Folate Therapy and In-Stent Restenosis
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《新英格兰医药杂志》
To the Editor: Lange et al. (June 24 issue)1 report an increase in the relative risk of restenosis after bare-metal stenting in patients receiving B vitamins to lower homocysteine levels. This seems to be in contrast to a previous report of a dramatic reduction in restenosis with the use of homocysteine-lowering B-vitamin treatment after coronary angioplasty.2 These two studies differ substantially (e.g., with respect to the vitamin dose, lesion length, and percutaneous coronary intervention procedures investigated). Mechanisms of restenosis in swine in response to arterial injury differ substantially between angioplasty and stenting.3 Homocysteine stimulates the proliferation of vascular smooth-muscle cells, presumably thereby contributing to neointimal thickening.4 Homocysteine metabolism in human vessels is limited to remethylation, because vitamin B6-dependent cystathionine synthase activity is absent in adult cardiovascular cells.5 The high dose of vitamin B6 used by Lange et al. thus cannot be effective as speculated. The two studies are not in conflict but instead may illustrate the procedure-specific mechanisms of damage and repair. They suggest that the lowering of homocysteine levels is beneficial both after angioplasty2 and in women, patients with diabetes, and those with hyperhomocysteinemia who are undergoing bare-metal stenting.1 Studies of the use of drug-eluting stents with specific patterns of action and vessel reaction are needed.
Olaf Stanger, M.D.
German, Austrian, and Swiss Homocysteine Society
5020 Salzburg, Austria
o.stanger@salk.at
Brian Fowler, M.D.
German, Austrian, and Swiss Homocysteine Society
4005 Basel, Switzerland
Wolfgang Herrmann, M.D.
German, Austrian, and Swiss Homocysteine Society
66421 Homburg, Germany
References
Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004;350:2673-2681.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Nakatani M, Takeyama Y, Shibata M, et al. Mechanisms of restenosis after coronary intervention: difference between plain old balloon angioplasty and stenting. Cardiovasc Pathol 2003;12:40-48.
Tsai JC, Perrella MA, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci U S A 1994;91:6369-6373.
Chen P, Poddar R, Tipa EV, et al. Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease. Adv Enzyme Regul 1999;39:93-109.
The authors reply: Stanger et al. suggest that the findings of our trial are complementary, rather than contradictory, to those of Schnyder et al.1 With respect to our finding that in patients with hyperhomocysteinemia (i.e., those with plasma homocysteine levels above 15 μmol per liter), folate-containing B vitamins tended to have a beneficial effect on stent restenosis, we concur with Schnyder et al. Thus, our study supports rather than refutes the hypothesis that lowering the level of homocysteine is beneficial after stenting. What was not sufficiently appreciated before our study is the strong proliferative effect of folate on neointimal growth, which exceeds the positive effect of lowering homocysteine levels, particularly in men without markedly elevated levels. With regard to such patients, the two studies came up with entirely contradictory findings, which can be explained only partially by differences in the study populations, vitamin content, and angioplasty technique.2 Notably, the study by Schnyder et al. did not include subjects with homocysteine levels higher than 13.5 μmol per liter. Studies are needed that will test the efficacy of homocysteine-lowering vitamin regimens containing betaine instead of folate.
Helmut Lange, M.D.
Klinikum Links der Weser
28355 Bremen, Germany
Harry Suryapranata, M.D.
Isala Klinieken
8011JW Zwolle, the Netherlands
hsuryapranata@diagram-zwolle.nl
References
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Herrmann HC. Prevention of cardiovascular events after percutaneous coronary intervention. N Engl J Med 2004;350:2708-2710.
Olaf Stanger, M.D.
German, Austrian, and Swiss Homocysteine Society
5020 Salzburg, Austria
o.stanger@salk.at
Brian Fowler, M.D.
German, Austrian, and Swiss Homocysteine Society
4005 Basel, Switzerland
Wolfgang Herrmann, M.D.
German, Austrian, and Swiss Homocysteine Society
66421 Homburg, Germany
References
Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004;350:2673-2681.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Nakatani M, Takeyama Y, Shibata M, et al. Mechanisms of restenosis after coronary intervention: difference between plain old balloon angioplasty and stenting. Cardiovasc Pathol 2003;12:40-48.
Tsai JC, Perrella MA, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci U S A 1994;91:6369-6373.
Chen P, Poddar R, Tipa EV, et al. Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease. Adv Enzyme Regul 1999;39:93-109.
The authors reply: Stanger et al. suggest that the findings of our trial are complementary, rather than contradictory, to those of Schnyder et al.1 With respect to our finding that in patients with hyperhomocysteinemia (i.e., those with plasma homocysteine levels above 15 μmol per liter), folate-containing B vitamins tended to have a beneficial effect on stent restenosis, we concur with Schnyder et al. Thus, our study supports rather than refutes the hypothesis that lowering the level of homocysteine is beneficial after stenting. What was not sufficiently appreciated before our study is the strong proliferative effect of folate on neointimal growth, which exceeds the positive effect of lowering homocysteine levels, particularly in men without markedly elevated levels. With regard to such patients, the two studies came up with entirely contradictory findings, which can be explained only partially by differences in the study populations, vitamin content, and angioplasty technique.2 Notably, the study by Schnyder et al. did not include subjects with homocysteine levels higher than 13.5 μmol per liter. Studies are needed that will test the efficacy of homocysteine-lowering vitamin regimens containing betaine instead of folate.
Helmut Lange, M.D.
Klinikum Links der Weser
28355 Bremen, Germany
Harry Suryapranata, M.D.
Isala Klinieken
8011JW Zwolle, the Netherlands
hsuryapranata@diagram-zwolle.nl
References
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Herrmann HC. Prevention of cardiovascular events after percutaneous coronary intervention. N Engl J Med 2004;350:2708-2710.