Cardiovascular Mechanismsof Functional Aerobic Impairment in Patients

with Coronary Heart DiseaseBy ROBERT A. BRUCE, M.D., FUSAKo KusuMI, M.S., MANFRED NIEDERBERGER, M.D.,

AND JOHN L. PETERSEN, M.D.

SUMMARYMaximal oxygen uptake (V02max) and functional aerobic impairment (FAI) were determined

by treadmill test in 42 men with coronary heart disease and in 11 slightly older healthy men.Patients were separated according to occurrence or nonoccurrence of angina with exercise. Atrest and at four levels of submaximal exercise on a bicycle ergometer, cardiac output (Q), usingthe direct Fick principle, heart rate (HR), mean systemic and pulmonary arterial pressures, andarterial-mixed venous oxygen difference (A-V 02 D) were evaluated in relation to relative aerobicrequirement (% V0,11J). Q was highly correlated with V02, and both the level and the rate ofchange of Q were lower in patients with angina at all submaximal workloads. Stroke volume(SV) and HR were significantly restricted at the higher workloads. Although peripheral resist-ance was increased, there was no compensatory increase in A-V 02 D. Both restricted SV andreduced HR are responsible for cardiovascular components of the abnormal FAI found in pa-tients with myocardial ischemia due to coronary arterial disease.

Additional Indexing Words:Angina Stroke volumeTreadmill testing

Coronary heart disease Maximal oxygen uptake

FUNCTIONAL AEROBIC IMPAIRMENT(FAI) represents the percentage difference

between functional aerobic power observed withmaximal exercise testing and that expected of ahealthy person of similar sex, age and habitualphysical activity status.' Since the FAI of ambula-tory patients with cardiovascular disease can bedetermined from duration of exercise with astandardized multistage treadmill protocol by usinga nomogram, the salient question arises as to howmuch restriction of stroke volume, heart rate,arterial-mixed venous oxygen difference and arterialpressure contributes to this cardiovascular impair-ment. Of these factors, the first two define cardiac

From the Division of Cardiology, Department ofMedicine, University of Washington, Seattle, Washington.Supported by grants RR37 from the National Institutes of

Health, Program Project Grant HL 13517-02 from theNational Heart and Lung Institute, Max Kade Foundation,Poncin Scholarship Fund of Seattle First National Bank, andthe Fraternal Order of Eagles.

Address for reprints: R. A. Bruce, M.D., Medicine-Cardiology, RG-20, University of Washington, Seattle,Washington 98195.

Received August 8, 1973; revision accepted for publica-tion November 29, 1973.

696

output, the third, peripheral extraction and thefourth, the pressure available for circulatory de-livery of oxygen.

This study analyzes the restrictive effects ofexertional myocardial ischemia by comparing thecirculatory responses to upright exercise of patientswith coronary heart disease, with and withoutangina pectoris, with slightly older healthy subjects.The experimental design required determination ofmaximal oxygen uptake of each individual in orderto scale four levels of submaximal exercise tophysiologically comparable relative aerobic require-ments.

Material and MethodsThe physical and clinical characteristics of 11

healthy middle-aged men and 42 male patients withcoronary heart disease (CHD) are listed in table 1.Although the patients averaged 51 ± 9 years and thenormal men 55 + 5 years, neither the ages nor the otherphysical characteristics showed significant differences.The study design was explained and informed consentwas obtained from each individual.The coronary patients were separated into two

groups, 19 who experienced typical anginal pain onmaximal exercise testing, and 23 who were limited byfatigue and dyspnea rather than chest pain. Maximaloxygen uptake was determined from the highest value

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FUNCTIONAL AEROBIC IMPAIRMENT IN CHD

Table 1

Subjects Studied

CHD patientsNormals (mean 4 SD)

Clinical Diagnosis (mean i SD) WXithout pain With pain

Physical characteristicsNumber 11 23 19Age (yr) 55 - 5 50 - 11 52 - 8Height (cm) 178 4 176 7 176 - 5Weight (kg) 76.5 4 78.3 11.1 78.6 12.7Relative wt (Cc) 94.9 - 7.6 99.6 - 12.6 99.2 - 13.8Rest SBP (mm Hg) 126 - 13 132 - 23 12.5 - 13Rest DBP(mm Hg) 84 - 13 83 - 13 82 - 12Differenices all N.S.

