REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity.

Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking1,2. The molecular mechanism that underlies this temporal pattern is unclear. Here we show that the nuclear receptors REV-ERB-α and REV-ERB-ß (referred to here as 'REV-ERB') in the GABAergic (γ-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCNGABA neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviours during regular light-dark cycles. REV-ERB regulates the rhythmic expression of genes that are involved in neurotransmission in the SCN, and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at waking leads to glucose intolerance, whereas restoration of the temporal pattern of either SCNGABA neuron firing or REV-ERB expression rescues the time-dependent glucose metabolic phenotype caused by REV-ERB depletion. In individuals with diabetes, an increased level of blood glucose after waking is a defining feature of the 'extended dawn phenomenon'3,4. Patients with type 2 diabetes with the extended dawn phenomenon exhibit a differential temporal pattern of expression of REV-ERB genes compared to patients with type 2 diabetes who do not have the extended dawn phenomenon. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, with implications for our understanding of the extended dawn phenomenon in type 2 diabetes.

Chinese Additive Anti-inflammatory Action for Aortopathy & Arteriopathy (5A) Registry protocol: rationale, design and methodology.

BACKGROUND: Acute aortic syndrome (AAS) is a life-threatening condition. Inflammation plays a key role in the pathogenesis, development and progression of AAS, and is associated with significant mortality and morbidity. Understanding the inflammatory responses and inflammation resolutions is essential for an appropriate management of AAS. METHOD: Thirty Chinese cardiovascular centers have collaborated to create a multicenter observational registry (named Chinese Additive Anti-inflammatory Action for Aortopathy & Arteriopathy [5A] registry), with consecutive enrollment of adult patients who underwent surgery for AAS that was started on Jan 1, 2016 and will be ended on December 31, 2040. Specially, the impact of inflammation and anti-inflammatory strategies on the early and late adverse events are investigated. Primary outcomes are severe systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), Sequential Organ Failure Assessment (SOFA) scores at 7 days following this current surgery. Secondary outcomes are SISR, 30-day mortality, operative mortality, hospital mortality, new-onset stroke, acute kidney injury, surgical site infection, reoperation for bleeding, blood transfusion and length of stay in the intensive care unit. DISCUSSION: The analysis of this multicenter registry will allow our better knowledge of the prognostic importance of preoperative inflammation and different anti-inflammatory strategies in adverse events after surgery for AAS. This registry is expected to provide insights into novel different inflammatory resolutions in management of AAS beyond conventional surgical repair. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04398992 (Initial Release: 05/19/2020).

Prognostic Implication of Pulmonary Arterial Pressure in Surgical Repair of Predominantly Congenital Mitral Valve Regurgitation-Based Intracardiac Abnormalities.

INTRODUCTION: Knowledge is limited regarding the significance of pulmonary arterial pressure (PAP) in predominantly congenital mitral valve regurgitation (MR)-based intracardiac abnormalities. METHODS: From a prospective cohort, we included 200 patients with congenital MR regardless of other associated intracardiac abnormalities (mean age 60.4 months, 67% female, systolic PAP (sPAP) 54.2 mm Hg) surgically repaired in 2012-2019 and followed up to 2020 (median 30.0 months). Significant pulmonary hypertension (PH) was defined as sPAP >50 mm Hg at rest or mean PAP >25 mm Hg on right heart catheterization. By perioperative sPAP changes, patients were stratified as group I (pre-normotension to post-normotension), group II (pre-hypertension to post-normotension), or group III (pre-hypertension to post-hypertension). Primary outcomes were the recurrence of MR (defined as the regurgitation grade of moderate or greater) and the progression of MR (defined as any increase in the magnitude of regurgitation grade after surgery). Cox proportional hazard and Kaplan-Meier curve were performed. RESULTS: There was no association between preoperative PH and the recurrent MR (adjusted hazard ratios [aHR]: 1.146 [95% CI: 0.453-2.899]) and progressive MR (aHR: 1.753 [95% CI: 0.807-3.804]), respectively. There were no significant differences among group I, group II, and group III in the recurrent MR but in the progressive MR. A dose dependency was identified for preoperative sPAP with recurrent MR (aHR: 1.050 [95% CI: 1.029-1.071]) and progressive MR risks (aHR: 1.037 [95% CI: 1.019-1.055]), respectively. CONCLUSIONS: Preoperative higher sPAP is associated with worse outcomes, warranting heightened attention to the identification of perioperative sPAP.

