comparison of the double two-step test and the maximal exercise

8
Comparison of the Double Two-Step Test and the Maximal Exercise Treadmill Test Studies in Coronary-Prone Subjects By SAMUEL BELLET, M.D., AND LAURIAN ROMAN, M.D. SUMMARY A comparison of the double two-step test and a more strenuous type of exercise test was made to assess the value of the latter procedure in increasing the sensitivity of the electrocardiographic exercise test. In young, normal women, 17 to 20 years of age, who represent a group with minimal chances for significant silent coronary heart disease, both the double two-step test and graded maximal exercise tests were always normal. This is consistent with the view that ischemic electrocardiographic changes are not usually elicited in subjects with normal coronary circulation, even after strenuous exercise. In middle-aged men and women, 40 to 65 years of age, in whom the possible exis- tence of clinically silent coronary heart disease was suggested by age and other para- meters (atypical chest pain, hypertension, or diabetes, or all three), the maximal exercise test on the treadmill, as compared to the double two-step test, increased the yield of positive electrocardiographic results by 12%. These findings suggest that, in selected "coronary-prone" subjects on whom the double two-step test is negative, increasing the amount of exercise might be of value in the evaluation of the exercise test. Additional Indexing Words: ECG exercise test Radioelectrocardiography Coronary atherosclerosis Myocardial ischemia THE VALUE of the electrocardiographic exercise test in the diagnosis of coronary heart disease, silent or clinically overt, has been well established.1-9 In recent years, various attempts have been made to improve the accuracy of the routine electrocardiographic exercise test. The meth- ods employed include: recording the elec- trocardiogram during exercise as well as in the postexercise period'0-13; employment of a more strenuous type of exercise than the usual double two-step test; and a combination From the Division of Cardiology, Philadelphia Gen- eral Hospital, Philadelphia, Pennsylvania. This work was aided by Grant HE-07364 from the National Institutes of Health, U. S. Public Health Service; Grant 66-561-2 from the Commonwealth of Pennsylvania; and by the Foundation for Cardiovas- cular Research, Philadelphia, Pennsylvania. 238 of both of these procedures.'14-7 Most of the studies in the last group have indicated that more strenuous exercise resulted in an in- creased yield of positive tests. However, the results of these studies have differed in many respects. Because of the importance and the relative paucity of such studies, the present investiga- tion was instituted: (1) to determine whether maximal strenuous exercise would produce an ischemic type of electrocardiographic change in young, normal subjects with a pre- sumably normal coronary circulation; and (2) to ascertain whether a more strenuous form of exercise than the two-step test in- creases significantly the yield of positive re- sults obtained in middle-aged subjects of both sexes in whom the possibility of coronary artery disease is high. Circulation, Volume XXXVI, August 1967 by guest on April 2, 2018 http://circ.ahajournals.org/ Downloaded from

Upload: trankiet

Post on 01-Feb-2017

220 views

Category:

Documents


1 download

TRANSCRIPT

Page 1: Comparison of the Double Two-Step Test and the Maximal Exercise

Comparison of the Double Two-Step Test andthe Maximal Exercise Treadmill Test

Studies in Coronary-Prone Subjects

By SAMUEL BELLET, M.D., AND LAURIAN ROMAN, M.D.

SUMMARYA comparison of the double two-step test and a more strenuous type of exercise test

was made to assess the value of the latter procedure in increasing the sensitivity ofthe electrocardiographic exercise test.

In young, normal women, 17 to 20 years of age, who represent a group with minimalchances for significant silent coronary heart disease, both the double two-step test andgraded maximal exercise tests were always normal. This is consistent with the viewthat ischemic electrocardiographic changes are not usually elicited in subjects withnormal coronary circulation, even after strenuous exercise.

In middle-aged men and women, 40 to 65 years of age, in whom the possible exis-tence of clinically silent coronary heart disease was suggested by age and other para-meters (atypical chest pain, hypertension, or diabetes, or all three), the maximal exercisetest on the treadmill, as compared to the double two-step test, increased the yield ofpositive electrocardiographic results by 12%. These findings suggest that, in selected"coronary-prone" subjects on whom the double two-step test is negative, increasing theamount of exercise might be of value in the evaluation of the exercise test.

