Myocardial perfusion imaging with PET-CT: let’s think global! 

This editorial refers to ‘Relationship between ischaemia, coronary artery calcium scores, and major adverse cardiovascular events’, by R. J.H. Miller et al., https://doi.org/10.1093/ehjci/jeac082.

Myocardial perfusion imaging (MPI) with positron emission tomography (PET) tracers is becoming more clinically accessible for the evaluation of patients with chronic coronary artery disease (CAD). PET-MPI offers high diagnostic performances for the identification of hemodynamically significant coronary stenosis.¹ In addition to the detection of segmental perfusion defects, the modelling of myocardial perfusion and tracer uptake during first-pass acquisitions allows for the quantification of myocardial blood flow (MBF) at rest and during pharmacological stress. The methodology used for the quantification of regional and global absolute MBF with PET has been extensively validated and is robust with consistent and comparable values among different centres across the World. The most commonly used metrics to evaluate the global perfusion of the left ventricle is myocardial flow reserve (MFR), which is calculated as the ratio between global absolute hyperaemic and rest MBF. Whilst a global MFR value >2.0 on PET-MPI excludes effectively high-risk CAD and confers a low risk of major adverse cardiovascular events (MACE) during follow-up,² MFR values <1.5 are associated with increased prevalence of high-risk anatomical forms of CAD and an elevated risk of MACE.³ In addition, most current PET systems have an integrated CT, which generates tissue attenuation maps for the correction of PET acquisitions, but may also be used to acquire EKG-gated CT acquisitions for coronary calcium arterial scoring (CACS). Hence, in patients with no established CAD, cardiac PET-MPI-CT protocols can offer to detect in a 30 min imaging session the presence and severity of segmental perfusion defects, measure global MFR, and estimate the extent of CAD with CACS.

In the interesting study of Miller et al.⁴ published in this issue of European Heart Journal Cardiovascular Imaging, the authors took advantage of the large clinical and imaging databases of the Cedars-Sinai Medical Centre of Los Angeles to analyze the outcome of patients with no established CAD imaged with PET-MPI and CACS as part of usual medical care. Patients who underwent coronary revascularization in the first 90 days after MPI-PET were excluded from primary analysis of the study. In the remaining 2507 patients, the incidence of MACE was collected retrospectively from their local healthcare database and national death registry. This study demonstrates nicely the complementary prognostic values of CACS and MPI-PET. In patients with high coronary calcification burden (CACS >400), the detection of segmental myocardial perfusion defects on PET-MPI was associated with a strong increase (two- to four-fold) of the incidence of MACE during follow-up suggesting an incremental value of perfusion imaging for risk stratification over coronary atherosclerotic burden in this group of patients. Furthermore, patients with low global MFR values (<1.5) showed an increased risk of MACE (two- to three-fold) underscoring the independent value of detecting a global decrease in myocardial perfusion for risk stratification. The reduction in MFR values observed with PET-MPI may be caused either by diffuse CAD, microvascular disease, or both. CACS provides a good estimate of the extent of CAD and may also help to refine the respective role of epicardial lesions and cardiac microvascular disease in the reduction of MFR detected with PET-MPI. Interestingly, the incremental prognostic value of low MFR was observed across all CACS values, even though the absolute rate of MACE was higher in patients with CACS >400, suggesting that both microvascular disease and diffuse CAD are associated with an increased incidence of MACE.

The results of Miller et al.⁴ underscore the need to further improve treatments given to the high-risk group of patients with low MFR and high CACS who had annualized event rates up to 18% in this study. A significant limitation of this study is its retrospective nature with the risk of bias or confounding factors related to differences in patient management or treatment based on the results of PET-MPI. Only approximatively 50% of patients were receiving aspirin, beta-blockers or statins at the time of PET-MPI. Patient treatments after PET-MPI and the association between drug intake and the incidence of MACE during follow-up were not collected and could thus not be accounted in the multivariable model. The ISCHEMIA trial evidenced that, in patients with segmental myocardial ischemia, coronary revascularization procedures improve patient’s symptoms, but do not significantly reduce MACE compared to optimal medical therapy.⁵ Most imaging techniques applied in the ISCHEMIA trial did, however, not include measurements of global MFR and may, thus, have underestimated the severity of balanced myocardial ischemia or microvascular disease in patients of the study. Interestingly, in a retrospective analysis of a large cohort of approximatively 13 000 patients imaged with PET-MPI, Patel et al.⁶ found that every 0.1 unit decrease in MFR was associated with a 9% greater hazard of all-cause death. In addition, patients with MFR <1.8 had a survival benefit with early revascularization, regardless of the type of revascularization chosen or the level of ischemia. In a smaller cohort of 329 patients referred for invasive coronary angiography after PET-MPI and followed for a median duration of 3.1 years,⁷ subjects with low MFR experienced event rates similar to those of subjects with high angiographic scores on invasive coronary angiography. Furthermore, among patients with low MFR, only patients who underwent coronary artery bypass grafting and not patients referred to percutaneous coronary intervention experienced event rates comparable with those with preserved MFR. Whilst the conclusions of these studies based on retrospective analysis of cohorts deserves to be interpreted with caution, they underscore the need for prospective clinical trials aimed at testing different treatment strategies in patients with low MFR with PET-MPI.

Since 40 years, SPECT-MPI has been an important tool to detect the presence of segmental myocardial ischemia caused by haemodynamically significant coronary stenosis but likely underestimated the presence and severity of balanced myocardial hypoperfusion. Owing to its capability to quantify precisely MBF, PET-MPI provides an opportunity to identify more accurately globally reduced myocardial perfusion. Future studies should help understand whether patients with low global MFR have an increased incidence of MACE because they are unrecognized and undertreated, or if they may benefit from more aggressive treatments of chronic CAD.

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Author notes