Update of green tea interactions with cardiovascular drugs and putative mechanisms.

Many patients treated with cardiovascular (CV) drugs drink green tea (GT), either as a cultural tradition or persuaded of its putative beneficial effects for health. Yet, GT may affect the pharmacokinetics and pharmacodynamics of CV compounds. Novel GT-CV drug interactions were reported for rosuvastatin, sildenafil and tacrolimus. Putative mechanisms involve inhibitory effects of GT catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and on both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, available data on GT interaction with CV compounds with a narrow therapeutic index, such as warfarin and tacrolimus, derive from single case reports. Conversely, GT interactions with simvastatin, rosuvastatin, nadolol and sildenafil were documented through pharmacokinetic studies. In these, the effect of GT or GT derivatives on drug exposure was mild to moderate, but a high inter-individual variability was observed. Further investigations, including studies on the effect of the dose and the time of GT intake are necessary to understand more in depth the clinical relevance of GT-CV drug interactions.

Increased Levels of Circulating Fatty Acids Are Associated with Protective Effects against Future Cardiovascular Events in Nondiabetics.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide, particularly in individuals with diabetes. The current study objective was to determine the circulating metabolite profiles associated with the risk of future cardiovascular events, with emphasis on diabetes status. Nontargeted metabolomics analysis was performed by LC-HRMS in combination with targeted quantification of eicosanoids and endocannabinoids. Plasma from 375 individuals from the IMPROVE pan-European cohort was included in a case-control study design. Following data processing, the three metabolite data sets were concatenated to produce a single data set of 267 identified metabolites. Factor analysis identified six factors that described 26.6% of the variability in the given set of predictors. An association with cardiovascular events was only observed for one factor following adjustment (p = 0.026). From this factor, we identified a free fatty acid signature (n = 10 lipids, including saturated, monounsaturated, and polyunsaturated fatty acids) that was associated with lower risk of future cardiovascular events in nondiabetics only (OR = 0.65, 0.27-0.80 95% CI, p = 0.030), whereas no association was observed among diabetic individuals. These observations support the hypothesis that increased levels of circulating omega-6 and omega-3 fatty acids are associated with protective effects against future cardiovascular events. However, these effects were only observed in the nondiabetic population, further highlighting the need for patient stratification in clinical investigations.

Vitamin D and acute myocardial infarction.

Vitamin D deficiency is a prevalent condition, cutting across all ethnicities and among all age groups, and occurring in about 30%-50% of the population. Besides vitamin D established role in calcium homeostasis, its deficiency is emerging as a new risk factor for coronary artery disease. Notably, clinical investigations have suggested that there is an association between hypovitaminosis D and acute myocardial infarction (AMI). Not only has it been linked to incident AMI, but also to increased morbidity and mortality in this clinical setting. Moreover, vitamin D deficiency seems to predispose to recurrent adverse cardiovascular events, as it is associated with post-infarction complications and cardiac remodeling in patients with AMI. Several mechanisms underlying the association between vitamin D and AMI risk can be involved. Despite these observational and mechanistic data, interventional trials with supplementation of vitamin D are controversial. In this review, we will discuss the evidence on the association between vitamin D deficiency and AMI, in terms of prevalence and prognostic impact, and the possible mechanisms mediating it. Further research in this direction is warranted and it is likely to open up new avenues for reducing the risk of AMI.

Old and new oral anticoagulants: Food, herbal medicines and drug interactions.

The most commonly prescribed oral anticoagulants worldwide are the vitamin K antagonists (VKAs) such as warfarin. Factors affecting the pharmacokinetics of VKAs are important because deviations from their narrow therapeutic window can result in bleedings due to over-anticoagulation or thrombosis because of under-anticoagulation. In addition to pharmacodynamic interactions (e.g., augmented bleeding risk for concomitant use of NSAIDs), interactions with drugs, foods, herbs, and over-the-counter medications may affect the risk/benefit ratio of VKAs. Direct oral anticoagulants (DOACs) including Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and thrombin inhibitor (dabigatran) are poised to replace warfarin. Phase-3 studies and real-world evaluations have established that the safety profile of DOACs is superior to those of VKAs. However, some pharmacokinetic and pharmacodynamic interactions are expected. Herein we present a critical review of VKAs and DOACs with focus on their potential for interactions with drugs, foods, herbs and over-the-counter medications.

