Aortic valve and coronary 18F-sodium fluoride activity: a common cause?

An understanding of the pathophysiology of a disease is crucial for the development and application of interventions. This is particularly salient for diseases which lack preventative therapies. Degenerative aortic stenosis is one such condition. Interest in improving our understanding of the biological processes governing aortic stenosis is therefore intense. This has become even more relevant in the current era of transcatheter heart valves, with the increasing number of potential candidates for intervention sharpening focus on the healthcare burden posed by this chronic disease. Degenerative aortic stenosis is the prototypical calcific valve disease, with complex biological processes occurring over years before manifesting as a clinical entity. Cellular injury, lipid deposition, and inflammation lead to valve interstitial cell differentiation and expression of pro-osteogenic factors that drive calcium deposition, ultimately resulting in outflow obstruction due to valvular stenosis. Similarities have been drawn between the early pathology of aortic stenosis and atherosclerosis, yet seminal randomized controlled trials of statin therapy failed to demonstrate benefit with regard to aortic stenosis progression. Although early calcification of the valve and coronary arteries may be a common response to injury and inflammation, the ultimate clinical effects are divergent. Progressive calcification is the predominant pathological process driving valve obstruction in aortic stenosis. In contrast, coronary macrocalcification is associated with stable atherosclerotic plaques that are less prone to rupture and appears to be accelerated by statin therapy. Further work is therefore required to understand the governing mechanisms and interactions of valvular and coronary calcification.


THE SETTING
An understanding of the pathophysiology of a disease is crucial for the development and application of interventions. This is particularly salient for diseases which lack preventative therapies. Degenerative aortic stenosis is one such condition. Interest in improving our understanding of the biological processes governing aortic stenosis is therefore intense. This has become even more relevant in the current era of transcatheter heart valves, with the increasing number of potential candidates for intervention sharpening focus on the healthcare burden posed by this chronic disease. 1 Degenerative aortic stenosis is the prototypical calcific valve disease, with complex biological processes occurring over years before manifesting as a clinical entity. Cellular injury, lipid deposition, and inflammation lead to valve interstitial cell differentiation and expression of pro-osteogenic factors that drive calcium deposition, ultimately resulting in outflow obstruction due to valvular stenosis. 2 Similarities have been drawn between the early pathology of aortic stenosis and atherosclerosis, 3 yet seminal randomized controlled trials of statin therapy failed to demonstrate benefit with regard to aortic stenosis progression. [4][5][6] Although early calcification of the valve and coronary arteries may be a common response to injury and inflammation, the ultimate clinical effects are divergent. Progressive calcification is the predominant pathological process driving valve obstruction in aortic stenosis. In contrast, coronary macrocalcification is associated with stable atherosclerotic plaques that are less prone to rupture and appears to be accelerated by statin therapy. 7 Further work is therefore required to understand the governing mechanisms and interactions of valvular and coronary calcification.

THE STUDY
In this issue of the Journal of Nuclear Cardiology, Nakamoto et al explore this relationship with a post hoc analysis from their previously published prospective 18F-sodium fluoride (18F-NaF) positron emission tomography-computed tomography (PET-CT) study. 8,9 18F-NaF is the current focus of multiple cardiac imaging studies, having previously been used as a bone tracer in oncology. The radiotracer binds to hydroxyapatite and serves as a marker of calcification activity in multiple cardiovascular disease states. In particular, increased 18F-NaF uptake has been demonstrated in high-risk and culprit coronary and carotid plaques. [9][10][11][12] It is also associated with faster aortic stenosis disease progression 13,14 and bioprosthetic aortic valve degeneration. 15 As such, there is appeal in using this imaging biomarker to investigate calcification activity in both aortic stenosis and coronary atherosclerosis.
The overall study cohort was comprised of 44 patients with known/suspected coronary artery disease, recruited between June 2014 and December 2018, who underwent computed tomography coronary angiography (CTCA) and were found to have at least one coronary 18F-NaF independently associated with more rapid bioprosthetic valve deterioration over 2 years. All patients who developed new bioprosthetic dysfunction had 18F-NaF uptake at baseline least one high-risk feature. The median coronary calcium score was 314 (28-1147) Agatston units. The main finding was an independent association between aortic valve TBR max and the presence of highrisk coronary plaque on multivariable linear regression (b = 0.56, P = .029) after adjusting for age, sex, coronary risk factors, statin use, and obstructive coronary stenosis; aortic valve calcium score was the only other independently associated covariable. Aortic valve TBR max was 1.60 ± 0.18 in patients with high-risk coronary plaque and 1.42 ± 0.13 in those without. Aortic valve TBR max had a modest correlation with baseline aortic valve calcium score (r = 0.54, P = .005). In the 11 patients who had follow-up CT scans, aortic valve TBR max correlated strongly with change in aortic valve calcium score (r = 0.74, P = .009).