Clinical classifications of CHI) patienitsAngina pectoris 7Myocardial inifarctioni 13Both AP anid MI 18Other probable ASHD 4Total 42

observed during the last 3-5 min of a multistagetreadmill test of maximal exercise.1 Oxygen uptake(VO,) was measured by the open-circuit method usingdual analysis of P02 in aliquots of expired air, first withand then without CO2 absorption in order to ascertainthe concentrations of 02 and C02, respiratory exchangeratio, and valid determinations of VO2.1 FAI was

determined from duration of this test by use of theappropriate nomograms for healthy men and those withcardiac disease.1 A bipolar precordial ECG lead was

monitored to detect any arrhythmia or change in STsegment displacement.

Usually on another day, a Swan-Ganz catheter was

positioned into a pulmonary artery by monitoringrecorded pressure, and another sampling catheter was

inserted by the Seldinger technique into either theradial or the brachial artery. When the subjects satupright, mean arterial pressures (P) were recordedwith transducers positioned at the level of the fourthanterior interspace. Heart rate (HR) was derived fromECG. VO2 and 02 contents of arterial and mixed venous

blood samples were determined at each period ofobservation. Oxygen contents of blood were determinedby the Van Slyke-Neill method or with a calibratedLex-09-Con analyzer.2 Cardiac output (Q) was deter-mined using the direct Fick principle.

The only complication was the occurrence in one

patient of minor pulmonary infarction at the site ofrepeated inflation of the Swan-Ganz balloon catheter.In consequence, frequent observations of the wedgedpulmonary arterial pressure were subsequently omittedfrom the procedure.

Observations were made during the fourth minute ofrest while sitting upright on a stationary Monark bi-cycle ergometer, and during the fourth minute of eachlevel of exercise in the upright posture, except duringthe highest level (third minute). Workloads were

initiated with pedaling at 50 rev/min against zero re-

Circulation, Volume XLIX, April 1974

sistance, and continued against increasing resistanceloads measured in watts. There were usually no restperiods between the increasing workloads, except for a

few minutes of rest just before the highest resistanceworkload. Each period of observation lasted four min-utes, except for the period of highest workload, whichwas usually reduced to three minutes.

Observations were evaluated in relation to relativeaerobic requirement, or percentage of maximal oxygen

uptake (VO9,iiax) measured for each person, to providea physiological basis for comparison.

Vooiax-Observed x 100

V-oina Observed VO.)IiiaxThus, observed Va.) during submaximal exercise on

the bicycle ergometer was related to highest possibleVo,,niax attained by maximal exercise on a treadmill.*100% VOiiiax-% V7, iax defines aerobic reserve formore strenuous exertion at a given submaximal work-load.

Significance of (mean) differences was evaluated byStudent's t-test for unpaired data.

ResultsMaximal Exercise on the Treadmill

Weight-adjusted V021n1.x of all 42 CHD patientsand of 11 healthy men averaged 24.5 6.1 and35.9 + 7.1 ml/ (kg min), respectively (P < 0.001).Mean durations were 382 + 136 sec versus 565 +

136 sec (P < 0.001), while FAI values were 30.715.3% versus 1.4 + 18.0% for these groups (P < 0.001).When the coronary patients were separated

according to whether or not they experiencedangina with exercise testing, mean duration aver-

aged 432 + 126 sec without angina versus 321 + 129sec with angina (P <0.01). Corresponding valuesfor FAI were 26 + 15% and 37 13% (P < 0.05). Asindicated in table 2, maximal heart rate, systolicpressure and pressure-rate product, as well as

changes in heart rate and changes in systolicpressure from minimal values at rest to those ofmaximal exercise were lowest in the anginapatients, intermediate in the non-angina patientsand highest in the healthy men. These observations,derived by clinical methods of monitoring ECG forheart rate and taking blood pressure by sphygmo-manometry, indicated significant differences inrelation to severity of coronary vascular disease as

manifested by angina.

