Medicine (Austin & Northern Health) - Theses
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ItemThe effect of sodium on sympathetic nervous system activity and endothelial function in people with type 2 diabetes( 2020)Lowering dietary sodium intake is recommended by public health bodies to lower blood pressure with the ultimate aim of reducing cardiovascular-related disease. However, lower sodium intake has been demonstrated in observational studies to be associated with adverse health outcomes such as higher cardiovascular-related morbidity and mortality in people with type 2 diabetes. They may be due to pleiotropic effects of sodium lowering, such as activation of the renin-angiotensin-aldosterone system (RAAS) and increases in circulating adrenaline and noradrenaline. Dedicated intervention trials are lacking but greatly needed to investigate the complex role of sodium on cardiovascular outcomes further. In an effort to underpin the mechanistic links behind the associations between low sodium intake and poorer cardiovascular outcomes in people with type 2 diabetes, the studies presented in this thesis aimed to examine the effect of sodium on cardiovascular health by measuring the primary endpoints of sympathetic nervous system activity, as assessed by microneurography, and endothelial function, as assessed by endoPAT and endothelial microparticle measurements, and the secondary endpoints of cardiac baroreflex, serum aldosterone, as markers of RAAS activity, and simultaneous measures of 24h blood pressure and heart rate variability. We demonstrated, that compared to other groups along the glucose continuum, individuals with treated type 2 diabetes who had low sodium intake presented with worse endothelial and baroreflex function. This occurred even though these individuals were appropriately managed for their cardio-metabolic risk factors and importantly, adhered to recommended low sodium intake guidelines. This study provided the rationale to conduct an interventional study where, for the first time, we assessed the effect of salt supplementation on cardiovascular endpoints of sympathetic activity and endothelial function as assessed by endoPAT, in people with type 2 diabetes. Salt supplementation was associated with a small increase in sympathetic activity. However, this did not reach levels associated with pathological disease states. Importantly, there were no detrimental effects on endothelial function or alterations in blood pressure. Interestingly improvements in baroreflex function and RAAS activity were seen. When participants were categorized based on salt-sensitivity, salt-resistant individuals demonstrated a trend towards improved endothelial function after salt supplementation. To explore the endothelial response further, we examined the association between habitual sodium intake, RAAS blockade, and endothelial function as assessed by circulating microparticles. Despite expecting higher endothelial microparticles being associated with lower sodium intake, we did not demonstrate any significant association between sodium intake and endothelial microparticles. However, we observed a trend towards higher erythrocyte-derived microparticle levels being associated with lower sodium excretion and higher platelet-derived microparticles being associated with the lowest tertile of 24hUNa excretion. Additionally, RAAS blockade was not associated with lower microparticles counts in the setting of a low sodium intake, questioning whether the therapeutic benefits of RAAS blockade may be attenuated during lower sodium intake. Despite public health bodies advocating for lowering dietary sodium, we demonstrated that these guidelines are simply not being met and sodium intake is unlikely to change over time. Furthermore, we compared the two most common methodologies used to estimate sodium intake in cardiovascular outcome trials which have largely formulated the basis of dietary sodium guidelines. We demonstrated poor agreement between 24h dietary recall and 24h urine sodium excretions, likely due to underestimation and underreporting of sodium intake via 24h dietary recall. Taken together, these findings begin to provide mechanistic insight that sodium lowering in people with type 2 diabetes may not provide the benefit on the sympathetic and endothelial system as intended. Therefore, the necessity for stringent sodium lowering is questioned in this population. Our studies additionally demonstrate the need for future studies to use sound methodological approaches to determine the ideal yet feasible dietary sodium intake targets in people with type 2 diabetes.