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Nutrition, Supplements, and Vitamins in Platelet Function and Bleeding
Abstract
Basic, experimental, and clinical studies have provided definite evidence on the key role played by platelets in the process of atherothrombosis. Interventional trials with aspirin (a platelet COX-1 inhibitor),1 thienopyridines such as ticlopidine or clopidogrel (a platelet P2Y12 receptor inhibitor),2 or the combination of the 2 drugs, ie, aspirin plus clopidogrel, reduced clinical outcomes in patients with acute coronary syndromes.3 A meta-analysis of trials with antiplatelet drugs in patients with stable atherosclerosis such as those with stable angina, peripheral arterial disease, or cerebrovascular disease confirmed the clinical efficacy of this drug category.4
Despite the success of interventional trials, the real world of atherothrombosis is complicated, with a high rate of morbility and mortality. Several issues related to the antiplatelet treatment may account for cardiovascular relapses. Poor compliance with an antiplatelet regimen may play a relevant role because the risk of adverse clinical outcome is higher in patients who do not adhere to aspirin treatment.5 Concomitant multiple antiatherosclerotic treatments are an important cause of poor aspirin compliance and should be taken into account in the monitoring of patients’ adherence to antiplatelet treatment.6 Insufficient antiplatelet effect by the present armamentarium may be another relevant explanation for vascular relapses7; thus, prasugrel, a P2Y12 receptor antagonist more potent than clopidogrel, improved vascular outcome in patients with acute coronary syndrome.8 Even if clinical investigation of more potent antiplatelet drugs represents an important future objective to improve the prevention of cardiovascular disease, a nonpharmacological approach to lower platelet function may be another intriguing prospective.
Observational and interventional studies have demonstrated that a significant reduction in cardiovascular events might be achieved by following particular diets or using specific nutrients.9 Relative to this, it is worthwhile to mention the significant reduction in cardiovascular events observed in …
... In the present study, a classic vitamin C supplement was assessed in rabbit platelets and showed a non-specific anti-platelet effect against the well-established inflammatory and thrombotic agonists, PAF and thrombin. Since ascorbic acid seems not to interact with the receptors of PAF and thrombin, while it possesses direct strong anti-oxidant properties by quenching superoxide radicals, it seems that the observed anti-platelet effects of vitamin C are derived from an indirect effect of vitamin C in the released superoxide radicals during activation of platelets by either PAF or thrombin [37]. During activation of platelets by such agonists, specific signaling takes place, in some of which the production of superoxide radicals is also involved, which in turn participate in propagating platelet activation and the thrombo-inflammatory response [37]. ...
... Since ascorbic acid seems not to interact with the receptors of PAF and thrombin, while it possesses direct strong anti-oxidant properties by quenching superoxide radicals, it seems that the observed anti-platelet effects of vitamin C are derived from an indirect effect of vitamin C in the released superoxide radicals during activation of platelets by either PAF or thrombin [37]. During activation of platelets by such agonists, specific signaling takes place, in some of which the production of superoxide radicals is also involved, which in turn participate in propagating platelet activation and the thrombo-inflammatory response [37]. Administration of vitamin C has been found to actually exert an anti-oxidant effect that resulted in platelet reactive oxygen species (ROS) inhibition and ultimately reduced platelet activation [36]. ...
... Administration of vitamin C has been found to actually exert an anti-oxidant effect that resulted in platelet reactive oxygen species (ROS) inhibition and ultimately reduced platelet activation [36]. Thus, it seems that an anti-oxidant treatment with vitamin C can inhibit both ROS and oxidized phospholipid PAF-R agonist activity, which are usually produced during an oxidative inflammatory response [8,11,12,37]. ...
The anti-oxidant properties of vitamin C and of phenolic compounds of citrus fruits are well established. However, the evaluation of the anti-inflammatory and antithrombotic potential of both vitamin C and of the more amphiphilic and lipophilic components of citrus fruits needs further attention. In this study, the anti-inflammatory and antithrombotic properties of vitamin C and of freshly squeezed juices and their lipid bioactives from the Navalina and Sanguine orange varieties and the Clementine variety of mandarins, as well as from their remaining by-products, were evaluated against the inflammatory and thrombotic pathways of the platelet-activating factor (PAF) and thrombin in platelets, as well as against PAF-biosynthesis in leukocytes. The non-oxidized juices of these citrus fruits and a vitamin C supplement showed stronger anti-PAF and antithrombin effects than their oxidized versions through their general anti-oxidant effect in platelets. The total lipids (TLs) and the HPLC-derived fractions of phenolic compounds and of polar lipid bioactives from both juices and their peels’ by-products showed a more specific stronger inhibitory effect against the inflammatory and thrombotic pathways of PAF and thrombin in platelets, while these bioactives strongly inhibited also the specific enzyme activities of the main biosynthetic enzymes of PAF in leukocytes. The stronger bioactivity of the dietary bioactives found in the juices of these citrus fruits against specific biochemical pathways of inflammation and thrombosis seems to act with synergy with the anti-oxidant potential of their vitamin C content, which further supports the notion that these juices are functional foods with anti-inflammatory protective health benefits. In addition, the presence of these dietary bioactive phenolic compounds and polar lipid bioactives in the remaining peels’ wastes further enhance the valorization of such food industry by-products as potential sources of anti-inflammatory bioactives to be used as ingredients for novel functional products.
... Огляди включаючи супероксид-аніон (О 2 -), перекис водню (H 2 O 2 ), гідроксильний радикал (-OH) та гідропероксид (ROOH) [4][5][6]. Концентрація АФК контролюється та зберігається завдяки антиоксидантам та іншим ферментам [7]. Якщо цей гомеостатичний стан порушується, наприклад, у випадку АГ, дисліпідемії, ЦД або ожиріння, рівні АФК зростають [8,9]. ...
... Про компанію «АстраЗенека» «АстраЗенека» -міжнародна науково-орієнтована біофармацевтична компанія, націлена на дослідження, розробку і виведення на ринок рецептурних препаратів переважно в таких терапевтичних областях, як онкологія, кардіологія, нефрологія і метаболізм, респіраторні та автоімунні захворювання. Компанія «АстраЗенека», що базується в Кембриджі (Великобританія), представлена більше ніж у 100 країнах світу, а її інноваційні препарати застосовують мільйони пацієнтів в усьому світі [7]. ...
За даними Всесвітньої організації охорони здоров’я, серцево-судинні захворювання (ССЗ) є однією з основних причин передчасної смерті та інвалідності населення, особливо серед осіб працездатного віку. Розвиток ССЗ залежить від факторів, що можуть бути модифіковані (рівень холестерину, маса тіла, куріння та артеріальний тиск) і таких, що не можуть бути модифіковані (вік, стать і спадковість). Провідну роль середатеросклеротичних факторів ризику, таких як артеріальна гіпертензія (АГ), дисліпідемія, захворювання периферичних артерій, метаболічний синдром, цукровий діабет (ЦД) та ожиріння відіграє оксидативний стрес (ОС). ОС та імунозапальні зміни, які є ланками патогенезу серцево-судинної дисфункції, можуть провокувати один одного за принципом «порочного кола». ССЗ набагато частіше зустрічається в пацієнтів із ЦД, а ОС відіграєпри цьому провідну роль. Популяційні дослідження продемонстрували, що 80% пацієнтів із ЦД помирають від ССЗ. На фоні гіперглікемії посилюється ОС, що призводить до ушкодження β-клітин острівців Лангерганса та прискорює прогресування серцево-судинних ускладнень. Для запобігання та усунення захворювань, які виникають внаслідок ОС, показаними є антиоксиданти. Протягом останніх десятиліть при вивченні впливів на ОС низку досліджень було націлено на екзогенне інгібування утворення активних форм кисню (АФК) додаванням екзогенних антиоксидантів, що не завжди було ефективним. Відтак зміцнення ендогенної антиоксидантної здатності може бути більш ефективним методом корекції ОС. Позитивний вплив сучасних препаратів, що використовуються в кардіологічній практиці, може бути обумовлений не тільки їх прямою дією, а й антиоксидантними й протизапальними ефектами. У статті представлені сучасні дані про системи, що беруть участь у формуванні та детоксикації АФК, взаємозв’язок між ОС та ССЗ, що дозволить краще зрозуміти механізми розвитку та прогресування ССЗ, які виникають на фоні ОС, розробити нові стратегії щодо покращення ендогенного антиоксидантного захисту, запобігти розвитку та прогресуванню ускладнень і смертності від ССЗ, особливо в пацієнтів високого та дуже високого серцево-судинного ризику.
... In most cases, the markers of cardiovascular risk and the markers of the effectiveness of the protective effect of the diet are considered to be the indicators of carbohydratelipid metabolism, but blood platelets, as targets of such interventions, are not widely recognised [18][19][20]. Data on dietary ingredients and their potential impacts on platelets include selected groups of substances, such as n-3 polyunsaturated fatty acids, vitamins and polyphenols [21]. Numerous platelet studies have predominantly focused on polyphenols present in the diet [22]. ...
The aggregation of blood platelets is the pivotal step that leads to thrombosis. The risk of thrombotic events increases with age. Available data suggest that minerals taken with diet can affect the course of thrombosis. However, little is known about the relationship between platelet aggregability and mineral intake with diet among elderly people. Thus, we evaluated the associations between the reactivities of platelets to arachidonic acid, collagen or ADP and the estimated quantities of minerals consumed as a part of the daily diet in 246 subjects aged 60–65 years (124 men and 122 women). The found simple (not-adjusted) Spearman’s rank negative correlations are as follows: 1. arachidonate-dependent aggregation and the amounts of potassium, zinc, magnesium, phosphorus, iron, copper and manganese; 2. collagen-dependent aggregation and the amounts of potassium, phosphorus, iron and zinc; and 3. ADP-dependent aggregation and the amounts of potassium, phosphorus and zinc. The negative associations between ADP-dependent platelet reactivity and the amount of potassium, phosphorus and zinc and between collagen-dependent aggregability and the amount of phosphorus were also noted after adjusting for a bunch of cardiovascular risk factors. Overall, in older subjects, the intake of minerals with diet is negatively related to blood platelet reactivity, especially in response to ADP. Diet fortification with some minerals may possibly reduce the thrombotic risk among elderly patients.
... In order to achieve a similar biochemical and nutritional profile of our volunteers between trials, dietary instructions were given before the interventions, which were similar to those given before the oral glucose tolerance test (OGTT) [25]. Additionally, the volunteers were advised to avoid polyphenol-rich food and foods rich in antiplatelet constituents for three consecutive days before trials [26]. Table 1 clearly shows that the dietary intake of macro-and micronutrients was similar between trials. ...
Postprandial dysmetabolism is a common entity of type 2 diabetes mellitus (T2DM) and may act as a daily stressor of the already dysfunctional diabetic platelets. This study aims to investigate whether oleocanthal-rich olive oils (OO), incorporated into a carbohydrate-rich meal, can affect postprandial dysmetabolism and platelet aggregation. Oleocanthal is a cyclooxygenase inhibitor with putative antiplatelet properties. In this randomized, single-blinded, crossover study, ten T2DM patients consumed five isocaloric meals containing 120 g white bread combined with: (i) 39 g butter, (ii) 39 g butter and 400 mg ibuprofen, (iii) 40 mL OO (phenolic content < 10 mg/Kg), (iv) 40 mL OO with 250 mg/Kg oleocanthal and (v) 40 mL OO with 500 mg/Kg oleocanthal. Metabolic markers along with ex vivo ADP- and thrombin receptor-activating peptide (TRAP)-induced platelet aggregation were measured before and for 4 h after the meals. The glycemic and lipidemic response was similar between meals. However, a sustained (90–240 min) dose-dependent reduction in platelets’ sensitivity to both ADP (50–100%) and TRAP (20–50%) was observed after the oleocanthal meals in comparison to OO or butter meals. The antiplatelet effect of the OO containing 500 mg/Kg oleocanthal was comparable to that of the ibuprofen meal. In conclusion, the consumption of meals containing oleocanthal-rich OO can reduce platelet activity during the postprandial period, irrespective of postprandial hyperglycemia and lipidemia.
... Although diet has not been specifically investigated in relation to antiplatelet resistance in HIV, there is strong justification for its contribution as a risk factor. Diets rich in micronutrients and vitamins, such as practiced among Mediterranean population, are reputed to lower cardiovascular risk factors due to antiplatelet effects [145]. It is speculated that individuals who do not partake these diets may be at risk of micronutrient deficiencies and rebound platelet hyperactivity. ...
