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Studies on Digitalis VI. Reduction of the Oxygen Debt after Exercise with Digoxin in Cardiac Patients without Heart Failure By RICHARD KAHLER, M.D., RONALD H. THOMPSON, PH.D., ELSWORTH R. BUSKIRK, PH.D., ROBERT L. FRYE, M.D., AND EUGENE BRAUNWALD, M.D. L. Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 T IS undisputed that the administration of digitalis to patients with many forms of congestive heart failure results in an improvement in both the clinical state and in the abnormal circulatory dynamics that are characteristic of heart failure.'-6 The effects of digitalis in subjects without heart failure are less well defined. Although some glycosides augment the contractile force of non- oxygen debt during exertion. The development of an oxygen debt is characteristic of congestive failure.'8' 19 It was therefore thought that accurate measurement of the oxygen debt after exercise might provide an appropriate means of evaluating the effects of cardiac glycosides on the adequacy of cir- culatory function. Description of Patients failing hearts of patients with heart disease,7 and increase the rate of intraventricular pressure development in intact normal subjects,8 these drugs have not been shown to elevate the cardiac output at rest and during exercise in normal subjects or in patients with heart disease without failure.9-15 When administered acutely to patients with "latent" heart failure, an improvement of circulatory dynamics occurs in some individuals, but not in all.16 In view of the conflicting interpretations of these observations, the role of digitalis in the treatment of patients with heart disease but without heart failure is not clear. Accordingly, the present investigation was designed to assess the effects of digitalis on the response of the cardiovascular system to the stress of muscular exercise in patients with heart disease and cardiac enlargement without clinical evidence of congestive heart failure. One of the fundamental functions of the cardiovascular system is delivery of oxygen for metabolism in tissues at rest and during activity. The inability of the cardiovascular system to perform this function adequately results in the accumulation of excess lactate,17 and the development of an abnormally high The three patients chosen as the subjects for this study all had inactive rheumatic valvular disease, cardiomegaly, and a history of cardiac decompensation some months or years previously, but had none of the clinical signs of congestive heart failure at the time of study. These three patients were selected because they were capable of performing light physical activities without cardiac symptoms in the absence of digitalis therapy. They did not complain of orthopnea or paroxysmal nocturnal dyspnea. Detailed and repeated physical -examinations during the course of the investigation failed to disclose rales at the lung bases at rest or during exercise; the patients were free from edema, had normal levels of systemic venous pressure, and did not have clinical evidence of hepatic enlargement. C.A. (no. 02-57-64) is a 54-year-old man with rheumatic mitral regurgitation and stenosis. Easy fatigability, exertional dyspnea, and peripheral edema had developed 5 years prior to study and he had been maintained on digitalis, a diuretic regimen, and a low-sodium diet for several years. Physical examination indicated the presence of rheumatic mitral regurgitation and stenosis. The electrocardiogram showed atrial fibrillation, left axis deviation, and left bundle-branch block. Chest x-ray and fluoroscopy revealed enlargement of the left atrium and left ventricle. The patient was maintained on a diet containing 1 Gm. of sodium daily and he received 1 Gm. of chlorothiazide daily throughout the study. He was studied on 10 occasions on nine separate days during three periods (fig. 1). During the first period he was maintained on a daily