Objectives: To study the clinical impact of a very high coronary artery calcium score (CAC >1000) in patients with no known coronary artery disease (CAD) and normal single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The secondary aim was to evaluate whether triple vessel disease would support the notion of balanced ischemia as an underlying mechanism of false negative SPECT MPI in patients with very high CAC. Background: No clinical data exists on the

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... value of extensive CAC in patients with normal SPECT MPI. Methods: 50 patients with suspected CAD and normal stress/rest SPECT MPI and CAC >1000 prospectively underwent invasive coronary angiography as standard of reference. Coronary lesions with ≥50% luminal diameter narrowing on invasive coronary angiography were considered as significant stenosis. Results: The median total CAC was 1975 (range 1018-8046). In 37/50 (74%) patients coronary angiography revealed 1-vessel disease (VD) (n = 15), 2-VD (n = 10) or 3-VD (n = 12). Twenty-six revascularizations (percutaneous coronary intervention/ coronary artery bypass grafting) were performed in 7 (6/1), 7 (6/1) and 12 (7/5) patients with 1-VD, 2-VD and 3-VD, respectively. Conclusions: In patients with normal SPECT MPI a CAC >1000 confers a high diagnostic added value for detecting CAD. This is not solely based on unmasking balanced ischemia due to epicardial 3-VD as it occurred predominately in patients with 1-VD and 2-VD. Key Words: Coronary artery disease, Coronary calcium score, balanced ischemia, normal SPECT/MPI 3 Word count: 225 4 Abbreviations CAD = coronary artery disease CAC = coronary artery calcium score CT = computed tomography ECG = electrocardiogram LVEF = left ventricular ejection fraction MPI = myocardial perfusion imaging PET= positron emission tomography SPECT = single photon emission computed tomography SSS = summed stress score TID = transient ischemic dilation VD = vessel disease