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Journal of the American College of Cardiology Vol. 43, No. 12, 2004© 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00Published by Elsevier Inc. doi:10.1016/j.jacc.2003.11.064

ncreased Left Ventricular Mass Is a Riskactor for the Development of a Depressedeft Ventricular Ejection Fraction Within Five Yearshe Cardiovascular Health Studyark H. Drazner, MD, MSC, FACC,* J. Eduardo Rame, MD, MPHIL,* Emily K. Marino, MS,¶

ohn S. Gottdiener, MD, FACC,† Dalane W. Kitzman, MD, FACC,‡ Julius M. Gardin, MD, FACC,§eri A. Manolio, MD, PHD,� Daniel L. Dries, MD, MPH,* David S. Siscovick, MD, MPH#allas, Texas; Roslyn, New York; Winston-Salem, North Carolina; Detroit, Michigan; Bethesda, Maryland;

nd Seattle, Washington

OBJECTIVES Our aim in this study was to determine whether increased left ventricular mass (LVM) is arisk factor for the development of a reduced left ventricular ejection fraction (LVEF).

BACKGROUND Prior studies have shown that increased LVM is a risk factor for heart failure but not whetherit is a risk factor for a low LVEF.

METHODS As part of the Cardiovascular Health Study, a prospective population-based longitudinalstudy, we performed echocardiograms upon participant enrollment and again at follow-up of4.9 � 0.14 years. In the present analysis, we identified 3,042 participants who had at baselinea normal LVEF and an assessment of LVM (either by electrocardiogram or echocardiogram),and at follow-up a measurable LVEF. The frequency of the development of a qualitativelydepressed LVEF on two-dimensional echocardiography, corresponding approximately to anLVEF �55%, was analyzed by quartiles of baseline LVM. Multivariable regressiondetermined whether LVM was independently associated with the development of depressedLVEF.

RESULTS Baseline quartile of echocardiographic LVM indexed to body surface area was associated withdevelopment of a depressed LVEF (4.8% in quartile 1, 4.4% in quartile 2, 7.5% in quartile 3,and 14.1% in quartile 4 [p � 0.001]). A similar relationship was seen in the subgroup ofparticipants without myocardial infarction (p � 0.001). In multivariable regression thatadjusted for confounders, both baseline echocardiographic (p � 0.001) and electrocardio-graphic (p � 0.001) LVM remained associated with development of depressed LVEF.

CONCLUSIONS Increased LVM as assessed by electrocardiography or echocardiography is an independentrisk factor for the development of depressed LVEF. (J Am Coll Cardiol 2004;43:2207–15)© 2004 by the American College of Cardiology Foundation

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ncreased left ventricular mass (LVM) and left ventricularLV) hypertrophy are important independent predictors ofardiovascular morbidity including heart failure in popula-ion studies (1–7). However, prior studies have not reportedow often the heart failure attributed to LV hypertrophyccurred in the setting of a depressed or preserved left

From the *Heart Failure Research Unit, Donald W. Reynolds Cardiovascularlinical Research Center, Division of Cardiology, Department of Internal Medicine,niversity of Texas Southwestern Medical Center, Dallas, Texas; †Division ofardiology, St. Francis Hospital, Roslyn, New York; ‡Cardiology Section, Depart-ent of Medicine, Wake Forest University School of Medicine, Winston-Salem,orth Carolina; §Division of Cardiology, St. John Hospital and Medical Center andayne State University, Detroit, Michigan; �Division of Epidemiology and Clinical

pplications, National Heart, Lung, and Blood Institute, Bethesda, Maryland;Department of Biostatistics, University of Washington, Seattle, Washington;Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology,niversity of Washington, Seattle, Washington. Drs. Drazner, Rame, Dries, andiscovick received support from the Donald W. Reynolds Cardiovascular Clinicalesearch Center, Dallas, Texas. Dr. Drazner was the recipient of a Clinical Scientistevelopment Award from the Doris Duke Charitable Foundation (New York, Nework). The research reported in this article was also supported by contractsO1-HC-85079 through NO1-HC-85086, NO1-HC-35129, and NO1-HC-

5103 from the National Heart, Lung, and Blood Institute. A full list of participatingHS investigators and institutions can be found via the homepage for CHS on theHLBI website.Manuscript received July 15, 2003; revised manuscript received November 17,

s003, accepted November 24, 2003.

entricular ejection fraction (LVEF) (7). Preserved LVEF isresent in a significant number of patients with heart failuren epidemiologic studies (8–10). Additionally, heart failuren the presence of LV hypertrophy and a preserved LVEF

See page 2216

ay be due to related diastolic dysfunction (11,12). To ournowledge, no large prospective cohort study has previouslyddressed whether increased LVM is an independent riskactor for a subsequent decrease in LVEF. The Cardiovas-ular Health Study (CHS), a large multicenter longitudinaltudy of elderly individuals in which echocardiograms wereerformed at baseline and repeated approximately five years

ater (13,14), afforded the opportunity to address thismportant question.

