Vascular Inflammation and Aortic Stiffness: Potential Mechanisms of Increased Vascular Risk in Chronic Obstructive Pulmonary Disease

ABSTRACT Background: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition in which an important extra-pulmonary manifestation is cardiovascular disease. We hypothesized that COPD patients would have increased aortic inflammation and stiffness, as candidate mechanisms mediating increased cardiovascular risk, compared to two negative control groups: healthy never-smokers and smokers without COPD. We also studied patients with COPD due to alpha-1 antitrypsin deficiency (α1ATD) as a comparator lung disease group. Methods: Participants underwent 18F-Fluorodeoxyglucose (FDG) positron emission tomography imaging to quantify aortic inflammation as the tissue-to-blood-ratio (TBR) of FDG uptake. Aortic stiffness was measured by carotid-femoral aortic pulse wave velocity (aPWV). Results: Eighty-five usual COPD (COPD due to smoking), 12 α1ATD-COPD patients and 12 each smokers and never-smokers were studied. There was no difference in pack years smoked between COPD patients and smokers (45±25 vs 37±19, p=0.36), but α1ATD patients smoked significantly less (19±11, p<0.001 for both). By design, spirometry measures were lower in COPD and α1ATD-COPD patients compared to smokers and never-smokers. Aortic inflammation and stiffness were increased in COPD (TBR: 1.90±0.38, aPWV: 9.9±2.6 m/s) and α1ATD patients (TBR: 1.94±0.43, aPWV: 9.5±1.8 m/s) compared with smokers (TBR: 1.74±0.30, aPWV: 7.8±1.8 m/s, p<0.05 all) and never-smokers (TBR: 1.71±0.34, aPWV: 7.9±1.7 m/s, p≤0.05 all). Conclusions: In this cross-sectional prospective study, novel findings were that both usual COPD and α1ATD-COPD patients have increased aortic inflammation and stiffness compared to smoking and never-smoking controls, regardless of smoking history. These findings suggest that the presence of COPD lung disease per se may be associated with adverse aortic wall changes, and aortic inflammation and stiffening are potential mechanisms mediating increased vascular risk observed in COPD patients

Molecular imaging of atherosclerosis with integrated PET imaging

Atherosclerotic diseases account for nearly half of all deaths and are leading causes of adult disability. Our understanding of how atherosclerosis leads to cardiovascular disease events has evolved: from a concept of progressive luminal narrowing, to that of sudden rupture and thrombosis of biologically active atheroma. In concert with this conceptual shift, contemporary imaging techniques now allow imaging of biological processes that associate with plaque instability: active calcification and plaque inflammation. This review focuses on opportunities provided by positron emission tomography/computed tomography, to identify these high-risk biological features of atherosclerosis.BH is supported by Research Training grant from Alexandria University. NRE is supported by a Research Training Fellowship from The Dunhill Medical Trust [Grant Number RTF44/0114]. JHFR is part supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, EPSRC, and the Wellcome Trust. AT reports grants from NIH/NHLBI, Actelion, Genentech and Takeda, and personal fees from Actelion, Amgen AstraZeneca, and Takeda, all outside the submitted work

PET imaging of the neurovascular interface in cerebrovascular disease

Cerebrovascular disease encompasses a range of pathologies affecting different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate metabolic processes that are key to pathogenesis. Although structural imaging has been a mainstay of stroke clinical care and research, it has limited ability to detect these pathophysiological processes in vivo. Positron emission tomography (PET) provides a means to detect and quantify metabolic processes in each facet of cerebrovascular disease non-invasively. The use of PET has helped shape the understanding of key concepts in cerebrovascular medicine, including the vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult, and the relationships between chronic hypoxia, neuroinflammation, and amyloid deposition in cerebral small vessel disease. This review considers how the ability to image these processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease and facilitated translational research to advance clinical care.N.R.E. is supported by a research training fellowship from The Dunhill Medical Trust (grant number RTF44/0114). J.M.T. is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). J.H.F.R. is part-supported by the Higher Education Funding Council for England (HEFCE), the British Heart Foundation, and the Wellcome Trust. H.S.M. is supported by the Medical Research Council (MRC) as a National Institute for Health Research (NIHR) Senior Investigator. E.A.W. is supported by the British Heart Foundation. H.S.M., J.H.F.R., and E.A.W. are supported by the NIHR Cambridge Biomedical Research Centre

