This study aimed to evaluate the feasibility of utilizing aortic Na[18F]F-PET/CT as a risk model for the emergence of MACE. The main results revealed a significant association between the predictive value of the total aortic cSUVmax in hybrid Na[18F]F-PET/low-dose CT scans, and the subsequent emergence of MACE during an approximately 4-year follow-up period. Survival analyses were comparable to the total aortic Agatston score and revealed a notable one-year survival rate, reflecting the early detection capability of Na[18F]F-PET/CT in identifying cardiovascular disease at its early stages. In this mostly oncological and elderly patient population, the predictive value of cSUVmax for MACE was comparable to the aortic Agatston score. These findings highlight the potential clinical utility of Na[18F]F-PET/CT as an imaging tool to predict the risk of MACE.

As stated before, the Agatston score is widely considered the gold standard for CT calcium scoring in cardiac CT scans in the clinical setting. Therefore, to examine the feasibility of the Na[18F]F-PET/CT scan as a risk model for MACE, both the cSUVmax and the Agatston score were incorporated for comparative purposes. Low-dose CT from PET/CT is not currently utilized in clinical risk modeling for MACE. However, by comparing patients in three groups rather than individually, our study provides a preliminary step towards integrating Na[18F]F-PET/CT into clinically established risk models for MACE. Besides, comparable with previous studies, which examined the predictive value of Na[18F]F uptake in coronary artery disease, we found a similar predictive value of the cSUVmax as well as the Agatston score [14, 18, 19]. However, the clinically added predictive value of Na[18F]F is due to its potential to provide earlier assessment of the atherosclerotic burden than currently used cardiac CT. This study demonstrates this predictive value of Na[18F]F for MACE in a relatively small cohort and short follow-up. Moreover, we believe this data contributes to the understanding of its role in risk assessment, especially in populations where traditional methods might lack the necessary sensitivity to detect subtle yet significant variations in cardiovascular risk. Large, longitudinal, prospective cohorts are needed to investigate its exact predictive value.

To the best of our knowledge, this is the first study to have evaluated the feasibility of utilizing aortic Na[18F]F-PET/CT as a risk model for MACE. Previous studies have investigated Na[18F]F uptake in the aorta. However, their focus did not include evaluating MACE or overall cardiovascular risk. For instance, Forsythe et al. and Syed et al. examined Na[18F]F uptake in acute aortic syndrome and abdominal aortic aneurysms, respectively [42, 43]. In contrast, Fiz et al. retrospectively explored the associations between baseline Na[18F]F uptake and the progression of atherosclerotic plaques within the abdominal aorta [44]. Fletcher et al. specifically explored the use of thoracic Na[18F]F PET to identify patients at the highest risk of ischemic stroke by using patients with stable CVD [45]. While Fletcher et al.’s findings are significant within the context of ischemic stroke, our study broadens the scope by encompassing various adverse cardiovascular events and patients without previously diagnosed CVD, providing a more comprehensive assessment of cardiovascular risk. Notably, all these studies demonstrated a positive correlation between Na[18F]F uptake and the occurrence of disease or the evolution of atherosclerotic plaques [42,43,44,45]. By incorporating analysis of aortic Na[18F]F uptake, we aimed to provide a more comprehensive evaluation of the risk of MACE, complementing the assessment of coronary arteries.

Other studies are primarily focused on assessing Na[18F]F uptake in the coronary arteries and the aortic valve [3, 14, 15, 18, 19, 46, 47]. However, molecular imaging of coronary artery atherosclerosis poses challenges due to constant cardiac and respiratory movements, making it difficult to accurately evaluate focal uptake of targeted tracers at the intended sites [16]. Recent research suggests that exploring vascular calcification in the aorta could provide additional predictive information for cardiovascular risk assessment [17]. Additionally, although carotid and femoral arteries are also critical sites for atherosclerotic plaque buildup, we did not include them due to technical limitations. Specifically, low-dose CT, which was used in our hybrid imaging approach, does not provide sufficient image quality to accurately distinguish and segment these smaller arteries. Future studies may benefit from using higher resolution imaging modalities to include carotid and femoral arteries, for a more comprehensive evaluation of systemic atherosclerosis.

Furthermore, the methodologies employed in previous studies for assessing cardiovascular risk are predominantly centered around the evaluation of coronary events. Although these studies demonstrated a similar outcome, the implementation of a composite endpoint such as MACE has become increasingly prevalent, given the growing emphasis on a comprehensive risk assessment in CVD research [20]. In line with this trend, we incorporated the MACE composite endpoint in our study to provide a more comprehensive evaluation of overall cardiovascular risk.

