Non-vitamin K antagonist oral anticoagulants in atrial fibrillation accompanying mitral stenosis: the concept for a trial.

Patients at thromboembolic risk with non-valvular atrial fibrillation (AF) can now be managed either with a vitamin K antagonist (VKA) or with a fixed dose of a non-VKA oral anticoagulant (NOAC), while patients with valvular AF have been restricted to VKAs on the basis of a potentially higher risk and different mechanism of thrombosis, and the lack of sufficient data on the efficacy of NOACs. The terms 'non-valvular AF' and 'valvular AF' have not been however consistently defined. 'Valvular' AF has included any valvular disorder, including valve replacement and repair. In AF with rheumatic mitral disease, observational studies strongly suggest that VKA treatment is valuable. These patients have not been included in NOAC trials, but there is also no stringent argument to have excluded them. This is at sharp variance from patients with mechanical valves, also excluded from the pivotal Phase III trial comparing warfarin with NOACs, but in whom a single Phase II trial of dabigatran etexilate against VKA treatment was stopped prematurely because of increased rates of thromboembolism as well as increased bleeding associated with dabigatran. Until more data are available, such patients should be therefore managed with VKAs. We here propose an open-label randomized trial of one of the NOACs against the best of treatment available in regions of the world in which rheumatic heart disease is still highly prevalent, aiming at showing the superiority of the NOAC used against current standard treatment

Aspirin for primary cardiovascular prevention: Why the wonder drug should not be precipitously dismissed

Primary cardiovascular prevention is the combined set of actions aimed at reducing the likelihood of symptomatic atherosclerotic disease or major adverse cardiovascular events (MACEs) in currently asymptomatic individuals. Older studies on aspirin for primary prevention were positive or neutral as to the primary ischemic endpoint (often represented by MACE), but the reduction in nonfatal ischemic events seemed largely counterbalanced by an increase in bleeding events. The 3 latest large randomized controlled trials on aspirin in primary prevention, all published in 2018, reached basically similar conclusions, leading to an intense debate on whether aspirin therapy is warranted in asymptomatic patients and whether there are subgroups that may benefit. In the present review, we provide an overview of the available evidence on aspirin for primary cardiovascular prevention, focusing on the results of meta-analyses and on strengths and pitfalls of meta-analytic assessments. Based on a meta-regression of the benefits and harm of aspirin therapy in primary prevention as a function of the 10-year risk of MACE, which is an alternative type of pooled analysis of available evidence, we propose a treatment algorithm acknowledging differences among patients and emphasizing the need for an individualized assessment of benefits and risks. Following general preventive measures (physical exercise, smoking cessation, treatment of hypertension and hypercholesterolemia, etc), a tailored approach to aspirin prescription is warranted. When patients are younger than 70 years of age, clinicians should assess the 10-year cardiovascular risk: when such risk is high and bleeding risk is low, aspirin treatment should still be considered, also taking patients' preferences into account

Aspirin for primary prevention of cardiovascular disease: Advice for a decisional strategy based on risk stratification

The need for aspirin therapy as part of primary prevention of cardiovascular (CV) disease is currently being highly debated, especially after 3 studies in different settings reported that a reduction in ischemic events is largely counterbalanced by an increase in bleeding events. One possible explanation for these results is the progressive reduction in the risk of major adverse cardiovascular events (MACE) as a result of primary prevention, which has accompanied global education programs that have led to patients smoking less, exercising more, and increasingly undertaking lipid-lowering therapies. Based on a meta-regression of the benefits and harmful effects of aspirin therapy in primary prevention as a function of the 10-year risk of MACE, we favor a differentiated and personalized approach that acknowledged differences between patients and emphasized an individualized assessment of benefits and risks. Following general preventive measures (physical exercise, cessation of smoking, treatment of hypertension and hypercholesterolemia, etc.), an individualized approach to prescribing aspirin is still warranted. When patients are less than 70 years of age, clinicians should assess the 10-year CV risk. Aspirin treatment should be considered only when the CV risk is very high and the bleeding risk is low, after taking into account the patient's preferences

