(Circulation. 1997;96:1863-1873.)
© 1997 American Heart Association, Inc.
Articles |
Distribution and Categorization of Echocardiographic Measurements in Relation to Reference Limits
The Framingham Heart Study: Formulation of a Height- and Sex-Specific Classification and Its Prospective Validation
From the National Heart, Lung, and Blood Institute's Framingham (Mass) Heart Study (all authors); the Divisions of Cardiology and Clinical Epidemiology, Beth Israel Hospital, Harvard Medical School, Boston, Mass (D.L.); the Cardiology Section (E.J.B.) and Department of Preventive Medicine and Epidemiology (R.S.V., M.G.L., D.L., E.J.B.), Boston (Mass) University School of Medicine; and the National Heart, Lung, and Blood Institute, Bethesda, Md (D.L.).
Correspondence to Emelia J. Benjamin. MD, ScM, Framingham Heart Study, 5 Thurber St, Framingham, MA 01701. E-mail emelia{at}fram.nhlbi.nih.gov
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Abstract |
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Background Despite widespread categorization of echocardiographic measurements, there are no standardized guidelines for partitioning values exceeding reference limits.
Methods and Results We used regression analyses to develop sex- and height-specific reference limits for cardiac M-mode measurements (left ventricular [LV] mass, LV wall thickness, and LV and left atrial dimensions) in a healthy reference sample (n=1099) from the Framingham Heart Study. We then examined the distribution of measurements in a broad sample (n=4957) and classified the measurements according to increasing deviation from the height- and sex-specific reference limits and the 95th, 98th, and 99th percentile values for the broad sample (categories 0 through 4, respectively). To validate the categorization scheme, we used multivariable proportional-hazards regression to assess the relations of LV mass and LV wall thickness categories to risk of cardiovascular events and the relations of left atrial size to risk of atrial fibrillation. During a mean follow-up period of 7.7 years, 587 subjects developed new cardiovascular disease events, and 166 subjects developed new-onset atrial fibrillation. After adjustment for known risk factors, there was a 1.2- and 1.3-fold risk of cardiovascular disease events per category of LV wall thickness and LV mass, respectively, and a 1.6-fold risk of atrial fibrillation per category of left atrial size.
Conclusions Using a large community-based study sample, we propose a classification scheme that provides a standardized and validated framework for partitioning echocardiographic measurements. If adopted, the categorization scheme should promote uniformity in describing measurements among echocardiographic laboratories and enhance the comprehensibility of measurements to clinicians.
Key Words: echocardiography • cardiovascular diseases • ventricles • atrium • follow-up studies
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Introduction |
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Reference values, often referred to as the "upper limits of normal," have been proposed for echocardiographic dimensions of cardiac chambers.1 2 3 4 5 6 7 8 9 10 The current practice in echocardiographic laboratories across the world is to categorize echocardiographic measurements as normal or into mild, moderate, or severe degrees of abnormality. For instance, the expressions "moderate concentric left ventricular hypertrophy" and "severe left atrial enlargement" are used widely to describe quantitative abnormalities of these cardiac structures. Despite the widespread use of such descriptive terms, there are no standardized guidelines in the echocardiographic literature regarding cut points for partitioning values exceeding reference limits. Furthermore, the current clinical practice of categorizing values exceeding reference limits is highly variable between and within institutions, neither height- nor sex-specific, and inadequately substantiated by scientific data.
The choice of cut points for classifying echocardiographic values (or any other quantitative clinical measurement) on an ordinal scale should be based on the distribution of these observations in relation to reference limits in a randomly selected noninstitutionalized sample of the general population.11 Such a classification system may be useful for descriptive purposes, for prognostication, and for the prevention and treatment of diseases.12 Previous publications from the Framingham Heart Study have evaluated the relations of echocardiographic variables as continuous measures to cardiovascular disease events. The objectives of the present investigation were twofold: (1) to develop a classification system of echocardiographic values exceeding reference limits in a community-based study sample and (2) to prospectively examine the utility of our categorization approach for predicting clinically important events during follow-up.
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Methods |
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Study Sample
The selection criteria and study design of the FHS (both original and offspring study cohorts) have been detailed extensively.13 14 Original subjects of the FHS who participated in the 16th biennial examination (1979 through 1981) and subjects of the Framingham Offspring Study who participated in the second offspring examination (1979 through 1983) constituted the study sample. The FHS examination has been approved by the Boston Medical Center Institutional Review Board, and all subjects gave informed consent before the examinations.
