Prognostic implications of subclinical left ventricular dilatation and systolic dysfunction in men free of overt cardiovascular disease (the framingham heart study)

MISCELLANEOUS

Prognostic Implications of Subclinical Left Ventricular Dilatation and Systolic Dysfunction Men Free of Overt Cardiovascular Disease (the Framingham Heart Study)

in

Michael S. Lauer, MD, Jane C. Evans, MPH, and Daniel Levy, MD

To determine the prognostic significance of asymptomatic left ventricular (LV) dilatation and LV systolic dysfunction, 1,493 men who were free of symptomatic cardiovascular disease underwent M-mode echocardiography and were then followed for a mean of 4.15 years. At baseline examination, II70 men (11.4%) had an abnormally high end-diastolic LV internal dimension (~56 mm) and 76 (5.1%) had an abnormally low fractional shortening (130%). During the follow-up period, 68 men experienced 92 cardiovascular disease events. After adjusting for age and traditional cardiovascular disease risk factors in proportionalhazards analyses, fractional shortening was a signiftcant independent predictor of cardiovascular risk (relative risk [RR] = 1.42,95% confidence interval [Cl] 1.12 to 1.81, for decrease of fractional shortening by 4%). Increased risk was also associated with combinations of low fractional shortening and high end-diastolic internal dimension (RR = 3.77,95% Cl 1.59 to 8.93) and with low percent fractional shortening with LV hypertrophy (RR = 5.93,95% Cl 1.97 to 17.85). In conclusion, subclinical LV dilatation and LV systolic dysfunction, although uncommon in men free of overt cardiovascular disease, are associated with increased risk for new cardiovascular disease events. (Am J Cardiol1992;70:1180-1184)

I

ncreasedleft ventricular (LV) volumesand LV systolic dysfunction have been shown to be powerful inde pendent predictors of adverse outcome in survivors of myocardial infarction1-3 and in patients with idiopathic dilated cardiomyopathy.4Consequently,the prevention of LV dilatation with afterload reduction5 and the optimal salvageof LV systolic function with thrombolysi&’ in patients with myocardial infarction are both strategiesconsideredpromising for improving long-term outcome. Recently, increasing interest has focused on patients with asymptomatic LV dysfunction in the hope that early treatment might improve survival and de creasethe incidence of clinical congestiveheart failure. Although there exist data on asymptomatic LV dysfunction in survivors of myocardial infarction, there are little data on the prevalenceof subclinical LV dilatation and LV systolic dysfunction in the general population. Accordingly, using echocardiography,we sought to define the prevalenceof asymptomatic LV dilatation and LV systolic dysfunction in male subjects of the Framingham Heart Study who were free of overt cardiovascular disease,and to determine whether theseabnormalities are associated with increased cardiovascular risk.

MerHODS Study -on: In 1948, 5,209 residents of Framingham, Massachusetts,who were between the ages of 28 and 62 years were enrolled in a prospectiveepide miologic study. The selection criteria and study design have been describedpreviously.8-11In 1971, children of the original study population and the spousesof those children were enrolled in the Framingham Offspring Study.’ I From 1979 to 1983 subjectsof the original cohort underwent their 16th biennial examination and subjectsin the Offspring Study underwent their second examination. All subjectsgave informed consentbefore each examination. Echocardiographic measurementsin a healthy referFrom the CardiovascularDivision, the Charles A. Dana ResearchInstitute and the Harvard-Thomdike Laboratory of the Department of ence population were used to define normal and abnorMedicine, Beth Israel Hospital and Harvard Medical School, Boston, mal population-based values for various echocardioand the Section of Cardiology, Lahey Clinic Medical Center, Burling- graphic parameters of LV size and function. These criton, the Framingham Heart-Study if the National Heart, Lung, aid teria were then applied to the broader population of Blood Institute, Framingham, and the Division of Cardiology and Cliical Epidemiology, Beth Israel Hospital, Boston, Massachusetts.This eligible subjects (see next). The reference population studv was su~uortedin hart bv Grant HL07374 and Contract NOlconsistedof 608 men who met the following criteria: (1) HCI38038 f;dm the Na’tionaiInstitutes of Health, Bethesda,Maryno overt evidence of cardiovascular disease,including land. Manuscript receivedMarch 2.1992; revisedmanuscript received coronary artery disease,valvular heart disease,congesand acceptedJune 23,1992. Address for reprints: Daniel Levy, MD, the Framingham Heart tive heart failure, cerebrovasculardisease,or peripheral artery disease;(2) no use of antihypertensive or cardioStudy, 5 Thurber Street, Framingham, Massachusetts01701. i 180

