Heart 1996;75:389-395

Aortic root complications in Marfan's syndrome:identification of a lower risk group

Malcolm E Legget, Trisha A Unger, Corrine K O'Sullivan, Todd R Zwink,Robin L Bennett, Peter H Byers, Catherine M Otto

Division of Cardiology,Department ofMedicine andDepartment ofPathology, UniversityofWashington, Seattle,Washington, USAM E LeggetT A UngerC K O'SullivanT R ZwinkR L BennettP H ByersC M OttoCorrespondence to:Dr Catherine M Otto,Division of Cardiology,Box 356422, University ofWashington, Seattle, WA98195, USA.Accepted for publication17 October 1995

AbstractObjectives-The purpose of this studywas to examine clinical and echocardio-graphic predictors of outcome in a cohortofpatients with Marfan's syndrome.Background-Serial echocardiographicmeasurements of aortic root dimensionsare an important clinical method formonitoring patients with Marfan's syn-drome. However, there are few data onthe prognostic importance of echocardio-graphic variables for risk stratificationand dming of aortic root replacement.Methods-In 89 consecutive patients withMarfan's syndrome (age range 1-54years) clinical and serial echocardio-graphic data (n = 62) were evaluated aspotential predictors of outcome (mean(range) follow up 4 (< 1-16) years). Aorticsinus diameter and an aortic ratio nor-malised for age and body surface areawere examined using Kaplan-Meier lifetable and Cox regression analysis, withthe end point defined as death or surgeryfor ascending aortic dissection and eventsdefined as an end point or surgery forascending aortic aneurysm.Results-Overall actuarial survival at twoand five years was 96% and 92% and eventfree survival was 85% and 76%, respec-tively. There were five deaths due to aorticdissection, four patients survived surgeryfor ascending dissection, and nine under-went root replacement with a compositegraft for ascending aneurysm. Those withaortic events were older (35 (12) v 25 (13)years, P = 0.007) and had greater initialaortic root dimensions (47 (14) v 33 (8)mm, P < 0.0001) and ratios (1.6 (0.5) v 1-3(0.2), P < 0.0001). In the 62 patients withserial echocardiographic follow up, therate of aortic root dilatation was morerapid in those with events (15 (17) v 0(3)0/olyear, P < 0.0001). UtiUising a Coxproportional hazards model, the groupswith an initial aortic ratio i 1'3 or anannual change in aortic ratio > 5% had arelative risk of an aortic complication of2*7 and 4*1, respectively (95% confidencelimits 1*5 to 4*8 and 1-8 to 9.3). Only oneof 31 patients with an initial aortic ratio of< 1.3 and a rate of change of < 5% had anevent (five year event free survival 97%).Conclusions-A low risk subgroup ofpatients with Marfan's syndrome can beidentified as those with an aortic ratio< 1.3 and an annual change in aortic ratioof < 5%. These findings are helpful in

optimising echocardiographic monitoringand risk stratification of patients withMarfan's syndrome.

(Heart 1996;75:389-395)

Keywords: Marfan's syndrome; aortic root complica-tions; echocardiography; prognosis

The Marfan syndrome is an autosomal domi-nant inherited disorder of connective tissuewith pleiotropic and variable manifestations inmultiple organ systems.' Aortic root pathol-ogy, including aneurysmal dilatation and dis-section, is the major cause of morbidity andmortality in these patients.2 Serial echocardio-graphic aortic root measurements are animportant means of surveillance, given theimproved long-term prognosis after aortic rootreplacement.3 It was suggested in a recentstudy that generalized aortic root dilatationwas a predictor of subsequent aortic complica-tions in patients with Marfan's syndrome.4However, that study4 and two other recentstudies56 showed wide variability in the ratesof change in aortic dimensions in cohorts ofpatients with Marfan's syndrome. For optimalmonitoring and risk stratification, more dataare needed to determine which clinical andechocardiographic variables predict outcomein patients with Marfan's syndrome.The aim of this study was to identify clinical

and echocardiographic predictors of outcomein a large cohort of patients with Marfan's syn-drome. We hypothesised that aortic complica-tions were more likely in those with (a) greaterinitial aortic root dimensions for age and bodysize and (b) more rapid progression of aorticdilatation.

