Matters of the heart : An exercise medicine approach to counteracting the adverse effects of androgen deprivation therapy in men with prostate cancer

Androgen deprivation therapy (ADT) is commonly prescribed for men with prostate cancer (PCa). Despite its clinical effectiveness, ADT is associated with several deleterious effects, including cardiovascular disease (CVD). Whilst epidemiological data suggests that ADT-treated men have an increased risk of all-cause and cardiovascular mortality and cardiovascular events, the underlying mechanisms are poorly understood. As CVD is the leading cause of death unrelated to PCa, elucidating these mechanisms would aid in identifying therapeutic targets for preventative strategies.

The primary aim of this thesis was to explore the underlying mechanisms of cardiovascular risk and the therapeutic role of exercise training in ADT-treated men. To achieve this, two systematic reviews, a cross-sectional study, and a randomised controlled trial were completed. Chapter One provides an overview, introduction and review of the literature related to this thesis. Chapter Two presents the results of a systematic review that comprehensively examined the influence of pre-existing CVD on all-cause mortality, cardiovascular mortality, and cardiovascular events in ADT-treated men. This review included prospective and retrospective cohort studies and randomised controlled trials that reported risk estimates separately for groups with pre-existing CVD diagnoses in ADT-treated men and included at least one endpoint for all-cause and cardiovascular mortality and cardiovascular events. Chapter Three presents the results of a published systematic review and meta-analysis, which evaluated the “effect of exercise training on cardiometabolic health in men with PCa receiving ADT.” Chapter Four presents the methodological approach for the experimental studies performed in Chapters Five and Six. Chapter Five presents the results of a cross-sectional study (assessments performed in parallel with the randomised controlled trial in Chapter Six) that compared measures of vascular health in 31 men commencing ADT (age: 66.5±9.9 years) and ten age-matched controls (age: 64.8±8.7 years). Chapter Six randomly assigned ADT-treated men (age: 66.6±9.2 years, n=16) to a three-month thrice-weekly aerobic and resistance exercise program or usual care (age: 66.3±10.2 years, n=15). Outcomes of Chapters Five and Six included blood biochemical markers, resting echocardiography, cardiac magnetic resonance imaging, body composition, vascular health, cardiorespiratory fitness, physical function, and a series of patient-reported outcomes. Lastly, Chapter Seven presents the thesis's strengths, limitations, and future directions.

Men with pre-existing CVD (chronic heart failure or prior myocardial infarction) treated with ADT reported higher rates of all-cause mortality than men without pre-existing CVD or those not treated with ADT (Chapter Two). Despite the inconsistencies and notable between-study clinical and methodological heterogeneity, observations regarding the risk of cardiovascular mortality or cardiovascular events in ADT-treated men with pre-existing CVD were inconclusive. In addition, the meta-analysis in Chapter Three showed that exercise training improved some, but not all, cardiometabolic health markers in ADT-treated men. While statistically significant effect estimates were observed between the exercise training and usual care groups, these estimates did not reach clinically meaningful thresholds, which suggested that the lower aerobic exercise training intensities were insufficient to induce beneficial cardiometabolic effects in ADT-treated men. Chapter Five showed that novel CVD (functional) markers, such as peak oxygen uptake (VO2peak; 23.7±4.5 vs. 32.8±8.3 ml/kg/min; P<0.001) and body fat percentage (29.8±6.8 vs. 23.9±9.4%; P=0.03) were statistically different between men commencing ADT and age-matched controls. Predictors of better cardiovascular health appear best reflected in those with a higher cardiorespiratory fitness level in all participants. Chapter Six showed that incorporating a three-month periodised aerobic and resistance training exercise intervention, including high-intensity interval training, mitigated adverse cardiac remodelling and improved VO2peak in ADT-treated men compared to usual care.

Overall, this thesis provides the foundation for future investigative studies to explore the impact of pre-existing CVD/risk factors in ADT-treated men and the potential influence on subclinical markers of CVD along the hypothesised clinical pathway to CVD events. These findings suggest that incorporating subclinical CVD markers and higher-intensity exercise regimens known to increase VO2peak may help reduce the CVD risk burden in ADT-treated men.