The effect of single nucleotide polymorphisms of oxidative stress genes and low grade inflammation upon pulse wave contour analysis, a useful non invasive, intermediate vascular phenotype.

Cardiovascular disease remains a major cause of mortality and morbidity and is underpinned by Oxidative stress, within which, inactivation of nitric oxide (NO) by superoxide (SO) and other reactive oxygen species is characteristic. Two major enzyme systems are implicated within oxidative stress; NAD(P)H oxidase and endothelial nitric oxide synthase (eNOS). eNOS generates NO while at the same time, and within the same cells, NAD(P)H plays a powerful role in the generation of SO. Evidence is accumulating that polymorphisms of the genes encoding these enzyme systems may play an important role in the pathophysiology of CAD. Additionally there has been much recent interest in both biochemical markers of oxidative stress and low grade chronic inflammation as well as a non invasive vascular phenotype, pulse wave analysis. This thesis reports a series of studies (utilising the techniques described in chapter 2) which aimed to ascertain:- The reproducibility of pulse contour analysis as a non invasive intermediate cardiovascular phenotype (Chapter 3). Whether common single nucleotide polymorphisms of the p22phox gene CYBA and the endothelial nitric oxide synthase gene, NOS3, have an effect upon arterial compliance in patients with coronary artery disease (Chapters 4,5 and 6). In healthy volunteers, free of cardiovascular disease whether a relationship existed between markers of low grade inflammation and arterial stiffness (Chapter 7). Chapter 3: The reproducibility of diastolic pulse wave contour analysis and its relation to systolic pulse contour analysis. This clinical study demonstrated that both large (C1) and small artery (C2) compliance values were reproducible and that there was a significant correlation between both Augmentation Index (AIx) and C1and AIx and C2 in healthy volunteers and though there was no association between AIx and C1 in patients with coronary artery disease AIx did correlate with C2 in this population. Chapter 4: The effect of the G894T SNP of the NOS3 gene upon arterial stiffness in patients with coronary artery disease. There was no association observed between this polymorphism and blood pressure or large artery compliance however ANOVA revealed a statistically significant association for TT homozygosity and small artery compliance. The highest small artery compliance was seen in the patients homozygous for the G allele, an intermediate value observed in heterozygotes and the lowest value demonstrated in patients homozygous for the T allele. Multiple regression analysis, examining the possible contribution of confounders showed that only small artery compliance was significant when NOS3 G894T genotype was assigned as the dependent variable. Chapter 5: The C242T single nucleotide polymorphism of the CYBA gene and blood pressure and arterial compliance in patients with coronary artery disease. We sought to examine the influence of the C242T SNP of CYBA upon vascular compliance and blood pressure using the dominant allele model. The presence of the 242T allele was associated with significantly higher systolic blood pressure. Patients homozygous for the C allele had lower systolic blood pressure than heterozygotes and patients homozygous for the T allele. There was no statistically significant effect upon diastolic blood pressure but there was however a significant association observed between the 242T allele and pulse pressure. Chapter 6: Combined analysis of NOS3 G894T and CYBA C242T genotypes upon arterial stiffness. In order to contrast the arterial stiffness between the favourable versus the non-favourable genotypes patients homozygous for the NOS3 G allele and homozygous for the CYBA C allele were compared with those homozygous for the NOS3T allele and possessing the CYBA 242T allele. The former displayed higher large and small artery compliance than the latter group. Multiple regression analysis, examining the possible contribution of confounders showed that only the large and small artery compliance values contributed significantly when genotype was assigned as the dependent variable. Chapter 7 Chronic low grade inflammation and insulin resistance and arterial compliance in healthy volunteers. Within healthy volunteers multiple regression analysis showed that small artery compliance was significantly associated with IL 6, CRP and ICAM. Augmentation index showed only an association with ICAM1. There was no significant correlation between Adiponectin levels and either of the arterial stiffness parameters studied. Conclusions Diastolic pulse wave contour analysis is a reproducible assessment of arterial stiffness with the potential to represent a high fidelity non invasive vascular phenotype. Small artery compliance is correlated with Augmentation Index and although the measurements are not analogous they both represent useful means of acquiring quantitative data concerning arterial stiffness. The 242T allele of the p22phox gene, CYBA, is associated with decreased large but not small artery compliance and increased systolic and pulse pressure. Homozygosity for a common NOS3 polymorphism (894 GT) was associated with decreased small artery compliance but not with large artery compliance or blood pressure. The markers of chronic inflammation Interleukin 6, ICAM and hsCRP but not Adiponectin, a marker of Insulin resistance, predict small artery compliance in healthy individuals apparently free of vascular disease

Development of non-invasive, optical methods for central cardiovascular and blood chemistry monitoring.

