Incidence, Predictors, and Implications of Secondary Aortic Intervention Following Thoracic Endovascular Aortic Repair for Type B Dissection.

BACKGROUND: Secondary aortic intervention (SAI) following thoracic endovascular aortic repair (TEVAR) is not uncommon. However, a satisfactory management system has not been established for these patients. We aimed to report our single-center experience with SAI after prior TEVAR for type B aortic dissection (TBAD). METHODS: From January 2010 to May 2017, 860 eligible patients with TBAD underwent TEVAR. One hundred seven (12.4%) patients required SAI, either endovascularly (n=76) or surgically (n=31). The main indications for SAI were entry flow (n=58 [54.2%]), aneurysm expansion of the proximal or remote aorta (n=26 [24.3%]), retrograde type A aortic dissection (n=11 [10.3%]), distal stent-graft-induced new entry tear (n=6 [5.6%]), and stent migration (n=4 [3.7%]). The Kaplan-Meier curves were generated to determine the degree of freedom from SAI and the prognosis. Cox proportional hazards were used to screen for risk factors for SAI and poor prognosis. RESULTS: The overall 30-day mortality rate after SAI was 4.7% (n=5): endovascular (n=2 [2.6%]) vs open surgery (n=3 [9.7%]; p=0.145). The cumulative survival rates with or without SAI were 86.3%±3.6% vs 95.7%±0.8% at 3 years and 82.0%±4.2% vs 92.2%±1.1% at 5 years, respectively (log-rank p<0.001). Although no significant difference in survival was observed, the incidence of SAI was significantly greater in patients who underwent TEVAR during the chronic phase (acute [11.6%] vs subacute [9.6%] vs chronic [27.8]; p<0.001). Multivariate regression analysis revealed that prior TEVAR in the chronic phase (hazard ratio [HR]=1.73, 95% confidence interval [CI]=1.03-2.90; p=0.039), maximum aortic diameter (HR=1.05, 95% CI=1.04-1.07; p<0.001), and arch involvement (HR=1.48, 95% CI=1.01-2.18; p=0.048) were predictors of the incidence of SAI. In addition, the maximum aortic diameter was demonstrated to be the only risk factor for prognosis after adjusting for confounding factors. CONCLUSIONS: Thoracic endovascular aortic repair for chronic TBAD patients should be reconsidered. Open surgery is preferable for those with proximal progression, whereas endovascular treatment is more suitable for distal lesions. Close surveillance and timely reintervention after TEVAR, whether via endovascular techniques or open surgery, are necessary to prevent devastating complications. CLINICAL IMPACT: The management of patients with type B aortic dissection (TBAD) after thoracic endovascular aortic repair (TEVAR) is challenging. We summarized our single-center experience regarding secondary aortic intervention after TEVAR for TBAD. We found that TEVAR for chronic TBAD patients should be carefully evaulated, and open surgery is recommended for those with proximal progession, while endovascular treatment is more preferable for distal lesions.

Assess the Outcomes of Transcatheter Aortic Valve Replacement in Bicuspid Valve with Mixed Disease versus Predominant Aortic Stenosis.

Purpose: In mixed aortic valve disease (MAVD), the results of transcatheter aortic valve replacement (TAVR) are conflicting. There is limited data on the outcomes of TAVR in patients with bicuspid aortic valve (BAV) and MAVD. The objective of this study is to compare outcomes after TAVR in BAV patients with MAVD and predominant aortic stenosis (PAS). Patients and Methods: Patients with BAV who underwent TAVR between January 2016 and April 2023 were included. The primary outcome was device success. The secondary endpoints were periprocedural mortality and other complications as defined by the Valve Academic Research Consortium-3 (VARC-3). Propensity score matching was used to minimize potential confounding. Results: A total of 262 patients were included in this study, 83 of whom had MAVD. The median age was 72 years, and 55.7% were male. The baseline comorbidity risk files were comparable between the two groups. Patients with MAVD had more mitral regurgitation, tricuspid regurgitation and pulmonary hypertension, larger annular and left ventricular outflow tract dimensions, and more severe calcification than PAS. In the unmatched population, MAVD patients had similar device success rate (69.9% vs 79.9%, P=0.075) and 30-day mortality (3.6% vs 3.4%, P=1) compared to PAS. Propensity score matching resulted in 66 patient pairs. Device success rate were still comparable in the matched population. Other clinical outcomes, including stroke, bleeding (type 2-4), major vascular complications, acute kidney injury (stage 2-4) and permanent pacemaker implantation, were comparable between the two groups. Multivariable logistic regression analysis did not show MAVD to be an independent negative predictor of device success. At one year, survival was similar between patients with MAVD and those with PAS. Conclusion: For the bicuspid valve, patients with MAVD had a more challenging anatomy. MAVD patients associated with comparable 30-day clinical outcomes after TAVR compared to PAS patients in patients with BAV.

