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The systemic renin-angiotensin system, an important regulator of cardiovascular homeostasis, is well described, though separate local systems exist in many tissues, the function of which is less well defined. There is evidence for their role in growth responses and cellular metabolism, particularly for the heart, and the understanding of these mechanisms is important, given the detrimental effect of excess cardiac hypertrophy. The examination of these local systems in humans is problematic, though a polymorphism in the human angiotensin converting enzyme (ACE) gene may be utilised to explore the mechanisms involved. This thesis examines the influence of the ACE gene polymorphism in exercise-induced cardiac hypertrophy. Subjects of DD genotype (associated with higher ACE levels) had greater left ventricular (LV) growth than those of II genotype, and the LV growth in DD subjects was disproportionate to the increase in lean body mass. Blockade of the angiotensin receptor with losartan had no effect on LV growth in either genotype, though the dose may have been inadequate. This and other recent studies support the role of the local renin-angiotensin system in human cardiac growth, with higher ACE levels being associated with greater growth. The appropriate indices for scaling LV mass to body size were also examined and lean body mass was found to be the only suitable index for simple ratio scaling. The renin-angiotensin system may also play a role in the efficiency of cellular metabolism. The ACE gene polymorphism was examined in elite endurance athletes, and the I allele (associated with lower ACE levels) was found to be more prevalent, suggesting a genetic advantage for endurance. In Olympic runners, the relative frequency of the I allele rose with the distance run. The data suggests greater efficiency associated with lower ACE levels, and the reduced cardiac growth associated with the II genotype may be related to this improved efficiency. Potential mechanisms are discussed. These results confirm the importance of local renin-angiotensin systems in exercise physiology and may relate closely to disease states. The importance of gene-environment interactions has also been shown.


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