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

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 impact of arteriovenous fistulas on aortic stiffness in patients with chronic kidney disease

Contexte. La création d'une fistule artérioveineuses (FAV) chez les patients atteints d'insuffisance rénale chronique (IRC) a des effets néfastes sur le profil central de l'onde de pouls, suggérant l'augmentation de la rigidité artérielle. Le but de la présente étude est d'évaluer de manière prospective l'effet de la création d'une FAV sur la rigidité artérielle. Méthode. Trente et un patients atteints d'IRC stade 5 ont subi une évaluation hémodynamique avant et 3 mois après la création d'une FAV. La pression artérielle (PA), l'analyse centrale et carotidienne du profil de l'onde de pouls et la vitesse de l'onde de pouls (VOP) carotido-fémorale et carotido-radiale ont été étudiées. Le test-t de Student et le test de Wilcoxon ont été utilisés pour comparer les paramètres hémodynamiques pré-FAV et post-FAV , le cas échéant. Pour déterminer l'association entre les variables, des corrélations de Pearson ainsi que des régressions linéaires simples et multiples ont été utilisées. Résultats. Après la création de la FAV, la PA périphérique et la PA centrale ont diminué, sans changements significatifs de la fréquence cardiaque (FC) ou de la pression puisée. La VOP carotido-fémorale (VOPc-f) a diminué de 13,2 ± 4,1 à 11,7 ± 3,1 m/s (P < 0,001). L'indice d'augmentation centrale a monté de 20,8% ± 11,5 à 23,7% ±11,6, à la limite de la signifiance statistique (P = 0,08). Le ratio de viabilité sous-endocardique a diminué de façon significative (153 % ± 34 versus 143 % ± 32, P < 0,05), principalement comme conséquence de la diminution de l'indice de temps de la pression diastolique (ITPD), sans modification significative de la durée diastolique. La réduction de la VOPc-f s'explique par les changements de la PA moyenne et de la FC (R =0,29). La réduction de l'ITPD était liée à des changements de la PA diastolique centrale et de la PA fin systolique centrale (R = 0,87). L'amélioration significative de la rigidité aortique est principalement le résultat de la réduction relative de la VOPc-f dans le sous-groupe de patients ayant une valeur basale de la VOPc-f supérieure à la valeur médiane de 13 m/s. Conclusion. La création de la FAV est associée à une amélioration passive de la rigidité aortique, en particulier chez les patients avec artères plus rigides. Cette amélioration de la rigidité artérielle pourrait être bénéfique pour le système cardiovasculaire

THE EFFECT OF Hibiscus.Sabdariffa. L ON BLOOD PRESSURE AND ARTERIAL STIFFNESS IN HUMANS

Cardiovascular diseases (CVD) are the foremost cause of death worldwide. The main risk factor for CVD is uncontrolled hypertension (HTN). The prescription of only anti-hypertensive regimens in the management of HTN is becoming more challenging due to the high cost and adverse effects linked to the persistent usage of the drugs. Eighteen participants completed the study by consuming 2g of Hibiscus sabdariffa or oolong tea twice daily for six weeks. We lost an additional twelve participants in the study due to the COVID-19 pandemic. Central arterial stiffness was analyzed as cfPWV using applanation tonometry technique. The HS tea intervention (n=11) had a significant positive effect on SBP (P =0.02), DBP (P =0.001) and HR (P =0.03). Also, the HS tea consumption led to a non-significant (p=0.44) reduction in cfPWV (-0.5m/s) when compared to control tea (+0.3m/s). Although, the decease in cfPWV could be clinically significant, but will need to be verified with larger sample size

Combination antiretroviral therapy -associated lipodystrophy : insights into pathogenesis and treatment

