Oral anticoagulation therapy in atrial fibrillation patients at high risk of bleeding: Clinical characteristics and treatment strategies based on data from the Polish multicenter register of atrial fibrillation (POL-AF).

BACKGROUND: Despite its benefits, oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF) is associated with hemorrhagic complications. AIMS: We aimed to evaluate clinical characteristics of AF patients at high risk of bleeding and the frequency of OAC use as well as identify factors that predict nonuse of OACs in these patients. METHODS: Consecutive AF patients hospitalized for urgent or planned reasons in cardiac centers were prospectively included in the registry in 2019. Patients with HAS-BLED ≥3 (high HAS-BLED group) were assumed to have a high risk of bleeding. RESULTS: Among 3598 patients enrolled in the study, 29.2% were at high risk of bleeding (44.7% female; median [Q1-Q3] age 72 [65-81], CHA2DS2-VASc score 5 [4-6], HAS-BLED 3 [3-4]). In this group, 14.5% of patients did not receive OACs, 68% received NOACs, and 17.5% VKAs. In multivariable analysis, the independent predictors of nonuse of oral OACs were as follows: creatinine level (odds ratio [OR], 1.441; 95% confidence interval [CI], 1.174-1.768; P <0.001), a history of gastrointestinal bleeding (OR, 2.918; 95% CI, 1.395-6.103; P = 0.004), malignant neoplasm (OR, 3.127; 95% CI, 1.332-7.343; P = 0.009), and a history of strokes or transient ischemic attacks (OR, 0.327; 95% CI, 0.166-0.642; P = 0.001). CONCLUSIONS: OACs were used much less frequently in the group with a high HAS-BLED score than in the group with a low score. Independent predictors of nonuse of OACs were creatinine levels, a history of gastrointestinal bleeding, and malignant neoplasms. A history of stroke or transient ischemic attack increased the chances of receiving therapy.

Statins and Cancer: A Complex Relationship Worth Exploring.

This Special Issue, entitled "Statins and Cancer", aims to demonstrate recent and new advances and future trends in using statins in the field of oncology [...].

Why Did All Patients with Atrial Fibrillation and High Risk of Stroke Not Receive Oral Anticoagulants? Results of the Polish Atrial Fibrillation (POL-AF) Registry.

BACKGROUND: Most atrial fibrillation (AF) patients are at high risk of thromboembolic, and the use of oral anticoagulants (OACs) is advised in such cases. The aim of the study was to evaluate the frequency at which OACs were used in patients with AF and high risk thromboembolic complications, and identify factors that result in OACs not being used in the researched group of patients. METHODS: The prospective, multicenter and non-interventional POL-AF registry is a study that includes AF patients from ten Polish cardiology centers. They were consecutively hospitalized between January and December of 2019. All the patients in the study were of high stroke risk. RESULTS: A total of 3614 patients with AF and high stroke risk were included. Among the total study population, 91.5% received OAC therapy; antiplatelet therapy was prescribed for 3.7% of patients, heparin for 2.7%, and 2.1% of patients did not receive any stroke prevention therapy. Independent predictors of no OAC prescription were intracranial bleeding (OR 0.15, 95%CI 0.07-0.35, p < 0.001), gastrointestinal bleeding (OR 0.25, 95%CI 0.17-0.37, p < 0.001), cancer (OR 0.37, 95%CI 0.25-0.55, p < 0.001), hospitalization due to acute coronary syndrome (OR 0.48, 95%CI 0.33-0.69, p < 0.001), and anemia (OR 0.62, 95%CI 0.48-0.81, p < 0.001). CONCLUSIONS: Most AF patients with a high thromboembolic risk received OACs. The factors predisposing a lack of OAC use in these patients were conditions that significantly increased the risk of bleeding complications.

BALLOON AORTIC VALVULOPLASTY WITH VALVER BALLOON CATHETER IN ADULTS WITH SEVERE AORTIC STENOSIS AS A BRIDGE OR PALLIATIVE TREATMENT.

