| 1. |
- Karlsson, Jerker, 1967-
(författare)
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Abdominal Aortic Wall Mechanics - Stress, Strain and Stiffness in A Medical Perspective : An Experimental Study in Man
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The stiffness of the abdominal aorta is considered a significant factor affecting the morbidity and mortality of cardiovascular disease. Estimating vascular stiffness is an integral part in cardiovascular risk assessment. Wall stress of the abdominal aorta appears to be a crucial factor in the remodeling of the arterial wall and the growth of aneurysms. Consequently, arterial mechanics plays a vital role in the function of the cardiovascular system. Therefore, there is a need for comprehensive studies of mechanical forces in the vessel wall to better understand the mechanisms behind normal and pathological changes that are significant for hypertension, atherosclerosis, and the development of arterial aneurysms. The aim of this study was to explore the blood pressure-induced forces in the aortic wall using a computational mechanical model, with particular attention to the effects of age, sex, and blood pressure on the remodeling process of the vessel wall. Methods: A computational model, comprising a solid mechanical model and a parameter identification process known as the Parameter Identification Method for Mechanical Parameters (PIMMP), was used to investigate the mechanical properties of the abdominal aortic vessel wall. Data for the model were obtained from the human abdominal aorta of volunteers: 30 healthy individuals, females (n=15) and males, divided into three age groups with an equal number of females and males (n=5 in each age group). Invasive blood pressure, measured via catheter, and diameter variation in the abdominal aorta, measured via ultrasound, were acquired to be used as input data for PIMMP. This dataset was utilized in Papers I, III, and IV. In Paper II, 24 datasets were generated, based on model parameters presented in the scientific literature. Results: Paper I reveals that elderly males exhibit both higher aortic wall stress and higher isotropic stress component, than females. With age, males show an increase in isotropic load-bearing fraction and a decrease in anisotropic load-bearing fraction, a trend not observed in females. Paper II validates an in silico aortic model against a computerized membrane model of an abdominal aorta. The membrane model accurately predicts stress states as well as the load-bearing fraction of anisotropic material across all blood pressure levels, independent of the transmural stress gradient. However, the model’s accuracy is limited due to insufficient in vivo axial loading information. Paper III demonstrates that changes in circumferential stretch have a more pronounced effect on longitudinal stress than the other way around. Both circumferential and longitudinal stiffnesses increase with age, irrespective of sex. However, sex-based differences in stiffness are observed when comparing younger and older groups. Paper IV investigates pulse wave velocity (PWV) calculations using the Moens-Korteweg equation and the Bramwell-Hill equation. PWV shows a positive association with both isotropic and anisotropic material properties, with a transition zone observed between diastolic and systolic blood pressures, to a positive association with anisotropic properties at systolic blood pressure. Furthermore, an increase in PWV with age, with no significant difference between sexes, is observed. The Extra Material suggests a deficiency in age-related wall stress regulation in males, potentially due to insufficient stiffness of anisotropic materials such as collagen. In contrast, females show an age-related increase in abdominal aortic wall thickness and anisotropic material stiffness, indicating adequate wall stress regulation. Conclusions: This doctoral dissertation focused on the effects of age and sex on the abdominal aortic wall. Overall, the findings suggest potential alterations in the collagen and elastin content during the remodeling of the abdominal aorta, which may differ between sexes. These alterations could be induced chemically or mechanically. The model has shown potential in identifying healthy individuals within a population. These insights may contribute to the understanding of cardiovascular health and disease progression.
