- Email: [email protected]
Effects of Increasing Doses of Alpha-Tocopherol in Providing Protection of Low-Density Lipoprotein from Oxidation
1. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, Teirstein PS, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S, for The Stent Restenosis Study Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994;331:496 –501. 2. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, van den Heuvel P, Delcan J, Morel M-A, for The Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331: 489 – 495. 3. Versaci F, Gaspardone A, Tomai F, Crea F, Chiareillo L, Giofre PA. A comparison of coronary-artery stenting with angioplasty for isolated stenosis of the proximal left anterior descending coronary artery. N Engl J Med 1997;336: 817– 822. 4. Eeckhout E, Kappenberger L, Goy JL. Stents for intracoronary placement: current status and future directions. J Am Coll Cardiol 1996;27:757–765. 5. Hasdai D, Berger PB, Bell MR, Rihal CS, Garratt KN, Holmes DR Jr, The changing face of coronary interventional practice. The Mayo Clinic experience. Arch Intern Med 1997;157:677– 682. 6. Weyman AE, Feigenbaum H, Dillon JC, Johnston KW, Eggleton RC. Nonin-
vasive visualization of the left main coronary artery by cross-sectional echocardiography. Circulation 1976;54:169 –174. 7. Presti CF, Feigenbaum H, Armstrong WF, Ryan T, Dillon JC. Digital twodimensional echocardiographic imaging of the proximal left anterior descending coronary artery. Am J Cardiol 1987;60:1254 –1259. 8. Petrovic O, Elsner GB, Wilensky RL, Swanson ST, Feigenbaum H. Transthoracic echocardiographic detection of coronary atherosclerosis. Am J Cardiol 1996;77:569 –574. 9. Faletra F, Cipriani M, Corno R, Cali G, Mantero A, Cantoni S, Formentini A, Battista Danzi G, Pezzano A. Transthoracic high-frequency echocardiographic detection of atherosclerotic lesions in the descending portion of the left coronary artery. J Am Soc Echocardiogr 1993;6:290 –298. 10. Kenny A, Shapiro LM. Transthoracic high-frequency two-dimensional echocardiography, Doppler and color flow mapping to determine anatomy and blood flow patterns in the distal left anterior descending coronary artery. Am J Cardiol 1992;69:1265–1268. 11. Ross Jr JJ, Ren JF, Land W, Chandrasekaran K, Mintz GS. Transthoracic high frequency (7.5 MHz) echocardiographic assessment of coronary vascular reserve and its relation to left ventricular mass. J Am Coll Cardiol 1990;16:1393–1397. 12. Faletra F, Cipriani M, De Chiara F, Quattrocchi G, Battista Danzi G, Gronda E, Frigerio M, Mangiavacchi M, Pezzano A. Imaging the left anterior descending coronary artery by high-frequency transthoracic echocardiography in heart transplant patients. Am J Cardiol 1995;75:855– 858.
Effects of Increasing Doses of Alpha-Tocopherol in Providing Protection of Low-Density Lipoprotein from Oxidation Cindy J. Fuller,
PhD, RD,
Beverley A. Huet,
he oxidative modification of low-density lipoprotein (LDL) has been proposed as a key T early step in atherogenesis. Furthermore, several 1–3
lines of evidence support the existence of oxidized LDL in vivo.1–3 The most persuasive evidence for the in vivo existence of oxidized LDL comes from animal studies, in which dietary antioxidant supplementation resulted in a reduction of atherosclerotic lesion area.3,4 Alpha-tocopherol (AT), the most active form of vitamin E, is the predominant lipophilic antioxidant in LDL.5 Dietary supplementation with AT reduced the extent of atherosclerotic lesions in several animal models.4 Previous studies from this laboratory and others have shown that pharmacologic doses of AT have been shown to reduce LDL oxidizability in healthy nonsmokers and smokers.6 –11 The threshold for statistically significant effects on LDL oxidizability varies, depending on the research methodology used. A previous study from this laboratory11 has demonstrated that dosages of $400 IU/day of all-racemic or synthetic AT for 8 From the Center for Human Nutrition and the Departments of Pathology, Internal Medicine, and Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center, Dallas, Texas, and the Department of Food, Nutrition, and Food Service Management, The University of North Carolina at Greensboro, Greensboro, North Carolina. This work was supported by grants from the American Heart Association, Hoffman-LaRoche, and the General Clinical Research Center (grant no. M101-RR00633) Bethesda, Maryland. Dr. Jialal’s address is: Department of Pathology and Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75235-9072. Manuscript received August 7, 1997; revised manuscript received and revised October 14, 1997. ©1998 by Excerpta Medica, Inc. All rights reserved.