dose of 0.25 mg. of digoxin. The glycoside was replaced by a placebo during the second period. He was then redigitalized with 4.75 mg. From the Cardiology Branch, National Heart Institute and the Metabolic Diseases Branch, National Institute of Arthritis and Metabolic Diseases, Bethes- da, Maryland. Circulation, Volume XXVII, March 1963 397 : 3-8INIA I I IRL ErI Al., ,8e'}S 70 BODY WEIGHT kg. 68 66 VENOUS PRESSURE 150 mmH20 50 DIGOXIN mg 1.0 5 Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 0 1000 SODIUM I NTAKE 500 mg 25 30 April /960 10 5 May /960 15 Figure 1 patient C.A. daring the period of studi. The of pressure Body weight and venous vertical arrows indicate the days on wvhich the exercise studies ivere, carried o't. Thie patient had been main tained on digoxini (0.25 tMg. doilu) for-' 3 Jircrs prior to /he first study period. of digoxin given over a 6-day period anid durling, the third period of the study lie wais maintained on 0.50 mg. of digoxin dailvy P.F (no. 02-28-79) is a 38-vear-old iiian iin whom a heart mnurmutr was detected in 1949 anld who developed exertional dvspnea and paroxysmalc:11 nocturnal dyspuean in 1957. On phvsical examiniation lie was eonsidered to liave rheumatic mnitral reonroitation. He had slight cardiae enlarfgemennt with left ventricular predominaiaee on roentgenogr11a,phic examiniation. The electrocardiog-raiii showed niormnal siinus rhy\-thm and left e-01-trieular hypertrophy and strain. However. eoi nbmi ned riglht and left heart eatheterizations in Fehruarv- 1959 dlemon-4rated that intracafrdie priezssirVs and the cardiac index were within. nornial liniits. -le was imaitained on a diet containing SOO 0iig. of sodiu tl a ad he receiv ed 50 lug, of hvdrochlorothiazide dailv throughout the study during which the oxyg en debt was mneasured. Two determinations of oxygen (lebt wer-e mnade wlhile lhe received 0.50 rtwig. of digoxin. and three studies were carried out after this drug had been diseontinued ancd a placebo haIdl l)eel mhbstituted. TIn addition. to- his. usal activities the patient walked 3 mtiles (tcailv without symptoms throughouLt the period of study. S.AT. (o. 03-54- 72). a 19-yeat o-ld girl kniowinl to have rheumnatic heart disease sinee 1949, developed signs and sym3ptoins of congestive heart failure for the first time during a recurrencee of acute rheumiatic fever in 1957. Shle was maintained on digitalis and a low--sodiumit diet and had no sy wptoiis except for occatsional pAplitations durin, strenuous exertionm. Onl exa inimati on she was coii sidered to hasve the itlir'lIiiurs of miiitral regurgitatiion anid stenosis aili aortic regrirgitation. The ejlec.ton idoi<gran3li showed siiiuiUe rli.vthni anid firstdegree atrioventrivular block, left atrial enlargement, auth left ventricular lbypertrophy. She received a diet conftaifnin-g 500 nig. of sodiunii dailv througlhout the study. The postexercise ox> geii debt was deteruiiined oni fidye occtasions, wbile she received nno medictation. Sh-ie was then digitalized with 2..50 nig. of dig,oxini du-lilgll a 4S-hiour period, received 0.50 wig. oni the third day and 0.25 iig. as daily mtnaintenance thereafter. Eight studies were carried out while she was receiving this dose (fig. (irc ulation, bsolni5XXII, MarchJ 399 STUDIES ON DIGITALIS 44 BODY WEIGHT 42 kg. 40 Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 Venous 150 Pressure mm H20 50 1.25 1.00 DIGOXIN .75 .50 mg. .25 SODIUM INTAKE 400 26 November 196/ 21 44 1 6 II December /96/ Figure 2 Body weight of patient S.M. during the period of study. The vertical arrows indicate the specific days on which the exercise studies were carried out. On several of these datys more than one oxygen debt after exercise was measured (table 1). The exercise studies were carried out on a motordriven treadmill at speeds of 2.1 to 2.5 miles per hour and at grades of 0 to 7.5 per cent. All patients had undergone extensive training on the treadmill