Carotenoids and cardiovascular disease: what research gaps remain?

PURPOSE OF REVIEW: Dietary and blood carotenoids, including alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, and beta-cryptoxanthin, have been examined in a number of epidemiological studies in recent years for the risk of cardiovascular disease. This review assimilated the existing and recent literature on carotenoids and cardiovascular disease and considered what research gaps may remain. RECENT FINDINGS: Numerous large cohort studies have been published in largely American men and women that have examined dietary intake or blood levels of total or individual carotenoids with the risk of various cardiovascular endpoints. Overall, early, promising results have grown increasingly inconsistent over time. More recently, studies examining lycopene and lutein/zeaxanthin have offered more promising data on a possible, but not yet established, inverse association with the risk of cardiovascular disease. Recent epidemiological data on beta-cryptoxanthin and cardiovascular disease are lacking. Primary and secondary prevention trials have extensively examined beta-carotene, but not other carotenoids, for the risk of cardiovascular disease as either the primary or secondary endpoint with largely null results. More recent studies have focused on individual carotenoids in relation to cardiovascular disease and require a more careful evaluation of potential mechanisms of effect. SUMMARY: The promise of early epidemiological studies on carotenoids and cardiovascular disease paved the way to largely disappointing results from several large prevention trials of beta-carotene. Emerging recent evidence of potential cardioprotective effects for lycopene and other carotenoids besides beta-carotene in the diet and blood suggest that there is more to be learned in the story of carotenoids and both atherosclerotic progression and clinically manifested cardiovascular disease.     

Dietary monounsaturated versus polyunsaturated fatty acids: which is really better for protection from coronary heart disease?

PURPOSE OF REVIEW: The purpose is to evaluate recent findings concerning dietary fats and the risk of coronary heart disease. Monounsaturated fatty acids are often regarded as healthy, and many have recommended their consumption instead of saturated fatty acids and polyunsaturated fatty acids. Support for the benefits of monounsaturated fatty acids comes largely from epidemiological data, but they have not been an isolated, single variable in such studies. Beneficial effects on the plasma lipid profile and LDL oxidation rates have also been identified. More recent findings have questioned the impact of suspected beneficial effects on coronary heart disease, indicating that studies with more conclusive endpoints are needed. RECENT FINDINGS: Human dietary studies often produce conflicting results regarding the effects of monounsaturated and polyunsaturated fatty acids on the plasma lipid profile. Monounsaturated and polyunsaturated fatty acids both appear to reduce total and LDL-cholesterol compared with saturated fatty acids; however, the effect on HDL is less clear. Lowered HDL levels in response to low-fat or polyunsaturated fatty acid diets and the decreased protection from oxidation of polyunsaturated fatty acid-enriched LDL may not indicate increased coronary heart disease risk. Several lines of evidence also suggest that polyunsaturated fatty acids may protect against atherosclerosis. SUMMARY: Recommendations to substitute monounsaturated fatty acids for polyunsaturated fatty acids or a low-fat carbohydrate diet seem premature without more research into the effects on the development of atherosclerosis. Current opinions favoring monounsaturated fatty acids are based on epidemiological data and risk factor analysis, but are questioned by the demonstrated detrimental effects on atherosclerosis in animal models.     

The gut microbiota-artery axis: A bridge between dietary lipids and atherosclerosis?

Atherosclerotic cardiovascular disease is one of the major leading global causes of death. Growing evidence has demonstrated that gut microbiota (GM) and its metabolites play a pivotal role in the onset and progression of atherosclerosis (AS), now known as GM-artery axis. There are interactions between dietary lipids and GM, which ultimately affect GM and its metabolites. Given these two aspects, the GM-artery axis may play a mediating role between dietary lipids and AS. Diets rich in saturated fatty acids (SFAs), omega-6 polyunsaturated fatty acids (n-6 PUFAs), industrial trans fatty acids (TFAs), and cholesterol can increase the levels of atherogenic microbes and metabolites, whereas monounsaturated fatty acids (MUFAs), ruminant TFAs, and phytosterols (PS) can increase the levels of antiatherogenic microbes and metabolites. Actually, dietary phosphatidylcholine (PC), sphingomyelin (SM), and omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been demonstrated to affect AS via the GM-artery axis. Therefore, that GM-artery axis acts as a communication bridge between dietary lipids and AS. Herein, we will describe the molecular mechanism of GM-artery axis in AS and discuss the complex interactions between dietary lipids and GM. In particular, we will highlight the evidence and potential mechanisms of dietary lipids affecting AS via GM-artery axis.     

