The Association of CHADS-P2A2RC Risk Score With Clinical Outcomes in Patients Taking P2Y12 Inhibitor Monotherapy After 3 Months of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention.

BACKGROUND AND OBJECTIVES: Concerns remain that early aspirin cessation may be associated with potential harm in subsets at high risk of ischemic events. This study aimed to assess the effects of P2Y12 inhibitor monotherapy after 3-month dual antiplatelet therapy (DAPT) vs. prolonged DAPT (12-month or longer) based on the ischemic risk stratification, the CHADS-P2A2RC, after percutaneous coronary intervention (PCI). METHODS: This was a sub-study of the SMART-CHOICE trial. The effect of the randomized antiplatelet strategies was assessed across 3 CHADS-P2A2RC risk score categories. The primary outcome was a major adverse cardiac and cerebral event (MACCE), a composite of all-cause death, myocardial infarction, or stroke. RESULTS: Up to 3 years, the high CHADS-P2A2RC risk score group had the highest incidence of MACCE (105 [12.1%], adjusted hazard ratio [HR], 2.927; 95% confidence interval [CI], 1.358-6.309; p=0.006) followed by moderate-risk (40 [1.4%], adjusted HR, 1.786; 95% CI, 0.868-3.674; p=0.115) and low-risk (9 [0.5%], reference). In secondary analyses, P2Y12 inhibitor monotherapy reduced the Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding without increasing the risk of MACCE as compared with prolonged DAPT across the 3 CHADS-P2A2RC risk strata without significant interaction term (interaction p for MACCE=0.705 and interaction p for BARC types 2, 3, or 5 bleeding=0.055). CONCLUSIONS: The CHADS-P2A2RC risk score is valuable in discriminating high-ischemic-risk patients. Even in such patients with a high risk of ischemic events, P2Y12 inhibitor monotherapy was associated with a lower incidence of bleeding without increased risk of ischemic events compared with prolonged DAPT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02079194.

Semiquantitative 18F-FDG PET/CT in monitoring glucocorticoid response of immunoglobulin G4-related effusive constrictive pericarditis: a case report.

BACKGROUND: Immunoglobulin G4 (IgG4)-related effusive constrictive pericarditis (ECP) is a rare manifestation of IgG4-related disease (IgG4-RD). It can lead to persistent pericardial fibrosis, resulting in cardiac tamponade, diastolic dysfunction, and heart failure. Glucocorticoids are the primary treatment for effectively reducing inflammation and preventing fibrosis. However, guidelines for monitoring treatment response are lacking and tapering glucocorticoid therapy for specific target organs remains a challenge. Recent studies on IgG4-RD have demonstrated that semiquantitative measurements of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the main involved organs in positron emission tomography/computed tomography (PET/CT) scanning are correlated to disease activity. We present a case of IgG4-related ECP to demonstrate the usefulness of 18F-FDG PET/CT for diagnosing and treatment follow-up of IgG4-related ECP. CASE PRESENTATION: Herein, a 66-year-old woman diagnosed with IgG4-related ECP presented with breathlessness, leg swelling, rales, and fever. Laboratory tests revealed markedly elevated levels of C-reactive protein, and transthoracic echocardiography revealed constrictive physiology with effusion. High IgG4 levels suggested an immune-related pathogenesis, while viral and malignant causes were excluded. Subsequent pericardial biopsy revealed lymphocyte and plasma cell infiltration in the pericardium, confirming the diagnosis of IgG4-related ECP. 18F-FDG PET/CT revealed increased uptake of 18F-FDG in the pericardium, indicating isolated cardiac involvement of IgG4-RD. Treatment with prednisolone and colchicine led to a rapid improvement in the patient's condition within a few weeks. Follow-up imaging with 18F-FDG PET/CT after 3 months revealed reduced inflammation and improved constrictive physiology on echocardiography, leading to successful tapering of the prednisolone dose and discontinuation of colchicine. CONCLUSION: The rarity of IgG4-related ECP and possibility of multiorgan involvement in IgG4-RD necessitates a comprehensive diagnostic approach and personalized management. This case report highlights the usefulness of 18F-FDG PET/CT in the diagnosis and treatment follow-up of isolated pericardial involvement in IgG4-RD.

Protective effect of secretory APE1/Ref-1 on doxorubicin-induced cardiotoxicity via suppression of ROS and p53 pathway.

