The Rate-Pressure Product as an Indexof Myocardial Oxygen Consumption

during Exercise in Patients with Angina PectorisFREDARICK L. GOBEL, M.D., LEONARD A. NORDSTROM, M.D.,

RICHARD R. NELSON, M.D., CHARLES R. JORGENSEN, M.D., AND YANG WANG, M.D.

With the technical assistance ofEdwin Ketola and Thomas D. Stoebe

SUMMARY In order to evaluate hemodynamic predictors ofmyocardial oxygen consumption (MVO,), 27 normotensive men withangina pectoris were studied at rest and during a steady state atsymptom-tolerated maximal exercise (STME). Myocardial bloodflow (MBF) was measured by the nitrous oxide method using gaschromatography. MBF increased by 71% from a resting value of57.4 ± 10.2 to 98.3 ± 15.6 ml/100 g LV/min (P < 0.001) duringSTME while MVO, increased by 81% from a resting value of6.7 ± 1.3 to 12.1 ± 2.8 ml O,/100 g LV/min (P < 0.001). MVO2

EASILY MEASURED PREDICTORS of myocardialblood flow (MBF) are necessary to evaluate objectively func-tional improvement in patients with ischemic heart disease.Symptomatic improvement may occur as a result of achange in life style with little or no ability to increase MBFor to perform more external work. In turn, a medicalregimen might result in an increase in the ability to performexternal work with little or no ability to increase MBF.Direct measurement of exercising MBF requires use of anindicator and catheterization of the coronary sinus (CS) andis therefore not applicable to a large patient population.

Previous work has demonstrated that changes in heartrate (HR) and the product of HR and blood pressure (BP)effect parallel changes in MBF and myocardial oxygen con-sumption (MVO,) in normal young men during upright ex-ercise in a variety of circumstances.` Because myocardialoxygen extraction (MA-VO,) may change from rest to exer-cise, hemodynamic predictors (HR X BP) appear to cor-relate better with MVO, than MBF.3 Although HR alonecorrelates well with MVO, it is necessary to include BP insituations where BP does not rise pari passu with HR, e.g.,isometric exercise4 or pacing-induced tachycardia.'Including the systolic ejection period (SEP) (e.g., thetension-time index or the triple product) does not improvethis correlation in normal young men.' Extrapolation fromnormal young men to patients with ischemic heart diseasemust be made with caution because changes in ventricularvolume, geometry, compliance and contractility, not in-cluded in currently used indices of MVO2, may not changeto the same extent during exercise in patients with ischemicheart disease. However, there is some information to suggestthat HR X BP is also a good index of MVO, in patients withischemic heart disease.5' 6 Furthermore, the duration of up-right exercise and the HR X BP product at the onset of

From the Department of Medicine, Cardiovascular Section, Veterans Ad-ministration Hospital and University of Minnesota, Minneapolis, Minnesota.

Address for reprints: Fredarick L. Gobel, M.D., 2545 Chicago AvenueSouth, Minneapolis, Minnesota 55404.

Received September 24, 1976; revision accepted October 3, 1977.

correlated well with heart rate (HR) (r = 0.79), with HR X bloodpressure (BP) (r = 0.83), and, adding end-diastolic pressure and peakLV dp/dt as independent variables, slightly improved this correlation(r = 0.86). Including the ejection period (tension-time index) did notimprove the correlation (r = 0.80). Thus, HR and HR X BP, botheasily measured hemodynamic variables, are good predictors ofMVO, during exercise in normotensive patients with ischemic heartdisease. Including variables reflecting the contractile state of theheart and ventricular volume may further improve the predictability.

angina pectoris are reproducible in a given patient withischemic heart disease when there is adherence to a suitableprotocol.7-9 Patients may exercise to a slightly higher HR XBP product after nitrates and a slightly lower HR X BPafter beta adrenergic blockade with propranolol'0 indicatingthat other factors are involved in determining MVO2. Thesefactors may include changes in ventricular volume" andcontractility.The present study extends the evaluation of hemodynamic

predictors of MVO, from normal subjects to patients withischemic heart disease. Changes in the contractile state ofthe heart and ventricular volume have been estimated in thisstudy.Measurement of MVO2 by the nitrous oxide (N,O)

method using Van Slyke manometry is laborious and timeconsuming and requires a considerable volume of blood. Wehave alleviated these problems by using gas chromatographyfor the measurement of N,O.