Submaximal Exercise on the Bicycle ErgometerAerobic requirements and hemodynamic respons-

*Normally peak V011 observed with exercise on a bicycleaverages only 94% of peak T02) observed in the same subjectsduring exercise on a treadmi]l.3

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BRUCE. KUSUMI, NIEDERBERGER, PETERSEN

Table 2

Responses to Maximal Exercise of Multistage Treadmill Test

CHD patientsNormals (mean i SD)

(mean + SD) Without pain \With pain

Number 11 2:) 19Duration (sec) 5)65 - 136 432 - 126t 3212 124$Max HlR (beats/mmil) 170 12 138 - 26 145 23tMax SBP (mm Hg) 199 i 19 172 -35)138 35tVo2max (ml /mil) 2727 - 467 2063 - 469$ 1698 3.58V02max (ml/[kg* mil> 35.9 7.1 26.6 -6.0$ 21.9 5.2$AHR (beats/min) (max-rest H1R) 10)9 17 81 23* 67 - 23ASBP (mm Hg) (max-rest BP) 7;3 22 41 ',4t433 - 27$Max PR/109 :337 40 27.5 X 1 * 2:31 - 71$FAI (C.c) 1 18 26 15$ 37- 13)

*P < 0.05, in relationi to normals.tP < 0.01, in relation to normals.++P < (.001, in relation to normals.

es to sitting at rest and to four levels of submaximalexercise in two groups of coronary patients andhealthy men are presented in table 3 and figures 1,2 and 3.Q was linearly related and directly proportional

to V02 (fig. 1). When coronary patients weresubdivided according to presence or absence ofexertional angina, the rate of change of Q relativeto Vo., (or slope of the regression line) was less in

c

.0

20

8

I6

14'

212

10

8

6

4

2

Subjects Studied

* Normal

o Cardiac without Pain

* Cardiac with Pain

Regression Equation N

Q = 4 * 5.6(V02) 42

6 = 2.7 - 62 M,O) 756. =.795.(V'2)Q = 3 7e+5.l(VO) 68

the angina patients (P <0.03). More importantly,the limits of Q and V02 at 87-90Y of Vo,nax weregreatly reduced (P < 0.001) in the angina patients.The component mechanisms of impaired circula-

tory delivery of oxygen are represented by three-dimensional diagrams of absolute values for theminimal and near-maximal aerobic requirementsobserved (fig. 2). Variations over all workloadsstudied are illustrated one variable at a time againstrelative aerobic requirements, or % Vo.,niax (fig. 3).The three-dimensional diagrams suggest a reducedSV, particularly in patients who develop pain ofangina with exertion, but little difference in eitherHR or A-V 02 D at rest. With near-maximalexercise, both SV and HR are restricted, especiallyin coronary patients with pain. Minor differencesin A-V 02 D are not statistically significant. Thus,although both Vo, and Q were greatly limited,

r SEE

.94 1.4

.92 1.4

.90 1.0

.5 1.0 1.5 2.0 2.5 3.0 3.5'02, liters/min

Figure 1Relationship of cardiac output to oxygen consumption inthree groups of subjects. Observations were made sitting at

rest and at four levels of upright exercise. Regression linesdefine ranges observed in each group. Note similarity ofslopes, intercepts, and coefficients of correlation. Note par-

ticularly that the upper limits for patients with angina are

greatly reduced.

Figure 2

Variations in circulatory delivery of oxygen in upright pos-

ture in normal men and two groups of male coronary pa-

tients at rest (on the left) and at near-maximal exercise

(on the right). Note that significant differences emerge withstrenuous exertion.

Circulation, Volume XLIX, April 1974

0a ~

698

N-,.. 1,(FA ,%

C.,di.,.. Ith..t P..-('Al,P6%)

C., d i... h P,,i,,(FA1,37%)

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FUNCTIONAL AEROBIC IMPAIRMENT IN CHD

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a150F

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Averaged responses of threegroups of subjects to uprightexercise, adjusted to relativeaerobic requirement (percent-ages of maximal oxygen up-

take) for each individualstnidied. Break in lines (- - - -)inidicates switch to the smallernumber of individuals who ex-

ercised at both higher work-loads. Asterisks indicate signifi-cance of differences fromhealthy subjects, i.e., *P < 0.05;**P < 0.01; and ***P < O.OO1.