GALNT2 as a novel modulator of adipogenesis and adipocyte insulin signaling

Background/objectives: A better understanding of adipose tissue biology is crucial to tackle insulin resistance and eventually coronary heart disease and diabetes, leading causes of morbidity and mortality worldwide. GALNT2, a GalNAc-transferase, positively modulates insulin signaling in human liver cells by down-regulating ENPP1, an insulin signaling inhibitor. GALNT2 expression is increased in adipose tissue of obese as compared to that of non-obese individuals. Whether this association is secondary to a GALNT2-insulin sensitizing effect exerted also in adipocytes is unknown. We then investigated in mouse 3T3-L1 adipocytes the GALNT2 effect on adipogenesis, insulin signaling and expression levels of both Enpp1 and 72 adipogenesis-related genes. Methods: Stable over-expressing GALNT2 and GFP preadipocytes (T 0 ) were generated. Adipogenesis was induced with (R+) or without (R−) rosiglitazone and investigated after 15 days (T 15 ). Lipid accumulation (by Oil Red-O staining) and intracellular triglycerides (by fluorimetric assay) were measured. Lipid droplets (LD) measures were analyzed at confocal microscope. Gene expression was assessed by RT-PCR and insulin-induced insulin receptor (IR), IRS1, JNK and AKT phosphorylation by Western blot. Results: Lipid accumulation, triglycerides and LD measures progressively increased from T 0 to T 15 R- and furthermore to T 15 R+. Such increases were significantly higher in GALNT2 than in GFP cells so that, as compared to T 15 R+GFP, T 15 R- GALNT2 cells showed similar (intracellular lipid and triglycerides accumulation) or even higher (LD measures, p < 0.01) values. In GALNT2 preadipocytes, insulin-induced IR, IRS1 and AKT activation was higher than that in GFP cells. GALNT2 effect was totally abolished during adipocyte maturation and completely reversed at late stage maturation. Such GALNT2 effect trajectory was paralleled by coordinated changes in the expression of Enpp1 and adipocyte-maturation key genes. Conclusions: GALNT2 is a novel modulator of adipogenesis and related cellular phenotypes, thus becoming a potential target for tackling the obesity epidemics and its devastating sequelae

Community detection with node attributes in multilayer networks

Community detection in networks is commonly performed using information about interactions between nodes. Recent advances have been made to incorporate multiple types of interactions, thus generalizing standard methods to multilayer networks. Often, though, one can access additional information regarding individual nodes, attributes, or covariates. A relevant question is thus how to properly incorporate this extra information in such frameworks. Here we develop a method that incorporates both the topology of interactions and node attributes to extract communities in multilayer networks. We propose a principled probabilistic method that does not assume any a priori correlation structure between attributes and communities but rather infers this from data. This leads to an efficient algorithmic implementation that exploits the sparsity of the dataset and can be used to perform several inference tasks; we provide an open-source implementation of the code online. We demonstrate our method on both synthetic and real-world data and compare performance with methods that do not use any attribute information. We find that including node information helps in predicting missing links or attributes. It also leads to more interpretable community structures and allows the quantification of the impact of the node attributes given in input

Non-Vitamin K antagonist oral anticoagulants for mechanical heart valves is the door still open?

