Mechanical Strain, Inflammatory Change and Arteriosclerotic Plaque Rupture

Arteriosclerotic Plaque Rupture

Arteriosclerotic plaque rupture is responsible for the majority of STEMI-type heart attacks and a proportion of strokes, transient ischaemic attacks and peripheral vascular ischaemic events [1-4]. Separation of the plaque from the underlying wall of the artery exposes the subjacent pro-thrombogenic surface of the arterial wall to circulating blood, and manifests clinically by triggering coagulation and platelet activation giving rise to local vessel occlusion by thrombus, or to distal platelet-fibrin embolization.

Mechanical Aspects

On the face of it, plaque rupture seems to be a simple mechanical event. A plaque will separate when the forces detaching it exceed those holding it to the wall of the artery [5]. The plaques most vulnerable are those where there is an elastic compliance mismatch between different parts of the plaque and the adjacent arterial wall, where the overlying capsule is thinned, or where the stenosis is such as to produce a lifting effect during peak flow [1,3, 6-10].

The study of what gives rise to these mechanical stresses acting on the plaque is therefore relevant. Known independent risk factors for acute cardiovascular events precipitated by plaque rupture include hypertension, and increased stiffness in the wall of large distributive arteries such as the aorta giving rise to elevated pulse pressure and sharp peak pressure waveforms [11,12]. Age, smoking and diabetes all contribute to arterial wall stiffness and hence to elevated pulse pressure [13-15]. Figure 1 shows the close relationship between pulse pressure and the Critical Displacement Force (CDF) acting on an artificial “plaque” subjected to pulsatile flow in an in-vitro perfusion rig [12] using porcine arteries.

The degree of stenosis produced by a plaque affects the stress placed upon it and the probability of rupture [16]. Here the relationship between the degree of plaque stenosis and rupture risk is not a linear one, with the combination of a moderate degrees of stenosis with high peak flow giving rise to the maximum transmural stress [17,18] suggesting the importance of shear strain and the Bernouilli effect in determining plaque stress. In the experimental model used in Figure 1 there was a doubling in the CDF on increasing the plaque induced occlusion from 17% to 40% but no further increase between 40- 60% occlusion, where the degree was such as to reduce peak flow velocity.

Figure 1: Demonstrating the close relation between the force acting on the plaque at the initiation of the sub-plaque cleavage plane (critical detachment force, CDF) and the pulse pressure, which is in turn a function of arterial wall stiffness (r=9, n13, p<001). An electromagnet has been used to hold the simulated “plaque” to the wall of the artery with a pressure that can be controlled through the power supplied to the magnet. The CDF is the pressure applied at the moment the first fissures appear below the plaque during the passage of the pulse wave.

Plaques situated at kinks or bends seem to be particularly at risk, where cyclical stretch results in arc bending [18]. Table 1 shows the effect of introducing different degrees of arc bending on the CDF during passage of the pulse pressure wave using the above experimental model. One might therefore expect to reduce the risk of plaque rupture by measures aimed to reduce hypertensive strain, particularly by controlling pulse pressure and large vessel wall stiffness.

Table 1: The effect of kink angle on CDF in the above in-vitro model. Multiple runs in a single artery.

IG: intervention group; CG: control group

Inflammatory Aspects

However, inflammation also comes into play. C-Reactive Protein (CRP), a measure of the systemic inflammatory response is a strong independent risk factor for the adverse cardiovascular events caused by plaque rupture [19] and vulnerable plaques contain focal deposits of inflammatory cells at the points where they tend to rupture [20,21]. These infiltrates are associated with the presence of particular matrix metalloproteinases which degrade the connective tissues substructure and weaken the attachment of the plaque to the arterial wall [22].

Is this inflammatory change due to underlying systemic inflammation or to a local inflammatory response? Certainly, low-grade chronic inflammation is a feature of elderly patients [23] and those suffering from chronic inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease. These patient groups are at an increased risk of coronary artery thrombosis [24,25]. Nevertheless, focal inflammation can also be the consequence recurrent mechanical strain, as is evidenced by overuse joint injuries and repetitive strain injuries [26]. The fact that focal accumulations of macrophages in plaques occur at points at where such strain might be expected to act [21,27] and that statins which stabilise plaque also impair monocyte-endothelial adhesion and translocation in response to an inflammatory stimulus, suggests a mechanism whereby a local inflammatory stimulus invoked by recurrent mechanical strain is the underlying cause of the local inflammatory response in the plaque [28]. This concept is supported by the close correlation observed between hypertension and CRP [29] and the fact that CRP falls in response to treatment with antihypertensive medication, and consequently reduction in hypertensive arterial wall stress [30] and it also falls when the local inflammatory response to this strain is blocked by statins – a property that appears to unrelated to their cholesterol lowering effects [31]. These observations suggest that, in the absence of other causes of inflammation, recurrent arterial wall strain injury is responsible for the CRP rise and the inflammatory change associated with hypertensive vessel wall injury and plaque separation.

Provocation of Inflammation by Repeated Mechanical Stress

The mechanism of the link between repetitive strain to the arterial wall and the development of a local inflammatory response remains to be fully elucidated, but a strong candidate is the degradation products of elastin. Elastin is the protein component of the arterial wall responsible for its passive elastic properties. It has a limited half-life, is not regenerated in the adult and it undergoes mechanical degradation in proportion to the number and the magnitude of the stress cycles to which it is subjected [32]. Elastin degradation products (EDPs) when combined with a receptor molecule are pro-inflammatory [32,33] and the EDP-receptor complex has been shown to stimulate macrophage chemotaxis [33].

Conclusion

The precipitating causes of plaque rupture involve both mechanical stress and inflammation. The observation that the inflammatory change appears to be consequent to the physical stress emphasises the importance of the factors giving rise to this stress, and by what mechanism they translate into inflammatory change around the plaque. Further work is required to elucidate the connection between the EDP-receptor complex and inflammatory change in the arterial wall. Primary therapeutic measures to reduce plaque rupture risk involve reducing mechanical stress on the plaque by the management of hypertension and arterial wall stiffness, notably by control of smoking and diabetes, and by the use of statins to reduce the inflammatory consequences and stabilise plaque. CRP may have a useful role in identifying clinically significant hypertension and in monitoring the effect of antihypertensive and statin treatment. Hypertensive patients at risk with raised CRP should be offered the option of statin prophylaxis irrespective of blood cholesterol levels. Lastly, on the basis of the present observations, we would propose a clinical scoring system for plaque vulnerability based on a combination of non-invasive imaging and clinical findings, such as:

i. Calcification pattern – scattered or napkin ring ii. Occlusion – moderate (30-60%) iii. Situation – kink or bend iv. Inflammation – highly sensitive CRP >3mg/L in absence of other underlying cause of inflammation v. Pulse pressure - >65mmHg

If clinically validated and indexed such a scoring system to assess plaque vulnerability could be usefully employed to guide treatment decisions.

Acknowledgement

The authors thank M. Joel Craveur for invaluable technical assistance with regard to the experimental work here cited.

Conflicts of Interest

No conflicts of interest declared. The experimental studies described were self-funded.

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