ETHODS

tudy population. There were 5,201 participants in theaseline CHS cohort, a National Heart, Lung, and Bloodnstitute-sponsored prospective cohort study previously de-
cribed in detail (15). Participants were �65 years of age,

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2208 Drazner et al. JACC Vol. 43, No. 12, 2004LVH and Subsequent Decrease in LVEF June 16, 2004:2207–15

on-institutionalized, and were recruited between 1989 and990. At baseline, subjects underwent a comprehensiveattery of examinations including laboratory evaluationsbtained after a 12-h fast (15,16), electrocardiography, andchocardiography. Subjects have been followed serially sincehe baseline evaluation including a repeat echocardiogramerformed in 1994 to 1995 (4.9 � 0.14 years after baselinetudy), herein termed “follow-up echocardiogram.” Theresent analysis includes those 3,042 participants with aaseline echocardiographic (n � 2,190) or electrocardio-raphic (n � 2,944) assessment of LVM, normal LVEF asssessed qualitatively by two-dimensional echocardiographyt baseline, and an assessment of LVEF on the follow-upchocardiogram (Fig. 1). A second cohort of African-

Abbreviations and AcronymsBSA � body surface areaCHS � Cardiovascular Health StudyCI � confidence intervalFS � fractional shorteningLV � left ventricularLVEF � left ventricular ejection fractionLVM � left ventricular mass

kFigure 1. Number of participants meeting inclusion criteria.

merican subjects was recruited into the CHS between992 and 1993 and had their baseline echocardiogram in994 and 1995; given the lack of a follow-up echocardio-ram, they were not included in the present analysis.lectrocardiography. Twelve-lead electrocardiogramsere obtained at baseline and at follow-up and were

nalyzed at a core facility. Left ventricular mass was esti-ated as previously described (17). Left ventricular hyper-

rophy, Q waves, and atrial fibrillation were defined basedn Minnesota codes (18).chocardiography. Echocardiographic images were ob-

ained using a standardized protocol and recorded ontouper VHS tape (13,14). The core reading center foraseline echocardiograms was located at University ofalifornia-Irvine, and for follow-up echocardiograms ateorgetown University, Washington, DC. The LVM was

alculated as described by Devereux et al. (19): LVM (g) �.80 � 1.04 [(ventricular septal thickness diastole � LViastolic dimension � ventricular posterior wall thicknessiastole)3 � (LV diastolic dimension)3] � 0.6. ExpectedVM was calculated for men as 16.6 � [weight (kg)]0.51

nd for women as 13.9 � [weight (kg)]0.51 as before (1,14).eft ventricular hypertrophy was defined as an observed/xpected LVM �1.45 (1,14). Fractional shortening (FS) athe endocardium and midwall was calculated from M-modeeasurements (20,21). Stress-adjusted FS was calculated,

nd ratios of observed/predicted FS in the lower 5% of aeference population deemed free of cardiac disease wereonsidered to be depressed (1,21). Left ventricular geometryas categorized into four mutually exclusive categoriesepending upon the presence of LV hypertrophy (observed/xpected LVM �1.45 as above) and/or increased relativeall thickness (defined as �0.48 [6]). As compared withormal geometry, concentric remodeling was defined as

ncreased relative wall thickness but observed/expectedVM �1.45, eccentric hypertrophy as observed/expectedVM �1.45 but no increased relative wall thickness, andoncentric hypertrophy as increased relative wall thicknessith observed/expected LVM �1.45.Qualitative assessment of LVEF was obtained by two-

imensional echocardiography (14). Left ventricular ejec-ion fraction was classified as normal, borderline, or abnor-al approximately corresponding to values �55%, �45%

nd �55%, or �45%, respectively (1,10,22). Regional wallotion was also qualitatively assessed as normal, borderline,

r abnormal (14). To assess agreement for qualitativessessment of LVEF between the baseline and follow-upchocardiography core centers, 238 baseline echocardio-rams were reinterpreted by the follow-up echocardiogra-hy core center in a blinded fashion. There was an 87.8%greement (kappa � 0.344) for whether LVEF was normalr not. This is comparable with assessments of inter-readergreement of the follow-up echocardiogram (n � 250,greement � 86.8%, kappa � 0.432) and, as previouslyeported, the baseline echocardiogram (agreement � 94%,
appa � 0.32) (14). Using two sets of baseline echocardio-