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vascular medications; (3) no diabetes mellitus; (4) systolic blood pressure < 140 mm Hg; (5) diastolic blood pressure <90 mm Hg; (6) body massindex (m kg/m*) >19 and <26, corresponding to Metropolitan Relative weights of >90% and <120%, respectively; (7) no pulmonary disease;and (8) adequate echocardiogramsfor the assessmentof LV dimensions and wall thicknesses. To be eligible for the broader study population, subjects had to meet the following criteria: (1) no evidence of pulmonary or cardiovascular disease(including clinical congestiveheart failure); (2) not currently receiving medical treatment for hypertension; and (3) adequate echocardiograms for the assessmentof LV dimensions and wall thicknesses.Criteria for cardiovascular disease diagnoseshave been reported previ~usly.~* BaaeBnem Examinations routinely included measurementsof resting blood pressure,anthropometric measurements, 12-lead electrocardiography, determination of blood glucose levels, assessmentof smoking status, measurement of total cholesterol and high-density lipoprotein levels, and echocardiography. Resting systolic and diastolic blood pressureswere measured in the left arm in the seatedposition using a mercury column sphygmomanometer.Two physician-measured systolic and diastolic pressureswere averaged to derive resting systolic and diastolic blood pressures. Subjects were considered smokers if they reported smoking any number of cigarettes per day regularly over the past year. Diabetes was diagnosedby previously describedcriteria.13 Data on smoking status and lipid parameters for membersof the original cohort were obtained from the 15th biennial examination. Alcohol consumption was measured using a validated formula described elsewhere.14 Outcosw even& Subjectswere followed through examination 19 for the original cohort and examination 3 for the Offspring Study subjects.At each examination, interim cardiovascular diseaseeventswere identified by medical history, physical examination, 1Zlead electrocardiography, and review of hospital records. Medical recordswere routinely obtained for subjectswho did not appear for an examination and were evaluated for evidence of incident cardiovascular disease.All suspected cardiovascular diise eventswere reviewed by 3 physicians who evaluated all pertinent records. The cardio vascular diseaseeventsincluded in this study were coronary artery disease,valvular heart disease,congestive heart failure, stroke or transient ischemic attack, intermittent claudication, and death due to cardiovascular disease.The echocardiograms were not used to determine the presenceor absenceof cardiovascular disease. All deaths were evaluated similarly, and the probable cause was established by a committee of 3 physicians after a review of the hospital records, autopsy findings, death certificates, and interviews with family members. -8phie methods Participants were studied in accordance with standard M-mode methods as previously reported15-19Over 90% of the M-mode images were obtained with 2-dimensional guidance. Subjects were not excluded on the basis of segmental wall motion abnormalities. End-diastolic measurements of LV internal dimension, and interventricular septal and

