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

Sammanfattning: 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 ADMin 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 regionalarterial 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 withresults 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, ininverse-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 elevatedFPG, 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 acausal risk factor for arteriosclerosis. However, this must be confirmed in future studies including newinterventions on hyperglycaemia to improve arteriosclerosis.