Michael J. B. Kutryk

Acute kidney injury following coronary angiography and percutaneous coronary intervention remains one of the most common complications of contemporary interventional cardiology. Historically referred to as contrast-induced nephropathy (CIN), the condition has undergone substantial conceptual evolution, with recognition that post-procedural renal dysfunction reflects the interaction between iodinated contrast media and patient- and procedure-related factors. This evolution has been accompanied by changes in diagnostic definitions, nomenclature, risk assessment, and preventive strategies. Current evidence supports a multifactorial pathophysiology involving renal vasoconstriction, medullary hypoxia, oxidative stress, endothelial dysfunction, inflammation, and direct tubular epithelial injury. Chronic kidney disease remains the strongest patient-related predictor of contrast-associated acute kidney injury (CA-AKI), whereas procedural risk is largely determined by contrast volume and procedural complexity. Contemporary risk prediction models integrate clinical and procedural variables to identify patients most likely to benefit from preventive measures. Prevention is centered on individualized risk reduction through contrast minimization, appropriate timing of repeat contrast exposure, and tailored intravascular volume expansion. Although numerous pharmacologic therapies have demonstrated biological plausibility and varying degrees of clinical efficacy, none are currently recommended for routine prophylaxis by contemporary international guidelines. Advances in procedural techniques, intracoronary imaging, physiological guidance, and individualized patient management have substantially reduced the incidence of CA-AKI. Future progress will depend on improved risk stratification, contrast-sparing technologies, and adequately powered randomized trials evaluating clinically meaningful renal and cardiovascular outcomes.

Atherosclerosis, a chronic inflammatory disease of the arteries, is the primary cause of ischemic heart disease and stroke, which are the leading drivers of global mortality and major contributors to disability. Important risk factors for atherosclerosis include insulin resistance (IR), hypertension and hyperlipidemia. IR-induced endothelial dysfunction, inflammation, dyslipidemia, vascular remodeling, and prothrombotic effects represent central mechanistic links between IR and atherosclerosis. In this review, these mechanisms are summarized and discussed by incorporating emerging mechanistic insights into IR-induced trained immunity, tissue-selective IR, and mitochondrial dysfunction, with an emphasis on their contributions to atherosclerosis. Furthermore, emerging therapeutic strategies using mesenchymal stem cells (MSCs) and their exosomes to improve IR are discussed, with a focus on their underlying mechanisms, as well as current challenges and outstanding issues in the field. While the current literature shows promising effects of MSCs and their exosomes in improving IR in cellular and animal models, clinical evidence remains limited. To harness the potential therapeutic benefits of MSCs and their exosomes, standardized manufacturing protocols and optimal routes of administration and dosing need to be determined.

An emerging field in cardiovascular research is the translational investigation of transfer RNA-derived small RNAs (tsRNAs). TsRNAs, a class of small non-coding RNA molecules, have been shown to modulate cellular functions by regulating gene expression post-transcriptionally. They are implicated in diverse pathological conditions, including cancer, cardiovascular disease (CVD), infectious disease, diabetes, neurological disease, and metabolic disorder. Accumulating evidence suggests tsRNAs as important players and biomarkers in CVD. Dysregulated tsRNAs are identified in atherosclerosis, heart failure, hypertension and other types of CVD. Bioinformatics and in vitro experimental analyses reveal that tsRNAs may participate in the regulation of endothelial and inflammatory cell interactions, endothelial cell and vascular smooth muscle cell proliferation and migration, and cardiac metabolism, mitophagy and remodeling, contributing to the pathogenesis of CVD. In addition, altered tsRNAs possess great diagnostic and prognostic potential in CVD. Nevertheless, there are currently no in vivo mechanistic studies using animal models, and the small sizes of reported clinical studies that examined tsRNAs limit their diagnostic and prognostic value. Although of promise, further research is needed to address the utility of tsRNAs in cardiovascular care. Keywords: transfer RNA-derived small RNAs gene regulation cardiovascular disease pathogenesis biomarker

