Malaria Vaccines: From the Past towards the mRNA Vaccine Era.

Plasmodium spp. is the etiological agent of malaria, a life-threatening parasitic disease transmitted by infected mosquitoes. Malaria remains a major global health challenge, particularly in endemic regions. Over the years, various vaccine candidates targeting different stages of Plasmodium parasite life-cycle have been explored, including subunit vaccines, vectored vaccines, and whole organism vaccines with Mosquirix, a vaccine based on a recombinant protein, as the only currently approved vaccine for Plasmodium falciparum malaria. Despite the aforementioned notable progress, challenges such as antigenic diversity, limited efficacy, resistant parasites escaping protective immunity and the need for multiple doses have hindered the development of a highly efficacious malaria vaccine. The recent success of mRNA-based vaccines against SARS-CoV-2 has sparked renewed interest in mRNA vaccine platforms. The unique mRNA vaccine features, including their potential for rapid development, scalability, and flexibility in antigen design, make them a promising avenue for malaria vaccine development. This review provides an overview of the malaria vaccines' evolution from the past towards the mRNA vaccine era and highlights their advantages in overcoming the limitations of previous malaria vaccine candidates.

Association of hydroxytyrosol enriched olive oil with vascular function in chronic coronary disease.

BACKGROUND: Hydroxytyrosol reduces low-density lipoprotein oxidation, contributing to prevention of atherosclerosis progression. METHODS: In a prospective, crossover, double-blind, placebo-controlled trial, 30 chronic coronary artery syndrome (CCAS) patients were randomized to 4 capsules/day, containing 412.5 mg olive oil with 2.5 mg hydroxytyrosol (OOHT) each one or placebo for 1 month and then were crossed over to the alternate treatment (placebo or OOHT). We measured (a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b) flow-mediated dilation (FMD), (c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography, (d) pulse wave velocity (PWV), and (e) oxidative stress, inflammatory biomarkers and blood lipids at baseline and after treatment. RESULTS: Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.8 ± .3 vs. 1.7 ± .4 µm, p = .040, 3.7 ± 2.1 vs. 6.5% ± 2.3%, p < .001, 2.3 ± .4 vs. 2.5 ± .4, p = .030 and 11.1 ± 1.8 vs. 11.8 ± 2.3 m/s, p = .002) while there was no effect after placebo (p = NS). No effect of OOHT treatment was observed on blood pressure. There was a parallel improvement of E' of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p < .05) but not after placebo. Compared to baseline, treatment with OOHT reduced malondialdehyde, a marker of lipid peroxidation, oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p < .05) in contrast to placebo. CONCLUSIONS: Hydroxytyrosol-enriched olive oil may have beneficial effects on endothelial, arterial and LV diastolic function likely by reducing oxidative and inflammatory burden in CCAS, though further studies are needed to confirm this mechanism.

Platelet-Mediated Transfer of Cardioprotection by Remote Ischemic Conditioning and Its Abrogation by Aspirin But Not by Ticagrelor.