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2209JACC Vol. 43, No. 12, 2004 Drazner et al.June 16, 2004:2207–15 LVH and Subsequent Decrease in LVEF

rams (set one: n � 81, set two: n � 41), the endocardial FSas recalculated at follow-up blinded to the original results.

n set one, the original mean FS was 43.2%, and, on blindedeassessment at follow-up, it was 44.6%. In set two, theriginal mean FS was 40.7%, and on reassessment it was5.2%.efinitions. Hypertension was categorized as present if

eated systolic blood pressure was 140 mm Hg or higher, oriastolic blood pressure was 90 mm Hg or higher, or theatient self-reported a history of hypertension in combina-ion with use of antihypertensive medication. Methods ofscertaining myocardial infarction (23) have been described.he outcome measure was the development of a depressedVEF as defined by a borderline or abnormal LVEF on the

ollow-up echocardiogram (see preceding text). These wererouped together because we have previously shown thatorderline LVEF is an independent risk factor for mortality22). However, we also performed a sensitivity analysis byonsidering subjects with follow-up borderline LVEF asaving not reached the outcome.tatistical analysis. Continuous variables are expressed asean � SD or median (25th, 75th percentile). Differences

n continuous variables were compared with the t test exceptor levels of C-reactive protein and serum insulin in whichhe Wilcoxon rank-sum test was used due to highly skewedistributions. The significance of differences in categoricalariables was assessed by chi-square analysis. Analysesncorporating LVM were performed with crude LVM andVM indexed to body surface area (BSA) or height.earson correlation coefficients between baseline electrocar-iographic LVM or baseline echocardiographic parametersnd follow-up echocardiographic parameters were calcu-ated. The frequency of the development of depressedVEF was calculated in the cohort by quartiles of baselineVM. The Cochran-Armitrage test of trend was used toetermine the significance of the association of LVMeasures and the development of a depressed ejection

raction. Similar analyses were performed in importantubgroups.

Logistic regression was used to determine the associationf either baseline LVM or baseline presence of LV hyper-rophy with incident depressed LVEF. Linear regressionas used to determine the association of LVM with

ollow-up mid-wall FS. Potential confounders includingemographics, baseline height and weight, hypertensiontatus, presence of coronary heart disease, atrial fibrillation,nd baseline endocardial FS were incorporated as covariatesn multivariable models. We excluded major residual con-ounding by those variables that were not included in thenal multivariable models but that differed significantlyetween participants who did or did not reach the outcomen univariate analysis by adding them back into the finalodel and verifying that the association of the covariate of

nterest and outcome was not changed appreciably. Modelsere also constructed in which LV diastolic dimension was

ntered as an independent variable in addition to either LV L

eptal wall thickness or posterior wall thickness to determinehich components of LVM were associated with theutcome. In a separate set of models, categorical patterns ofV geometry were entered as an independent variable.nalyses were performed with SPSS software (SPSS Inc.,hicago, Illinois), and p � 0.05 was used as criteria for

tatistical significance.issing data. A separate analysis was performed to address

he impact of missing data introduced by the requirement toave a follow-up CHS echocardiogram. In 131 participantsho did not have a follow-up CHS echocardiogram butere otherwise eligible for inclusion in the present study, we

scertained whether they had developed a depressed LVEFrom echocardiograms that had been performed as part oflinical care (and had been reassessed by CHS investigatorss previously described [1]). The baseline LVM of thoseho developed a depressed LVEF was compared with theaseline LVM of the remainder of the subjects without aollow-up echocardiogram who did not have a knownistory of heart failure (including heart failure as a cause ofeath).

ESULTS

aseline characteristics, interim clinical events, and follow-p. The baseline characteristics are shown in Table 1,tratified by whether baseline LVM was above or below theedian value (137 g). Subjects with higher LVM were more

ften men with a history of hypertension, diabetes mellitus,nd prior coronary heart disease. As would be expected, theomponent measures of LVM (LV diastolic dimension andosterior wall and septal wall thickness) also differed signif-cantly between the two groups. When stratifying the cohortnto quartiles of baseline echocardiographic LVM, theomponent values of LVM in quartile four were: LViastolic dimension 5.4 � 0.6 cm, septal wall thickness 1.0

