By Robert Zelis, M.D., Dean T. Mason, M.D., and Eugene Braunwald, M.D.

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Partitin f Bld Flw t the Cutaneus and Muscular Beds f the Frearm at Rest and during Leg Exercise in Nrmal Subjects and in Patients with Heart Failure By Rbert Zelis, M.D., Dean T. Masn, M.D., and Eugene Braunwald, M.

1 Partitin f Bld Flw t the Cutaneus and Muscular Beds f the Frearm at Rest and during Leg Exercise in Nrmal Subjects and in Patients with Heart Failure By Rbert Zelis, M.D., Dean T. Masn, M.D., and Eugene Braunwald, M.D. ABSTRACT The purpse f this study was t determine the relative effects f varius levels f exercise n bld flw t skin and muscle f the resting extremity f nrmal subjects and the manner in which this distributin is mdified by cngestive heart failure. Bld flw t the skin and muscle f the frearm was determined plethysmgraphically with the aid f epinephrine intphresis at rest and during supine leg exercise in 12 nrmal subjects and in 9 patients with failure. In nrmal resting subjects, frearm bld flw averaged 6.30 ml/min/100 ml, 52% partitined t muscle and 48% t skin. In the patients, frearm bld flw averaged 2.94 ml/min/100 ml, with 48% t muscle and 52% t skin. In nrmal subjects perfrming mild exercise, frearm muscle flw was nt significantly changed, but during mderate and strenuus activity it was significantly reduced. Cutaneus bld flw, hwever, declined early at all levels f exertin. In the nrmal subjects, cutaneus hyperemia ccurred late during mderate exercise but with strenuus exercise, was delayed until after exercise had been discntinued. In cntrast, in the patients, frearm muscle bld flw decreased strikingly during leg exercise, cutaneus flw fell and remained depressed during the entire perid f exercise, and n pstexercise hyperemia ccurred. Thus, in cngestive heart failure, bth the cutaneus and muscle beds f the frearm are abnrmally cnstricted at rest, there is excessive vascnstrictin in bth beds during leg exercise, and pstexercise cutaneus vasdilatin is ablished. ADDITIONAL KEY WORDS heat dissipatin sympathetic tne It is nw clear that during muscular exercise substantial circulatry changes ccur in nnexercising parts f the bdy. There is cnsiderable disagreement, hwever, cncerning the relative distributin f bld flw t Frm the Cardilgy Branch, Natinal Heart Institute, Bethesda, Maryland The present address f Dr. Zelis and f Dr. Masn is Cardipulmnary Sectin, Department f Medicine, University f Califrnia Schl f Medicine, Davis, Califrnia Dr. Braunwald's present address is Department f Medicine, University f Califrnia San Dieg Schl f Medicine, La Jlla, Califrnia Received December 10, Accepted fr publicatin April 8, epinephrine intphresis vascnstrictin the vascular beds f skin and muscle in the nnexercising limbs. Part f the prblem stems frm the difficulties inherent in measuring bld flw by plethysmgraphic techniques during exercise in subjects wh are nt highly trained (1-4). Until recently, this questin had been apprached principally by measuring heat exchange (5-7) r changes in skin temperature in the hand (8, 9), venus xygen saturatin f the superficial and deep frearm veins (6, 7, 10, 11), and clearance f radiactive sdium frm frearm muscle (6, 7), methds which prvide nly qualitative infrmatin cncerning changes in bld flw. Furthermre, bld flw t the hand is Circulatin Research, Vl. XXIV, June