several times weekly for 4 to 6 weeks prior to the study. Thus, they were thoroughly familiar with the procedure so that alterations in their performnance during the period of investigation could not be attributed to further training during the study. The specific conditions under which each patient was studied are presented in detail in table 1. The exercise was carried out in a Mfetabolic Chamber, which is an air-conditioned Circulation, Volume XXVII, March 1963 room maintained at constant temperature and humidity. The open-circuit method of indirect calorimetry was employed for measurement of oxygen consumption ( °2 ) . The technic and instrumentation employed have been described in detail elsewhere (fig. 3).20 Briefly, the subject's head is enclosed by a light vinyl plastic hood suspended from the ceiling. A relatively large volume of fresh air enters the hood through an imperfect seal about the shoulders. Air is continuously drawn from the hood through appropriate tubing at a constant rate approximating 10 times the subject's respiratory minute volume during 4KAIHIlER ET AL, 400 Table 1 ,Summnary of Oxygen Debts after E.rercise Pre-exercise Exercise conditions Pt. B.S.A. M.- Digoxin C.A. 1.88 + I_ Date M.P.H. 4/26/60 4/ 29 5/5 2.1 5/6 5 1fl0 5/17 5,119 -f (.8. #1I 5f6'/60 1.96 5)/]Q, Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 p F.X-x 2-3 - 2.327 ** + 21 :1 12/ 12 7 11/28 496 433 768 733 14 10 190 10' 210 10' 184 4105 7'40" 7,8" 245 222) 4386 3305 1,009 661 20 10' 2940 1.1 40 3882 3055 427 10' 1' .336 11 340 13,010 16,338 1,301 2,124 10 10' 10, 3329 17,185 2,406 7"35,' '10" 41"f 400 330 11,481 13,672 1,837 2.461 14 16 195 1941 893 2.5 2.5 41" 1 62 2090 836 4'41" " 4'41 4'4t1 " 4 41 170 .3 2102 2026 1791 883 851 210 0 2.1 0 2.1. 2.1 2,1 2. 0 At.- _. 0 2.1 2.},1 0 10 i .3 7.5D%<c I .0 2.5 I .0 .1 .5 2.5 i..) 168 188 27 20 ils 413 15 594 698 17 17 11 1) 1s 46 40 42 788 42 44 35 + 12/5 2.5 2.5 1 5* 'L95 . 2. 15I 1 5' 173 + 12/ 7 2065 3830 3743 4800 5717 3554 4818 195 4466 402 9 1804 1817 433 418 260 25 2 24 23 + 12o/8 11/21 2.5 3 4'4 1 " 10' 190 -. 3 102 180 15' 15' 160 2.5 -D _ 11/22 C.8. #2 1.40 182 176 258 21 2 2'35 0 . 11/21 -4- lo, 10' 0' 1' excess V02 %0 10' -, 2.1. 11/22/61. 1.34 ml./min. 10' 0 2. 25 S.M. excess Vo2 Dur. Min. /Sec. 02 debt Total 02 debt ml. 3543 4330 2844 3665 3590 2753 3494 2.1 2/1161 2/8 Grade Total excess V02 ml. 12/1191 61 12/19 12/19 12/19 ) .0 .t 2.5 2,5 2.5: 5 i5 2.5) 4'41 4'41 195 " " 15 2.) 200 221 202 185 3250 3600 766 20 14 624 13 686 462 530 12 13 11 8 I *Body weight was 112.64 Kg. on 2/1, 110.27 Kg. on 2/8, anld 109.27 Kg. on 2/10. C.S. #1 weighed 71.4 Kg., C(.S. #2 weighed 45.4 Kg. Pt., patient; B.S.A., bod(y surface area in MV.2; C.S., control stubject; +, study doae while patient was receiving digoxin; -, no digoxin; V 02, oxygen Consumption; patienit earried external weiglht totaling 14.7,2 Kg. dulring the study designatecd with * * The total flow rate of air is continuously monitored and aliquots of the stream are directed to a modified Beckman F3 paramagnetic oxygen analyzer, located outside the chamber. The analyzer functions with an operational sensitivity of about ±0.02 per cent oxygen on thje seale range used. It is calibrated and standardized with gases of knoxwn oxygen concentrations. The output of the gas analyzer was recorded on a Leeds-Northtup recorder at intervals of 3 seconds. The response of the svstena to a known square wave change exercise. of gas concentration in the hood was determined and utilized in the calculation of the oxygen (lebt following exercise (fig. 4). The total excess .'02 resulting fronit exercise was calculated as the of the excess oxy,gen above control levels con- sum sumed during the actual exercise period and the oxygen debt (fig. 4). All subjects were studied in the postabsorptive state and were weighed every morning after voiding. A minimum period of 20 minutes with the patient sitting on a chair placed