No description available.

In calcific aortic valve disease, the early sclerotic valve lesion is similar to the atherosclerotic arterial plaque, but at the later stage calcification prevails. Our aim was to assess the association of several new potential risk factors, eg. systemic inflammation, neurohormonal activation and altered calcium metabolism with aortic stenosis (AS) in patients with significant coronary artery disease..

Atherothrombosis can induce acute myocardial infarction and stroke by progressive stenosis of a blood vessel lumen to full occlusion. The goal of this research is to determine what shear rates are pertinent to an occluding blood vessel, the rate of thrombus growth relative to wall shear rates, and to develop a predictive model for estimating length of time to thrombus occlusion for a given atherosclerotic lesion. Computational studies of severely stenotic idealized vessels were performed to investigate the wall shear rates that may exist. The study shows that maximum shear rates in severe short stenoses were found to exceed 250,000 1/s (9,500 dynes/cm2). We utilize an in vitro experiment consisting of blood flow through a collagen coated stenosis to study the rate of thrombus growth. Growth is monitored through light microscopy and a camera. Computational fluid dynamics are used to determine shear rates along the thrombus surface as it grows. We found a strong positive correlation between thrombus growth rates and shear rates up to 6,000 1/s after a log-log transformation (r=0.85, p<0.0001). Growth rates at pathologic shear rates were typically 2-4 times greater than for physiologic shear rates below 400 s-1. To determine whether transport or kinetic binding limits the rate of thrombus growth, a computational model of platelet transport was developed. The model allows for thrombus growth by occluding computational cells. We show that thrombus is transport rate-limited for shear rates below 6,000 1/s, while it is more likely to be kinetic rate-limited for higher shear rates. Predictions of occlusion times based on the model demonstrate that increases in stenosis severity results in decreased time to occlusion.

Les maladies cardio-vasculaires sont responsables de la vaste majorité des décès dans les pays industrialisés. La plupart de ces maladies sont dues à l'athérosclérose, processus manifesté par le développement de lésions (plaques d'athéromes) dans les parois vasculaires. La présence de ces plaques conduit à la réduction de la lumière du vaisseau et, par conséquent, à des complications graves, tel que l'infarctus du myocarde. Les patients ont pour issue la méthode d'angioplastie qui consiste à écraser la plaque athéromateuse à l'aide d'un ballonnet pour accroître la lumière du vaisseau obstrué. Toutefois, cette intervention entraîne une abrasion de l'endothélium et un étirement important des cellules musculaires lisses (CML) situées dans la profondeur de la paroi. Chez environ un tiers à la moitié des patients, la multiplication des CMLs conduit à une nouvelle réduction de la lumière artérielle. C'est la resténose. Les travaux de recherche ont permis le déploiement de plusieurs thérapies pharmacologiques et mécaniques mais les résultats tant anticipés suite aux études animales ne sont pas reproductibles chez l'humain pour la vaste majorité des tactiques. Notre équipe s'est intéressée au Système Rénine-Angiotensine (SRA) car son implication dans la resténose est non-négligeable. De plus, le succès des inhibiteurs de l'enzyme de conversion de l'angiotensine (iECA) chez l'animal a confirmé son rôle. Cependant, les essais cliniques ne sont guère convaincants et c'est ce qui a incité plusieurs à s'intéresser aux récepteurs de !'angiotensine II (Ang Il). Nos études antérieures avec le modèle de la carotide de rat ont révélé que les antagonistes non-peptidiques de l' Ang II sélectifs pour AT[indice inférieur 1] diminuaient partiellement la prolifération néointimale. Parallèlement, nous avions traité nos animaux avec un antagoniste peptidique non-sélectif pour réaliser que ce dernier en inhibait la presque totalité. Notre hypothèse de travail est que les antagonistes nonpeptidiques et les iECAs ont une efficacité limitée sur la réduction myointimale. Nous avons effectué une courbe dose-réponse avec un antagoniste non-peptidique sélectif pour AT[indice inférieur 1] et une seconde courbe avec un antagoniste non-peptidique mais sélectif pour les deux sous-types de récepteurs (AT[indice inférieur 1] et AT[indice inférieur 2]. De plus, nous avons traité nos animaux avec un iECA seul et combiné avec un antagoniste non-peptidique. Le bilan confirme l'efficacité limitée des antagonistes non-peptidiques de I' Ang II et établit que la coapplication de drogues ne suffit pas pour réduire la prolifération néointimale avec la même efficacité qu'observée avec l'antagoniste peptidique. Dans un deuxième temps, nous avons cherché à développer un nouveau modèle animal de la resténose afin de palier aux critiques dont font l'objet les modèles actuels et aussi permettre la validation de nos données antérieures. Nous suggérons que le furet pourrait devenir une bonne alternative aux modèles existants.

