Non-lipid-rich low attenuation plaque with intraplaque haemorrhage assessed by multimodality imaging: a case report

Background The lipid-rich necrotic core is a major pathological hallmark of acute coronary syndrome. Low attenuation plaque (LAP) on coronary computed tomography angiography (CCTA), defined as plaque CT attenuation of <30 Hounsfield units, is commonly believed to correspond to the lipid component. This report presents a non-lipid-rich LAP with intraplaque haemorrhage of the left main coronary artery (LM), as assessed by CCTA, near-infrared spectroscopy (NIRS), and non-contrast magnetic resonance imaging (MRI) using coronary atherosclerosis T1-weighted characterisation with integrated anatomical reference technique, recently developed by our group. Case Summary A 75-year-old woman presented with chest discomfort on exertion. CCTA revealed severe stenosis of the mid-left circumflex coronary artery and minimal stenosis with a large eccentric LM plaque. The LM lesion had an LAP, with a minimum plaque attenuation of 25 Hounsfield units. On non-contrast T1-weighted MRI, a high-intensity plaque with a plaque-to-myocardium signal intensity ratio of 3.02 was observed within the vessel wall, indicating intraplaque haemorrhage. NIRS categorised the lesion as non-lipid-rich, with a maximum lipid core burden index in 4 mm of 169. Discussion Intraplaque haemorrhage is a key feature of plaque instability, which is different from the lipid-rich necrotic core. Non-contrast T1-weighted MRI is ideal for detecting intraplaque haemorrhage with short T1 values. The imaging findings suggest that LAP on CCTA may represent not only lipid-rich plaques but also intraplaque haemorrhage. MRI provides a unique insight into plaque vulnerability from a different perspective than lipid assessment. Multimodality imaging, including MRI, facilitates the understanding complicated plaque morphologies.

18Fluorodeoxyglucose uptake in relation to fat fraction and R2* in atherosclerotic plaques, using PET/MRI: a pilot study

Inflammation inside Atherosclerotic plaques represents a major pathophysiological process driving plaques towards rupture. Pre-clinical studies suggest a relationship between lipid rich necrotic core, intraplaque hemorrhage and inflammation, not previously explored in patients. Therefore, we designed a pilot study to investigate the feasibility of assessing the relationship between these plaque features in a quantitative manner using PET/MRI. In 12 patients with high-grade carotid stenosis the extent of lipid rich necrotic core and intraplaque hemorrhage was quantified from fat and R2* maps acquired with a previously validated 4-point Dixon MRI sequence in a stand-alone MRI. PET/MRI was used to measure 18F-FDG uptake. T1-weighted images from both scanners were used for registration of the quantitative Dixon data with the PET images. The plaques were heterogenous with respect to their volumes and composition. The mean values for the group were as follows: fat fraction (FF) 0.17% (± 0.07), R2* 47.6 s−1 (± 10.9) and target-to-blood pool ratio (TBR) 1.49 (± 0.48). At group level the correlation between TBR and FFmean was − 0.406, p 0.19 and for TBR and R2*mean 0.259, p 0.42. The lack of correlation persisted when analysed on a patient-by-patient basis but the study was not powered to draw definitive conclusions. We show the feasibility of analysing the quantitative relationship between lipid rich necrotic cores, intraplaque haemorrhage and plaque inflammation. The 18F-FDG uptake for most patients was low. This may reflect the biological complexity of the plaques and technical aspects inherent to 18F-FDG measurements.Trial registration: ISRCTN, ISRCTN30673005. Registered 05 January 2021, retrospectively registered.