Variations in HDL-carried miR-223 and miR-135a concentrations after consumption of dietary trans fat are associated with changes in blood lipid and inflammatory markers in healthy men - an exploratory study

A high consumption of trans fatty acids (TFAs) is associated with an increased risk of cardiovascular diseases (CVDs). High-density lipoproteins (HDLs) have many cardioprotective properties and transport functional microRNAs (miRNAs) to recipient cells. We hypothesized that dietary TFAs modify the HDL-carried miRNA profile, therefore modulating its cardioprotective properties. We assessed whether consumption of dietary TFAs modifies HDL-carried miR-223-3p and miR-135a-3p concentration and the inter-relationship between diet-induced changes in HDL-carried miRNA concentration and CVD risk markers. In a double blind, randomized, crossover, controlled study, 9 men were fed each of 3 experimental isoenergetic diets: 1) High in industrial TFA (iTFA; 3.7% energy); 2) High in TFA from ruminants (rTFA; 3.7% energy); 3) Low in TFA (control; 0.8% energy) for 4 weeks each. HDLs were isolated by ultracentrifugation and miRNAs were quantified by RT-qPCR. Variations in HDL-miR-223-3p concentration were negatively correlated with variations in HDL-cholesterol after the iTFA diet (r_s = 0.82; P = 0.007), and positively correlated with variations in C-reactive protein concentration after the rTFA diet (r_s = 0.75; P = 0.020). Variations in HDL-miR-135a-3p concentration were positively correlated with variations in total triglyceride (TG) concentration following the iTFA diet (r_s = ?0.82; P = 0.007), and with variations in low-density lipoprotein (LDL)-TG concentration following the rTFA diet (r_s = 0.83; P = 0.005), compared to the control diet. However, the consumption of dietary TFAs has no significant unidirectional impact on HDL-carried miR-223-3p and miR-135a-3p concentrations. Our results suggest that the variability in the HDL-carried miRNAs response to TFA intake, by being associated with variations in CVD risk factors, might reflect physiological changes in HDL functions.     

Cardioprotective prostacyclin signaling in vascular smooth muscle

Prostacyclin plays an important cardioprotective role, which has been increasingly appreciated in recent years in light of adverse effects of COX-2 inhibitors in clinical trials. This cardioprotection is thought to be mediated, in part, by prostacyclin inhibition of platelet aggregation. Multiple lines of evidence suggest that prostacyclin additionally protects from cardiovascular disease by pleiotropic effects on vascular smooth muscle. Genetic deletion of the prostacyclin receptor in mice revealed an important role for prostacyclin in preventing the development of atherosclerosis, intimal hyperplasia, and restenosis. In vitro studies have shown these effects may be due to prostacyclin inhibition of vascular smooth muscle cell proliferation and migration. Prostacyclin has also been shown to promote vascular smooth muscle cell differentiation at the level of gene expression through the Gs/cAMP/PKA pathway. Recently identified single nucleotide polymorphisms in the prostacyclin receptor that compromise receptor function suggest that some genetic variations may predispose individuals to increased cardiovascular disease. Herein, we review the literature on the cardioprotective effects of prostacyclin on vascular smooth muscle, and the underlying molecular signaling mechanisms. Understanding the role of prostacyclin and other eicosanoid mediators in the vasculature may lead to improved therapeutic and preventative options for cardiovascular disease.     

Cardioprotective effects of vegetables: Is nitrate the answer?

A diet rich in fruits and vegetables is associated with a lower risk of certain forms of cancer and cardiovascular disease, but the mechanisms behind this protection are not completely understood. Recent epidemiological studies suggest a cardioprotective action afforded specifically by green leafy vegetables. We here propose that these beneficial effects are related to the high content of inorganic nitrate, which in concert with symbiotic bacteria in the oral cavity is converted into nitrite, nitric oxide, and secondary reaction products with vasodilating and tissue-protective properties.     

