Aortic valve imaging using 18F-sodium fluoride: impact of triple motion correction

BACKGROUND: Current (18)F-NaF assessments of aortic valve microcalcification using (18)F-NaF PET/CT are based on evaluations of end-diastolic or cardiac motion-corrected (ECG-MC) images, which are affected by both patient and respiratory motion. We aimed to test the impact of employing a triple motion correction technique (3 × MC), including cardiorespiratory and gross patient motion, on quantitative and qualitative measurements. MATERIALS AND METHODS: Fourteen patients with aortic stenosis underwent two repeat 30-min PET aortic valve scans within (29 ± 24) days. We considered three different image reconstruction protocols; an end-diastolic reconstruction protocol (standard) utilizing 25% of the acquired data, an ECG-gated (four ECG gates) reconstruction (ECG-MC), and a triple motion-corrected (3 × MC) dataset which corrects for both cardiorespiratory and patient motion. All datasets were compared to aortic valve calcification scores (AVCS), using the Agatston method, obtained from CT scans using correlation plots. We report SUV(max) values measured in the aortic valve and maximum target-to-background ratios (TBR(max)) values after correcting for blood pool activity. RESULTS: Compared to standard and ECG-MC reconstructions, increases in both SUV(max) and TBR(max) were observed following 3 × MC (SUV(max): Standard = 2.8 ± 0.7, ECG-MC = 2.6 ± 0.6, and 3 × MC = 3.3 ± 0.9; TBR(max): Standard = 2.7 ± 0.7, ECG-MC = 2.5 ± 0.6, and 3 × MC = 3.3 ± 1.2, all p values ≤ 0.05). 3 × MC had improved correlations (R(2) value) to the AVCS when compared to the standard methods (SUV(max): Standard = 0.10, ECG-MC = 0.10, and 3 × MC = 0.20; TBR(max): Standard = 0.20, ECG-MC = 0.28, and 3 × MC = 0.46). CONCLUSION: 3 × MC improves the correlation between the AVCS and SUV(max) and TBR(max) and should be considered in PET studies of aortic valves using (18)F-NaF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40658-022-00433-7

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

Cardiovascular magnetic resonance and positron emission tomography in the assessment of aortic stenosis

