5. Rychik J, Rome JJ, Collins MH, DeCampli WM, Spray TL. The hypoplasticleft heart syndrome with intact atrial septum: atrial morphology, pulmonaryvascular histopathology and outcome. J Am Coll Cardiol 1999;34:554–560.6. Jacobs ML. Hypoplastic left heart syndrome. Kaiser LR, Kraon IL, Spray TL,eds. Mastery of Cardiothoracic Surgery. Philadelphia: Lippincott-Raven Publish-ers, 1998:861–862.

7. Weinberg PM, Chin AJ, Murphy JD, Pigott JD, Norwood WI. Postmortemechocardiography and tomographic anatomy of hypoplastic left heart syndromeafter palliative surgery. Am J Cardiol 1986;58:1228–232.8. Park SC, Neches WH, Mullins CE, Girod DA, Olley PM, Falkowski G,Garibjan VA, Mathews RA, Fricker FJ, Beerman LB, et al. Blade atrial septos-tomy: collaborative study. Circulation 1982;66:258–266.

Effect of Acute Intake of Red Wine on Flow-MediatedVasodilatation of the Brachial Artery

Masayoshi Hashimoto, MD, PhD, Seungbum Kim, MD, PhD, Masato Eto, MD, PhD,Katsuya Iijima, MD, Junya Ako, MD, Masao Yoshizumi, MD, PhD,

Masahiro Akishita, MD, PhD, Kazuo Kondo, MD, PhD, Hiroshige Itakura, MD, PhD,Kazuaki Hosoda, BSc, Kenji Toba, MD, PhD, and Yasuyoshi Ouchi, MD, PhD

F low-mediated vasodilatation (FMD) induced byreactive hyperemia is known to be endothelium

dependent, and this can be detected during reactivehyperemia by high-resolution ultrasound techniqueson superficial arteries.1,2 We tested the hypothesis thatacute intake of red wine may exert a positive effect onFMD in men.

• • •Eleven healthy men (aged 34 � 1 year) were

enrolled in this study. All subjects were asymptom-atic, normotensive, nondiabetic, and life-time non-smokers. Each subject gave written informed consentbefore enrollment in this study after receiving a thor-ough explanation of the study design and protocol.This study was performed in agreement with theguidelines approved by the ethics committee of ourinstitution.

No alcohol was allowed at least 48 hours beforeeach study. No coffee, tea, green tea, or other bever-age except water was allowed throughout the day onthe examination days. The subjects were allowed tohave their usual breakfast on the ultrasound examina-tion days. The same type of lunch box was served toeach subject at noon on each examination day. Nofood intake was allowed after lunch. Each study wasscheduled to start between 5 and 6 P.M. Each subjectwas allocated to drink 500 ml of water, Japanesevodka (shochu, 0.8 g/kg ethanol), red wine (ChateauBeychevelle 1994, 0.8 g/kg ethanol), and red winewithout alcohol on 4 different evenings. Beverageswere randomly assigned to the subjects. Red winewithout alcohol, which contains red wine constituentsexcept alcohol, was prepared by Suntory ResearchCenter (Osaka, Japan). Briefly, the ethanol in red winewas removed by evaporation under reduced pressure

(40°C) and the resulting aqueous solution was dilutedwith distilled water. After the initial ultrasound mea-surement, each subject was asked to drink the bever-age over 30 minutes. Examinations were scheduled tobe performed before intake, and at 30 and 120 minutesafter completion of drinking each beverage. Twohours and 20 minutes after drinking, sublingual nitro-glycerin was administered to measure nitroglycerin-induced vasodilatation.

Blood sampling was performed at the time of eachultrasound examination to measure serum concentrationsof nitrites/nitrates, thiobarbituric acid-reactive substances(TBARS), uric acid, and other biochemical parameters.Nitrites/nitrates, stable metabolites of nitric oxide, weremeasured with an autoanalyzer (flow injection analyzer,TCI-NOX1000, Tokyo Kasei Kogyo, Tokyo, Japan) us-ing a method based on the Greiss reaction.3 Serum levelsof TBARS were measured as an index of lipoproteinoxidation.4 Serum levels of uric acid were measured bythe uricase method.5

FMD and nitroglycerin-induced vasodilatation ofthe brachial artery were measured by an examiner whowas unaware of the subjects’ clinical condition andwhich beverage the subjects had taken. Studies wereperformed according to the method described previ-ously.1,2,6 Examinations were conducted by the sameexaminer throughout this study. The diameter of theartery was measured with an ultrasound machine(SSA-270A, Toshiba, Tokyo, Japan) using a 7.5-MHzlinear array transducer.1,2,6 Changes in diameter of thebrachial artery were measured at rest, during reactivehyperemia before drinking, and 30 and 120 minutesafter drinking each beverage. Sublingual nitroglycerinspray (300 �g, Myocol Spray, Toa Eiyo Co., Tokyo,Japan) was administered 140 minutes after drinkingeach beverage to measure nitroglycerin-induced vaso-dilatation. Ultrasound images were recorded on S-VHS videotape using a video cassette recorder (SLV-RS7, Sony, Tokyo, Japan).

All data are expressed as mean � SEM. Differ-ences between pre- and postintake of the beveragewere analyzed by Student’s paired t test. A p value�0.05 was considered statistically significant. Tocompare data of nitroglycerin-induced vasodilatation

From the Department of General Internal Medicine, Kobe UniversitySchool of Medicine, Kobe; Department of Geriatric Medicine, Grad-uate School of Medicine, University of Tokyo, Tokyo; Department ofGeriatric Medicine, Kyorin University School of Medicine, Tokyo; TheNational Institute of Health and Nutrition, Tokyo; and Suntory ResearchCenter, Osaka, Japan. Dr. Ouchi’s address is: 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: youchi-tky@umin.ac.jp. Manu-script received July 3, 2001; revised manuscript received and ac-cepted August 14, 2001.

1457©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matterThe American Journal of Cardiology Vol. 88 December 15, 2001 PII S0002-9149(01)02137-3

after the 4 kinds of beverages, analysis of variance formultiple comparisons was performed. When statisti-cally significant effects were found, the Bonferronitest was used to isolate the difference between groups.

All subjects completed the study without any troubleand/or any acute alcohol-related problems. Heart rateincreased after intake of Japanese vodka and red wine,which both contained alcohol (Table 1). Brachial arterydiameters before and after forearm occlusion are alsolisted in Table 1. FMD improved 120 minutes after redwine (Figure 1). An improvement was also observed 30and 120 minutes after intake of red wine without alcohol.FMD significantly decreased 30 and 120 minutes afterintake of Japanese vodka. Nitroglycerin-induced vasodi-latation 140 minutes after intake of the 4 kinds of bev-erage was 16.0 � 1.6% for water (n � 10), 17.3 � 1.3%for red wine without alcohol (n � 9), 10.6 � 1.1% forJapanese vodka (n � 9), and 11.6 � 1.3% for red wine(n � 9). No significant difference was observed betweenwater and red wine without alcohol, or between Japanesevodka and red wine. Serum level of nitrite/nitrate de-creased 120 minutes after intake of both Japanese vodka(45.2 � 6.1 to 42.0 � 5.7 �mol/L, p �0.01) and redwine without alcohol (44.2 � 5.6 to 36.2 � 3.8 �mol/L,p �0.05). Serum level of TBARS was decreased 120minutes after intake of Japanese vodka (4.1 � 0.4 to 3.7� 0.3 �mol/L, p �0.05). Serum level of uric acid beforethe intake of red wine was 379 � 19 �mol/L, andincreased 30 and 120 minutes after red wine intake (416� 18 and 408 � 17 �mol/L, each p �0.01). Serum levelof uric acid was decreased 120 minutes after intake ofred wine without alcohol (370 � 22 vs 383 � 21 �mol/Lbefore intake, p �0.01).

• • •This is the first report to confirm that red wine

intake improves FMD in men. No improvement of

FMD was observed after intake ofwater or Japanese vodka (shochu),which is considered to be pure alco-hol. We also found that FMD im-proved after intake of red wine with-out alcohol. This phenomenon mayindicate that the constituent(s) of redwine, and not alcohol, improve en-dothelial function.

Because subjects who drank Jap-anese vodka and red wine containingthe same amount of alcohol had sim-ilar systolic blood pressure, heartrate, and brachial baseline diameterchange after intake, it is unlikely thatthese factors influenced the differ-ence in FMD. It is well known, andwe also confirmed, that FMD is in-versely related to baseline vessel di-ameter.1,2,6 Because baseline vesseldiameter increases after intake ofJapanese vodka or red wine, if endo-thelial function is preserved at thesame level, it is natural that FMDwould decrease. However, to thecontrary, FMD increased 2 hours af-

ter red wine intake; in fact, it was extremely high 2hours after red wine intake when one considers thedilated baseline vessel diameter before reactive hyper-emia.

