Smoking as a Risk Factor in Atherosclerotic Cardiovascular Disease

Vasomotor Dysregulation

Nitric oxide plays an important role in the vasodilator function of the endothelium. The physiologic reaction to increased blood flow is an increase in cellular calcium, stimulating production of nitric oxide. Diffusion of nitric oxide from the endothelium into the smooth muscle cells mediates vessel wall relaxation, reducing vascular tone. In contrast, smoking inhibits endothelial production of nitric oxide and triggers sympathomimetic stimulation and therefore release of catecholamines, prompting smooth muscle cell activation and vasoconstriction reducing peripheral blood flow. Association of smoking with the level of coronary blood flow is variable. On the one hand it seems to be increased when smoking cigarettes, though less than expected for the amount of cardiac work increase; on the other hand a decrease in coronary blood flow has been documented in patients with existing coronary heart disease.

Inflammation

Smoking instigates an inflammatory process that leads to atherosclerosis. Generally, cigarette smoke causes leukocytosis and an increase in several inflammatory serum markers (e.g., interleukins, tumor necrosis factor α, and C-reactive protein), reflecting a chronic inflammatory process and functional abnormality, a thorough disorder of homeostasis—a systemic disease. Locally, at the vessel wall, this promotes specific changes. In brief, smoking prompts leukocyte adhesion, activation, and migration.

First, expression of leukocyte adhesion molecules (e.g., vascular cell adhesion molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-1]) on the endothelium is up-regulated. This is mediated by the decreased endothelial nitric oxide content and altered shear stress and hemodynamics at the vessel’s surface caused by smoking. Chemokines (e.g., monocyte chemotactic protein 1 [MCP-1]) directly attract monocytes, and their adhesion to endothelium further compromises its nitric oxide synthesis.

In addition, free radicals oxidize low-density lipoprotein (LDL) cholesterol, which activates monocytes as well. Activated monocytes then migrate through the chronically injured endothelium into the intima and release messenger substances that mediate vascular smooth muscle cell proliferation and attract even more macrophages. Complement activation and stimulated T lymphocytes also perpetuate the ongoing process by releasing proinflammatory cytokines, stimulating the whole course of inflammation. Endocytosis of cholesterol by the attracted cells creates foam cells, which found atherosclerotic plaques. Angiogenesis and neovascularization further distort the overlying endothelium, unsettling the vessel wall.

Eventually, inflammatory cells lead to destruction of the fibrous cap. Characterization of the stability and vulnerability of a plaque is difficult and appropriate imaging techniques for identification of plaques at risk and possible prediction of progression are still lacking.

Thrombosis

Plaque instability, rupture, and sudden thrombosis are also based on changes in hemodynamic stress, rheologic properties of the blood, altered platelet function, and changes in pro- and antithrombotic factors. There is a considerable association between smoking and the risk for an acute myocardial infarction, leading to more sudden cardiac deaths in smokers compared to nonsmokers.

Platelet activation and adhesion is substantial in this process of coronary vessel occlusion and ensuing cardiac ischemia. Aggregation of platelets is stimulated in smokers: Limited availability of nitric oxide and distorted platelet sensitivity to nitric oxide cause pathologic platelet activation. Oxidative stress activates platelet thromboxane receptors and smooth muscle cells, which leads to production of (platelet) tissue factor, a promoting protein in the blood coagulation cascade.

Plasminogen activation has been shown to be lower and fibrinogen plasma levels to be higher in smokers. The lack of plasmin, an active protease, reduces degradation of fibrin clots—fibrinolysis—increasing the risk of thrombosis. Excretion of thromboxane metabolites, a surrogate marker for platelet activation and turnover, is pronounced in people who smoke. Smoking is associated with increased carboxyhemoglobin concentrations and red blood cell mass (hematocrit). In turn, blood viscosity is higher and is linked with stroke and peripheral arterial occlusive disease.