PURPOSE: The role of platelets during myocardial ischemia/reperfusion (I/R) is ambivalent. They contribute to injury but also to cardioprotection. Repeated blood flow restriction and reperfusion in a tissue/organ remote from the heart (remote ischemic conditioning, RIC) reduce myocardial I/R injury and attenuate platelet activation. Whether or not platelets mediate RIC's cardioprotective signal is currently unclear. METHODS AND RESULTS: Venous blood from healthy volunteers (without or with pretreatment of 500/1000 mg aspirin or 180 mg ticagrelor orally, 2-3 h before the study, n = 18 each) was collected before and after RIC (3 × 5 min blood pressure cuff inflation at 200 mmHg on the left upper arm/5 min deflation). Washed platelets were isolated. Platelet-poor plasma was used to prepare plasma-dialysates. Platelets (25 × 103/µL) or plasma-dialysates (1:10) prepared before and after RIC from untreated versus aspirin- or ticagrelor-pretreated volunteers, respectively, were infused into isolated buffer-perfused rat hearts. Hearts were subjected to global 30 min/120 min I/R. Infarct size was stained. Infarct size was less with infusion of platelets/plasma-dialysate after RIC (18 ± 7%/23 ± 9% of ventricular mass) than with platelets/plasma-dialysate before RIC (34 ± 7%/33 ± 8%). Aspirin pretreatment abrogated the transfer of RIC's cardioprotection by platelets (after/before RIC, 34 ± 7%/33 ± 7%) but only attenuated that by plasma-dialysate (after/before RIC, 26 ± 8%/32 ± 5%). Ticagrelor pretreatment induced an in vivo formation of cardioprotective factor(s) per se (platelets/plasma-dialysate before RIC, 26 ± 7%/26 ± 7%) but did not impact on RIC's cardioprotection by platelets/plasma-dialysate (20 ± 7%/21 ± 5%). CONCLUSION: Platelets serve as carriers for RIC's cardioprotective signal through an aspirin-sensitive and thus cyclooxygenase-dependent mechanism. The P2Y12 inhibitor ticagrelor per se induces a humoral cardioprotective signal.

Herpes Zoster Reactivation After COVID-19 Vaccine with Focus on Postherpetic Neuralgia Prevention: A Case Series.

Introduction: Herpes zoster (HZ), also known as shingles, is caused by the reactivation of the varicella-zoster virus (VZV). There have been several reports of HZ associated with COVID-19 vaccination, and the outcomes have varied. Case Presentation: In this report, we present 4 cases of patients who experienced HZ reactivation after receiving a COVID-19 vaccine. These individuals sought treatment at a pain management center due to postherpetic neuralgia (PHN). While HZ itself can be treated, post-herpetic neuralgia can persist for years, significantly impacting the patients' quality of life. Therefore, early recognition of this adverse effect is crucial, and patients should receive specialized analgesic support promptly to prevent the development of chronic pain.

Association of Hypoglycemia with Biomarkers of Oxidative Stress and Antioxidants: An Observational Study.

Hypoglycemia has been associated with complications from the vasculature. The contributing effects of oxidative stress (OS) on these actions have not been sufficiently studied, especially in daily, routine clinical practice. We examined the association of hypoglycemia encountered in daily clinical practice with biomarkers of OS and endogenous antioxidant activity in persons with diabetes [type 1 (T1D) or type 2 (T2D)], as well as individuals without diabetes, with a history of hypoglycemia. Several biomarkers of OS (MDA, ADMA, ox-LDL, 3-NT, protein carbonyls, 4-HNE, TBARS) and antioxidant capacity (TAC, superoxide scavenging capacity, hydroxyl radical scavenging capacity, reducing power, ABTS) were measured. Blood was drawn at the time of hypoglycemia detection and under euglycemic conditions on a different day. A total of 31 participants (mean age [±SD] 52.2 ± 21.1 years, 45.2% males) were included in the study. There were 14 (45.2%) persons with T2D, 12 (38.7%) with T1D, and 5 (16.1%) without diabetes. We found no differences in the examined biomarkers. Only TBARS, a biomarker of lipid peroxidation, showed lower values during hypoglycemia (p = 0.005). This finding needs confirmation in more extensive studies, given that MDA, another biomarker of lipid peroxidation, was not affected. Our study suggests that hypoglycemia encountered in daily clinical practice does not affect OS.

Endothelial Dysfunction Is Associated with Decreased Nitric Oxide Bioavailability in Dysglycaemic Subjects and First-Degree Relatives of Type 2 Diabetic Patients.