OBJECTIVE: The aim: We aimed to assess the feasibility and safety of performing balloon aortic valvuloplasty (BAV) with Valver balloon catheter (Balton, Poland) in adults with severe aortic stenosis as a bridge or palliative treatment. PATIENTS AND METHODS: Materials and methods: We identified consecutive patients who underwent BAV procedures between May 2019 and March 2020 using Valver balloon catheters. Demographic data, medical history, and clinical characteristics were retrospectively collected in all study patients together with periprocedural data as well as 12-month follow-up data. RESULTS: Results: We included 18 patients. The mean population age was 78.1±8.9 years, and women were 61.1%. The most common co-morbidities were arterial hypertension (88.9%), dyslipidemia (83.3%), and coronary artery disease (72.2%). The baseline mean aortic valve pressure gradient was 49.94±27.02 mmHg and the mean aortic valve area (AVA) was 0.65±0.20 cm2. In all cases, the procedure was performed from the femoral access via the 8F sheath. Two Valver balloon catheter sizes were used 18x40mm (33.3%) and 20x40mm (66.7%). Three periprocedural complications were observed, and none was associated with the Valver balloon catheter per se. The transthoracic echocardiography after the procedure revealed a decrease in the mean pressure gradient of 11.1±8.85 mmHg, and an increase in AVA of 0.21±0.19 cm2. At 12-month follow-up, the mortality rate was 38.9%. CONCLUSION: Conclusions: BAV is a procedure increasingly performed in catheterization laboratories worldwide. This paper confirmed the relative safety of BAV with Valver balloon catheters in the modern era, showing a low incidence of valve and vascular complications.

Carcinoid Heart Disease: How to Diagnose and Treat in 2020?

Neuroendocrine tumors (NETs, originally termed "carcinoids") create a relatively rare group of neoplasms with an approximate incidence rate of 2.5 to 5 cases per 100 000 persons. Roughly 30% to 40% of subjects with NETs develop carcinoid syndrome (CS), and 20% to 50% of subjects with CS are diagnosed with carcinoid heart disease (CaHD). The long-standing exposure to high serum serotonin concentration is one of the crucial factors in CaHD development. White plaque-like deposits on the endocardial surface of heart structures with valve leaflets and subvalvular apparatus thickening (fused and shortened chordae; thickened papillary muscles) are characteristic for CaHD. NT pro-BNP and 5-hydroxyindoleacetic acid are the 2 most useful screening markers. Long-acting somatostatin analogs are the standard of care in symptoms control. They are also the first-line treatment for tumor control in subjects with a metastatic somatostatin receptor avid disease. In cases refractory to somatostatin analogs, several options are available. We can increase a somatostatin analog to off-label doses, add telotristat ethyl or administer peptide receptor radionuclide therapy. Cardiac surgery, which mainly involves valve replacement, is presently the most efficient strategy in subjects with advanced CaHD and can relieve unmanageable symptoms or be partly responsible for better prognosis.

Statins use and cancer: an update.

After initial concerns regarding the association of statins with increased incidences of cancer and elevated cancer-related mortality, there are now plenty of data on the antitumor, cytostatic and cytotoxic effectiveness of this class of drugs. Here, we present a short review of possible mechanisms of antineoplastic activity obtained from preclinical research and the influence of statins on cancer treatment. In the second part of the article, we focus on the most recent data from observational clinical trials, as well as meta-analyses regarding cancer incidence and mortality in patients treated with statins.

Dedicated bifurcation stents or regular drug eluting stents in distal left main stenosis: A retrospective study.

BACKGROUND: In the distal left main (LM) atherosclerosis mainly develops within bifurcation or trifur-cation. The aim of this study was to analyze the strategy of distal LM stenosis treatment and associated clinical outcomes in a large hospital in Northern Poland. METHODS: The study population consisted of consecutive patients with stable coronary artery disease or acute coronary syndrome (ACS) and distal LM stenosis who were hospitalized between June 2012 and June 2013. Patients were treated with regular drug-eluting stents (rDES), including bioresorbable vascular scaffolds, or dedicated bifurcation stents (BiOSS LIM®). Clinical outcomes were analyzed at 12, 24 and 36 months. Primary endpoint was cumulative major adverse cardiovascular events (MACE) inducing rate of cardiac death, myocardial infarction, and target lesion revascularization (TLR) after 36 months. RESULTS: One hundred and two patients were identified, 90 of whom were treated with percutaneous coronary intervention (56 rDES, including 9 Absorb, and 34 BiOSS) with no stent implantation fail-ure. In 15 (16.7%) patients rDES was required within side branch (SB). After 36 months MACE rate was 19.0% (BiOSS: 18.8% vs. rDES 19.2%), whereas TLR rate was 10.7% (BiOSS 12.5% vs. rDES 9.6%). In logistic regression for 36-month TLR rate proximal optimization technique (OR 0.311, 95% CI 0.211-0.644) was a prognostic factor of better clinical outcome, whereas non-ST-elevation ACS (OR 2.211, 95% CI 1.642-5.110), ST-elevation myocardial infarction (OR 2.771, 95% CI 1.325-7.209) and SB stenting (OR 1.141, 95% CI 1.002-1.881) were risk factors of poor outcome. CONCLUSIONS: Regular drug-eluting stents as well as dedicated bifurcation BiOSS LIM® stents enabled a simple and fast distal LM treatment option with a single stent. Both resulted in comparable MACE and TLR rates.

