Nitroglycerin use and adverse clinical outcomes in elderly patients with acute coronary syndrome.

OBJECTIVE: The primary care for acute coronary syndrome (ACS) includes the administration of nitroglycerin (GTN). This study aimed to investigate the association between the use of GTN before percutaneous coronary intervention (PCI) for ACS and clinical outcomes. METHODS: Nine-hundred and forty-seven patients who underwent PCI for ACS were examined and classified into two groups: those who were treated with GTN before PCI (GTN group) and those who were not (non-GTN group). The incidence of major adverse cardiovascular events (MACE), which consist of all-cause mortality, non-fatal myocardial infarction, stroke and rehospitalisation for heart failure at 1 year, was compared between the two groups. RESULTS: This study identified 289 patients with ACS who used GTN preceding PCI. Pre-PCI systolic blood pressure was significantly lower in the GTN group than in the non-GTN group (median (IQR); 132.0 (110.0-143.5) mm Hg vs 134.0 (112.0-157.0) mm Hg, respectively, p=0.03). Multivariate Cox regression analysis indicated that GTN use preceding PCI showed an independent association with the incidence of MACE (HR 1.57; 95% CI 1.09-2.28; p=0.016). Overall, the incidence of MACE 1 year after PCI for ACS was significantly higher in the GTN group than in the non-GTN group (log-rank test, p=0.024); however, this trend was consistently found in elderly patients aged ≥75 years (p=0.002) but not in non-elderly patients aged <75 years (p=0.773). CONCLUSIONS: GTN use preceding PCI for ACS is associated with lower blood pressure and adverse clinical outcomes in elderly patients.

Intralesional pentraxin 3 increases with atherosclerotic disease progression, but may protect from thrombosis: Friend or foe?

AIM: To investigate the role of pentraxin 3 (PTX3) in atherosclerotic disease progression and plaque destabilization, as well as in coronary restenosis after directional coronary atherectomy (DCA). MATERIALS AND METHODS: PTX3 contents of early and advanced atherosclerotic lesions of the aorta obtained at autopsy were determined by ELISA and Western blot. Also, coronary plaques of patients with acute coronary syndrome (ACS) or stable angina pectoris (SAP) obtained by DCA were analyzed by immunohistochemistry for PTX3. The effects of PTX3 on smooth muscle cells (SMCs) and thrombogenesis were investigated with cultured human coronary artery SMCs and a flow chamber system, respectively. RESULTS: Advanced atherosclerotic lesions contained a significantly larger amount of PTX3 than early lesions (ELISA: 9.96 ± 2.77 ng/100 mg tissue, n = 8 vs 0.24 ± 0.18 ng/100 mg tissue, n = 6, P = 0.0097). Also, ACS plaques contained a significantly larger amount of PTX3 than SAP plaques (PTX3 immunohistochemistry-positive area percentage: 2.88 ± 0.53 %, n = 22 vs 0.67 ± 0.27 %, n = 23, P = 0.0009). Curiously, the patients who would remain free of post-DCA restenosis (n = 19) had plaques with a significantly higher PTX3 immunohistochemistry-positive area percentage than those who would develop restenosis (n = 12) (2.32 ± 0.49 % vs 0.49 ± 0.17 %, P = 0.002). In the mechanistic part of the study, PTX3 inhibited SMC proliferation and migration. PTX3 also inhibited platelet thrombus formation in the condition simulating arterial blood flow. CONCLUSIONS: PTX3 is increased in advanced (vs early) atherosclerotic lesions and unstable (vs stable) coronary plaques. The inhibitory effects of PTX3 on SMCs and thrombogenesis suggest that intraplaque PTX3 might have atheroprotective effects.

Very Late Stent Thrombosis Complicating Immune Thrombocytopenia: Insights From Optical Coherence Tomography and Thrombopathology.

Immune thrombocytopenia (ITP) carries bleeding and thrombotic risks; however, thromboses associated with ITP have not been histologically examined. This report presents optical coherence tomography images of the culprit lesion and histology of coronary aspirates in very late stent thrombosis complicating severe ITP, providing evidence of platelet-rich thrombus formation. (Level of Difficulty: Advanced.).

