Denne PhD-afhandling er baseret på tre originale manuskrifter. Studierne er gennemført på den Kardiologiske Forskningsenhed, OUH Svendborg Hospital.Baggrund Type 2 diabetes mellitus er en betydelig risikofaktor for iskæmisk hjertesygdom. Patienter med type 2diabetes har en høj byrde af traditionelle risikofaktorer, og behandlingen af disse medfører en betydeligreduktion i dødelighed og risikoen for blodprop i hjertet. Til trods for god risikofaktor-kontrol og normalisering af LDL med kolesterolsænkende medicin er disse patienter fortsat i øget risiko for blodprop i hjertet. Dette fænomen betegnes residualrisiko og har været i fokus i de seneste år. Hovedformålet med denne afhandling var at undersøge og beskrive åreforkalkning i asymptomatiske patienter med type 2diabetes som ikke er kendt med iskæmisk hjertesygdom. Delformål 1) At beskrive forekomsten af høj risiko plaque (HRP) og sammenhængen med risikofaktorer samt den koronare kalk score (CACS). 2) At undersøge sammenhængen mellem ændringer i kolesterol, triglycerider, og langtidsblodsukker i forhold til sammensætning og progression af koronar åreforkalkning 3) At evaluere sammenhængen mellem GLP-1 antagonisten liraglutide og ændringer i det totale plaque volumen samt plaque komposition ved opfølgning efter et år. Metode Dette studie var det prospektivt observationsstudie og patienterne blev rekrutteret og undersøgt i perioden fra marts 2016 til september 2017. Patienter med type 2 diabetes uden symptomer og historik mediskæmisk hjertesygdom blev inviteret til at deltage i studiet. Hjerte-CT blev udført ved studiets start og efter et års opfølgning. Det totale plaque-volumen samt plaque sammensætning og højrisiko plaque-morfologi(HRP) blev estimeret ved studiets start og ved opfølgning efter et år. Kliniske data som blodtryk, hjertekardiogram, medicinsk behandling, diabetiske komplikationer, samt blodprøver blev indsamlet ved studietsstart og ved opfølgning efter et år. Opsummering af afhandlingens hovedfund:1) HRP blev observeret hos 37% af patienterne og var associeret med højere langtidsblodsukker, større tobaks-eksponering og mandligt køn. HRP blev identificeret i alle CACS grupper inklusiv CACS på nul.2) Stigende triglycerider var associeret med progression af både høj-risiko plaque og det total plaque volumen. Stigningen i triglycerider var tæt associeret med stigning i vægt, stagnerende HbA1c, samtfaldende lever attenuation. Ydermere var der en klar sammenhængen mellem stigende triglycerider og rest-partikel kolesterol.3) Ændringer i det totale plaque volumen var ikke associeret med liraglutid behandling. Analysen af plaque kompositionen viste, at liraglutide behandling var associeret med øget progression af fibrøst plaque.KonklusionKonklusionen på dette studie er at hjerte-CT er noninvasiv metode som muliggør at karakterisere typen af åreforkalkning samt ændringer over tid. Høj-risiko plaque morfologi blev identificeret hos 37% af patienterne og var associeret med risikofaktorerne langtidsblodsukker, tobaks-eksponering, og mandligt køn, men kunne ikke udelukkes ved fraværet af koronar kalk. En stigning i triglycerider var associeret med plaque progression af høj risiko plaque og en en forværring af den glukometaboliske kontrol samt stigende rest-partikel kolesterol. Liraglutide behandling var associeret med øget progression af fibrøst plaque og er en mulig mekanisme som kan forklare den kardiovaskulære risikoreduktion associeret med liraglutid behandling. This PhD thesis is based on three original manuscripts, and the studies were carried out at the Cardiovascular Research Unit at OUH Svendborg.BackgroundIschemic heart disease remains the leading cause of mortality in type 2 diabetes mellitus (T2D). Despite a significant risk reduction in the last decades, T2D remains associated with twice the risk of all-cause mortality, mainly due to coronary artery disease (CAD). Coronary computed tomography angiography(CCTA) allows the characterization of coronary artery plaque and disease progression, and several studies have demonstrated that high-risk plaque (HRP) is associated with acute coronary syndrome (ACS). Risk stratification of asymptomatic diabetes is challenging and a better understanding of the extent and progression of coronary atherosclerosis in relation to patient characteristics and risk factors is of interest. The overall aim of this PhD study was to assess plaque characteristics and predictions of plaque progression in a cohort of asymptomatic patients with diabetes without CAD. Study objective:1) To assess the prevalence of HRP in asymptomatic T2D and the relationship between HRP and cardiovascular disease (CVD) risk factors, diabetes profile, and the coronary artery calcium score(CACS).2) To assess the association of changes in lipoproteins and glycated hemoglobin (HbA1c) in relation to changes in HRP volumes.3) To assess changes in the total atheroma (TAV) and composition from baseline to follow-up stratified by liraglutide treatmentMethods This PhD thesis is based on data from a prospective observational study performed between March 2016and September 2017 at Odense University Hospital Svendborg. Patients were asymptomatic and without a history of CAD. Serial CCTA was performed to assess total atheroma volume (TAV) and plaque composition at baseline and one-year follow-up. In addition, CACS was assessed from non-enhanced images. A clinical assessment including blood pressure, electrocardiogram, current medication, diabetic complications, and blood test was performed at baseline and at follow-up. The main findings of this PhD thesis were:1) HRP was identified in 37% of patients and was associated with higher HbA1c, greater tobacco exposure, and male gender. HRP was detected in all groups of CACS, and the absence of coronary artery calcium (CACS = 0) could not rule out HRP.2) An increase in triglycerides was associated with the progression of HRP as well as an overall plaque progression. Changes in triglycerides were closely associated with weight gain, stagnant HbA1c, and evidence of increased hepatic fat accumulation. Furthermore, there was a strong association between the increase in triglyceride and the increase in remnant cholesterol.3) We found no association between changes in TAV and liraglutide treatment. The secondary endpoint, changes in plaque composition stratified by liraglutide treatment was positive, and a significant increase in the fibrous plaque volume was detected in the liraglutide treated patients.ConclusionsIn conclusion, CCTA is a non-invasive examination that allows the characterization of plaque composition and changes over time. HRP was detected in 37% of the patients and was associated with higher HbA1c,tobacco exposure, and male gender. Our results warrant caution for use of calcium scoring in this patient group as the absence of coronary artery calcium could not rule out CAD. We found a significant association between an increase in triglyceride levels and HRP progression. The data suggested that this finding was mediated by an increase in remnant cholesterol driven by a worsening in glucometabolic control. Finally, liraglutide was associated with an increase in fibrous plaque which could indicate plaque stabilization. To the best of our knowledge, this study is the first study to assess the association between liraglutide treatment and coronary atherosclerosis in humans.