The effect of probucol on femoral atherosclerosis: The Probucol Quantitative Regression Swedish Trial (PQRST)

Walldius, Göran; Erikson, Uno; Olsson, Anders; Bergstrand, Lott; Hådell, Karin; Johansson, Jan; Kaijser, L.; Lassvik, C.; Mølgaard, Jørgen; Nilsson, Sven Erik G.; Elinder, Liselotte Schäfer; Stenport, G; Holme, Ingar

doi:10.1016/0002-9149(94)90579-7

Cited by 229 publications

(76 citation statements)

References 22 publications

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“…Another possibility is that the effects of vitamin E on lesion development may vary with anatomical location. It is noteworthy that probucol, a potent lipid-soluble antioxidant, did not prevent progression of femoral artery lesions in a human clinical trial (38) or of lesion development in abdominal aortas or iliac arteries of nonhuman primates (39).…”

Section: Discussionmentioning

confidence: 95%

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Terasawa

Ladha

Leonard

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

224

156

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Although lipid peroxidation in the subendothelial space has been hypothesized to play a central role in atherogenesis, the role of vitamin E in preventing lipid peroxidation and lesion development remains uncertain. Here we show that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the ␣-tocopherol transfer protein gene (Ttpa) increased the severity of atherosclerotic lesions in the proximal aorta. The increase was associated with increased levels of isoprostanes, a marker of lipid peroxidation, in aortic tissue. These results show that vitamin E deficiency promotes atherosclerosis in a susceptible setting and support the hypothesis that lipid peroxidation contributes to lesion development. Ttpa ؊/؊ mice are a genetic model of vitamin E deficiency and should be valuable for studying other diseases in which oxidative stress is thought to play a role.antioxidants O xidative modification of lipoproteins (e.g., low-density lipoproteins) has been hypothesized to play a key role in the pathogenesis of atherosclerosis (1, 2). Because vitamin E is the most potent lipid-soluble antioxidant normally found on lipoproteins in the plasma, there is strong interest in the relationship between vitamin E levels and the development of atherosclerosis. In animal models and human clinical trials, studies of the effects of vitamin E supplementation on atherosclerosis have yielded conf licting results (3-8), and little is known about the effects of vitamin E deficiency on atherosclerosis development (9).The major form of vitamin E in human plasma and tissues is ␣-tocopherol (10). ␣-Tocopherol enrichment of plasma and tissues is mediated by the ␣-tocopherol transfer protein (␣-TTP), a cytosolic lipid-transfer protein expressed in the liver (11)(12)(13)(14). Although the mechanism is unknown (15), ␣-TTP is believed to selectively transfer ␣-tocopherol from lipoproteins taken up by hepatocytes via the endocytic pathway to newly secreted lipoproteins, which facilitate its delivery to peripheral tissues (12). Humans with ␣-TTP gene defects have extremely low plasma ␣-tocopherol concentrations and develop severe neurodegenerative disease unless they are treated with high doses of vitamin E (16-18).To investigate the relationship between vitamin E deficiency and atherosclerosis, we used gene targeting to disrupt the mouse ␣-TTP gene (Ttpa) and generate a genetic model of vitamin E deficiency. We then crossed the ␣-TTP-deficient mice (Ttpa Ϫ/Ϫ ) mice with apolipoprotein (apo) E knockout (Apoe Ϫ/Ϫ ) mice (19), which spontaneously develop atherosclerosis on a chow diet (20,21). This enabled us to generate Apoe Ϫ/Ϫ mice with different Ttpa genotypes (ϩ͞ϩ, ϩ͞Ϫ, and Ϫ͞Ϫ) to test the hypothesis that ␣-TTP and vitamin E deficiency increase atherosclerosis in a susceptible setting. Materials and MethodsGeneration of ␣-TTP Knockout Mice. A 14-kb 129͞Sv genomic clone containing the Ttpa gene was isolated and subcloned into pBSSKII. A sequence replacement vector was constructed by PCR amplifica...

