Arterial tissue stress and the geography of atheroma

The initiation and progression of atherosclerosis is due to the interplay between biology and mechanics but whilst there is significant knowledge around the link with intimal injury, risk factor elimination has only made a limited impact on sequelae. Our current understanding pays little attention to the location of atheroma, which is, by and large predictable; for example, the carotid, aortic, femoral and coronary bifurcations; origins of branch vessels from the arch and abdominal aorta; and areas of external constraint such as the superficial femoral artery in the adductor canal. It is well documented that the variable blood flow patterns at these anatomical locations lead to low and oscillatory shear stress, and thus contribute to intimal injury and consequent lipid deposition. Yet it is also well established that the stresses within the arterial wall tissue itself (i.e., the tensile force per unit cross-sectional area of tissue that occurs due to the expansion and contraction of the vessel during the cardiac cycle) are of a far greater order of magnitude (e. g., tissue stress 1 MPa; shear stress 1 Pa), and it is this tissue stress that leads to remodelling and increases in arterial wall thickness to try normalise the stress when subjected to, for example, prolonged hypertension. Therefore, tissue stress clearly influences structural behaviour, but until recently we have been limited in our ability to visualise this influence, beyond changes in wall thickness visible with ultrasound or other modalities. Modern imaging techniques such as intravascular ultrasound and optical coherence tomography allow us to visualise the arterial wall and plaque in high resolution. Compositional changes in plaque occurring in areas with high structural stress result in greater vulnerability, whereas areas with low shear stress enabling more plaque growth can now be determined, and so perhaps tissue stress is just as important as shear stress in the development of plaque, but we simply could not appreciate its importance. This is highly relevant when we consider that prevention as we know it, along with risk factor management does not eliminate atherosclerosis and the modern armamentarium for treatment of lesions is entirely dependent on mechanical devices subject to structural failure. The accepted theory of atherosclerosis (low shear stress on the endothelium leading to intimal injury and lipid uptake) is supported by therapeutic and dietary trials based on the identified risk factors that are preventative for arterial adverse events, especially in the coronary system where the investigations have been most intense. It is therefore entirely reasonable to conclude that the accepted theory is beyond question. There are several scenarios that do not fit within the accepted theory; why do some lesions that restrict flow apparently spare and appear to protect downstream vessels? Why is the upper limb spared in comparison with the lower? Why is the peroneal artery in the leg spared when the anterior and posterior tibial vessels are heavily involved? Why is atheroma never seen in the venous system (unless arterialised) and why is not plaque formed after iatrogenic intimal damage rather than neointimal hyperplasia? The common denominators for atherogenesis are pulse pressure and sites of tissue stress and it is this which we need to understand more in order to make sense of the geography of predisposed atheroma sites as they might pertain to device failure as well as prevention of atherosclerosis. Whilst there is a great deal known about the role of vasa vasora (VV) from the point of view of plaque rupture and neoangiogenesis, most of the evidence is based on animals and the small amount of human data is from the coronary circulation only. Furthermore, there is little known about their response to tissue stress. One alternative hypothesis is that the penetrating branches of the vv are subject to mechanical stress as they pass through the layers of the artery wall where they may be injured. This injury could lead to microhaemorrhage, release of cholesterol from red cell membranes and plasma and an inflammatory response to heal the lesion. However, the healing lesion is still subject to the same tissue stress, so further injury occurs, and so on, in a cycle of repeated injury and healing, with the enlarging plaque acting as a larger nidus for ongoing injury. Such a theory would still explain all the scenarios described earlier without contradicting the knowledge of known predisposing factors and accelerators for atherogenesis. Rapid growth in computational fluid dynamics and finite element analysis enables us to study the forces and reactive changes in the arterial system more realistically than before. These techniques have been used extensively in the oil and gas industry where flow in pipes and stress fracture are well understood, and have already been able to relate tissue stress to coronary plaque rupture or the ratio of tissue stress to strength when assessing risk in patients with abdominal aortic aneurysm. Perhaps they could prove a role for tissue stress in fracture of the penetrating branches of the vv causing microhaemorrhage and plaque initiation also? Computing the tissue stress where radial stress from pulsation, intramural shear stress from longitudinal interlayer movement and torque from external tissue constraints might reveal the impact on the penetrating branches of the vv and where they are most vulnerable to injury, by comparing known predisposed sites to those which are usually spared. If atherogenesis is a consequence of vv injury, it would explain the prevalence of atherosclerosis in diabetics where the small vessel pathology and sequence of arteriolar haemorrhages followed by cholesterol deposits and scarring can be observed directly in the fundus of the eye where structural stresses can be measured. More recently, there has been a renewed focus on the vv, and contemporary techniques to visualise them may shed more light on their relevance. If the focus for atherogenesis shifts from intimal injury to intramural injury, it will reorganise atherogenic theory for vessels large enough to have vv; it will not change risk factors management and it may answer some of the questions posed by the inexplicable clinical observations alluded to earlier. Most importantly, if the basic science thoughts behind atherogenesis change, so too may the pathways to prevention, prophylaxis and therapies.