Reviewing the cardiovascular and other health effects of olive oil: Limitations and future directions of current supplement formulations.

AIMS: We reviewed the literature to date for high-level evidence on the cardiovascular and other health effects of olive oil with a focus on the amount, frequency of use and type of olive oil consumed in prior studies. A total of twelve prospective cohort studies with sample sizes of at least 4000 individuals and one meta-analysis were identified. DATA SYNTHESIS: The majority of cohorts followed individuals aged ≥55 years old, free of cardiovascular disease (CVD) at baseline but at high risk, over periods of 4-10 years and with daily consumption amounts of 10-35 g/day. With the exception of the PREDIMED cohort that employed extra virgin olive oil, most remaining studies did not differentiate between different types of olive oil. Taken together, the data suggests an association between greater olive oil consumption and a lower CVD incidence/mortality and stroke risk. We use this information to evaluate the use of commercially available, capsule-based olive oil dietary supplements and suggest future directions. Notably, achieving minimum total daily doses described in the aforementioned studies would be challenging with current market formulations of olive oil supplements dosed at 1-1.25 g/capsule. CONCLUSIONS: Outside of mechanistic studies, little progress has been made in determining the olive oil component(s) underlying the observed health effects given the lack of compositional reporting and consistency across large scale human studies. We propose the use of supplements of varying composition, such as varying total phenolic content, in pragmatic trial designs focused on low-cost methodologies to address this question.

Platelet-conditioned media induces an anti-inflammatory macrophage phenotype through EP4.

BACKGROUND: Platelets are increasingly recognized as immune cells. As such, they are commonly seen to induce and perpetuate inflammation; however, anti-inflammatory activities are increasingly attributed to them. Atherosclerosis is a chronic inflammatory condition. Similar to other inflammatory conditions, the resolution of atherosclerosis requires a shift in macrophages to an M2 phenotype, enhancing their efferocytosis and cholesterol efflux capabilities. OBJECTIVES: To assess the effect of platelets on macrophage phenotype. METHODS: In several in vitro models employing murine (RAW264.7 and bone marrow-derived macrophages) and human (THP-1 and monocyte-derived macrophages) cells, we exposed macrophages to media in which non-agonized human platelets were cultured for 60 minutes (platelet-conditioned media [PCM]) and assessed the impact on macrophage phenotype and function. RESULTS: Across models, we demonstrated that PCM from healthy humans induced a pro-resolving phenotype in macrophages. This was independent of signal transducer and activator of transcription 6 (STAT6), the prototypical pathway for M2 macrophage polarization. Stimulation of the EP4 receptor on macrophages by prostaglandin E2 present in PCM, is at least partially responsible for altered gene expression and associated function of the macrophages-specifically reduced peroxynitrite production, increased efferocytosis and cholesterol efflux capacity, and increased production of pro-resolving lipid mediators (ie, 15R-LXA4 ). CONCLUSIONS: Platelet-conditioned media induces an anti-inflammatory, pro-resolving phenotype in macrophages. Our findings suggest that therapies targeting hemostatic properties of platelets, while not influencing pro-resolving, immune-related activities, could be beneficial for the treatment of atherothrombotic disease.

Cardiovascular Disease Prevention: The Earlier the Better? A Review of Plant Sterol Metabolism and Implications of Childhood Supplementation.

Atherosclerosis is the underlying cause of major cardiovascular events. The development of atherosclerotic plaques begins early in life, indicating that dietary interventions in childhood might be more effective at preventing cardiovascular disease (CVD) than treating established CVD in adulthood. Although plant sterols are considered safe and consistently effective in lowering plasma cholesterol, the health effects of early-life supplementation are unclear. Studies suggest there is an age-dependent effect on plant sterol metabolism: at a younger age, plant sterol absorption might be increased, while esterification and elimination might be decreased. Worryingly, the introduction of low-cholesterol diets in childhood may unintentionally favor a higher intake of plant sterols. Although CVD prevention should start as early as possible, more studies are needed to better elucidate the long-term effects of plant sterol accumulation and its implication on child development.

Comparison between red wine and isolated trans-resveratrol on the prevention and regression of atherosclerosis in LDLr (-/-) mice.

