EDITORIAL COMMENT
Aortic Stenosis: It Is a Hot TopicThe Link to Coronary Artery Disease*
Blase A. Carabello, MD, FACC*
Department of Medicine, Baylor College of Medicine, and the Veterans Affairs Medical Center, Houston, Texas.
* Reprint requests and correspondence: Dr. Blase A. Carabello, Veterans Affairs Medical Center, Medical Service (111), 2002 Holcombe Boulevard, Houston, Texas 77030. (Email: blaseanthony.carabello{at}med.va.gov).
Key Words: aortic stenosis • valvular heart disease • inflammation
For the past 60 years the primary focus of our attention in aortic stenosis (AS) has been on the severity of left ventricular outflow obstruction as it related to symptoms, left ventricular function, longevity, and the proper timing of valve replacement. In developed nations rheumatic fever waned as a cause of AS, and until 15 years ago the most common cause of AS was classified as "calcific degeneration"—whatever that meant. Then Otto et al. (1) called our attention to the similarities between the plaque of coronary atherosclerosis and the initial lesion of AS. Otto et al. (2) also noted an increased risk for patients with aortic sclerosis. Because aortic sclerosis imparts almost no hemodynamic consequences of its own, it seemed likely that aortic sclerosis was a marker for the co-presence of coronary artery disease (CAD) that in turn was the cause of increased mortality (3). Subsequently, several studies found commonality between the risk factors for AS and CAD, especially with regard to lipid abnormalities (4–8). These observations were tested in at least 2 animal models that confirmed a role for lipids in causing AS. Rabbits fed a high-cholesterol, high-vitamin D diet developed AS (9), as did mice deficient in low-density lipoprotein (LDL) receptors (10). And although there are conflicting data regarding the effectiveness of statins (the principle therapy for the prevention of the adverse effects of CAD), in preventing the progression of AS (11) the data taken as a whole suggest that statins do have a role in retarding the worsening of AS (12–15), again suggesting an AS–CAD link. In addition, aortic atherosclerosis and AS are often present in the same patients (16), further strengthening the argument.
During this period of evolution in our understanding of the etiology of AS, there was also marked advancement in our understanding of CAD leading to the recognition that this disease was inflammatory in nature and that markers of inflammation added important negative prognostic information over and above the traditional lipid markers (17). Of interest, thermal examination of CAD plaques found some to be "hot" with temperatures increasing in a gradation from patients with stable angina to those with acute coronary syndromes to patients suffering a myocardial infarction (18). Thermal heterogeneity was also found in carotid endarterectomy specimens (19).
Perhaps then, it is not so surprising that in this issue of the Journal, Toutouzas et al. (20) found increased temperature variability in the valves of patients with AS. Heterogeneous increases in plaque temperature corresponded with other evidence of inflammation, including lymphocyte infiltration, calcium deposition, the presence of tissue necrosis factor- , and interleukin-6. Virtually none of these findings extended to valves from patients with aortic insufficiency where valve pathology is quite different and not thought to be atherosclerotic. Thus, this study brings the relationship of AS to CAD and other forms of atherosclerosis yet closer and makes it even more interesting. But why then do only approximately one-half of the patients with severe AS also have severe CAD? Does this discrepancy indicate that the 2 conditions also have major differences? Perhaps yes, perhaps no. One could also ask: Why do some patients with severe left anterior descending artery (LAD) disease have angiographically pristine circumflex and right coronary arteries? Or why do some patients with severe peripheral vascular disease have no angiographically detectable CAD at all? Or why is the internal mammary artery, of similar size to the LAD, almost always free from atherosclerosis? Clearly many answers are not yet in.
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Why Do Patients Develop AS?
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The answer to the question posed is obviously unknown, because we have no unifying hypothesis for atherosclerosis in general, but there are some intriguing hints. First, there is much circumstantial evidence that hemodynamic stress plays a role. Calcium deposition occurs primarily on the aortic side of the valve where turbulence and shear stresses are highest. Second, AS occurs sooner and more often in patients with bicuspid aortic valves. Presumably such valves have poorer hemodynamic characteristics than normal tricuspid aortic valves. It should be noted that bicuspid aortic valves are also associated with abnormalities in the NOTCH 1 gene that also regulates calcium deposition (21,22). Thus, bicuspid aortic valve could lead to AS through 2 different mechanisms, hemodynamic stress and genetic dysregulation of bone-forming pathways. Third, although often depicted as symmetrical, tricuspid aortic valves rarely are (23). In fact it is unusual for all 3 leaflets to have the same area, and therefore stresses on the leaflets vary (24). It is possible that leaflet areas of higher stress are where AS begins. Admittedly this would be a very difficult hypothesis to test. An in vivo stress analysis would have to be performed when the valve was normal then followed until AS began to develop. But if most aortic valves have unequal stresses placed upon them, why don't most people develop AS? It is probable that stress is only the first step in the pathophysiology of AS, and in the absence of other downstream abnormalities, AS does not occur. It is likely that the next step involves LDL. High LDL levels are associated with endothelial dysfunction, nitric oxide deficiency, and increased superoxide activity in AS (10,25–27). Thus, mechanical stress combined with factors that promote oxidative stress support an inflammatory cascade leading to further valve disruption ultimately activating pathways leading to calcium deposition and bone formation (28). In this regard Shetty et al. (29) demonstrated deficient osteoprotegerin, a protein that promotes osteoclast activity in severely calcified aortic allografts. Osteoclasitc inactivity could then potentiate bone formation (29). Furthermore, Rajamannan et al. (30) found that Watanabe rabbits, deficient in LDL receptors, fed a high cholesterol diet had up-regulation of Lrp5, an LDL-related receptor that can activate bone formation.
Thus, there might be a stream of biological events starting with hemodynamic stress, incorporating LDL that causes oxidative stress, leading to inflammation and calcification and bone formation, culminating in severe AS. If so, then there are obviously a host of elements in this cascade that could be targeted for the prevention or retardation of progression of the disease.
We have come a long way in our understanding of AS from the time of my fellowship when we called it a degenerative disease—code for "we don't know what's going on here"—to our current understanding of the disease as an active inflammatory process with much in common with CAD. We have a long way to go, but wouldn't it be exciting if both diseases shed light on each other, forming a unifying mechanism for how atherosclerosis develops.
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Footnotes
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* 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. 
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References
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