Mohammed M. Chowdhury

Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging

Background Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. Objectives This study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. Methods We confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis. Results Target SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients. Conclusions We validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)

A Comparative Study of Carotid Atherosclerotic Plaque Microvessel Density and Angiogenic Growth Factor Expression in Symptomatic Versus Asymptomatic Patients

OBJECTIVE A challenge facing clinicians is identifying patients with asymptomatic carotid disease at risk of plaque instability. We hypothesise that locally released angiogenic growth factors contribute to plaque instability. METHODS Carotid endarterectomy specimens from eight symptomatic and eight asymptomatic patients were interrogated for microvessel density and angiogenic growth factor expression histologically using immunofluorescence, and biochemically using quantitative real-time polymerase chain reaction (q-RT-PCR). Bio-Plex suspension array was used to assess circulating biomarkers in venous blood from the same patients and six healthy age-matched controls. RESULTS Immunofluorescence demonstrated significantly greater neovessel density in symptomatic plaques (P=0.010) with elevated expression of hepatocyte growth factor (HGF) (P=0.001) and its receptor MET (P=0.011) than in asymptomatic plaques. The q-RT-PCR demonstrated up-regulation of Endoglin (CD105), HGF (P=0.001) and MET (P=0.011) in the plaques of symptomatic versus asymptomatic patients. Bio-Plex suspension array demonstrated elevated HGF (P=0.002) serum levels in symptomatic versus asymptomatic patients and healthy controls, and decreased platelet-derived growth factor (PDGF) (P=0.036) serum levels in symptomatic versus asymptomatic patients. CONCLUSION Plaque instability may be mediated by HGF-induced formation of new microvessels, and decreased vessel stability resulting from decreased PDGF. Suspension array technology has the potential to identify circulating biomarkers that correlate with plaque rupture risk.

PET Imaging of Atherosclerotic Disease: Advancing Plaque Assessment from Anatomy to Pathophysiology.

Atherosclerosis is a leading cause of morbidity and mortality. It is now widely recognized that the disease is more than simply a flow-limiting process and that the atheromatous plaque represents a nidus for inflammation with a consequent risk of plaque rupture and atherothrombosis, leading to myocardial infarction or stroke. However, widely used conventional clinical imaging techniques remain anatomically focused, assessing only the degree of arterial stenosis caused by plaques. Positron emission tomography (PET) has allowed the metabolic processes within the plaque to be detected and quantified directly. The increasing armory of radiotracers has facilitated the imaging of distinct metabolic aspects of atherogenesis and plaque destabilization, including macrophage-mediated inflammatory change, hypoxia, and microcalcification. This imaging modality has not only furthered our understanding of the disease process in vivo with new insights into mechanisms but has also been utilized as a non-invasive endpoint measure in the development of novel treatments for atherosclerotic disease. This review provides grounding in the principles of PET imaging of atherosclerosis, the radioligands in use and in development, its research and clinical applications, and future developments for the field.

Premorbid function, comorbidity, and frailty predict outcomes after ruptured abdominal aortic aneurysm repair.

OBJECTIVE Strategies to improve outcomes for patients with ruptured abdominal aortic aneurysm (rAAA) are becoming more evident. The aging population, however, continues to make the decision to intervene often difficult, especially given that traditional risk models do not reflect issues of aging and frailty. This study aimed to integrate measures of function alongside comorbidity- and frailty-specific factors to determine outcome. METHODS Patients treated for a rAAA between January 2006 and April 2014 were assessed. Demographics, mortality, and requirement for care after discharge as well as a variety of measures of function (physical, social, and psychological) and comorbidity were recorded. The primary outcome was 1-year mortality. Outcome models were generated using multivariate logistic regression and were compared with models of vascular frailty and AAA-related outcome. RESULTS Of 184 patients treated, 108 (59%) underwent an open surgical repair. The overall 30-day and 1-year mortality were 21.5% and 31.4%, respectively, with an overall median hospital length of stay of 13 days (interquartile range, 6-27 days). An optimal logistic regression model for 12-month mortality used Katz score, Charlson score, number of admission medicines, visual impairment, hearing impairment, hemoglobin level, and statin use as predictors, achieving an area under the receiver operating characteristic curve of 0.84. CONCLUSIONS This novel rAAA model incorporating function and comorbidity offers good predictive power for mortality. It is quick to calculate and may ultimately become helpful for both counseling and selection of patients and comparative audit at a time when outcome in patients with rAAA increasingly comes under the spotlight.

