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In conclusion, this study shows that during va-sovagal syncope, a certain hormonal profile is ex-hibited, which points to an involvement of centralserotonergic activation.

1. Kaufmann H. Neurally mediated syncope: pathogenesis, diagnosis, and treat-ment. Neurology 1995;45(suppl5):S12–S18.2. Rea RF, Thanes MD. Neural control mechanisms and vasovagal syncope. JCardiovasc Electrophysiol 1993;4:587–595.3. Saxena PR, Villalon CM. Cardiovascular effects of serotonin agonists andantagonists. J Cardiovasc Pharmacol 1990;15(suppl 7):S17–S34.4. Ramage AG. Influence of 5-HT1A receptor agonists on sympathetic andparasympathetic nerve activity. J Cardiovasc Pharmacol 1990;15(suppl7):S75–S85.5. Kubo T, Taguchi K, Ozaki S, Amano M, Ishizuka T. 8-OH-DPAT-inducedhypotensive action and sympathoexcitatory neurons in the dorsal ventrolateralmedulla of the rat. Brain Res Bull 1995:36:405–411.6. Seletti B, Benkelfat C, Blier P, Annable L, Gilbert F, de Montigny C. Se-rotonin1A receptor activation by flesinoxan in humans. Body temperature andneuroendocrine responses. Neuropsychopharmacology 1995;13:93–104.7. Golden RN, Hsiao JK, Lane E, Ekstrom D, Rogers S, Hicks R, Potter WZ.Abnormal neuroendocrine responsivity to acute i.v. clomipramine challenge indepressed patients. Psychiatry Res 1990;31:39–47.8. Matzen S, Secher NH, Knigge U, Pawelczyk JH, Perko G, Iversen H, BachFW, Warberg J. Effect of serotonin receptor blockade on endocrine and cardio-vascular responses to head-up tilt in humans. Acta Physiol Scand1993;149:163–176.

9. Fitzpatrick A, Theodorakis G, Vardas P, Kenny RA, Travill CM, Ingram A,Sutton R. The incidence of malignant vasovagal syndrome in patients withrecurrent syncope. Eur Heart J 1991;12:389–394.10. Schally AV. Aspects of hypothalamic regulation of the pituitary gland.Science 1978;202:18–22.11. Charney DS, Woods SW, Goodman WK, Henninger GR. Serotonin functionin anxiety. II. Effects of the serotonin against MCPP in panic disorder patientsand healthy subjects. Psychopharmacology 1987;92:14–24.12. O’Kenae V, Dinan TG. Prolactin and cortisol responses to d-fenfluraminein major depression: evidence for diminished responsivity of central serotoner-gic function. Am J Psychiatr 1991;148:1009–1015.13. Hollander E, Cohen LJ, DeCaria C, Saoud JB, Stein DJ, Cooper TB, IslamNN, Liebowitz MR, Klein DF. Timing of neuroendocrine responses and effectof m-CPP and fenfluramine plasma levels in OCD. Biol Psychiatry1993;34:407–413.14. Clarke DE. A synopsis of the pharmacology of clinically used drugs at 5-HT receptors and uptake sites. In: Olesen J, Saxena PR. eds. 5-Hydroxytryp-tamine Mechanisms in Primary Headaches. New York: Raven Press, Ltd.,1992:118–128.15. Mandal AK, Kellar KJ, Gillis RA. The role of serotonin-1A receptor acti-vation and alpha-1 adrenoceptor blockade in the hypotensive effect of 5-methyl-urapidil. J Pharmacol Exp Ther 1991;257:861–869.16. van Zwieten PA, Blauw GJ, van Brummelen P. Pharmacological profile ofantihypertensive drugs with serotonin receptor and a-adrenoceptor activity.Drugs 1990;40(suppl 4):1–8.17. Van de Qar LD. Neuroendocrine pharmacology of serotonergic (5-HT) neu-rons. Ann Rev Pharmacol Toxicol 1991;31:289–320.18. Grubb BP, Wolfe DA, Samoil D, Temesy-Armos P, Hahn H, Elliott L.Usefulness of fluoxetine hydrochloride for prevention of resistant upright tiltinduced syncope. PACE 1993;16:458–464.

