Analysis of local hemodynamics in central and peripheral arteries

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.To understand the function of the cardiovascular system, the propagation of waves in arteries has to be investigated, since they carry information which can be used for the prevention and diagnosis of cardiovascular diseases. The main goal of this thesis is to improve the understanding of wave propagation in central and peripheral arteries studying the local hemodynamics of the ascending aorta, the carotid artery and the femoral artery by analysing human, animal and in vitro data. Also, another aim is to introduce a technique for non-invasive determination of the local arterial distensibility, the wave speed, and wave intensities. Arterial hemodynamics is here studied using wave intensity analysis, a time domain technique based on pressure and velocity measurements that is derived from the 1D theory of wave propagation in elastic tubes. Also, variations of this technique were used, such as (i) the non-invasive wave intensity analysis that relies on diameter and velocity measurements and (ii) the reservoir-wave approach in which pressure is considered the sum of a pressure due to the elastic properties of the arteries and a pressure due to the travelling wave. To identify the correct analysis to describe the wave propagation in the ascending aorta using pressure and velocity measurements, the hemodynamics of the canine ascending aorta was studied invasively using the traditional wave intensity (or waveonly) analysis and the reservoir-wave approach in both control condition and during total aorta occlusions in order to provide clear reflection sites. The models produced a remarkably similar wave intensity curves, although the intensity magnitudes were different. The reservoir-wave model always yielded lower values for all hemodynamic parameters studied. Both models led to the conclusion that distal occlusions have little or no effect on hemodynamics in the ascending aorta. Since the ascending aorta is not an accessible vessel its examination in clinical routine is challenging. More superficial arteries, such as carotid, radial, brachial and femoral arteries, might be easier to examine, in particular using ultrasound equipment that is normally available in the clinic. These considerations led to the second study of this thesis that is the introduction of a new technique for the non-invasive determination of arterial distensibility, local wave speed and wave intensities to study arterial hemodynamics in humans. The technique relies only on diameter and velocity measurements that can be obtained using ultrasound. In particular, the technique was used for the first time to study the hemodynamic of the carotid and femoral arteries in a large population of healthy humans to investigate the changes with age and gender. The carotid artery was more affected by the aging process than the femoral artery, even in healthy subjects. Local wave speed, distensibility and hemodynamic wave intensity parameters (except the reflection index) had strong correlations with age at the carotid artery. The mechanical properties and hemodynamic parameters of the femoral artery were not significantly age-dependent, but local wave speed, distensibility and forward wave intensity were significantly gender-dependent. The findings of the first and second studies contributed to the design of the third study. The carotid artery is an elastic artery relatively close to the heart and thus the hemodynamics of this vessel is related to left ventricular function. For this reason, the carotid hemodynamics of the same healthy population was investigated for the first time using the reservoir-wave approach. Pressure and velocity measurements were separated into their reservoir and excess components and the effects of age and gender on these parameters were studied. It was found that in the carotid artery reservoir and excess components are strongly affected by the ageing process. From the above studies some questions about the hemodynamics of central arteries remained unsolved. For this reason it was decided to carry out in vitro experiments in a mock circulatory system to investigate the effects of variation of compliance and stroke volume on the reservoir and excess pressure components of the ascending aorta. This allows for the study of different physiological and pathological conditions, such as age, hypertension, atherosclerosis and ventricular dysfunction in relation to vascular compliance and stroke volume. The reservoir and excess components of the measured pressure wave were both significantly related to aortic compliance and stroke volume, but the reservoir pressure had a stronger relationship with aortic compliance compared with the excess pressure and its magnitude increased more significantly when the aorta became stiffer. Wave speeds, calculated using measured and excess pressures, followed the same pattern, but the one calculated using excess pressure was smaller than the other. Wave speed was strongly related to aortic compliance, but not to the change of stroke volume. In conclusion, the use of the wave-only and the reservoir-wave models led to different values of wave speed and intensities that can be explained considering the anatomy of the arterial system. Notably, elastic and muscular arteries are differently affected by age and gender. The hemodynamics of the carotid artery are strongly related to age also in healthy subjects. Pressure and flow velocity in the carotid artery can be separated into their reservoir and excess components. The new non-invasive technique based on diameter and velocity measurements could be relevant in clinical practice as a screening tool