Calcifications in carotid atheromas can be detected in a panoramic radiograph (PR) of the jaws. A carotid artery calcification (CAC) can indicate presence of significant (≥ 50%) carotid stenosis (SCS). The aim of this thesis was to (1) determine the prevalence of SCS and burden of atherosclerotic disease among patients revealing CACs in PRs, (2) determine the prevalence of CACs in PRs among patients with SCS, (3) analyze whether the amount of calcium and/or (4) the radiographic appearance of the CACs, can improve the positive predictive value (PPV) for SCS detection among patients with CACs in PRs. The thesis is based on four cross-sectional studies. Two patient groups were prospectively and consecutively studied. Group A represented a general adult patient population in dentistry examined with PR presenting incidental findings of CACs. These patients were examined with carotid ultrasound for presence or absence of SCS and their medical background regarding atherosclerotic related diseases and risk factors was reviewed. An age and gender matched reference group was included for comparisons. Group B comprised patients with ultrasound verified SCS, examined with PR prior to carotid endarterectomy. The PRs were analysed regarding presence of CACs. The extirpated plaques were collected and examined with cone-beam computed tomography (CBCT) to determine the amount of calcium. The radiographic appearance of CACs in PRs from Group A and B were evaluated for possible association with presence of SCS. In Group A, 8/117 (7%) of patients with CAC in PRs revealed SCS in the ultrasound examination, all were found in men (8/64 (12%)). Patients with CACs in PRs revealed a higher burden of atherosclerotic disease compared to participants in the reference group (p &lt;0.001). In Group B, where all patients had SCS, 84% revealed CACs in PRs and 99% of the extirpated plaques revealed calcification. CACs with volumes varying between 1 and 509 mm3 were detected in the PRs. The variation in volume did not correlate to degree of carotid stenosis. The radiographic appearance that was most frequently seen in neck sides with SCS (65%) was also frequently found in neck sides without SCS (47%) and therefore the PPV did not improve compared to the PPV solely based on presence of CACs. CACs in PRs are more associated with SCS in men than in a general population and patients with CACs in PRs have a higher burden of atherosclerotic disease. The majority of patients with SCS show CACs in PRs and the majority of extirpated carotid plaques reveal calcification. The volume of CAC and specified radiographic appearance does not increase the PPV for SCS in patients with CACs in PRs. In conclusion patients with CACs in PRs, and without previous record of cardiovascular disease, should be advised to seek medical attention for screening of cardiovascular risk factors. / Bakgrund Inom ramen för specialist- och allmäntandvård utförs panoramaröntgen-undersökningar dagligen på såväl barn som vuxna. En panoramaröntgenbild (PB) är en översiktsbild som är specifikt anpassad till att återge området för tänder och käkar. Utöver det, avbildas även delar av halsen och som bifynd ibland förkalkningar belägna i området för halspulsådern (karotiskärlet). Dessa förkalkningar kallas för karotisförkalkningar och är ett tecken på åderförkalkning. Åderförkalkning består i huvudsak av en fettrik plackansamling i kärlväggen. Placket kan med tiden förkalkas till varierande grad. Det är dessa förkalkningar vi kan se i PB. När en åderförkalkning ökar i volym kan den utgöra en förträngning i kärlet. Då förträngningen av kärldiametern är ≥ 50% benämns åderförkalkningar belägna i karotiskärlet för ”signifikanta karotisstenoser” (SKS). Graden av förträngning bedöms som regel med ultraljudsundersökning av halskärlen. Bitar av SKS kan lossna varvid det bildas små blodproppar. Eftersom halspulsådern