Stress Myocardial Perfusion Imaging Interpretation From the Viewpoint of Fractional Flow Reserve

Abstract

Background: Myocardial perfusion imaging (MPI) and fractional flow reserve (FFR) are established approaches to the assessment of myocardial ischemia. Recently, various FFR cutoff values were proposed, but the diagnostic accuracy of MPI in identifying positive FFR using various cutoff values is not well established.

Methods and Results: We retrospectively studied 273 patients who underwent stress MPI and FFR within a 3-month period. Results for FFR were obtained from 218 left anterior descending artery (LAD) lesions and 207 non-LAD lesions. Stress MPI and FFR demonstrated a good correlation in the detection of myocardial ischemia. However, the positive predictive value (PPV) of FFR for detecting MPI-positive lesions at the optimal FFR thresholds was insufficient (44% for LAD and 65% for non-LAD lesions). This was caused by a sharp drop in PPV at an FFR threshold of 0.7 or more. Notably, 41% of the lesions with normal MPI demonstrated FFRs <0.80. However, MPI-negative lesions had an extremely low lesion rate with FFR <0.65 (6%). Conversely, 78% and 41% of MPI-positive lesions had FFR <0.80 and <0.65, respectively.

Conclusions: The data confirmed that decisions based on MPI are reasonable because MPI-negative patients have an extremely low rate of lesions with a FFR below the cutoff point for a hard event, and MPI-positive lesions include many lesions with FFR <0.65.

Traditionally, stress myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is proposed for evaluating the need for revascularization of coronary stenosis.^1–4 It is well established that normal stress MPI is associated with a low risk of hard cardiac events and reflects a good prognosis. Therefore, patients with normal stress MPI do not require revascularization, even if invasive coronary angiography (CAG) reveals severe stenosis.

Editorial p 2050

Recently, fractional flow reserve (FFR) has become an important tool for choosing between revascularization and medical treatment alone for coronary stenosis.^5–8 Recent randomized trials have clearly demonstrated the obvious clinical benefits of percutaneous coronary intervention (PCI) for coronary lesions with abnormal FFR. However, we sometimes encounter patients with positive FFR but normal MPI and find it difficult to decide on the course of treatment in such cases.

This study retrospectively analyzed stress MPI from the viewpoint of FFR using a cadmium-zinc-telluride (CZT) camera (D-SPECT). Additionally, we assessed the clinical usefulness of FFR and stress MPI.

Methods

Patients

We retrospectively studied 273 consecutive patients who underwent both stress MPI using a CZT camera and FFR within a 3-month period between October 2016 and May 2018. The exclusion criteria for analysis were as follows: history of coronary artery bypass grafting (CABG), recent history of acute myocardial infarction (AMI) or unstable angina pectoris (UAP) within 1 month prior to the SPECT study, and recent history of PCI within 1 month prior to the SPECT study. Informed consent was given by all the patients, and the study was approved by the institutional ethics committee (no. 2020003).

Myocardial Perfusion Imaging

Stress Protocol The patients were instructed to abstain from any products containing caffeine for 12 h before the test. In addition, β-blockers, calcium-channel antagonists, and nitrates were terminated for at least 12 h before the test. Stress testing was performed using adenosine (140 μg/kg/min) for 6 min, and when possible, low-level adjunctive ergometer exercise was performed during the adenosine infusion.⁹

Simultaneous Acquisition of Rest ^{99 m}Tc-Tetrofosmin/Stress ²⁰¹Tl Dual-Isotope Protocol

This protocol, which was originally reported in 2016, shows better diagnostic ability than the standard rest-stress ^{99 m}Tc-tetrofosmin protocol with a short examination time.^10,11

The patients were first injected with 259±45 MBq of ^{99 m}Tc-tetrofosmin, and then underwent an adenosine stress test with an injection of 74±3 MBq ²⁰¹Tl (Nihon Medi-Physics, Tokyo, Japan) 3 min after initiating the adenosine infusion. The first simultaneous acquisition was performed on completion of the adenosine stress test. The second simultaneous acquisition was started 1 h after the first. The patients were advised to ingest food during both acquisitions (Figure 1A).^10,11 The first acquisition image was mainly used for interpretation, but if it was poor due to extracardiac uptake, the second acquisition image was used to assist interpretation.

Figure 1.

(A) Stress protocol. MPS, myocardial perfusion single-photon emission computed tomography; SDI protocol, simultaneous acquisition of ^{99 m}Tc-tetrofosmin/stress ²⁰¹Tl dual-isotope protocol. (B) Left ventricular segmentation bull’s-eye plots for the 17 segments and coronary artery territories.