110

0 10 20 30 40 50 60 70 80 90

% V02mOX

peripheral extraction was nearly as great as ineither patients without pain or healthy men; indeed,this corroborated the symptomatic evidence of a

close approximation to actual V02max.Further insights into component mechanisms of

impairment are provided by examination of therelationships of these and other variables to severallevels of relative aerobic requirement, or % V02max(fig. 3). Now it becomes apparent that there is littledifference in mean values of SV or in peripheralresistance between patients who developed exer-

tional pain and those without pain. When aerobicrequirement exceeds 605o Vo2max, there is a signifi-cant restriction in HR, together with an inadequateincrement in systemic mean arterial pressure (PSA).Pressure-rate product (PR) is also lower, yet thechanges in ratio of systemic mean to pulmonaryCirculation, Volume XLIX, April 1974

mean (PPA) arterial pressure are not altered inrelation to coronary disease or occurrence of chestpain. To emphasize the circumstances of theseobservations, the lower physical workloads in watts

and lower absolute VO2 requirements at near-

maximal effort for these three groups are alsoshown in figure 3.

DiscussionFAI of ambulatory cardiac patients represents a

quantitative objective assessment of total cardiovas-cular function in relation to expected values of

V02nmax in appropriate healthy peers.' Thus, itcontrasts in method and in frame of reference to thetraditional subjective appraisal of symptoms, as

recalled, in relation to "ordinary" activities ofundefined severity, scaled from class I to class IV

699

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BRUCE, KUSUMI, NIEDERBERGER, PETERSEN

Table 3

Hemodynamic Responses at Rest and to Upright Exercise

Rest Exercise 1Normal CHD Normal CHD

Without pain With pain Without pain With pain

No. of observations 11 23 19 14 17 22

Workload (watts) 0 0 0 14 29 12 19 11 1.5Vo2 (ml/min) 317 - 48 302 - 49 296 - a7 633 - 294 628 - 219 528 - 137%oVo2max 12 2 15 4 18 -3 22 9 29 8 30 - 7FAI (%) 0* 19 26* 1,3 37 - 13t 0 19 29*13t 37 - 13tSV (nil) 70 - 25 63- 15 59 * 18 83 - 20 83 *23 73 14HR (beats/min) 81 - 15 77 - 12 80 - 17 93 - 21 84 * 18 83 * 15A-V02D (ml/liter) 39 - 10 64 - 13 66 - 11 81 - 16 91 15 84 12Q (liters/min) 5.500 1.29 4.87 - 1.21 4.66 - 1.60 7.63 - 2.29 6.87 * 1.93 6.27 1.15*PSA (mm Hg) 99 16 102 - 13 104 14 110 * 13 119 17 111 *16PPA (mm Hg) 11 *-2 12 3 11 4 15 4 18 4 13*4PSA/PPA 9.11 - 1.61 9.25 * 2.23 10.06 * 3.32 7.75 - 1.63 6.93 * 1.47 7.66 - 1.75tRSA (dyne-cm-sec-5) 1515 * 337 1789 547 1908 * 449* 1228 * 263 1459 366 1438 - 194RPA (dyne-cm-sec-5) 170 - 43 205 90 201 64 160 31 216 60t 193 46*PR/100 81 19 79 18 83 22 104 31 101 33 93*27

Abbreviations: A-V 02 D = Arteriovenous oxygen difference; HR = Heart rate; PSA, PPA Mean systemic, pulmonary arterialpressure; PR = Pressure-rate produce; = Cardiac output; RSA, RPA = Mean systemic, pulmonary arterial resistance; SV = Strokevolume; V02 = Oxygen uptake.*P < 0.05.tP < 0.01.tP < 0.001.

according to the criteria of the New York HeartAssociation.4 FAI can be derived rapidly, reliablyand safely by using a standardized multistagetreadmill protocol of supervised maximal exercisetesting and simple nomogram.'

The significance of V'2max is that it definescardiovascular functional capacity for circulatorydelivery of oxygen, since it is precisely equal to theproduct of Qmax and A-V 02 Dmax.5 In health,

NORMAL VARIATIONS IN V A

.b[ :1 7OSERVED | 35.1 ! 74

2[ Ns2S ~~~~~~36,3t 7

TN. 31 52 3 ± 5 6

U, mi _ 547t7.6

V 0 363t77

.i_6 33.3 t79

0 0o±1°nm/kg mn

Figure 4

Comparison of predicted and observed mean VOma foreight subgroups of healthy middle-aged persons.' Note vari-ations with sex, age and activity status, agreement withineach subset, and smaller standard deviations of valuespredicted from regression in these three variables.