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| 2. |
- Cao, Ziquan, 1982-
(författare)
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VEGF-mediated vascular functions in health and disease
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Angiogenesis is essential for physiological processes including embryonic development, tissue regeneration, and reproduction. Under various pathological conditions the same angiogenic process contribute to the onset, development, and progression of many human diseases including cancer, diabetic complications, ocular disease, chronic inflammation and cardiovascular disease. Vascular endothelial growth factor (VEGF) is a key angiogenic factor for physiological and pathological angiogenesis. In addition to its strong angiogenic activity, VEGF also potently induces vascular permeability, often causing tissue edema in various pathological tissues. VEGF transduces its vascular signal through two tyrosine kinase receptors-VEGFR1 and VEGFR2, the latter being a functional receptor that mediates both angiogenic and vascular permeability effects. To study physiological and pathological functions of VEGF, we developed novel zebrafish disease models that permit us to study hypoxia-induced retinopathy and cancer metastasis processes. We have also administered anti-VEGF and anti-VEGFR specific antibodies to healthy mice to study the homeostatic role of VEGF in the maintenance of vascular integrity and its functions in various tissues and organs.Finally, using a zebrafish model, we evaluated if VEGF expression is regulated by circadian clock genes. In paper I, we developed protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1:EGFP zebrafish were placed in hypoxic water for 3-10 days with retinal neovascularization being analyzed using confocal microscopy. This model provides a unique opportunity to kinetically study the development of retinopathy in adult animals using non-invasive protocols and to assess the therapeutic efficacy of orally administered anti-angiogenic drugs. In paper II, we developed a zebrafish metastasis model to dissect the complex events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells were implanted into the perivitelline cavity of 48-hour-old zebrafish embryos, which were subsequently placed in hypoxic water for 3 days. Tumor cell invasion, metastasis and pathological angiogenesis were analyzed using fluorescent microscopy in the living fish. The average experimental time for this model is 7 days. Our protocol offers an opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis. In paper III, we show that systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody cause global vascular regression in mice. Among all examined tissues, the vasculature in endocrine glands, intestinal villi, and the uterus are most affected in response to VEGF or VEGFR-2 blockades. Pro-longed anti-VEGF treatment resulted in a significant decrease in the circulating levels of the predominant thyroid hormone, free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid function. These findings provide structural and functional bases of anti-VEGF-specific druginduced side effects in relation to vascular changes in healthy tissues. In paper IV, we show that disruption of the circadian clock by constant exposure to light coupled with genetic manipulation of key genes in the zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. These results offer mechanistic insights into the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis. Overall, the results in this thesis provide further insight to angiogenic mechanistic properties in tissues and suggest possible novel therapeutic targets for the treatment of various angiogenesis-dependent diseases.
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| 3. |
- Dahlén, Elsa, 1975-
(författare)
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Markers of subclinical atherosclerosis and arterial stiffness in type 2 diabetes
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Type 2 diabetes is a common disease with increased mortality and morbidity due to cardiovascular disease (CVD). This thesis is based on three studies that evaluated traditionally used and emerging risk markers to identify individuals with high-risk of developing CVD in middle-aged men and women with type 2 diabetes. One study was conducted to compare the equivalence between two different ultrasound techniques to measure intima-media thickness since IMT was used to evaluate subclinical atherosclerosis as a surrogate endpoint.Methods: Data from the cohort study, cardiovascular risk in type 2 diabetes – a prospective study in primary care (CARDIPP) was used in paper I, III and IV. In paper I, baseline data from the first 247 subjects was analysed. Associations between traditionally measured lipids, apolipoproteins, glycaemic control and low-grade inflammation and IMT were analysed.In paper III, the full baseline cohort, with data from 761 subjects from the CARDIPP study was cross-sectionally analysed regarding correlations between abdominal obesity measured as waist circumference (WC) and sagittal abdominal diameter (SAD), inflammatory markers and IMT and pulse wave velocity (PWV). In paper IV, the associations reported in paper I and III were