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Echocardiographic reference values for aortic root size: The Framingham Heart Study
Echocardiographic Reference Values for Aortic Root Size" The Framingham Heart Study Ramachandran S. Vasan, MD, Martin G. Larson, ScD, Emelia J. Benjamin, MD, ScM, and Daniel Levy, MD, Boston, Massachusetts, and Bethesda, Maryland
The objectives o f this study were to develop sex-, age-, and body size-specific n o m o g r a m s and partition values for upper and lower limits o f M - m o d e echocardiographic aortic root measurements derived from a large population-based cohort. The study sample consisted o f 1433 male and 1816 female participants in the Framingham Heart Study and Framingham Offspring Study w h o were normotensive and free o f clinically apparent heart disease at the baseline examination. Aortic root measurements were obtained by M - m o d e echocardiography by a leading-edge to leading-edge technique. The relations o f age and measures o f body size with aortic root dimensions were evaluated with sex-specific correlations and multiple stepwise linear
A g e - rdilation e l a to fethedaortic r o o t is the m o s t c o m m o n cause o f aortic regurgitation in developed countries in b o t h surgical pathologic series 1'2 and clinical case series. 3'4 The prevalence o f aortic regurgitation increases as a function o f aortic r o o t size. 5 Aortic r o o t size is also o f therapeutic and prognostic importance in subjects with Marfan's syndrome 6"7 and for the surgical m a n a g e m e n t o f aortic insufficiency. 4 Therefore it is i m p o r t a n t to establish partition values for detection o f a dilated aortic root. Biologic variables that have been recognized to influence aortic r o o t size include age, sex, and indexes o f b o d y size. 8 xo Reference values and n o m o g r a m s have been developed to detect aortic r o o t dilation in adults,9 12 but sex-, age-, and b o d y size-specific par-
From the Framingham Heart Study, the Divisions of Cardiology and Clinical Epidemiolog% Beth Israel Hospital, the Cardiology Section, Boston City Hospital, Boston University School of Medicine, and the National Heart, Lung and Blood Institute, Bethesda. Supported in part through National Institutes of Health/National Heart, Lung and Blood Institute contract NOI-HC-38038 and National Institute of Neurologic Disorders and Stroke grant 2-ROI-NS-17950A1. Dr. Vasan's research fellowship was made possible by a grant from Merck & Co. Inc. Reprint requests: Daniel I~W, MD, Framingham Heart Study, 5 Thurber St., Framingham, MA 01701. Copyright 9 1995 by the American Society of Echocardiography. 0894 7317/95 $5.00 + 0 27/1/64510
regression analyses. Age was the most important determinant o f aortic root size in both men and w o m e n in the multivariable regression models. Models with age and body surface area yielded R 2values o f 0.214 in men and 0.222 in women. Models with age and height yielded lower R 2 values o f 0.136 in m e n and 0.181 in women. Thus aortic root dimensions vary widely with the age, sex, and body size o f individuals. Sex-specific reference nomograms o f aortic root dimensions in relation to age and body size (body surface area or height) are presented to facilitate the detection o f abnormalities o f aortic root size. (J AM Soc ECHOCARDIOGR 1995;8:793800.)
tition values have n o t been formulated. Previous studies o f aortic r o o t size were n o t population based, the n u m b e r o f subjects studied was small, and no study included a sufficient n u m b e r o f subjects bey o n d the seventh decade o f life, thereby limiting the generalizability o f the p r o p o s e d reference values. The objectives o f this study were to develop sexand age-specific n o m o g r a m s and partition values for upper and lower limits o f M - m o d e echocardiographic aortic r o o t measurements derived from a large population-based cohort.
METHODS
Study Sample The selection criteria and study design of the Framingham Heart Study and the Framingham Offspring Study have been detailed extensively. 13'~4Subjects of the Framingham Heart Study who participated in the sixteenth biennial examination (1979 to 1981) and subjects of the Framingham Offspring Study who participated in the second Off'spring examination ( 1979 to 1983) constituted the sample used in this investigation. At these index examinations, M-mode echocardiograms were performed uniformly on participating subjects. Subjects were excluded if they fulfilled any of the following criteria, in hierarchical order: (1) use of antihypertensive medications or systolic blood pressure of 140 mm Hg or greater or diastolic blood pressure of 90 mm Hg or greater at the index examination 793
794
Journal of the American Society of Echocardiography November-December 1995
Vasari et al.
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Body Surface Area (m 2) Figure I Predicted upper and lower limits of aortic root diameter in women as function of age and body surface area. Upper set of lines indicates 95th percentiles and lower set oflinesindicates 5th percentiles of aortic root dimensions. Select appropriate set of lines. Within set, select appropriate line for age marked on right. Follow line to appropriate body surface area on horizontal axis. Extrapolate to y axis for reference limit of aortic root dimension.
Table 1 Clinical and echocardiographic characteristics of subjects Variable
Age (yr) Weight (kg) Height (m) Body surface area (m2) Systolic blood pressure (mrn Hg) Diastolic blood pressure (mm Hg) Aortic root (mm)
Men
Women
(n = 1433)
(n = 1816)
46 + 13 80 _+11 1.75 _+0.07 1.95 + 0.15 120 + 10 76 + 7 32 + 3
47 + 13 62 _+10 1.61_+0.06 1.64 + 0.13 115 + 12 72 + 7 28 + 3
V a l u e s are m e a n _+ S D .