2 800 ZELIS, MASON, BRAUNWALD dramatically influenced by psychic stimuli, and the hand arteriles are capable f nly passive dilatin (12-14). Therefre, hand bld flw cannt be cnsidered t be representative f skin bld flw in ther areas, such as the frearm, in which bth active and passive dilatin f cutaneus bld vessels can take place (14-17). Despite these limitatins in previus studies, tw facts seemed clearly evident: (1) vascnstrictin mediated by the sympathetic nervus system appears t ccur in the nnexercising limbs (1-9), and (2) there is a need t dissipate the excess heat generated by the increased metablic activity f the exercising muscles (3,4,6,7,18). The purpse f the present study was t characterize the peripheral circulatry respnse f the resting limbs f nrmal subjects t varying levels f exercise and f patients with heart failure t strenuus exercise. The latter grup was studied because, in the presence f cngestive heart failure, the cntrl f the peripheral circulatin is f particular imprtance, since it is respnsible fr the distributin f a limited ttal cardiac utput t critical areas. In particular, we wished t determine whether the heart failure state altered the balance between the need fr heat dissipatin and the need t cnserve and redistribute the limited cardiac utput. T answer these questins, the partitin f bld flw t the skin and muscle in the frearm was studied at rest and during leg exercise in nrmal subjects, and the results were cmpared with thse btained in patients with cngestive heart failure. Methds Twelve nrmal male subjects (ages 19 t 36 years) and 9 patients with cngestive heart failure (ages 28 t 44) were studied. The patients with heart failure (3 wmen, 6 men) all had rheumatic heart disease and were in functinal classes II r III accrding t the New Yrk Heart Assciatin classificatin. Frearm bld flw was measured simultaneusly in bth arms with the subjects supine and in the basal, pstabsrptive state at a rm temperature f 27 C. With the subjects' arms at the level f the sternal angle, frearm bld flw was measured by the venus cclusin technique (19), utilizing a single strand, mercury-in-rubber strain-gauge plethysmgraph, as previusly described (20, 21). Circulatin t the hand was arrested by inflating a cuff arund the wrist fr at least 1 minute befre the determinatin f bld flw. Epinephrine intphresis was perfrmed n ne arm by the technique f Cper et al. (22) as mdified by Cllins and Ludbrk (23). This cnsisted f wrapping the thrughly cleansed arm in a gauze bandage saked with epinephrine hydrchlride 1:2000 (ph 4.5). The gauze was cvered by aluminum fil, which served as the psitive electrde, and was secured by an elastic bandage. The leg served as the negative electrde and was similarly wrapped, except that saline replaced the epinephrine slutin. Essentially cmplete intphresis ccurred with a current f 20 ma applied fr 20 minutes and was assured at the end f the study by nting an average increase in bld flw in the cntrl arm f 81% in respnse t bdy heating and nly an 8% increase in the treated arm. N increase in heart rate r change in bld flw in the cntrl arm ccurred after intphresis. Nrmal subjects perfrmed mild, mderate, and strenuus leg exercise in the supine psitin by pedaling a bicycle ergmeter at lads f 40, 330, and 1080 t 2240 ft-lb/min, increasing heart rate frm 68 t 89, 101, and 128 beats/min, respectively. They were allwed t rest between each level f exertin until frearm bld flw and heart rate returned t cntrl values and were stable. Patients with heart failure were studied at rest and during exercise which they cnsidered t be strenuus but which ranged nly frm 40 t 330 ft-lb/min, depending n the individual's exercise tlerance. Heart rate increased frm 78 t 132 beats/min. Bld flw was measured every 15 secnds fr 2 minutes befre exercise. Three bld flw measurements were made and averaged during each f the 6 minutes f exercise. At the cmpletin f exercise, measurements f bld flw were made at 15-secnd intervals fr 10 minutes. Muscle bld flw was assumed t be the flw measured in the arm in which intphresis had been perfrmed; skin bld flw was calculated as the difference between the bld flw measurement in the cntrl arm (ttal frearm bld flw) and the arm n which epinephrine intphresis had been perfrmed. REST Results At rest, the bld flw in the cntrl frearm in the nrmal subjects averaged (SEM) ml/min/100 ml f frearm, Circulatin Research, Vl. XXIV, June 1969