MS,
and Ishwarlal Jialal,
MD, PhD
weeks were required to have a significant effect on LDL oxidative kinetics (lag phase). In a 6-week long study, Simons et al12 found that 500 IU/day of AT reduced LDL oxidizability. Another study13 with a small number of subjects (n 5 8) found that 300 IU/day AT reduced both LDL and high-density lipoprotein (HDL) oxidizability. However, Princen et al14 noted significant effects on the lag phase of LDL oxidation at doses of $25 IU/day when subjects took consecutively increasing doses of AT. Significant reductions in the oxidation rate were not seen until subjects took 400 IU/day of AT. It is unknown whether higher dosages of AT can confer additional beneficial effects on LDL oxidizability. This study, a post hoc analysis of published data,11 examines if higher dosages of AT could have a greater effect on LDL oxidation than the threshold dosage of 400 IU/day. •••
The subject inclusion criteria and the study protocol and methods have been detailed previously.11 Briefly, healthy nonsmoking men were randomly assigned to receive either 400, 800, or 1,200 IU/day of AT for 8 weeks. The AT was in the form of all-rac-AT and was supplied by Hoffmann-LaRoche (Nutley, New Jersey). At 0 and 8 weeks, fasting blood samples were collected from each subject for lipid and lipoprotein profiles, plasma AT, ascorbate and b-carotene levels, and for LDL isolation. LDL isolated by preparative ultracentrifugation was extensively dialyzed before oxidation.11 The oxidation of LDL was undertaken in a cell-free system with 5 mmol/L copper in phosphate buffered 0002-9149/98/$19.00 PII S0002-9149(97)00873-4
231
TABLE I Effect of 400, 800 and 1,200 IU/day of Alpha-Tocopherol (AT) on Plasma and Low-Density Lipoprotein (LDL) Antioxidant Levels and LDL Oxidation Kinetics 400 IU/day
Lipid standardized AT (mmol/mmol) median change (%) LDL AT (nmol/mg protein) median change (%) Conjugated dienes Lag phase (min) median change (%) Oxidation rate, DA234/h median change (%) TBARS Lag phase (min) median change (%) Oxidation rate, (nmol MDA/mg protein/h) median change (%)
800 IU/day
Week 0
Week 8
3.0 6 0.5
6.3 6 1.5 111
861
14 6 4
96 84 6 11
107 6 14 28 2.4 6 0.7 1.8 6 0.5 221 83 6 7
104 6 19 15 44 6 7 29 6 8.3 234
Week 0
1,200 IU/day
Week 8
3.1 6 0.7 8.0 6 2.8 145‡ 7.3 6 3 18 6 12 151 95 6 14
170 6 82 37 2.4 6 0.6 1.0 6 0.4 263† 89 6 13
143 6 66 36 41 6 8.3 21 6 6.4 250
Week 0 3.2 6 0.3 863
Week 8 11.2 6 3.0 260* 22 6 12 158
86 6 12
145 6 20 63* 2.3 6 0.6 0.9 6 0.2 263* 81 6 10
139 6 35 64* 44 6 11.9 23 6 11.6 255
Data are expressed as mean 6 1 SD or percent. *p ,0.01, 400 IU/day versus 1,200 IU/day. † 0.01 , p ,0.05, 400 IU/day versus 800 IU/day, nonsignificant after adjustment for multiple testing. ‡ 0.01 , p ,0.05, 800 IU/day versus 1,200 IU/day, nonsignificant after adjustment for multiple testing.
