Rationale and Design of the SOTA-P-CARDIA Trial (ATRU-V): Sotagliflozin in HFpEF Patients Without Diabetes.

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of heart failure (HF). This syndrome is associated with an elevated morbi-mortality, and effective therapies are urgently needed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the first pharmacological class that has demonstrated to reduce hospitalization and cardiovascular mortality in large clinical trials in HFpEF. Furthermore, the dual SGLT 1/2 inhibitor sotagliflozin has shown a reduction in cardiovascular outcomes in diabetic HF patients, regardless of ejection fraction Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) Trial, and prevents the development of HF in patients with diabetes and chronic kidney disease Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial. The major objective of the Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial (NCT05562063) is to investigate whether the observed cardiorenal benefits of sotagliflozin in HF patients with diabetes can be extended to a non-diabetic population. The SOTA-P-CARDIA is a prospective, randomized, double-blinded, placebo-controlled study that will randomize non-diabetic patients with the universal definition of HFpEF (ejection fraction > 50% assessed the day of randomization). Qualifying patients will be randomized, in blocks of 4, to receive either sotagliflozin or placebo for a period of 6 months. The primary outcome is changes in left ventricular mass by cardiac magnetic resonance from randomization to end of the study between the groups. Secondary end points include changes in peak VO2; myocardial mechanics, interstitial myocardial fibrosis, and volume of epicardial adipose tissue; distance in the 6-min walk test; and quality of life. Finally, the authors expect that this trial will help to clarify the potential benefits of the use of sotagliflozin in non-diabetic HFpEF patients.

Prolyl Hydroxylase Inhibitors: a New Opportunity in Renal and Myocardial Protection.

Hypoxia, via the activity of hypoxia-inducible factors (HIFs), plays a crucial role in fibrosis, inflammation, and oxidative injury, processes which are associated with progression of cardiovascular and kidney diseases. HIFs are key transcription heterodimers consisting of regulatory α-subunits (HIF-1α, HIF-2α, HIF-3α) and a constitutive ß-subunit (HIF-ß). The stability of HIFs is regulated by the prolyl hydroxylases (PHDs). Specific PHD inhibitors (PHD-i) are being investigated as a therapeutic approach to modulate the cellular signaling pathways and harness the native protective adaptive responses to hypoxia. Selective inhibition of PHD leads to the stabilization of the HIFs, which is the transcriptional gatekeeper of a multitude of genes involved in angiogenesis, energy metabolism, apoptosis, inflammation, and fibrosis. PHD-i downregulate hepcidin, improve iron absorption, and increase the endogenous production of erythropoietin. Furthermore, this pharmacological group has also been proven to ameliorate ischemic injuries in several organs, opening a new and promising field in cardiovascular research.. In this review, we present the basic and clinical potential of PHD-i treatment in different scenarios, such as ischemic heart disease, cardiac hypertrophy and heart failure, and their interplay with other pharmacological agents with proven cardiovascular benefits, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

Effects of electret coating technology on coronary stent thrombogenicity.

Stent thrombosis (ST) is a catastrophic event and efforts to reduce its incidence by altering blood-stent interactions are longstanding. A new electret coating technology that produces long-lasting negative charge on stent surface could make them intrinsically resistant to thrombosis. We assessed the thrombogenicity of stents using an annular perfusion model with confocal microscopy, and determined the efficacy of electret coating technology to confer thrombo-resistant properties to standard stents. Using an annular perfusion chamber, Bare Metal Stent (BMS), standard uncoated DES (DES), and Electret-coated DES (e-DES) were exposed to human blood under arterial flow conditions. Deposits of fibrinogen and platelets on the stent surface were analyzed using immunofluorescence staining and confocal microscopy. Surface coverage by fibrinogen and platelets and the deposit/aggregate size were quantified using computerized morphometric analysis. The experimental methodology produced consistent, quantifiable results. Area of stent surface covered by fibrinogen and platelets and the average size of the deposits/aggregates were lowest for e-DES and highest on BMS, with DES in the middle. The size of fibrinogen-deposits showed no differences between the stents. The testing methodology used in our study successfully demonstrated that electret coating confers significant antithrombotic property to DES stents. These findings warrant confirmation in a larger study.

