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The hidden potential of statins
SCIENCE AND MEDICINE
Radiotherapy for restenosis proves its peripheral potential his week, Austrian experts report that endovascular radiotherapy can almost halve the restenosis rate after femoropopliteal angioplasty. According to lead author Erich Minar (University of Vienna General Hospital, Vienna, Austria), endovascular brachytherapy is the first intervention shown in a randomised trial to improve the outcome of angioplasty for peripheral vascular disease. Angioplasty of femoropopliteal stenoses can improve claudication symptoms, but the restenosis rate is high. Studies in animal models show that intravascular irradiation can reduce smooth-muscle proliferation —thought to be the key mechanism of restenosis—and might also prevent vessel shrinkage. So, following a successful pilot study, Minar and colleagues randomly assigned 113 patients with new or recurrent femoropopliteal narrowing to receive angioplasty with or without endovascular brachytherapy (12 Gy from an
T
Iridium-192 source). Participants and interventionalists were aware of treatment allocation. No adverse events were related to brachytherapy. At 6-months’ follow-up, the team found that addition of brachytherapy significantly reduced restenosis rate (28·3% with brachytherapy vs 53·7% without). However, Minar points out that by 12 months about one-third of brachytherapy patients experienced recurrence. One explanation could be that the brachytherapy dose was inadequate to wholly prevent smooth-muscle proliferation, including possible migration of smooth-muscle cells from the adventitia. Another factor could be “dose inhomogeneity”, which might be improved by use of newer catheters with the capacity to centre themselves within the vessel lumen (Circulation 2000; 102: 2694–99). In an accompanying editorial, Paul Teirstein (Scripps Clinic, La Jolla, CA, USA) writes that the report “adds considerably to the growing body of
evidence that radiation therapy is an effective anti-restenosis treatment”. Minar adds that the recent approval by the FDA of the first brachytherapy systems—for intracoronary irradiation of in-stent restenosis—indicates the growing acceptance of the technique. Although Teirstein believes that “radiation is not a ‘cure-all’. . . Our failures, however, do provide us with the opportunity for improvement”. And, explains Minar, having positively influenced the high recurrence rate in the peripheral circulation, “our aim is to further reduce restenosis rate and perhaps even abolish it altogether”, through optimisation of brachytherapy and possibly with the concurrent use of stents. Before peripheral endovascular brachytherapy can be widely adopted for clinical use, however, he advocates awaiting the results of ongoing multicentre, randomised, doubleblinded trials in Austria and the USA. Kelly Morris
The hidden potential of statins
Sitosterolaemia solved?
F
in animal models will be necessary to assess whether the postulated immunomodulation occurs in vivo and how much it contributes to the overall effect of statins”. Mach confirms that some of that work has already begun. “The inhibition of HMG-CoA reductase by statins influences a broad spectrum of cellular protein expression, and we are now searching downstream the HMG-CoA reductase pathway to find out which proteins impact on MHC-II expression”, explains Mach. In theory, this could lead to the development of new drugs that are able to influence MHC-II expression, but that do not exhibit lipid-lowering properties. Parallel work in vivo aims to find out whether statins can positively influence transplantation outcomes, or whether they have any effect on immune, or auto-immune disease processes. Whilst Mach predicts that the first use of statins for transplantation may happen in the next 3 years, Palinski is more cautious. “A clinical indication in humans may take significantly longer; I would not want to raise false hopes that this is about to become a clinical reality.”
dentification of mutations in the genes responsible for transport of cholesterol across the cell membrane could explain why individuals with sitosterolaemia develop coronary heart disease at an early age. In sitosterolaemia, the intestinal barrier, which partly blocks absorption of plant sterols and cholesterol, is disrupted, resulting in high plasma cholesterol. Knut Berge and colleagues from the University of Texas, USA, identified seven different mutations in two genes, ABCG5 and ABCG8, located on chromosome 2p21, which encode transporters of cholesterol, in patients with sitosterolaemia. They proposed that since these genes are highly expressed in the liver and intestine, the liver X receptor (LXR) could control their expression (Science 2000; 290: 1771–75). Aldons J Lusis (University of California, USA) says that the study “addresses the mystery of how dietary cholesterol is absorbed but dietary plant sterols are excluded. But it also helps explain how cholesterol absorption and excretion are regulated, knowledge very relevant to heart disease.” He concludes that the nuclear receptor LXR could be a target for developing drugs to decrease serum cholesterol.