Oxidative stress plays an important role in the pathogenesis of diabetes. We investigated oxidative stress and nitrite/nitrate concentrations at baseline and during postprandial hyperglycaemia in 40 first-degree relatives (FDRs) of diabetic patients with normal oral glucose tolerance test (OGTT) results, 40 subjects with abnormal OGTT results (dysglycaemic) and 20 subjects with normal OGTT results (normoglycaemic). Malondialdehyde (MDA), protein carbonyls (PCs), nitrite/nitrate plasma levels, the perfused boundary region (PBR­Glycocheck) of the sublingual microvessels, a marker of glycocalyx integrity, coronary flow reserve (CFR) and left ventricular global longitudinal strain (GLS) were assessed at 0 and 120 min of the OGTT. Insulin sensitivity was evaluated using Matsuda and the insulin sensitivity index (ISI). In all subjects, there were no significant changes in MDA or PC after the OGTT (p > 0.05). Compared with normoglycaemic subjects, FDRs and dysglycaemic subjects had significantly decreased nitrite/nitrate levels (−3% vs. −24% vs. −30%, respectively), an increased PBR and reduced CFR and GLS at 120 min (p < 0.05). The percent reduction in nitrite/nitrate was associated with abnormal Matsuda and ISI results, reversely related with the percent increase in PBR (r = −0.60) and positively related with the percent decrease in CFR (r = 0.39) and GLS (r = 0.48) (p < 0.05). Insulin resistance is associated with reduced nitric oxide bioavailability and coronary and myocardial dysfunction in FDRs and dysglycaemic subjects.

Climate Changes Exacerbate the Spread of Ixodes ricinus and the Occurrence of Lyme Borreliosis and Tick-Borne Encephalitis in Europe-How Climate Models Are Used as a Risk Assessment Approach for Tick-Borne Diseases.

Climate change has influenced the transmission of a wide range of vector-borne diseases in Europe, which is a pressing public health challenge for the coming decades. Numerous theories have been developed in order to explain how tick-borne diseases are associated with climate change. These theories include higher proliferation rates, extended transmission season, changes in ecological balances, and climate-related migration of vectors, reservoir hosts, or human populations. Changes of the epidemiological pattern have potentially catastrophic consequences, resulting in increasing prevalence of tick-borne diseases. Thus, investigation of the relationship between climate change and tick-borne diseases is critical. In this regard, climate models that predict the ticks' geographical distribution changes can be used as a predicting tool. The aim of this review is to provide the current evidence regarding the contribution of the climatic changes to Lyme borreliosis (LB) disease and tick-borne encephalitis (TBE) and to present how computational models will advance our understanding of the relationship between climate change and tick-borne diseases in Europe.

Novel Evidence-Based Combination of Plant Extracts with Multitarget Mechanisms of Action for the Elimination of Hot Flashes during Menopause.

Hot flashes are considered the most bothersome complaint during menopause. Although hormone therapy is an effective option to relieve hot flashes, it has been associated with significant side effects. The aim of our study is to suggest a novel combination of different plant extracts with distinct mechanisms of action against hot flashes. We selected the rhizome of Glycyrrhiza glabra L. (Fabaceae), the rhizome of Actaea racemosa L. (Ranunculaceae), the aerial parts of Hypericum perforatum L. (Hypericaceae) to produce extracts rich in bioactive phytochemicals and the seed oil of Oenothera biennis L. (Onagraceae). We investigated their estrogenic and antioxidant potential and their inhibitory effect against prostaglandin D2 receptor 1 (DP1) as a novel mechanistic pathway for vasodilation in hot flashes, alone or in combination. The phytochemical footprint of the extracts was analyzed using HPLC-PDA and UPLC-HRMS. We observed that the tested extracts possess different mechanisms of action. A. racemosa exerts a beneficial activation of the estrogen receptor, H. perforatum possesses the highest antioxidant capacity and the seed oil of O. biennis inhibits the DP1 receptor. The triple combination in the optimal doses pertains to efficacy against all three mechanisms of action, serves as a multitarget plant-based therapy and could serve as a novel strategy for the alleviation of hot flashes in postmenopausal women.

Effects of a 12-Month Treatment with Glucagon-like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter-2 Inhibitors, and Their Combination on Oxidant and Antioxidant Biomarkers in Patients with Type 2 Diabetes.