Rationale and Design of the EMPA-TROPISM Trial (ATRU-4): Are the "Cardiac Benefits" of Empagliflozin Independent of its Hypoglycemic Activity?

The SGLT2 inhibitor empagliflozin reduced cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in diabetic patients. We have recently demonstrated the efficacy of empagliflozin in ameliorating HF and improving cardiac function in a non-diabetic porcine model of HF mediated via a switch in myocardial metabolism that enhances cardiac energetics. Therefore, we hypothesized that the cardiac benefits of empagliflozin can also be extended to non-diabetic HF patients. The EMPA-TROPISM clinical trial is a randomized, double-blind, parallel group, placebo-controlled, trial comparing the efficacy of and safety of empagliflozin in non-diabetic HF patients. Eighty patients with stable HF for over 3 months, LVEF < 50%, and New York Heart Association functional class II to IV symptoms will be randomized to empagliflozin 10 mg for 6 months or placebo. All patients will undergo cardiac magnetic resonance (CMR), cardiopulmonary exercise test (CPET), 6-min walk test, and quality of life questionnaires. The primary outcome is the change in left ventricular end-diastolic volume measured by CMR. Secondary end-points include change in peak VO2 (CPET); change in LV mass, in LVEF, in myocardial mechanics (strains), in left atrium volumes, in RV function and volumes, in interstitial myocardial fibrosis, and in epicardial adipose tissue (CMR); change in the distance in the 6-min walk test; and changes in quality of life (Kansas Cardiomyopathy questionnaire [KCCQ-12] and the 36-Item Short Form Survey [SF-36]). Safety issues (e.g., hypoglycemia, urinary infections, ketoacidosis,…) will also be monitored. In summary, EMPA-TROPISM clinical trial will determine whether the SGLT2 inhibitor empagliflozin improves cardiac function and heart failure parameters in non-diabetic HF patients (EMPA-TROPISM [ATRU-4]: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic activity; NCT 03485222).

Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity?

Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the USA; it affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with substantial cardiovascular (CV) morbidity and mortality. T2DM is a pathological condition characterized by elevated levels of glucose and associated with high CV risk. Traditional hypoglycemic drugs have demonstrated their capability for effective and maintained management of high glucose levels, but they have not significantly impacted on the incidence of CV events. Recently, a new class of hypoglycemic agents, SGLT-2 receptor inhibitors, has been developed. The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk. The dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35 and 32% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively. These effects are even more important given the difficulties for treating concomitant HF in T2DM patients. These surprising results have been also corroborated by another agent of this class, canagliflozin, and the CANVAS trial. The magnitude of these somehow surprising cardiac benefits attained in the absence of major differences in glycemic, lipid, or blood pressure (BP) control has led to several groups to suggest that these benefits may be independent of its hypoglycemic activity and whether this new class could be considered a "cardiac" drug. The objective of this review has been to review the different hypotheses proposed to explain the cardiac benefits of this new class of antidiabetic drugs.

Pathophysiology of acute coronary syndrome.

Despite improvements in interventional and pharmacological therapy for atherosclerotic disease, it is still the leading cause of death in the developed world. Hence, there is a need for further development of more effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Recent research in the last decade has changed our view of acute coronary syndrome (ACS): from a mere lipid deposition to an inflammatory disease; from ACS exclusively due to plaque rupture to the novel definitions of plaque erosion or calcified nodule; from the notion of a superimposed thrombus with necessary lethal consequences to the concept of healed plaques and thrombus contributing to plaque progression. In the hope of improving our understanding of ACS, all these recently discovered concepts are reviewed in this article.

Uncovering the Role of Epicardial Adipose Tissue in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure. Obesity is a modifiable risk factor of HFpEF; however, body mass index provides limited information on visceral adiposity and patients with similar anthropometrics can present variable cardiovascular risk. Epicardial adipose tissue (EAT) is the closest fat deposit to the heart and has been proposed as a biomarker of visceral adiposity. EAT may be particularly important for cardiac function, because of its location (under the pericardium) and because it acts as a metabolically active endocrine organ (which can produce both beneficial and detrimental cytokines). In this paper, the authors review the role of EAT in normal and pathologic conditions and discuss the noninvasive imaging modalities that allow its identification. This review highlights EAT implications in HFpEF and discuss new therapies that act on EAT and might also exert beneficial effects on the cardiovascular system.

