Nik Joshi

Coronary Arterial 18F-Sodium Fluoride Uptake : A Novel Marker of Plaque Biology

OBJECTIVES With combined positron emission tomography and computed tomography (CT), we investigated coronary arterial uptake of 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) as markers of active plaque calcification and inflammation, respectively. BACKGROUND The noninvasive assessment of coronary artery plaque biology would be a major advance particularly in the identification of vulnerable plaques, which are associated with specific pathological characteristics, including micro-calcification and inflammation. METHODS We prospectively recruited 119 volunteers (72 ± 8 years of age, 68% men) with and without aortic valve disease and measured their coronary calcium score and 18F-NaF and 18F-FDG uptake. Patients with a calcium score of 0 were used as control subjects and compared with those with calcific atherosclerosis (calcium score >0). RESULTS Inter-observer repeatability of coronary 18F-NaF uptake measurements (maximum tissue/background ratio) was excellent (intra-class coefficient 0.99). Activity was higher in patients with coronary atherosclerosis (n = 106) versus control subjects (1.64 ± 0.49 vs. 1.23 ± 0.24; p = 0.003) and correlated with the calcium score (r = 0.652, p < 0.001), although 40% of those with scores >1,000 displayed normal uptake. Patients with increased coronary 18F-NaF activity (n = 40) had higher rates of prior cardiovascular events (p = 0.016) and angina (p = 0.023) and higher Framingham risk scores (p = 0.011). Quantification of coronary 18F-FDG uptake was hampered by myocardial activity and was not increased in patients with atherosclerosis versus control subjects (p = 0.498). CONCLUSIONS 18F-NaF is a promising new approach for the assessment of coronary artery plaque biology. Prospective studies with clinical outcomes are now needed to assess whether coronary 18F-NaF uptake represents a novel marker of plaque vulnerability, recent plaque rupture, and future cardiovascular risk. (An Observational PET/CT Study Examining the Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis; NCT01358513).

Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation?

AIMS The pathophysiology of aortic stenosis shares many similarities with atherosclerosis and skeletal bone formation. Using non-invasive imaging, we compared aortic valve calcification and inflammation activity with that measured in atherosclerosis and bone. METHODS AND RESULTS Positron emission and computed tomography was performed using 18F-sodium fluoride (18F-NaF, calcification) and 18F-fluorodeoxyglucose (18F-FDG, inflammation) in 101 patients with calcific aortic valve disease (81 aortic stenosis and 20 aortic sclerosis). Calcium scores and positron emission tomography tracer activity (tissue-to-background ratio; TBR) were measured in the aortic valve, coronary arteries, thoracic aorta, and bone. Over 90% of the cohort had coexistent calcific atheroma, yet correlations between calcium scores were weak or absent (valve vs. aorta r(2) = 0.015, P = 0.222; valve vs. coronaries r(2) = 0.039, P = 0.049) as were associations between calcium scores and bone mineral density (BMD vs. valve r(2) = 0.000, P = 0.766; vs. aorta r(2) = 0.052, P = 0.025; vs. coronaries r(2) = 0.016, P = 0.210). 18F-NaF activity in the valve was 28% higher than in the aorta (TBR: 2.66 ± 0.84 vs. 2.11 ± 0.31, respectively, P < 0.001) and correlated more strongly with the severity of aortic stenosis (r(2) = 0.419, P < 0.001) than 18F-NaF activity outwith the valve (valve vs. aorta r(2) = 0.167, P < 0.001; valve vs. coronary arteries r(2) = 0.174, P < 0.001; valve vs. bone r(2) = 0.001, P = 0.806). In contrast, 18F-FDG activity was lower in the aortic valve than the aortic atheroma (TBR: 1.56 ± 0.21 vs. 1.81 ± 0.24, respectively, P < 0.001) and more closely associated with uptake outwith the valve (valve vs. aorta r(2) = 0.327, P < 0.001). CONCLUSION In patients with aortic stenosis, disease activity appears to be determined by local calcific processes within the valve that are distinct from atherosclerosis and skeletal bone metabolism.

Salt in the wound: 18 F-fluoride positron emission tomography for identification of vulnerable coronary plaques

Ischaemic vascular events occur in relation to an underlying vulnerable plaque. The pathological hallmarks of high-risk plaques are well described and include inflammation and microcalcification. To date, non-invasive imaging modalities have lacked the spatial resolution to detect these processes with the necessary precision to facilitate clinical utility. Positron emission tomography (PET) using targeted radiopharmaceuticals affords a highly sensitive tool for identifying features of interest and has been in use for several decades in oncological practice. Recent developments have created hybrid scanning platforms which add the detailed spatial resolution of computed tomography (CT) and, for the first time, made imaging of individual coronary plaques feasible. In this study we compared the utility of PET-CT using (18)F-fluoride and (18)F-fluorodeoxglucose ((18)F-FDG) to detect high-risk or ruptured atherosclerotic plaques in vivo. (18)F-fluoride localized to culprit and vulnerable plaques as determined by a combination of invasive imaging and histological tissue examination. In contradistinction, (18)F-FDG analysis was compromised by non-specific myocardial uptake that obscured the coronary arteries. We discuss the findings of this study, the limitations of the current approach of vulnerable plaque assessment and some on-going developments in cardiovascular imaging with (18)F-fluoride.