försörjer främre hjärnhalvan med blod så kan dessa bitar täppa till ett av hjärnans blodförsörjande kärl och leda till stroke (slaganfall). För att minska risken att drabbas av stroke kan man ibland operera bort SKS (karotisplacket). Syfte Syftet med denna avhandling var att ta reda på (1) hur många av de patienter som blir undersökta med PB inom tandvården som uppvisar karotisförkalkningar, hur stor andel som har SKS samt utreda om patienter med förkalkningar i PB i större utsträckning är drabbade av hjärtkärlsjukdomar/risk faktorer, (2) hur ofta utopererade karotisplack innehåller kalk och hur ofta patienter med känd SKS uppvisar karotisförkalkningar i PB, (3) huruvida förkalkningsmängden i utopererade karotisplack är korrelerad till förträngningsgrad, och (4) huruvida det finns något specifikt radiografiskt utseende på karotisförkalkningar i PB som kan användas för att identifiera en större andel patienter med SKS bland patienter som uppvisar karotisförkalkningar i PB, det vill säga minska risken för att skicka patienter utan SKS på ultraljudsundersökning. Material och metoder Materialet bestod av två huvudgrupper av patienter. Grupp A bestod av patienter undersökta inom tandvården med PB som uppvisat karotisförkalkningar. Alla dessa patienter undersöktes med ultraljud för att bedöma förekomst av SKS. Den medicinska journalen granskades avseende tidigare förekomst av åderförkalkningsrelaterade sjukdomar och risk faktorer. En köns- och åldersmatchad kontrollgrupp utan karotisförkalkningar i PB analyserades på motsvarande sätt för jämförelse. Grupp B bestod av patienter med känd SKS som före operativt avlägsnande av karotisplack undersöktes med PB. PB granskades avseende förekomst av karotisförkalkning och utopererade karotisplack avseende kalkinnehåll. Förkalkningsmängden i de utopererade karotisplacken korrelerades dels till möjlighet att identifiera karotisförkalkning i PB samt till förträngningsgraden i kärlen. Karotisförkalkningarnas utseende delades in i grupper för att utvärdera om vissa utseenden i större utsträckning kunde associeras till förekomst av SKS. Resultat I Grupp A uppvisade 8/117 (7%) patienter SKS, alla var män, 8/64 (12%). Patienter med karotisförkalkningar i PB hade oftare åderförkalkningsrelaterade sjukdomar och risk faktorer (p &lt; 0,001). I Grupp B hade 84% av patienterna med SKS karotisförkalkning i PB. Bland de utopererade karotisplacken innehöll 99% förkalkningar och förkalkningsvolymen varierade från 1-509 mm3. Möjligheten att upptäcka karotisförkalkning i PB var oberoende av om förkalkningsvolymen var stor eller liten. Förkalkningsvolymen var heller inte korrelerad till hur stor förträngning av kärlet en SKS (≥ 50%) orsakat. Ett radiografiskt utseende på karotisförkalkningar i PB noterades i 65% av de halssidor som hade en SKS. Detta specifika radiografiska utseende återfanns dock även i 47% av halssidor utan SKS. Andelen falskt positiva patienter var således fortsatt hög. Slutsats Vi fann att 12% män med karotisförkalkningar i PB, undersökta i en generell population inom tandvården, uppvisar SKS. Patienter med karotisförkalkningar i PB uppvisar fler riskfaktorer och är oftare drabbade av hjärt-kärlsjukdomar än patienter utan karotisförkalkningar i PB. Majoriteten av patienter med SKS uppvisar karotisförkalkningar i PB och nära 100% av utopererade karotisplack innehåller kalk. Förkalkningsmängden påverkar inte möjligheten att upptäcka karotisförkalkning i PB. Förkalkningsmängd och specificerade radiografiska utseenden hos karotisförkalkningar i PB förutsäger inte SKS bättre än definitionen ”förkalkning ja eller nej”. Dessa parametrar kan således inte användas till att förfina urvalet bland patienter som uppvisar karotisförkalkning i PB mot högre andel patienter med SKS. Individer med karotisförkalkningar i PB bör uppmanas konsultera vården för undersökning av eventuella risk faktorer för hjärt-kärlsjukdom.