Despite the extensive use of combined antiretroviral therapy (cART) for effective human immunodeficiency viral (HIV) suppression, people living with HIV have an increased risk of cardiovascular events compared to the general population. Antiplatelet agents are recommended for primary prevention and treatment of individuals at risk of ischaemic stroke and heart attack. However, these guidelines and recommendations are hinged on data from non-HIV populations. Accumulating evidence has revealed that response to antiplatelet agents varies in people living with HIV compared to non-HIV individuals. The variability may be attributed to consequences of HIV infection, metabolic derangements, and effects of cART and other drug interactions. Given that interventions employed in primary and secondary prevention of cardiovascular events heavily rely on guidelines developed for the general population that emphasize on identification, optimization and stratification of traditional risk factors, there is need to tailor these interventions with knowledge of HIV status and co-administration of cART. This chapter will synthesize the current topic regarding antiplatelet agents in people living with HIV. Specifically, we will critically examine the effects of individual antiplatelet agents on platelet function tests, drug interactions with cart and clinical data on the reduction of cardiovascular events.
... Vitamin E supplementation can also potentially interact with medications such as simvastatin (Zocor) and niacin, chemotherapy and radiotherapy, and anticoagulants and antiplatelet medications Cheung et al., 2001;Doyle et al., 2006;Block et al., 2007;Lawenda et al., 2008;Violi et al., 2010;Pastori et al., 2013). Decreased concentrations of mRNA for hepatic organic anion transporting polypeptide 3 (OATP3) transport proteins have been found in rats that were injected with α-tocopherol (Podszun and Frank, 2014). ...
The eye is particularly susceptible to oxidative stress and disruption of the delicate balance between oxygen-derived free radicals and antioxidants leading to many degenerative diseases. Attention has been called to all isoforms of vitamin E, with α-tocopherol being the most common form. Though similar in structure, each is diverse in antioxidant activity. Preclinical reports highlight vitamin E’s influence on cell physiology and survival through several signaling pathways by activating kinases and transcription factors relevant for uptake, transport, metabolism, and cellular action to promote neuroprotective effects. In the clinical setting, population-based studies on vitamin E supplementation have been inconsistent at times and follow-up studies are needed. Nonetheless, vitamin E’s health benefits outweigh the controversies. The goal of this review is to recognize the importance of vitamin E’s role in guarding against gradual central vision loss observed in age-related macular degeneration (AMD). The therapeutic role and molecular mechanisms of vitamin E’s function in the retina, clinical implications, and possible toxicity are collectively described in the present review.
... Platelets, which play a key role in the atherothrombosis mechanism via the release of inflammatory and pro-thrombotic molecules, are also able to produce ROS [30]. Currently, we know that, upon activation, platelet ROS, mainly produced by NADPH oxidase, are implicated in several processes, including the propagation of platelet activation, releasing platelet agonists such as Adenosine Diphosphate (ADP), forming isoprostanes and ox-LDL, and releasing pro-atherogenic molecules such as CD40 ligand (CD40L) [31]. Several studies demonstrated a key role for Nox2-mediated ROS formation in eliciting platelet activation. ...
Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted in the liver, is a key regulator of cholesterol homeostasis inducing LDL receptors’ degradation. Beyond lipid metabolism, PCSK9 is involved in the development of atherosclerosis, promoting plaque formation in mice and human, impairing the integrity of endothelial monolayer and promoting the events that induce atherosclerosis disease progression. In addition, the PCSK9 ancillary role in the atherothrombosis process is widely debated. Indeed, recent evidence showed a regulatory effect of PCSK9 on redox system and platelet activation. In particular, the role of PCSK9 in the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2) system, of MAP-kinase cascades and of CD36 and LOX-1 downstream pathways, suggests that PCSK9 may be a significant cofactor in atherothrombosis development. This evidence suggests that the serum levels of PCSK9 could represent a new biomarker for the occurrence of cardiovascular events. Finally, other evidence showed that PCSK9 inhibitors, a novel pharmacological tool introduced in clinical practice in recent years, counteracted these phenomena. In this review, we summarize the evidence concerning the role of PCSK9 in promoting oxidative-stress-related atherothrombotic process.
... Previous studies found an increased risk of bleeding from vitamin E supplements in patients who take anticoagulants and have vitamin K deficiency. Hence, vitamin E supplementation should be avoided in high-risk groups, given that no such complications were found in a healthy population, even in high dose vitamin E supplement at a dose 2000 IU per day [48][49][50]. ...
Vitamin E is a strong anti-oxidative stress agent that affects the bone remodeling process. This study evaluates the effect of mixed-tocopherol supplements on bone remodeling in postmenopausal osteopenic women. A double-blinded, randomized, placebo-controlled trial study was designed to measure the effect of mixed-tocopherol on the bone turnover marker after 12 weeks of supplementation. All 52 osteopenic postmenopausal women were enrolled and allocated into two groups. The intervention group received mixed-tocopherol 400 IU/day, while the control group received placebo tablets. Fifty-two participants completed 12 weeks of follow-up. Under an intention-to-treat analysis, vitamin E produced a significant difference in the mean bone resorption marker (serum C-terminal telopeptide of type I collagen (CTX)) compared with the placebo group (−0.003 ± 0.09 and 0.121 ± 0.15, respectively (p < 0.001)). In the placebo group, the CTX had increased by 35.3% at 12 weeks of supplementation versus baseline (p < 0.001), while, in the vitamin E group, there was no significant change of bone resorption marker (p < 0.898). In conclusion, vitamin E (mixed-tocopherol) supplementation in postmenopausal osteopenic women may have a preventive effect on bone loss through anti-resorptive activity.
... High levels of proinflammatory cytokines and reactive oxygen species secreted by alveolar macrophages and activated epithelial cells activate platelets in the pulmonary circulation [75]. Activated platelets themselves become a significant source of proinflammatory cytokines and reactive oxygen species [76][77][78]. Neutrophils and platelets form complexes that move more slowly through the circulation, which in combination with increased endothelial adhesion leads to increased sequestration of neutrophils and platelets in small blood vessels of the lungs [79][80][81]. Activated platelets and neutrophils mutually enhance the production of proinflammatory cytokines and reactive oxygen species [82][83][84][85][86]. ...
Coronavirus Disease (COVID-19) is caused by the RNA virus SARS-CoV-2. The primary receptor for the virus is most likely Angiotensin-converting enzyme 2 (ACE2), and the virus enters the body by infecting epithelial cells of the respiratory tract. Through the activation of Toll Like Receptors (TLRs), epithelial cells begin to synthesize various biologically active molecules. The pathophysiology of the COVID 19 is primarily attributed to the hyperactivation of host's immune system due to direct damage to the cells, with consequent release of proinflammatory substances, but also due to the activation of the innate immune response through the activation of alveolar macrophages and dendrite cells (DC). A strong proinflammatory reaction causes damage to alveolar epithelial cells and vascular endothelium. Respiratory epithelial cells, alveolar macrophages and DC are likely to be the most important cells involved in the innate immune response to the virus, since prolonged and excessive SARS-CoV-2-induced activation of these cells leads to the secretion of cytokines and chemokines that massively attract leukocytes and monocytes to the lungs and cause lung damage.
... The most convincing evidence for dietary compounds that reduce platelet activation has been found in the consumption of LC-PUFAs [116][117][118]. Byelashov et al. reported that docosahexaenoic acid (DHA) reduced blood platelet aggregation [119]. ...
Metabolic syndrome increases the risk of vascular dementia and other neurodegenerative disorders. Recent studies underline that platelets play an important role in linking peripheral with central metabolic and inflammatory mechanisms. In this narrative review, we address the activation of platelets in metabolic syndrome, their effects on neuronal processes and the role of the mediators (e.g., serotonin, platelet-derived growth factor). Emerging evidence shows that nutritional compounds and their metabolites modulate these interactions—specifically, long chain fatty acids, endocannabinoids and phenolic compounds. We reviewed the role of activated platelets in neurovascular processes and nutritional compounds in platelet activation.
... Further, it is able to disrupt the disulfide linkage found in fibrin fibrils in blood clot owing to its antioxidant properties [31]. Similarly, many other antioxidants increase the bleeding time [32]. Hence, from the present antithrombotic parameters measured, F3 does not have any significant anti-coagulant properties that may affect patients who are on warfarin or other anticoagulant therapy. ...
Bromelain consisting of a number of proteolytic enzymes possess anticancer and thrombotic properties. Hence, four chromatically separated fractions were examined for their proteolytic, anticancer and antithrombotic activity. Bromelain fractions were separated using ion-exchange column chromatography. Proteolytic properties were assessed using standard azocasein assay. Anticancer properties were first assessed using four different cell lines PANC-1, HEP 2B, HEP 3G and OVCAR-3 on cells grown in 96 well plates. Subsequently, fraction 2 and fraction 3 combined with gemcitabine were tested in ASPC-1 cells. Then cytotoxicity of fraction 3 was compared to bromelain in combination with doxorubicin and N-acetylcysteine on HEP G2 and HEP 3B cells. Finally, the anticoagulation effect of fraction 3 or bromelain combined with N-acetylcysteine was evaluated using human blood. Fraction 3 showed the highest proteolytic activity (5% greater than standard bromelain) whilst others were less active. Cytotoxicity as assessed by IC50 indicated fraction 3 to be the most potent whilst the others did not follow their proteolytic potency order. OVCAR-3 was the most sensitive amongst the cell lines. Fraction 3 showed higher potency in combination with gemcitabine in ASPC-1 cells compared to fraction 2. Similarly, fraction 3 in combination with doxorubicin showed higher toxicity when compared to bromelain. Fraction 3 or bromelain only showed thrombolytic activity in combination with N-acetylcysteine. Fraction 3 may be developed for clinical use since it showed better cytotoxicity compared to bromelain.
... [42] This diet has been reportedly demonstrated to reduce cardiovascular events but with higher bleeding times, which is likely to impact bleeding complications. [43,44] To our knowledge, this is the first study to focus on the nutritional status of bleeding complications in patients under VKA treatment. Nevertheless, our study has several limitations that must be acknowledged. ...
... Crucially ,the subsequent release of these inflammatory mediators into the pulmonary vasculature plays an indispensable role in the development of ARDS by initiating a series of events which results in the activation of vascular endothelial cells (Frantzeskaki et al. , 2017, Han and Mallampalli, 2015, Huang et al. , 2018, platelets (El Haouari, 2019, Freedman, 2008, Violi et al. , 2010, neutrophils (Øynebråten et al. , 2015, Sonmez andSonmez, 2017), ultimately resulting in the formation of platelet neutrophil complexes at the surface of the endothelium (Finsterbusch et al. , 2018, Sreeramkumar et al. , 2014, Stark, 2019. The formation of these complexes encourages and enables the recruitment of highly cytotoxic neutrophils and inflammatory activated platelets into the alveolar space and pulmonary intestinal resulting in a host of pathogenic consequences, as discussed below (Frantzeskaki et al., 2017, Han and Mallampalli, 2015, Huang et al., 2018. ...
Background
COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS.
Main body
The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of NET producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID19 are discussed in detail.
... This is of importance from a pathophysiological perspective as PA is a major source of systemic inflammation and oxidative stress [159,160]. Activated platelets secrete high levels of PICs and ROS and a plethora of chemokines, TNF superfamily members and adhesion factors which make an independent and collective contribution to initiating or exacerbating levels of EC activation and dysfunction [161][162][163], reviewed in [164]. For example, the TNF superfamily member LIGHT enhances platelet EC adhesion, EC dysfunction and EC activation by stimulating elevated activity of NF-κB via a pathway dependent on MAPK [165][166][167]. ...
Background:
Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined.
Main text:
Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction.
Conclusions:
Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.
... Reduction of PAF-induced platelet aggregation in vitro, in vivo, and ex vivo -Potential anti-inflammatory effects -Affects PAF metabolism in vitro, in vivo, and ex vivo -Reduction of thrombin, ADP, and collagen-induced platelet aggregation in vitro -derived oils (e.g., olive oil), nuts, and seeds -Reduction of PAF, ADP, thrombin, and collagen-induced platelet aggregation in PRP and whole blood in vitro and ex vivo -Reduction of PAF and Reduction of PAF platelet aggregation and metabolism in vitro and in vivo -Anti-inflammatory -Low vitamin D associated with higher platelet reactivity of type-III collagen-induced aggregation -Binding to glycoprotein IIb/IIIa -Interactions with fibrinogen and its receptor.-Reduction of thrombin formation -Reduction of ADP-Reduction of platelet aggregation -Anti-inflammatory effects -Affects PAF metabolism in vitro, in vivo, and ex vivo -Reduction of tissue factor synthesis -Regulation of endothelial function -Inhibition of COX and LOX pathways(41,54,(76)(77)(78)(79)(80)(81) ADP, adenosine diphosphate, COX-1, cyclooxygenase-1; Lp-PLA 2 , lipoprotein-associated phospholipase A 2 ; PAF, platelet-activating factor; PRP, platelet-rich plasma. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease (COVID-19), is a contagion that has rapidly spread around the globe. COVID-19 has caused significant loss of life and disrupted global society at a level never before encountered. While the disease was predominantly characterized by respiratory symptoms initially, it became clear that other systems including the cardiovascular and neurological systems were also involved. Several thrombotic complications were reported including venous thrombosis, vasculitis, cardiomyopathy, and stroke. Thrombosis and inflammation are implicated in various non-communicable diseases (NCDs). This is of significant concern as people with pre-existing conditions such as cardiovascular disorders, renal disorders, obesity, metabolic syndrome, and diabetes are at greater risk of severe COVID-19 infection. Consequently, the research surrounding the use of anticoagulants, antiplatelet, and antithrombotic strategies for prophylaxis and treatment of COVID-19 is of critical importance. The adoption of a healthy diet, physical exercise, and lifestyle choices can reduce the risk factors associated with NCDs and the thrombo-inflammatory complications. In this review, these thrombotic complications and potential foods, nutraceuticals, and the antithrombotic constituents within that may prevent the onset of severe thrombotic complications as a result of infection are discussed. While nutrition is not a panacea to tackle COVID-19, it is apparent that a patient's nutritional status may affect patient outcomes. Further intensive research is warranted to reduce to incidence of thrombotic complications.