Assessment of calcification and inflammation with positron emission tomography in aortic stenosis and atherosclerosis

Abstract Background Calcification and inflammation are key pathological processes in aortic stenosis and atherosclerosis. Using combined positron emission tomography and computed tomography (PET/CT), we sought to investigate their contribution to disease progression in aortic stenosis and to help identify vulnerable atherosclerotic plaque. Methods In the first part of the study patients with calcific aortic valve disease stenosis were prospectively compared with age-matched and sex-matched controls with normal valves. Aortic valve severity was determined at baseline and 1 year by echocardiography and CT calcium scoring. Calcification and inflammation in the valve were assessed by sodium 18-fluoride (NaF) and 18-fluorodeoxyglucose (FDG) uptake with PET. In the second part of the study NaF and FDG activity was assessed in the coronary arteries both in patients with stable coronary disease and in patients after myocardial infarction. Findings 101 patients with aortic stenosis were compared with 20 controls. Tracer activity (target to background ratio [TBR]) was higher in patients with aortic stenosis than in controls (mean NaF 2·87 [SD 0·82] vs 1·55 [0·17], FDG 1·58 [0·21] vs 1·30 [0·13]; both p r 2 =0·540) with a more modest increase observed for FDG ( r 2 =0·218). Baseline NaF correlated closely with alkaline phosphatase staining on immunohistochemistry ( r 2 =0·79) and was a better predictor of disease progression at 1 year ( r 2 =0·44, n=20) than was FDG ( r 2 =0·02) or baseline calcium score ( r 2 =0·36, current best predictor). Increased NaF activity was observed in 45 (42%) of 106 patients with stable coronary atherosclerosis and was localised to individual coronary plaques. These patients had higher rates of previous major adverse cardiovascular events (p=0·016) and higher Framingham risk scores (p=0·011) than did patients without increased uptake. In patients after myocardial infarction (n=15) intense NaF activity was observed at the site of the culprit lesion, with increased uptake compared with the maximum uptake elsewhere in the coronary arteries (TBR median 1·56 [IQR 1·49–1·82] vs 1·23 [1·15–1·48], p=0·02). Interpretation In the valve, NaF holds promise in predicting aortic stenosis progression. In the coronary arteries it identifies culprit plaque post myocardial infarction and stable patients at elevated cardiac risk. Funding British Heart Foundation.

POSITRON EMISSION TOMOGRAPHY TO IDENTIFY RUPTURED AND VULNERABLE CORONARY PLAQUES

Background Non-invasive imaging to identify vulnerable or ruptured coronary artery plaque would represent a major clinical advance. Using positron emission tomography (PET) and computed tomography (CT), we investigated coronary uptake of 18F-fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) in patients with acute myocardial infarction or stable angina. Methods Forty patients with acute myocardial infarction and 40 with stable angina underwent electrocardiogram-gated 18F-NaF and 18F-FDG PET-CT and invasive coronary angiography. 18F-NaF uptake was compared with virtual histology intravascular ultrasound in patients with stable angina, and with histology in 12 carotid endartectomy specimens. Results Intense focal 18F-NaF uptake occurred at the site of plaque rupture in 37 (93%) patients with myocardial infarction (tissue-to-background ratio [TBR], 1.66 [1.40–2.25] versus 1.24 [1.06–1.38]; culprit versus maximal non-culprit, P<0.001). In patients with stable angina, 18 (45%) had focal plaque 18F-NaF uptake (2.10 [1.71–2.81]) that, compared to plaques without uptake, had more high-risk features: positive remodeling (vessel area 24 [17–27] versus 14 [12–18] mm2; P=0.002), necrotic core (24.6% [20.5–28.8] verses 18.0% [14.0–22.4], P=0.001) and microcalcification (73 versus 21%, P=0.002). Carotid plaque rupture also co-localized with ex vivo 18F-NaF uptake and was associated with areas of apoptosis, necrosis and active calcification. Myocardial uptake markedly hampered 18F-FDG assessment in most patients (55%) and even where coronary uptake was discernible, there were no differences between culprit and non-culprit lesions (1.71 [1.40–2.13] versus 1.58 [1.28–2.01]; P=0.34). Conclusions 18F-NaF holds major promise as a novel biomarker of coronary plaque vulnerability and rupture with implications for the diagnosis, investigation and treatment of coronary artery disease.