Osteoartroosi kardiovaskulaarne ja metaboloomiline profileerimine

Väitekirja elektrooniline versioon ei sisalda publikatsiooneOsteoartroos on krooniline liigeshaigus, mis haarab sagedamini käe-, põlve-, puusa- ja lülisamba liigeseid ning põhjustab valu ja liigesliikuvuse piiratust. Osteoartroosiga patsientide arv on suur ning tegemist on kõige kiiremini kasvava liigeshaiguse patsiendigrupiga. Tänaseni puudub haiguse tekkemehhanismidest piisav arusaam, et efektiivselt pidurdada haiguse kulgu. Osteoartroosi on pikalt peetud kõhre mehhaanilisest kulumisest tingitud haiguseks, aga viimastel aastatel on ilmnenud üha rohkem tõendeid, et haiguse arengus mängivad olulist rolli süsteemne alaäge põletik, muutused ainevahetuses ja arterite jäikuses. Osteoartroosiga patsientidel on leitud kõrgem südame- ja veresoonkonna haiguste risk, kuid täpsemad mehhanismid selle võimaliku seose taga on teadmata. Selle doktoritöö eesmärgiks oli selgitada osteoartroosi ja arterite funktsiooni ning oksüdatiivse stressi ja ainevahetushäirete (sh metaboolse sündroomi) vahelisi seoseid. Lisaks oli eesmärgiks kirjeldada osteoartroosi lipiidide ainevahetusega seotud madalmolekulaarsete ühendite profiili. Selle doktoritöö raames läbiviidud uuringusse kaasati 70 lõppstaadiumis osteoartroosiga patsienti Tartu Ülikooli Kliinikumi ortopeedia osakonnast ning kontrollgruppi 82 ilma osteoartroosita uuritavat Tartumaa perearstide nimistutest. Arterite jäikuse mõõtmised tehti Endoteeli Keskuses ning biokeemiliste markerite mõõtmised TÜ Kliinikumi ühendlaboris ning bio- ja siirdemeditsiini instituudi biokeemia osakonnas. Töö tulemusena leidsime uudse seose aordi jäikuse ja osteoartroosi raskusastme vahel. Osteoartroosiga patsientide arterid olid võrreldes kontrollgrupi liikmete arteritega jäigenenud. Lisaks leidsime, et osteoartroosi korral esineb organismis kõrgem oksüdatiivse stressi tase, mis on seotud ka osteoartroosi raskusastmega. Kirjeldasime, et osteoartroosi korral esinevad lipiidide ainevahetuse häired, mis on seotud arterite funktsiooniga ja aitavad selgitada osteoartroosi ning südame- ja veresoonkonnahaiguste vahelist seost. Selle uuringu tulemusena tuvastatud seosed osteoartroosi ja lipiidide ainevahetuse, oksüdatiivse stressi ja arterite funktsiooni vahel võivad tulevikus aidata välja töötada uusi ründepunkte osteoartroosi ravimisel.Osteoarthritis is a chronic joint disease that most frequently affects the hand, knee and hip joints, and the spine. Osteoarthritis manifests mainly as pain and serious loss of function. The prevalence of osteoarthritis is high and it is the fastest growing musculoskeletal disorder. Furthermore, osteoarthritis is the leading cause of pain in elderly. There is no cure for the disease and treatment focuses on pain relief and on preserving the function of affected joints. For a long time osteoarthritis was thought to be a non-inflammatory degenerative „wear and tear“ disease of the articular cartilage. However, in recent years several studies have found that systemic low-grade inflammation, metabolic disturbances and arterial dysfunction are involved in development of osteoarthritis. Osteoarthritis patients have increased cardiovascular disease risk, but the mechanisms behind the association are largely unknown. The aims of this thesis were to determine associations between osteoarthritis, and arterial function, metabolic disturbances and oxidative stress. In addition, we aimed to describe the metabolic profile of low molecular weight lipid related compunds in osteoarthritis patients. Seventy end-stage knee and hip osteoarthritis patients from the department of orthopaedics of Tartu University Hospital and 82 non-osteoarthritis controls from the same geographic regioon were enrolled in the study. Measurements of arterial stiffness were conducted at the Endothelial Centre, University of Tartu. Biochemical markers were measured at the Department of Biochemistry, Institute of Biomedicine and Translational Medicine and at the United Laboratories of the University of Tartu. As a result of the study, we found that severity of osteoarthritis was associated with aortic stiffness. The arterial stiffness of the osteoarthritis patients was significantly higher compared with the controls. In addition, the level of oxidative stress was higher in the osteoarthritis patients and correlated with severity of osteoarthritis. We found that lipid metabolism was associated with osteoarthritis and also with arterial stiffness, which might hence explain the association between osteoarthritis and cardiovascular disease. In conclusion, this thesis describes associations of osteoarthritis with arterial stiffness, high-grade oxidative stress and lipid metabolism and might help to design new targets in finding cure for the disease

