Causal relationship between immune cells and aortic aneurysms: a Mendelian randomization study.

OBJECTIVES: The causal association between immune cell traits and aortic aneurysm remains unknown. METHODS: We performed a bidirectional two-sample Mendelian randomization analysis to explore the causality between 731 immune cell characteristics and the risk of abdominal aortic aneurysm and thoracic aortic aneurysms through publicly available genetic data, respectively. To examine heterogeneity and horizontal pleiotropy, Cochran's Q test and MR-Egger intercept were utilized. Additionally, multivariable Mendelian randomization analysis and meta-analysis were performed in further analysis. RESULTS: We found that 20 immune phenotypes had a suggestive causality on abdominal aortic aneurysm, and 15 immune phenotypes had a suggestive causal effect on thoracic aortic aneurysm. After further false discovery rate adjustment (q value <0.1), CD20 on IgD+ CD38- B cell (q = 0.053) and CD127 on CD28+ CD4+ T cell (q = 0.096) were associated with an increased risk of abdominal aortic aneurysm, respectively, indicating a significant causality between them. After adjusting for smoking, there is still statistical significance between CD127 on CD28+ CD4+ T cell and abdominal aortic aneurysm. However, after adjusting for lipids, no statistical significance can be observed between CD127 on CD28+ CD4+ T cells and abdominal aortic aneurysm. Furthermore, there is still statistical significance between CD20 on IgD+ CD38- B cells and abdominal aortic aneurysm after adjusting for lipids and smoking, which was further identified by meta-analysis. CONCLUSIONS: We found a causal association between immune cell traits and aortic aneurysm by genetic methods, thus providing new avenues for future mechanism studies.

Burden, Trends, and Inequalities of Heart Failure Globally, 1990 to 2019: A Secondary Analysis Based on the Global Burden of Disease 2019 Study.

Background Heart failure is a public health issue worldwide. However, no comprehensive study on the global burden of heart failure and its contributing causes has been reported. The present study aimed to quantify the burden, trends, and inequalities of heart failure globally. Methods and Results Heart failure data were extracted from the Global Burden of Diseases 2019 study. The number of cases, age-standardized prevalence, and years lived with disability in different locations from 1990 to 2019 were presented and compared. Joinpoint regression analysis was performed to assess trends in heart failure from 1990 to 2019. In 2019, the global age-standardized prevalence and years lived with disability rates for heart failure were 711.90 (95% uncertainty interval [UI], 591.15-858.29) and 63.92 (95% UI, 41.49-91.95) per 100 000 population, respectively. In general, the age-standardized rate decreased globally at an average annual percentage change of 0.3% (95% UI, 0.2-0.3). However, the rate increased at an average annual percentage change of 0.6% (95% UI, 0.4-0.8) from 2017 to 2019. Several nations and territories demonstrated an increased trend from 1990 to 2019, especially in less-developed countries. Ischemic heart disease and hypertensive heart disease accounted for the highest proportion of heart failure in 2019. Conclusions Heart failure remains a major health problem, with increased trends possible in the future. Efforts for prevention and control of heart failure should focus more on less-developed regions. It is essential to prevent and treat primary diseases such as ischemic heart disease and hypertensive heart disease for the control of heart failure.

A hiPSC-derived lineage-specific vascular smooth muscle cell-on-a-chip identifies aortic heterogeneity across segments.