Antithrombotic and prohemorrhagic actions of different concentrations of apixaban in patients exposed to single and dual antiplatelet regimens.

We evaluated modifications in the hemostatic balance of different concentrations of apixaban (APIX) in 25 healthy donors and 53 patients treated with aspirin (ASA, n = 21), ASA and clopidogrel (ASA + CLOPI, n = 11), or ASA and ticagrelor (ASA + TICA, n = 21). Blood samples from participants were spiked ex vivo with apixaban 0 (APIX0), 40 (APIX40), and 160 ng/mL (APIX160). We assessed the effects of APIX on (1) clot formation, by ROTEM thromboelastometry; (2) thrombin generation primed by platelets; and (3) platelet and fibrin interactions with a thrombogenic surface, in a microfluidic model with circulating blood. APIX caused dose-related prolongations of clotting time with minimal impact on other ROTEM parameters. Thrombin generation was significantly inhibited by APIX160, with ASA + TICA actions showing the strongest inhibition (p < 0.01 vs APIX0). Microfluidic studies showed that APIX160 was more potent at suppressing platelet and fibrin interactions (p < 0.001 vs. APIX0). APIX40 demonstrated a consistent antithrombotic action but with a favorable protective effect on the structural quality of fibrin. APIX potentiated the antithrombotic effects of current antiplatelet regimens. APIX at 40 ng/mL, enhanced the antithrombotic action of single or dual antiplatelet regimens but was more conservative for hemostasis than the 160 ng/mL concentration.

A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial.

AIMS: Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM. METHODS AND RESULTS: Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used. CONCLUSION: In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel.

SGLT2i in heart failure: can their benefits be expanded across the entire spectrum of ejection fraction?

The publication of the EMPEROR-Preserved trial and data on the benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF)> 40% represent a significant step forward in the treatment of HF with preserved EF. Given these results, in February 2022 the US Food and Drug Administration approved the use of empaglifozin in adults with HF with reduced or preserved EF. However, more detailed analysis of the EMPEROR-Preserved trial led to doubts about the effect of empagliflozin in patients with an EF of> 60% this patient group is widely heterogeneous and, probably, a single phenotype cannot be considered in treatment goals or the clinical approach. Moreover, EF occurs on a continuum and classifications of HF according to arbitrary cut-points in EF do not appear consistent with recent evidence, which points to a gradual shift and considerable overlap in underlying mechanisms, phenotypes and treatment response over the spectrum of EF. Enhanced knowledge of pathophysiological mechanisms is essential to establish new therapeutic targets, interpret the results of clinical trials, and develop targeted and effective therapies.

Empagliflozin improves quality of life in nondiabetic HFrEF patients. Sub-analysis of the EMPATROPISM trial.

BACKGROUND AND AIMS: Initially considered as just anti-diabetic agents, SGLT2-i show remarkable cardiac and renal benefits independently of its hypoglycemic activity. METHODS: We used the Kansas City Cardiomyopathy Questionnaire (KCCQ), which has recently been qualified as a Clinical Outcome Assessment, in the EMPATROPISM trial. RESULTS: A significant mean improvement of 22 points with KCCQ was seen with Empagliflozin versus only 2 points in the Placebo. The proportion of patients experiencing clinically important changes in the Empagliflozin group was higher. Patients with the lowest starting KCCQ score saw significantly greater improvements. CONCLUSIONS: Empagliflozin benefits quality of life in the non-diabetic, ethnic minority represented, EMPATROPISM trial population.

Not only how much, but also how to, when measuring epicardial adipose tissue.