AIMS: The clinical application of doxorubicin (DOX), a potent anthracycline anticancer drug that effectively treats various malignancies, is limited by its side effects, such as cardiomyopathy. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that can be secreted and is a promising target for the reduction of DOX-induced inflammation and oxidative stress. We aimed to investigate the protective role of secretory APE1/Ref-1 against DOX-induced cardiac injury. METHODS AND RESULTS: Designated adenoviral preprotrypsin-leading sequence APE1/Ref-1 (Ad-PPTLS-APE1/Ref-1) was used to overexpress secretory APE1/Ref-1 and assess its role in preventing DOX-induced cardiomyopathy in vitro. Our findings revealed that exposure to secretory APE1/Ref-1 significantly decreased N-terminal pro-B-type natriuretic peptide levels in DOX-treated H9C2 cells. In addition, secretory APE1/Ref-1 reduced the severity of cardiomyocyte injury and apoptosis in both in vitro and in vivo DOX-induced cardiotoxicity models. The observed cardioprotective effects of secretory APE1/Ref-1 were mediated via inhibition of the p53 signalling pathway and enhancement of cell viability through attenuation of oxidative stress in DOX-treated cardiomyocytes. CONCLUSIONS: Our study provides evidence that secretory APE1/Ref-1 has the potential to inhibit DOX-induced cardiac toxicity by inhibiting oxidative stress and p53 related apoptosis both in vitro and in vivo. These findings suggest that secretory APE1/Ref-1 supplementation is a promising strategy to attenuate DOX-induced cardiomyocyte damage in a preclinical model. Further clinical investigations are essential to validate the therapeutic efficacy and safety of the intervention in human subjects.

Rapidly Progressive Metastatic Angiosarcoma of the Heart: A Case Report.

Cardiac angiosarcoma is a rare, malignant neoplasm affecting the heart. We present the clinical history of a 40-year-old patient diagnosed with metastatic angiosarcoma of the heart. The patient complained of shortness of breath, and a cardiac computed tomography scan revealed a mass in the right atrium and pericardial effusion. Transthoracic and transesophageal echocardiography provided detailed anatomical and functional information, and cardiac magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography/computed tomography were used to assess distant metastasis and characterize the mass in detail. Early differential diagnosis and comprehensive evaluation of a cardiac mass are vital for determining appropriate treatment strategies to improve patient outcomes. The pathological results from the endocardial biopsy confirmed the diagnosis of primary angiosarcoma. The patient underwent surgical resection of the right atrial mass but died within one month because of the locally advanced nature of the angiosarcoma and its rapid progression. The patient's medical journey sheds light on the challenges associated with diagnosing and treating this rare condition, particularly the rapid progression of its cardiac manifestations.

The Risk of Heart Failure Progression in Patients With Patent Foramen Ovale: Differential Risk Associated With Device Closure.

BACKGROUND: A patent foramen ovale (PFO) can unload left atrial pressure via an interatrial shunt. We investigated whether device closure of PFO is associated with a subsequent risk of heart failure (HF), particularly in patients with structural heart disease or atrial fibrillation (AF). METHODS: We enrolled 4,804 consecutive patients who underwent transesophageal echocardiography at tertiary medical centers in Korea between 2007 and 2019. The primary outcome was the 4-year risk of HF hospitalization. Underlying structural heart disease was determined by echocardiography. RESULTS: A PFO was observed in 981 (20.4%) patients, where 161 underwent device closure. During follow-up (median, 3.5 [1.4-6.4] years), the primary outcome was lower in patients with PFO than in those without (2.6% vs 4.0%; adjusted hazard ratio [aHR], 0.65; 95% CI, 0.45-0.94; P = .021). Among the patients with PFO, the primary outcome was higher in the device closure group than in the no-closure group (5.5% vs 1.2%; aHR, 5.59; 95% CI, 4.26-7.34; P < .001). A consistent result was found in patients with structural heart disease or AF (9.6% vs 3.9%; aHR, 2.55; 95% CI, 1.95-3.33; P < .001), demonstrating an increased risk of the primary outcome proportionate to the number of combined structural abnormalities. However, no significant association was observed between the primary outcome and PFO closure in those without structural heart disease or AF (1.7% vs 1.5%; aHR, 1.22; 95% CI, 0.99-1.50; P = .054). CONCLUSION: Patients with underlying structural heart disease or AF may be predisposed to symptomatic HF progression after PFO closure. Therefore, careful medical surveillance with optimal risk management is needed in these patients.

Prevalence and Prediction of Aneurysmal Dilatation of the Abdominal Aorta in Koreans: Results of Screening During Transthoracic Echocardiographic Examination.

