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Influence of Genetics and Mechanical Properties on Large Arteries in Man
Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. , 77 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1340
National Category
Physiology
Identifiers
URN: urn:nbn:se:liu:diva-86144ISBN: 978-91-7519-761-6 (print)OAI: oai:DiVA.org:liu-86144DiVA: diva2:575004
Public defence
2013-01-25, Orginalet, Qulturum, Hus B4, , Länssjukhuset Ryhov, Jönköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2017-03-27Bibliographically approved
List of papers
1. The popliteal artery, an unusual muscular artery with wall properties similar to the aorta: Implications for susceptibility to aneurysm formation?
Open this publication in new window or tab >>The popliteal artery, an unusual muscular artery with wall properties similar to the aorta: Implications for susceptibility to aneurysm formation?
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2004 (English)In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 39, no 4, 836-842 p.Article in journal (Refereed) Published
Abstract [en]

Objective: The popliteal artery is, after the aorta, the most common site for aneurysm formation. Why the popliteal artery is more susceptible than other peripheral muscular arteries is unknown. An important factor may be differences in arterial wall composition as compared with other peripheral muscular arteries, which in turn affect wall properties. These are however unknown. We studied the mechanical wall properties of the popliteal artery in healthy subjects. Material and Methods: An ultrasound echo-tracking system was used to measure pulsatile changes in popliteal diameter in 108 healthy subjects (56 female, 52 male, age range, 9-82 years). In combination with blood pressure, stiffness (β), strain, cross-sectional artery wall compliance coefficient (CC), and distensibility coefficient (DC) were calculated. Intima-media thickness (IMT) was registered with a Philips P700 ultrasound scanner. Results: The popliteal diameter increased with age, and was larger in male subjects than in female subjects (P < .001). Fractional diameter change (strain) decreased with age (P < .001), and strain values were lower in male subjects than in female subjects (P < .01). Accordingly, stiffness increased with age (P < .001), with higher stiffness values in male subjects (P < .01). DC decreased with age (P < .001), with lower DC values in male subjects (P < .01). CC decreased with age, with no difference between genders (P < .001). IMT increased with age (P < .001), with higher IMT values in male subjects (P < .001). The increase in IMT did not affect distensibility. Conclusion: The wall properties of the popliteal artery are affected by age and gender, not only with an increase in diameter, but also with an age-related decrease in distensibility, with male subjects having lower distensibility than in female subjects. This seems not to be the behavior of a true muscular artery, but of a central elastic artery, such as the aorta, and might have implications for susceptibility to arterial dilatation, as well as the association of aneurysm formation between the aorta and the popliteal artery.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24039 (URN)10.1016/j.jvs.2003.12.005 (DOI)3595 (Local ID)3595 (Archive number)3595 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
2. Low wall stress in popliteal artery – other mechanisms responsible for the predilection of aneurysmal dilatation?
Open this publication in new window or tab >>Low wall stress in popliteal artery – other mechanisms responsible for the predilection of aneurysmal dilatation?
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: The popliteal artery (PA) is, after aorta, the most common site for aneurysm formation. Why the PA is more susceptible than other peripheral muscular arteries is unknown. We hypothesised that the wall composition, which in turn affects wall properties, as well as the circumferential wall stress imposed on the arterial wall, might differ compared to other muscular arteries. The aim was to study the circumferential wall stress of the PA in healthy subjects with the adjacent muscular common femoral artery (CFA) as a comparison.

Material and Methods: Ninety-four healthy subjects were included in this study (45 males, range 10-78 years and 49 females, range 10-83 years). The lumen diameter (LD) and intima-media thickness (IMT) in the PA and CFA were investigated with a Philips P700 ultrasound device. Together with blood pressure the circumferential wall stress was defined according to the law of Laplace adjusted for IMT.

Results: The diameter increased with age in both PA and CFA (P<.001), with males having larger diameter than females (P<.001). IMT increased with age in both PA and CFA (P<.001), with higher IMT values in males only in PA (P<0.001). The calculated wall stress was unchanged with age in both arteries, but lower in PA than in CFA in both male and female subjects (P<0.001).

Conclusion: This study shows that the popliteal and common femoral artery wall stress is maintained during ageing, probably due to compensatory remodeling response with an increase in arterial wall thickness. However, the stress imposed on the popliteal artery wall is quite low, indicating that other mechanisms than wall stress contribute to the process of pathological arterial dilatation in the popliteal artery.

