Labile Hypertension: A Faulty Concept?The Framingham Study

W. B. KANNEL, M.D., PAUL SORLIE, M.S., AND TAVIA GORDON

SUMMARY Labile blood pressure elevation is believed to have less clinical significance than "fixedhypertension." This assertion was examined in the Framingham cohort of 5209 men and women followed for20 years for the development of cardiovascular events in relation to three routinely measured blood pressures ateach of 10 biennial examinations.

Variability of pressure judged from the standard deviation about the mean of three pressures was not a con-

sistent characteristic of subjects from one examination to the next (r = 0.07). Higher pressures were more

labile than low ones, so that "fixed hypertensives" actually had more labile pressures than did so-called labilehypertensives. Lability also increased with age.

Labile hypertension, determined during a 1-hour period of observation, adds nothing to the ability of themean blood pressure to predict cardiovascular disease. The mean, minimum and maximum of three pressuresmeasured during an examination were equally efficient predictors of cardiovascular disease. In multivariateanalysis, for any given average pressure, risk of cardiovascular events was unaffected by the degree ofvariability of the pressure. It is recommended that the average of a series of pressures be used to determinerisk, preferably over more than one examination.

LABILE HYPERTENSION is regarded as arelatively innocuous antecedent of "fixed" hyperten-sion.1 As such, it is common clinical practice to con-sider labile hypertension unworthy of treatment.2The purpose of this report is to examine the concept

of labile hypertension and its role in the developmentof cardiovascular disease in the Framingham Study.This cohort has been followed over 20 years for thedevelopment of cardiovascular disease in relation tothree routinely obtained biennial blood pressures. Thelability of pressure is calculated from these readingsand its net effect on risk of cardiovascular disease,taking the average level of pressure into account, isascertained.

Methods

The Framingham cohort consists of 2336 men and2873 women ages 30-62 years at entry to the study in1948-1952. They received a standardized, routinereexamination for the development of cardiovasculardisease every 2 years. Cardiovascular events and mor-tality that occurred in the 20 years of follow-up wereascertained by means of these biennial cardiovascularexaminations and surveillance of hospital admissionsand deaths. Criteria for cardiovascular end pointshave been given elsewhere.3The examination procedures, sampling, type of

follow-up and response rates have been described indetail previously.4 The examination procedure in-cludes blood pressure measurements, an ECG, a car-

From the Framingham Heart Disease Epidemiology Study,Framingham, Massachusetts, the Boston University School ofMedicine, Evans Memorial Research Foundation, Department ofMedicine, Boston, Massachusetts, and the Biometrics ResearchBranch, NHLBI, NIH, Bethesda, Maryland.

Address for correspondence: Paul D. Sorlie, National Institutesof Health, 7550 Wisconsin Avenue, Room 2A06, Bethesda,Maryland 20205.

Received April 25, 1979; revision accepted November 30, 1979.Circulation 61, No. 6, 1980.

1183

diovascular physical examination and history, acigarette history and a variety of blood chemistries, in-cluding cholesterol, lipoproteins and blood sugar.3

Systolic and diastolic pressures were obtained usinga mercury sphygmomanometer with a 14-cm cuff longenough to fit the most obese arm. The subject wasseated and the left arm was used. Recommendationsof the American and British Heart Associations werefollowed.5 Palpation was used to check auscultatoryfindings. Diastolic pressure was read at the fifthKorotkoff phase. Readings were made to the nearesteven number. Beginning in 1950, three pressures wereobtained routinely on each subject: one by the nurseand two by the examining physician - one at the startof the exam, the other at the end of the interview afterthe blood specimen was obtained.The relation of the various components of pressure

under consideration - the mean, minimum, max-imum and variability - to subsequent appearance ofcardiovascular disease was evaluated by estimating alogistic function using the methods of Walker-Duncan6 and Truett-Cornfield.7 These evaluations usea person-exams approach in which blood pressures atall 10 exams are considered. Thus, the assessment ofcardiovascular risk is based on all available bloodpressures and not on a single initial reading.The within-person standard deviation was used to

assess the variability of the pressure. Because only twoor three blood pressures were used to estimate thisvariability, the standard deviation was adjusted for thebias caused by small numbers.8 9 When two bloodpressures are available, the standard deviation is theabsolute difference of the two measurements mul-tiplied by a constant. Thus, in some analyses, the ab-solute difference between the blood pressures is usedas a description of within-person variability.