Coronary CT angiography features of ruptured and high-risk atherosclerotic plaques: Correlation with intra-vascular ultrasound

BACKGROUND: Features of ruptured and high-risk plaque have been described on coronary computed tomography angiography (coronary CTA), but not systematically assessed against intravascular ultrasound (IVUS). We examined the ability of coronary CTA to identify IVUS defined ruptured plaque and Virtual Histology Intravascular Ultrasound (VH-IVUS) defined thin-cap fibroatheroma (TCFA). METHODS: Sixty-three patients (32 with acute coronary syndrome and 31 with stable angina) underwent coronary CTA, IVUS and VH-IVUS. Plaque rupture on CTA was defined as intra-plaque contrast and its frequency compared with IVUS-defined plaque rupture. We then examined the relationship of conventional coronary CTA high-risk features (low attenuation plaque, positive remodeling, spotty calcification and the Napkin-Ring sign) in VH-IVUS-defined TCFA. We compared these with a novel index based on quantifying the ratio of necrotic core to fibrous plaque using x-ray attenuation cut-offs derived from the relationship of plaque to luminal contrast attenuation. RESULTS: Of the 71 plaques interrogated with IVUS, 39 were ruptured. Coronary CTA correctly detected 13-ruptured plaques with 3 false positives giving high specificity (91%) but low sensitivity (33%). None of the conventional coronary CTA high-risk features were significantly more frequent in the higher-risk (VH-IVUS defined thin-cap) compared with thick-cap fibroatheroma. However, the new index (necrotic core/fibrous plaque ratio) was higher in thin-cap (mean 0.90) vs. thick-cap fibroatheroma (mean 0.59), p < 0.05. CONCLUSIONS: Compared with intravascular ultrasound, coronary CTA identifies ruptured plaque with good specificity but poor sensitivity. We have identified a novel high-risk feature on coronary CTA (necrotic core/fibrous plaque ratio that is associated with VH-IVUS defined-TCFA.Supported by a British Heart Foundation grant FS/10/025/2819

Positron Emission Tomography and Magnetic Resonance Imaging of Cellular Inflammation in Patients with Abdominal Aortic Aneurysms.

OBJECTIVES: Inflammation is critical in the pathogenesis of abdominal aortic aneurysm (AAA) disease. Combined (18)F-fludeoxyglucose ((18)F-FDG) positron emission tomography with computed tomography (PET-CT) and ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) are non-invasive methods of assessing tissue inflammation. The aim of this study was to compare these techniques in patients with AAA. MATERIALS AND METHODS: Fifteen patients with asymptomatic AAA with diameter 46 ± 7 mm underwent PET-CT with (18)F-FDG, and T2*-weighted MRI before and 24 hours after administration of USPIO. The PET-CT and MRI data were then co-registered. Standardised uptake values (SUVs) were calculated to measure (18)F-FDG activity, and USPIO uptake was determined using the change in R2*. Comparisons between the techniques were made using a quadrant analysis and a voxel-by-voxel evaluation. RESULTS: When all areas of the aneurysm were evaluated, there was a modest correlation between the SUV on PET-CT and the change in R2* on USPIO-enhanced MRI (n = 70,345 voxels; r = .30; p < .0001). Although regions of increased (18)F-FDG and USPIO uptake co-localised on occasion, this was infrequent (kappa statistic 0.074; 95% CI 0.026-0.122). (18)F-FDG activity was commonly focused in the shoulder region whereas USPIO uptake was more apparent in the main body of the aneurysm. Maximum SUV was lower in patients with mural USPIO uptake. CONCLUSIONS: Both (18)F-FDG PET-CT and USPIO-MRI uptake identify vascular inflammation associated with AAA. Although they demonstrate a modest correlation, there are distinct differences in the pattern and distribution of uptake, suggesting a differential detection of macrophage glycolytic and phagocytic activity respectively.This research was supported by grants from the National Institutes of Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (11/20/03), the British Heart Foundation (PG/09/083) and the Evelyn Trust (09/22). Dr. McBride is supported by the Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine. Dr. Joshi is supported by Chief Scientist Office (ETM/160). Dr. van Beek is supported by the Scottish Imaging Network e a Platform of Scientific Excellence. The work of Dr. Rudd is part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation and the Wellcome Trust. Dr. Newby is supported by the British Heart Foundation (CH/09/002). The Wellcome Trust Clinical Research Facility and the Clinical Research Imaging Centre are supported by National Health Service Research Scotland through National Health Service Lothian.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ejvs.2015.12.01