Cardiovascular disease and sepsis are leading causes of mortality, morbidity and high cost in hospitals around the world. Failure of the circulatory system during cardiogenic shock and sepsis both can significantly impair the perfusion of oxygen through organs, resulting in poor patient outcome if not detected and corrected early. Another common disorder which goes hand-in-hand with cardiovascular disease is Diabetes Mellitus. Diabetes is a metabolic disorder resulting from the inability of the body to regulate the level of glucose in the blood. The prevalence of diabetes worldwide is increasing faster than society’s ability to manage cost effectively, with an estimated 9% of the world population diagnosed with metabolic disease. The current gold standard measurements for venous oxygen saturation, arterial pulse wave velocity (PWV), and diabetes management through blood glucose concentration monitoring are all invasive. Invasive measurements increase risk of infection and com- plications, are often high cost and disposable, and have a low patient compliance to regular measurements. The aim of this thesis is to develop non-invasive methods of monitoring these important dynamic physiological variables, including, venous oxygen saturation, pulse wave velocity, and blood glucose concentration. A novel photoplethysmography-based NIR discrete wavelength spectrometer was developed using LEDs to both emit light, and detect the light reflected back through the tissue. Using LEDs to detect light simplifies sensing circuit design, lowering hardware costs, allowing adaptable sensing specific to the needs of the user. A reflectance pulse oximeter was developed to measure the oxygen saturation at both the external jugular vein, and carotid artery. Measuring the jugular venous pulse (JVP) allows estimation of the venous oxygen saturation through either the JVP, or through breathing induced variation of the JVP. In addition to oxygenation, the de- vice developed is capable of adapting the sensing layout to measure the arterial pulse waveform at multiple sites along a peripheral artery, such as the carotid or radial. The PWV local to the carotid artery, and radial artery can then be measured, providing key information of cardiovascular risk. A novel algorithm for PWV measurement over multiple pulse waveforms was also developed. Expanding the sensor to use multiple different wavelength LEDs allow discrete spectroscopy in pulsatile blood. An absorption model of components in blood at specific wavelengths was created to isolate the spectral fingerprint of glucose. The sensor successfully measured the oxygen saturation at the carotid artery, and external jugular vein across 15 subjects, giving mean oxygen saturations of 92% and 85% respectively, within the expected physiological ranges. Venous oxygen saturation calculated using breathing induced changes to JVP was 3.3% less than when calculated on the JVP alone, with a standard deviation of 5.3%, compared to 6.9%. Thus, future work on the sensor will focus on extraction of the breathing induced venous pulse, rather than measuring from the JVP itself. The PWV on the carotid and radial artery was successfully measured within the ex- pected physiological ranges, with the novel phase difference algorithm proving more robust to noise than the gold standard foot-foot method. The phase difference method returned a mean PWV at the radial artery of 4.7 ±0.6 m s−1, and a mean CoV of 20%, compared to 4.0 ±1.4 m s−1, and a moan CoV of 58% for the foot-foot method. The proof of concept PWV sensor gives promising results, but needs to be calibrated against invasive gold standards, such as aorta and femoral pressure catheters. A glucose trial involving adult and neonatal subjects provided validation of the NIR non-invasive pulse glucometer. The sensor has an R2 of 0.47, and a mean absolute relative difference (MARD) of 19% compared to gold standard reference measurements. Clarke error grid analysis returns 85% of measurements in Zone A, 11% in Zone B, and 4% in Zone C. While the sensor is not as accurate as the gold standard invasive measurements, the ability to constantly measure without any pain or discomfort will help increase measurement compliance, improving user quality of life, plus further development may improve this. Overall, this thesis provided novel contributions in non-invasive venous oxygen saturation, PWV, and glucose concentration monitoring. The adaptability of the sensor shows promise in helping reduce the pain and inconvenience of the current invasive measurements, especially in diabetes management, where the sensor has the most potential for impact