Endothelin-1 (ET-1) plays a critical role in diabetic vasculopathy. Although clinical trials have shown promise for ET-1 receptor antagonists in treating diabetic nephropathy, their clinical use remains limited by adverse effects. MiR-454-3p targets ET-1. This study aimed to investigate the role of miR-454-3p in modulating ET-1 expression and related molecular changes in endothelial cells (ECs) under high glucose conditions using both bioinformatics and experimental approaches. Bioinformatics analysis identified 10 miR-454-3p target genes expressed in ECs previously implicated in diabetic vascular complications: ET-1, GJA1, IRF1, PIK3CB, TRPC3, SLMAP, ESR1, ITGB8, MAPK1, and PPARG. With the exception of PPARG, which protects ECs from hyperglycemia-induced damage, all have been reported to exacerbate endothelial dysfunction. Western blotting showed that high glucose increased ET-1 expression in human umbilical vein ECs (HUVECs) and human dermal microvascular endothelial cells (HDMECs), while miR-454-3p overexpression significantly suppressed this effect in both cell types. Conditioned medium (CM) from HUVECs transfected with miR-454-3p mimics enhanced eNOS expression in recipient cells, compared to control CM. Pre-treatment of HUVEC control CM with an anti-ET-1 antibody also increased eNOS expression, supporting that miR-454-3p promotes NOS production partly via ET-1 suppression. MiR-454-3p overexpression in HUVECs did not affect PPARG expression or cell proliferation. In conclusion, miR-454-3p overexpression inhibits high glucose-induced ET-1 expression in HUVECs and HDMECs, and promotes eNOS production without affecting PPARG expression in HUVECs. Our findings suggest that miR-454-3p modulates ET-1 expression under hyperglycemic conditions in vitro, which may provide a foundation for future studies exploring its potential application in managing diabetic vasculopathy.

Studies examining the role of albumin-corrected anion gap (ACAG), an emerging promising prognostic biomarker for critical illnesses, in predicting mortality of ICU patients with heart failure (HF) are limited. We aimed to analyze the relationship between ACAG and short- and medium-term all-cause mortality in HF patients with a single ICU admission. Data on HF patients in the Medical Information Mart for Intensive Care-IV (MIMIC-Ⅳ) database were extracted and analyzed. The restricted cubic spline (RCS) model, Kaplan–Meier curve, univariate and multivariate Cox regression, propensity score matching, and mediation analysis were used to assess the association between ACAG concentrations at admission and 30-day and 365-day mortality. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive ability of ACAG for mortality. A total of 4,821 patients were included in this study. The RCS model showed a linear relationship between ACAG and mortality. Based on this result, patients were divided into two groups: ACAG ≥18 mmol/L and ACAG 2 and hemoglobin but positively associated with heart rate, ALT, AST, creatinine, and blood urea nitrogen. In conclusion, there is a significant positive association between ACAG and short- and medium-term all-cause mortality in HF patients with a single ICU admission. The ACAG index should be combined with other clinical markers to ensure accurate risk stratification. Clinicians should be cautious in solely relying on ACAG for decision-making.

Elevated albumin-corrected anion gap (ACAG) levels have been shown to be associated with increased mortality in various critical illnesses; however, data specifically addressing heart failure (HF) complicated by acute kidney injury (AKI) are lacking. Data from ICU patients with HF complicated by AKI between 2008 and 2022 were extracted and analyzed from the MIMIC-IV database. The association between baseline ACAG levels and all-cause mortality was assessed using multiple statistical methods, including variance inflation factor analysis, restricted cubic spline (RCS) modeling, Kaplan–Meier analysis, univariate and multivariate Cox regression, subgroup analysis, mediation analysis, and receiver operating characteristic (ROC) curve analysis. A total of 5425 patients were included in this study. RCS analysis showed a linear relationship between ACAG and mortality (p = 0.075 for nonlinearity). The Kaplan–Meier curve and multivariate Cox regression analysis revealed a positive relationship between ACAG and mortality at both 30 and 365 days post ICU admission. These results were confirmed by subgroup analysis. Mediation analysis showed SAPS II, bicarbonate, BUN, creatinine, hemoglobin, Charlson and ASP III mediated the association between ACAG and all-cause mortality, accounting for 32.34%, − 30.59%, 32.28%, 19.83%, 7.57%, 7.58%, and 25.64% of the mediating effect, respectively (all p values < 0.001). The AUC value for predicting 30-day mortality was 0.643 for ACAG, greater than 0.616 for albumin and 0.604 for AG. For predicting 365-day mortality, the AUC value was 0.641 for ACAG, greater than 0.626 for albumin and 0.597 for AG. Elevated ACAG is associated with increased mortality in HF patients with AKI, emphasizing the importance of monitoring metabolic parameters in this population. ACAG may be a valuable prognostic marker for HF and AKI. Further research is warranted to determine whether targeted interventions to correct metabolic acidosis could improve outcomes in this vulnerable patient group.

