Exercise central haemodynamics: physiology and clinical relevance in patients with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (T2DM) are at an increased risk of target organ damage, compared to non-diabetic individuals. The reason for this remains to be fully elucidated, however, high blood pressure (BP) or hypertension (measured in the clinic from the brachial artery) is likely to play a contributory role. Recent evidence suggests that central (or aortic) BP and related haemodynamics may be more closely related to cardiovascular risk than other surrogate markers (including brachial BP). Furthermore, studies have shown that the BP response to light to moderate intensity exercise is predictive of cardiovascular events and mortality, independently of resting brachial BP and other cardiovascular risk factors. Despite this, the association between light to moderate exercise central haemodynamics and target organ damage in patients with T2DM has never been assessed. Therefore, the broad aim of this thesis was to examine the haemodynamic differences and consequent target organ damage between patients with T2DM and non-diabetic controls under resting conditions as well as in response to light to moderate intensity exercise. In study 1 (Chapter 2 Part II) the difference between central and brachial systolic BP in patients with T2DM compared to non-diabetic controls was examined by systematic review and meta-analysis of 17 individual studies (including 2,711 patients with T2DM and 10,460 non-diabetic controls). The main finding from this study was that despite patients with T2DM having elevated central haemodynamics indicative of systolic stress, there was no difference in the level of central to brachial systolic BP or pulse pressure amplification. However, the level of amplification differed throughout T2DM duration. Furthermore, large variation in systolic BP amplification was observed in both patients with T2DM (range= 2.0 ‚- 16.6 mmHg) and non-diabetic controls (range= 1.0 ‚- 16.1 mmHg), suggesting that risk related to central systolic BP cannot be estimated simply from a measure of brachial BP. Study 2 (Chapter 3) examined central haemodynamics in order to determine the association between aortic stiffness and augmentation index (a purported surrogate marker of aortic stiffness) in 53 patients with T2DM and 53 non-diabetic controls. This study showed that despite patients with T2DM having increased aortic stiffness, there was no difference in augmentation index compared to non-diabetic controls (p=0.184), and augmentation index was not related to aortic stiffness in either group (p>0.05 for both). These findings suggest that augmentation index should not be used as a marker of aortic stiffness in either individuals with or without T2DM. Study 3 (Chapter 4) sought to determine an explanation as to why patients with T2DM have abnormal brain structure (specifically grey matter atrophy) by examining the effect of potential mediators (including brachial BP, abdominal obesity and physical activity) on the association between T2DM and grey matter atrophy in 258 patients with T2DM and 302 non- diabetic controls. This study found that the association between T2DM and grey matter atrophy was substantially attenuated by abdominal obesity (32%) above and beyond other cardiovascular risk factors including resting brachial BP and, therefore, abdominal obesity may be a target for interventions that aim to maintain brain structure in patients with T2DM. This was an analysis of a convenience sample in which exercise central haemodynamic data was not available and, therefore, the association between these parameters and grey matter atrophy was unable to be determined. In study 4 (Chapter 5) exercise central haemodynamics (including aortic reservoir pressure and excess pressure) were measured in both patients with T2DM (n=37) and non-diabetic controls (n=37) and the association of these variables with grey matter atrophy was examined. This study found that excess pressure integral was significantly elevated in patients with T2DM (compared to non-diabetic controls) both at rest and in response to exercise (p<0.001 for both); however, aortic stiffness was the strongest independent predictor of grey matter atrophy (p=0.036). In non-diabetic controls, excess pressure integral was independently related to grey matter atrophy (p=0.043), thus providing the first evidence that excess pressure may be a novel cardiovascular risk factor related to brain atrophy and a useful clinical marker to identify individuals at risk related to BP in future. Study 5 (Chapter 6) sought to determine the association between exercise central haemodynamics (including excess pressure integral) and kidney function (both at rest and in response to the stress induced by light to moderate intensity exercise) in 39 patients with T2DM compared to 39 non-diabetic controls. In this study, exercise induced-albuminuria was observed in patients with T2DM in response to light to moderate intensity exercise. Importantly, excess pressure measured during exercise was associated with exercise-induced albuminuria in patients with T2DM, independently of resting brachial BP (p=0.003), therefore, suggesting that exercise excess pressure may be an important marker to identify individuals at increased risk related to abnormal renal function. Finally, in study 6 (Chapter 7) the effect of abnormal haemodynamics (in particular brachial to radial systolic BP amplification) on the accuracy of central BP estimated using radial applanation tonometry, was examined in 20 patients with T2DM and 20 non-diabetic age- matched controls at rest and in response to light to moderate exercise. During the candidature of this thesis, radial applanation tonometry was the most widely accepted non-invasive method to estimate central BP. This study found that resting radial systolic BP was significantly higher than brachial systolic BP in both patients with T2DM (136 ¬± 19 vs 127 ¬± 17 mmHg) and non-diabetic controls (135 ¬± 12 vs 121 ¬± 11 mmHg; p<0.001 for both). Furthermore, in both groups, brachial to radial systolic BP amplification resulted in significant underestimation in central BP using radial tonometry. The exercising results were similar to the resting data and are presented in Appendix II, as they did not form part of the final submitted manuscript (Chapter 7). These findings have significant implications for the refinement of methods that determine central BP non-invasively. Overall, the work contained in this thesis supports that patients with T2DM have abnormal central haemodynamics compared to non-diabetic controls at rest, however, for the first time has shown that these patients have abnormal central haemodynamics in response to light to moderate exercise. Furthermore, this research program has shown that exercise central haemodynamics are related to target organ damage in patients with T2DM, independently of resting brachial BP and other cardiovascular risk factors. Finally, this research highlights the necessity to refine the methods that estimate central BP non-invasively. Taken together, this thesis provides novel information and represents a significant advancement in understanding the relationship between exercise central haemodynamics and target organ damage in patients with T2DM.