Evaluation of pulse wave analysis to assess coronary artery disease

Conventional risk factors for cardiovascular disease, such as age, gender, hyperlipidaemia and hypertension are useful clinical markers of coronary artery disease (CAD) in asymptomatic patients or those without a prior history of atherosclerosis. In patients referred for a cardiology opinion, modification of risk factors by lifestyle changes and cardiac medications as well as confounding co-morbidities limit the value of these markers. Patients are often referred for diagnostic coronary angiography to determine the presence and severity of CAD, stratify the risk of future events and determine appropriate management. Despite the use of a variety of tests to best identify those requiring angiography, up to half of all patients referred do not have significant disease. Pulse wave analysis (PWA) is a novel method to derive indices of central (aortic) blood pressure and arterial stiffness. Pressure waveforms are obtained non-invasively from the radial artery using a simple tonometry method and have been shown to correlate with clinical outcomes and cardiovascular events in selected populations. This thesis will explore, for the first time, the clinical potential for PWA as a non-invasive marker of CAD in an unselected contemporary cohort of patients referred for elective coronary angiography. The main hypotheses tested are first that PWA is a suitable tool for clinical use, including those with cardiac and non-cardiac co-morbidities and second that abnormalities of PWA are independent predictors of the presence and severity of CAD. Data have been derived from a prospective, protocol-driven, multi-centre cohort of 550 patients recruited from 2006-8. Results suggest that PWA has a useful clinical role in stratifying the risk of coronary disease. PWA variables were independent of conventional blood pressure measurement and superior to baseline risk factors, biomarkers and other non-invasive tests

Non-invasive vascular assessment in people with type 2 diabetes: Diagnostic performance of Plethysmographic-and-Doppler derived ankle brachial index, toe brachial index, and pulse volume wave analysis for detection of peripheral arterial disease

Objective: There is evidence that standard assessment techniques for detecting PAD might be of less diagnostic accuracy in people with type 2 diabetes. The aim of this study was to examine diagnostic performance of Plethysmographic-and-Doppler derived ankle brachial index, toe brachial index, and Pulse volume waveform analysis for detecting PAD in people with T2DM. Methods: In this cross-sectional study 303 patients with T2DM were included in the study. The participants underwent ABI measurement, applying both Plethysmographic and Doppler derived devices, as well as TBI, PVW was also recorded for each patient. Diagnostic performance of each test for detecting PAD, applying ultrasound Doppler scan as the reference standard, was measured. Moreover, the best cut-off point for each method to detect PAD was determined. Results: PVW showed the highest sensitivity (81.8) for detecting PAD, followed by ABIDOP (72.7), and ABIPLE (20). However, all devices showed an excellent specificity for detecting PAD. The optimal cut-off point for diagnosis of PAD was 0.9 for ABIDOP, 1.2 for ABIPLE, and 0.38 for TBI. Conclusion: Within this population of patients with T2DM, TBI less than 0.38 provided the best sensitivity for detection of PAD followed by PVW, ABIDOP � 0.9, and ABIPLE < 1.2. © 2019 Primary Care Diabetes Europ

Is there a Benefit to Screening for Abdominal Aortic Aneurysm in the Irish Male Population between the ages of 55 to 75 years; an Ideal Opportunity Group for Evaluating Cardiovascular Risk Factors?