Modulation of enzymatic activities by n-3 polyunsaturated fatty acids to support cardiovascular health

Epidemiological evidence from Greenland Eskimos and Japanese fishing villages suggests that eating fish oil and marine animals can prevent coronary heart disease. Dietary studies from various laboratories have similarly indicated that regular fish oil intake affects several humoral and cellular factors involved in atherogenesis and may prevent atherosclerosis, arrhythmia, thrombosis, cardiac hypertrophy and sudden cardiac death. The beneficial effects of fish oil are attributed to their n-3 polyunsaturated fatty acid (PUFA; also known as omega-3 fatty acids) content, particularly eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3). Dietary supplementation of DHA and EPA influences the fatty acid composition of plasma phospholipids that, in turn, may affect cardiac cell functions in vivo. Recent studies have demonstrated that long-chain omega-3 fatty acids may exert beneficial effects by affecting a wide variety of cellular signaling mechanisms. Pathways involved in calcium homeostasis in the heart may be of particular importance. L-type calcium channels, the Na+-Ca2+ exchanger and mobilization of calcium from intracellular stores are the most obvious key signaling pathways affecting the cardiovascular system; however, recent studies now suggest that other signaling pathways involving activation of phospholipases, synthesis of eicosanoids, regulation of receptor-associated enzymes and protein kinases also play very important roles in mediating n-3 PUFA effects on cardiovascular health. This review is therefore focused on the molecular targets and signaling pathways that are regulated by n-3 PUFAs in relation to their cardioprotective effects.     

Nutrition and hypertension

There has been a good deal of interest in the relation of nutrition to cardiovascular diseases and this is likely to continue. We consider recent research developments concerned with the well known examples of the association of high salt intake with hypertension and of saturated fats with atherosclerosis. Some of the difficulties encountered in the investigation of dietary factors in hypertension are similar to those encountered in the investigation of dietary factors in atherosclerosis and coronary heart disease. Much additional research, which takes into account the multifactorial nature of cardiovascular disease, is needed to determine the effects of diet on the development and treatment of these diseases.     

Anti-inflammatory drugs and atherosclerosis

PURPOSE OF REVIEW: Inflammation contributes to the formation and progression of atherosclerosis and the therapeutic potential of some anti-inflammatory drugs has been evaluated for possible antiatherosclerotic effects. This review will briefly describe the mechanisms underlying the inflammation-atherosclerosis connection, the effect of various anti-inflammatory therapies on atherosclerotic disease and a sampling of the potential targets and agents under evaluation. RECENT FINDINGS: Some agents with anti-inflammatory properties appear to have beneficial effects on atherosclerosis or subsequent risk for cardiovascular events, while others have been disappointing. The anti-inflammatory actions of statins have been linked retrospectively with their favorable effects on atherosclerosis progression and clinical outcomes. The cardiovascular safety of COX-2 inhibitors is being assessed prospectively in patients with atherosclerosis. Potential new therapeutic agents targeting other inflammatory mechanisms and oxidative stress are being evaluated in animal models and clinical trials. SUMMARY: Due to the contributory inflammatory pathways in atherosclerosis, the properties of existing and novel anti-inflammatory agents are being carefully and actively evaluated in cardiovascular disease. Advances in our understanding of both atherosclerosis and the inflammatory contributors may play an important role in future strategies to decrease the incidence of atherosclerotic cardiovascular disease.     