The role of invasive diagnostics and its impact on the treatment of dilated cardiomyopathy: A systematic review.

BACKGROUND: Dilated cardiomyopathy is one of the most frequent causes of non-ischemic heart failure. Many factors including genetic disorders, infectious agents, toxins, drugs and autoimmune disorders might take part in the development of dilated cardiomyopathy. Diagnosis of left ventricular dilatation is most often limited to performing echocardiography and excluding ischemic etiology (coronary angiography). Since many pathologies take place at the cellular and subcellular level the only way to clarify the etiology of the disease is to examine the myocardium itself (endomyocardial biopsy). METHODS: A systematic literature search was conducted for studies published between September 2000 and September 2015 using the PubMed database. RESULTS: Of 7104 studies identified, 73 studies were included in this review. Controversies raised by opponents of the endomyocardial biopsy collide with the low percentage of serious complications confirmed in several single-center registries. Based on the available data the overall complication rate varies from 1% to about 3%, with 0.5% risk of serious complications. According to the current recommendations of the European and American scientific societies endomyocardial biopsy should be performed in most cases of left ventricular dilatation and heart failure of non-ischemic etiology. Endomyocardial biopsy allows for making the diagnosis and providing prognostic information especially in patients with familial dilated cardiomyopathy, diabetic cardiomyopathy with dilated phenotype, alcoholic cardiomyopathy, peripartum cardiomyopathy, iron overload cardiomyopathy, as well as inflammatory and viral cardiomyopathy. Iron overload cardiomyopathy, peripartum cardiomyopathy, inflammatory and viral cardiomyopathy are potentially treatable and reversible. CONCLUSIONS: Targeted therapies are more effective when started early before myocardial injury becomes irreversible. Unfortunately, non-invasive techniques are not precise enough to decide if and which targeted therapy is required. Therefore endomyocardial biopsy should be mainly recognized as the essential diagnostic tool and should not be postponed.

Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies.

Clinical trials with SRC family kinases (SFKs) inhibitors used alone or in a combination with anti-CD20 monoclonal antibodies (mAbs) are currently underway in the treatment of B-cell tumors. However, molecular interactions between these therapeutics have not been studied so far. A transcriptional profiling of tumor cells incubated with SFKs inhibitors revealed strong downregulation of MS4A1 gene encoding CD20 antigen. In a panel of primary and established B-cell tumors we observed that SFKs inhibitors strongly affect CD20 expression at the transcriptional level, leading to inhibition of anti-CD20 mAbs binding and increased resistance of tumor cells to complement-dependent cytotoxicity. Activation of the AKT signaling pathway significantly protected cells from dasatinib-triggered CD20 downregulation. Additionally, SFKs inhibitors suppressed antibody-dependent cell-mediated cytotoxicity by direct inhibition of natural killer cells. Abrogation of antitumor activity of rituximab was also observed in vivo in a mouse model. Noteworthy, the effects of SFKs inhibitors on NK cell function are largely reversible. The results of our studies indicate that development of optimal combinations of novel treatment modalities with anti-CD20 mAbs should be preceded by detailed preclinical evaluation of their effects on target cells.

Dedicated bifurcation paclitaxel-eluting stent BiOSS Expert® in the treatment of distal left main stem stenosis.

OBJECTIVES: The aim of this study was to assess prospectively the effectiveness and safety profile of distal left main stem (LMS) stenosis treatment with dedicated bifurcation paclitaxel-eluting stent BiOSS Expert®. BACKGROUND: Angioplasty of distal LMS stenosis is always a high-risk procedure, and optimal treatment is uncertain. METHODS: This was a prospective international 2-center study, which enrolled patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) or stable angina with distal left main stenosis. All patients were treated with the dedicated bifurcation stent BiOSS Expert®. Provisional T-stenting was the obligatory strategy. Angiographic control was performed after 12 months. The primary end-point was cumulative rate of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 12 months. Angiographic end-points included late lumen loss, percent diameter stenosis, and binary restenosis rate. RESULTS: A total of 54 patients with distal LMS stenosis were enrolled. Seven patients (13%) were enrolled during NSTE-ACS, 77.8% were hypertensive, 27.8% were diabetic, 51.9% had previous MI, 53.7% underwent prior percutaneous coronary intervention, and 16.7% coronary artery bypass graft. The mean SYNTAX score was 21.52 ± 6.50. The device success rate was 100%. The mean BiOSS Expert stent parameters were as follows: 4.07 ± 0.26 mm × 3.36 ± 0.26 mm × 16.61 ± 1.72 mm and in side branch the other stent (classical drug-eluting stent) was implanted in 25.9% of cases. The overall TLR was 9.3%. There were no death, stent thrombosis, or acute MI. In the univariate regression analysis, the only factor associated with higher risk for TLR was the SYNTAX score value. CONCLUSIONS: The dedicated bifurcation stent BiOSS Expert® proved to be a feasible device, with promising safety and long-term clinical effectiveness in the treatment of distal LMS stenosis.