CORONARY ARTERIAL 18F-NAF UPTAKE: A NOVEL MARKER OF PLAQUE BIOLOGY

Results: Repeatability statistics for the measurement of the coronary 18F-NaF uptake (max TBR) were excellent (intra-class coeficient 0.99). Activity was higher in patients with coronary atherosclerosis versus controls (1.64±0.49 vs 1.23±0.24; p 1000 displayed normal uptake. Patients with increased coronary 18F-NaF (n=40) had higher rates of prior cardiovascular events (P=0.02) and angina (p=0.02) and higher Framingham risk scores (P=0.01). By contrast quantiication of coronary 18F-FDG activity was hampered by myocardial uptake and not increased in those with atherosclerosis versus controls (p=0.50). Conclusion: 18F-NaF is a promising new approach for the assessment of coronary plaque biology and appears to be a novel marker of vulnerability, recent plaque rupture and cardiovascular risk

B Assessment of valvular calcification and inflammation by positron emission tomography

Background The pathophysiology of aortic stenosis is incompletely understood and the relative contributions of valvular calcification and inflammation to disease progression are unknown. Methods Patients with aortic sclerosis and mild, moderate and severe stenosis were prospectively compared to age and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by sodium 18-fluoride (18F-NaF) and 18-fluorodeoxyglucose (18F-FDG) uptake using positron emission tomography. Histological analysis was performed on the valves of five patients who subsequently underwent aortic valve replacement. Results 121 subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent inter-observer repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than control subjects (18F-NaF: 2.87±0.82 vs 1.55±0.17; 18F-FDG: 1.58±0.21 vs 1.30±0.13; both p<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r2=0.540, p<0.001) and colocalised to osteocalcin staining on histology. Uptake was observed both in the presence and absence of underlying calcium on CT with the latter predominating. 18F-FDG displayed a more modest increase in activity with valve severity (r2=0.218; p<0.001) and mapped to areas of macrophage accumulation. Among patients with aortic stenosis, 91% had increased 18F-NaF (>1.97) and 35% increased 18F-FDG (>1.63) uptake. A weak correlation between the activities of these tracers was observed (r2=0.174, p<0.001) and while 18F-NaF activity was higher in the aortic valve than aortic atheroma (2.68±0.84 vs 2.07±0.30; p<0.001) the reverse was true for 18F-FDG (1.56±0.21 vs 1.80±0.25; p<0.001). Conclusions Positron emission tomography is a novel, feasible and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. Calcification appears to be the predominant process that is particular to the valve and disproportionate to the degree of inflammation, indicating it to be a more attractive target for therapeutic intervention.

IN VIVO ASSESSMENT OF CELLULAR INFLAMMATION FOLLOWING ACUTE MYOCARDIAL INFARCTION

Background Inflammation following myocardial infarction has detrimental effects on reperfusion, myocardial remodelling and left ventricular function. MRI using ultrasmall superparamagnetic particles of iron oxide (USPIO) can be used to detect cellular inflammation in tissues. Methods 15 patients were recruited up to 5 days after ST-segment elevation myocardial infarction. Nine patients underwent cardiac MRI (3 Tesla) at baseline, and at 24 and 48 h following infusion of USPIO (4 mg/kg; Ferumoxytol, AMAG). Six control patients underwent the same scanning protocol without infusion of USPIO. T2*-weighted multi-gradient-echo sequences were acquired and R2* maps (inverse of T2*) were generated to assess USPIO accumulation. Baseline scans were registered to subsequent 24 and 48 h scans and the infarct zone was defined on Gadolinium-enhanced T2-weighted images. An “object map” was created that defined corresponding regions of interest (ROI) on all scans for each subject. The ROIs included infarct zone, peri-infarct zone, remote myocardium, liver, blood pool and skeletal muscle. The R2* values for each ROI was calculated. Results In the control group, the R2* value in the infarct zone remained constant: baseline, 0.047 s−1 (95% CI 0.034 to 0.059); 24 h, 0.043 s−1 (95% CI 0.035 to 0.052) and 48 h, 0.040 s−1 (95% CI 0.024 to 0.056). In the infarct zone, the R2* value increased from a baseline of 0.041 s−1 (95% CI 0.029 to 0.053) to 0.164 s−1 (95% CI 0.125 to 0.204) at 24 h and 0.128 s−1 (95% CI 0.097 to 0.158) at 48 h following USPIO administration (p<0.01; non-parametric repeated measure one-way ANOVA, Dunns post test comparison). Conclusion USPIO are taken up into the infarcted myocardium following acute myocardial infarction and can be quantified by MRI. This approach appears to image infarct-related cellular inflammation and represents an important novel method of assessing recovery following acute myocardial infarction.Abstract 084 Figure 1 In this subject, late gadolinium enhancement had revealed an infarct of the anterior left ventricular wall. Panels A and B are R2 acquisition images of the same subject taken on day 1 (A, pre-USPIO), and day 2 (B post-USPIO) in a patient given ferumoxytol. The white arrow indicates the area of infarction corresponding to the late gadolinium enhancement. In this area there is sequential higher uptake of USPIO as indicated by the red/green colour in this area. This is consistent with neutrophil and macrophage influx. Ferumoxytol is also taken up by the liver reticulo-endothelial system (grey arrow). These findings are confirmed by the quantitative analysis of the R2* signal (Panel C).Abstract 084 Figure 2 Comparison of R2* signal in different tissues. Highest uptake of USPIO is seen in the infarct zone, liver and blood pool. There is a small increase in R2* signal in the remote myocardium. There is no increase in R2* signal in the control group for any tissue.