Introduction: Combination antiretroviral therapy (cART) has decreased morbidity and mortality of individuals infected with human immunodeficiency virus type 1 (HIV-1). Its use, however, is associated with adverse effects which increase the patients risk of conditions such as diabetes and coronary heart disease. Perhaps the most stigmatizing side effect is lipodystrophy, i.e., the loss of subcutaneous adipose tissue (SAT) in the face, limbs and trunk while fat accumulates intra-abdominally and dorsocervically. The pathogenesis of cART-associated lipodystrophy is obscure. Nucleoside reverse transcriptase inhibitors (NRTI) have been implicated to cause lipoatrophy via mitochondrial toxicity. There is no known effective treatment for cART-associated lipodystrophy during unchanged antiretroviral regimen in humans, but in vitro data have shown uridine to abrogate NRTI-induced toxicity in adipocytes. Aims: To investigate whether i) cART or lipodystrophy associated with its use affect arterial stiffness; ii) lipoatrophic SAT is inflamed compared to non-lipoatrophic SAT; iii) abdominal SAT from patients with compared to those without cART-associated lipoatrophy differs with respect to mitochondrial DNA (mtDNA) content, adipose tissue inflammation and gene expression, and if NRTIs stavudine and zidovudine are associated with different degree of changes; iv) lipoatrophic abdominal SAT differs from preserved dorsocervical SAT with respect to mtDNA content, adipose tissue inflammation and gene expression in patients with cART-associated lipodystrophy and v) whether uridine can revert lipoatrophy and the associated metabolic disturbances in patients on stavudine or zidovudine based cART. Subjects and methods: 64 cART-treated patients with (n=45) and without lipodystrophy/-atrophy (n=19) were compared cross-sectionally. A marker of arterial stiffness, heart rate corrected augmentation index (AgIHR), was measured by pulse wave analysis. Body composition was measured by magnetic resonance imaging and dual-energy X-ray absorptiometry, and liver fat content by proton magnetic resonance spectroscopy. Gene expression and mtDNA content in SAT were assessed by real-time polymerase chain reaction and microarray. Adipose tissue composition and inflammation were assessed by histology and immunohistochemistry. Dorsocervical and abdominal SAT were studied. The efficacy and safety of uridine for the treatment of cART-associated lipoatrophy were evaluated in a randomized, double-blind, placebo-controlled 3-month trial in 20 lipoatrophic cART-treated patients. Results: Duration of antiretroviral treatment and cumulative exposure to NRTIs and protease inhibitors, but not the presence of cART-associated lipodystrophy, predicted AgIHR independent of age and blood pressure. Gene expression of inflammatory markers was increased in SAT of lipodystrophic as compared to non-lipodystrophic patients. Expression of genes involved in adipogenesis, triglyceride synthesis and glucose disposal was lower and of those involved in mitochondrial biogenesis, apoptosis and oxidative stress higher in SAT of patients with than without cART-associated lipoatrophy. Most changes were more pronounced in stavudine-treated than in zidovudine-treated individuals. Lipoatrophic SAT had lower mtDNA than SAT of non-lipoatrophic patients. Expression of inflammatory genes was lower in dorsocervical than in abdominal SAT. Neither depot had characteristics of brown adipose tissue. Despite being spared from lipoatrophy, dorsocervical SAT of lipodystrophic patients had lower mtDNA than the phenotypically similar corresponding depot of non-lipodystrophic patients. The greatest difference in gene expression between dorsocervical and abdominal SAT, irrespective of lipodystrophy status, was in expression of homeobox genes that regulate transcription and regionalization of organs during embryonal development. Uridine increased limb fat and its proportion of total fat, but had no effect on liver fat content and markers of insulin resistance. Conclusions: Long-term cART is associated with increased arterial stiffness and, thus, with higher cardiovascular risk. Lipoatrophic abdominal SAT is characterized by inflammation, apoptosis and mtDNA depletion. As mtDNA is depleted even in non-lipoatrophic dorsocervical SAT, lipoatrophy is unlikely to be caused directly by mtDNA depletion. Preserved dorsocervical SAT of patients with cART-associated lipodystrophy is less inflamed than their lipoatrophic abdominal SAT, and does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal SAT is in expression of transcriptional regulators, homeobox genes, which might explain the differential susceptibility of these adipose tissue depots to cART-induced toxicity. Uridine is able to increase peripheral SAT in lipoatrophic patients during unchanged cART.Johdanto: Ihmisen immuunikatoviruksen (HIV) hoitoon käytetyt lääkeyhdistelmät ovat vähentäneet HIV-positiivisten henkilöiden sairastuvuutta ja kuolleisuutta. Yhdistelmähoitoon liittyy kuitenkin vakavia sivuvaikutuksia, jotka lisäävät potilaiden riskiä sairastua mm. diabetekseen ja sepelvaltimotautiin. Yksi leimaavimpia sivuvaikutuksia on lipodystrofia eli ihonalaisen rasvakudoksen häviäminen (lipoatrofia) kasvoista, raajoista ja vatsalta samalla kun rasvaa kertyy ylen määrin vatsaonteloon ja niskaan. Ilmiön syyt ovat epäselvät. Useiden HIV:ta vastaan suunnattujen lääkeaineiden on epäilty aiheuttavan lipodystrofiaa mm. tuhoamalla mitokondrioita, solujen energiatehtaita . Lipodystrofiaan ei ole tehokasta hoitoa, ellei HIV-lääkitystä muuteta, mutta esim. uridiini on ollut lupaava apu solumallitutkimusten valossa. Tavoitteet: Tutkia liittyykö yhdistelmähoitoon tai sen käyttöön liittyvään lipodystrofiaan verisuonien jäykistymistä, onko lipoatrofinen rasvakudos tulehtunutta verrattuna ei-lipoatrofiseen rasvakudokseen, eroaako lipoatrofinen ei-lipoatrofisesta rasvakudoksesta mm. mitokondriomäärän ja aineenvaihduntaan vaikuttavien geenien ilmentymisen suhteen sekä poikkeaako lipodystrofiassa paremmin säilyvä niskan rasva häviävästä vatsan ihonalaisrasvasta ja onko se mahdollisesti ruskeata rasvaa. Lisäksi tutkimme, voiko ravintolisänä käytetty uridiini parantaa lipoatrofiaa ja siihen liittyviä aineenvaihduntahäiriöitä, kuten rasvamaksaa ja heikentynyttä insuliiniherkkyyttä. Menetelmät: Tutkimuksiin osallistui 64 HIV-positiivista yhdistelmähoidettua potilasta, joista 45:lla oli ja 19:lla ei ollut kehittynyt lääkitykseen liittyviä rasvakudoksen muutoksia. Verisuonijäykkyys tutkittiin pulssiaaltoanalyysilla, kehon koostumus mitattiin kaksienergisella röntgenabsorptiometria- sekä magneettikuvaantamisella ja maksan rasvapitoisuus protonispektroskopialla. Rasvakudosnäytteet otettiin potilaiden vatsan ja niskan ihoalaisrasvasta ja niistä mitattiin eri geenien ilmentymistä sekä mitokondrioiden ja tulehdussolujen määrää mm. DNA:n monistustekniikalla ja kudosleikevärjäyksin. Uridiinin tehoa lipoatrofian hoidossa arvioitiin 3kk satunnaistetussa lumelääkekontrolloidussa tutkimuksessa, johon osallistui 20 HIV-positiivista yhdistelmähoidettua lipoatrofista henkilöä. Tulokset: HIV-lääkityksen kesto, mutta ei lipodystrofia, altistaa verisuonien jäykistymiselle iästä ja verenpainetasosta riippumatta. Lipoatrofisessa rasvakudoksessa tulehdukseen liittyvien geenien ilmentyminen ja tulehdussolujen määrä ovat lisääntyneet, kun taas mitokondriomäärä sekä rasvasolujen muodostumiseen ja toimintaan liittyvien geenien ilmentyminen vähentyneet verrattuna ei-lipoatrofiseen rasvakudokseen. Lipodystrofiassa säilyvä/lisääntyvä niskan rasva on vähemmän tulehtunutta kuin herkemmin häviävä vatsan ihonalaisrasva eikä se ole ruskeata rasvaa. Lipodystrofisten henkilöiden niskan rasvassa on vähemmän mitokondrioita kuin ei-lipodystrofisten henkilöiden niskan rasvassa, vaikka kudokset ovat ulkoisesti samannäköisiä. Niskan ja vatsan alueen ihonalaisrasva eroaa eniten ns. homeobox-geenien ilmentymisessä eli sellaisten geenien, jotka määrittelevät kudosten sijainnin ja ominaisuudet sikiökehityksen varhaisvaiheessa. Uridiini lisää ihonalaisrasvan määrää lipoatrofisilla potilailla, mutta ei vaikuta maksan rasvapitoisuuteen tai insuliiniherkkyyteen. Johtopäätökset: HIV:n hoitoon käytettyjen lääkkeiden pitkäaikaiskäyttö lisää verisuonien jäykkyyttä ja siten potilaiden riskiä sairastua sydän- ja verisuonitauteihin. Lipoatrofinen rasva on tulehtunut ja sen mitokondriovarannot vähentyneet. Koska mitokondrioiden vähyys on todettavissa niskarasvassa myös sellaisilla lipodystrofisilla henkilöillä, joilla se on säilynyt atrofialta, mitokondriokatoa ei voida pitää lipoatrofiaa suoraan aiheuttavana tekijänä. Niskan ja vatsan ihonalaisrasvan merkittävin ero on elinkehitystä ohjaavissa geeneissä, mikä voi selittää kudosten erilaisen alttiuden lääkkeiden sivuvaikutuksille. Uridiini on tehokas hoito HIV-potilaiden lipodystrofiaan muuttumattoman yhdistelmähoidon aikana