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis.

Development of non-surgical treatment of human abdominal aortic aneurysm (AAA) has clinical significance. Colchicine emerges as an effective therapeutic regimen in cardiovascular diseases. Yet, whether colchicine slows AAA growth remain controversy. Here, we demonstrated that daily intragastric administration of low-dose colchicine blocked AAA formation, prevented vascular smooth muscle cell (SMC) phenotype switching and apoptosis, and vascular inflammation in both peri-aortic CaPO4 injury and subcutaneous angiotensin-II infusion induced experimental AAA mice models. Mechanistically, colchicine increased global mRNA stability by inhibiting the METTL14/YTHDC1-mediated m6A modification, resulting in increased sclerostin (SOST) expression and consequent inactivation of the WNT/ß-catenin signaling pathway in vascular SMCs from mouse AAA lesions and in cultured human aortic SMCs. Moreover, human and mouse AAA lesions all showed increased m6A methylation, decreased SOST expression, and skewed synthetic SMC de-differentiation phenotype, compared to those without AAA. This study uncovers a novel mechanism of colchicine in slowing AAA development by using the METTL14/SOST/WNT/ß-catenin axis to control vascular SMC homeostasis in mouse aortic vessels and in human aortic SMCs. Therefore, use of colchicine may benefit AAA patients in clinical practice.

Efficacy and safety of sacubitril/valsartan in chronic Type B aortic dissection combined with mild hypertension.

BACKGROUND: Optimal antihypertensive medication for chronic Type B aortic dissection remains undecided. This study compared the efficacy and safety of sacubitril/valsartan with valsartan to determine suitable antihypertensive drug combinations. METHODS: In this single-center, open-label, randomized, controlled trial, patients with chronic Stanford type B aortic dissection and mild hypertension were randomized to receive sacubitril/valsartan 100/200 mg or valsartan 80/160 mg. The primary endpoint was the reduction in mean sitting systolic blood pressure (msSBP) at Week 8 in patients with sacubitril/valsartan versus valsartan. Key secondary endpoints included changes in 1) mean sitting diastolic blood pressure (msDBP); 2) pulse pressure; and 3) mean ambulatory blood pressure for 24-hour, daytime, and nighttime. Safety assessments included adverse events and serious adverse events. This trial was registered with the Chinese Clinical Trial Registry, identifier: ChiCTR2300073399. RESULTS: A total of 315 patients completed the study. Sacubitril/valsartan provided a significantly greater reduction in msSBP than valsartan at Week 8 (between-treatment difference: -5.1 mm Hg [95% confidence interval (CI) -5.8 to -4.5], P < 0.001). Reductions in msSBP, msDBP, and pulse pressure as well as the mean ambulatory blood pressure for 24-hour, daytime, and nighttime, were significantly greater in sacubitril/valsartan compared with valsartan (all P < 0.001). No excessive episodes of adverse events occurred in the sacubitril/valsartan group. CONCLUSION: Sacubitril/valsartan and valsartan reduced BP compared with baseline values. However, sacubitril/valsartan improved blood pressure control to a greater extent than valsartan. It may offer a new treatment option for patients with mild hypertension and chronic Type B aortic dissection.

The causal relationship between metabolic syndrome and its components and cardiovascular disease: A mendelian randomization study.