Diet and endothelial function

Endothelial dysfunction is one of the earliest events in atherogenesis. A consequence of endothelial damage is a lower availability of nitric oxide (NO), the most potent endogenous vasodilator. NO inhibits platelet aggregation, smooth muscle cell proliferation and adhesion of monocytes to endothelial cells. Endothelial dysfunction is present in patients with cardiovascular disease and/or coronary risk factors, such as hypertension, dyslipidemia, diabetes, smoking or hyperhomocysteinemia. At present, soluble markers and high resolution ultrasound of the brachial artery, have provided simple tools for the study of endothelial function and the effects of several interventions. It has been demonstrated that dietary factors may induce significant changes on vascular reactivity. Nutrients, such as fish oil, antioxidants, L-arginine, folic acid and soy protein have shown an improvement in endothelial function that can mediate, at least partially, the cardioprotective effects of these substances. Attention has been focused on dietary patterns in populations with lower prevalence of cardiovascular disease. There is some evidence suggesting that Mediterranean diet characterized by high consumption of vegetables, fish, olive oil and moderate wine consumption may have a positive effect on endothelial function. These results give us evidence on the significant role of diet on endothelial function and its impact on the pathogenesis of atherosclerosis.     

Research progress of ghrelin on cardiovascular disease

Ghrelin, a 28-aminoacid peptide, was isolated from the human and rat stomach and identified in 1999 as an endogenous ligand for the growth hormone secretagogue-receptor (GHS-R). In addition to stimulating appetite and regulating energy balance, ghrelin and its receptor GHS-R1a have a direct effect on the cardiovascular system. In recent years, it has been shown that ghrelin exerts cardioprotective effects, including the modulation of sympathetic activity and hypertension, enhancement of the vascular activity and angiogenesis, inhibition of arrhythmias, reduction in heart failure and inhibition of cardiac remodeling after myocardial infarction (MI). The cardiovascular protective effect of ghrelin may be associated with anti-inflammation, anti-apoptosis, inhibited sympathetic nerve activation, regulated autophagy, and endothelial dysfunction. However, the molecular mechanisms underlying the effects of ghrelin on the cardiovascular system have not been fully elucidated, and no specific therapeutic agent has been established. It is important to further explore the pharmacological potential of ghrelin pathway modulation for the treatment of cardiovascular diseases.     

血浆同型半胱氨酸水平升高与动脉粥样硬化

心血管疾病已成为当今全球性致残与致死的最重要原因之一。目前确定的冠心病的危险因素主要包括高龄、血脂异常、高血压、糖尿病、吸烟、肥胖症。大量的临床试验及流行病学研究已经证实血浆同型半胱氨酸水平升高是心血管疾病的一个独立的危险因素。健康人的血浆同型半胱氨酸水平为5～10μmol／L。血浆同型半胱氨酸水平严重升高的主要原因是胱硫醚-β-合成酶(cystathionine-β-synthase,CBS)基因的缺陷。CBS基因缺陷的纯合体可导致血浆同型半胱氨酸水平升高至100～500μmol／L。血浆同型半胱氨酸水平严重升高的病人通常伴随神经系统异常、早发性的动脉粥样硬化。叶酸、维生素B6和B12治疗能降低血浆同型半胱氨酸的水平并改善血管内皮功能、减少经皮冠状动脉腔内成形术(percutaneou stransluminal coronary angioplasty,PTCA)术后并发症。迄今为止,血浆同型半胱氨酸水平升高引起心血管疾病的发病机制并未完全明了,目前认为主要与以下几个方面有关：(1)内皮细胞损伤及功能障碍。我们实验室在CBS基因敲除的小鼠模型上证实血浆同型半胱氨酸水平升高能抑制eNOS的活性,导致主动脉内皮功能的障碍。我们还在细胞模型上证实了同型半胱氨酸能显著抑制内皮细胞的增殖。(2)KH固醇和甘油三脂生物合成代谢异常。我们实验室在apoE、CBS双基因敲除的小鼠模型上证实血浆同型半胱氨酸水平升高能改变肝脏的脂肪代谢,增加巨噬细胞对修饰LDL的摄取,从而导致胆固醇脂和甘油三脂在血管壁的堆积,促进主动脉粥样斑块的形成。(3)刺激血管平滑肌细胞增殖。此外还发现同型半胱氨酸能激活蛋白激酶C信号途径,促进胶原蛋白的合成,抑制弹性蛋白和胶原蛋白的交联。(4)激活血栓形成。(5)激活单核细胞。目前认为同型半胱氦酸主要通过以下几个化学机制致病;(1)自氧化产生活性氧。同型半胱氨酸在自氧化的过程中能产生大量的活性氧,从而引起血液中脂蛋白和细胞膜脂质的过氧化损伤,并进一步引起内皮功能的障碍。(2)在腺苷的参与下形成SAH,一种甲基转移抑制剂,导致细胞内的低甲基化。(3)与一氧化氮结合形成亚硝酰物。(4)参与蛋白质的合成。总之,我们和其他实验室的研究结果均表明同型半胱氨酸不仅与动脉粥样硬化相关,而且具有致病效应。尽管补充叶酸、维生素B6和B12等治疗能降低血浆同型半胱氨酸的水平,但是否能降低心血管疾病的风险仍有待于大量的动物研究及临床试验。     