A well-known limitation of cardiovascular quantification in PET/CT is the time-consuming and labor-intensive manual delineation of the entire aorta, hence making it clinically infeasible. The development of automated segmentation and quantification methods provides a clear and efficient approach to evaluating a patient's risk of experiencing a MACE [48]. Future studies should utilize these automated analysis tools to assess their clinical feasibility. This could potentially serve as a valuable tool for both initial diagnosis and ongoing vascular disease monitoring.

This study has its limitations. First, this was a retrospective study. Second, it should be noted that the patient group employed in this study largely consisted of individuals diagnosed with bone, breast or prostate cancer, rather than the ideal group of individuals solely at risk of CVD. With this current population, patients may have succumbed to cancer-related mortality rather than experiencing a MACE. In regard to the study population, detailed information regarding the type of cancer, stage of their evolutionary metabolic disease, and their treatment regimen was not systematically collected in this study. The diverse types of cancer and their respective treatments could affect the aortic uptake of Na[18F]F, potentially impacting our results. For example, it is noteworthy to consider the potential influence of current standard treatments such as bisphosphonates or denosumab on the process of (micro)calcification, particularly in the context of patients with cancer-related bone pathology. These medications, commonly prescribed to mitigate bone loss and skeletal-related events in individuals with bone metastases, may inadvertently affect the dynamics of (micro)calcification, potentially confounding the interpretation of cardiovascular imaging findings [49, 50]. This heterogeneity in patient characteristics underscores the importance of considering these factors in future studies. Future research should stratify patients based on cancer type, stage, and treatment to minimize bias and improve the accuracy of the findings. Furthermore, future investigations should aim to elucidate the interplay between these treatments and cardiovascular risk markers, including the implications for (micro)calcification processes observed in imaging modalities. Third, with only twelve patients experiencing a composite cardiovascular end-point during follow-up, the robustness of the conclusions is limited. Fourth, hospitalization may have occurred at other medical institutions. Regrettably, it cannot be excluded that certain hospitalizations have been missed. However, medical events are consistently documented in the electronic patient file system which largely covers this limitation. However, the results still showed a positive and significant association of cSUVmax with MACE and the results were comparable with those of prior studies. Fifth, the Agatston score was calculated in the aorta in low-dose CT and not in diagnostic CT. Besides, two different scanners were used, a conventional and digital PET system. Noise most probably influenced these scores. However, we still observed differences in event rates between the three different groups. To ultimately confirm the influence of different scanners, the positive predictive value of the Na[18F]F-PET/CT scan, and whether Na[18F]F is an earlier predictor than conventional CT calcium scoring, large prospective studies are needed with patients earlier in the atherosclerotic process comparing Na[18F]F PET with diagnostic CT. Given the limited number of MACE events, the Cox regression analysis in this study only included age as a factor. Last, MACE was defined as the composite of myocardial infarction, CVA, the first detection of aortic aneurysms, and hospitalization due to acute heart failure. This end-point is non-specific because it includes cardiac and non-cardiac complications. However, there has not yet been a consensus about how to define MACE [20]. While myocardial infarction and CVAs are widely accepted as strong MACE criteria, consensus has not yet been reached on whether aortic aneurysms and hospitalization due to acute heart failure should be included in the MACE criteria. Establishing a standardized MACE definition is essential to reduce heterogeneity and ensure the reproducibility of future studies. Furthermore, while our composite endpoint was intended to improve the robustness of our analysis, we acknowledge that it encompasses both cardiac and non-cardiac complications, which may dilute the specificity of our findings. Future studies with larger populations are necessary to validate these specific correlations and enhance the clinical utility of Na[18F]F-PET/CT in predicting regional cardiovascular events.

In conclusion, the study findings highlight the potential clinical utility of Na[18F]F-PET/CT as an imaging tool to predict the risk of MACE. This study demonstrated a significant association between Na[18F]F uptake and an increased risk of MACE, comparable to the association between aortic Agatston scores and MACE. While our study provides evidence to support the feasibility of using Na[18F]F-PET/CT as a risk predictor for cardiovascular events, further prospective research is needed to confirm and broaden these results. Future studies should compose individuals solely at an earlier phase of CVD risk to ultimately assess the feasibility of using Na[18F]F-PET/CT as a risk model for MACE.