Of 6216 subjects who attended the index examinations, 1259 subjects (20.3%) with inadequate M-mode echocardiograms were excluded from the present investigation. The study sample included two groups. The larger group, called the broad sample, included all 4957 who had adequate M-mode echocardiograms. A healthy subgroup of 1099 subjects, henceforth called the reference sample, was selected from the broad sample to formulate reference limits. The reference sample included subjects between the ages of 20 and 45 years who were not obese (body mass index between 19 and 26 kg/m2), who were of average height (1.5 to 1.9 m in men and 1.4 to 1.8 m in women), and who were free of cardiovascular disease, hypertension,15 AF, diabetes mellitus, and cardiac medication use.
Echocardiographic Methods
All subjects underwent routine M-mode
echocardiography. In >90% of subjects,
two-dimensional guided M-mode echocardiograms were obtained from the
left parasternal window.16 All measurements were made
according to the American Society of
Echocardiography guidelines.17 Three
measurements were averaged for each value. The following
echocardiographic variables were studied in the
present investigation: LA dimensions, LV mass, LV wall thickness,
and LV end-diastolic and end-systolic internal
dimensions. LV mass was calculated thus: LV
mass=0.8[1.04(LVIDD+IVST+PWT)3-(LVIDD)3]+0.6,
where LVIDD represents LV end-diastolic internal
dimension and IVST and PWT indicate the end-diastolic
thicknesses of the interventricular septum and LV posterior
wall, respectively.18 End-diastolic LV wall
thickness was calculated as IVST+PWT.
Analysis and Statistical Methods
Development of Classification for Values Exceeding Reference
Limits
All analyses were sex-specific. Height was used for
indexation of echocardiographic variables because
the use of body surface area may inappropriately mask obesity-related
alterations in cardiac structure.19 20 21 22 For each
echocardiographic variable Y, logarithmic
regression analyses were performed using the reference sample
with height as the predictor variable, thus: log
Y=ß0+ß1 log(height)+E, where
ß0 is the Y-axis intercept, ß1 is the
slope, and E is an error term. The predicted value of Y was calculated
as Yp=exp[ß0+ß1 log(height)].
The 95th percentile value of Y was calculated for the reference sample
as Y95=Yxexp(1.645xroot mean square error). The values of
Y95 represent the sex- and height-specific
reference limits for the variable. Reference limits (regression
coefficients and the values of [height]k,
k being sex-specific and echocardiographic
variable–specific) for LV wall thickness, LV internal dimensions,
and LV mass have been published previously.19 20 The
distribution of the ratio of the raw observation divided by the value
predicted for height and sex, ie, Y/Yp, in the broad sample
was studied. The sex- and height-specific 95th, 98th, and 99th
percentile values of the echocardiographic variable
in the broad sample were determined subsequently from the corresponding
percentiles of the ratio. We classified values of each
echocardiographic variable into the following five
categories based on sex- and height-specific percentiles (indicating
increasing deviation from the reference limits): category 0 (reference
limits), value 
95th percentile of the reference sample; category 1,
95th percentile of reference sample<value95th percentile of broad
sample; category 2, 95th percentile of broad sample<value98th
percentile of broad sample; category 3, 98th percentile of broad
sample<value99th percentile of broad sample; and category 4, value
>99th percentile of broad sample.
Relations of Categories of Echocardiographic
Variables to Clinical Outcomes
To assess the validity and prognostic significance of the
proposed classification scheme, we evaluated the risk of adverse
clinical outcomes among subjects in the five proposed categories of
each echocardiographic variable (as defined at the
baseline examination) during a follow-up period of up to 11 years.