Methodology

Patient Material

The study population consists of 27 men symptomaticfrom ischemic heart disease. One patient did not have cor-onary arteriography but had electrocardiographic (ECG)evidence of an inferior myocardial infarction. The other 26patients had coronary arteriography: patients 2-4 had cor-onary arterial obstruction of greater than 70% of one cor-onary artery, patients 5-9 had greater than 70% obstructionof two coronary arteries, and patients 10-27 had greaterthan 70% obstruction of three coronary arteries (table 1). Allpatients complained of chest pain; ten patients also com-plained of dyspnea. The mean age was 50 ± 7 years (range39-67 years). Patients were similar in size with the meanbody surface area being 1.94 ± 0.15 mi. Patients with aresting diastolic BP greater than 100 mm Hg, ECG evidenceof left ventricular hypertrophy, valvular heart disease orother serious systemic disease were excluded from the study.Also excluded were patients who were unable to exercise

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against at least a 25 watt external workload and remain freeof chest pain. All patients were in sinus rhythm and hadECG evidence of either infarction (19 patients) or ischemicST-segment depression at rest or during exercise. Digitaliswas given to five patients and was the sole medication ad-ministered prior to the study. All patients underwentdiagnostic cardiac catheterization for the evaluation ofischemic heart disease, and informed consent for the ad-ditional studies was obtained in each case.

Procedure

The experimental protocol was as follows:Day I - supine exercise to determine symptom-tolerated

maximal exercise (STME);Day 2 - hemodynamic studies.On day 1 patients were brought to the cardiac catheteriza-

tion laboratory in a fasting state. Supine bicycle exercise wasperformed against an external workload for a 10-minute in-terval followed by a 20-minute recovery period by whichtime the HR X BP had returned to baseline. Following eachrecovery period the workload was increased by 25 watt in-crements until the patient developed grade II chest painprior to completion of ten minutes of work. Patients were in-structed to grade chest pain from 0 to IV. Grade I chest painwas considered to be mild pain, approximately 25% of themost severe pain experienced by the patient. On occasionthis was atypical of the patient's usual anginal pain and wasfelt to be due to musculoskeletal discomfort and notmyocardial ischemia. Grade II pain, about 50% of the mostsevere pain, was considered to be of a quality such that thepatient would usually take a nitroglycerin tablet. Grade IIIpain would be equivalent to 75% of the patient's most severepain, while grade IV would be equivalent to the most severepain that the patient experienced, comparable in many in-stances to that of acute myocardial infarction. This gradingsystem has been used successfully by others.12 The test wasstopped at grade II chest pain regardless of the degree ofST-segment depression. Thus, the greatest externalworkload that could be performed for ten minutes withoutchest pain was determined and used as the externalworkload on day 2.On day 2 patients were brought to the catheterization

laboratory in a fasting state. The resting study preceded theexercise study in all cases. Woven Dacron catheters werepositioned with the tips in the pulmonary artery wedge(PAW) and the CS 3 cm from the left heart border. A 75 cmTeflon arterial catheter was introduced percutaneously intothe right brachial artery and the tip positioned in the apex ofthe left ventricle (LV). The mid-chest level at the angle ofLouis was used as the zero reference. Left ventricular end-diastolic pressure (LVEDP) was measured at the onset ofisovolumic contraction where the downstroke of the A wavemet the upstroke of the LV pressure wave. Cardiac output(CO) was determined from indocyanine-green dye (Cardio-Green) curves.

Immediately following the indicator dilution curves, in-halation of 15% N2O commenced simultaneously withsampling from the CS and central Ao. Four samples wereobtained during the initial two minutes and seven samplesduring the subsequent seven minutes.