Additional Indexing Words:ECG exercise testRadioelectrocardiography Coronary atherosclerosis

Myocardial ischemia

THE VALUE of the electrocardiographicexercise test in the diagnosis of coronary

heart disease, silent or clinically overt, hasbeen well established.1-9

In recent years, various attempts have beenmade to improve the accuracy of the routineelectrocardiographic exercise test. The meth-ods employed include: recording the elec-trocardiogram during exercise as well as inthe postexercise period'0-13; employment ofa more strenuous type of exercise than theusual double two-step test; and a combination

From the Division of Cardiology, Philadelphia Gen-eral Hospital, Philadelphia, Pennsylvania.

This work was aided by Grant HE-07364 fromthe National Institutes of Health, U. S. Public HealthService; Grant 66-561-2 from the Commonwealth ofPennsylvania; and by the Foundation for Cardiovas-cular Research, Philadelphia, Pennsylvania.

238

of both of these procedures.'14-7 Most of thestudies in the last group have indicated thatmore strenuous exercise resulted in an in-creased yield of positive tests. However, theresults of these studies have differed in manyrespects.

Because of the importance and the relativepaucity of such studies, the present investiga-tion was instituted: (1) to determine whethermaximal strenuous exercise would producean ischemic type of electrocardiographicchange in young, normal subjects with a pre-sumably normal coronary circulation; and(2) to ascertain whether a more strenuousform of exercise than the two-step test in-creases significantly the yield of positive re-sults obtained in middle-aged subjects ofboth sexes in whom the possibility of coronaryartery disease is high.

Circulation, Volume XXXVI, August 1967

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

Page 2: Comparison of the Double Two-Step Test and the Maximal Exercise

EXERCISE TESTS IN CORONARY HEART DISEASE

Table 1Rates Reached During Maximal

Heartrates / min Group A Group B

100-119 0 5120-139 0 26140-159 16 37160-179 24 22180-199 20 0200+ 0 0

Total 60 93

MethodsTwo groups of subjects were studied: (A)

60 young, normal, female student nurses, aged17 to 20 years, all of whom had normal restingelectrocardiograms and no evidence of heartdisease; and (B) 150 middle-aged subjects ofboth sexes, aged 40 to 65 years, who manifestedvarious types of atypical chest pain, hypertension,or diabetes mellitus, or all three, but no electro-cardiographic signs of myocardial infarction or

ischemia. Subjects with clinical evidence of cor-

onary heart disease (typical angina pectoris or

electrocardiographic signs of myocardial infarc-tion or both) were not included in this study.

All studies were performed in the morningin a room with a temperature of 70 to 72 F afterthe subjects had fasted over night. In both groupsof subjects, an initial resting 12-lead electro-cardiogram was followed by a double two-steptest. This test was performed by the technique

60T GROUP A

50o 1

CO)

IN)

40-

30-

20-

10 -

45

I 2 3 4 5 6Stacges of exercise compLetedA

Figure 1

Highest stage of exercise completed on the tread-mill by group A (see text).Cifculation, Volume XXXVI, August 1967

60- - GROUP B

0049)oa eN

40 ~~~~0MCN.30{ z

~19 20

101

:1. 2 3 4 5 6Stcages of exercise compLeted.

Figure 2

Highest stage of exercise completed on the treadmillby group B (see text). Every stage represents 3 minof walking on a treadmill. In stage 1, the speed is 1.7miles per hour with a grade of 10%; in stage 2, thespeed is 2.5 miles per hour with a grade of 12%; andin stage 3, the speed is 3.4 miles per hour and thegrade is 14%. In stage 4, the speed is 4.2 miles per

hour with a grade of 16%; in stage 5, the speed is 5.0miles per hour with a grade of 18%.

of radioelectrocardiography; leads II, V4, andV6 were recorded before, during, and afterexercise. The method, technique, and electrodeplacement have been described in previous pub-lications." 12, 18'c A maximal exercise test was

recorded 30 minutes after the completion of thedouble two-step test in all subjects of group Abut only in those subjects of group B who pre-

sented negative double two-step tests.The multistage maximal exercise test em-

ployed was similar to that described by Doanand associates.17 This consisted of treadmill ex-

ercise performed in successive 3-minute periodsof gradually increasing severity. The test was

