The remodelling of extracellular matrix (ECM) in tissues plays a pivotal role in many chronic diseases. Two conditions that share the ECM remodelling as an important determinant are coronary artery disease (CAD) and ascending aortic (AA) dilation, together accounting for a significant amount of morbidity and mortality worldwide. Through atherosclerosis and medial degeneration, respectively, these diseases advance slowly but with a varying risk of sudden and sometimes fatal complications. Thus, there is an ongoing and intensive search for tools that could predict the risk of disease progression and ultimately events. With recent advancements, it is now possible to quantify circulating biomarkers reflecting tissue ECM remodelling, that could hopefully become such tools. The thesis, comprised of four studies, investigates these ECM biomarkers and their role in CAD and AA dilation.

Study 1 and 2 build upon a recent finding showing that circulating pro-α1 chain in type I collagen (COL1α1) was inversely associated with incident CAD in the general population. Due to the novelty of the finding, our goal with Study 1 was to replicate these results and further explore temporal patterns of COL1α1 after a myocardial infarction. The results affirmed that COL1α1 indeed was inversely related to incident CAD but that levels were stable right after and up to 6 months after an acute myocardial infarction. We also found that women exhibited significantly higher levels of the protein compared to men and that COL1α1 was associated with a biomarker of type I collagen synthesis but not to the corresponding degradation biomarker nor to inflammation or troponins. In Study 2, we examined the relationship between COL1α1 levels and coronary atherosclerosis cross-sectionally using coronary computed tomography angiography data from the Swedish general population showing an inverse association to different measures of coronary atherosclerosis. Interestingly, the strongest associations were with high-risk features such as presence of non-calcified plaques and high-grade coronary stenosis. Several correlations to clinical characteristics were replicated from Study 1, condensing into an inverse association between COL1α1 levels and components of the metabolic syndrome.

In Study 3 and 4, middle-aged individuals with mild-to-moderate AA dilation from the general population were examined. These patients are often less studied compared to patients with more severe disease, although they constitute the majority of AA dilations. It is also a population that is believed to increase as the growing usage of imaging finds these incidentally. Study 3 aimed to find potential biomarker candidates in this type of population. Both recognized ECM biomarkers and exploratory biomarkers were quantified in plasma through multiplex systems. From these efforts, tissue inhibitor of matrix metalloproteinases-4 (TIMP-4) was brought forward as a biomarker inversely related to AA growth rate. In the exploratory biomarker panel, several other biomarker candidates and biological pathways were identified. Study 4 tried to expand the biological understanding of AA dilation through the combination of biomarkers and 4D magnetic resonance imaging. Intriguingly, both COL1α1 and interleukin-6 showed significant correlations to important parameters of AA hemodynamic patterns pertaining to aspects of wall shear stress in cases with AA dilation.

On a broader scale, this thesis emphasizes the importance of ECM remodelling in cardiovascular disease and also underlines the potential of measuring these processes through circulating biomarkers. It identifies COL1α1 as a potentially useful biomarker in CAD. In mild-to-moderate AA dilation, TIMP-4 emerged as a biomarker candidate and COL1α1 together with interleukin-6 might represent pathological processes from adverse hemodynamics on the aortic wall. At the same time, the studies were subject to several limitations that spur the need for larger and methodologically more robust studies in the future.