Changes in arterial stiffness and other cardiovascular risk variables following specific exercise programmes

June 2012 Arterial stiffness is one of the major risk factors and markers of cardiovascular disease (CVD). An increase in the arterial stiffness is influenced by various factors such as age, lifestyle, genetics and the presence of other cardiovascular risks such as obesity and diabetes. Arterial stiffness is a consistent thread in this thesis. This thesis investigates the effects of exercise-based management programmes for CVD and risk factors with a focus on carotid-radial applanation tonometry which is a specific non-invasive technique for measuring arterial stiffness. Erectile dysfunction is a marker of CVD and is associated with endothelial dysfunction that leads to arterial stiffness. The effects of centrebased, supervised and exercise-based cardiac rehabilitation (CR) programmes were studied on the changes in arterial stiffness, erectile dysfunction and quality of life of patients with CVD. Despite the effectiveness of CR programmes, there is poor attendance at these programmes and unsupervised home-based, IT (information technology)-supported programmes could improve patient participation and cost effectiveness. Moreover, earlier identification of risks and appropriate management can reduce the incidence of CVD. There are no such programmes for early stages of CVD in practice, especially in developing countries such as India. A 12-week, IT-supported home-based exercise programme in India, for patients with metabolic syndrome was developed and studied. In general, arterial stiffness was improved in both centre-based and home-based exercise programmes. There were acute increases in arterial stiffness following exercise in healthy Caucasians and South Asians as well as people with metabolic syndrome. Carotid-radial pulse wave analysis could be a simple and reliable prognostic tool in exercise based rehabilitation programmes

MR assessment of end-organ damage in the metabolic syndrome and diabetes mellitus

The first part of this thesis focuses on assessing end-organ damage in individuals with the metabolic syndrome and diabetes mellitus using magnetic resonance imaging (MRI) and spectroscopy (1H-MRS). We performed cross sectional and intervention studies to investigate the contribution of obesity, dietary conditions, metabolic environment and exogenous disruptors (chemotherapy) to cardiovascular end-organ damage and the reversibility of this damage with a low caloric diet. The effects of interventions, dietary as well as non-dietary, were explored using imaging technology. As ethnicity is an important aspect of the pathophysiology in diabetes mellitus, we also examined the influence of ethnic factors on diabetes mellitus and its complications. The second part of this thesis focuses on safety, feasibility and implementation of innovative MR techniques at higher field strengths for assessment of cardiovascular disease.Nederlandse Hartstichting, Novo Nordisk B.V., Boehringer Ingelheim B.V., Servier Nederland Farma B.V., Ipsen Farmaceutica B.V., Guerbet Nederland B.V. and Sanofi Nederland B.V.UBL - phd migration 201

Effect of a Single High-Fat Meal and Vitamins on the Circulatory Response to Local Heat in Koreans and Caucasians

Blood flow mediated by the vascular endothelium plays an important role in removing heat from the skin. Asians who have thrifty genes have impaired endothelial function (EF) due to the westernized high fat (HF) dietary lifestyle. Hypertriglyceridemia (HTG) can produce free radicals which reduces the bioavailability of the endothelium derived relaxing factor, nitric oxide (NO). EF, as measured by the blood flow response (BFR) to heat, occlusion and the free radical concentration after a single HF meal has not been studied in Korean-Asians compared to Caucasians. The purpose of this study was to evaluate baseline and postprandial EF as related to oxidative stress from a single HF and low fat (LF) meal and the effects of vitamins on scavenging free radicals and improving EF in Korean-Asians compared to Caucasians. This was done by assessing skin BFR to vascular occlusion and local heat and analyzing malondialdehyde (MDA) levels after ingestion of a HF and LF meal before and after vitamin intake. Ten Caucasians and ten Koreans participated in the study (mean age 25.3 ± 3.6 years). BFR to vascular occlusion and local heat and oxidative stress was assessed after a single HF and LF meal at 2 hours compared to baseline. After administration of vitamins (1000mg vitamin C, 800IU vitamin E, and 300mg Coenzyme Q-10) for 14 days, the same measurements were repeated. The results of this investigation showed that the skin BFR to vascular occlusion and local heat at baseline was significantly lower in Koreans than Caucasians. The skin BFR to vascular occlusion and local heat following a HF meal significantly decreased and free radicals significantly increased at 2 hours compared to baseline in Koreans (p\u3c.001), but not in Caucasians. Also, the skin BFR to vascular occlusion (p=0.001) and local heat (p=0.003) was significantly lower and free radicals (p=0.004) were significantly higher at 2 hours after the HF meal in Koreans than Caucasians. When vitamins were given, the BFR to vascular occlusion and local heat before and after HF meal was not significantly different in both Koreans and Caucasians. These findings suggest that Koreans may have lower EF than Caucasians which may be explained, in part, by genetic variation. Also, even a single HF meal can reduce EF through an oxidative stress mechanism but can be blocked by antioxidant vitamins in Koreans. In conclusion, Korean-Asians are probably more susceptible to skin damage during heat application due to lower endothelial function compared to Caucasians if Koreans eat high fat foods. However, reduced endothelial function may be prevented by taking antioxidant vitamins

