ABSTRACT Background and Aims Composite lipid indices are closely related to the risk and poor prognosis of diseases. However, there are no studies on the prognostic value of Castelli's risk indices‐I and II (CRI‐I, CRI‐II) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Therefore, the aim of this study was to investigate the association of CRI‐I and CRI‐II with the prognosis of patients with ACS undergoing PCI. Patients and Methods A total of 1475 patients with ACS undergoing PCI were consecutively enrolled in this prospective cohort study from January 2016 to December 2018. The CRI‐I and CRI‐II were measured. The endpoints were MACEs, including all‐cause mortality, requirement of rehospitalization for severe heart failure, recurrence of myocardial infarction, in‐stent restenosis, and reaccept PCI. Follow‐up data were collected via clinical visits or telephone calls at 1, 3, 6, and 12 months and annually thereafter. Result Multivariable Cox regression analysis revealed that the risk of MACEs increased gradually with increasing CRI‐I and CRI‐II. The cumulative survival rate in the CRI‐I ≥ 3.350 and CRI‐II ≥ 1.697 groups was significantly lower than that in the CRI‐I < 3.350 and CRI‐II < 1.697 groups, respectively (log‐rank tests: all p < 0.001). The nomogram demonstrated good predictive performance for the 1‐, 2‐, and 3‐year survival probability. Conclusions CRI‐I ≥ 3.350 and CRI‐II ≥ 1.697 could serve as independent predictors of MACEs in patients with ACS undergoing PCI.

BACKGROUND AND AIMS:The geriatric nutritional risk index (GNRI) has shown good predictive value for some diseases. However, its association with major adverse cardiovascular events (MACEs) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) remains uncertain. This study investigated the correlation between the GNRI and MACEs. PATIENTS AND METHODS:This was a prospective cohort study. We consecutively enrolled 1515 ACS patients who underwent PCI. The median duration of follow-up was 1000 days. The primary endpoints were MACEs, including all-cause mortality, severe heart failure rehospitalization, revascularization, acute myocardial infarction (AMI) recurrence, and restenosis/intrastent thrombosis. RESULTS:ROC curve analysis revealed an area under the curve of 0.603, with a GNRI cutoff value of 110.78. Cox regression analysis indicated that lower GNRI levels were independently associated with an increased risk of MACEs, a finding supported by risk score assessments. Kaplan-Meier survival curves and log-rank tests indicated significantly lower cumulative survival rates in patients with lower GNRI value. Lower GNRI levels were also correlated with a higher risk of rehospitalization and cardiovascular death, as confirmed by the competing risk model. These associations remained significant after adjustments (all p for interaction > 0.05). RCS analysis and trend tests (all p < 0.05) further supported these findings. CONCLUSION:GNRI, as an indicator of nutritional status, was correlated with the risk of MACEs in ACS patients undergoing PCI, particularly in predicting cardiac death and rehospitalization, suggesting that the GNRI level may serve as a valid indicator for predicting poor prognosis in patients with ACS undergoing PCI.