No description available.

Atherosclerosis is one of the main diseases responsible for the high global mortality rate involving heart and blood vessel disorders. The build-up of fatty materials in the inner wall of the human artery prevents sufficient oxygen and nutrients reaching the organs of the body. Atherosclerosis is a chronic, long term condition, which develops and progresses over time; however, the disease does not present any symptoms until an advanced stage is reached, which results in potential permanent debility and sometimes sudden death. This thesis is concerned with the progression of atherosclerosis in an artery with mild stenosis that has resulted in a 30% reduction in its diameter. To this end, data on the low wall shear stress has been correlated with the atherosclerotic prone region. In a stenosed artery, this region corresponds to the separation zone that is formed distal to the lumen reduction. Atherosclerosis is a complex phenomenon, and not only involves wall shear stress, but also cellular interactions. Previous research has shown that even in the absence of wall biological effects, the blood cell distribution is strongly influenced by the hydrodynamics of the fluid. The mechanisms of blood cell distribution and the dynamic behaviour of the blood flow were investigated by developing a physical model of the stenosed artery, and by using particles to represent the presence of the blood cells. Particle Image Velocimetry system was employed and the size of particles were the 10μm and 20μm. The flow field was characterised and the particle distribution was measured. The characteristics of steady flow in the stenosed artery at Reynolds numbers of 250 and 320 revealed the importance of fluid inertia and the shear gradient distal to stenosis. Unequal distribution of the particles modelling the blood cells was observed, as more particles occupied the recirculation zones than the high shear region and central jet. The particle migration was found to depend on the particle size, particle concentration and fluid flow rates. The results suggested that the presence of similar effects in the real human arterial system may be significant to the progression of atherosclerotic plaques. At lower Reynolds number of 130, a particle depleted layer was observed at the wall region. In physiological flow the cell free layer will prevent the transport of oxygen and nitrogen oxide (NO) to the muscle tissues. A numerical method was used to simulate the flow characteristics measured in the experiment. The numerical results revealed the importance of the hydrodynamic mechanism of particle migration. Drag and lift forces were found to affect the residence time of particles in the recirculation region. The findings of this work have suggested that for a complex geometry like a large stenosed artery at physiological flow rates, hydrodynamic forces are important in cell migration in the flow separation zone. Even without biological forces, the cells migrate to the low wall shear stress region. For computational dynamics studies, this study has demonstrated the need for higher-order modelling at the cellular level in order to establish the particle migration mechanisms.

Introduction Coronary artery disease (CAD) is the most common cause of death in Europe and North America and early detection of atherosclerosis is a clinical priority. Diagnosis of CAD remains conventional angiography, although recent technology has introduced non-invasive imaging of coronary arteries using computed tomographic coronary angiography (CTCA), which enables the detection and quantification of coronary artery calcification (CAC). CAC forms within the arterial wall and is usually found in or adjacent to atherosclerotic plaques and is consequently known as sub-clinical atherosclerosis.  The conventional cardiovascular (CV) risk factors used to quantify the estimated 10-year coronary event risk comprise dyslipidaemia, hypertension, diabetes mellitus, obesity, smoking and family history of CAD. Nevertheless, their relationship with significant (&gt;50%) stenosis, their interaction with the CAC score and their predictive ability for CAC presence and extent has not been fully determined in symptomatic patients.   Methods   For Papers 1-4 we took patients from the Euro-CCAD cohort, an international study established in 2009 in Umeå, Sweden. The study data gave us the CAC score and the CV risk factor profile in 6309 patients, together with angiography results for a reduced cohort of 5515 patients. In Papers 1 and 2 we assessed the risk factors for significant stenosis, including CAC as a risk factor. Paper 2 carried out this analysis by geographical region: Europe vs USA and northern vs southern Europe. Paper 3 investigated the CV risk factors for CAC presence, stratified by age and gender, while Paper 4 assessed the CV risk factors for CAC extent, stratified by gender.  