3 SKIN AND MUSCLE BLOOD FLOW WITH EXERCISE 801 NORMAL Mderate E«. FOREARM BLOOD FLOW ml /min /100 ml TOTAL (C) MUSCLE (El SKIN ic-e) NORMAL Strenuus Ex TOTAL MUSCLE SKIN CHF Strenuus Ex. TOTAL MUSCLE SKIN FIGURE 1 Plethysmgraphic tracings illustrating the respnse f bld flw in a nrmal subject perfrming mderate and strenuus supine leg exercise and a patient in heart failure (CHF) perfrming strenuus exercise. Tracings were taken at rest (A) and during the first (B) and last (C) 3 minutes f exercise and after exercise (D). In each tracing, C represents the bld flw frm the cntrl arm and E the bld flw frm the arm n which epinephrine intphresis had been perfrmed. Skin bld flw was calculated as the difference between these tw measurements (C E). The severity and duratin f exercise are as defined in the text. Ex. = exercise. while muscle bld flw averaged 3.26 ± 0.22 ml/min/100 ml, and skin bld flw averaged 3.04 ± 0.51 ml/min/100 ml. All f these values were significantly lwer in patients with heart failure, averaging 2.94 ±0.53 ml/min/100 ml (P<.01) fr ttal bld flw and 1.40±.09 ml/min/100 ml (P <.01) fr muscle flw and 1.53 ±0.39 (P<0.02) fr skin flw. In nrmal subjects, an average f 52% f the ttal bld flw was distributed t muscle and 48% t skin. In patients with heart failure, these averages were 48% and 52%, respectively, percents which did nt differ significantly frm thse bserved in the nrmal subjects. EXERCISE Nrmal Subjects During the first 3 min- utes f mderate r strenuus exercise, there was a significant reductin in muscle bld flw in nrmal subjects (Figs. 1 and 2). The maximum decrease averaged 0.45 ± 0.19 ml/ min/100 ml (P<.05) and 0.72 ±0.26 (P <.05) ml/min/100 ml frm cntrl values fr the mderate and strenuus levels f exercise, respectively (Figs. 1 and 2). During the last 3 minutes f exercise the muscle bld flw averaged 106%, 88%, and 96% f cntrl values fr mild, mderate, and strenuus exercise, respectively; these values were nt significantly different frm cntrl. During the pstexercise cntrl perid, muscle bld flw was als similar t the preexercise cntrl bservatins. Skin bld flw during the first 3 minutes f Circulaiin Research, Vl. XXIV, June 1969

4 ZELIS, MASON, BRAUNWALD N 0 R M A L * MILD MOD. STR. STR. ISCLE BLC n / 100 ml _j LAJ - t z " -1.0 T 1 W syyv 1 PERCENT CHANGE P > 05 <. 05 <.05 4C.OI FIGURE 2 Decreases in bld flw in frearm muscle during the first 3 minutes f supine leg exercise. Md. = mderate; Str. = strenuus; CHF = cngestive heart failure. FLO a m IKIN V) U. O LU O PERCENT E -0.5 c -1.0 'i -1.5 "i CHANGE NORMAL MILD MOD. STR. \ <05 I CHf STR - I <.05 FIGURE 3 Decreases in bld flw in frearm skin during the first 3 minutes f supine exercise. The severity f exercise was as described in the text. Md. = mderate; Str. = strenuus; CHF = cngestive heart failure. -98 exercise was significantly reduced in nrmal subjects at all three levels f exertin (Figs. 1 and 3). The maximum decrease during the early perid f exercise averaged 1.06 ± 0.39, 0.95 ±0.19, and 2.16 ±0.91 ml/min/100 ml, respectively, fr mild, mderate, and strenuus exercise. Althugh during the last 3 minutes f mild exercise, nrmal subjects tended Circulatin Research, Vl. XXIV, June 1969

5 SKIN AND MUSCLE BLOOD FLOW WITH EXERCISE 803 N 0 R M A L CHF O c z + I.D ~^ +1 -U n ^ +0.5 Ll_ = e 0 UJ ^ z j i. MILD rfl MOD. STR. PERCENT CHANGE P <.05 -II FIGURE 4 Decreases in bld flw in frearm skin during the last 3 minutes f supine leg exercise. The severity f exercise was as described in the text. Md. = mderate; Str. = strenuus; CHF = cngestive heart failure. I Li_ 5 m S ^ 3 c "Z. E U- s O Cj C UJ ^ ri PERCENT CHANGE P 1 N 0 1? M MILD T <.0l :.0l MOD. j + 96 /. S7 r /? <.05 CHF 1 Sfff. T + 4 >.5 FIGURE 5 Maximum increase in bld flw in frearm skin during the 10 minutes fllwing supine leg exercise. The severity f exercise was as described in the text. Md. == mderate, Str. = strenuus, CHF = cngestive heart failure. t shw an increase in skin bld flw abve cntrl resting values, this change was nt statistically significant, and it was nly with mderate exercise that there was a significant cutaneus hyperemia (+0.89 ± 0.31 ml/min/ 100 ml) (P <.05) (Figs. 1 and 4). After exercise had been discntinued, skin bld flw cnsistently increased. The maximum increase Circulatin Research, Vl. XXIV, June 1969