Category 0 served as the reference group with which the other
categories were compared. The a priori hypothesis was that an
increase in risk of adverse clinical events would be observed across
the five categories of each echocardiographic
variable. Analyses relating to categories of LV mass, LV
wall thickness and LA dimensions are presented here. The
relations of LV mass and LV wall thickness to the incidence of
cardiovascular disease events and of LA dimensions to
the incidence of new-onset AF were examined with sex-stratified Cox
regression,23 adjusted for known risk factors for these
outcomes. The end points were selected a priori on the basis of
previous studies reporting an association of increasing LV
mass24 25 26 27 28 29 and LV wall thickness25 27 with
risk of cardiovascular events and of increasing LA size
with risk of AF.30 31 All study subjects were under
periodic surveillance for development of cardiovascular
disease events with the aid of medical history, hospitalization
records, and communication with personal physicians. All suspected
new cardiovascular events were reviewed by a panel of
three investigators who evaluated all pertinent available medical
records. Cardiovascular disease events included
coronary heart disease (angina pectoris, coronary
insufficiency, myocardial infarction, and sudden or nonsudden death
attributable to coronary heart disease), congestive heart
failure, cerebrovascular disease (stroke or transient ischemic
attack), and intermittent claudication. Criteria for these events have
been detailed previously.32 A diagnosis of AF on follow-up
was made on the basis of documentation of AF or flutter on ECGs
obtained from the FHS examination, hospital records, or private
physician records. For examining the impact of LA size categories
on risk of AF, we excluded subjects with AF at or before baseline
(n=82).
Adjustment for Covariates
For multivariable analyses examining
cardiovascular events as the outcome, hazard ratios
were adjusted for the following covariates: sex, age (years),
diastolic blood pressure (mm Hg), pulse pressure (mm Hg),
the ratio of total to HDL cholesterol, body mass index
(weight in kg/[height in m]2), and the following
dichotomous variables: hypertension, smoking, diabetes mellitus,
and prior cardiovascular disease.24 The
covariates included in the multivariable models evaluating AF as
the outcome event included age (years), hypertension status, diabetes
mellitus, ECG LV hypertrophy, valve disease, and prior
cardiovascular disease.33 Hypertension was
defined according to the JNC-V criteria as a systolic blood
pressure value 
140 mm Hg, a diastolic blood
pressure value 90 mm Hg,15 or current drug
treatment for hypertension. Valve disease was defined as the presence
of a diastolic murmur or a systolic murmur (grade
3/6 or more) on precordial auscultation at baseline. Criteria for
other risk factors have been detailed previously.34 Only
subjects with complete information regarding the covariates were
included for the proportional-hazards analyses.
Choice of Statistical Models
We investigated whether the risk of adverse events
differed among categories of echocardiographic
variables using the several multivariable statistical models:
models incorporating clinical variables only; multicategory models,
in which risk of adverse outcome in each category was compared with
that associated with category 0; trend models, in which we investigated
whether there was a stepwise increase in risk of adverse outcome from
one category to the next higher one; and threshold models, in which we
tested whether there was a particular category above which there was
increased risk of adverse outcomes (eg, risk of adverse events in
subjects in categories 0 and 1 versus risk in subjects in categories 2,
3, and 4).
To explore the impact of sex on the risks associated with the echocardiographic categories, we performed secondary analyses incorporating interaction terms. All analyses were performed with the SAS System (SAS Institute Inc) procedures REG35 and PHREG36 on a SUNsparc 2 workstation; a two-sided value of P<.05 assessed statistical significance.
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Results |
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Study Sample
The characteristics of the study subjects are summarized in Table 1
. Compared with the reference sample,
subjects in the broad sample were older, heavier, and had higher blood
pressure, body mass index, and mean values for the
echocardiographic measurements studied. In the broad
sample, the prevalence of cardiovascular disease was as
follows: hypertension, 33.1%; coronary disease, 6.7%;
congestive heart failure, 0.9%; and AF, 1.7%. These conditions were
grounds for exclusion from the reference sample.
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Classification of Values Exceeding Reference Limits
In general, we noted a significant relation between height and
echocardiographic variables in both sexes. The
distributions of the ratio of observed to sex- and height-predicted
values were examined for each echocardiographic
variable; the Figure displays the
distribution of this ratio for LA dimension, LV mass, LV wall
thickness, and LV end-diastolic dimension. Approximately
one quarter of men and one third of women exceeded reference limits for
LV wall thickness, LV mass, and LA dimension. Eleven percent of men and
9% of women exceeded reference limits for LV end-diastolic
dimension. Tables 2 and 3 provide the sex- and height-specific
cut points for the five proposed categories of each
echocardiographic variable derived from the
percentiles of the ratio of observed to sex- and height-predicted
values in the reference (category 0) and broad (categories 1 through 4)
samples.