Coronary artery bypass grafting (CABG) reconstructs the blood supply for treating coronary heart disease. One of the most used conduits is the great saphenous vein, but its effect is limited, owing to lower long-term patency versus arterial grafts. This study devised a 3D bio-printed stent, comprising of genetically modified human bone marrow mesenchymal stem cells (BMSCs), to improve venous graft patency. BMSCs and endothelial cells (ECs) were obtained from sternal bone marrow and discarded saphenous veins, respectively. BMSCs were transduced with lentivirus overexpressing sirtuin-3 (SIRT3) and seeded on a 3D bio-printed matrix stent, comprising of hyaluronic acid methacryloyl and gelatin methacryloyl (HAMA/GelMA). A rat CABG model was established, via generating a jugular vein-common carotid artery arteriovenous graft. The SIRT3-BMSC-seeded stent was “wrapped” around this venous graft, serving as an extravascular stent. An in vitro model was also devised, in which lipopolysaccharide (LPS)-pre-treated ECs were co-cultured with SIRT3-BMSCs, followed by evaluating mitochondrial transferal and tunneling nanotube (TNT) formation-related functional changes. Immunoprecipitation was used to examine SIRT3-vasodilator-simulated phosphoprotein (VASP) interactions. Rat arteriovenous graft model found that SIRT3-BMSC+stent, compared to Control, Stent, and BMSC+stent groups, had the greatest graft vessel diameter, maximum blood flow velocity during systole and CD31+ EC area, along with the lowest cell proliferation and inflammatory cell infiltration; therefore, SIRT3-BMSC+stent had the greatest inhibitory effects on venous graft neointimal formation. In vitro, LPS-pre-treated ECs, after co-culture with SIRT3-BMSCs, restored endothelial, along with lowering mesenchymal marker expression. Furthermore, mechanistic analyses revealed increased SIRT-BMSC-to-LPS-pre-treated EC mitochondrial transfer, facilitated by TNTs formed between SIRT3-BMSCs and ECs. This mitochondrial transfer was mediated via SIRT3-VASP interactions, in which SIRT3 deacetylates VASP to promote TNT. SIRT3-BMSC/HAMA/GelMA extravascular stent could effectively lower arteriovenous graft dilation and inhibit neointimal formation, possibly via SIRT3 deacetylation of VASP, thereby promoting TNT formation, and subsequently, mitochondrial transfer from BMSCs to ECs to improve EC function. Thus, the extravascular stent was able to provide external support, along with facilitating BMSC therapeutic effects.

The transplantation of human bone marrow mesenchymal stem cells (hMSCs) exhibits promising therapeutic effects in the treatment of myocardial infarction (MI), however, its clinical application is limited due to the low survival rate of the transplanted cells. Three-dimensional (3D) bioprinted tissue engineering patches have demonstrated efficacy as a delivery approach to enhance the viability and engraftment of stem cells. In this study, we have developed a novel hMSCs tissue-engineered patch equipped with a nano-slow-release system using 3D bioprinting technology. The patch is based on a matrix material consisting of methacrylated gelatin (GelMA) and chitosan nanoparticles loaded with vascular endothelial growth factor (VEGF), which possesses pro-angiogenic effects. The resulting patch demonstrated excellent compatibility with hMSCs and enabled stable, sustained VEGF release.In vivoresults showed that the patch significantly reduced cardiomyocyte apoptosis three days after MI, and improved cardiac function and myocardial fibrosis at 28 d post-surgery. These effects were closely associated with the patch's potent angiogenic properties and favorable stem cell survival. In conclusion, this study successfully developed a 3D-printed tissue engineering patch with strong potential for clinical application, offering a promising new approach for the treatment of MI.

Background This study aimed to investigate the association of pan-immune-inflammation value (PIV), PIV/HDL-C (high-density lipoprotein cholesterol), PIV*LDL-C (low-density lipoprotein cholesterol) with the prognosis of patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Methods A total of 1360 patients with ACS undergoing PCI were consecutively enrolled in this study. They were divided into major adverse cardiovascular events (MACEs) (n = 58) and non-MACEs (n = 1302) groups. The PIV, PIV/HDL-C, and PIV*LDL-C values were measured. The endpoints were MACEs, including cardiogenic mortality, recurrence of myocardial infarction, in-stent restenosis, and rehospitalization for severe heart failure. Results The multivariable Cox regression analysis showed that PIV ≥355.79 (hazard ratio [HR]: 2.006, 95% confidence interval [CI]: 1.165-3.455), PIV/HDL-C ≥ 282.86 (HR: 1.987, 95% CI: 1.119-3.527), and PIV*LDL-C ≥ 1431.58 (HR: 2.071, 95% CI: 1.206-3.556) were all independent predictors of MACEs in patients with ACS undergoing PCI (all P < .05). The cumulative survival rates were significantly lower for patients with higher PIV, PIV/HDL-C, and PIV*LDL-C than for patients with lower values of these indices (log-rank tests: all P < .05). Conclusion Higher PIV, PIV/HDL-C, and PIV*LDL-C were independent prognostic factors for patients with ACS undergoing PCI and may be novel biomarkers for predicting MACEs.

