healthy individuals, arteriovenous O2 difference at V̇ O2peak is the key determinant of exercise tolerance in individuals with HCM. ii) A 16-week novel lifestyle intervention may significantly improve vasodilation (i.e., blood pressure), which is related to cardiac remodelling, and QoL. However, no change in exercise tolerance or cardiac function in individuals with HCM was observed. iii) reduced mitochondrial complex I (CI) activity and mitochondrial biogenesis may be associated with the cardiac pathological alterations in ageing and HCM. xxv In conclusion, the findings of the present thesis add knowledge about the deficiencies in cardiovascular function caused by primary ageing with the novel inclusion of physical activity category as a confounding factor in final analysis. Providing key information for improvement of clinical interventions to help prevent a state of dependence in our ageing population. Next, the present thesis helped to further define the underlying mechanisms of exercise intolerance in individuals with HCM by the novel addition of comparing the clinical population to healthy individuals, which is imperative to help define therapeutic targets to lessen the burden to those individuals affected. A novel lifestyle intervention in individuals with HCM combining increased physical activity and NO3 - supplementation may positively impact long-term outcomes in this clinical population. Finally, the work provides a platform for further investigation into the contribution of mitochondrial function in pathological cardiac hypertrophy in ageing and HCM after the novel assessment of CI and CIV function in an aged and HCM mouse cardiac phenotype model. In individuals with HCM, the present thesis suggests that lifestyle interventions incorporating NO3 - supplementation and increased physical activity may improve factors associated with long-term outcomes such as QoL and blood pressure. Following the completion of a clinical trial including a larger study population and dissecting of the combined intervention, lifestyle behaviours may be implemented into clinical care after the completion of a clinical trial with a larger study population.