Comparison of Early Target Organ Damage BetweenBlacks and Whites With Mild Systemic

Arterial HypertensionRoland E. Schmieder, MD, Jurgen K. Rockstroh, MD, Gerd Luchters, MS, Uschi Hammerstein, MS,

and Franz H. Messerli

To identify possible racial differences in hyperten-sion-related target organ damage we designed a

study comparing systemic and renal hemodynamicsas well as cardiac structural adaptation in a popula-tion of well-matched pairs of white and black hy-pertensive patients. We considered renal blood flowand cardiac output as well as renal and total periph-eral resistance as surrogates for early vascular in-volvement of the renal and systemic circulation inhypertensive disease.1–3

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The study population was composed of 204 whitehypertensive patients (European American whites)and 79 black hypertensive patients (African-Ameri-cans). All patients with high blood pressure (BP)were referred to the outpatient clinic of the OchsnerClinic to assess the cause and stage of arterial hy-pertension. Established hypertension was consideredto be present if casual blood pressure wasú140 mmHg systolic or/and 90 mm Hg diastolic on ¢3 suc-

From the Department of Medicine IV, University of Erlangen-Nurem-berg, Nuremberg; Department of Medicine, University of Bonn,Bonn, Germany; and Department of Medicine, Division of Hyperten-sion, Ochsner Medical Institutions, New Orleans, Louisiana. Dr.Schmieder’s address is: University of Erlangen-Nuremberg, Depart-ment of Medicine IV, 90471 Nuremberg, Germany, Breslauerstraße201. Manuscript received October 15, 1996; revised manuscriptreceived and accepted February 26, 1997.

cessive measurements (within 2 weeks) taken with aregular cuff for lean subjects and with a large cufffor obese patients. Each participant had a completeclinical workup to exclude secondary causes of ar-terial hypertension in the manner previously re-ported.4,5 Most hypertensive patients had not beenpreviously treated for high BP. In those who hadreceived treatment, antihypertensive medication wasdiscontinued ¢4 weeks before the invasive andechocardiographic study. The protocol of the studywas approved by the institutional investigation com-mittee and informed consent was obtained from eachpatient.

Of the original 204 white and 79 black hyperten-sive patients consecutively enrolled in the study pro-tocol, matched pairs were formed by computer anal-ysis with the following matching criteria: same sex,difference in mean arterial pressure õ5 mm Hg, inweight õ15 kg, and age õ10 years. The computer-ized matching program identified 42 pairs for sub-sequent analysis. The hemodynamic study was per-formed between 8 and 11 A.M., after overnightfasting and without premedication as previously re-ported.4,5 In brief, polyethylene tubing was intro-duced into an antecubital vein and into the brachialartery and advanced to the level of the superior venacava and the ascending aorta, respectively. Contin-uous intraarterial pressure was recorded at rest, and

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TABLE I Characteristics of 42 Matched Pairs of Black andWhite Hypertensives (as a result of creating matched pairs viacomputer analysis)

Parameter

WhiteHypertensives

(n Å 42)

BlackHypertensives

(n Å 42)Difference

Black/White

Age (yr) 41 { 9 40 { 9 0.9 { 5Weight (kg) 85 { 17 87 { 17 01.8 { 6Height (m) 1.71 { 0.09 1.72 { 0.02 00.07 { 0.06Body surface

area (m2) 1.97 { 0.02 1.99 { 0.21 00.02 { 0.01Body mass index

(kg/m2) 29 { 5 29 { 5 00.46 { 3Men/women 23/19 23/19 0Systolic pressure

(mm Hg) 149 { 16 150 { 15 0.02 { 10Diastolic pressure

(mm Hg) 95 { 8.5 94 { 9 00.46 { 3

Data expressed as mean { SD.

mean arterial pressure was obtained by electrical in-tegration. Cardiac output in the supine position wasmeasured in triplicate using indocyanine green dye.Heart rate was measured by continuous electrocar-diogram. Renal plasma flow was determined fromthe disappearance of a single injection of 131I-para-aminohippuric acid, using 2-compartment modelsfor calculations.4,6,7 Stroke volume, total peripheralresistance, renal blood flow, renal fraction of cardiacoutput (renal blood flow divided by cardiac output),and renal resistance were calculated by standard for-mulas. Compliance of large arteries was estimatedby calculating pulse pressure divided by strokevolume.8