Hypertension was designated when two pressuredeterminations exceeded 160/95 mm Hg, normoten-sion was indicated by pressures consistently below140/90 mm Hg, and intermediate pressures weredesignated "borderline."3

by guest on July 2, 2018http://circ.ahajournals.org/

Dow

nloaded from

VOL 61, No 6, JUNE 1980

Results

Variability

Blood pressure is acknowledged to be a mea-surement that fluctuates physiologically in response tochanges in physical activity, emotion, mood,wakefulness and other demands for greater tissue per-fusion. Therefore, pressures under office conditionsare sometimes variable. This has engendered skep-ticism about the value of a single blood pressurereading.

However, it is difficult to discern what mostphysicians or texts mean by the term "labile hyperten-sion." Presumably it means that, using some arbitrarydefinition of "hypertension," the pressure measure-ment, when repeated, is below this arbitrary level andin the borderline or normal range.When examined in this way, 35% of male and 27%

of female hypertensives on one biennial examinationwere borderline or normotensive on the next (table 1).By this criterion, those subsequently found to be nor-motensive might be judged very labile, and thoseborderline moderately so.

However, this concept of "lability" is confoundedby the statistical phenomenon of regression toward themean. A subgroup selected because it is above averagepressure and then remeasured, will be closer to themean for the entire sample and hence lower on thesecond measurement.One indication of the lability of the blood pressure

is the standard deviation about the mean of a series ofpressures obtained over an hour on a particular bien-nial examination. An approximation of this standarddeviation for two measurements is the absolutedifference between the measurements. About 65% ofthose examined had differences in two systolicmeasurements, made by a physician, of less than 10mm Hg; for diastolic, 81% had a difference less than10 mm Hg. Differences greater than 20 mm Hg oc-curred in less than 10% of persons for systolic and inonly 2% for diastolic (table 2).The variation of blood pressure during the 1-hour

exam did not appear to be a repeatable characteristicof a subject. The variation at one moment was un-related to variation at another. While the bloodpressures themselves were highly correlated in a sub-ject from one exam to the next (table 3), the correla-tion of standard deviations of blood pressure from oneexamination to another is extremely low whether 2years or 18 years apart (0.08 and 0.04, respectively).

Analysis of subjects who had all 10 examinationsshows that extreme variability of systolic blood pres-

TABLE 1. Hypertensive Status at Examination 3 vs Exami-nation 4: Men and Women Ages 30-62 Years at Entry. Framing-ham Study

Percent hypertensiveat exam 4

Pressure status at exam 3 Men Women

Normotensive 3% 2%

TABLE 2. Distribution of Differences Between Two Physician-measured Blood Pressures at One Examination: FraminghamStudy, Examination 3, Men and Women Ages 34-66 Years

Percent with specified differenceDifferences Systolic Diastolic(mm Hg) Men Women Men Women

0-9 65 65 82 8010-19 26 26 16 1820-29 7 6 2 2> 30 2 2 0.2 0.2

TABLE 3. Correlation of Blood Pressures Between Initialand Later Examinations: Framingham Study, Men and WomenAges 30-62 Years at Entry

Systolic DiastolicLater exam Men Women Men Women

Exam 2 (2 yrslater) 0.67 0.80 0.60 0.69

Exam 10 (18 yrslater) 0.47 0.55 0.38 0.43

sure repeated on many examinations is a rare finding(table 4). In comparing the number of personswith high variability with that expected from thebinomial function, there are slightly more subjectsobserved than expected in those categories with themore frequent occurrences (three or more exams withhigh variability). This is consistent with the small butpositive correlation coefficient described earlier.However, the magnitude is very small. If four or moreoccurrences of high variability may be thought to in-dicate an individual with "characteristically highvariability," there are only 12 more individuals soobserved than expected out of a population of 1785.

