Quantifying microcalcification activity in the thoracic aorta

Thoracic aortic calcification is an important pathological entity underlying both intimal atherosclerotic disease and medial degenerative processes.1 High-density macro-calcified lesions in the aortic wall can be readily identified using computed tomography (CT) and are associated with an increased risk of stroke and mortality.1-4 However, these lesions represent a late and stable stage of vascular wall pathology where active disease processes may have become quiescent.5 In contrast, microcalcification - typically defined as lesions <50 µm - cannot be detected on conventional imaging but can identify regions of active vascular disease.6,7¹⁸F-Sodium fluoride (¹⁸F-NaF) is a positron emitting radiotracer that allows the detection of microcalcification activity by positron emission tomography (PET),8 providing a marker of aortic disease which might further improve risk prediction. Indeed, coronary ¹⁸F-NaF PET has recently demonstrated its ability to improve risk prediction beyond that afforded by CT calcium score.9,10 Thus, there is interest in developing summary quantitative methods of measuring ¹⁸F-NaF uptake in the aorta, which may provide similarly important prognostic information.

Quantification of ¹⁸F-sodium fluoride uptake in the thoracic aorta currently involves labour intensive analysis of multiple regions of interest across sequential axial slices and calculating mean and maximum intensity uptake values. These values are then normalized to blood pool activity to generate mean (TBRmean) and maximum (TBRmax) tissue to background ratios respectively.11-13 Typically, TBRmax values are influenced by only a small number of the most intense pixels within a volume of interest and may not accurately reflect the overall PET activity within that volume (Figure 1). A simple, robust and time-efficient technique that could provide a summary measure of PET uptake across the thoracic aorta would be a major advance. We, therefore, aimed to develop a novel method of quantifying the burden of 18F-NaF uptake across both the ascending aorta and aortic arch (aortic microcalcification activity, AMA) and to assess its repeatability, reproducibility and time-efficiency compared with current standard approaches. Finally, we provide a comparison between each method and well validated clinical risk scores for future risk of cardiovascular events.14,15

¹⁸F-Sodium fluoride uptake was present in the ascending aorta and aortic arch of all twenty patients (Table 1). Uptake was seen in the aortic wall, although the pattern and degree of uptake varied markedly between patients (Figure 3). The AMA method was nearly 5 times quicker to perform than TBR analyses (3.4±0.5 versus 15.1±1.7 min, P<0.0001)

Molecular imaging techniques are increasingly being used for investigating disease activity in the cardiovascular system. We describe a novel method, AMA, which quantifies ¹⁸F-NaF across both the ascending aorta and aortic arch, providing a measure of overall burden of disease activity in these vessels. We demonstrate this method as being highly reproducible and more time efficient than the whole vessel technique. Moreover, it can be performed with a non-contrast CT, and does not require advanced post-processing techniques, such as motion or time-delay correction, making it potentially more widely applicable. Finally, out of all methods assessed, AMA had the strongest correlation with Framingham stroke risk score and the revised Framingham stroke risk score. These results pave the way for future research investigating whether AMA holds advantages in terms of tracking disease progression and response to therapy as well as improving the prognostic performance of aortic PET.

There are several conceptual advantages to providing a more global assessment of ¹⁸F-NaF activity across the aorta than is provided by standard approaches. The TBRmax values in particular are based upon a small number of highly intense pixels and provide information about the peak intensity of a lesion. On the other hand, AMA incorporates both voxel intensity and volume, providing a global quantification of disease burden. These two approaches may have strengths under differing circumstances. For example, the whole vessel TBRmax and most diseased segment approaches may be more helpful in assessing diseases that are initiated by a threshold effect, such as plaque rupture or aortic dissection. In contrast, other diseases may be best captured by describing the overall burden of disease and AMA, such as aneurysm expansion or aortitis. However, theoretical application of such approaches does have limitations and depends on a number of factors. For example, we recently demonstrated that the summary measure of coronary microcalcification activity was the strongest predictor of future coronary events in patients with multivessel disease.9 This probably reflects the fact that plaque rupture commonly heals spontaneously without causing myocardial infarction and therefore a measure of overall disease activity is more powerful than focusing on a single lesion TBRmax. Whether a single intense lesion or overall disease activity better reflects risk of subsequent events in thoracic aortic disease, such as stroke in atherogenic patients or complications of thoracic aneurysm disease, remains to be seen.

In contrast to our findings in the coronary arteries,18 background and motion corrections make minimal difference to overall AMA reproducibility. The time-delay blood pool correction accounts for the different elimination rates between the coronary arteries and blood pool seen over time.18,20 However, the elimination rates for the aorta over the same periods are different to those seen in the coronaries (Supplemental Figure 3). The time-delay blood pool correction formula used in coronary microcalcification activity should, therefore, not be applied to the AMA measurements. Motion correction is necessary in assessing the uptake in the coronary arteries as they are relatively small vessels, with potential contamination from surrounding structures (e.g. mitral valve annular calcification), partial volume effects and marked movement throughout the cardiac cycle. The aorta, on the other hand, is a large and relatively stationary vessel, with little contamination from surrounding structures and reduced suseptability to potential partial volume effects, although these still may be present. Moreover, our technique for drawing AMA volumes of interest was standardised to 4 mm beyond the maximal lumen diameter, likely incorporating most aortic movement. This probably explains why motion correction had no effect on AMA values.

It is important to highlight some limitations to our study. Due to well documented problems with spinal contamination influencing accurate ¹⁸F-NaF assessment in the descending thoracic aorta, we chose to limit our AMA analysis to the ascending aorta and aortic arch. Importantly our AMA approach could also be applied to other tracers used to assess disease activity in the aorta (e.g. ¹⁸F-FDG or ⁶⁸Ga-Dotatate), where such contamination is not an issue and where a global assessment of uptake might also include activity in the descending aorta. Although we have demonstrated the favourable efficiency, reproducibility and repeatability of AMA with positive correlations with clinical risk scores, whether or not AMA will improve the prediction of disease progression and cardiovascular events remains to be seen.

Aortic microcalcification activity is a simple, repeatable and reproducible method for quantifying ¹⁸F-NaF uptake in the ascending aorta and arch that is significantly and substantially quicker to perform compared with alternative methods and correlates with validated cardiovascular risk scores.

In conclusion, we have provided a detailed description of how to assess global ¹⁸F-NaF activity across both the ascending aorta and aortic arch using a time efficient approach that demonstrates highly favourable repeatability and reproducibility. Studies assessing the ability of AMA to track disease progression and response to therapy as well as predicting cardiovascular outcomes are now required to validate AMA as a novel biomarker of aortic disease.