Moderate consumption of red wine has been widely associated with reduced cardiovascular risk, mainly due to its composition in phenolic compounds with antioxidant activity, such as resveratrol. The objective of this study was to compare the effect of red wine vs. trans-resveratrol consumption on the prevention and regression of atherosclerosis in LDLr (-/-) mice. This study consisted of two protocols: "Prevention" (PREV) and "Regression" (REGR). Both protocols included four groups: red wine (WINE), dealcoholized red wine (EXT), trans-resveratrol (RESV), and control (CONT). In PREV protocol, animals received a regular diet for 8 weeks and then switched to an atherogenic diet for the following 8 weeks, while the opposite was performed in REGR. Animals that received atherogenic diet after an initial period of standard diet (PREV) gained more body weight (39.25±2.30%) than the opposite (29.27±1.91%, P=.0013), suggesting an interaction between age and weight gain. Trans-resveratrol showed the highest hypocholesterolemic effect during PREV, reducing total cholesterol, LDL-C, VLDL-C and HDL-C. Supplementation with trans-resveratrol and dealcoholized red wine changed the fatty acids profile in the liver in both protocols, leading to an increase of MDA concentrations and SOD activity in the PREV protocol. In conclusion, supplementation with trans-resveratrol, red wine and the same wine without alcohol altered biomarkers of oxidative stress and lipidemia but had no effect on the prevention or regression of fatty streaks. These data suggest that cardiovascular protection associated with the "French Paradox" may be a result of synergistic effects between wine and the Mediterranean diet.

Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine

OBJECTIVE: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supple-mentation were identified after multivariate analysis (n»10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6e12.RESULTS: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% 3.7,P».002) and C-reactive protein ( 35.5% 5.9,P».03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced bycholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol effluxcapacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. Trial registration: ClinicalTrials.gov, NCT02732223.

Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine.

OBJECTIVE: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supplementation were identified after multivariate analysis (n = 10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6-12. RESULTS: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% ± 3.7, P = .002) and C-reactive protein (-35.5% ± 5.9, P = .03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol efflux capacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02732223.

Enhancing stability of echium seed oil and beta-sitosterol by their coencapsulation by complex coacervation using different combinations of wall materials and crosslinkers.

Intake of omega-3 fatty acids and phytosterols aids in the reduction of cholesterol and serum triglycerides. However, both fatty acids and phytosterols are susceptible to oxidation. This work coencapsulated echium oil (source of stearidonic and alpha-linolenic fatty acids) and beta-sitosterol (phytosterol) by complex coacervation using different combinations of wall materials, and sinapic acid (SA) and transglutaminase as crosslinkers. High encapsulation yields were obtained (29-93% for SA; 68-100% for the mixture of oil and phytosterols) and retention of 49-99% and 16% for encapsulated and free SA, at 30 days-storage. Treatment with gelatin-arabic gum and 0.075 g SA/g gelatin showed the best results: 0.07 mg MDA/g capsule, and retention of 96, 90 and 74% for alpha-linolenic, stearidonic acid and beta-sitosterol at 30 days of storage, respectively. Thus, coencapsulation of echium oil and phytosterol using SA as the crosslinker was possible, obtaining effective vehicles for protection and application of these compounds in foods.

Bioactive compounds as an alternative for drug co-therapy: Overcoming challenges in cardiovascular disease prevention.

Different pharmacological interventions have been applied with success to reduce the progression of atherosclerosis. However, many patients are not good responders or must interrupt treatment due to adverse effects. Bioactive compounds such as omega-3 fatty acids (n-3 FA), plant sterol esters (PSE) and phenolic compounds (PHC) are natural molecules with great potential to reduce the atherosclerosis burden by reducing inflammation, LDL cholesterol (LDL-C) and oxidative stress, respectively. Although their physiological effects on biomarkers are much lower than those expected by drugs used for the same purpose, bioactive compounds can easily be incorporated into the daily diet and present no adverse effects. However, little is known about the combination of n-3 FA, PSE, PHC, and drugs in atherosclerosis progression. This review article summarizes potential effects of co-therapies involving n-3 FA, PSE, and PHC combined with major hypolipidemic drugs on atherosclerosis biomarkers and clinical outcomes. Evidence of additive and/or complementary effects regarding drugs action reveals possible roles for bioactive compounds in disease management. Pharmaceutical companies, physicians, and food scientists should be prepared to better understand this type of interaction and its consequences in terms of efficacy and life quality.

Changes in High-Density Lipoprotein Cholesterol Efflux Capacity After Bariatric Surgery Are Procedure Dependent.