FMD was elevated 30 minutes after intake of redwine without alcohol. On the other hand, FMD waselevated 2 hours after intake of red wine. This time lagmay result from the difference in absorption and main-tenance of these compounds in vivo. Because there arelimited data concerning the absorption of polyphe-nolic compounds,7 we are not able to reach a conclu-sion on this issue. The other possibility is the effect ofalcohol, which dilates resting vessels, on the basalbrachial diameter. The basal brachial diameter in-creased after red wine consumption; therefore, it islikely that FMD 30 minutes after red wine intakeshowed a smaller value than it ordinarily would have.Parasympathetic nervous system activation is knownafter alcohol consumption. The relative inactivation ofthe sympathetic nervous system may affect endothe-lial function.8 We could not neglect this effect on theendothelium. Further studies are needed to form aconclusion.

Previous studies have demonstrated endothelium-dependent vasorelaxing activity in rat aortic ringstreated with red wine, grape juice, grape skin prod-ucts, or red wine polyphenolic compounds.9,10 Becausethis phenomenon was completely abolished by N-omega-nitro-L-arginine-methyl-ester, which is a nitricoxide synthase inhibitor, it was thought that this en-dothelium-dependent vasorelaxing activity resultedfrom enhanced synthesis of nitric oxide rather thanenhanced biologic activity of nitric oxide or protectionagainst breakdown by a superoxide anion.10 Similarresults have also been demonstrated using human cor-onary arteries in vitro.11 However, in this study, the

TABLE 1 Systolic Blood Pressure, Heart Rate, and Brachial Artery Diameter Beforeand After Beverage Intake

Before Intake

After Intake

30 min 120 Min

Water (n � 11)Systolic blood pressure (mm Hg) 112 � 4 114 � 3 114 � 4Heart rate (beats/min) 65 � 3 62 � 3 62 � 3Brachial artery diameter at rest (mm) 4.4 � 0.2 4.5 � 0.1 4.5 � 0.1Brachial artery diameter in RH (mm) 4.8 � 0.2 4.8 � 0.1 4.8 � 0.2

Japanese vodka (n � 11)Systolic blood pressure (mm Hg) 116 � 5 116 � 6 110 � 4Heart rate (beats/min) 64 � 3 75 � 3† 76 � 3*Brachial artery diameter at rest (mm) 4.5 � 0.1 4.8 � 0.1† 5.0 � 0.1†

Brachial artery diameter in RH (mm) 4.8 � 0.2 5.1 � 0.1 5.3 � 0.1Red wine without alcohol (n � 11)

Systolic blood pressure (mm Hg) 110 � 4 122 � 4* 115 � 4Heart rate (beats/min) 69 � 2 65 � 3 66 � 2Brachial artery diameter at rest (mm) 4.5 � 0.1 4.4 � 0.1 4.5 � 0.1Brachial artery diameter in RH (mm) 4.8 � 0.2 5.0 � 0.2† 4.9 � 0.2†

Red wine (n � 11)Systolic blood pressure (mm Hg) 112 � 4 108 � 5 114 � 5Heart rate (beats/min) 64 � 2 74 � 3* 75 � 3*Brachial artery diameter at rest (mm) 4.5 � 0.1 4.9 � 0.1† 5.0 � 0.1†

Brachial artery diameter in RH (mm) 4.8 � 0.2 5.2 � 0.1 5.4 � 0.1†

*p �0.05; †p �0.01 versus before intake.RH � reactive hyperemia.

1458 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 88 DECEMBER 15, 2001

serum level of nitrite/nitrate was not increased afterthe intake of either red wine, red wine without alcohol,Japanese vodka, or water.

Hertog et al12 reported that dietary antioxidantflavonoids were suggested to reduce coronary arterydisease in the Zutphen elderly study. Since then, an-tioxidant effects of red wine have also been reportedin humans.13–15 However, TBARS showed no differ-ence after red wine intake. Uric acid has been sug-gested to act as an antioxidant in human serum.16 Theserum level of uric acid is reported to increase afterred wine intake, which was also confirmed in thisstudy.17 However, the serum level of uric acid de-creased 120 minutes after red wine without alcoholintake (p �0.05). These results are controversial;however, based on our results, it is possible that acuteintake of red wine exerts antioxidative effects. Re-cently, in animal experiments, red wine consumptionreduced the progression of atherosclerosis in apoli-poprotein E deficient mice.18 This effect is reported tobe associated with reduced susceptibility of low-den-sity lipoprotein to oxidation and aggregation. Further,in a human study, grape juice intake improved endo-thelial function with the reduction of low-density li-poprotein oxidation.19 These findings also support theidea that red wine works as an antiatherogenic factor.