*The instrumentation complies with the specifi-cations of the American Heart Association. 9, 20 TheSanborn specifications (Viso 100 Recorder) statethat the response ranges from 0.1 to 80 cycles persec. The response of the RKG 100 is from 0.15 toabout 1,000 cycles per sec. At various degrees ofsensitivity, the curve of the Sanborn electrocardiogramalone and the combined Sanborn plus the RKG systemwere almost identical. Comparison of the ECG's takensimultaneously by the RKG and the standard San-born ECG before, during, and after exercise con-sistently shows no difference in the contours of theECG.18

Maximal HeartExercise Test

239

I

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

Page 3: Comparison of the Double Two-Step Test and the Maximal Exercise

BELLET, ROMAN

double two-step testV6 A

lying

standing

during exer.30 sec

60 sec

180 sec

after exer.stot

I min

3 min

5 mi'n

treodmill testV6 B

contro I

1.7 mph10 % grode

| ¶I2.5mph12 % grade

uI tt ( 3.4mph

i14 grade

kL4~44~statI IA

5 min

~~~~mi n

Figure 3

Lead V.: The comparative effect of a double two-step test and a treadmill test. The patient,aged 51 years, complained of vague discom-Wfort in his chest which was not clearly related toexertion or excitement.

(A. Double two-step test) Note that the lying and standitng positions show relatively littlechange in the T waves or ST segments. During exercise, note the flattening of the T waves andjunctional ST depression from 30 to 180 sec. The junctional ST depression is also present inthe postexercise period; these changes are slight and are not significant.

(B. Treadmill test) The control (in standing position) is within normal range. Note theprogressive ST-segment depression with the treadmill exercise test. Marked ST depressionsare observed with the second stage. The stat tracing taken immediatelyl after exercise showsmoderate ST-segment depression; this becomes more marked at 1 mrmin; and at 3 anid 5 miin asignificant ischenic type of ST depression is observed.

halted when the subject experienced chest painor was too tired to continue.

Criteria for a positive test were restricted to

isclhemic-type ST depressioni> 1 mm or theappearance of muiltiple prematuire ventricularconltractionls duiring or within the first 5 minutes

Cir ulation, Volnine XXXVI, Auguss 1967

240

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

Page 4: Comparison of the Double Two-Step Test and the Maximal Exercise

EXERCISE TESTS IN CORONARY HEART DISEASE

lying

londing

during20 sec

exer.

8 0 sec

140 sec

af ter exer.

I min

3 mn

5 min

treadmill test

V4

contro

12¶O grade

;:- 34 mph14 grade

stat

I min

~~~~~~mi nK.f . . H

Figure 4

Lead V,,. Patient, 45 years old, had hlypertension (blood pressure, 170/ 110 1mm Hg). Therewas no history of precordial or substernial pain.

(A. Double two-step test) Note the normal control while patient was lying and standing.Slight S T-segment depressions are observed dturing exercise and in the postexercise period.However, these changes cannot be said to be significant.

(B. Treadmill test) Note progressive ST-segment depressions. The postexercise tracings takenat 3 and 5 min show significant ischemic ST-segment depressions; these were not observedwith the double two-step tests.

Circulatin, Volullic XXXVI, Augxust 1967

double two-step test

V4 A

241

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

Page 5: Comparison of the Double Two-Step Test and the Maximal Exercise

BELLET, ROMAN

after exercise. Tracings which did not showthese changes were considered to constitute anegative test.

Results

In group A (60 young student nurses),none of the subjects developed ischemicchanges or multiple premature ventricularcontractions during either the double two-step test or the maximal exercise test. Theperformance of group A, evaluated by thehighest stage which the subjects completedduring the treadmill test, is presented in fig-ure 1. Almost all subjects (58 of the 60 sub-jects) were able to continue the graded ex-ercise to the fourth or fifth stage; the test wasusually stopped after this stage because ofexhaustion. In only two subjects was the testdiscontinued after the third stage becauseof marked exhaustion.The maximal heart rates reached during

treadmill exercise are shown in table 1. Thosein group A ranged from 140 to 200/min.This illustrates the amount of physical effortentailed during the performance of th:s test.