Introduction: Abdominal Aortic Aneurysm (AAA) screening programmes have been carried out worldwide on males between the ages of 65-75 years. The results of such programmes show AAA screening to be beneficial and cost effective. In the Multicentre Aneurysm Screening Study conducted in the United Kingdom, the incidence of AAA was 4.9%. Early diagnoses of AAA’s have reduced AAA related deaths by 42%. This study investigated the incidence of AAA in Irish males between the ages of 55-75 years and incorporated an assessment of cardiovascular risk factors. A younger group of males were screened to see if there was any benefit in screening for AAA and to determine the incidence of cardiovascular risk factors in this younger population. Method: From April 2006 to December 2007, males ages between 55-75 years living in the catchment area of the hospital, were invited to participate in the screening programme. A ultrasound scan of their aortas was preformed and a finger prick blood test was carried out to assess their cardiovascular risk factor status. Results: Nine hundred and four participants were screened. Of these, 17 (1.9%) participants had an undiagnosed AAA, of which 4.2% were aged between 65-75years and 0.6% aged between 55-64 years. The incidence for hypertension, 33% had been previously diagnosed with hypertension, with 165 of these uncontrolled. In the participants with no history of HTN, 31% had an elevated blood pressure reading. The study found, 26% had a previous history of hypercholesterolemia, with 70% of these remaining uncontrolled. Of those with no previous history of hypercholesterolemia, 33% had an elevated reading. The glucose results revealed 3% of the total participants had a raised glucose level with had no previous history of DM. Of those who were being treated for diabetes, 49% showed poor sugar control. Only 63% (573) of all participants agreed to have their body mass index measured. Of these, 16% were found to be morbidly obese and 64% were overweight. Conclusion: The incidence of AAA in males between 65-75 years is similar to other worldwide studies, therefore screening would be beneficial in Ireland. However, screening males of 55-65 years was not proven to be beneficial. Cardiovascular risk factors, such as hypertension, hypercholesterolemia and diabetes are very prevalent in Ireland. In this study 8 the prevalence of cardiovascular risk factors were high. Of those who have been diagnosed with a cardiovascular risk factor, many remain uncontrolled despite treatment. There was also a larger number of the screened population undiagnosed for their risk factors. Therefore screening for cardiovascular risk factors is a necessity and it can easily be incorporated in to other screening programmes

Measures Of Ejection Duration In Normal Weight And Overweight Adolescent Children

The aim of this study was to determine how measures of ejection duration, subendocardial viability ratio, and central arterial health are affected by the overweight condition in a sample of adolescent children. 34 sex and age-matched adolescent children were studied, with half of the total sample (17, 11 male, 6 female) overweight. In one laboratory visit, anthropometric measures, body composition analysis, and non-invasive measures of central cardiovascular health, including heart rate (HR), aortic systolic blood pressure (ASBP), carotid- femoral pulse wave velocity (cf-PWV), ejection duration in milliseconds (EDms) and relative (ED%), and the subendocardial viability ratio (SEVR) were performed. cf-PWV and ASBP were significantly greater, and SEVR lower in overweight compared to normal weight participants. Measures of ED% and HR were not significantly different between groups despite a positive trend in mean values with overweight status and moderate effect sizes for both. Overweight adolescents report unfavorable cardiovascular changes as measured by cf-PWV, ASBP, and SEVR. Although significance was not observed, our findings indicate that the ED% may still lend to the assessment of CVD risk in a larger sample including more obese adolescents

Defining Cardiovascular Dysfunction in the Metabolic Syndrome: therapeutic and nutritional approaches to treatment

Metabolic syndrome (MetS) is a complex disease state defined by the manifestation of a cluster of cardiovascular (CV) risk factors including, abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Individuals afflicted with MetS have been demonstrated to assume the burden of a 3-fold increased risk of cardiovascular disease (CVD) mortality, myocardioal infarction, stroke, type II diabetes (T2DM) and all cause mortality. The national prevalence of hyperglycemia and abdominal obesity paralleled by a surge in sedentary lifestyle behavior underscore the importance of early identification and treatment of MetS. Deleterious adaptations to both vascular and myocardial structure and function have been demonstrated in MetS. Alterations in CV function associated with accelerated arterial aging have been implicated in the association between MetS and CVD. The underlying pathophysiology of MetS is not well understood and CV dysfunction has not been comprehensively examined in a MetS population free from confounding pathologies including T2DM and/or overt CVD. Furthermore, the effects of therapeutic lifestyle interventions for targeting subclinical CV dysfunction in MetS without T2DM and/or overt CVD require investigation. Therefore, the directive of the studies included in this dissertation was to perform a comprehensive assessment of CV function to validate the presence of CV dysfunction in MetS and to evaluate practical therapeutic strategies for improving cardiac and arterial dysfunction associated with MetS. Results from these studies identified subclinical left ventricular (LV) diastolic dysfunction at rest LV systolic dysfunction during exercise. Additionally, it was discovered that deleterious adaptations to large artery structure and function occur in individuals with MetS. Importantly, these alterations occurred in the absence of chronic disease including T2DM and clinical CVD. These results suggest for the first time that CV dysfunction does occur in individuals afflicted with MetS without T2DM and/or CVD. The investigation of exercise training as a therapeutic strategy for targeting arterial dysfunction revealed improvements in central arterial stiffness, central systolic blood pressure and aerobic capacity after 8 weeks of moderate/high intensity aerobic training. During peak exercise we have demonstrated improvements in arterial-ventricular coupling, LV contractility, peripheral vascular resistance, and aerobic capacity after 8 weeks of aerobic training in MetS. Exercise training was unable, however, to improve resting LV structure, LV diastolic function, or metabolic profile. Results from our investigation using a nutritional therapeutic approach to CV dysfunction in MetS demonstrate similar inconclusive findings. Single-dose supplementation with two doses of trans-resveratrol demonstrated no conclusive therapeutic potential for improving arterial stiffness or reducing central systolic blood pressure. These results would suggest that a greater understanding of the underlying pathology of MetS is required for identifying and optimizing therapeutic approaches to its treatment. Taken together the results of these collective documents demonstrate an understanding of the synergistic effects of co-occurring risk factors on CV function in the absence of chronic clinical disease. Further, these results highlight therapeutic and nutritional strategies for targeting CV dysfunction in MetS