prospectively investigated with data from the first year of follow-up four years after the baseline investigations in CARDIPP-revisited.In paper II a study was performed on 24 young healthy subjects, both men and women. IMT was measured in the common carotid artery (CCA) and in the abdominal aorta (AA), by two skilled ultrasonographers, with 2 different ultrasound techniques in a randomised order.Results: ApoB/apoA-I ratio (r=0.207, p=0.001), apoB (r=0.166, p=0.009) and non HDLcholesterol (nHDL-c) (0.129, p=0.046) correlated with IMT.In CCA IMT was equivalent using B-mode- and M-mode respectively. However in AA, IMT was 11.5% thicker using B-mode.Abdominal obesity were significantly correlated with; IL-6 and CRP (both p<0.001, WC and SAD respectively), IMT (WC p=0.012, SAD p=0.003) and PWV (p<0.001 WC and SAD respectively). Adjusting for age, sex, treatment with statins, systolic blood pressure (SBP), Body Mass Index (BMI), CRP and HbA1c, SAD (p=0.047) but not WC, remained associated with IMT.There were significant correlations between apoB (r=0.144, p=0.03) and CRP (r=0.172, p=0.009) measured at baseline and IMT measured at follow-up. After adjustment for sex, age, treatment with statins and Hba1c, the associations remained statistically significant. HbA1c, total cholesterol or LDL-cholesterol did not correlate to IMT at follow-up. Baseline body mass index (BMI) (r=0.130, p=0.049), WC (r=0.147, p=0.027) and SAD (r=0.184, p=0.007) correlated to PWV at follow-up. Challenged with sex, SBP and HbA1c, the association between SAD, not WC nor BMI, and PWV remained statistically significant (p=0.036).Conclusions: There was a significant association between apoB/apoA-I ratio and IMT. The association was independent of conventional lipids, CRP, glycaemic control and use of statins. Both SAD and WC were associated with inflammation, atherosclerosis and arterial stiffness. However, SAD was slightly more robustly associated to subclinical organ damage, compared with WC. Prospectively; apoB and CRP, but not LDL-cholesterol predicted increased subclinical atherosclerosis. Furthermore, SAD was more independent in predicting arterial stiffness over time, compared with WC, in middle-aged men and women with type 2 diabetes.The two different ultrasound techniques, B-mode and M-mode, measured different IMT thickness in the aorta, emphasizing the importance of using similar technique when comparing the impact of absolute values of IMT on cardiovascular disease.
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| 4. |
- E:son Jennersjö, Pär, 1956-
(författare)
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Risk factors in type 2 diabetes with emphasis on blood pressure, physical activity and serum vitamin D
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundType 2 diabetes is a common chronic disease with a two-fold increased risk for cardiovascular morbidity and mortality and has an increasing prevalence worldwide. This thesis is based on a study conducted in primary health care in Östergötland and Jönköping, Sweden. The aim of the thesis was to evaluate new risk markers to identify patients with high risk of developing cardiovascular disease in middle-aged men and women with type 2 diabetes.MethodsData from the cohort study CArdiovascular Risk in type 2 DIabetes – a Prospective study in Primary care (CARDIPP) was used. In paper III data were also used from CARDIPP-Revisited where all participants in the CARDIPP study were invited four years after the baseline investigation for a re-investigation. In paper IV data were used from CAREFUL which is a control group of 185 subjects without diabetes. The investigation included a standard medical history including data on diabetes duration and on-going medication. Anthropometric data were recorded and both office and ambulatory blood pressure were measured. The patients filled out a detailed questionnaire and physical activity was measured by using waist-mounted pedometers. Pedometer-determined physical activity was classified in four groups: Group 1: <5000 steps/day (‘sedentary’); Group 2: 5000-7499 steps/day (‘low active’); Group 3: 7500-9999 steps/day (‘somewhat active’); Group 4: and ≥10 000 steps/day (‘active’). Blood samples were drawn for routine analyses and also frozen for later analyses. The investigations at the departments of physiology included echocardiography, measurements of the carotid intima-media thickness, applanation tonometry and measurements of sagittal abdominal diameter.ResultsPaper 1:Patients with a non-dipping systolic blood pressure pattern showed higher left ventricular mass index and pulse wave velocity (PWV) compared with patients with ≥10% decline in nocturnal systolic blood pressure. Patients with <10% decline in nocturnal systolic blood pressure had higher BMI and sagittal abdominal diameter, lower GFR and higher albumin:creatinine ratio and also higher levels of NT-proBNP than patients with a dipping pattern of the nocturnal blood pressure.Paper 2:The number of steps/day were inversely significantly associated with BMI, waist circumference and sagittal abdominal diameter, levels of CRP, levels of interleukin-6 and PWV.Paper 3:At the 4-year follow-up the change in PWV (ΔPWV) from baseline was calculated. The group with the lowest steps/day had a significantly higher increase in ΔPWV compared with the group with the highest steps/day. The associations between baseline steps/day and ΔPWV remained after further adjustment in a multivariate linear regression statistically significant (p=0.005). 