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Relation of Category of Echocardiographic
Variable to Clinical Outcome
Unadjusted Event Rates According to Category of Variable
Three subjects were lost to follow-up. During follow-up of the
remaining 4954 subjects (mean age, 7.7 years; range, 0.4 to 11 years),
587 subjects experienced a new cardiovascular event; 55
of these new events were fatal. There were 166 subjects with new-onset
AF among the 4872 subjects free of AF at baseline. Crude rates for new
events increased across categories of LV mass, LV wall thickness, and
LA size (Tables 4 through 6). Among
men and women with a measurement of LV mass or LV wall thickness
suggestive of extreme deviation from reference limits (category 4),
>60% developed new cardiovascular disease events on
follow-up; in comparison, <10% of the subjects in category 0
experienced a new event. Categories of LV mass or LV wall thickness
between these two extremes (categories 1 through 3) had intermediate
rates of new cardiovascular disease events. For
categories of LA dimension, AF rates rose in stepwise fashion; >60%
of subjects in category 4 developed AF, compared with 2% of subjects
in category 0.
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Multivariable Analyses
Irrespective of the choice of the statistical model, a significant
risk gradient for adverse events was evident across the categories of
LV mass, LV wall thickness, and LA dimensions for both sexes after
adjustment for other known risk factors. In general, trend models were
roughly comparable to the five category models in terms of risk
prediction but incorporated fewer variables (ie, were more
parsimonious). The threshold models were inferior to the
trend and five category models but were better than multivariable
models that included only clinical predictors (data not shown). The
results of the trend and five-category models are shown in Tables 4 through 6
. There was a 1.2- to 1.3-fold increase in hazard for new
cardiovascular disease events per increase in category
of LV wall thickness and LV mass, respectively (trend model). There was
a 1.6-fold increase in hazard of AF per increase in category of LA
dimension (trend model); a 4.4-fold hazard was seen for subjects in the
highest category of LA dimension compared with those in the lowest
category. There were no significant sex differences in the risks
associated with LV mass and LV wall thickness categories (probability
values for the respective interaction terms were .29 and .68). There
was a 29% greater risk for AF across LA size categories in women than
in men (P=.08).
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Discussion |
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Need for Classifying Echocardiographic Values in Relation to Reference Limits
Because of the plethora of tests in medicine, raw values of clinical measurements often are poorly comprehended by nonspecialists. Understandably, nonspecialists frequently cannot recall cut points for abnormality, much less retain a sense of how far an abnormal value has strayed from normal.37 Clinical chemists have tried to resolve this dilemma by presenting any observed value in relation to its reference limits.38 Classification of abnormal clinical measurements on an ordinal scale, ie, within reference limits and with increasing degrees of deviation from reference limits, is an attractive option because clinicians tend to think in terms of categories when they interpret quantitative clinical data.39 Besides making clinical data more comprehensible to nonspecialists, classification also renders the available information more manageable.40
When standards for categorization of laboratory tests are absent, clinicians set their own informal criteria for converting noncategorical data into categorical information. This was well illustrated by a study addressing the interpretation of objective measures by physicians; the larger the physician's own set of reference values was, the greater was the leniency in the interpretation of such data.41 We searched the literature for cut points for classifying echocardiographic values exceeding the reference limits but failed to find standardized guidelines. Despite the routine use of descriptive categories in echocardiography laboratories, there is little scientific literature to support such practice.
Development and Validation of Our Classification
There is no universally accepted method for categorizing
continuous variables.42 43 44 In the present
investigation, we developed a classification system for
echocardiographic reference limits that attempted to
meet two broad objectives: standardization of
echocardiographic interpretation and clinical
sensibility.39 To achieve the latter goal, we sought to
develop a classification system that was straightforward,
user-friendly, evidence based, and based on appropriate
physiological variables. Because
echocardiographic measurements are dependent on sex as
well as on body size,19 20 45
echocardiographic variables should be classified
with reference to sex and to anthropometric measurements. We chose
height as a physiological obesity-independent
determinant of echocardiographic measurements. Although
age is an important determinant of cardiac
dimensions,21 46 47 we avoided
formulating age-dependent cut points because of uncertainty in
distinguishing the physiological from the
pathological effects of aging on the heart.48
By examining the distribution of values in a broad study sample that included healthy and diseased individuals, we developed a classification in which each echocardiographic variable could be partitioned into four categories based on increasing degrees of deviation from reference limits (category 0). The present investigation suggested that echocardiographic measurements exceeding height- and sex-specific reference limits were associated with an adverse prognosis; furthermore, the greater the extent of deviation, the worse the prognosis. Results of trend models indicated a stepwise increase in hazard per category increase in LV mass (1.3-fold risk of cardiovascular disease events), LV wall thickness (1.2-fold risk of cardiovascular events), and LA size (1.6-fold risk of AF). The adverse impact associated with values in categories 1 through 4 (compared with category 0) was evident in both sexes, persisted in multivariable analyses adjusting for the impact of other known risk factors, and was generally consistent within the various statistical models explored.