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Section: Discussionmentioning

confidence: 95%

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Terasawa

Ladha

Leonard

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

224

156

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“…Therefore, even if the teams that designed the first generation of human trials had wanted to use a marker, that is, something that would tell them whether or not the antioxidant was "working," they would not have found a tested, reliable method. In fact, with the exception of the Swedish probucol study, in which efficacy was shown with respect to inhibition of LDL oxidation ex vivo, 46 none of the reported human trials to date has attempted to assess the efficacy of their antioxidant regimen. Thus, there is no way for us to know whether there was any reason to expect a positive result-there was no independent measure of efficacy.…”

Section: The Need For Markers To Assess Whether or Not Oxidation Of Lmentioning

confidence: 99%

Is the Oxidative Modification Hypothesis Relevant to Human Atherosclerosis?

2002

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S everal large-scale, double-blind, placebo-controlled trials have shown convincingly that neither ␤-carotene 1-3 nor vitamin E, alone [3][4][5] or in combination with other antioxidant vitamins, 6 reduces the risk of fatal or nonfatal infarction (or other hard clinical end points) in an unselected population of people with established coronary heart disease (CHD) or at high risk of CHD. Two end point trials, much smaller trials that used vitamin E, have reported positive results, 7,8 and one trial, which used ultrasound, showed that a combination of vitamins E and C slowed the progression of carotid artery lesions. 9 However, these are far outweighed by the negative results in the other, much larger trials. Certainly there is no basis for recommending vitamin E supplementation to patients with CHD, especially because it may blunt the effectiveness of hypolipidemic therapy with statins and niacin. 6 A surprisingly large fraction of cardiologists (Ϸ40%) have been recommending such regimens 10 despite warnings that this use was premature. 11 At first glance, it might seem that these negative results close the book and that additional clinical trials of any antioxidants would be pointless. Closer examination, we believe, will show that such a conclusion would be premature and inappropriate. 12 The hypothesis that oxidative modification of LDL plays a significant role in atherogenesis in humans is not necessarily disproved by the failure of these particular clinical trials any more than a negative trial of an ineffectual antibiotic in Pneumococcal pneumonia would prove that pneumonia is not a bacterial disease. The oxidative modification hypothesis is not that vitamin E will ameliorate the human disease but that oxidative modification of LDL and/or other oxidative events play a significant role in human atherogenesis as it does in animal models of atherogenesis. A corollary of the hypothesis is that some appropriate antioxidant intervention, at some appropriate dosage, in appropriately selected patients over an appropriate time interval has the potential to improve prognosis. Otherwise, of course, the role of oxidation would remain of academic interest only. In the present report, we put the currently available information into context by briefly reviewing the origins of the LDL modification hypothesis and explaining why the trials to date have not adequately tested the basic hypothesis, as pointed out by a number of authors. 12-21 It would be a mistake to jettison as irrelevant to humans a hypothesis that is so strongly supported by many epidemiological studies and by so many positive results in several animal models, including nonhuman primates, and with the use of several different antioxidant compounds. 12 Instead, perhaps we should be reexamining the science underlying the hypothesis and asking what additional basic information we need to design trials that will appropriately test the hypothesis. Origins of the Oxidative Modification HypothesisThe concept that circulating LDL must undergo some kind of structura...

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“…The incidence of major cardiac events was also significantly lower with probucol than in the control group in FAST (2.4% versus 13.6%; P<0.05). The results of the Probucol Quantitative Regression Swedish Trial (PQRST) appear to be discordant with those described here, but the design of that study raised several important issues (48). The primary end point of that study was lumen volume of femoral arteries using three-dimensional angiography, an approach rarely used in other clinical trials.…”

Section: Cart-1mentioning

confidence: 57%

Antioxidants: The good, the bad and the ugly

Tardif¹

2006

Canadian Journal of Cardiology

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The effect of probucol on femoral atherosclerosis: The Probucol Quantitative Regression Swedish Trial (PQRST)

Cited by 229 publications

References 22 publications

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Is the Oxidative Modification Hypothesis Relevant to Human Atherosclerosis?

Antioxidants: The good, the bad and the ugly

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