New Ideas on Pathology of Restenosis
RESTENOSIS is both bane and embarrassment to cardiologists. Despite the effectiveness of percutaneous transluminal coronary angioplasty (PTCA) as a means of treating coronary artery disease, its long-term benefits remain tempered by restenosis, which develops in 30% to 50% of patients within 6 months after the procedure is done.
During the nearly 2 decades that PTCA has been performed, cardiologists have attempted to decrease this disconcerting number, proposing various theories and devising trials to test them. Studies recently reported at the American College of Cardiology meeting in Orlando, Fla, make evident the need to revise traditionally held views on the pathophysiology of restenosis.
Obviously, a better understanding of how and why restenosis occurs is key to finding rational ways of preventing or treating it.
The prevailing view is that the angioplasty procedure damages the coronary wall, leading to platelet activation, which causes vascular smooth muscle cells to proliferate and migrate to the damaged area of the vessel where they accumulate. This creates an extracellular matrix that forms an intimal lesion, resulting in the loss of lumen cross-sectional area, thus impeding blood flow.
Martin B. Leon, MD, director of cardiovascular research at the Washington Cardiology Center at Washington Hospital Center, Washington, DC, proposes a further hypothesis. Leon and colleagues suggest that while these mechanisms do occur, they cannot be decoupled from another process that may contribute even more to late lumen cross-sectional area loss. The Washington group calls it "retraction fibrosis." The process is also referred to as geometric remodeling, and the pathology, Leon says, may largely involve the adventitia (the outer layer of the coronary arteries) rather than the media (the middle layer from which the migrating smooth muscle cells are thought to originate).
Directional coronary atherectomy (DCA) provided Leon with tissue specimens to evaluate this hypothesis. His center and 3 others are conducting a study of 200 consecutive patients who underwent DCA guided by intravascular ultrasound. Leon reported in Orlando on data obtained from the first 100 patients in that series.
"When we look at directional atherectomy, we see very little tissue growth in these specimens," he said. "We do see a dramatic increase in remodeling or a decrease in the vessel wall cross-sectional area, and 90% of the late lumen loss in this trial was due not to tissue growth but to a reduction in vessel size.
"This was almost counterintuitive. We thought that with aggressive atherectomy and deep vessel wall injury, we would initiate more of a tissue response and a proliferative response. But, in fact, we saw less. We saw more in the way of retraction and shrinkage of the vessel. Clearly, late lumen loss was correlated much more closely with remodeling than with tissue growth."
Leon's study team also began to see other changes 5 months after atherectomy: instead of vessels showing remodeling and shrinking, they expanded, resulting in arterial dilatation. "We didn't quite know what to make of this," he said. "Between 20% and 25% of the patients showed a late increase of the cross-sectional area. These patients have much more in the way of tissue growth, less late lumen loss, a much higher frequency of late lumen gain, and, in fact, half the restenosis rate.
"Teleologically, we think we're seeing the vessel's attempt to compensate or telescope the atherosclerotic process to maintain lumen dimensions. What triggers this process is completely unknown."
Do Stents Make a Difference?
Patterns of arterial responses following transcatheter therapy are beginning to emerge, Leon said. Differences are seen depending on whether or not metal coronary stents have been placed in the arteries to prop them open and keep blood flowing. In clinical trials, stents have proved their value in stabilizing blood vessels during angioplasty and in helping prevent restenosis afterward.
Cardiologists are using them increasingly.
When his group studies nonstented lesions, Leon said, "What we are finding most commonly is some tissue growth, but predominantly a retraction of the vessel and occasionally, in some patients, dilatation associated with an even greater increase in plaque mass and preservation of lumen dimensions."
Leon referred to a Japanese study of a series of patients that used serial ultrasound imaging in the coronary arteries just before and after intervention, 24 hours later, 1 month later, and 6 months later--again, to confirm the presence and define the time course of remodeling and tissue growth after both PTCA and directional coronary atherectomy.
"Typically," Leon said, "they saw, for example, the proximal right coronary artery treated effectively, with little reduction in lumen caliber at 24 hours, but after 1 month the vessel comes back to where it was postprocedure. Then after 6 months, there was significant narrowing, that is, clinical restenosis. Is this hyperplasia or arterial remodeling?"
According to Leon, changes examined over time show an increase in lumen cross-sectional area associated with the procedure, a slight further increase that is not significant at the first 24 hours, and then a further significant increase in lumen dimension at 1 month marked by an occasional dilation of the vessel associated with some increase in plaque mass. This is not an acute process, Leon notes, and late lumen loss correlates much better with remodeling than with tissue growth.
