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Genes influence smoking behavior, affect the metabolism of nicotine and specific chemicals produced during combustion, and enhance (or diminish) pathomechanistic pathways associated with the atherogenic potential of smoking, including oxidative stress, its inflammatory burden or procoagulant potential. Genome-wide association studies have revolutionized the search for new functional genetic markers with ever increasing marker density and the precision in identifying new genetic loci without the need for prior knowledge of functional pathways. Nevertheless, the statistical challenge remains to identify the few true positives, the need for replication of findings and the tedious work of identifying functional genetic variants and their mode of action. Genetic variation within a gene or in areas of the genetic code that control the expression of such a gene is far from being understood. Major advances include the detection of large-scale copy-number variants in the human genome and the demonstration of the decisive role of ‘miRNA’ in controlling gene expression. The role of the genomic methylation pattern in controlling the transcription of the underlying genetic sequence and its role in interacting with environmental influences have yet to be explored in depth. Although candidate genes and their genetic variants have been associated with atherosclerosis and cigarette smoking, a major breakthrough has still to be made.

The normal endothelium inhibits platelet and leukocyte adhesion to the vascular surface maintaining a balance of profibrinolytic and prothrombotic activity. Endothelial function is assessed largely as endothelium-dependent vasomotion, partly based on the assumption that impaired endothelium-dependent vasodilation reflects the alteration of important endothelial functions. Atherosclerotic risk factors, such as hypercholesterolemia, hypertension, diabetes and smoking, are associated with endothelial dysfunction. In the diseased endothelium, the balance between pro- and antithrombotic, pro- and anti-inflammatory, pro- and antiadhesive or pro- and antioxidant effects shifts towards a proinflammatory, prothrombotic, pro-oxidative and proadhesive phenotype of the endothelium. A common mechanism underlying endothelial dysfunction is related to the increased vascular production of reactive oxygen species. Recent studies suggest that inflammation per se, and C-reactive protein in particular, may contribute directly to endothelial dysfunction. The loss of endothelial integrity is a hallmark of atherosclerosis and the causal possible link between each individual risk factor, the development of atherosclerosis and the subsequent clinical events, such as myocardial infarction or stroke.

Smoking cigarettes induces rapidly occuring and reversible functional changes in the cardiovascular system, which precede morphologic changes. These functional changes are also related to atherosclerotic disease development and thus may qualify as prognostic parameters in chronic smokers. As opposed to smoking-induced morphologic changes functional alterations occur and revert within minutes, thus, allowing for the detection of smoking-induced effects on the cardiovascular system within minutes following exposure to mainstream smoke. Some alterations represent ‘direct’ changes (e.g., endothelial function), others reflect changes in a different organ system (e.g., the autonomous nervous system influencing heart rate variability), while some represent the sum of alterations in many organs and systems (e.g., exercise performance influenced by the autonomous nervous and by endothelial and cardiac function). Since a specific functional parameter usually changes with at least one or several others, caution should be exercised when trying to establish a direct cause relationship between the alteration of a single parameter and a clinical outcome.

Potential mechanisms and biomarkers of atherosclerosis related to cigarette smoking – a modifiable risk factor for that disease – are discussed in this article. These include smoking-associated inflammatory markers, such as leukocytes, high-sensitivity C-reactive protein, serum amyloid A, ICAM-1 and IL-6. Other reviewed markers are indicative for smoking-related impairment of arterial endothelial function (transcapillary leakage of albumin, inhibition of endogenous nitric oxide synthase activity and reduced endothelium-dependent vasodilation) or point to oxidative stress caused by various chemicals (cholesterol oxidation, autoantibodies to oxidized low-density lipoprotein, plasma levels of malondialdehyde and F2-isoprostanes and reduced antioxidant capacity). Smoking enhances platelet aggregability, increases blood viscosity and shifts the pro- and antithrombotic balance towards increased coagulability (e.g., fibrinogen, von Willebrand factor, ICAM-1 and P-selectin). Insulin resistance is higher in smokers compared with nonsmokers, and hemoglobin A1c is dose-dependently elevated, as is homocysteine. Smoke exposure may influence the kinetics of markers with different response to transient or chronic changes in cigarette smoking behavior.