AIM: To investigate the causal relationship between metabolic syndrome (MetS) and its components and 14 cardiovascular diseases using Mendelian randomization (MR). METHODS: We used summary statistics from large-scale genome-wide association studies of MetS, its components, and cardiovascular diseases. We performed a two-sample MR analysis using the inverse-variance weighted method and other sensitivity methods. We also performed multivariate MR to adjust for potential risk factors. RESULTS: Our study found that MetS was causally associated with an increased risk of ischemic stroke, abdominal aortic aneurysm, pulmonary embolism, coronary heart disease, heart failure, and peripheral artery disease. Waist circumference was causally associated with an increased risk of 6 cardiovascular diseases. Type 2 diabetes mellitus, diastolic blood pressure, systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol were all causally associated with coronary heart disease, with varying causal relationships with the remaining 5 cardiovascular diseases. Multivariate MR showed that, except for ischaemic stroke, waist circumference remained causally associated with the remaining five cardiovascular diseases after adjusting for potential confounders. CONCLUSION: Our study provides evidence that metabolic syndrome is causally associated with 6 cardiovascular diseases. Waist circumference is the most important component of these relationships. These findings have implications for the prevention and management of metabolic syndrome and cardiovascular diseases.

Systemic immune-inflammation index predicts the clinical outcomes in patients with acute uncomplicated type-B aortic dissection undergoing optimal medical therapy.

BACKGROUND: Optimal medical therapy (OMT) for uncomplicated type B aortic dissection (uTBAD) provides excellent short-term outcomes during follow up; however, its long-term therapeutic effectiveness is unsatisfactory. This study evaluated the predictive value of systemic immune-inflammation index (SII) for adverse events among patients with acute uTBAD undergoing OMT. METHODS: We performed a retrospective analysis of a prospectively maintained database between 2013 and 2020. The primary end point in this study was composite outcomes including aortic intervention, all-cause mortality, retrograde type A aortic dissection (rTAAD) and aortic diameter growth > 5 mm. The patients were divided into high and low SII groups according to the optimal cut-off value of SII as determined using the receiver operating characteristic curve. Cox proportional hazards models were constructed to estimate the hazards ratios and identify the predictors of composite outcomes. RESULTS: A total of 124 patients with acute uTBAD who underwent OMT were enrolled. One patient died during hospitalisation. At the end of a mean follow-up duration of 51 ± 23 months, 53 (43.1%) patients experienced composite outcomes, 15 patients (12.2%) died, 31 (25.2%) underwent aortic intervention, 21 (17.1%) exhibited diameter growth of > 5 mm, and 2 developed rTAAD. The patients were divided into low SII group (n = 78, 62.9%) and high SII group (n = 46, 37.1%) as per the optimal cut-off SII value of 1449. The incidence of composite outcomes in high SII group was significantly higher than that in low SII (28 [60.9%] vs. 26[33.3%], p < 0.01). Patients with high SII demonstrated significantly higher mortality rate than those with a low SII (11 [23.9%] vs. 5 [6.4%], respectively; p < 0.01). In addition, the high SII group had significantly higher rate of aortic-related reinterventions than the low SII group (16 [34.8%] vs. 15 [19.2%], p = 0.03). Multivariable Cox analyses showed that a high SII score was independently associated with composite outcomes rate (hazard ratio, 2.15; 95% confidence interval, 1.22-3.78; p < 0.01). CONCLUSIONS: The long-term therapeutic effectiveness of OMT alone in patients with acute uTBAD is unsatisfactory. An SII > 1449 at the time of diagnosis is an independent predictor of OMT failure.

CIRC_0033530 KNOCKDOWN ALLEVIATES LIPOPOLYSACCHARIDE-INDUCED ACUTE LUNG INJURY MODEL OF HUMAN LUNG FIBROBLASTS BY MIR-1184/TLR4 AXIS.