Echocardiographic studies were conducted by us-ing an ultrasonoscope (Smith-Kline Ecoline 28 andToshiba, respectively) interfaced with a stripchart re-corder and a probe measuring 1.27 cm in diameter.Ultrasonic emission characteristics were as follows:frequency 1,000/s, wavelength 2.25 MHz, and focallength of 10 cm. Immediately after the invasive mea-surements the patient rested for 10 minutes, then 2-dimensional-guided M-mode echocardiograms wererecorded with the patient in half-left-sided positionand appropriate adjustments of the damp, reject, andgain modalities were made to obtain a good defini-tion of the left ventricular (LV) walls and cavities.End-diastolic dimensions were measured at the peakof the R wave of the simultaneously recorded elec-trocardiogram and at the nadir of septal motion, re-spectively.9 End-diastolic LV posterior wall and sep-tal wall thicknesses were measured according to thestandard measurement convention of the AmericanSociety of Echocardiography.10 All echocardiogramswere read by 2 physicians who were blinded to thepatients data, and the average for each parameter wascomputed from 5 consecutive cardiac cycles. Rela-tive wall thickness was determined by dividing pos-terior wall thickness by half the end-diastolic diam-eter.11 LV mass was determined according to theformula of Devereux and Reicheck.12

All statistical analyses were made on an IBM-4381 computer by using SAS programs.13 To ex-clude any influence of underlying cofactors or biasby the investigators matched pairs were formed bycomputer analysis. Matching criteria in order of pri-ority were difference in mean arterial blood pressureõ5 mm Hg, in weight õ15 kg, in age õ10 years,and same sex. All matching criteria had to be met inorder to be included into the study. Linear correlationcoefficients and t tests were used when indicated.Unless otherwise specified, all data are expressed asmean { SD.

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The clinical characteristics of the 42 matchedpairs of black and white hypertensives are depictedin Table I. Since invasive systemic and renal hemo-dynamic measurements were determined at rest,mean arterial BP at rest was chosen as BP matchingcriteria. Mean arterial pressure turned out to benearly identical in white (105.1 { 10.8 mm Hg) andin black patients (105.4 { 10.1 mm Hg). Both hy-

pertensive subgroups were further compared with re-gard to systolic and diastolic BP, heart rate, age, sex,weight, body surface area, and body mass index (Ta-ble I). Table II lists the results for all systemic hemo-dynamics in both study populations. Cardiac output,heart rate, stroke volume, and conversely total pe-ripheral resistance did not differ between black andwhite hypertensive patients. Arterial compliance oflarge arteries as evaluated by stroke volume/pulsepressure was nearly identical in black and white pa-tients. As age, sex, obesity, and mean arterial pres-sure were matched successfully with no significantdifference between blacks and whites, no further ad-justment for confounding factors was necessary. Re-nal plasma flow, renal blood flow, and converselyrenal vascular resistance were compared in the in-vestigated matched pairs (Table II). The percentageof cardiac output distributed to the kidney was 18%in black and white patients. Hence, at any given levelof arterial BP hemodynamic correlates for renal vas-cular changes were similar in white and black hy-pertensives, suggesting equivalent involvement ofthe kidney.

The echocardiographic parameters for bothgroups are shown in Table III. Only half of the pa-tients disclosed evidence for hypertension-associatedLV hypertrophy in both study populations; compar-ison of matched pairs showed no differences in LVmass between black and white hypertensives. Simi-larly relative wall thickness as a parameter of con-centric LV hypertrophy was not significantly differ-ent in both groups. Indexes of systolic function asfiber fractional shortening also were compared be-tween black and white hypertensives. Thus, no racialdifferences were found in the extent of cardiac struc-tural and functional adaptation within the examinedstudy populations.