New echocardiographic and translational tools in valvular and ischemic heart disease

The advent of new methodologies applied to echocardiography, such as tissue Doppler imaging, 2D speckle tracking for myocardial deformation, and myocardial work assessment, has provided additional tools, capable of finer and earlier diagnosis of myocardial dysfunction. In addition, the ability to evaluate endothelial function and measure platelet aggregation has allowed to identify patients at increased risk for cardiovascular events and potential target of pharmacological treatment. In this research project we explored the role of these innovative and advanced tools, like strain parameters, myocardial work indices, and percentage of platelet aggregation, in the diagnosis of physiopathological mechanism underlying valvular and ischemic heart disease. Furthermore, we evaluated the prognostic value of speckle tracking echocardiography in aortic stenosis patients, from asymptomatic status to transcatheter aortic valve implantation, and its accuracy in the prediction of coronary artery disease. Finally, we investigated how factors such as hyperglycemia, hypercholesterolemia and uremia affect endothelial and platelet function, detecting new compounds able to counteract their pathological effects. To date, most of these investigated methodologies are mainly used for research purpose; further and larger studies are needed to definitely attest their adding value, in order to include their use in the routine clinical practice

Functional changes of the vasculature in HIV/AIDS patients on Haart and Haart Naïve HIV participants

The present study sought to explore the functional changes that occur in the vasculature of HIV positive participants of African origin in Mthatha district of South africa which might lead to increased risk in their cardiovascular system. Available literature shows that arterial stiffness plays an important role in cardiovascular events such as stroke, vasculitis and myocardial infarction. Measurement of (aortic pulse wave velocity; PWV) provides some of the strongest evidence concerning the prognostic significance of large artery stiffening. This study was aimed at investigating the relationship between anthropometry, age, E-Selectin level, cytokine levels, haemodynamic variables, blood counts and blood lipid profile with pulse wave velocity. Some traditional cardiovascular risk factors such as alcohol, and smoking were also taken into account. This was a cross-sectional study comprising of 169 participants (62 males and 107 females). 63 were HIV negative (group A), 54 HIV positive on treatment (group B), and 52 were HIV positive not on treatment (group C). Pulse wave velocity (PWV) was assessed using the Sphygmocor Vx. Statistically, ANOVA was used for variables with normal distribution and non parametric tests were used for variables with skewed distribution. Notable significant differences were seen in the means of the following variables across all the 3 groups. Conclusion: This study showed that HIV infected patients with or without antiretroviral therapy have increase arterial stiffness which is associated with an increased cardiovascular risk. The sphygmocor is an accurate, non invassive and useful tool in the evaluation of arterial stiffness and its use in clinical practice should be encouraged. PWV and the augmentation index (AIx) are the two major non- iv invasive methods of assessing arterial stiffness. Life style modification should be incorporated into the management of HIV patients so as the continuous monitoring of their haematological and lipid profile

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

The assessment of echocardiographic and tissue Doppler profiles of asymptomatic follow-up patients in cardiology practice