Patients and methodsPATIENTSThe records of 100 patients with definiteMarfan's syndrome referred to the Universityof Washington Medical Center or Children'sHospital and Medical Center genetics clinicsbetween 1977 and 1994 were reviewed forpossible inclusion in this study. Follow upinformation was available or could be obtainedin 89 patients (from 68 families) who comprisethe study group. Most individuals withMarfan's syndrome in our geographical areaare referred to these clinics, even when the pri-mary physician is not university affiliated. Inaddition, the local Marfan society was con-tacted to ensure that all known individuals

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with Marfan's syndrome were included. Thediagnosis of the Marfan's syndrome was madeaccording to the criteria of Pyeritz andMcKusick' and only patients satisfying strictdiagnostic criteria were included. The mean(range) period of follow up from the initialdiagnosis of Marfan's syndrome was 4(< 1-16) years. The protocol for this studywas approved by the University of Washingtonand Children's Hospital Institutional ReviewBoards and informed consent was obtained.

FOLLOW UPClinical, echocardiographic, and outcomedata available were collected by reviewinggenetics clinic and hospital charts and tele-phone interview. A standardized data collec-tion form was utilised, which includeddemographic details, vital statistics, whetheraortic root surgery had been performed, and a

detailed account of the patient's usage of Pblocking medication. The defined outcomeswere (a) the end point of death or root replace-ment for ascending dissection or (b) ascendingaortic events defined as those with an end pointplus those undergoing surgery for ascendingaortic aneurysm. The decision to performaortic surgery was made by each patient'sphysician based on clinical, as well as echocar-diographic, data. The aortic root ratio or thechange in root ratio was not used in clinicaldecision making. In addition to aortic rootdilatation, the indications for aneurysmsurgery included increasing aortic regurgita-tion or new cardiac symptoms, or both, inseven (78%) of nine of these patients.

There were four patients with descendingaortic dissections of whom only one was con-sidered to have reached an end point (one alsohad aortic root replacement for ascendinganeurysm). The other three patients with iso-lated descending aortic dissections were cen-

sored at the time of the event but were notconsidered an end point, as the study goal wasto predict ascending aortic complications. Onepatient died after descending aortic dissection.Inclusion of this death as an end point doesnot change the statistical significance of theresults. Patients were also grouped into thosereceiving blocking drugs for > 12 monthsand those who never received them or tookthem for < 12 months.

ECHOCARDIOGRAPHIC FOLLOW UPEchocardiographic data were available in 80(90%) of 89 patients. Serial echocardiographicstudies were available in 62 (70%) of 89patients with a median (range) of serial studiesper patient of 4-6 (2-13). Patients who hadnot had an echocardiogram within the previ-ous year underwent a clinical evaluation andechocardiographic examination focusing on

aortic dimensions and pathology at the

University of Washington Medical Center (n= 18).

Detailed measurements of the aortic rootwere made in the parasternal long axis viewaccording to the method of Roman et a!7 by aninvestigator unaware of clinical outcome in the98 echocardiograms in which the original

video tape could be obtained. In the otherstudies (n = 199) official reports were used.Aortic diameter measurements were madeusing the leading edge technique at end dias-tole (defined as the peak of the R wave on theelectrocardiogram). Maximal diameter mea-surements were recorded at the aortic annulus,the sinuses of Valsalva, the sinotubular junc-tion, and proximal ascending aorta 1-2 cmabove the sinotubular junction. All diameterswere measured perpendicular to the long axisof the aorta.The maximum dimension of the sinuses of

Valsalva (available in all studies) was used tocalculate an aortic ratio. The observed dimen-sion was divided by the predicted dimensionbased on age and body surface area using thefollowing established regression formulasderived from normal individuals:7

Children (age < 18 years): predicted sinusdimension (cm) =

102 + (0-98 x BSA (m2))Adults (age 18-40 years): predicted sinus

dimension (cm) =0.97+(1-12 x BSA(m2))

Adults (> 40 years): predicted sinusdimension (cm) =

1-92 + (0-74 x BSA (m2))where BSA is body surface area.

