The Complex Cardiac Atherosclerotic Disorder: The Elusive Role of Genetics and the New Consensus of Systems Biology Approach

Abstract

<p>The present technological status of genetics and genomics or the genome-wide association studies (GWAS) are insufficient to explain complex diseases like atherosclerosis and coronary artery disease (CAD). It appears that the genetic risk variants of atherosclerosis are activated concurrently with functionally active specific environmental risk factors. With the systems biology methodological approach the atherosclerotic process and CAD are better explained and studied as a unified entity with significant clinical consequences.</p><p>Systems biology is an alternative approach for the study of atherosclerosis and CAD. With the systems biology approach the follow-up of the atherosclerotic process requires four conceptual areas of study: 1) the two potential directions, the bottom-up direction (functional composition from genes to phenotypes) and the top-down direction (functional decomposition from phenotypes to genes); 2) the four disciplines or levels of complexity: the genomic, the cellular, the modular and the model (clinical phenotype) level; 3) the concept of network construction; 4) the atherosclerotic plaque development and progression across all levels of complexity.</p><p>The systems biology methodology is holistic in conception. The proposed systems patterns are able to follow up the progressive nature of atherosclerosis and to explain the appearance of the clinical cardiovascular phenotypes. The phenotypes of CAD are integrated clinical wholes that determine through constrains and therapeutic procedures the behavior of the biological parts in the lower levels of complexity. This way of thinking is leading from genomics, through networks, to the mainstay of clinical cardiology. </p>

Conceptual Foundations of Systems Biology Explaining Complex Cardiac Diseases

“…The term of modules in CAD includes the coronary artery status like the pre-existent or post-acute artery obstruction, degree of coronary stenosis, coronary collaterals, myocardial or arterial remodeling and the environmental factors. Clinical phenotypes are the various appearances of CAD, like myocardial infarction, acute coronary syndromes and asymptomatic CAD [20]. …”

“…In addition, the location and “the size of a myocardial infarction (phenotype higher level) will impose the extent of the post-infarction collaterals and the size of the myocardial remodeling (modular lower level)” [20]. This reasoning will influence clinical decision for medical or invasive therapy (Figure 3).…”

“…The majority of coronary obstructions are not followed by myocardial infarctions but a lot of people are asymptomatic without ischemia or develop silent myocardial ischemia or angina. For a myocardial infarction to develop other internal and/or external environmental factors are obviously required [20]. …”

“…A sigmoidal (S-shaped) curve of development depicts atherosclerotic plaque and CAD progression “with a slow initial growth period of 30–50 years, followed by a fast expanding asymptomatic period of 10 years, and eventually by a final period with clinical symptoms” [20,51]. Genome-wide association studies (GWAS) were used to study complex diseases like CAD in order to identify loci connected with a particular disease.…”

“…In coronary arteries, there is significant link between concentration of circulating plasma LDL and turbulent flow in areas of bifurcations or curbs. It was found that “in a top-down direction, in areas of bifurcation or trifurcation, the wall shear stress (WSS) is changing endothelial cells’ genes expression, which, in a bottom-up direction, promotes arterial remodeling and atherosclerosis” [20,71,72]. …”