on the treadmill Circulation, Volime XXVII, .Mlarch 1960 401 STUDIES ON DIGITALIS CHAMBER GAS VOLUME METER l GAS ANALYZERSj REC.A RIAMLI CORRECTION CALIBRATION 4TS\CEL __ _ \DATA HANDLI NG Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 |SYSTEM __ PAPER TAPE COMPUTOR Figure 3 Block diagram of instrumentation in Metaboli c Chamber. in the Metabolic Chamber was allowed for stabilization prior to the measurement of Vo2 before exercise, which was also made with the patient in the sitting position. When a stable V before exercise was achieved, the subject was asked to stand and start walking. The transition from sitting to walking or vice versa took 15 seconds or less. Immediately following the exercise the patient returned to the sitting position and the oxygen debt was recorded. An investigator wearing a separate hood continuously observed the subject in the Metabolic Chamber during the exercise periods. Two subjects, each with a normal cardiovascular system and of body builds and weights comparable to two of the patients, were exercised under identical conditions to those employed for the patients. The resultant oxygen debts of control subject no. 1 were compared with those of patient C.A., while the debts of subject no. 2 were pared with those of patient S.M. Results 02 com- The dietary sodium intake, body weight, admninistradebt measurements were carried out in patients C.A. and S.M. are illustrated in figures 1 and 2. Patient P.F. 's body weight on the days of study is shown in table 1. No notable changes occurred in the patients' subjective condivenous pressure, periods of drug tion, and days on which oxygein Circulation, Volume XXVII, March 1963 tions, body weights, or venous pressures when digoxin was discontinued or restarted. During the first period of study, while patient C.A. was receiving digoxin, the oxygen debts following two 10-minute walks were 496 ml. and 433 ml., respectively. During these two studies the oxygen debts averaged 12 per cent of the total excess Vo2 resulting from exercise. During the second period, while receiving the placebo, the resting vTo tended to be higher than during the prior period when on digoxin. The oxygen debts rose to 768 ml., 733 ml., and 718 ml., representing, on the average, 22.3 per cent of the total excess Vo2 resulting from exercise. When digoxin was reinstituted, resting VO2 fell and the oxygen debts fell to 413 ml., 594 ml., and 698 ml., with the oxygen debts averaging 16.3 per cent of the total excess Vo2 resulting from exercise. In addition, the oxygen debt following a shorter (7 min. 40 see.) walk equaled 1,009 ml. when the patient was not receiving digoxin, and declined to 661 ml. after the glycoside was reinstituted. Control subject no. 1 developed oxygen debts of 427 and 336 ml. respectively during two 10-minute walks and 40()C- IK\ LFE2V E rl' A' L. 402A 1000 F- 0 Potient C.A r D'goor'n * No Digoxin 900 A Control su bjecI!/1 800 700 F- 0 STOP EXERCISE START EXERCISE 600 1- Figure 4 (} ni / ?'fan Jse t7Hlly ( 'Itn;fr 1 f11 ll//l I) n to1(111 Vo in )(patient S.M. Du ri nl till pre U ei period, 102 eqiltl.l('(l .19,- mil.z Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 . Th(, ofz.set (n114 the 1. nitexe C1r(-is( afre in(ldaated b)lii - U eli -al (ifll, iii s/ i pp/I tf'tall/I ?lU iH 1 ' /c Sod11 1hle (f'coi'S, oJ1U/eli, (e1aborc l bifl.i, Coni.i 1(t4l PM (-710R'11i Of] tlii0?':llit f(.1 l( 'i.e 1)wo'to)1d. 7?i e ilst ifn1,(e }ltif lZy Hs rej i)'siblc m't, th P 'r ttee n io 1, ?t I f (. pO1ti(i / 0) 111/ h Ii i f U r ( is tI (ofl.stilfoll Th 02 DEBT 500 Fml. n (i/Ud HJIreIl Is Me f/ 1. I 400 F- AL 300- Tb1 t(iib'ff .:, .~ In. { , Isf .S1110/// t J tJ J Unf i( }X,.