This allowed for comparisons of aortic rootdimensions among all patients regardless ofage and body size. For example, an aorticsinus ratio of 1-3 indicates a 30% enlargementof the aortic root above the mean for thatpatient's age and body surface area. The rateof aortic root dilatation normalized for age andbody size was calculated by determining thechange in aortic ratio between the final andinitial echocardiograms and dividing by theinterval between them in years. Mitral valveprolapse and aortic regurgitation were evalu-ated using established cross sectional echocar-diographic and colour Doppler diagnosticcriteria.8-'0

STATISTICAL ANALYSISDemographic and echocardiographic variablesin patients with versus those without an aorticevent or end point were compared using X2analysis for dichotomous variables and theunpaired Student's t test for continuous vari-ables. Data are presented as mean (one SD).Kaplan-Meier life table analysis was per-formed for overall and event free survival. Thelog rank test was used to examine differencesbetween survival curves in those who hadtaken / blocking medication for > one year or< one year. The time period of one year for /3blocker treatment was chosen because somepatients took /B blockers for only a few daysand then discontinued them because of sideeffects. The results are not affected by using adifferent cut off point (e.g. one month) forduration of / blocker treatment.Cox proportional hazards regression was

performed to examine baseline variables thatwere found on univariate analysis to be associ-ated with a poor outcome. For the Cox regres-sion model, an aortic ratio > or < 1-3, and an

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Aortic root complications in Marfan's syndrome: identification of a lower risk group

Table 1 Demographic and echocardiographic features of89 patients with Marfan syndrome

Feature

Mean (SD) (range) age at entry (years)Age < 18 years at enrolment (%)Sex (M(F)Family history (%)Organ system (%)

CardiovascularMusculoskeletalOcular

Clinical findings (%)Mitral prolapseSpinal deformityHyperextensibilityEctopia lentis

,B blocker treatment (%)> 1 year< 1 year

Aortic regurgitation (%)NoneMild to moderateSevereUnknown

Mitral regurgitation (%)NoneMild to moderateSevereUnknown

21 (13) (1-54)4649/4056

919483

63385444

3664

71113

15

5925

115

Cu

:3C,,a)

4-

EC)

1 0+

0.9 Total survia

0 -- --0.8 S .Es-vent free survival

0.7 _-

0 1 2 3 4 5 6Time after presentation (years)

No at follow up

62 50 41 31 25 18

Figure 1 Kaplan-Meier total survival ( ), survivalwithout dissection of the ascending aorta (....) and event

free survival (---- -) in 89 patients with Marfan'ssyndrome.

annual rate of change of aortic ratio >e or

< 5% were used as break points to compare

outcome. These break points were usedbecause 1-3 was the mean ratio for the entirecohort, and an annual rate of change of 5%represents approximately a 2 mm increase inaortic root dimension in adults, which wouldbe detectable by cross sectional echocardiogra-phy. Age was included in the model to allowfor any possible confounding effect of age on

aortic dilatation. Follow up time for each ofthese analyses was calculated as the time fromthe first genetics clinic visit (the time whenMarfan's syndrome was definitely diagnosed)to an end point or until the end of the study.Statistical package for the social sciences(SPSS for Windows, version 6&0) with defaultsettings was used for all statistical analyses.

