Association of Pre-PCI Blood Pressure and No-Reflow in Patients with Acute ST-Elevation Coronary Infarction.

Background: Previous studies have established blood pressure (BP) as a pivotal factor influencing no-reflow following primary percutaneous coronary intervention (PCI) in patients with ST-elevation acute coronary infarction (STEMI). However, no relevant study has been conducted to investigate the optimal range of BP associated with the lowest risk of no-reflow among STEMI patients so far. Therefore, our objective was to evaluate the association between pre-PCI BP and the occurrence of no-reflow in patients with STEMI. Method: We included 1025 STEMI patients undergoing primary PCI. The BP pre-PCI was categorized into 20-mmHg increments. Logistic models were employed to assess the association of no-reflow with systolic blood pressure (SBP) or diastolic blood pressure (DBP). Three sensitivity analyses were conducted to further confirm the robustness of the association between blood pressure and no-reflow. Results: SBP or DBP exhibited a U-shaped curve association with no-reflow. No-reflow was higher in patients with lower SBP (<100 mmHg) (adjusted hazard ratio (OR) 3.64, 95% confidence interval (CI) 1.84,7.21; p < 0.001) and lower DBP (<60 mmHg) (OR 3.28, 95% CI 1.63,6.49; p < 0.001) [reference: 120 ≤SBP <140; 80 ≤DBP <100 mmHg], respectively. Furthermore, no-reflow was higher in patients with higher SBP (≥160 mmHg) (OR 2.07, 95% CI 1.27,3.36; p = 0.003) and DBP (≥100 mmHg) (OR 3.36, 95% CI 2.07,5.46; p < 0.001), respectively. The results of sensitivity analyses were consistent with the above findings. Conclusion: Maintaining a pre-PCI SBP within the range of 120 to 140 mmHg and a DBP within the range of 80 to 100 mmHg may be confer benefits to patients with STEMI in no-reflow.

A Prediction Model Based on Systemic Immune-Inflammatory Index Combined with Other Predictors for Major Adverse Cardiovascular Events in Acute Myocardial Infarction Patients.

Objective: To evaluate the prognostic value of the systemic immune-inflammatory index (SII) for predicting in-hospital major adverse cardiovascular events (MACEs) in patients with acute myocardial infarction (AMI) and establish a relevant nomogram. Methods: This study included 954 AMI patients. We examined three inflammatory factors (SII, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR)) to see which one predicts in-hospital MACEs better. The predictors were subsequently screened using bidirectional stepwise regression method, and a MACE nomogram was constructed via logistic regression analysis. The predictive value of the model was evaluated using the area under the curve (AUC), sensitivity and specificity. In addition, the clinical utility of the nomogram was evaluated using decision curve analysis. We also compared the nomogram with the Global Registry of Acute Coronary Events (GRACE) scoring system. Results: 334 (35.0%) patients had MACEs. The SII (AUC =0.684) had a greater predictive value for in-hospital MACEs in AMI patients than the PLR (AUC =0.597, P<0.001) or NLR (AUC=0.654, P=0.01). The area under the curve (AUC) of the SII-based multivariable model for predicting MACEs, which was based on the SII, Killip classification, left ventricular ejection fraction, age, urea nitrogen (BUN) concentration and electrocardiogram-based diagnosis, was 0.862 (95% CI: 0.833-0.891). Decision curve and calibration curve analysis revealed that SII-based multivariable model demonstrated a good fit and calibration and provided positive net benefits than the model without SII. The predictive value of the SII-based multivariable model was greater than that of the GRACE scoring system (P<0.001). Conclusion: SII is a promising, reliable biomarker for identifying AMI patients at high risk of in-hospital MACEs, and SII-based multivariable model may serve as a quick and easy tool to identify these patients.

Noninvasive photoacoustic computed tomography/ultrasound imaging to identify high-risk atherosclerotic plaques.

PURPOSE: Noninvasive detection of high-risk plaques is still challenging. In this study, we aimed to noninvasively assess αvß3-integrin expression using a customed photoacoustic (PA) computed tomography (PACT)/ultrasound (US) system in atherosclerotic lesions of varying degrees of severity and to explore its potential value for detecting high-risk plaques. METHODS: We constructed αvß3-integrin-targeted ultrasmall gold nanorods (AuNRs) with cyclo Arg-Gly-Asp (cRGD) and tested their properties. Employing C57BL/6 J (wild-type, WT) mice and apolipoprotein E gene knockout (ApoE-/-) mice fed either a chow diet or a high-fat/high-cholesterol diet (HFHCD), we established varying degrees of lesion severity. In vivo PACT/US imaging was performed to assess αvß3-integrin expression in the 4 groups by cRGD-AuNRs. Further histopathologic examination was conducted to evaluate the plaque vulnerability indicators. RESULTS: The data showed that cRGD-AuNRs exhibited excellent photothermal conversion capacity, stability, targeting ability, and biocompatibility. The immunohistochemical results indicated that αvß3-integrin was upregulated with increasing aggravation of the lesions. In vivo PACT/US imaging showed good consistency with αvß3-integrin expression. Notably, ApoE-/- mice fed a HFHCD showed an abrupt PA intensity increase compared with the other groups. The histopathologic examination verified that the atherosclerotic plaques of ApoE-/- mice fed the HFHCD developed unstable phenotypes. Correlation analysis showed that PA intensity was mainly related to inflammation and angiogenesis among all of the indicators. CONCLUSION: Our data indicated that αvß3-integrin is an effective indicator of plaque instability, and noninvasive PACT/US molecular imaging assessment of αvß3-integrin holds promise in detecting high-risk plaques.

Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis.

BACKGROUND: Thrombotic events cannot be completely prevented by antithrombotics, implicating a therapeutic gap due to inflammation, a not yet sufficiently addressed mechanism. Neutrophil extracellular traps (NETs) are an essential interface between inflammation and thrombosis, but exactly how the NETotic process is initiated and maintained during arterial thrombosis remains incompletely understood. METHODS AND RESULTS: We found that the plasma concentrations of C5a were higher in patients with ST-elevation myocardial infarction (STEMI) than in patients with angina and higher in mice with left common carotid artery (LCCA) thrombosis induced by FeCl3 than in control mice. We observed that the thrombus area and weight were decreased and that NET formation in the thrombi was reduced in the group treated with the selective C5aR1 receptor inhibitor PMX53 compared with the NaCl group. In vitro, NETosis was observed when C5a was added to neutrophil cultures, and this effect was reversed by PMX53. In addition, our data showed that C5a increased the production of mitochondrial reactive oxygen species (ROS) and that the promotion of NET formation by C5a was mitochondrial ROS (Mito-ROS) dependent. Furthermore, we found that C5a induced the production of Mito-ROS by inhibiting mitochondrial STAT3 activity. CONCLUSIONS: By inhibiting mitochondrial STAT3 to elicit Mito-ROS generation, C5a triggers the generation of NETs to promote the development of arterial thrombosis. Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis.

The Association Between Visceral Adiposity Index and Worsening Renal Function in the Elderly.

Background: Visceral adiposity index (VAI) is an indicator of visceral fat accumulation and dysfunction. However, little is known about whether VAI is associated with worsening renal function (WRF) in the elderly. Therefore, our study aimed to explore the association between VAI and WRF among the elderly population. Methods: In total, 5,583 elderly participants (aged ≥ 65 years) who participated in the annual health checkups at least twice between January 2017 and July 2021 were enrolled and divided into four groups according to the VAI quartiles. The primary endpoint was incident chronic kidney disease (CKD), defined as incident estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The secondary endpoint was rapid kidney function decline (RKFD), defined as decline in eGFR of 40%. To evaluate the association between VAI and WRF, three Cox regression models were conducted, where VAI was treated as a continuous variable and a categorical variable (Q1 as reference), respectively. Subgroup analysis in participants with different baseline characteristics was also performed. Results: During a median of 2.46 year follow-up, 931 (16.68%) participants developed CKD. After fully adjusting for confounding factors, VAI was significantly associated with incident CKD (HR, 1.052; 95% CI: 1.029-1.076, p < 0.001), and RKFD (HR, 1.077; 95% CI: 1.041-1.114, p < 0.001). Moreover, compared to those with the lowest VAI quartiles, subjects with the highest quartiles had a higher risk of incident CKD (HR, 1.286; 95% CI: 1.033-1.601, p = 0.024), and RKFD (HR, 1.895; 95% CI: 1.086-3.307, p = 0.025). The risk of incident CKD also tended to increase with elevated VAI quartiles (all p-values for trend <0.05). This positive association remained consistent among participants with different genders, baseline weights, or kidney functions. Conclusion: In our study, elevated VAI was associated with increased risk of incident CKD and RKFD in the elderly population.

Nomogram to predict rapid kidney function decline in population at risk of cardiovascular disease.