Overview of green tea interaction with cardiovascular drugs.

Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a "natural" and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that "more-is-better".

Exploring newer cardioprotective strategies: ω-3 fatty acids in perspective.

In the 1980s, observational retrospective studies showed an inverse relation between coronary heart disease (CHD) and consumption of fish containing fatty acids that belong to the omega (ω)-3 family. Large case-control studies and prospective intervention trials consistently showed that ω-3 fatty acids supplementation lowers fatal myocardial infarction (MI) and sudden cardiac death. By analysing the strengths of the results of individual studies and how the meta-analyses agree with them, putting together relevant backgrounds, and identifying open questions, the following findings/directions emerge. (i) Dietary and non-dietary intake of ω-3 fatty acids reduces overall mortality, mortality due to MI, and sudden death in patients with CHD; (ii) Fish oil consumption directly or indirectly affects cardiac electrophysiology. Fish oil reduces heart rate, a major risk factor for sudden death; (iii) Among patients with implantable cardioverter defibrillators, ω-3 fatty acids do not reduce the risk of ventricular tachycardia/ventricular fibrillation and may actually be pro-arrhythmic; (iv) The consumption of ω-3 fatty acids leads to a 10-33% net decrease of triglyceride levels. The effect is dose-dependent, larger in studies with higher mean baseline triglyceride levels, and consistent in different populations (healthy people, people with dyslipidaemia, diabetes, or known cardiovascular risk factors); (v) Outcomes for which a small beneficial effect ω-3 fatty acids is found include blood pressure (about 2 mmHg reduction), re-stenosis rates after coronary angioplasty (14% reduction), and exercise tolerance testing. Major experimental data provide strength (biological plausibility) for these findings, and define directions for newer clinical trials with ω-3 fatty acids.

Homocysteine and arterial thrombosis: Challenge and opportunity.

The correlation between homocysteine and vascular disease has been assessed in several clinical studies that demonstrated that elevation of plasma total homocysteine (tHcy) was an independent risk factor for atheriosclerotic disease. Major advances of homocysteine metabolism disorders have been made during the last few years, encompassing the rare homozygous enzyme deficiencies, as well as more common milder abnormalities. In experimental and clinical studies, a homocysteine-mediated oxidant stress has been shown to trigger platelet activation, in turn leading to a tendency to thrombosis, in patients with severe hyperhomocysteinaemia. Likewise, the hypomethylation hypothesis on acquired hyperhomocysteinaemia (chronic renal disease) and the interrelationship between hyperhomocysteinaemia and impaired fibrinolysis, have added further biological plausibility to the role for hyperhomocysteinaemia in vascular medicine. However, whether hyperhomocysteinaemia is causal or a marker of vascular disease, and whether plasma tHcy is only an indicator of the metabolic status remains to be clarified. The role of the intake of some vitamins (folic acid, vit.B12, vit.B6) on cardiovascular disease (CVD) is poorly understood: in spite of the lowering of homocysteine (Hcy) levels, vitamin supplementation failed to exert significant effects on cardiovascular risk. On the other hand, although some lipid-modifying treatments increase Hcy levels in diabetics, there is no evidence that this attenuates the beneficial effects of such treatments on the cardiovascular risk. Because of these uncertainties in the area, the data available do not provide support for routine screening and treatment for elevated Hcy to prevent CVD.

Effect of n-3 fatty acids on carotid atherosclerosis and haemostasis in patients with combined hyperlipoproteinemia: a double-blind pilot study in primary prevention.