Relationship between coronary artery calcium score and bleeding events after percutaneous coronary intervention in chronic coronary syndrome.

The relationship between coronary artery calcium (CAC) and bleeding events after percutaneous coronary intervention (PCI) in patients with chronic coronary syndrome (CCS) is not well established. This study aimed to examine the association between CAC scores and clinical outcomes after PCI in patients with CCS. This retrospective observational study included 295 consecutive patients who underwent multidetector computer tomography and were scheduled for their first elective PCI. Patients were categorized into two groups based on the CAC scores (low: ≤ 400 or high: > 400). The bleeding risk was evaluated using the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria. The primary clinical outcome was a major bleeding event within 1 year after PCI, defined as Bleeding Academic Research Consortium (BARC) 3 or 5. The high CAC score group had a higher proportion of patients meeting the ARC-HBR criteria than the low CAC score group (52.7% vs. 31.3%, p < 0.001). Kaplan-Meier survival analysis showed that the incidence of major bleeding events was higher in the high CAC score group as compared to the low CAC score group (p < 0.001). Furthermore, multivariate Cox regression anal ysis revealed that a high CAC score was an independent determinant of major bleeding events during the first year after PCI. A high CAC score is significantly associated with the incidence of major bleeding events after PCI in CCS patients.

Optimal Antithrombotic Therapy in Patients Undergoing Percutaneous Coronary Intervention: A Focused Review on High Bleeding Risk.

Dual antiplatelet therapy (DAPT) is a therapeutic cornerstone to prevent stent thrombosis following percutaneous coronary intervention (PCI) for coronary artery disease (CAD). However, the longer the DAPT duration, the higher the incidence of bleeding and mortality. Since the advent of second-generation drug-eluting stents (DES), the continuous evolution of DES has reduced the thrombotic risk and allowed for a shorter DAPT duration. On the other hand, concerns on the elevated risk of bleeding during antithrombotic therapy have been further raised due to the growing number of elderly CAD patients with multiple comorbidities. The consequent debate topic over post-PCI antithrombotic therapy has shifted from simply reducing thrombotic risk to safely minimizing bleeding risk. Due to the significant impact of bleeding on clinical outcomes, including prognosis, current guidelines on antithrombotic therapy for CAD prioritize stratification of patients at a high bleeding risk (HBR) as the top consideration in determining post-PCI antithrombotic therapy. Achieving optimal antithrombotic therapy for each patient undergoing PCI requires a better understanding of the clinical variables constituting the balance of bleeding and thrombotic risk. This review highlights relevant evidence required to optimize antithrombotic therapy for HBR patients undergoing PCI.

Cardiac Strangulation Due to Partial Pericardial Defect Presenting as Acute Myocardial Infarction.

A 79-year-old man with chest pain and dyspnea underwent emergency percutaneous coronary intervention for acute myocardial infarction. However, he died 17 days later due to refractory heart failure. An autopsy revealed cardiac strangulation caused by herniation of the apical heart through a pericardial defect due to partial absence of the pericardium. (Level of Difficulty: Advanced.).

A likely unavoidable clinical scenario during treatment for venous thromboembolism complicated with severe immune thrombocytopenia: A case report.

Patients with immune thrombocytopenia have increased risks of bleeding and thrombosis. The acute-phase treatment for venous thromboembolism complicated with severe immune thrombocytopenia involves a "platelet dilemma" in therapeutic decision-making.

Frailty Status Predicts New Long-term Care Insurance Certification in Hepatitis C Patients Receiving Antiviral Therapy.