COMMENTS
In this interesting imaging substudy of patients with coronary plaque and subclinical aortic valve calcification, the investigators have demonstrated a modest correlation between aortic valve 18F-NaF and the presence of high-risk coronary atherosclerosis. In the context of this small post hoc analysis, the pathophysiological implications of this observation are uncertain. It may reflect similarities between the early stages of aortic stenosis and coronary atherosclerosis. However, both conditions are common and become more prevalent with increasing age, while high-risk plaque features on CTCA are frequently seen in patients with coronary atherosclerosis (e.g., 676/2890 and 608/1123 patients in the PROMISE and SCOT-HEART randomized controlled trials, respectively). 16,17 Although calcium metabolism is a key process in both aortic stenosis and coronary artery disease, its role in the complex mechanisms governing these processes may differ. Therefore, while the present study demonstrates the co-existence of aortic valve microcalcification and high-risk coronary plaque, further inferences remain speculative at this stage.
Importantly, the authors do provide further evidence that baseline aortic valve 18F-NaF PET activity predicts progression of valve calcification. Notably, this correlation was observed in a cohort of patients without aortic stenosis, albeit in a subset of the study cohort. These results are in keeping with the existing body of observational data to date ( Table 1) and suggest that 18F-NaF PET may be helpful in identifying the minority of patients with aortic sclerosis who go on to develop obstructive stenosis. Larger studies are required to consolidate this finding, while the implications of radiation exposure in this otherwise healthy patient group need to be considered.
This was a retrospective analysis of a small cohort, and the usual caveats apply. Additionally, there was also a preponderance of males (80%), which leaves open the question as to whether findings would be reproducible in both men and women-an important point, given the increasing appreciation of gender disparities in the pathophysiology and clinical presentation of aortic stenosis. 18,19 Several points should be noted about the imaging analysis undertaken. The authors did not include the presence of spotty calcification or the napkin-ring sign, well-described adverse coronary plaque characteristics, 20 in their analysis. Furthermore, aortic valve 18F-NaF uptake was measured only in regions of visual valve calcification on CT; the highest maximum standardized uptake value of these regions of interest was used to calculate the TBR max . This method may miss 18F-NaF uptake in regions of the valve that do not have visually apparent calcification. 13,14 Previous data have explored the optimum method of quantifying aortic valve 18F-NaF, demonstrating a most diseased segment technique that incorporates regions of interest around the entire valve area in en face slices to be the most reproducible, correlating strongly with native and bioprosthetic valve disease progression. 14,15,21 Here, the authors demonstrate a similarly good level of interobserver agreement with their technique. Ultimately, validation against clinical outcomes will be required to demonstrate the incremental benefit of this imaging modality and the various image analysis techniques.

CONCLUSION
Nakamoto et al have added to the growing body of literature investigating the associations between baseline vascular 18F-NaF uptake and calcification progression and highlighted a potential association with high-risk coronary plaque. The mechanisms and clinical implications of these correlations require further prospective research, interest in which is rightly engendered by these early observational studies.

Disclosures
All authors declare that they have no conflict of interest.