Imbalance between oxidative stress burden and antioxidant capacity is implicated in the course of atherosclerosis among type 2 diabetic patients. We addressed the effects of insulin, glucagon-like peptide-1 receptor agonists (GLP1-RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on levels of oxidant and antioxidant biomarkers. We recruited a total of 160 type 2 diabetics, who received insulin (n = 40), liraglutide (n = 40), empagliflozin (n = 40), or their combination (GLP-1RA+SGLT-2i) (n = 40). We measured at baseline, at 4 and at 12 months of treatment: (a) Thiobarbituric Acid Reactive Substances (TBARS), (b) Malondialdehyde (MDA), (c) Reducing Power (RP), (d) 2,2¢-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) radical (ABTS) and (e) Total Antioxidant Capacity TAC). Dual treatment resulted in significant improvement of TBARS, MDA, and ABTS at four months compared with the other groups (p < 0.05 for all comparisons). At twelve months, all participants improved TBARS, MDA, and ABTS (p < 0.05). At 12 months, GLP1-RA and GLP-1RA+SGLT2-i provided a greater reduction of TBARS (-8.76% and -9.83%) compared with insulin or SGLT2i (-0.5% and 3.22%), (p < 0.05). GLP1-RA and GLP-1RA+SGLT-2i showed a greater reduction of MDA (-30.15% and -31.44%) compared with insulin or SGLT2i (4.72% and -3.74%), (p < 0.05). SGLT2i and GLP-1RA+SGLT2-i showed increase of ABTS (12.87% and 14.13%) compared with insulin or GLP1-RA (2.44% and -3.44%), (p < 0.05). Only combined treatment resulted in increase of TAC compared with the other groups after 12 months of treatment (p < 0.05).12-month treatment with GLP1-RA and SGLT2i resulted in reduction of biomarkers responsible for oxidative modifications and increase of antioxidant biomarker, respectively. The combination treatment was superior and additive to each separate agent and also the beneficial effects appeared earlier.

Association of COVID-19 with impaired endothelial glycocalyx, vascular function and myocardial deformation 4 months after infection.

AIMS: SARS-CoV-2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers 4 months after COVID-19 infection. METHODS AND RESULTS: In a case-control prospective study, we included 70 patients 4 months after COVID-19 infection, 70 age- and sex-matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow-mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV), (v) global left and right ventricular longitudinal strain (GLS), and (vi) malondialdehyde (MDA), an oxidative stress marker, thrombomodulin and von Willebrand factor as endothelial biomarkers. COVID-19 patients had similar CFR and FMD as hypertensives (2.48 ± 0.41 vs. 2.58 ± 0.88, P = 0.562, and 5.86 ± 2.82% vs. 5.80 ± 2.07%, P = 0.872, respectively) but lower values than controls (3.42 ± 0.65, P = 0.0135, and 9.06 ± 2.11%, P = 0.002, respectively). Compared to controls, both COVID-19 and hypertensives had greater PBR5-25 (2.07 ± 0.15 µm and 2.07 ± 0.26 µm, P = 0.8 vs. 1.89 ± 0.17 µm, P = 0.001), higher PWV (carotid-femoral PWV 12.09 ± 2.50 vs. 11.92 ± 2.94, P = 0.7 vs. 10.04 ± 1.80 m/s, P = 0.036) and impaired left and right ventricular GLS (-19.50 ± 2.56% vs. -19.23 ± 2.67%, P = 0.864 vs. -21.98 ± 1.51%, P = 0.020 and -16.99 ± 3.17% vs. -18.63 ± 3.20%, P = 0.002 vs. -20.51 ± 2.28%, P < 0.001). MDA and thrombomodulin were higher in COVID-19 patients than both hypertensives and controls (10.67 ± 0.32 vs 1.76 ± 0.03, P = 0.003 vs. 1.01 ± 0.05 nmol/L, P = 0.001 and 3716.63 ± 188.36 vs. 3114.46 ± 179.18 pg/mL, P = 0.017 vs. 2590.02 ± 156.51 pg/mL, P < 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress and endothelial dysfunction markers. CONCLUSIONS: SARS-CoV-2 may cause endothelial and vascular dysfunction linked to impaired cardiac performance 4 months after infection.