... Platelets in the pulmonary vasculature are also targets for activation by the high levels of PICs and ROS secreted by alveolar macrophages and activated type II epithelial cells (Pignatelli et al. , 2005); (reviewed by (Qiao et al. , 2018)). Activated platelets (AP) also become a significant source of PICs and ROS (El Haouari, 2019, Freedman, 2008, Violi et al. , 2010 reviewed in (Hamilos et al. , 2018). Importantly, APs also secrete several chemokines, most notably RANTES, and CCL4, also known as platelet factor 4 (PF4), which increase neutrophil activation, survival, recruitment to the endothelium and subsequent tethering to EC (Øynebråten et al. , 2015, Sonmez andSonmez, 2017). ...
In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.
... The beneficial effects of polyphenols are in part related to their antioxidant and anti-thrombotic properties. Polyphenols in cocoa and extra virgin olive oil can regulate platelet function, as demonstrated by the inhibitory effect of polyphenol-rich nutrients on platelet activation [100]. Catechin and epicatechin from cocoa and polyphenols from extra virgin olive oil exert their antiplatelet effect through the down regulation of NOX2 and the consequent reduction in the formation of ROS [101][102][103]. ...
Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers.
... Adherence to the Med-diet has been linked to reduced morbidity and mortality, especially for cardiovascular and cerebrovascular causes, with biological and mechanistic explanations that underlie this relationship [4,28]. However, in recent years, there has been a progressive loss of healthy and beneficial dietary models, such as the Mediterranean dietary pattern [4][5][6]. ...
Background:
The reasons behind low adherence to the Mediterranean diet (Med-diet) are still not entirely known. We aimed to evaluate the effect of biological (i.e., sex-related) and psycho-socio-cultural (i.e., gender-related) factors on Med-diet adherence.
Methods:
Baseline Med-diet adherence was measured using a self-administered questionnaire among adults with ischemic heart disease (IHD) from the EVA (Endocrine Vascular Disease Approach) study. A multivariable analysis was performed to estimate the effect of sex- and gender-related factors (i.e., identity, roles, relations, and institutionalized gender) on low adherence.
Results:
Among 366 participants (66 ± 11 years, 31% women), 81 (22%) adults with low adherence demonstrated higher rates of diabetes, no smoking habit, lower male BSRI (Bem Sex Role Inventory) (median (IQR) 4.8 (4.1 to 5.5) vs. 5.1 (4.5 to 5.6) and p = 0.048), and higher Perceived Stress Scale 10 items (PSS-10) (median (IQR) 19 (11 to 23) vs. 15 (11 to 20) and p = 0.07) scores than those with medium-high adherence. In the multivariable analysis, only active smoking (odds ratio, OR = 2.10, 95% confidence interval, CI 1.14 to 3.85 and p = 0.017), PPS-10 (OR = 1.04, 95% CI 1.00 to 1.08, and p = 0.038) and male BSRI scores (OR = 0.70, 95% CI 0.52 to 0.95, and p = 0.021) were independently associated with low adherence.
Conclusions:
Male personality traits and perceived stress (i.e., gender identity) were associated with low Med-diet adherence regardless of the sex, age, and comorbidities. Therefore, gender-sensitive interventions should be explored to improve adherence in IHD.
... Therefore, in virtue of its antioxidant property, low SA could result in an impaired reactive oxidant species scavenging and eventually platelet activation [16]. There is, in fact, overwhelming evidence that reactive oxidant species are powerful triggers of platelet activation and thrombus growth [17][18][19]. ...
The predictive role of serum albumin (SA) has been evaluated in primary prevention studies. We want to assess the association of SA with the subsequent risk of cardiovascular events (CVE) in primary and secondary prevention studies. We performed a systematic review and Bayesian meta-regression analysis. Studies were identified by PubMed and EMBASE database using a combination of the following terms and MeSH terms: “serum albumin”, “myocardial infarction, “cardiovascular events”, “percutaneous coronary intervention” and “coronary restenosis”. No time restriction of the research was applied. Two experienced physicians reviewed data on outcome measures and assessed the quality rating. The main outcomes were CVE including myocardial infarction, coronary heart disease, percutaneous coronary intervention and coronary restenosis. 15 studies of SA and CVE were identified involving 65,077 subjects with a mean age of 57.89 ± 6.05 years and a mean follow-up of 9.4 (±5.56) years. Subjects under SA cut-off of 3.8 g/dL had a combined hazard ratio (HR) for CVE of 2.16 [95% confidence interval (CI) 1.93–2.45]. An increased risk for CVE was also evident using SA as a continuous variable (HR = 1.89, 95% CI 1.5–2.39). Females and males had a similar risk for CVE (HR 2.46, 95% CI 1.92–3.16, and HR 1.46, 95% CI 1.27–1.69, respectively). We found a similar risk of CVE between primary and secondary prevention studies (HR 1.79, 95% CI 1.5–2.17, and HR 2.47, 95% CI 2.24–2.75, respectively). Low SA levels are associated with an increased risk of CVE, not only in subjects free from CVE, but also in patients who already experienced a CVE.
... NOX1 and NOX2 are reported as the major complexes to generate reactive oxygen species in platelets [74][75][76]. Earlier studies by Violi and colleagues suggested that reactive oxygen species generated from NOX promote platelet activation [77][78][79][80] implicated NOX in platelet function. Studies of individuals with chronic granulomatous disease, an xlinked genetic deficiency in the cybb1 allele, or with deficiencies in any member of the NOX protein complex, showed decreased platelet activation [77,[80][81][82]. ...
Scavenger receptor CD36 is a multifunctional membrane protein that promotes thrombosis in conditions of oxidative stress such as metabolic disorders including dyslipidemia, diabetes mellitus, and chronic inflammation. In these conditions, specific reactive oxidant species are generated that are context and cell dependent. In the vasculature, CD36 signaling in smooth muscle cells and endothelial cells promotes generation of reactive oxygen species, genetic downregulation of antioxidant genes, and impaired smooth muscle and endothelial function. In hematopoietic cells, CD36 signaling enhances platelet dysfunction thus decreasing the threshold for platelet activation and accelerating arterial thrombosis, whereas in macrophages, CD36 promotes lipid-laden foam cell formation and atherosclerosis. These clinically significant processes are mediated through complex redox regulated signaling mechanisms that include Src-family kinases, MAP kinases and other downstream effectors. We provide an overview of CD36 signaling in vascular redox stress highlighting the role in oxidant generation in vascular and hematopoietic cells, but with special emphasis on platelets and dyslipidemia.
... Conversely, there is evidence that some supplements may be harmful to health and may interact with prescription medicines. [61,62] Consumers should be aware of unsubstantiated advertising claims relating to long-term health benefits. ...
South Africa (SA) is home to a heterogeneous population with a wide range of cardiovascular risk factors. Cholesterol reduction in combination with aggressive management of modifiable risk factors, including nutrition, physical activity, blood pressure and smoking, can help to reduce and prevent morbidity and mortality in individuals who are at increased risk of cardiovascular events. This updated consensus guide to management of dyslipidaemia in SA is based on the updated European Society of Cardiology and European Atherosclerosis Society dyslipidaemia guidelines published in 2016. For individuals who are not considered to be at high or very high cardiovascular risk, the decision whether to treat and which interventional strategy to use is based on a cardiovascular risk score calculated using total cholesterol, high-density lipoprotein cholesterol (HDL-C), gender, age and smoking status. The cardiovascular risk score refers to the 10-year risk of any cardiovascular event and includes 4 categories of risk (low, moderate, high and very high). People with established cardiovascular disease, diabetes mellitus, chronic kidney disease and genetic or severe dyslipidaemias are considered to already be at high or very high risk and do not require risk scoring. Therapeutic lifestyle change is the mainstay of management for all patients. The need for and intensity of drug therapy is determined according to baseline low-density lipoprotein (LDL-C) levels and the target LDL-C concentration appropriate to the individual. LDL-C treatment targets are based on pre-treatment risk and are as follows: <3 mmol/L in low- and moderate risk cases; <2.5 mmol/L and a reduction of at least 50% if the baseline concentration is 2.5 - 5.2 mmol/L in high-risk cases; and <1.8 mmol/L and a reduction of at least 50% if the baseline concentration is 1.8 - 3.5 mmol/L in very high-risk cases. A statin is usually recommended first-line; the specific agent is based on the required degree of cholesterol reduction, comorbidities and co-prescribed medication. Special attention should be paid to children with a family history of genetic or severe dyslipidaemia, who should be screened for dyslipidaemia from 8 years of age. In SA, HIV infection is not considered to be a significant cardiovascular risk factor and treatment recommendations for HIV-positive individuals are the same as for the general population, with careful choice of pharmacotherapy to avoid potential adverse drug-drug interactions. The benefit of statins in individuals older than 70 years is uncertain and clinical judgement should be used to guide treatment decisions and to avoid side-effects and overmedication in this group.
... The involvement of ROS in atherothrombosis process is including nitric oxide (NO) inactivation or NO synthase inhibition and platelet activation via overexpression of platelet eicosanoids and platelet NO inhibition, which finally contribute to the arterial dysfunction. (64,65) Besides LDL, sphingolipids are also proven to have a potent biological effects in atherosclerotic process. Ceramides are a group of sphingolipids generated from hydrolysis of sphingomyelin by sphingomyelinases, neutral sphingomyelinases, and acidic sphingomyelinases (A-SMase). ...
BACKGROUND: Atherosclerosis is a leading cause of vascular disease worldwide. During the past several decades, landmark discoveries in the field of vascular biology have evolved our understanding of the biology of blood vessels and the pathobiology of local and systemic vascular disease states and have led to novel disease-modifying therapies for patients. This review is made to understand the molecular mechanism of atherosclerosis for these future therapies.CONTENT: Advances in molecular biology and -omics technologies have facilitated in vitro and in vivo studies which revealed that blood vessels regulate their own redox milieu, metabolism, mechanical environment, and phenotype, in part, through complex interactions between cellular components of the blood vessel wall and circulating factors. Dysregulation of these carefully orchestrated homeostatic interactions has also been implicated as the mechanism by which risk factors for cardiopulmonary vascular disease lead to vascular dysfunction, structural remodeling and, ultimately, adverse clinical events.SUMMARY: Atherosclerosis is a heterogeneous disease, despite a common initiating event of apoB-lipoproteins. Despite of acute thrombotic complications, an adequate resolution response is mounted, where efferocytosis prevents plaque necrosis and a reparative scarring response (the fibrous cap) prevents plaque disruption. However, a small percentage of developing atherosclerotic lesions cannot maintain an adequate resolution response, which leading to the formation of clinically dangerous plaques that can trigger acute lumenal thrombosis and tissue ischemiaand infarction.KEYWORDS: atherosclerosis, oxidative stress, inflammation, efferocytosis, foam cells, thrombosis
... Currently, oxidative stress is defined as an event where a transient or permanent perturbation in the oxidative balance state generates physiological consequences within the cell, depending on the specific target and ROS concentrations. In physiological conditions, ROS concentrations fluctuate in a controlled manner and are modulated by enzymatic and non-enzymatic antioxidant systems [2]. If this homeostatic state fails, such as in the case of hypertension, dyslipidaemia, diabetes, and obesity and acute conditions such as sepsis and respiratory failure, ROS levels increase [3,4]. ...
The role of oxidative stress in the onset and progression of atherosclerosis and its impact on the development of cardiovascular events has been widely described. Thus, an increased oxidative stress has been described in several atherosclerotic risk factors, such as hypertension, dyslipidaemia, peripheral artery disease, metabolic syndrome, diabetes and obesity. Among others, specific oxidative pathways involving both pro-oxidant and antioxidant enzymes seem to play a major role in the production of reactive oxidant species (ROS), such as NADPH oxidase, myeloperoxidase, superoxide dismutase, glutathione peroxidase. In this review, we will discuss 1) the most relevant enzyme systems involved in the formation and detoxification of ROS, 2) the relationship between oxidative stress and cardiovascular risk, and 3) therapeutic implications to modulate oxidative stress.