In conclusion, the present investigation demon-strates that endothelium-dependent vasodilatationimproves after acute intake of red wine or red winewithout alcohol in men. Our results indicate thatother constituent(s) of red wine, and not alcohol,improve endothelial function.

1. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI,Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelialdysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–1115.2. Hashimoto M, Kozaki K, Eto M, Akishita M, Ako J, Iijima K, Kim S, TobaK, Yoshizumi M, Ouchi Y. Association of coronary risk factors and endothelium-dependent flow-mediated dilatation of the brachial artery. Hypertens Res 2000;23:233–238.3. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, TannenbaumSR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem1982;126:131–138.4. Yagi K. Lipid peroxides and human diseases. Chem Phys Lipids 1987;45:337–351.5. Kabasakalian P, Kalliney S, Westcott A. Determination of uric acid in serum,with use of uricase and a tribromophenol-aminoantipyrine chromogen. Clin Chem1973;19:522–524.6. Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, Toba K, Sagara Y,Taketani Y, Orimo H, Ouchi Y. Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation1995;92:3431–3435.7. Laparra J, Michaud J, Lesca MF, Blanquet P, Masquelier J. Autoradiographicstudy of the localization of tetrahydroxyflavanediol-C14 in mice. Scie Nat 1973;276:2847–2850.8. Martinez C, Vila JM, Aldasoro M, Medina P, Chuan P, Lluch S. The humandeferential artery: endothelium-mediated contraction in response to adrenergicstimulation. Eur J Pharmacol 1994;261:73–78.9. Fitzpatrick DF, Hirschfield SL, Coffey RG. Endothelium-dependent vasore-laxing activity of wine and other grape products. Am J Physiol 1993;265:774–778.10. Andriambeloson E, Kleschyov AL, Muller B, Beretz A, Stoclet JC, Andriantsi-tohaina R. Nitric oxide production and endothelium-dependent vasorelaxation in-duced by wine polyphenols in rat aorta. Br J Pharmacol 1997;120:1053–1058.11. Flesch M, Schwarz A, Bohm M. Effects of red and white wine on endothe-lium-dependent vasorelaxation of rat aorta and human coronary arteries. Am JPhysiol 1998;275:1183–1190.12. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietaryantioxidant flavonoids and risk of coronary heart disease: the Zutphen ElderlyStudy. Lancet 1993;342:1007–1011.13. Kondo K, Matsumoto A, Kurata H, Tanahashi H, Koda H, Amachi T, ItakuraH. Inhibition of oxidation of low-density lipoprotein with red wine. Lancet1994;344:1152.14. Fuhrman B, Lavy A, Aviram M. Consumption of red wine with meals reducesthe susceptibility of human plasma and low-density lipoprotein to lipid peroxi-dation. Am J Clin Nutr 1995;61:549–554.

FIGURE 1. Percent FMD changes after 4 kinds of beverage. Data are expressed as mean � SEM. *p <0.05; **p <0.01 versus beforeintake. N.S. � not significant.

BRIEF REPORTS 1459

15. Whitehead TP, Robinson D, Allaway S, Syms J, Hale A. Effect of red wineingestion on the antioxidant capacity of serum. Clin Chem 1995;41:32–35.16. Wayner DD, Burton GW, Ingold KU, Barclay LR, Locke SJ. The relativecontributions of vitamin E, urate, ascorbate and proteins to the total peroxylradical-trapping antioxidant activity of human blood plasma. Biochim BiophysActa 1987;924:408–419.17. Day A, Stansbie D. Cardioprotective effect of red wine may be mediated byurate. Clin Chem 1995;41:1319–1320.

18. Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman R, Elis A,Aviram M. Reduced progression of atherosclerosis in apolipoprotein E-deficientmice following consumption of red wine, or its polyphenols quercetin or catechin,is associated with reduced susceptibility of LDL to oxidation and aggregation.Arterioscler Thromb 1997;17:2744–2752.19. Stein JH, Keevil JG, Wiebe DA, Aeschlimann S, Folts JD. Purple grape juiceimproves endothelial function and reduces the susceptibility of LDL cholesterol tooxidation in patients with coronary artery disease. Circulation 1999;100:1050–1055.

