Review
Natural antioxidant compounds in risk factors for CVD

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Abstract

The benefits of drug treating hypertension, hyperglycemia and hyperlipidemias in terms of reduction of CVD morbidity and mortality are well established. However, there is epidemiological evidence that consumption of certain foods results to a reduction in myocardial infarction markers. Given in many reviews is the impact of dietary antioxidants pertained to LDL oxidation and to vascular endothelial dysfunction. The potential of a diet rich in these compounds on the management of hypertension, hyperglycemia and hyperlipidemias is hereby criticized. Although their clinical use not always translates into clinical benefit, data are motivating. In the future, these agents may be very important complementary treatment options for subjects with high risk for CVD.

Introduction

Cardiovascular disease (CVD) remains the principle cause of death in both developed and developing countries, accounting for roughly 20% of all worldwide deaths per year. It comprises its own set of pathologies, chief among which are atherosclerosis, hypertension, congestive heart failure, cardiomyopathy, coronary heart disease, hypertrophy, arrhythmias, ventricular fibrillation, ventricular tachycardia, myocardial infarction, and stroke.

The concept of CVD has changed during the last decades, and the nature of CVD as a multifactorial disease has become clear. It is practical to divide the CVD risk factors into three categories, namely lifestyle factors, biochemical factors and personal characteristics. Lifestyle factors have an important role in the CVD risk both at the population and at the individual level. They include a diet high in saturated fat, in energy and in cholesterol, obesity, tobacco smoking, excess alcohol consumption and physical inactivity. These are factors that, on the one hand, could lower the CVD risk significantly after modification, but, on the other hand, are quite difficult to modify. Personal characteristics, such as age, sex and genes, may play a major role in the development of CVD, however these factors cannot be changed by the treatment choices available.

Elevated BP is frequently associated with other CVD risk factors, such as smoking, diabetes, insulin resistance, dyslipidemias, and obesity. According to epidemiological studies and after adjustment for confounding factors, high BP is an important risk factor for CVD [1]. The treatment of hypertension reduces the risk of CVD in clinical drug intervention trials. In addition, lifestyle interventions for mildly elevated BP have also been effective in risk reduction [1]. The mechanism whereby hypertension predisposes to CVD is probably related to the fact that high blood BP accelerates the atherosclerotic process as well as to the pressure effects leading to progressive dilation and rupture of large and small vessels.

Elevated glucose intolerance seems to play a critical role in the progression of the disease. The glucose intolerance that accompanies diabetes mellitus is a direct effect of overweight and is often associated with hypertriglyceridemia, hypertension, elevated LDL cholesterol, and depressed HDL. There is evidence documenting that diabetes mellitus has a vasculotoxic effect, which is greatest for instantaneous peripheral vascular disease. However, CHD and stroke are its most common manifestations. In diabetic women, the risk for CVD is three times as high as it is in women without diabetes mellitus, while in diabetic men the risk is twice as high as it is in men without diabetes mellitus [2].

A mixture of chronic processes and acute events characterizes the pathophysiology of atherosclerosis and CVD. The most important pathogenic processes, which are determined partly genetically and partly environmentally, are dyslipidemia, hypertension, endothelial dysfunction, diabetes, and cardiac and vascular hypertrophy.

Given in a former review was the effect of natural dietary antioxidants pertained to LDL oxidation, to vascular endothelial dysfunction and to gene regulation [3]. Given in this review is the evidence of their link to CVD prevention, as to the inhibition of three major risk factors, namely hypertension, hyperglycemia and hyperlipidemias. Oxidative stress has been suggested to be involved in hypertension, hyperglycemia and hyperlipidemia. There is evidence that oxidative stress is increased in hypertension. The increase in BP may enhance vascular production of superoxide independently of the renin-angiotensin system [4]. Then again, angiotensin system activation is associated with vascular production of O2radical dot [5]. Either the first or the second mechanism, induction of oxidative stress occurs via the activation of NADPH oxidase enzyme. The relation between oxidative stress and hypertension was established in humans by Sanguigni et al. [6]. Suggested was that patients with hypertension have enhanced platelet formation mediated by AT1 receptors, as well as that NADPH-oxidase plays a pivotal role in enhanced formation of oxygen-free radical production. Enhanced oxidative stress by the vessel wall reduces the vasodilatory property of endothelium inhibiting NO activity [3], thus inducing progression of atherosclerotic disease.

Endothelium dependent vasodilation is reduced in patients with diabetes and that vitamin C is able to prevent it, meaning a role for oxygen-free radicals in reducing the vasodilatory property of endothelium [7]. Hyperglycaemia enhances oxidative stress and induces vascular damage via several pathways, including the formation of the advanced glycated end products (AGE) that are proatherogenic and prothrombotic substances. Furthermore glucose alters the balance between free radicals in endothelial cells and NO does no exert its vasodilatory and antioxidant effect [8]. The mechanism via which hyperglycemia induces oxidative stress is NAD(P)H oxidase and COX activation [9]. Vascular expression of NAD(P)H oxidase has been found overexpressed in diabetic patients [10].