New research development on trans fatty acids in food: Biological effects,analytical methods,formation mechanism,and mitigating measures

The trans fatty acids (TFAs) in food are mainly generated from the ruminant animals (meat and milk) and processed oil or oil products. Excessive intake of TFAs (>1% of total energy intake) caused more than 500,000 deaths from coronary heart disease and increased heart disease risk by 21% and mortality by 28% around the world annually, which will be eliminated in industrially-produced trans fat from the global food supply by 2023. Herein, we aim to provide a comprehensive overview of the biological effects, analytical methods, formation and mitigation measures of TFAs in food. Especially, the research progress on the rapid, easy-to-use, and newly validated analytical methods, new formation mechanism, kinetics, possible mitigation mechanism, and new or improved mitigation measures are highlighted. We also offer perspectives on the challenges, opportunities, and new directions for future development, which will contribute to the advances in TFAs research.     

Anti‐atherosclerotic effects of vitamin E – myth or reality?

Atherosclerosis and its complications such as coronary heart disease, myocardial infarction and stroke are the leading causes of death in the developed world. High blood pressure, diabetes, smoking and a diet high in cholesterol and lipids clearly increase the likelihood of premature atherosclerosis, albeit other factors, such as the individual genetic makeup, may play an additional role. Several epidemiological studies and intervention trials have been performed with vitamin E, and some of them showed that it prevents atherosclerosis. For a long time, vitamin E was assumed to act by decreasing the oxidation of LDL, a key step in atherosclerosis initiation. However, at the cellular level, vitamin E acts by inhibition of smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxLDL uptake and cytokine production, all reactions implied in the progression of atherosclerosis. Recent research revealed that these effects are not the result of the antioxidant activity of vitamin E, but rather of precise molecular actions of this compound. It is assumed that specific interactions of vitamin E with enzymes and proteins are at the basis of its non-antioxidant effects. Vitamin E influences the activity of several enzymes (e.g. PKC, PP2A, COX-2, 5-lipooxygenase, nitric oxide synthase, NADPH-oxidase, superoxide dismutase, phopholipase A2) and modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins). These interactions promise to reveal the biological properties of vitamin E and allow designing better strategies for the protection against atherosclerosis progression.     

Metabolic and health effects of isomeric fatty acids

PURPOSE OF REVIEW: Isomeric fatty acids have the same number of carbon and hydrogen atoms, but may have distinct metabolic and health effects. Two well-known examples of isomeric fatty acids are cis and trans monounsaturated fatty acids, and conjugated isomers of linoleic acid (CLA). The purpose of this review is to summarize recent findings from human studies on the metabolic and health effects of these two classes of isomeric fatty acids. RECENT FINDINGS: Apart from an unfavorable effect on serum lipoproteins, trans monounsaturated fatty acids from hydrogenated oils may increase plasma markers for a low-grade inflammatory state. From epidemiological studies, however, it is not possible to conclude if effects of ruminant and industrial trans fatty acids on cardiovascular risk are different. In contrast to in-vitro and animal studies, there are no indications that in humans the two most common CLA isomers (cis9,trans11-CLA and trans10,cis12-CLA) affect body composition differently. Longer-term supplementation, however, may slightly decrease body fat mass without apparent effects on plasma markers for glucose and lipid metabolism. Other studies have even reported adverse effects of CLA supplementation on insulin resistance and lipid peroxidation. SUMMARY: Evidence is increasing that trans monounsaturated fatty acids from hydrogenated oils increase plasma markers of low-grade chronic inflammation. From epidemiological studies, however, it is not clear if effects of ruminant and industrial trans fatty acids on cardiovascular risk are different. Effects of CLA on body composition remain controversial and more research is needed before the widely available CLA supplements should be advocated as an adjunct to control body weight.     