(n = 2422); (2) clinically apparent aortic or mitral valvular disease as identified by the presence of a diastolic murmur or systolic murmur (grade 3 / 6 or more) on precordial auscultation ( n = 81); (3) history of clinically apparent coronary heart disease or congestive heart failure or atrial fibrillation at or before the index examination ( n = 173); (4) use of other cardiovascular medications at the index examination (n = 105); (5) age less than 20 or 90 years or greater (n = 10); (6) presence of morbid
obesity, defined as body mass index greater than 35 k g / m 2 ( n = 73); or (6) unavailable or technically inadequate echocardiogram at the index examination (n-- 101). Methods of Measurement
Body height and weight measurements were obtained at the index examination. Body surface area was calculated according to the Du Bois formula) 5 All subjects underwent M-mode echocardiography. M-mode echocardiograms of the aortic root were obtained from the left parasternal window. In more than 90% of the subjects, M-mode studies were guided by two-dimensional echocardiography. All studies were performed with a 2.25 MHz, 1.25 cm diameter, unfocused transducer (K.B. Aerotech, Lewiston, Pa.) and a Hoffrel 201 ultrasound receiver (Hofffel Instruments, Norwalk, Conn.) interfaced with a Honeywell 1856 strip chart recorder (Honeywell, Minneapolis, Minn.). Aortic root size was measured according to the guidelines of the American Society of Echocardiography by a leading-edge to leading-edge measurement of the maximal distance between the anterior aortic root wall and the posterior aortic root wall at end diastole.16
Journal o f the American Society o f Echocardiography Volume 8 Number 6
44
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F i g u r e 2 Predicted u p p e r a n d lower limits o f aortic r o o t diameter in m e n as function o f age a n d b o d y surface area. Upper set of lines indicates 9 5 t h percentiles and lower set of lines indicates 5 t h percentiles o f aortic r o o t dimensions. Select appropriate set o f lines. W i t h i n set, select appropriate line for age marked o n right. Follow line to appropriate b o d y surface area o n h o r i z o n t a l axis. Extrapolate to y axis for refcrernce limit o f aortic r o o t dimension.
Table 2
Regression o f aortic r o o t d i m e n s i o n o n age a n d measures o f b o d y size in m e n a n d w o m e n Intercept
Age ( y r )
BSA ( m 2)
Height (m)
Model 1
Do
SE
~
SE
92
SE
Men Women Model 2 Men Women
15.11 14.52
1.003 0.791
0.09 0.09
0.006 0.004
6.72 5.73
0.469 0.449
14.19 10.79
1.984 1.710
0.088 0.099
0.006 0.005
~2
SE
R o o t MSE
2.67 2.52 8.04 7.89
1.068 0.995
2.80 2.59
R 2 = 0.214 in men and 0.222 in w o m e n / b r model I and 0.136 in men and 0.181 in women for model 2. R 2 is the proportion of total variability in aortic root dimensions that is explained by age and the measure of body size used in the model. The 5th and 95th percentile values for aortic room dimension in either sex can be calculated from the regression equations: (1) aortic r o o t = [30+(~ a X a g r 2 1 5 MSE; (2) aortic r o o t = J 8 0 + ([3~ x age) + ([32 x height) +_ 1.645 x Root MSE. [3, Regression coefficient; SE, standard error o f the regression coefficient; Root MSE, square root of the mean squared error; BSA, body surface area.
Statistical
Methods
All analyses were sex specific. T h e data werc e x a m i n e d for skewness a n d departures from normality a n d were inspected for the presence of" outliers. Aortic r o o t size was e x a m i n e d in relation to age with scatterplots, Multiple stepwise linear regression was used to evaluate the influ-
ence o f age, height, weight, body mass index, and body surface area o n aortic r o o t dimensions. 17 Sex-specific reference intervals for each decade o f age (starting from the t h i r d decade) a n d across a range o f b o d y sizes were comp u t e d with regression equations t h a t incorporated the m o s t significant predictor variables for aortic root dimen-
796
Journal of the American Society of Echocardiograptty November-December 1995
Vasan et al,
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Height (m) Figure 3 Predicted upper and lower limits of aortic root diameter in women as function of age and height. L~per set of lines indicates 95th percentiles and lower set of lines indicates 5th percentiles of aortic root dimensions. Select appropriate set of lines. Within set, select appropriate line for age marked on ridbt. Follow line to appropriate height on horizontal axis. Extrapolate to y axis for reference limit of aortic root dimension.
sion. All statistical analyses were per~brmed ~4th the statistical analysis system (SAS) ~s on a Sun spare 2 workstation (Sun Microsystems Inc., Mountain Vim~; Calif.).
RESULTS Study Sample O f the 2803 m e n and 3411 w o m e n who attended the index examinations, 1433 men (51%) and 1816 w o m e n (53%) ranging in age fi'om 20 to 88 years were eligible for analysis alter exclusions (2965 subjeers) were made for the criteria mentioned earlier. The clinical and echocardiographic characteristics o f the subjects are shown in Table l. Mean aortic root size was larger in men than in women. The variables correlated with aortic root diameter were analyzed by sex-specific multiple linear regression models. Models with (1) age alone and (2) age plus body surface area and (3) age and height were
studied. These variables were selected on the basis o f observations that they are the major determinants o f echocardiographic aortic root size~9; these variables have also been shown to be the principal determinants of the diameter o f the abdominal aorta. 2~ Age was the most important determinant o f aortic root size in both men ( r = 0.319) and w o m e n (r = 0.39). After adjustment for age, the correlation o f height and aortic root size was 0.195 in men and 0.183 in women. Age-adjusted correlation coefficients tbr body surface area were 0.354 in men and 0.287 in women. Models with weight or body surface area in addition to age were interchangeable in terms o f the coefficient o f determination (R2= 0.224 and 0.214 with the inclusion of weight or body surface area, respectively, in men; R 2 = 0.218 and 0.222 with the inclusion o f the same variables in women). The regression coefficients for sex-specific models with age and measures o f body size (body surface area and height) are shown in Table 2.