Hypercholesterolemia is associated with enhanced oxidative stress. For example, free radicals and F2 isoprostanes have been found to be elevated in the arteries of hypercholesterolaemic animals or in the urine of patients with high serum cholesterol, respectively [11], [12]. Cholesterol has been shown to activate the metabolism of the arachidonic acid pathway [13], which is associated with NAD(P)H oxidase activation [9]. When treating hypercholesterolaemic patients with an inhibitor of HMG-CoA-reductase reduced formation of TNFa by monocytes was observed, suggesting a relation between cholesterol and intracellular formation of pro-oxidant cytokines [14].

As the term implies “antioxidant” refers to any molecule capable of stabilizing or deactivating free radicals before they attack cells. Based on the ‘oxidation theory’ for CVD, dietary antioxidants have attracted considerable attention as agents that protect cells or molecules from oxidative stress. The primary mechanism of its cardioprotective effect is likely through its effectiveness in oxidative stress. Hence, most in vitro, controlled intervention, ex vivo and animal model studies are designed as to determine the impact of dietary antioxidants against LDL oxidation, which plays a key role in the early atherogenic process, and vascular endothelial dysfunction [3]. For example, recent studies support the correlation between vitamin E supplementation, increased plasma vitamin levels and enhanced in vitro oxidative resistance of the respective isolated LDL [15], [16]. In a randomized double-blind cross-over trial, supplementation with dehydrated juice concentrates from mixed fruit and vegetables resulted in a positive correlation of plasma vitamin C with the resistance of LDL to oxidation [17]. Cocoa supplementation in healthy subjects for 28 days significantly increased plasma epicatechin and catechin levels and decreased platelet function [18]. Yet, evidence that these compounds augment defense against LDL oxidation and endothelial dysfunction in vivo is not compelling. In human clinical trials, the doses of antioxidants supplemented do not always show to inhibit lipid peroxidation convincingly. Results are contrasting and not always consistent with the in vitro findings. On the other hand, studies in animal models of atherosclerosis most clearly show an anti-atherogenic effect of dietary antioxidants, however, they focus mainly on early atherosclerotic events and not in advanced atherosclerosis as in humans. Also, the capacity of dietary antioxidants to modulate gene expression has been investigated chiefly during the last decade. Knowledge about the cellular effects of dietary antioxidant compounds has been obtained mostly by studies on cell tissue cultures in vitro and on experimental animal models. Furthermore, observational studies are based upon measurements of micronutrient intakes through the use of dietary recall questionnaires, and despite the interesting results, they may be vague. Nevertheless, these studies have been the origin, the scientific setting, to perform interventions in order to determine whether there is an impact against the three major CVD risk factors namely hypertension, hyperglycemia and hyperlipidemia, and, if there is, to estimate the size of this impact. Most studies conducted in humans are “therapeutic” interventions and comprise monotherapies, or combined antioxidant therapies or certain dietary patterns. Estimated are chiefly BP values, glucose and insulin levels, triglyceride-, total cholesterol-, apo-B-, LDL cholesterol- and HDL cholesterol-levels, as well as lipid peroxides.

Section snippets

Dietary antioxidants in hypertension

Arterial hypertension is defined as systolic BP of greater than 140 mmHg or diastolic BP of greater than 90 mmHg. Because risk for CVD is linear throughout the whole range of blood pressure, even those who are not classically defined as ‘hypertensive’ may still be at a risk [19]. It is well established that oxidative stress in hypertensive patients is dramatically increased, thus increasing the risk for CVD [20]. Many clinical trials have shown that reductions in blood pressure reduce the

Dietary antioxidants in hyperglycemia

The etiology and pathophysiology leading to hyperglycemia are markedly different among patients with diabetes mellitus. In insulin dependent diabetes hyperglycemia occurs due to insufficiency of secretion or action of endogenous insulin, while in non-insulin dependent diabetes mellitus (NIDDM) lifestyle factors, such as obesity, contribute to its development. NIDDM is increasing throughout the world and particularly in economically developed countries. The leading cause of mortality and

Dietary antioxidants in hyperlipidemias

Certain genetic traits may influence cholesterol metabolism and levels of production of cholesterol and other fats. Elevated cholesterol levels increase the risk for vascular problems [60]. Specific genetic (familial) diseases of lipoprotein metabolism have been identified in medicine, termed as “hyperlipidemias”, among which the most common, cause high cholesterol or high triglyceride levels. The therapeutic options available to clinicians treating hyperlipidemias in the last decade have

Observational studies on the efficacy of antioxidants in the prevention of cardiovascular events

There is a large body of observational (epidemiological, case-control, or prospective and retrospective cohort) studies on the dietary antioxidant intake link to prevention of CVD progression. Amongst the most established are: (i) the CHAOS study where an inverse correlation between death for myocardial infarction and vitamin E was observed [91], (ii) the WHO/MONICA project has been one of the largest studies to analyse the behaviour of vitamin E in populations with different incidence of CHD

Conclusive marks and future prospects

Substantial progress has been made concerning our knowledge of bioactive components in foods and their contribution to homeostasis and disease prevention. Information arising from both basic research and large clinical studies continues to inform the viable contribution of dietary antioxidants in the management of CVD development. In the above discussion, critically reviewed is the clinical research evidence linked to effects on hypertension, hyperglycemia and hyperlipidemias. Generally,

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