Does intensive blood pressure control benefit type B aortic dissection patients who undergoing surgical repair?

OBJECTIVES: The aim of this research is to determine the optimum blood pressure (BP) control goal for hypertensive type B aortic dissection (TBAD) patients undergoing surgery. METHODS: Between January 2019 and April 2021, 259 hypertensive TBAD patients undergoing surgery were included in the research. 98 patients received intensive BP control with a target of systolic BP (SBP) < 120 mmHg, and 161 received standard BP control targeting SBP between 120 and 140 mmHg. Clinical data from two groups were compared. RESULTS: Patients who received intensive BP control experienced a significantly higher incidence of acute kidney injury (AKI) postoperatively (21/98, 21.4% vs 14/161, 8.7%, p = 0.004). The intensive group took more anti-hypertensive drugs per day compared with the standard group (1.9 vs 1.5, p < 0.001). Triple-drug combination treatment was more frequent in the intensive group (38.8% vs 14.3%, p < 0.001), as were angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB; 67.3% vs 44.7%, p 0.001), and thiazide-like diuretic (44.9% vs 18.0%, p < 0.001). CONCLUSIONS: Intensive BP control treatment increases the incidence of AKI and raises the utilization of the anti-hypertensive drug, but did not reduce the operative mortality and late mortality in TBAD patients undergoing surgical repair.

Differences between sexes in patients who underwent total arch replacement and frozen elephant trunk procedures for acute dissection.

OBJECTIVE: To analyze the effect of sex on the short-time prognosis in two different age subgroups (≤55 years old and >55 years old). METHODS: From January 2009 to 2019, 1522 patients with DeBakey I acute aortic dissection (AAD) underwent frozen elephant trunk and total arch replacement at a Tertiary Center in China were divided into female group (n = 324) and male group (n = 1198). The demographic characteristics, clinical presentation, management, short-term outcomes were described in the different sex groups. The risk factors of 30-days mortality for females and males were identified by univariate and multivariable logistic regression analysis. Then, random Forest regression was used to analyze the association between age and 30-days mortality in the different sexes groups. The cut-off age for 30-days mortality in females was then identified as 55 years. The patients were divided into two subgroups: young patients (≤55 years old) and elderly patients (>55 years old). Clinical prognosis between different sex groups was further compared in the age subgroups. RESULTS: Approximately four-fifths of the patients were males. Males with DeBakey I AAD were younger than females (47 vs 52 years; p < 0.01). The proportion of males gradually declined with age. The cut-off age for 30-days mortality in females and males was identified as 55 years old and 63 years old, respectively. In young patients (≤55 years old), the 30-days mortality rate for females was lower than males (hazard ratio [HR, 2.02, p < 0.05). Following adjustment using the multivariable Cox regression analysis, females were identified as an independent protective factor for 30-days mortality (HR, 2.24, p = 0.03). CONCLUSIONS: Our study showed that females present with DeBakey I AAD less frequently than males and they tend to present with DeBakey AAD later in life. In young patients, females had better early outcomes despite similar time for symptom onset to diagnosis and surgical technique than males.

Haematocrit differences modify the association of cardiopulmonary bypass reoxygenation with acute kidney injury after paediatric Tetralogy of Fallot repair.