BACKGROUND: Aortic aneurysm (AA) is an enlargement of the aorta to greater than 1.5 times normal size. Although the US guideline recommends ultrasound screening for abdominal AA (AAA) in men older than 65 years regardless of symptoms, limited data describe the prevalence of AAA in Korea. In this study, we screened patients for AAA during transthoracic echocardiographic examination (TTE). METHODS: We screened for AAA in all consecutive subjects older than 60 years who underwent TTE. We defined AAA as an abdominal aorta with the diameter greater than 30 mm. RESULTS: We analyzed 5,679 persons (2,272 females, 74 ± 8 years old). The mean size of the abdominal aorta was 19.0 ± 6.1 mm. The prevalence of AAA was 2.9% (165/5,679) and was significantly higher in males (4.7% vs. 1.1%, p < 0.001). AAA was significantly associated with male sex (odds ratio [OR] = 3.098, 95% confidence interval [CI] = 1.971-4.870, p < 0.001), older age (OR = 1.074, 95% CI = 1.050-1.097, p < 0.001), non-diabetes (OR = 1.886, 95% CI = 1.264-2.813, p < 0.001), dyslipidemia (OR = 1.475, 95% CI = 1.019-2.135, p = 0.040), ever-smoker (OR = 2.090, 95% CI = 1.448-3.015, p < 0.001), chronic kidney disease (CKD, OR = 1.757, 95% CI = 1.182-2.612, p = 0.005), and coronary artery disease (CAD, OR = 2.452, 95% CI = 1.742-3.451, p < 0.001). A prediction score with a multivariate model (range: 3.34-10.51) detected AAA with a sensitivity of 79.4% and a specificity of 66.8% with a reference value > 6.8 (area under the curve = 0.799). CONCLUSIONS: In Korea, the prevalence of AAA was 2.9% in subjects older than 60 years during TTE, and AAA was significantly associated with older age, male sex, non-diabetes, dyslipidemia, ever-smoker, CKD, and CAD. Prediction score (> 6.8%) detected AAA with a sensitivity of 79.4% and a specificity of 66.8%.

Meta-analysis of proton pump inhibitors induced risk of community-acquired pneumonia.

PURPOSE: Proton pump inhibitors (PPIs), one of the most widely used medications, are commonly used to suppress several acid-related upper gastrointestinal disorders. Acid-suppressing medication use could be associated with increased risk of community-acquired pneumonia (CAP), although the results of clinical studies have been conflicting. DATA SOURCES: A comprehensive search of MEDLINE, EMBASE and Cochrane library and Database of Systematic Reviews from the earliest available online year of indexing up to October 2018. STUDY SELECTION: We performed a systematic review and meta-analysis of observational studies to evaluate the risk of PPI use on CAP outcomes. DATA EXTRACTION: Included study location, design, population, the prevalence of CAP, comparison group and other confounders. We calculated pooled odds ratio (OR) using a random-effects meta-analysis. RESULTS OF DATA SYNTHESIS: Of the 2577 studies screening, 11 papers were included in the systematic review and 7 studies with 65 590 CAP cases were included in the random-effects meta-analysis. In current PPI users, pooled OR for CAP was 1.86 (95% confidence interval (CI), 1.30-2.66), and in the case of recent users, OR for CAP was 1.66 (95% CI, 1.22-2.25). In the subgroup analysis of CAP, significance association is also observed in both high-dose and low-dose PPI therapy. When stratified by duration of exposure, 3-6 months PPIs users group was associated with increased risk of developing CAP (OR, 2.05; 95% CI, 1.22-3.45). There was a statistically significant association between the PPI users and the rate of hospitalization (OR, 2.59; 95% CI, 1.83-3.66). CONCLUSION: We found possible evidence linking PPI use to an increased risk of CAP. More randomized controlled studies are warranted to clarify an understanding of the association between PPI use and risk of CAP because observational studies cannot clarify whether the observed epidemiologic association is a causal effect or a result of unmeasured/residual confounding.

Statins use and its impact in EGFR-TKIs resistance to prolong the survival of lung cancer patients: A Cancer registry cohort study in Taiwan.

Statins have been shown to be a beneficial treatment as chemotherapy and target therapy for lung cancer. This study aimed to investigate the effectiveness of statins in combination with epidermal growth factor receptor-tyrosine kinase inhibitor therapy for the resistance and mortality of lung cancer patients. A population-based cohort study was conducted using the Taiwan Cancer Registry database. From January 1, 2007, to December 31, 2012, in total 792 non-statins and 41 statins users who had undergone EGFR-TKIs treatment were included in this study. All patients were monitored until the event of death or when changed to another therapy. Kaplan-Meier estimators and Cox proportional hazards regression models were used to calculate overall survival. We found that the mortality was significantly lower in patients in the statins group compared with patients in the non-statins group (4-y cumulative mortality, 77.3%; 95% confidence interval (CI), 36.6%-81.4% vs. 85.5%; 95% CI, 78.5%-98%; P = .004). Statin use was associated with a reduced risk of death in patients the group who had tumor sizes <3 cm (hazard ratio [HR], 0.51, 95% CI, 0.29-0.89) and for patients in the group who had CCI scores <3 (HR, 0.6; 95% CI, 0.41-0.88; P = .009). In our study, statins were found to be associated with prolonged survival time in patients with lung cancer who were treated with EGFR-TKIs and played a synergistic anticancer role.