Inflammatory diseases contribute to secondary osteoporosis. Hypertension is a highly prevalent inflammatory condition that is clinically associated with reduced bone mineral density and increased risk of fragility fracture. In this study, we showed that a significant loss in bone mass and strength occurs in two preclinical models of hypertension. This accompanied increases in immune cell populations, including monocytes, macrophages, and IL-17A-producing T cell subtypes in the bone marrow of hypertensive mice. Neutralizing IL-17A in angiotensin II-infused mice blunted hypertension-induced loss of bone mass and strength as a result of decreased osteoclastogenesis. Likewise, the inhibition of the CSF1 receptor blunted loss of bone mass and prevented loss of bone strength in hypertensive mice. In an analysis of UK Biobank data, circulating bone remodeling markers exhibited striking associations with blood pressure and bone mineral density in more than 27,000 humans. These findings illustrate a potential mechanism by which hypertension activates immune cells in the bone marrow, encouraging osteoclastogenesis and eventual loss in bone mass and strength.

Purpose:Acute myocardial infarction (AMI) is a major contributor to death. The purpose of this study is to explore circulating biomarkers for AMI diagnosis from the perspectives of immunological microenvironment and N6-methyladenosine (m6A) RNA methylation regulation. Patients and Methods:The GSE59867 dataset was used to download platform and probe data for conducting differential analysis of m6A regulators. A diagnostic nomogram was created utilizing the random-forest method and evaluated for predictive power. m6A-related gene patterns were identified, and their immune microenvironment characteristics were analyzed. Peripheral blood samples were obtained for validation in patient-based investigations using RT-qPCR. The association between m6A regulators and clinical parameters was examined via Spearman correlation analysis. Results:With a predictive nomogram model developed using key m6A regulators, two distinct m6A subtypes were identified, showing significant variations in infiltrating immunocyte abundance. In confirmation of the model prediction, examination of patient blood identified METTL3, WTAP, RBM15, ALKBH5, FTO, and FMR1 as novel circulating biomarkers for AMI diagnosis. METTL3 and FTO were identified as promising biomarkers for AMI given that they showed a positive correlation with left ventricular ejection fraction. Conclusion:The study identified six m6A regulators as circulating biomarkers for AMI diagnosis and suggested a potential role for m6A-mediated immune cell infiltration in the pathogenesis of AMI.

Background: Postural orthostatic tachycardia syndrome (POTS) commonly affects young females and is characterized by orthostatic intolerance and fatigue. Its etiology is unclear, and no specific therapies are available. Circulating T cell/monocyte complexes (doublets) occur in conditions such as active tuberculosis and dengue fever. Ongoing immune activation can promote autonomic dysfunction and mimic many aspects of POTS. We have also shown that isolevuglandin (IsoLG)-adducted proteins accumulate in several cardiovascular conditions and can serve as antigens presented by myeloid cells to T cells, thereby engaging the adaptive immune response. Hypothesis: IsoLG-adducts accumulate in POTS and are presented to T cells, leading to increased circulating doublets and ongoing immune activation. Methods and Results: POTS (N=8) and LCPOTS (N=23) patients exhibited a greater increase in heart rate (HR) during a 10-minute upright tilt compared to controls (N=10) (47.75 ± 7, 50.23 ± 4.6 vs. 20.33 ± 3.17 bpm, p<0.01, Figure). Circulating doublets, analyzed by flow cytometry, were detected in POTS and LCPOTS with high TCR/HLA FRET (p<0.005), but were very low in control subjects. Doublets exhibited higher levels of IL-17A and IFN-γ compared to non-complexed T cells, along with a significant increase in intracellular IsoLG-adducts compared to non-complexed monocytes. Notably, the percentage of IFN-γ+ and IL-17A+ T cells in the doublets of POTS and LCPOTS subjects positively correlated with clinical parameters (ΔHR) in the tilt table test (Figure). POTS and LCPOTS exhibited a significantly increased proportion of intermediate (CD14highCD16high) and non-classical monocytes (CD14LowCD16high) compared to healthy controls. In contrast to these flow cytometric properties, traditional markers of inflammation were less discriminatory. 87.5% of patients were in the low to normal range of CRP, and 62.5% had D-dimer levels below 0.27 ng/mL. WBC counts were also normal among patients. Conclusion: POTS and LCPOTS patients exhibit altered immune profiles, characterized by elevated circulating T cell-monocyte doublets and a distinct monocyte subtype profile. The increased levels of IsoLG-adducts in these immune complexes suggest that ongoing intracellular oxidation of arachidonic acid is a likely pathogenic mechanism and provides a previously unrecognized therapeutic avenue.