Journal of the American SocieEy of Echocardiography Volmne 8 Number 6
g s s a n et al.
797
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Figure 4 Predicted upper and lower limits of aortic root diameter in men as function of age and height. Upper set of lines indicates 95th percentiles and lower set of" lines indicates 5th percentiles of aortic root dimensions. Select appropriate set of lines. Within set, select appro~ priate line fbr age marked on right. Follow line to appropriate height on horizontal axis. Extrapolate to y axis for reference limit of aortic root dimensiom
Figures 1 and 2 depict the predicted sex- and body surface area-specific 5th and 95th percentiles of aortic root dimensions for different age groups according to the regression equation: aortic root = 130+ t31 x age + 13~.x body surface area. The partition values for aortic root size determined by the empiric observations were in near-perfect agreement with those obtained according to the regression equations. Figures 3 and 4 present sex- and height-specific 5th and 95th percentile values fbr aortic root dimem sions for i0-year age increments according to the regression equation: aortic root = 130+ 131 x age + 132 x height. Several statistics werc examined as part of regression-diagnostics analysisJ 7 No outliers or observations with excessive leverage were observed. Furthermore, regression residuals had appropriately normal distributions in both sexes.
DISCUSSION Principal
Findings
This study presents sex-, age-, and body size-specific upper and lower partition values for echocardiographic aortic root dimensions based on observations in a large number of normotensive adults from a populafon-based reference sample. Two sets of reference intcrvals are provided: one set based on age and body surface area and the other based on age and height. Wc chose to prescnt reference values with two differcnt measures of body size because there is no consensus in the literature rcgarding the ideal method for indexing echocardiographic dimensions. Although body surface area is the most common measure used for indexing in the published cchocardiograpic litcrature, the use o f height-based indexing urould have the advantage o f " n o t forgiving" tbr obesity-
798
Journal of thc American Society of Echocardiography November-December 1995
Vasari et al.
related variations sions. 22
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Comparison with Previous Studies It has been recommended that any study that defines rcfercnce values must describe the refcrencc population and the way it was chosen, the physiologic conditions under which the obscrvations wcre obtained, the techniques for obtaining thc observations, and the analytic methods used for calculating the rcference intcrvals. 2s Most o f thc previous cchocardiographic studies o f aortic root dimensions do not meet these spccifications. 9-n'24-29 Reference values for echocardiographic variables should bc derived from a random sampling o f healthy individuals. Previous studies that have pro~dded refercnce intcrvals for echocardiographic aortic root size eithcr did not detail thc sampling methods used for the selection o f subjects 1x'24 or used relatives o f patients, 9'2s volunteer employees, ~~ or subjects who underwent echocardiography to exclude congenital heart disease. 9'28'29 In this study, selection bias was minimized because of the elimination o f clinical referral patterns; also in view o f the frequent longitudinal surveillance o f study subjects, exclusions tbr the presence o f cardiovascular disease are likely to be more complete in this study. Most prior studies also did not account for age or sex-related diffkrences in aortic root dimensions. Age is an important determinant of aortic root size, 9'3~ and we have recently found important sex-related differences in aortic root dimensions. 19 Failure to partition the study sample based on sex and age could, therefore, result in reference intervals that are wider. One previous study did provide age- and sexspecific aortic root measurements, but the sample was small ( n = 196) and did not include subjects beyond the age 0 f 6 5 years. ~6 The small size of samples used to provide reference intervals is also a major limitation of all previous studies. To decrease the uncertainty with regard to the reference intervals, a sample size o f at least 200 observations is r e c o m m e n d e d ? ~ The large sample size o f this study increases the precision o f the reference ranges suggested; the 90% confidence interval for each age interval was narrow. The excellent agreement between the reference ranges with both parametric and nonparametric estimates o f percentile is a strength o f this study and is a reflection o f the large sample size. Previous studies also did not provide details regarding the statistical methods used, especially regarding the presence or absence of outliers, the nature o f the distribution o f reference values, the exact transformation procedure used (if any) for generating ganssian partition values, and the confidence
limits of the reference range suggested. Such information is critical for the standardization of reference values. 32
Limitation o f the Study It has been stated that two-dimensional cchocardiography offers advantages over M-mode studies for the measurement o f aortic root dimensions, and the lack o f perfect agreement between measurements with the two techniques has been noted previously.9"26 However, in this study, M-mode measurements o f the aortic root were guided by t~rodimensional scans, and under these circumstances the enhanced rccording o f individual targets and thc higher sampling rate o f M-mode echocardiography are advantageous for thc purpose ofmcasurcmcnts? 3 The study sample was overhwelmingly white; the application o f the reference intervals suggested in this study to nonwhite adults or two-dimensional echocardiographic measurements o f the aortic root may be inappropriatc. Our study provides little information on thc size o f the ascending thoracic aorta, because aortic size was measured only at the level o f the valve leaflets. Ideally, high left parasternal, right parastcrnal, and other modified views should be combined with the standard left parasternal views for obtaining the maximal aortic root diameter. Bccausc these modified views are not performed routinely in our laboratory, it is possible that maximal aortic root diametcr was underestimated in some paticnts. Interobserver and intraobserver variability in the measurement o f aortic root diameter was not obtained in this study. Howcver, prior studies have demonstratcd the excellent reproducibility of M - m o d c cchocardiographic aortic root mcasurements? 4 Because physical examination underestimates the presence o f aortic regurgitation, partition values for aortic root size in this study may be slightly wider because o f the inability to cxclude subjects with clinically occult aortic rcgurgitation. The partition values for abnormal aortic root sizc provided in this study use gaussian statistics. Thus 5% o f " n o r m a l " subjects arc arbitrarily placed above and 5% below the reference limits defined by 5th and 95th percentiles. The reference intervals indicate the probability o f observing a given value o f aortic root dimension only if the subject were to belong to the reference group. There is a need to define aortic root dimensions at which there is a risk o f morbidity or death based on the long-term follow-up o f a sufficient number o f unselected subjects with a clear definition of adverse outcomes. Such information that describes "decision levels" or threshold values (above or below which clinicians should respond to the quantitative value) cannot be obtained from a cross-sectional study.
