1-Year Mortality Prediction through Artificial Intelligence Using Hemodynamic Trace Analysis among Patients with ST Elevation Myocardial Infarction.

Background and Objectives: Patients presenting with ST Elevation Myocardial Infarction (STEMI) due to occlusive coronary arteries remain at a higher risk of excess morbidity and mortality despite being treated with primary percutaneous coronary intervention (PPCI). Identifying high-risk patients is prudent so that close monitoring and timely interventions can improve outcomes. Materials and Methods: A cohort of 605 STEMI patients [64.2 ± 13.2 years, 432 (71.41%) males] treated with PPCI were recruited. Their arterial pressure (AP) wave recorded throughout the PPCI procedure was analyzed to extract features to predict 1-year mortality. After denoising and extracting features, we developed two distinct feature selection strategies. The first strategy uses linear discriminant analysis (LDA), and the second employs principal component analysis (PCA), with each method selecting the top five features. Then, three machine learning algorithms were employed: LDA, K-nearest neighbor (KNN), and support vector machine (SVM). Results: The performance of these algorithms, measured by the area under the curve (AUC), ranged from 0.73 to 0.77, with accuracy, specificity, and sensitivity ranging between 68% and 73%. Moreover, we extended the analysis by incorporating demographics, risk factors, and catheterization information. This significantly improved the overall accuracy and specificity to more than 76% while maintaining the same level of sensitivity. This resulted in an AUC greater than 0.80 for most models. Conclusions: Machine learning algorithms analyzing hemodynamic traces in STEMI patients identify high-risk patients at risk of mortality.

Impact of Zn2+ on ABC Transporter Function in Intact Isolated Rat Brain Microvessels, Human Brain Capillary Endothelial Cells, and in Rat in Vivo.

ABC transporters act as efflux pumps, thereby influencing the pharmacokinetics and efficacy of many drugs. Zinc (Zn) is an essential trace element contributing to cellular growth and differentiation. It is increasingly recognized as an intracellular messenger. The present study aims at investigating the impact of Zn2+ on the function and regulation of ABC transporters at the blood-brain barrier (BBB). ABC transporter function was first studied in isolated rat brain capillaries. Zn2+ rapidly stimulated the activity of the multidrug resistance-related protein 2 (Mrp2), p-glycoprotein (P-gp), and breast cancer resistance protein (Bcrp). These short-term effects were independent of transporter de novo synthesis but based on Zn2+ triggering intracellular signaling to stimulate basal transport activity. Studies focused on Mrp2 and P-gp showed that Zn2+ induced signaling through an endothelin receptor type B (ETB)/nitric oxide synthase (NOS)/protein kinase C (PKC) pathway and caused, specifically, an activation of the isoform PKCα. Studies revealed signaling through the phosphatidylinositol 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway, as well as induction of the downstream target serum- and glucocorticoid-inducible kinase 1 (SGK1). Short-term effects of Zn2+ were also demonstrated in human hCMEC/D3 cells. An initial in vivo study in rats suggested enhanced P-gp transport activity at the BBB due to elevated Zn2+ plasma levels. This work provides the first evidence for Zn2+ being a regulator of basal ABC transporter activity at the BBB, driving a rapid and nongenomic stimulation of transport function.

Zinc chloride rapidly stimulates efflux transporters in renal proximal tubules of killifish (Fundulus heteroclitus).

Multidrug resistance-related protein 2 (Mrp2) is an ATP-driven efflux pump at the luminal membrane in renal proximal tubules. It acts as detoxification mechanism by transporting xenobiotics and metabolic products into urine. The trace element zinc is essential for cellular growth, differentiation and survival. It modulates immune response and is used as dietary supplement. Here, we found that 0.1-10µM ZnCl2 rapidly stimulated transport of the Mrp2 probe substrate Texas Red (TR) in isolated killifish renal proximal tubules, which provide an established model system to measure efflux transporter activity by using fluorescent probe substrates, confocal microscopy and image analysis. This stimulation was insensitive to the translation inhibitor cycloheximide (CHX), but it was quickly reversed by removing ZnCl2 from the incubation medium. ZnCl2-induced transport stimulation was abolished by inhibitors and antagonists of the endothelin receptor type B (ETB)/nitric oxide synthase (NOS)/protein kinase C (PKC) pathway. Moreover, ZnCl2-induced effects were blocked by inhibition of PKCα using Gö6976 and PKCα inhibitor peptide C2-4. Both the phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002 and the mammalian target of rapamycin (mTOR) inhibitor rapamycin abolished ZnCl2-induced transport stimulation. Furthermore, the stimulating effects of ZnCl2 were blocked by GSK650394, an inhibitor of the downstream target serum- and glucocorticoid-inducible kinase 1 (SGK1). ZnCl2 also stimulated transport mediated by P-glycoprotein (P-gp) and Breast cancer resistance protein (Bcrp). This is the first report about zinc affecting efflux transporter activity and demonstrates that ZnCl2 triggers a suite of signaling events to evoke a rapid stimulation of ABC transporter-mediated efflux in killifish proximal tubules.