Advanced

Epidemiological, mechanistic and genetic aspects of vascular ageing and arterial stiffness in the population

Gottsäter, Mikael LU (2017)
Abstract (Swedish)
The core feature of vascular ageing is the age-associated stiffening of the large, elastic arteries, or arteriosclerosis. This results in a diminished volume-buffering function and is therefore central for the increase in systolic blood pressure and pulse pressure seen with advancing age. Since there are considerable individual differences regarding the rate of vascular ageing, the aim was to describe vascular ageing and its relation to hemodynamic, circulating, morphological and genetic markers using cross-sectional and longitudinal data.

This thesis is based on epidemiological data from the Malmö Diet and Cancer Study, a population-based cohort from the city of Malmö, Sweden.

In Paper 1, adrenomedullin (ADM), a... (More)
The core feature of vascular ageing is the age-associated stiffening of the large, elastic arteries, or arteriosclerosis. This results in a diminished volume-buffering function and is therefore central for the increase in systolic blood pressure and pulse pressure seen with advancing age. Since there are considerable individual differences regarding the rate of vascular ageing, the aim was to describe vascular ageing and its relation to hemodynamic, circulating, morphological and genetic markers using cross-sectional and longitudinal data.

This thesis is based on epidemiological data from the Malmö Diet and Cancer Study, a population-based cohort from the city of Malmö, Sweden.

In Paper 1, adrenomedullin (ADM), a vasoactive peptide mainly produced by endothelial cells, was investigated. The results showed that ADM was positively associated with brachial pulse pressure and both carotid intima-media thickness and atherosclerotic plaques in adjusted models. This suggests a role for ADM
in early hemodynamic pathophysiology related to arteriosclerosis and atherosclerosis.

In Paper 2 and Paper 3, predictive and cross-sectional assocations between arterial stiffness and cardiovascular risk markers were investigated. In Paper 2, the stiffness of the abdominal aorta was assessed by ultrasound while in Paper 3 carotid-femoral pulse wave velocity (c-f PWV) was used, measuring regional
arterial stiffness along the carotid–aortic–iliac–femoral arterial segment. In Paper 3, markers of impaired glucose metabolism, dyslipidemia (high triglycerides, low high-lipoprotein cholesterol; HDLc), and waist circumference were all independent, non-hemodynamic, long-term predictors of arterial stiffness, following full adjustment in both sexes. Smoking, low density lipoprotein cholesterol (LDLc), and estimated glomerular filtration rate (eGFR) were not associated with arterial stiffness. These results were partly concurrent with
results from Paper 2, the main difference being that insulin resistance and low HDLc were associated with abdominal aortic stiffness among women, but not among men.

In Paper 4, Mendelian randomization was used as a method of identifying causal risk factors for arterial stiffness, measured as c-f PWV. Genetic risk scores (GRS) were used as instrumental variables. Arterial stiffness was associated with GRS for fasting plasma glucose (FPG) and type 2 diabetes (T2D). However, in
inverse-variance weighted analyzes, significance for FPG β coefficients remained (p=0.006) but the relationship between T2D β coefficients was lost (p=0.88). GRSs for body mass index, systolic blood pressure, LDLc, HDLc and triglycerides were not associated with arterial stiffness. In conclusion, genetically elevated
FPG, but not genetically elevated risk of T2D, was associated with arterial stiffness, suggesting a causal stiffening effect of glycemia on the arterial wall, independently of T2D.

