Sex Differences in Bleeding Risk Associated With Antithrombotic Therapy Following Percutaneous Coronary Intervention.

Background: Antithrombotic therapy is crucial for secondary prevention of cardiovascular disease (CVD), but women with CVD may face increased bleeding complications post-percutaneous coronary intervention (PCI) under antithrombotic therapy. However, women are often underrepresented in clinical trials in this field, so evidence for sex-specific recommendations is lacking. Methods and Results: A search on PubMed was conducted for English-language articles addressing bleeding complications and antithrombotic therapy in women. Despite women potentially showing higher baseline platelet responsiveness than men, the clinical implications remain unclear. Concerning antiplatelet therapy post-PCI, although women have an elevated bleeding risk in the acute phase, no sex differences were observed in the chronic phase. However, women require specific considerations for factors such as age, renal function, and weight when determining the dose and duration of antiplatelet therapy. Regarding anticoagulation post-PCI, direct oral anticoagulants may pose a lower bleeding risk in women compared with warfarin. Concerning triple antithrombotic therapy (TAT) post-PCI for patients with atrial fibrillation, there is a lack of evidence on whether sex differences should be considered in the duration and regimen of TAT. Conclusions: Recent findings on sex differences in post-PCI bleeding complications did not provide enough evidence to recommend specific therapies for women. Further studies are needed to address this gap and recommend optimal antithrombotic therapy post-PCI for women.

Impact of the time-to-target rate of urine volume concept on the outcome of acute decompensated heart failure.

BACKGROUND: Early decongestion with diuretics could improve clinical outcomes. This study aimed to examine the impact of the time-to-target rate of urine volume (T2TUV) concept on the outcome of acute decompensated heart failure (ADHF). METHODS: This multicenter retrospective study included 1670 patients with ADHF who received diuretics within 24 h of admission. T2TUV was defined as the time from admission to the rate of urine volume of 100 ml/h. The primary outcomes were in-hospital death, mortality, and re-hospitalization for 1 year. RESULTS: A total of 789 patients met the inclusion criteria (T2TUV on day 1, n = 248; day 2-3, n = 172; no target rate UV, n = 369). In-hospital mortality in the day 1 group was significantly lower (2.7% vs. 5.9% vs. 11.1%; p < 0.001) than that of other groups. The mortality and re-hospitalization for 1 year in the day 1 group was significantly lower (event-free rate: 67.7% vs. 54.1% vs. 56.9%; log-lank p = 0.004) than that of other groups. In multivariate analysis, predictors of T2TUV at day 1 were age (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.04, p = 0.007), previous hospitalized heart failure (OR: 1.47, 95% CI: [1.03-2.12], p = 0.03), N-terminal-pro B type natriuretic peptide per 1000 pg/ml (OR: 1.02, 95% CI: 1.01-1.04, p = 0.007), carperitide (OR: 0.69, 95% CI: 0.48-0.99, p = 0.05), and early administration of tolvaptan (OR: 0.6, 95% CI: 0.42-0.85, p = 0.004). CONCLUSIONS: T2TUV of less than day 1 was associated with lower in-hospital mortality and decreased mortality and re-hospitalization at 1 year.

Predictors of Poor Very Early Diuretic Response and Effectiveness of Early Tolvaptan in Symptomatic Acute Heart Failure.

BACKGROUND: Diuretic response (DR) in patients with symptomatic acute decompensated heart failure (ADHF) has an impact on prognosis. This study aimed to identify predictive factors influencing acute 6 h poor DR and to assess DR after early administration of tolvaptan (TLV). METHODS: This multicenter retrospective study included 1670 patients who were admitted for ADHF and received intravenous furosemide within 1 h of presentation in clinical scenario 1 or 2 defined based on initial systolic blood pressure ≥100 mmHg with severe symptoms (New York Heart Association class III or IV (n = 830). The score for the poor DR factors in the very acute phase was calculated in patients treated with furosemide-only diuretics (n = 439). The DR to TLV administration was also assessed in patients who received an additional dose of TLV within 6 h (n = 391). RESULTS: The time since discharge from the hospital for a previous heart failure < 3 months (odds ratio [OR] 2.78, 95% confidence interval [CI] 1.34-5.83; p = 0.006), loop diuretics at admission (OR 3.05, 95% CI 1.74-5.36; p < 0.0001), and estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 (OR 2.99, 95% CI 1.58-5.74; p = 0.0007) were independent determinants of poor DR. The frequency of poor DR according to the risk stratification group was low risk (no risk factor), 18.9%; middle risk (one risk factor), 33.1%; and high risk (two to three risk factors), 58.0% (p < 0.0001). All risk groups demonstrated a significantly lower incidence of poor DR with early TLV administration: 10.7% in the early TLV group versus 18.9% in the loop diuretics group (p = 0.09) of the low-risk group; 18.4% versus 33.1% (p = 0.01) in the middle-risk group, and 20.2% versus 58.0% (p < 0.0001) in the high-risk group. CONCLUSION: Early administration of TLV in patients with predicted poor DR contributed to a significant diuretic effect and suppression of worsening renal function.

The comparison of endothelial function between conduit artery and microvasculature in patients with coronary artery disease.