Treatment of aortoiliac aneurysms with the iliac bifurcated device for preservation of internal iliac artery flow.

Introduction: The iliac bifurcated device (IBD) is an innovative endovascular device for aortoiliac aneurysm repair. The objective of this study is to provide further evidence on the efficacy and safety of the device. Study Design: Case series study with retrospective analysis of prospectively collected nonrandomized data. Methods: Between 2007 and 2010, all consecutive IBD placements were analyzed. The main outcomes included (1) technical failure; (2) morbidity and mortality; and (3) late outcomes. Prospective follow-up was performed by interval computed tomography scanning. Results: In all, 27 consecutive patients had elective placement of 28 IBDs. Mean operating time was 251.1 ± 65.4 minutes, mean fluoroscopy time was 63.9 ± 27.2 minutes, and mean contrast volume used was 186.2 ± 106.7 mL. Periprocedural type I endoleak occurred in 2 patients. No aneurysm-related adverse events were recorded. Conclusion: We demonstrate that IBDs can be used in patients with aortoiliac aneurysms and are associated with satisfactory medium-term results as expressed by high patency and low reintervention rates.

Assessment of Renal Injury in Patients Undergoing Elective EVAR Using Urinary Neutrophil Gelatin-Associated Lipocalin, Interleukin 18, and Retinol-Binding Protein

Acute kidney injury (AKI) is a recognized complication post-endovascular aneurysm repair (EVAR). Neutrophil gelatin-associated lipocalin (NGAL), interleukin 18 (IL-18), and retinol-binding protein are emerging urinary biomarkers that have shown promise in detecting subclinical and clinical renal impairment. In this study, we assessed changes in these urinary biomarkers as well as serum creatinine (SCr) in patients undergoing EVAR. Urine samples were collected prospectively at 5 time points for each recruited patient: pre-EVAR (baseline) and 6, 12, 24, and 48 hours after the procedure for serial assessment of urinary biomarkers. Serum creatinine was quantified preoperatively and at 24 and 48 hours postoperatively. Serial changes of urinary biomarkers and SCr were assessed. A significant increase in NGAL and IL-18 from baseline was observed (P < .05), as early as 6 hours for NGAL. A significant rise in levels of NGAL and IL-18 precedes the significant rise in SCr. These findings highlight the potential of emerging urinary biomarkers in detecting early AKI following EVAR.

Editor's Choice – Calcification of Thoracic and Abdominal Aneurysms is Associated with Mortality and Morbidity

Introduction Cardiovascular events are common in people with aortic aneurysms. Arterial calcification is a recognised predictor of cardiovascular outcomes in coronary artery disease. Whether calcification within abdominal and thoracic aneurysm walls is correlated with poor cardiovascular outcomes is not known. Patients and methods Calcium scores were derived from computed tomography (CT) scans of consecutive patients with either infrarenal (AAA) or descending thoracic aneurysms (TAA) using the modified Agatston score. The primary outcome was subsequent all cause mortality during follow-up. Secondary outcomes were cardiovascular mortality and morbidity. Results A total of 319 patients (123 TAA and 196 AAA; median age 77 [71–84] years, 72% male) were included with a median follow-up of 30 months. The primary outcome occurred in 120 (37.6%) patients. In the abdominal aortic aneurysm group, the calcium score was significantly related to both all cause mortality and cardiac mortality (odds ratios (OR) of 2.246 (95% CI 1.591–9.476; p < 0.001) and 1.321 (1.076–2.762; p = 0.003)) respectively. In the thoracic aneurysm group, calcium score was significantly related to all cause mortality (OR 6.444; 95% CI 2.574–6.137; p < 0.001), cardiac mortality (OR 3.456; 95% CI 1.765–4.654; p = 0.042) and cardiac morbidity (OR 2.128; 95% CI 1.973–4.342; p = 0.002). Conclusions Aortic aneurysm calcification, in either the thoracic or the abdominal territory, is significantly associated with both higher overall and cardiovascular mortality. Calcium scoring, rapidly derived from routine CT scans, may help identify high risk patients for treatment to reduce risk.