*XtiH s 15; H Sell t(f4 b1) 1/ic.;i' ,,of the 541j)JlWe 1 / 111/ ((1 ,1/(01, 2 200 2.J 0 7f Ilis oxyg1en del)ts av-eraged 101 A) er Hiolit if tlle total excess Vo, resulting fr1m1 (xereise Jtable 1, fig. 5K Patient P.F. was exereised oni a sigo-le oc(casion for 10 minutes while reeeiving digoxini ani-d developed ali oxygell debt of 1301 itil. this value represented 10 per lient of the total eXCess Vo2 resulting fromii exercise. After discontinuation of this nmedication, thie oxygo_en debt for the sauie exercise rose to 2,124 ani(d 9,406 mnl. o11 two oeeTasions, wx itli tlhe debts averagino, 13.5 per eent of tlhe total excessxx o, ressulting from exereise. lIn additionl. the oxYg-Yen debt following a shorter period of exercise (7 min. 35 sec.i" equaled 1.837 ml. during digoxin adminiistration and rose to 2,461 ml. after the glycoside was discontiniued (table 1, fig. 6). Patienit S.A1 was exereised for 15 minmtes on two oceasions while not receivino dioyoxini and developed oxygen debts of 624 ml. aid( 686 mul. respectively , with these debts represeimting. on] thle average, 12.5 per cent o-f til total excess V02 resulting froml exercise. During digoxin administration the restinog st02 values were comparable to those obtained 100 r II 2. / mph 0 %grode 1O minss CONDI 77ONS OF EXERCISE 0 Figure 5 Oxigei debts iOl pati( at C(1 flien onf or off diqyoxin, an-?d in control subjectfn. 1, ztchose fweight 012(, bod1! build resemlble(d thaoc of patielit C.A. The co0fltiitlOlfS eh 0 xerc e i( i. riod0 re ai-IdiNated Hep at tile bo0tftonl (f tlef f/ure. lurillng thle preiolls period, auiel tIfie oxygen debts after exercise deelilled to) 4-62 il., 5830 11m., and 402 mul. During these tlhree studies the oxygen debts averaged 11.0 per cent of the total excess Vo,2 resulting front:l exereise. The normal subject developed debts of 260 mnl. and 252 nil. with tile oxvyen debts averaging i-a per cellt of the total eXcess Vo2 resIlting fromn. exercise. Tit addition, patient S.M. was exercised botlh witIl and witloUit digoxin allmillistration under three oth-er conditions (table 1. . Under eaeTi condition the oxyrgen debts after exercise were alwax s lower duringc dgio-xin adinimstration (tab-le L fi. 7)1 Discussion The oxygen debt measured following the Circltatfion, VolwOie XVI XX Mardb 196f 403 STUDIES ON DIGITALTIS 1000 r Potient P X 2400 O O Digoxin * No Digoxin 2800 PotienI S M. 900 H 0 8001- subject 02 0 0 S 0 2000 0 700 e 0 02 0 DEBT 1600 600 K ml 0 0 02 1200 K DEBT 500 Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 1 t 2.5 mph 7.5 %grode /O m ins 2.5 7.5 7 *400 H CON1DITIONS OF EXERCISE 0 0 400[K 300 K f I ~t 0 Figure 6 Oxygen debts in p,atient P.F. when on or off digoxin. The conditions of each exercise period are indicated at the bottom of the figure. completion of exercise represents the summation of instantaneous oxygen deficits accumulated during the entire exercise period. Measurement of this variable is a sensitive technic for assessing the adequacy of the circulatory system, especially when au individual can be employed as his own control. If the delivery of oxygen is only slightly impaired by an inability of the cardiac output to rise adequately during exercise, the circulatory deficit may be difficult or impossible to detect by the measurement of cardiac output alone, but a measurable oxygen debt may accumulate. For example, an increase from 300 to 600 ml. of the oxygen debt incurred during two 10-minute periods of identical exercise represents a rise of 100 per cent and nmay easily be detected by the methods employed in this study. If it is assumed that the cardiac output is constant during the entire exercise period, the higher oxygen debt would be associated with an oxygen delivery which is only 30 ml. per minute lower during the study in which the oxygen debt was greater. If an arterio-mixed Circulation, Volume XXVII, March 1963 0 - ml. 800 H Digoxin A Control 0 0 0 Digoxin * No 0 200K 2.55 5 100 r 4I'I It 2.5 5 '41" 2.5 3 /0' 2.5 mph 2.5 %grode JS' CONDITIONS OF EXERCISE 0' Figure 7 Oxygen debts in patient S.M. when on or off digoxin. Four levels of exercise were employed and these are indicated at the bottom of the figure. The triangles present