ResultsDEMOGRAPHIC FEATURESTable 1 lists the demographic and clinicalcharacteristics of the 89 patients with Marfan'ssyndrome. There were 49 males and 40females with an age range from 1 to 54(median 21) years. Cardiovascular and mus-

culoskeletal features were present in nearly allpatients. Ocular findings were present in 83%of patients and included iridodonesis, lens dis-location, or a history of retinal detachment. Apositive family history of Marfan's syndromewas present in 56% of patients, while 44%represented new mutations. Although 45%(37 of 83 patients) of patients had taken ,Bblocking medication at some time in the followup period, only 36% (30 of 83) took p blockerscontinuously for greater than 12 months. pblocker history was unknown in six patients.

OVERALL SURVIVAL AND EVENT-FREE SURVIVAL

Figure 1 shows Kaplan-Meier life table analysisfor overall survival, freedom from aortic dis-section, and event free actuarial survival.Actuarial survival at two and five years for thewhole group was 96% and 92%, and freedomfrom all events was 85% and 76%, respec-

tively. The Kaplan-Meier mean total survivalwas 14-6 (95% confidence intervals (CI) 13-4to 15-8) years and mean event free survivalwas 12-0 (95% CI) 10-3 to 13-6) years frompresentation.

At follow up 71 of 89 patients were alivewith no ascending aortic complications. The18 end points included five deaths due toascending dissection, four patients who sur-

vived emergency aortic root replacement forascending aortic dissection, and nine patientswho underwent a composite graft replacementfor ascending aortic aneurysm (table 2).Surgery or death occurred < one year after theinitial diagnosis in 11 of 18 patients with an

end point, thus, follow up is shorter in thosewith an event. The mean (range) age at deathwas 30 (17-54) years and for all aortic compli-cations was also 30 (10-54) years.

CLINICAL CHARACTERISTICS OF THOSE WITHAND THOSE WITHOUT AORTIC COMPLICATIONSThere were no significant differences betweenthose with and those without aortic complica-tions other than an older age and shorterfollow up period in those with aortic complica-tions (table 3). Fifty three per cent of thosehaving an aortic complication had a firstdegree relative with an aortic complication or

died due to aortic dissection. Results are simi-lar if only those with a definite end point(death or dissection) are compared with theremainder of the study group.

ECHOCARDIOGRAPHIC FOLLOW UPIn the 80 patients with one or more echocar-diograms, the initial aortic sinus dimension inthose with an aortic complication averaged 47(range 31-83) mm compared with 33 (range20-50) mm in those without a complication(P < 0.0001). This was reflected in the aorticratio which averaged 1 6 in those with an

event compared with 1-3 in those without (P <

0-0001). The initial aortic ratio was > 1-3 in77% of patients with a complication versus

35% of patients without (X2 = 0-01). Similarchanges were seen in the aortic dimensions at

7

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Table 2 Clinical and echocardiographic features of 18 patients with aortic complications or who died

Initial sinus Interval Final sinus IntervalAge dimension between dimension A Aortic before

Sex (years) ratio echos ratio* ratiot complicationt Complication Outcome

M 22 83/2 6 1 day Death due to ascend- Death 2 months after aortic root anding dissection valve replacement

Recurrent cardiac arrest, poor leftventricular function

F 36 42/1-3 1 month Death due to ascend- Death during emergency aortic surgerying dissection

M 18 48/1-8 2 years Death due to ascend- Death during emergency aortic surgerying dissection

M 19 46/1-7 6 years Death due to ascend- Sudden deathing dissection Postmortem examination confirmed

ascending dissectionF 26 38/1-3 6 months Death due to ascend- Died 16 days after emergency aortic

ing dissection surgery at 10 weeks postpartumF 31 34/1-2 10 years 42/1-4 0-02 8 months Ascending dissection Successful composite graft repair

Alive at 5 yearsF 32 42/1-5 1 year Ascending dissection Successful composite graft repair

Alive 13 years after operationM 43 Not done Ascending dissection Composite graft repair