... Firstly, the authors cannot completely rule out that some voluntary blood donors have taken acetylsalicylic acid or non-steroidal anti-inflammatory drugs by mistake in the days before blood donation, influencing collagen-and AA-induced IQC measurements. Nutritional polyphenols may also influence platelet aggregation [39]. Secondly, distinct reduced ADP-activated platelet aggregation in stored platelet concentrates is already observed after 24 h [40], increasing variance (CV) of ADP-activated IQC measurements near zero values (% aggregation and AUC). ...
Background:
Standardized commercially available control material for internal quality control (IQC) of light transmission aggregometry (LTA) is still lacking. Moreover, the provision of normal blood donors to provide fresh platelets is difficult in small laboratories, where "volunteers" may be of short supply.
Objectives:
To evaluate the implementation of buffy-coat-derived pooled platelet concentrates (PCs) for IQC material of LTA.
Methods:
We used buffy-coat-derived pooled PCs from the blood bank as IQC material for LTA. On each weekend one PC was prepared (> 200 mL) and aliquoted from the original storage bag on a daily basis in four baby bags (40 - 50 mL), which were delivered from Monday to Friday to our laboratory. The IQC measurements of at least 85 workweeks (from Monday to Friday) were evaluated with this new IQC material. LTA was performed on a four channel Chronolog 700 Aggregometer (Chronolog Corporation, Havertown, Pennsylvania, USA) (agonists: collagen, adenosine diphosphate [ADP], arachidonic acid [AA], thrombin receptor activator peptide-6 [TRAP-6]).
Results:
The medians of platelet aggregation from IQC measurements were with collagen, ADP, and AA from Monday to Friday 68.0 - 59.5, 3.0 - 2.0, and 51.0 - 50.0%, and the mean of platelet aggregation with TRAP-6 71.2 - 66.4%, respectively.
Conclusions:
Buffy-coat-derived pooled PCs serve as a reliable and robust IQC material for LTA measurements and would be beneficial for the whole laboratory procedure and employees' safety. This article is protected by copyright. All rights reserved.
... ROS are implicated in the process of atherothrombosis with other mechanisms including arterial dysfunction via NO inactivation or NO synthase inhibition and platelet activation via overexpression of platelet eicosanoids and platelet NO inhibition. 2 Among the enzymatic pathways involved in ROS formation, NADPH oxidase (Nox) is among the most important cellular producers of ROS. 3 The Nox family includes several isoforms including the phagocytic Nox2, which is a key component of the innate immune system because it greatly contributes to bacterial killing. 4 Nox2 is a transmembrane protein whose gp91 phox and gp22 phox subunits form a membranebound heterodimeric flavocytochrome b558, which acts as a catalytic core. ...
The phagocytic cell enzyme NADPH oxidase-2 (Nox2) is critical for killing micro-organisms via production of reactive oxygen species and thus is a key element of the innate immune system. Nox2 is also detectable in endothelial cells and platelets where it has vasoconstrictive and aggregating properties, respectively. Patients with X-linked chronic granulomatous disease with hereditary Nox2 deficiency not only have impaired bacterial killing but, in association with loss of Nox2 function, also have enhanced carotid artery dilation, impaired platelet-related thrombosis, and reduced carotid atherosclerotic burden. Experimental studies corroborated these reports in chronic granulomatous disease by demonstrating (1) Nox2 is upregulated in atherosclerotic plaque, and this upregulation significantly correlates with oxidative stress and (2) pharmacological inhibition of Nox2 is associated with a delayed atherosclerotic progression in animal models. Furthermore, the role of Nox2 in platelet-associated thrombosis was substantiated by experiments showing impaired platelet activation in animals treated with a Nox2 inhibitor or impaired platelet aggregation along with reduced platelet-related thrombosis in the mouse knockout model of Nox2. Interestingly, in chronic granulomatous disease patients and in the mouse knockout model of Nox2, no defects of primary hemostasis were detected. This review analyses experimental and clinical data suggesting Nox2 is a potential target for counteracting the atherothrombotic process.
... Polyphenolics and antioxidant rich diets have been investigated for prevention of thrombotic diseases (80)(81)(82). We did not find a correlation between polyphenolics/ antioxidant contents of various fruits and vegetables and their experimental antithrombotic effect (Table 2). ...
In the quest for prevention of atherothrombotic diseases, an antithrombotic diet may offer a promising approach. The major stumbling block in finding an effective diet is the lack of pathophysiological relevant techniques to detect potential antithrombotic effects of various diet components. Platelet function and coagulation/fibrinolysis tests currently in use do not allow assessment of global thrombotic status and their value in screening diet-components for antithrombotic effects. Recently, we combined the point-of-care shear-induced ex vivo thrombosis test (Global Thrombosis Test-GTT) with the Flow-mediated Vasodilation (FMV) in vivo test and found that the combination improved the assessment of thrombotic status in humans and could be used for screening diet-components for antithrombotic effects. In the present experiments, a combination of GTT, hemostatometry, laser-induced thrombosis tests and FMV were employed for screening. The results show that the overall antithrombotic effect is determined by the effect on thrombus formation and endogenous thrombolytic activities. This study showed a great variation in the observed antithrombotic effect between the tested varieties. Antithrombotic activities were independent from polyphenolic content or antioxidant activities. The presented experimental techniques seem to be suitable for establishing an antithrombotic diet, which may be effective in the prevention of atherothrombotic cardiovascular diseases in humans.
... It was previously shown that mackerel consumption (~ 1 g EPA+DHA/d, 4 wks) 250 reduced PMA in healthy young men [16]. The difference in outcome might be due to individual 251 variability, as well as the presence of other components in mackerel, such as selenium or vitamins 252 [32]. Consistent with this, the same authors recently reported that fish oil supplementation (2 g/d, 6 253 wks) had no effect on PMA and other markers of platelet monocyte activation in CHD patients [17]. ...
Background and aims:
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil are postulated to have favourable effects on platelet, endothelial and vascular function. We investigated whether EPA has differential effects on in vivo platelet aggregation and other markers of cardiovascular risk compared to DHA.
Methods and results:
Following a 2 wk run-in taking encapsulated refined olive oil, 48 healthy young men were randomly allocated using a parallel design to receive EPA-rich (3.1 g EPA/d) or DHA-rich (2.9 g DHA/d) triglyceride concentrates or refined olive oil (placebo), for a total supplementary lipid intake of 5 g/d. The specified primary outcome was change in platelet monocyte aggregates (PMA); secondary outcomes were capillary density, augmentation index, digital pulse volume measurements, 24 h ambulatory BP, plasma 8-isoprostanes-F2α. Changes in the proportions of DHA and EPA in erythrocytes and non-esterified fatty acid composition indicated compliance to the intervention. There was no significant treatment effect on PMA (P = 0.382); mean changes (%) (95% CI) were placebo -0.5 (-2.0, 1.04), EPA 0.4 (-0.8, 1.6), DHA 0.3 (-1.5, 2.0). R-QUICKI, an index of insulin sensitivity, was greater following EPA compared to placebo (P < 0.05). No other significant differences were noted.
Conclusion:
Neither EPA- nor DHA-rich fish oil supplementation influence platelet-monocyte aggregation or several markers of vascular function after 6 wk in healthy young males. This trial was registered at clinicaltrials.gov as NCT01735357.
... The mechanism for increased bleeding may include inhibitory effects of these medications on platelet functions mediated through several different pathophysiological pathways [6], including adenosine diphosphate-(ADP) [7], collagen-(COL) [8] and adrenaline-induced inhibition of platelet aggregation [9]. Furthermore, thromboxane B2 levels [10], platelet P-selectin expression [11], platelet CD63 expression [12] and arachidonic acid levels of platelet phospholipids [13,14] may also be affected. ...
Several of these medicines have been reported to increase bleeding or enhance the effect of other drugs that
increase bleeding. The Swedish Medical Products Agency recommends cessation of the use of the naturopathic
medicines echinacea, fish oil, ginkgo biloba, ginseng, St. John’s wort, valeriana and garlic 2 weeks before surgery.
The aim of this pilot study was to examine the effects of these 7 naturopathic medicines in healthy humans by
utilising multiple electrode aggregometer (Multiplate) and viscoelastic rotational thromboelastometer (ROTEM) to
obtain data for sample size calculation before a larger trial.
Methods: Thirty-five healthy volunteers ingested one of the listed naturopathic medicines for 7 days. Each naturopathic
medicine was taken in a recommended standard dose by 5 volunteers. ROTEM clot initiation (CT), clot formation (CFT),
α-angle (AA) and clot structure (MCF) were analysed with tissue factor activated (EXTEM) and native (NATEM)
assays. The Multiplate platelet aggregation area under curve (AUC) was measured with adenosine diphosphate
(ADP), collagen (COL) and arachidonic acid (ASPI) assays.
Results: Multiplate with ADP agonist decreased from 73 ± 8.7 AUC to 60 ± 5.9 AUC (P = 0.003, 95 % confidence
interval (CI) −19.2 to −7.6) after medication with fish oil, but fish oil had no effect on COL or ASPI reagents. None
of the other naturopathic medicines had any effect on Multiplate aggregometry. ROTEM NATEM-CFT increased
from 217 ± 32 s to 283 ± 20 (P = 0.009, 95 % CI 26.8 to 107), and NATEM-AA decreased from 52 ± 3.9° to 44 ± 2.3°
(P = 0.009, 95 % CI −12.0 to −3.2) after medication with fish oil. There were no significant changes in the other
NATEM or EXTEM parameters. The other naturopathic medicines had no significant effects on ROTEM or Multiplate
aggregometry.
Conclusions: We have demonstrated that a recommended standard intake of 1260 mg Ω-3 polyunsaturated fatty
acids (fish oil) daily – but not echinacea, ginkgo biloba, ginseng, St. John’s wort, valeriana or garlic – may decrease
platelet aggregation and clot formation. A larger trial in this setting would be meaningful to perform.
The European Society of Cardiology together with the European Atherosclerosis Society published updated dyslipidaemia guidelines in 2011. SA Heart and the Lipid and Atherosclerosis Society of Southern Africa officially adopt these guidelines. This statement adapts aspects of the guidelines to the South African situation. Using the updated Framingham risk charts, interventional strategies are based according to the cardiovascular risk score and low-density lipoprotein cholesterol (LDL-C) levels. The Framingham risk score refers to the 10-year risk of any cardiovascular event, and includes four categories of risk. Treatment targets are those of the European guidelines. The LDL-C goal is 1.8 mmol/l for the very high-risk group (30%), 2.5 mmol/l for the high-risk group (15 - 30%), and 3 mmol/l for those below 15% risk. Intensive management of dyslipidaemia in South Africa will significantly reduce the cardiovascular disease health burden.
BACKGROUND
Although artificial and non-nutritive sweeteners are widely used and generally recognized as safe by the US and European Union regulatory agencies, there have been no clinical trials to assess either long-term cardiovascular disease risks or short-term cardiovascular disease–relevant phenotypes. Recent studies report that fasting plasma levels of erythritol, a commonly used sweetener, are clinically associated with heightened incident cardiovascular disease risks and enhance thrombosis potential in vitro and in animal models. Effects of dietary erythritol on thrombosis phenotypes in humans have not been examined.
METHODS
Using a prospective interventional study design, we tested the impact of erythritol or glucose consumption on multiple indices of stimulus-dependent platelet responsiveness in healthy volunteers (n=10 per group). Erythritol plasma levels were quantified with liquid chromatography tandem mass spectrometry. Platelet function at baseline and following erythritol or glucose ingestion was assessed via both aggregometry and analysis of granule markers released.
RESULTS
Dietary erythritol (30 g), but not glucose (30 g), lead to a >1000-fold increase in erythritol plasma concentration (6480 [5930–7300] versus 3.75 [3.35–3.87] μmol/L; P <0.0001) and exhibited acute enhancement of stimulus-dependent aggregation responses in all subjects, agonists, and doses examined. Erythritol ingestion also enhanced stimulus-dependent release of the platelet dense granule marker serotonin ( P <0.0001 for TRAP6 [thrombin activator peptide 6] and P =0.004 for ADP) and the platelet α-granule marker CXCL4 (C-X-C motif ligand-4; P <0.0001 for TRAP6 and P =0.06 for ADP). In contrast, glucose ingestion triggered no significant increases in stimulus-dependent release of either serotonin or CXCL4.
CONCLUSIONS
Ingestion of a typical quantity of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity in healthy volunteers, raising concerns that erythritol consumption may enhance thrombosis potential. Combined with recent large-scale clinical observational studies and mechanistic cell-based and animal model studies, the present findings suggest that discussion of whether erythritol should be reevaluated as a food additive with the Generally Recognized as Safe designation is warranted.
REGISTRATION
URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04731363.