804 ZELIS, MASON, BRAUNWALD abve cntrl values at this time was +1.76 ±0.45, +1.96 + 0.34, and +3.15 ±1.

6 804 ZELIS, MASON, BRAUNWALD abve cntrl values at this time was ±0.45, , and ±1.46 ml/ min/100 ml fr the mild, mderate, and strenuus levels f exercise, respectively (Figs, land 5). Patients with. Heart Failure. Like nrmal subjects, patients with heart failure demnstrated a significant reductin f muscle bld flw during the first 3 minutes f leg exercise (-0.76±0.21 ml/min/100 ml) (P<0.01) (Figs. 1 and 2). Bld flw fell t an average f 64% f the preexercise cntrl level during the last 3 minutes f leg exercise and 71% f the preexercise cntrl level during the pstexercise perid f bservatin. Patients with heart failure, like nrmal subjects, exhibited a significant reductin in skin bld flw during the first 3 minutes f leg exercise, this reductin averaging 1.50 ±0.39 ml/min/100 ml (P<0.01) (Figs. 1 and 3). Hwever, unlike the nrmal subjects, in whm cutaneus bld flw rse r was unchanged during the last 3 minutes f exercise, the maximum skin bld flw in the patients with heart failure remained significantly belw the preexercise cntrl values ( 0.79 ±0.25 ml/min/100 ml (P<0.02)) at this time (Figs. 1 and 4). Als, unlike the findings in nrmal subjects, in whm cutaneus vasdilatin ccurred immediately fllwing exercise, the maximum bserved bld flw during the pstexercise cntrl perid did nt differ significantly frm the preexercise cntrl value (Figs. 1 and 5). Discussin The apprximately equal partitin f bld flw t the vascular beds f skin and muscle in nrmal subjects is in agreement with the wrk f Cper et al. (22), Edhlm et al. (24), and Knts et al. (25), wh used a similar technique f intphresis. Bld flw t bth skin and muscle was depressed in patients with heart failure, althugh the distributin between skin and muscle flw did nt differ significantly frm that in nrmal subjects. Cper and assciates have stated (22), and we agree, that skin bld flw is highly variable even amng nrmal individuals. Muscle bld flw at rest is a mre stable measurement and better suited fr cmparisn between individuals. The present investigatin is the first demnstratin that bld flw t resting muscle is reduced in cngestive heart failure. We have nt defined the relative rles played by augmented sympathetic tne and the increased stiffness f the resistance vessels, which has recently been described in patients with heart failure (21), in prducing this decreased muscle bld flw at rest. It is als pssible that the bserved differences in resting frearm muscle bld flw culd be partially accunted fr by the differences in sex and physical activities f the tw grups. In the nrmal subjects during the first 3 minutes f exercise, resting muscle bld flw decreased. It appears that as the stress f exercise increased, the reductin f muscle bld flw became mre marked. This finding is cnsistent with the reprt f Blair et al. (3), wh fund that the increase in ttal frearm vascular resistance paralleled the increase in the severity f exercise. By the technique f selective cutaneus and deep nerve blckade they attributed this respnse slely t increased muscle vascnstrictin. Hwever, the findings f ur study suggest that bth the skin and muscle vessels exhibit augmented vascular tne early during exercise. Blair et al. (3), Bishp et al. (6), and Muth et al. (7) have reprted an unchanged bld flw in the resting muscles during exercise, but Muth et al. suggested that muscle bld flw might decrease with mre stressful exercise. The findings f the present investigatin are in accrd with this suggestin. A majr finding in ur study was that during the latter half f the exercise perid, the level f skin bld flw depended n the severity f the exercise. The ability t dissipate heat by increasing skin bld flw became apparent nly when nrmal subjects perfrmed mderate exercise. Presumably, nt as much heat required dissipatin during mild exercise. Mre imprtant, it appears that with severe exercise, cutaneus vasdilatin and heat dissipatin were delayed in nrmal subjects until after the 6-minute perid f exercise had ended. This is cnsistent with the Circulatin Research, Vl. XXIV, June 1969

SKIN AND MUSCLE BLOOD FLOW WITH EXERCISE 805 premise that with increasing severity f exertin, greater sympathetic vascnstrictin f the cutaneus bed ccurred.