BACKGROUND: Little is known regarding the potential impact of haematocrit differences in the association between cardiopulmonary bypass reoxygenation and acute kidney injury following Tetralogy of Fallot repair. METHODS: We investigated the association of perfusate oxygenation during aortic occlusion associated with acute kidney injury between 204 normal and 248 higher haematocrit children with Tetralogy of Fallot, aged 1 month-18 years, who were surgically repaired in 2012-2018. Normal and higher haematocrit children were defined as having a preoperative haematocrit within and above age- and sex-specific reference intervals, respectively. Acute kidney injury was determined as a binary variable according to the Kidney Disease Improving Global Outcomes criteria. RESULTS: After adjusting for baseline and clinical covariates, a significant interaction between the haematocrit and continuous perfusate oxygenation on acute kidney injury was found (pinteraction = 0.049): a higher perfusate oxygenation was associated with a greater acute kidney injury risk among higher haematocrit children (adjusted odds ratio = 1.50, 95% confidence interval = [1.02, 2.22] per SD, p = 0.038) but not among normal haematocrit children (adjusted odds ratio = 0.91, 95% confidence interval = [0.51, 1.63] per SD, p = 0.73). After a similar adjustment, there was a marginal interaction between tertiles of perfusate oxygenation and haematocrit on acute kidney injury (pinteraction = 0.09): the middle and top tertiles of perfusate oxygenation were associated with a trend towards increased acute kidney injury risks among higher haematocrit children (adjusted odds ratio = 1.69, 95% confidence interval = [0.61, 4.66]; adjusted odds ratio = 2.25, 95% confidence interval = [0.84, 5.99], respectively) but not among normal haematocrit children (adjusted odds ratio = 1.16, 95% confidence interval = [0.46, 2.94]; adjusted odds ratio = 0.45, 95% confidence interval = [0.15, 1.36], respectively) compared with the bottom tertile. CONCLUSION: Preoperative haematocrit differences significantly modify the association of perfusate oxygenation with acute kidney injury, highlighting differential control of reoxygenation for different haematocrit children with Tetralogy of Fallot in the management of cardiopulmonary bypass.

Non-monotonic dose-response effects of arsenic on glucose metabolism.

BACKGROUND: Inorganic arsenic (iAs) is a widespread environmental toxin. In addition to being a human carcinogen, its effect on diabetes has started to gain recognition recently. Insulin is the key hormone regulating systemic glucose metabolism. The in vivo effect of iAs on insulin sensitivity has not been directly addressed. OBJECTIVES: Here we use mouse models to dissect the dose-dependent effects of iAs on glucose metabolism in vivo. METHODS: We performed hyperinsulinemic-euglycemic clamp, the gold standard analysis of systemic insulin sensitivity. We also performed dynamic metabolic testings and RNA-seq analysis. RESULTS: We found that a low-dose exposure (0.25 ppm iAs in drinking water) caused glucose intolerance in adult male C57BL/6 mice, likely by disrupting glucose-induced insulin secretion without affecting peripheral insulin sensitivity. However, a higher-dose exposure (2.5 ppm iAs) had diminished effects on glucose tolerance despite disrupted pancreatic insulin secretion. Insulin Clamp analysis showed that 2.5 ppm iAs actually enhanced systemic insulin sensitivity by simultaneously enhancing insulin-stimulated glucose uptake in skeletal muscles and improved insulin-mediated suppression of endogenous glucose production. RNA-seq analysis of skeletal muscles revealed that 2.5 ppm iAs regulated expression of many genes involved in the metabolism of fatty acids, pyruvate, and amino acids. CONCLUSION: These findings suggest that iAs has opposite glycemic effects on distinct metabolic tissues at different dose thresholds. Such non-monotonic dose-response effects of iAs on glucose tolerance shed light on the complex interactions between iAs and the systemic glucose metabolism, which could potentially help reconcile some of the conflicting results in human epidemiological studies.

Targeting histone deacetylase in cardiac diseases.