0.2 cm, and posterior wall thickness 0.95 � 0.1 cm. Aorrelation matrix of baseline electrocardiographic LVMnd echocardiographic parameters with follow-up echocar-iographic parameters is shown (Table 2) (p � 0.001 for allorrelations). Baseline LV dimensions, echocardiographicVM, and electrocardiographic LVM were strongly andirectly related to follow-up LV dimensions and inverselyith follow-up FS measures. Baseline FS measures were

nversely related to follow-up LV dimensions and directlyelated to follow-up FS measures. During follow-up (Table), participants who had higher baseline LVM were moreikely to have a clinical event related to coronary arteryisease (composite measure of myocardial infarction, percu-aneous coronary angioplasty, or coronary artery bypassraft). They also were more likely to develop atrial fibrilla-ion. A number of parameters on the follow-up echocardio-rams differed between those with a higher or lower baseline
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ollow-up LV function and its association with baselineVM. Of the 3,042 participants with baseline assessmentf LVM, 265 (8.7%) developed depressed LVEF during the5 years of follow-up. Those participants who did reach the

utcome were more likely to have an interval myocardialnfarction (16%) than those who did not reach the outcome3%, p � 0.001). As would be expected, there were aumber of significant differences in measurements from theollow-up echocardiograms of participants who reached the

able 1. Baseline Clinical Characteristics*

Characteristics

Baseline EMass Below t

n � 1

ge (yrs) 71.2 �thnicityCaucasian 1,042 (African American 45 (Other 8 (ale gender 215 (iabetes mellitusNone 999 (Fasting blood glucose �125 mg/dl 47 (History of treated diabetes 40 (

asting glucose (mg/dl) 103 �ypertensive 477 (

moking statusNever 579 (Former 388 (Current 127 (istory ofCoronary heart disease‡ 134 (Heart failure 14 (

se of medicationsACE-I 42 (Beta-blockers 115 (Diuretics 202 (Calcium channel blockers 89 (

ystolic blood pressure (mm Hg) 131 �eart rate (beats/min) 64 �eight (kg) 65.0 �

ody mass index (kg/m2) 25 �erum creatinine (mg/dl) 1.0 �-reactive protein (mg/l) 1.6 (0.8erum cholesterol (mg/dl) 220 �erum insulin (IU/ml) 11 (9,lectrocardiographic variablesAtrial fibrillation 16 (Q waves 26 (LV hypertrophy 14 (LV mass (g) 134 �

chocardiographic variablesLeft atrial dimension (cm) 3.6 �Posterior wall thickness, diastole (cm) 0.77 �Ventricular septal thickness, diastole (cm) 0.79 �LV diastolic dimension (cm) 4.6 �LV systolic dimension (cm) 2.6 �Endocardial FS (%) 43 �Midwall FS (%) 24 �

Data are presented as n (%) or means � SD except for C-reactive protein and seruass � 137 g; ‡coronary heart disease includes myocardial infarction, angina, coronACE-I � angiotensin-converting enzyme inhibitors; FS � fractional shortening.

utcome as compared with those who did not. These h

ncluded a larger LV diastolic dimension (5.3 � 0.8 vs..7 � 0.5), LV systolic dimension (3.6 � 1.0 vs. 2.7 � 0.5),nd left atrial dimension (4.2 � 0.8 vs. 4.0 � 0.9), and lowerndocardial FS (33 � 11 vs. 43 � 8), and midwall FS21 � 7 vs. 23 � 4), respectively (p � 0.001 for allomparisons).

The percentage of participants who developed a de-ressed LVEF, stratified by quartiles of baseline LVM (Fig.A), LVM indexed to BSA (Fig. 2B), and LVM indexed to

LVedian†

Baseline Echo LVMass Above the Median†

n � 1,095 p Value

71.6 � 4.7 0.0380.152

1,044 (95.3)49 (4.5)2 (0.2)

587 (53.6) � 0.001� 0.001

946 (86.6)82 (7.5)65 (5.9)

108 � 28 � 0.001638 (58.4) � 0.001

� 0.001489 (44.7)509 (46.6)95 (8.7)

171 (15.6) 0.02621 (1.9) 0.307

57 (5.2) 0.150159 (14.5) 0.005253 (23.1) 0.008133 (12.1) 0.002

137 � 21 � 0.00162 � 10 � 0.001

75.4 � 12.7 � 0.00127 � 4 � 0.0011.1 � 0.3 � 0.001

1.7 (0.9, 3.0) 0.002207 � 37 � 0.00113 (10, 17) � 0.001

30 (2.7) 0.05243 (4.0) 0.05044 (4.1) � 0.001

161 � 27 � 0.001

4.0 � 0.6 � 0.0010.90 � 0.13 � 0.0010.96 � 0.18 � 0.0015.2 � 0.6 � 0.0013.0 � 0.6 � 0.00142 � 8 � 0.00123 � 4 � 0.001

lin where median (25th, 75th percentile) is reported; †median left ventricular (LV)ery bypass grafting, or percutaneous transluminal angioplasty.

