Assessment of coronary anatomy and flow for optimized diagnosis and prognostication in CAD

This editorial refers to ‘Warranty period of coronary computed tomography angiography and [15O]H2O positron emission tomography in symptomatic patients’, by R. Jukema et al., https://doi.org/10.1093/ehjci/jeac258. Positron emission tomography (PET)-determined myocardial perfusion and concurrently myocardial blood flow (MBF) in mL/g/min during pharmacologic stress and at rest with corresponding myocardial flow reserve (MFR) has emerged as a pivotal for the detection of haemodynamically obstructive coronary artery disease (CAD) and/or coronary microvascular dysfunction (CMD).1–3 While the assessment of the relative distribution of the left ventricular radiotracer uptake with PET reliably identifies down-stream and flow-limiting epicardial lesions, it may be less precise in the assessment and characterization of the ischaemia burden in multi-vessel, or it may even miss diffuse ischaemia due to significant flow-limiting left main and/or three-vessel CAD.4 Such limitation in the assessment of the overall ischaemic burden may be overcome by adding the concurrently measured regional and global MFR.5 While PET-determined regional perfusion deficit has been widely established as critical tool for prognostication of patients with suspected CAD, evaluating the concurrently measured global MFR adds further incremental information on future cardiovascular outcome.4–6 In the recent decade, contrast computed tomographic angiography (CTA) has emerged as a reliable clinical imaging tool to exclude obstructive CAD in symptomatic patients with low-to-intermediate probability for the presence of CAD, carrying important diagnostic and prognostic implications.7 For the time being, it remains uncertain whether PET perfusion-flow assessment following coronary CTA provides incremental prognostic information beyond coronary CTA. Jukema et al.8 report of an event-free (warranty) period in a large cohort of patients with suspicion for CAD over a median follow-up of 7 years. The main findings are three-fold: (i) standalone imaging with normal coronary CTA conferred a warranty period exceeding 10 years; (ii) coronary CTA with non-obstructive (or anatomically plaque burden with <50% narrowing) was associated with a warranty period of about 5 years; and (iii) normal MFR, as determined with 15O-water PET, had a two years longer warranty period than in patients with reduced MFR independent of coronary CTA results. The study included a large cohort of 2575 patients with suspicion for CAD undergoing coronary CTA and/or 15O-water PET. Patients were grouped according to results of coronary CTA as no CAD, non-obstructive CAD, or obstructive CAD. As regards 15O-water PET, hyperaemic MBF ≤2.3 mL/min/g defined for the presence of ischaemia. The warranty period was defined as the time for which the cumulative event-rate of death and non-fatal myocardial infarction was below 5%. As it was observed, of the 2575 included patients, 1319 (51.2%) underwent coronary CTA only, 48% (1237) sequential coronary CTA and 15O-water PET, and 0.74% (19) 15O-water PET only. During a median follow-up of 7 years, 163 deaths and 68 non-fatal myocardial infarctions occurred. The observation that normal coronary CTA mediated a warranty period beyond 10 years in principle is in line with previous investigations but of longer duration.7 At first sight, the latter observation may be surprising but is related to the definition of the warranty period with an event rate of less than 5%. Thus, there was still a minor event-rate of death and non-fatal myocardial infarction during the study period of ten years but minor. It is important to keep in mind that normal findings on coronary CTA may not identify endothelial dysfunction of the epicardial artery, in particular in patients with diabetes mellitus, which may be associated with increased endothelial thrombogenicity characterized by the activation of coagulation factors, platelet hyperactivity, and hypofibrinolysis.9 Early stages of the development of CAD may lead to plaque erosion that in conjunction with increased coronary endothelium endothelial thrombogenicity may lead adhesive thrombus formation with acute thrombotic occlusion of the epicardial artery causing an acute coronary syndrome with myocardial infarction, ventricular arrhythmia, and/or sudden cardiac death. Interestingly, when coronary CTA identified non-obstructive coronary plaque burden, then the warranty-period came down to 5 years as compared more than 10 years in those with completely normal coronary CTA. This may not be surprising as non-obstructive coronary plaque burden and, in particular, with further active progression may lead to plaque rupture with acute thrombotic occlusion with acute coronary syndrome and its cardiovascular sequelae.9 Of further interest, patients without CAD and normal hyperaemic MBF >2.3 mL/g/min (n = 126) had a longer warranty period than those patients with reduced hyperaemic MBF ≤2.3 mL/min/g (n = 23) suggestive of coronary microvascular dysfunction (warranty period ≥10 years vs. 8 years). In addition, patients with non-obstructive CAD and preserved hyperaemic MBF >2.3 mL/g/min (n = 269) presented a longer warranty period when compared to those patients with reduced hyperaemic MBF (n = 73) (7 years vs. 5 years). When looking at the patient group with obstructive CAD, normal hyperaemic MBF (n = 288) still conferred a warranty period of 3 years but only 1 year in those patients with reduced hyperaemic MBFs (n = 257). Thus, while the initiation and progression of CAD is paralleled by a progressive reduction in the warranty period, normal hyperaemic MBFs adds an addition 2 years warranty period in each category of coronary CTA findings. Such observations suggest hyperaemic MBF increases as a pivotal modulator of coronary vascular health. Hyperaemic coronary flow increases lead to a flow-mediated and thus endothelium-dependent vasodilation in upstream larger pre-arteriolar and epicardial arteries that contributes to about 20–25% to the overall hyperaemic flow increases.2,4 The flow-mediated release of nitric oxide from the endothelium into the sub-intimal and intimal space of the artery causing not only a relaxation of the vascular smooth muscle cells with a commensurate vasodilation but also mediating numerous athero-protective effects. It is important to keep in mind that reductions in hyperaemic MBF ≤2.3 mL/min/g may not necessarily related to obstructive CAD but may also origin from coronary microvascular dysfunction.4,10 In this respect, relative stress MBF can be calculated for each standard coronary territory using a territory with the highest mean absolute stress MBF as a reference region.11 For example, patients having at least on region with relative stress MBF <80% of the reference region defines a significant stress-flow heterogeneity signifying haemodynamically significant obstructive CAD. The disadvantage of a serial approach with contrast CTA and omission of 15O-water PET is the loss of information of the presence of coronary microvascular dysfunction as functional substrate for anginal symptoms.3 PET-determined coronary microvascular dysfunction does not only carry important diagnostic and prognostic information, but it is also amenable to treatment specific medical treatment to improve symptoms and potentially outcome.1 Taken together, the findings of Jukema et al.8 provide unique information of contrast CTA as standalone imaging modality to identify no evident CAD and non-obstructive CAD conferring a warranty period of more than 10 and 5 years, respectively. Independent of coronary anatomy, adding 15O-water PET to quantify stress MBF may further refine the prognostication in these patients. The current study may suggest serial application of contrast CTA and 15O-water PET for a comprehensive assessment of coronary anatomy and function as a unique pathway for individualized and image-guided cardiovascular treatment in patients with suspicion for CAD and/or coronary microvascular dysfunction. T.H.S. received Departmental fund from Washington University (No 12-3271-93128) in St. Louis, MO, USA; research grant support from GE Healthcare and the National Heart, Lung, and Blood Institute of the National Institutes of Health (grant 1R01HL142297-01A1). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. No new data were generated or analysed in support of this research (editorial).