Insulin resistance, ethnicity and cardiovascular risk

Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality. The literature supports a series of established risk factors for CVD: age, gender, family history of CVD, ethnicity (un-modifiable); and high blood pressure, blood cholesterol, TGs, LDL, diabetes, pre-diabetes, obesity, smoking, physical inactivity, stress and unhealthy diet (modifiable). High blood pressure (hypertension) shares many of these risk factors. However, much of the variance/risk in both conditions cannot be explained. This has led to a search for novel risk factors, including insulin resistance and subclinical inflammation, the significance of which at present are controversial, particularly in relation to hypertension. There are also ethnic differences in the incidence, prevalence, risk factors and progression of cardiovascular disease. In some populations CVD occurs at an earlier age and progresses more rapidly. In this thesis I worked on two datasets in relation to hypertension, cardiovascular disease and their risk factors: (i) the RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) study (chapters 2, 3, 5 and 6); and (ii) routinely-collected national data in Scotland via the SDRN (Scottish Diabetes Research Network) and SCI-Diabetes (chapter 2 and 7). Work on data from the RISC cohort focused on the relation between clamp-measured insulin sensitivity (its unique feature), inflammatory markers and hypertension; the SDRN work addressed ethnic differences in relation to diabetes and CVD. The first study (Chapter 3) examined the importance of insulin sensitivity/resistance in the development of hypertension and change in blood pressure over three years of follow-up in the healthy European (EU) RISC population. Systolic BP (SBP) was higher at baseline in insulin resistant (IR) women. There was no difference in BP in relation to IR in men. After adjustment for age, BMI, baseline BP and other covariates, low insulin sensitivity (M/I) predicted a longitudinal rise in SBP in women but not men, and SBP over time did not increase in insulin sensitive women. The second study (Chapter 4) was a systematic review of the relationships between two markers of low grade inflammation (IL-6 and CRP) and BP/hypertension, considering the roles of adiposity and insulin resistance. The systematic review showed evidence of considerable variation in the relationships amongst low grade inflammation, adiposity, insulin resistance and the development of hypertension. There appeared to be a positive association in the literature between CRP and DBP in younger individuals, although none of the studies were adjusted for insulin sensitivity determined by clamp technique. This association was further explored using RISC study data in Chapter 5 with stratification by sex and adjusting for clamp-derived insulin sensitivity. The third study (Chapter 5) examined the relationship of inflammatory markers with the development of hypertension and change in blood pressure over three years in the same healthy European population and whether any relationship was independent of clamp-measured insulin sensitivity (IS). High sensitivity C reactive protein (hsCRP) predicted prospective change in diastolic BP independent of insulin sensitivity and BMI whereas IL-6 had no relation with BP (both systolic and diastolic) or the incidence of hypertension. The fourth study (Chapter 6) evaluated all available predictors of BP rise over time (both systolic and diastolic) in a healthy EU population; moreover the significance of different predictors was examined within subgroups defined by age and sex. This analysis showed that baseline BP was the principal determinant of follow-up BP in all age and sex groups. Obesity was the second most important predictor (BMI in adults aged 30-44 years; percent change in BMI in middle age people aged 45-60 years). Lifestyle factors influenced BP via their effect on BMI. People who maintained their BMI during the three year follow-up did not exhibit a rise in BP (whether systolic or diastolic). Other important predictors identified in this analysis were insulin sensitivity in middle aged women and hsCRP in adult men. The fifth study (chapter 7) evaluated the role of ethnicity in the development of cardiovascular disease in people with type 2 diabetes living in Scotland. Over a follow-up of seven years, Pakistani people had increased risk of CVD and Chinese people had decreased risk of CVD as compared to White population. Pakistanis had an increased risk of CVD at a younger age independent of other conventional risk factors. In summary, insulin sensitivity and inflammation influence blood pressure, but their role is not generalised across different age and sex groups. BMI and change in BMI are important predictors of follow-up BP in adults and middle age healthy people, supporting a role for maintenance of BMI in preserving cardiovascular health. In addition to the known ethnic differences in the development of diabetes, I identified ethnic differences in the development of CVD

