Diabetes Mellitus-Associated Atherosclerosis

While diabetes mellitus is most often associated with hypertension, dyslipidemia, and obesity, these factors do not fully account for the increased burden of cardiovascular disease in patients with the disease. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease and, more specifically, diabetes-associated atherosclerosis. In addition to the recognized metabolic abnormalities associated with diabetes mellitus, upregulation of putative pathological pathways such as advanced glycation end products, the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines have been shown to play a causal role in atherosclerotic plaque formation and may explain the increased risk of macrovascular complications. This review discusses the methods used to assess the development of atherosclerosis in the clinic as well as addressing novel biomarkers of atherosclerosis, such as low-density lipoprotein receptor-1. Experimental models of diabetes-associated atherosclerosis are discussed, such as the streptozocin-induced diabetic apolipoprotein E knockout mouse. Results of major clinical trials with inhibitors of putative atherosclerotic pathways are presented. Other topics covered include the role of HMG-CoA reductase inhibitors and fibric acid derivatives with respect to their lipid-altering ability, as well as their emerging pleiotropic anti-atherogenic actions; the effect of inhibiting the renin-angiotensin system by either ACE inhibition or angiotensin II receptor antagonism; the effect of glycemic control and, in particular, the promising role of thiazolidinediones with respect to their direct anti-atherogenic actions; and newly emerging mediators of diabetes-associated atherosclerosis, such as advanced glycation end products, vascular endothelial growth factor and platelet-derived growth factor. Overall, this review aims to highlight the observation that various pathways, both independently and in concert, appear to contribute toward the pathology of diabetes-associated atherosclerosis. Furthermore, it reflects the need for combination therapy to combat this disease.     

Endothelial therapy of atherosclerosis and its risk factors

Atherosclerosis is a chronic systemic disease of the vasculature with an inflammatory component. It accounts for the majority of cardiovascular morbidity and mortality in industrialized countries and its incidence is increasing in developing countries. The impairment of vascular endothelial cell function in atherosclerosis and in conditions associated with increased cardiovascular risk is an important determinant of disease progression. The reduction of endothelium-dependent relaxation in the coronary and systemic circulation in atherosclerosis is in part due to decreased bioavailability of nitric oxide and increased release of oxygen-derived free radicals. Atherosclerosis also increases the formation of vasoconstrictors and growth factors, adhesion of leukocytes, thrombosis, inflammation, cell proliferation, as well as increases in vascular tone. Here we review mechanisms and therapeutic approaches to improve endothelial pathways in atherosclerosis. Restoration of NO bioactivity through pharmacological inhibition of the renin-angiotensin system, statin therapy, or endothelin receptor blockade, ameliorates vascular function in experimental hypercholesterolemia, hypertension and heart failure. These treatments also have therapeutic benefit for patients at risk or with overt atherosclerosis, to reduce vascular and myocardial complications of this disease.     

The AGE/RAGE axis in diabetes-accelerated atherosclerosis

1. There is increasing evidence that advanced glycation end-products (AGEs) and their interaction with the receptor RAGE play a pivotal role in atherosclerosis, in particular in the setting of diabetes. 2. Previous studies have shown that inhibition of AGE accumulation and RAGE expression in diabetes by either reduction of the formation of AGEs or cross-link breakers was associated with reduced atherosclerosis and renal disease. Advanced glycation end-products bind to RAGE, thereby leading to activation of a range of inflammatory and fibrotic pathways causing tissue injury. Different splice variants of RAGE exist, including a soluble form that lacks the intracellular domain and fails to induce signal transduction. Therapeutic approaches using soluble RAGE as a decoy binding protein for circulating AGE have been effective in preventing externally induced arterial injury and atherosclerosis in the absence and presence of diabetes. 3. In order to delineate the role of RAGE in vascular disease in more detail, it was necessary to create RAGE(-/-) mice, as well as transgenic mice overexpressing RAGE in endothelial cells. It was shown that RAGE overexpression was associated with increased vascular injury, nephropathy and retinopathy. 4. In contrast, RAGE deletion was associated with partial vascular protection, such as reduced neointima formation after arterial denudation, as well as protection from diabetic nephropathy. The present review summarizes the evidence for RAGE being a pro-inflammatory and pro-fibrotic receptor. 5. Further studies are needed to delineate the effect of RAGE deletion and overexpression in diabetic macrovascular disease. Based on these findings, RAGE could be a potential therapeutic target in combating inflammatory vascular diseases, including diabetes-associated atherosclerosis.     