Subsequent descending dissectionAlive 8 years after operation

M 34 Not done Ascending dissection Composite graft repairSubsequent arch descending dissection 1 year

after operation and with revision ofascending graft

Alive 3 years after second operationM 24 49/1-4 8 months 61/1-7 0 5 1 month Ascending aneurysm Composite graft subsequent revision 7 years

later and descending aortic replacement12 years later

AliveM 43 34/1 0 6 years 51/1-5 0 09 2 months Ascending aneurysm David's procedure (graft and resuspension of

native aortic valve)Alive 6 months after operation

M 46 64/1 8 2 months Ascending aneurysm Composite graftAlive 8 years after operation

M 19 31/1-3 8 years 58/1-8 0-06 5 months Ascending aneurysm Composite graftSubsequent infection and reoperation 1 year later

F 32 Not done 1 day Ascending aneurysm Alive 5 years after operation redo AVR16 years after operation

F 24 38/1-3 9 years 70/2 4 0-13 5 days Ascending aneurysm Composite graft alive 9 years after operationM 31 34/1 0 10 years 60/1-8 0-08 2 months Ascending aneurysm Composite graft lost to follow up after operationF 38 55/1 6 13 months Ascending aneurysm Composite graft alive 9 years after operationM 10 57/2 8 2 days Ascending aneurysm Alive 4 years post-composite graft

*Sinus dimension in millimetres; ratio is dimensionless on final echocardiogram before complication occurred. tChange in aortic ratio between first and lastechocardiograms divided by interval in years. Multiply a 100 for % change/year. tTime interval between final echocardiographic study and aortic complication.

the sinotubular junction and ascending aorticlevels, although the number of measurementswas smaller. The mean sinotubular junctiondimension on the final echocardiogram inthose with versus those without an aorticcomplication was 41 (10) v 31 (5) mm (P =0'001). Similarly, the ascending aortameasured 35 (11) v 27 (7) mm (P = 0 03).Although the average sinus of Valsalva dimen-sion on the most recent echocardiographicstudy before the aortic complication was 51(range 38-83) mm, it is noteworthy that fourpatients (all women) had an aortic root dimen-sion of only between 38 and 46 mm in theyear before aortic dissection. Only one of thesewomen was postpartum (fig 2).

Table 4 compares echocardiographic find-ings in the 62 patients with serial studies. The

Table 3 Comparison of clinicalfindings in 89 patients with and without an event*No event Event

Feature (n = 71) (n = 18) p Value

Enroiment age (year) 19 (12) 29 (12) 0 003Age at follow up (year) 25 (13) 35 (12) 0 007Body surface area (m2) 1-5 (0 5) 1-8 (0 6) 0 05Sex (M/F)(%) 55/45 56/44 NSFollow up (year) 4-7 (4-5) 1-6 (2-7) 0-0041B blocker treatment 37 58 NSDuration of ,B blocker treatment (months) 20 (43) 40 (58) NSFamily history (%) 57 44 NSEctopia lentis (%) 47 32 NSSpinal deformity (%) 36 47 NSMitral prolapse (%) 60 74 NS

Values are mean (SD) unless specified otherwise. *Events defined as death or surgery forascending aortic dissection or aneurysm. NS, not significant.

mean baseline sinus dimension and aortic ratiowere no different in those who developed acomplication versus those who remained eventfree. However, the changes in aortic sinusdimension and aortic ratio/year of follow upwere significantly greater in those with a com-plication than in those without. The annualrate of change in aortic ratio was > 5% inonly four (8%) of 51 of those without a com-plication compared with five (83%) of six ofthose with a complication (XI = 0-O01) (table4). A more rapid rate of dilatation (i.e. >5%/year) was detected only in patients whowere subsequently referred for aortic rootreplacement for ascending aneurysm. Serialechocardiographic data were available only inone patient with acute ascending dissection

30

Co.-

cnm 2

._4.) 1.3

0 1

v

v

-

DissectionAneurysm

No event Died Asc Ao surgery

Figure 2 Initial aortic sinus ratio in those with no event,those who died, and those who underwent surgery forascending aortic (ASC Ao) dissection or aneurysm.