End-of-Life Care-Related Publications inCardiology Journals

Nirav J. Mehta, MD, Ijaz A. Khan, MD, Rajal N. Mehta, MD, Furqan Tejani, MD,Balendu C. Vasavada, MD, and Terrence J. Sacchi, MD

Numerous studies have demonstrated that physi-cians as a group fail to spend sufficient time with

terminally ill patients and their families, and often aretoo ill equipped in managing complicated, sensitive,and demanding circumstances surrounding the care ofpatients with a terminal illness.1–8 Therefore, the Na-tional Institutes of Health and many philanthropicorganizations such as the Robert Wood Johnson Foun-dation have devoted generous funds to support andpromote the education and research on this subject.Although heart disease is the leading cause of death inthe United States, and a large portion of in-hospitalcare of critically ill patients is delivered by cardiolo-gists, the body of literature on cardiologists’ educa-tion, knowledge, and attitude toward the end-of-life careissues is limited.9–19 We examined the end-of-life care-related topics in leading cardiology journals and com-pared them with the similar contents published in theleading journals of other medical specialties.

• • •Peer-reviewed journals with an estimated circula-

tion of �5,000 were selected for study. Seventeenspecialty journals, including 5 cardiology journals,were reviewed (Table 1). The journals of 2 separatespecialties—pulmonary medicine and critical caremedicine—are considered under a single, combinedspecialty of pulmonary and critical care medicine.Two leading medical journals, The New EnglandJournal of Medicine and The Journal of the AmericanMedical Association were included as other medicaljournals because their scope is not limited to theinternal medicine only.

A National Library of Medicine (MEDLINE)search was performed for each journal included in thestudy to identify articles published on the end-of-lifeissues during a 16-year period from 1985 to 2000. Thefinal search commands were reviewed under each ofthe following search topics: end of life care, terminal

care, hospice, do not resuscitate (DNR), living will,advance directive, and medical futility. After review-ing, the cited items were categorized on the basis oftheir types and contents.

Six categories for the published articles were de-termined. All surveys, interviews, retrospective orprospective chart reviews, and single or multicentercontrolled trials related to end-of-life care issues weregrouped under the category of study articles. Alleditorials related to the end-of-life topics were in-cluded under the category of editorials. The reviewarticles included all articles with comprehensive over-view or discussion on the end-of-life related topics.All letters to the editor addressing end-of-life relatedissues were categorized as letters. The statements orguidelines regarding end-of-life care issues endorsedby the professional societies were included under thestatements category. All other published items notfitting in any of the above categories were included ingeneral category, journal articles. Published itemswere excluded from the study if end-of-life issueswere mentioned very briefly with negligible informa-tion content or were not discussed at all. To assess thedegree of exposure that nonmedical people get regard-ing end-of-life care issues through newspapers, wealso searched the last 5-year archives of The New YorkTimes for publication of articles under the explodedheading: End of Life Care.

All variables are categorical and are expressed aspercentages. Chi-square statistics or Fisher’s exact testwas used for analysis as appropriate. A p value �0.05was considered significant. All statistical analyseswere performed using the computer software package,SPSS 7.0 (SPSS Inc., Chicago, Illinois).

• • •The number of articles on the study subject iden-

tified from these 17 journals was 1,129. Figure 1shows the percentage of publications on end-of-lifecare-related topics in each specialty. The Journal ofthe American Medical Association and The New En-gland Journal of Medicine published the highest num-bers of end-of-life care-related articles (359 articles,32%), whereas the cardiology journals published theleast number of these items (34 articles, 3%). Thejournals of internal medicine had 240 articles pub-

From the Division of Cardiology, Departments of Medicine, CreightonUniversity School of Medicine, Omaha, Nebraska; and Long IslandCollege Hospital, Brooklyn, New York. Dr. Khan’s address is: Creigh-ton University Cardiac Center, 3006 Webster Street, Omaha, Ne-braska 68131-2044. E-mail: ikhan@cardiac.creighton.edu. Manu-script received April 12, 2001; revised manuscript received andaccepted August 21, 2001.

1460 ©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matterThe American Journal of Cardiology Vol. 88 December 15, 2001 PII S0002-9149(01)02138-5