For the exercise study the feet were positioned on aLanooy supine bicycle ergometer with the resistance set at

the predetermined workload. Pressures were continuouslymonitored from the LV, PAW and CS and were recordedafter three minutes of exercise. Inhalation of 15% N2O com-menced simultaneously with sampling from the CS and Ao.Five samples were obtained during the initial two minutesand twenty seconds and four samples during the next fourminutes. CO was then measured as at rest. Pressures wererecorded and the exercise procedure was terminated. Theleft atrium or LV and each coronary artery were then selec-tively injected with contrast material.An Electronics for Medicine oscilloscopic photographic

recorder and Statham P23 Db strain gauge transducers wereused for recording pressure. The catheter-manometer re-cording systems for the arterial measurements exactly asused in our study, had a frequency response which was flat to50 ± 27 Hz.The tension time index (TTI)/beat was measured from

Ao pressure tracings recorded at paper speeds of 200mm/sec by integrating the systolic portion of the Ao tracingwith a polar planimeter. Complexes were measured overseveral respiratory cycles prior to and after the inhalation ofN2O. Systolic ejection period (SEP) was estimated to thenearest 0.002 sec. The TTI/min was calculated as theproduct of the TTI/beat and the HR. The HR X BP refersto the product of the peak systolic Ao pressure and HR. Thetriple product (HR X BP X SEP) was calculated from theHR, peak systolic Ao pressure and SEP. Left ventricularminute work (LVMW) in kg-m/min was calculated as theproduct of the CO (L/min), mean systolic Ao pressure and0.0144.N2O was measured using a Beckman gas chromatograph

equipped with a thermal conductivity detector. The ap-paratus for liberating N20 from blood consisted of aspecially constructed chamber with a ground glass joint un-der a stainless steel head with a septum for injecting bloodsamples. Blood samples (250 ,l) were injected into thechamber and mixed with reagents for three minutes at100°C; helium then carried the gas from the reactionchamber to the column where N2O was separated from 02,CO2, and N2 and detected by thermal conductivity. Thequantity of N2O was directly proportional to the integratedarea which was calibrated using blood with known N2O con-centrations. N2O concentration measured by gas chroma-tography was compared with N2O concentration measuredby the manometric technique.MBF was calculated from exponential curves fitted to the

data points by a Control Data 3300 computer program,using the Hartley modification of the Gauss-Newton itera-tive procedure."2 A smooth aortic curve was best fitted to atwo exponential equation and a smooth CS curve to a threeexponential equation. The area between the curves wascalculated using the trapezoid method. MBF was then calcu-lated from the venous N2O content at equilibrium and themean arteriovenous N2O difference. A N2O partitioncoefficient of 1.0 was used to make our data more compar-able to previous data even though 0.934 has recently beenshown to be more correct.14 MBF was calculated after in-halation of N20 for seven minutes at rest and for four min-utes during exercise. MA-VO2 difference was measureddirectly using a Beckman spectrophotometer and arterialblood as a blank.15 MVO2 was then calculated as the productof MBF and the MA-VO2 difference and expressed as ml 02

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consumption/100 g LV/min. Coronary vascular resistancewas calculated as the quotient of the difference of the Ao andCS pressure and MBF and expressed as mm Hg/ml/100 gLV/min.LV function was evaluated by measuring the rate of rise of

pressure (dp/dt) in the Ao and LV with a resistancecapacitance differentiator. Single plane cineangiography at60 frames per second in the 450 right anterior oblique posi-tion was used to determine ventricular dimensions in all pa-tients at rest. Seventy-six percent methylglucaminediatrizoate (Renografin) was injected either as an 80 mlbolus into the left atrium (23 patients) or as a 50 ml bolusinto the LV (four patients). Angiography was performed 30minutes after termination of the exercise study. X-raymagnification was calculated from a wire grid. Ventricularvolumes were then calculated according to the method ofGreene et al.16 with the short axis calculated from the area ofthe ventricle.17 Volumes were calculated from the first threeconsecutive beats after opacification to avoid makingmeasurements where the contrast material may influenceventricular function.'8 19 In two patients premature ven-tricular contractions precluded measurements of ventricularvolume.The contractile state of the heart was estimated at rest and

during exercise from the rate of rise of aortic and left ven-tricular pressure. In five patients (nos. 2, 7, 8, 10, 14) a breakin the rise of the LV pressure curve indicated mechanical in-terference with the recording and derivatives of these pres-sure curves were excluded. LV dp/dt at a developed pres-sure (DP) of 40 mm Hg and dp/dt at a total pressure (TP) of50 mm Hg were measured at rest and during exercise in anattempt to exclude changes due to the Frank-Starlingmechanism as previously reported.20' 21 Regression analysiswas carried out by two variable analysis and multiplevariable analysis where products (e.g., HR X BP) were con-sidered as a single variable (table 3).