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Aortic root complications in Marfan's syndrome: identification of a lower risk group

Table 4 Serial echocardiographic findings (n = 62)

No event Event(n = 56) (n = 6) p Value

Body surface area 1-6 (0 5) 1 9 (0 3) NSSinus dimension (mm) (n = 62)

Baseline 34 (8) 37 (6) NSFollow up 38 (7) 57 (10) < 0 0001A sinus 5 (5) 20 (9) < 0-0001A sinus/year 0-7 (1) 5 ± 6 < 0-0001

Sinus ratio (n = 57)Baseline 1 3 (0 2) 1-2 (0 2) NSFollow up 1 3 (0 2) 1-8 (0 4) < 0 0001A ratio 0-03 (0-1) 0 6 (0 3) < 0 0001A ratio/year 0 00 (0 03) 0 15 (0-17) < 0 0001

Values are mean (SD). NS, not significant.

Figure 3 Examples of therate of change in aorticsinus ratio over the followup period. In these 12patients with Marfan 'ssyndrome, two underwentsurgery for ascendingaortic aneurysm andincreasing aorticregurgitation (A----)while the remaining 10had no aortic complications( )-

1*9

1.70; 1-5

m 1.3.C

LI 1.1

O o.o 0.9

0.7

1 .0(

M 0.9

J 0-8u,a) 0.7a)

0.6-c0)> 0.5

A

0.40

c0

0)

.)

4--

0

cn

0 1 3 5 7 9 11 13 15

Follow up (years)

1.0

0.9

0.8

0.7

B

17 _ _ _ _ _e_) O_ _ , ____-6 O. __)_'-- --

Ao ratio < 1.3

1 2 3 4 5 6 7Follow up duration (years)

Ao ratio < 1-3P = 0-02

Ao ratio a 1.3 10.6 _

0.5

1 2 3 4 5Follow up duration (years)

6 7

Figure 5 Cox proportional hazards model showing (A)event free survival and (B) survival without ascendingaortic dissection in patients with an initial aortic sinus(Ao) ratio of < 1 3 versus those with a ratio of > 1 3.

who had an annual increase in aortic ratio (atthe sinus) of 2%/year (table 2). It is notewor-thy that the rate of change in the aortic rootratio was heterogeneous among the studygroup (fig 3) with some patients having littlechange over long follow up intervals.

COX REGRESSION ANALYSISCox regression analysis was performed toexamine the independent predictive value ofthe initial aortic ratio on outcome. The Coxmodel included age as a covariate to avoid anypotential bias and as seen in fig 4, the aorticroot ratio is not related to age. In patients with atleast one echocardiogram (n = 80), the relativerisk of an aortic complication in those with anaortic ratio of > 1-3 was 2-7 (95% CI 1-5 to4-8, X2 = 0 007) (fig 5) and the risk of death oraortic dissection was 3-6 (95% CI 1-2 to 10-5,X2 = 0 02). For those patients who had two ormore echocardiograms (n = 62), the relativerisk of aortic complications was 4 1 (95% CI1 8 to 9-3, X2 = 0-0005) in those with an annualchange in the aortic ratio > 0 05, however therelative risk for death or dissection alone wasnot significant because of the small number ofend points in this subgroup.

Figure 4 Initial aorticsinus ratio versus ageshowing that there is nosignificant relation betweenthese two variables.Patients with no event(0), those who died (F),and those who hadascending aortic surgery fordissection (A) oraneurysm (A) areindicated.