Monte Carlo and Tissue-Phantom studies of Photoacoustic Imaging of Carotid Intraplaque Haemorrhage

Strokes are the second leading cause of death worldwide. Vulnerable carotid plaques are a primary cause of stroke, with carotid Intraplaque Haemmorrghages being a key feature of vulnerability. MR imaging, which is sensitive to the presence of endogenous Methemoglobin (MetHb), is used to detect IPH. MRI is however expensive, and not readily available. We propose the use of Photoacoustic Imaging (PAI) for the detection of IPH, with MetHb being the primary PA imaging target. I examine the feasibility of this approach by performing Monte Carlo studies of light propagation, energy deposition and PA generation in tissuemimicking models, as well as experimental PA measurements of MetHb in tissue-mimicking phantoms. I show that is possible to achieve an SNR of ∼50dB at the average carotid artery depth of ∼21mm, with the possibility of imaging up to ≥ 32mm in Type I skin using commonly available hardware.

Monte Carlo and Tissue-Phantom studies of Photoacoustic Imaging of Carotid Intraplaque Haemorrhage

Strokes are the second leading cause of death worldwide. Vulnerable carotid plaques are a primary cause of stroke, with carotid Intraplaque Haemmorrghages being a key feature of vulnerability. MR imaging, which is sensitive to the presence of endogenous Methemoglobin (MetHb), is used to detect IPH. MRI is however expensive, and not readily available. We propose the use of Photoacoustic Imaging (PAI) for the detection of IPH, with MetHb being the primary PA imaging target. I examine the feasibility of this approach by performing Monte Carlo studies of light propagation, energy deposition and PA generation in tissuemimicking models, as well as experimental PA measurements of MetHb in tissue-mimicking phantoms. I show that is possible to achieve an SNR of ∼50dB at the average carotid artery depth of ∼21mm, with the possibility of imaging up to ≥ 32mm in Type I skin using commonly available hardware.

Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization

Objective Statins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear. Therefore, we discriminated statin’s lipid-lowering dependent and independent effects on IPA and IPH. Approach and results ApoE3*Leiden mice are statin-responsive due to ApoE and LDLR presence, but also allow to titrate plasma cholesterol levels by diet. Therefore, ApoE3*Leiden mice were fed a high-cholesterol-inducing-diet (HCD) with or without atorvastatin (A) or a moderate-cholesterol-inducing-diet (MCD). Mice underwent vein graft surgery to induce lesions with IPA and IPH. Cholesterol levels were significantly reduced in MCD (56%) and HCD + A (39%) compared to HCD with no significant differences between MCD and HCD + A. Both MCD and HCD + A have a similar reduction in vessel remodeling and inflammation comparing to HCD. IPA was significantly decreased by 30% in HCD + A compared to HCD or MCD. Atorvastatin treatment reduced the presence of immature vessels by 34% vs. HCD and by 25% vs. MCD, resulting in a significant reduction of IPH. Atorvastatin’s anti-angiogenic capacity was further illustrated by a dose-dependent reduction of ECs proliferation and migration. Cultured mouse aortic-segments lost sprouting capacity upon atorvastatin treatment and became 30% richer in VE-Cadherin expression and pericyte coverage. Moreover, Atorvastatin inhibited ANGPT2 release and decreased VE-Cadherin(Y685)-phosphorylation in ECs. Conclusions Atorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization.

Metformin directly suppresses atherosclerosis in normoglycaemic mice via haematopoietic adenosine monophosphate-activated protein kinase

Aims Atherosclerotic vascular disease has an inflammatory pathogenesis. Heme from intraplaque haemorrhage may drive a protective and pro-resolving macrophage M2-like phenotype, Mhem, via AMPK and activating transcription factor 1 (ATF1). The antidiabetic drug metformin may also activate AMPK-dependent signalling. Hypothesis: Metformin systematically induces atheroprotective genes in macrophages via AMPK and ATF1, thereby suppresses atherogenesis. Methods and results Normoglycaemic Ldlr−/− hyperlipidaemic mice were treated with oral metformin, which profoundly suppressed atherosclerotic lesion development (P < 5 × 10−11). Bone marrow transplantation from AMPK-deficient mice demonstrated that metformin-related atheroprotection required haematopoietic AMPK [analysis of variance (ANOVA), P < 0.03]. Metformin at a clinically relevant concentration (10 μM) evoked AMPK-dependent and ATF1-dependent increases in Hmox1, Nr1h2 (Lxrb), Abca1, Apoe, Igf1, and Pdgf, increases in several M2-markers and decreases in Nos2, in murine bone marrow macrophages. Similar effects were seen in human blood-derived macrophages, in which metformin-induced protective genes and M2-like genes, suppressible by si-ATF1-mediated knockdown. Microarray analysis comparing metformin with heme in human macrophages indicated that the transcriptomic effects of metformin were related to those of heme, but not identical. Metformin-induced lesional macrophage expression of p-AMPK, p-ATF1, and downstream M2-like protective effects. Conclusion Metformin activates a conserved AMPK-ATF1-M2-like pathway in mouse and human macrophages, and results in highly suppressed atherogenesis in hyperlipidaemic mice via haematopoietic AMPK.