Relationship between Aortic pulse wave velocity and left ventricular mass in a group of African ancestry is not accounted for by Aortic pressures

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, for the degree of Master of Science in Medicine. Johannesburg, 2017.Aortic pulse wave velocity (PWV) and backward waves, as determined from wave separation analysis, predict cardiovascular events beyond brachial blood pressure (BP). However, the extent to which these aortic hemodynamic variables contribute independent of each other is uncertain. In 749 randomly selected participants of African ancestry we therefore assessed the extent to which relationships between aortic PWV or backward wave pressures (Pb)(and hence central aortic pulse pressure [PPc]) and left ventricular mass index (LVMI) occur independent of each other. Aortic PWV, PPc, forward wave pressure (Pf) and Pb were determined using radial applanation tonometry and SphygmoCor software and LVMI using echocardiography. 44.5% of participants had an increased LVMI-ht1.7. With adjustments for age, brachial systolic BP or PP and additional confounders, PPc and Pb, but not Pf was independently related to LVMI and LV hypertrophy (LVH) in both men and women. However, PWV was independently associated with LVMI in women (partial r=0.16, p<0.001), but not in men (partial r=0.03) and PWV was independently associated with LVH in women (p<0.05), but not in men (p=0.07). With PWV and Pb included in the same multivariate regression models, PWV (partial r=0.14, p<0.005) and Pb (partial r=0.10, p<0.05) contributed to a similar extent to variations in LVMI in women. In addition, with PWV and Pb included in the same multivariate regression models, PWV (p<0.05) and Pb (p<0.02) contributed to LVH in women. In conclusion, aortic PWV and backward wave pressure (and hence pulse pressure) although both associated with LVMI and LVH, produce effects which are independent of each other.LG201