ABSTRACT: Background: Circular RNAs have been reported to be involved in regulating the progression of sepsis and sepsis-associated damage. Herein, this work investigated whether circ_0033530 had roles in the process of septic acute lung injury (sepsis-ALI) and its associated mechanism. Methods: Lipopolysaccharide (LPS)-stimulated human lung fibroblasts MRC-5 were used to mimic the cell model of sepsis-ALI in vitro . Levels of genes and proteins were detected by quantitative real-time polymerase chain reaction and Western blotting. Functional experiments were conducted using 5-ethynyl-2'-deoxyuridine assay, Cell Counting Kit-8 assay, flow cytometry, and enzyme-linked immunosorbent assay. The interaction between miR-1184 and circ_0033530 or toll-like receptor 4 (TLR4) was confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. Results: Circ_0033530 expression was lower in sepsis patients and LPS-induced fibroblasts than those in healthy control and untreated cells. Functionally, knockdown of circ_0033530 protected fibroblasts against LPS-induced proliferation arrest, apoptosis, and inflammatory response. Mechanistically, circ_0033530 acted as a sponge for miR-1184, and TLR4 RNA was targeted by miR-1184, indicating the circ_0033530/miR-1184/TLR4 axis. Further rescue experiments showed that circ_0033530 silencing-mediated growth inhibition and inflammation on fibroblasts were attenuated by miR-1184 downregulation or TLR4 upregulation. Conclusion: Circ_0033530 knockdown alleviated LPS-induced proliferation arrest, apoptosis, and inflammation in lung fibroblasts by miR-1184/TLR4 axis, and provided molecular theoretical basis for circ_0033530 on the pathogenesis of sepsis-ALI.

Objective assessment of visual attention in orthognathic surgery training based on eye tracking.

The aim of this study was to investigate the differences in visual attention between novices and orthognathic experts, as well as to provide evidence for use in developing and optimizing training strategies for orthognathic surgery. Novice and orthognathic experts were recruited, and their distributions of visual attention were monitored via an eye-tracking device while they watched orthognathic surgery videos. The percentages of visual fixation duration devoted to the areas of interest - surgical objects, instruments controlled by the main surgeon, and instruments controlled by the assistants - in each orthognathic surgery section were analyzed and compared between the two groups using repeated-measures factorial analysis of variance (ANOVA). In total, there were 18 participants, comprising both novices (n = 9) and experts (n = 9). For all sections of orthognathic surgery, the percentage of fixation duration on surgical objects was significantly higher for the novices than for the experts (p = 0.031, p = 0.005, p = 0.026, p = 0.047, p = 0.047, p = 0.031, p = 0.027, p = 0.034, p = 0.008, and p = 0.016). During the maxillary segment separation as part of Le Fort I osteotomy and the splitting of the mandible as part of bilateral sagittal split osteotomy, the novices also had a higher percentage of fixation duration on the instruments controlled by the main surgeon, as compared with the experts (p = 0.007 and p = 0.048, respectively). Novices invested great cognitive effort into the surgical objects in each section of orthognathic surgery, including the instruments controlled by the main surgeon in the maxillary segment separation and the splitting of the mandible. Strengthening this aspect of instruction could help novices reduce their cognitive load and achieve mastery more efficiently.

Positive additive interaction effects of age, sex, obesity, and metabolic syndrome on left ventricular dysfunction.

OBJECTIVE: This study aims to explore the association between metabolic syndrome (MetS) and left ventricular diastolic dysfunction (LVDD) and systolic dysfunction (LVSD), defined by impaired global longitudinal strain (GLS), and assess additive and multiplicative interactions among age, sex, obesity, and MetS regarding LVDD and LVSD. METHODS: We prospectively recruited 5503 participants from the China PEACE (Patient-Centered Evaluative Assessment of Cardiac Events) Million Persons Project with complete echocardiography exam. Multivariable logistic models were used to calculate adjusted odds ratios to evaluate both additive and multiplicative interactions. RESULTS: The mean age was 56.59 years; 59.4% were women, 46.7% had MetS, 26.6% had left ventricular hypertrophy, 46.3% had LVDD, and 12.50% had impaired GLS. Compared to the non-MetS, the odds ratio (OR) of LVDD and impaired GLS in MetS were 1.40 (1.20-1.64) and 1.26 (1.03-1.54), respectively. For LVDD, relative excess risk due to additive interaction (RERI) for women and MetS, elderly and MetS, obesity and MetS were 0.76 (0.02-1.50), 35.65 (17.51-53.79), and 2.14 (0.66-3.62), respectively, thus suggesting additive interactions. For impaired GLS, RERI for obesity and MetS was 3.37 (0.50-6.24), thus suggesting additive interactions. CONCLUSIONS: The MetS is independently associated with LVDD and impaired GLS. From the public health implications, prevention of MetS in women, elderly, and obese individuals might result in a greater reduction of LVDD and LVSD risk in cardiovascular high-risk population.