23% of the variation in the study could be explained by our model. Every 1000 extra steps at baseline reduced the change in ΔPWV by 0.103 m/s between baseline and follow-up.Paper 4:Low vitamin D levels were associated with significantly increased risk for premature mortality in men with type 2 diabetes. High levels of parathyroid hormone were associated with significantly increased risk for premature mortality in women with type 2 diabetes. These relationships were still statistically significant also when two other well-established risk markers for mortality, PWV and carotid intima-media thickness, were added to the analyses.ConclusionsAmbulatory blood pressure recording can by addressing the issue of diurnal blood pressure variation, explore early cardiovascular organ damage and microvascular complications that goes beyond effects of standardised office blood pressure measurements. Pedometer-determined physical activity may serve as a surrogate marker for inflammation and subclinical organ damage in patients with type 2 diabetes. There is novel support for the durable vascular protective role of a high level of daily physical activity, which is independent of BMI and systolic blood pressure. The use of pedometers is feasible in clinical practice and provides objective information not only about physical activity but also the future risk for subclinical organ damage in middle-aged people with type 2 diabetes. Our results indicate that low vitamin D levels in men or high parathyroid hormone levels in women give independent prognostic information of an increased risk for total mortality.
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| 5. |
- Wijkman, Magnus
(författare)
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Acute, ambulatory and central blood pressure measurements in diabetes
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: In patients with diabetes, high blood pressure is an established risk factor for cardiovascular disease. The aim of this thesis was to explore the associations between blood pressure levels measured with different techniques and during different circumstances, and the degree of cardiovascular organ damage and subsequent prognosis in patients with diabetes.Methods: We analysed baseline data from patients with type 2 diabetes who participated in the observational cohort study CARDIPP (Cardiovascular Risk factors in Patients with Diabetes – a Prospective study in Primary care), and longitudinal data from patients registered in the Swedish national quality registry RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive care Admissions). Patients in CARDIPP underwent nurse-recorded, 24-hour ambulatory and non-invasive central blood pressure measurements. Patients in RIKS-HIA had their systolic blood pressure measured upon hospitalisation for acute chest pain.Results: In CARDIPP, nearly one in three patients with office normotension (<130/80 mmHg) were hypertensive during the night (≥120/70 mmHg). This phenomenon, masked nocturnal hypertension, was significantly associated with increased arterial stiffness and increased central blood pressure. Furthermore, nearly one in five CARDIPP patients with office normotension had high central pulse pressure (≥50 mmHg), and there was a significant association between high central pulse pressure and increased carotid intima-media thickness and increased arterial stiffness. Among CARDIPP patients who used at least one antihypertensive drug, those who used beta blockers had significantly higher central pulse pressure than those who used other antihypertensive drugs, but there were no significant between-group differences concerning office or ambulatory pulse pressures. In CARDIPP patients with or without antihypertensive treatment, ambulatory systolic blood pressure levels were significantly associated with left ventricular mass, independently of central systolic blood pressure levels. When RIKS-HIA patients, admitted to hospital for chest pain, were stratified in quartiles according to admission systolic blood pressure levels, the risk for all-cause one-year mortality was significantly lower in patients with admission systolic blood pressure in the highest quartile (≥163 mmHg) than in patients with admission systolic blood pressure in the reference quartile (128-144 mmHg). This finding remained unaltered when the analysis was restricted to include only patients with previously known diabetes.Conclusions: In patients with type 2 diabetes, ambulatory or central blood pressure measurements identified patients with residual risk factors despite excellent office blood pressure control or despite ongoing antihypertensive treatment. Ambulatory systolic blood pressure predicted left ventricular mass independently of central systolic blood pressure. In patients with previously known diabetes who were hospitalised for acute chest pain, there was an inverse relationship between systolic blood pressure measured at admission and the risk for one-year all-cause mortality.