Thus, although pressures do vary some during anoffice examination (table 1), there is little evidence tosupport the contention that there are actually iden-tifiable persons in a population who characteristically

TABLE 4. Number of Subjects with High Variability (HV)*of Systolic Blood Pressure on 10 Framingham Examinations:Observed and Expected

Number of subjectsNumber of Framingham exams with HVwith high within-person variability Observed Expectedt

No. of exams with HV 857 7771 of 10 574 6742 of 10 240 2633 of 10 92 614 of 10 17 95of 10 3 16oflO 2 07 or more 0 0

1785 1785

*High variability means difference > 20 mm Hg betweensystolic pressures taken by two examiners.

tExpected is based on binom-iial function with an overallprobability of HV of 0.07983.

Borderline 21% 21%High 65% 73%

1184 CIRCULATION

by guest on July 2, 2018http://circ.ahajournals.org/

Dow

nloaded from

LABILE HYPERTENSION/Kannel et al.

TABLE 5. Within-person Variation of Systolic Blood Pressureby Age and Sex, Framingham Heart Study. Examination 3

Average within-person standard Number of

Age deviation persons measured(years) Men Women Men Women35-39 6.74 5.68 367 40540-44 6.74 6.65 365 45345-49 6.94 7.13 317 40750-54 7.61 7.99 261 36755-59 8.40 8.52 275 33260-64 8.74 10.32 205 254

have unusually labile pressures on a number of caminations. However, systolic blood pressuvariability is related to age, with the older subje(having higher variability, at least in the age ran35-64 years (table 5). Furthermore, all pressures a

to some extent labile, and high pressures are actuamore labile than low ones. Even after adjusting iage, within-person variability increases withcreasing systolic pressure (fig. 1). Hence, pressures 1above the arbitrary dividing line between "hypertesion" and normal or borderline pressures, commorregarded as "fixed hypertension," are actually mclabile than those close to this arbitrary boundary ausually regarded as labile.

Lability and Risk

"Basal" pressures have been considered the bobasis for judging the need for treatment.1 2 Those relevated under basal conditions were often in the p;judged innocuous and thought not to require trelment. As an extension of this concept, physicians hatended to use the lowest pressure recorded on a paticas the most valid for evaluating risk.

In the Framingham cohort, the lowest presst

Xs

z0

Fe

5

-L'a

z

0

cc

LAJCL

11.0

9.0

7.0

5.0 l-

Men----

Women

m110 110-119 120-129 130-139 140-149

SYSTOLIC BLOOD PRESSURE (MM-Hg)

FIGURE 1. Age-adjusted, within-person variation

systolic blood pressure (mm Hg) according to level,amination 3. Men and women ages 35-64 years.

TABLE 6. Regression of Incidence of Cardiovascular Diseaseon Three Blood Pressures: Men and Women Ages 45-74 Years.Framingham Study 20-Year Follow-up

Regression coefficients for SBPMeasurement (independent variables: SBP, age)of three pressures Men Women

Minimum 0.0177 0.0204Mean 0.0178 0.0210Maximum 0.0163 0.0195

Abbreviation: SBP = systolic blood pressure.

TABLE 7. Incidence of Cardiovascular Disease at BorderlinePressures in Men Ages 45-74 Years: Framingham Study20-year Follow-up

Classification of 2-yearsystolic pressure age-adjusted(mm Hg) on three Population No. of incidence ratereadings at risk cases (%)

Maximum > 140;mean < 140 1497 56 3.7

Mean > 140;minimum < 140 893 48 5.3

Minimum, mean,maximum > 140 2723 177 6.0

Normotensive(maximum <

140) 4520 111 2.6

clx-irectsigeire,llyforin-fare,n-nly:reLnd

recorded during an office visit was not a better predic-est tor than the average pressure. The mean, minimumlot and maximum of three pressures taken during anast office examina+:jn are, judging from the regression ofat- incidence of cardiovascular disease on them, virtuallyive indistinguishable predictors of cardiovascular diseaseent (table 6). The similarity of the regression coefficients

in table 6 indicates that the relative risk is similar forare the three measures of blood pressure. For example, if

the blood pressure were to differ by 20 mm Hg, the ap-proximate relative risk for the minimum, mean andmaximum would be, respectively, 1.43, 1.43 and 1.39for men.

However, because of the relationship among theminimum, the mean and the maximum pressures, theabsolute risks are different (table 7). If only the max-imum of three readings is over 140 mm Hg, the otherreadings will be lower, resulting in a lower risk of car-diovascular disease in this group. This risk is still 42%higher than that for normotensives. If the minimum ishigh, this reflects a higher average pressure, whichresults in a higher risk - more than twice that of nor-motensives.

