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This study firstly developed a hiPSC-derived lineage-specific SMC-on-a-chip model and identified the segmental aortic heterogeneity. The model can be used for disease modelling, drug testing and personalised treatment.

Xiaonan Zhou,1,2,&ast; Kai Zhu,1,2,&ast; Yiqiu Zhang,3– 5,&ast; Yang Ming,1,2 Dai Shi,3– 5 Hui Tan,3– 5 Bitao Xiang,1,2 Shichao Zhu,1,2 Dengfeng Cheng,3– 5 Hao Lai,1,2 Chunsheng Wang,1,2 Guobing Liu3– 5 1Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, People’s Republic of China; 3Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 4Institute of Nuclear Medicine, Fudan University, Shanghai, 200032, People’s Republic of China; 5Shanghai Institute of Medical Imaging, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guobing Liu, Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Tel +8618317086732, Fax +86-21-62489191, Email liu.guobing@zs-hospital.sh.cn Chunsheng Wang, Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Email wangchunsheng@fudan.edu.cnPurpose: To investigate the feasibility of a pre-targeted imaging strategy based on the cycloaddition between 1,2,4,5-terazine (Tz) and trans-cyclooctene (TCO) for evaluating CD11b expression in inflammatory aortic aneurysm (AA) using single photon emission computed tomography/computed tomography (SPECT/CT).Methods: C57BL/6J mice were fed β-aminopropionitrile (1 g/kg/day) for 4 weeks to establish AA models. Anti-CD11b-TCO was synthesized and 99mTc-HYNIC-PEG11-Tz was designed for pre-targeted SPECT/CT. The affinity and specificity of the probe for the inflammatory cell line Raw-264.7 were investigated. Then, anti-CD11b-TCO pre-targeted and 99mTc-HYNIC-PEG11-Tz based SPECT/CT were performed to detect in vivo inflammation in AA. Finally, ex vivo aortic breast-specific gamma imaging (BSGI), Western blot assays, and immunohistochemical CD11b staining were performed to confirm the in vivo findings of SPECT/CT.Results: In the AA models, 65.22% (15/23) had aortic lesions, including 43.48% (10/23) AA lesions. The anti-CD11b-TCO presented with a high TCO coupling ratio (7.43), and the 99mTc-HYNIC-PEG11-Tz showed high radio-purity (> 95%), good in vitro stability and a rapid clearance rate. Additionally, anti-CD11b-TCO and 99mTc-HYNIC-PEG11-Tz presented high click rate (∼ 89%). The in vitro clicked compound, 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b, showed high affinity and specificity for Raw-264.7 cells. 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b pre-targeting SPECT/CT successfully demonstrated inflammatory AA with a high AA-to-background ratio in AA mice, compared to AA mice that were injected with 99mTc-HYNIC-Tz/TCO-IgG (8.13 versus 3.71, P < 0.001) and control mice injected with 99mTc-HYNIC-Tz/TCO-anti-CD11b (8.13 versus 3.66, P < 0.001). This result was confirmed by ex vivo BSGI performed immediately after SPECT/CT and immunohistochemical CD11b staining.Conclusion: SPECT/CT imaging using the anti-CD11b-TCO/Tz-PEG11-HYNIC-99mTc based pre-targeting imaging strategy allows for the detection of inflammation in progressive AA.Keywords: aortic aneurysm, inflammation, SPECT/CT, CD11b, macrophage

Background The impact of new‐onset atrial fibrillation (AF) after aortic valve (AV) surgery on mid‐ and long‐term outcomes is under debate. Here, we sought to follow up heart rhythms after AV surgery, and to evaluate the mid‐term prognosis and effectiveness of treatment for patients with new‐onset AF. Methods This single‐center cohort study included 978 consecutive patients (median age, 59 years; male, 68.5%) who underwent surgical AV procedures between 2017 and 2018. All patients with postoperative new‐onset AF were treated with Class III antiarrhythmic drugs with or without electrical cardioversion (rhythm control). Status of survival, stroke, and rhythm outcomes were collected and compared between patients with and without new‐onset AF. Results New‐onset AF was detected in 256 (26.2%) patients. For them, postoperative survival was comparable with those without new‐onset AF (1‐year: 96.1% vs. 99.3%; adjusted P = .30), but rate of stroke was significantly higher (1‐year: 4.0% vs. 2.2%; adjusted P = .020). With rhythm control management, the 3‐month and 1‐year rates of paroxysmal or persistent AF between patients with and without new‐onset AF were 5.1% versus 1.3% and 7.5% versus 2.1%, respectively (both P

Aortic aneurysm (AA) remains one of the primary causes of death worldwide. Of the major treatments, prophylactic operative repair is used for AA to avoid potential aortic dissection or rupture. To halt the development of AA and alleviate its progression into aortic dissection, pharmacological treatment has been investigated for years. Currently, β-adrenergic blocking agents, losartan, irbesartan, angiotensin-converting-enzyme inhibitors, statins, antiplatelet agents, doxycycline, and metformin have been investigated as potential candidates for preventing AA progression. However, the paradox between preclinical successes and clinical failures still exists, with no medical therapy currently available for ideally negating the disease progression. This review describes the current drugs used for pharmacological management of AA and their individual potential mechanisms. Preclinical models for drug screening and evaluation are also discussed to gain a better understanding of the underlying pathophysiology and ultimately find new therapeutic targets for AA.