In group B (150 middle-aged subjects ofboth sexes), 57 subjects (38%) presentedpositive double two-step tests; in these, themaximal exercise test was not performed be-cause it would not have provided additionaldiagnostic information.The remaining 93 subjects in group B

presented negative double two-step tests.Their performance in the treadmill test isshown in figure 2. The stage reached duringthe maximal exercise test and the sex dis-tribution in each stage are indicated. Mostsubjects completed the third or fourth stage.Generally, men were able to continue thetest longer than women. The five subjectswho reached the fifth stage were all men;14 of the 19 who were able to complete onlytwo stages were women. As can be seen intable 1, the maximal heart rate in group Bvaried from 100 to 200/min; however, most ofthe rates fell within the range of 120 to 180/min.

In seven of these 93 subjects with negativedouble two-step tests, the maximal exercise

test resulted in the appearance of ischemicchanges in the electrocardiogram (figs. 3 and4). This represents a 12% additional yield tothe 57 subjects with positive double two-steptests. Exercise-induced multiple prematureventricular contractions were not observed inthis group. Five of the seven subjects withpositive treadmill tests were men; four of theseven completed three stages of graded ex-ercise, and the other three completed thefourth stage.

DiscussionSignificance of ElectrocardiographicExercise TestsThe value of the electrocardiographic ex-

ercise test as an objective method for thediagnosis of overt or clinically silent coronaryheart disease has been studied extensively inthe past 25 years.1-16 In the majority ofsubjects with clinically clear-cut coronaryheart disease the electrocardiographic exer-cise test was found positive, although theresults obtained by various authors differedto some extent.2A4 11-13 Of particular interestare the long-term prospective studies whichhave shown correlation between positive ex-ercise tests and incidence of subsequent coro-nary heart disease.5-9 Robb and Marks6 fol-lowed 1,659 applicants for life insurance,most of whom had some type of chest pain,and found that among those who showedischemic ST depression after exercise, thesubsequent mortality due to coronary heartdisease was six times that among those withnegative exercise tests. In a comparable study,Mattingly5 obtained similar results, and a cor-relation between positive electrocardiographicexercise tests and severe, diffuse coronaryatherosclerosis was found at postmortem ex-amination. Prospective studies of normalsubjects5' 7 8 have also shown subsequent cor-onary heart disease to be significantly morefrequent among subjects with positive exer-cise tests than among those with negativetests.Our recent personal experience further

supports these findings.9 During a 3-yearfollow-up of 795 normal males, aged 30 to

Circulation, Volume XXXVI, August 1967

242

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

Page 6: Comparison of the Double Two-Step Test and the Maximal Exercise

EXERCISE TESTS IN CORONARY HEART DISEASE

65, the incidence of coronary episodes wasalmost 10 times greater in the group withinitially positive exercise tests than in thegroup with negative tests.These observations have led many workers

in this field,5' 6, 17 including ourselves, to feelthat in the absence of other causes of im-paired coronary blood flow or of disturbedionic membrane exchanges in the myocardialcell (for example, congenital or rheumaticheart disease, myocardiopathies, severe ane-mia, electrolyte imbalance, or digitalis ther-apy), a positive electrocardiographic exercisetest is in most instances due to coronaryheart disease, overt or clinically silent. Ex-ceptions are possible but are relatively un-common.

Value of Strenuous Types of Exercise Tests

In most of the above-mentioned studies,the electrocardiogram was recorded duringor after a double two-step test. In recentyears, in an attempt to improve the accuracyof the exercise test, more strenuous types ofexercise have been used. Several studiesemploying a maximal type of exercise havebeen performed on a treadmill or with othertechniques and compared with the two-steptest.A number of studies were performed on

groups of physically active subjects. Doanand associates'7 reported that among 201normal men in top form of physical training,34 to 60+ years of age, maximal exerciseincreased the number having positive exercisetests from two (1%) detected by the doubletwo-step test to 18 (9%) during maximal ex-ercise. Therefore, these authors claimed thatmaximal exercise increases the sensitivity ofthe electrocardiographic exercise test ninefoldin comparison to the double two-step test.However, Sheffield and co-workers14 did notfind a single positive test among 112 healthysubjects, aged 14 to 94, although strenuousexercise (treadmill exercise, climbing stairs,walking, or bicycling) was continued untilthe subject reached 85% of his age-predictedmaximal heart rate. Berkson and co-workers'5employing strenuous treadmill exercise in a

Circulation, Volume XXXVI, August 1967

group of physically active, healthy, middle-aged men, found positive tests (ischemicST-segment depression) in 44% of cases. Inthis study, no comparison with the two-steptest was performed.

