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

Research output: ThesisDoctoral Thesis (compilation)

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.

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.

Details

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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical and Health Sciences

Keywords

Translated title of the contributionEpidemiologiska, mekanistiska och genetiska spekter av vaskulärt åldrande och artärstyvhet i populationen
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2017 May 5
Place of PublicationLund
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-7619-433-1
Publication statusPublished - 2017
Publication categoryResearch

Bibliographic note

Defence details Date: 2017-05-05 Time: 13:00 Place: Lilla Aulan, MFC, ingång 59, Skånes Universitetssjukhus i Malmö. External reviewer(s) Name: Spaak, Jonas Title: associate professor Affiliation: Karolinska Institutet --- ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:53

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