BACKGROUND: Flow-mediated dilation (FMD) and reactive hyperemia-peripheral arterial tonometry (RH-PAT) are both established modalities to assess vascular endothelial function. However, clinical significance of FMD and RH-PAT may be different because these methods measure vascular function in different vessels (conduit arteries and resistance vessels). METHODS: To elucidate differences in the clinical significance of FMD and RH-PAT, a simultaneous determination of FMD was performed and reactive hyperemia index (RHI) measured by RH-PAT in 131 consecutive patients who underwent coronary angiography for suspicion of coronary artery disease (CAD). RESULTS: There was no significant correlation between FMD and RHI in patients overall. When patients were divided into four groups: FMD ≥ 6%/RHI ≥ 1.67 group, FMD ≥ 6%/RHI < 1.67 group, FMD < 6%/RHI ≥ 1.67 group and FMD < 6%/RHI < 1.67 group, the highest incidence of multivessel CAD was seen in the FMD < 6%/RHI < 1.67 group (52%). Multiple logistic regression analysis showed that a prevalence of both FMD < 6% and RHI < 1.67 was an independent predictor of multivessel CAD (odds ratio: 4.160, 95% confidence interval: 1.505-11.500, p = 0.006). RHI was negatively correlated with the baseline vessel diameter (R = -0.268, p = 0.0065) and maximum vessel diameter (R = -0.266, p = 0.0069) in patients with FMD < 6%, whereas these correlations were absent in patients with FMD ≥ 6%. CONCLUSIONS: Present results suggest that noninvasive assessment of vascular endothelial functions provide pathophysiological information on both conduit arteries and resistance vessels in patients with CAD.

Early surgical intervention and optimal medical treatment for Candida parapsilosis endocarditis.

We herein report the case of a 72-year-old man with endocarditis of the aortic valve who underwent urgent aortic valve replacement 36 hours after admission due to an aggravation of aortic valve regurgitation. Postoperative cultures of the blood and site of valve vegetation identified Candida parapsilosis as a pathogen. Antifungal therapy with amphotericin B and fluconazole was initiated after surgical treatment. Thereafter, the patient displayed a favorable clinical course. Candida parapsilosis endocarditis involving the native valves is extremely rare and associated with a very high mortality rate. Prompt surgical treatment and the aggressive use of antifungal agents are required to save the patient's life.

Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.

Placenta growth factor stimulates the growth of Philadelphia chromosome positive acute lymphoblastic leukemia cells by both autocrine and paracrine pathways.

Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases. On the other hand, expression level of VEGF was not different between Ph(+) and Ph(-) cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph(+)), and Nalm6 (Ph(-)). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph(+) ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph(+) ALL.

ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma.

ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer. In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB. In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family. Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences. In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells. Furthermore, ARK5 promoter activity was dramatically decreased by mutation or deletion of MARE sequences. Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter. Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity. IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines. Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas.

Global real-time quantification/reverse transcription-polymerase chain reaction for detecting proto-oncogenes associated with 14q32 chromosomal translocation in multiple myeloma.

A global real-time quantitative/reverse transcription-polymerase chain reaction technique for detecting the expression of six 14q32 chromosomal translocation-associated proto-oncogenes in marrow plasma cells was established and applied to myeloma specimens. This technique is an alternative method of detecting 14q32 rearrangements and allows investigation of the relationship between proto-oncogene expression and clinical features.

Autocrine pathway of angiopoietins-Tie2 system in AML cells: association with phosphatidyl-inositol 3 kinase.

Hematopoietic cells and endothelial cells are mutually correlated in their development and growth. Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietins (Angs), are thought to be associated with leukemia cell growth. In this study, we examined if the Angs-Tie2 autocrine pathway works in primary AML cells or not by using soluble Tie2-Fc, which inhibits Angs from binding to Tie2 receptor. After 48 h of culture with Tie2-Fc, nine AML cells from 19 examined samples were not influenced by Tie2-Fc (group A), while AML cells from remaining 10 patients demonstrated remarkable reduction of cell number by Tie2-Fc treatment (group B). Tie2 receptor, upon binding to Angs, are known to activate phosphatidyl-inositol 3 kinase (PI3 kinase). Then, we examined the effect of LY294002, a potent PI3 kinase inhibitor, on primary AML cells. Cell number reduction effect by the treatment of LY294002 was much more prominent in cells of group B than of group A. In addition, extent of cell number reduction by Tie2-Fc and LY294002 was quite well correlated. These observations demonstrated that cells from a part of AML were dependent on autocrine Angs-Tie2 pathway. This notion was further supported by the study of two AML cell lines, KG-1 and HL-60: the growth of KG-1 was suppressed by Tie2-Fc, and also by anti-Tie2 antibody, which inhibits receptor-ligand interaction, while that of HL-60 was not suppressed by Tie2-Fc or anti-Tie2 antibody. Our results will help to explore the angiogenesis-oriented or endothelial cell-mediated therapy for leukemia.

Acute promyelocytic leukemia with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

We report a case of acute promyelocytic leukemia (APL) with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus (EBV) infection. A 33-year-old woman was admitted because of APL. After complete remission was obtained with the use of all-trans retinoic acid (ATRA), intensive chemotherapy was administered. She developed high grade fever and severe systemic erythematous eruptions followed by cervical lymphoadenopathy, hepatosplenomegaly, hepatitis and hypotension in a state of myelosuppression during consolidation chemotherapy. Systemic corticosteroids alleviated the symptoms. Since an anti-EB VCA IgM antibody titer was continuously positive, persistent infection of EBV was suspected. In this case, EBV infection may have contributed to the development of drug-induced hypersensitivity syndrome.