Journal of the AmericanSociety of Echocardiography Volume 8 Number 6
Vasan et al.
Implications A o r t i c r o o t d i l a t i o n is b c i n g d e t e c t e d m o r e freq u e n t l y b c c a u s e o f t h e w i d e s p r e a d use o f c c h o c a r d i o g r a p h y . C o m p a r i n g an o b s c r v e d v a l u e o f a o r t i c r o o t d i m c n s i o n w i t h t h a t p r e d i c t c d in r e l a t i o n t o t h e a g e , sex, a n d b o d y surface area ( o r h e i g h t ) o f t h c indiv i d u a l m a y bc o f assistance in d e c i d i n g w h e t h e r t h e o b s e r v e d v a l u e is o f p a t h o l o g i c significance. S e q u e n tial e n l a r g c m e n t o f t h e a b d o m i n a l a o r t a has b e e n o b s e r v e d in i n d i v i d u a l s w h o s e a b d o m i n a l a o r t i c dia m e t e r e x c e e d s t h e r e f e r e n c e intervals, a n d it has been suggested that such individuals undergo rescann i n g regularly, as P r o s p e c t i v e studies are r e q u i r e d t o determine whether individuals with aortic root diame t e r e x c e e d i n g t h e r e f e r e n c e i n t e r v a l s h a v e similar progressive aortic root dilation.
10.
11.
12. 13.
14.
15.
Conclusions T h i s s t u d y p r o v i d e s a g e - a n d scx-specific r c f c r e n c e i n t e r v a l s for e c h o c a r d i o g r a p h i c a o r t i c r o o t size derived from a large random sample of normotensive a d u l t s in t h e g e n e r a l p o p u l a t i o n . T h e s e r e f e r e n c e values will h e l p clinicians i n t e r p r e t t h e o b s e r v e d aortic r o o t d i m e n s i o n s in t h e c o n t e x t o f t h e age, sex, a n d b o d y size o f an i n d i v i d u a l .
16.
17.
18.
Special thanks go to Sonya Vaziri, M D , for her assistance in compilation o f the data set used in this study.
19.
REFERENCES
20.
1. Davies MJ. PathologT of cardiac valves. Boston: Butterworths, 1980:37-61. 2. Olson LI, Subramaniam R, Edwards WD. Surgical pathology of pure aortic insufficiency: a study of 225 cases. Mayo Clin Proc 1984;59:835-41. 3. Roman MI, Devereux RB, Niles NW, et al. Aortic root dilatation as a cause of isolated, severe aortic regurgitation: prevalence, clinical and echocardiographic pattcrns, and relation to left ventricular hypertrophy and function. Ann Intern Med 1987;106:800-7. 4. Michel PL, Acar J, Chomette G, Iung B. Degenerative aortic regurgitation. Eur Heart J 1991;12:875-82. S. Sedcr JD, Burkc JF, Pauletto FJ. Prevalence of aortic regurgitation by color flow Doppler in relation to aortic root size. J AM Soc ECHOCARDIOGR1990;3:316-9. 6. Fox R, Ren J, Pannidis IP, Kotler MN, Mintz GS, Ross J. Anuloaortic ectasia: a clinical and echocardiographic study. Am J Cardiol 1984;54:177-81. 7. Brown OR, DeMots H, Kloster FE, Roberts A, Menashe VD, Beals RK. Aortic root dilatation and mitral valve prolapse in Marfan's syndrome: an echocardiographic study. Circulation 1975;52:651-7. 8. Francis GS, Hagan AD, Oury J, O'Rourke RA. Accuracy of echocardiography for assessing aortic root diameter. Br Heart J 1975;37:376-8. 9. Roman MJ, Devereux RB, Kramer-Fox R, O'Loughlin J.
21. 22.
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28.