Background Aortic stenosis is not only characterized by progressive valve narrowing but also by the hypertrophic response of the left ventricle that ensues. In this most common valvular condition novel imaging approaches (cardiovascular magnetic resonance [CMR] and positron emission tomography [PET]) have shown promise in the assessment of disease progression and risk stratification. The central aim of this thesis was to investigate the potential of CMR imaging to refine risk prediction and to improve the imaging protocol of 18F-sodium fluoride PET for aortic stenosis. Methods and Results Asymmetric wall thickening in aortic stenosis In a prospective observational cohort study, 166 patients with aortic stenosis (age 69, 69% males, mean aortic valve area 1.0±0.4cm2) and 37 age and sex-matched healthy volunteers underwent phenotypic characterisation with comprehensive clinical, imaging and biomarker evaluation. Asymmetric wall thickening on both echocardiography and cardiovascular magnetic resonance was defined as regional wall thickening ≥13 mm and >1.5-fold the thickness of the opposing myocardial segment. Asymmetric wall thickening was observed in 26% (n=43) of patients with aortic stenosis using magnetic resonance and 17% (n=29) using echocardiography. Despite similar demographics, co-morbidities, valve narrowing, myocardial hypertrophy and fibrosis, patients with asymmetric wall thickening had increased cardiac troponin I and brain natriuretic peptide concentrations (both p<0.001). Over 28 [22, 33] months of follow-up, asymmetric wall thickening was an independent predictor of aortic valve replacement or death whether detected by magnetic resonance (HR=2.15; 95 CI 1.29 to 3.59; p=0.003) or echocardiography (HR=1.79; 95 CI 1.08 to 3.69; p=0.021). Animal model of pressure overload We performed serial Cardiac Magnetic Resonance (CMR) imaging every 2-week in 31 mice subjected to pressure overload (continuous angiotensin II infusion) for 6 weeks and investigated reverse remodelling by repeating CMR 1 month following normalization of afterload (n=9). Cine CMR was used to measure left ventricular volumes, mass, and systolic function whilst myocardial fibrosis was assessed using indexed ECV (iECV) calculated from T1-relaxation times acquired with a small animal modified look-locker inversion recovery sequence. During the initial phase of increased pressure afterload indices of left ventricular hypertrophy (0.091 [0.083, 0.105] vs 0.123 [0.111, 0.138] g) and myocardial fibrosis (iECV: 0.022 [0.019, 0.024] vs 0.022 [0.019, 0.024] mL) increased in line with blood pressure measurements (65.1±12.0 vs 84.7±9.2 mmHg) whilst left ventricular ejection fraction (LVEF, 59.3 [57.6, 59.9] vs 46.9 [38.5, 49.6] %) deteriorated significantly (all p≤0.01 compared to baseline). During the reverse remodelling phase blood pressure normalized (68.8±5.4 vs 65.1±12.0 mmHg, p=0.42 compared to baseline). Whilst LV mass (0.108 [0.098, 0.116] vs 0.091 [0.083, 0.105] g) and iECV (0.034 [0.032, 0.036] vs 0.022 [0.019, 0.024] mL) improved both remained elevated compared to baseline (p<0.05). Similarly, the LVEF remained impaired 51.1 [42.9, 52.8] vs 59.3 [57.6, 59.9] %, p=0.03. There was a strong association between LVEF and iECV values during pressure overload (r=-0.88, p<0.001). Gender differences in aortic stenosis Two hundred forty-nine patients (66±13 years, 30% women) with at least mild AS were recruited from two prospective observational cohort studies and underwent comprehensive Doppler echocardiography and CMR exams. On CMR, T1 mapping was used to quantify extracellular volume (ECV) fraction as a marker of diffuse fibrosis, and late gadolinium enhancement (LGE) was used to assess focal fibrosis. There was no difference in age between women and men (66±15 vs 66±12 years, p=0.78). However, women presented a better cardiovascular risk profile than men with less hypertension, dyslipidemia, diabetes, and coronary artery disease (all p≤0.10). As expected, LV mass index measured by CMR was smaller in women than in men (p<0.0001). Despite fewer comorbidities, women presented larger ECV fraction [29.0 (27.4-30.6) vs. 26.8 (25.1-28.7) %, p<0.0001] and similar LGE [4.5 (2.3- 7.0) vs. 2.8 (0.6-6.8) %, p=0.20] than men. In multivariable analysis, female sex remained an independent determinant of higher ECV fraction and LGE (both p≤0.05). Prior CT angiography for PET Forty-five patients (age 67.1±6.9 years, 76% males) underwent CTA (CTA1) and combined 18F-NaF PET/CTA (CTA2) imaging within 14 [10,21] days. We fused CTA1 from visit one with 18F-NaF PET from the second visit (PET) and compared visual pattern of activity, maximal standard uptake values (SUVmax) and target to background (TBR) measurements on (PET/CTA1) fused versus hybrid (PET/CTA2) data. On PET/CTA2, 226 coronary plaques were identified. Fifty-eight coronary segments from 28 (62%) patients had high 18F-NaF uptake (TBR>1.25), whilst 168 segments had lesions with 18F-NaF TBR ≤1.25. Uptake in all lesions was categorized identically on co-registered PET/CTA1. There was no significant difference in 18F-NaF uptake values between PET/CTA1 and PET/CTA2 (SUVmax: 1.16±0.40 vs. 1.15±0.39, p=0.53; TBR:1.10±0.45 vs. 1.09±0.46, p=0.55). The intraclass correlation coefficient for SUVmax and TBR was 0.987 (95%CI 0.983 to 0.991) and 0.986 (95%CI 0.981 to 0.992). There was no fixed or proportional bias between PET/CTA1 and PET/CTA2 for SUVmax and TBR. Cardiac motion correction of PET scans improved reproducibility with tighter 95% limits of agreement (±0.14 for SUVmax and ±0.15 for TBR vs. ±0.20 and ±0.20 on diastolic imaging; p<0.001). Delayed PET imaging Twenty patients (67±7years old, 55% male) with stable coronary artery disease underwent coronary CT angiography and PET/CT both 1 h and 3 h after the injection of 266.2±13.3 MBq of 18F-NaF. We compared the visual pattern of coronary uptake, maximal background (blood pool) activity, noise, standard uptake values (SUVmax), corrected SUV (cSUVmax) and target to background (TBR) measurements in lesions defined by CTA on 1h vs 3h post injection 18F-NaF PET. On 1h PET 26 CTA lesions with 18F-NaF PET uptake were identified in 12 (60%) patients. On 3h PET we detected 18F-NaF PET uptake in 7 lesions which were not identified on the 1h PET. The median cSUVmax and TBR values of these lesions were 0.48 [interquartile range (IQR) 0.44-0.51] and 1.45 [IQR, 1.39-1.52] compared to -0.01 [IQR, -0.03-0.001] and 0.95 [IQR, 0.90-0.98] on 1h PET, both p<0.001. Across the entire cohort 3h PET SUVmax values were similar to 1h PET measurements 1.63 [IQR, 1.37-1.98] vs. 1.55 [IQR, 1.43-1.89], p=0.30 and the background activity was lower 0.71 [IQR, 0.65-0.81] vs. 1.24 [IQR, 1.05-1.31], p<0.001. On 3h PET, the TBR values, cSUVmax and the noise were significantly higher (2.30 [IQR, 1.70-2.68] vs 1.28 [IQR, 0.98-1.56], p<0.001; 0.38 [IQR, 0.27-0.70] vs 0.90 [IQR, 0.64-1.17], p<0.001 and 0.10 [IQR, 0.09-0.12] vs. 0.07 [IQR, 0.06-0.09], p=0.02). The median cSUVmax and TBR values increased by 92% (range: 33-225%) and 80% (range: 20-177%). Conclusions In aortic stenosis, asymmetric wall thickening is associated with adverse prognosis, in this condition there are significant differences in the fibrosis burden between male and female patients and the adverse remodeling of the ventricle can be reproduced in a simple animal model of pressure overload. For 18F-NaF PET utilizing a CT angiography acquired before the PET acquisition enables adequate uptake quantification and delayed emission scanning facilitates image analysis

