Arteriosclerosis: A population-based approach to aetiology and disease risk

Arteriosclerosis constitutes a massive burden on public health as it is the leading cause of cardiovascular events, including coronary heart disease and stroke. Despite advances in the field of medicine and epidemiology, many facets regarding the multifactorial origin of arteriosclerosis and its consequences remain incompletely understood. This thesis draws attention to current gaps in knowledge and opens avenues for future investigations.
Chapter 2 of this thesis is devoted to questions with regard to the aetiology of arteriosclerosis. In chapter 2.1 the prevalence and risk factors of vertebrobasilar artery calcification are described. Vertebrobasilar artery calcification is prevalent in 21% of middle-aged and elderly persons. Smoking, hypertension, and diabetes are the most important risk factors for vertebrobasilar artery calcification in both women and men. In chapter 2.2 we provided insights into the development of arteriosclerosis by studying the natural course of arteriosclerosis in different arteries covering a 14-year timespan. We show that a quarter to one-third of individuals without vertebrobasilar artery calcification at baseline developed vertebrobasilar artery calcification during follow-up. We found a considerable increase in volumes of coronary artery calcification, aortic arch calcification, extracranial carotid artery calcification, and intracranial carotid artery calcification. Several cardiovascular risk factors are associated with change in arterial calcification in different arteries. In chapter 2.3 we studied the association between lipoprotein(a) and arteriosclerosis in different arteries. We found that higher levels of lipoprotein(a) are associated with a larger burden of arteriosclerosis across the whole arterial system. In addition, overall, effect estimates for the association of lipoprotein(a) with arterial calcification are similar for women and men. This points towards a potential of lipoprotein(a) lowering therapies to lower the burden of arterial calcification throughout the arterial system in both men and women. Subsequently, instead of focussing on single risk factors, in chapter 2.4 we shed light on aggregated risk profiles for arteriosclerosis. Clusters of traditional cardiovascular risk factors show differing associations depending on the location of arteriosclerosis and sex. The findings provide insights into the aggregation of single cardiovascular risk factors and indicate a potential for sex-specific and location-dependent strategies for cardiovascular risk reduction.
Chapter 3 of this thesis focusses on consequences of arteriosclerosis. In this regard, we elucidate the role of arteriosclerosis in the aetiology of various (sub)clinical disease manifestations as well as its potential for the prediction of disease. Chapter 3.1 starts with highlighting the importance of prevention of intracranial arteriosclerotic disease. There is a considerable window of opportunity for early prevention of intracranial arteriosclerotic disease, in particular by gaining more insights into the prevalence of intracranial arteriosclerotic disease, and by studying the existence of distinct morphological subtypes of intracranial arteriosclerosis along with the pathophysiology of these subtypes and the potential clinical consequences. Consequently, in chapter 3.2 we show that distinct morphological subtypes of intracranial arteriosclerosis exist among middle-aged and elderly persons. The internal elastic laminal subtype is most common, followed by the intimal subtype of intracranial arteriosclerosis. Both subtypes are associated with a higher risk of stroke. Chapter 3.3 further unravels the link between intracranial arteriosclerosis and neurological disorders by focussing on the longitudinal association of intracranial arteriosclerosis with structural brain changes. We show that intracranial arteriosclerosis is associated with accelerating structural brain changes over time. In chapter 3.4 and 3.5 the emphasis lies on prediction of disease. In chapter 3.4 we assessed the added value of arterial calcification in different arteries, beyond traditional cardiovascular risk factors, for the prediction of cardiovascular disease. While coronary artery calcification remains the most robust predictor in both sexes, in women only, the value of intracranial carotid artery calcification in terms of prediction and reclassification of cardiovascular disease is similar to that of the coronary arteries. These findings suggest a potential of assessment of intracranial arteriosclerosis in women, though it must be established whether eventual clinically relevant benefits outweigh the costs and harms from additional radiation exposure. In chapter 3.5 we assessed the added value of information on carotid plaque components to the sex-specific prediction of atherosclerotic cardiovascular disease. We show that intraplaque haemorrhage is a robust predictor of incident atherosclerotic cardiovascular disease in women, beyond traditional risk factors and other plaque characteristics. These findings signify a potential of intraplaque haemorrhage as marker of plaque vulnerability, particularly in women. Chapter 3.6 focusses on the link between two of the leading causes of morbidity and mortality: vascular disease and cancer. We show that a large burden of systemic vascular disease may be present before clinical manifestation of cancer.
Lastly, in chapter 4, the main findings are presented in light of current knowledge, and methodological considerations are discussed. In addition, chapter 4 provides recommendations for future research. Further research into the pathophysiology of arteriosclerosis and subsequent consequences may elaborate on novel risk factors for the development of arteriosclerosis, aggregation of risk factors, specific arteriosclerotic subtypes, and plaque components. These multifactorial facets also create opportunities for better risk prediction and stratification, which is desirable to facilitate the development of preventive interventions to reduce the burden of cardiovascular disease.