V02max in liters/min is proportional to body weight,especially lean body mass,6 and varies normallywith sex, age and physical activity status.*7, 8Whenthese characteristics are defined, V02max may bepredicted from regression equations.' The agree-ment between mean predicted and mean observedvalues for eight subgroups of healthy middle-agedpersons is shown in figure 4. Finally, when FAI isdetermined, average % V02max expected in normalpeers equals 100 minus FAI. When derived with theappropriate nomogram, either duration of exerciseto obtain 0% FAI (i.e., 100 of average normalpredicted Vo2max for a given age) or the equivalentage in years for the duration observed may bereadily ascertained.

Earlier studies of cardiovascular components ofVOomax in cardiac patients appear to be limited tothose of Blackmon and associates on patients withmitral stenosis.9 Several observations from thatstudy are relevant. At any level of work in theupright posture, a plateau in Vo2 occurred within 2-3 minutes. The approach to V02ma, was normal even

*For clinical purposes, an active person is one whoparticipates in physical activities equivalent to jogging orrunning, long enough to develop sweating, at least once aweek, regularly.

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FUNCTIONAL AEROBIC IMPAIRMENT IN CHD

Exercise 2 Exercise 3 Exercise 4Normal CHD Normal CHD Normal CHD

Without pain With pain Without pain With pain Without pain With pain

10 22 19 14 18 18 4 18 9

76 28 49 19t 45 18$ 123 32 90 27t 80 23t 150 20 117 30 89 29t1296 - 308 1029 253* 920 - 212t 1814 363 1461 309t 1274 2631 2356 - 337 1808 433* 1342 327$48 6 49 4 54 5 69 5 70 8 74 4 87 7 89 7 90 7-1*16 29 12t 36 14t 4 18 22 17t 36 13t -6 17 22 16t 38 13t106 20 87 20* 87 19* 107 24 82 14t 82 18t 98 10 89 18 76 17*110 16 110 21 104 19 134 17 138 21 128 24 163 15 153 23 131 23*111 13 110 19 103 12 129 18 130 18 124 14 147 8 134 16 136 *22

11.67- 2.43 9.44 2.12* 8.89 1.74t 14.27 2.92 11.35 2.36t 10.78 1.72$ 16.12 2.49 13.75 3.82 9.83 1.51$116 14 121 19 117 16 125 15 135 20 121 17 140 13 132 17 125 1919 4 21 5 19 5 23*6 28 6 24 5 29 8 32 8 23 6

6.28- 1.03 4.46 1.50* 4.97 1.93 5.32 - 1.23 3.13 - 0.89 3.66 1.17 5.00 0.80 2.99 1.00 3.52 1.33816 - 104 1069 282* 1076 179t 723 - 96 984 - 236t 965 212t 704 74 827 247 1019 96$132 25 183 58* 170 39* 142 37 208 86* 190 59* 143 24 211 121 197 80130 32 134 38 123* 3 170* 3 186 43 156 43 229 35 202 45 166 49*

though level of Vo2max was greatly reduced,primarily because of restricted SV. Accordingly,V02max was considered to provide the most informa-tion for the least clinical procedure. Incrementsin HR, A-V 02 D and blood lactate concentrationwere normal, as were decrements in estimatedhepatic blood flow at any level of submaximalexercise, but only when evaluated in relation to per-centage of maximal oxygen uptake.Malmborg studied hemodynamic responses to

upright exercise in 38 patients with coronary heartdisease at various levels of submaximal exercisescaled to absolute values of aerobic requirements,regardless of the capacity of the patients tested.'0At given submaximal workloads, stroke volume andcardiac output were lower in the patients than in 11healthy older men;" the values in the patients whowere unable to perform at 600 kpm (100 watts)were even lower. There uas no correlation betweenhemodynamic responses to exercise and coronaryarteriographic findings at rest, nor to electrocardio-graphic changes with exercise. Manifestations ofleft-ventricular failure during exercise in patientswith a tolerance for less than 600 kpm/minemphasized the importance of exercise tolerance forevaluation of patients with coronary disease.The salient findings of the present study are that

SV and Q were reduced, while peripheral resistancewas increased at submaximal workloads, whether ornot angina was experienced. The rate of change in

