The metabolic syndrome affects 30% of the US population with increasing prevalence. In this paper, we explore the relationship between the metabolic syndrome and the incidence and severity of cardiovascular disease in general and coronary artery disease (CAD) in particular. Furthermore, we look at the impact of metabolic syndrome on outcomes of coronary revascularization therapies including CABG, PTCA, and coronary collateral development. We also examine the association between the metabolic syndrome and its individual component pathologies and oxidative stress. Related, we explore the interaction between the main external sources of oxidative stress, cigarette smoke and air pollution, and metabolic syndrome and the effect of this interaction on CAD. We discuss the apparent lack of positive effect of antioxidants on cardiovascular outcomes in large clinical trials with emphasis on some of the limitations of these trials. Finally, we present evidence for successful use of antioxidant properties of pharmacological agents, including metformin, statins, angiotensin II type I receptor blockers (ARBs), and angiotensin II converting enzyme (ACE) inhibitors, for prevention and treatment of the cardiovascular complications of the metabolic syndrome.
Metabolic syndrome is a term that describes a cluster of independent risk factors that increase the likelihood of cardiovascular disease [
Increased cardiovascular risk in the metabolic syndrome is the result of a complex interaction of the individual risk factors that is not fully understood. For example, although central obesity is a defining characteristic of the metabolic syndrome, a study of middle aged men with metabolic syndrome found that cardiovascular risk is also increased independently of body mass index with the metabolic syndrome [
Increased oxidative stress has emerged as playing a central role in metabolic syndrome and its component pathologies and may be a unifying factor in the progression of this disease. Reactive oxygen species (ROS) are highly reactive derivatives of oxygen metabolism. These short-lived molecules play important roles in normal physiological processes such as gene expression and signal transduction. In a healthy condition, ROS are maintained at an optimal level due to a balance between their production and elimination by enzymatic (superoxide dismutase, glutathione, catalase, peroxidase) and nonenzymatic (vitamins C and E) antioxidants. In a pathological state such as the metabolic syndrome, an increased oxidant capacity coupled with decreased antioxidant capacity creates an unbalanced environment that results in oxidative stress. Increased ROS levels manifested during oxidative stress have toxic effects on cells and tissues through increased oxidation of carbohydrates, lipids, and proteins. ROS have been shown to play a major role in the development and progression of cardiovascular disease [
Patients with metabolic syndrome often develop advanced atherosclerosis. Oxidative stress plays a central role in the initiation and progression of atherosclerosis. NAD(P)H oxidases are the primary source of ROS in the vasculature. Increased expression and activity of the phagocytic NAD(P)H oxidases with a parallel increase of oxidized LDL (oxLDL) and nitrotyrosine levels accompanied by thickened intima to media ratio in the carotid arteries, indicative of early subclinical atherosclerosis, have been demonstrated in metabolic syndrome patients [
Recently, there has been some attempts to define the contribution of the individual components of the metabolic syndrome to oxidative stress evident in the metabolic syndrome patients. Obesity is a core component in the development of metabolic syndrome and plays a central role in amplified oxidative stress. Obese patients have shown oxidative stress-induced decreased vasodilatory response to acetylcholine, which was inversely related to body mass index, waste to hip ratio, fasting insulin, and insulin resistance [
The isolated contribution of insulin resistance to oxidative stress is difficult to asscertain. Studies which address the question of oxidative stress in type II diabetes typically do not distinguish between the study participants on the basis of obesity or their lipid profile. Since both obesity and dyslipidemia, independently, significantly contribute to oxidative stress, and obesity is the primary risk factor for the development of insulin resistance, with dyslipidemia now emerging as a possible contributing factor, this presents a significant obstacle with respect to determining whether insulin resistance alone elevates oxidative stress in humans. Likewise, the animal models of insulin resistance are obese, and the insulin resistance develops secondary to obesity. Increased ROS have also been shown to have a causal role insulin resistance [
While hyperglycemia per se is not a defining parameter of the metabolic syndrome, hyperglycemia, which results from primary
Dyslipidemia, characterized by elevated LDL and triglycerides and decreased HDL, is also a frequent component of the metabolic syndrome phenotype. A positive correlation between elevated LDL and triglycerides and low HDL and oxidative stress in animal models is well established. LDL receptor-deficient mice fed a cholesterol-enriched diet developed elevated LDL levels and consequently oxidative stress [
Hypertension is another component of the metabolic syndrome which is independently associated with increased cardiovascular risk. While animal models of hypertension have also been rather consistently associated with elevated oxidative stress, whether hypertension alone increases oxidative stress in humans is somewhat controversial. One study found no difference in markers of oxidative stress when comparing hypertensive and normotensive patients [