posterior wall thicknesseswere obtained using the criteria of the American Society for Echocardiography convention; end-systolic LV internal dimension was also similarly measured.LV masswas measuredusing Penn convention measurementsin conjunction with the formula of Devereux and Reichek.15Total LV wall thickness was calculated as the sum of the end-diastolic thicknessesof the interventricular septum and posterior wall. Percent fractional shortening was calculated as the ratio of the difference of end-diastolic and end-systolic LV internal dimensionsto end-diastolic LV internal dimension multiplied by 100. LV hypertrophy was defined as LV mass(divided by height) equal to or exceedingthe 95th percentile of the abovedescribcd referencepopulation. In a similar manner, values for excessivewall thickness, high end-diastolic LV internal dimension, and high end-systolic internal dimension were established. A low fractional shortening was defined as a value equal to or less than the fifth percentile of the reference population. The mean reference values and standard deviations for the various echocardiographicparameterswere: LV mass/height, 100.3 f 22.9 g/m; total LV wall thickness, 18.5 f 2.3 mm; end-diastolic LV internal diiension, 50.5 f 3.8 mm; end-systolic LV internal dimension, 32.5 f 3.4 mm; and fractional shortening, 35.7 f 3.6%. Abnormal values were as follows: LV hypertrophy, 1141 g/m; excessiveLV wall thickness, 222 mm; high end-diastolic LV internal dimension, 256 mm; high end-systolicinternal dimension, 238 mm; and low fractional shortening, 130%. StatMeal mahock: Unless otherwise stated, cata gorical comparisonswere made using chi-square analySki.

The mean follow-up period for this study was 4.15 years. The 4-year incidence of the outcome eventswas examined as a function of the presenceor absenceof certain echocardiographic abnormalities (such as the presence or absence of low fractional shortening) or combinations of echocardiographic abnormalities (such as both low fractional shortening and hiih end-diastolic LV internal dimension). Age-adjusted rates of card& vascular diseaseoutcome eventswere calculated by the direct method. Multivariate analyses were performed for subjects for whom complete data on risk factors were available. The Cox proportional-hazards model*Owas used to examine the relations betweenechocardiographicparameters of LV size and function to the incidence of cardiovascular diseaseevents.The covariates in the multivariate Cox analyseswere chosenbecauseof their potential roles as risk factors for cardiovascular disease.*’They included age, diastolic pressure,pulse pressure,regular cigarette smoking during the past year (yes = 1; no = 0), ratio of total to high-density lipoprotein cholesterol, diabetes (yes = 1; no = 0) and obesity (defined as the body massindex, or weight in kg divided by the height in meters squared [kg/m*]). Age-adjusted and risk factor-adjusted relative-risk values (and 95% confidence intervals [CI]) for outcome events were calculated for 1 standard deviation increments of echocardiographic LV parametersand for the SYSTOLIC DYSFUNCTION AND PROGNOSIS

1181

TABLE I Population Studied and Incidence of Outcome Events Characteristics Seen at index examination Free of cardiovascular disease and adequate echocardiogram Subjects with incident cardiovascular disease Subjects with incident congestive heart failure Subjects with incident cardiovascular mortality Subjects with incident mortality (includes all causes of death)

r TABLE II

Characteristics

2,805 1,493 68 (4.6%) 5 (0.3%) 8 (0.5%) 45 (3.0%)

of Study Subjects

Characteristics Mean age (years) Mean diastolic blood pressure (mm Hg) Mean pulse pressure (mm Hg) Cigarette smokers (%) Cholesterol:HDL ratio Diabetes mellitus (%I Alcohol consumption (ml/week) Body mass index tkg/m2) LV mass/height (g/m) Total wall thickness (mm) End-diastolic LV internal dimension (mm) End-systolic LV internal dimension (mm) Fractional shortening (%I t

No. of Subjects

Values 46.0 e 12.1 80.0 f 9.0 45.6 f 6.5 40.0 5.0 2 1.6 1.8 142.4 2 172.5 26.3 r 3.5 110.0 2 26.6 19.3 + 2.5 51.0 2 3.9

Abnormakty

Values Prevalence

Left ventricular hypertrophy Thick left ventricular walls High end-diastolic internal dimension High end-systolic internal dimension Low % fractional shortening Low % fractional shortening and high end-diastolic internal dimension Low fractional shortening and left ventricular hypertrophy

170 302 186 126 76 34

(11.4%) (20.2%) (12.5%) (8.4%) (5.1%) (2.3%)

11 (0.7%)

TABLE IV Age-Adjusted Relative Risks of Cardiovascular Disease Events in Men: Results of Bivariate Proportion-Hazards Analyses Parameter

Increment

LV mass/height (g/m) Total wall thickness (mm) End-diastolic LV internal dimension (mm) End-systolic LV internal dimension (mm) Fractional shortening (%)

25 2 4

1.29 (1.07-1.56) 1.13 (0.97-1.32) 1.17 (0.93-1.47)

4

1.38 (1.11-1.73)

-4

Relabve Risk

1.51 (1.19-1.91)

Increments correspond to 1 standard deviation change of the respective echocardlographic parameter. Values given are relative risks and 95% confidence intervals. LV = left ventricular.