Histone deacetylases (HDAC) catalyze the removal of acetylation modifications on histones and non-histone proteins, which regulates gene expression and other cellular processes. HDAC inhibitors (HDACi), approved anti-cancer agents, emerge as a potential new therapy for heart diseases. Cardioprotective effects of HDACi are observed in many preclinical animal models of heart diseases. Genetic mouse models have been developed to understand the role of each HDAC in cardiac functions. Some of the findings are controversial. Here, we provide an overview of how HDACi and HDAC impact cardiac functions under physiological or pathological conditions. We focus on in vivo studies of zinc-dependent classical HDACs, emphasizing disease conditions involving cardiac hypertrophy, myocardial infarction (MI), ischemic reperfusion (I/R) injury, and heart failure. In particular, we review how non-biased omics studies can help our understanding of the mechanisms underlying the cardiac effects of HDACi and HDAC.

Prognostic implication of residual inflammatory trajectories in acute type I aortic dissection: dual-center prospective cohort study.

BACKGROUND: Peripheral platelet-white blood cell ratio (PWR) integrating systemic inflammatory and coagulopathic pathways is a key residual inflammatory measurement in the management of acute DeBakey type I aortic dissection (AAD); however, trajectories of PWR in AAD is poorly defined. METHODS: Two AAD cohorts were included in two cardiovascular centers (2020-2022) if patients underwent emergency total arch replacement with frozen elephant trunk implantation. PWR data were collected over time at baseline and five consecutive days after surgery. Trajectory patterns of PWR were determined using the latent class mixed modelling (LCMM). Cox regression was used to determine independent risk factors. By adding PWR Trajectory, a user-friendly nomogram was developed for predicting mortality after surgery. RESULTS: Two hundred forty-six patients with AAD were included with a median follow-up of 26 (IRQ 20-37) months. Three trajectories of PWR were identified [cluster α 45(18.3%), ß105 (42.7%), and γ 96 (39.0%)]. Cluster γ was associated with higher risk of mortality at follow-up (crude HR, 3.763; 95% CI: 1.126-12.574; P =0.031) than cluster α. By the addition of PWR trajectories, an inflammatory nomogram, composed of age, hemoglobin, estimated glomerular filtration rate, and cardiopulmonary time was developed and internally validated, with adequate discrimination [the area under the receiver-operating characteristic curve 0.765, 95% CI: 0.660-0.869)], calibration, and clinical utility. CONCLUSION: Based on PWR trajectories, three distinct clusters were identified with short-term outcomes, and longitudinal residual inflammatory shed some light to individualize treatment strategies for AAD.

Anti-inflammatory response-based risk assessment in acute type A aortic dissection: A national multicenter cohort study.

Background: Early identification of patients at high risk of operative mortality is important for acute type A aortic dissection (TAAD). We aimed to investigate whether patients with distinct risk stratifications respond differently to anti-inflammatory pharmacotherapy. Methods: From 13 cardiovascular hospitals, 3110 surgically repaired TAAD patients were randomly divided into a training set (70%) and a test set (30%) to develop and validate a risk model to predict operative mortality using extreme gradient boosting. Performance was measured by the area under the receiver operating characteristic curve (AUC). Subgroup analyses were performed by risk stratifications (low versus middle-high risk) and anti-inflammatory pharmacotherapy (absence versus presence of ulinastatin use). Results: A simplified risk model was developed for predicting operative mortality, consisting of the top ten features of importance: platelet-leukocyte ratio, D-dimer, activated partial thromboplastin time, urea nitrogen, glucose, lactate, base excess, hemoglobin, albumin, and creatine kinase-MB, which displayed a superior discrimination ability (AUC: 0.943, 95 % CI 0.928-0.958 and 0.884, 95 % CI 0.836-0.932) in the derivation and validation cohorts, respectively. Ulinastatin use was not associated with decreased risk of operative mortality among each risk stratification, however, ulinastatin use was associated with a shorter mechanical ventilation duration among patients with middle-high risk (defined as risk probability >5.0 %) (ß -1.6 h, 95 % CI [-3.1, -0.1] hours; P = 0.048). Conclusion: This risk model reflecting inflammatory, coagulation, and metabolic pathways achieved acceptable predictive performances of operative mortality following TAAD surgery, which will contribute to individualized anti-inflammatory pharmacotherapy.

