Computed tomography and positron emission tomography in the assessment of aortic valve disease
Cartlidge, Timothy Robert Graham
Introduction Native and bioprosthetic aortic valve diseases are an increasingly common clinical challenge as a consequence of the ageing demographic and the expansion of new valve technology. In both conditions, there remains substantial scope to broaden our understanding of the pathophysiology, improve diagnostic sensitivity and accuracy, and develop new markers of disease activity with which to measure therapeutic effect. Computed tomography (CT) and positron emission tomography (PET) are non-invasive imaging assessments that combine high resolution anatomical detail with real-time functional information about disease activity, and as such are ideally suited to complement echocardiography in the investigation of native and bioprosthetic aortic valve diseases. Methods Aortic Stenosis Volunteers with aortic stenosis (n=143) across a range of severity underwent echocardiography, CT aortic valve calcium scoring and contrast-enhanced CT angiography. Aortic valve fibrosis and calcification were quantified to produce two novel measures: the fibro-calcific ratio and fibro-calcific burden. From the same study population, a subset of 15 volunteers underwent hybrid 18F-fluoride PET/CT on two separate occasions and we investigated different methods of image analysis to optimise accuracy and reproducibility. Bioprosthetic Valves Explanted degenerated bioprosthetic valves (n=16) were examined ex vivo using histopathology and preclinical 18F-fluoride PET/CT. Patients with bioprosthetic aortic valves (n=78) were then recruited into two cohorts, with and without prosthetic valve dysfunction, and underwent in-vivo contrast-enhanced CT angiography, 18F-fluoride PET, and serial echocardiography over 2 years of follow-up. Results Aortic Stenosis Contrast-enhanced CT calcium volume correlated closely with conventional CT calcium score in the aortic valve (r=0.86, p=<0.001). Fibrosis dominated in mild aortic stenosis while calcification dominated in severe stenosis (fibro-calcific ratio: 1.33 [0.91-2.4]) versus 0.53 [0.35-1.05] respectively; p=0.001). Males exhibited more calcium than fibrosis, with the reverse true for females (fibro-calcific ratio: 0.89 [0.45-1.54] versus 1.49 [0.82-5.74] respectively; p=0.001). The fibro-calcific burden demonstrated the strongest correlation with peak aortic-jet velocity (r=0.71, p<0.001), especially in women (r=0.77, p=0.001) where it outperformed CT calcium score (p=0.027). In our investigation of 18F-fluoride-PET/CT, contrast-enhanced, ECG-gated PET/CT provided superior spatial localisation of 18F-fluoride uptake. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in variability from 25% to <10%. Bioprosthetic Valves In degenerated bioprosthetic valves ex vivo, calcification was the most prevalent pathological feature (87%), whilst thrombus (40%) and pannus overgrowth (47%) were other common findings. All valves exhibited 18F-fluoride uptake on PET, with a strong positive correlation between 18F-fluoride uptake and calcium volume (r=0.73, p=0.0031). 18F-Fluoride uptake was highest in regions of leaflet calcification but also localised to regions of organised thrombus, fibrosis and features of matrix degradation on histopathology. In the cohort study of patients with bioprosthetic aortic valves, all those with recognised valve dysfunction exhibited abnormalities on CT and high 18F-fluoride uptake. In the 71 patients without valve dysfunction, 20% had leaflet pathology on CT and 34% had increased 18F-fluoride uptake (target-to-background ratio 1.55 [1.44-1.88]). Patients with increased 18F-fluoride uptake exhibited more rapid deterioration in valve function than those without (annualised change in peak transvalvular velocity: 0.30 [0.13-0.61] versus 0.01 [-0.05-0.16] ms-1/year, p<0.001). 18F-Fluoride uptake correlated with deterioration in all echocardiographic measures of valve function (e.g. change in peak velocity, r=0.72; p<0.001) and, on multivariable analysis, was the only independent predictor of future bioprosthetic dysfunction. Conclusions In both native aortic valve disease and bioprosthetic valve disease, CT and 18F-fluoride PET afford valuable insights into disease mechanisms, inform patient risk stratification and prognosis, and provide biomarkers of disease activity that may be used for the development of future therapeutic interventions.