Lower limb arterial calcification (LLAC) scores in patients with symptomatic peripheral arterial disease are associated with increased cardiac mortality and morbidity

Aims The association of coronary arterial calcification with cardiovascular morbidity and mortality is well-recognized. Lower limb arterial calcification (LLAC) is common in PAD but its impact on subsequent health is poorly described. We aimed to determine the association between a LLAC score and subsequent cardiovascular events in patients with symptomatic peripheral arterial disease (PAD). Methods LLAC scoring, and the established Bollinger score, were derived from a database of unenhanced CT scans, from patients presenting with symptomatic PAD. We determined the association between these scores outcomes. The primary outcome was combined cardiac mortality and morbidity (CM/M) with a secondary outcome of all-cause mortality. Results 220 patients (66% male; median age 69 years) were included with follow-up for a median 46 [IQR 31–64] months. Median total LLAC scores were higher in those patients suffering a primary outcome (6831 vs. 1652; p = 0.012). Diabetes mellitus (p = 0.039), ischaemic heart disease (p = 0.028), chronic kidney disease (p = 0.026) and all-cause mortality (p = 0.012) were more common in patients in the highest quartile of LLAC scores. The area under the curve of the receiver operator curve for the LLAC score was greater (0.929: 95% CI [0.884–0.974]) than for the Bollinger score (0.824: 95% CI [0.758–0.890]) for the primary outcome. A LLAC score ≥ 4400 had the best diagnostic accuracy to determine the outcome measure. Conclusion This is the largest study to investigate links between lower limb arterial calcification and cardiovascular events in symptomatic PAD. We describe a straightforward, reproducible, CT-derived measure of calcification—the LLAC score.M.M.C. is supported by the Royal College of Surgeons of England Fellowship Programme and a British Heart Foundation Research Fellowship award FS/16/29/31957. J.M.T. is supported by a Wellcome Trust Research Training Fellowship (104492/Z/14/Z). J.H.F.R. is part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, HEFCE and the Wellcome Trust

Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis

$\textbf{BACKGROUND}$: 18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan-rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging. $\textbf{METHODS AND RESULTS}$: Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias -0.05, limits of agreement -0·20 to +0·11). $\textbf{CONCLUSIONS}$: Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies. $\textbf{CLINICAL TRIAL REGISTRATION}$ - URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.The study was funded by the British Heart Foundation (FS/14/78/31020). Drs Pawade, Cartlidge, Jenkins, Dweck, and Newby are supported by the British Heart Foundation (SS/CH/09/002/26360, FS/13/77/30488, SS/CH/09/002/2636, FS/14/78/31020, and CH/09/002). Dr Newby is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr Dweck is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015. Dr Adamson is supported by New Zealand Overseas Training and Research Fellowship (1607) and Edinburgh and Lothians Health Foundation (50–534). The Wellcome Trust Clinical Research Facility and the Clinical Research Imaging Centre are supported by NHS Research Scotland (NRS) through NHS Lothian. Dr Rudd is partly supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust

Vascular Imaging With 18^{18}F-Fluorodeoxyglucose Positron Emission Tomography Is Influenced by Hypoxia

This study was funded by a programme grant (RG/10/007/28300) from the British Heart Foundation (BHF). Dr. Joshi was supported by a BHF Clinical Research Training Fellowship (FS/12/29/29463), a British Atherosclerosis Society Binks Trust Travel Award, and a Raymond and Beverly Sackler PhD Studentship. Dr. Manavaki is funded by the NIHR Cambridge Biomedical Research Centre. Dr. Rudd is partially supported by the NIHR Cambridge Biomedical Research Centre, the BHF, The Wellcome Trust, and the EPSRC Cambridge Centre for Mathematical Imaging in Healthcare

Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs