Cardiovascular Molecular Calcification Assessed by 18F-NaF PET CT

Study Overview
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Brief Summary
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The purpose of the CAMONA study is to demonstrate the feasibility of cardiovascular molecular calcification (CMC) assessment by means of 18F-sodium-fluoride (18F-NaF) positron emission tomography (PET) computed tomography (CT) in a prospective cohort of healthy control subjects and subjects with cardiovascular disease.

Detailed Description
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Atherosclerosis associated cardiovascular disease (CVD) remains a significant cause of morbidity and mortality. Asymptomatic individuals with a moderate to high-risk of developing acute atherosclerotic cardiovascular events will benefit most from intensive evidence-based medical interventions. The traditional approach to identify patients with moderate to high-risk of CVD involves quantifying the presence of CVD risk factors. Based on gender, age, smoking, systolic blood pressure and cholesterol levels, risk stratification algorithms such as the Framingham Risk Score (FRS) and the European SCORE system can predict the 10-year risk of cardiovascular death. However, these algorithms are associated with several limitations, including misclassification of women and individuals with high levels of a single risk factor. The risk is underestimated in these individuals. Therefore, these individuals are not eligible for treatment by current criteria of CVD prevention guidelines. Several studies indicate that the traditional risk score models leave room for improvement, as they work reasonably well for populations, but remain suboptimal for individual subjects. New risk parameters are discovered on a regular basis. One of these parameters is cardiovascular molecular calcification (CMC). This entity can be detected and quantified by 18F-NaF PET CT. It has been hypothesized that CMC can be detected years, maybe even decades, before coronary artery calcium scoring (CACS) can be detected by conventional imaging modalities like multislice CT. Theoretically, this tool can detect patients at a very early stage of the disease. Providing evidence-based treatment to these individuals can, theoretically, improve the prevention of CVD. Before this hypothesises can be tested, the feasibility of 18F-NaF PET CT has to be demonstrated in both healthy controls as well as in subjects with cardiovascular disease.

Official Title
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Cardiovascular Molecular Calcification Assessed by 18F-NaF PET CT: The CAMONA Study

Conditions
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Cardiovascular Disease, Atherosclerosis, Angina Pectoris

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 21 - 80 years Healthy controls: No prior history or symptoms of cardiovascular disease Cardiology subjects: Eligibility for CACS due to symptoms suggesting angina pectoris. Cardiology subjects: HeartSCORE > 0%. Exclusion Criteria: Pregnancy Extensive physical activity or extensive partying passed 24 hours History of malignant neoplasms with past 5 years Known immunodeficiencies History of deep vein thrombosis or acute pulmonary embolism within the previous three months History of alcohol abuses, illicit drug use, or drug abuse, or significant mental illness Initiation of statin-therapy within 3 months prior to consideration of study enrolment History of autoimmune disease, such as systemic lupus erythematosus, inflammatory bowel disease, sarcoidosis, rheumatoid arthritis, or psoriasis. Participation in any clinical trial of an investigational drug, device, or medical procedure within 30 days prior to baseline of the study Enrolment or planned enrolment in another clinical trial during the study period