Acquisition Protocol and Image Reconstruction Data were acquired in the list mode using the CZT camera (D-SPECT; Spectrum Dynamics Medical, Caesarea, Israel), which is operated with 9 mobile blocks of pixelated CZT detectors associated with a wide-angle, square-hole, tungsten collimator. Each block recorded a total of 120 projections via a region-centric acquisition that maximizes counts emanating from the areas of the heart, which were previously defined on a short pre-scan acquisition.^12–14 The selected photopeak windows of ^{99 m}Tc and ²⁰¹Tl were as follows: 130–150 keV for ^{99 m}Tc, and 64–77 keV and 157.4–177.4 keV for ²⁰¹Tl.¹⁵ Scatter correction via the iterative deconvolution method was applied to the ²⁰¹Tl images. The images were acquired by setting the scan time to obtain at least a 1-mega left ventricular (LV) count of ²⁰¹Tl after scattering correction.

Image Interpretation The SPECT images were semiquantitatively scored by 2 experienced physicians (I.K. and H.M.). The LV wall was divided into 17 segments according to the American Heart Association consensus, and a semiquantitative scoring system in each of the segments was used and scored on a 5-point scale (0, normal uptake; 1, mildly reduced uptake; 2, moderately reduced uptake; 3, severely reduced uptake; and 4, almost no uptake).^16,17 The combined scores of all 17 segments in the stress and rest images provided the summed stress score (SSS) and summed rest score (SRS), respectively. The summed difference score (SDS) was defined as the difference between the SSS and SRS.¹⁸ In this model, the left anterior descending artery (LAD) distribution territory consists of 7 segments (i.e., segments 1, 2, 7, 8, 13, 14, and 17); the left circumflex artery (LCx) consists of 5 segments (5, 6, 11, 12, and 16); and the right coronary artery (RCA) consists of 5 segments (3, 4, 9, 10, and 15) (Figure 1B). The MPI findings were considered positive in the relevant coronary territory when the SDS in each territory was ≥2.¹⁹

CAG and FFR Procedure

The patients were instructed to abstain from any products containing caffeine for 12 h before undergoing angiography. CAG and pressure wire assessments of coronary stenoses were performed using conventional approaches.

Intracoronary nitrate (300 μg) was administered to all patients before the pressure wires were introduced. Equalization of the pressure wires was performed 1–2 mm distal to the guiding catheter. Correct equalization was confirmed during a 20-s acquisition period. After equalization, the wire was passed through the stenosed area and positioned at least 20 mm distal to the target lesion. The distal position of the pressure wire was documented on angiography. The FFR measurements were performed using an intracoronary injection of nicorandil (2 mg) or 12 mg of papaverine for the left coronary artery, 8 mg of papaverine for the RCA, or intravenous ATP (180 μg·min⁻¹·kg⁻¹) infusion for 3 min.^20,21 Two different thresholds were set up: 0.80 for a well-recognized cutoff for the indication of revascularization and 0.65 for the cutoff for preventing a hard endpoint by revascularization.

Statistical Analysis

Patient characteristics were summarized as the mean±standard deviation for continuous variables, and frequencies and proportions for categorical variables. The differences in the distribution of continuous and categorical variables between groups were compared using Student’s t-test. Receiver-operating characteristic (ROC) curve analysis was performed to evaluate the discriminative value of FFR for the presence of reversible perfusion defects based on the area under the curve (AUC). A two-sided P value <0.05 was considered statistically significant, and all statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).

Results

Patient Characteristics

Of the 283 patients enrolled, 10 were excluded because of a history of CABG or a recent history of AMI, UAP, or PCI. The remaining 273 patients were analyzed (mean age 72.0±9.6 years; 76% male; 79% had hypertension; 70% had dyslipidemia; 40% had diabetes mellitus) (Table 1).

Table 1. Patients’ Characteristics

n	273
Age (years)	72.0±9.6
Male	207 (76%)
Body mass index	24.5±3.5
Hypertension	216 (79%)
Dyslipidemia	192 (70%)
Diabetes	108 (40%)
Current smoking	52 (19%)
Chronic kidney disease	53 (19%)
Prior AMI	56 (21%)
Prior PCI	122 (45%)
Atrial fibrillation	12 (4%)
CLBBB	7 (3%)
β-blocker	65 (24%)
Nitrates	62 (23%)
Calcium-channel blocker	135 (49%)
ACEI/ARB	34 (12%)
Statin	167 (61%)
Aspirin	188 (65%)

ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin II receptor blocker; CLBBB, complete left bundle branch block; PCI, percutaneous coronary intervention.

