Author + information
- †Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa
- ‡Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa
- §Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado
- ↵∗Reprint requests and correspondence:
Dr. Donald Heistad, Departments of Internal Medicine and Pharmacology, University Of Iowa Hospitals, 200 Hawkins Drive, E311 GH, Iowa City, Iowa 52242.
- aortic stenosis
- calcific aortic valve disease
- lipoprotein-associated phospholipase A2
- Doppler echocardiography
These are certain signs to know
Faithful friend from flattering foe…
—William Shakespeare, Sonnets to Sundry Notes of Music. VI (1)
There has been great progress in treatment of aortic stenosis, with development of prosthetic, bioprosthetic, and percutaneous prosthetic valves. A medical treatment for aortic stenosis, however, remains elusive.
In these comments, we consider 2 questions. In addition to being a biomarker, is lipoprotein-associated phospholipase A2 (LpPLA2) a promising target to slow progression of aortic stenosis? In light of evidence that inhibitors of LpPLA2 are ineffective in acute coronary syndrome or stable ischemic heart disease, what makes aortic stenosis a more promising target?
Analysis of a subgroup of the prospective, randomized PROGRESSA (Metabolic Determinants Of The Progression Of Aortic Stenosis) study (2) suggests that, in patients with mild (but not moderate/severe) aortic stenosis, plasma LpPLA2 activity is predictive of rate of progression of aortic stenosis. One implication of the finding is that LpPLA2 may be useful as a predictor of patients that may be at greatest risk of developing severe aortic stenosis, and therefore may be appropriate for an experimental treatment. Another implication, which is not as well founded, is that LpPLA2 may be a therapeutic target in patients with mild aortic stenosis. This latter possibility can be viewed as high risk/high gain.
An appropriate question relates to biologic plausibility: is LpPLA2 involved in development and progression of aortic stenosis? If so, it is an attractive target for treatment. If not, its potential role is limited to a biomarker.
LpPLA2 as a Biomarker
The West of Scotland Coronary Prevention Study Group suggested that LpPLA2 is associated with atherosclerotic vascular disease (3). LpPLA2 is an enzyme expressed by inflammatory cells in atherosclerotic plaques, and is found in the circulation bound to low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol, and lipoprotein(a) (4).
The possibility that LpPLA2 might be causally related to atherosclerosis, and perhaps unstable plaques, was supported by treatment with an LpPLA2 in a porcine experimental model (5). Because lysophospholipids are chemoattractants, an inhibitor of LpPLA2 might be protective. On the other hand, because LpPLA2 may be protective, by converting a toxic phospholipid to a lysophospholipid, an inhibitor of LpPLA2 may be harmful. Several trials indicate that LpPLA2 is a disappointing target for treatment of acute coronary syndrome and stable ischemic heart disease (6–8).
In the STABILITY trial, darapladib (an inhibitor of Lp-PLA2) failed to reduce the risk of death, myocardial infarction, or stroke in patients with stable coronary artery disease (6). Similarly, in the SOLID-TIMI 52 trial, darapladib failed to reduce the risk of major coronary events in patients with recent acute coronary syndrome (7). In the VISTA-16 trial, varespladib, an inhibitor of secretory Lp-PLA2, increased the risk of myocardial infarction in patients with recent acute coronary syndrome, leading to early termination of the trial (8). The failure of these inhibitors to improve cardiovascular outcomes reflects gaps in our knowledge of the pathobiology of Lp-PLA2.
LpPLA2 in Aortic Stenosis
In this issue of iJACC, Capoulade et al. (2) report that higher plasma Lp-PLA2 activity is associated with more rapid progression of aortic stenosis, as measured by Doppler echocardiography (Figure 1). This effect was noted only in the subset of patients with mild stenosis (defined as peak aortic jet velocity <3.0 m/s) at baseline. Thus, Lp-PLA2 was a marker of progression of aortic stenosis, and the authors suggested that it should be considered as a target for clinical trials in patients with mild aortic stenosis.
In light of failure of several trials in relation to coronary heart disease, why is there reason to suggest that aortic stenosis may be more amenable to reduction of LpPLA2? There are several differences between blood vessels and the aortic valve (2,9), which may predict a different role for LpPLA2. The differences between blood vessels and the aortic valve reduce the predictive value of trials in vascular disease.
The authors focus on calcification of the aortic valve as the predominant mechanism for stenosis. This assumption is far from conclusive. In patients, calcification may not be associated with severity of aortic stenosis (10). We have suggested that the term “fibrocalcific aortic valve stenosis” may be more accurate than calcific aortic stenosis (11), because it is not clear whether fibrosis and/or calcification are predominant mechanisms of stenosis.
Medical Treatment of Aortic Stenosis
An important question is that, because no medical treatment has been effective in slowing progression of aortic stenosis, is treatment possible? It is of interest, and not surprising, that levels of LpPLA2 are associated with slower progression only in mild, but not moderate/severe, aortic stenosis. Capoulade et al. (2) speculate that early aortic stenosis is lipid-mediated, and therefore associated with LpPLA2, and more advanced aortic stenosis is associated with calcification, and therefore is not associated with LpPLA2.
In light of efficacy of “statins” in treatment of atherosclerotic coronary disease, why are statins ineffective in slowing progression of aortic stenosis (11)? One possibility is that trials of statins in aortic stenosis have targeted patients with moderate/severe stenosis, and not mild stenosis. Another explanation may involve consequences of reduction of LDL in unstable plaques in blood vessels, versus effects on the aortic valve. In unstable plaques, reduction of LDL with statins results in reduction of lipids and inflammatory cells, with replacement by fibrous tissue (and perhaps calcium). These changes in composition of the vessel reduce the risk of plaque rupture. Similar structural changes may occur in the aortic valve: reduction of LDL may reduce lipids and inflammatory cells, with replacement by fibrous tissue.
A key point is that functional consequences of these tissue changes may differ profoundly: fibrosis probably is protective in the unstable plaque, but harmful in the aortic valve. We do not know whether these observations and speculation are pertinent to the association of LpPLA2 with progression of aortic stenosis. It is challenging to identify a specific mechanism that may explain failure of treatment with LpPLA2 in acute coronary syndrome and stable ischemic heart disease versus prediction of efficacy of treatment in aortic stenosis.
It seems premature to consign Lp-PLA2 as a target for fibrocalcific aortic valve stenosis, especially keeping in mind the results of the VISTA-16 trial, which showed an increased incidence of myocardial infarction. One would be reluctant to treat patients with a secretory phospholipase A2 inhibitor (varespladib), with the goal of slowing progression of aortic stenosis but with the possibility of increasing the risk of myocardial infarction (7). A trial with darapladib to slow progression of aortic stenosis may have fewer safety concerns. Further work is needed to elucidate the role of Lp-PLA2 in the pathophysiology of aortic stenosis—to establish its role as a biomarker (i.e., a friend with a warning), or a foe with potential as a therapeutic target.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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