Conventional two-dimensional cell culture techniques and animal models have been used in the study of human thoracic aortic aneurysm and dissection (TAAD). However, human TAAD sometimes cannot be characterized by animal models. There is an apparent species gap between clinical human studies and animal experiments that may hinder the discovery of therapeutic drugs. In contrast, the conventional cell culture model is unable to simulate in vivo biomechanical stimuli. To this end, microfabrication and microfluidic techniques have developed greatly in recent years, providing novel techniques for establishing organoids-on-a-chip models that replicate the biomechanical microenvironment. In this study, a human aorta smooth muscle cell organ-on-a-chip (HASMC-OOC) model was developed to simulate the pathophysiological parameters of aortic biomechanics, including the amplitude and frequency of cyclic strain experienced by human aortic smooth muscle cells (HASMCs) that play a vital role in TAAD. In this model, the morphology of HASMCs became elongated in shape, aligned perpendicularly to the strain direction, and presented a more contractile phenotype under strain conditions than under static conventional conditions. This was consistent with the cell orientation and phenotype in native human aortic walls. Additionally, using bicuspid aortic valve-related TAAD (BAV-TAAD) and tricuspid aortic valve-related TAAD (TAV-TAAD) patient-derived primary HASMCs, we established BAV-TAAD and TAV-TAAD disease models, which replicate HASMC characteristics in TAAD. The HASMC-OOC model provides a novel in vitro platform that is complementary to animal models for further exploring the pathogenesis of TAAD and discovering therapeutic targets.

Air pollution is a major public health concern worldwide. Exposure to fine particulate matter (PM2.5) is closely associated with cardiovascular diseases. However, the effect of PM2.5 exposure on thoracic aortic aneurysm and dissection (TAAD) has not been fully elucidated. Diesel exhaust particulate (DEP) is an important component of PM2.5, which causes health effects and is closely related to the incidence of cardiovascular disease. In the current study, we found that DEP exposure increased the incidence of aortic dissection (AD) in β-aminopropionitrile (BAPN)-induced thoracic aortic aneurysm (TAA). In addition, exposure to PM2.5 increased the diameter of the thoracic aorta in mice models. The number of apoptotic cells increased in the aortic wall of PM2.5-treated mice, as did the protein expression level of BAX/Bcl2 and cleaved caspase3/caspase3. Using a rhythmically stretching aortic mechanical simulation model, fluorescent staining indicated that PM2.5 administration could induce mitochondrial dysfunction and increase reactive oxygen species (ROS) levels in human aortic smooth muscle cells (HASMCs). Furthermore, ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathways participated in the apoptosis of HASMCs after PM2.5 exposure. Therefore, we concluded that PM2.5 exposure could exacerbate the progression of TAAD, which could be induced by the increased apoptosis in HASMCs through the ERK1/2 MAPK signaling pathway.

Objective In the absence of randomized trials, the optimal approach to managing coexisting severe carotid and coronary diseases remains controversial. The aim of this study was to present the midterm follow-up results of patients who received a coronary artery bypass graft (CABG) after carotid revascularization and to compare the risk-adjusted outcomes of two approaches to carotid revascularization in the CABG population in a single center. Methods From January 2011 to December 2016, 245 patients underwent carotid revascularization within 90 days before CABG in Fuwai Hospital, including 32 who received combined carotid endarterectomy (CEA) and CABG (CEA-CABG), 208 who received staged carotid artery stenting (CAS) before CABG (CAS before CABG), and 5 who underwent a hybrid procedure of carotid stenting and coronary surgery (combined CAS-CABG). The primary composite end points were all-cause death, stroke, and myocardial infarction (MI). Therefore, the multivariable logistic regression analyses and propensity score-adjusted multiphase hazard function model were used to analyze the association between the types of revascularization, complications, and risk-adjusted mortality. Results One patient (3.13%) died 6 months after the CABG surgery in the combined CEA-CABG group. In the staged CAS group, 9 patients (4.33%) died after CABG surgery, including 3, 2, and 4 patients who died within 30 days, 1 year, and after 1 year (mean time after CABG surgery, 39 months; adjusted odds ratio [OR], 2.188; 95% confidence interval [CI], 0.251-19.093; P = .479), respectively. Stroke was observed in three patients (9.38%) in the combined CEA group and in 12 patients (5.77%) in the staged CAS group (OR, 0.625; 95% CI, 0.133-2.935; P = .552). The rates of MI were 6.25% and 7.21% for the combined and staged groups, respectively (adjusted OR, 1.249; 95% CI, 0.250-6.324; P = .787). In addition, composite events occurred in five (15.63%) and 33 patients (15.87%) in the combined and staged groups, respectively (adjusted OR, 1.362, 95% CI, 0.455-4.077; P = .581). No statistically significant differences were observed in the overall midterm incidences of mortality, stroke, MI, and composite events. Conclusions Carotid revascularization is a safe and effective treatment for patients with concomitant carotid and cardiac disease. Combined CEA-CABG and staged CAS-CABG are associated with similar risks of mortality, stroke, or MI in the midterm outcomes.