Thesis (M. Tech.) -- Central University of Technology, Free State, 2010This main aim of this study was to assess patients in a general cardiology practice in order to determine the systolic and diastolic profiles of these patients. The aim was also to determine what effect life style and risk factors may have on the echocardiographic variables measured during such an examination. The specific aim of this study was the importance of not only examining the systolic function but the necessity to also examine the diastolic profile of patients. Life-style plays an important role, with the main culprit being obesity. Obesity was the single most important factor that affected the diastolic profile of patients seen in this study. With obesity a combination of other risk factors related to obesity was observed. Most abnormalities found due to these risk factors were associated with diastolic changes in the left ventricle. Echocardiography is routinely used in daily practice, but the diagnostic value of this tool can be enhanced if proper analyses of the systolic as well as the diastolic profiles are determined. Many cardiologists only measure the systolic function of the heart as an indication of the well- being of the left ventricle, although in this study it was proven that systolic function did not alter with ageing or with changes in the risk profile. Hundred-and-twelve patients, divided into three age groups, were evaluated in this study. Both systolic and diastolic variables were measured and analysed for abnormalities. None of these patients had systolic function abnormalities, although they had detectable anatomic changes due to ageing, obesity and hypertension. Several abnormalities were found on the diastolic profile of these patients. Muscle thickness increased due to obesity and hypertension and even with ageing, but with no significant abnormalities in the systolic function of the heart. There was a slight increase in the circumferential shortening of the left ventricle and that both the septal and longitudinal functions decreased with ageing. It is noteworthy that even where the systolic function remained normal in ageing subjects, their diastolic profiles changed significantly. Assessment of left ventricular function required a meticulous and systematic approach. In this study forty- one percent of patients visiting this general practice had abnormalities of their diastolic function although their systolic function was normal. It was found that with ageing, especially in the older age group, important abnormalities occur in their diastolic profile. The most common changes were that the E- peak velocity decreased and that the Apeak velocity of the trans-mitral flow increased. It seemed that passive filling decreased with ageing but that active filling increased simultaneously, causing the cardiac output to remain constant in older subjects. This is important to know because diseases affecting the atrium may have a profound effect on the cardiac output of older patients, even if they have normal systolic function, (due to the decreased passive filling they need their active filling or atrial contraction to support a normal cardiac output). An important marker will be to look at the ratio of the E/A- velocities in older patients to determine the ratio of active against passive filling. Other than that, a relatively new tool in echocardiography called tissue Doppler was used to determine what happened to the muscle with ageing. Here it was demonstrated that the different layers of the left ventricle acted differently with ageing. Results showed that the longitudinal fibres weakened with ageing although the circumferential fibres remained unchanged or even strengthened with ageing. It was apparent in this study that the traditional use of only systolic function may not be adequate when evaluating relative asymptomatic patients presenting at a general cardiology practice. It is important to also evaluate the diastolic profiles of these patients in order to scientifically quantify their heart health, even in asymptomatic patients. It is important to routinely evaluate the diastolic profile of patients so that early detection of these diastolic variables can be detected and timely consideration for its treatment can be given by their cardiologist. It is also important to take note of the significance of the obesity problem and the effect it has on the heart’s health. In conclusion, this study emphasizes the importance of the echocardiographic evaluation of diastolic cardiac function in addition to routine systolic evaluation in asymptomatic patients. This will enable the clinician to detect abnormalities early and tailor therapy accordingly. Lifestyle related risk factors, especially obesity, also have significant effects on diastolic cardiac function

Echocardiography

The book "Echocardiography - In Specific Diseases" brings together contributions from well- known researchers from around the world, some of them specialized in imaging science in their clinical orientation, but also representatives from academic medical centers. Each chapter is structured and written to be accessible to those with a basic knowledge of echocardiography but also to be stimulating and informative to experts and researchers in the field of echocardiography. This book is primarily aimed at cardiology fellows during their basic echocardiography rotation, fellows of internal medicine, radiology and emergency medicine, but also experts in echocardiography. During the past few decades technological advancements in echocardiography have been developing rapidly, leading to improved echocardiographic imaging using new techniques. The authors of this book tried to explain the role of echocardiography in several special pathologies, which the readers may find in different chapters of the book

Age-associated Arterial Remodelling and Cardiovascular Diseases

Arterial remodelling is a major risk factor for a variety of age-related diseases and represents a potential target for therapeutic development. During ageing, the structural, mechanical and functional changes of arteries predispose individuals to the development of diseases related to vascular abnormalities in vital organs such as the brain, heart, eye and kidney. For example, aortic stiffness increases nonlinearly with advancing age – a few percent prior to 50 years of age but over 70% after 70 years of age. The elevated stiffness in large elastic arteries leads to increased transmission of high pressure to downstream smaller blood vessels, in turn affecting the microcirculation and end-organ functions. Meanwhile, the augmented remodelling of small arteries accelerates central arterial stiffening. This chapter is to provide an overview of age-associated changes in the arterial wall and their contributions to both central and peripheral vascular abnormalities associated with ageing. Therapeutics that specially target the different aspects of arterial remodelling are expected to be more effective than the traditional medications, particularly for the treatment and management of vascular ageing-related diseases.published_or_final_versio