Cardiovascular disease (CVD) is currently one of the prevalent causes of human death. Iron is one of the essential trace elements in the human body and a vital component of living tissues. All organ systems require iron for various metabolic processes, including myocardial and skeletal muscle metabolism, erythropoiesis, mitochondrial function, and oxygen transport. Its deficiency or excess in the human body remains one of the nutritional problems worldwide. The total amount of iron in a normal human body is about 3–5 g. Iron deficiency may cause symptoms such as general fatigue, pica, and nerve deafness, while excessive iron plays a crucial role in the pathophysiological processes of the heart through ferroptosis triggered by the Fenton reaction. It differs from other cell death modes based on its dependence on the accumulation of lipid peroxides and REDOX imbalance, opening a new pathway underlying the pathogenesis and mechanism of CVDs. In this review, we describe the latest research progress on the mechanism of ferroptosis and report its crucial role and association with miRNA in various CVDs. Finally, we summarise the potential therapeutic value of ferroptosis-related drugs or ferroptosis inhibitors in CVDs.
An accurate and comprehensive assessment of platelet function is essential for managing patients who receive antiplatelet therapies or require platelet transfusion either for treating active bleeding or for prophylaxis. Platelets contribute to clotting by undergoing a series of highly regulated functional responses including adhesion, spreading, granular secretion, aggregation, and cytoskeletal contraction. However, current platelet function assays evaluate only partial aspects of this intricate process and often under non-physiological testing conditions. Herein, we describe the development of a new approach to measure multiple key platelet function-related parameters, in a more physiologically relevant ex vivo semi-rigid microenvironment using a membrane capacitance sensor (MCS). MCS response to clotting provided three sensing parameters with sensitivities towards platelet counts, stimulation strengths, and activation pathways. Live confocal fluorescent imaging of stimulated platelets on MCS suggests that the presented system can readily and accurately convert the dynamics of cytoskeletal reorganization into analyzable electrical signals. Together, this new completely electrical sensing platform can be a promising diagnostic venue to recognize the impairment of primary hemostatic functions, evaluate the efficacy of therapeutic interventions, and gain further insights into the mechanisms of platelets in hemostasis and thrombosis.
Diabetes Mellitus is a metabolic disorder characterized by hyperglycemia(increase mount of insulin)according to grotesque in insulin secretion, insulin action or both Diabetes milletus is one such disease which is causing serious trouble to human health, In addition to that rapid increase in diabetesmilletus is becoming a serious menacing to mankind in all parts of the world, The result parameters showing that there is a significantly increased (p< 0.05) in sugar compared to control in group while there is a significantly increased (p< 0.05) in cholesterol, triglyceride, LDL, AST, ALT in diabetic rats compared to control. While show significantly decreased in HDL in diabetic when used extract of Citrus limon is decreased the levels of (sugar, cholesterol, triglyceride, AST, ALT) and improve the level of HDL Because have many phytochemical such as (saponin, flavonoids, antioxidants). Also showing significantly decreased (p< 0.05) in WBC, RBC, Hb in Diabetes mellitus, but when use ECl that increase the amount of (WBC, RBC, Hb).
Introduction: Aspirin and clopidogrel are mainstays in secondary stroke prevention; however, some patients do not demonstrate optimal antiplatelet effects from these therapies. Objectives: The primary objective of this study was to determine if pharmacist medication intervention paired with anti-platelet medication monitoring with whole blood aggregometry improved responsiveness to antiplatelet treatment when compared with standard-of-care, alone in patients at risk of recurrent stroke or transient ischemic attack (TIA). Methods: This retrospective chart review at an outpatient neurology practice examined patients treated post-stroke or post-TIA between 2005 and 2017. Patients were categorized as either having undergone platelet function testing (PFT) with pharmacist intervention and standard-of-care or standard-of-care alone. Patient populations for each group were matched based on age, sex, and ABCD² risk scores. Pharmacotherapeutic management and interventions were assessed in each group. Results: A total of 342 patients were included as two matched groups (n = 171 for each group) with parallel baseline characteristics. Drug-drug interactions were identified (P <.0001), and counseling on adherence (P =.0008) occurred statistically significantly more often with a pharmacist involved in patient care. After pharmacist intervention and PFT, 83% of patients were considered responsive to their antiplatelet therapy compared with 27% at baseline in the pharmacist intervention group (P <.0001). Conclusion: Pharmacist interventions optimized secondary stroke/TIA prophylaxis therapy, decreased drug-drug interactions, and increased adherence counseling. Patients who underwent PFT and pharmacist intervention transitioned from nonresponsive to responsive to their antiplatelet therapy regimen.
The Mediterranean diet is among the most well researched dietary patterns for the prevention of cardiovascular (CV) disease with study types ranging from large scale observational studies to randomized controlled clinical trials. The diet is predominantly comprised of plant-based foods and whole grains, with lesser amounts of dairy products, fish, poultry, eggs, olive oil, and wine. The diet has been associated with an overall lifestyle pattern that also includes physical activity and communal gatherings making it difficult to separate out the health benefit of any individual dietary or lifestyle component. Overall, the diet has been associated with improvement in CV risk factors (lipids, blood pressure, glucometabolic state, weight), metabolic syndrome, systemic inflammation, oxidative stress, endothelial function, and CV events. With a large body of evidence for the Mediterranean diet and significant overlap with other diets shown to have benefit for CV disease reduction, dietary counseling encouraging the main components of the diet should be at the core of CV care.
Introduction: Hemorrhage occurs in 7-10% of patients treated with vitamin K antagonist (VKA), with major bleeding in 1-3%. Impact of nutritional status on the bleeding risk of patients on anticoagulants is still poorly documented. Our study aimed to analyze the link between the nutritional status of patients on VKA and the occurrence of hemorrhagic events. We also analyzed micronutrients status.
Methods: A case-control, monocentric, and prospective study was conducted from August 2012 to October 2015. The case patients were those presenting with major bleeding and control patients those without any bleeding under VKA treatment.
Results: Overall, 294 patients under VKA treatment were paired according to age, gender, and index normalized ratio (INR). Out of these, 98 (33.3%) had major bleeding and 196 (66.7%) did not have any bleeding. Additionally, more than two-thirds of patients displayed undernutrition, which was more prevalent in bleeding than non-bleeding patients (OR = 1.85, CI95%: 1.07-3.21). There was a higher bleeding risk for those with severe undernutrition (OR = 2.66, CI95%: 1.58-4.46), with no difference found concerning moderate undernutrition. Bleeding patients had lower plasma-zinc concentrations than non-bleeding patients (9.4 ± 3.6 vs. 10.5 ± 3.7 μmol/L, p = 0.003); among them, there was a higher rate of patients with plasma zinc under 5 μmol/L (9% vs. 2%, p < 0.001).
Conclusion: Patients with undernutrition on VKA exhibit a significantly higher bleeding risk, which increases three-fold in case of severe undernutrition. The evaluation of nutritional status provides additional, valuable prognosis information prior to initiating VKA therapy. CLINICALTRIALS.
Gov number: NCT01742871.
Keywords: Anticoagulant agent; Bleeding; Micronutrient; Undernutrition.
The main function of blood platelets is to form hemostatic plugs and enable thrombosis. These properties, however, can be greatly influenced by dietary components which may inhibit certain steps of platelet activation, including platelet aggregation. Such inhibition can play a role in the prophylaxis and treatment of cardiovascular diseases associated with blood platelet hyperactivation. In fact, plant and fish oils have been identified and specifically used for this purpose. Numerous in vivo and in vitro experiments have explored the potential use of these oils to inhibit platelet activation as well as their role in reducing oxidative stress and blood pressure, and lowering triglyceride and cholesterol. This chapter presents and compares the anti-platelet effects of fish and plant oils and their constituents, especially fatty acids. Studies on healthy subjects and patients with various cardiovascular diseases are also examined. Findings indicate that both fish and plant oils contain protective components with anti-platelet activity having clearly defined mechanisms of action. Although both are excellent sources of omega fatty acids and vitamins, plant oils contain components with cardioprotective benefit in hypercholesterolemics, i.e., phytosterols. Plant oils may hence play a key role in strategies for preventing and treating cardiovascular diseases associated with platelet hyperactivation. Further studies are clearly needed to determine the precise dose of these components needed for effective prophylaxis and treatment.
Aims:
Hydrogen (H2) has antioxidant effects. The pharmacologic function of H2 in platelets is not yet clear. Therefore, in this study we sought to investigate the inhibitory effects of H2 on in vitro platelet activation and in vivo prevention of thrombus formation.
Main methods:
After platelets were incubated with H2-rich saline (HRS), platelet adhesion in whole human blood was assessed in fibrinogen-coated perfusion chambers, while rat platelet aggregation induced by ADP, collagen and H2O2 was detected through light transmission aggregometry. The level of P-selectin, thromboxane B2, nitric oxide (NO), malondialdehyde, reactive oxygen species (ROS), cGMP, extracellular signal-regulated kinases 1 and 2 (p-ERK1/2), and fibrinogen binding to platelets were evaluated in vitro. Besides, the in vivo effects were examined in arterio-venous shunt thrombosis, FeCl3-induced artery thrombus formation, and tail bleeding time in mice and rats.
Key findings:
HRS prolonged tail bleeding time in mice and rats, decreased thrombus weight and prolonged the time to occlusion in rat and mouse thrombosis models in vivo and inhibited platelet adhesion as well as aggregation in vitro. Additionally, HRS decreased P-selectin expression, release of thromboxane B2, ROS, and fibrinogen binding, but enhanced NO levels in H2O2-exposed platelets. HRS also decreased malondialdehyde levels in plasma of the rat arterial thrombosis or H2O2-exposed platelet model. Moreover, HRS increased cGMP level, decreased p-ERK1/2 (diminished with KT5823) in the platelets stimulated by H2O2.
Significance:
These results suggest that H2 has antithrombotic effects, which may be due to its antioxidant property and subsequent inhibition of platelet activation via NO/cGMP/PKG/ERK pathway.
Background:
The extent to which omega-3 fatty acid status is related to risk for death from any cause and for incident cardiovascular disease (CVD) remains controversial.
Objective:
To examine these associations in the Framingham Heart Study.
Design:
Prospective and observational.
Setting:
Framingham Heart Study Offspring cohort.
Measurements:
The exposure marker was red blood cell levels of eicosapentaenoic and docosahexaenoic acids (the Omega-3 Index) measured at baseline. Outcomes included mortality (total, CVD, cancer, and other) and total CVD events in participants free of CVD at baseline. Follow-up was for a median of 7.3 years. Cox proportional hazards models were adjusted for 18 variables (demographic, clinical status, therapeutic, and CVD risk factors).
Results:
Among the 2500 participants (mean age 66 years, 54% women), there were 350 deaths (58 from CVD, 146 from cancer, 128 from other known causes, and 18 from unknown causes). There were 245 CVD events. In multivariable-adjusted analyses, a higher Omega-3 Index was associated with significantly lower risks (P-values for trends across quintiles) for total mortality (P = .02), for non-CVD and non-cancer mortality (P = .009), and for total CVD events (P = .008). Those in the highest (>6.8%) compared to those in the lowest Omega-3 Index quintiles (<4.2%) had a 34% lower risk for death from any cause and 39% lower risk for incident CVD. These associations were generally stronger for docosahexaenoic acid than for eicosapentaenoic acid. When total cholesterol was compared with the Omega-3 Index in the same models, the latter was significantly related with these outcomes, but the former was not.
Limitations:
Relatively short follow-up time and one-time exposure assessment.
Conclusions:
A higher Omega-3 Index was associated with reduced risk of both CVD and all-cause mortality.
Purpose of review:
The primary objective of this review is to identify dietary patterns with beneficial effects on cardiovascular health of adults with type 2 diabetes.
Recent findings:
The prevalence of diabetes is increasing globally. People with diabetes have a greater risk for cardiovascular disease. Mediterranean diet, dietary approaches to stop hypertension diet, vegetarian diet, traditional Korean diet, Japanese diet, and low-glycemic-index diet can reduce cardiovascular disease risk in people with diabetes. Dietary intake is a key modifiable factor in the management of diabetes and plays a significant role in limiting the incidence of cardiovascular diseases.
Background:
The prognostic value of circulating polyunsaturated fatty acid (PUFA) levels is unclear.
Objectives:
To determine the associations between red blood cell (RBC) PUFA levels and risk for death.
Methods:
This prospective cohort study included 6501 women aged 65 to 80 years who participated in the Women's Health Initiative Memory Study (enrolment began 1996). RBC PUFA levels were measured at baseline and expressed as a percent of total RBC PUFAs. PUFAs of primary interest were the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum (the Omega-3 Index). PUFAs of secondary interest included the 2 major n-6 PUFAs, linoleic acid and arachidonic acid, and the PUFA factor score (a calculated variable including 6 PUFAs that accounts for their intercorrelations). The primary outcome was total mortality through August 2014.
Results:
After a median of 14.9 years of follow-up, 1851 women (28.5%) had died. RBC levels of EPA and DHA were higher in the survivors (P < .002 for each). In the fully adjusted models, the hazard ratios (99% confidence intervals) for mortality associated with a 1 standard deviation PUFA increase for total mortality were 0.92 (0.85, 0.98) for the Omega-3 Index, 0.89 (0.82, 0.96) for EPA, 0.93 (0.87, 1.0) for DHA, and 0.76 (0.64, 0.90) for the PUFA factor score. There were no significant associations of alpha-linolenic acid, arachidonic acid or linoleic acid with total mortality.