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| 6. |
- Björck, Hanna, 1979-
(författare)
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Vessel wall integrity : influence of genetics and flow
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease (CVD) is the major cause of death worldwide. Underlying causes, such as atherosclerosis and hypertension, are associated with remodeling of the vessel wall ultimately leading to loss of structural integrity. There are a number of factors that can influence vascular remodeling and hence structural integrity. The overall aim of this thesis was to investigate aortic wall integrity in relation to genetics and blood flow.The influence of SNPs within the currently most robust susceptibility locus identified for CVD (chromosome 9p21.3) on abdominal aortic integrity was studied in elderly individuals. In men, risk-variants were associated with a decreased abdominal aortic stiffness, independent of other factors related to arterial stiffness. Impaired mechanical properties of the abdominal aortic wall may explain the association between chromosome 9p21.3 and vascular disease.Plasminogen activator inhibitor 1 (PAI-1) is the key inhibitor of fibrinolysis, and involved in several processes associated with vascular remodeling. We investigated the impact of the PAI-1 4G/5G polymorphism on central aortic blood pressure as this pressure more strongly relates to cardiovascular morbidity and mortality than the peripheral pressure. Elderly women carrying the 4G/4G genotype had higher central aortic blood pressure than women carrying the 5G/5G genotype. The association was regardless of other risk factors related to hypertension, suggesting that an impaired fibrinolytic potential may play an important role in the development of hypertension in women.Blood flow is a strong determinant of arterial growth and vascular function. We investigated flow-dependent gene expression and vessel wall morphology in the rat aorta under physiological conditions. Microarray analysis revealed a strong differential gene expression between disturbed and uniform flow pattern regions, particularly associated with transcriptional regulation. Moreover, several genes related to Ca2+ signalling were among the most highly differentially expressed. Up-regulation of Ca2+-related genes may be due to endothelial response to disturbed flow and assembly of cilia, consequently leading to functional and structural modifications of the vessel wall.Bicuspid aortic valve (BAV) is a congenital disorder associated with disturbed ascending aortic blood flow. Using a new strategy to dissect flow-mediated gene expression we identified several novel flow-associated genes, particularly related to angiogenesis, wound healing and mechanosensing, showing differential expression in the ascending aorta between BAV and tricuspid aortic valve patients. Fifty-five percent of the identified genes were confirmed to be flowresponsive in the rat aorta. A disturbed flow, and consequently an altered gene expression, may contribute to the increased aneurysm susceptibility associated with BAV morphology.