In a further subanalysis the 42 available pairswere divided into 2 groups according to their meanarterial pressure (split-half technique). Subsequently,the 21 pairs of black and white hypertensives withhigher BP levels (mean arterial BP in blacks 114 {

BRIEF REPORTS 1697

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TABLE II Systemic and Renal Hemodynamics in White Versus Black Hypertensives

WhiteHypertensives

(n Å 42)

BlackHypertensives

(n Å 42)Difference

Black/White

Systemic hemodynamicsMean arterial pressure (mm Hg) 105 { 11 105 { 10 00.3 { 2Cardiac output (L/min) 6.01 { 1.2 5.92 { 1.2 0.1 { 1Stroke volume (ml) 90 { 22 90 { 9 00.2 { 25Heart rate (beats/min) 68 { 9 67 { 11 1.4 { 13Total peripheral resistance

(mm Hg/L/min) 18.3 { 4.5 18.5 { 4.4 0.4 { 13Stroke volume/pulse pressure

(ml/mm Hg) 1.55 { 0.5 1.53 { 0.5 0.4 { 13Renal hemodynamics

Renal plasma flow (ml/min) 640 { 161 630 { 180 10.8 { 248Renal blood flow (ml/min) 1,052 { 287 1,017 { 307 35 { 413Renal vascular resistance

(mm Hg/ml/min) 106 { 29 113 { 40 07 { 41Renal fraction of cardiac output (%) 18 { 4 18 { 5.8 00.04 { 7

Data expressed as mean { SD.

TABLE III Echocardiographic Findings in White Versus Black Hypertensives

Parameter

WhiteHypertensives

(n Å 17)

BlackHypertensives

(n Å 17)

DifferenceBlack/White

(n Å 17)

Septal wall thickness (mm) 10.2 { 1.5 10.2 { 2.4 0.09 { 2.49Posterior wall thickness (mm) 9.8 { 1.4 9.6 { 1.4 0.15 { 1.94Relative wall thickness 0.04 { 0.01 0.04 { 0.01 0.001 { 0.01Diastolic diameter (mm) 48 { 6 49 { 7 01.46 { 8.8LV mass (g) 217 { 70 225 { 71 07.7 { 97.9LV mass index (g/m2) 119 { 41 125 { 40 03.19 { 51.9Ejection fraction (%) 54 { 12 59 { 10 04.5 { 15Fractional fiber shortening (%) 32 { 9 36 { 8 03.3 { 11

Data expressed as mean { SD.

8 mm Hg vs mean arterial BP in whites 114 { 8 mmHg) as well as the 21 pairs with lower BP levels(mean arterial BP in black hypertensives 99 { 12 vsmean arterial BP in white hypertensives 97 { 5 mmHg) were analyzed for possible racial disparities.Within the subanalysis no significant differencescould be found between various indexes of targetorgan damage or organ structural adaptation at high(black vs white hypertensives with high mean arte-rial BP: total peripheral resistance 21 { 4 vs 20 { 7mm Hg/min/L; stroke volume/pulse pressure 1.35 {0.4 vs 1.32 { 0.4 ml/mm Hg; renal vascular resis-tance 128 { 44 vs 117 { 27 mm Hg/ml/min; LVmass index 136 { 48 vs 126 { 27 g/m2) and lowlevels (not shown) of mean arterial pressure in theexamined groups.

j j j

The principal results of this study are that afterforming matched pairs, taking into account age, sex,weight, and level of arterial BP, no racial disparitiesexisted in hypertension-related target organ damagebetween black and white hypertensive patients withfairly mild hypertension. The observations onnonexisting racial differences in cardiac structure arecompatible with data from some studies but not fromothers, including those from the present labora-

tory.14–17 The prevailing controver-sial results may partially be ex-plained by inadequate matching ofblack and white hypertensives (i.e.,differences in levels of BP eleva-tion, duration of hypertension,weight, age, sex, and antihyperten-sive treatment). Although recently ahigher left ventricular mass indexand relative wall thickness as wellas an increased impairment of dia-stolic function was found in blackswhen compared with white hyper-tensives with similar BP levels andknown duration of hypertension, thequestion arises whether black pa-tients may have suffered from a de-layed diagnosis possibly due to dif-ferences in socioeconomic status.14