In paper 5 we carried out a systematic review and meta-analysis of all studies of the risk factor predictors of CAC presence, extent and progression in symptomatic patients. From a total of 884 studies, we identified 10 which fitted our inclusion criteria, providing us with a total of 15,769 symptomatic patients. All 10 were entered in the systematic review and 7 were also eligible for the meta-analysis.   Results Paper 1:           Among risk factors alone, the most powerful predictors of significant coronary stenosis were male gender followed by diabetes, smoking, hypercholesterolaemia, hypertension, family history of CAD and age; only obesity was not predictive. When including the log transformed CAC score as a risk factor, this proved the most powerful predictor of &gt;50% stenosis, but hypercholesterolaemia and hypertension lost their predictive ability. The conventional risk factors alone were 70% accurate in predicting significant stenosis, the log transformed CAC score alone was 82% accurate but the combination was 84% accurate and improved both sensitivity and specificity.  Paper 2:           Despite some striking differences in profiles between Europe and the USA, the most important risk factors for &gt;50% stenosis in both groups were male gender followed by diabetes. When the log CAC score was included as a risk factor, it became by far the most important predictor of &gt;50% stenosis in both continents, followed by male gender. In the northern vs southern Europe comparison the result was similar, with the log CAC score being the most important predictor of &gt;50% stenosis in both regions, followed by male gender.  Paper 3:           Independent predictors of CAC presence in males and females were age, dyslipidaemia, hypertension, diabetes and smoking, with the addition of family history of CAD in males; obesity was not predictive in either gender. The most important predictors of CAC presence in males were dyslipidaemia and diabetes, while among females the most important predictors of CAC presence were diabetes followed by smoking. When analysed by age groups, in both males and females aged &lt;70 years, diabetes, hypertension and dyslipidaemia were predictive, with diabetes being the strongest; in females aged &lt;70 years, smoking was also predictive. Among those aged ≥70 years, the results are completely different, with only dyslipidaemia being predictive in males but smoking and diabetes were predictive in females.  Paper 4:           In the total cohort, age, male gender, diabetes, obesity, family history of CAD and number of risk factors predicted an increasing CAC score, with the most important being male gender and diabetes. In males, hypertension and dyslipidaemia were also predictive, although diabetes was the most important predictor. Diabetes was similarly the most important risk factor in females, followed by age and number of risk factors. Among patients with CAC, hypertension, dyslipidaemia and diabetes predicted CAC extent in both males and females, with diabetes being the strongest predictor in males followed by dyslipidaemia, while diabetes was also the strongest predictor in females, followed by hypertension. Quantile regression confirmed the consistent predictive ability of diabetes.  Paper 5:           In the systematic review, age was strongly predictive of both CAC presence and extent but not of CAC progression. The results for CAC presence were overwhelmed by data from one study of almost 10,000 patients, which found that white ethnicity, diabetes, hypertension and obesity were predictive of CAC presence but not male gender, dyslipidaemia, family history or smoking. With respect to CAC extent, only male gender and hypertension were clearly predictive, while in the one study of CAC progression, only diabetes and hypertension were predictive. In the meta-analysis, hypertension followed by male gender, diabetes and age were predictive of CAC presence, while for CAC extent mild-moderate CAC was predicted by hypertension alone, whereas severe CAC was predicted by hypertension followed by diabetes.   Conclusion Our investigation of the Euro-CCAD cohort showed that the CAC score is far more predictive of significant stenosis than risk factors alone, followed by male gender and diabetes, and there was little benefit to risk factor assessment over and above the CAC score for &gt;50% stenosis prediction. Regional variations made little difference to this result. Independent predictors of CAC presence were dyslipidaemia and diabetes in males and diabetes followed by smoking in females. The risk factor predictors alter at age 70. The most important risk factor predictors of CAC extent were male gender and diabetes; when analysed by gender, diabetes was the most important in both males and females. Our studies have consistently shown the strong predictive ability of male gender in the total cohort and diabetes in males and females and this is reflected in the meta-analysis, which also found hypertension to be independently predictive. Interestingly, dyslipidaemia does not appear to be a strong risk factor.

