Short summary

Cardiovascular disease (CVD) is one of the leading causes of death in the Western Society. Patients with type 2 diabetes mellitus (T2DM) or dysglycemia have an increased risk of developing CVD. Furthermore, T2DM have an increased risk of developing heart failure, especially non-systolic, whether or not this is correlated to stepwise abnormal glyemic status is not fully investigated. In this descriptive study, 800 asymptomatic men aged 65-74 without known CVD or diabetes will be included. Oral glucose tolerance test (OGTT), echocardiography, blood sample and coronary CT angiography (CCTA) will be performed at the inclusion.

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Rationale

To our knowledge no studies have investigated coronary artery plaque burden and morphology in asymptomatic men aged 65-74 years with focus on the influence of three different glycemic status (see Study objectives) in individuals without known type 2 diabetes mellitus (T2DM). Due to the expectance of increasing number of patients with T2DM and dysglycemia the coming years, it must be foreseen that the number of patients with cardiovascular disease will increase in this group of patients. It is mandatory that we increase our knowledge, especially about the development of coronary atherosclerosis and left ventricular function. We expect that this study will bring further light on these important aspects of dysglycemia and hopefully give information to improve treatment and prophylaxis.

Study objectives:

1. To explore coronary plaque morphology and burden in asymptomatic men aged 65-74 with:
1. Normal OGTT
2. Dysglycemia (impaired fasting glucose (IFG) or impaired glucose tolerance) (IGT))
3. OGTT within the diabetic interval in individuals without known T2DM
2. To investigate the possible relationship between coronary plaque burden and morphology to:
1. Systolic function and 2D speckle-tracking to explore presence of segmental dysfunction
2. Diastolic dysfunction
3. To assess the possible correlation between glycemic status and:
1. Systolic function and 2D speckle-tracking to explore presence of segmental dysfunction
2. Diastolic dysfunction

Beyond above mentioned study objectives, we also intend to explore the following areas:

1. Coronary plaque morphology and burden to:
1. HOMA-IR and HbA1c
2. Inflammatory markers
2. Glycemic status to: 
1. HOMA-IR and HbA1c
2. Inflammatory markers 

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Description of the cohort

A population of 800 participants will be collected from the DANCAVAS study (OP_122). Briefly, the DANCAVAS study will include 45.000 men age 65-74 years. 15.000 of the total DANCAVAS population will be randomly selected to CCTA (non-contrast calcium score), the resulting 30.000 constitutes the control group. The CCTA will be performed in four Danish cities. Our population will include those participants in the DANCAVAS study who will undergo CCTA in the city of Svendborg. In our study we will perform following examination in addition to those performed in the DANCAVAS study: one CCTA (contrast enhanced), one echocardiography and one OGTT.

Based on one fasting plasma glucose and one OGTT per participant, this population will be divided into three groups, one with normal glycemic status, one with dysglycemia (either IFG or IGT) and one with diabetic OGTT without known T2DM. In this study, we use the WHO guidelines, in dividing our population into mentioned groups. 

Criteria of inclusion and exclusion

Criteria of inclusion:

• 65-74 years old
• Capable of giving written informed consent

Criteria of exclusion:

• Body mass index (BMI) >35
• Atrial fibrillation and other tachyarrhythmia that unable CCTA analysis
• Estimates Glomerular filtration rate (eGFR) <45 ml/min
• Contrast allergy
• Critical illness with <5 years life expectancy
• Untreated hyperthyroid
• History of coronary artery disease (CAD) or apoplexy
• Known Diabetes Mellitus
• Symptoms of CAD

Data and biological material

• Oral Glucose Tolerance Test (OGTT)
  OGTT will be performed in the population within 1-6 weeks of the CCTA. The OGTT will be per-formed according to Danish and European guidelines. We will use the WHO´s definitions, in subdi-viding the participants in the mentioned groups of different glycemic status. 
• Echocardiography
  We will evaluate the echocardiography Standard measurements of left ventricular (LV) systolic function, LV diastolic function and 2D speckle-tracking measurements (global longitudinal stain). All measurements will be according to Danish and European guidelines. 
• Coronary CT-Angiography (CCTA)
  The Cardiac CT scanner, GE revolution, will be used. CAC score will be evaluated using unenhanced scans. Later contrast enhanced scans using 256-slice, ECG-gated, will be performed. The total radiation dose for one CCTA with contrast and one CCTA without contrast is 1-3 millisivert (mS). To reduce risk of contrast related affection of the kidney function a recent eGFR must be obtained before scanning and the patients will be sufficiently hydrated.
  All CTTA scans will be assessed by an observer blinded to patient characteristics. Dedicated software for CCTA analysis of coronary plaque burden and morphology will be used.  
• Population characteristics
  Baseline data will be collected from journal system and/or by questionnaires and includes demographic, former CVD disease, presence of dysglycemia, T2DM, hypertension, hypocho-lesteremia, smoking habits, medicine as well as paraclinical parameters including BMI, blood pressure and ankle/brachial index.
• Blood sample including HOMA-IR analysis
  Following will be analyzed; Total cholesterol, LDL, Triglycerides, HDL, Creatinine, Sodium, Potassi-um, HbA1c, Thrombocytes, Hs-CRP, Leucocytes, fasting Insulin, fasting C-peptide, fasting plasma glucose, Monocytes and Hemoglobin. HOMA-IR will be estimated according to Matthews et al.. Ad-ditionally, approximately 30 ml blood will be collected to form a biobank. The purpose of the biobank is future investigation of the influence of inflammatory markers on atherosclerosis and glycemic status. 

Collaborating researchers and departments

Cardiovascular Research Unit, Odense University Hospital, Svendborg

• Kenneth Egstrup, Professor, MD, DMSci
• Jess Lambechtsen, MD, PhD
• Søren Auscher, MD, PhD

Department of Endocrinology, Odense University Hospital, Svendborg

• Klaus Levin, MD, PhD

Department of Cardiology and Cardiovascular, Odense University Hospital

• Axel Diederichsen, MD, PhD 
• Jes S. Lindholt, PhD

Department for Cancer and Inflammation, Institute of Molecular Medicine, University of Southern Denmark, Odense

• Uffe Holmskov, Professor, MD., DMSc.i, PhD
• Grith Lykke Sørensen, associate professor, cand.scient, PhD