BACKGROUND: To develop a reliable model to predict rapid kidney function decline (RKFD) among population at risk of cardiovascular disease. METHODS: In this retrospective study, key monitoring residents including the elderly, and patients with hypertension or diabetes of China National Basic Public Health Service who underwent community annual physical examinations from January 2015 to December 2020 were included. Healthy records were extracted from regional chronic disease management platform. RKFD was defined as the reduction of estimated glomerular filtration rate (eGFR) ≥ 40% during follow-up period. The entire cohort were randomly assigned to a development cohort and a validation cohort in a 2:1 ratio. Cox regression analysis was used to identify the independent predictors. A nomogram was established based on the development cohort. The concordance index (C-index) and calibration plots were calculated. Decision curve analysis was applied to evaluate the clinical utility. RESULTS: A total of 8455 subjects were included. During the median follow-up period of 3.72 years, the incidence of RKFD was 11.96% (n = 1011), 11.98% (n = 676) and 11.92% (n = 335) in the entire cohort, development cohort and validation cohort, respectively. Age, eGFR, hemoglobin, systolic blood pressure, and diabetes were identified as predictors for RKFD. Good discriminating performance was observed in both the development (C-index, 0.73) and the validation (C-index, 0.71) cohorts, and the AUCs for predicting 5-years RKFD was 0.763 and 0.740 in the development and the validation cohort, respectively. Decision curve analysis further confirmed the clinical utility of the nomogram. CONCLUSIONS: Our nomogram based on five readily accessible variables (age, eGFR, hemoglobin, systolic blood pressure, and diabetes) is a useful tool to identify high risk patients for RKFD among population at risk of cardiovascular disease in primary care. Whereas, further external validations are needed before clinical generalization.

Nomogram to predict risk of incident chronic kidney disease in high-risk population of cardiovascular disease in China: community-based cohort study.

AIMS: To develop a nomogram for incident chronic kidney disease (CKD) risk evaluation among community residents with high cardiovascular disease (CVD) risk. METHODS: In this retrospective cohort study, 5730 non-CKD residents with high CVD risk participating the National Basic Public Health Service between January 2015 and December 2020 in Guangzhou were included. Endpoint was incident CKD defined as an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 during the follow-up period. The entire cohorts were randomly (2:1) assigned to a development cohort and a validation cohort. Predictors of incident CKD were selected by multivariable Cox regression and stepwise approach. A nomogram based on these predictors was developed and evaluated with concordance index (C-index) and area under curve (AUC). RESULTS: During the median follow-up period of 4.22 years, the incidence of CKD was 19.09% (n=1094) in the entire cohort, 19.03% (727 patients) in the development cohort and 19.21% (367 patients) in the validation cohort. Age, body mass index, eGFR 60-89 mL/min/1.73 m2, diabetes and hypertension were selected as predictors. The nomogram demonstrated a good discriminative power with C-index of 0.778 and 0.785 in the development and validation cohort. The 3-year, 4-year and 5-year AUCs were 0.817, 0.814 and 0.834 in the development cohort, and 0.830, 0.847 and 0.839 in the validation cohort. CONCLUSION: Our nomogram based on five readily available predictors is a reliable tool to identify high-CVD risk patients at risk of incident CKD. This prediction model may help improving the healthcare strategies in primary care.

Global computational alignment of tumor and cell line transcriptional profiles.

Cell lines are key tools for preclinical cancer research, but it remains unclear how well they represent patient tumor samples. Direct comparisons of tumor and cell line transcriptional profiles are complicated by several factors, including the variable presence of normal cells in tumor samples. We thus develop an unsupervised alignment method (Celligner) and apply it to integrate several large-scale cell line and tumor RNA-Seq datasets. Although our method aligns the majority of cell lines with tumor samples of the same cancer type, it also reveals large differences in tumor similarity across cell lines. Using this approach, we identify several hundred cell lines from diverse lineages that present a more mesenchymal and undifferentiated transcriptional state and that exhibit distinct chemical and genetic dependencies. Celligner could be used to guide the selection of cell lines that more closely resemble patient tumors and improve the clinical translation of insights gained from cell lines.

Identification of Transcriptional Variation in Aortic Remodeling Using a Murine Transverse Aortic Constriction (TAC) Model.

Arterial remodeling is a major pathological consequence of hypertension, which is recognized as the most common chronic non-communicable disease. However, the detailed mechanism of how arterial remodeling is induced by hypertension has not yet been fully elucidated. Evaluating the transcriptional changes in arterial tissue in response to elevated blood pressure at an early stage may provide new insights and identify novel therapeutic candidates in preventing arterial remodeling. Here, we used the ascending aorta of the transverse aortic constriction (TAC) model to induce arterial remodeling in C57BL/6 male mice. Age-matched mice were subjected to sham surgery as controls. The TAC model was only considered successful if the mice conformed to the criteria (RC/LC blood flow velocity with 5-10-fold change) 1 week after the surgery. Two weeks after surgery, the ascending aorta developed severe remodeling in TAC mice as compared to the sham group. High throughput sequencing was then applied to identify differentially expressed (DE) transcripts. In silicon analysis were then performed to systematically network transcriptional changes. A total of 1,019 mRNAs were significantly changed between TAC and the sham group at the transcriptional level. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis revealed that stress/stimulus/immune-related biological processes played a crucial role during arterial remodeling. Our data provide a comprehensive understanding of global gene expression changes in the TAC model, which suggests that targeting inflammation and vascular smooth cell transformation are potential therapeutic strategies to interfere with the aortic remodeling at an early stage in the development of hypertension.

Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling.

Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.