Conclusions:
Higher RBC levels of marine n-3 PUFAs were associated with reduced risk for all-cause mortality. These findings support the beneficial relationship between the Omega-3 Index and health outcomes.
Omega-3 long-chain polyunsaturated fatty acids (n-3 PUFA) play an important role in the regulation of cellular membrane structure and function. They are essential for mammalian cells as they are not able to synthesize their precursor α-linolenic acid (18:3n-3), which can then be converted to more biologically active n-3 PUFA, EPA, and DHA, by a series of desaturation and elongation reactions. In recent years, it has been found that increased intake of n-3 PUFA is associated with a reduced risk of cardiovascular morbidity and mortality. Fish is the main dietary source of n-3 PUFA, although the concentration of n-3 PUFA is below the large amounts required to achieve the therapeutic benefits derived from EPA and DHA. This led to the development of formulations of n-3 PUFA containing high concentrations of purified EPA and DHA in a fixed, predefined ratio, with higher but different oral bioavailability and reasonable patient compliance to be used for dietary supplementation. This article reviews the pharmacokinetic profile of n-3 PUFA, including the digestion and bioavailability, tissular distribution (incorporation in plasma lipids, blood cells, and cell membranes), metabolism (β-oxidation, enzymatic biotransformation, synthesis of eicosanoids and other lipid mediators such as resolvins and protectins), and excretion. Factors that modulate oral bioavailability of n-3 PUFA (chemical and galenic formulations, food intake) are also analyzed. Additionally, the safety profile of n-3 PUFA, with particular attention to an increased bleeding risk, drug interactions, and contraindications, is reviewed.
p>Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver a scientific opinion on the Tolerable Upper Intake Level (UL) of the n-3 LCPUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). Available data are insufficient to establish a UL for n-3 LCPUFA (individually or combined) for any population group. At observed intake levels, consumption of n-3 LCPUFA has not been associated with adverse effects in healthy children or adults. Long-term supplemental intakes of EPA and DHA combined up to about 5 g/day do not appear to increase the risk of spontaneous bleeding episodes or bleeding complications, or affect glucose homeostasis immune function or lipid peroxidation, provided the oxidative stability of the n-3 LCPUFAs is guaranteed. Supplemental intakes of EPA and DHA combined at doses of 2 6 g/day, and of DHA at doses of 2 4 g/day, induce an increase in LDL-cholesterol concentrations of about 3 % which may not have an adverse effect on cardiovascular disease risk, whereas EPA at doses up to 4 g/day has no significant effect on LDL cholesterol. Supplemental intakes of EPA and DHA combined at doses up to 5 g/day, and supplemental intakes of EPA alone up to 1.8 g/day, do not raise safety concerns for adults. Dietary recommendations for EPA and DHA based on cardiovascular risk considerations for European adults are between 250 and 500 mg/day. Supplemental intakes of DHA alone up to about 1 g/day do not raise safety concerns for the general population. No data are available for DPA when consumed alone. In the majority of the human studies considered, fish oils, also containing DPA in generally unknown (but relatively low) amounts, were the source of EPA and DHA.</p
The long-chain polyunsaturated fatty acids (LC-PUFA) of both the n-3 and n-6 families have been extensively studied in a wide variety of disease conditions, but in none more than cardiovascular disease (CVD). The principal n-6 fatty acid in the diet is linoleic acid, and for the n-3 family, the plant-derived alpha-linoleic acid and the major marine-derived eicosapentaenoic and docosahexaenoic acids. Current evidence indicates that higher vs. lower intakes of both families of fatty acids reduce risk for CVD. This review examines the latest evidence to support that claim. Sources of both families of fatty acids, their mechanisms of action, and the utility of blood fatty acid testing are also discussed.
Objective:
To systematically review all the prospective cohort studies that have analysed the relation between adherence to a Mediterranean diet, mortality, and incidence of chronic diseases in a primary prevention setting.
Design:
Meta-analysis of prospective cohort studies.
Data sources:
English and non-English publications in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials from 1966 to 30 June 2008. Studies reviewed Studies that analysed prospectively the association between adherence to a Mediterranean diet, mortality, and incidence of diseases; 12 studies, with a total of 1 574,299 subjects followed for a time ranging from three to 18 years were included.
Results:
The cumulative analysis among eight cohorts (514,816 subjects and 33,576 deaths) evaluating overall mortality in relation to adherence to a Mediterranean diet showed that a two point increase in the adherence score was significantly associated with a reduced risk of mortality (pooled relative risk 0.91, 95% confidence interval 0.89 to 0.94). Likewise, the analyses showed a beneficial role for greater adherence to a Mediterranean diet on cardiovascular mortality (pooled relative risk 0.91, 0.87 to 0.95), incidence of or mortality from cancer (0.94, 0.92 to 0.96), and incidence of Parkinson's disease and Alzheimer's disease (0.87, 0.80 to 0.96).
Conclusions:
Greater adherence to a Mediterranean diet is associated with a significant improvement in health status, as seen by a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and incidence of Parkinson's disease and Alzheimer's disease (13%). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of major chronic diseases.
Moderate regular alcohol intake has been found to be associated with a decreased risk for coronary heart disease and stroke. We investigated the effects of acute intake of red wine (60 g ethanol) and a standard dinner under controlled conditions on haemostatic factors. Shear-induced platelet aggregation (SIPA) decreased after the intake of alcohol irrespective of whether the subjects were fasting or not, and also after the intake of food. The intake of alcohol inhibited the postprandial increase of von Willebrand factor multimers. Plasma levels of plasminogen activator inhibitor 1 activity (PAI-1) and serum triglycerides were increased by alcohol. Excretion of the platelet thromboxane A 2 metabolites 11-dehydrothromboxane B 2 and 2,3-dinorthromboxane B 2 , as well as the endothelial prostacyclin metabolite 2,3-dinor-6-ketoprostaglandin F 1 &agr;, into urine was not influenced by either alcohol or food. We conclude that eating a dinner together with red wine has no untoward effect on SIPA and that the decrease of SIPA is not specific for alcohol.
Although a wealth of literature links dietary factors and coronary heart disease (CHD), the strength of the evidence supporting valid associations has not been evaluated systematically in a single investigation.
We conducted a systematic search of MEDLINE for prospective cohort studies or randomized trials investigating dietary exposures in relation to CHD. We used the Bradford Hill guidelines to derive a causation score based on 4 criteria (strength, consistency, temporality, and coherence) for each dietary exposure in cohort studies and examined for consistency with the findings of randomized trials.
Strong evidence supports valid associations (4 criteria satisfied) of protective factors, including intake of vegetables, nuts, and "Mediterranean" and high-quality dietary patterns with CHD, and associations of harmful factors, including intake of trans-fatty acids and foods with a high glycemic index or load. Among studies of higher methodologic quality, there was also strong evidence for monounsaturated fatty acids and "prudent" and "western" dietary patterns. Moderate evidence (3 criteria) of associations exists for intake of fish, marine omega-3 fatty acids, folate, whole grains, dietary vitamins E and C, beta carotene, alcohol, fruit, and fiber. Insufficient evidence (< or =2 criteria) of association is present for intake of supplementary vitamin E and ascorbic acid (vitamin C); saturated and polyunsaturated fatty acids; total fat; alpha-linolenic acid; meat; eggs; and milk. Among the dietary exposures with strong evidence of causation from cohort studies, only a Mediterranean dietary pattern is related to CHD in randomized trials.
The evidence supports a valid association of a limited number of dietary factors and dietary patterns with CHD. Future evaluation of dietary patterns, including their nutrient and food components, in cohort studies and randomized trials is recommended.
The aim of this review is to discuss the accumulating evidence that suggests that grape extracts and purified grape polyphenols possess a diverse array of biological actions and may be beneficial in the prevention of some inflammatory-mediated diseases including cardiovascular disease. The active components from grape extracts, which include the grape seed, grape skin, and grape juice, that have been identified thus far include polyphenols such as resveratrol, phenolic acids, anthocyanins, and flavonoids. All possess potent antioxidant properties and have been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. These compounds also possess a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic, antiarrhythmic, and vasorelaxation actions. Although not exclusive, antioxidant properties of grape polyphenols are likely to be central to their mechanism(s) of action, which also include cellular signaling mechanisms and interactions at the genomic level. This review discusses some of the evidence favoring the consumption of grape extracts rich in polyphenols in the prevention of cardiovascular disease. Consumption of grape and grape extracts and/or grape products such as red wine may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease.
To systematically review all the prospective cohort studies that have analysed the relation between adherence to a Mediterranean diet, mortality, and incidence of chronic diseases in a primary prevention setting.
Meta-analysis of prospective cohort studies.
English and non-English publications in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials from 1966 to 30 June 2008. Studies reviewed Studies that analysed prospectively the association between adherence to a Mediterranean diet, mortality, and incidence of diseases; 12 studies, with a total of 1 574,299 subjects followed for a time ranging from three to 18 years were included.
The cumulative analysis among eight cohorts (514,816 subjects and 33,576 deaths) evaluating overall mortality in relation to adherence to a Mediterranean diet showed that a two point increase in the adherence score was significantly associated with a reduced risk of mortality (pooled relative risk 0.91, 95% confidence interval 0.89 to 0.94). Likewise, the analyses showed a beneficial role for greater adherence to a Mediterranean diet on cardiovascular mortality (pooled relative risk 0.91, 0.87 to 0.95), incidence of or mortality from cancer (0.94, 0.92 to 0.96), and incidence of Parkinson's disease and Alzheimer's disease (0.87, 0.80 to 0.96).
Greater adherence to a Mediterranean diet is associated with a significant improvement in health status, as seen by a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and incidence of Parkinson's disease and Alzheimer's disease (13%). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of major chronic diseases.
The mechanisms through which moderate wine consumption reduces ischemic cardiovascular events are not yet fully unraveled. Grape extracts or a mixture of the polyphenols contained in wine were previously shown to increase nitric oxide (NO); however, little information is available on the effect of resveratrol, one of the main polyphenols of wine, on platelet NO production. We assessed the effects of resveratrol, at the concentrations attainable after moderate wine intake, on platelet NO production and the mechanism of this activity. Twenty healthy volunteers were studied before and after 15 d of controlled white or red wine intake (300 mL/d). After wine intake, plasma resveratrol and the release of NO by stimulated platelets increased significantly. Resveratrol, at the concentrations detected in plasma after wine intake, was incubated in vitro with washed platelets and several variables related to NO production and to signal transduction were measured. Resveratrol in vitro enhanced significantly the production of NO by stimulated platelets, the activity of platelet NO synthase (NOS), phosphorylation of protein kinase B, an activator of the endothelial NOS (eNOS), and phosphorylation of vasodilator-activated protein (VASP), an expression of the biologic activity of NO in platelets. Simultaneously, we observed decreased phosphorylation of P38 mitogen-activated protein kinase (p38MAPK), a proinflammatory pathway in human platelets, a reduction of the activity of NADPH oxidase, a major source of reactive oxygen species (ROS) and of the generation of O(2)(-) radicals, as detected by cytochrome C reduction. In conclusion, resveratrol, at concentrations attainable after moderate wine intake, activates platelet eNOS and in this way blunts the proinflammatory pathway linked to p38MAPK, thus inhibiting ROS production and ultimately platelet function. This activity may contribute to the beneficial effects of moderate wine intake on ischemic cardiovascular disease.
Intakes of alcohol and saturated fatty acids were determined through a dietary questionnaire from 1600 men (aged 49-66 y) in the Caerphilly Prospective Heart Disease Study. Platelet aggregation induced by thrombin adenosine disphosphate (ADP), and collagen was studied in subjects who had fasted and had not recently taken drugs affecting platelets. In subjects who drank alcohol, the odds ratio of a high response to aggregation was significantly reduced (primary ADP, P less than 0.05; secondary ADP, P less than 0.001; collagen, P less than 0.02). The significance was enhanced by adjusting for smoking and by including only the subjects with a high intake of saturated fatty acids or a low intake of polyunsaturated fatty acids. By contrast, the responsiveness to thrombin was slightly increased at all levels of alcohol consumption. We therefore suggest that part of the effects of alcohol on coronary heart disease may be mediated by a dose-dependent effect on certain platelet functions, modulated by the intake of dietary fat.
Platelet function and fatty acid composition were investigated in 30 healthy male subjects who ate a controlled-saturated-fatty-acid (baseline) diet for 3 wk and then consumed either safflower oil or canola oil as a major fat source for 8 wk. Fatty acid composition of platelet phospholipids reflected changes in dietary fatty acid composition. Compared with baseline a 35% decrease (P less than 0.05) in arachidonic acid was observed in platelet phospholipids of the canola-oil diet group while long chain n-3 fatty acids rose 7-26% (P greater than 0.05). Compared with baseline both unsaturated-fatty-acid diets reduced platelet aggregation at 3 wk of oil-based diet feeding (P less than 0.01) whereas only canola oil influenced platelet function (lowered ATP secretion) at 8 wk (P less than 0.01). No significant difference was observed in thromboxane B2 concentrations between oil-treatment groups at 8 wk. Both oil-based diets had short-term beneficial effects on platelet function but the effect of canola oil persisted longer.
