A large number of cardiac catheterizations are performed each year, primarily to diagnose heart disease. However, a cardiac catheterization is an invasive procedure which is associated with serious complications such as heart infarction, stroke, and death. Therefore, there is a need for non-invasive procedures to diagnose coronary heart disease. The purpose of this study is, therefore, to assess the diagnostic accuracy of non-invasive cardiac imaging modalities for the detection of heart disease in patients presenting for the first time to the cardiologist with chest pain.

Coronary artery disease (CAD) remains the leading cause of morbidity and mortality in Western civilized countries. Early detection of CAD allows optimal therapeutic management in order to decrease morbidity and mortality. In the Netherlands 80,000 invasive coronary angiographies are performed each year. Invasive coronary angiography (ICA), particularly in conjunction with fractional flow reserve (FFR) measurements, is considered the gold standard in diagnosing and evaluating the severity of CAD in the current era. FFR measurements during ICA are useful in determining whether a coronary stenosis is functionally important. An FFR < 0.80 is considered abnormal, reflecting a hemodynamic significant coronary stenosis. ICA has superior spatial and temporal resolution compared with non-invasive imaging techniques. However, ICA is an invasive procedure which is associated with a low, though significant, complication rate including bleeding, coronary artery dissections, cerebral embolism, cardiac arrhythmias, myocardial infarction and death. Moreover, ICA provides only limited information on the presence of atherosclerotic plaques not associated with luminal stenosis. Furthermore, conventional catheter angiography without the advent of FFR measurements, is not able to provide information about the hemodynamic significance of a significant luminal stenosis (≥ 70%), i.e. whether a coronary artery stenosis is leading to myocardial perfusion abnormalities. Therefore, there is a need for non-invasive imaging techniques for diagnosing and evaluating the hemodynamic significance of CAD. Non-invasive techniques can serve as a gatekeeper for invasive coronary angiographies in order to decrease the number of purely diagnostic invasive angiographies and associated morbidity and mortality. The detection and management of cardiovascular disease increasingly utilize non-invasive cardiac imaging in patients with suspected or known CAD. By more accurately identifying patients who are eligible for coronary revascularization with the use of non-invasive cardiac imaging, the number of unnecessary invasive diagnostic coronary angiographies can be decreased.

Study design

Positron emission tomography:

PET images will be acquired using a Gemini Time-of-Flight (TF) 64 scanner (Philips Healthcare, Best, The Netherlands). Quantitative myocardial perfusion at rest and during hyperemia in ml -1. min -1. g -1 of myocardial tissue will be measured using oxygen-15-labelled water (H215O). Pharmacological stress is induced by infusion of adenosine intravenously at a rate of 140 µg/kg/min. Two minutes after the start of adenosine vasodilation reaches a steady state and H215O will be given intravenously as a bolus followed with the start of a 6-minutes emission scan. Directly after the PET sequence, a low dose CT attenuation scan (CTAC) is acquired after which the infusion of adenosine is terminated. Technetium-99m sestamibi is injected intravenously after the second CTAC scan. A stress SPECT-scan is performed 45 minutes after the stress PET scan.

Single photon emission computed tomography:

SPECT imaging will be performed according to standard clinical protocols for myocardial perfusion imaging. All patients will undergo SPECT-imaging(Symbia T2, Siemens, The Hague, The Netherlands) on a during hyperaemia induced by infusion of adenosine at a rate of 140mcg/kg/min, using a dose of 400 megabecquerel (MBq) of Technetium (99mTc) tetrofosmin. Tetrofosmin will be administered during adenosine induced stress during the time of the PET stress perfusion scan. Directly after the stress SPECT-sequence, a low dose CT-attenuation scan (CTAC) will be performed. A SPECT- rest imaging scan will be performed 72 hours after the stress SPECT scan on the day of the catheterization.

Computed tomography:

Patients will undergo a coronary calcium score (CTCAC) and CT coronary angiography scan on a 256-slice CT scanner (Philips Brilliance iCT, Philips Healthcare, Best, the Netherlands). Prospective ECG-gating (Step & Shoot Cardiac, Philips Healthcare, Best, The Netherlands) at 75 % of the R-R interval will be performed in order to minimize radiation burden.

Invasive coronary angiography:

ICA will be performed via a transfemoral of transradial approach according to the standard procedure. Iodized contrast will be given intracoronary during the procedure to evaluate the coronary artery lumen. The operator and an interventional cardiologist blinded to the findings obtained with non-invasive imaging will evaluate the ICA images. ICA imaging will be performed with a biplane or monoplane cardiovascular X-ray system (Allura Xper FD 10/10, Philips Healthcare, Best, The Netherlands) in at least two orthogonal directions. After primary coronary angiography, FFR will be measured in all coronary arteries, using a 0.014-inch sensor tipped guide wire. A stenosis with a FFR < 0.80 will be considered as a hemodynamic significant stenosis. Clinical decision making will be based on the findings obtained with ICA and FFR measurements and will be made by the interventional cardiologist.

Inclusion Criteria:

• First presentation to cardiologist with suspected coronary artery disease
• No documented prior history of coronary artery disease
• Intermediate pre-test likelihood for coronary artery disease as defined by Diamond and Forrester criteria
• Clinically referred for invasive coronary angiography
• Age above 40 years

Exclusion Criteria:

• History of severe chronic obstructive pulmonary disease (COPD) or chronic asthma
• Pregnancy
• Renal failure ( i.e. estimated glomerular filtration rate < 45 mL/min)
• Use of sildenafil (Viagra) or dipyridamole (Persantin) that can not be terminated.
• Contra-indications for β-blockers
• Allergic reaction to iodized contrast
• Concurrent or prior (within last 30 days) participation in other research studies using investigational drugs
• Claustrophobia
• Significant co-morbidities
• Atrial fibrillation, second or third degree atrioventricular block
• Tachycardia
• Acute myocardial infarction
• Heart failure
• Left ventricle ejection fraction estimated < 50%
• Cardiomyopathies
• Previous radiation exposure in the diagnostic work-up
• Subjects intended for short-term medical treatment or an invasive coronary intervention
• No informed consent

Outpatient clinic of the VU University Medical Center hospital in Amsterdam.