saline for 8 hours.11 Two indexes of oxidation were used in this study. The amount of conjugated dienes formed during LDL oxidation was determined by monitoring the absorbance of LDL against a phosphate buffered saline blank at 234 nm.11 Data are expressed as the increase in conjugated dienes over baseline (DA234). The lipid peroxide content of oxidized LDL was measured by a modification of the thiobarbituric acid-reactive substances (TBARS) assay.8 The TBARS activity are expressed as malondialdehyde equivalents/mg LDL protein using freshly diluted 1,1,3,3-tetramethoxypropane as the standard. The lag phase and oxidation rate of LDL oxidation were derived as previously described.11 Results are expressed as mean 6 SD or for skewed data as the median. One-way analysis of variance was used to assess differences between groups at baseline. Comparisons of 0- and 8-week data (pre- and postsupplementation) were previously reported.11 For AT levels and oxidation kinetic parameters, percent change from baseline was computed for each subject and was compared between groups using the WilcoxonRank sum test. Because this was a subgroup analysis and multiple testing has occurred, the level of significance was set at a 5 0.01. Analyses were performed using BMDP statistical software (SPSS Inc., Chicago, Illinois). There were no differences between the 3 groups for age, body mass index, plasma fatty acids, lipids and lipoproteins, and antioxidant status. Also, at baseline, there were no significant differences between the groups with respect to LDL oxidation kinetics (lag phase and propagation rate). Table I displays the plasma and LDL AT concentrations for the 3 groups following supplementation. Although the increment in lipid standardized AT was significantly higher in the 1,200 IU/day group compared with the 400 IU/day, the increase in LDL AT was 232 THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 81
not statistically significant. No other intergroup comparison was significant. For both the conjugated dienes assay and the TBARS assay, there was a significant prolongation of the lag phase for the 1,200 IU/day group relative to the 400 IU/day group. Although the decrease in the propagation rate was significantly different for the conjugated dienes assay between the 1,200 and 400 IU/day groups, the decrease obtained from the TBARS assay was not significant. Furthermore, there were no significant differences when the 800 IU/day group was compared with the 1,200 IU/day or 400 IU/day groups at the 0.01 level of significance. •••
The results of the present analysis indicate that 1,200 IU/day all-rac-AT can further protect LDL against oxidation. For both the conjugated dienes and the TBARS assays, the percent change in the duration of the lag phase for the 1,200 IU/d group was significantly increased relative to the 400 IU/ day group. The percent change in the oxidation rate was greater for the conjugated diene assay only. This difference could be attributed to the fact that the conjugated diene assay is superior to the TBARS assay as a measure of LDL oxidation.7 The decreased oxidation of LDL could also be due to decreased seeding of LDL with lipid hydroperoxides by AT supplementation. The results of the current analysis are in contrast to Simons et al12 who reported that the percent changes in lag time and oxidation rate did not differ between 500, 1,000, and 1,500 IU/day of AT over a 6-week period. It should be noted that the subjects in this particular study also followed an isocaloric diet with ,30% of energy from fat. This could have blunted AT absorption from the diet. The subjects in the present investigation were advised to adhere JANUARY 15, 1998
to their normal diets and activities.11 This may also account for the disparity between plasma and LDL change in response to AT supplementation; for example, the subjects in the current study on 400 IU/day had a median 96% increase in LDL AT, whereas the subjects taking 500 IU/day in the Simons study had only a median 62% increase.12 Suzukawa et al13 reported that subjects who took 150 IU/day of AT for 1 week, followed by 300 IU/day for 3 weeks, showed significant changes in both lag time and oxidation rate. Their increase in LDL AT was comparable to the one seen at 400 IU in the current study (90% vs 96%). Princen et al14 did not directly compare AT dosages in their study except for versus the placebo phase. Their study design was one where subjects took sequentially increasing dosages of AT for 2-week periods, which could have confounded their findings because there was no washout phase between doses. Although they saw a significant increase in the lag phase of LDL oxidation at 25 IU/day, they did not see a significant decrease in the oxidation rate until dosages of 400 and 800 IU/day were taken. They also did not see the magnitude of changes in the LDL oxidation kinetics as was seen in the present study, despite comparable increases in plasma and LDL AT (plasma 119, LDL 80% at 400 IU/day; plasma 159, LDL 123% at 800 IU/day).11,14 In conclusion, the results of this post hoc data analysis demonstrate that 1,200 IU/day of AT is more potent in decreasing the oxidative susceptibility of LDL than 400 IU/day. Thus, AT at these higher doses (1,200 IU/day), in addition to decreasing LDL oxidation, has antiatherogenic effects on monocyte and/or macrophages, a pivotal cell in atherogenesis.15
Acknowledgment: The authors graciously thank Elizabeth Thurston for manuscript preparation. 1. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA,
Watson AD, Lusis AJ. Atherosclerosis: basic mechanisms, oxidation, inflammation and genetics. Circulation 1995;91:2488 –2496. 2. Parthasarathy S, Rankin SM. Role of oxidized LDL in atherogenesis. Prog Lipid Res 1992;31:127–143. 3. Fuller CJ, Jialal I. Antioxidants and LDL oxidation. In: Garewal H, ed. Antioxidants & Disease Prevention. Boca Raton: CRC Press, 1997;115–130. 4. Janero DR. Therapeutic potential of vitamin E in the pathogenesis of spontaneous atherosclerosis. Free Radic Biol Med 1991;11:129 –144. 5. Traber MG, Sies H. Vitamin E in humans: demand and delivery. Ann Rev Nutr 1996;16:321–347. 6. Princen HMG, van Poppel G, Vogelezang C, Buytenhek R, Kok FJ. Supplementation with vitamin E but not b-carotene in vivo protects low density low density lipoprotein from lipid peroxidation in vitro: effect of cigarette smoking. Arterioscler Thromb 1992;12:554 –562. 7. Dieber-Rotheneder M, Puhl H, Waeg G, Striegl G, Esterbauer H. Effect of oral supplementation with d-alpha-tocopherol on the vitamin E content of human low density lipoproteins and resistance to oxidation. J Lipid Res 1991;32:1325–1332. 8. Jialal I, Grundy SM. Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J Lipid Res 1992;33: 899 –906. 9. Reaven PD, Khouw A, Beltz WF, Parthasarathy S, Witztum JL. Effect of dietary antioxidant combinations in humans: protection of LDL by vitamin E but not by b-carotene. Arterioscler Thromb 1993;13:590 – 600. 10. Harats D, Ben-Naim M, Dabach Y, Hollander G, Havivi E, Stein O, Stein Y. Effect of vitamin C and E supplementation on susceptibility of plasma lipoproteins to peroxidation induced by acute smoking. Artherosclerosis 1990;85:47–54. 11. Jialal I, Fuller CJ, Huet BA. The effect of alpha-tocopherol supplementation on LDL oxidation: a dose response study. Arterioscler Thromb Vasc Biol 1995; 15:190 –198. 12. Simons LA, Von Konigsmark M, Balasubramaniam S. What dose of vitamin E is required to reduce susceptibility of LDL to oxidation? Aust NZ J Med 1996;26:496 –503. 13. Suzukawa M, Ishikawa T, Yoshida H, Nakamura H. Effect of in vivo supplementation with low dose vitamin E on susceptibility of low density lipoprotein and high density lipoprotein to oxidative modification. J Am Coll Nutr 1995;14:46 –52. 14. Princen HMG, van Duyvenvoorde W, Buytenhek R, van der Laarse A, van Poppel G, Leuven JAG, van Hinsbergh VWM. Supplementation with low doses of vitamin E protect LDL from lipid peroxidation in men and women. Arterioscler Thromb Vasc Biol 1995;15:325–333. 15. Devaraj S, Li DJ, Jialal I. The effects of alpha-tocopherol supplementation on monocyte function: decreased lipid oxidation, interleukin-1 secretion and monocyte adhesion to endothelium. J Clin Invest 1996;98:756 –763.
Safety and Feasibility of Same Day Discharge in Patients Undergoing Radiofrequency Catheter Ablation Amit M. Vora,
MD,
Martin S. Green,
adiofrequency catheter ablation has been well established as a safe and effective procedure for R various tachyarrhythmias. Cost-effective analysis 1,2
for symptomatic and drug resistant tachycardias due to atrioventricular (AV) reciprocating tachycardia with accessory pathway connections,3 AV nodal reentrant tachycardia,4 and atrial flutter and/or fibrillation have shown ablation to be less costly compared with longFrom the University of Ottawa Heart Institute, Ottawa, Ontario, Canada. Dr. Green’s address is: University of Ottawa Heart Institute, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9. Manuscript received April 30, 1997; revised manuscript received and accepted October 17, 1997. ©1998 by Excerpta Medica, Inc. All rights reserved.