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy control subjects<br>Age: 21 - 80 years No prior history or symptoms of cardiovascular disease The investigators aim to include equal numbers of females and males. Furthermore, the investigators aim to include patients in six different age strata: 21-30, 31-40, 41-50, 51-60, 61-70, 71-80. | |
| Subjects with cardiovascular disease<br>Age: 21 - 80 years HeartSCORE > 0% Symptoms of angina pectoris The investigators aim to include equal numbers of females and males. Furthermore, the investigators aim to include patients in six different age strata: 21-30, 31-40, 41-50, 51-60, 61-70, 71-80. Also, the investigators aim to include patients in 3 strata of HeartSCORE risk: low risk (1-4%), mild risk (5-9%) and high risk (> 9%) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standardized uptake value (SUV) of 18F-NaF | The SUV is a validated semi-quantitative assessment of PET radiotracer uptake. The SUV of 18F-NaF will be determined in the aorta, carotid arteries, coronary arteries, iliac arteries and the femoral arteries. | Up to 7 days after the day of PET CT acquisition | 
| Target to background ratio (TBR) of 18F-NaF | The TBR is a validated semi-quantitative assessment of PET radiotracer uptake. The TBR of 18F-NaF will be determined in the aorta, carotid arteries, coronary arteries, iliac arteries and the femoral arteries. | Up to 7 days after the day of PET CT acquisition | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standardized uptake value (SUV) of 18F-Fluorodeoxyglucose (18F-FDG) | The SUV is a validated semi-quantitative assessment of PET radiotracer uptake. The SUV of 18F-FDG will be determined in the aorta, carotid arteries, iliac arteries and the femoral arteries. | Up to 7 days after the day of PET CT acquisition | 
| Target to background ratio (TBR) of 18F-FDG | The TBR is a validated semi-quantitative assessment of PET radiotracer uptake. The TBR of 18F-FDG will be determined in the aorta, carotid arteries, iliac arteries and the femoral arteries. | Up to 7 days after the day of PET CT acquisition | 
| Correlation between the TBR of 18F-NaF/18F-FDG and traditional cardiovascular risk factors. | The traditional cardiovascular risk factors consist of: Smoking, pack years; Alcohol, units/week; Blood pressure, mean arterial pressure, mmHg; Body mass index, kg/m2; Waist circumference, cm; History of cardiovascular disease; Family history of cardiovascular disease; Medication usage; Age; Gender. | The cardiovascular risk factors will be determined, on average, 1 hour before 18F-NaF / 18F-FDG injection; which ever comes first | 
| Correlation between the TBR of 18F-NaF/18F-FDG and blood markers of atherosclerosis. | Blood markers: Total cholesterol, mmol/L; LDL cholesterol, mmol/L; HDL cholesterol, mmol/L; Triglycerides, mmol/L; Homocysteine, mmol/L; Fasting plasma glucose, mmol/L; HBA1c, mmol/mol; High sensitivity C-reactive protein, nmol/L; Fibrinogen, umol/L; Leukocyte differentiation, cells/L; Creatinine, umol/L; | The blood draw will be performed, on average, 1 hour before the 18F-FDG PET CT scan and the blood markers will determined in upto 48 hours after the 18F-FDG PET CT scan | 
| Correlations between 18F-NaF TBR, 18F-FDG TBR, and CT calcification scoring | Correlation between the degree of 18F-NaF uptake, 18F-FDG uptake, CT-Calcification scoring and the various arterial segments (aorta, carotid arteries, iliac arteries and the femoral arteries. | Up to 7 days after the day of PET CT acquisition | 
| Target to background ratio (TBR) of 18F-NaF | 18F-NaF PET/CT images will be acquired at 45, 90 and 180 minutes after intravenous injection of the compound in a subset of 40 patients. The TBR of 18F-NaF will be determined at each time point and compared to allow determining the optimum tracer circulation time for maximum contrast between the vessel wall and blood pool. | Up to 7 days after the day of PET CT acquisition | 
| Target to background ratio (TBR) of 18F-FDG | 18F-FDG PET/CT images will be acquired at 90 and 180 minutes after intravenous injection of the compound in a subset of 40 patients. The TBR of 18F-NaF will be determined at both time points and compared to allow determining the optimum tracer circulation time for maximum contrast between the vessel wall and blood pool. | Up to 7 days after the day of PET CT acquisition | 
| Correlation between 18F-NaF / 18F-FDG uptake and 18F-FDG uptake in the brain | 18F-FDG uptake in the brain will be quantified by calculating the mean and maximum partial-volume corrected SUV. | Up to 7 days after the day of PET CT acquisition | 
| Correlation between 18F-NaF TBR and 18F-NaF TBR two years after the baseline scan. | The TBR will be determined in various segments of the arterial tree. | 2 years | 
| Correlation between 18F-FDG TBR and 18F-FDG TBR two years after the baseline scan. | The TBR will be determined in various segments of the arterial tree. | 2 years | 
| Correlation between the TBR of 18F-NaF/18F-FDG and HeartSCORE | The HeartSCORE will be calculated according to the current HeartSCORE protocol for Denmark. | Up to 7 days after the day of PET CT acquisition | 
| Correlation between the TBR of 18F-NaF/18F-FDG and Framingham Risk Score | The Framingham Risk Score will be calculated according to the current recommendations by the Framingham Heart Study group | Up to 7 days after the day of PET CT acquisition | 
| Correlation between 18F-NaF / 18F-FDG uptake and 18F-NaF / 18F-FDG uptake in the vertebral body | 18F-NaF uptake in the 1st, 3rd and 5th lumbar vertebral body will be quantified by calculating the mean and maximum partial-volume corrected SUV. | Up to 7 days after the day of PET CT acquisition | 
| Arterial Calcification Score | Arterial Calcification Scoring will be determined in Agatston Units as well as in volumetric units in all segments of the arterial tree (coronary arteries, aorta, carotid arteries, iliac and femoral arteries. | Up to 7 days after the day of PET CT acquisition | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atherosclerosis, Sodium-Fluoride, 18F-Sodium Fluoride, 18F-NaF, fluorodeoxyglucose, 18F-FDG, FDG, Positron emission tomography, PET