OBJECTIVE: High-density lipoprotein cholesterol efflux capacity (CEC) is inversely associated with incident cardiovascular events, independent of high-density lipoprotein cholesterol. Obesity is often characterized by impaired high-density lipoprotein function. However, the effects of different bariatric surgical techniques on CEC have not been compared. This study sought to determine the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on CEC. APPROACH AND RESULTS: We prospectively studied severely obese, nondiabetic, premenopausal Hispanic women not using lipid medications undergoing RYGB (n=31) or SG (n=36). Subjects were examined before and at 6 and 12 months after surgery. There were no differences in baseline characteristics between surgical groups. Preoperative CEC correlated most strongly with Apo A1 (apolipoprotein A1) concentration but did not correlate with body mass index, waist:hip, high-sensitivity C-reactive protein, or measures of insulin resistance. After 6 months, SG produced superior response in high-density lipoprotein cholesterol and Apo A1 quantity, as well as global and non-ABCA1 (ATP-binding cassette transporter A1)-mediated CEC (P=0.048, P=0.018, respectively) versus RYGB. In multivariable regression models, only procedure type was predictive of changes in CEC (P=0.05). At 12 months after SG, CEC was equivalent to that of normal body mass index control subjects, whereas it remained impaired after RYGB. CONCLUSIONS: SG and RYGB produce similar weight loss, but contrasting effects on CEC. These findings may be relevant in discussions about the type of procedure that is most appropriate for a particular obese patient. Further study of the mechanisms underlying these changes may lead to improved understanding of the factors governing CEC and potential therapeutic interventions to maximally reduce cardiovascular disease risk in both obese and nonobese patients.

Combined bioactive approach over atherosclerosis risk biomarkers / Abordagem combinada de compostos bioativos sobre biomarcadores de risco para aterosclerose

Atherosclerosis, one major cause of morbidity and mortality worldwide, is a complex and multifactorial disease that involves three mainly conditions: chronic inflammation, dyslipidemia and oxidative stress. Although statins are the first-line therapy for LDL cholesterol (LDL-C) lowering, the efficacy of cardiovascular events prevention is limited to 30-40%. This residual risk brought attention to the need of new therapies and clinical targets beyond LDL-C, such as inflammation and oxidative stress. Importantly, suboptimal treatment and/or statin discontinuation due to adverse effects have also been a very challenging clinical problem. Complementary diet therapy can be an effective and safe approach to support pharmacological treatment, especially when drugs alone are insufficient to attenuate risk factors and/or the recommended dose is not well tolerated. The aim of this study was to evaluate the effects of three bioactive components, namely omega-3 fatty acids, plant sterols and polyphenols, on markers of dyslipidemia, inflammation and oxidative stress in patients treated with statins. A randomized, crossover clinical study was carried out, with the participation of 53 subjects. At each intervention period, study participants received a packaged for the functional or control treatment. Functional treatment consisted of fish oil (1.7 g of EPA+DHA/day), chocolate containing plant sterols (2.2 g/day) and green tea (two tea sachets/day). Control treatment consisted of soy oil softgels, regular chocolate and anise tea. After 6 weeks of intervention, functional treatment reduced plasma LDL-C (-13.7% ± 3.7, p=0.002) and C-reactive protein (-35.5% ± 5.9, p=0.027). Plasma triacylglycerol (-15.68% ± 5.94, p=0.02) and MDA (-40.98% ± 6.74, p=0.04) were reduced in subgroups of patients (n=23) with baseline values above the median (93 mg/dL and 2.23 umol/L, respectively). Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its endogenous synthesis. After multivariate analysis, patients identified as "good responders" to supplementation (n=10) were recruited for a pilot protocol of statin dose reduction with complementary diet therapy. Responders received the functional treatment for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6 to 12. No difference was observed for plasma lipids and inflammation biomarkers, cholesterol efflux capacity or HDL particle number after statin dose reduction when compared to standard therapy. Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. This may be particularly helpful for the many patients with, and at risk for, CVD who cannot tolerate high-dose statin therapy