Optical coherence tomography criteria for defining functional severity of intermediate lesions: a comparative study with FFR.

Fractional flow reserve (FFR) is the gold standard in the assessment of severity of the coronary stenosis. The aim of the study was to compare optical coherence tomography (OCT) obtained intermediate coronary lesions lumen areas measurements with FFR assessments, with the goal to develop an OCT threshold to identify significant coronary stenosis. 48 patients (mean age 65 ± 10 years) was enrolled for the study. Within this population, 71 intermediate coronary lesions were investigated using both FFR and OCT. High dose bolus of Adenosine (120 µg) was used to obtain coronary hyperemia. OCT imaging was performed using non-occlusive technique to assess minimal lumen area (MLA) and diameter. The OCT cut-off value that showed the best correlation with the FFR cut-off of 0.80 was the MLA less than 2.05 mm2 (accuracy 87%, sensitivity 75%, specificity 90%, p < 0.001). The study did not disclose any relationship between FFR value and the lesion length. Vessel size influenced the OCT cut-off values, with greater values being found in presence of arteries with a reference diameter greater than 3.0 mm. OCT derived minimal lumen area might be complementary to FFR measurement in identifying ischemia related lesions. Further studies are warranted to assess threshold values in relation to vessel size and location.

Prenyltransferases regulate CD20 protein levels and influence anti-CD20 monoclonal antibody-mediated activation of complement-dependent cytotoxicity.

Anti-CD20 monoclonal antibodies (mAbs) are successfully used in the management of non-Hodgkin lymphomas and chronic lymphocytic leukemia. We have reported previously that statins induce conformational changes in CD20 molecules and impair rituximab-mediated complement-dependent cytotoxicity. Here we investigated in more detail the influence of farnesyltransferase inhibitors (FTIs) on CD20 expression and antitumor activity of anti-CD20 mAbs. Among all FTIs studied, L-744,832 had the most significant influence on CD20 levels. It significantly increased rituximab-mediated complement-dependent cytotoxicity against primary tumor cells isolated from patients with non-Hodgkin lymphomas or chronic lymphocytic leukemia and increased CD20 expression in the majority of primary lymphoma/leukemia cells. Incubation of Raji cells with L-744,832 led to up-regulation of CD20 at mRNA and protein levels. Chromatin immunoprecipitation assay revealed that inhibition of farnesyltransferase activity was associated with increased binding of PU.1 and Oct-2 to the CD20 promoter sequences. These studies indicate that CD20 expression can be modulated by FTIs. The combination of FTIs with anti-CD20 mAbs is a promising therapeutic approach, and its efficacy should be examined in patients with B-cell tumors.

Statins impair glucose uptake in tumor cells.

Statins, HMG-CoA reductase inhibitors, are used in the prevention and treatment of cardiovascular diseases owing to their lipid-lowering effects. Previous studies revealed that, by modulating membrane cholesterol content, statins could induce conformational changes in cluster of differentiation 20 (CD20) tetraspanin. The aim of the presented study was to investigate the influence of statins on glucose transporter 1 (GLUT1)-mediated glucose uptake in tumor cells. We observed a significant concentration- and time-dependent decrease in glucose analogs' uptake in several tumor cell lines incubated with statins. This effect was reversible with restitution of cholesterol synthesis pathway with mevalonic acid as well as with supplementation of plasma membrane with exogenous cholesterol. Statins did not change overall GLUT1 expression at neither transcriptional nor protein levels. An exploratory clinical trial revealed that statin treatment decreased glucose uptake in peripheral blood leukocytes and lowered (18)F-fluorodeoxyglucose ((18)F-FDG) uptake by tumor masses in a mantle cell lymphoma patient. A bioinformatics analysis was used to predict the structure of human GLUT1 and to identify putative cholesterol-binding motifs in its juxtamembrane fragment. Altogether, the influence of statins on glucose uptake seems to be of clinical significance. By inhibiting (18)F-FDG uptake, statins can negatively affect the sensitivity of positron emission tomography, a diagnostic procedure frequently used in oncology.