MD,
and Anthony S. L. Tang,
MD
term drug therapy and repeat hospitalization. In the early 1990s the hospital stay following radiofrequency ablation varied from 2 to 7 days with primary concern for AV block, recurrence of arrhythmia, and other vascular or cardiac complications. As worldwide experience with ablation accumulated and safety was better established, consideration was given to shortening hospital stay.5,6 With increasing experience over the past few years, our policy in the recent years has been to discharge patients undergoing radiofrequency ablation for various tachyarrhythmias on the same day if they lived within city limits. We therefore analyzed our data on ablation procedures to determine the safety and feasibility of same day discharge. 0002-9149/98/$19.00 PII S0002-9149(97)00887-4
233
vasive visualization of the left main coronary artery by cross-sectional echocardiography. Circulation 1976;54:169 –174. 7. Presti CF, Feigenbaum H, Armstrong WF, Ryan T, Dillon JC. Digital twodimensional echocardiographic imaging of the proximal left anterior descending coronary artery. Am J Cardiol 1987;60:1254 –1259. 8. Petrovic O, Elsner GB, Wilensky RL, Swanson ST, Feigenbaum H. Transthoracic echocardiographic detection of coronary atherosclerosis. Am J Cardiol 1996;77:569 –574. 9. Faletra F, Cipriani M, Corno R, Cali G, Mantero A, Cantoni S, Formentini A, Battista Danzi G, Pezzano A. Transthoracic high-frequency echocardiographic detection of atherosclerotic lesions in the descending portion of the left coronary artery. J Am Soc Echocardiogr 1993;6:290 –298. 10. Kenny A, Shapiro LM. Transthoracic high-frequency two-dimensional echocardiography, Doppler and color flow mapping to determine anatomy and blood flow patterns in the distal left anterior descending coronary artery. Am J Cardiol 1992;69:1265–1268. 11. Ross Jr JJ, Ren JF, Land W, Chandrasekaran K, Mintz GS. Transthoracic high frequency (7.5 MHz) echocardiographic assessment of coronary vascular reserve and its relation to left ventricular mass. J Am Coll Cardiol 1990;16:1393–1397. 12. Faletra F, Cipriani M, De Chiara F, Quattrocchi G, Battista Danzi G, Gronda E, Frigerio M, Mangiavacchi M, Pezzano A. Imaging the left anterior descending coronary artery by high-frequency transthoracic echocardiography in heart transplant patients. Am J Cardiol 1995;75:855– 858.
Effects of Increasing Doses of Alpha-Tocopherol in Providing Protection of Low-Density Lipoprotein from Oxidation Cindy J. Fuller,
PhD, RD,
Beverley A. Huet,
he oxidative modification of low-density lipoprotein (LDL) has been proposed as a key T early step in atherogenesis. Furthermore, several 1–3
lines of evidence support the existence of oxidized LDL in vivo.1–3 The most persuasive evidence for the in vivo existence of oxidized LDL comes from animal studies, in which dietary antioxidant supplementation resulted in a reduction of atherosclerotic lesion area.3,4 Alpha-tocopherol (AT), the most active form of vitamin E, is the predominant lipophilic antioxidant in LDL.5 Dietary supplementation with AT reduced the extent of atherosclerotic lesions in several animal models.4 Previous studies from this laboratory and others have shown that pharmacologic doses of AT have been shown to reduce LDL oxidizability in healthy nonsmokers and smokers.6 –11 The threshold for statistically significant effects on LDL oxidizability varies, depending on the research methodology used. A previous study from this laboratory11 has demonstrated that dosages of $400 IU/day of all-racemic or synthetic AT for 8 From the Center for Human Nutrition and the Departments of Pathology, Internal Medicine, and Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center, Dallas, Texas, and the Department of Food, Nutrition, and Food Service Management, The University of North Carolina at Greensboro, Greensboro, North Carolina. This work was supported by grants from the American Heart Association, Hoffman-LaRoche, and the General Clinical Research Center (grant no. M101-RR00633) Bethesda, Maryland. Dr. Jialal’s address is: Department of Pathology and Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75235-9072. Manuscript received August 7, 1997; revised manuscript received and revised October 14, 1997. ©1998 by Excerpta Medica, Inc. All rights reserved.