7 SKIN AND MUSCLE BLOOD FLOW WITH EXERCISE 805 premise that with increasing severity f exertin, greater sympathetic vascnstrictin f the cutaneus bed ccurred. Late during the curse f exercise skin bld flw reflected a summatin f the ppsing effects f the need t dissipate heat and f generalized vascnstrictin. In any ne individual the directin f change depends n which f these ppsing influences predminates. The relatinship between these tw determinants f skin bld flw has nt been fully appreciated in the past and serves t explain the variatin in the respnse f the xygen saturatin f the brachial vein which has been bserved late during exercise (6). In patients with cngestive heart failure there were significant reductins f bld flw in bth muscle and skin in the resting frearm during the first 3 minutes f leg exercise. The degree t which frearm bld flw was reduced was prprtinately greater than that seen in nrmal subjects at levels f exercise which, thugh strenuus fr the patients with heart failure, were mild r mderate when perfrmed by nrmal subjects. The reductin f muscle bld flw during exercise we bserved is cnsistent with the finding f Muth et al. (7), wh shwed that patients with heart failure have a decreased clearance f radiactive sdium in frearm muscle during exercise. It wuld appear that, as in the nrmal subjects, the severity f exercise is the mst imprtant determinant f this vascnstrictive respnse, which presumably is mediated by the sympathetic nervus system. In cntrast t the finding in nrmal subjects, bld cntinued t be shunted frm the cutaneus bed in patients with heart failure, despite the need t dissipate heat during the final 3 minutes f exercise. Furthermre, the stimulus fr cutaneus vascnstrictin was nt cmpletely eliminated in the patients with heart failure even after exercise had ceased, since they did nt have pstexercise cutaneus hyperemia. These results help t explain the bservatin f Dnald et al. (10) that axillary venus O2 cntent remained depressed in patients with symptmatic heart disease thrughut the entire curse f exercise. Circulatin Reiearch, Vl. XXIV, June 1969 Althugh we did nt measure heat dissipatin frm the frehead, scalp, and hands, the studies f Dnald et al. suggest that the cutaneus vascnstrictin we bserved in the frearm was representative f the entire limb. Thus, patients with heart failure d nt appear t generate as much heat as d nrmal subjects, since they cannt wrk as strenuusly and their very intense sympathetic vascnstrictin prevents them frm dissipating this heat frm the frearm cutaneus bed in a nrmal manner. The finding that in patients with heart failure the cutaneus bld vessels d nt dilate nrmally during and after exercise may als explain the heat intlerance ften seen in these subjects. Acknwledgments The authrs gratefully acknwledge the technical assistance f Mrs. Mimi Winterhalter and the nursing assistance f Miss Isabelle Ambrse. References 1. GRANT, R. T.: Observatins n the bld circulatin in vluntary muscle in man. Clin. Sci. 3: 157, HARPUDER, K., LOWENTHAL, M., AND BLATT, S.: Peripheral and visceral vascular effects f exercise in erect psitin. J. Appl. Physil. 11: 185, BLAIR, D. A., GLOVER, W. E., AND RODDIE, I. C.: Vasmtr respnses in the human arm during leg exercise. Circulatin Res. 9: 264, BEVECARD, B. S., AND SHEPHERD, J. T.: Reactin in man f resistance and capacity vessels in frearm and hand t leg exercise. J. Appl. Physil. 21: 123, STEWART, G. N.: Studies n circulatin in man: 1. Measurement f bld flw in hands. Heart 3: 33, BISHOP, J. M., DONALD, K. W., TAYLOR, S. H., AND WORMALD, P. N.: Bld flw in the human arm during supine leg exercise. J. Physil. (Lndn) 137: 294, MUTH, H. A. V., WORMALD, P. N., BISHOP, J. M., AND DONALD, K. W.: Further studies f bld flw in the resting arm during supine leg exercise. Clin. Sci. 17: 603, CHRISTENSEN, E. H., NIELSON, M., AND HANNISDAHL, B.: Investigatins f circulatin in skin at beginning f muscular wrk. Acta Physil. Scand. 4: 162, BARGER, A. C, GREENWOOD, W. F., DIPALMA, J. R., STOKES, J., AND SMITH, L. H.: Venus pressure and cutaneus reactive hyperemia in