Antitumor effects of the combination of cholesterol reducing drugs.

There are a number of potential mechanisms linking cholesterol homeostasis to processes that are tightly linked with carcinogenesis. Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR), the rate-limiting enzyme in the mevalonic acid synthesis pathway, exert cytostatic and cytotoxic effects towards tumor cells. It seems that the cytostatic and cytotoxic effects of statins result from blocking protein prenylation, leading to inhibition of isoprenoid compound synthesis. Another compound which affects cholesterol metabolism is the plant alkaloid berberine. The aim of this study was to investigate potential antitumor effects of lovastatin combined with berberine. Combined with berberine, lovastatin appeared to exert potentiated cytostatic and/or cytotoxic effects against human MDA-MB231 breast cancer and murine Panc 02 pancreatic cancer cells. The obtained results indicated that the effect of berberine is not dependent on blocking protein prenylation in cells, and the toxic effect of lovastatin combined with berberine is reversed by addition of the substrates of this pathway to the level brought out by lovastatin alone. Lovastatin-berberine combination caused cell cycle inhibition in G1 phase after 48 h of incubation with drugs. In a Panc 02 pancreatic cancer model in mice, lovastatin-berberine combination slightly, but significantly, slowed down tumor growth. Taking into account the number of patients treated with the investigated drugs one may suppose that the described interactions may be of clinical value.

Optimization of activation requirements of immature mouse dendritic JAWSII cells for in vivo application.

Dendritic cells (DCs) are specialized antigen-presenting cells that are present in peripheral tissues in a resting (immature) state. Their activation is a critical step in the initiation of the primary immune response. In the present study, we optimized in vitro conditions for maturation of commercially available immortalized mouse dendritic precursor JAWSII cells. These cells express surface markers and have properties that are typical of immature DCs and macrophages (e.g. MHC class I and II markers, CD80 molecules, high endocytic capacity), as well as TLR1, TLR3, TLR4, TLR6, and TLR7 receptors. When stimulated with poly I:C (and also LPS) JAWSII cells produced large amounts of IL-6, TNF-α and MCP-1. Incubation of JAWSII cells with IFN-γ markedly increased expression of MHC class I molecules and, more importantly, combination of this cytokine with poly I:C significantly increased expression of CD40 surface protein and CD11c, the most characteristic marker of mouse DCs. The combination of both agents also inhibited the endocytic abilities of JAWSII cells. In in vivo migration studies, exposure of JAWSII cells to poly I:C and IFN-γ led to increased accumulation of these cells in regional lymph nodes. Functional in vivo studies showed that tumor cell lysate-pulsed and subsequently poly I:C/IFN-γ-stimulated JAWSII cells promoted development of specific T cells in lymph nodes. Our studies show that the combination of optimal endogenous and exogenous ligands may induce phenotypic and functional maturation of JAWSII cells necessary for the accomplishment of their antigen-presenting function in vivo.

Molecular mechanisms of the antitumor effects of anti-CD20 antibodies.

Anti-CD20 monoclonal antibodies (mAbs) have become the mainstay in the treatment of non-Hodgkin's lymphomas and have shown significant activity in patients with B-cell chronic lymphocytic leukemia. Antitumor action of these antibodies results from triggering of indirect effector mechanisms of the immune system that include activation of complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or phagocytosis. Moreover, some studies indicate direct influence of anti-CD20 mAbs on tumor cells that leads to induction of various types of cell death. Despite the wealth of data on the mechanisms of cytotoxicity that accumulated over the last two decades their relative contribution to the therapeutic outcome is still difficult to predict in individual patients. Elucidation of molecular mechanisms of anti-CD20 mAbs action is necessary to deliver their maximal activity in rationally designed combinations with other therapeutic approaches and to design next generation anti-CD20 mAb with improved ability to eliminate tumor cells.

Cardiotoxicity of the anticancer therapeutic agent bortezomib.

Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca(2+) fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs.

Proteolytic pathways involved in modulation of CD20 levels.

Recent observations indicate that rituximab-resistant lymphoma cells exhibit upregulation of components of the ubiquitin-proteasome system (UPS). Therefore, proteasome inhibitors including the clinically approved bortezomib might influence the levels of CD20, a rituximab target antigen. We observed that incubation of tumor cells with rituximab leads to increased levels of ubiquitinated CD20. However, inhibition of the UPS is not associated with upregulation, but rather with a counterintuitive downregulation of surface CD20 levels that increases resistance of tumor cells to rituximab-mediated cytotoxicity. Although preliminary observations indicate that CD20 might be a substrate for two proteolytic systems, the mechanisms as well as significance of these findings require further studies.