Effects of Anti-Inflammatory Treatment and Surgical Intervention on Endothelial Glycocalyx, Peripheral and Coronary Microcirculatory Function and Myocardial Deformation in Inflammatory Bowel Disease Patients: A Two-Arms Two-Stage Clinical Trial.

Sixty inflammatory bowel disease (IBD) patients (45 Crohn disease and 15 ulcerative colitis, 40 ± 13 years, 53% male) were examined at baseline and 4 months after intervention (surgical (35 patients) or anti-TNFa treatment (25 patients)). IBD severity, using Mayo score, Harvey-Bradshaw Index (HBI) and biomarkers, was correlated with cardiovascular markers. At baseline, the disease severity, the white blood cells (WBC) values and the reducing power (RP) were significantly correlated with the aortic pulse wave velocity (PWV) (r = 0.4, r = 0.44 and r = 0.48, p < 0.05) and the lateral mitral E' velocity (r = 0.35, p < 0.05 and r = 0.3, p < 0.05). Four months after intervention, there was a reduction of WBC (1962.8/mm3 ± 0.425/mm3, p < 0.001), C-reactive protein (CRP) (8.1 mg/L ± 1.7 mg/L, p < 0.001), malondialdehyde (MDA) (0.81 nmol/mg ± 0.37, p < 0.05) and glycocalyx perfused boundary region (PBR 5-25) (0.24 µm ± 0.05 µm, p < 0.01). Moreover, the brachial flow mediated dilatation (FMD), the coronary flow reserve (CFR) and the left ventricle global longitudinal strain (LV GLS) were significantly improved for both groups (4.5% ± 0.9%, 0.55 ± 0.08, 1.4% ± 0.35%, p < 0.01), while a more significant improvement of PWV/GLS was noticed in the anti-TNFa group. IBD severity is associated with vascular endothelial, cardiac diastolic, and coronary microcirculatory dysfunction. The systemic inflammatory inhibition and the local surgical intervention lead to significant improvement in endothelial function, coronary microcirculation and myocardial deformation.

Differential effects of heat-not-burn and conventional cigarettes on coronary flow, myocardial and vascular function.

We compared the effects of Heat-not-Burn cigarette (HNBC) to those of tobacco cigarette (Tcig), on myocardial, coronary and arterial function as well as on oxidative stress and platelet activation in 75 smokers. In the acute study, 50 smokers were randomised into smoking a single Tcig or a HNBC and after 60 min were crossed-over to the alternate smoking. For chronic phase, 50 smokers were switched to HNBC and were compared with an external group of 25 Tcig smokers before and after 1 month. Exhaled carbon monoxide (CO), pulse wave velocity (PWV), malondialdehyde (MDA) and thromboxane B2 (TxB2) were assessed in the acute and chronic study. Global longitudinal strain (GLS), myocardial work index (GWI), wasted myocardial work (GWW), coronary flow reserve (CFR), total arterial compliance (TAC) and flow-mediated dilation (FMD) were assessed in the chronic study. Acute HNBC smoking caused a smaller increase of PWV than Tcig (change 1.1 vs 0.54 m/s, p < 0.05) without change in CO and biomarkers in contrast to Tcig. Compared to Tcig, switching to HNBC for 1-month improved CO, FMD, CFR, TAC, GLS, GWW, MDA, TxB2 (differences 10.42 ppm, 4.3%, 0.98, 1.8 mL/mmHg, 2.35%, 19.72 mmHg%, 0.38 nmol/L and 45 pg/mL respectively, p < 0.05). HNBCs exert a less detrimental effect on vascular and cardiac function than tobacco cigarettes.Trial registration Registered on https://clinicaltrials.gov/ (NCT03452124, 02/03/2018).

Acute administration of the olive constituent, oleuropein, combined with ischemic postconditioning increases myocardial protection by modulating oxidative defense.