Consumption of n-3 polyunsaturated fatty acids (n-3 PUFAs) is associated with a reduced incidence of coronary arterial diseases. Dietary n-3 PUFAs act via several mechanisms. They depress plasma lipids, especially triglycerides (TGs), by inhibiting hepatic TGs and possibly apoprotein synthesis. They replace arachidonic acid (AA) in phospholipid pools with eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA). EPA and DHA, when released, inhibit cyclooxygenase and lipoxygenase and reduce eicosanoid synthesis, particularly thromboxane (TXA2) and leukotriene B4 (LTB4), by platelets and macrophages. Reduction of the proaggregatory, vasoconstrictive TXA2 decreases the thrombotic tendency of platelets. This is augmented by the limited depression of the vasoactive antiaggregatory prostacyclin (PGI2) and the generation of antiaggregatory prostaglandin I3 (PGI3) from EPA. The n-3 PUFAs also depress eicosanoid metabolism in platelets, monocytes, and macrophages, and thereby may retard the initiation and progress of atherogenesis. n-3 PUFAs reduce blood pressure and blood viscosity and modulate membrane fluidity and associated enzyme and receptor functions. The collective effects of n-3 PUFAs may account for the reduction in coronary arterial disease in populations consuming foods containing n-3 PUFAs.
Platelet adhesiveness was tested ex vivo in a group of six normal individuals receiving varying doses of alpha-tocopherol. Adhesion to glass slides coated with fibronectin, collagen, fibrinogen, or plasma proteins was studied by perfusing platelet-rich plasma through a flow chamber that allowed time- and space-resolved observations of platelet adhesion. Platelet adherence was measured in an area of parallel flow lines and low shear rate under standardized conditions before and after dietary supplementation with vitamin E at doses of 200 and 400 IU/d. Platelet adherence differed in magnitude depending on the adhesive surface. There was a distinct preference of platelets to adhere to sites that had been previously occupied. A remarkable decrease in platelet adherence was observed after vitamin E supplementation. The average decrease in adhesion after 2 weeks of 200 IU vitamin E was 75%. After 2 weeks of 400 IU vitamin E, platelet adhesion was reduced by 82%. The inhibitory activity of alpha-tocopherol was dose dependent and correlated well with the increase in alpha-tocopherol concentration in platelets after supplementation. Scanning electron microscopy revealed a striking decrease of pseudopodium formation in alpha-tocopherol- enriched platelets. Our results suggest that vitamin E may also be an effective antiadhesive agent in vivo.
Background-Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F-2-isoprostane 8-iso-prostaglandin (PG)F-2 alpha, a bioactive product of arachidonic acid peroxidation, is enhanced in DM and contributes to platelet activation. Methods and Results-Urine samples were obtained from 85 diabetic patients and 85 age- and sex-matched healthy subjects for measurement of immunoreactive 8-iso-PGF(2 alpha) and 11-dehydro-thromboxane B-2 (TXM), an in vivo index of platelet activation. Sixty-two had non-insulin-dependent (NID)DM, and 23 had insulin-dependent (ID) DM, Vitamin E supplementation, metabolic control, and cyclooxygenase inhibitors were used to investigate the mechanisms of formation of 8-iso-PGF(2 alpha) in this setting. Urinary 8-iso-PGF(2 alpha) excretion was significantly higher (P=0.0001) in NIDDM patients (419 +/- 208 pg/mg creatinine; range 160 to 1014) than in age-matched control subjects (208 +/- 92; 41 to 433), Urinary 8-iso-PGF(2 alpha) was linearly correlated with blood glucose and urinary TXM. 8-iso-PGF(2 alpha) excretion was also significantly (P=0.0001) higher in IDDM patients (400 +/- 146; 183 to 702) than in control subjects (197 +/- 69; 95 to 353), Vitamin E supplementation (600 mg/d for 14 days) was associated with a statistically significant reduction in both urinary 8-iso-PGF(2 alpha) (by 37%) and TXM (by 43%) in 10 NIDDM patients. Improved metabolic control was associated with a significant (P=0.0001) reduction in 8-iso-PGF(2 alpha) and TXM excretion by 32% and 41%, respectively, in 21 NIDDM patients. 8-iso-PGF(2 alpha) was unchanged after 2-week dosing with aspirin and indobufen despite profound suppression of TXM excretion. Conclusions-We conclude that DM is associated with increased formation of F-2-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired glycemic control and persistent platelet activation. These results provide a rationale for dos-finding studies of antioxidant treatment in diabetes.
It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease, cancer, and other adverse outcomes. METHODS: 20,536 UK adults (aged 40-80) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo. Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants. An average of 83% of participants in each treatment group remained compliant during the scheduled 5-year treatment period. Allocation to this vitamin regimen approximately doubled the plasma concentration of alpha-tocopherol, increased that of vitamin C by one-third, and quadrupled that of beta-carotene. Primary outcomes were major coronary events (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. FINDINGS: There were no significant differences in all-cause mortality (1446 [14.1%] vitamin-allocated vs 1389 [13.5%] placebo-allocated), or in deaths due to vascular (878 [8.6%] vs 840 [8.2%]) or non-vascular (568 [5.5%] vs 549 [5.3%]) causes. Nor were there any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death (1063 [10.4%] vs 1047 [10.2%]), non-fatal or fatal stroke (511 [5.0%] vs 518 [5.0%]), or coronary or non-coronary revascularisation (1058 [10.3%] vs 1086 [10.6%]). For the first occurrence of any of these "major vascular events", there were no material differences either overall (2306 [22.5%] vs 2312 [22.5%]; event rate ratio 1.00 [95% CI 0.94-1.06]) or in any of the various subcategories considered. There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause. INTERPRETATION: Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe. But, although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.
OBJECTIVE: To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. DESIGN: Collaborative meta-analyses (systematic overviews). INCLUSION CRITERIA: Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. STUDIES REVIEWED: 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. MAIN OUTCOME MEASURE: "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. RESULTS: Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. CONCLUSIONS: Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.
Background There is conflicting evidence on the benefits of foods rich in vitamin E (alpha-tocopherol), n-3 polyunsaturated fatty acids (PUFA), and their pharmacological substitutes. We investigated the effects of these substances as supplements in patients who had myocardial infarction. Methods From October, 1993, to September, 1995, 11324 patients surviving recent (less than or equal to 3 months) myocardial infarction were randomly assigned supplements of n-3 PUFA (Ig daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy endpoint was death, non-fatal myocardial infarction, and stroke. Intention-to-treat analyses were done according to a factorial design (two-way) and by treatment group (four-way). Findings Treatment with n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary endpoint (relative risk decrease 10% [95% CI 1-18] by two-way analysis, 15% [2-26] by four-way analysis). Benefit was attributable to a decrease in the risk of death (14% [3-24] two-way, 20% [6-33] four-way) and cardiovascular death (17% [3-29] two-way, 30% [13-44] four-way). The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint (14% [1-26]) and for fatal events (20% [5-33]). Interpretation Dietary supplementation with n-3 PUFA led to a clinically important and satistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.
Background. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. Methods. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. Results. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha- tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. Conclusions. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.
Background:
It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease, cancer, and other adverse outcomes.
Methods:
20,536 UK adults (aged 40-80) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo. Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants. An average of 83% of participants in each treatment group remained compliant during the scheduled 5-year treatment period. Allocation to this vitamin regimen approximately doubled the plasma concentration of alpha-tocopherol, increased that of vitamin C by one-third, and quadrupled that of beta-carotene. Primary outcomes were major coronary events (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.
Findings:
There were no significant differences in all-cause mortality (1446 [14.1%] vitamin-allocated vs 1389 [13.5%] placebo-allocated), or in deaths due to vascular (878 [8.6%] vs 840 [8.2%]) or non-vascular (568 [5.5%] vs 549 [5.3%]) causes. Nor were there any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death (1063 [10.4%] vs 1047 [10.2%]), non-fatal or fatal stroke (511 [5.0%] vs 518 [5.0%]), or coronary or non-coronary revascularisation (1058 [10.3%] vs 1086 [10.6%]). For the first occurrence of any of these "major vascular events", there were no material differences either overall (2306 [22.5%] vs 2312 [22.5%]; event rate ratio 1.00 [95% CI 0.94-1.06]) or in any of the various subcategories considered. There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause.
Interpretation:
Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe. But, although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.
To the Editor:
In their excellent review, Steinberg and Witztum1 focused their attention on the different reasons why treatment with natural antioxidants has so far not convinced us that they may prevent atherosclerotic progression and its cardiovascular complications. The use of reliable biological markers of oxidative stress, identification of a population suitable for antioxidant treatment, and the choice of an adequate daily regimen of antioxidants are important points that would help us plan future trials with antioxidants. In accordance with the authors, we believe that knowledge of the intrinsic mechanism leading to LDL oxidation in vivo and the balance between oxidant stress and natural antioxidant defense is likely a crucial element for exploring the role of …
Pregnancy-associated plasma protein A (PAPP-A) and matrix metalloproteinase 9 (MMP-9), both zinc-binding endopeptidases, are abundantly expressed in ruptured and eroded plaques in patients with acute coronary syndromes (ACS). The adhesion molecule CD-40 ligand (CD40L), expressed on activated platelets and T-lymphocytes, can activate metalloproteinases and thereby promote plaque-rupture. N-3 fatty acids, through their anti-inflammatory and anti-thrombotic properties, might reduce the levels of these proatherosclerotic markers and thereby the development of ACS. 300 patients were randomized on day 4 to 6 following an acute myocardial infarction (MI) to receive either 4 g of n-3 fatty acids or a similar daily dose of corn oil for at least one year. We compared levels of PAPP-A, MMP-9 and sCD-40 L at baseline and 12 months in each group, and also looked for inter-group changes. In the omega-3 group, the median level of PAPP-A rose from 0.47 mU/l to 0.56 mU/l (p < 0.001). In the same group, sCD-40 L decreased from a mean baseline value of 5.19 ng/ml to 2.45 ng/ml (p < 0.001) and MMP-9 decreased nonsignificantly from 360.50 ng/ml to 308.00 ng/ml. Corresponding values for the corn oil group were 0.54 mU/l to 0.59 mU/l for PAPP-A (p = 0.007), 5.27 ng/ml to 2.84 ng/ml for sCD-40 L (p < 0.001) and 430.00 ng/ml to 324.00 ng/ml for MMP-9 (p = ns), respectively. In conclusion; both interventions resulted in a significant rise in PAPP-A, a significant decrease in sCD40L and a non-significant decrease in MMP-9 after 12 months of treatment in MI survivors. No inter-group differences were noted.
Coronary artery disease is responsible for much mortality and morbidity around the world. Platelets are involved in atherosclerotic disease development and the reduction of platelet activity by medications reduces the incidence and severity of disease. Red wine and grapes contain polyphenolic compounds, including flavonoids, which can reduce platelet aggregation and have been associated with lower rates of cardiovascular disease. Citrus fruits contain different classes of polyphenolics that may not share the same properties. This study evaluated whether commercial grape, orange and grapefruit juices, taken daily, reduce ex vivo platelet activity. In a randomized cross-over design, ten healthy human subjects (ages 26-58 y, five of each gender) drank 5-7.5 mL/(kg. d) of purple grape juice, orange juice or grapefruit juice for 7-10 d each. Platelet aggregation (whole blood impedance aggregometry, Chronolog Model #590) at baseline was compared to results after consumption of each juice. Drinking purple grape juice for one week reduced the whole blood platelet aggregation response to 1 mg/L of collagen by 77% (from 17.9 +/- 2.3 to 4.0 +/- 6.8 ohms, P = 0.0002). Orange juice and grapefruit juice had no effect on platelet aggregation. The purple grape juice had approximately three times the total polyphenolic concentration of the citrus juices and was a potent platelet inhibitor in healthy subjects while the citrus juices showed no effect. The platelet inhibitory effect of the flavonoids in grape juice may decrease the risk of coronary thrombosis and myocardial infarction.
Several recent studies have indicated the possible beneficial effects of antioxidants, specifically vitamin E, in primary and secondary coronary prevention. These studies suggest that a diet enriched in vitamin E is insufficient to have a significant protective effect, whereas supplements, in excess of 200 international units (IU) per day, are efficacious in preventing coronary disease in both men and women. The mechanisms by which vitamin E may exert its protection are uncertain, but, vitamin E is lipophilic and has been shown to inhibit the oxidative modification of low density lipoprotein (LDL), a process thought to be of crucial importance in atherogenesis. We have also previously shown that alpha-tocopherol (the biologically most potent isomer of vitamin E) has important direct effects on vascular endothelial and smooth muscle cells. In the present study we have investigated the effects of oral supplements of vitamin E (400 IU per day) on platelet and mononuclear cell function in patients with hypercholesterolaemia. We found that although vitamin E supplementation had no significant effect on mononuclear cell adhesion ex vivo, it had a significant effect on the thrombin-induced platelet aggregation (P < 0.01; ANOVA): 6 weeks after starting the vitamin E supplements, the mean EC50 for thrombin-induced aggregation increased 132% (P < 0.05; paired t-test) compared to treatment with placebo. The effects of vitamin E on platelet function may, in part, explain its anti-atherogenic properties.