Injectable and Conductive Nanomicelle Hydrogel with α-Tocopherol Encapsulation for Enhanced Myocardial Infarction Repair.

Substantial advancements have been achieved in the realm of cardiac tissue repair utilizing functional hydrogel materials. Additionally, drug-loaded hydrogels have emerged as a research hotspot for modulating adverse microenvironments and preventing left ventricular remodeling after myocardial infarction (MI), thereby fostering improved reparative outcomes. In this study, diacrylated Pluronic F127 micelles were used as macro-cross-linkers for the hydrogel, and the hydrophobic drug α-tocopherol (α-TOH) was loaded. Through the in situ synthesis of polydopamine (PDA) and the incorporation of conductive components, an injectable and highly compliant antioxidant/conductive composite FPDA hydrogel was constructed. The hydrogel exhibited exceptional stretchability, high toughness, good conductivity, cell affinity, and tissue adhesion. In a rabbit model, the material was surgically implanted onto the myocardial tissue, subsequent to the ligation of the left anterior descending coronary artery. Four weeks postimplantation, there was discernible functional recovery, manifesting as augmented fractional shortening and ejection fraction, alongside reduced infarcted areas. The findings of this investigation underscore the substantial utility of FPDA hydrogels given their proactive capacity to modulate the post-MI infarct microenvironment and thereby enhance the therapeutic outcomes of myocardial infarction.

Operative Mortality After Type A Aortic Dissection Surgery: Differences Based on Sex and Age.

Background: There is controversy regarding sex differences in short-term mortality in acute type A aortic dissection (ATAAD). Objectives: This study aimed to investigate the impact of sex differences on 30-day operative mortality after ATAAD surgery and to determine if other covariates modify the association. Methods: Consecutive patients (N = 5670) with surgically repaired ATAAD were identified from the multicenter China 5A study. The primary outcome was operative mortality. The age dependency was modeled using a cubic spline curve. Results: There were 1,503 females (26.5%) and 4,167 males (73.5%). Females were older and had a lower percentage of comorbidities compared with males. Females had higher mortality compared to males (10.2% vs 8.2%, P = 0.019); however, there was no difference after propensity analyses (adjusted OR: 1.334 [95% CI: 0.918-1.938]). There was an interaction with sex and age (P interaction = 0.035): older age was associated with higher odds of operative mortality among females (OR: 1.045 [95% CI: 1.029-1.061]) compared with males (OR: 1.025 [95% CI: 1.016-1.035]). The risk of mortality for males and females appears to diverge at 55 years of age (P interaction = 0.019): females under 55 years of age had similar odds to males (OR: 0.852 [95% CI: 0.603-1.205]) but higher odds when over 55 years (OR: 1.420 [95% CI: 1.096-1.839]) compared to males. Conclusions: Under the age of 55 years, females have similar odds of operative mortality compared with males; however, over the age of 55 years females have higher odds than males. Understanding differences in risk allows for individualized treatment strategies. (Additive Anti-inflammatory Action for Aortopathy & Arteriopathy; NCT04398992).

Continuous contractile force and electrical signal recordings of 3D cardiac tissue utilizing conductive hydrogel pillars on a chip.