Background: Psoriasis is a common autoimmune disease that affects 3% of the adult population. Hypertension is common in humans with Psoriasis and T cells are known to contribute to both conditions. Isolevuglandins (IsoLGs) are peroxidation products of arachidonic acid that rapidly adduct to lysine, forming neoantigen peptides which are presented by class 1 major histocompatibility complexes (MHCs). These IsoLG-adducted peptides stimulate T cell activation, cytokine production and ultimately lead to disease manifestations. We recently identified 4 peptides that when IsoLG-adducted are antigenic in hypertension. Hypothesis: IsoLG-specific T cells are similar between hypertension and psoriasis. Methods: We employed an experimental model of psoriasis caused by keratinocyte-specific overexpression of Tie2 (KC-Tie2, n = 7) and employed littermate controls (n = 7). Mice were studied at 10 to 12 weeks of age. We created fluorescently labeled probes composed of the murine class I MHC H2-D b complexed with IgG and loaded with the pro-hypertensive antigenic peptide cadherin 16 (CDH16), IsoLG adducted (Figure 1A). This was employed in flow cytometric analysis of skin and spleen of KC-Tie2 and littermate control mice. Results: Using radiotelemetry, we confirmed that KC-Tie2 mice develop modest blood pressure elevations by 10-12 weeks of age (daytime systolic pressure 111 ± 3 in KC-Tie2 vs 101 ± 2 mmHg in littermate controls p < 0.007). In the skin of littermate controls, only 2 ± 1 % of total CD8+ T cells were recognized by the IsoLG-adducted CDH16/H2-D b probe, while in the inflamed skin of KC-Tie2 mice, 8 ± 2% of CD8+ T cells were specific for this peptide (p < 0.004, Figure 1B). In the spleen, virtually no IsoLG-adducted CDH16 specific CD8+ T cells were present (Figure 1C). The non-adducted CDH16/H2-D b probe did not bind to T cells in any tissue examined. Conclusions: T cells specific for IsoLG adducts that form in hypertension are also markedly increased in the inflamed skin of mice with experimental psoriasis. Unlike hypertension, in which these cells are also present in the spleen, we observe virtually no IsoLG-specific splenic T cells in psoriasis, suggesting specificity of T cell localization between the two conditions. These observations might explain the increased prevalence of hypertension in patients with psoriasis.

Myocardial ischemia-reperfusion (MI/R) injury limits the therapeutic effects of revascularization in acute myocardial infarction. In this study, we investigated whether human SIRT3 (hSIRT3) and TIMP3 (hTIMP3) could achieve targeted delivery with the assist of cationic microbubbles (CMBs) and a synergistic protection effect on porcine MI/R myocardium. Firstly, CMBs carrying the hSIRT3 or hTIMP3 plasmids were used individually or synergistically for cardiac-targeted delivery in MI/R pigs. After 7 days of observation, hSIRT3 and hTIMP3 were mainly enriched in myocardium, especially in the infarction center, without additional increase in cTNI and pathological damage to non-cardiac organs. At the same time, hSIRT3 and hTIMP3 exerted a protective role against myocardial injury, as gene therapy significantly inhibited myocardial apoptosis, inflammation and oxidative damage. After 90 days of observation, hSIRT3 and hTIMP3 application exerted an inhibiting effect on development of heart failure, as the strategy significantly increased the density of vascular, and limited the myocardial fibrosis, area scar size, the decline of cardiac function. As expected, collaborative applications of hSIRT3 and hTIMP3 showed a better protective effect than hSIRT3 or hTIMP3 application alone. Collectively, hSIRT3 and hTIMP3 delivered with CMBs in heart could exert positive effect on myocardial protection after MI/R in pigs.