Association between the non-HDL-cholesterol to HDL- cholesterol ratio and abdominal aortic aneurysm from a Chinese screening program.

BACKGROUND: Abdominal aortic aneurysms (AAAs) can result in high mortality upon rupture but are usually undiagnosed because of the absence of symptoms in the early stage. Ultrasound screening is regarded as an impactful way to prevent the AAA-related death but cannot be performed efficiently; therefore, a target population, especially in Asia, for this procedure is lacking. Additionally, although dyslipidaemia and atherosclerosis are associated with AAA. However, it remains undetermined whether the non-high-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol ratio (NHHR) is associated with AAA. Therefore, this study was aimed at examining whether NHHR is associated with AAA. METHOD: A total of 9559 participants who underwent AAA screening at Guangdong Provincial People's Hospital and through screening in two communities in Dongguan, from June 2019 to June 2021 joined in this screening program. The diagnosis of AAA was confirmed by the ultrasound examination of the abdominal aorta rather than any known or suspected AAA. Clinical and laboratory data of participants were collected. The participants were separated into a normal group and an AAA group according to the abdominal aortic status. To eliminate confounding factors, a propensity score matching (PSM) approach was utilized. The independent relationship between NHHR and AAA was assessed through the utilization of multivariable logistic regression analysis. In addition, internal consistency was evaluated through subgroup analysis, which controlled for significant risk factors. RESULTS: Of all the participants, 219 (2.29%) participants were diagnosed with AAA. A significant elevation in NHHR was identified in the AAA group when contrasted with that in the normal group (P < 0.001). As demonstrated by the results of the multivariable logistic regression analysis, AAA was independently associated with NHHR before (odds ratio [OR], 1.440, P < 0.001) and after PSM (OR, 1.515, P < 0.001). Significant extension was observed in the areas under the receiver operating characteristic curves (AUROCs) of NHHR compared to those of single lipid parameters before and after PSM. An accordant association between NHHR and AAA in different subgroups was demonstrated by subgroup analysis. CONCLUSION: In the Chinese population, there is an independent association between NHHR and AAA. NHHR might be propitious to distinguish individuals with high risk of AAA.

Feasibility and safety of Stanford A aortic dissection complete endovascular repair system in a porcine model.

BACKGROUND: Acute type A aortic dissection (ATAAD) is a catastrophic disease with high morbidity and mortality. Although open surgery is still the gold standard for the treatment of ATAAD, some patients, with advanced age and multiple comorbidities, can only receive medical management alone. Nowadays, thoracic aortic endovascular repair (TEVAR) provides a potential treatment option for the patient with ATAAD, but traditional stent grafts (SGs), which are not designed for the ATAAD, are inapplicable to the unique anatomy of the aortic arch. Therefore, we innovatively created the BRIDGE system (Chuangxin Medical, Shenzhen, China), a complete endovascular reconstruction system designed to treat ATAAD. This study aimed to evaluate the feasibility and safety of the novel Stanford A aortic dissection complete endovascular reconstruction system in a porcine model. METHOD: The BRIDGE system consists of the type A stent system and the type C stent system. Between November 2020 and March 2021, three white swine were utilized in the study. The BRIDGE system was deployed via the transcatheter approach under angiographic guidance. The swine(n = 3) treated with our system were evaluated using angiography before sacrifice 1-month after implantation, which was followed by gross specimen evaluation and histological examination of harvested tissues. RESULT: The acute procedure success rate was 100% (3/3). The immediate post-procedural angiography showed that both type A SGs and type C SGs were deployed in satisfactory locations, with patency of the supra-aortic trunk and no endoleak. The cumulative mortality of 30-day was 0% without any adverse events. No device migration or leakage was observed angiographically, before sacrifice. The gross observation confirmed a type A SG covered part of the entry of anonyma. Favorable endothelialization, no thrombogenesis, and slight inflammatory infiltration of the tissues around the device were confirmed by microscopic examinations in all pigs. CONCLUSION: It was feasible and secure to use Stanford A aortic dissection complete endovascular reconstruction system to implement a transcatheter endovascular repair in a porcine model. With this novel system, treating acute type A aortic dissection may be more efficient and secure in human.