Heart-on-chip emerged as a potential tool for cardiac tissue engineering, recapitulating key physiological cues in cardiac pathophysiology. Controlled electrical stimulation and the ability to provide directly analyzed functional readouts are essential to evaluate the physiology of cardiac tissues in the heart-on-chip platforms. In this scenario, a novel heart-on-chip platform integrating two soft conductive hydrogel pillar electrodes was presented here. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts were seeded into the apparatus to create 3D human cardiac tissues. The application of electrical stimulation improved functional performance by altering the dynamics of tissue structure and contractile development. The contractile forces that cardiac tissues contract was accurately measured through optical tracking of hydrogel pillar displacement. Furthermore, the conductive properties of hydrogel pillars allowed direct and non-invasive electrophysiology studies, enabling continuous monitoring of signal changes in real-time while dynamically administering drugs to the cardiac tissues, as shown by a chronotropic reaction to isoprenaline and verapamil. Overall, the platform for acquiring contractile force and electrophysiological signals in situ allowed monitoring the tissue development trend without interrupting the culture process and could have diverse applications in preclinical drug testing, disease modeling, and therapeutic discovery.

Contemporary use and outcome of Cabrol shunt in type A aortic dissection surgery: insight from China 5A study.

OBJECTIVE: Cabrol shunt has been introduced for surgical repair of type A aortic dissection (TAAD) without robust evidence supporting its routine preventive use. METHODS: Adult patients with TAAD from China 5A study were included if surgically repaired between 2016 and 2022. Primary outcome was operative mortality according to Society of Thoracic Surgeons criterion. Overall, we compared clinical outcomes in patients with and without Cabrol shunt, and subgroup analysis were further examined between Cabrol shunt and outcome among patients with or without root replacement. RESULTS: 3283 patients were finally identified for analysis, with median age of 51 (IQR 41-59) years, 2389 men, and 2201 treated with Cabrol shunt technique. Cabrol shunt-treated patients were more severely ill before surgery than those without Cabrol shunt. Overall, the rate of operative mortality was 6.6% (146/2201 in Cabrol shunt group and 71/1082 in non-Cabrol shunt group), with no association between Cabrol shunt and operative mortality (OR 1.012 (95% CI 0.754 to 1.357); p=0.938). Stratified by root replacement, Cabrol shunt was associated with similar risk of operative mortality either in patients without root replacement (OR 1.054 (0.747 to 1.487); p=0.764) or in patients with root replacement (OR 1.194 (0.563 to 2.536); p=0.644) (P interaction=0.765). Results were similar in multiple sensitivity analysis. CONCLUSION: Cabrol shunt was not associated with either a greatly lowered or an increased risk of operative mortality, regardless of aortic root replacement. Our study did not support the use of Cabrol shunt as a routine preventive strategy in the treatment of TAAD. TRIAL REGISTRATION NUMBER: NCT04398992.

Inflammatory profiles define phenotypes with clinical relevance in acute type A aortic dissection.

Association of distinct inflammatory profiles with short-term mortality is little known in type A aortic dissection (TAAD). Latent class analysis was used to identify distinct inflammatory profiles based on leukocyte, neutrophils, monocyte, lymphocytes, platelet, fibrinogen, D-dimer, neutrophils-lymphocyte ratio, platelet-lymphocyte ratio, and lymphocyte-monocyte ratio. We identified 193 patients with median age of 56 (IQR 47-63) years and 146 males. Patients were divided as hyper-inflammatory profiles (84 [43.5%]) and hypo-inflammatory profiles (109 [56.5%]). Although baseline characteristics were not different, hyper-inflammatory patients had higher 6-month mortality (20 [23.8%] vs. 11 [10.1%]; P = 0.014) and 30-day mortality (18 [21.4%] vs. 9 [8.3%], P = 0.009) than hypo-inflammatory patients. After adjustment for potential confounders, hyper-inflammatory profiles remain associated with higher risk of 6-month mortality than hypo-inflammatory profiles (adjusted OR 2.427 [95%CI 1.154, 5.105], P = 0.019). Assessment of preoperative inflammatory profiles adds clarity regarding the extent of inflammatory response to TAAD aetiopathologies, highlighting individual anti-inflammatory pharmacotherapy for TAAD. ClinicalTrials.gov Identifier: NCT04398992.