Celastrol suppresses expression of adhesion molecules and chemokines by inhibiting JNK-STAT1/NF-κB activation in poly(I:C)-stimulated astrocytes.

In the central nervous system, viral infection can induce inflammation by up-regulating pro-inflammatory mediators that contribute to enhanced infiltration of immune cells into the central nervous areas. Celastrol is known to exert various regulatory functions, including anti-microbial activities. In this study, we investigated the regulatory effects and the mechanisms of action of celastrol against astrocytes activated with polyinosinic-polycytidylic acid (poly(I:C)), a synthetic dsRNA, as a model of pro-inflammatory mediated responses. Celastrol significantly inhibited poly(I:C)-induced expression of adhesion molecules, such as ICAM-1/VCAM-1, and chemokines, such as CCL2, CXCL8, and CXCL10, in CRT-MG human astroglioma cells. In addition, celastrol significantly suppressed poly(I:C)-induced activation of JNK MAPK and STAT1 signaling pathways. Furthermore, celastrol significantly suppressed poly(I:C)-induced activation of the NF-κB signaling pathway. These results suggest that celastrol may exert its regulatory activity by inhibiting poly(I:C)-induced expression of pro-inflammatory mediators by suppressing activation of JNK MAPK-STAT1/NF-κB in astrocytes. [BMB Reports 2017; 50(1): 25-30].

Validation of Three Platelet Function Tests for Bleeding Risk Stratification During Dual Antiplatelet Therapy Following Coronary Interventions.

BACKGROUND: Although low platelet reactivity (LPR) is commonly detected during bleeding, a validated threshold for reliable DAPT bleeding risk stratification is lacking. We tested the diagnostic utility of 3 conventional platelet-activity assays to define the predictive value (if any) of LPR for bleeding. HYPOTHESIS: We hypothesized whether one of these tests be better than any others for predicting bleeding events. METHODS: Patients (n = 800) following drug-eluting stent implantation received DAPT. Bleeding was assessed by Bleeding Academic Research Consortium (BARC) classification and events were collected for 1 year after stenting. Platelet reactivity was measured by light transmittance aggregometry (LTA), VerifyNow, and multiple electrode aggregometry (MEA). The LPR values for bleeding event stratification were defined as ≤15% for LTA, ≤139 PRU for VerifyNow, and ≤25 U for MEA. RESULTS: Bleeding events occurred in 18 patients (2.3%). All tests distinguished LPR as an independent predictor for bleeding by univariate analysis ([HR]: 5.00, 95% [CI]: 1.8-14.0, P = 0.002 for LTA; HR: 21.3, 95% CI: 6.2-73.0, P < 0.0001 for VerifyNow; and HR: 7.4, 95% CI: 2.2-25.5, P = 0.002 for MEA). Multivariate analysis revealed that only VerifyNow (HR: 11.5, 95% CI: 2.9-45.7, P < 0.0004) remained an independent predictor for bleeding. However, the specificity (81.5%, 60.2%, and 81.7%, respectively) and sensitivity (61.1%, 83.3%, and 83.2%, respectively) of all 3 tests were quite low. CONCLUSIONS: Among 3 conventional platelet-activity assays, VerifyNow was better than LTA or MEA for triaging future bleeding risks. However, all 3 tests failed to reliably predict future bleeding.

2,3-Dimethoxy-2'-hydroxychalcone ameliorates TNF-α-induced ICAM-1 expression and subsequent monocyte adhesiveness via NF-kappaB inhibition and HO-1 induction in HaCaT cells.

Up-regulation of adhesion molecules plays an important role in the infiltration of leukocytes into the skin during the development of various inflammatory skin diseases, such as atopic dermatitis. In this study, we investigated the modulatory effects of 2,3-dimethoxy-2'-hydroxychalcone (DMHC) on tumor necrosis factor (TNF)-α-induced intercellular adhesion molecule-1 (ICAM-1) expression and monocyte adhesiveness, as well as the molecular mechanisms underlying its action in the HaCaT human keratinocyte cell line. Pre-treating HaCaT cells with DMHC significantly suppressed TNF-α-induced ICAM-1 expression and subsequent monocyte adhesiveness. DMHC inhibited TNF-α-induced activation of NF-κB. In addition, DMHC induced HO-1 expression as well as NRF2 activation. Furthermore, HO-1 knockdown using siRNA reversed the inhibitory effect of DMHC on TNF-α-induced ICAM-1 expression and adhesion of monocytes to keratinocytes. These results suggest that DMHC may inhibit TNF-α-induced ICAM-1 expression and adhesion of monocytes to keratinocytes by suppressing the signaling cascades leading to NF-κB activation and inducing HO-1 expression in keratinocytes.