Epicardial Adipose Tissue (EAT) is drawing increasing attention. As a quantifiable, modifiable, and potentially new cardiovascular therapeutic target, its accurate measurement is particularly relevant. In Cardiac Magnetic Resonance (CMR) different methods can be used to assess EAT burden. We take advantage of CMR-studies of EMPATROPISM trial to assess EAT through three different methods, evaluate the effect of Empagliflozin and look for significant difference in the ability to detect changes in serial measurements. In some settings such as treatment-induced changes or patient follow-up, multi-slice method of EAT evaluation provides higher accuracy to detect significant differences, otherwise unnoticed by single-slice approaches.

Experimental models for the investigation of high-density lipoprotein-mediated cholesterol efflux.

Reduction of low-density lipoprotein cholesterol by statin therapy has only modestly decreased coronary heart disease (CHD)-associated mortality in developed countries, which has prompted the search for alternative therapeutic strategies for CHD. Epidemiologic and interventional studies have clearly established an inverse association between plasma levels of high-density lipoprotein (HDL) cholesterol and incidence of atherosclerosis. The atheroprotective benefits of HDL are not only dependent on HDL concentrations (quantity), but also on HDL function (quality). Therefore, several techniques have been recently developed to assess the different properties of HDL. Because reverse cholesterol transport (RCT) is considered a key player in the beneficial action of HDL, this review focuses on the different methods used to evaluate cholesterol efflux. Measuring the in vivo function of HDL could be of significant importance for both the clinical evaluation of an individual patient and to evaluate the effectiveness of different RCT-enhancing therapeutic approaches.

Leuko-platelet index predicts thrombotic events in patients with acute coronary syndrome.

PURPOSE: To evaluate the predictive value of a bedside index in hospitalized patients with acute coronary syndromes (ACS). METHODS: We studied the association of leuko-platelet index (LPI: platelet count * leukocyte count/108) with risk of mortality, shock, or heart failure (combined end point-CEP), and with the response to antiplatelet therapy, measured by light transmission aggregometry. RESULTS: In the derivation cohort we included 1100 patients with non STEM-ACS, GRACE score of 133 ± 52, Crusade score 24,3 ± 14, 66% male, 65 + 11 years. LPI was 17 (12-24). LPI was higher (19 (13-25)) in patients with MI than in patients with unstable angina (16 (12-22) in (p < 0.001)). A total of 115 patients (10.5%) had the CEP. CEP was associated to LPI (OR 1.04 (1.002-1.08), p = 0.03), age (OR 1.01 (0.97-1.05), p = 0.62) and GRACE>140 (OR 8.1 (2.2-29), p = 0.02). LPI (OR 1.04 (1.004-1.07) p = 0.03) and GRACE score (OR 1.02 (1.01-1.03) p < 0.01) were associated to cardiovascular mortality. We confirmed these results in the validation cohort #1 (686 patients, 61 + 11 years old, 47% nonST-ACS, 53% ST-ACS, 21% had CEP) and in validation cohort #2 (218 patients, 56.8% males, 73 + 7 years old, 79% nonST-ACS, GRACE score 136 + 30) and 8.3% with CEP. We used the cutoff points of LPI obtained in the derivation cohort (>24). CONCLUSIONS: LPI > 24 was associated to CEP (OR (1.7-5.2), p 0.01), independently of age (OR 1 (0.98-1.02), p = 0.8), and GRACE score (OR 1.01 (0.99-1.01), p 0.69), and It was associated to antiplatelet resistance (OR 1.03 (95% CI 1.00-1.06) p = 0.05).

Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study.

