Experimental (ex-vitro) study on the redox state of the vascular grafts

Background: It is known that statins improve clinical outcome of patients with atherosclerosis. However, the exact mechanism of the pleotropic effects of statins on vascular function remains unclear. In the present study we examined the direct effect of atorvastatin on the vascular oxidative stress.Methods: Saphenous vein and internal-mammary artrery vascular grafts were used to our experiments. These grafts were ex-vivo exposed to various atorvastatin concentrations in LDL-free environment. Superoxide production was measured by using lucigenin-enhanced luminometry The NADPH- dependent superoxide was examoned by adding NADPH. The effect of aorvastatin on ENOS coupling was also examined,using eNOS inhibitor, LNAME. Results: Statins signnificantly reduced total vascular superoxide production. Ex-vivo exposure of vascular grafts to atorvastatin reduced NADPH-dependent superoxide production, and improved eNOS coupling. These effects were reversed when mevalonate was added, ndicating that statins act by inhibiting mevalonate pathway in vascular wall. By using confocal microscopy and DHE we have also examined the local effect of atorvastatin on vascular wall.Conclusions: Statins reduce total superoxide production and NADPH-dependent superoxide production, by actin on the mevalonate pathway in the vascular wall. Moreover statins improve eNOS coupling, independently of their LD- lowering effects. These findings provide new insights into the mechanism regulating the beneficial vascular effects of statins in humans.Εισαγωγή: Είναι ευρέως αποδεκτό πως οι στατίνες βελτιώνουν τα κλινικά αποτελέσματα των ασθενών με αθηροσκλήρωση. Ωστόσο ασαφείς παραμένουν οι μηχανισμοί των πλειοτροπικών δράσεων των στατινών στην ενδοθηλιακή λειτουργία. Στη συγκεκριμένη μελέτη ερευνήσαμε την επίδραση της ατορβαστατίνης στους μηχανισμούς οξειδωτικού στρες στο αγγειακό τοίχωμα.Μέθοδοι: Τεμάχια φλεβικών και αρτηριακών μοσχευμάτων ασθενών που επρόκειτο να υποβληθούν σε επέμβαση αορτοστεφανιαίας παράκαμψης χρησιμοποιήθηκαν σε ex-vivo πειράματα. Tα μοσχεύματα εκτέθηκαν σε ατορβαστατίνη σε ex-vivo, ελέυθερες από LDL συνθήκες. H συνολική παραγωγή υπεροξειδικών ριζών μελετήθηκε με τη μέθοδο της λουμινομετρίας λουσιγενίνης. Παρουσία NADPH διερευνήθηκε η επίδραση των στατινών στην προερχόμενη από την NADPH οξειδάση παραγωγή υπεροξειδικών ριζών, ενώ με την προσθήκη του αναστολέα της eNOS, LNAME, προσδιορίστηκε η επίδραση των στατινών στη σύζευξη της eNOS. Τα πειράματα αυτά επαναλήφθηκαν παρουσία μεβαλονικού οξέος. Αποτελέσματα: Οι στατίνες ελάττωσαν σε στατιστικά σημαντικό βαθμό τη συνολική παραγωγή οξειδωτικών ριζών στο αγγειακό τοίχωμα και οδήγησαν σε ελαττωμένη παραγωγή υπεροξειδικών ριζών από την NADPH οξειδάση και βελτίωση της σύζευξης της eNOS. Η προσθήκη μεβαλονικού οξέος οδήγησε σε αναστροφή των αποτελεσμάτων αυτών. Συμπεράσματα: Οι στατίνες δρώντας στο μονοπάτι του μεβαλονικού οξέος στο αγγειακό τοίχωμα, ελαττώνουν τη συνολική παραγωγή και την NADPH-εξαρτώμενη παραγωγή υπεροξειδικών ριζών, ενώ βελτιώνουν τη σύζευξη της eNOS, ανεξάρτητα από τις αντιλιπιδαιμικές τους ιδιότητες. Τα ευρήματα αυτά δίνουν νέες πληροφορίες αναφορικά με τη δράση των στατινών στη βελτίωση της ενδοθηλιακής λειτουργίας

The Impact of Antiplatelet Treatment on Endothelial Function

The vascular endothelium comprises a continuous single cell layer of endothelial cells which line the entire cardiovascular system. Impaired endothelial function underlies the pathogenesis and contributes to the progression of atherosclerosis. Oxidative stress, vasoconstriction, inflammation, proliferation and thrombosis occur in dysfunctional endothelium while the latter, is primarily mediated by platelet activation and adherence to vascular wall. Despite the primary action of antiplatelet agents including aspirin, P2Y12 ADP receptor antagonists and glycoprotein IIb/IIIa inhibitors, a growing body of literature suggests that an important mechanism of their action involves complex modulation of endothelial function via platelet-endothelial interactions, modification of the inflammatory cytokine cascade and nitric oxide mediated effects. These agents represent the mainstay in pharmacological treatment of all aspects of cardiovascular disease both in primary and secondary prevention. However beyond these properties, it is important to note that pharmacological modification of endothelial dysfunction has been postulated as a therapeutic target for reduction of cardiovascular events