Oleuropein, one of the main polyphenolic constituents of olive, is cardioprotective against ischemia reperfusion injury (IRI). We aimed to assess the cardioprotection afforded by acute administration of oleuropein and to evaluate the underlying mechanism. Importantly, since antioxidant therapies have yielded inconclusive results in attenuating IRI-induced damage on top of conditioning strategies, we investigated whether oleuropein could enhance or imbed the cardioprotective manifestation of ischemic postconditioning (PostC). Oleuropein, given during ischemia as a single intravenous bolus dose reduced the infarct size compared to the control group both in rabbits and mice subjected to myocardial IRI. None of the inhibitors of the cardioprotective pathways, l-NAME, wortmannin and AG490, influence its infarct size limiting effects. Combined oleuropein and PostC cause further limitation of infarct size in comparison with PostC alone in both animal models. Oleuropein did not inhibit the calcium induced mitochondrial permeability transition pore opening in isolated mitochondria and did not increase cGMP production. To provide further insights to the different cardioprotective mechanism of oleuropein, we sought to characterize its anti-inflammatory potential in vivo. Oleuropein, PostC and their combination reduce inflammatory monocytes infiltration into the heart and the circulating monocyte cell population. Oleuropein's mechanism of action involves a direct protective effect on cardiomyocytes since it significantly increased their viability following simulated IRI as compared to non-treated cells. Οleuropein confers additive cardioprotection on top of PostC, via increasing the expression of the transcription factor Nrf-2 and its downstream targets in vivo. In conclusion, acute oleuropein administration during ischemia in combination with PostC provides robust and synergistic cardioprotection in experimental models of IRI by inducing antioxidant defense genes through Nrf-2 axis and independently of the classic cardioprotective signaling pathways (RISK, cGMP/PKG, SAFE).

Chronic Empagliflozin Treatment Reduces Myocardial Infarct Size in Nondiabetic Mice Through STAT-3-Mediated Protection on Microvascular Endothelial Cells and Reduction of Oxidative Stress.

Aims: Empagliflozin (EMPA) demonstrates cardioprotective effects on diabetic myocardium but its infarct-sparing effects in normoglycemia remain unspecified. We investigated the acute and chronic effect of EMPA on infarct size after ischemia-reperfusion (I/R) injury and the mechanisms of cardioprotection in nondiabetic mice. Results: Chronic oral administration of EMPA (6 weeks) reduced myocardial infarct size after 30 min/2 h I/R (26.5% ± 3.9% vs 45.8% ± 3.3% in the control group, p < 0.01). Body weight, blood pressure, glucose levels, and cardiac function remained unchanged between groups. Acute administration of EMPA 24 or 4 h before I/R did not affect infarct size. Chronic EMPA treatment led to a significant reduction of oxidative stress biomarkers. STAT-3 (signal transducer and activator of transcription 3) was activated by Y(705) phosphorylation at the 10th minute of R, but it remained unchanged at 2 h of R and in the acute administration protocols. Proteomic analysis was employed to investigate signaling intermediates and revealed that chronic EMPA treatment regulates several pathways at reperfusion, including oxidative stress and integrin-related proteins that were further evaluated. Superoxide dismutase and vascular endothelial growth factor were increased throughout reperfusion. EMPA pretreatment (24 h) increased the viability of human microvascular endothelial cells in normoxia and on 3 h hypoxia/1 h reoxygenation and reduced reactive oxygen species production. In EMPA-treated murine hearts, CD31-/VEGFR2-positive endothelial cells and the pSTAT-3(Y705) signal derived from endothelial cells were boosted at early reperfusion. Innovation: Chronic EMPA administration reduces infarct size in healthy mice via the STAT-3 pathway and increases the survival of endothelial cells. Conclusion: Chronic but not acute administration of EMPA reduces infarct size through STAT-3 activation independently of diabetes mellitus.

PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation.