OBJECTIVES: The goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial fibrosis, and aortic stiffness in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: Several randomized clinical trials have established the benefits of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i) in HFrEF, independent of their hypoglycemic effects. The mechanisms of the benefits of SGLT2-i in HFrEF have not been well defined. METHODS: This study was a secondary analysis of patients enrolled in the EMPA-TROPISM [ATRU-4] (Are the cardiac benefits of Empagliflozin independent of its hypoglycemic activity?) clinical trial. It was a double-blind, placebo-controlled randomized clinical trial investigating the effect of empagliflozin in nondiabetic patients with HFrEF. Patients underwent cardiac magnetic resonance at baseline and after 6 months. Interstitial myocardial fibrosis was calculated by using T1 mapping (extracellular volume). Aortic stiffness was calculated by using pulsed wave velocity, and EAT was measured from the cine sequences. RESULTS: Empagliflozin is associated with significant reductions in EAT volume (-5.14 mL; 95% CI: -8.36 to -1.92) compared with placebo (-0.75 mL; 95% CI: -3.57 to 2.06; P < 0.05); this finding was paralleled by reductions in subcutaneous adipose tissue area (-5.33 cm2 [95% CI: -12.61 to 1.95] vs 9.13 cm2 [95% CI: -2.72 to 20.99]; P < 0.05). Empagliflozin-treated patients reported a reduction in extracellular volume (-1.25% [±0.56 95% CI] vs 0.24% [±0.57 95% CI]; (P < 0.01)]; specifically, empagliflozin reduced both matrix volume (-7.24 mL [95% CI: -11.59 to -2.91] vs 0.70 mL [95% CI: -0.89 to 2.29]; P < 0.001) and cardiomyocyte volume (-11.08 mL [95% CI: -19.62 to -2.55] vs 0.80 mL [95% CI: -1.96 to 3.55]; P < 0.05). Pulsed wave velocity was also significantly reduced in the empagliflozin group (-0.58 cm/s [95% CI: -0.92 to -0.25] vs 0.60 cm/s [95% CI: 0.14 to 1.06]; P < 0.01). Using proteomics, empagliflozin was associated with a significant reduction in inflammatory biomarkers. CONCLUSIONS: Empagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in nondiabetic patients with HFrEF. These results shed new light on the mechanisms of action of the benefits of SGLT2-i. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity [ATRU-4] [EMPA-TROPISM]; NCT03485222).

Thrombi of different pathologies: implications for diagnosis and treatment.

OPINION STATEMENT: Stroke is the second leading cause of cardiovascular mortality in the modern world, accounting for 80% of strokes of ischemic origin. There are two main etiologies of ischemic stroke: 70% to 80% are caused by carotid atherosclerotic plaque rupture and superimposed thrombus formation, whereas 30% are caused by systemic embolism of a cardiac thrombus (mainly in atrial fibrillation [AF] patients). Therefore, antithrombotic therapy is the cornerstone of stroke treatment. In AF patients, thrombotic risk should be assessed by means of the CHADS2 score. Patients with a score of 0 should be treated with aspirin; for those with a score of 1, oral anticoagulation (target international normalized ratio, 2-3) or aspirin is recommended. For patients with a CHADS2 score ≥2, oral anticoagulation with warfarin should be initiated (unless contraindicated). If warfarin is contraindicated, antithrombotic treatment should be prescribed (the combination of aspirin and clopidogrel seems to be superior to aspirin alone). For primary prevention in atherosclerotic patients, low-dose aspirin is useful only in women older than 45 years who are not at risk for intracranial hemorrhage and do not have gastrointestinal intolerance (a very small but significant effect). For secondary prevention in atherosclerotic patients, antithrombotic therapy should be administered. It is recommended that patients who do not require anticoagulation receive clopidogrel or a combination of aspirin and dipyridamole. Alternatively, aspirin alone or triflusal may be used. Within 4.5 h of onset of acute stroke, thrombolytic therapy (recombinant tissue plasminogen activator) must be injected urgently (unless contraindicated). Dabigatran is a new oral anticoagulant (competitive thrombin inhibitor) with a promising role in stroke prevention; at low doses, it is noninferior to warfarin for stroke prevention and is safer, whereas at high doses, it is superior to warfarin in stroke prevention with the same incidence of bleeding. Percutaneous left atrial appendage occluders recently were approved for systemic embolism prevention. The use of warfarin after implantation is still under discussion. Dronedarone, a new antiarrhythmic agent, has been shown to decrease cardiovascular mortality and stroke in patients with AF. Carotid endarterectomy surgery is indicated in symptomatic patients with stenosis greater than 70% and in selected patients with 50% to 70% stenosis. Currently, carotid endarterectomy surgery is superior to carotid angioplasty and stenting.

Are the antidiabetic SGLT2 inhibitors a cardiovascular treatment? / ¿Son los inhibidores del receptor SGLT2 fármacos antidiabéticos o cardiovasculares?

