CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH MYOCARDIAL INFARCTION AND NON-OBSTRUCTED CORONARY ARTERIES THESIS FOR DOCTORAL DEGREE ( Ph . D . ) By

Cardiovascular disease (CVD) is the number one cause of death worldwide. In Sweden, almost 30 000 people suffer an acute myocardial infarction (AMI) each year and, despite the greatly improved survival after AMI, CVD remains the leading cause of death among women and men. During the last decade, there has been increasing awareness of the significant minority of patients with acute myocardial infarction, for whom invasive coronary angiography (ICA) does not show any coronary artery stenoses. This condition is called myocardial infarction and non-obstructed coronary arteries (MINOCA) and is still incompletely understood. Another condition that has gained increasing attention is Takotsubo syndrome (TS), also known as stress-induced cardiomyopathy or the broken heart syndrome. Patients with TS may be considered a sub-group of MINOCA. Important advances in coronary computed tomography angiography (CTA) technology have enabled safe and accurate non-invasive imaging of the coronary arteries. In contrast to ICA, coronary CTA allows for detection of non-obstructive as well as obstructive coronary artery disease (CAD). Coronary CTA is also useful for assessment of plaque characteristics and detection of myocardial bridging (MB). In order to improve CVD risk prediction, numerous risk markers have emerged, among them carotid artery intima-media thickness (IMT), endothelial function determined by digital reactive hyperemia peripheral arterial tonometry (RH-PAT) and different categories of circulating biomarkers. Coronary CTA plaque burden has a prognostic value in CVD risk assessment, but its association with other risk markers is incompletely studied. There were two major aims of this thesis. The first aim was to investigate the underlying mechanisms of MINOCA (study I and III). The second aim was to examine the association between coronary CTA plaque burden and other risk markers of CVD (study II and IV). In study I we compared coronary CTA plaque burden in MINOCA patients and controls, matched by age and gender. We found that coronary CTA plaque burden was similar in the two groups and that a large proportion of MINOCA patients (42%) had no signs of CAD at coronary CTA. Non-obstructive CAD is most likely not a frequent cause of MINOCA. In study II, 58 volunteers, free from clinical CVD, underwent testing for IMT and RH-PAT as well as coronary CTA. More than half of the study group had evidence of subclinical CAD at coronary CTA. There was no association between IMT or RH-PAT and presence or extent of CAD. Neither evaluation of IMT nor RH-PAT can reliably be used to predict coronary CTA plaque burden in clinically healthy subjects. In study III the prevalence of MB, determined by coronary CTA, was compared for MINOCA patients, including a subgroup with TS, and matched controls. The MB depiction rate of coronary CTA and ICA was compared. MB was frequent, with a similar prevalence in MINOCA patients, patients with TS and controls, suggesting MB is not a frequent cause of MINOCA or TS. Coronary CTA detects significantly more MB than ICA. In study IV, 115 subjects with predominantly low-to-intermediate CVD risk and normal or mildly reduced kidney function, underwent coronary CTA and laboratory testing. The groups without and with CAD differed with regard to levels of adiponectin, lipoprotein(a) and cystatin C. However, in a multivariable logistic regression model, only male sex and levels of cystatin C were independently associated with non-obstructive CAD at coronary CTA. In conclusion, non-obstructive CAD is not a frequent cause of MINOCA in patients with angiographically normal or near-normal coronary arteries. MINOCA should probably not be considered a definitive diagnosis, but rather a working diagnosis, warranting additional diagnostic evaluation. TS, which is one of the possible underlying causes of MINOCA, is most likely not caused by MB. For TS, future consensus on the diagnostic criteria will facilitate research on pathophysiological mechanisms, diagnosis, prognosis and patient management. Circulating cystatin C was associated with non-obstructive CAD and may thus have a potential to serve as a screening test for subclinical CAD. However, CVD risk assessment is complex and large-scale studies are necessary to investigate which combination of imaging parameters and other risk markers yields the most accurate individual risk prediction. LIST OF SCIENTIFIC PAPERS The thesis is based on the following four papers, referred to in the text by their roman numerals: I. Brolin EB, Jernberg T, Brismar TB, Daniel M, Henareh L, Ripsweden J, Tornvall P, Cederlund K. Coronary plaque burden, as determined by cardiac computed tomography, in patients with myocardial infarction and angiographically normal coronary arteries compared to healthy volunteers: a prospective multicenter observational study. PloS one 2014;9(6):e99783. doi: 10.1371/journal.pone. 0099783. II. Brolin EB, Agewall S, Brismar TB, Caidahl K, Tornvall P, Cederlund K. Neither endothelial function nor carotid artery intima-media thickness predicts coronary computed tomography angiography plaque burden in clinically healthy subjects: a cross-sectional study. BMC Cardiovasc Disord 2015;15:63. doi: 10.1186/s12872-015-0061-x. III. Brolin EB, Brismar TB, Collste O, Y-Hassan S, Henareh L, Tornvall P, Cederlund K. Prevalence of myocardial bridging in patients with myocardial infarction and nonobstructed coronary arteries. Am J Cardiol 2015. Advance online publication. doi: 10.1016/j.amjcard. 2015.09. 017. IV. Brolin EB, Agewall S, Cederlund K, Ekenbäck C, Henareh L, Malmqvist K, Rück A, Svensson A, Tornvall P. Cystatin C is associated with nonobstructive coronary artery disease determined by coronary computed tomography angiography. Submitted manuscript.