Strengths and Limitations
Any classification may be justified on the basis of its peremptory
assignment, its consensual validation, or external
documentation.40 Peremptory assignment is desirable when
data have no inherent meaning (eg, zip codes). A consensual approach
involves establishing a standard by common agreement of experts in the
field. External documentation (validation by application) requires
providing independent evidence that justifies the creation of the
proposed categories. We chose the latter method because we believe that
it was unbiased and scientifically more rigorous. Furthermore, the
ability of any classification system to predict risk of adverse events
considerably enhances its utility to the clinician. The longitudinal
design of the FHS facilitated such prospective validation.
To the best of our knowledge, except for LV mass,49 the present investigation is the first systematic attempt at classifying echocardiographic values exceeding reference limits. The a priori definition of cut points based on the distribution of the echocardiographic measurements instead of post hoc generation based on clinical outcome events is an additional strength of our study.44 The large, community-based study sample used for deriving our reference limits and for developing and validating our classification approach makes the present investigation unique. In comparison, previous reports of echocardiographic reference limits1 2 3 4 5 6 7 8 9 10 have been based on percentile estimates drawn from cross-sectional samples of smaller numbers of healthy subjects. Previous investigations from the FHS19 50 and elsewhere1 2 3 4 5 6 7 8 9 10 have not subdivided the values exceeding reference limits for practical use by clinicians.
The exclusion of subjects without satisfactory echocardiograms (who are generally sicker) may have resulted in the lowering of thresholds for abnormal values. The use of M-mode measurements presents other potential limitations. Cardiac disease may result in distorted LV geometry with the possibility of underestimating or overestimating LV mass.51 Furthermore, M-mode technology (transducer sensitivity, etc) has changed over the past two decades because the echocardiograms were performed. In addition, categories based on M-mode measurements may not be generalizable to two-dimensional echocardiographic measurements. Nonetheless, previous investigations have found reasonable agreement between measurements made by the two techniques.6 52 Finally, it is possible for a patient to shift between categories simply on the basis of limitations in the reproducibility of echocardiographic measurements.53
Because the generation and validation of our classification are based on ambulatory subjects, its prognostic relevance in hospitalized subjects is unknown. A related potential limitation is that in addition to age, the cut points are largely dependent on the prevalent pattern and severity of cardiac disease in the study participants. For instance, cut points for varying degrees of LV hypertrophy and LV dilatation obtained from our study sample may differ substantially from those obtained from subjects in hypertension and heart failure clinics, respectively. Nonetheless, it is heartening to note that the prevalence of cardiovascular disease in our study sample was consistent with that observed in the general US population.54 Furthermore, although we have demonstrated significant prognostic value of this categorization scheme, the therapeutic implications of our classification, if any, are unknown. Last, given the largely white racial composition of the Framingham sample, readers should exercise caution in extrapolating the study results to other racial groups.
Clinical Implications
Scrutiny of our cut points reveals that there are some challenges
to currently used thresholds for quantitative
echocardiographic abnormalities. For example, a sum of
septal and posterior LV wall thicknesses of 20 mm is regarded as
normal by most clinicians. Nonetheless, we would classify this value as
above reference limits in a woman or in a short man; such a value for
wall thickness (category 1) is associated with a 1.2-fold risk of
cardiovascular disease events compared with values
within reference limits. These observations underscore the weaknesses
inherent in the use of traditional reference limits that establish an
arbitrary dichotomous threshold (mean±2 SD or 95th percentile) without
providing insights into risks associated with various levels of the
echocardiographic variable.
By classifying echocardiographic values on an ordinal scale reflecting an increasing hazard for morbid events across categories, we have reported a framework that will promote greater consistency in echocardiographic interpretation and will provide prognostic information. Such a standardized classification is particularly important in an era when the nonspecialist not only orders echocardiograms but also is expected to interpret and act on the results of the studies.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by NIH/NHLBI contract NOI-HC-38038 and NINDS grant 2-ROI-NS-17950-11. Dr Vasan's research fellowship was made possible by a grant from Merck & Co Inc.
Received December 9, 1996; revision received March 25, 1997; accepted April 26, 1997.
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