Proximal vs Extensive Repair in Acute Type A Aortic Dissection Surgery.

BACKGROUND: This purpose of this study was to evaluate the impact of proximal vs extensive repair on mortality and how this impact is influenced by patient characteristics. METHODS: Of 5510 patients with acute type A aortic dissection from 13 Chinese hospitals (2016-2021) categorized by proximal vs extensive repair, 4038 patients were used for for model derivation using eXtreme gradient boosting and 1472 patients for model validation. RESULTS: Operative mortality of extensive repair was higher than proximal repair (10.4% vs 2.9%; odd ratio [OR], 3.833; 95% CI, 2.810-5.229; P < .001) with a number needed to harm of 15 (95% CI, 13-19). Seven top features of importance were selected to develop an alphabet risk model (age, body mass index, platelet-to-leucocyte ratio, albumin, hemoglobin, serum creatinine, and preoperative malperfusion), with an area under the curve of 0.767 (95% CI, 0.733-0.800) and 0.727 (95% CI, 0.689-0.764) in the derivation and validation cohorts, respectively. The absolute rate differences in mortality between the 2 repair strategies increased progressively as predicted risk rose; however it did not become statistically significant until the predicted risk exceeded 4.5%. Extensive repair was associated with similar risk of mortality (OR, 2.540; 95% CI, 0.944-6.831) for patients with a risk probability < 4.5% but higher risk (OR, 2.164; 95% CI, 1.679-2.788) for patients with a risk probability > 4.5% compared with proximal repair. CONCLUSIONS: Extensive repair is associated with higher mortality than proximal repair; however it did not carry a significantly higher risk of mortality until the predicted probability exceeded a certain threshold. Choosing the right surgery should be based on individualized risk prediction and treatment effect. (ClinicalTrials.gov no. NCT04918108.).

Inflammatory risk stratification individualizes anti-inflammatory pharmacotherapy for acute type A aortic dissection.

The systemic benefits of anti-inflammatory pharmacotherapy vary across cardiovascular diseases in clinical practice. We aimed to evaluate the application of artificial intelligence to acute type A aortic dissection (ATAAD) patients to determine the optimal target population who would benefit from urinary trypsin inhibitor use (ulinastatin). Patient characteristics at admission in the Chinese multicenter 5A study database (2016-2022) were used to develop an inflammatory risk model to predict multiple organ dysfunction syndrome (MODS). The population (5,126 patients from 15 hospitals) was divided into a 60% sample for model derivation, with the remaining 40% used for model validation. Next, we trained an extreme gradient-boosting algorithm (XGBoost) to develop a parsimonious patient-level inflammatory risk model for predicting MODS. Finally, a top-six-feature tool consisting of estimated glomerular filtration rate, leukocyte count, platelet count, De Ritis ratio, hemoglobin, and albumin was built and showed adequate predictive performance regarding its discrimination, calibration, and clinical utility in derivation and validation cohorts. By individual risk probability and treatment effect, our analysis identified individuals with differential benefit from ulinastatin use (risk ratio [RR] for MODS of RR 0.802 [95% confidence interval (CI) 0.656, 0.981] for the predicted risk of 23.5%-41.6%; RR 1.196 [0.698-2.049] for the predicted risk of <23.5%; RR 0.922 [95% CI 0.816-1.042] for the predicted risk of >41.6%). By using artificial intelligence to define an individual's benefit based on the risk probability and treatment effect prediction, we found that individual differences in risk probability likely have important effects on ulinastatin treatment and outcome, which highlights the need for individualizing the selection of optimal anti-inflammatory treatment goals for ATAAD patients.

Anti-Inflammatory Effect of Ulinastatin on the Association Between Inflammatory Phenotypes in Acute Type A Aortic Dissection.