Objective:
To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.
Design:
Collaborative meta-analyses (systematic overviews).
Inclusion criteria:
Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen.
Studies reviewed:
287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens.
Main outcome measure:
"Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death.
Results:
Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000.
Conclusions:
Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.
To the Editor: In their randomized controlled trial, Dr Sesso and colleagues1 tested the hypothesis that antioxidant supplements could reduce the risk of a composite end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Patients were randomly allocated to antioxidant treatment (400 IU of vitamin E every other day or 500 mg of vitamin C daily) or to placebo and followed up for 8 years. During the follow-up neither vitamin E nor vitamin C reduced the risk of major cardiovascular events, suggesting that these supplements are not indicated to prevent atherosclerotic progression and its vascular complications. This finding is in line with the majority of interventional trials with antioxidants showing that antioxidants such as vitamins E and C are unable to influence vascular outcome in patients at risk of or with previous cardiovascular disease.2
Mechanical reperfusion with stenting for ST-elevation myocardial infarction (STEMI) is supported by dual antiplatelet treatment with aspirin and clopidogrel. Prasugrel, a potent and rapid-acting thienopyridine, is a potential alternative to clopidogrel. We aimed to assess prasugrel versus clopidogrel in patients undergoing percutaneous coronary intervention (PCI) for STEMI.
We undertook a double-blind, randomised controlled trial in 707 sites in 30 countries. 3534 participants presenting with STEMI were randomly assigned by interactive voice response system either prasugrel (60 mg loading, 10 mg maintenance [n=1769]) or clopidogrel (300 mg loading, 75 mg maintenance [n=1765]) and were unaware of the allocation. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Efficacy analyses were by intention to treat. Follow-up was to 15 months, with secondary analyses at 30 days. This trial is registered with ClinicalTrials.gov, number NCT00097591.
At 30 days, 115 (6.5%) individuals assigned prasugrel had met the primary endpoint compared with 166 (9.5%) allocated clopidogrel (hazard ratio 0.68 [95% CI 0.54-0.87]; p=0.0017). This effect continued to 15 months (174 [10.0%] vs 216 [12.4%]; 0.79 [0.65-0.97]; p=0.0221). The key secondary endpoint of cardiovascular death, myocardial infarction, or urgent target vessel revascularisation was also significantly reduced with prasugrel at 30 days (0.75 [0.59-0.96]; p=0.0205) and 15 months (0.79 [0.65-0.97]; p=0.0250), as was stent thrombosis. Treatments did not differ with respect to thrombolysis in myocardial infarction (TIMI) major bleeding unrelated to coronary-artery bypass graft (CABG) surgery at 30 days (p=0.3359) and 15 months (p=0.6451). TIMI life-threatening bleeding and TIMI major or minor bleeding were also similar with the two treatments, and only TIMI major bleeding after CABG surgery was significantly increased with prasugrel (p=0.0033).
In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding.
Several studies have documented an inverse association between adherence to the Mediterranean diet and risk of coronary heart disease (CHD), but few data are available on the relationship between Mediterranean diet and risk of stroke.
For the present study, 74,886 women 38 to 63 years of age in the Nurses' Health Study, a cohort study of female nurses, without a history of cardiovascular disease and diabetes were followed up from 1984 to 2004. We computed an Alternate Mediterranean Diet Score from self-reported dietary data collected through validated food frequency questionnaires administered 6 times between 1984 and 2002. Relative risks for incident CHD, stroke, and combined fatal cardiovascular disease were estimated with Cox proportional-hazards models adjusted for cardiovascular risk factors. During 20 years of follow-up, 2391 incident cases of CHD, 1763 incident cases of stroke, and 1077 cardiovascular disease deaths (fatal CHD and strokes combined) were ascertained. Women in the top Alternate Mediterranean Diet Score quintile were at lower risk for both CHD and stroke compared with those in the bottom quintile (relative risk [RR], 0.71; 95% CI, 0.62 to 0.82; P for trend<0.0001 for CHD; RR, 0.87; 95% CI, 0.73 to 1.02; P for trend=0.03 for stroke). Cardiovascular disease mortality was significantly lower among women in the top quintile of the Alternate Mediterranean Diet Score (RR, 0.61; 95% CI, 0.49 to 0.76; P for trend<0.0001).
A greater adherence to the Mediterranean diet, as reflected by a higher Alternate Mediterranean Diet Score, was associated with a lower risk of incident CHD and stroke in women.
Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements. A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer.
To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men.
The Physicians' Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled.
Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.
Prostate and total cancer.
During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85-1.09; P = .58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years; HR, 1.04; 95% CI, 0.95-1.13; P = .41). There was also no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI, 0.92-1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years; HR, 1.02; 95% CI, 0.90-1.15; P = .80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk.
In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.
clinicaltrials.gov Identifier: NCT00270647.
Dark chocolate (DC) is one of the richest sources of flavonoids. Since DC has been demonstrated to have beneficial effects on the cardiovascular system, our study examined its effect on platelet reactivity, inflammation, and lipid levels in healthy subjects.
In 28 healthy volunteers, we analyzed the effect of one week of DC (providing 700 mg of flavonoids/day). The primary outcome was to determine the effects of DC consumption on platelet activity measured by flow cytometry (adenosine diphosphate [ADP]- and arachidonic acid [AA]-induced total and activated glycoprotein (GP) IIb/IIIa as well as P-selectin expression). In addition to this, we measured the effect of DC on high-sensitivity C-reactive protein (hsCRP), high-density lipid cholesterol (HDL) and low-density lipid cholesterol (LDL) levels.
Following seven days of regular DC ingestion, LDL fell by 6% (120 +/- 38 vs 112 +/- 37 mg/dL, P < 0.018) and HDL rose by 9% (66 +/- 23 vs 72 +/- 26 mg/dL, P < 0.0019). ADP- and AA-induced activated GPIIb/IIIa expression was reduced by DC [27.3 +/- 27.8 vs 17.4 +/- 20.5 mean fluorescence intensity (MFI), P < 0.006; and 9.2 +/- 6.5 vs. 6.1 +/- 2.2 MFI, P < 0.005, respectively]. DC reduced hsCRP levels in women (1.8 +/- 2.1 vs. 1.4 +/- 1.7 mg/dL, P < 0.04).
One week of DC ingestion improved lipid profiles and decreased platelet reactivity within the total group while reducing inflammation only in women. Regular dark chocolate ingestion may have cardioprotective properties. Further long-term research is warranted to evaluate the effect of flavonoids on cardiovascular health and to determine whether DC's beneficial effects are related to flavonoids or some yet unknown component. This research is based on a larger study which was presented at the American Heart Association Scientific Sessions 2007.
Basic research and observational studies suggest vitamin E or vitamin C may reduce the risk of cardiovascular disease. However, few long-term trials have evaluated men at initially low risk of cardiovascular disease, and no previous trial in men has examined vitamin C alone in the prevention of cardiovascular disease.
To evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of major cardiovascular events among men.
The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31, 2007. There were 14,641 US male physicians enrolled, who were initially aged 50 years or older, including 754 men (5.1%) with prevalent cardiovascular disease at randomization.
Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.
A composite end point of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death).
During a mean follow-up of 8 years, there were 1245 confirmed major cardiovascular events. Compared with placebo, vitamin E had no effect on the incidence of major cardiovascular events (both active and placebo vitamin E groups, 10.9 events per 1000 person-years; hazard ratio [HR], 1.01 [95% confidence interval {CI}, 0.90-1.13]; P = .86), as well as total myocardial infarction (HR, 0.90 [95% CI, 0.75-1.07]; P = .22), total stroke (HR, 1.07 [95% CI, 0.89-1.29]; P = .45), and cardiovascular mortality (HR, 1.07 [95% CI, 0.90-1.28]; P = .43). There also was no significant effect of vitamin C on major cardiovascular events (active and placebo vitamin E groups, 10.8 and 10.9 events per 1000 person-years, respectively; HR, 0.99 [95% CI, 0.89-1.11]; P = .91), as well as total myocardial infarction (HR, 1.04 [95% CI, 0.87-1.24]; P = .65), total stroke (HR, 0.89 [95% CI, 0.74-1.07]; P = .21), and cardiovascular mortality (HR, 1.02 [95% CI, 0.85-1.21]; P = .86). Neither vitamin E (HR, 1.07 [95% CI, 0.97-1.18]; P = .15) nor vitamin C (HR, 1.07 [95% CI, 0.97-1.18]; P = .16) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke (HR, 1.74 [95% CI, 1.04-2.91]; P = .04).
In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events. These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men.
clinicaltrials.gov Identifier: NCT00270647.
Omega-3 fatty acids (n-3 FA) from oily fish are clinically useful for lowering triglycerides and reducing risk of heart attacks. Accordingly, patients at risk are often advised to take both aspirin and n-3 FA. However, both of these agents can increase bleeding times, and the extent to which the combination inhibits platelet function is unknown. The purpose of this pilot study was to determine the effects of a prescription omega-3 FA product (P-OM3) and aspirin, alone and in combination, on platelet aggregation assessed by whole blood impedance aggregometry (WBA). Ten healthy volunteers provided blood samples on four separate occasions: Day 1, baseline; Day 2, one day after taking aspirin (2 x 325 mg tablets); Day 29, after 28 days of P-OM3 (4 capsules/day); and Day 30, after one day of combined P-OM3 and aspirin. WBA was tested with two concentrations of collagen, with ADP and with a thrombin receptor activating peptide (TRAP). Compared to baseline, aspirin alone inhibited aggregation only with low-dose collagen stimulation; P-OM3 alone did not inhibit aggregation with any agonist; and combined therapy inhibited aggregation with all agonists but TRAP. Significant interactions between interventions were not observed in response to any agonist. In conclusion, P-OM3 alone did not inhibit platelet aggregation, but did (with two agonists) when combined with aspirin. Since previous studies have not reported a clinically significant risk for bleeding in subjects on combined therapy, P-OM3 may safely enhance the anti-platelet effect of aspirin.
Death from cardiovascular disease is rare among Eskimos. Haemostasis was investigated in twenty-one Greeland Eskimos and twenty-one age and sex matched Danish controls. Platelet lipid analysis demonstrated that a high consumption of omega-3 polyunsaturated fatty acids (such as cis 5, 8, 11, 14, 17-eicosapentaenoic acid [C20:5]) by Eskimos increased the proportion of omega-3 polyunsaturated fatty acids in the platelets. The Eskimos had a significantly longer bleeding-time due to a reduction in platelet aggregation. It is suggested that C20:5 in the platelets is converted by the vascular-wall tissue to an anti-aggregatory prostacyclin. Partial dietary substitution of arachidonic acid by eicosapentaenoic acid may reduce the incidence of thrombotic disorders, including myocardial infarction.
Vitamin B6 has an antithrombotic effect. This, based on the results of in vitro studies, has been attributed to an antiplatelet effect. We assessed the in vivo effect of vitamin B6 by measuring the effect of long-term administration of vitamin B6 on platelet function and blood coagulation. Vitamin B6 (pyridoxine hydrochloride), 100mg twice daily p.o. for fifteen days, was administered to 10 healthy volunteers. The bleeding time was measured before the first dose and 15 days after. A baseline value, the acute effect, chronic effect, and the acute-on-chronic effect of vitamin B6 was estimated by measuring platelet function. The following tests were performed: platelet aggregation induced by collagen, ADP and epinephrine; thromboxane A2 (TxA2)-production and prostacyclin inhibition of ADP-induced aggregation. The effects on the coagulation system were monitored by measuring: the prothrombin time, activated partial thromboplastin time and levels of coagulation factor. Vitamin B6 significantly prolonged the bleeding time from 4.1 +/- 1.1 minutes to 6.8 +/- 1.0 minutes (p = 0.0063). Aggregation of platelets with collagen was slightly but not significantly inhibited. Platelet aggregation induced with the agonists ADP or epinephrine was significantly inhibited by vitamin B6, and the platelets tended to aggregate at a slightly decreased rate. The mean TxA2-production was slightly, but not significantly, decreased. Vitamin B6 had no effect on the sensitivity of platelets to prostacyclin, or on the coagulation system. Our results indicate that the antithrombotic effects of vitamin B6 is limited to inhibition of platelet function; there was no measurable influence on coagulation. The results of this in vivo study are however such that clinical trials are warranted to further assess the efficacy of vitamin B6 as an antiplatelet drug.