data obtained from control subject no. 2 whose weight and body build reseemb led those of patient C. A. venous oxygen difference during exercise of 12 vol. per cent is assumed, the difference in cardiac outputs during the two periods would be only 250 ml. per minute, a value that is impossible or extremely difficult to measure reliably by the best technics available to the clinical investigator. It was with these considerations in mind that the measurement of the oxygen debt after exercise rather than the more usual approach of measuring cardiac output at rest and during exertion was selected for studying the effects of digitalis. In 1931, Harrison, Calhoun, and Turley2' studied the effects of digitalis in a group of K AIILER EP l Al. 404 c!ardiae patients with exertiomal dyspnea, some of whoml also had paroxysmal niocturnal dyspnea. These investigators observed that concomitant with the patients symllptomlatic im.provement, the ratio of venitilationi to vital durinig exercapacity ve(itilatiomi inldex tiont dimriniished. Nylin2 not-ed that the Vo2 itueasured several m:inlutes after exer(eise dedlinied followinrg patienit digitalization in a singole ithli heart disease and exertional dysplnea. Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 Although the patients utilized in the prescut studies had previously experienlced congestive heart failure aiid although some dimiinutioin int cardiac reserve persisted, they wvere. compensated in the abseiice of digitalis therapy and wvere able to performi their norntial everyday activities xvithout sym-ptomns. Indeed, patient P.F. walked 11/½ miles twice dlailv without diseomnfort while the studies were beinog clarried out. The administration withldrawal of digitalis in these patien-ts did not result in anyy apparenit subjective changes or alterationis of weight?. venous pressure, or of cardiac size, as determined by chest or roenitgenograms. On the basis of these obser- vationis and r-neasurem:leilts there was no evidenee that the effects of digitalis adminlistration wecre benieficial. However, detailed and repeated nieasureinents of the absolute oxygen debt after exercise always revealed lower valuies while the patients were receiving digoxini, although there was comisiderable variationi individual studies. There was also conisiderable variationi in the total exeess Yo resultinig fromn idenitieal exercise periods in each patient, but the adninistrationi of digoxin did not appear to affeet this -variable. The ehanges in the oxygemi debt Avere therefore accomiipanied by declines in the ratio of the oxygen debt to the total excess VoY- resultinrg froml exercise. However, in. spite of the Ireduction of the oxygeni debt during digoxin-i administration, it was apparenit that in two of time three patients studied, tIme debts did niot decline to the levels observed in subjects with niormnal cardiovascular systems (figs. a aId 7) These reductionis of thel oxygen debts after exercise withouit coneoinutant chamiges ini among the total oxygen eost of exercise are consistenit with the hypothesis that in these three patients digitalis in-iproved the (leliverv of OXygen to the systemnie vascular bed during exertion, anid thus permitted the oxygen delivery to mneet the oxygen requiremlents ill a mriore satisfactory fashioin. These observationis suggest strongly tlhat. in the tl-hree patients studied, the digitalis glyeoside resulted in signiifi(alit improvementt of over all circulatory func(tionl in spite of the absenee of any appareilt elinical benefits. Firomii a therapeutic poinlt of view it therefore appears that at least some patients x it1l enlargedlhearts without leart failure are beniefited bv digitalis adniiiiiistration, Summary TThree patienits with aecqtlired vatlvular hieart disease anid cardiac enlargemienat who were able to perforn-i lnormal every day activ ity without diffieulty in the absenee of digitalis therapy were exercised while receiving