Relationship Between the Pharmacokinetics of Levosimendan and Its Effects on Cardiovascular System

Levosimendan, a Ca2+ sensitizer, has emerged as an alternative option of pharmacologic inotropic support in patients with decompensated heart failure. In contrast to classic inotropes, rather than interfering with intracellular Ca2+ levels in myocytes, levosimendan improves cardiac performance via Ca2+ sensitization and K+ channel-mediated peripheral vasodilatation. A two compartment pharmacokinetic model with zero-order input and first-order elimination has been found to describe best the pharmacokinetics of levosimendan. Although oral levosimendan has high bioavailability (approximate to 85%), in clinical practice it has been hitherto administered intravenously. Levosimendan has total clearance 175-250 mL/h/kg and most importantly a short half-life (about 1.5 hours). Therefore, this drug has a special pharmacokinetic interest: It is one of the few drugs used in cardiovascular medicine, whose prolonged action is not due to the drug itself but it is mainly due to its active metabolite OR-1896 (similar to 80 hours half life). Other metabolites with possible pharmacologic effect are N-conjugated OR-1855 (M7), N-hydroxylated OR-1855 (M8), N-hydroxylated OR-1896 (M10), O-glucuronide OR-1896 (M9) and O-sulfate (M11) of N-hydroxylated OR-1896. Initial reports on levosimendan’s use in severe heart failure were positive and levosimendan has already been routinely used for the treatment of patients with decompensated heart failure, while it has been included to the European Society of Cardiology guidelines for the treatment of acute heart failure (class of recommendation IIb, level of evidence B). However, recent clinical trials have failed to demonstrate a clear benefit of levosimendan on survival, compared to other classic inotropic agents in patients requiring inotropic support. In this review article we provide a pharmacokinetic approach for the use of levosimendan in cardiovascular system by discussing its metabolism and mainly the pharmacology of its active metabolites in humans

The Role of Cardiovascular Magnetic Resonance Imaging in the Assessment of Myocardial Fibrosis in Young and Veteran Athletes: Insights From a Meta-Analysis

Background: Cardiac magnetic resonance (CMR) combined with late gadolinium enhancement (LGE) has revealed a non-negligible increased incidence of myocardial fibrosis (MF) in athletes compared to healthy sedentary controls.Objective: The aim of this systematic research and meta-analysis is to investigate and present our perspective regarding CMR indices in athletes compared to sedentary controls, including T1 values, myocardial extracellular volume (ECV) and positive LGE indicative of non-specific fibrosis, also to discuss the differences between young and veteran athletes.Methods: The protocol included searching, up to October 2021, of MEDLINE, EMBASE, SPORTDiscus, Web of Science and Cochrane databases for original studies assessing fibrosis via CMR in athletes. A mean age of 40 years differentiated studies’ athletic populations to veteran and young.Results: The research yielded 14 studies including in total 1,312 individuals. There was a statistically significant difference in LGE fibrosis between the 118/759 athletes and 16/553 controls (Z = 5.2, P < 0.001, I-2 = 0%, P-I = 0.45). Notably, LGE fibrosis differed significantly between 546 (14.6%) veteran and 140 (25.7%) young athletes (P = 0.002). At 1.5T, T1 values differed between 117 athletes and 48 controls (P < 0.0001). A statistically significant difference was also shown at 3T (110 athletes vs. 41 controls, P = 0.0004), as well as when pooling both 1.5T and 3T populations (P < 0.00001). Mean ECV showed no statistically significant difference between these groups.Conclusions: Based on currently available data, we reported that overall LGE based non-specific fibrosis and T1 values differ between athletes and sedentary controls, in contrast to ECV values. Age of athletes seems to have impact on the incidence of MF. Future prospective studies should focus on the investigation of the underlying pathophysiological mechanisms

Catheter Ablation for Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis

Background: Catheter ablation (CA) for atrial fibrillation (AF) has been proposed as a means of improving outcomes among patients with heart failure and reduced ejection fraction (HFrEF) who are otherwise receiving appropriate treatment. Unlike HFrEF, treatment options are more limited in patients with preserved ejection fraction (HFpEF) and the data pertaining to the management of AF in these patients are controversial. The aim of this systematic review and meta-analysis was to investigate the effects of CA on outcomes of patients with AF and HFpEF, such as functional status, post-procedural complications, hospitalization, morbidity and mortality, based on data from observational studies. Methods: We systematically searched the electronic databases MEDLINE, PUBMED, EMBASE and the Cochrane Library for Central Register of Clinical Trials until May 2020. Results: Overall, the pooling of our data showed that sinus rhythm was achieved long-term in 58.0% (95% CI 0.44–0.71). Long-term AF recurrence was noticed in 22.3% of patients. Admission for HF occurred in 6.2% (95% CI 0.04–0.09) whilst all-cause mortality was identified in 6.3% (95% CI 0.02–0.13). Conclusion: This meta-analysis is the first to focus on determining the benefits of a rhythm control strategy for patients with AF and HFpEF using CA, suggesting it may be worthwhile to investigate the effects of a CA rhythm control strategy as the default treatment of AF in HFpEF patients in randomized trials