Thus, there is no question that persistently elevatedbasal pressures are associated with a high risk of car-diovascular disease. The lowest pressure obtained in

_j the office is, when elevated, clearly associated with a150+ high risk (fig. 2). Also, at any level of pressure the risk

is greater when it is the lowest than when it is thehighest of a series of pressures. This is merely a reflec-

of tion of the higher average pressure of the former. Inex- any event, the converse is not true. It is not safe to dis-

regard patients whose pressures fail to be persistently

1185

by guest on July 2, 2018http://circ.ahajournals.org/

Dow

nloaded from

VOL 61, No 6, JUNE 1980

4cc

0us

4IL

0

0

(.5

c-0LA.

zWa

z

ccC,,

zLuC,,

Lu,

a

12%

8%

4%

- Minimum of 3 readings

Mean of 3 readings,

-- Maximum of

-_. ,,

a a-

74- 110- 120- 130- 140- 150- 160- 170- 180- 190+109 119 129 139 149 159 169 179 189

SYSTOLIC BLOOD PRESSURE

FIGURE 2. Fitted incidence of cardiovascular disease bylevel of systolic blood pressure (minimum, mean or maxi-mum of three readings). Men ages 45-74 years, age-adjustedincidence. Framingham Heart Study.

elevated on every determination if the averagepressure is high.

It would seem that the best indicator of risk is theaverage of a series of office pressures rather than thelowest reading. Though all measures demonstratenearly equal relative risks, the average of a serieswould yield a more precise estimate of a person'sblood pressure.Whereas the risk of cardiovascular disease is best

judged from the average of a series of pressures, therisk is unaffected by the variability of these pressuresabout the mean. Patients whose pressures are more"labile" have no lower risk of cardiovascular eventsthan those whose pressures were less variable. In fact,taken alone, the risk of cardiovascular disease actuallyincreases with the degree of variability in pressure(table 8). However, this reflects only the higheraverage pressure of those with more variable values.When this is adjusted for the mean level of pressure bycomputing coefficients of variation, there is no rela-tion of variability to risk.

TABLE 8. Cardiovascular Disease by Pressure Variabilityin Men Ages 45-74 Years: Framinyham Study 20-year Follow-up

Unadjusted foraverage pressure Adjusted for

Standard average pressuredeviation 2-year Coefficient of 2-yearof pressure incidence variation incidence(mm Hg) rate (%) (* rate (%)

0-4 3.7 0-0.9 4.25-9 4.0 1.0-1.9 2.610-14 4.5 2.0-2.9 3.515+ 5.7 3.0+ 4.5

Standardizedslope 0.129 0.051

Age-adjusted 2.74 1.02

*Coefficient of variation is the within-person standarddeviation of pressure divided by within-person mean pressure.

TABLE 9. Cardiovascular Disease vs Systolic Level, Labilityand Age: Framingham Study 20-year Follow-up, Ages 45-74 Years

Standardized multiple logistic coefficientsMen Women

SBP lability 0.027 0.080

SBP level 0.357* 0.420*Age 0.303* 0.458*

p <0.001.Abbreviation: SBP = systolic blood pressure.

A surer way of disentangling the effects of labilityfrom the pressure level is to compute multivariateregression coefficients, allowing an interpretation ofthe net effect of each component of the pressure. Thisshows coefficients for lability that are neither substan-tial nor statistically significant and they are notnegative (table 9). Thus, there is no indication of alesser risk in relation to lability, taking the level ofpressure into account. In fact, there is no suggestion ofany influence of lability, one way or the other, on riskof cardiovascular sequelae of hypertension.

DiscussionBlood pressure is a dominant contributor to the

major cardiovascular diseases, particularly for strokeand cardiac failure.'0' 11 Epidemiologic data haveclearly shown that casual office pressures are highlypredictive of subsequent incidence of cardiovasculardisease. Physicians appear convinced that they can im-prove on this by attention to the lability, systolic anddiastolic components, repeated measurements over aperiod of observation and basal pressures.