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| 7. |
- Gårdhagen, Roland
(författare)
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Turbulent Flow in Constricted Blood Vessels : Quantification of Wall Shear Stress Using Large Eddy Simulation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The genesis of atherosclerosis has previously been shown to be affected by the frictional load from the blood on the vessel wall, called the wall shear stress (WSS). Assessment of WSS can therefore provide important information for diagnoses, intervention planning, and follow‐up. Calculation of WSS requires high‐resolved velocity data from the vessel, which in turn can be obtained using computational fluid dynamics (CFD). In this work large eddy simulation LES was successfully used to simulate transitional flow in idealized as well as subject specific vessel models. It was shown that a scale resolving technique is to prefer for this application, since much valuable information otherwise is lost. Besides, Reynolds‐Averaged Navier‐Stokes (RANS) models have generally failed to predict this type of flow.Non‐pulsating flows of Reynolds numbers up to 2 000 in a circular constricted pipe showed that turbulence is likely to occur in the post‐stenotic region, which resulted in a complex WSS pattern characterized by large spatial as well temporal fluctuations in all directions along the wall. Time averaged streamwise WSS was relatively high, while time averaged circumferential WSS was low, meaning that endothelial cells in that region would be exposed to oscillations in a stretched state in the streamwise direction and in a relaxed state in the circumferential direction.Since every vessel is unique, so is also its WSS pattern. Hence the CFD simulations must be done in subject specific vessel models. Such can be created from anatomical information acquired with magnetic resonance imaging (MRI). MRI can also be used to obtain velocity boundary conditions for the simulation. This technique was used to investigate pulsating flow in a subject specific normal human aorta. It was shown that even the flow in healthy vessels can be very disturbed and turbulence like, and even for this case large WSS variations were seen. It was also shown that regions around branches from the aorta, known to be susceptible for atherosclerosis, were characterized by high time averaged WSS and high oscillatory shear index.Finally, the predictive capability of CFD was investigated. An idealized model of a human aorta with a coarctation and post‐stenotic dilatation was studied before and after a possible repair of the constriction. The results suggested that small remaining abnormalities in the geometry may deteriorate the chances for a successful treatment. Also, high values of shear rate and Reynolds stresses were found in the dilatation after the constriction, which previous works have shown means increased risk for thrombus formation and hemolysis.
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| 8. |
- Renner, Johan, 1977-
(författare)
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Towards Subject Specific Aortic Wall Shear Stress : a combined CFD and MRI approach
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The cardiovascular system is an important part of the human body since it transports both energy and oxygen to all cells throughout the body. Diseases in this system are often dangerous and cardiovascular diseases are the number one killer in the western world. Common cardiovascular diseases are heart attack and stroke, which origins from obstructed blood flow. It is generally important to understand the causes for these cardiovascular diseases. The main causes for these diseases are atherosclerosis development in the arteries (hardening and abnormal growth). This transform of the arterial wall is believed to be influenced by the mechanical load from the flowing blood on the artery and especially the tangential force the wall shear stress. To retrieve wall shear stress information in arteries invivo is highly interesting due to the coupling to atherosclerosis and indeed a challenge. The goal of this thesis is to develop, describe and evaluate an in-vivo method for subject specific wall shear stress estimations in the human aorta, the largest artery in the human body. The method uses an image based computational fluid dynamics approach in order to estimate the wall shear stress. To retrieve in-vivo geometrical descriptions of the aorta magnetic resonance imaging capabilities is used which creates image material describing the subject specific geometry of the aorta. Magnetic resonance imaging is also used to retrieve subject specific blood velocity information in the aorta. Both aortic geometry and velocity is gained at the same time. Thereafter the image material is interpreted using level-set segmentation in order to get a three-dimensional description of the aorta. Computational fluid dynamics simulations is applied on the subject specific aorta in order to calculate time resolved wall shear stress distribution at the entire aortic wall included in the actual model.This work shows that it is possible to estimate subject specific wall shear stress in the human aorta. The results from a group of healthy volunteers revealed that the arterial geometry is very subject specific and the different wall shear stress distributions have general similarities but the level and local distribution are clearly different. Sensitivity (on wall shear stress) to image modality, the different segmentation methods and different inlet velocity profiles have been tested, which resulted in these general conclusions:The aortic diameter from magnetic resonance imaging became similar to the reference diameter measurement method.The fast semi-automatic level-set segmentation method gave similar geometry and wall shear stress results when compared to a reference segmentation method.Wall shear stress distribution became different when comparing a simplified uniform velocity profile inlet boundary condition with a measured velocity profile.The method proposed in this thesis has the possibility to produce subject specific wall shear stress distribution in the human aorta. The method can be used for further medical research regarding atherosclerosis development and has the possibility for usage in clinical work.