Transcatheter aortic valve replacement with the VenusA-Pro and VenusA-Plus systems: preliminary experience in China.

Background: The outcomes of transcatheter aortic valve replacement (TAVR) employing the second-generation retrievable VenusA-Pro and VenusA-Plus delivery systems with the self-expanding VenusA-Valve have not been described yet. This study aims to report the outcomes of these two second-generation delivery systems. Methods: From January 2022 to April 2023, we prospectively enrolled patients with severe aortic stenosis undergoing TAVR with VenusA-Pro from three centers across China in this first-in-man study and retrospectively identified those undergoing TAVR with VenusA-Plus. All outcomes were reported according to the Valve Academic Research Consortium 3 definition. The primary outcome was 30-day all-cause mortality. Results: A total of 156 patients were included, of which 46 underwent TAVR with VenusA-Pro and 110 underwent TAVR with VenusA-Plus. The Society of Thoracic Surgeons median score was 2.1%, bicuspid anatomy prevalence rate was 55.1%, and the mean aortic root calcification volume was 693 mm3. The technical success rate was 91.7%, comparable between the VenusA-Pro and VenusA-Plus groups (87.0% vs. 93.6%, P = 0.169). The 30-day all-cause mortality was 2.6%, similar between the VenusA-Pro and VenusA-Plus groups (2.2% vs. 2.7%, P = 0.842). No myocardial infarction occurred. The incidences of stroke (0.6%), major bleeding (3.8%), major vascular complications (5.1%), acute kidney injury (9.0%), permanent pacemaker implantation (5.1%), new-onset atrial fibrillation (5.8%), and moderate-to-severe paravalvular aortic regurgitation (6.0%) were favorable and comparable between the two groups. The clinical outcomes were similar between the patients with bicuspid and tricuspid aortic valve, except that the incidence of permanent pacemaker implantation was lower in patients with bicuspid anatomy (1.2% vs. 10.6%, P = 0.010). Conclusions: The 30-day outcomes of TAVR with VenusA-Pro and VenusA-Plus were favorable and comparable.

Hybrid Technique Outcomes for High-Risk Uncomplicated Type B Aortic Dissection With Landing Zone 1.

In this report, we analyzed the outcomes of the hybrid technique for high-risk uncomplicated type B aortic dissection with landing zone 1. We enrolled 80 patients from January 2016 to January 2020 and retrospectively analyzed their outcomes, including mortality, aortic-related adverse events, and aortic remodeling. The mean age was 51.6 ± 9.9 years, and 68.0% (54 of 80) were men. Technical success was achieved in 100% of cases (80 of 80), and 30-day mortality was 4% of patients (n = 3), including 2 dissection-related deaths. Immediate endoleaks occurred in 16 patients, including 11 type Ia and 5 type II. Four patients (5%) developed minor strokes postoperatively, and no short-term spinal cord ischemia and re-intervention occurred. The average length of stay was 20 ± 8 days. The overall mortality was 8% after a median follow-up of 44 months (38 to 52). Five patients (7%) developed strokes, and 11 (16%) had late endoleaks, including 1 type Ia, 5 type Ib, and 3 type II. Four re-interventions (5%) were necessary, 3 for endoleaks and 1 for retrograde type A dissection. Three bypass graft occlusions (5%) and 5 stoma stenoses (8%) were observed in the latest follow-up computed tomography. In conclusion, the hybrid technique with landing zone 1 might be a viable alternative to open aortic arch replacement in patients at high risk with uncomplicated type B aortic dissection with acceptable early and late outcomes. However, stroke and endoleak complications should be further addressed.

Integrating oculomics with genomics reveals imaging biomarkers for preventive and personalized prediction of arterial aneurysms.