Furthermore, unlike the other component pathologies of the metabolic syndrome, hypertension is itself a multifactorial disease with a variety of possible etiologies. Oxidative stress has been shown to increase deoxycorticosterone acetate- (DOCA-) salt [
Although a definition of the metabolic syndrome in children has not been agreed upon, development of characteristics of metabolic syndrome is increasingly prevalent in children and adolescents. Childhood obesity has been associated with development of cardiovascular risk factors [
Cigarette smoke and air pollution are the most significant external sources of oxidative stress. Epidemiological studies have demonstrated a clear association between increased air pollution and human morbidity and mortality. Production of ROS is the fundamental mechanism which mediates these detrimental effects [
Smoking and air pollution interact with the metabolic syndrome in ways which are as yet insufficiently understood but clearly combine to deliver a cardiovascular risk factor which is greater than the sum of its parts. Smokers and ex-smokers are more likely to have metabolic syndrome than nonsmokers [
Secondary to numerous studies having reported similar effects [
Moreover, studies in animal models and humans suggest that long-term exposure to environmental pollutants promotes development of insulin resistance, hyperglycemia, hypertension, obesity and the metabolic syndrome. Workers in refineries and residents in surrounding areas have been found to have high incidence of the metabolic syndrome [
Several studies have investigated a role for dietary influence on oxidative status. Mediterranean-style diet intervention consisting of increased intake of whole grains, fruits, vegetables, nuts, and olive oil for two years resulted in decreased CRP levels as well as improved insulin resistance and endothelial function [
Metabolic syndrome patients have a significantly greater risk for the development of cardiovascular disease in general and coronary artery disease (CAD) in particular. Several studies report a correlation between metabolic syndrome and carotid atherosclerosis [
The etiology for these phenomena may be related to elevated oxidative stress in the metabolic syndrome. Increased oxidative stress has been strongly associated with atherosclerosis leading to CAD [
In addition to more severe CAD with worse long-term prognosis, current revascualrization therapies, coronary artery bypass grafting (CABG), and percutaneous transluminal coronary angioplasty (PTCA) in metabolic syndrome patients are associated with higher procedural risk and poorer long-term outcomes [
With the limited effectiveness of the current treatments for occlusive CAD in the metabolic syndrome patient population, significant effort has been aimed at developing alternative means for coronary revascualrization. Narrowing of the coronary arteries due to accumulation of atherosclerotic plaque leads to decrease in blood flow to distal tissue. In response to increased myocardial oxygen demand, heart tissue distal to the occlusion undergoes transient, repetitive ischemia (RI) as in stable angina pectoris. The physiological response of the heart is to enlarge native collateral arterioles to conduit vessels in a process termed coronary collateral growth or arteriogenesis [
Studies in animal models of diabetes and the metabolic syndrome support the findings in humans. Coronary collateral growth in response to coronary artery occlusion has been shown to be impaired in rat models of the metabolic syndrome [
Oxidative stress is emerging as a major underlying mechanism of impaired collateral growth in the metabolic syndrome. It has now been clear for several years that an optimal amount of ROS or an optimal redox state of the cell (redox window) is absolutely required for coronary collateral growth. This topic was recently extensively reviewed [
Of the possible sources of ROS, the sources most important for the regulation of coronary collateral growth have not yet been entirely resolved. Strong evidence now points to the mitochondrial sources of ROS. In a recent study, the mitochondria-targeted antioxidant MitoQ nearly completely restored coronary collateral growth in a rat model of the metabolic syndrome, the Zucker obese fatty rat (ZOF) [
Results from clinical trials for improving cardiovascular outcomes by antioxidant therapy have, however, been inconsistent and confusing. Antioxidant supplementation in humans has not been as successful as expected although some studies have been promising. The HOPE and HOPE-TOO clinical trials evaluated long-term vitamin E therapy in patients at least 55 years old who had either vascular disease or diabetes mellitus. There was no improvement in cardiovascular outcomes. Alarmingly, there was an increase in heart failure and heart-failure-related hospitalizations [
However, multiple factors complicate the interpretation of the results of these trials. First, whether the antioxidant interventions actually succeeded in reducing oxidative stress in patients enrolled in the HOPE and the MRC/BHF trials was never ascertained [
Second, the effectiveness of antioxidants used in clinical trials is low. Both vitamins E and C have actually been shown to have some prooxidant effects in vitro [
The beneficial effect of lowering oxidative stress on cardiovascular outcomes in metabolic syndrome patients can perhaps be further supported by beneficial effects of the drugs typically used to treat the metabolic syndrome and/or its various components, specifically metformin, statins, ACE inhibitors, and ARBs. All of these pharmacological agents have been found to have beneficial cardiovascular effects independent of their original purpose, that is, glycemic control (metformin), lipid lowering (statins), and blood pressure regulation (ACE inhibitors and ARBs). These beneficial cardiovascular effects may be mediated by their antioxidant properties. Metformin has been shown to decrease intracellular ROS by upregulating thioredoxin in cell culture [