Results

In 46 consecutive studies N20 measurements made by thegas chromatographic method were nearly the same asmeasurements made by the manometric method. Linearregression analysis demonstrated a strong positive correla-tion (r = 0.99, N = 553) between volume % N20 by the twomethods. Although nearly the same, the mean differencebetween the two methods was 0.39 ± 0.30 volume % withthe gas chromatographic method giving the higher reading(P < 0.001). Linear regression analysis of MBF determinedby the two methods also demonstrated a positive correlation(r= 0.90, N = 46). The mean difference between the twomethods was 2.9 ± 10.0 ml blood/100 g LV/min and wasnot significant.Hemodynamic data are indicated in table 1. For the entire

group the CO increased by 58% and the stroke volume by14% (74 + 13 to 84 + 18 ml/beat) during exercise (bothP < 0.001). Seven patients had a resting cardiac index below2.5 L/min/m2 (nos. 4, 8, 18, 19, 22, 25, 27). In patient 27grade II chest pain developed after measurement of MBFand precluded measurement of an exercise CO. During exer-cise the mean HR increased by 36%, the mean LVEDPdoubled and the PAW increased by 88% (all P < 0.001).Since the measurement of LVEDP was made after the A

wave, the mean PAW was usually lower than the LVEDP.Elevation of the legs immediately prior to exercise resultedin a mean 1 mm Hg rise in PAW pressure. Eight patientshad an increase in the exercising PAW greater than 8 mmHg and two patients (nos. 10, 27) had an increase in PAWpressure greater than 20 mm Hg from rest to exercise. Thelatter two patients had severe three vessel coronary arterydisease but neither developed chest pain at the time thePAW pressure was measured or during measurement ofMVO2. In no patient were measurements made at grade IIpain and in most patients measurements were made in thecomplete absence of pain.The LV was outlined without premature ventricular con-

tractions in 25 patients. Thirteen of the 27 patients had nodiscernible contraction abnormality. Two patients (nos. 21,26) had dyskinetic aneurysms and 12 patients had akinesisor hypokinesis of either the anterior or inferior ventricularwall. The mean ventricular end-diastolic (181 + 76 ml) andend-systolic volumes (70 + 44 ml) were normal (table 1).There was no correlation between resting EDV and LVEDP(r = 0.08) or resting PAW (r = -0.15) or the increase inPAW during exercise (r = 0.31). The ejection fraction wasgreater than 70% in seven patients and less than 50% in onlyfour patients, with a mean value of 62 + 14%.

During exercise the HR X BP increased by 54%, theHR X BP X SEP by 45%, the TTI by 42% and the LVMWby 79% (all P < 0.001). The ratio of LVMW and MVO2 didnot change (table 2).Mean peak LV dp/dt increased by 64% during exercise

(P < 0.001) (table 2). Since the mean diastolic BP also in-creased by 8% from a resting value of 79 + 10 to an exercisevalue of 85 + 11 mm Hg and the LVEDP increased by100%, the resulting increase in LV dp/dt may have been in-fluenced by these changes in ventricular loading. The in-crease in exercising LVEDP made measurement of thederivative at a total pressure of 50 mm Hg difficult and it didnot change during exercise. The LV derivative, measured ata DP of 40 mm Hg, was significantly increased by 374 mmHg/sec during exercise (28%, P < 0.01). Aortic dp/dt alsoincreased significantly during exercise.MBF increased by 72% during exercise (P < 0.001) and

the MA-VO2 difference widened slightly by 5% (P < 0.02).MVO2 correlated well with HR alone (0.79) and with

HR X BP (r= 0.83) (fig. 1, table 3). The TTI and HR XBP X SEP were slightly poorer correlates than HR X BP.When LVEDP and LV dp/dt measured both at rest and dur-ing exercise were added to HR X BP the correlation wasslightly better (r = 0.86) (table 3).

