Original Article
Interaction of impaired myocardial flow reserve and extent of myocardial ischemia assessed using 13N-ammonia positron emission tomography imaging on adverse cardiovascular outcomes

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Abstract

Background

Myocardial flow reserve (MFR) and the extent of myocardial ischemia identify patients at high risk of major adverse cardiovascular events (MACEs). Associations between positron emission tomography (PET)-assessed extent of ischemia, MFR, and MACEs is unclear.

Method

Overall, 640 consecutive patients with suspected or known coronary artery disease undergoing 13N-ammonia myocardial perfusion PET were followed-up for MACEs. Patients were categorized into three groups based on myocardial ischemia severity: Group I (n = 335), minimal (myocardial ischemia < 5%); Group II (n = 150), mild (5–10%); and Group III (n = 155), moderate-to-severe (> 10%).

Results

Cardiovascular death and MACEs occurred in 17 (3%) and 93 (15%) patients, respectively. Following statistical adjustment for confounding factors, impaired MFR (global MFR < 2.0) was revealed as an independent predictor of MACEs in Groups I (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.48–5.64; P = 0.002) and II (HR, 3.40; 95% CI 1.37–8.41; P = 0.008) but was not significant in Group III (HR, 1.15; 95% CI 0.59–2.26; P = 0.67), with a significant interaction (P < 0.0001) between the extent of myocardial ischemia and MFR.

Conclusion

Impaired MFR was significantly associated with increased risk of MACEs in patients with ≤ 10% myocardial ischemia but not with those having > 10% ischemia, allowing a clinically effective risk stratification.

Introduction

The diagnostic and prognostic benefits of myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are important. The magnitude of ischemia on SPECT-MPI scans could be a gatekeeper to identify ideal revascularization candidates with improved long-term major adverse cardiac event (MACE) outcomes.1 Patients with 10–12.5% myocardial ischemia may have a survival benefit with early revascularization.1,2 The diagnostic accuracy of MPI using 82Rb- or 13N-ammonia PET appears to be superior to that of SPECT-MPI, although its disadvantages include lower patient access, higher costs, and technical/logistical difficulties related to radiotracer use.3 Reportedly, patients with higher PET-MPI-measured ischemia levels had a greater survival benefit from early revascularization with a potential ischemia threshold of 5%, lower than that for SPECT-MPI.4 Thus, PET-MPI allows accurate obstructive coronary artery disease (CAD) detection, myocardial ischemia assessment, and discrimination between low- and high-risk patients for MACEs, helping to identify ideal revascularization candidates with improved long-term cardiovascular outcomes.5

PET can provide quantitative myocardial perfusion measurement, offering information on macro- and microcirculation, leading to more accurate detection of early and advanced CAD. Quantitative myocardial flow reserve (MFR), calculated as the ratio of hyperemic to resting myocardial blood flow (MBF), integrates the hemodynamic effects of epicardial coronary stenosis, diffuse atherosclerosis, and microvascular dysfunction, contributing to risk estimation for future MACEs.6,7 Moreover, the combined MFR and myocardial ischemia measurements could identify at-risk patients.8 However, the relationships among PET-assessed extent of myocardial ischemia, MFR, and MACEs are unknown. MFR is associated with MACEs independently of angiographic score and modifies the effect of revascularization with an interaction between myocardial ischemia and early revascularization.4,9 Therefore, we investigated the clinical impact of impaired MFR in predicting future MACEs when combined with the extent of myocardial ischemia, assessed using 13N-ammonia PET-MPI, considering the effect of early revascularization. We examined the annualized MACE rates for each ischemia level and the prognostic value of MFR over the semi-quantitative assessment of myocardial ischemia.

Section snippets

Study population

Myocardial perfusion and MFR were assessed in 675 consecutively admitted patients with suspected or known CAD from January 2017 to April 2021 at our institution (Figure 1). Patients with cardiomyopathy (n = 26), severe valvular disease (n = 3), and congenital heart disease (n = 6) were excluded. The remaining 640 patients were categorized into three groups based on the extent of total myocardial ischemia indicated by the summed difference score (SDS) assigned segmentally by software: Group I (n

Patient and imaging characteristics

Baseline and PET imaging characteristics for Groups I-III are presented in Tables 1 and 2. Overall, the patients were predominantly male (n = 451, 71%), with a median age of 72 years; 17% had a history of MI, and early revascularization was performed in 33%. The incidence of early revascularization was 18%, 35%, and 63% in Groups I-III, respectively (P < 0.001). There was a higher proportion of males (P = 0.002), pretest CAD probability scores (P < 0.001), and incidence of previous MI (P <

Discussion

This study is the first to demonstrate the added and independent prognostic value of MFRimpaired and the differential effect of MFRimpaired based on the myocardial ischemia level assessed by PET-MPI. In Groups I and II, MFRimpaired allowed for further risk stratification (high and low) for MACEs. Conversely, MFRimpaired was not associated with reduced event-free survival for MACEs in Group III. These results remained unchanged when adjusted for prognostic scores instead of pretest CAD

New knowledge gained

Our study clarified an interaction between myocardial ischemia severity and PET-measured MFR to predict future MACEs in patients with suspected or known CAD. A similar interaction was observed for hard events, highlighting the robustness of the association. Quantitation with MFR had significant prognostic power in addition to semi-quantitative findings and pretest CAD probability scores. Accordingly, our study provided evidence to support the combination of myocardial ischemia and global MFR

Conclusions

MFRimpaired was independently associated with a higher MACE risk in patients with ≤ 10% myocardial ischemia but not in those with > 10% myocardial ischemia. The robustness of this result was supported by the similar association observed after statistically adjusting for prognostic scores instead of pretest CAD probability scores or after replacing MACEs with hard events with first revascularization after PET as a time-dependent variable. Our findings depict the significance of risk

Disclosures

Shiro Miura, Atsutaka Okizaki, Hiraku Kumamaru, Osamu Manabe, Masanao Naya, Chihoko Miyazaki, and Takehiro Yamashita have no conflicts of interest to declare.

Funding

None.

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