Our results support that global and regional MFR, stress MBF, and MFC radius, as assessed by using the latest advances in 82Rb PET imaging, are powerful predictors of cardiovascular event, outperforming traditional cardiovascular risk factors such as the presence of known CAD or history of myocardial infarction. In a comprehensive analysis, we show similar results for global and regional MFR, stress MBF, and MFC radius as prognostic factors.
Our study has notable strengths. We utilized state-of-the-art 82Rb PET imaging, using the latest advances in SiPM PET technology, including a Time of Flight of 214 ps and smaller crystals with higher PET resolution, which greatly ameliorate the image quality as compared to conventional PET with photomultiplier tubes (11). We used standardized automated post processing protocols of the dynamic data including dual spillover, global partial-volume recovery and motion corrections, and resting rate-pressure-product (RPP) adjustments (13, 14). PET perfusion was quantified by automated, purely objective measurements. All scans were performed using the same machine and the same acquisitions protocols. We had a 99% successful follow-up rate. We also used a novel quantification technique, MFC radius, that allows per patient single continuous variables to stratify MFC, and, therefore, represents a straightforward tool to select an optimal threshold value for MFC.
There is a major interest in using accurate non-invasive parameters to improve patient assessment and risk stratification. In this line, absolute quantification of the myocardial perfusion as assess by PET/CT offers a powerful opportunity to tackle this challenge (15, 16). However, the most reliable quantitative variable on 82Rb cardiac PET/CT for predicting MACE is not fully established and is unknown using SiPM technology. Our similar results for global and regional MFC radius, MFR, and stress MBF as prognostic factors were unexpected and show some conflicting results with previous studies.
First, the funding that both global reduced MFR and stress MBF are similar as prognostic factors and are not additive have previously shown conflicting results. Regarding the prediction of cardiovascular deaths, Gupta et al. investigated the importance of global stress MBF and MFR (10). In this study, in univariable analyses, patients with concordant impaired stress MBF and MFR yielded the highest risk of cardiovascular mortality, whereas patients with normal stress MBF and MFR depicted the lowest risk. However, in multivariable analysis, those authors reported that the cardiovascular mortality was independently driven by global MFR, irrespective of whether the global stress MBF was impaired or preserved. Similar findings had been reported by Fukushima et al. in a cohort with almost the same number of patients and using the same radiotracer (82Rb) that in the current study, but with previous PET technology (17). Taqueti et al. demonstrated that the prognostic value of MFR for the occurrence of MACE was independent of the extent and severity of coronary lesions as evaluated on coronary angiography, but stress MBF was not included in multivariable analysis (18). In an observational study by Patel et al., a threshold of 1.8 for global MFR has been identified to yield a benefit of coronary revascularization over medical treatment, independently of the art of revascularization or the extent of myocardial ischemia at the semi-quantitative analysis, but, again, stress MBF was not studied (19). In the current study using SiPM PET/CT, a threshold of 1.98 for global MFR was retained as the maximum cutoff for MACE prediction, which was interestingly close to their threshold of 1.8 obtained for a different purpose. Contrary, other studies reported that global stress MBF was independently predictive for events, whereas global MFR was not (20, 21).
Regional quantitative parameters as expressed by MFC have shown promising clinical data. Gould et al. showed in recent observational studies with large cohorts over long-term follow-up that the extent of severe regional impairment of MFC, expressed as percentage of left ventricular per-pixel regional MFC, provide optimal risk stratification and is associated with a survival benefit gained by revascularization (8, 9). This risk stratification was not entirely assessed by global MFR and global stress MBF (9). Even limited extended area of abnormal regional MFC (< 0.5% of the left ventricle) were shown to be predictive of MACE, when integrating the relative stress perfusion (9). Using severe regional MFC impairment as target for revascularization, Bober et al. shown a significant increase of stress MBF was obtained in myocardial territories with impaired MFC, whereas there was no increase in stress MBF in territories with normal MFC (22). Recently, Miura et al. found in a retrospective study that impaired regional modified MFC (utilizing average MFR and stress MBF values for each coronary territory) was associated with both cardiovascular death and MACE, but no comparison was done with traditional quantitative parameters such as stress MBF or MFR (23). In the current study we used a novel quantification technique, MFC radius, that allows per patient single continuous variables to stratify MFC, and, therefore, allows us to select an optimal threshold value for MFC. Using this new tool with a new PET technology, we found that both global and regional MFC values are powerful predictors of cardiovascular event, independent from traditional cardiovascular risk factors, but being similar to global and regional stress MBF or MFR.
Considering regional stress MBF and MFR, our results are consistent with Bom et al. who found in a [15O]water PET study that both global and regional stress MBF had prognostic value in predicting cardiac events, while that the combination of global and regional stress MBF did not improve the prognostic performance compared to either alone (20). Harjulahti et al. found similar results using also [15O]water PET (4). In contrast, Von Felten et al. recently demonstrated using 13N-ammonia, an independent prognostic value of regional MFR < 2, being superior to global stress MBF and MFR (24). In this study the authors emphasized several methodological differences for regional measurements between them: (i) a decrease in at least two adjacent segments, (ii) Bom et al.: continuous variables computed as the average MFR values from the two adjacent segments with the lowest values, and (iii) Harjulahti et al.: a single segment with stress MBF lower than 2.3 ml/g/min. In the current study, the first using the latest SiPM technology, regional absolute perfusion measurements as defined as minimal average values among the 3 vascular territories were not significant predictors of worse outcome as compared to global absolute perfusion measurements. Reduced global or regional minimum MFC radius, MFR or stress MBF were associated with similar risks of MACE after adjustments of different parameters such as previous history of MI or known CAD. Our results suggest that all these variables have similar significance for the prediction of cardiovascular events and could be applied in a similar way for risk stratification or to potentially guide the risk-based clinical decision to defer for coronary angiography.
This study must be interpreted in the context of its single-center design, with a relatively modest sample size, which limits extensive subgroup analysis for outcomes. The period of follow-up was middle range, with a low incidence of hard cardiac events such as cardiac death. MFC, MFR, and stress MBF have, by definition, interactions. Therefore, these parameters could not be assessed as independent predictors between them without collinearity. Our study emphasized myocardial blood flow measurements, and left ventricular ejection fraction, left ventricular volumes, regional wall motion, coronary artery calcium score and semi-quantitative evaluation of relative perfusion defects were not assessed in this study despite representing important information that could be part of routine PET/CT imaging.