Extensive evidence from epidemiologic, genetic, and clinical intervention studies has indisputably shown that elevated low-density lipoprotein cholesterol (LDL-C) concentrations play a central role in the pathophysiology of atherosclerotic cardiovascular disease. Apart from LDL-C, also triglycerides independently modulate cardiovascular risk. Reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma LDL-C, but it is also associated with a reduction in triglyceride levels potentially through modulation of the expression of free fatty acid transporters. Preclinical data indicate that PCSK9 is up-regulated in the ischaemic heart and decreasing PCSK9 expression impacts on infarct size, post infarct inflammation and remodeling as well as cardiac dysfunction following ischaemia/reperfusion. Clinical data support that notion in that PCSK9 inhibition is associated with reductions in the incidence of myocardial infarction, stroke, and coronary revascularization and an improvement of endothelial function in subjects with increased cardiovascular risk. The aim of the current review is to summarize the current knowledge on the importance of free fatty acid metabolism on myocardial ischaemia/reperfusion injury and to provide an update on recent evidence on the role of hyperlipidemia and PCSK9 in myocardial infarction and cardioprotection.

The incidence of recurrent cardiovascular events among acute coronary syndrome patients treated with generic or original clopidogrel in relation to their sociodemographic and clinical characteristics. The Aegean study.

INTRODUCTION: The use of generic drugs is continuously growing; however, there are limited epidemiological data regarding the therapeutic equivalence of each original drug formulation with its generic counterparts. We evaluated the 12-month composite endpoint of recurrent acute myocardial infarction, ischaemic stroke, cardiac deaths, or hospitalisation due to a major bleeding in acute coronary syndrome (ACS) patients treated with original clopidogrel or a generic clopidogrel formulation, in relation to sociodemographic and clinical characteristics. MATERIAL AND METHODS: Consecutive Greek ACS patients (n = 1194) hospitalised in the Aegean islands and the Attica region were enrolled. Clopidogrel treatment was recorded either as original clopidogrel hydrogen sulphate (Plavix®/Iscover®) or as a generic clopidogrel besylate formulation (Clovelen®). The composite endpoint was recorded at 12-month follow-up. RESULTS: The 12-month composite endpoint was 3.9% (4.6% in the Aegean islands and 3.5% in the Attica area, p > 0.05). The respective incidence in men was 4.0% and in women 3.8% (p > 0.05). Overall, generic and original clopidogrel use was 87% and 13% of patients, respectively. No significant differences were observed between original and generic clopidogrel use and 12-month composite endpoint incidence. Subgroup analysis with gender, region of residence, and clinical and lifestyle factors as strata did not reveal any significant outcomes. Haemorrhage incidence did not exceed 1% in the total sample. CONCLUSIONS: The use of a generic clopidogrel besylate formulation was quite high in both urban and insular areas of Greece and had similar efficacy and safety profile with the original clopidogrel salt, supporting the routine use of this low-cost generic clopidogrel in the management of cardiovascular disease patients.

Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19.

We investigated the effects of tocilizumab on endothelial glycocalyx, a determinant of vascular permeability, and myocardial function in rheumatoid arthritis (RA). Eighty RA patients were randomized to tocilizumab (n = 40) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and glucocorticoids (GC) (n = 40) for 3 months. Forty healthy subjects with similar age and sex served as controls. We measured: (a)perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b)pulse wave velocity (PWV), (c)global LV longitudinal strain (GLS), (d)global work index (GWI) using speckle tracking echocardiography and e)C-reactive protein (CRP), malondialdehyde (MDA) and protein carbonyls (PCs) as oxidative stress markers at baseline and post-treatment. Compared to controls, RA patients had impaired glycocalyx and myocardial deformation markers (P < 0.05). Compared with baseline, tocilizumab reduced PBR(2.14 ± 0.2 versus 1.97 ± 0.2 µm; P < 0.05) while no significant differences were observed post-csDMARDs + GC(P > 0.05). Compared with csDMARDs + GC, tocilizumab achieved a greater increase of GLS, GWI and reduction of MDA, PCs and CRP(P < 0.05). The percent improvement of glycocalyx thickness (PBR) was associated with the percent decrease of PWV, MDA, PCs and the percent improvement of GLS and GWI(P < 0.05). Tocilizumab improves endothelial function leading to a greater increase of effective myocardial work than csDMARDs + GC through a profound reduction of inflammatory burden and oxidative stress. This mechanism may explain the effects of tocilizumab on COVID-19. CLINICAL TRIAL REGISTRATION: url: https://www.clinicaltrials.gov. Unique identifier: NCT03288584.