Discussion

Results from this study indicate that HR X BP, easilymeasured hemodynamic variables, are valid predictors ofMVO2 during exercise in a population of men with ischemicheart disease when appropriately selected. The many formsof therapy available for the treatment of angina pectoriscoupled with the complex nature of the response to treat-ment make such objective methods of evaluating improve-ment mandatory. In addition to the placebo effect from bothmedical and surgical treatment, factors such as a change inlife style or physical size may result in symptomatic but notfunctional improvement. Physical conditioning and medical

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therapy may result in an increase in exercise tolerance withlittle or no ability to increase MBF or MVO2 during exer-cise. The ability to document significant increases in MVO2during exercise with medical or after surgical therapy wouldbe of considerable help in evaluating patients. Currentlyavailable methods for measuring MVO2 are too complex tobe widely applicable to a large patient population. That theHR X BP is a good index of MVO2 in patients with ischemicheart disease has also been reported by Holmberg et al. whofound similar results using different methodology in pa-tients who were not nearly as functionally limited as the pa-tients included in this study.6

In this study the HR alone correlated as well with MVO2as the HR X BP as previously reported in a study ofdynamic leg exercise in normals.2 Nevertheless it is impor-tant to include the BP for a comprehensive index of themetabolic load on the heart. There are several lines ofevidence for this assertion. It is clear that increases in HRaccount for only a fraction of the increase in coronary bloodflow with exercise.22 HR correlated with MVO2 (r = 0.88)nearly as well as HR X BP (r = 0.90) in a previous study2because BP and HR were correlated (r = 0.73). Re-analysisof previously published data2 by a multivariable rather thana two variable technique yielded a regression equation ofMV02 = 0.24 HR + 0.16 BP + 29.9 (r = 0.89). Since theranges of the two variables were similar (HR 99-173beats/min; BP 111-160 mm Hg) the size of the coefficientsin the equation indicates the relative importance of the twovariables. When one considers interventions where BP doesnot rise with HR, such as atrial pacing, the necessity of in-cluding BP in the index becomes even more evident. Theslope of the regression line of MVO2 on HR is much lowerduring atrial pacing than during dynamic leg exercise, butthe relationship between MV02 and HR X BP falls alongthe same regression line.5 Corresponding to the upper limitof the patient with angina to increase coronary bloodflow232 24 is the fact that there is a characteristic HR X BP atwhich angina occurs in a given patient which is reproducibleon repeated bouts of exercise,7-9 " even over long periods oftime,7' 1' after meals or cigarette smoking,26 27 regardless ofchanges in exercise tolerance. Similarly, angina occurs at alower workload but a similar HR X BP with dynamic armwork as compared with dynamic leg work.28-30 A similarHR X BP and coronary venous flow at angina have beenreported when atrial pacing is compared with exercise.32When the BP is altered by an infusion of angiotensin,pacing-induced angina continues to occur at the sameHR X BP.34With the exception of LV dp/dt measured at a total

pressure of 50 mm Hg, contractility indices measured in thisstudy increased during exercise. The contractile state of theheart is an important determinant of MVO235 36 but LVdp/dt may be influenced by changes in preload and afterloadoccurring during exercise.20 Accordingly, we included a con-tractility index which could be measured at rest and duringexercise and which could be adapted to changes in preloadand afterload.20' 21 The possibility of distortion of pressurepulses using fluid-filled catheters rather than catheter tipmanometers was diminished by using a system with an ap-propriate frequency response, flush solutions free of air

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FIGURE 1. The correlations between myocardial oxygen consumption (M VO2) (left panel) and myocardial bloodflow(MBF) (right panel) and hemodynamic variables are illustrated. The regression linefor the 27 patients is indicated by thesolid line, while dashed lines indicate 95% confidence zones for the individual points. The shaded area indicates 95% confi-dence limits for the slope of the regression line.

bubbles and by including only those pressures where the up-

stroke was smooth and the pressure contour was optimum.37In spite of these precautions additional subtle changes in thecontractile state may have been overlooked.

The relationship between HR X BP and MVO2 in thisstudy [MVO, = 0.08 (HR X BP X 10-2) - 0.15] was

slightly different from that reported in young men during up-right exercise [MVO2 = 0.17 (HR X BP X 10-2) -5.31]4

TABLE 3. Correlations of MBF and MVO2 with Several Variables

Independent variables Dependent variables1 2 3 MVO2 MBF Number

HR 0.79 0.81 54HR X BP 0.83 0.79 54HR X BP X SEP 0.79 0.76 54HR X BP SEP 0.83 0.79 54TTI 0.80 0.77 54HR X BP PAW 0.83 0.81 54HR X BP LVEDP 0.83 0.81 54HR X BP Ao dp/dt 0.85 0.81 53HR X BP LV dp/dt 0.85 0.8a 46HR X BP LV dp/dt DP 40 mm Hg 0.84 0.82 46HR X BP LVEDP Ao dp/dt 0.84 0.80 53HR X BP LVEDP LV dp/dt 0.86 0.85 46

