¹⁸F-Sodium Fluoride PET Imaging Passes an Important Milestone Toward Noninvasive Prediction of Clinical Events

Coronary artery disease remains a leading cause of death worldwide. Prediction of those at risk of clinical events has long been a priority, allowing for the selection of those patients most likely to benefit from aggressive therapies or interventions. This is of particular relevance with the recent emergence of novel but expensive therapeutic strategies such as PCSK-9 or interleukin-1-beta inhibition.

The development of noninvasive imaging for risk stratification in atherosclerosis and coronary artery disease has spanned many strategies, including measuring the luminal stenosis on coronary artery computed tomography (CT) and magnetic resonance imaging (MRI), characterizing the plaque burden and vulnerable features of the vessel wall and plaque on MRI, measuring the burden of calcification with coronary calcium scoring on CT, and investigating the underlying inflammatory processes driving the development of the disease. Recently, the CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) (1) proved the long-held theory that inflammation is a driving force of cardiovascular disease. Imaging of inflammation in the vessel wall in atherosclerosis using ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) has shown promise for some time (2). ¹⁸F-FDG, a glucose analogue, is taken up by metabolically active cells, and in inflammation, the elevated uptake in tissues with macrophages and other inflammatory cells, compared to normal surrounding tissues, identifies atherosclerotic activity and active plaque on PET imaging. ¹⁸F-FDG PET has shown success in the carotid arteries (3,4) and the aorta (5), has been used as an endpoint in clinical trials (6), and has been associated with a predilection for future cardiovascular events (7). Despite the success of ¹⁸F-FDG PET imaging of culprit coronary artery plaque in acute coronary syndrome (8), investigations in the coronary arteries are especially problematic for ¹⁸F-FDG because of the small caliber of the vessels and the proximity to the myocardium, which often shows intense physiological uptake in the cardiomyocytes.

The emergence of ¹⁸F-sodium fluoride as a specific radiotracer for microcalcification, a process that accompanies inflammation in coronary artery disease, has opened a new frontier for the evaluation of the inflammatory process in coronary artery disease. Previous work has shown that ¹⁸F-sodium fluoride uptake is an indicator of microcalcification and has demonstrated the association between ¹⁸F-sodium fluoride uptake on PET imaging and disease states across multiple cardiovascular disease settings (9). In a landmark paper by Joshi et al. (10), ¹⁸F-sodium fluoride uptake identified the culprit plaque in patients with recent myocardial infarction and was present in plaques with multiple adverse characteristics in patients with stable disease.

In the paper by Kwiecinski et al. (11) in this issue of the Journal, the authors have advanced this technique, passing the important milestone of demonstrating the ability of ¹⁸F-sodium fluoride PET to predict clinical events in a prospective study. Given the low frequency of recurrence of cardiovascular events, an imaging study with clinical endpoints is a challenging task for which the authors should be congratulated.

The study by Kwiecinski et al. (11) has a number of notable aspects. The ability of ¹⁸F-sodium fluoride PET to predict clinical events where conventional coronary calcium scoring and clinical scores did not is striking. It underlines the premise that ¹⁸F-sodium fluoride is a marker of disease activity and represents a current and active increase in risk compared to the longer-term makers of propensity for disease and cumulative disease burden represented by clinical risk scores and calcium scores. The introduction of the quantitative coronary microcalcification activity (CMA) (12) is a significant advantage in this study. The parameter provides a comprehensive score to evaluate overall risk from the whole coronary artery tree. Something to bear in mind is the potential dependence of this integrative parameter on the circulation time of the radiotracer before imaging and the noise level in the atrium used to set the quantitative level for positive uptake. The authors have accounted for this by using a recently proposed scheme to correct for circulation time (13); a standard dosing, circulation time, and image reconstruction protocol; and a comparative target-to-background ratio that has an intrinsic self-normalization. However, the potential of CMA is borne out in the results of the study, which show that CMA was the sole independent predictor of major adverse cardiovascular events. Importantly, this study has been done in a multicenter setting, indicating the wider applicability and relevance of the technique.

Having passed the milestone of demonstrating the ability of ¹⁸F-sodium fluoride PET imaging to predict clinical events, there is greater potential for this advanced noninvasive imaging to play an increasing role in the management of coronary artery disease, meeting the important unmet clinical need of risk stratification for patients with advanced coronary artery disease. The success of ¹⁸F-sodium fluoride, a cheap and readily available radiotracer, is significant in increasing the potential for more widespread use. We await further research exploring the comparative roles for other radiotracers: ¹⁸F-FDG, the nonspecific inflammation marker, and others such as ⁶⁸Ga-DOTATATE, (⁶⁸Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA]-octreotate), the highly specific tracer targeting somatostatin type 2 receptors on the surface of macrophages that has recently been demonstrated in myocardial infarction and carotid and coronary arteries (14). With proven successes, such as in the paper by Kwiecinski et al. (11), the imaging technology will continue to improve to enhance its capabilities. Further advances in low-dose CT and other technologies such as hybrid PET/MRI, will offer imaging with lower radiation doses, more suitable for a wider patient group. Furthermore, PET/MRI may continue to improve on the motion correction tools used in the paper by Kwiecinski et al. (11), further improving the quantitative accuracy and robustness of the imaging methods. Finally, the ability of imaging to identify not only those at risk of clinical events but those who are at reduced risk has the potential, as the authors have pointed out, to both advance and reduce the aggressiveness of treatment. With this, advanced noninvasive imaging with ¹⁸F-sodium fluoride PET has the potential to optimize treatment of coronary artery disease in a cost-effective way. The work of Kwiecinski et al. (11) is a significant step toward these important goals.