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eight (Fig. 2C), are shown. Irrespective of indexation

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ethod, increasing quartile of LVM was associated with theevelopment of a depressed ejection fraction. This associa-ion remained true in a variety of subgroups (Fig. 3).aseline echocardiographic LVM indexed to BSA was alsossociated with a decrease in FS from baseline to follow-upchange in FS: 0 � 9.4 in quartile 1 vs. �1.5 � 9.9 inuartile 4 of baseline LVM, p � 0.03). In unadjustedegression models using the entire cohort, baseline electro-ardiographic and echocardiographic LVM (Table 4) andV hypertrophy were also each significantly associated with

ncident depressed LVEF and inversely with follow-upid-wall FS (p � 0.005 for all).

ensitivity analysis. A sensitivity analysis was performedn which subjects with follow-up borderline LVEF werelassified as having not reached the outcome. A depressedVEF at follow-up occurred in 2% of participants using thisefinition. Baseline LVM indexed to BSA remained asso-

able 2. Correlation Matrix of Baseline Echocardiographic Paramchocardiographic Parameters*

Follow-UpEchocardiographic

Parameter

Baseline E

LV DiastolicDimension

LV SystolicDimension (

V diastolic dimension 0.506 0.470V systolic dimension 0.397 0.466S (endocardial) �0.152 �0.281S (midwall) �0.077 �0.145V mass 0.496 0.392

Pearson correlations are shown. Number of observations for correlations ranges fromFS � fractional shortening; LV � left ventricular.

able 3. Interim Clinical Events and Follow-Up Assessment*

Variables

BaselinMass Belo

n �

ystolic blood pressure on follow-up (mm Hg) 13iastolic blood pressure on follow-up (mm Hg) 6

nterim clinical events (%)Myocardial infarction 3Heart failure 3Coronary artery bypass graft 1Composite CAD event† 4Angina 8

ollow-up electrocardiogram (%)Interim Q waves 6Interim atrial fibrillation 1

ollow-up echocardiogramMidwall FS (%) 2Endocardial FS (%) 4LV hypertrophy† (%) 7LV mass (g) 12Left atrial dimension (cm) 3.LV diastolic dimension (cm) 4.LV systolic dimension (cm) 2.LV function

Normal 1,04Mild decrease 3Moderate/severe decrease 1

Data are presented as n (%) or mean � SD; †interim composite coronary artery diseasransluminal angioplasty. Left ventricular (LV) hypertrophy was defined as observed

FS � fractional shortening.

iated with the outcome (percentage developing a depressedVEF in quartiles 1 through 4 of baseline echocardio-raphic LVM indexed to BSA was: 1.1%, 0.5%, 1.1%, and.6%, respectively; p � 0.001). Using quartiles of baselinelectrocardiographic LVM index, the percentage of partic-pants developing a depressed LVEF was 0.3%, 1.4%, 2.7%,nd 3.4%, respectively (p � 0.001). The risk ratio for theevelopment of a depressed LVEF associated with quartileof baseline echocardiographic LVM index as comparedith quartile 1 was 4.3 (95% confidence interval (CI) 1.8 to0.6; p � 0.001).

ultivariable analysis. In multivariable models that ad-usted for potential confounders, baseline electrocardio-raphic and echocardiographic LVM were each indepen-ently associated with the development of depressed LVEFnd inversely with follow-up midwall FS (Table 4). Theesults were nearly identical when baseline midwall FS was

s or Electrocardiographic LV Mass With Follow-Up

ardiogramBaseline

ElectrocardiographicLV Mass

Scardial)

FS(Midwall) LV Mass

.228 �0.093 0.472 0.434

.319 �0.184 0.363 0.346

.276 0.188 �0.125 �0.142

.144 0.151 �0.144 �0.133

.123 �0.084 0.603 0.534

6 to 2,126. p � 0.001 for all correlations.

o LVMedian

5

Baseline Echo LVMass Above the Median

n � 1,095 p Value

0 135 � 21 0.0031 69 � 11 0.345

) 53 (5.1) 0.108) 75 (6.9) � 0.001) 47 (4.4) � 0.001) 88 (8.6) � 0.001) 153 (15.4) � 0.001

) 100 (9.6) 0.001) 41 (3.8) 0.001

23 � 4 � 0.00142 � 9 � 0.001

) 176 (21.9) � 0.0012 170 � 47 � 0.001.6 4.2 � 1.2 � 0.001.5 5.0 � 0.6 � 0.001.5 3.0 � 0.7 � 0.001

� 0.001.7) 973 (88.9)) 92 (8.4)) 30 (2.7)

D) event included myocardial infarction, coronary artery bypass graft, or percutaneousted LV mass ratio �1.45 as before (1,14).