Aortic aneurysm (AA), a potentially lethal condition with the characteristic of aortic dilatation, can only be treated by surgical or endovascular procedures. The underlying mechanisms of AA are unclear and early preventive treatment is still insufficient due to segmental aortic heterogeneity and the limitations of current disease models. Here, we firstly established a comprehensive lineage-specific vascular smooth muscle cell (SMC)-on-a-chip model using human induced pluripotent stem cells to yield cell lineages representing different segments of the aorta and tested the constructed organ-on-a-chip model under various tensile stress conditions. Bulk RNA sequencing, RT-qPCR, immunofluorescence, western blot and FACS analyses were performed to discover the segmental aortic heterogeneity of response for tensile stress and drug testing. The appropriate stretching frequency for all lineages of SMCs was 1.0 Hz, paraxial mesoderm (PM) SMCs were more sensitive to tensile stress than lateral mesoderm (LM) SMCs and neural crest (NC) SMCs. These differences may be related to the different transcriptional profiles of the tension-stressed distinct lineage-specific vascular SMCs, specifically in relation to the PI3K-Akt signaling pathway. Also, the organ-on-a-chip displayed contractile physiology, perfect fluid coordination, and was conducive to drug testing, displaying heterogeneous segmental aortic responses. Compared with LM-SMCs and NC-SMCs, PM-SMCs were more sensitive to ciprofloxacin. The model is evaluated as a novel and suitable supplement to AA animal models for determining differential physiology and drug response in different parts of the aorta. Furthermore, this system could pave the way for disease modeling, drug testing, and the personalized treatment of patients with AA in the future.

Nicotinamide Mononucleotide Alleviates Angiotensin II-Induced Human Aortic Smooth Muscle Cell Senescence in a Microphysiological Model.

ABSTRACT: The occurrence and development of aortic aneurysms are accompanied by senescence of human aortic smooth muscle cells (HASMCs). Because the mechanism of HASMC senescence has not been fully elucidated, the efficacy of various antisenescence treatments varies. Decreased nicotinamide adenine dinucleotide (NAD + ) levels are one of the mechanisms of cell senescence, and there is a lack of evidence on whether increasing NAD + levels could alleviate HASMC senescence and further retard the progression of aortic aneurysms.We constructed an HASMC-based organ-on-a-chip microphysiological model. RNA sequencing was performed on cell samples from the vehicle control and angiotensin II groups to explore biological differences. We detected cellular senescence markers and NAD + levels in HASMC-based organ-on-a-chip. Subsequently, we pretreated HASMC using the synthetic precursor of NAD + , nicotinamide mononucleotide, and angiotensin II treatment, and used rhythmic stretching to investigate whether nicotinamide mononucleotide could delay HASMC senescence.The HASMC-based organ-on-a-chip model can simulate the biomechanical microenvironment of HASMCs in vivo, and the use of angiotensin II in the model replicated senescence in HASMCs. The senescence of HASMCs was accompanied by downregulation of the expression level of nicotinamide phosphoribosyltransferase and NAD + . Pretreatment with nicotinamide mononucleotide significantly increased the NAD + level and alleviated the senescence of HASMCs, but did not change the expression level of nicotinamide phosphoribosyltransferase.Our study provides a complementary research platform between traditional cell culture and animal experiments to explore HASMC senescence in aortic aneurysms. Furthermore, it provides evidence for NAD + boosting therapy in the clinical treatment of aortic aneurysms.

PM2.5 exposure exacerbates mice thoracic aortic aneurysm and dissection by inducing smooth muscle cell apoptosis via the MAPK pathway.

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 ß-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.

Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm.

Ciprofloxacin use may be associated with adverse aortic events. However, the mechanism underlying the effect of ciprofloxacin on the progression of thoracic aortic aneurysm (TAA) is not well understood. Using an in vitro microphysiological model, we treated human aortic smooth muscle cells (HASMCs) derived from patients with bicuspid aortic valve- or tricuspid aortic valve-associated (BAV- or TAV-associated) TAAs with ciprofloxacin. TAA C57BL/6 mouse models were utilized to verify the effects of ciprofloxacin exposure. In the microphysiological model, real-time PCR, Western blotting, and RNA sequencing showed that ciprofloxacin exposure was associated with a downregulated contractile phenotype, an upregulated inflammatory reaction, and extracellular matrix (ECM) degradation in the normal HASMCs derived from the nondiseased aorta. Ciprofloxacin induced mitochondrial dysfunction in the HASMCs and further increased apoptosis by activating the ERK1/2 and P38 mitogen-activated protein kinase pathways. These adverse effects appeared to be more severe in the HASMCs derived from BAV- and TAV-associated TAAs than in the normal HASMCs when the ciprofloxacin concentration exceeded 100 µg/mL. In the aortic walls of the TAA-induced mice, ECM degradation and apoptosis were aggravated after ciprofloxacin exposure. Therefore, ciprofloxacin should be used with caution in patients with BAV- or TAV-associated TAAs.

