Graham McKillop

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).

Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients With Aortic Stenosis

Background— The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown. Methods and Results— Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one 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 interobserver 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 in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r2=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r2=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r2=0.174, 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. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Abdominal Aortic Aneurysm Growth Predicted by Uptake of Ultrasmall Superparamagnetic Particles of Iron Oxide A Pilot Study

Background— Abdominal aortic aneurysms are a major cause of death. Prediction of aneurysm expansion and rupture is challenging and currently relies on the simple measure of aneurysm diameter. Using MRI, we aimed to assess whether areas of cellular inflammation correlated with the rate of abdominal aortic aneurysm expansion. Methods and Results— Stable patients (n=29; 27 male; age, 70±5 years) with asymptomatic abdominal aortic aneurysms (4.0 to 6.6 cm) were recruited from a surveillance program and imaged using a 3-T MRI scanner before and 24 to 36 hours after administration of ultrasmall superparamagnetic particles of iron oxide (USPIO). The change in T2* value on T2*-weighted imaging was used to detect accumulation of USPIO within the abdominal aortic aneurysm. Histological examination of aneurysm tissue confirmed colocalization and uptake of USPIO in areas with macrophage infiltration. Patients with distinct mural uptake of USPIO had a 3-fold higher growth rate (n=11, 0.66 cm/y; P=0.020) than those with no (n=6, 0.22 cm/y) or nonspecific USPIO uptake (n=8, 0.24 cm/y) despite having similar aneurysm diameters (5.4±0.6, 5.1±0.5, and 5.0±0.5 cm, respectively; P>0.05). In 1 patient with an inflammatory aneurysm, there was a strong and widespread uptake of USPIO extending beyond the aortic wall. Conclusions— Uptake of USPIO in abdominal aortic aneurysms identifies cellular inflammation and appears to distinguish those patients with more rapidly progressive abdominal aortic aneurysm expansion. This technique holds major promise as a new method of risk-stratifying patients with abdominal aortic aneurysms that extends beyond the simple anatomic measure of aneurysm diameter. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794092.

Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience.

Background—Inflammation following acute myocardial infarction (MI) has detrimental effects on reperfusion, myocardial remodelling, and ventricular function. Magnetic resonance imaging using ultrasmall superparamagnetic particles of iron oxide can detect cellular inflammation in tissues, and we therefore explored their role in acute MI in humans. Methods and Results—Sixteen patients with acute ST-segment elevation MI were recruited to undergo 3 sequential magnetic resonance scans within 5 days of admission at baseline, 24 and 48 hours following no infusion (controls; n=6) or intravenous infusion of ultrasmall superparamagnetic particles of iron oxide (n=10; 4 mg/kg). T2*-weighted multigradient-echo sequences were acquired and R2* values were calculated for specific regions of interest. In the control group, R2* values remained constant in all tissues across all scans with excellent repeatability (bias of −0.208 s−1, coefficient of repeatability of 26.96 s−1; intraclass coefficient 0.989). Consistent with uptake by the reticuloendothelial system, R2* value increased in the liver (84±49.5 to 319±70.0 s−1; P<0.001) but was unchanged in skeletal muscle (54±8.4 to 67.0±9.5 s−1; P>0.05) 24 hours after administration of ultrasmall superparamagnetic particles of iron oxide. In the myocardial infarct, R2* value increased from 41.0±12.0 s−1 (baseline) to 155±45.0 s−1 (P<0.001) and 124±35.0 s−1 (P<0.05) at 24 and 48 hours, respectively. A similar but lower magnitude response was seen in the remote myocardium, where it increased from 39±3.2 s−1 (baseline) to 80±14.9 s−1 (P<0.001) and 67.0±15.7 s−1 (P<0.05) at 24 and 48 hours, respectively. Conclusions—Following acute MI, uptake of ultrasmall superparamagnetic particles of iron oxide occurs with the infarcted and remote myocardium. This technique holds major promise as a potential method for assessing cellular myocardial inflammation and left ventricular remodelling, which may have a range of applications in patients with MI and other inflammatory cardiac conditions. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01323296.