The FFR results were obtained from 218 LAD lesions (mean 0.76±0.11) and 207 non-LAD lesions (mean 0.81±0.14), including 106 for LCx (mean 0.83±0.14) and 101 for RCA lesions (mean 0.80±0.14). The FFR with a positive MPI demonstrated a significantly lower value than that with a negative MPI for both LAD (mean 0.65±0.14 vs. 0.78±0.08, P<0.001), and non-LAD lesions (mean 0.72±0.16 vs. 0.85±0.11, P<0.001) and for all vessels (mean 0.69±0.15 vs. 0.81±0.10, P<0.001) (Table 2).

Table 2. Lesion Characteristics

	MPI negative	MPI positive	All
FFR value (mean±SD)
LAD	0.78±0.08 (n=175)	0.65±0.14* (n=43)	0.76±0.11 (n=218)
Non-LAD	0.85±0.11 (n=148)	0.72±0.16* (n=59)	0.81±0.14 (n=207)
All	0.81±0.10 (n=323)	0.69±0.15* (n=102)	0.78±0.13 (n=425)
Lesion severity with FFR measurement (≥90% / 75% / 50% / <50%) (n(%))
LAD	35 (16) / 98 (45) / 69 (32) / 16 (7)
Non-LAD	66 (32) / 91 (44) / 48 (23) / 2 (1)
All	101 (24) / 189 (44) / 117 (28) / 18 (4)

*P<0.001. FFR, fractional flow reserve; LAD, left anterior descending coronary artery; SD, standard deviation.

Regarding lesion severity with FFR measurement, 16% of the LAD lesions had >90% stenosis, 45% had 75% stenosis, and 39% had ≤50% stenosis. In contrast, for non-LAD lesions 32% had >90% stenosis, 44% had 75% stenosis, and 24% had ≤50% stenosis.

Figure 2 is a scatter plot of the FFR values in negative and positive MPI lesions, both of which showed a wide scatter of FFR values.

Figure 2.

Dot plot of FFR from stress MPI results. FFR, fractional flow reserve; LAD, left anterior descending coronary artery; MPI, myocardial perfusion imaging.

In terms of the difference between negative and positive MPI findings, the MPI-positive lesions had physiologically severe lesions.

Diagnostic Performance of Stress MPI in Detecting Positive FFR

The optimal FFR thresholds required from the ROC curves of FFR defining MPI-positive lesions were 0.755, 0.795, and 0.765 for LAD, non-LAD, and all vessel analyses, respectively (Supplementary Figure).

The respective sensitivity and specificity at these threshold values were sufficient: 82% and 71% for LAD, 78% and 83% for non-LAD, and 74% and 78% for all vessel analyses. However, the PPV at these threshold values was insufficient: 44% for LAD, 63% for non-LAD, and 51% for all vessel analyses. This was caused by a sharp drop in PPV at the FFR threshold of ≥0.7 for both LAD and non-LAD lesions (Figure 3).

Figure 3.

Relationship between sensitivity, specificity, PPV, and NPV regarding FFR threshold. AUC, area under the curve; FFR, fractional flow reserve; LAD, left anterior descending coronary artery; NPV, negative predictive value; PPV, positive predictive value.

Interpretation of Negative and Positive MPI From the FFR Viewpoint

The positive rate of stress MPI at the FFR ranges of 0.71–0.75 and 0.76-0.80 was low: 20% and 11% for LAD, 36% and 36% for non-LAD, and 24% and 20% for all vessel analysis, respectively. Even at the FFR range of 0.66–0.70 for LAD, which was considered a moderately ischemic finding, the positive rate of stress MPI was only 41% (Figure 4).

Figure 4.

Positive rate of stress MPI in each FFR range. FFR, fractional flow reserve; LAD, left anterior descending coronary artery; MPI, myocardial perfusion imaging. Blue bars, negative FFR; yellow bars, mildly positive FFR; red bars, severely positive FFR.

In contrast, the negative predictive value (NPV) was sufficiently high regardless of the FFR threshold. Evidently, most patients with normal stress MPI had a FFR ≥0.65 for both LAD and non-LAD lesions (Figure 2). Moreover, at the FFR threshold value of 0.65, the NPV was also sufficiently high: 93% for LAD, 94% for non-LAD, and 94% for all vessel analyses (Figure 5).

Figure 5.

Comparison of sensitivity, specificity, PPV, and NPV regarding FFR threshold. FFR, fractional flow reserve; NPV, negative predictive value; PPV, positive predictive value. Blue bars, FFR threshold of 0.80; red bars, FFR threshold of 0.65.

Discussion

Both stress MPI and FFR are routinely used for evaluating myocardial ischemia in clinical situations. However, we sometimes encounter dissociation between MPI and FFR and need to contemplate the treatment plan in such cases. In this study, we clarified the correlation between stress MPI and FFR.