8 806 ZELIS, MASON, BRAUNWALD exhausting exercise and certain ther circulatry stresses. J. Appl. Physil. 2: 81, DONALD, K. W., BISHOP, J. M., AND WADE, O. L.: Changes in the xygen cntent f axillary venus bld during leg exercise in patients with rheumatic heart disease. Clin. Sci. 14: 531, MITCHELL, J. H., SPROULE, B. J., AND CHAPMAN, C. B.: Factrs influencing respiratin during heavy exercise. J. Clin. Invest. 37: 1693, GASKELL, P.: Are there vasdilatr nerves t vessels f the hands? J. Physil. (Lndn) 131: 647, ALLWOOD, M. J., BARCROFT, H., HAYES, J. P. L. A., AND HIRSJARVI, E. A.: Effect f mental arithmetic n bld flw thrugh nrmal, sympathectmized, and hyperhydrtic hand. J. Physil. (Lndn) 148: 108, RODDIE, I. C, SHEPHERD, J. T., AND WHELAN, R. F.: Cntributin f cnstrictr and dilatr nerves t skin vasdilatin during bdy heating. J. Physil. (Lndn) 136: 489, EDHOLM, O. G., FOX, R. H., AND MACPHERSON, R. K.: Vasmtr cntrl f cutaneus bld vessels in human frearm. J. Physil. (Lndn) 139: 455, BLAIR, D. A., GLOVER, W. E., AND RODDIE, I. C.: Cutaneus vasmtr nerves in upper arm calf and thigh. J. Physil. (Lndn) 153: 232, Fx, R. H., AND HILTON, S. M.: Bradykinin frmatin in human skin as a factr in heat vasdilatatin. J. Physil. (Lndn) 142: 219, DONALD, K. W., WORMALD, P. M., TAYLOR, S. H., BISHOP, J. M.: Changes in the xygen cntent f the femral venus bld and leg bld flw during leg exercise in relatin t cardiac utput respnse. Clin. Sci. 16: 567, HEWLETT, A. W., AND VAN ZWALUWENBURC, J. G.: Rate f bld flw in the arm. Heart 1: 87, MASON, D. T., AND BRAUNWALD, E.: Studies n digitalis: X. Effects f uabain n frearm vascular resistance and venus tne in nrmal subjects and patients in heart failure. J. Clin. Invest. 43: 532, ZELIS, R., MASON, D. T., AND BRAUNWALD, E.: A cmparisn f the effects f vasdilatr stimuli n peripheral resistance vessels in nrmal subjects and in patients with cngestive heart failure. J. Clin. Invest. 47: 960, COOPER, K. E., EDHOLM, O. G., AND MOTTRAM, R. F.: Bld flw in skin and muscle f the human frearm. J. Physil. (Lndn) 128: 258, COLLINS, G. M., AND LUDBROOK, J.: Behavir f vascular beds in the human upper limb at lw perfusin pressure. Circulatin Res. 21: 319, EDHOLM, O. C, FOX, R. H., AND MACPHERSON, R. K.: Effect f bdy heating n the circulatin in skin and muscle. J. Physil. (Lndn) 134: 612, KONTOS, H. A., RICHARDSON, D. W., AND PATTERSON, J. L., JR.: Bld flw and metablism f frearm muscle in man at rest and during sustained cntractin. Am. J. Physil. 211: 869, Circulatin Research, Vl. XXIV, June 1969

M.R.C.Path. causes to the raised plasma urea in patients admitted

M.R.C.Path. causes to the raised plasma urea in patients admitted Pstgradcuate Medical Jurnal (January 1979) 55, 1-14 The cause f the raised plasma urea f acute heart failure R D THOMAS MRCP D B MORGAN MRCPath ALISON NWILL AIMLS Departments f Cardilgy and Chemical Pathlgy,