32.8 2 3.6 35.9 k 3.7

vmes gwen are mean + sranaaro aev~arm HDL = high-density lipoprotein; LV = leftventr~cular.

presenceor absenceof certain echocardiographicabnormalities or combinations of echocardiographic abnormalities. A detailed analysis of alcohol consumption and LV mass and geometry in the Framingham cohorts has been reported elsewhere.l4 A similar analysis was performed in the subset for this study using multivariate linear regression analysis relating alcohol consumption to LV mass,wall thickness, systolic and diastolic internal dimension, and fractional shortening. RESULTS mm of &dy popuMo~ The characteristics of the main study population are summarized in Tables I and II. In all, 1,493 men met the criteria for study entry. Over 4 to 6 years of follow-up there were 92 cardiovascular diseaseevents in 68 men (4.6%) (50 cohort and 18 offspring subjects). Only 5 men (0.3%) developed overt clinical congestive heart failure and only 8 (0.5%) died of cardiovascular causes.Becauseof the small number of outcome events in this relatively healthy population, only total cardiovascular disease events were studied in detail. The clinical and echocardiographiccharacteristics of the study subjects are summarized in Table II. Rw~ot~~The prevalencesof cchocardiographic LV abnormalities in the main study population are summarized in Table III. Criteria for LV hypertrophy were fulfilled in 170 subjects(11.4%) (18JXGofcohortvs lO.l%ofoffspring, i 182

TABLE Ill Prevalence of Abnormal Echocardiographic in the Study Population

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TABLE V Age- and Risk Factor-Adjusted Relative Risks of Cardiovascular Disease Events in Men: Results of Multivariate Proportional-Hazards Analyses Parameter

Increment

LV mass/height (g/m) Total wall thrckness (mm) End-diastolic LV internal dimension (mm) End-systolic LV internal dimension (mm) Fractional shortening (%)

25 2 4

1.11 (0.89-1.40) 1.00 (0.84-1.19) 1.13 (0.89-1.43)

4

1.30 (1.03-1.65)

-4

Relative Risk

1.42 (1.12-1.81)

Increments correspond to 1 standard deviation change of the respective echocardiographic parameter. Values given are relative risks and 95% confidence Intervals. Risk factors in multivariate proportional-hazards models included age, diabetes, smoking, cholesterol to high-density lipoprotein ratio, diastolic blood pressure, pulse pressuS and body mass index. LV = left ventricular.

p = 0.005). The prevalenceof a high LV end-diastolic dimension was 186 of 1,493 (12.5%); a high LV endsystolic dimension was observed in 126 men (8.3%) (3.7% of cohort vs 9.0% of offspring, p = 0.023). Low fractional shortening was less common, occurring in 76 subjects (5.1%). The combination of low fractional shortening and high end-diastolic internal dimension was observedin 34 men (2.3%). Eleven men (0.7%) had the combination of low fractional shortening and LV hypertrophy. After adjusting for age, systolic blood pressureand body massindex in stepwisemultivariate linear regression analyses,alcohol consumption was an independent predictor of LV mass (p = 0.013) and LV end-systolic dimension (p = 0.026); there was a trend relating alcohol use to decreasedfractional shortening (p = 0.071). Alcohol consumption was not related to LV wall thicknessor LV end-diastolic dimension. NOVEMBER 1, 1992