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ncorporated as a covariate instead of baseline endocardialS. Similarly, when LVM indexed to BSA was entered as aovariate instead of crude LVM (height and weight re-oved from models) or when baseline blood glucose or

lood pressure were entered into the models as covariatesnstead of diabetes or hypertension status, the results weressentially identical to those shown in Table 4. The riskatio associated with baseline echocardiographic LV hyper-rophy for incident depressed LVEF in multivariable anal-sis using the same confounders as in Table 4 was 2.2 (95%I 1.3 to 3.4; p � 0.001). In multivariable analyses stratifiedy gender using the same covariates as in Table 4, thessociation between LVM (per 50.9 g) and development ofdepressed LVEF persisted in women (risk ratio 1.6 [95%I 1.1 to 2.4; p � 0.02]) and in men (risk ratio, 1.5 [95%I 1.1 to 2.1; p � 0.02]).entricular diastolic dimension, wall thickness, and their

ssociation with depressed ejection fraction. Becausechocardiographic LVM is a calculation derived from LViastolic dimension and wall thickness (ventricular septumnd LV posterior wall), we assessed which of these subcom-onents of calculated LVM was associated with the out-ome. A series of models was constructed in which LViastolic dimension was entered with either ventriculareptal or posterior wall thickness as independent variablesTable 4). In the analyses that included diastolic dimensionnd septal wall thickness, both remained associated with the

igure 3. Subgroup analysis: percentage of participants developing aepressed left ventricular ejection fraction by baseline quartile of echocar-iographic left ventricular mass (LVM) indexed to body surface areaBSA). “No coronary artery disease” subgroup consisted of participantsithout prevalent or interval myocardial infarction, coronary artery bypassrafting, or percutaneous transluminal angioplasty. “No diabetes” and “noeart failure” excluded participants with these conditions present ataseline, and “no atrial fibrillation” excluded those with atrial fibrillation ataseline or during follow-up. P � 0.001 for the association of LVM/BSAnd incident depressed ejection fraction for all groups shown. White bars

quartile 1; bars with horizontal lines � quartile 2; bars with diagonalines � quartile 3; black bars � quartile 4. Quartile values of echocardio-raphic LVM/BSA are as reported in Figure 2.

igure 2. Percentage of participants developing a depressed left ventricularjection fraction by baseline quartile of left ventricular mass (LVM) (A)nd LVM indexed to body surface area (BSA) (B) or height (C). BaselineVM was assessed by echocardiography or electrocardiography (ECG). P0.001 for the association of LVM irrespective of indexation method with

ncident depressed ejection fraction in all cases. White bars � quartile 1;ars with horizontal lines � quartile 2; bars with diagonal lines �uartile 3; black bars � quartile 4. Quartiles of echocardiographic LVMg): �114.7, 114.8 to 137.2, 137.4 to 165.7, �165.7, respectively.uartiles of electrocardiographic LVM (g): �128.1, 128.1 to 145.4,

45.43 to 167.2, and �167.2, respectively. Quartiles of echocardiographicVM/BSA (g/m2): �67.7, 67.8 to 79.2, 79.3 to 93.5, and �93.5,

espectively. Quartiles of electrocardiographic LVM/BSA (g/m2): �76.9,6.9 to 83, 83.1 to 90.3, and �90.3, respectively. Quartiles of echocardio-raphic LVM/height (g/m): �70.40, 70.42 to 84.13, 84.14 to 99.97, and99.97, respectively. Quartiles of electrocardiographic LVM/height (g/m):79.48, 79.49 to 88.51, 88.52 to 99.49, and �99.49, respectively.
evelopment of a depressed LVEF and lower follow-up

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idwall FS. However, in the adjusted models in which bothV diastolic dimension and posterior wall thickness were

ncluded as independent variables, there was no significantssociation of posterior wall thickness with incident de-ressed LVEF.The baseline geometry of the LV was classified as being

ormal (n � 1,856) or as having concentric remodeling (n �4), eccentric hypertrophy (n � 218), or concentric hypertro-hy (n � 26). The percentage of participants who developed aepressed LVEF at follow-up among these four groups was.7%, 8.3%, 16.5%, and 3.8%, respectively (p � 0.001). Indjusted multivariable models using the same covariates as inable 4, eccentric hypertrophy remained associated with theevelopment of a depressed LVEF (relative risk 2.3; 95% CI.4 to 3.6) but concentric remodeling (relative risk 1.2; 95% CI.4 to 3.5) and concentric hypertrophy (relative risk 0.8; 95%I 0.1 to 6.3) did not.articipants excluded due to a missing follow-up echo-

ardiogram. Of 5,201 participants in CHS, 1,581 werexcluded from analysis in this study due to the lack of a

able 4. Unadjusted and Adjusted Regression Analysis

Outcome: Depresse

Independent Variables†UnadjusteRisk Rati

chocardiographic LV mass(per 50.9 g)

1.8

lectrocardiographic LV mass(per 39.2 g)

2.0

V diastolic dimension andseptal wall thickness§

Diastolic dimension(per 0.8 cm)