Morphological and electrophysiological differences between the Caucasian and South Asian Atrium

Introduction: South Asians (SAs) have a low prevalence of atrial fibrillation (AF) compared with Caucasians despite a higher prevalence of hypertension, diabetes mellitus and coronary artery disease. The aim of this thesis was to determine whether this was related to an under-detection of the arrhythmia and if not, whether differences in left atrial (LA) size, electrophysiological properties or autonomic function in SAs might help to explain this disparity. Methods: Retrospective and prospective cohort studies were performed on SA and Caucasian participants using data from implantable cardiac devices, cardiac magnetic resonance imaging scans, invasive electrophysiology studies and a range of non-invasive cardiac investigations. Results: The cumulative incidence of subclinical AF was significantly lower in SAs compared with Caucasians (log rank p=0.002) with an annual event rate of 6.9% versus 13.9%. In comparison with Caucasians, SAs were of a smaller height with lower lean body mass and higher waist:hip ratio; had lower minimum (27.7±11.1 ml vs 34.9±12.3 ml, p=0.002) and maximum LA volumes (64.7±21.1 ml vs 80.9±22.5 ml, p<0.001) even after matching for body surface area; lower P wave dispersion (males 28.0(12)ms vs 25.0(12)ms, p=0.039; females 24.0(12)ms vs 22.0(12)ms, p=0.004) and P wave terminal force in lead V1 (males 0.031(0.04)mm•s vs 0.021(0.03) mm•s, p=0.023; females 0.036(0.04)mm•s vs 0.034(0.04)mm•s, p=0.030), electrophysiological variations related to the inhomogeneity of LA conduction and LA size respectively; increased heart rate (82.5(18)bpm vs 78.0(18)bpm, p=0.024), lower atrioventricular (280(50)ms vs 300(60)ms, p=0.001) and ventriculoatrial (300(60)ms vs 320(93)ms, p=0.013) effective refractory periods and lower heart rate variability (in SA males), suggestive of sympathetic predominance. Conclusions: SAs have reduced LA size and evidence of increased sympathetic tone and reduced inhomogeneity in LA conduction. The morphological, electrophysiological and autonomic differences identified in SAs may help to explain why this ethnic group has a lower prevalence of AF

Ocular and systemic markers for vascular function in those at risk of type 2 diabetes mellitus and cardiovascular disease

The devastating impact of Type 2 Diabetes Mellitus (T2DM) -related morbidity and mortality on global healthcare is escalating with higher prevalences of obesity, poor diet, and sedentary lifestyles. Therefore, the clinical need for early diagnosis and prevention in groups of high-risk individuals is necessary. The purpose of this thesis was to investigate the use of surrogate markers, namely retinal vascular function, to determine future vascular endothelial dysfunction, atherosclerosis, large vessel disease and cardiovascular risk in certain groups. This namely covered normoglycaemic and normotensive South Asians (SAs), those with Impaired-Glucose Tolerance (IGT) and individuals with a familial history (FH) of T2DM. Additionally the effect of overweight and obesity was studied. The techniques and modified protocols adopted for this thesis involved the investigation of endothelial function by means of vascular reactivity at the ocular and systemic level. Furthermore, the relationships between retinal and systemic function with circulating markers for endothelial cell function and cardiovascular risk markers were explored. The principal studies and findings of the research were: Vascular Function in Normoglycaemic Individuals with and without a FH of T2DM WE FH individuals exhibited higher levels of total cholesterol levels that correlated well with the retinal arterial dilation amplitude to flicker light stimulus. However this did not extend to noticeable differences in markers for endothelial cell damage and impaired retinal and systemic function. Vascular Function in Normoglycaemic South-Asians vs. White-Europeans without a FH and Vascular Disturbances Compared to healthy WEs (normo -glycaemic and -tensive), SA participants exhibited levels of dyslipidaemia and a state of oxidative stress that extended to impaired vascular function as detected by reduced brachial artery flow-mediated dilation, slower retinal arterial vessel dilation reaction times (Appendix 3) and steeper constriction profiles. Furthermore, gender sub-group analysis presented in a sub-chapter shows that SA males demonstrated 24-hour systemic blood pressure (BP) and heart rate variability (HRV) abnormalities and heightened cardiovascular disease (CVD) risk. Vascular Function in Individuals Newly Diagnosed with IGT as compared to Normoglycaemic Healthy Controls Newly-diagnosed WE and SA IGT patients showed a greater risk for CVD and T2DM progression by means of 24-hour BP abnormalities, dyslipidaemia, increased carotid artery intimal-media thickness (c-IMT), Framingham scores and cholesterol ratios. Additionally, pre-clinical markers for oxidative stress and endothelial dysfunction, as evident by significantly lower levels of plasma glutathione and increased levels of von-Willebrand factor in IGT individuals, extended to impaired vascular systemic and retinal function compared to normal controls. This originally shows retinal, systemic and biochemical disturbances in newly-diagnosed IGT not previously reported before. Vascular Function in Normal, Overweight and Obese Individuals of SA and WE Ethnicity In addition to the intended study chapters, the thesis also investigated the influence of obesity and overweight on vascular function. Most importantly, it was found for the first time that compared to lean individuals it was overweight and not obese individuals that exhibited signs of vascular systemic and ocular dysfunction that was evident alongside markers of atherosclerosis, CVD risk and endothelial damage