BACKGROUND: Intake of n-3 polyunsaturated fatty acids (n-3 PUFA) either from natural sources or dietary supplementation is inversely associated with atherothrombosis. AIM: A double-blind pilot study was designed to address the impact of n-3 PUFA on atherosclerosis, haemostasis and vascular status in patients with combined hyperlipoproteinemia. METHODS: Carotid intima-media thickness (C-IMT), texture of intima-media complex (T-IMC), lipids and platelet function were evaluated in 64 patients with combined hyperlipoproteinemia who received placebo or n-3 PUFA (6 g/day) for 2 years. C-IMT and T-IMC were assessed by B-mode ultrasound. Lipids and platelet function were determined by validated methods. RESULTS: C-IMT increased in placebo, but not in n-3 PUFA group with respect to baseline. In contrast T-IMC decreased in n-3 PUFA, but not in placebo; in both cases, however, treatment effect did not reach statistical significance. A fall of triglycerides, concomitant to a rise of high- and low-density lipoprotein cholesterol (HDL and LDL), was observed in the active treated group. Platelet function was significantly reduced by n-3 PUFA. CONCLUSIONS: Results show a favourable effectiveness of n-3 PUFA on IMT progression and T-IMC that deserves to be confirmed in larger studies. Despite the small sample size, the beneficial effect of n-3 PUFA on platelet function, triglycerides and HDL-C is clearly highlighted.

Minor components of olive oil modulate proatherogenic adhesion molecules involved in endothelial activation.

The Mediterranean diet reduces the risk of coronary artery disease as a consequence of its high content of antioxidants, namely, hydroxytyrosol (HT) and oleuropein aglycone (OleA), typical of virgin olive oil. Because intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) and E-selectin are crucial for endothelial activation, the role of the phenolic extract from extra virgin olive oil (OPE), OleA, HT, and homovanillyl alcohol (HVA) on cell surface and mRNA expression in human umbilical vascular endothelial cells (HUVEC) was evaluated. OPE strongly reduced cell surface expression of ICAM-1 and VCAM-1 at concentrations physiologically relevant (IC50 < 1 microM), linked to a reduction in mRNA levels. OleA and HT were the main components responsible for these effects. HVA inhibited cell surface expression of all the adhesion molecules, whereas the effect on mRNA expression was weaker. These results supply new insights on the protective role of olive oil against vascular risk through the down-regulation of adhesion molecules involved in early atherogenesis.

Reduced in vivo oxidative stress following 5-methyltetrahydrofolate supplementation in patients with early-onset thrombosis and 677TT methylenetetrahydrofolate reductase genotype.

The protective role of folate in vascular disease has been related to antioxidant effects. In 45 patients with previous early-onset (at age <50 years) thrombotic episodes and the 677TT methylenetetrahydrofolate reductase genotype, we evaluated the effects of a 28 d-course (15 mg/d) of 5-methyltetrahydrofolate (MTHF) on homocysteine metabolism and on in vivo generation of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable marker of oxidative stress. At baseline, patients' fasting total homocysteine (tHcy) was 11.5 micromol/l (geometric mean) and urinary excretion of 8-iso-PGF2alpha was 304 pg/mg creatinine, with the highest metabolite levels in the lowest quartile of plasma folate distribution (P < 0.05). After 5-MTHF supplementation, plasma folate levels increased approximately 13-fold (P < 0.0001 versus baseline); tHcy levels (6.7 micromol/l, P < 0.0001) and urinary 8-iso-PGF2alpha (254 pg/mg creatinine, P < 0.001) were both significantly lowered, their reduction being proportional to baseline values (r = 0.98 and r = 0.77, respectively) and maximal in patients with the lowest pre-supplementation folate levels (P < 0.05). The effects on folate (P < 0.0001) and tHcy (P = 0.0004) persisted for at least up to 2 months after withdrawing 5-MTHF. In parallel with long-lasting tHcy-lowering effects, a short-course 5-MTHF supplementation reduces in vivo formation of 8-iso-PGF2alpha in this population, supporting the antioxidant protective effects of folate in vascular disease.