Advanced imaging to detect disease burden, activity and progression in coronary artery disease and aortic valve disease

INTRODUCTION: Coronary artery disease and aortic stenosis represent two important manifestations ofcardiovascular disease, a dominant cause of morbidity and mortality in the UK andworldwide. In recent years, advances in modern imaging techniques have transformedour understanding of the pathophysiology of these underlying disease states, enablingthe detailed characterisation of disease processes and the identification of a largenumber of potential therapeutic targets. To address the increasing burden ofcardiovascular disease, improved identification of patients at risk of diseaseprogression and future events is crucial. Application of advanced non-invasiveimaging will be instrumental in achieving this goal and could enable improvedtargeting of existing or novel therapies directed against these disease processes.The objective of this thesis was to investigate the ability of novel advanced noninvasiveimaging to quantify disease burden, to measure disease activity and to assessdisease progression in both coronary artery disease and aortic valve disease.METHODS AND RESULTS:•THE ASSOCIATION BETWEEN NON-INVASIVE FRACTIONAL FLOW RESERVE ANDPLAQUE BURDEN IN NON-OBSTRUCTIVE ATHEROSCLEROSIS - The association between nonobstructive atherosclerosis and non-invasive fractionalflow reserve derived from computed tomography (FFRCT) measured in distalcoronary vessels was investigated in 155 patients undergoing computed tomographycoronary angiography with greater than 25% coronary stenosis in at least oneepicardial vessel. Plaque analysis was performed on all vessels with between 25-70%stenosis using dedicated software (Autoplaque, Cedars Sinai Medical Center, LosAngeles, USA). Multiple plaque components including calcified plaque (CP) volume,non-calcified plaque (NCP) volume, low density plaque (LD-NCP) volume,remodelling index (RI) and contrast density difference (CDD) were quantified. Anabnormal distal vessel FFRCT (V-FFRCT) was defined as ≤0.75. Total plaque volume,calcified plaque volume, noncalcified plaque volume and low-density plaque volumewere higher in vessels with an abnormal V-FFRCT compared to those with a normalV-FFRCT (p1.25)correlated with change in calcium score at one year (Spearman’s Rho 0.37, p<0.0001).Participants with evidence of increased ¹⁸F-fluoride uptake at baseline demonstratedmore rapid progression of coronary calcification at one year (change in calcium score,97 [39-166] versus 35 [7-93] AU; p<0.0001). When individual coronary segments withincreased ¹⁸F-fluoride activity were compared to negative reference plaques in thesame participant, segments with increased ¹⁸F-fluoride uptake demonstratedprogressive calcification at one year (from 95 [30-209] AU to 148 [61-289] AU;p<0.001) whereas there was no change in calcium score for reference segments (from46 [16-113] to 49 [20-115] AU; p=0.329).• IMAGE OPTIMISATION AND MOTION CORRECTION OF CORONARY PET-CT: The effect of different PET reconstruction algorithms and application of cardiacmotion correction upon coronary 18F-fluoride PET activity was assessed in a cohort ofpatients with a recent diagnosis of Acute Coronary Syndrome (n=22). Image qualitywas assessed using Signal-to-Noise Ratio (SNR). An optimal balance between signalintensity and noise was achieved using 24 subsets, 4 iterations, point-spread-functionmodelling, time of flight and 5-mm post-filtering which provided the highest medianSNR. A novel cardiac motion correction method led to improved SNR of culprit plaques (24.5[19.9-31.5]) when compared to the standard method of using PET datafrom the diastolic cardiac phase only (15.7[12.4-18.1]; p<0.001). Further, motioncorrectionled to a greater SNR difference between culprit and reference lesions (10.9[6.3-12.6]) compared to diastolic (6.2 [3.6-10.3] p=0.001) and summed data (7.1 [4.8-11.6] p=0.001).• CT-AVC AND ECHOCARDIOGRAPHY IN THE PROGRESSION OF AORTIC STENOSIS: In a study of participants with aortic stenosis, the reproducibility of CT calcium scoringof the aortic valve as well as its ability to detect changes in disease severity over timewas assessed and compared with echocardiography, the current gold standard imagingtechnique in aortic stenosis. In a group of 15 participants who underwent repeat CTscanning within four weeks, quantification of aortic valve calcification by CT (CTAVC)was reproducible (limits of agreement -12 to 10%, ICC 0.99). Peak aortic jetvelocity was the most reproducible measure of aortic stenosis severity onechocardiography (limits of agreement -7 to 17%; ICC 0.96). In a second cohort ofpatients, progression of calcification on CT and haemodynamic progression byechocardiography was assessed and a ratio of annualised disease progression andmeasurement variability was generated and used to estimate numbers of patientsrequired to detect annualised changes in disease severity on both modalities. CT-AVCdemonstrated a favourable progression-to-variability ratio (Cohen’s d statistic 3.12)versus echocardiography (Cohen’s d statistic for peak velocity 0.71), suggesting fewerpatients would be required to detect changes in disease progression.• CARDIAC MOTION CORRECTION APPLIED TO PET-CT AND PET-MR OF THE AORTICVALVE: The application of cardiac motion correction was investigated in a group ofparticipants with aortic stenosis undergoing 18F-fluoride PET-CT (n=5) and PET-MR(n=1). When compared to the standard method of utilising PET data acquired duringthe diastolic phase only, the application of cardiac motion correction improved signalto noise ratio (48.8 vs 21.2; p<0.05) and tissue to background ratio (3.1 vs 2.5 p<0.05). CONCLUSIONS: The application of advanced non-invasive imaging techniques can provide novelmeasures of disease burden, activity and progression in both coronary atherosclerosisand aortic stenosis