MS,
and Ishwarlal Jialal,
MD, PhD
weeks were required to have a significant effect on LDL oxidative kinetics (lag phase). In a 6-week long study, Simons et al12 found that 500 IU/day of AT reduced LDL oxidizability. Another study13 with a small number of subjects (n 5 8) found that 300 IU/day AT reduced both LDL and high-density lipoprotein (HDL) oxidizability. However, Princen et al14 noted significant effects on the lag phase of LDL oxidation at doses of $25 IU/day when subjects took consecutively increasing doses of AT. Significant reductions in the oxidation rate were not seen until subjects took 400 IU/day of AT. It is unknown whether higher dosages of AT can confer additional beneficial effects on LDL oxidizability. This study, a post hoc analysis of published data,11 examines if higher dosages of AT could have a greater effect on LDL oxidation than the threshold dosage of 400 IU/day. •••
The subject inclusion criteria and the study protocol and methods have been detailed previously.11 Briefly, healthy nonsmoking men were randomly assigned to receive either 400, 800, or 1,200 IU/day of AT for 8 weeks. The AT was in the form of all-rac-AT and was supplied by Hoffmann-LaRoche (Nutley, New Jersey). At 0 and 8 weeks, fasting blood samples were collected from each subject for lipid and lipoprotein profiles, plasma AT, ascorbate and b-carotene levels, and for LDL isolation. LDL isolated by preparative ultracentrifugation was extensively dialyzed before oxidation.11 The oxidation of LDL was undertaken in a cell-free system with 5 mmol/L copper in phosphate buffered 0002-9149/98/$19.00 PII S0002-9149(97)00873-4
231
TABLE I Effect of 400, 800 and 1,200 IU/day of Alpha-Tocopherol (AT) on Plasma and Low-Density Lipoprotein (LDL) Antioxidant Levels and LDL Oxidation Kinetics 400 IU/day
Lipid standardized AT (mmol/mmol) median change (%) LDL AT (nmol/mg protein) median change (%) Conjugated dienes Lag phase (min) median change (%) Oxidation rate, DA234/h median change (%) TBARS Lag phase (min) median change (%) Oxidation rate, (nmol MDA/mg protein/h) median change (%)
800 IU/day
Week 0
Week 8
3.0 6 0.5
6.3 6 1.5 111
861
14 6 4
96 84 6 11
107 6 14 28 2.4 6 0.7 1.8 6 0.5 221 83 6 7
104 6 19 15 44 6 7 29 6 8.3 234
Week 0
1,200 IU/day
Week 8
3.1 6 0.7 8.0 6 2.8 145‡ 7.3 6 3 18 6 12 151 95 6 14
170 6 82 37 2.4 6 0.6 1.0 6 0.4 263† 89 6 13
143 6 66 36 41 6 8.3 21 6 6.4 250
Week 0 3.2 6 0.3 863
Week 8 11.2 6 3.0 260* 22 6 12 158
86 6 12
145 6 20 63* 2.3 6 0.6 0.9 6 0.2 263* 81 6 10
139 6 35 64* 44 6 11.9 23 6 11.6 255
Data are expressed as mean 6 1 SD or percent. *p ,0.01, 400 IU/day versus 1,200 IU/day. † 0.01 , p ,0.05, 400 IU/day versus 800 IU/day, nonsignificant after adjustment for multiple testing. ‡ 0.01 , p ,0.05, 800 IU/day versus 1,200 IU/day, nonsignificant after adjustment for multiple testing.