Developments in PET-MRI for Radiotherapy Planning Applications

The hybridization of magnetic resonance imaging (MRI) and positron emission tomography (PET) provides the benefit of soft-tissue contrast and specific molecular information in a simultaneous acquisition. The applications of PET-MRI in radiotherapy are only starting to be realised. However, quantitative accuracy of PET relies on accurate attenuation correction (AC) of, not only the patient anatomy but also MRI hardware and current methods, which are prone to artefacts caused by dense materials. Quantitative accuracy of PET also relies on full characterization of patient motion during the scan. The simultaneity of PET-MRI makes it especially suited for motion correction. However, quality assurance (QA) procedures for such corrections are lacking. Therefore, a dynamic phantom that is PET and MR compatible is required. Additionally, respiratory motion characterization is needed for conformal radiotherapy of lung. 4D-CT can provide 3D motion characterization but suffers from poor soft-tissue contrast. In this thesis, I examine these problems, and present solutions in the form of improved MR-hardware AC techniques, a PET/MRI/CT-compatible tumour respiratory motion phantom for QA measurements, and a retrospective 4D-PET-MRI technique to characterise respiratory motion. Chapter 2 presents two techniques to improve upon current AC methods that use a standard helical CT scan for MRI hardware in PET-MRI. One technique uses a dual-energy computed tomography (DECT) scan to construct virtual monoenergetic image volumes and the other uses a tomotherapy linear accelerator to create CT images at megavoltage energies (1.0 MV) of the RF coil. The DECT-based technique reduced artefacts in the images translating to improved μ-maps. The MVCT-based technique provided further improvements in artefact reduction, resulting in artefact free μ-maps. This led to more AC of the breast coil. In chapter 3, I present a PET-MR-CT motion phantom for QA of motion-correction protocols. This phantom is used to evaluate a clinically available real-time dynamic MR images and a respiratory-triggered PET-MRI protocol. The results show the protocol to perform well under motion conditions. Additionally, the phantom provided a good model for performing QA of respiratory-triggered PET-MRI. Chapter 4 presents a 4D-PET/MRI technique, using MR sequences and PET acquisition methods currently available on hybrid PET/MRI systems. This technique is validated using the motion phantom presented in chapter 3 with three motion profiles. I conclude that our 4D-PET-MRI technique provides information to characterise tumour respiratory motion while using a clinically available pulse sequence and PET acquisition method

XXIV congreso anual de la sociedad española de ingeniería biomédica (CASEIB2016)

En la presente edición, más de 150 trabajos de alto nivel científico van a ser presentados en 18 sesiones paralelas y 3 sesiones de póster, que se centrarán en áreas relevantes de la Ingeniería Biomédica. Entre las sesiones paralelas se pueden destacar la sesión plenaria Premio José María Ferrero Corral y la sesión de Competición de alumnos de Grado en Ingeniería Biomédica, con la participación de 16 alumnos de los Grados en Ingeniería Biomédica a nivel nacional. El programa científico se complementa con dos ponencias invitadas de científicos reconocidos internacionalmente, dos mesas redondas con una importante participación de sociedades científicas médicas y de profesionales de la industria de tecnología médica, y dos actos sociales que permitirán a los participantes acercarse a la historia y cultura valenciana. Por primera vez, en colaboración con FENIN, seJane Campos, R. (2017). XXIV congreso anual de la sociedad española de ingeniería biomédica (CASEIB2016). Editorial Universitat Politècnica de València. http://hdl.handle.net/10251/79277EDITORIA