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- Björck, Hanna, 1979-
(author)
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Vessel wall integrity : influence of genetics and flow
- 2012
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Doctoral thesis (other academic/artistic)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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| 2. |
- Dahlén, Elsa, 1975-
(author)
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Markers of subclinical atherosclerosis and arterial stiffness in type 2 diabetes
- 2011
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Doctoral thesis (other academic/artistic)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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| 3. |
- De Basso, Rachel
(author)
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Influence of genetics and mechanical properties on large arteries in man
- 2013
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Doctoral thesis (other academic/artistic)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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| 4. |
- Ljungberg, Liza, 1980-
(author)
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Angiotensin-converting enzyme in cardiovascular function and dysfunction
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system, converting angiotensin I to the vasoactive peptide angiotensin II, and degrading bradykinin. Angiotensin II is a multifunctional peptide, acting on a number of different tissues. A common genetic variation in the gene encoding ACE; ACE I/D polymorphism influences the level of ACE in the circulation, and has been linked to increased risk for cardiovascular disease. This thesis aimed to explore the connection between ACE and cardiovascular function and dysfunction.The impact of nicotine and nicotine metabolites on ACE in cultured human endothelial cells was studied. Nicotine as well as nicotine metabolites induced increased ACE activity in cultured human endothelial cells. In elderly men a higher ACE level was seen in smokers compared to non-smokers. Furthermore, diabetes was associated with higher circulating ACE. Increased ACE level may represent a cellular mechanism which contributes to vascular damage.Elderly men carrying the ACE D allele had higher abdominal aortic stiffness compared to men carrying the I/I genotype. Our data suggest that the mechanism by which the ACE D allele modulates aortic wall mechanics is independent of circulating ACE levels. Previous studies have indicated a link between the D allele and abdominal aortic aneurysm. Increased aortic stiffness suggests impaired vessel wall integrity, which combined with local hemodynamic and/or inflammatory factors may have a role in aneurysm formation.Subjects with left ventricular dysfunction had higher levels of circulating ACE compared to those with normal left ventricular function, while there was no association between ACE and central hemodynamics. ACE might play a role in the pathogenesis of left ventricular dysfunction and our findings suggest a direct effect on the heart rather than affecting central blood pressure.
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| 5. |
- Wijkman, Magnus
(author)
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Acute, ambulatory and central blood pressure measurements in diabetes
- 2012
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Doctoral thesis (other academic/artistic)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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