saline for 8 hours.11 Two indexes of oxidation were used in this study. The amount of conjugated dienes formed during LDL oxidation was determined by monitoring the absorbance of LDL against a phosphate buffered saline blank at 234 nm.11 Data are expressed as the increase in conjugated dienes over baseline (DA234). The lipid peroxide content of oxidized LDL was measured by a modification of the thiobarbituric acid-reactive substances (TBARS) assay.8 The TBARS activity are expressed as malondialdehyde equivalents/mg LDL protein using freshly diluted 1,1,3,3-tetramethoxypropane as the standard. The lag phase and oxidation rate of LDL oxidation were derived as previously described.11 Results are expressed as mean 6 SD or for skewed data as the median. One-way analysis of variance was used to assess differences between groups at baseline. Comparisons of 0- and 8-week data (pre- and postsupplementation) were previously reported.11 For AT levels and oxidation kinetic parameters, percent change from baseline was computed for each subject and was compared between groups using the WilcoxonRank sum test. Because this was a subgroup analysis and multiple testing has occurred, the level of significance was set at a 5 0.01. Analyses were performed using BMDP statistical software (SPSS Inc., Chicago, Illinois). There were no differences between the 3 groups for age, body mass index, plasma fatty acids, lipids and lipoproteins, and antioxidant status. Also, at baseline, there were no significant differences between the groups with respect to LDL oxidation kinetics (lag phase and propagation rate). Table I displays the plasma and LDL AT concentrations for the 3 groups following supplementation. Although the increment in lipid standardized AT was significantly higher in the 1,200 IU/day group compared with the 400 IU/day, the increase in LDL AT was 232 THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 81
not statistically significant. No other intergroup comparison was significant. For both the conjugated dienes assay and the TBARS assay, there was a significant prolongation of the lag phase for the 1,200 IU/day group relative to the 400 IU/day group. Although the decrease in the propagation rate was significantly different for the conjugated dienes assay between the 1,200 and 400 IU/day groups, the decrease obtained from the TBARS assay was not significant. Furthermore, there were no significant differences when the 800 IU/day group was compared with the 1,200 IU/day or 400 IU/day groups at the 0.01 level of significance. •••
The results of the present analysis indicate that 1,200 IU/day all-rac-AT can further protect LDL against oxidation. For both the conjugated dienes and the TBARS assays, the percent change in the duration of the lag phase for the 1,200 IU/d group was significantly increased relative to the 400 IU/ day group. The percent change in the oxidation rate was greater for the conjugated diene assay only. This difference could be attributed to the fact that the conjugated diene assay is superior to the TBARS assay as a measure of LDL oxidation.7 The decreased oxidation of LDL could also be due to decreased seeding of LDL with lipid hydroperoxides by AT supplementation. The results of the current analysis are in contrast to Simons et al12 who reported that the percent changes in lag time and oxidation rate did not differ between 500, 1,000, and 1,500 IU/day of AT over a 6-week period. It should be noted that the subjects in this particular study also followed an isocaloric diet with ,30% of energy from fat. This could have blunted AT absorption from the diet. The subjects in the present investigation were advised to adhere JANUARY 15, 1998
to their normal diets and activities.11 This may also account for the disparity between plasma and LDL change in response to AT supplementation; for example, the subjects in the current study on 400 IU/day had a median 96% increase in LDL AT, whereas the subjects taking 500 IU/day in the Simons study had only a median 62% increase.12 Suzukawa et al13 reported that subjects who took 150 IU/day of AT for 1 week, followed by 300 IU/day for 3 weeks, showed significant changes in both lag time and oxidation rate. Their increase in LDL AT was comparable to the one seen at 400 IU in the current study (90% vs 96%). Princen et al14 did not directly compare AT dosages in their study except for versus the placebo phase. Their study design was one where subjects took sequentially increasing dosages of AT for 2-week periods, which could have confounded their findings because there was no washout phase between doses. Although they saw a significant increase in the lag phase of LDL oxidation at 25 IU/day, they did not see a significant decrease in the oxidation rate until dosages of 400 and 800 IU/day were taken. They also did not see the magnitude of changes in the LDL oxidation kinetics as was seen in the present study, despite comparable increases in plasma and LDL AT (plasma 119, LDL 80% at 400 IU/day; plasma 159, LDL 123% at 800 IU/day).11,14 In conclusion, the results of this post hoc data analysis demonstrate that 1,200 IU/day of AT is more potent in decreasing the oxidative susceptibility of LDL than 400 IU/day. Thus, AT at these higher doses (1,200 IU/day), in addition to decreasing LDL oxidation, has antiatherogenic effects on monocyte and/or macrophages, a pivotal cell in atherogenesis.15