Studies have also been performed on sub-jects with various types of myocardial ab-normality. In a study of 24 subjects withvarious types of heart disease, Doan and as-sociates17 reported that the two-step testswere positive in eight and the maximal ex-ercise test was positive in an additional five.Sheffield and co-workers14 employing bothtests on the same group of patients withcoronary heart disease obtained approxi-mately 20 to 25% more positive results fromthe maximal exercise test than from the dou-ble two-step test.

These results show considerable diversity.Our primary aim in the present study was

to determine whether ischemic electrocardio-graphic changes could be induced by exercisein subjects with normal coronary circulation.Previous work has shown the absence of posi-tive electrocardiographic findings in young,normal male subjects even after strenuousexercise.'14 17 We elected to study young wom-en because the possibility of silent coronaryheart disease is minimal in this group. In ourseries of young normal women, the exercisetest was normal with both the two-step andthe maximal exercise technique. Our findingstherefore confirm the fact that ischemic elec-trocardiographic changes are not elicited,even by strenuous exercise, in subjects withnormal hearts and presumably normal coro-nary circulation.

In group B, comprised of 150 middle-agedsubjects of both sexes with hypertension, dia-betes, or atypical chest pain, the double two-step test was positive in 57 cases. As waspreviously mentioned, the maximal exercisetest was not performed in these subjects asno additional information would have beenprovided. The high incidence of positive ex-ercise tests was to be expected in such agroup of subjects who are known to becoronary prone and in whom clinically silentcoronary heart disease is frequent. We

243

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

Page 7: Comparison of the Double Two-Step Test and the Maximal Exercise

BELLET, ROMAN

have reported our findings in such groupspreviously.21' 22 In 100 hypertensive subjectsfree of symptomatic coronary heart diseaseand of rheumatic or congenital heart disease,the incidence of positive double two-steptests was 37%.21 Moreover, in a similar groupof diabetic patients without overt symptomsof heart disease, the electrocardiographic ex-ercise test was positive in 22% of cases.22The maximal exercise test was subsequently

performed and found to be positive in sevenof the 93 subjects of group B in whom thedouble two-step test was negative. Thus, incomparison with the double two-step test,the additional yield of positive results dueto more strenuous exercise was 12%.Our present study therefore appears to

indicate that, in selected "coronary-prone" sub-jects with negative double two-step tests, theperformance of more strenuous exercise maybe helpful in evaluation of the electrocardio-graphic exercise test.

AcknowledgmentWe wish to thank Mrs. Rosemary Dresner and

Mrs. Christine Amentt, radioelectrocardiographic tech-nicians, for their assistance in this project.

References1. MASTER, A. M., FRIEDMAN, R., AND DACK, S.:

Electrocardiogram after standard exercise as afunctional test of the heart. Amer Heart J24: 777, 1942.

2. ROSENFELD, I., MASTER, A. M., AND ROSENFELD,C.: Recording the electrocardiogram during theperformance of the Master two-step test. Cir-culation 29: 204, 1965.

3. SCHERF, D., AND SCHAFFER, A. I.: Electrocardio-graphic exercise test. Amer Heart J 43: 927,1952.

4. LEPESCHKIN, E.: Exercise test in the diagnosisof coronary heart disease. Circulation 22: 986,1960.

5. MATTINGLY, T. W.: The postexercise electrocar-diogram: Its value in the diagnosis and prog-nosis of coronary heart disease. Amer J Cardiol9: 395, 1962.

6. ROBB, G. P., AND MARKs, H. H.: Latent coro-nary artery disease: Determination of its pres-ence and severity by the exercise electrocardio-gram. Amer J Cardiol 13: 603, 1964.