Pathogenesis of type 2 diabetes and cardiovascular disease in South Asians: effects of dietary interventions on metabolism and cardiovascular function

People of South Asian origin have an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people of Western European descent. Not only is the prevalence of these diseases higher in South Asians, they also occur at a younger age and lower BMI, and have a more severe course. The high prevalence of T2D and CVD in South Asians, who comprise one fifth of the total world__s population, poses a major health and socioeconomic burden worldwide. The underlying cause of this excess risk is, however, still poorly understood. The studies described in this thesis were performed to gain more insight in the pathogenesis of T2D and CVD in South Asians and to provide new leads for preventive strategies and treatment options. For this purpose sophisticated techniques were used such as hyperinsulinemic-euglycemic clamp with stable isotopes, indirect calorimetry, skeletal muscle biopsies, MRI and spectroscopy, and brown fat quantification using PET-CT-imaging, combined with short-term dietary interventions, in healthy lean young adult men and overweight adult men. These studies have led to a number of promising areas for further research. It seems that not one, but multiple metabolic mechanisms have been affected, most likely due to gene-environment interactions.UBL - phd migration 201

Vascular effects of isometric handgrip training (IHG): influence of ethnicity and ageing.

It is established that isometric handgrip (IHG) training reduces resting arterial blood pressure (ABP) in hypertensives and normotensives. However, the mechanisms are unclear. The aim of this project was to test whether IHG training with one arm improves endothelium-dependent vasodilation (EDD) including that mediated by nitric oxide (NO) and prostacyclin (PGI2) in young White European (WE) men, and in young South Asian (SA) and older WE men who have recognised endothelial dysfunction. IHG training was performed with the dominant hand, (four 3-minute contractions at 30% of their maximum voluntary contraction (MVC) at 5 min intervals) 4 days/week for 4 weeks. MVC was increased in the trained arm, but not the non-trained arm of all groups; resting ABP was reduced in older men only. However, IHG training increased muscle performance in the non-trained and trained arm of all groups during rhythmic handgrip at 60% MVC for 3 min. Further, exercise hyperaemia evoked by these contractions, and reactive hyperaemia were increased in both the trained arm and non-trained arm of young and older WE, but not in the non-trained arm of young SA men. In addition, IHG training augmented the increased venous efflux of NO metabolites from the non-trained arm during reactive hyperaemia in older men, but decreased it in young WE and SA men, whilst augmenting the increase in PGI2 efflux in young SA men only. Finally, during a single bout of IHG training, limb blood flow increased progressively with repeated IHGs in contralateral arm and ipsilateral leg of WEs, and to a lesser extend in forearm of SAs. These responses were attenuated by cyclooxygenase (COX) inhibition in WEs but enhanced in SAs implicating vasodilator and vasoconstrictor COX products respectively. These new findings indicate that just 4 weeks of IHG training improves muscle performance and endothelial dilator function in young healthy WE men and particularly in older WE men, but not in young SAs. The acute effects of IHG training on blood flow in the resting limbs are consistent with shear stress providing the stimulus for improved endothelium-dependent dilatation in young and older WEs but suggest the release of vasoconstrictor COX products may limit the beneficial effects in young SAs. The mechanisms require further investigation. However, in older WE men, IHG training may provide a useful, non-pharmacological tool for improving EDD and reducing ABP and cardiovascular risk, but more intense or longer IHG training may be required even in young SA men to achieve such effects. Keywords: Isometric handgrip training, hypertension, arterial blood pressure, endothelium dependent vasodilation, South Asian ethnicity, ageing