A lower socioeconomic status inblack subjects has been repeatedlyclaimed to account for the higherprevalence of elevated BP in theblack population and its related car-diovascular and renal complica-tions.15 In our study mainly patientswith mild hypertension were in-cluded, thereby decreasing the pos-sibility of bias by delayed diagnosis,whereas the previously mentionedstudy14 examined untreated hyper-tensive patients with a higher meanarterial BP at study entry, indicatinga more advanced stage of arterialhypertension. Accordingly, some

differences between the study findings may be a re-sult of the different severity of arterial hypertension.Looking for racial disparities in mild hypertensivesoffers the advantage that changing severity in targetorgan damage over time between racial populationsmay help develop therapeutic strategies early in theonset of hypertensive disease. However, we wouldlike to stress that further subanalysis in our patientswith higher BP levels failed to show racial differ-ences in hypertensive disease.

In a recent study on renal hemodynamics, blackand white patients who were matched for BP andage showed similar values for renal plasma andblood flow.18 However, in response to a high dietarysalt intake, black hypertensives responded with a sig-nificantly higher increase in glomerular filtrationrate.18 The authors concluded that glomerular filtra-tion in response to a high salt intake, which is com-mon in westernized countries, may be a mechanismcontributing to the racial disparities in hypertension-related renal disease.

In conclusion, after controlling for the con-founding factors such as age, sex, weight, and arterial pressure that interact with hypertension-relatedtarget organ damage, no racial disparities could be

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detected between matched black and white patientswith mild essential hypertension.

1. Schmieder RE, Messerli FH. Does obesity influence early target damage inhypertensive patients? Circulation 1993;87:1482–1488.2. Castleman B, Smithwick RH. Relation of vascular disease to hypertensivestate: adequacy of renal biopsy as determined from study of 500 patients. NEngl J Med 1948;239:729–732.3. Freis ED. Hemodynamics of hypertension. Physiol Rev 1960;40:27–534. Messerli FH, deCarvalho JGR, Christie B, Frohlich ED. Systemic and re-gional hemodynamics in low, normal and high cardiac output borderline hy-pertension. Circulation 1978;58:441–448.5. Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Cardiovasculareffects of verapamil in patients with essential hypertension. Circulation1987;75:1030–1036.6. Tauxe WN, Maher FT, Taylor WF. Effective renal plasma flow: estimationfrom the theoretical volumes of distribution of intavenously injected 131I or-thioodo hippurate. Mayo Clin Proc 1971;46:524–531.7. Silikas GI, Jack D, Edelman CM Jr, Chervu LR, Blaufox MD, Spitzer A.Simultaneous measurement of glomerular filtration rate and renal plasma flowusing plasma disappearance curves. J Pediatr 1973;83:749–757.8. Ventura HO, Messerli FH, Aristimuno GG et al. Impaired systemic arterialcompliance in borderline hypertension. Am Heart J 1984;108:132–136.9. Friedman MJ, Roeske WR, Sahn DJ, Larson D, Goldberg S. Accuracy of M-mode echocardiographic measurements of the left ventricle. Am J Cardiol1982;49:716–722.10. Sahn DJ, de Maria A, Kisslo J, Weyman A, and The Committee on M-Mode Standardization of the American Society of Echocardiography. Rec-

ommendations regarding quantitation in M-mode echocardiography:results of a survey of echocardiographic measurements. Circulation1978;58:1972–1083.11. Devereux RB, Savage DD, Sachs I, Laragh JH. Relation of hemodynamicload to left ventricular hypertrophy and performance in hypertension. Am JCardiol 1983;51:171–176.12. Devereux RB, Alonso DR, Lutas EM et al. Echocardiographic assessmentof left ventricular hyper trophy: comparison to necropsy findings. Am J Cardiol1986;57:450–458.13. SAS Institute Inc. SAS User’s Guide. Statistics Version. Fifth ed. Cary,North Carolina, SAS Institute Inc, 1985.14. Mayet J, Shahi M, Foale RA, Poulter NR, Sever PS, Thom SA. Racialdifferences in cardiac structure and function in essential hypertension. Br MedJ 1994;308:1011–1014.15. American Heart Association. Cardiovascular disease and stroke in African-Americans and other racial minorities in the United States: a statement for healthprofessionals. Circulation 1991;83:1462–1480.16. Lee DK, Marantz PR, Devereux RB, Kligfield P, Alderman MH. Left ven-tricular hypertrophy in black and white hypertensives. Standard electrographiccriteria overestimate racial differences in prevalence. JAMA 1992;267:3294–3299.17. Dunn FG, Oigman W, Sungaard-Riise K, Messerli FH, Ventura H,Reisen E. Racial differences in cardiac adaptation to essential hypertensiondetermined by echocardiographic indexes. J Am Coll Cardiol 1983;1:1348–1351.18. Parmer RJ, Stone RA, Cervenka JH. Renal hemodynamics in essential hy-pertension. Racial differences in response to changes in dietary sodium. Hy-pertension 1994;24:752–757.19. Hammond IW, Alderman MH, Devereux RB, Luras EM, Laragh JH. Con-trast in cardiac anatomy and function between black and white patients withhypertension. J Natl Med Ass 1984;76:247–255.