The effects of endogenous and exogenous androgens on cardiovascular disease risk factors and progression

Cardiovascular disease incidence rates have long been known to significantly differ between the two sexes. Estrogens alone fail to explain this phenomenon, bringing an increasing amount of attention to the role of androgens. Contrary to what was initially hypothesized, androgens seem to have an overall cardioprotective effect, especially in men. Recent studies and published data continue to support this notion displaying a consistent inverse correlation with atherosclerosis progression and cardiovascular disease both in regressive and prospective study models. Clinical studies have also revealed what seems to be a differential androgenic effect on various cardiovascular risk factors between men and women. Further insight indicates that in order to avoid confusion it may be also preferable to separately examine the effects of endogenous androgen levels from exogenous testosterone administration, as well as discern the differential results of low to normal and supraphysiological administration doses. This review summarizes old and recent data according to the above distinctions, in an attempt to further our understanding of the role of androgens in cardiovascular disease.     

HDL revisited: new opportunities for managing dyslipoproteinaemia and cardiovascular disease

Low concentrations of high-density lipoprotein (HDL) cholesterol constitute a risk factor for coronary heart disease (CHD). There is increasing evidence that increasing HDL-cholesterol levels reduces cardiovascular risk. The phenotype of low HDL cholesterol with or without elevated triglycerides is common and it is characteristic of patients with central obesity, insulin resistance, hypertension and type 2 diabetes mellitus; conditions associated with increased cardiovascular risk and are part of the rubric of the metabolic syndrome. Epidemiological, experimental and clinical trial evidence suggests that there is a good rationale for raising HDL-cholesterol in these and other high-risk patients. The protective effect of HDL-cholesterol against atherosclerosis and cardiovascular disease is mediated by both enhanced reverse cholesterol transport (RCT) and by direct anti-atherosclerotic mechanisms. Recent studies have elucidated mechanisms whereby HDL acts to reduce cardiovascular risk, supporting the rationale for targeting of HDL with lipid-modifying therapy. Ongoing investigation of mechanisms by which HDL acts to reduce the risk of atherosclerosis will provide opportunities for the development of new therapeutic strategies to decrease the risk of atherosclerosis.     

Redox signaling in central neural regulation of cardiovascular function

One of the most prominent concepts to emerge in cardiovascular research over the past decade, especially in areas focused on angiotensin II (AngII), is that reactive oxygen species (ROS) are critical signaling molecules in a wide range of cellular processes. Many of the physiological effects of AngII are mediated by ROS, and alterations in AngII-mediated redox mechanisms are implicated in cardiovascular diseases such as hypertension and atherosclerosis. Although most investigations to date have focused on the vasculature as a key player, the nervous system has recently begun to gain attention in this field. Accumulating evidence suggests that ROS have important effects on central neural mechanisms involved in blood pressure regulation, volume homeostasis, and autonomic function, particularly those that involve AngII signaling. Furthermore, oxidant stress in the central nervous system is implicated in the neuro-dysregulation associated with some forms of hypertension and heart failure. The main objective of this review is to discuss the recent progress and prospects for this new field of central redox signaling in cardiovascular regulation, while also addressing the molecular tools that have spurred it forward.     

Anti-atherosclerotic and anti-diabetic properties of probucol and related compounds

Probucol is a diphenolic compound with anti-oxidant and anti-inflammatory properties that reduces atherosclerosis and restenosis. Unfortunately, adverse effects on blood lipoproteins and cardiac electrophysiology have curtailed its use as a drug. Compounds related to probucol that have improved efficacy without the adverse effects offer promise as novel therapies of cardiovascular disease. Recent results suggest that these compounds may be used for the prevention of type 2 diabetes, a disease that is increasing in prevalence and importance world-wide. In this review, the molecular mechanisms underlying the beneficial activities of probucol and related compounds are described.