Diabetic nephropathy (DN) is an important complication in diabetic patients that severely impacts their quality of life and life expectancy. Although metabolic and inflammatory responses induced by hyperglycemia are considered the primary pathogenic factors of DN, the specific molecular mechanisms involved remain unclear. Here, we investigated the role of insulin-like growth factor-binding protein 5 (IGFBP5) in DN using in vitro cell experiments and mouse models. We assessed the effects of high-glucose conditions on IGFBP5 expression in glomerular endothelial cells and evaluated its regulatory effects on glycolysis, NLRP3 inflammasome activation, endothelial‒mesenchymal transition (EndoMT), and histone lactylation via the suppression of IGFBP5. Furthermore, we evaluated the effects of IGFBP5 on renal fibrosis and confirmed its regulatory mechanisms in DN model mice. Knockdown of IGFBP5 inhibited high glucose-induced EndoMT in glomerular endothelial cells, which could also be suppressed by the NLRP3 inflammasome inhibitor MCC950. In addition, silencing of IGFBP5 decreased glycolytic activity and histone lactylation, thereby inhibiting the activation of the NLRP3 inflammasome and EndoMT. Furthermore, in mouse models of DN, IGFBP5 knockdown alleviated renal fibrosis and reduced glycolysis, histone lactylation, NLRP3 inflammasome activation and EndoMT. IGFBP5 promotes NLRP3 inflammasome-induced EndoMT and renal fibrosis by regulating glycolysis-mediated histone lactylation, accelerating the progression of DN. These findings provide a new potential therapeutic target for DN.

AIMS:T cells contribute to hypertension; however, hypertension occurs in settings of T cell deficiency. METHODS AND RESULTS:We studied two colonies of T/B cell-deficient RAG-1-/- mice with disparate responses to angiotensin II, being one protected from blood pressure increase and the other one responsive. This difference depends on the capability of hypertensive RAG-1-/- mice to expand natural killer and innate lymphoid cells (NK/ILCs) that produce pro-hypertensive cytokines. This process is regulated by the DNA methylation status of the β2 adrenergic receptor (β2-AdR). Angiotensin II caused blood pressure elevation in T and NK/ILCs-deficient mice only when either T or NK/ILCs cells were adoptively reconstituted. Additional studies showed NK cell expansion in humans that underwent B cell depletion, and this was augmented in those with hypertension. CONCLUSIONS:These findings illustrate that the modulation of NK/ILCs activation by adrenergic signalling governs an escape mechanism in lymphocyte-deficient host, enabling the development of hypertension.

Aging is a significant risk factor for cardiovascular diseases, with ischemic heart disease (IHD) being the leading cause of cardiovascular-related mortality. Inhibition of FOXO4, which selectively eliminates senescent cells, offers protective effects on the aging myocardium. However, the removal of senescent cells may lead to a reduction in tissue cell density, thereby exacerbating tissue space formation and perivascular fibrosis. Therefore, selectively eliminating senescent cells in the aging heart, while simultaneously replenishing therapeutic bone marrow-derived mesenchymal stem cells (BMSCs), holds substantial therapeutic potential for synergistically combating cardiac aging. This study proposes a promising cardiac rejuvenation strategy using ultrasound-targeted microbubble destruction (UTMD)-mediated delivery of shFOXO4/SDF1 to eliminate cellular senescence and enhance BMSC homing. Transcriptomic analysis identified FOXO4 as a pivotal transcription factor in cardiac aging, with FOXO4 protein predominantly expressed in cardiac fibroblasts (CFs) and vascular endothelial cells in the myocardium of aged rats. Knockdown of FOXO4 in aging CFs reversed cellular senescence, and co-culturing these rejuvenated CFs with BMSCs further enhanced the reversal of senescence and bolstered resistance to oxidative stress. The use of UTMD for delivering shFOXO4/SDF1 in dual-gene therapy significantly enhanced BMSC homing, ameliorating cardiac aging, oxidative stress, and inflammation. In an ischemia-reperfusion injury (MIRI) model, pretreatment with shFOXO4/SDF1 effectively reduced cardiomyocyte apoptosis, promoted neovascularization, reduced infarct size, and improved cardiac function. The combined removal of senescent cells and enhanced BMSC homing synergistically ameliorated cardiac aging and improved post-MIRI prognosis in aging hearts. These findings provide novel insights and potential therapeutic strategies for addressing cardiac aging and age-related heart diseases.

