Improvement in quantitative myocardial perfusion metrics after revascularization in chronic coronary artery disease

This editorial refers to ‘The impact of coronary revascularization on vessel-specific coronary flow capacity and long-term outcomes: a serial [¹⁵O]H₂O positron emission tomography perfusion imaging study’ by de Winter R.W. et al., https://doi.org/10.1093/ehjci/jeab263

In chronic coronary artery disease (CAD), myocardial revascularization aims to improve myocardial perfusion for symptom relief or to reduce the risk of myocardial infarction (MI) and death.¹ Cardiac imaging plays an important role in the identification of patients who are most likely to benefit from myocardial revascularization.^1,2 Observational studies indicate a survival benefit from myocardial revascularization over medical therapy in patients with moderate-to-severe myocardial ischaemia.³ However, the ISCHEMIA trial did not find a reduction in risk of MI or death between such patients randomized to initial invasive or conservative strategy, although symptoms and quality of life improved upon revascularization.⁴ Consequently, there has been an increased interest in methods to identify lesions with the highest potential for improved perfusion after revascularization.

Quantification of myocardial blood flow (MBF) during pharmacologically induced hyperaemia and calculation of coronary flow reserve (CFR) can improve the assessment of myocardial ischaemia over the relative assessment of regional perfusion defects.⁵ Quantification also enables assessment of changes in regional perfusion after revascularization to gain insights into determinants of improved MBF upon revascularization.^6,7

Coronary flow capacity (CFC) is a concept that integrates hyperaemic MBF and CFR into a single parameter providing a comprehensive assessment of the physiologic severity of CAD.⁸ While CFR provides a well-validated index incorporating both epicardial and microcirculatory contributions, CFR alone does not distinguish between alterations in baseline vs. hyperaemic flow. Indeed, reduced CFC by intracoronary flow measurement showed a high performance for predicting an increase in coronary flow after percutaneous coronary intervention, compared with the conventional cut-off values for fractional flow reserve (FFR), instantaneous wave-free ratio, and CFR.⁹ Originally based on positron emission tomography (PET) with rubidium-82 [⁸²Rb] tracer, CFC is applicable to other modalities measuring coronary flow. Quantitative myocardial perfusion PET using ¹⁵O-water has been shown to accurately detect haemodynamically significant CAD^10,11 and provide information on future risk of cardiac events.^12,13 However, there is limited information on the effect of revascularization on CFC and other perfusion metrics based on ¹⁵O-water PET.

In the study by de Winter et al.,¹⁴ investigators evaluated hyperaemic MBF, CFR, and CFC in 314 patients who had undergone ¹⁵O-water PET myocardial perfusion imaging both before and on average 96 days after percutaneous or surgical myocardial revascularization. Ischaemic CFC was defined based on thresholds of hyperaemic MBF and CFR associated with FFR ≤0.80 in a previous study using ¹⁵O-water PET.¹⁰ Furthermore, the investigators subdivided ischaemic vessels into those with moderately or severely reduced CFC, the latter showing both hyperaemic MBF ≤1.5 mL/g/min and CFR ≤1.5. Minimally reduced CFC and normal flow were categorized based on average values of hyperaemic MBF and CFR in a cohort of patients in whom obstructive CAD was excluded. The study demonstrated improvements in vessel-specific CFC as well as hyperaemic MBF and CFR after successful revascularization. Reduced baseline CFC was an independent predictor of an increase in hyperaemic MBF and CFR. Furthermore, there was an association between improvement in CFC and a lower rate of composite outcome (death or MI) during a median follow-up of 3.5 years.

In their study, de Winter et al. adopted the concept of CFC into ¹⁵O-water PET perfusion imaging. Similar to other techniques,^6,8,9 CFC assessed by ¹⁵O-water PET appeared as a predictor of improvement in myocardial perfusion. In a previous study, both hyperaemic MBF and CFR by ¹⁵O-water were predictors of death or MI, but only hyperaemic MBF remained an independent predictor in an adjusted model.¹³ It is conceivable that patients with discordant reduction have a milder degree of perfusion impairment and lower potential to increase myocardial perfusion than those with concordantly reduced hyperaemic MBF and CFR. It will be interesting to see whether CFC is a better predictor of treatment response than hyperaemic MBF or CFR alone.

Categorization of impairment of myocardial perfusion is an inherent part of the concept of CFC.^8,9 This facilitates diagnostic and prognostic decision-making. However, given that severity of myocardial perfusion abnormalities is a continuum, thresholds may vary depending on perfusion tracer and methods to relate absolute myocardial perfusion values to haemodynamically significant CAD. For instance, a wide range of hyperaemic MBF values above the ischaemic threshold is a typical characteristic of ¹⁵O-water PET. Originally, the categorization of CFC was based on per-pixel combinations of hyperaemic MBF and CFR by ⁸²Rb PET associated with clinical features of ischaemia.^8,15 In the study of de Winter et al.,¹⁴ thresholds to define CFC categories using ¹⁵O-water PET were introduced, but they remain to be validated in an external patient cohort. In particular, differentiation between severe and moderate ischaemia as well as mildly reduced and normal CFC expand previously validated thresholds for ischaemia. Mild reduction of CFC was defined as hyperaemic MBF or CFR below the mean values of normal myocardium, although such cutoffs have not been linked with ischaemia.¹⁴ Notably, in the study of de Winter et al.,¹⁴ perfusion was averaged over large vascular territories that is likely to have an effect on thresholds and dilute the effect of revascularization in the presence of focal abnormalities.

Interestingly, improvement of CFC upon revascularization was independently associated with a lower incidence of death or non-fatal MI after revascularization. This finding is in line with previous observation that revascularization of lesions associated with severe CFC reduction was associated with reduced risk of death and MI.¹⁵ Outcome analyses are important to confirm the value of CFC in predicting response to revascularization, but require large patient cohorts, particularly when a control group not undergoing myocardial revascularization and other markers of disease phenotype, such as atherosclerotic plaque location and characteristics, are included.

The authors should be congratulated for their findings in a relatively large prospectively recruited cohort of patients undergoing serial ¹⁵O-water PET before and after myocardial revascularization.¹⁴ The study demonstrates the initial application of the concept of CFC into ¹⁵O-water PET perfusion imaging as a determinant of improved myocardial perfusion and outcomes upon revascularization. The study supports the concept that quantitative PET perfusion metrics may help to identify patients benefitting most from myocardial revascularization.

Conflict of interest: Authors acknowledge financial support by grants from the Academy of Finland, the Finnish Foundation for Cardiovascular Research and State Research Funding of Turku University Hospital. Antti Saraste discloses speaker or consultancy fees from Amgen, Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim and Pfizer. J.K. is director of Turku PET Centre and discloses speaker fees from GE Healthcare, Merck, Lundbeck, Pfizer, Boehringer-Ingelheim, Pfizer and Bayer, and study protocol consultancy fees from GE Healthcare and AstraZeneca. T.M. reports no other conflicts of interest.

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