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| 9. |
- De Basso, Rachel
(författare)
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Influence of genetics and mechanical properties on large arteries in man
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Arterial pathology is the major contributor to cardiovascular diseases and mortality. The mechanical properties of arteries are independent factors for cardiovascular disease and mortality, where genetics influence the structure of the arterial wall, which may result in change in arterial stiffness. The aims of this thesis were to study the mechanical properties of the popliteal artery (PA) in healthy subjects and the influence of angiotensin-converting enzyme (ACE) polymorphism and Fibrillin-1 (FBN1) polymorphism on large arteries. Further, the impact of FBN1 polymorphism on cardiovascular morbidity and mortality was investigated.The PA is, after the abdominal aorta, the most common site of aneurysmal development. The PA was studied in healthy subject with ultrasound and the diameter increased and the distensibility decreased with age, with men having lower distensibility than women. This seems not to be the behavior of a true muscular artery but rather of a central elastic artery such as the aorta, and might have implications for the susceptibility to aneurysm formation, as well as the association of dilating disease between the PA and the aorta. The wall stress in the PA was low and unaffected by age, probably caused by a compensatory remodeling response with an increase in wall thickness. This indicates that other mechanisms than wall stress contribute to the process of pathological dilatation in the PA.The ACE D allele may be associated with abdominal aortic aneurysm. Elderly men with the ACE D allele were associated with increased abdominal aortic stiffness compared to men carrying the I/I genotype. This suggests that the ACE D allele impairs arterial wall integrity, and in combination with local hemodynamic and other genetic factors it may have a roll in aneurysm formation.The FBN1 2/3 genotype has been associated with increased systolic blood pressure. The FBN1 2/3 genotype in middle-aged men was associated with increased abdominal aortic stiffness and blood pressure which indicates an increased risk for developing cardiovascular disease. The increased presence of plaque in the carotid artery of middle-aged men with the FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden, but did however not affect the risk of cardiovascular events and/or death in this population. This relationship needs to be studied further.
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| 10. |
- Hager, Jakob, 1967-
(författare)
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Abdominal Aortic Aneurysm : Aspects on how to affect mortality from rupture
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abdominal Aortic Aneurysm (AAA) is a disease that mainly affects elderly men, and ruptured AAA (rAAA) is associated with a mortality of > 80%. AAA seldom gives any symptoms prior to rupture.The aims of this thesis were to investigate different aspects of how to affect mortality from rAAA.In Study I, we identified 849 patients treated for rAAA during 1987-2004, and studied the 30-day survival after surgery, depending on whether they came directly to the treating hospital (one-stop) or were transferred via another hospital (two-stop). A two-stop referral pattern resulted in a 27% lower population-based survival rate for patients 65-74 years of age. However, the consequences would be small even if a one-stop referral pattern could be generally accomplished, due to the huge over-all mortality related to rAAA, hence an argument to find and treat AAA before rupture, e.g. by screening.In Study II, we examined the AAA-prevalence and the risk factors for AAA among 70-year-old men. The screening-detected AAA-prevalence was 2.3%, thus less than half the predicted. The most important risk factor was smoking.In Study III, we compared the screening-detected AAA-prevalence, the attendance rate, and the rate of opportunistic detection of AAA, between almost 8000 65- and 6000 70-year-old men. There was no difference in the screening-detected prevalence; probably due to the fact that almost 40% of the AAAs among the 70-year-old were already known prior to screening, compared to roughly 25% in the 65-year-old. The attendance rate was higher among the 65-year-old men, 85.7% compared 84.0% in the 70-year-old. Thus, there is no benefit of screening for AAA among 70- instead of 65-year-old men.In Study IV, a cost-effectiveness analysis, we found that screening for AAA still appears to be cost-effective, despite profound changes in disease pattern and AAA-management.In conclusion, we found that mortality from rAAA is not affected in any substantial way by different referral patterns and hence centralisation of services for AAA/rAAA is not a solution. A better alternative is to prevent rupture through early detection by screening. Screening 65-year-old men for AAA still appears to be cost-effective, despite profound changes in disease pattern and AAA-management during the last decade. Screening 70- instead of 65-year-old men will not increase the efficacy of screening.
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