Objective: Arterial aneurysms are life-threatening but usually asymptomatic before requiring hospitalization. Oculomics of retinal vascular features (RVFs) extracted from retinal fundus images can reflect systemic vascular properties and therefore were hypothesized to provide valuable information on detecting the risk of aneurysms. By integrating oculomics with genomics, this study aimed to (i) identify predictive RVFs as imaging biomarkers for aneurysms and (ii) evaluate the value of these RVFs in supporting early detection of aneurysms in the context of predictive, preventive and personalized medicine (PPPM). Methods: This study involved 51,597 UK Biobank participants who had retinal images available to extract oculomics of RVFs. Phenome-wide association analyses (PheWASs) were conducted to identify RVFs associated with the genetic risks of the main types of aneurysms, including abdominal aortic aneurysm (AAA), thoracic aneurysm (TAA), intracranial aneurysm (ICA) and Marfan syndrome (MFS). An aneurysm-RVF model was then developed to predict future aneurysms. The performance of the model was assessed in both derivation and validation cohorts and was compared with other models employing clinical risk factors. An RVF risk score was derived from our aneurysm-RVF model to identify patients with an increased risk of aneurysms. Results: PheWAS identified a total of 32 RVFs that were significantly associated with the genetic risks of aneurysms. Of these, the number of vessels in the optic disc ('ntreeA') was associated with both AAA (ß = -0.36, P = 6.75e-10) and ICA (ß = -0.11, P = 5.51e-06). In addition, the mean angles between each artery branch ('curveangle_mean_a') were commonly associated with 4 MFS genes (FBN1: ß = -0.10, P = 1.63e-12; COL16A1: ß = -0.07, P = 3.14e-09; LOC105373592: ß = -0.06, P = 1.89e-05; C8orf81/LOC441376: ß = 0.07, P = 1.02e-05). The developed aneurysm-RVF model showed good discrimination ability in predicting the risks of aneurysms. In the derivation cohort, the C-index of the aneurysm-RVF model was 0.809 [95% CI: 0.780-0.838], which was similar to the clinical risk model (0.806 [0.778-0.834]) but higher than the baseline model (0.739 [0.733-0.746]). Similar performance was observed in the validation cohort, with a C-index of 0.798 (0.727-0.869) for the aneurysm-RVF model, 0.795 (0.718-0.871) for the clinical risk model and 0.719 (0.620-0.816) for the baseline model. An aneurysm risk score was derived from the aneurysm-RVF model for each study participant. The individuals in the upper tertile of the aneurysm risk score had a significantly higher risk of aneurysm compared to those in the lower tertile (hazard ratio = 17.8 [6.5-48.8], P = 1.02e-05). Conclusion: We identified a significant association between certain RVFs and the risk of aneurysms and revealed the impressive capability of using RVFs to predict the future risk of aneurysms by a PPPM approach. Our finds have great potential to support not only the predictive diagnosis of aneurysms but also a preventive and more personalized screening plan which may benefit both patients and the healthcare system. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00315-7.

Association between triglyceride glucose-body mass index and hypertension in Chinese adults: A cross-sectional study.

The triglyceride glucose-body mass index (TyG-BMI) has been considered an alternative marker of insulin resistance (IR). This cross-sectional study was designed to mainly investigate the association between TyG-BMI, triglyceride glucose combined with body mass index, and hypertension in Chinese adults. The relationship between TyG-BMI and hypertension was examined by multivariate logistic regression and restricted cubic spline model. Multiple logistic regression models were also performed to examine the associations between the individual components of TyG-BMI (BMI, TyG index, TG and FBG) and hypertension. The incremental ability of TyG-BMI versus its individual components for hypertension discrimination was evaluated by C-statistic and net reclassification index. Subgroup analysis was performed to examine potential interactions. A total of 92,545 participants (38.9% men, mean age 53.7 years) were included for final analysis. Logistic regression models showed TyG-BMI and its individual components were all significantly associated with the odds of hypertension (p for trend < .001). The restricted cubic spline regression manifested a linear association between TyG-BMI and hypertension (p for non-linear = .062). The addition of TyG-BMI, in comparison with each individual component, exhibited the maximum incremental value for the discrimination of hypertension on the basis of base model (C-statistic: 0.679, 95% CI: 0.675-0.683 for base model vs. 0.695, 95% CI: 0.691-0.699 for base model + TyG-BMI; net reclassification index: 0.226, 95% CI: 0.215-0.234). TyG-BMI was significantly associated with the odds of hypertension and can be a better discriminator of hypertension.