The sodium-glucose co-transporter 2 inhibitors (SGLT2i) were first conceived to treat type 2 diabetes due to their hypoglycaemic effect. However, due to an increasing number of studies, SGLT2i are changing the way we treat, and understand, diabetes, and cardiovascular risk, in general. The EMPA-REG OUTCOME clinical trial, in 2015, showed for the first time that empagliflozine - a glucose lowering agent - lowers the risk of death from cardiovascular causes and death from any cause. Also, this SGLT2i lowered hospital admission for heart failure and delayed renal function worsening. From then on, other clinical trials with SGLT2i such as CANVAS (canagliflozin) and DECLARE-TIMI-58 (dapagliflozin) confirmed these positive effects. With a proven and non-related glucose-lowering effect on heart failure, overall death, cardiovascular death, and renal function, SGLT2i stands out among the rest of anti-diabetic drugs. Since its role in treating patients with heart failure and type 2 diabetes has been undoubtedly established, new studies are paving the way for non-diabetic patients as well. A potential paradigm shift is being witnessed and, probably, the dawn of a new field, cardio-endocrinology, which involves new and far-reaching pharmacological agents.

Internalization of microparticles by platelets is partially mediated by toll-like receptor 4 and enhances platelet thrombogenicity.

BACKGROUND AND AIMS: Circulating platelet microparticles (PMP) are the most abundant in bloodstream, are highly procoagulant and contribute to cross-talk with inflammatory cells. The aim of the present study was to investigate the interactions of PMP with platelets and explore the involvement of toll-like receptor 4 (TLR-4). METHODS: PMP were separated by ultracentrifugation of expired platelet concentrates and added to: i) washed platelets, to confirm uptake, by flow cytometry and confocal and transmission electron microscopy, ii) platelet rich plasma (PRP), to assess changes in platelet function due to uptake by aggregometry in response to ADP; and iii) whole blood, to evaluate heterotypic aggregate (HA) formation by flow cytometry. Moreover, whole blood previously enriched with platelets with internalized PMP was used to explore modifications in thromboelastometry parameters (ROTEM). The inhibitory action of anti-TLR-4 was investigated. RESULTS: Confocal and ultrastructural microscopy studies revealed PMP internalization by platelets. Flow cytometry showed PMP-platelet association (p < 0.01 vs controls, at different PMP dilutions). PMP, at 1/20 dilution, increased HA (p < 0.05 vs controls), the percentage of maximal platelet aggregation to ADP (p < 0.05 vs controls), and accelerated clotting and clot formation times (p < 0.05 vs controls). Incubation of platelets with anti-TLR-4 prior to exposure to PMP reduced PMP-platelet association (p < 0.05 vs absence of the antibody), prevented HA formation, reduced maximal platelet aggregation and normalized ROTEM parameters. CONCLUSIONS: Platelets exhibit internalization ability towards their own PMP, a process that potentiates their thrombogenicity and is partially mediated by the innate immunity receptor TLR-4.

Genesis and dynamics of atherosclerotic lesions: implications for early detection.

Atherosclerosis is a diffuse pathological process characterized by the deposition of lipid and other blood-borne material within the arterial wall of almost all vascular territories. Cholesterol accumulation plays a central role in atherogenesis. It is the result of an imbalance between cholesterol influx and efflux. The disease progresses silently with focal clinical manifestation due to plaque rupture with superimposed thrombus: atherothrombosis. It has been shown that the atherosclerotic plaque composition rather than the degree of arterial stenosis can be the determinant of rupture. This has led to the search for new imaging techniques that can provide information about plaque composition. Ultrasound measurements of carotid and aortic wall thickness are an accurate 'noninvasive' technique that permits correlation with clinical events. Magnetic resonance imaging can evaluate in detail the arterial anatomy of almost all vascular territories. Multidetector computed tomography recently emerged for measuring luminal stenosis, coronary calcium, and even the extent of non-calcified coronary plaque volume. Next future is the molecular imaging based on the knowledge of molecular mechanisms involved in the genesis and progression of atherosclerotic lesions and the contrast agent able to identify different molecules and/or cells in the target zone.