Ticagrelor downregulates the expression of proatherogenic and proinflammatory miR125-b compared to clopidogrel: A randomized, controlled trial.

BACKGROUND: Platelet P2Y12 antagonist ticagrelor reduces cardiovascular mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets release proatherogenic and proinflammatory microRNAs, including miR-125a, miR-125b and miR-223, we hypothesized that the expression of these miRNAs is lower on ticagrelor, compared to clopidogrel. OBJECTIVES: We compared miR-125a, miR-125b and miR-223 expression in plasma of patients after AMI treated with ticagrelor or clopidogrel. METHODS: After percutaneous coronary intervention on acetylsalicylic acid and clopidogrel, 60 patients with first AMI were randomized to switch to ticagrelor or to continue with clopidogrel. Plasma expression of miR-223, miR-125a-5p, miR-125b was measured using quantitative polymerase chain reaction at baseline and after 72 h and 6 months of treatment with ticagrelor or clopidogrel in patients and one in 30 healthy volunteers. Multiple electrode aggregometry using ADP test was used to determine platelet reactivity in response to P2Y12 inhibitors. RESULTS: Expression of miR-125b was higher in patients with AMI 72 h and 6 months, compared to healthy volunteers (p = 0.001), whereas expression of miR-125a-5p and miR-223 were comparable. In patients randomized to ticagrelor, expression of miR-125b decreased at 72 h (p = 0.007) and increased back to baseline at 6 months (p = 0.005). Expression of miR-125a-5p and miR-223 was not affected by the switch from clopidogrel to ticagrelor. CONCLUSIONS: Ticagrelor treatment leads to lower plasma expression of miR-125b after AMI, compared to clopidogrel. Higher expression of miR-125b might explain recurrent thrombotic events and worse clinical outcomes in patients treated with clopidogrel, compared to ticagrelor.

SGLT2 Inhibitors vs. GLP-1 Agonists to Treat the Heart, the Kidneys and the Brain.

Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like-peptide-1 receptor (GLP-1-R) agonists are novel therapeutic agents used for the management of type 2 diabetes mellitus (T2DM). Recently, large-scale randomized clinical trials have been conducted to assess the cardiovascular safety of these medications. The findings of these trials have revealed that both SGLT2 inhibitors and GLP-1-R agonists exhibit favorable cardioprotective effects, including reduction in cardiovascular and all-cause mortality, a decreased risk of chronic kidney disease progression, a decrease in hospitalization for heart failure (HF), an effect shown by SGLT2 inhibitors, and stroke prevention, an effect shown by GLP-1-R agonists. Based on the results from above studies, the European and American Diabetes Associations have issued new recommendations strongly endorsing the use of SGLT2 inhibitors and GLP-1-R agonists in combination with metformin for patients with T2DM who have additional cardiovascular (CV) comorbidities or risk factors. The primary aim of this combined therapy is to prevent CV events. Although both medication groups offer beneficial effects, they demonstrate slightly different profiles. SGLT2 inhibitors have exhibited better effects regarding a reduced incidence of HF, whereas GLP-1-R agonists have shown a reduced risk of CV events, particularly stroke. Moreover, recent European Society of Cardiology as well as American College of Cardiology and American Heart Association guidelines of HF treatment stressed the importance of SGLT2 inhibitor administration in patients with HF regardless of T2DM. In this context, we present and discuss the outcomes of the most recent trials investigating the impact of SGLT2 inhibitors and GLP-1-R agonists on renal and cardiovascular outcomes in patients, both with and without T2DM. Additionally, we explore the synergistic effects of combining SGLT2 inhibitors and GLP-1-R agonists in patients with cardiovascular disease.

The Effect of a Vegan Diet on the Cardiovascular System.

The vegan diet, often known as a plant-rich diet, consists primarily of plant-based meals. This dietary approach may be beneficial to one's health and the environment and is valuable to the immune system. Plants provide vitamins, minerals, phytochemicals, and antioxidants, components that promote cell survival and immune function, allowing its defensive mechanisms to work effectively. The term "vegan diet" comprises a range of eating patterns that prioritize nutrient-rich foods such as fruits and vegetables, legumes, whole grains, nuts, and seeds. In comparison to omnivorous diets, which are often lower in such products, the vegan diet has been favorably connected with changes in cardiovascular disease (CVD) risk markers such as reduced body mass index (BMI) values, total serum cholesterol, serum glucose, inflammation, and blood pressure. Reduced intake of low-density lipoprotein (LDL), saturated fat, processed meat, and greater consumption of fiber and phytonutrients may improve cardiovascular health. However, vegans have much smaller amounts of nutrients such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), selenium, zinc, iodine, and vitamin B12, compared to non-vegans, which may lead to detrimental cardiovascular effects. This review aims to present the effect of plant-based diets (PBDs), specifically vegan diets, on the cardiovascular system.

