Assessment of Coronary Artery Disease by Non-Invasive and Invasive Diagnostic Modalities

Non-invasive imaging by means of CCTA, SPECT, PET and CMR is central in diagnosing coronary artery disease (CAD). When obstructive CAD is suspected, patients may undergo invasive coronary angiography (ICA) with fractional flow reserve (FFR), the reference standard for significant epicardial CAD and the main benchmark in this thesis. The aim was to improve the diagnostic work-up of suspected CAD by evaluating non-invasive and invasive imaging against FFR and [15O]H2O PET, validating novel CMR- and CCTA-derived parameters, and assessing their prognostic value. Part I – Novel parameters and perfusion. In PACIFIC-1 substudies, [15O]H2O PET showed the highest accuracy for FFR-defined CAD. The CCTA-derived lumen volume-to-LV-mass ratio (V/M) correlated only weakly with FFR and PET. CMR-derived myocardial blood flow (MBF) showed only moderate correlation with PET and did not reflect PET values. CMR T1 mapping (ΔT1) diverged from PET perfusion and detected impaired perfusion poorly, failing to confirm earlier reports. Low-attenuation plaque (LAP) was independently associated with hyperaemic MBF and outperformed non-calcified plaque volume, whereas pericoronary adipose tissue attenuation (PCATa) was not. Sex differences in plaque burden were modest and largely disappeared in vessels with FFR-defined significant CAD. Part II – Diagnostic performance. PACIFIC-2 included patients with documented CAD and demonstrated accuracies of CMR (64%), SPECT (65%), and PET (75%) that did not differ significantly but were lower than in PACIFIC-1, driven by more false positive findings, questioning MPI's gatekeeping role for ICA. Quantitative flow ratio (QFR) correlated well with FFR and outperformed MPI in both cohorts (PACFIC-1 and 2) (accuracy 88% and 84%), though false positives rose in the PACIFIC-2 substudy. A machine-learning CCTA algorithm achieved an AUC of 0.92, comparable to FFRct. Image quality significantly affected CCTA and SPECT accuracy, but not quantitatively assessed PET. Part III – Effect of PCI. Residual QFR correlated moderately with post-PCI FFR, with low sensitivity but high specificity for suboptimal results, useful for procedural planning but not yet clinically ready. Right ventricular side-branch occlusion during CTO PCI of the RCA did not significantly reduce RV function at three months. Part IV – Prognostic value. Reduced global and regional hyperaemic MBF and MFR predicted death and non-fatal MI, with hMBF the only independent predictor. PET-derived ischemic burden thresholds (24% for hMBF, 28% for MFR) stratified risk, with hMBF burden remaining independently predictive. RCA PCATa added incremental prognostic value over established CCTA and PET parameters. Overall, CCTA-derived markers of atherosclerosis (obstructive CAD, high-risk plaque) outperformed PET-derived ischemia for prognosis. Future perspectives. [15O]H2O PET offers the highest diagnostic accuracy but remains limited by cyclotron dependence and lack of FDA approval, potentially addressed by mini-cyclotrons and the RAPID-WATER-FLOW trial. CMR perfusion is advancing but constrained by imperfect contrast kinetics. MPI's role may nonetheless diminish, given limited accuracy in prior CAD and the ISCHEMIA trial findings. CCTA is expanding rapidly: FFRct, quantitative plaque and inflammation analysis, AI/ML integration, and photon-counting CT are extending its use even to advanced CAD. CCTA is expected to become the preferred modality across patient profiles in the coming decades.