Author + information
- Published online October 15, 2018.
- Michael Ragosta, MD∗ ()
- ↵∗Address for correspondence:
Dr. Michael Ragosta, Cardiac Catheterization Laboratories, Box 800158, Cardiovascular Division, University of Virginia Health System, Charlottesville, Virginia 22908.
The traditional risk factors responsible for atherosclerosis such as diabetes, hyperlipidemia, hypertension, and tobacco abuse wreak their havoc on our vasculature by highly complex and interactive mechanisms. All arteries and segments are exposed to these systemic conditions in a similar and uniform fashion, yet why does atherosclerosis involve some arterial segments, but not others? The observation that atherosclerotic disease more commonly occurs at areas of disturbed flow such as near branch points, at the outer wall of bifurcations, and along the inner wall of curvatures was made in the 19th century and suggested a role for local factors in the pathogenesis of this disease (1).
The term “wall shear stress” is used to describe the force exerted by the flowing blood on the intimal surface of the vessel wall and is primarily due to friction. Initially, it was theorized that the forcible impact of the blood (i.e., high wall shear stress) around these areas of nonlaminar flow might mechanically damage the lining of the artery wall, initiating the disease process. However, the magnitude of wall shear stress forces that might potentially develop within the vasculature are not sufficient to injure the endothelium. Interestingly, it has been determined that it is low wall shear stress that is associated with lesion development at these locations. Using cadavers, Caro et al. (2) studied the distribution of early-stage atherosclerotic lesions in the aorta and major branches, and found that high shear stress zones such as the inner wall at sites of branching had much less disease than the outer wall, or zones of low wall shear stress. The coronary vasculature, with its complex patterns of branching and curved segments, has many areas of disturbed laminar flow, turbulence, and eddy currents, and thus contains many zones of low wall shear stress. Based on several human studies, the relationship between the development and progression of coronary artery atherosclerotic lesions in areas of low fluid velocity and low wall shear stress has been well-established, and this is now an accepted “risk factor” (3–5).
Why does low wall shear stress cause atherosclerosis? Initially, it was thought that the slow flow and low wall shear stress in these zones provided lipid molecules within the blood lumen more opportunity to enter the vessel wall, but this oversimplified view of the atherosclerotic process was quickly dismissed. Attention then centered on the endothelium. Animal models associated low wall shear stress with endothelial dysfunction (6). Although the precise mechanisms are not clearly defined, it appears that mechanoreceptors on the surface of endothelial cells sense and respond to changes in wall shear stress causing the suppression of atheroprotective genes and the up-regulation of proatherosclerotic genes in regions of disturbed and low flow and low wall shear stress. The consequences of these gene alterations on a molecular level are numerous and include a reduction in the bioavailabilty of nitric oxide, the down-regulation of prostacyclin, the up-regulation of endothelin-1, the promotion of oxidative stress, inflammation, and LDL uptake, as well as the promotion of vascular cell migration, differentiation, and proliferation (7). Additional effects include adverse changes in extracellular matrix turnover, an increase in plaque thrombogenicity, and adverse effects on vascular remodeling that may lead to a vulnerable plaque (7).
Although all this makes for a very tidy story, a direct link between low wall shear stress and endothelial function had not been previously shown in humans. The study by Kumar et al. (8) in this issue of JACC: Cardiovascular Interventions supports an association between low wall shear stress and epicardial endothelial dysfunction, at least in early coronary disease. In a carefully designed research study, the authors used tools such as coronary pressure, flow measurement, and the assessment of coronary endothelial function by measuring the coronary arterial segments’ response to acetylcholine infusion, and coupled these measurements with a highly sophisticated analyses of coronary velocity profile to quantify arterial wall shear stress. They found that arterial segments with low wall shear stress had more vasoconstriction in response to acetylcholine and, thus, had worse endothelial function as compared with segments with intermediate or high wall shear stress. Importantly, low wall shear stress was independently associated with severe endothelial dysfunction. Another recently published study also found an association between low wall shear stress and epicardial endothelial function but also discovered abnormalities in microvascular endothelial function and noted that these may occur before abnormalities in epicardial endothelial function, suggesting that microvascular endothelial dysfunction precedes abnormal epicardial dysfunction (9).
The study by Kumar et al. (8) is an elegant translational research study that enhances our understanding of the pathobiology of coronary artery disease and strengthened the relationship between low wall shear stress and endothelial dysfunction. As with most interesting studies, this work raises numerous questions. The finding of a clear association does not establish causation. Is it possible that endothelial dysfunction disturbs flow and leads to abnormal flow patterns and low wall shear stress rather than the reverse? The work by Siasos et al. (9) cited earlier discovered abnormalities in microvascular endothelial function downstream from areas of low wall shear stress, and in some cases, the microvascular endothelial abnormalities were present without epicardial endothelial dysfunction. This supports a scenario in which traditional risk factors first cause microvascular dysfunction, which then disturbs flow that lowers upstream wall shear stress, which subsequently causes epicardial endothelial dysfunction (9).
Perhaps more important questions relate to this study’s clinical relevance. Can this information be used to modify risk or alter the natural history of coronary disease? Because the major determinants of low wall shear stress are primarily based on anatomic features (i.e., bifurcation geometry and degree of vessel curvature) for which we have no ability to alter, it seems unlikely that this information can be used to reduce risk or favorably change the natural history of disease. If we knew that a patient had areas of low wall shear stress, might we be more aggressive in treating the underlying systemic risk factors? Perhaps, but at present, these data demonstrate merely a convincing association. We do not have any longitudinal data regarding either the natural history of low wall shear stress on atherosclerotic disease progression or the impact that modification of systemic risk factors might have on endothelial function or atherosclerotic disease progression within zones of low wall shear stress. Also, both this work and the one by Siasos et al. (9) included patients with early and non–flow-limiting disease; it would be interesting to know whether segments with no atherosclerosis, but low wall shear stress and endothelial dysfunction, are more likely to develop obstructive atherosclerotic lesions, or whether mild atherosclerotic lesions with low wall shear stress are more likely to experience an acute coronary syndrome. Clearly, more work is needed, and the assessment of wall shear stress as a research tool should lead to much future work along these lines. What about a direct clinical application? Is there any clinical role for measuring wall shear stress? Unlike the widespread adoption of techniques originally developed as research tools to assess coronary physiology, such as fractional flow reserve, unless an easy noninvasive method to measure coronary wall shear stress is developed, it is not practical for a clinician to measure wall shear stress in patients undergoing coronary angiography, and thus, a direct clinical application of this concept is not likely. Despite this, we should applaud the work by investigators like Kumar et al. (8) for expanding our knowledge of the complex process leading to coronary atherosclerosis, and we should support similar work going forward along these lines.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Ragosta has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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