MicroRNAs, a class of small non-coding RNA molecules that regulate gene expression post-transcriptionally, are implicated in various pathological conditions including diabetes mellitus (DM). DM has been increasingly recognized as an inflammatory disease and monocytes play a key role in propagating inflammation under hyperglycemic conditions. We hypothesize that high glucose dysregulates microRNAs to promote monocyte inflammatory activity, which may contribute to the pathogenesis of DM. THP-1 monocytes were cultured in normal (5 mM) and high (25 mM) glucose conditions. RT-qPCR and Western blotting were performed to assay microRNAs and proteins, respectively. Monocytes were transfected with microRNA mimics using Lipofectamine RNAiMAX reagent. THP-1 monocyte growth was assessed using Calcein-AM dye and a Boyden chamber assay was applied to measure monocyte migration. The results showed that high glucose downregulated miR-139-5p associated with increased protein expression of CXCR4, an experimentally validated target of miR-139-5p. Correspondingly, treatment with high glucose resulted in a significant increase in THP-1 cell migration towards SDF-1, a cognate ligand for CXCR4. MiR-139-5p overexpression inhibited high glucose-induced CXCR4 expression, leading to reduced cell migration towards SDF-1. High glucose did not affect THP-1 monocyte growth. In conclusion, the miR-139-5p-CXCR4 axis may play a role in high glucose-induced inflammation by regulating monocyte migration.

Background: Thrombosis is a common cause of vascular prosthesis failure. Antibody coating of prostheses to capture circulating endothelial progenitor cells to aid endothelialization on the device surface appears a promising solution to prevent thrombus formation. Compared with random antibody immobilization, oriented antibody coating (OAC) increases antibody-antigen binding capacity and reduces antibody immunogenicity in vivo. Currently, few OAC methods have been documented, with none possessing clinical application potential. Results: Dopamine and the linker amino-PEG8-hydrazide-t-boc were successfully deposited on the surface of cobalt chromium (CC) discs, CC stents and expanded polytetrafluoroethylene (ePTFE) grafts under a slightly basic condition. CD34 antibodies were immobilized through the reaction between aldehydes in the Fc region created by oxidation and hydrazides in the linker after t-boc removal. CD34 antibody-coated surfaces were integral and smooth as shown by scanning electron microscopy (SEM), had significantly reduced or no substrate-specific signals as revealed by X-ray photoelectron spectroscopy, were hospitable for HUVEC growth as demonstrated by cell proliferation assay, and specifically bound CD34 + cells as shown by cell binding testing. CD34 antibody coating turned hydrophobic property of ePTFE grafts to hydrophilic. In a porcine carotid artery interposition model, a confluent monolayer of cobblestone-shaped CD31 + endothelial cells on the luminal surface of the CD34 antibody coated ePTFE graft were observed. In contrast, thrombi and fibrin fibers on the bare graft, and sporadic cells on the graft coated by chemicals without antibodies were seen. Conclusion: A universal, OAC method was developed. Our in vitro and in vivo data suggest that the method can be potentially translated into clinical application, e.g., modifying ePTFE grafts to mitigate their thrombotic propensity and possibly provide for improved long-term patency for small-diameter grafts.

Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by aberrant angiogenesis and vascular malformations. Mutations in the transforming growth factor beta co-receptor, endoglin (ENG), account for approximately half of known HHT cases and cause abnormal angiogenic activity in endothelial cells (ECs). To date, how ENG deficiency contributes to EC dysfunction remains to be fully understood. MicroRNAs (miRNAs) regulate virtually every cellular process. We hypothesized that ENG depletion results in miRNA dysregulation that plays an important role in mediating EC dysfunction. Our goal was to test the hypothesis by identifying dysregulated miRNAs in ENG-knockdown human umbilical vein endothelial cells (HUVECs) and characterizing their potential role in EC function. We identified 32 potentially downregulated miRNAs in ENG-knockdown HUVECs with a TaqMan miRNA microarray. MiRs-139-5p and -454-3p were found to be significantly downregulated after RT-qPCR validation. While the inhibition of miR-139-5p or miR-454-3p had no effect on HUVEC viability, proliferation or apoptosis, angiogenic capacity was significantly compromised as determined by a tube formation assay. Most notably, the overexpression of miRs-139-5p and -454-3p rescued impaired tube formation in HUVECs with ENG knockdown. To our knowledge, we are the first to demonstrate miRNA alterations after the knockdown of ENG in HUVECs. Our results indicate a potential role of miRs-139-5p and -454-3p in ENG-deficiency-induced angiogenic dysfunction in ECs. Further study to examine the involvement of miRs-139-5p and -454-3p in HHT pathogenesis is warranted.