Thematic issue-topic--diabetic cardiovascular disease--an unmet medical need: emerging targets and therapies-introduction to the special issue

The major cause of death and complications in patients with type 2 diabetes is cardiovascular disease. Cardiovascular complications that are often associated with diabetes include heart failure, acute myocardial infarction (MI), peripheral vascular disease, and cerebrovascular disease. More than 60% of all patients with type 2 diabetes die of cardiovascular disease, and an even greater percentage have serious complications. The impact of glucose lowering on cardiovascular complications is a hotly debated issue and recent large clinical trials, the Action in Diabetes and Vascular Disease (ADVANCE), Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Trial (VADT) reported no significant decrease in cardiovascular events with intensive glucose control. Risk remains high even after correcting diabetes-associated dyslipidemia (high triglycerides and low HDL). Several mechanisms are likely to contribute to the accelerated atherosclerosis and increased cardiovascular disease risk seen in type 2 diabetics. Of these, postprandial hyperglycemia/lipemia, insulin resistance and inflammation may be the most important and under controlled contributing factors to vascular disease. The goal of this thematic issue is to address limitations of current therapies and review emerging research and therapeutic approaches that target inflammation, insulin resistance and other pathological mechanisms that contribute to cardiovascular disease in diabetes.     

Telmisartan for the reduction of cardiovascular morbidity and mortality

Cardiovascular disease (CVD) poses a significant healthcare and economic burden on societies and individuals. Angiotensin II is a key component of the renin-angiotensin system that plays a central role in atherosclerotic mechanisms that contribute to CVD. Renin-angiotensin system blockers are widely used to reduce cardiovascular (CV) risk owing to their potential both to lower blood pressure, a CV risk factor, and to attenuate the atherosclerotic disease process directly. Telmisartan has a number of pharmacological properties that distinguish it from other angiotensin II receptor blockers (ARBs) - the longest plasma half-life, highest lipophilicity and strongest receptor binding affinity in class. The ONTARGET(?) trial showed that telmisartan is as effective as ramipril in reducing CV morbidity (including myocardial infarction and stroke) and mortality in a broad range of patients at increased CV risk. Evidence from other ARBs remains largely restricted to patients with heart failure, diabetic nephropathy or specific subsets of hypertensive patients. Telmisartan is, therefore, the only ARB with a broad indication for CV risk reduction in patients with atherothrombotic disease or diabetes with end-organ damage.     

Inhibition of the renin-angiotensin system and cardio-renal protection: focus on losartan and angiotensin receptor blockade

Angiotensin II plays a central role in the pathogenesis and progression of proteinuric nephropathies and related cardiovascular complications. Losartan is a selective non-peptide angiotensin Type 1-receptor blocker (ARB) with unique uricosuric effect, not shared by other ARBs. Losartan has demonstrated renoprotective effects in animals and humans with diabetic and non-diabetic renal diseases similar to those of angiotensin-converting enzyme inhibitors, with a lower incidence of dry cough and angioneurotic oedema. A reduced incidence of cerebrovascular events and diabetes has been reported in hypertensive patients with left ventricular hypertrophy on losartan therapy compared with patients treated with atenolol. Whether ARBs have superior cardioprotective effects, compared with other blood pressure medications, is still unknown. Combined angiotensin-converting enzyme inhibitor and ARB therapy improves renal outcomes in non-diabetic nephropathies more than single drug renin-angiotensin system inhibition. Whether this also applies to diabetic nephropathy and related cardiovascular outcomes is still unknown.     