0

._

4-

Cl

c.0

0

2.E

2.C

1 .5

1*C

0.5

A lower risk group was defined as patientswith an initial aortic ratio < IP3 and a rate ofchange of aortic ratio < 5%/year. Only one(3%) of 31 of these patients had an aortic com-plication compared with 14 (36%) of 39patients who had an initial aortic ratio of > 1-3or an annual rate of change of > 5%. The rela-tive risk of a complication in this low risk sub-group was 0 3 (95% CI 0 09 to 0-71, X2 =0-001). The predictive value of these variablesin predicting freedom from an event was there-fore 97%. Dissection or death occurred in onlyone (3%) of 31 of this low risk subgroup versussix (15%) of 39 with an aortic ratio > 1-3 orannual rate of change > 5%. Use of this moredefinitive end point did not reach statistical sig-nificance because of the small number of endpoints.To examine the effect of patients who pre-

sented acutely on the Cox regression model,the eight patients with follow up times < onemonth were excluded from analysis. Similarresults were obtained with a relative risk of acomplication of 2-8 (95% CI 1P4 to 5-5) forthose with an initial aortic ratio of > 1-3 and arelative risk of 5 9 (95% CI 2.0 to 17.3) forthose with a rate of change in aortic ratio of >0-05/year.

v v Aneurysm ,B BLOCKER TREATMENT

* v Dissection Thirty patients received p blockers for > one* Death year while 53 patients either never received ,Bo No event blockers or took them for < one year. Aortic

0 v ratios and the change in ratio between initial-- 8 ° * ° v and final echocardiograms did not differ,°°309 °v o°o3o v O O between these groups. Actuarial freedom from_o ~°O¢) ° 'x99 o6 oall events was no different in those receiving ,B

o 0o blockers (69%, nine events in 28 patients) com-, I pared with those not receiving /3 blockers (85%,0 10 20 30 40 50 60 eight events in 55 patients) at five years (P =

Age (years) not significant, log rank test).

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DiscussionECHOCARDIOGRAPHIC PREDICTORS OFOUTCOMEThis study demonstrates that echocardio-graphic variables are powerful predictors of out-come in patients with Marfan's syndrome. Inthose in whom serial echocardiographic mea-surements of aortic dimensions were available,the rate of dilatation of the aortic root was sig-nificantly more rapid in those with complica-tions. The mean change in aortic ratio in thosesuffering a complication was 0-15/year indicat-ing an average increase of 15% in aortic dimen-sion/year, after allowing for the effect ofincreasing age and body size. This contrastswith almost no change in the aortic ratio seen inthose not experiencing a complication. Thus,an annual change in the aortic ratio < 5% indi-cates that the patient is unlikely to suffer an aor-tic complication (predictive value 92%). In anindividual patient with Marfan's syndrome, aconsistent pattern of change on serial echo-cardiography is helpful in distinguishing pro-gressive root dilatation from measurementvariability.

Although the number of serial echocardio-graphic studies in patients with a complicationwas small because a number of patients hadtheir complication soon after their initial study,our findings remain significant even when thesepatients are excluded. Thus, the finding ofmore rapid dilatation underscores the need formore frequent surveillance especially in patientsat high risk, either because of a strong familyhistory of aortic complication, or significantaortic dilatation at baseline.The importance of calculating an aortic ratio

also must be emphasised. Aortic dimensionswere between 38 and 46 mm in four patientsrecorded within one year of ascending dissec-tion. These four patients (all women) had bodysurface areas between 1-70 and 2-27 m2n, so thattheir aortic ratios were between 1-3 and 1-4. Aswomen generally have a smaller body size, themagnitude of aortic dilatation may not beappreciated when only the absolute sinusdimension is considered. The prognostic valueof the aortic ratio is further emphasised by theCox proportional hazards model. Patients withan initial aortic sinus ratio > 1-3 had an almostthreefold risk of an aortic complication over thefollow up period compared with that in thosewith an aortic ratio < 1-3. In a man with a bodysurface area of20 m2n, an aortic ratio of 1-3 cor-responds to an aortic sinus dimension ofapproximately 42 mm. In a woman with a bodysurface area of 1 8 m2n, a ratio of 1-3 corre-sponds to an aortic sinus dimension of 39 mm.The current general recommendation for pro-phylactic aortic root replacement is at an aorticdimension of 55-60 mm,"1-15 which would cor-respond to an aortic ratio of 1-7-1 9 in the maleand 1)8-2)0 in the female examples given here.In our population a substantial number of com-plications occurred in patients with aortic rootdimensions less than that for which prophylacticroot replacement is routinely performed (fig 2)as noted in other studies.61617 However, nocomplications occurred in patients with an aor-tic ratio < 1-3.

