Table 1.

A mechanistic understanding of myocardial infarction from pathways to clinical events

Diseases span over multiple layers of complex mechanisms, from impaired signaling pathways to clinical events. Myocardial infarction is a typical illustration.
• From arterial wall cell dysfunction to sudden death, a large number of genes, molecular species, cell types, endocrine and paracrine, as well as neurological regulations, are involved, with feedback loops and redundancies.
• Atherosclerosis is a disease located at discrete sites of the arterial tree. To this date, the triggering event is not fully established. A recent theory defines the entry of monocytes into the arterial wall as the primary cause. But this yields little explanation as to why these monocytes pass through the endothelium in the first place. Nevertheless, it has been established that atherogenesis involves several molecular species and cells: circulating lipoproteins and their oxidized derivatives, endothelial cells, circulating monocytes, macrophages, smooth muscle cells, and extracellular proteins (elastin, collagens, enzymes such as metalloproteases).
• Biological phenomena as diverse as inflammation, cell migration, free radical production, ageing, etc., are also involved. Plaque anatomy and arterial wall structure, as well as phenotypes and proportions of the aforementioned components, are playing a role in the ultimate event, the plaque rupture.
• Critical to the rupture process are fatigue (arterial wall, plaque fibrous cap) and stress-related mechanical phenomena (shear, pulse). Plaque rupture eventually enables interactions between plaque and blood components, leading to the occurrence of a clot. The clot may obstruct the arterial lumen leading to a global ischemia of the downstream tissues, migrate to block a smaller artery or stay in its initial location and end up being incorporated in the plaque after its fibrous organization.
• A coronary plaque rupture can thus result in a variety of outcomes: sudden death, acute coronary infarction, unstable angina, silent infarction, or increased coronary stenosis. When the artery lumen is narrow enough, effort angina or heart failure can occur. Heart failure can also be caused by healed myocardial infarction(s). While atherosclerotic plaque takes decades to build up, its rupture and ischemic consequences develop over a short timespan.