Comparison of the Level of Awareness about the Transmission of Echinococcosis and Toxocariasis between Pet Owners and Non-Pet Owners in Greece.

Ζoonotic parasitic diseases that can occur through animal contact pose risks to pets, their owners and to their bond. This study aims to assess the level of knowledge about zoonoses, specifically echinococcosis and toxocariasis, among cat/dog owners and non-pet owners in Greece. Multiple-choice questionnaires were designed to obtain data regarding the knowledge of pet and non-pet owners on echinococcosis and toxocariasis, including signs and symptoms of these zoonoses, ways of transmission and precautions that need to be taken into account in order to avoid it. A total of 185 questionnaires were retrieved and data was expressed as absolute (Ν) and relative frequencies (%). Associations between pet ownership, residence and outcome variables were evaluated using the Fisher exact test and Chi-squared test, respectively. Multifactorial linear regression analysis was used to investigate the cross-sectional association between demographic characteristics and the awareness of helminthic zoonoses. All tests were two-sided and statistical significance was set at p < 0.05. Our study revealed a disturbing lack of awareness of echinococcosis and toxocariasis (mean zoonotic knowledge score 8.11 ± 3.18) independently of pet ownership. Surprisingly, in some cases the ignorance of pet owners exceeded that of non-pet owners. Given the progressive impact of toxocariasis in public health and the high prevalence of echinococcosis in the Mediterranean region, measures should be taken to inform people about zoonoses and eliminate their putative transmission.

Effects of electronic cigarette on platelet and vascular function after four months of use.

We examined the effects of electronic cigarette on platelet and vascular function after 4 months of use compared to tobacco smoking. Forty smokers without cardiovascular disease were randomized to smoke either conventional cigarettes or an electronic cigarette (nicotine concentration of 12 mg/ml). At baseline and after four months, we measured a) platelet function by Platelet Function Analyzer PFA-100 and Light Transmission Aggregometry, b) pulse wave velocity, c) plasma malondialdehyde levels as oxidative stress index and d) the exhaled CO level. After 4 months, continuation of conventional cigarette smoking further impaired platelet function compared to vaping as assessed by PFA (mean increase 27.1 vs 11.6 s, p for interaction = 0.048) and by LTA (decline 24.1 vs 9.4%, p for interaction = 0.045). Conversely, compared to smoking, vaping resulted in greater reduction of exhaled CO (6.9 ppm vs 2.6, p for interaction < 0.001), improvement of PWV (decrease of 0.8 m/s vs increase of 0.8 m/s, p for interaction = 0.020) and reduction of MDA (reduction 0.13 vs increase 0.19 nmol/L, p for interaction = 0.035). Switching to electronic cigarette for 4 months has a neutral effect on platelet function while it reduces arterial stiffness and oxidative stress compared to tobacco smoking.

ß-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease.

BACKGROUND AND AIMS: Increased ß-amyloid and decreased mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization. PATIENTS AND METHODS: In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: (a) maximum platelet aggregation to adenosine diphosphate (ADP) by light transmission aggregometry (LTAmax), (b) malondialdehyde (MDA), as oxidative stress marker, (c) MOTS-c, (d) ß-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up. RESULTS: Out of 121 patients, 32 showed HPR (LTAmax > 48%,). At baseline, HPR was associated with ß-amyloid > 51 pg/ml (p = 0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, ß-amyloid > 51 pg/ml and MOTS-c < 167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p < 0.05) after adjusting for confounders and medication. There was significant interaction between HPR and ß-amyloid or MOTS-c for the prediction of MACE (p < 0.05). Patients with HPR and ß-amyloid > 51 mg/dl or HPR and MOTS-c concentration < 167 ng/ml had a fourfold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p < 0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD. CONCLUSIONS: Increased ß-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT04027712.