National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-86142 (URN)
Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2017-03-27
3. Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele
Open this publication in new window or tab >>Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele
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2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 3, 309-316 p.Article in journal (Refereed) Published
Abstract [en]

Objective: A genetic polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with abdominal aortic aneurysm and a link between aortic aneurysm and aortic stiffness has been suggested. The aim of this study was to explore the links between ACE I/D polymorphism, circulating ACE, and abdominal aortic wall integrity as reflected by abdominal aortic wall stiffness.

Material: The study population consisted of 406 subjects (212 men and 194 women) aged 70-88 years.

Methods: The mechanical properties of the abdominal aorta were determined 3-4 cm proximal to the aortic bifurcation using a Wall Track System. ACE-genotype was determined by PCR followed by gel electrophoresis, and circulating ACE level was measured by ELISA.

Results: Men carrying the ACE D allele had lower distensibility coefficient than II carriers (ID/DD 8.09 vs II 10.38, P=0.017). Multiple regression analyses showed additional associations between the ACE D allele and increased stiffness β as well as reduced cross-sectional compliance.

Conclusion: This study showed that men carrying the ACE D allele have stiffer abdominal aortas compared to II carriers. Deranged abdominal aortic stiffness indicates impaired vessel wall integrity, which along with other local predisposing factors, may be of importance in aneurysmal disease.

Place, publisher, year, edition, pages
Elsevier, 2011
Keyword
Aorta; Arterial stiffness; Distensibility; Gene polymorphism; Mechanical properties
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67213 (URN)10.1016/j.ejvs.2011.04.010 (DOI)000295061800007 ()
Available from: 2011-04-04 Created: 2011-04-04 Last updated: 2017-12-11Bibliographically approved
4. Influence of fibrillin-1 genotype on the aortic stiffness in men
Open this publication in new window or tab >>Influence of fibrillin-1 genotype on the aortic stiffness in men
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2005 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 99, no 3, 1036-1040 p.Article in journal (Refereed) Published
Abstract [en]

Aortic stiffness is a predictor of cardiovascular mortality. The mechanical properties of the arterial wall depend on the connective tissue framework, with variation in fibrillin-1 and collagen I genes being associated with aortic stiffness and/or pulse pressure elevation. The aim of this study was to investigate whether variation in fibrillin-1 genotype was associated with aortic stiffness in men. The mechanical properties of the abdominal aorta of 79 healthy men (range 28-81 yr) were investigated by ultrasonographic phase-locked echo tracking. Fibrillin-1 genotype, characterized by the variable tandem repeat in intron 28, and collagen type I alpha 1 genotype characterized by the 2,064 OT polymorphism, were determined by using DNA from peripheral blood cells. Three common fibrillin-1 genotypes, 2-2, 2-3, and 2-4, were observed in 50 (64%), 10 (13%), and 11 (14%) of the men, respectively. Those of 2-3 genotype had higher pressure strain elastic modulus and aortic stiffness compared with men of 2-2 or 2-4 genotype (P = 0.005). Pulse pressure also was increased in the 2-3 genotype (P = 0.04). There was no significant association between type 1 collagen genotype and aortic stiffness in this cohort. In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease. Copyright © 2005 the American Physiological Society.

Keyword
blood pressure, collagen, elastin, mechanics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-29056 (URN)10.1152/japplphysiol.00554.2004 (DOI)14310 (Local ID)14310 (Archive number)14310 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13
5. Increased carotid plaque burden in men with the Fibrillin-1 2/3 genotype
Open this publication in new window or tab >>Increased carotid plaque burden in men with the Fibrillin-1 2/3 genotype
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2014 (English)In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 41, no 9, 637-642 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Fibrillin-1 is an important constituent of the vascular wall and earlier studies have indicated an effect of the Fibrillin-1 (FBN1) 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim was to determine if the FBN1 2/3 genotype was associated with presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects.

Material and Method: The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; aged 45-69 years) recruited from the Malmö Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima media thickness (IMT) of the carotid artery were assessed by ultrasound. Incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality was monitored during a mean of 13.2 years follow-up.

Results: The most common FBN1 genotypes were 2/2, 2/3 and 2/4 which accounted for 92.2% (n=5317) of the subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, CCA diameter and IMT in men and women. Presence of plaque in the carotid artery was higher in men with genotype 2/3 as compared to the 2/2 and 2/4 genotypes, (55% vs. 46% and 50%, p=0.007). No similar difference was observed in women. No significant relationship was observed between FBN1 genotypes and incidence of CVD or all-cause mortality.

Conclusions: The increased prevalence of plaque in the carotid artery of middle-aged men with FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden. 

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keyword
IMT, cardiovascular risk, blood pressure, arterial wall, human
National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-86143 (URN)10.1111/1440-1681.12259 (DOI)000344348100004 ()24837032 (PubMedID)
Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2017-12-07Bibliographically approved

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