Biomarker-based approach to determine etiology and severity of pulmonary hypertension: Focus on microRNA.

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the pulmonary arteries, and defined by elevated pulmonary arterial pressure, measured during right heart catheterization. There are three main challenges to the diagnostic and therapeutic process of patients with PAH. First, it is difficult to differentiate particular PAH etiology. Second, invasive diagnostic is required to precisely determine the severity of PAH, and thus to qualify patients for an appropriate treatment. Third, the results of treatment of PAH are unpredictable and remain unsatisfactory. MicroRNAs (miRNAs) are small non-coding RNAs that regulate post transcriptional gene-expression. Their role as a prognostic, and diagnostic biomarkers in many different diseases have been studied in recent years. MiRNAs are promising novel biomarkers in PAH due to their activity in various molecular pathways and processes underlying PAH. Lack of biomarkers to differentiate between particular PAH etiology and evaluate the severity of PAH, as well as paucity of therapeutic targets in PAH open a new field for the possibility to use miRNAs in these applications. In our article, we discuss the potential of miRNAs use as diagnostic tools, prognostic biomarkers and therapeutic targets in PAH.

Safety and Efficacy of DOACs in Patients with Advanced and End-Stage Renal Disease.

The prevalence of chronic kidney disease (CKD) is increasing due to the aging of the population and multiplication of risk factors, such as hypertension, arteriosclerosis and obesity. Impaired renal function increases both the risk of bleeding and thrombosis. There are two groups of orally administered drugs to prevent thromboembolic events in patients with CKD who require anticoagulation: vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). Although VKAs remain the first-line treatment in patients with advanced CKD, treatment with VKAs is challenging due to difficulties in maintaining the appropriate anticoagulation level, tendency to accelerate vascular calcification and faster progression of CKD in patients treated with VKAs. On the other hand, the pleiotropic effect of DOACs, including vascular protection and anti-inflammatory properties along with comparable efficacy and safety of treatment with DOACs, compared to VKAs observed in preliminary reports encourages the use of DOACs in patients with CKD. This review summarizes the available data on the efficacy and safety of DOACs in patients with CKD and provides recommendations regarding the choice of the optimal drug and dosage depending on the CKD stage.

Statins in COVID-19 Therapy.

Inhibitors of 3-hydroxy-3methylgultaryl-coenzyme A reductase (statins) are one of the main groups of drugs used in preventing and treating cardiovascular diseases worldwide. They are widely available, cheap, and well-tolerated. Based on statins' pleiotropic properties, including improvement of endothelial dysfunction, antioxidant properties, atherosclerotic plaque stabilization, and inhibition of inflammatory responses, it can be hypothesized that the use of statins, at least as an adjuvant in antiviral therapy, may be justified. All these effects might be especially beneficial in patients with COVID-19, suffering from endothelial dysfunction, microvascular and macrovascular thrombosis, and cytokine storm. Here, we review the recent data regarding the pathophysiology of SARS-CoV-2 activity in host cells, proposed COVID-19 therapy, the pleiotropic activity of statins, and statins in clinical trials in respiratory infections. According to the guidelines of the European and American Cardiac Societies, in patients with cardiovascular disease or high cardiovascular risk with concomitant COVID-19 it is recommended to continue statin treatment. However, the initiation of statin therapy de novo in COVID-19 treatment should only be done as part of a clinical trial.

Inclisiran-Silencing the Cholesterol, Speaking up the Prognosis.

The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%-20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.

Prostacyclin Analogues Inhibit Platelet Reactivity, Extracellular Vesicle Release and Thrombus Formation in Patients with Pulmonary Arterial Hypertension.