Inhibition of the renin-angiotensin system and cardio-renal protection: focus on losartan and angiotensin receptor blockade

Angiotensin II plays a central role in the pathogenesis and progression of proteinuric nephropathies and related cardiovascular complications. Losartan is a selective non-peptide angiotensin Type 1-receptor blocker (ARB) with unique uricosuric effect, not shared by other ARBs. Losartan has demonstrated renoprotective effects in animals and humans with diabetic and non-diabetic renal diseases similar to those of angiotensin-converting enzyme inhibitors, with a lower incidence of dry cough and angioneurotic oedema. A reduced incidence of cerebrovascular events and diabetes has been reported in hypertensive patients with left ventricular hypertrophy on losartan therapy compared with patients treated with atenolol. Whether ARBs have superior cardioprotective effects, compared with other blood pressure medications, is still unknown. Combined angiotensin-converting enzyme inhibitor and ARB therapy improves renal outcomes in non-diabetic nephropathies more than single drug renin-angiotensin system inhibition. Whether this also applies to diabetic nephropathy and related cardiovascular outcomes is still unknown.     

The potential role of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy

Diabetic neuropathy is a debilitating disorder that occurs in more than 50 percent of patients with diabetes. Evidence suggests that there are at least five major pathways involved in the development of diabetic neuropathy: metabolic, vascular, immunologic, neurohormonal growth factor deficiency, and extracellular matrix remodeling. In light of the complicated etiologies, an effective treatment for diabetic neuropathy has not yet been identified. Hyperglycemia increases tissue angiotensin II, which induces oxidative stress, endothelial damage and other pathologies including vasoconstriction, thrombosis, inflammation and vascular remodeling. Angiotensin converting enzyme inhibition and/or blocking of the angiotensin II receptor are recognized as first line treatment for nephropathy and cardiovascular disease in diabetes patients. A new class of drug in late stages of development is vasopeptidase inhibitors. This drug inhibits both angiotensin converting enzyme activity and neutral endopeptidase. Neutral endopeptidase is a protease that degrades a number of biologically active peptides including vasoactive peptides. However, little information is available about the potential benefits of these drugs on diabetic neuropathy. Pre-clinical studies suggest that these drugs may be useful in treating diabetic complications involving vascular tissue. The purpose of this review is to evaluate the use of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy.     

Endothelial dysfunction and coronary atherosclerosis

Increasing evidence has revealed that endothelial cells play an important role in the pathogenesis of development and progression of atherosclerosis. Endothelial dysfunction induces disruption of the balance between vasoconstrictive factors and vasodilatory factors secreted from endothelial cells. Among these factors, NO and angiotensin II are especially important factors, and have been shown to exert various direct effects on the endothelial functions that are closely related to the pathogenesis of atherosclerosis. Endothelial dysfunction induces decreased NO bioactivity and increased angiotensin II expression, which increase oxidative stress and expression of adhesion molecules, cytokines, and chemokines. These conditions mediate inflammation, proliferation, and thrombogenesis in vessel wall and promote atherosclerotic lesions. On the other hand, therapies that improve endothelial dysfunction, such as administration of HMG-CoA reductase inhibitors or angiotensin converting inhibitors, have been demonstrated to reduce cardiovascular events and strokes. In this article, we focus on NO and angiotensin II and describe their roles in the pathogenesis of atherosclerosis.     

The role of AGEs in cardiovascular disease

Advanced glycation end-products (AGEs) are generated in the diabetic milieu, as a result of chronic hyperglycemia and enhanced oxidative stress. These AGEs, via direct and receptor dependent pathways promote the development and progression of cardiovascular disease. AGEs accumulate at many sites of the body including the heart and large blood vessels in diabetes. These modified proteins interact with receptors such as RAGE to induce oxidative stress, increase inflammation by promoting NFkappaB activation and enhance extracellular matrix accumulation. These biological effects translate to accelerated plaque formation in diabetes as well as increased cardiac fibrosis with consequent effects on cardiac function. Strategies to reduce the ligation of AGEs to their receptors such as agents which reduce AGE accumulation, soluble RAGE which acts as a competitive antagonist to the binding of AGEs to RAGE and genetic deletions of RAGE appear to attenuate diabetes associated atherosclerosis. Benefits on cardiac dysfunction with these inhibitors of the AGE/RAGE axis are not as well characterised. In conclusion, therapeutic strategies targeting AGEs appear to have significant clinical potential, often in combination with currently used agents such as inhibitors of the renin-angiotensin system, to reduce the major burden of diabetes, its associated cardiovascular complications.     