The estimated prevalence of mitral or aortic valvular heart disease is ≈2.5% in the general population of Western countries, and is expected to rise with population aging. A substantial proportion of patients with valvular heart disease undergoes surgical valve replacement. Mechanical heart valves are much more durable than bioprostheses, and are thus preferentially implanted in patients with a longer life expectancy, but have the major drawback of requiring lifelong anticoagulation to prevent valve thrombosis because of their higher thrombogenicity. The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing vitamin K antagonists in many settings, including bioprostheses, because of their favorable safety and efficacy profiles. However, mechanical heart valves currently pose an absolute contraindication to NOACs based on the results of a single phase II study comparing dabigatran and warfarin (RE-ALIGN [Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement]). That trial was stopped prematurely because of an excess of both stroke and bleeding with the dabigatran doses tested. Because of such negative findings, research in this area has been halted. We believe that several aspects of both the preclinical studies and the RE-ALIGN trial should be critically reevaluated. In our opinion, 1 single trial with a single NOAC does not represent sufficient evidence for dismissing a therapeutic strategy, anticoagulation with NOACs, that has shown better safety and at least similar efficacy as warfarin in the setting of atrial fibrillation and venous thromboembolism,. Herein, we reevaluate this topic to identify the patient profile that has the greatest likelihood of benefit from some of the NOACs, with a focus on factor Xa inhibitors, thus providing some perspectives for basic and translational research

Aspirin Therapy for Primary Prevention: The Case for Continuing Prescribing to Patients at High Cardiovascular Risk-A Review

Current evidence supports the use of low-dose aspirin for secondary cardiovascular prevention. By contrast, the benefit-to-risk ratio of aspirin use in primary prevention is debated: Three contemporary randomized control trials have been conflicting, and meta-analyses have concluded for an unclear clinical benefit, based on the consideration that the reduction in thromboembolic events is counterbalanced by increased bleeding. The primary prevention setting is, however, a heterogeneous mix of subjects at highly variable cardiovascular risk. One possible explanation for the uncertainty of data interpretation is the progressive reduction in risk of major adverse cardiovascular events (MACEs) in primary prevention that has accompanied global education programs, leading patients to smoke less, exercise more, and increasingly take lipid-lowering therapies. Based on a meta-regression of the benefits and harm of aspirin therapy in primary prevention as a function of the 10-year risk of MACE, we favor a nuanced approach still, however, based on the evaluation of cardiovascular risk, acknowledging differences between patients and emphasizing an individualized assessment of both benefits and harm. After optimal control of cardiovascular risk factors, and when patients are less than 70 years of age, clinicians should assess the risk of MACE and base decision on such stratification, considering the risk of bleeding and patient preferences. Clinicians would then advise the use of aspirin in primary prevention patients at the highest risk of MACE who do not have a prohibitive risk of bleeding, and in the majority of cases after initiation of properly titrated statin therapy

Pre-treatment high-sensitivity troponin T for the short-term prediction of cardiac outcomes in patients on immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) are an emerging option for several advanced metastatic cancers, but may have cardiotoxic effects. The prognostic value of high-sensitivity troponin T (hs-TnT) before treatment start has never been investigated. Materials and methods: Thirty consecutive patients underwent measurement of hs-TnT before starting ICI therapy (pembrolizumab, 23%; nivolumab, 12%; atezolizumab, 6%; durvalumab, 5%). The primary endpoint of cardiovascular death, stroke or transient ischaemic attack, pulmonary embolism and new-onset heart failure, and the secondary endpoint of progression of cardiac involvement according to the CARDIOTOX classification were evaluated after 3 months from the first cycle. Results: Patients (median age 68 years, 77% men, 13% with coronary artery disease, 90% current or former smokers, 67% overweight or obese and 43% hypertensive) had a median hs-TnT of 12 ng/L (interquartile interval 8-23). The primary endpoint occurred only in patients with hs-TnT ≥ 14 ng/L at baseline. Therefore, only patients who had hs-TnT ≥ 14 ng/L before the first cycle died had a stroke/TIA or new-onset HF. Furthermore, nine out of 13 patients with the secondary endpoint (progression of cardiac disease) had hs-TnT ≥ 14 ng/L before the first cycle (P =.012). AUC values were 0.909 for the primary endpoint and 0.757 for the secondary endpoint. The best cut-off was 14 ng/L for both the primary (100% sensitivity, 73% specificity) and secondary endpoints (sensitivity 75%, specificity 77%). Conclusions: In patients on ICIs, baseline hs-TnT predicts a composite cardiovascular endpoint and the progression of cardiac involvement at 3 months, with 14 ng/L as the best cut-off