The management of the asymptomatic patients with severe aortic stenosis (AS) is challenging; clinicians have to balance the risks of early surgery against the risk that irreversible myocardial damage may occur with a conservative management strategy. It has become increasingly apparent that prognosis in asymptomatic AS depends not only on the degree of valvular stenosis, but also on the myocardial response to pressure overload and understanding the mechanisms of myocardial decompensation may help to guide management in the future. The degree of myocardial fibrosis, microvascular dysfunction, hypertrophy and left ventricular (LV) geometry may all play important roles. However, current guidelines for management of asymptomatic AS limit assessment of the myocardium to the measurement of ejection fraction with echocardiography. More advanced techniques may provide greater information that could be clinically useful. This thesis seeks to further our understanding of the mechanisms of the myocardial response to AS, using Cardiac Magnetic Resonance (CMR) in patients with moderate and severe AS. Myocardial perfusion in AS is examined in chapter 3. The results show that CMR first pass perfusion can be carried out safely and is well tolerated by AS patients. Microvascular dysfunction in these patients was associated with age, exercise time and markers of diastolic dysfunction. Myocardial strain is examined in chapter 4, utilizing a new software tool to look at strain throughout the left ventricle, and also to explore the relationship between strain and myocardial fibrosis. The results show that there are significant variations in circumferential strain measurements, depending on slice position in the LV, and also that there was no relationship found between strain and the degree of LV fibrosis. In chapter 5, the potential of CMR T1 mapping to identify fibrosis is examined using a new shortened non-contrast sequence (ShMOLLI - Shortened Modified Look-Locker Inversion) developed in our unit. CMR T1 values were validated against histological quantification of myocardial fibrosis in a large group of moderate and asymptomatic AS. A good correlation was found between ShMOLLI derived T1 values, with T1 values increasing with the severity of AS. The clinical value of measuring myocardial perfusion and LV global strain is examined in chapter 6 by linking these to prognosis. Measurement of circumferential strain could predict prognosis in asymptomatic AS, but myocardial perfusion showed poor ability to predict events. In conclusion, this thesis offers further insights into the changes that occur in the myocardium of patients with asymptomatic moderate and severe AS, using established and new CMR techniques. The clinical value of measuring these CMR parameters to aid risk stratification is shown, and the future potential for monitoring new therapies in these patients is discussed in the final chapter.

Original research submitted as partial fulfillment of the requirements for the Masters in Medicine degree in Orthopaedic surgery at the University of Witwatersrand, Johannesburg, April 2014 / Objectives 1. Assessment of radiological parameters of spinal stenosis using Magnetic Resonance imaging. 2. Clinical assessment of patients with Oswestry disability index and Neurogenic claudication outcome score questionnaires. 3. To assess correlation between clinical assessment questionnaires’ scores and radiological parameters. Background. Spinal stenosis is a common presentation in the elderly and a reason for surgical intervention. Diagnostic criteria are still inconclusive. There is poor correlation between clinical and radiological findings. New observations have been described and whether they improve diagnostic criteria remains to be seen. Methods. 30 patients with spinal stenosis were included in the study. The 2 questionnaires were administered and Magnetic Resonance Imaging copies were obtained. Questionnaires and images were analyzed. Osirix programme was used to analyze the images and do the measurements. Data was entered onto an excel sheet and analyzed using Statistica software. Frequencies and correlations were done. Results. The age range was between 41 and 85.There were 22 females and 8 males. L4/L5 was the commonest level involved in 23 patients. Multilevel involvement was 23% and those patients had a higher morphological grade, which was statistically insignificant. The commonest morphological grade was C. Sedimentation was positive in 93% of the patients. The Oswestry disability Index and Neurogenic Claudication Outcome score were negatively correlated, which was statistically significant, p = 0.0004. There was no correlation between clinical and radiological features. Conclusion. Spinal stenosis remains a clinical dilemma. There is variability within the population and lack of correlation between clinical and radiologic features. Radiological features however correlate with each other, but do not help with optimizing patient care.