Levels of galectin-3 (GAL-3), a pro-inflammation biomarker, are closely associated with a diagnosis of acute coronary syndrome (ACS). However, the predictive ability of GAL-3 for long-term adverse prognosis in ACS has not been well-investigated. This prospective cohort study aimed to evaluate the predictive value of GAL-3 using classification and regression tree (CART) analysis. A total of 134 patients with ACS at The Affiliated Hospital of Chengde Medical University were consecutively enrolled between January 2016 and May 2017. All included patients (102 [76.1

Background: Hypertensive stimuli increase reactive oxygen species (ROS) production and the formation of Isolevuglandins (IsoLGs) that modify self-proteins, forming IsoLG-adducts that are immunogenic. Dendritic cells (DCs) with these adducts migrate to spleen and secondary lymphoid organs and activate T cells that recognize the IsoLG adduct-MHC-I complex. Activated T cells then infiltrate target tissues, including the kidney and vasculature, release cytokines, and cause organ damage. We have identified four isoLG-adducted peptides presented by murine class-I major histocompatibility complex (H2-D b ), triggering CD8 + T cell activation and promoting hypertension in male mice. Hypothesis: Sex influences the immunogenicity of IsoLG-adducts and the accumulation of T cells specific for these adducts in hypertension. Methods and Results: Ang II infusion (490 ng/kg/min X 2 weeks) induced identical blood pressure elevations in 12-week-old male and female C57Bl/6 mice (Figure Panel A). Despite this similar degree of hypertension, we observed a markedly different degree of renal but not vascular inflammation. Male mice exhibited a marked increase in CD8 + T cells detected by isoLG-adducted SGLT2 and CDH-16 peptide/H2-D b /IgG probes in the kidney, while female mice did not. We also employed Nur77- GFP mice to monitor acutely activated T cell receptors and observed that these predominantly exist in the TCR-specific T cells in male but not female mice. These changes in renal T cell accumulation were associated with striking differences in renal function. Albuminuria, serum creatinine, and urinary NGAL levels were elevated in hypertensive male but not female mice, and the ability to secrete a volume challenge was reduced in male but not female mice (Panel C-D). We have previously shown that catecholamines induce IsoLG formation. In keeping with this, we found that male mice exhibited a striking increase in urinary norepinephrine, while female mice did not (Panel B). Heart rate variability was similar between male and female mice during Ang II infusion. Conclusion: While the hypertensive response to Ang II is similar between male and female mice, female mice show protection against renal T cell activation and renal dysfunction. The similar levels of hypertension may indicate vascular inflammation, which is comparable between male and female mice and can contribute to increased systemic vascular resistance and vascular remodeling.

Immune checkpoint inhibitors (ICIs) block immunoregulatory receptor-ligand interactions and robustly increase survival of cancer patients but frequently result in immune-related adverse events (irAEs). While rheumatologic toxicities are commonly reported as irAEs, the effect of immune checkpoint blockade on the underlying mechanisms of ICI-induced fractures and bone loss is controversial, with reports of both positive and negative effects on bone mass in preclinical models. However, no previous reports have investigated the impact of ICIs on females or aged mice, or on fracture risk in either sex. We report that global deletion of programmed cell death protein 1 (PD-1) broadly results in bone loss in skeletally mature male and female PD-1-/- mice, with a sexually divergent phenotype in adolescent mice, decreased bone strength in adult males and young females, and expansion of multiple T cell subsets in the bone marrow. In a model of pharmacologic PD-1 blockade, administration of α-PD-1 reduced bone mass, expanded multiple T cell subsets in the bone marrow, and increased osteoclast activity and resorptive capacity. T cell deficient mice were resistant to osteoclast-mediated bone loss following α-PD-1 therapy, suggesting that T cells in the bone marrow are necessary for bone loss in the setting of ICI therapy. These findings may be leveraged to identify patients at greater fracture risk following ICI therapy due to enrichment of effector T cell populations in the bone marrow.