Our study findings clearly indicated that stress MPI and FFR demonstrate a good correlation in detecting myocardial ischemia. Similar to the results of previous reports,^5–8 the best FFR cutoff value for diagnosing myocardial ischemia assessed by perfusion imaging was 0.75–0.80 in both LAD and non-LAD lesions. For mildly positive FFR from 0.65 to 0.80, many discordant cases of positive FFR but negative stress MPI were observed. In terms of PPV, the adequate FFR threshold was approximately 0.65. In cases of normal stress MPI, the incidence of lesions with FFR <0.65 was rare.

Risk Evaluation by FFR and MPI

It is well recognized that event rates in patients with normal stress MPI are extremely low. The estimated annual rate of MI or cardiac death has been reported to be ≤0.6%.^3,4 Therefore, MPI serves as a traditional gatekeeper, accurately identifying low-risk patients, and appropriately directing others for invasive CAG or revascularization.

Recently, many landmark trials for FFR have been reported, and FFR has become the gold standard for decision-making regarding revascularization in patients with stable coronary artery disease. The threshold of 0.80 distinguishes coronary lesions that will benefit from revascularization with a reduction in major adverse cardiovascular events (MACE).^5–7 However, discrepancies between stress MPI and FFR have been described in 10–40% of patients.²² In most of the landmark studies on FFR, the definition of MACE includes not only hard events, such as MI or cardiac death, but also repeat or urgent revascularization. Furthermore, revascularization accounts for a high proportion of MACE. In the DEFER study, repeat revascularization occurred in 25% of primary endpoints in the reference group.⁵ In the FAME study, repeat vascularization occurred in 50% of primary endpoints in the FFR group.⁶ In the FAME2 study, urgent revascularization occurred in 37% of the primary endpoints in the PCI plus medical therapy group.⁷ Similarly, the IRIS-FFR Registry demonstrated fascinating data showing that the threshold of FFR where revascularization is preferable to optimal medical therapy differed according to the definition of MACE. When MACE was defined as cardiac death, AMI, or coronary revascularization, the threshold was 0.79. However, when MACE was defined as either cardiac death or AMI, the threshold of FFR was 0.65.⁸ This is consistent with our findings, which showed that the positive rate of stress MPI dropped sharply when the threshold of FFR exceeded 0.65 in LAD and >0.70 in non-LAD lesions. Moreover, when the stress MPI was normal, FFR was normal or mildly positive. Therefore, MPI is probably a more efficient diagnostic tool for the prediction of hard cardiac events than for soft endpoints including revascularization.

Discordance Between FFR and Stress MPI

In most cases of discordance between FFR and MPI there was mildly positive FFR ranging from 0.65 to 0.80 with normal MPI. Moreover, there were a few other cases of discordance with severely positive FFR <0.65 with normal MPI, and normal FFR with positive stress MPI. In the former cases, balanced ischemia and diffuse atherosclerosis that is not generating a large, focal step-up of the pressure gradients along the coronary tree might lead to an underestimation of the visual defect scoring of MPI. In the latter cases, microvascular disease, such as myocardial hypertrophy, hemodialysis, and additional coronary stenoses in the more distal side compared with the site where FFR was measured and inferior attenuation of MPI might lead to discordance.²³

Study Limitations

Firstly, because this study was conducted retrospectively in a single institution and included a small number of patients, there may be selection bias in patient selection and the presenting lesions for assessing the diagnostic accuracy of MPI and FFR. Secondly, we analyzed only the data with single-point FFR values and did not analyze the pullback FFR information. Therefore, we did not evaluate the effects of location and proportion of the lesions. Finally, we did not include outcome data in this study.

Conclusions

Lesions with normal MPI findings may be safely deferred from the viewpoint of preventing hard event such as cardiac death or MI. Abnormal MPI may effectively identify high-risk patients.

In the case of mildly positive FFR ranging from 0.65 to 0.80, many discordant cases with positive FFR but negative MPI may present, especially in LAD lesions. In these cases, the risk of hard events may be low even if PCI has not been performed due to normal MPI. Therefore, a carefully selected treatment plan considering the patient’s background, presence of symptoms under optimal medical therapy, and risk of coronary intervention should be implemented in such cases.

Acknowledgments

We express special thanks to Ryo Kajiura RT, Takahito Mizusaki RT, and Shunsuke Imai RT for their work in collecting and analyzing all study-related data. We also thank Editage (www.editage.jp) for English language editing.

Funding

This research received no grants from any funding agency in the public, commercial or not-for-profit sectors.

Disclosures

H.M. declares lecture fees from Abbott Vascular Japan, Phillips, Boston Scientific Japan, Zeon Mecical, and Nihon Medi-physics.

IRB Information

The Ethics Committee of Gifu Heart Center (no. 2020003).

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0122

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