Abbreviations: HR hbeart rate; BP blood pressure; MVO2 myocardial oxygen consumption; MBF = myocardial bloodflow; SEP = systolic ejection period; TTI tension-time index; Ao = aorta; LV = left ventricle; DP = developed pressure; LVEDP= left ventricular end-diastolic pressure; PAW = pulmonary artery wedge.

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HRx BPx 10-2360

FIGURE 2. Regression line for patients from this study (line 4)compared with the regression line from data reported for patientswith ischemic heart disease during supine exercise (line 3).6 Theregression lines for normal subjects are indicated by line I (uprightexercise)4 and line 2 (supine exercise).6

but it agrees closely with the relationship reported by Holm-berg during supine exercise in men with ischemic heart dis-ease using different methodology [MVO2 = 0.08(HR X BP X 10-2), + 2.45, r = 0.86] (fig. 2).6 At the lowerHR X BP products measured in patients in this studyMVO2 was just slightly less than reported for normal sub-jects, and at higher HR X BP products this difference in-creased. This difference may be partly explained bydifferences in posture38' 39 and blood catecholamine levelswhich are significantly higher in the upright than in thesupine posture.40' 1 Alternatively, a reduction in oxygensupply may decrease contractility in patients with ischemicheart disease which would, in turn, further reduce oxygencost.6 The use of central aortic catheters in our studies ob-viates the effects of differences in peripheral augmentation ofsystolic BP due to age. This difference in the relationshipbetween HR X BP and MVO2 was not due to over-

estimating coronary blood flow nor to increases in ven-

tricular volume in these patients since these factors wouldhave resulted in changes in the opposite direction.The question arises as to whether these results obtained

using the BP measured through an aortic catheter can be ex-

trapolated to the situation using a pneumatic BP cuff andKorotkoff sounds, since the systolic BP may be significantlyhigher peripherally than centrally and the degree of augmen-tation may vary with age.42"- Although it may be oc-

casionally difficult to accurately measure the cuff BP duringexercise, good agreement between direct and indirectmeasurement of brachial artery systolic pressure has beenreported.47 Available data indicate that although peripheralaugmentation of the systolic BP may change the slope of therelationship between MVO2 and HR X BP, the same degreeof correlation remains.46 48

Certain methodological precautions must be considered inthe measurement of MBF by inert gas methods. There mustbe a sufficient period of myocardial saturation and theanalytical technique must be sufficiently sensitive to allowfor resolution of small A-V differences.49 Our analytical

technique is sufficiently sensitive to quantify small changesin tracer concentration (0.77 ± 0.052 volume % or 1.75% offinal aortic N2O concentration). It is possible that we haveoverestimated the contribution from portions of the heartwith normal blood flow and underestimated the contributionfrom areas with reduced blood flow. The fact that our meanresting coronary blood flow (57.4 ± 10.1 ml/100 g LV/min)is nearly identical to that reported using helium as an in-dicator (54 ± 11 ml/100 g LV/min)50 in a similar group ofpatients lends support to our data. Attempts to assess theimportance of these methodological considerations arelimited by the lack of a primary standard of measurementagainst which the N2O technique can be compared in exer-cising man.The HR X BP product (or the shorter term "rate-pres-

sure product"9' 10, 25, 38 which we also prefer) is the indexwhich best correlates with MVO2 and is therefore the criticalone in defining the response of the coronary circulation tomyocardial metabolic demands. The relationship betweenthe rate-pressure product (RPP) and MVO2 may changeslightly with interventions that alter ventricular volume andcontractility, which is the most likely explanation for thefact that patients develop chest pain at a slightly higher RPPafter nitrates and a slightly lower RPP after beta adrenergicblockade with propranolol.10 25

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VOL 57, No 3, MARCH 1978

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F L Gobel, L A Norstrom, R R Nelson, C R Jorgensen and Y Wangin patients with angina pectoris.

The rate-pressure product as an index of myocardial oxygen consumption during exercise

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1978 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.57.3.549

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