Cerebrovascular disease is a major public health problem, which is only expected to increase in future years as our population ages at an accelerated pace.
One important and quite plausible cause of both the imaged silent strokes and vascular cognitive decline, is the loss of structural stability and breaking up of atherosclerotic plaque, which over time may initiate the cerebral decline. We studied one important site which is accessible for noninvasive examination that is carotid atherosclerotic plaque and tested the hypothesis that the physical structural stability of plaque is measurable. When this stability is disturbed, we hypothesize that it is related through increased emboli to a decline in cerebral function. If this relationship is established, it opens wide frontiers for further investigation of the pathophysiology and potential future prevention of such a devastating disorder as silent stroke and vascular cognitive decline.
Imaging criteria for treatment until now has focused primarily on percent stenosis and ulceration of the carotid vessel. However, the literature suggests that the process of developing symptoms of carotid plaques mostly involves factors beyond the geometry of such lesions. Thus, we must consider the biochemical, genetic and physical structural properties of the plaques, which may predispose to clinical decline.
A series of studies have suggested that cerebral emboli as measured by transcranial Doppler (TCD) may predict vascular cognitive impairment. In studies17,18
, in patients with carotid stenotic disease transcranial Doppler placed distal to the lesion and measured for a period of one hour showed a bimodal distribution. The presence of measurable microemboli during that time correlated with functional cognitive impairment suggesting a functional deficit beyond that of traditional markers of stroke symptomatology.
Considerable debate remains regarding the cause of vascular cognitive impairment and brain atrophy. Multiple cortical infarcts are believed to cause dementia19
and cerebrovascular disease may increase the severity of classic Alzheimer’s disease19
. However, studies have suggested that this vascular component may be a result of cumulative microvascular changes with white, gray and hippocampal volume loss over time being more important than specific subcortical lacunes19
. The primary microvascular process may be worsened by chronic micro emboli. The suspected relationship of significant atherosclerotic carotid disease to cognition suggests that the pathophysiology of cognitive decline may be influenced by a microembolic process taking place in select carotid plaques above and beyond those processes which produce large clinically recognizable strokes and TIAs. The need to look at the pathophysiology of carotid atherosclerotic disease beyond simple parameters of degree of stenosis or irregularity of surface has led us to look at the structural stability of these plaques as a potential marker for risk of both clinically evident emboli as well as subclinical microemboli.
Carotid artery atherosclerosis is a particular presentation of the larger systemic disease of atherosclerosis which affects many organs. Although stroke is a major cause of death and disability in the USA, many studies have suggested that symptomatically sensitive areas such as the coronary arteries, the carotid arteries and the descending aorta have a stereotypic pattern of plaque development, which is likely to be influenced by a wide variety of modifiers20,21,22,23,24,25
In humans, carotid artery atherosclerosis is far more common than the major strokes, i.e. sudden motor, sensory, visual and speech deficits, which clinicians recognize from carotid embolic disease26,27
. Proliferation of smooth muscle cells, formation of connective tissue, cholesterol deposition, calcification and extravasation of inflammatory cells are all thought to promote atherosclerotic plaque formation. Less is known about the factors that predispose a given atherosclerosis plaque to become symptomatic. At the systemic level, smoking, dietary lipid intake, diabetes, hypertension and infection might promote plaque maturation and rupture28,29,30,31,32
The clinically evident neurological deficits that follow stroke (i.e. motor, sensory, speech and vision) have been used to classify the stroke and provide some information about the prognosis and pathophysiology. Studies have suggested that a consistent increase in atherosclerosis is seen with age and it may be studied by such noninvasive testing as ultrasonic analysis of plaque at the carotid arteries3,33,34,35,36,37,38,39
. The disease process may be further modified by smoking, dietary lipid intake, diabetes, hypertension, and possibly by other factors such as infection, inflammation, and flow characteristics22,26,40,41,42,43,44
. It is the latter, the distribution of local flow, which suggests a particular vulnerability of the carotid bifurcation in the neck to atherosclerotic development. The carotid arteries are extremely high flow vessels, as 20% of the cardiac output is delivered to the brain mainly through these 4-5 mm diameter vessels. Flow is therefore robust but remarkably laminar. This flow is disrupted considerably at the first major flow divider, the bifurcation of the internal and external carotids of the neck. Long-standing flow studies have suggested that turbulence here creates a back wall injury on the internal carotid at its origin, at which point a constant process of repair and cellular activity may be ongoing45,46,47,48
. Local events significantly affect the progress of atherosclerosis. Theories of atherogenesis suggest that plaque may form at this area and may be enhanced by processes which increase local oxidation in the presence of abnormal circulating cholesterol moieties49,50,51,52
. We have studied these events for signature genetic markers7,8
The clinical pathophysiology of carotid atherosclerosis had originally emphasized flow stenosis. However, since the pioneering work of C. Miller Fisher, it has been suggested that a second mechanism present in both the coronaries and carotids may be of great importance, the mechanism of artery-to-artery emboli53,54
. Because of the extreme eloquence of critical regions of the cerebral vasculature, even moderate emboli may produce devastating and clinically relevant consequences when arriving at the brain. At the same time multiple small emboli may cause atrophy and multiple small infarcts that are not recognized as a single event but rather as a progressive decline in function and cognition. Clinical trials of treatments for carotid atherosclerotic disease such as, ACAS, the asymptomatic carotid artery plaque study have taken the practical NASCET step of categorizing carotid atherosclerosis by the degree of narrowing or stenosis of flow38,55,56,57,58
. This has been necessary to allow variable methods of measuring carotid atherosclerosis, angiography, etc. to make meaningful comparisons of measurements. Nevertheless, each study has emphasized the importance of emboli in the pathophysiology of clinical symptoms. Such studies have led to the logical conclusion that it would be clinically important if physicians could identify not only the presence of atherosclerotic plaques, but also those plaques which are biochemically or functionally more likely to produce symptoms, generally by the creation of emboli59
. That is to say, can we clinically differentiate carotid atherosclerotic plaques at greater risk of causing symptoms and then direct therapies towards those aspects which predispose a plaque to becoming symptomatic?