18 F-FDG Uptake on PET/CT in Symptomatic versus Asymptomatic Carotid Disease: a Meta-Analysis

Introduction The role of positron emission tomography (PET)/computed tomography (CT) in the determination of inflammation in arterial disease is not well defined. This can provide information about arterial wall inflammation in atherosclerotic disease, and may give insight into plaque stability. The aim of this review was to perform a meta-analysis of PET/CT with 18F-FDG (fluorodeoxyglucose) uptake in symptomatic and asymptomatic carotid artery disease. Methods This was a systematic review, following PRISMA guidelines, which interrogated the MEDLINE database from January 2001 to May 2017. The search combined the terms, “inflammation”, “FDG”, and “stroke”. The search criteria included all types of studies, with a primary outcome of the degree of arterial vascular inflammation determined by 18F-FDG uptake. Analysis involved an inverse weighted variance estimate of pooled data, using a random effects model. Results A total of 14 articles (539 patients) were included in the meta-analysis. Comparing carotid artery 18F-FDG uptake in symptomatic versus asymptomatic disease yielded a standard mean difference of 0.94 (95% CI 0.58–1.130; p < .0001; I2 = 65%). Conclusions PET/CT using 18F-FDG can demonstrate carotid plaque inflammation, and is a marker of symptomatic disease. Further studies are required to understand the clinical implication of PET/CT as a risk prediction tool.

Mechanochemical Ablation for Treatment of Truncal Venous Insufficiency: A Review of the Current Literature

Mechanochemical ablation (MOCA) is a nonthermal nontumescent technique used in the treatment of superficial venous disease. This review analyzed the available data on the efficacy and safety of MOCA. A systematic literature search was performed. Of 101 studies identified, 14 were suitable for inclusion. The studies were found to be heterogeneous in design, and the quality of evidence was found to be low or very low. MOCA was demonstrated to be effective in the short-term with minimal complications. Consensus guidelines and definitions of reporting outcome measures must be standardized to allow comparison with other techniques.

208 Arterial Inflammation and Calcification in Patients with Lower Limb Atherosclerosis using PET/CT Analysis: A Proof-of-Principle Study

Introduction Lower limb peripheral arterial disease (PAD) is common. Atherosclerotic development is linked with inflammatory and calcific processes occurring at the vessel wall, having been evaluated in the coronary and carotid circulation using PET/CT analysis with the 18F FDG (inflammation) and 18F NaF (calcification) tracers. Methods 8 patients (16 legs; 5 men, median age 74.5 years; IQR (69.5–77.5)) with a diagnosis of intermittent claudication were prospectively recruited to the study. PET/CT analysis was undertaken in each patient using both tracers. The lower limb arterial tree was examined from the aortic bifurcation to the ankle. The degree of arterial calcification (AC) was measured using a modified Agatston score. Arterial 18F-NaF and 18F-FDG uptake was determined using standard protocols and measured by drawing regions of interest and normalised to tracer levels in the common femoral vein to obtain the arterial target-to-background ratio (TBR). Correlation between tracer uptake and AC was determined using Pearson’s correlation. Results The overall whole limb median (IQR) TBR levels for 18F NaF was 1.30 (0.98–1.74) and for 18F FDG was 1.42 (1.11–1.75). The median limb AC score was 1954.5 (1198–3216). A positive correlation was observed when arterial 18F FDG uptake was correlated with 18F NaF uptake (p = 0.000, r = 0.611) and AC score (p = 0.009, r = 0.654). An inverse correlation was found when correlating 18F NaF tracer uptake with AC score (p = 0.004, r=–0.765). Conclusion Lower limb disease progression will lead to increased atherosclerotic burden with a potential risk of amputation. This study is the first to determine the inter-relationship between inflammation and calcification within the lower limb arterial tree. Further studies are required to look at longer-term sequelae of atherosclerotic progression/development.