Comparison of carotid atherosclerotic plaques between subjects in Northern and Southern China: a Chinese atherosclerosis risk evaluation study

Background and purposeTo investigate differences in the characteristics of carotid atherosclerotic plaques of symptomatic subjects in northern and southern China using MRI.MethodsSixty-three subjects in northern China (mean age: 59.1±8.6 years, 45 men) and 56 subjects in southern China (mean age: 60.4±8.6 years, 38 men) were included. All subjects underwent carotid artery multicontrast vessel wall MRI. Plaque morphology, calcification, lipid-rich necrotic core, intraplaque haemorrhage, luminal surface disruption and high-risk plaque were measured and identified. All plaque characteristics were compared between subjects in northern and southern China using Mann-Whitney U test or χ2 test.ResultsCompared with subjects in southern China, those in northern China had significantly greater areas for lumen (57.7±14.9 mm2 vs 50.4±18.3 mm2, p=0.009), wall (38.4±13.1 mm2 vs 31.9±11.7 mm2, p<0.001) and total vessel (96.1±20.2 mm2 vs 82.4±22.7 mm2, p=0.001) and mean wall thickness (1.25±0.43 mm vs 1.13±0.40 mm, p=0.019). χ2 analysis showed that subjects in northern China tended to have a higher prevalence of intraplaque haemorrhage (14.3% vs 5.4%, p=0.106) and high-risk plaque (20.6% vs 10.7%, p=0.140) than those in southern China, although these differences were not statistically significant (all p>0.05).ConclusionSubjects in northern China have significantly larger vessel size and may have a higher prevalence of vulnerable plaques than those in southern China. Our findings provide additional perspective to optimise the management of cerebrovascular disease in individuals in different regions in China.Trial registration numberNCT02017756

Different risk factors in identical features of intracranial atherosclerosis plaques in the posterior and anterior circulation in high-resolution MRI

Background: We constructed a high-volume registry to identify whether risk factors of intracranial atherosclerotic plaque (ICAP) features differ in the posterior and anterior circulation in patients with symptomatic intracranial atherosclerotic stenosis (ICAS) investigated by high-resolution magnetic resonance imaging (HRMRI). Methods: The registry was constructed for patients with symptomatic ICAS who underwent HRMRI for culprit plaques. ICAP-vulnerable features included positive remodelling, diffuse distribution, intraplaque haemorrhage and strong enhancement. Results: We analysed risk factors for the same ICAP features between the posterior and anterior circulation in data of 97 patients in the posterior circulation and 105 patients in the anterior circulation ICAPs. In patients with diffuse distribution, the probability of being female were lower [odds ratio (OR):0.08; 95% confidence interval (CI):0.02–0.34; p = 0.001] and having diabetes mellitus was higher (OR: 7.75; 95% CI:1.75–34.39; p = 0.007) in posterior circulation patients. In patients with strong enhancement, the probability of having diabetes was higher in posterior circulation patients (OR:6.71; 95% CI:1.37–32.81; p = 0.019). Conclusions: Our results demonstrate more risk factors in the posterior than in the anterior circulation in patients with the same ICAP-vulnerable features, highlighting the need for stratification of risk factors in symptomatic ICAPs. Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02705599.