2.0

Septal thickness(per 0.2 cm)

1.3

V diastolic dimension andposterior wall thickness§


2.0

Posterior wall thickness(per 0.2 cm)

1.3

Outcome: Follow-Up Midwa

Independent Variables†Unadjuste

�-Coefficie

chocardiographic LV mass(per 50.9 g)

�0.6

lectrocardiographic LV mass(per 39.2 g)

�0.6

V diastolic dimension andseptal wall thickness§


�0.5

Septal thickness(per 0.2 cm)

�0.7

V diastolic dimension andposterior wall thickness§


�0.5

Posterior wall thickness(per 0.2 cm)

�0.4

Logistic regression was used for the outcome of depressed ejection fraction and linef change for all independent variables; ‡Adjusted for age, gender, white race, heighttatus (including myocardial infarction, percutaneous angioplasty, or coronary arteryaseline or during follow-up). Models incorporating echocardiographic and electrocarhortening; §Both LV diastolic dimension and wall thickness (either septal or poste

ollow-up echocardiogram with an assessment of LVEF as d

result of death (n � 533), loss of contact (n � 229), aollow-up echocardiogram without assessment of LVEF (n

179), and a follow-up visit with no echocardiogrambtained (e.g., home visit, nursing home visit, or phonenformation only; n � 640). In comparing participants whoid not have a follow-up echocardiogram with an LVEFssessment to those who did, the former were older (74 �

years vs. 72 � 5 years, respectively), had a higherroportion of men (44% vs. 39%), diabetes (10.2% vs..3%), hypertension (62% vs. 53%), atrial fibrillation (3.7%s. 1.8%), larger echocardiographic baseline LVM (154 �4 g vs. 145 � 44 g), and lower baseline mid-wall FS (23 �% vs. 24 � 4%); p � 0.005 for all comparisons.Of 1,581 subjects without a CHS follow-up echocar-

iogram, 131 had an echocardiogram performed forlinical care that subsequently had been reviewed by CHSnvestigators (1). Of these, 69 subjects had a depressedVEF. The baseline echocardiographic LVM indexed toSA was higher in those subjects who developed aepressed LVEF (n � 42) as compared with the remain-

Ejection Fraction*

95%Confidence

Intervals p ValueAdjusted‡Risk Ratio

95%Confidence

Intervals p Value

1.5, 2.0 � 0.001 1.5 1.2, 1.8 � 0.001

1.7, 2.3 � 0.001 1.5 1.2, 1.8 � 0.001

1.7, 2.4 � 0.001 1.8 1.4, 2.2 � 0.001

1.1, 1.6 0.001 1.2 1.0, 1.5 � 0.05

1.6, 2.4 � 0.001 1.7 1.4, 2.1 � 0.001

1.1, 1.6 0.005 1.1 0.9, 1.4 0.27

ctional Shortening Percent*

95%Confidence

Intervals p ValueAdjusted‡

�-Coefficient

95%Confidence

Intervals p Value

�0.86, �0.4 � 0.001 �0.5 �0.7, �0.1 0.001

�0.9, �0.4 � 0.001 �0.1 �0.4, 0.02 0.4

�0.8, �0.2 � 0.001 �0.4 �0.7, �0.1 0.01

�0.9, �0.4 � 0.001 �0.5 �0.8, �0.3 � 0.001

�0.7, �0.2 0.001 �0.3 �0.6, �0.05 0.02

�0.7, �0.2 � 0.001 �0.3 �0.5, 0.01 0.06

ession for midwall fractional shortening; †Interquartile ranges were used as the unitne weight, diabetes or hypertension at baseline, baseline and interval coronary arterygraft), and presence of Q waves or atrial fibrillation on electrocardiogram (either atphic left ventricular (LV) mass were also adjusted for baseline endocardial fractionalll) were entered as covariates in the same model.

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chocardiogram and no history of heart failure (LVM/SA 98 � 29 g/m2 vs. 86 � 26 g/m2, respectively; p �.002). A similar relationship was seen with baselinelectrocardiographic LVM indexed to BSA in comparinghese two groups (92 � 15 [n � 67] g/m2 vs. 85 � 12 [n

1,225] g/m2, respectively; p � 0.001).

ISCUSSION

eft ventricular hypertrophy is associated with a number ofdverse clinical outcomes including the development ofeart failure (1–7). However, because LV hypertrophy islso associated with diastolic dysfunction, which may alsoause heart failure (11,12), it has been unclear whetherncreased LVM and LV hypertrophy predispose to a de-ressed LVEF in humans. Echocardiographic studies thatave associated increased LVM with subtle abnormalities inystolic function, such as midwall FS (20,21,24), and earlier,mall case series of patients with various stages of hyperten-ive heart disease (25,26) have been cross-sectional inature. As such, they did not clarify whether ventricularypertrophy led to the ventricular systolic dysfunction, orhether the hypertrophy resulted from changes in systolic

unction and ventricular dilation (27). Recent data havehown that changes in LVM while on antihypertensiveherapy are inversely related to changes in systolic function28,29).