Circadian variations in aortic stiffness, sympathetic vasoconstriction, and post-ischemic vasodilation in adults with and without type 2 diabetes.

The current literature reveals a lack of information on the circadian variations of some important cardiovascular risk factors related to the work of the heart or the capacity to provide blood and oxygen to various tissues. These factors include aortic stiffness, peripheral vasoconstrictor responsiveness, and post-ischemic vasodilation capacity. Furthermore, it is not clear whether the impact of an external stressor capable of activating the sympathetic nervous system could have greater repercussions on the cardiovascular system in the morning than in the evening. Given the higher incidence of acute cardiovascular events in the morning than in the evening, the studies undertaken in this thesis aim to investigate the circadian variations of these factors that are linked to cardiovascular risk, both at rest and during acute activation of the sympathetic nervous system. Type 2 diabetes (T2DM) is a condition that induces deleterious changes in cardiovascular function, impacting cardiovascular mortality and morbidity. Thus, the impact of diabetes will be evaluated. As a secondary purpose, considering the sex differences in the incidence and prognosis of cardiovascular disease, the effect of sex will be evaluated. Aortic stiffness proved not to be increased in the morning compared to the evening at specific times when the cardiovascular risk is significantly different, both at rest and during sympathetic activation. However, while healthy older women show similar aortic stiffness values compared to their male counterparts during acute stress, older women with T2DM reported greater aortic stiffness compared to men with T2DM. The post-ischemic forearm vasodilation is blunted in the morning compared to the evening in healthy elderly and such an attenuated vasodilation capacity impairs blood flow supply towards the ischemic area. The presence of T2DM does not affect vasodilation capacity and reactive hyperemia, but induces circadian variations in arterial pressure. The peripheral vasoconstriction triggered by a standardized sympathetic stressor is similar between morning and evening, regardless of the presence of T2DM and reduced baseline vascular conductance values in the morning. However, the peripheral vasoconstriction responsiveness is blunted in individuals with T2DM than in healthy ones as sympathetic activation induces vasodilation on the contralateral forearm in individuals with T2DM and vasoconstriction in healthy age-matched subjects. This finding highlights a neurovascular response to an external stressor altered by T2DM. Taken together, our findings suggest that the baseline state of constriction of the peripheral vascular tissue is greater in the morning than in the evening, but this fact is not due to greater sympathetic vasoconstriction responsiveness in the morning. Higher morning vasoconstriction at baseline however affects the capacity of a vascular tissue to dilate and, in turn, to supply blood to an ischemic tissue. Similar sympathetic vasoconstriction responsiveness between morning and evening is a likely factor explaining similar or lower values of central artery stiffness in the morning than in the evening, not only at rest but also during sympathetic excitation. Paradoxically, adults with T2DM report an increase in sympathetic-mediated dilatation capacity on the vascular tissue, which might be a defense mechanism that allows to reduce the central pressor response during sympathetic excitation