Author + information
- †Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- ‡Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. Amir Lerman, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55906.
Stroke is a leading cause of morbidity, mortality, and disability worldwide, and the disease burden has progressively increased over the past decades. A rising interest in identifying risk factors for cerebrovascular disease may finally shift the focus to prevention of future events (1). Several studies have investigated carotid disease, and specifically carotid stiffness, as a risk factor for the development of cerebrovascular disease and incident stroke. These studies have been limited, however, by inconsistent results. Some reported a significant association between carotid stiffness and stroke, whereas others failed to identify an association.
In this issue of the Journal, van Sloten et al. (2) have filled this gap by conducting the first systematic review and meta-analysis investigating carotid stiffness and incident stroke with data from cohorts using measures of both carotid stiffness as well as carotid-femoral pulse wave velocity, a measure of aortic stiffness. This allowed them to investigate the association between carotid stiffness and stroke and its independence of aortic stiffness. The authors also evaluated carotid stiffness as a risk factor for stroke by quantifying incremental value of carotid stiffness for stroke risk prediction beyond the Framingham stroke risk score factors and carotid-femoral pulse wave velocity, and studied the association between carotid stiffness and other cardiovascular outcomes. The study found that greater carotid stiffness was associated with increased incident stroke, cardiovascular events, and cardiovascular all-cause mortality, but not with an increased risk of coronary heart disease events. Increased carotid artery stiffness was associated with a higher incidence of stroke and cardiovascular events and greater cardiovascular and all-cause mortality.
This paper is important not only because of its novel findings and the gap of knowledge it bridges, but also because of the potential implications of integrating these findings into clinical practice and the underlying physiological mechanisms that may explain the relationship. The authors speculate that carotid stiffness leads to higher pulsatile pressure due to increased flow load on the brain, and that carotid stiffness may be a marker of vascular and biological aging. Certainly, these factors may play a role in explaining the reported findings. Yet, it is important to consider other physiological factors, including vascular dysfunction and remodeling, oxidative stress, and inflammation, as potential contributing factors.
As the authors report, carotid stiffness leads to increased pulsatile pressure and flow load, characterized by increased pulse pressure. Pulse pressure has been associated with vascular dysfunction (3,4). In rabbit carotid arteries, increased pulse pressure was associated with endothelial dysfunction, which was restored with superoxide dismutase, suggesting that oxidative stress may play a role in increased pulse pressure in the carotid arteries (5). It is difficult to identify whether vascular dysfunction precedes or succeeds increases in carotid stiffness. In the hypertensive rat model, increased pulse pressure has been shown to follow development of endothelial dysfunction (6,7). Moreover, antihypertensive medications reduce pulse pressure and improve vascular function, suggesting a link between both processes (8). Increased carotid artery stiffness and pulsatile pressure may be mediated by endothelial dysfunction, which is independently associated with stroke (9). Thus, vascular dysfunction and remodeling may lead to both increased pulse pressure and risk of stroke.
Additionally, carotid stiffness may be an index of underlying vascular disease, manifesting by abnormal vascular function and remodeling, a common precursor to cardiovascular disease, carotid stiffness, and cerebrovascular disease. Endothelial dysfunction is considered to be the initial step of atherosclerosis (10). Several studies have linked vascular dysfunction to incident stroke and cerebrovascular disease (9,11). We have previously reported that in patients with early coronary atherosclerosis, the presence of coronary endothelial dysfunction was associated with a higher cumulative cerebrovascular event rate than in patients with adequate endothelial function (9). This underscored the systemic nature of vascular dysfunction and supported a vascular mechanism of cerebrovascular events unrelated to atherosclerotic plaques. Thus, carotid stiffness and increased pulse pressure, as suggested by the current study, may introduce yet another potential mechanism linking abnormal vascular dysfunction and remodeling and stroke.
Atrial fibrillation (AF), another risk factor for stroke, was not addressed in the current paper. AF may be associated with underlying systemic vascular disease, dysfunction, and inflammation that further increase the risk of cerebrovascular disease. Interestingly, in patients with acute myocardial infarction, parameters of endothelial dysfunction are independently associated with symptomatic AF (12). AF has been associated with impaired vascular function that improves with restoration of sinus rhythm (13,14). Thus, other risk factors for incident stroke, such as unrecognized AF, are linked to vascular dysfunction, suggesting that vascular disease and endothelial dysfunction may be common mechanisms contributing to stroke (Figure 1).
Additionally, the previously reported association of vascular dysfunction with stroke has been attributed to a proinflammatory, proliferative, pro-oxidant, and procoagulatory milieu, which contributes to formation and rupture of plaques (9,15). Homocysteine levels in patients with inflammatory bowel disease have been independently associated with increased carotid artery thickness, suggesting a link between inflammation and carotid remodeling (16). AF has also been associated with increased inflammation, postulated as a possible additional mechanism increasing risk of stroke in patients with AF. The prothrombotic environment in AF has been thought to stem from inflammation, vascular dysfunction and remodeling, coagulation activation, platelet activation, and increased fibrinolytic activity (17). Interleukin-6 has been linked to endothelial activation and endothelial cell damage as well as increased platelet aggregation, and increased interleukin-6 levels have been associated with AF, potentially further explaining increased stroke risk in these patients (18).
Taken together, a number of studies have underscored the importance of vascular dysfunction and remodeling in the development of cerebrovascular disease. The findings of the current study can also be explained by the association of arterial stiffness with underlying vascular dysfunction and remodeling. Several risk factors for cerebrovascular disease, including traditional cardiovascular risk factors for stroke, inflammation, carotid thickness, AF, and others, have been associated with underlying vascular dysfunction, suggesting that this may be a common mechanism responsible for development of both carotid artery stiffness and stroke. Understanding the role of underlying vascular disease and aging, inflammation, and vascular dysfunction is important, as it might allow providers to screen for and manage endothelial dysfunction with aggressive risk factor modification in an effort to prevent adverse outcomes.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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