Serum Levels of Soluble Form of Fas Molecule inPatients With Congestive Heart Failure

Masaki Okuyama, MD, Seiji Yamaguchi, MD, Naoki Nozaki, MD, Minako Yamaoka, MD,Masanori Shirakabe, MD, and Hitonobu Tomoike, MD

Fas, also called APO-1, is a type I membrane pro-tein of 45 kDa which is expressed in various tis-

sues and cells including the thymus, liver, ovary,lung, and heart.1–3 Fas is a member of tumor necrosisfactor (TNF)/nerve growth factor (NGF) receptorfamily,4 and mediates apoptosis when cross-linkedwith agonistic anti-Fas or anti-APO-1 antibody,5,6 orFas ligand (FasL).7 Fas plays an important role in thenegative selection of autoreactive T cells.8 However,roles of Fas remain obscure in other tissues and inpathophysiologic conditions. Apoptotic cell deathcan occur in cardiomyocytes by hypoxia3 and over-stretching,9 in which Fas was upregulated in cardio-myocytes. Recently, apoptotic myocardial cell deathhas been reported to occur in patients with end-stagecardiomyopathy10 and arrhythmogenic right ventric-ular dysplasia.11 A soluble form of Fas (sFas) lackingthe transmembrane domain was found in sera of hu-man subjects and at least partially blocked apoptosisinduced by the antibody to Fas.12 Circulating levels

From The First Department of Internal Medicine, Yamagata UniversityMedical School, Yamagata, Japan. This study was supported byGrants 05670592, 07670750, 08457200, and 06274202from the Ministry of Education, Science and Culture, Japan and bygrants for Research on Cardiovascular Disease from the Ministry ofHealth and Welfare (5S-3), Japan. Dr. Yamaguchi’s address is: TheFirst Department of Internal Medicine, Yamagata University School ofMedicine, 2-2-2 Iida-Nishi, Yamagata 990-23, Japan. Manuscriptreceived December 23, 1996; revised manuscript received February26, 1997, and accepted February 27.

of sFas increased in patients with autoimmune dis-eases.12 Among numerous studies to be performedfor the purpose of understanding the pathophysio-logic implications of sFas in cardiovascular disease,it seems of primary importance to determine the cir-culating level of sFas and the relation between thesFas level and the severity of the diseases. In thepresent study, we measured the circulating level ofsFas in patients with congestive heart failure. Fur-ther, we also investigated the relation of sFas to sol-uble forms of 2 different TNF receptors of 55 and75 kDa (sTNF-RI and sTNF-RII, respectively)which inhibit biologic activities of TNFa,13–16 i.e.,the trigger of apoptosis.17,18

j j j

The present study included 61 patients with var-ious degrees of congestive heart failure. Thirty-eightwere men and 23 women (age range 24 to 80 years,mean 61). The cause of congestive heart failure wasdilated cardiomyopathy in 26 patients, ischemic car-diomyopathy in 8 patients, valvular heart disease(predominant in regurgitation in aortic and/or mitralvalve disease) in 24 patients, and myocarditis in 3patients (acute phase myocarditis in 2 and chronicphase in 1). Thirty-five were in New York Heart As-sociation (NYHA) functional class II, 18 were inNYHA class III, and 8 were in NYHA class IV. Allpatients had no clinical and laboratory evidence ofneoplasm or autoimmune disease. Patients with ab-