Casual pressures can be obtained more repro-ducibly by standardizing the measurement situation,making sure that the subject is tranquil and rested,and by acclimatization through repeated measure-ments."' 12 Whether this is a more appropriate mea-surement for evaluating risk is uncertain. It can beargued that a casual measurement is more represen-tative and relevant.9' 10 The initial examination bloodpressure measurement at Framingham was somewhathigher on average than on later exams, presumablydue to the novelty of the procedure, and predicted car-diovascular disease at least as well as pressures onlater exams.9

Variation in blood pressure has been examinedpreviously, but its significance in evaluating risk hasnot been clearly determined.'13-5 The lack of precisionin the diagnosis of "hypertension" is surprising, con-sidering that it is a prevalent and powerful contributorto cardiovascular disease. Over the years, hyperten-sion has been subdivided into malignant and benignand labile and fixed varieties in an attempt to dis-tinguish severe from mild forms of the disease process.The malignant or accelerated variety appears to be

a distinct entity with a unique vascular pathology - anecrotizing, fibrinoid arteriolar process. Labilehypertension has no such distinguishing features. Infact, almost all normotensive persons occasionally

1186 CIRCULATION

by guest on July 2, 2018http://circ.ahajournals.org/

Dow

nloaded from

LABILE HYPERTENSION/Kannel et al.

have pressures above the arbitrary normal limits.'6' '7Likewise, almost all patients with so called fixedhypertension occasionally have pressures below theconventionally designated hypertensive limits.Perhaps a useful characterization of lability could bearrived at by responses to standard stimuli or byanalysis of long-term chronobiological fluctuations.'8By current definitions, however, and by short-termobservations, the entity does not appear to be a persis-tent individual characteristic or to have clinicalsignificance.Clinical Implications

As assessed by repeated 1-hour clinic visits, nosupport can be found for the concept that there is a

discrete subgroup of the population with characteris-tically labile pressures. However, there are other defi-nitions and descriptions of labile blood pressures.

Many distraught patients will have an elevatedpressure in the physician's office but will later exhibitwhat is considered a nonhypertensive pressure.

Recognition of this appears to be responsible for thetraditional concept of fixed and labile hyperten-sion.'9' 20 Those who accept this distinction as validhave concluded that "basal" blood pressures are morereliable determinants of the prognosis in hypertensionthan are casual pressures.2"22 While this may seemreasonable on a priori grounds, given the knownvariability of blood pressure, casual pressures predictoutcomes surprisingly well. In regard to cardio-vascular sequelae, it appears that the only reason thatfixed hypertension is associated with a higher risk thanlabile hypertension and basal pressure elevations carry

a higher risk is that the average pressure of basal orfixed hypertension is higher. It would therefore appear

more logical to rely on the average pressure ratherthan on such ambiguous indicators as basal or fixedstates of hypertension. It is not safe to rely on thelowest pressure recorded on a patient as an indicatorof the need for treatment.

Caldwell et al.23 found that near-basal pressures

were no more accurate as indicators of cardiorenalmanifestations of hypertension than were casualpressures.

It may be unwise to label a patient hypertensive on

the basis of a single office blood pressure. It does notappear to be good practice to place such patients, whomay have been transiently emotionally upset, on a

lifetime of antihypertensive therapy on the basis ofone office blood pressure reading. However, it wouldappear equally unwise to conclude that the patientwho occasionally has a nonhypertensive bloodpressure is in no jeopardy.

Greater attention to diastolic than systolic casualoffice pressures, contrary to widely held belief, addsnothing to the precision of risk estimates.'011Disregarding those with isolated systolic elevations isalso a mistake.'0 More important in assessing thegravity of the average blood pressure is the height ofthe systolic pressure, the number of associated car-

diovascular risk factors and whether or not there istarget organ involvement.' This is true whether thepressure elevation is labile or fixed.