Construction of a Human Aorta Smooth Muscle Cell Organ-On-A-Chip Model for Recapitulating Biomechanical Strain in the Aortic Wall.

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.

Patient-derived microphysiological model identifies the therapeutic potential of metformin for thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) is the permanent dilation of the thoracic aortic wall that predisposes patients to lethal events such as aortic dissection or rupture, for which effective medical therapy remains scarce. Human-relevant microphysiological models serve as a promising tool in drug screening and discovery. METHODS: We developed a dynamic, rhythmically stretching, three-dimensional microphysiological model. Using patient-derived human aortic smooth muscle cells (HAoSMCs), we tested the biological features of the model and compared them with native aortic tissues. Drug testing was performed on the individualized TAA models, and the potentially effective drug was further tested using ß-aminopropionitrile-treated mice and retrospective clinical data. FINDINGS: The HAoSMCs on the model recapitulated the expressions of many TAA-related genes in tissue. Phenotypic switching and mitochondrial dysfunction, two disease hallmarks of TAA, were highlighted on the microphysiological model: the TAA-derived HAoSMCs exhibited lower alpha-smooth muscle actin expression, lower mitochondrial membrane potential, lower oxygen consumption rate and higher superoxide accumulation than control cells, while these differences were not evidently reflected in two-dimensional culture flasks. Model-based drug testing demonstrated that metformin partially recovered contractile phenotype and mitochondrial function in TAA patients' cells. Mouse experiment and clinical investigations also demonstrated better preserved aortic microstructure, higher nicotinamide adenine dinucleotide level and lower aortic diameter with metformin treatment. INTERPRETATION: These findings support the application of this human-relevant microphysiological model in studying personalized disease characteristics and facilitating drug discovery for TAA. Metformin may regulate contractile phenotypes and metabolic dysfunctions in diseased HAoSMCs and limit aortic dilation. FUNDING: This work was supported by grants from National Key R&D Program of China (2018YFC1005002), National Natural Science Foundation of China (82070482, 81771971, 81772007, 51927805, and 21734003), the Science and Technology Commission of Shanghai Municipality (20ZR1411700, 18ZR1407000, 17JC1400200, and 20YF1406900), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and Shanghai Municipal Education Commission (Innovation Program 2017-01-07-00-07-E00027). Y.S.Z. was not supported by any of these funds; instead, the Brigham Research Institute is acknowledged.

CD11b-Based Pre-Targeted SPECT/CT Imaging Allows for the Detection of Inflammation in Aortic Aneurysm.

Purpose: 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 ß-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.

Rhythm outcomes after aortic valve surgery: Treatment and evolution of new-onset atrial fibrillation.

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 < .001). Multivariate models showed that advanced age, impaired ejection fraction, new-onset AF and discontinuation of beta-blockers were predictors of AF at 1 year. CONCLUSIONS: In most cases, new-onset AF after AV surgery could be effectively converted and suppressed by rhythm control therapy. Nevertheless, new-onset AF predisposed patients to higher risks of stroke and AF within 1 year, for whom prophylactic procedures and continuous beta-blockers could be beneficial.

Current Pharmacological Management of Aortic Aneurysm.

ABSTRACT: 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, ß-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.

Midterm results of coronary artery bypass graft surgery after synchronous or staged carotid revascularization.

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.