BACKGROUND/AIM: Direct-acting antiviral (DAA) therapies for patients with hepatitis C virus (HCV) infection deliver higher cure rates and lower frequencies of adverse events than existing therapies, though DAA treatment costs $45,000-64,000 in Japan. The prognosis of patients who require new long-term care insurance (LTCI) certification is inferior to that of patients who do not. Here, we clarify the factors associated with new LTCI certification in elderly patients with HCV infection who undergo DAA therapy. PATIENTS AND METHODS: We retrospectively surveyed 53 patients aged ≥70 years who were treated with DAAs, and evaluated the factors associated with new LTCI certification. RESULTS: Of 53 patients, 10 required new LTCI certification. Age ≥85 years and a modified Japanese Cardiovascular Health Study index ≥2 were independently associated with new LTCI certification. CONCLUSION: In elderly HCV patients, poor frailty status strongly predicted new LTCI certification after DAA therapy.

Intracellular glutamine level determines vascular smooth muscle cell-derived thrombogenicity.

BACKGROUND AND AIMS: The everolimus-eluting stent (EES), one of the effective stents for in-stent restenosis (ISR), has a lower incidence of stent thrombosis; however, the underlying mechanism remains unknown. This study aimed to identify the effects of everolimus on vascular metabolism and thrombogenicity and examine their mechanistic link. METHODS: EESs and bare-metal stents were implanted in rabbit iliac arteries with smooth muscle cell (SMC)-rich neointima induced by endothelial denudation. Four weeks after stent implantation, the stented arteries were examined for histological analysis and metabolomics. Additionally, everolimus effects in coronary artery SMCs metabolism, tissue factor (TF) expression, and procoagulant activity were assessed in vitro. RESULTS: EES-implanted arteries showed decreased neointima formation, less SMCs infiltration, and reduced TF expression. Concomitantly, they were metabolically characterized by increased levels of metabolites in amino acids, such as glutamine. Similarly, everolimus increased intracellular glutamine levels, decreased TF expression, and reduced procoagulant activity in SMCs in vitro. On the contrary, exogenous glutamine administration also increased intracellular glutamine level, decreased TF expression, and reduced procoagulant activity despite enhanced mammalian target of rapamycin (mTOR) activity. CONCLUSIONS: Intracellular glutamine level is likely to determine vascular SMC-related thrombogenicity regardless of mTOR pathway activity. Therefore, increased intracellular glutamine level might contribute partially to the beneficial effect of EES use on stent thrombosis.

Upregulated Kynurenine Pathway Enzymes in Aortic Atherosclerotic Aneurysm: Macrophage Kynureninase Downregulates Inflammation.

AIMS: Inflammation and hypertension contribute to the progression of atherosclerotic aneurysm in the aorta. Vascular cell metabolism is regarded to modulate atherogenesis, but the metabolic alterations that occur in atherosclerotic aneurysm remain unknown. The present study aimed to identify metabolic pathways and metabolites in aneurysmal walls and examine their roles in atherogenesis. METHODS: Gene expression using microarray and metabolite levels in the early atherosclerotic lesions and aneurysmal walls obtained from 42 patients undergoing aortic surgery were investigated (early lesion n=11, aneurysm n=35) and capillary electrophoresis-time-of-flight mass spectrometry (early lesion n=14, aneurysm n=38). Using immunohistochemistry, the protein expression and localization of the identified factors were examined (early lesion n=11, non-aneurysmal advanced lesion n=8, aneurysm n=11). The roles of the factors in atherogenesis were analyzed in macrophages derived from human peripheral blood mononuclear cells. RESULTS: Enrichment analysis using 35 significantly upregulated genes (log2 ratio, ＞3) revealed the alteration of the kynurenine pathway. Metabolite levels of tryptophan, kynurenine, and quinolinic acid and the kynurenine-to-tryptophan ratio were increased in the aneurysmal walls. Gene and protein expression of kynureninase and kynurenine 3-monooxygenase were upregulated and localized in macrophages in the aneurysmal walls. The silencing of kynureninase in the cultured macrophages enhanced the expression of interleukin-6 and indoleamine 2,3-dioxygenase 1. CONCLUSION: Our study suggests the upregulation of the kynurenine pathway in macrophages in aortic atherosclerotic aneurysm. Kynureninase may negatively regulate inflammation via the kynurenine pathway itself in macrophages.

Mechanistic Model Describing the Uptake of Chemicals by Aquatic Integrative Samplers: Comparison to Data and Implications for Improved Sampler Configurations.