Background:Acute coronary syndrome (ACS) is closely associated with inflammation status. The systemic inflammation score (SIS), which is calculated using the serum albumin level and lymphocyte-to-monocyte ratio (LMR), has emerged as a valuable biomarker for predicting the clinical outcomes of several diseases. Nonetheless, the value of SIS in predicting the long-term prognostic risk in patients with ACS undergoing percutaneous coronary intervention (PCI) remains unknown. We aimed to explore the associations of SIS with major adverse cardiovascular events (MACEs), all-cause mortality, and cardiovascular death. Methods:This prospective cohort study consecutively enrolled 1582 patients with ACS who underwent PCI at the Department of Cardiology in the Affiliated Hospital of Chengde Medical University (Chengde, China) between January 2016 and December 2018. The primary endpoint was MACEs, including all-cause mortality, rehospitalization for heart failure, revascularization, recurrence of acute myocardial infarction, and restenosis/intrastent thrombosis. Results:The Kaplan-Meier survival analysis revealed that a high SIS was correlated with MACEs and all-cause mortality and that increasing SIS was independently associated with the risks of MACEs and all-cause mortality by Cox regression. Landmark analysis provided evidence for the time window of predictive ability, which could guide clinical applications. A clear correlation between the increasing tendency of hazard ratio in patients with ACS undergoing PCI and the risks of MACEs or all-cause mortality was noted (p for trend <0.05). The sensitivity analysis with a competing risk model showed that high SIS level was correlated with the risks of cardiac death and rehospitalization. The mediation analysis revealed that the hemoglobin level exerted a mediating effect on the relationship between SIS and MACEs. Conclusion:The SIS exhibited a strong correlation with the risks of MACEs and all-cause mortality. Notably, the SIS was particularly effective in predicting the risk of cardiac death and likelihood of rehospitalization.

ABSTRACT Purpose To investigate the role of the systemic inflammatory response index (SIRI) and high‐density lipoprotein cholesterol (HDL‐C) and low‐density lipoprotein cholesterol (LDL‐C) levels in predicting the risk of major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Patients and Methods Overall, 1377 patients with ACS who underwent PCI between January 2016 and December 2018 were consecutively enrolled. The patients were divided into MACEs (n = 60) and non‐MACEs (n = 1317) groups. The study endpoints were MACEs, including cardiac‐related mortality and rehospitalization for severe heart failure (HF), myocardial infarction (MI), and in‐stent restenosis. Results Both groups showed significant differences in the patients with age > 65 years, history of HF, acute MI, cardiogenic shock, left ventricular ejection fraction < 40%, SIRI ≥ 2.848, SIRI/HDL‐C ≥ 1.977, and SIRI × LDL‐C ≥ 4.609. The Kaplan–Meier curve showed that the low SIRI group had higher cumulative survival than the high SIRI group. Additionally, the univariate and multivariate Cox proportional hazards model demonstrated that SIRI ≥ 2.848, SIRI/HDL‐C ≥ 1.977, and SIRI × LDL‐C ≥ 4.609 were independent risk factors for patients with ACS undergoing PCI. Restricted cubic spline models were generated to visualize the relationship between SIRI, SIRI/HDL‐C, and SIRI × LDL‐C and the prognostic risk. Conclusion SIRI ≥ 2.848, SIRI/HDL‐C ≥ 1.977, and SIRI × LDL‐C ≥ 4.609 were all independent prognostic risk factors in patients with ACS undergoing PCI, which may be useful markers for assessment for long prognosis.