References

1. Smirk FH, Veale AMO, Alstad KS: Basal and supplementalblood pressures in relationship to life expectancy and hyperten-sion symptomotology. NZ Med J 58: 711, 1959

2. Freis ED: VA cooperative study on anti-hypertensive agents:effects of treatment on morbidity and hypertension. JAMA202: 1028, 1970

3. Shurtleff D: Some characteristics related to the incidence ofcardiovascular disease and death. Framingham Study. 18-yearfollow-up. In An Epidemiological Investigation of Car-diovascular Disease, section 30, edited by Kannel WB, GordonT. Washington DC, US Government Printing Office, 1974

4. GordonT, Kannel WB: The Framingham Massachusetts Studytwenty years later. In The Community as an EpidemiologicLaboratory: A Casebook of Community Studies, edited byKessler IJ, Levin ML. Baltimore, John Hopkins Press, 1970, pp123-146

5. Joint Recommendations of the American Heart Associationand the Cardiac Society of Great Britain and Ireland: Stan-dardization of blood pressure readings. Am Heart J 18: 95,1939

6. Walker SH, Duncan DB: Estimation of the probability of anevent as a function of several independent variables. Biometrika54: 167, 1967

7. Truett J, Cornfield J, Kannel WB: A multivariate analysis ofthe risk of coronary heart disease in Framingham. J ChronicDis 20: 511, 1967

8. Pearson ES, Hartley HD: Biometrika Tables for Statisticians,vol 1. Cambridge, University Press, 1954, pp 18, 184

9. Gordon T, Sorlie P, Kannel WB: Problems in the assessment ofblood pressure: the Framingham Study.IntJ Epidemiol 5: 327,1976

10. Kannel WB, Sorlie P: Hypertension in Framingham. InEpidemiology and Control of Hypertension, edited by Paul 0.Miami, Symposia Specialists, 1975

11. Kannel WB, Dawber TR, Sorlie P, Wolf PA: Components ofblood pressure and risk of atherothrombotic brain infarction:The Framingham Study. Stroke 7:327, 1976

12. Rose GA, Blackburn H: Cardiovascular Survey Methods.(Monograph 56) Geneva, WHO Press, 1968

13. Gordon T: Blood pressure of adults by age and sex. US1960-1962. PHS no. 1000, series 11, no. 4. Washington DC,US Government Printing Office, 1964

14. Glock CY, Vought RL, Clark EG: Studies in hypertension. II.Variability of daily BP. Measurements in the same persons overa 3-week period. J Chronic Dis 4: 469, 1956

15. Armitage P, Fox W, RoseGA, Tiaber CU: The variability ofcasual blood pressure: survey experience. Clin Sci 30: 337, 1966

16. Halberg F, Haus E, Ahlgren A, Halberg E, StrobelH, AngellarA, Kuhl, JFW, Lucas R, Gedgaudas E, Leong J: Blood pressureself measurement for computer-monitored health assessmentand the teaching of chronobiology in high schools. InChronobiology. Proceedings of the International Society forthe Study of Biological Rhythms, Little Rock, Arkansas, 1971,edited by Scheving LE, Halberg F, Pauly JG, Toyko, IgakuShoin Ltd, 1974, pp 372-378

17. Pickering G: Hypertension: definitions, natural histories, con-sequences. Am J Med 52: 570, 1972

18. Bartter FC, Delea CS, Baker W, Halberg F, Lee JK: Chrono-biology in the diagnosis and treatment of Mesor-hypertension.Chronbiologia 3:199, 1976

19. Freis ED: The treatment of hypertension. Am J Med 52: 664,1972

20. Perloff D: Diagnostic assessment of the patient with hyperten-sion. Geriatics 31: 77, 1976

21. Alam GM, Smirk FH: Casual and basal blood pressure inBritish and Egyptian men. Br Heart J 5:152, 1943

22. Harlan WR, Osborne RK, Graybiel A: Prognostic value of thecold pressor test and the basal blood pressure. Am J Cardiol 13:683, 1964

23. Caldwell JR, Schork MA, Aiken RD: Is near basal bloodpressure a more accurate predictor of cardiorenalmanifestations of hypertension than casual blood pressure? JChronic Dis 31: 507, 1978

1187

by guest on July 2, 2018http://circ.ahajournals.org/

Dow

nloaded from

W B Kannel, P Sorlie and T GordonLabile hypertension: a faulty concept? The Framingham study.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1980 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.61.6.1183

1980;61:1183-1187Circulation. 

http://circ.ahajournals.org/content/61/6/1183the World Wide Web at:

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

  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. Permissions and Rights Question and Answer information about this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. FurtherEditorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center, not theCirculationpublished in Requests for permissions to reproduce figures, tables, or portions of articles originallyPermissions:

by guest on July 2, 2018http://circ.ahajournals.org/

Dow

nloaded from