Kathryn Senior
Minal Chande
rancois Mach (Geneva Medical School, Switzerland) and colleagues reveal this week that statins, the most powerful class of lipid-lowering drugs available, inhibit the expression of MHC-II by some antigen-presenting cells. This will not affect the way statins are used for heart-disease patients but “it may open up new clinical indications for statin treatment”, says Mach, “such as the prevention of graft atherosclerosis after organ transplants”. The researchers showed that statins act as direct inhibitors of the induction of MHC-II expression by interferon gamma, and thus act as repressors of MHC-II-mediated T-cell activation. The effect was seen in several cell types, including primary human endothelial cells and monocyte-macrophages (Nature Med 2000; 6: 1399–1402). “It is possible that this effect of statins may prevent some of the changes seen in atherosclerosis or in other diseases involving chronic inflammation”, comments Wulf Palinksi, author of an accompanying News and Views article. While welcoming the new study, Palinski warns that, because of the complexity of the cellular and molecular interactions taking place in atherosclerosis, “extensive studies
1906
I
THE LANCET • Vol 356 • December 2, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Radiotherapy for restenosis proves its peripheral potential his week, Austrian experts report that endovascular radiotherapy can almost halve the restenosis rate after femoropopliteal angioplasty. According to lead author Erich Minar (University of Vienna General Hospital, Vienna, Austria), endovascular brachytherapy is the first intervention shown in a randomised trial to improve the outcome of angioplasty for peripheral vascular disease. Angioplasty of femoropopliteal stenoses can improve claudication symptoms, but the restenosis rate is high. Studies in animal models show that intravascular irradiation can reduce smooth-muscle proliferation —thought to be the key mechanism of restenosis—and might also prevent vessel shrinkage. So, following a successful pilot study, Minar and colleagues randomly assigned 113 patients with new or recurrent femoropopliteal narrowing to receive angioplasty with or without endovascular brachytherapy (12 Gy from an
T
Iridium-192 source). Participants and interventionalists were aware of treatment allocation. No adverse events were related to brachytherapy. At 6-months’ follow-up, the team found that addition of brachytherapy significantly reduced restenosis rate (28·3% with brachytherapy vs 53·7% without). However, Minar points out that by 12 months about one-third of brachytherapy patients experienced recurrence. One explanation could be that the brachytherapy dose was inadequate to wholly prevent smooth-muscle proliferation, including possible migration of smooth-muscle cells from the adventitia. Another factor could be “dose inhomogeneity”, which might be improved by use of newer catheters with the capacity to centre themselves within the vessel lumen (Circulation 2000; 102: 2694–99). In an accompanying editorial, Paul Teirstein (Scripps Clinic, La Jolla, CA, USA) writes that the report “adds considerably to the growing body of
evidence that radiation therapy is an effective anti-restenosis treatment”. Minar adds that the recent approval by the FDA of the first brachytherapy systems—for intracoronary irradiation of in-stent restenosis—indicates the growing acceptance of the technique. Although Teirstein believes that “radiation is not a ‘cure-all’. . . Our failures, however, do provide us with the opportunity for improvement”. And, explains Minar, having positively influenced the high recurrence rate in the peripheral circulation, “our aim is to further reduce restenosis rate and perhaps even abolish it altogether”, through optimisation of brachytherapy and possibly with the concurrent use of stents. Before peripheral endovascular brachytherapy can be widely adopted for clinical use, however, he advocates awaiting the results of ongoing multicentre, randomised, doubleblinded trials in Austria and the USA. Kelly Morris
The hidden potential of statins
Sitosterolaemia solved?
F
in animal models will be necessary to assess whether the postulated immunomodulation occurs in vivo and how much it contributes to the overall effect of statins”. Mach confirms that some of that work has already begun. “The inhibition of HMG-CoA reductase by statins influences a broad spectrum of cellular protein expression, and we are now searching downstream the HMG-CoA reductase pathway to find out which proteins impact on MHC-II expression”, explains Mach. In theory, this could lead to the development of new drugs that are able to influence MHC-II expression, but that do not exhibit lipid-lowering properties. Parallel work in vivo aims to find out whether statins can positively influence transplantation outcomes, or whether they have any effect on immune, or auto-immune disease processes. Whilst Mach predicts that the first use of statins for transplantation may happen in the next 3 years, Palinski is more cautious. “A clinical indication in humans may take significantly longer; I would not want to raise false hopes that this is about to become a clinical reality.”
dentification of mutations in the genes responsible for transport of cholesterol across the cell membrane could explain why individuals with sitosterolaemia develop coronary heart disease at an early age. In sitosterolaemia, the intestinal barrier, which partly blocks absorption of plant sterols and cholesterol, is disrupted, resulting in high plasma cholesterol. Knut Berge and colleagues from the University of Texas, USA, identified seven different mutations in two genes, ABCG5 and ABCG8, located on chromosome 2p21, which encode transporters of cholesterol, in patients with sitosterolaemia. They proposed that since these genes are highly expressed in the liver and intestine, the liver X receptor (LXR) could control their expression (Science 2000; 290: 1771–75). Aldons J Lusis (University of California, USA) says that the study “addresses the mystery of how dietary cholesterol is absorbed but dietary plant sterols are excluded. But it also helps explain how cholesterol absorption and excretion are regulated, knowledge very relevant to heart disease.” He concludes that the nuclear receptor LXR could be a target for developing drugs to decrease serum cholesterol.
Kathryn Senior
Minal Chande
rancois Mach (Geneva Medical School, Switzerland) and colleagues reveal this week that statins, the most powerful class of lipid-lowering drugs available, inhibit the expression of MHC-II by some antigen-presenting cells. This will not affect the way statins are used for heart-disease patients but “it may open up new clinical indications for statin treatment”, says Mach, “such as the prevention of graft atherosclerosis after organ transplants”. The researchers showed that statins act as direct inhibitors of the induction of MHC-II expression by interferon gamma, and thus act as repressors of MHC-II-mediated T-cell activation. The effect was seen in several cell types, including primary human endothelial cells and monocyte-macrophages (Nature Med 2000; 6: 1399–1402). “It is possible that this effect of statins may prevent some of the changes seen in atherosclerosis or in other diseases involving chronic inflammation”, comments Wulf Palinksi, author of an accompanying News and Views article. While welcoming the new study, Palinski warns that, because of the complexity of the cellular and molecular interactions taking place in atherosclerosis, “extensive studies
1906
I
THE LANCET • Vol 356 • December 2, 2000
For personal use only. Not to be reproduced without permission of The Lancet.