The CHS database has detailed measurements of cardiacimensions including LVM, and, by restricting our analysiso those subjects with a normal LVEF at baseline, we foundn association between baseline LVM and LV hypertrophyith incident depressed LVEF at a follow-up of �5 years.he LVM remained associated with incident depressedVEF in important subgroups including women; thoseith no evident baseline abnormalities of systolic function

s measured by stress-adjusted FS and regional wall motioncore; those free of coronary heart disease at baseline and atollow-up; those without diabetes, prevalent heart failure, ortrial fibrillation. In addition to its association with theevelopment of a depressed LVEF, baseline LVM was alsossociated with lower midwall FS at follow-up. The asso-iation of LVM and LV hypertrophy with incident de-ressed LVEF was independent of potential confounders inultivariable analysis. In total, these data show that LVM

nd LV hypertrophy are risk factors for the development ofdepressed LVEF within five years in older adults.actors contributing to fall in LVEF. The mechanismsy which increased LVM leads to a depressed LVEF remainll-defined. Myocardial infarction is traditionally viewed asn obligatory event in the transition to depressed systolicunction (30), and is an important risk factor, occurring in6% of those who did develop a depressed LVEF asompared with 3% of those who did not. However, theresent study also demonstrates that there must be otherechanisms operative, because increased LVM remained

ssociated with the development of depressed LVEF in t

articipants free of clinically manifest coronary heart diseasencluding myocardial infarction (Fig. 3). Potential mecha-isms that have previously been shown to be associated with

ncreased LVM are neurohormonal activation (31) andbnormalities in myocyte perfusion even in the absence ofpicardial coronary artery stenoses (32).entricular wall thickness and chamber dimension. An

ncrease in LVM may occur either through an increase inV chamber dimensions or wall thickness. Previous data

howing increased echocardiographic LVM to be associatedith adverse clinical outcomes have not assessed whether

hese relationships were true for both chamber dilation andncreased wall thickness (3–5). The Framingham Hearttudy investigators have shown that increased LV cavity size

s associated with a number of adverse outcomes includingeart failure (33,34). Our study is the first to our knowledgeo show that LV diastolic dimension and ventricular septalall thickness are associated, independently of each other,ith the development of a depressed LVEF and a decrease

n mid-wall FS. The importance of LV dilation as a riskactor for the subsequent fall in LVEF is reinforced by thessociation of eccentric hypertrophy (increased LVM due toncreased LV volume with normal relative wall thickness)ut not concentric hypertrophy with the development of aepressed LVEF in multivariable models.tudy limitations. There are important limitations in thisnalysis. The development of a depressed LVEF may beecondary to a difference in echocardiographic interpreta-ion that occurred over the five years of follow-up. However,ther echocardiographic parameters were consistent with arue difference between the two groups, and blinded rein-erpretation at follow-up of baseline studies had estimates ofS that were higher rather than lower than the originalalues. The true incidence of depressed LVEF cannot bealculated due to the lack of a follow-up echocardiogram insizable fraction of the participants. Given that the partic-

pants who did not have follow-up echocardiograms hadower midwall FS at baseline than the participants who didave follow-up echocardiograms, the true percentage ofarticipants who progressed to a depressed LVEF is likelyigher than we found. Although a considerable number ofubjects had missing follow-up CHS echocardiograms andere excluded from the primary analysis, the association ofVM and depressed LVEF appeared robust in thosearticipants as ascertained by an analysis of echocardiogramsbtained for clinical care. The LVEF is afterload-dependentnd likely underestimated the baseline presence of LVystolic dysfunction (21). However, the LVEF is the mostommon measure of systolic function, and a reduced LVEFas immediate clinical applicability.onclusions. We have shown that increased LVM,hether measured by the electrocardiogram or echocardio-ram, is an independent risk factor for the subsequentevelopment of a depressed LVEF in older adults at �5ears of follow-up. An eccentric pattern of cardiac hyper-
rophy as occurs with LV chamber dilation is a particularly

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trong risk factor for this outcome. The association betweenncreased LVM and development of depressed LVEF per-ists even among subjects without myocardial infarction,uggesting that there are additional pathophysiologic mech-nisms through which increased LVM is associated with aubsequent fall in the LVEF.

eprint requests and correspondence: Dr. Mark H. Drazner,323 Harry Hines Boulevard, Dallas, Texas 75390-9047. E-mail:[email protected].

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