Angiotensin II and the cardiac complications of diabetes mellitus

The prevalence of diabetes has reached epidemic proportions in the developed world and is expect to increase to 5.4% by 2025. This has resulted in an unprecedented number of patients experiencing the macro- and micro-vascular complications of diabetes, such as renal, retinal, neurological and cardiac dysfunction. Premature coronary artery disease and cardiac failure are vastly over-represented in the diabetic population, with significant morbidity and mortality. In fact, the rate of cardiac events in patients with diabetes is equivalent to non-diabetic patients with a previous myocardial infarction. Epidemiological evidence, combined with the results of large scale trials blocking the renin-angiotensin system (RAS) have provided data to support the hypothesis that angiotensin II and its interaction with the metabolic changes associated with diabetes mellitus is responsible for the pathogenesis of many of these complications. This review focuses on the role of the RAS and the development of diabetic cardiac disease.     

Diabetic heart and the cardiovascular surgeon

The importance of diabetes mellitus (diabetes) as a cause of mortality and morbidity is well known. The number of patients increases alongside aging of the population and increase in the prevalence of obesity and sedentary life style. Diabetes affects approximately 8% of the USA population.Type I (insulin-dependent) diabetes occurs in 20% of cases, and type II (insulin-independent or maturity onset) diabetes occurs in 80% of the diabetic population diabetes mellitus type II is preceded by longstanding asymptomatic hyperglycemia, which accounts for the development of long-term diabetic complications. The main macrovascular complications for which diabetes has been a well established risk factor throughout the cardiovascular system, are: coronary artery disease (CAD), peripheral vascular disease (PVD), increased intima-media thickness (IMT) and stroke. Considering the cardiovascular surgeon, diabetes is associated with an increased rate of early and late complications following coronary artery bypass grafting. Diabetic patients have also been known to have an increased incidence of complications after elective major vascular surgery such as carotid endarterectomy (CEA) and leg amputations due to PVD. Cardiovascular surgeons frequently treat diabetic patients either because diabetes is incidental to another disease requiring surgery, or due to diabetes-related complication such as occlusive vascular disease, neuropathy or infection. Approximately 50% of diabetics undergo one,or more operations during their lifetime. This paper reviews the relationship between diabetic patients and their cardiovascular surgeons. In order to understand this relationship, one must first examine the underlying mechanisms by which hyperglycemia causes hazardous pre and post operative consequences. Then, one must examine the existing evidence of how diabetes correlates with these cardiovascular consequences, followed by the need for multidisciplinary team work which helps the surgeon to cope with diabetic patients.     

End-organ protection in patients with hypertension: focus on the role of angiotensin receptor blockers on renal function

The renin-angiotensin system (RAS) plays a key role in a number of pathophysiological mechanisms that are involved in the development and progression of cardiovascular and renal disease. For these reasons, pharmacological antagonism of this system, particularly the blockade of formation or the receptor antagonism of angiotensin II, has been demonstrated to be an effective and safe strategy to reduce the burden of cardiovascular disease. Among different drug classes, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have provided an excellent alternative to ACE inhibitors, representing a more selective and a better tolerated pharmacological approach to interfere with the RAS. Results derived from large, international, randomized clinical trials have consistently indicated that ARB-based therapeutic strategies may effectively provide cardiovascular and renal disease prevention and protection in different clinical conditions across the entire cardiovascular continuum. This article reviews the pathophysiological rationale of RAS involvement in the pathogenesis of renal diseases, focusing on the beneficial effects provided by ARBs in terms of renal protection.     

Angiotensin II-type 1 receptor interaction upregulates vascular endothelial growth factor messenger RNA levels in retinal pericytes through intracellular reactive oxygen species generation

The renin-angiotensin system has been implicated in the development and progression of atherosclerosis, thereby contributing to adverse cardiovascular events. However, its role in diabetic retinopathy remains to be elucidated. Since pericyte loss and dysfunction have been considered as one of the characteristic changes of the early phase of diabetic retinopathy, we investigated the effects of angiotensin II (Ang II) on the growth and function of bovine cultured retinal pericytes. Ang II stimulated intracellular reactive oxygen species (ROS) generation in pericytes in a dose-dependent manner. Telmisartan, a newly developed Ang II type 1 receptor antagonist, completely inhibited ROS generation in pericytes induced by Ang II. Ang II decreased DNA synthesis in pericytes, which was significantly prevented by an antioxidant N-acetylcysteine. Furthermore, telmisartan or N-acetylcysteine were found to completely inhibit the Ang II-induced upregulation of vascular endothelial growth factor messenger RNA levels in pericytes. The present results suggest that Ang II-type 1 receptor interaction could induce pericyte loss and dysfunction through intracellular ROS generation, thus being involved in the development and progression of diabetic retinopathy.     

Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin

Type 2 diabetes mellitus (T2DM) is a disease characterized by inadequate beta-cell response due to progressive insulin resistance that typically accompanies physical inactivity and weight gain. T2DM is associated with substantial morbidity and mortality related to the associated atherosclerotic cardiovascular risks and diabetic vasculopathies, including microangiopathies (e.g., blindness and renal failure) and macroangiopathies (atherosclerosis). The increasing global prevalence of T2DM is linked to the rising rates of obesity, especially abdominal obesity. Visceral fat accumulation is upstream of obesity-related disorders including atherosclerotic cardiovascular disease (ACVD), and is associated with impaired insulin sensitivity and atherosclerosis through dysregulated production of adipocytokines, especially hypoadiponectinemia. This review article discusses the pathophysiological mechanisms responsible for T2DM and atherosclerosis, focusing on adiponectin. Clinical and experimental studies have shown that hypoadiponectinemia contributes to a variety of life style-related diseases including T2DM and atherosclerosis. It is likely that life-style modification, visceral fat reduction and use of medications that increase serum adiponectin levels (e.g., rimonabant, thiazolidinediones, fibrates, angiotensin receptor blocker and mineralocorticoid receptor blockade) when provided in combination can improve hypoadiponectinemia and thus prevent the development of life style-related diseases including T2DM and ACVD.     

Metabolic syndrome-interdependence of the cardiovascular and metabolic pathways

The metabolic syndrome is a worldwide epidemic, setting the stage for type 2 diabetes and its microvascular complications, and acceleration of macrovascular disease. Insulin resistance, hyperglycemia, dyslipidemia, hypertension, thrombotic disorders and adiposity define the metabolic syndrome and contribute to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Angiotensin II contributes to the development and progression of cardiovascular and renal endpoints and, as such, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors demonstrate a protective effect. Ligands for the peroxisome proliferator-activated receptor gamma (PPAR gamma), appear to impact favourably on atherosclerosis through both direct and indirect mechanisms. In humans, these ligands improve endothelial function, attenuate albuminuria and hypertension, and potentially prevent conversion of prediabetes to type 2 diabetes. Statins also have proven benefit in decreasing overall cardiovascular and stroke mortality and morbidity. The combination of angiotensin II blockade, statin therapy and PPAR gamma activation might emerge as an important global therapeutic strategy in the metabolic syndrome and diabetes. Further studies are needed to determine whether they have synergistic effects to protect the vasculature.     

Influence of short-term experimental diabetes on blood pressure and heart rate in response to norepinephrine and angiotensin II in the conscious rat

Hypertension, atherosclerosis, arteriosclerosis, and cardiomyopathy account for 80% of all diabetic deaths. A paucity of data exists concerning reactivity of the diabetic vasculature to vasopressor substances. The purpose of this investigation was to determine the influence of short-term (4-5 weeks) diabetes on the responsiveness of the cardiovascular system to vasopressor substances in the intact conscious rat. Diabetes was chemically induced with streptozotocin (65 mg/kg i.v.) in 42-43-days-old, nonfasted, male Sprague-Dawley--derived rats. Direct blood pressure and heart rate were recorded, and responses to the vasopressor agonists norepinephrine and angiotensin II were obtained. Short-term diabetic rats were hypotensive and had lower heart rates when compared with control rats. Blood pressure responses to norepinephrine and angiotensin II were depressed in the short-term diabetic rat; however, the baroreceptor reflexes in these rats were more sensitive to increases in blood pressure. Therefore, it appears that there is some type of nonspecific alteration in the responsiveness of the cardiovascular system to the vasopressor agonists in the short-term diabetic rat.     