799
Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am I Cardiol 1989;64:507-12. NidorfSM, Picard MH, Triulzi MO, et al. New perspectives in the assessment of cardiac chamber dimensions during development and adulthood. J Am Coil Cardiol 1992;19: 983-8. Henry WL, GaMin JM, Ware IH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation 1980;62:1054-61. Feigenbaum H. Echocardiography. Sth ed. Philadelphia: Lea & Febiger, I994:661. Dawber TR, Meadors GF, Moore FE. Epidemiologic approaches to heart disease: the Framingham Study. Am J Public Health 1951;41:279-86. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families: the Framingham Offpsring Study. Am J Epidemiol 1979; 110:281-90. Du Bois D, Du Bois EF. Clinical calorimetry, X: a formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916;17:86371. Sahn DJ, DeMaria A, Kisslo }', Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-83. Klcinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariable methods. 2nd ed. Boston: PWS-Kent, 1988:102-227. SAS Institute Inc. SAS/STAT user's guide, version 6. 4th ed, vol 2. Cary, North Carolina: SAS Institute Inc., 1989. Vasari RS, Larson MG, LeW D. Determinants ofechocardiographic aortic root size: the Framingham Heart Study. Circu lation I995;91:734-40. Pearce WH, Slaughter MS, LeMaire S, et al. Aortic diameter as a function of age, gender, and body surface area. Surgery 1993;114:691-7. Sonesson B, Hansen F, Sandgren T. Infrarenal aortic diameter in the healthy person. Eur l Vase Surg 1994;8:89-95. Levy D, Savage DD, Garrison RJ, Anderson KM, I~nnel WB, Castelli WB. Echocardiographic criteria for left ventricular hypertrophy: the Framingham Heart Study. Am I Cardiol 1987;59:956-60. Sunderman FW Jr. Current concepts of "normal values," "reference values" and "discrimination values" in clinical chemistry. Clin Chem 1975;21:1873-7. Epstein ML, Goldberg SJ, Mien HD, Konecke L, Wood J. Great vessel, cardiac chamber and wall growth pattern in normal children. Circulation 1975;51:1124-30. Habbal ME, Somerville l- Size of the normal aortic root in normal subjects and in those with left ventricular outflow obstruction. Am J Cardiol 1989;63:322-6. Valdez RS, Motta JA, London E, et al. Evaluation of the echocardiogram as an epidemiologic tool in an asymptomatic population. Circulation 1979;60:921-9. Schnittger I, Gordon EP, Fitzgerald Pl, Popp RL. Standardized intracardiac measurements of two-dimensional echocardiography, l Am Coll Cardiol 1983;2:934-8. Snider AR, Enderlein MA, Teitel DF, Juster PP. Twodimensional echocardiographic determination of aortic and pulmonary artery sizes from infancy to adulthood in normal subjects. Am J Cardiol 1984;53:218-24.
800
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29. Roge CLL, Silverman NH, Hart PA, Ray PM. Cardiac structure growth pattern determined by echocardiography. Circulation 1978;57:285-90. 30. Gerstenblith G, Fredriksen J, Yin FCP, Fortuin NJ, Lakatta EG, Weisf~ldt ML. Echocardiographic assessment of a normal adult aging population. Circulation 1977;56:273-8. 31. Altman DG. Practical statistics for medical research. 1st ed. London United Kingdom: Chapman and Hall, 1991: 419-26. 32. Solberg HE. Approved recommendations (1987) on
Journal of the American Society of Echocardiography November-December 1995
the theory of reference values, part 5: statistical treatment of collected reference values: determination of reference limits. J Clin Chem Clin Biochem 1987;25: 645-56. 33. Weyman AE. Principles and practice of echocardiography. 2nd ed. Philadelphia: Lea & Febiger, 1994:295-9. 34. Pietro DA, Voelkel AG, Ray BJ, Parisi AF. Reproducibility of echocardiography. Chest 1981;79:29-32. 35. Liddington MI, Heather BP. The relation between aortic diameter and body habitus. Eur J Vase Surg 1992;6: 89-92.
The objectives o f this study were to develop sex-, age-, and body size-specific n o m o g r a m s and partition values for upper and lower limits o f M - m o d e echocardiographic aortic root measurements derived from a large population-based cohort. The study sample consisted o f 1433 male and 1816 female participants in the Framingham Heart Study and Framingham Offspring Study w h o were normotensive and free o f clinically apparent heart disease at the baseline examination. Aortic root measurements were obtained by M - m o d e echocardiography by a leading-edge to leading-edge technique. The relations o f age and measures o f body size with aortic root dimensions were evaluated with sex-specific correlations and multiple stepwise linear
A g e - rdilation e l a to fethedaortic r o o t is the m o s t c o m m o n cause o f aortic regurgitation in developed countries in b o t h surgical pathologic series 1'2 and clinical case series. 3'4 The prevalence o f aortic regurgitation increases as a function o f aortic r o o t size. 5 Aortic r o o t size is also o f therapeutic and prognostic importance in subjects with Marfan's syndrome 6"7 and for the surgical m a n a g e m e n t o f aortic insufficiency. 4 Therefore it is i m p o r t a n t to establish partition values for detection o f a dilated aortic root. Biologic variables that have been recognized to influence aortic r o o t size include age, sex, and indexes o f b o d y size. 8 xo Reference values and n o m o g r a m s have been developed to detect aortic r o o t dilation in adults,9 12 but sex-, age-, and b o d y size-specific par-
From the Framingham Heart Study, the Divisions of Cardiology and Clinical Epidemiolog% Beth Israel Hospital, the Cardiology Section, Boston City Hospital, Boston University School of Medicine, and the National Heart, Lung and Blood Institute, Bethesda. Supported in part through National Institutes of Health/National Heart, Lung and Blood Institute contract NOI-HC-38038 and National Institute of Neurologic Disorders and Stroke grant 2-ROI-NS-17950A1. Dr. Vasan's research fellowship was made possible by a grant from Merck & Co. Inc. Reprint requests: Daniel I~W, MD, Framingham Heart Study, 5 Thurber St., Framingham, MA 01701. Copyright 9 1995 by the American Society of Echocardiography. 0894 7317/95 $5.00 + 0 27/1/64510
regression analyses. Age was the most important determinant o f aortic root size in both men and w o m e n in the multivariable regression models. Models with age and body surface area yielded R 2values o f 0.214 in men and 0.222 in women. Models with age and height yielded lower R 2 values o f 0.136 in m e n and 0.181 in women. Thus aortic root dimensions vary widely with the age, sex, and body size o f individuals. Sex-specific reference nomograms o f aortic root dimensions in relation to age and body size (body surface area or height) are presented to facilitate the detection o f abnormalities o f aortic root size. (J AM Soc ECHOCARDIOGR 1995;8:793800.)
tition values have n o t been formulated. Previous studies o f aortic r o o t size were n o t population based, the n u m b e r o f subjects studied was small, and no study included a sufficient n u m b e r o f subjects bey o n d the seventh decade o f life, thereby limiting the generalizability o f the p r o p o s e d reference values. The objectives o f this study were to develop sexand age-specific n o m o g r a m s and partition values for upper and lower limits o f M - m o d e echocardiographic aortic r o o t measurements derived from a large population-based cohort.