A aterosclerose, uma importante causa mundial de morbidade e mortalidade, é uma doença complexa e multifatorial que envolve três principais condições: inflamação crônica, dislipidemia e estresse oxidativo. Embora as estatinas sejam fármacos de primeira linha para redução de LDL colesterol (LDL-C), sua eficácia na prevenção de eventos cardiovasculares é limitadada a 30-40%. Este risco cardiovascular residual evidencia a necessidade de novas terapias e marcadores clínicos que vão além do LDL-C, como inflamação e estresse oxidativo. Não obstante, tratamento subótimo e/ou interrupção do uso de estatinas devido à ocorrencia de efeitos adversos também é um grave obstáculo na clínica médica. Neste contexto, a terapia dietética complementar representa uma abordagem efetiva e segura para o suporte do tratamento farmacológico, especialmente quando as drogas são insuficientes para atenuar fatores de risco e/ou quando a dose recomendada não é bem tolerada. O objetivo do presente estudo foi avaliar o efeito de três compostos bioativos - ácidos graxos ômega 3, fitosteróis e polifenóis - sobre marcadores de inflamação, lipemia e estresse oxidativo em indivíduos tradados com estatinas. Foi realizado um estudo clínico randomizado, de delineamento crossover, com a participação de 53 voluntários. A cada período de intervenção, os participantes receberam um tratamento funcional ou controle. O tratamento funcional foi composto por cápsulas de óleo de peixe (1.7 g/dia de EPA+DHA), chocolate contendo fitosteróis (2.2 g/dia) e chá verde (dois sachês/dia). O tratamento controle foi composto por cápsulas de óleo de soja, chocolate sem adição de fitosteróis e chá de anis. Após 6 semanas de intervenção, o tratamento funcional reduziu a concentração plasmática de LDL-C (-13.7% ± 3.7, p=0.002) e proteína C-reativa (-35.5% ± 5.9, p=0.027). Triglicerídeos (- 15.68% ± 5.94, p=0.02) e malondialdeído (-40.98% ± 6.74, p=0.04) foram reduzidas apenas em subgrupos de indivíduos que apresentavam valores basais acima da mediana (93 mg/dL e 2.23 umol/L, respectivamente). A análise de latosterol e campesterol no plasma sugeriu que a intensidade da redução de LDL-C não foi influenciada pela síntese endógena de colesterol, mas sim pela taxa de absorção. Após análise multivariada dos resultados, pacientes identificados como "good responders" à suplementação (n=10) foram recrutados para um estudo piloto de redução da dosagem da estatina, aliado à terapia dietética complementar. Estes pacientes receberam o tratamento funcional por 12 semanas: durante as 6 primeiras semanas mantevese a dosagem de estatina, que em seguida foi reduzida em 50% das semanas 6 a 12. Não foram observadas diferenças para os marcadores plasmáticos de lipídeos, inflamação, capacidade de efluxo de colesterol ou número de partículas de HDL após a redução da dose de estatina, quando comparada à terapia convencional. Embora limitado pelo reduzido número de pacientes, o estudo demonstra o potencial para uma nova abordagem terapêutica, combinando reduzida dose de estatina com específicos compostos bioativos. Esta pode ser uma importante alternativa para muitos pacientes em risco cardiovascular e que são intolerantes à terapia com altas doses de estatina.

Mate tea prevents oxidative stress in the blood and hippocampus of rats with acute or chronic ethanol administration.

OBJECTIVE: The aim of this study was to evaluate the influence of acute and chronic intake of mate tea on the effects elicited by acute and chronic administration of ethanol. METHODS: Oxidative stress was evaluated by measuring thiobarbituric acid-reactive substances (TBARS), as well as the activities of the antioxidant enzymes, catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) in the hippocampus and blood of rats. Male Wistar rats were randomly assigned to four groups, for both acute and chronic treatment: (1) control group, (2) treated group, (3) intoxicated group, (4) and intoxicated group treated with mate tea. RESULTS: Both ethanol administrations significantly increased TBARS in plasma and hippocampus of rats and altered antioxidant enzyme activities, changes which were reverted by mate tea administration. CONCLUSIONS: Data indicate that acute and chronic ethanol administration induced oxidative stress in hippocampus and blood and that mate tea treatment was able to prevent this situation.

Protective effect of antioxidants on cerebrum oxidative damage caused by arginine on pyruvate kinase activity.

We have demonstrated that acute arginine administration decreases antioxidant defenses and compromises enzymes of respiratory chain in rat brain. In this study we evaluated in vivo and in vitro effect of arginine on pyruvate kinase activity, as well as its effect on an important parameter of oxidative stress namely thiobarbituric acid-reactive substances (TBA-RS) in cerebrum of rats. We also tested the influence of antioxidants, namely alpha -tocopherol plus ascorbic acid on the effects elicited by arginine in order to investigate the possible participation of free radicals on the effects of arginine on these parameters. Results showed that arginine acute administration inhibited pyruvate kinase activity in cerebrum of rats, as well as increased TBA-RS. By the other hand, arginine added to the incubation medium, in vitro studies, did not alter these parameters in rat cerebrum. In addition, pretreatment with antioxidants prevented the reduction of pyruvate kinase activity and the increase of TBA-RS caused by arginine. The data indicate that acute administration of arginine induces lipid peroxidation in rat cerebrum and that the inhibition of pyruvate kinase activity caused by this amino acid was probably mediated by free radicals since antioxidants prevented such effect. It is presumed that these results might be associated, at least in part, with the neuronal dysfunction of patients affected by hyperargininemia. Finally, we suggest that the administration of antioxidants should be considered as an adjuvant therapy to specific diets in hyperargininemia.