In Vivo Mononuclear Cell Tracking Using Superparamagnetic Particles of Iron Oxide Feasibility and Safety in Humans

Background— Cell therapy is an emerging and exciting novel treatment option for cardiovascular disease that relies on the delivery of functional cells to their target site. Monitoring and tracking cells to ensure tissue delivery and engraftment is a critical step in establishing clinical and therapeutic efficacy. The study aims were (1) to develop a Good Manufacturing Practice–compliant method of labeling competent peripheral blood mononuclear cells with superparamagnetic particles of iron oxide (SPIO), and (2) to evaluate its potential for magnetic resonance cell tracking in humans. Methods and Results— Peripheral blood mononuclear cells 1–5×109 were labeled with SPIO. SPIO-labeled cells had similar in vitro viability, migratory capacity, and pattern of cytokine release to unlabeled cells. After intramuscular administration, up to 108 SPIO-labeled cells were readily identifiable in vivo for at least 7 days using magnetic resonance imaging scanning. Using a phased-dosing study, we demonstrated that systemic delivery of up to 109 SPIO-labeled cells in humans is safe, and cells accumulating in the reticuloendothelial system were detectable on clinical magnetic resonance imaging. In a healthy volunteer model, a focus of cutaneous inflammation was induced in the thigh by intradermal injection of tuberculin. Intravenously delivered SPIO-labeled cells tracked to the inflamed skin and were detectable on magnetic resonance imaging. Prussian blue staining of skin biopsies confirmed iron-laden cells in the inflamed skin. Conclusions— Human peripheral blood mononuclear cells can be labeled with SPIO without affecting their viability or function. SPIO labeling for magnetic resonance cell tracking is a safe and feasible technique that has major potential for a range of cardiovascular applications including monitoring of cell therapies and tracking of inflammatory cells. Clinical Trial Registration— URL: http://www.clinicaltrials.gov; Unique identifier: NCT00972946, NCT01169935.

Left Ventricular Hypertrophy with Strain and Aortic Stenosis

Background— ECG left ventricular hypertrophy with strain is associated with an adverse prognosis in aortic stenosis. We investigated the mechanisms and outcomes associated with ECG strain. Methods and Results— One hundred and two patients (age, 70 years [range, 63–75 years]; male, 66%; aortic valve area, 0.9 cm2 [range, 0.7–1.2 cm2]) underwent ECG, echocardiography, and cardiovascular magnetic resonance. They made up the mechanism cohort. Myocardial fibrosis was determined with late gadolinium enhancement (replacement fibrosis) and T1 mapping (diffuse fibrosis). The relationship between ECG strain and cardiovascular magnetic resonance was then assessed in an external validation cohort (n=64). The outcome cohort was made up of 140 patients from the Scottish Aortic Stenosis and Lipid Lowering Trial Impact on Regression (SALTIRE) study and was followed up for 10.6 years (1254 patient-years). Compared with those without left ventricular hypertrophy (n=51) and left ventricular hypertrophy without ECG strain (n=30), patients with ECG strain (n=21) had more severe aortic stenosis, increased left ventricular mass index, more myocardial injury (high-sensitivity plasma cardiac troponin I concentration, 4.3 ng/L [interquartile range, 2.5–7.3 ng/L] versus 7.3 ng/L [interquartile range, 3.2–20.8 ng/L] versus 18.6 ng/L [interquartile range, 9.0–45.2 ng/L], respectively; P<0.001) and increased diffuse fibrosis (extracellular volume fraction, 27.4±2.2% versus 27.2±2.9% versus 30.9±1.9%, respectively; P<0.001). All patients with ECG strain had midwall late gadolinium enhancement (positive and negative predictive values of 100% and 86%, respectively). Indeed, late gadolinium enhancement was independently associated with ECG strain (odds ratio, 1.73; 95% confidence interval, 1.08–2.77; P=0.02), a finding confirmed in the validation cohort. In the outcome cohort, ECG strain was an independent predictor of aortic valve replacement or cardiovascular death (hazard ratio, 2.67; 95% confidence interval, 1.35–5.27; P<0.01). Conclusion— ECG strain is a specific marker of midwall myocardial fibrosis and predicts adverse clinical outcomes in aortic stenosis.

Prevalence of coronary artery calcification in patients undergoing assessment for orthotopic liver transplantation.

