Current Concepts of Cardiovascular Risk Factors: Endothelial Dysfunction Therapy, And Outcomes

Endothelial dysfunction is a well-established response to cardiovascular risk factors and precedes the development of atherosclerosis. Endothelial dysfunction is involved in lesion formation by the promotion of both the early and late mechanisms of atherosclerosis including up-regulation of adhesion molecules, increased chemokine secretion and leukocyte adherence, increased cell permeability, enhanced low-density lipoprotein oxidation, platelet activation, cytokine elaboration, and vascular smooth muscle cell proliferation and migration.

Endothelial dysfunction is a term that covers diminished production/availability of nitric oxide and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. Also, when cardiovascular risk factors are treated the endothelial dysfunction is reversed and it is an independent predictor of cardiac events. We review the literature concerning endothelial dysfunction in regard to its pathogenesis, treatment, and outcome.

During the last 2 decades, it has been shown that the vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homeostasis. The basic mechanisms involved in atherogenesis indicate that deleterious alterations of endothelial physiology, otherwise known as endothelial dysfunction, represent a key early step in the development of atherosclerosis and are also involved in plaque progression and the occurrence of atherosclerotic complications. The resulting imbalance leads to an impairment of endothelium-dependent vasodilation, which is the functional characteristic of endothelial dysfunction. In addition to impaired endothelium-dependent vasodilation, endothelial dysfunction also comprises a specific state of endothelial activation, which is characterized by a proinflammatory, proliferative, and procoagulant states that favor all stages of atherogenesis.

The endothelium maintains normal vascular tone and blood fluidity, with no or little expression of proinflammatory factors under normal homeostatic conditions. However, both traditional and novel cardiovascular risk factors including smoking, aging, hypercholesterolemia, hypertension, hyperglycemia, and a family history of premature atherosclerotic disease are all associated with alteration in endothelial function.

Oxidative stress and endothelial cell dysfunction

Reactive oxygen species (ROS) are generated at sites of inflammation and injury, and at low concentrations can function as signaling molecules participating in the regulation of fundamental cell activities such as cell growth and cell adaptation responses; whereas at higher concentrations, ROS can cause cellular injury and death.

Chronic exposure to cardiovascular risk factors and oxidative stress overwhelms the defense mechanisms of the vascular endothelium, which is followed by ED and the loss of the endothelium's integrity, smooth muscle cell proliferation and migration, and leukocyte adhesion and migration. Much evidence has been pointing to ED as one of the major pathologic changes between exposure to the cardiovascular risk factors and the development of atherosclerotic cardiovascular disease.

Role of NO and oxidative stress

The progression from ED to atherosclerosis is complex and multifactorial. As the endothelial function deteriorates, vascular homeostasis becomes impaired and leads to reduced anti-oxidant and anti-inflammatory effects, increased vascular permeability to lipoproteins, and the increased expression of inflammatory cytokines and adhesion molecules. Among various complex mechanisms, oxidative stress appears to be the most common underlying mechanism for the development of ED.

Chronic inflammation

Inflammation is another common underlying mechanism of ED, and there seems to be a causal relationship between oxidative stress and inflammation. Under physiological conditions, the endothelium controls vascular inflammation by releasing NO. However, a dysfunctional endothelium will promote ROS generation and aggravate vascular inflammation, which is detrimental to the vascular system. Oxidative stress may amplify the vascular inflammation signaling pathways, and inflammatory cells increasingly release superoxide. There are numerous inflammatory markers associated with endothelial dysfunction and atherosclerosis.

Infection

Endothelial dysfunction and atherosclerosis are also affected by infection and its immune-mediated injury. Epidemiological studies indicate infectious agents may predispose patients to atherosclerosis and its clinical events. Viruses, such as cytomegalovirus and herpes simplex virus-1, and bacteria, such as Chlamydia pneumoniae and Helicobacter pylori, have reported to be associated with coronary artery disease (CAD) in humans.

Vitamin D deficiency

Among several cardiovascular risk factors, vitamin D (1α, 25-dihydroxycholecalciferol) deficiency is emerging as a new candidate. Vitamin D appears to participate indirectly in atherosclerosis and systemic inflammation. Including endothelial cells, vitamin D receptors (VDRs) are present in all cells implicated in atherosclerosis. In patients with subclinical atherosis and slow coronary blood flow, a strong association was found between vitamin D deficiency and endothelial dysfunction.

Shear stress

Although the entire vascular tree is exposed to the systemic risk factors of ED, atherosclerotic lesions usually generate at specific arterial regions, such as bifurcations, branching points, and the inner aspect of curved segments of the coronary artery. Locally disturbed shear stress by pulsatile blood flow is one of the modulators of the atherogenic process and accounts for the regional and clinical variability of atherosclerosis.

Beta blockers

Unlike first- and second-generation β-blockers, third-generation β-blockers, such as carvedilol and nebivolol have favorable effects on endothelial function. Both drugs have been reported to stimulate β3 receptors, which activates eNOS and has antioxidant effects and the increased release of NO.

Estrogens

There have been reports about estrogens that are able to improve endothelial function through antioxidant properties that increase NO expression and promote the degradation of superoxide anion radicals.

The functional integrity of the endothelium is a fundamental element for vascular health. Many studies have established that ED could be an early integrated index of all atherogenic and atheroprotective indicators present in an individual. Until now, several biochemical markers and functional studies have led to the development of early detection and therapeutic interventions for ED.