METHODS
Study Sample The selection criteria and study design of the Framingham Heart Study and the Framingham Offspring Study have been detailed extensively. 13'~4Subjects of the Framingham Heart Study who participated in the sixteenth biennial examination (1979 to 1981) and subjects of the Framingham Offspring Study who participated in the second Off'spring examination ( 1979 to 1983) constituted the sample used in this investigation. At these index examinations, M-mode echocardiograms were performed uniformly on participating subjects. Subjects were excluded if they fulfilled any of the following criteria, in hierarchical order: (1) use of antihypertensive medications or systolic blood pressure of 140 mm Hg or greater or diastolic blood pressure of 90 mm Hg or greater at the index examination 793
794
Journal of the American Society of Echocardiography November-December 1995
Vasari et al.
38
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Body Surface Area (m 2) Figure I Predicted upper and lower limits of aortic root diameter in women as function of age and body surface area. Upper set of lines indicates 95th percentiles and lower set oflinesindicates 5th percentiles of aortic root dimensions. Select appropriate set of lines. Within set, select appropriate line for age marked on right. Follow line to appropriate body surface area on horizontal axis. Extrapolate to y axis for reference limit of aortic root dimension.
Table 1 Clinical and echocardiographic characteristics of subjects Variable
Age (yr) Weight (kg) Height (m) Body surface area (m2) Systolic blood pressure (mrn Hg) Diastolic blood pressure (mm Hg) Aortic root (mm)
Men
Women
(n = 1433)
(n = 1816)
46 + 13 80 _+11 1.75 _+0.07 1.95 + 0.15 120 + 10 76 + 7 32 + 3
47 + 13 62 _+10 1.61_+0.06 1.64 + 0.13 115 + 12 72 + 7 28 + 3
V a l u e s are m e a n _+ S D .
(n = 2422); (2) clinically apparent aortic or mitral valvular disease as identified by the presence of a diastolic murmur or systolic murmur (grade 3 / 6 or more) on precordial auscultation ( n = 81); (3) history of clinically apparent coronary heart disease or congestive heart failure or atrial fibrillation at or before the index examination ( n = 173); (4) use of other cardiovascular medications at the index examination (n = 105); (5) age less than 20 or 90 years or greater (n = 10); (6) presence of morbid
obesity, defined as body mass index greater than 35 k g / m 2 ( n = 73); or (6) unavailable or technically inadequate echocardiogram at the index examination (n-- 101). Methods of Measurement
Body height and weight measurements were obtained at the index examination. Body surface area was calculated according to the Du Bois formula) 5 All subjects underwent M-mode echocardiography. M-mode echocardiograms of the aortic root were obtained from the left parasternal window. In more than 90% of the subjects, M-mode studies were guided by two-dimensional echocardiography. All studies were performed with a 2.25 MHz, 1.25 cm diameter, unfocused transducer (K.B. Aerotech, Lewiston, Pa.) and a Hoffrel 201 ultrasound receiver (Hofffel Instruments, Norwalk, Conn.) interfaced with a Honeywell 1856 strip chart recorder (Honeywell, Minneapolis, Minn.). Aortic root size was measured according to the guidelines of the American Society of Echocardiography by a leading-edge to leading-edge measurement of the maximal distance between the anterior aortic root wall and the posterior aortic root wall at end diastole.16
Journal o f the American Society o f Echocardiography Volume 8 Number 6
44
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F i g u r e 2 Predicted u p p e r a n d lower limits o f aortic r o o t diameter in m e n as function o f age a n d b o d y surface area. Upper set of lines indicates 9 5 t h percentiles and lower set of lines indicates 5 t h percentiles o f aortic r o o t dimensions. Select appropriate set o f lines. W i t h i n set, select appropriate line for age marked o n right. Follow line to appropriate b o d y surface area o n h o r i z o n t a l axis. Extrapolate to y axis for refcrernce limit o f aortic r o o t dimension.
Table 2
Regression o f aortic r o o t d i m e n s i o n o n age a n d measures o f b o d y size in m e n a n d w o m e n Intercept
Age ( y r )
BSA ( m 2)
Height (m)
Model 1
Do
SE
~
SE
92
SE
Men Women Model 2 Men Women
15.11 14.52
1.003 0.791
0.09 0.09
0.006 0.004
6.72 5.73
0.469 0.449
14.19 10.79
1.984 1.710
0.088 0.099
0.006 0.005
~2
SE
R o o t MSE
2.67 2.52 8.04 7.89
1.068 0.995
2.80 2.59
R 2 = 0.214 in men and 0.222 in w o m e n / b r model I and 0.136 in men and 0.181 in women for model 2. R 2 is the proportion of total variability in aortic root dimensions that is explained by age and the measure of body size used in the model. The 5th and 95th percentile values for aortic room dimension in either sex can be calculated from the regression equations: (1) aortic r o o t = [30+(~ a X a g r 2 1 5 MSE; (2) aortic r o o t = J 8 0 + ([3~ x age) + ([32 x height) +_ 1.645 x Root MSE. [3, Regression coefficient; SE, standard error o f the regression coefficient; Root MSE, square root of the mean squared error; BSA, body surface area.