Patients with advanced liver disease are at increased risk of cardiovascular events, especially following orthotopic liver transplantation (OLT). Coronary artery calcification (CAC) is a novel and independent predictor of cardiovascular risk, but its prevalence and utility in patients with cirrhosis are unknown. The aim of this study was to define the prevalence of CAC and its association with markers of disease severity and standard measures of cardiovascular risk in a large cohort of patients undergoing OLT assessment. A single‐center, prospective, observational study of 147 consecutive patients undergoing assessment for OLT was performed. CAC scores were derived with the Agatston method from thoracic computed tomography scans and correlated with cardiovascular risk factors and measures of liver disease severity. There were 101 patients (66 males) with a mean age of 53.2 years; 46 patients were excluded because the CAC score was not reported. The median CAC score was 40 HU (range, 0‐3533). Correlations were identified between the CAC score and age (r = 0.477; P < 0.001), male sex (r = 0.262; P = 0.008), family history of cardiovascular disease (r = 0.208; P = 0.036), Framingham risk score (r = 0.621; P < 0.001), Model for End‐Stage Liver Disease score (r = 0.221; P = 0.027), systolic blood pressure (r = 0.285; P = 0.004), diastolic blood pressure (r = 0.267; P = 0.007), cytomegalovirus status (r = 0.278; P = 0.005), fasting glucose (r = 0.330; P = 0.001), number of coronary vessels involved (r = 0.899; P < 0.001), and components of the metabolic syndrome (r = 0.226; P = 0.026). After multivariate analysis, age, systolic blood pressure, fasting glucose, number of features of metabolic syndrome, and number of vessels involved remained significantly associated with CAC. In conclusion, this study identified a high prevalence of occult coronary artery disease in patients undergoing OLT assessment and identified a strong relationship between CAC scores and a limited number of specific cardiovascular risk factors. The usefulness of these factors in predicting perioperative and postoperative cardiovascular events in patients undergoing OLT requires prospective evaluation. Liver Transpl 14:1725–1731, 2008.

MRI using ultrasmall superparamagnetic particles of iron oxide in patients under surveillance for abdominal aortic aneurysms to predict rupture or surgical repair: MRI for abdominal aortic aneurysms to predict rupture or surgery-the MA(3)RS study.

Introduction Population screening for abdominal aortic aneurysms (AAA) halves the associated mortality and has led to the establishment of national screening programmes. Prediction of aneurysm growth and rupture is challenging and currently relies on serial diameter measurements with ultrasound. Recently, a novel MRI-based technique using ultrasmall superparamagnetic particles of iron oxide (USPIO) has demonstrated considerable promise as a method of identifying aneurysm inflammation and expansion. Methods and analysis The MA3RS study is a prospective observational multicentre cohort study of 350 patients with AAA in three centres across Scotland. All participants will undergo MRI with USPIO and aneurysm expansion will be measured over 2 years with CT in addition to standard clinical ultrasound surveillance. The relationship between mural USPIO uptake and subsequent clinical outcomes, including expansion, rupture and repair, will be evaluated and used to determine whether the technique augments standard risk prediction markers. To ensure adequate sensitivity to answer the primary question, we need to observe 130 events (composite of rupture or repair) with an estimated event rate of 41% over 2 years of follow-up. The MA3RS study is currently recruiting and expects to report in 2017. Discussion This is the first study to evaluate the use of USPIO-enhanced MRI to provide additional information to aid risk prediction models in patients with AAA. If successful, this study will lay the foundation for a large randomised controlled trial targeted at applying this technique to determine clinical management. Trial registration number Current Controlled Trials: ISRCTN76413758.

Valvular (18)F-Fluoride and (18)F-Fluorodeoxyglucose Uptake Predict Disease Progression and Clinical Outcome in Patients With Aortic Stenosis.

18F-Fluoride is a positron emission tomography (PET) radiotracer that preferentially binds to regions of newly forming vascular microcalcifications beyond the resolution of computed tomography (CT) [(1)][1]. 18F-Fluorodeoxyglucose (18F-FDG) has been widely used to measure vascular inflammation [(2

Iterative reconstruction and individualized automatic tube current selection reduce radiation dose while maintaining image quality in 320-multidetector computed tomography coronary angiography

Aim To assess the effect of two iterative reconstruction algorithms (AIDR and AIDR3D) and individualized automatic tube current selection on radiation dose and image quality in computed tomography coronary angiography (CTCA). Materials and methods In a single-centre cohort study, 942 patients underwent electrocardiogram-gated CTCA using a 320-multidetector CT system. Images from group 1 (n = 228) were reconstructed with a filtered back projection algorithm (Quantum Denoising Software, QDS+). Iterative reconstruction was used for group 2 (AIDR, n = 379) and group 3 (AIDR3D, n = 335). Tube current was selected based on body mass index (BMI) for groups 1 and 2, and selected automatically based on scout image attenuation for group 3. Subjective image quality was graded on a four-point scale (1 = excellent, 4 = non-diagnostic). Results There were no differences in age (p = 0.975), body mass index (p = 0.435), or heart rate (p = 0.746) between the groups. Image quality improved with iterative reconstruction and automatic tube current selection [1.3 (95% confidence intervals (CI): 1.2–1.4), 1.2 (1.1–1.2) and 1.1 (1–1.2) respectively; p < 0.001] and radiation dose decreased [274 (260–290), 242 (230–253) and 168 (156–180) mGy cm, respectively; p < 0.001]. Conclusion The application of the latest iterative reconstruction algorithm and individualized automatic tube current selection can substantially reduce radiation dose whilst improving image quality in CTCA.