Approaches to prevention of cardiovascular complications and events in diabetes mellitus

Diabetes mellitus affects about 8% of the adult population. The estimated number of patients with diabetes, presently about 170 million people, is expected to increase by 50-70% within the next 25 years.Diabetes is an important component of the complex of 'common' cardiovascular risk factors, and is responsible for acceleration and worsening of atherothrombosis. Major cardiovascular events cause about 80% of the total mortality in diabetic patients. Diabetes also induces peculiar microangiopathic changes leading to diabetic nephropathy conducive to end-stage renal failure, and to diabetic retinopathy that may progress to vision loss and blindness.In terms of major cardiovascular events, coronary heart disease and ischaemic stroke are the main causes of morbidity and mortality in diabetic patients. Peripheral arterial disease frequently occurs, and is more likely to be conducive to critical limb ischaemia and amputation than in the absence of diabetes. Although there are a number of differences in the pathogenesis and clinical features of diabetic macroangiopathy and microangiopathy, these two entities often coexist and induce mutually worsening effects. Endothelial injury, dysfunction and damage are common starting points for both conditions. Causes of endothelial injury can be distinguished into those 'common' to nondiabetic atherothrombosis, such as hypertension, dyslipidaemia, smoking, hypercoagulability and platelet activation; and those more specific and in some cases 'unique' to diabetes and directly related to the metabolic derangement of the disease, such as (i) desulfation of glycosaminoglycans (GAGs) of the vascular matrix; (ii) formation of advanced glycation end-products (AGE) and their endothelial receptors (RAGE); (iii) oxidative and reductive stress; (iv) decline in nitric oxide production; (v) activation of the renin-angiotensin aldosterone system (RAAS); and (vi) endothelial inflammation caused by glucose, insulin, insulin precursors and AGE/RAGE. Prevention of major cardiovascular events with the antithrombotic agent aspirin (acetylsalicylic acid) is widely recommended, but reportedly underutilised in patients with diabetes. However, some data suggest that aspirin may be less effective than expected in preventing cardiovascular events and especially mortality in patients with diabetes, as well as in slowing progression of retinopathy.In contrast, a recent study found picotamide, a direct thromboxane inhibitor, to be superior to aspirin in diabetic patients. Clopidogrel was either equivalent or less active in diabetic versus nondiabetic patients, depending upon different clinical settings.Recent studies have shown that some GAG compounds are able to reduce micro- and macroalbuminuria in diabetic nephropathy, and hard exudates in diabetic retinopathy, but it is as yet unknown whether these agents also influence the natural history of microvascular complications of diabetes. Lifestyle changes and physical exercise are also essential in preventing cardiovascular events in diabetic patients. Available data on the control of the metabolic state and the main risk factors show that careful adjustment of blood sugar and glycated haemoglobin is more effective in counteracting microvascular damage than in preventing major cardiovascular events. The latter objective requires a more comprehensive approach to the whole constellation of risk factors both specific for diabetes and common to atherothrombosis. This approach includes lifestyle modifications, such as dietary changes and smoking cessation and the use of HMG-CoA reductase inhibitors (statins), which are able to correct the lipid status and to prevent major cardiovascular events independently of the baseline lipidaemic or cardiovascular status. Tight control of hypertension is essential to reduce not only major cardiovascular events but also microvascular complications. Among antihypertensive measures, blockade of the RAAS by means of ACE inhibitors or angiotensin II receptor antagonists recently emerged as a potentially polyvalent approach, not only for treating hypertension and reducing cardiovascular events, but also to prevent or reduce albuminuria, counteract diabetic nephropathy and lower the occurrence of new type 2 diabetes in individuals at risk.     

Thyroid hormone and atherosclerosis

It is generally accepted that the euthyroid state is preferred for the cardiovascular system because both hyperthyroidism and hypothyroidism cause or accelerate cardiovascular diseases. And hypothyroidism is known to be associated with atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension and impaired endothelial function. In addition, recent studies suggest that hypothyroidism is associated with the emerging risk factors for atherosclerosis such as hyperhomocysteinemia and an increase in C-reactive protein level. Thyroid hormone also has direct anti-atherosclerotic effects such as blood vessel dilatation, production of vasodilatory molecules, and inhibition of angiotensin II receptor expression and its signal transduction. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modifying risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in atherogenesis and a possible application of thyroid hormone mimetics for the therapy of hypercholesterolemia and atherosclerosis.