Background: Acute type A aortic dissection (ATAAD) is a heterogeneous systemic inflammatory response syndrome. Identification of distinct inflammatory phenotypes may allow more precise therapy and improved care. We aim to investigate whether distinct inflammatory subphenotypes exist in ATAAD patients and respond differently to pharmacotherapies. Methods: Retrospective analysis of data sets was conducted from the Additive Anti-inflammatory Actions for Aortopathy & Arteriopathy (5A) III study. Inflammatory subphenotypes were derived among 2008 ATAAD patients who received surgical repair at 11 Chinese hospitals (2016-2020) using latent class analysis applied to 14 laboratory signatures within 6 hours of hospital admission. Outcomes included operative mortality (Society of Thoracic Surgeons definition), derived subphenotype frequency, and the potential consequences of phenotype frequency distributions on the treatment effects. Results: The median (interquartile range) age of patients was 54 (45-62) years, and 1423 (70.9%) were male. A two-class (two subphenotype) model was an improvement over a one-class model (P<·001), with 1451 (72.3%) patients in the hypoinflammatory subphenotype group and 557 (27.7%) in the hyperinflammatory subphenotype group. Patients with the hyperinflammatory subphenotype had higher operative mortality (71 [12.7%] vs 127 [8.8%]; P=0·007) than did those with the hypoinflammatory subphenotype. Furthermore, the interaction between ulinastatin treatment and subphenotype is not significant for operative mortality (P=0.15) but for ventilator time (P=0·04). Conclusion: Two subphenotypes of ATAAD were identified in the 5A cohort that correlated with clinical outcomes, with significant interaction effect between anti-inflammatory treatment and subphenotypes for ventilator time, suggesting these phenotypes may help in understanding heterogeneity of treatment effects. Trial Registration: Clinical Trials. Gov: number NCT04918108.

Prognostic Impact of Systemic Coagulation-Inflammation Index in Acute Type A Aortic Dissection Surgery.

Background: A novel hematologic parameter, systemic coagulation-inflammation (SCI) index reflecting inflammation and coagulation pathways could be easily obtained from clinically routine laboratory findings. We hypothesize that the SCI index has prognostic implication in predicting operative mortality for patients with acute type A aortic dissection (ATAAD). Objectives: This study aims to investigate the prognostic value of the SCI index and to establish an SCI-adding nomogram for mortality prediction in ATAAD patients. Methods: A total of 1,967 ATAAD patients surgically repaired were collected from 12 Chinese cardiovascular centers by the 5A (Additive Anti-inflammatory Action for Aortopathy & Arteriopathy [Multicenter Retrospective Study]) study III (2016-2020). SCI index was calculated as platelet count × fibrinogen/white blood cell count on admission. By adding SCI index, a nomogram was developed and evaluated for 90-day mortality prediction with conventional predictors via the Cox model with 10-fold cross-validation. Results: Patients were stratified with low SCI (<40), middle SCI (40-100), or high SCI (>100). The 90-day survival rates increased with SCI index (low 86.9%; [95% CI: 84.9%-89.0%], middle 92.7% [95% CI: 90.9%-94.9%], and high 96.4% [95% CI: 94.2%-98.6%]; log-rank P < 0.001). SCI index is independently associated with 90-day mortality (adjusted hazard ratio: 0.549; 95% CI: 0.424-0.710; P < 0.001). The addition of SCI index provided significantly incremental prognostic value to base model including age, serum creatinine, DeBakey class, and location of intimal entry (area under the curve: 0.677; 95% CI: 0.641-0.716 vs 0.724; 95% CI: 0.685-0.760; P = 0.002), which was confirmed by net reclassification improvement index (0.158; 95% CI: 0.065-0.235; P < 0.001) and integrated discrimination improvement index (0.070; 95% CI: 0.007-0.036; P < 0.001). Conclusions: SCI index is easily obtainable, performs moderately well as a predictor of short-term mortality in ATAAD patients, and may be useful for risk stratification in emergency settings. (Additive Anti-inflammatory Action for Aortopathy & Arteriopathy [Multicenter Retrospective Study] III NCT04918108).