7. BRODY, A. J.: Master two-step exercise test inclinically unselected patients. JAMA 171: 1195,1959.

8. RUMBALL, C. A., AND AcHEsON, E. C.: Latent

coronary heart disease detected by electrocar-diogram before and after exercise. Brit Med J1: 423, 1963.

9. BELLET, S., ROMAN, L., NICHOLS, G. J., AND

MULLER, 0. F.: Detection of the coronary-prone subject in a normal population by radio-electrocardiographic exercise test: Follow-upstudies. Amer J Cardiol 19: 783, 1967.

10. BELLET, S., DELIYIANNIS, S., AND ELIAKIM, M.:Electrocardiogram during exercise as recordedby radioelectrocardiography. Amer J Cardiol8: 385, 1961.

1 1. BELLET, S., ELIAKIM, M., DELIYIANNIS, S., AND

LAVAN, D. W.: Radioelectrocardiography dur-ing exercise in patients with angina pectoris.Circulation 25: 5, 1962.

12. BELLET, S., MULLER, 0. F., LAVAN, D. W.,NICHOLS, G. J., AND HERRING, A. B.: Radio-electrocardiography during exercise in patientswith the anginal syndrome: Use of multipleleads. Circulation 29: 355, 1964.

13. ABARQUEZ, R. F., KINTANAR, Q., VALDE, E.,AND DAYRIT, C.: Evaluation of some criteriafor the dynamic and post-exercise electrocar-diogram in diagnosing coronary insufficiency.Amer J Cardiol 14: 310, 1964.

14. SHEFFIELD, L. T., HOLT, J. H., AND REEVES, T. J.:Exercise graded by heart rate in electrocardio-graphic testing for angina pectoris. Circula-tion 32: 622, 1965.

15. BERKSON, D. M., STAMLER, J., AND JACKSON,W.: Precordial electrocardiogram during andafter strenuous exercise. Amer J Cardiol 18:43, 1966.

16. BELLET, S., ELIAKIM, M., DELIYIANNIS, S., ANDFIGALLO, E.: Radioelectrocardiographic changesduring strenuous exercise in normal subjects.Circulation 25: 686, 1962.

17. DOAN, A. E., PETERSON, D. R., BLACKMON, J. R.,AND BRUCE, R. A.: Myocardial ischemia aftermaximal exercise in healthy men: A methodfor detecting potential coronary heart disease?Amer Heart J 69: 11, 1965.

18. BELLET, S., AND MULLER, 0. F.: Electrocardio-gram during exercise: Its value in the diag-nosis of angina pectoris. Circulation 32: 477,1965.

19. WILSON, F. N., ET AL.: Recommendations forstandardization of electrocardiographic and vec-torcardiographic leads. Circulation 10: 564,1954.

20. LEPESCHKIN, E.: Electrocardiographic instrumen-tation. Progr Cardiov Dis 5: 498, 1963.

21. BELLET, S., AND ROMAN, L.: Exercise test inhypertensive subjects studied by radioelectro-cardiography. Amer J Med Sci. In press.

22. BELLET, S., AND ROMAN, L.: Exercise test indiabetic patients as studied by radioelectrocar-diography. Circulation 36: 245, 1967.

Circulation, Volume XXXVI, August 1 967

244

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from

Page 8: Comparison of the Double Two-Step Test and the Maximal Exercise

SAMUEL BELLET and LAURIAN ROMANTest: Studies in Coronary-Prone Subjects

Comparison of the Double Two-Step Test and the Maximal Exercise Treadmill

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1967 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.36.2.238

1967;36:238-244Circulation. 

http://circ.ahajournals.org/content/36/2/238located on the World Wide Web at:

The online version of this article, along with updated information and services, is

  http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. and Rights Question and Answer

Permissionsthe Web page under Services. Further information about this process is available in thewhich permission is being requested is located, click Request Permissions in the middle column ofClearance Center, not the Editorial Office. Once the online version of the published article for

can be obtained via RightsLink, a service of the CopyrightCirculationoriginally published in Requests for permissions to reproduce figures, tables, or portions of articlesPermissions:

by guest on April 2, 2018

http://circ.ahajournals.org/D

ownloaded from