LONG-TERM OUTCOME IN PATIENTS WITHMARFAN'S SYNDROMEWith current cardiac surgical techniquesand improved echocardiographic monitoring,long-term survival in patients with Marfan'ssyndrome is reasonably good. However, there isa substantial incidence of aortic complications.All deaths in this series were due to aortic dis-section, including two patients not previouslyknown to have Marfan's syndrome or aorticroot pathology. While the 20% incidence ofaortic complications over a mean follow upperiod of four years is similar to that in recentlypublished series,3-5 the survival of 92% for thewhole cohort at five years seems to be better,probably because all patients underwent a com-posite graft usually with the classic Bentall'stechnique'8 rather than the older technique ofan interposition tube graft. There were no earlypostoperative deaths with elective surgery (n =9) for aortic dilatation. With emergency surgeryfor dissection, four (50%) of eight patients diedintraoperatively or in the early postoperativeperiod. The long-term survival of patients withaortic complications who survived surgery wasexcellent, with no known deaths a mean of 8- 1years after aortic root replacement. However,four of 13 patients surviving aortic surgeryrequired reoperation, two for further dissection,one because of graft infection, and one becauseof severe bioprosthetic aortic valve incompe-tence. These data are in agreement with previ-ous studies showing a five and 10 year actuarialsurvival after composite graft repair between 71and 93% and 54 and 76%, respectively.'"-'3

OTHER PREDICTORS OF OUTCOMEThe importance of factors not evaluated in thisstudy cannot be discounted. For example, thehigh incidence of complications in patientswho had first degree relatives with aortic com-plications emphasises the adverse prognosticimportance of a positive family history of aorticdissection.'5 19 In addition, cardiovascular riskmay differ within families as well as with somemembers having milder phenotypes not asso-ciated with aortic involvement.20The retrospective nature and relatively

small sample size of this study make interpre-tation of the data pertaining to ,B blocker treat-ment difficult. Some patients presentedacutely with dissection and previously undiag-nosed Marfan's syndrome, a bias that favours/3 blockade. Conversely, it is likely that thosewith more severe disease (e.g. family history,larger aortic dimension, and rapid rate of aorticdilatation) were selected for treatment whichwould bias against /B blockade. Overall, no sig-nificant differences between the two groupswere observed.

ConclusionsLong-term prognosis in patients with Marfan'ssyndrome is reasonably good, but a significantnumber of aortic complications occur, even inpatients with only moderately dilated aorticroots. Until a molecular based approach iswidely available that will identify patients athigh cardiovascular risk, echocardiographic

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Aortic root complications in Marfan's syndrome: identification ofa lower risk group

variables will remain the most important prog-nostic indicators. The present study suggeststhat any patient with an aortic ratio > 1-3(30% greater than normal) or a change in aor-tic ratio > 5%/year should be followed closelyas there is a high risk of complications.Patients with aortic ratios of < 1-3 and a rateof change of < 5% seem to be at low risk.Prospective validation of these proposed criteriais needed.

We are grateful to the Washington State Marfan Associationfor their cooperation and to Sharon Kemp for typing this man-uscript. MEL was supported by a grant from the NationalHeart Foundation of New Zealand, and TAU by a grant fromthe University of Washington Medical Student ResearchTraining Program. This study was supported in part by a grantfrom the United States Public Health Service (AR 21557).

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