However, using stents changes the picture. "When you do serial ultrasound studies in patients with stents, you see that the stent does not remodel; it stays the same. The lumen does decrease in dimension." Therefore, he says he thinks the decrease in lumen dimension is due mainly to "an increase in tissue growth, intimal hyperplasia, neointima formation, and, perhaps, a little plaque prolapse through the struts of the stent. This is quite different from what we have just seen.
"In stented lesions, late lumen loss correlates dramatically with tissue growth and not at all with any remodeling phenomenon. These are discordant,divergent mechanisms."
Despite the fact that there is 4 times as much tissue growth over a stent, Leon explained, restenosis rates are significantly less. Although stents clearly increase late tissue formation, the associated lumen gain still has an attenuating affect on restenosis.
So in stented lesions, 99% of late lumen loss is due to tissue growth, in comparison with nonstented lesions, where the loss is closer to 30%.
Therefore, Leon said, in-stent restenosis is an important phenomenon and an excellent target for antiproliferative therapy. Studies on this are being done by others using angiopepsin in pig hearts.
Leon concluded by noting that since stents reduce restenosis by achieving a better postprocedural result and eliminating geometric remodeling, and because this offsets the stent-related increase in tissue growth, stented lesions may be the ideal model for studying neointimal tissue formation.
What's in store for clinicians? "These findings suggest to us that the elimination of restenosis may require a combined approach," he said, "including a mechanical device to resist geometric remodeling and a pharmacologic agent to inhibit cellular proliferation."
Role of Smooth Muscle Cells
Another cardiologist questioning assumptions regarding the development of restenosis is Roger J. Laham, MD, a fellow in the Vascular Biology Unit and the Cardiovascular Division of the Department of Medicine at Harvard Medical School, Beth Israel Hospital, Boston, Mass. He noted that despite the lack of direct evidence for vascular smooth muscle cell migration and proliferation in restenosis following coronary angioplasty, both processes have been assumed to play a central role in the undesired result.
This has led to a variety of strategies to prevent or retard the proliferation and migration of vascular smooth muscle, but since these approaches have been unsuccessful in humans, the validity of these assumptions, particularly the importance of cell proliferation, has been questioned.
For this reason, Laham and his colleagues at Beth Israel Hospital decided to study smooth muscle cell behavior in primary and restenotic coronary plaques obtained from therapeutic DCA procedures carried out in 62 consecutive patients at the hospital. Of these 62 patients, 48 had de novo coronary artery disease and 14 had restenotic disease. In all cases, the retrieved atherectomy tissue was labeled with thymidine to assess the proliferation potential of smooth muscle cells and cultured using an explant outgrowth technique to determine in situ smooth muscle cell migration patterns over time. The tissue was placed on a petri dish and smooth muscle cells were allowed to migrate outside the tissue; they started to proliferate on the culture plate.
Another set of atherectomy specimens, obtained from a group of 27 consecutive patients, provided 17 primary and 10 restenotic coronary lesions that were subjected to immunohistochemical staining to determine proliferative activity of the smooth muscle cells.
The study found significantly higher thymidine uptake in tissue derived from restenotic lesions than in tissue from primary lesions, a finding confirmed by immunostaining. As with thymidine uptake, only a small percentage of cells showed staining. However, in both assays, restenotic lesions showed significantly higher concentrations than did primary lesions. Laham explained that although the number of proliferating cells in restenotic samples appears to be small, this does not rule out smooth cell proliferation as a logically
important event in the development of restenosis.
"Indeed," he notes, "thymidine labeling provides only a snapshot of the frequency of cell division during the time of labeling. Even the observed rate of 2 cell divisions per 100 cells over 12 hours [the labeling period] would, if maintained for the entire duration of the process, translate into a 1248-fold increase in the number of cells in the specimen over a 6-month period. Thus,100 cells would yield 102 cells in 12 hours, and 127 251 cells in 6 months."
Furthermore, he said, "since the proliferative rate as suggested by a number of studies in animal models is significantly higher initially after the angioplasty, it is easy to see how a low subsequent proliferative rate would still be consistent with a substantial cumulative increase in cell number within a restenotic lesion."
Laham's group also found that smooth muscle cells derived from restenotic lesions had significantly higher intrinsic migratory activity than cells derived from primary lesions. The ability of these cells from restenotic lesions to move faster is further evidence of the more aggressive biological activity of these lesions.
Laham said these findings of higher biological activity of restenotic tissue may explain the higher restenosis rates seen with angioplasty of restenotic lesions and may account for the lesion-to-lesion variation in the development of restenosis seen clinically. Therefore, it is possible that a lesion that a priori has a higher proportion of cells capable of faster migration, growth, or roliferation may behave in a more active manner than another lesion not displaying similar biological characteristics.
The message for clinicians, Laham said in an interview, is that treatment modalities targeted at inhibiting smooth muscle cell proliferation or migration may provide an approach to preventing restenosis.
Regards,
Sri. |