Q for an increment in V02 and HR at workloadsgreater than 60% of VC2max were also lower, makingCirculation, Volume XLIX, Api 1974

the values of Q and Vo2 even lower at near-maximalexercise in patients with anginal pain. Peripheralextraction of 02 defined by A-V 02 D, was notsignificantly restricted. Since patients with anginaalso tended to have lower systemic arterial pressure(and pressure-rate product) when aerobic require-ments exceeded 60% VO2max, the pressure availablefor perfusion of stenotic coronary arteries issuboptimal. Thus, angina patients not only experi-ence pain, but, more importantly, they exhibit muchlower limits of V02 and Q from restrictions of bothSV and HR at workloads that are only modest inabsolute terms but nevertheless stressful in relativeterms. These mechanisms compound the myocardialischemia of exertion imposed by coronary vasculardisease, while enhanced peripheral resistance ap-pears to be a desirable, albeit in some instancesexcessive compensation. Evidence for the latter isimplied in the transient and significant increase in

V02max when coronary patients, whether they expe-rience angina or not, are treated with nitroglyc-erin.12These findings have been supplemented by

somewhat parallel observations of McDonough andassociates who found that coronary patients whenexercised to maximum on a treadmill exhibitedplateaus in both V02 and Q when they had partialsupport of the catheterized arm long enough tomake these observations.13 Furthermore, anginapatients had lower Vomax and Qmax, and IQ actuallyfell, while V0o was maintained by a slightly greaterA-V 02 D with the last minute of exercise.

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BRUCE, KUSUMI, NIEDERBERGER, PETERSEN

AcknowledgmentThe authors are indebted to colleagues and reviewers,

particularly Dr. Loring B. Rowell and Dr. John R.McDonough, for helpful criticisms and suggestions in thepresentation of these data. The editorial and typingassistance of Alison Ross and Robert Braunwart are alsoacknowledged.

References1. BRUCE RA, KusuMI F, HOSMER D: Maximal oxygen

intake and nomographic assessment of functionalaerobic impairment in cardiovascular disease. AmHeart J 85: 546, 1973

2. Kusu\II F, BuTrs WC, RUFF WL: Superior analyticalperformance by electrolytic cell analysis of bloodoxygen content. J Appl Physiol 35: 299, 1973

3. SHEPHARD RV, ALEEN C, BENADE AVS, DAVIES CTM,DI PRANIPERO PE, HEDMANS R, MERRIMAN JE,MYHRE K, SIMMONS R: The maximal oxygen intake.An international reference standard of cardiorespira-tory fitness. Bull WHO 38: 757, 1968

4. CRITERIA COMMITTEE OF THE NEW YORK HEARTASSOCIATION: Diseases of the Heart and BloodVessels, ed 6. Boston, Little, Brown, 1964

5. MITCHELL JH, SPROULE BJ, CHAPMAN CB: Thephysiological meaning of the maximal oxygen intaketests. J Clin Invest 37: 538, 1958

6. BUSKIRK E, TAYLOR HL: Maximal oxygen intake andits relation to body composition with special referenceto chronic physical activity and obesity. j ApplPhysiol 11: 72, 1957

7. ROBINSON S: Experimental studies of physical fitness inrelation to age. Arbeitsphysiologie 10: 251, 1938

8. ASTRAND P-O: Physical performance as a function ofage. JAMA 204: 105, 1968

9. BLACKMON JR, ROWELL LB, KENNEDY JW, TwIss RD,CONN RD: The physiological significance of maximaloxygen intake in "pure" mitral stenosis. Circulation36: 497, 1967

10. MALMBORG RP: A clinical and hemodynamic analysis offactors limiting the cardiac performance in patientswith coronary heart disease. Acta Med Scand 177(suppl 426): 1, 1965

11. GRANATH A, JONssoN BN, STRANDEL T: Circulation inhealthy old men, studied by right heart catheteriza-tion and during exercise in supine and sittingpositions. Acta Med Scand 175 (ssuppl 414): 1964

12. DETRY JR, BRUCE RA: Effects of nitroglycerin on"maximal" oxygen intake and exercise electrocardio-gram in coronary heart disease. Circulation 43: 155,1971

13. MCDONOUGH JR, DANIELSON RA, WILLS RE, VINEDL: Maximal cardiac output in patients with cardiacdisease. Am J Cardiol 32: 23, 1974

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PETERSENROBERT A. BRUCE, FUSAKO KUSUMI, MANFRED NIEDERBERGER and JOHN L.

Coronary Heart DiseaseCardiovascular Mechanisms of Functional Aerobic Impairment in Patients with

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1974 American Heart Association, Inc. All rights reserved.

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