It is also now accepted that the numerous positive effects of some statins in the cardiovascular system are mediated independently of their lipid-lowering effect via a direct decrease in oxidative stress. As mentioned earlier in this paper, short-term pravastatin treatment reduced MI size in hypercholesterolemic rabbits through reduction in peroxynitrate and nitrotyrosine formation [
Several clinical trials have documented beneficial effects of ACE inhibitors and ARBs on cardiovascular end-points in type II diabetic and metabolic syndrome patients without hypertension. The HOPE study showed a 22% reduction in cardiovascular events (MI, stroke, cardiac arrest, revascualrization, heart failure, death) in metabolic syndrome patients and without hypertension treated with an ACE inhibitor, ramipril versus metabolic syndrome patients without hypertension not treated with an ACE inhibitor [
In addition to lowering oxidative stress, Ang II blockade has been shown to have marked positive effects on insulin resistance, glucose tolerance, and the lipid profile. In a rat model of insulin resistance and renin-angiotensin system (RAS) overactivity, the TG(mREN2)27 rat, administration of an ARB improved insulin sensitivity, stimulated glucose transport into muscle, and reduced oxidative stress [
These effects are likely also indirectly mediated through the Ang II-generated oxidative stress, since Ang II has been shown to inhibit Akt phosphorylation and, consequently, GLUT-4 transporter translocation to the plasma membrane in an NAD(P)H oxidase-dependent manner via tyrosine nitration, probably through formation of peroxynitrate [
In conclusion, it is clear that metabolic syndrome is associated with increased oxidative stress. Furthermore, it appears that some component pathologies of the metabolic syndrome contribute to a higher percentage of total oxidative stress than others; however, additional studies are needed to determine the exact contribution of individual components to total oxidative stress.
It is also clear that the metabolic syndrome is a strong risk factor for the development and increased severity of cardiovascular disease in general and occlusive CAD in particular and confers a greater risk than the sum of its individual components. However, the presence of which individual component or what exact combination of individual components confers the greatest risk for CAD development remains a matter of debate and may be gender-specific with abdominal obesity in combination with low HDL and elevated oxLDL conffering the greatest risk for men, while hyperglycemia provides the greatest risk factor for women. Moreover, metabolic syndrome is a predictor of higher procedural risk and poorer postprocedure outcomes for revascualrization therapies, PTCA, and CABG, with insulin resistance and hyperglycemia confering the greatest negative effect. Finally, development of coronary collaterals is also severely compromised in the metabolic syndrome. Although the exact contribution of individual pathologies of the metabolic syndrome to oxidative stress is difficult to conclusively determine, it is certain that oxidative stress is highly elevated in the metabolic syndrome. We believe that ample evidence points to this increased oxidative stress being the major unifying mechanism which underlies the increased propensity for CAD development, greater severity of CAD at a younger age, and poorer treatment outcomes.
Air pollution and cigarette smoke pose a greater risk of adverse cardiovascular events for people with the metabolic syndrome possibly because of the increased oxidative stress in the metabolic syndrome, which is further elevated by the aromatic hydrocarbon and metal nanoparticle components of these environmental pollutants leading to activation of well-known detrimental cascades of events that link oxidative stress to exascerbation of cardiovascular disease.
Finally, we would like to emphasize that despite the reported lack of success of large antioxidant trials, we believe that antioxidants might be useful for treatment and prevention of cardiovascular disease in metabolic syndrome patients. Several lines of evidence support this opinion. First, the drugs currently used to successfully retard the progression of cardiovascular and renal disease in patients with the metabolic syndrome all have strong direct antioxidant effects. Second, the effect of antioxidants on cardiovascular indexes was significant in metabolic syndrome patients in carefully designed studies where oxidative stress was in fact lowered. We suggest that experiences to date speak to the necessity of conducting well-designed large-scale trials which would include carefully selected populations of metabolic syndrome patients. On a related note, it is obvious that the metabolic syndrome is a distinct and complex phenotype with a set of as yet incompletely understood interactions which presents a unique set of challenges. Thus, cardiovascular disease in the metabolic syndrome cannot be adequately studied in a healthy animal model or in animal models which represent one of its component pathologies. It is therefore critical that therapeeutic endeavors aimed at resolution of CAD in the metabolic syndrome, including coronary revascualrization, be studied in animal models of the metabolic syndrome.
This paper was supported by AHA 11PRE7690011 (R. Hutcheson) and NIH R01 HL093052 (P. Rocic).