In a cohort of symptomatic patients referred to coronary computed tomography angiography (CCTA), the investigators aim:

1. To investigate and compare the diagnostic precision of Rubidium Positron Emission Tomography (Rb PET) and 3 Tesla Cardiac Magnetic Resonance imaging (3T CMRI) in patients where CCTA does not exclude significant coronary artery disease (CAD) using invasive coronary angiography with fractional flow reserve (ICA-FFR) as reference standard.
2. To evaluate the diagnostic precision of quantitative flow ratio (QFR) and ICA-FFR in patients where CCTA does not exclude significant CAD using Rb PET and 3T CMRI as reference standard.
3. To show superiority for the CADScor®System compared to the Diamond-Forrester score in detection of CAD with CCTA and ICA quantitative coronary angiography (ICA-QCA) as reference standard.
4. To study the diagnostic accuracy of computed tomography fractional flow reserve (CT-FFR) in patients where CCTA does not exclude significant CAD with ICA-FFR as reference standard.
5. To identify and characterize genetic risk variants´ and circulating biomarkers´ importance in developing CAD.
6. To evaluate the bone mineral density in the hip and spine and correlate this to the degree of vascular calcification.

CCTA has become the preferred diagnostic modality for symptomatic patients with low to intermediate risk of CAD. Of the patients examined, CCTA exclude cardiovascular disease in 70-80% with an excellent negative predictive value of more than 95%. Having a low positive predictive value, however, CCTA often overestimates the severity of CAD, especially in patients with moderate to severe coronary calcification. Following CCTA, patients are hence unnecessarily tested using golden standard ICA-FFR. These ICAs often show no obstructive coronary stenosis and are therefore not followed by revascularization. The issues outlined raises the question of whether it is possible (1) to make a more precise risk stratification and consequently better selection of patients prior to CCTA and (2) to reduce the number of patients referred for unnecessary ICAs following CCTA.

In patients with suspicion of coronary stenosis detected by CCTA, current guidelines recommend verification of myocardial ischemia. In Dan-NICAD 2, we intend to investigate the diagnostic accuracy of advanced non-invasive myocardial perfusion imaging tests; Rb PET and 3T CMRI. These examinations have shown a high diagnostic accuracy in symptomatic patients with high risk of ischemic heart disease. However, the diagnostic accuracy is not investigated in patients as follow-up after CCTA.

An alternative way to increase the diagnostic accuracy of CCTA and thus avoid unnecessary downstream testing using ICA is to utilize the ability to extract physiological information from the anatomical CCTA images. CT-FFR has in previous studies shown promising results. CT-FFR has not been head to head compared against Rb PET and 3T CMRI.

Obtained during ICA, QFR is a novel wire-free approach for fast computation of FFR with potential to increase the global use of physiological lesion assessment. QFR is superior to traditional assessment of intermediate coronary lesions (ICA-QCA diameter stenosis). However, disagreement between FFR and QFR has been identified in up to 20% of all measurements.

Acoustic detections of coronary stenosis from automatically recorded and analyzed heart sounds is a newly developed technology potentially useful for pre-test risk stratification before e.g. CCTA. One of these devices, the CADScor®System, has previously shown an area under the receiver operating characteristic curve (AUC of ROC) of 70-80% compared to conventional ICA-QCA. This indicates that the CADScor®System could potentially supplement clinical assessment of CAD and be used for risk stratification prior to CCTA.

The investigators aim to obtain blood samples for biobank purposes and record heart sounds with the CADScor®System in 2000 patients that by clinical evaluation undergo CCTA. In approximately 400 patients (20%), CCTA does not exclude significant CAD. These patients are all examined using Rb PET, 3T CMRI, and ICA with QCA. In patients with a coronary diameter stenosis of 30-90% determined during the ICA examination, FFR, coronary flow reserve (CFR) and QFR is performed.

Inclusion Criteria:

• Patients with an indication for CCTA.
• Qualified patients who have signed a written informed consent form.

Exclusion Criteria:

CADScor specific

• Fragile or compromised skin in the area for application of the CADScor®Patch.
• Known allergy to polyacrylate adhesives.
• Significant operation scars or abnormal body shape in left IC4 (4th Inter Costal region).
• Use of vasodilating agents at the same day and prior to CAD-score measurements.

Demography and co-existing cardiac morbidity specific

• Age below 30 years.
• Patients having a donor heart, a mechanic heart, or mechanical heart pump.
• Suspicion acute coronary syndrome Previous revascularization.

Scan specific

CCTA:

• Pregnant women, including women who are potentially pregnant or lactating.
• Reduced kidney function, with an estimated glomerular filtration rate (eGFR) < 40 mL/min.
• Allergy to X-ray contrast medium.

CMRI and PET:

• Contra-indication for adenosine (severe asthma, advanced AV block, or critical aorta stenosis).
• Contra-indications for MRI (implanted medicinal pumps or nerve stimulators, magnetic foreign objects in sensitive areas, i.e. the eye).
• Patients having an ICD or pacemaker, a cochlea implant, or metal clips evaluated by the including doctor.

General:

- Patients not able to breath-hold (COPD/asthma).

Patients with an indication for CCTA.