Risk of car&vasadar disease even& The relative risks (RR) of cardiovascular diseaseeventsaccording to echocardiographic parameters are summarized in Tables IV and V. When controlling for age in bivariate Cox proportional-hazards models, LV mass,end-systolic LV internal dimension and fractional shortening were significant predictors of cardiovascular disease events (all p <0.05). Of note, end-diastolic LV internal dimension was not a significant predictor of cardiovascular diseaseevents. After controlling for cardiovascular diseaserisk factors (as well as age), only end-systolic LV internal dimension and fractional shortening remained significant predictors of cardiovascular diseaseevents.A 1 standard deviation decreasein fractional shortening (or 4%) was associatedwith a RR of 1.42 (95% CI 1.12 to 1.81). In further analyses, subsets of male subjects with low fractional shortening were evaluated; these analyses are summarized in Table VI. Low fractional shortening itself was associatedwith an RR of 2.63 (95% CI 1.20 to 5.76). Despite the low prevalence,subjectswith both low percent fractional shortening and a high end-diastolic LV internal dimension had a markedly elevated age- and risk factor-adjusted RR for cardiovascular diseaseevents (RR = 3.77, 95% CI 1.39 to 7.60). Similarly subjects with both low fractional shortening and LV hypertrophy had an RR of 5.93 (95% CI 1.97 to 17.85). The combination of a high end-diastolic LV internal dimension and LV hypertrophy did not confer a significantly increased risk of cardiovascular disease events. The age-adjusted rates of total cardiovascular diseaseeventsin men are shown in Figure 1. The incidence of cardiovascular disease events in men with normal echocardiographic parameterswas 10 per 1,000 personyears. Among men with low fractional shortening, the incidence was 28 events per 1,000 person-years (p = 0.005). With both low fractional shortening and high end-diastolic LV internal dimension there were 45 events per 1,000 person-years (p = 0.003), and with

TABLE VI Age- and Risk Factor-Adjusted Relative Risks of Disease Events in High-Risk Subset Men Cardiovascular

Subset

no.

Low fractlonal shortening Low fractional shortening and high end-diastolic LV internal dimension Low fractional shortening and LV hypertrophy

76 34

2.63 (1.20-5.76) 3.77 (1.59-8.93)

11

5.93 (1.97-17.85)

Relatwe Risk

Values given are relatwe risks and 95% confidence intervals. Risk factors in multivariate proportional hazards models mcluded age, diabetes, smokiw cholesterol to high-density licowotem ratio, dlastollc blood !xessure, wise pressureand body tnass in&x. LV = left ventricular.

both low fractional shortening and LV hypertrophy there were 119 events per 1,000 person-years (p = 0.002).

DISCUSSION

The principal finding of this study is that subclinical LV dilatation and LV systolic dysfunction, although uncommon in the general population of men, are asscciated with a significantly increased risk of cardiovascular diseasesequelae.For the purposesof a large population-based epidemiologic study, this study used 2-dimensional-guided M-mode echocardiography to assess LV chamber size and systolic function. The validity of using M-mode measurementsof LV size and function has been previously demonstrated.22Furthermore, >90% of the M-mode images analyzed in this study were obtained with the aid of 2-dimensional imaging; this improves the quantitative reliability of M-mode echccardiography.23 There are some important limitations in this study. The Framingham population is overwhelmingly white; thus, the data cannot be generalized to a black population. The incidences of overt congestive heart failure and cardiovascular death were low; it is possible that longer follow-up would have yielded significant results

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SYSTOLIC DYSFUNCTION AND PROGNOSIS

1183

relating to these outcome events. Another potential problem relates to the lack of correction of LV size for body size. At this time, optimal normalization of LV parametersfor body size is an unsettled issuethat is the subject of ongoing research at a number of centers including the Framingham Heart Study. In this healthy Framingham population consisting of men free of known cardiovascular disease,it appears that impaired LV systolic function, particularly when associatedwith LV dilatation or LV hypertrophy, is an independent risk factor for cardiovascular disease se quelae after controlling for standard cardiovascular risk factors. LV dilatation alone, however, does not confer an increased risk for adverseoutcome. The therapeutic and preventative implications of strategiesto identify efficiently persons with subclinical LV dilatation or systolic dysfunction require further study. REFERENCES

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