a plaeebo anid againi while receivinlg digffoxin Digoxin administrationi did n:ot produce, a signifieant chanrge in body weight or in the subjective condition of the inidividuals. Varying degrees of exercise wvere performiied on1 a treadmnill in a Metabolic Chamrlber anid oxygen consumption was miieasured coiitinuouslv before, during, aind after the period of exercise, utilizing a contirnuous gas flow paramiagnetie oxvgen analyzer. The oxygen debt that developed durinig digoxini adminiistrationi was coilpared to that observed durinig placebo admimilistration. In all patielnts the oxygeie debt was slmaller durinog the period of digoxin adminiistrationi, although the external work performled was identical. In the first patient, following a 7minute walk, the oxygen debt wvas 33 per cent muore and followinig a 10-miiiniute walk it averaged 40 per cenit more while inot receivinlg di(goxin than wlihen receiving this drug. In tlIe seconid subject the oxygen debt following a -muilute walk was 34 per cent more and following ai 10-iniriute walk it averaged 74 per cenat more wheni he was not receiving digoxin than vwheni receivinig this drug. In the third subject the oxygen debts were 46 per cent and 41 per cenit greater following 10- anid 15Circulation. Volunui;XXVII, NiMarch 1963 STFUDIES ON DIGITALIS iinute walks respectively, whleni she was niot receiviniog digoxin. The accumnulationi of a smiialler oxygen debt following exercise while these subjects were receiving digoxin indicates that the functional status of their circulatory system was improved by the drug. It would appear that digitalis administration is beneflcial to at least some patients who have cardiac disease and enlarged hearts and some decrease in cardiae reserve without signs or symptoms of heart failure. References Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 1. MCMICHAEL, J., AND SHARPEY SCHAFER, E. P.: The action of intravenous digoxin in man. Quart. J. Med. 12: 1"23, 1944. 2. BLOOMFIELD, R. A., RAPOPORT, B., MILNOS, J. P., LONG, W. K., 'MEBANE, J. G., AND ELLIS, L. B.: Effects of cardiac glycosides upon dynamics of circulation in congestive heart failure; ouabain. J. Clin. Invest. 27: 588, 1948. 3. 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G.: Studies on digitalis. IV. Observations in man on the effects of digitalis preparations on the contractility of the non-failiing heart aind on total vascular resistance. J. Clin. Invest. 40: 52, 1961. 8. MASON, D. T., AND BRAUNWALD, E.: Inotropic effects of a digitalis glycoside on nion-failinig lhearts studied in intact human subjects. Clini. Res. 10: 176, 1962. 9. BURWELL, C. S., NEIGHBORS, DEW., AND REGENS, E. M.: The effect of digitalis upon the output of the heart in niormal man. J. Clin. Invest. 5: 125, 1927. Circulation, Volume XXVII, March 196,3 405 10. STEWART, H. J., AND COHN, A. E.: Studies on the effect of the action of digitalis on the output of blood from the heart. III. Part I. The effect on the output in normal human hearts. Part 2. The effect on the output of hearts in heart failure with congestion in human beings. J. Clin. Invest. 11: 917, 1932. 11. HARVEY, R. M., FERRER, M. I., CATHCART, R. T., AND ALEX \NDER, J. 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Med. 48: 1203, 1931. 22. NYLIN, G.: L 'influence de la digitale sur la dette relative d 'oxygene dans 1 'insuffisance cardiaque latenite a rhythme eardiaque normal. Arch. mal. coeur 32: 1010, 1939. Studies on Digitalis: VI. Reduction of the Oxygen Debt after Exercise with Digoxin in Cardiac Patients without Heart Failure RICHARD L. KAHLER, RONALD H. THOMPSON, ELSWORTH R. BUSKIRK, ROBERT L. FRYE and EUGENE BRAUNWALD Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017 Circulation. 1963;27:397-405 doi: 10.1161/01.CIR.27.3.397 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1963 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. 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