Statistical
Methods
All analyses were sex specific. T h e data werc e x a m i n e d for skewness a n d departures from normality a n d were inspected for the presence of" outliers. Aortic r o o t size was e x a m i n e d in relation to age with scatterplots, Multiple stepwise linear regression was used to evaluate the influ-
ence o f age, height, weight, body mass index, and body surface area o n aortic r o o t dimensions. 17 Sex-specific reference intervals for each decade o f age (starting from the t h i r d decade) a n d across a range o f b o d y sizes were comp u t e d with regression equations t h a t incorporated the m o s t significant predictor variables for aortic root dimen-
796
Journal of the American Society of Echocardiograptty November-December 1995
Vasan et al,
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Height (m) Figure 3 Predicted upper and lower limits of aortic root diameter in women as function of age and height. L~per set of lines indicates 95th percentiles and lower set of lines indicates 5th percentiles of aortic root dimensions. Select appropriate set of lines. Within set, select appropriate line for age marked on ridbt. Follow line to appropriate height on horizontal axis. Extrapolate to y axis for reference limit of aortic root dimension.
sion. All statistical analyses were per~brmed ~4th the statistical analysis system (SAS) ~s on a Sun spare 2 workstation (Sun Microsystems Inc., Mountain Vim~; Calif.).
RESULTS Study Sample O f the 2803 m e n and 3411 w o m e n who attended the index examinations, 1433 men (51%) and 1816 w o m e n (53%) ranging in age fi'om 20 to 88 years were eligible for analysis alter exclusions (2965 subjeers) were made for the criteria mentioned earlier. The clinical and echocardiographic characteristics o f the subjects are shown in Table l. Mean aortic root size was larger in men than in women. The variables correlated with aortic root diameter were analyzed by sex-specific multiple linear regression models. Models with (1) age alone and (2) age plus body surface area and (3) age and height were
studied. These variables were selected on the basis o f observations that they are the major determinants o f echocardiographic aortic root size~9; these variables have also been shown to be the principal determinants of the diameter o f the abdominal aorta. 2~ Age was the most important determinant o f aortic root size in both men ( r = 0.319) and w o m e n (r = 0.39). After adjustment for age, the correlation o f height and aortic root size was 0.195 in men and 0.183 in women. Age-adjusted correlation coefficients tbr body surface area were 0.354 in men and 0.287 in women. Models with weight or body surface area in addition to age were interchangeable in terms o f the coefficient o f determination (R2= 0.224 and 0.214 with the inclusion of weight or body surface area, respectively, in men; R 2 = 0.218 and 0.222 with the inclusion o f the same variables in women). The regression coefficients for sex-specific models with age and measures o f body size (body surface area and height) are shown in Table 2.
Journal of the American SocieEy of Echocardiography Volmne 8 Number 6
g s s a n et al.
797
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Figure 4 Predicted upper and lower limits of aortic root diameter in men as function of age and height. Upper set of lines indicates 95th percentiles and lower set of" lines indicates 5th percentiles of aortic root dimensions. Select appropriate set of lines. Within set, select appro~ priate line fbr age marked on right. Follow line to appropriate height on horizontal axis. Extrapolate to y axis for reference limit of aortic root dimensiom
Figures 1 and 2 depict the predicted sex- and body surface area-specific 5th and 95th percentiles of aortic root dimensions for different age groups according to the regression equation: aortic root = 130+ t31 x age + 13~.x body surface area. The partition values for aortic root size determined by the empiric observations were in near-perfect agreement with those obtained according to the regression equations. Figures 3 and 4 present sex- and height-specific 5th and 95th percentile values fbr aortic root dimem sions for i0-year age increments according to the regression equation: aortic root = 130+ 131 x age + 132 x height. Several statistics werc examined as part of regression-diagnostics analysisJ 7 No outliers or observations with excessive leverage were observed. Furthermore, regression residuals had appropriately normal distributions in both sexes.
DISCUSSION Principal
Findings
This study presents sex-, age-, and body size-specific upper and lower partition values for echocardiographic aortic root dimensions based on observations in a large number of normotensive adults from a populafon-based reference sample. Two sets of reference intcrvals are provided: one set based on age and body surface area and the other based on age and height. Wc chose to prescnt reference values with two differcnt measures of body size because there is no consensus in the literature rcgarding the ideal method for indexing echocardiographic dimensions. Although body surface area is the most common measure used for indexing in the published cchocardiograpic litcrature, the use o f height-based indexing urould have the advantage o f " n o t forgiving" tbr obesity-
798
Journal of thc American Society of Echocardiography November-December 1995
Vasari et al.