Acknowledgment: The authors graciously thank Elizabeth Thurston for manuscript preparation. 1. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA,
Watson AD, Lusis AJ. Atherosclerosis: basic mechanisms, oxidation, inflammation and genetics. Circulation 1995;91:2488 –2496. 2. Parthasarathy S, Rankin SM. Role of oxidized LDL in atherogenesis. Prog Lipid Res 1992;31:127–143. 3. Fuller CJ, Jialal I. Antioxidants and LDL oxidation. In: Garewal H, ed. Antioxidants & Disease Prevention. Boca Raton: CRC Press, 1997;115–130. 4. Janero DR. Therapeutic potential of vitamin E in the pathogenesis of spontaneous atherosclerosis. Free Radic Biol Med 1991;11:129 –144. 5. Traber MG, Sies H. Vitamin E in humans: demand and delivery. Ann Rev Nutr 1996;16:321–347. 6. Princen HMG, van Poppel G, Vogelezang C, Buytenhek R, Kok FJ. Supplementation with vitamin E but not b-carotene in vivo protects low density low density lipoprotein from lipid peroxidation in vitro: effect of cigarette smoking. Arterioscler Thromb 1992;12:554 –562. 7. Dieber-Rotheneder M, Puhl H, Waeg G, Striegl G, Esterbauer H. Effect of oral supplementation with d-alpha-tocopherol on the vitamin E content of human low density lipoproteins and resistance to oxidation. J Lipid Res 1991;32:1325–1332. 8. Jialal I, Grundy SM. Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J Lipid Res 1992;33: 899 –906. 9. Reaven PD, Khouw A, Beltz WF, Parthasarathy S, Witztum JL. Effect of dietary antioxidant combinations in humans: protection of LDL by vitamin E but not by b-carotene. Arterioscler Thromb 1993;13:590 – 600. 10. Harats D, Ben-Naim M, Dabach Y, Hollander G, Havivi E, Stein O, Stein Y. Effect of vitamin C and E supplementation on susceptibility of plasma lipoproteins to peroxidation induced by acute smoking. Artherosclerosis 1990;85:47–54. 11. Jialal I, Fuller CJ, Huet BA. The effect of alpha-tocopherol supplementation on LDL oxidation: a dose response study. Arterioscler Thromb Vasc Biol 1995; 15:190 –198. 12. Simons LA, Von Konigsmark M, Balasubramaniam S. What dose of vitamin E is required to reduce susceptibility of LDL to oxidation? Aust NZ J Med 1996;26:496 –503. 13. Suzukawa M, Ishikawa T, Yoshida H, Nakamura H. Effect of in vivo supplementation with low dose vitamin E on susceptibility of low density lipoprotein and high density lipoprotein to oxidative modification. J Am Coll Nutr 1995;14:46 –52. 14. Princen HMG, van Duyvenvoorde W, Buytenhek R, van der Laarse A, van Poppel G, Leuven JAG, van Hinsbergh VWM. Supplementation with low doses of vitamin E protect LDL from lipid peroxidation in men and women. Arterioscler Thromb Vasc Biol 1995;15:325–333. 15. Devaraj S, Li DJ, Jialal I. The effects of alpha-tocopherol supplementation on monocyte function: decreased lipid oxidation, interleukin-1 secretion and monocyte adhesion to endothelium. J Clin Invest 1996;98:756 –763.
Safety and Feasibility of Same Day Discharge in Patients Undergoing Radiofrequency Catheter Ablation Amit M. Vora,
MD,
Martin S. Green,
adiofrequency catheter ablation has been well established as a safe and effective procedure for R various tachyarrhythmias. Cost-effective analysis 1,2
for symptomatic and drug resistant tachycardias due to atrioventricular (AV) reciprocating tachycardia with accessory pathway connections,3 AV nodal reentrant tachycardia,4 and atrial flutter and/or fibrillation have shown ablation to be less costly compared with longFrom the University of Ottawa Heart Institute, Ottawa, Ontario, Canada. Dr. Green’s address is: University of Ottawa Heart Institute, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9. Manuscript received April 30, 1997; revised manuscript received and accepted October 17, 1997. ©1998 by Excerpta Medica, Inc. All rights reserved.
MD,
and Anthony S. L. Tang,
MD
term drug therapy and repeat hospitalization. In the early 1990s the hospital stay following radiofrequency ablation varied from 2 to 7 days with primary concern for AV block, recurrence of arrhythmia, and other vascular or cardiac complications. As worldwide experience with ablation accumulated and safety was better established, consideration was given to shortening hospital stay.5,6 With increasing experience over the past few years, our policy in the recent years has been to discharge patients undergoing radiofrequency ablation for various tachyarrhythmias on the same day if they lived within city limits. We therefore analyzed our data on ablation procedures to determine the safety and feasibility of same day discharge. 0002-9149/98/$19.00 PII S0002-9149(97)00887-4
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