Aquatic integrative passive samplers are used to determine aqueous concentrations of polar organic pollutants, yet their uptake mechanisms are poorly understood. We introduce a one-dimensional model to simulate uptake by a passive sampler, Chemcatcher. The model considers the uptake as molecular diffusion through a series consisting of the aqueous boundary layer (ABL), the membrane filter (MF), and the sorbent disk with concurrent sorption by matrix of the MF and the disk. Uptake profiles of ∼20 polar chemicals measured over a week and a month were accurately modeled. Characteristic behaviors such as lag phases, linear and curved uptake, and equilibrating behavior were explained well by the model. As the model is mechanistically based, it was able to show the combined influences of the MF/water ( KMF/w) and disk/water ( Kdisk/w) partition coefficients, diffusion coefficients, and the ABL thickness on the sampling rates. On the basis of the model results, we offer three concrete recommendations for achieving the linear uptake needed for measuring time-weighted average concentrations: (i) use a MF that does not significantly sorb chemicals (e.g., log KMF/w < 3) to avoid lag phases, (ii) use a sorbent with strong sorption properties (e.g., log Kdisk/w > 6) for effective trapping of chemicals on the disk top layer, and (iii) make the ABL and/or the MF thicker so that the diffusion toward the disk slows.

Indoleamine 2,3-dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages.

BACKGROUND: Recent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme of the Kyn pathway. OBJECTIVE: The present study aimed to localize IDO1 in human coronary atherosclerotic plaques from patients with angina pectoris and define its role in plaque thrombogenicity. METHODS: Immunohistochemical methods were applied to localize IDO1 in coronary atherosclerotic plaques from patients with stable (SAP) and unstable (UAP) angina pectoris. The role of IDO1 in tissue factor (TF) expression was investigated in THP-1 macrophages activated by interferon (IFN)γ and tissue necrosis factor (TNF)α. RESULTS: We localized IDO1 mainly in CD68-positive macrophages within atherosclerotic plaques, and in close association with TF. Areas that were immunopositive for IDO1, TF, and CD3-positive T lymphocytes were significantly larger in plaques from patients with UAP than SAP. Macrophages activated by IFNγ and TNFα upregulated IDO1 expression, increased the Kyn/Trp ratio and enhanced TF expression and activity, but not TF pathway inhibitor expression. The IDO1 inhibitor epacadostat significantly reduced the Kyn/Trp ratio, TF expression and activity, as well as NF-κB (p65) binding activity in activated macrophages. Inhibition of the aryl hydrocarbon receptor that binds to Kyn, also reduced Kyn-induced TF expression in activated macrophages. CONCLUSION: Indoleamine 2,3-dioxygenase 1 expressed in coronary atherosclerotic plaques might contribute to thrombus formation through TF upregulation in activated macrophages.

Characterizing Sorption and Permeation Properties of Membrane Filters Used for Aquatic Integrative Passive Samplers.

Aquatic integrative passive sampling is a promising approach to measure the time-weighted average concentration, yet our understanding for the sampling mechanisms of polar organic contaminants should be further advanced to fully exploit the potential of the method for real-world applications. This study aimed to characterize the sorption and permeation properties of poly(ether sulfone) (PES) and poly(tetrafluoroethylene) (PTFE) membrane filters (MFs) used for passive samplers. Batch sorption experiments with 14 probe chemicals showed that the sorption by PES was generally strong, with the respective sorption coefficients greater than the octanol-water partition coefficients by 2-3 log units. In contrast, the PTFE filter exhibited no significant sorption for all tested chemicals, representing a promising candidate MF that avoids lag-times and slow responses to fluctuating concentrations. Permeation experiments in a glass cell system and successive modeling demonstrated that, if no sorption to the MF occurs, the MF permeation of a chemical can be fully described with a first-order model that considers the transfer through the aqueous boundary layers and the diffusion in water-filled MF pores. Significant sorption to the MF coincided with substantial delay of permeation, which was successfully modeled with the local sorption equilibrium assumption. These findings have implications for improved sampler configurations and successful models for the chemical uptake.