related variations sions. 22
in
echocardiographic
dimen-
Comparison with Previous Studies It has been recommended that any study that defines rcfercnce values must describe the refcrencc population and the way it was chosen, the physiologic conditions under which the obscrvations wcre obtained, the techniques for obtaining thc observations, and the analytic methods used for calculating the rcference intcrvals. 2s Most o f thc previous cchocardiographic studies o f aortic root dimensions do not meet these spccifications. 9-n'24-29 Reference values for echocardiographic variables should bc derived from a random sampling o f healthy individuals. Previous studies that have pro~dded refercnce intcrvals for echocardiographic aortic root size eithcr did not detail thc sampling methods used for the selection o f subjects 1x'24 or used relatives o f patients, 9'2s volunteer employees, ~~ or subjects who underwent echocardiography to exclude congenital heart disease. 9'28'29 In this study, selection bias was minimized because of the elimination o f clinical referral patterns; also in view o f the frequent longitudinal surveillance o f study subjects, exclusions tbr the presence o f cardiovascular disease are likely to be more complete in this study. Most prior studies also did not account for age or sex-related diffkrences in aortic root dimensions. Age is an important determinant of aortic root size, 9'3~ and we have recently found important sex-related differences in aortic root dimensions. 19 Failure to partition the study sample based on sex and age could, therefore, result in reference intervals that are wider. One previous study did provide age- and sexspecific aortic root measurements, but the sample was small ( n = 196) and did not include subjects beyond the age 0 f 6 5 years. ~6 The small size of samples used to provide reference intervals is also a major limitation of all previous studies. To decrease the uncertainty with regard to the reference intervals, a sample size o f at least 200 observations is r e c o m m e n d e d ? ~ The large sample size o f this study increases the precision o f the reference ranges suggested; the 90% confidence interval for each age interval was narrow. The excellent agreement between the reference ranges with both parametric and nonparametric estimates o f percentile is a strength o f this study and is a reflection o f the large sample size. Previous studies also did not provide details regarding the statistical methods used, especially regarding the presence or absence of outliers, the nature o f the distribution o f reference values, the exact transformation procedure used (if any) for generating ganssian partition values, and the confidence
limits of the reference range suggested. Such information is critical for the standardization of reference values. 32
Limitation o f the Study It has been stated that two-dimensional cchocardiography offers advantages over M-mode studies for the measurement o f aortic root dimensions, and the lack o f perfect agreement between measurements with the two techniques has been noted previously.9"26 However, in this study, M-mode measurements o f the aortic root were guided by t~rodimensional scans, and under these circumstances the enhanced rccording o f individual targets and thc higher sampling rate o f M-mode echocardiography are advantageous for thc purpose ofmcasurcmcnts? 3 The study sample was overhwelmingly white; the application o f the reference intervals suggested in this study to nonwhite adults or two-dimensional echocardiographic measurements o f the aortic root may be inappropriatc. Our study provides little information on thc size o f the ascending thoracic aorta, because aortic size was measured only at the level o f the valve leaflets. Ideally, high left parasternal, right parastcrnal, and other modified views should be combined with the standard left parasternal views for obtaining the maximal aortic root diameter. Bccausc these modified views are not performed routinely in our laboratory, it is possible that maximal aortic root diametcr was underestimated in some paticnts. Interobserver and intraobserver variability in the measurement o f aortic root diameter was not obtained in this study. Howcver, prior studies have demonstratcd the excellent reproducibility of M - m o d c cchocardiographic aortic root mcasurements? 4 Because physical examination underestimates the presence o f aortic regurgitation, partition values for aortic root size in this study may be slightly wider because o f the inability to cxclude subjects with clinically occult aortic rcgurgitation. The partition values for abnormal aortic root sizc provided in this study use gaussian statistics. Thus 5% o f " n o r m a l " subjects arc arbitrarily placed above and 5% below the reference limits defined by 5th and 95th percentiles. The reference intervals indicate the probability o f observing a given value o f aortic root dimension only if the subject were to belong to the reference group. There is a need to define aortic root dimensions at which there is a risk o f morbidity or death based on the long-term follow-up o f a sufficient number o f unselected subjects with a clear definition of adverse outcomes. Such information that describes "decision levels" or threshold values (above or below which clinicians should respond to the quantitative value) cannot be obtained from a cross-sectional study.
Journal of the AmericanSociety of Echocardiography Volume 8 Number 6
Vasan et al.
Implications A o r t i c r o o t d i l a t i o n is b c i n g d e t e c t e d m o r e freq u e n t l y b c c a u s e o f t h e w i d e s p r e a d use o f c c h o c a r d i o g r a p h y . C o m p a r i n g an o b s c r v e d v a l u e o f a o r t i c r o o t d i m c n s i o n w i t h t h a t p r e d i c t c d in r e l a t i o n t o t h e a g e , sex, a n d b o d y surface area ( o r h e i g h t ) o f t h c indiv i d u a l m a y bc o f assistance in d e c i d i n g w h e t h e r t h e o b s e r v e d v a l u e is o f p a t h o l o g i c significance. S e q u e n tial e n l a r g c m e n t o f t h e a b d o m i n a l a o r t a has b e e n o b s e r v e d in i n d i v i d u a l s w h o s e a b d o m i n a l a o r t i c dia m e t e r e x c e e d s t h e r e f e r e n c e intervals, a n d it has been suggested that such individuals undergo rescann i n g regularly, as P r o s p e c t i v e studies are r e q u i r e d t o determine whether individuals with aortic root diame t e r e x c e e d i n g t h e r e f e r e n c e i n t e r v a l s h a v e similar progressive aortic root dilation.
10.
11.
12. 13.
14.
15.
Conclusions T h i s s t u d y p r o v i d e s a g e - a n d scx-specific r c f c r e n c e i n t e r v a l s for e c h o c a r d i o g r a p h i c a o r t i c r o o t size derived from a large random sample of normotensive a d u l t s in t h e g e n e r a l p o p u l a t i o n . T h e s e r e f e r e n c e values will h e l p clinicians i n t e r p r e t t h e o b s e r v e d aortic r o o t d i m e n s i o n s in t h e c o n t e x t o f t h e age, sex, a n d b o d y size o f an i n d i v i d u a l .
16.
17.
18.
Special thanks go to Sonya Vaziri, M D , for her assistance in compilation o f the data set used in this study.
19.
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20.
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