(1) Background: Prostacyclin analogues (epoprostenol, treprostinil, and iloprost) induce vasodilation in pulmonary arterial hypertension (PAH) but also inhibit platelet function. (2) Objectives: We assessed platelet function in PAH patients treated with prostacyclin analogues and not receiving prostacyclin analogues. (3) Methods: Venous blood was collected from 42 patients treated with prostacyclin analogues (49.5 ± 15.9 years, 81% female) and 38 patients not receiving prostacyclin analogues (55.5 ± 15.6 years, 74% female). Platelet reactivity was analyzed by impedance aggregometry using arachidonic acid (AA; 0.5 mM), adenosine diphosphate (ADP; 6.5 µM), and thrombin receptor-activating peptide (TRAP; 32 µM) as agonists. In a subset of patients, concentrations of extracellular vesicles (EVs) from all platelets (CD61+), activated platelets (CD61+/CD62P+), leukocytes (CD45+), and endothelial cells (CD146+) were analyzed by flow cytometry. Platelet-rich thrombus formation was measured using a whole blood perfusion system. (4) Results: Compared to controls, PAH patients treated with prostacyclin analogues had lower platelet reactivity in response to AA and ADP (p = 0.01 for both), lower concentrations of platelet and leukocyte EVs (p ≤ 0.04), delayed thrombus formation (p ≤ 0.003), and decreased thrombus size (p = 0.008). Epoprostenol did not affect platelet reactivity but decreased the concentrations of platelet and leukocyte EVs (p ≤ 0.04). Treprostinil decreased platelet reactivity in response to AA and ADP (p ≤ 0.02) but had no effect on the concentrations of EVs. All prostacyclin analogues delayed thrombus formation and decreased thrombus size (p ≤ 0.04). (5) Conclusions: PAH patients treated with prostacyclin analogues had impaired platelet reactivity, EV release, and thrombus formation, compared to patients not receiving prostacyclin analogues.

LDL-Cholesterol and Platelets: Insights into Their Interactions in Atherosclerosis.

Atherosclerosis and its complications, including acute coronary syndromes, are the major cause of death worldwide. The two most important pathophysiological mechanisms underlying atherosclerosis include increased platelet activation and increased low-density lipoproteins (LDL) concentration. In contrast to LDL, oxidized (ox)-LDL have direct pro-thrombotic properties by functional interactions with platelets, leading to platelet activation and favoring thrombus formation. In this review, we summarize the currently available evidence on the interactions between LDL-cholesterol and platelets, which are based on (i) the presence of ox-LDL-binding sites on platelets, (ii) generation of ox-LDL by platelets and (iii) the role of activated platelets and ox-LDL in atherosclerosis. In addition, we elaborate on the clinical implications of these interactions, including development of the new therapeutic possibilities. The ability to understand and modulate mechanisms governing interactions between LDL-cholesterol and platelets may offer new treatment strategies for atherosclerosis prevention.

Antiplatelet effects of prostacyclin analogues: Which one to choose in case of thrombosis or bleeding?

Prostacyclin and analogues are successfully used in the treatment of pulmonary arterial hypertension (PAH) due to their vasodilatory effect on pulmonary arteries. Besides vasodilatory effect, prostacyclin analogues inhibit platelets, but their antiplatelet effect is not thoroughly established. The antiplatelet effect of prostacyclin analogues may be beneficial in case of increased risk of thromboembolic events, or undesirable in case of increased risk of bleeding. Since prostacyclin and analogues differ regarding their potency and form of administration, they might also inhibit platelets to a different extent. This review summarizes the recent evidence on the antiplatelet effects of prostacyclin and analogue in the treatment of PAH, this is important to consider when choosing the optimal treatment regimen in tailoring to an individual patients' needs.

Role of P2Y Receptors in Platelet Extracellular Vesicle Release.

Platelet extracellular vesicles (PEVs) are potential new biomarkers of platelet activation which may allow us to predict and/or diagnose developing coronary thrombosis before myocardial necrosis occurs. The P2Y1 and P2Y12 receptors play a key role in platelet activation and aggregation. Whereas the P2Y1 antagonists are at the preclinical stage, at present, the P2Y12 antagonists are the most effective treatment strategy to prevent stent thrombosis after percutaneous coronary intervention. Despite an increasing number of publications on PEVs, the mechanisms underlying their formation, including the role of purinergic receptors in this process, remain an active research field. Here, we outline the clinical relevance of PEVs in cardiovascular disease, summarize the role and downstream signalling of P2Y receptors in platelet activation, and discuss the available evidence regarding their role in PEV formation.

Macroscopic role of microparticles in cardiovascular disease.

Microparticles, also termed extracellular vesicles (EVs) are novel candidate markers of platelet activation and ongoing inflammation in vivo. Different subtypes of EVs are released from platelets, endothelial cells and leukocytes. Blood concentration of EV subtypes in patients with acute myocardial infarction, stroke and peripheral artery disease correlated with the severity of the disease. Accumulating data indicate that EVs may contribute to the development of atherosclerosis and its complications. Measurement of EV concentrations might become an element of minimally-invasive diagnostic tests, allowing for early diagnosis of cardiovascular disease (CVD), risk stratification and monitoring of therapy in patients with high cardiovascular risk. It also may allow to monitor the response to antiplatelet therapy with acetylsalicylic acid or P2Y12 antagonists. Isolation and detection of EVs have been recently standardized, allowing for further development of research on these promising biomarkers. EV-based tests might eventually be implemented into every-day clinical practice as well as in multicenter clinical trials.