Ectomesenchymal Six1 controls mandibular skeleton formation.

Craniofacial development requires intricate cooperation between multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the role of Six1 in mandible development using a Six1 knockout mouse model (Six1 -/- ) and a cranial neural crest-specific, Six1 conditional knockout mouse model (Six1 f/f ; Wnt1-Cre). The Six1 -/- mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Notably, the Six1 f/f ; Wnt1-Cre mice recapitulate the microsomia phenotype of Six1 -/- mice, thus demonstrating that the expression of Six1 in ectomesenchyme is critical for mandible development. We further showed that the knockout of Six1 led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of Six1 in C3H10 T1/2 cells reduced their osteogenic capacity in vitro. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonic skeletal development. In particular, we showed that Six1 binds to the promoter of Bmp4, Fat4, Fgf18, and Fgfr2, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in regulating mandibular skeleton formation during mouse embryogenesis.

Group 2 Innate Lymphoid Cells Protect Mice from Abdominal Aortic Aneurysm Formation via IL5 and Eosinophils.

Development of abdominal aortic aneurysms (AAA) enhances lesion group-2 innate lymphoid cell (ILC2) accumulation and blood IL5. ILC2 deficiency in Rorafl/fl Il7rCre/+ mice or induced ILC2 depletion in Icosfl-DTR-fl/+ Cd4Cre/+ mice expedites AAA growth, increases lesion inflammation, but leads to systemic IL5 and eosinophil (EOS) deficiency. Mechanistic studies show that ILC2 protect mice from AAA formation via IL5 and EOS. IL5 or ILC2 from wild-type (WT) mice, but not ILC2 from Il5-/- mice induces EOS differentiation in bone-marrow cells from Rorafl/fl Il7rCre/+ mice. IL5, IL13, and EOS or ILC2 from WT mice, but not ILC2 from Il5-/- and Il13-/- mice block SMC apoptosis and promote SMC proliferation. EOS but not ILC2 from WT or Il5-/- mice block endothelial cell (EC) adhesion molecule expression, angiogenesis, dendritic cell differentiation, and Ly6Chi monocyte polarization. Reconstitution of WT EOS and ILC2 but not Il5-/- ILC2 slows AAA growth in Rorafl/fl Il7rCre/+ mice by increasing systemic EOS. Besides regulating SMC pathobiology, ILC2 play an indirect role in AAA protection via the IL5 and EOS mechanism.

The etiology, clinical features, and treatment options of hemifacial microsomia.

The second most frequent craniomaxillofacial congenital deformity is hemifacial microsomia (HFM). Patients often accompany short mandible, ear dysplasia, facial nerve, and soft tissue dysplasia. The etiology of HFM is not fully understood. To organize the possible up-to-date information on the etiology, craniofacial phenotypes, and therapeutic alternatives in order to fully comprehend the HFM. Reviewing the potential causes, exploring the clinical features of HFM and summarizing the available treatment options. Vascular malformation, Meckel's cartilage abnormalities, and cranial neural crest cells (CNCCs) abnormalities are three potential etiology hypotheses. The commonly used clinical classification for HFM is OMENS, OMENS-plus, and SAT. Other craniofacial anomalies, like dental defects, and zygomatic deformities, are still not precisely documented in the classification. Patients with moderate phenotypes may not need any treatment from infancy through adulthood. However, patients with severe HFM require to undergo multiple surgeries to address facial asymmetries, such as mandibular distraction osteogenesis (MDO), autologous costochondral rib graft (CCG), orthodontic and orthognathic treatment, and facial soft tissue reconstruction. It is anticipated that etiology research will examine the pathogenic mechanism of HFM. A precise treatment for HFM may be possible with thoroughly documented phenotypes and a pathogenic diagnosis.

Eosinophils protect pressure overload- and ß-adrenoreceptor agonist-induced cardiac hypertrophy.

AIMS: Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy. METHODS AND RESULTS: A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and ß-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient ΔdblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. ΔdblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type (WT) mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In ΔdblGATA and WT mice, administration of ECP mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-ß signalling and fibrotic protein synthesis. The use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-ß signalling. CONCLUSION: Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of ECPs in this human CVD.