To summarize, in a population-based cohort, the risk markers for arteriosclerosis differ from risk markers for atherosclerosis. Results from Mendelian randomization analyses suggest that fasting plasma glucose is a
causal risk factor for arteriosclerosis. However, this must be confirmed in future studies including newinterventions on hyperglycaemia to improve arteriosclerosis. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • associate professor Spaak, Jonas, Karolinska Institutet
organization
alternative title
Epidemiologiska, mekanistiska och genetiska spekter av vaskulärt åldrande och artärstyvhet i populationen
publishing date
type
Thesis
publication status
published
subject
keywords
Vascular ageing, Arterial stiffness
pages
80 pages
publisher
Lund University, Faculty of Medicine
defense location
Lilla Aulan, MFC, ingång 59, Skånes Universitetssjukhus i Malmö.
defense date
2017-05-05 13:00
ISBN
978-91-7619-433-1
language
English
LU publication?
yes
id
5d0024c0-e965-4ea5-b6c2-4655015a29c6
date added to LUP
2017-04-19 18:34:16
date last changed
2017-04-20 15:13:20
@phdthesis{5d0024c0-e965-4ea5-b6c2-4655015a29c6,
  abstract     = {The core feature of vascular ageing is the age-associated stiffening of the large, elastic arteries, or arteriosclerosis. This results in a diminished volume-buffering function and is therefore central for the increase in systolic blood pressure and pulse pressure seen with advancing age. Since there are considerable individual differences regarding the rate of vascular ageing, the aim was to describe vascular ageing and its relation to hemodynamic, circulating, morphological and genetic markers using cross-sectional and longitudinal data.<br/><br/>This thesis is based on epidemiological data from the Malmö Diet and Cancer Study, a population-based cohort from the city of Malmö, Sweden.<br/><br/>In Paper 1, adrenomedullin (ADM), a vasoactive peptide mainly produced by endothelial cells, was investigated. The results showed that ADM was positively associated with brachial pulse pressure and both carotid intima-media thickness and atherosclerotic plaques in adjusted models. This suggests a role for ADM<br/>in early hemodynamic pathophysiology related to arteriosclerosis and atherosclerosis.<br/><br/>In Paper 2 and Paper 3, predictive and cross-sectional assocations between arterial stiffness and cardiovascular risk markers were investigated. In Paper 2, the stiffness of the abdominal aorta was assessed by ultrasound while in Paper 3 carotid-femoral pulse wave velocity (c-f PWV) was used, measuring regional<br/>arterial stiffness along the carotid–aortic–iliac–femoral arterial segment. In Paper 3, markers of impaired glucose metabolism, dyslipidemia (high triglycerides, low high-lipoprotein cholesterol; HDLc), and waist circumference were all independent, non-hemodynamic, long-term predictors of arterial stiffness, following full adjustment in both sexes. Smoking, low density lipoprotein cholesterol (LDLc), and estimated glomerular filtration rate (eGFR) were not associated with arterial stiffness. These results were partly concurrent with<br/>results from Paper 2, the main difference being that insulin resistance and low HDLc were associated with abdominal aortic stiffness among women, but not among men.<br/><br/>In Paper 4, Mendelian randomization was used as a method of identifying causal risk factors for arterial stiffness, measured as c-f PWV. Genetic risk scores (GRS) were used as instrumental variables. Arterial stiffness was associated with GRS for fasting plasma glucose (FPG) and type 2 diabetes (T2D). However, in<br/>inverse-variance weighted analyzes, significance for FPG β coefficients remained (p=0.006) but the relationship between T2D β coefficients was lost (p=0.88). GRSs for body mass index, systolic blood pressure, LDLc, HDLc and triglycerides were not associated with arterial stiffness. In conclusion, genetically elevated<br/>FPG, but not genetically elevated risk of T2D, was associated with arterial stiffness, suggesting a causal stiffening effect of glycemia on the arterial wall, independently of T2D.<br/><br/>To summarize, in a population-based cohort, the risk markers for arteriosclerosis differ from risk markers for atherosclerosis. Results from Mendelian randomization analyses suggest that fasting plasma glucose is a<br/>causal risk factor for arteriosclerosis. However, this must be confirmed in future studies including newinterventions on hyperglycaemia to improve arteriosclerosis.},
  author       = {Gottsäter, Mikael},
  isbn         = {978-91-7619-433-1},
  keyword      = {Vascular ageing,Arterial stiffness},
  language     = {eng},
  pages        = {80},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Epidemiological, mechanistic and genetic aspects of vascular ageing and arterial stiffness in the population},
  year         = {2017},
}