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Progression from Normal to Reduced Left Ventricular EjectionFraction in Patients With Concentric Left Ventricular Hypertrophy

After Long-Term Follow-Up

Arun Krishnamoorthy, MDa, Timothy Brown, BSa, Colby R. Ayers, MSb, Sachin Gupta, MD, MScc,J. Eduardo Rame, MD, MPhild, Parag C. Patel, MDc, David W. Markham, MD, MScc, and

Mark H. Drazner, MD, MScc,*

Whether concentric left ventricular (LV) hypertrophy (LVH) is a common precursor todepressed LV ejection fraction (EF) in humans is uncertain. From 1992 through 1994, 555patients at our institution underwent echocardiography and had LVH (posterior or septalwall thickness >1.3 cm or concentric LVH noted) and normal LVEF. Of these, 220 (40%)had a follow-up assessment of LVEF by December 2008. The duration of follow-up wasclassified as short (<7.5 years) or long (>7.5 years) term. The primary outcome was thedevelopment of a qualitatively depressed LVEF (mildly, moderately, or severely depressed).After a median follow-up of 7.5 years, 20% of the patients with concentric LVH developeda low LVEF. A low LVEF developed in 13% of subjects without interval myocardialinfarction (MI) and 50% of subjects with interval MI during short-term follow-up(p <0.005). A low LVEF developed in 20% of subjects without interval MI and 44% ofsubjects with interval MI during long-term follow-up (p � 0.01). Of the subjects whodeveloped a reduced LVEF, the relative wall thickness (median 0.5, 25th to 75th percentile0.4 to 0.6) at follow-up was consistent with a concentric, rather than eccentric, phenotype.In conclusion, in patients with concentric LVH, the transition from a normal LVEF to a lowLVEF was relatively infrequent (20%) after long-term follow-up in the absence of interval MIand usually did not result in a change in the LV geometry from a concentric to an eccentric

phenotype. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:997–1001)

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In the classic model of hypertensive heart disease, chron-ically elevated blood pressure often leads to concentric leftventricular (LV) hypertrophy (LVH), followed by LV dila-tion and systolic dysfunction manifesting as a reduced LVejection fraction (EF).1 This transition from concentric LVHto LV failure with systolic dysfunction has been shown inanimal models2–4 and in patients with aortic stenosis.5

However, no large, longitudinal studies of hypertensivepatients with concentric LVH have demonstrated whetherthis transition occurs commonly in this population.6 In theCardiovascular Health Study, an increased LV mass was arisk factor for the development of a low LVEF after 5 years;however, it was eccentric and not concentric LVH that wasassociated with this outcome.7 We previously reported thatonly 18% of 159 patients with concentric LVH and a normalLVEF in the Parkland Memorial Hospital echocardiographydatabase developed a low LVEF after a median follow-up ofapproximately 4 years.8 To further characterize the transi-ion from concentric LVH to reduced LVEF, we reanalyzedhis echocardiographic cohort after a longer period of fol-

From the Departments of aInternal Medicine and bClinical Sciences,nd cDivision of Cardiology, University of Texas Southwestern Medical

Center, Dallas, Texas; and dDivision of Cardiology, Department of Internaledicine, University of Pennsylvania, Philadelphia, Pennsylvania. Man-

script received April 17, 2011; revised manuscript received and accepteday 26, 2011.

*Corresponding author: Tel: (214) 645-7500; fax: (214) 645-7501.

6E-mail address: mark.drazner@utsouthwestern.edu (M.H. Drazner).

002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2011.05.037

ow-up. We hypothesized that the transition from concentricVH with a normal LVEF to a depressed LVEF would

emain infrequent despite the longer follow-up.

ethods

The reports from transthoracic echocardiograms per-ormed at Parkland Memorial Hospital in Dallas, Texas,rom June 1992 to August 1994 were screened; all studiesere obtained for clinical indications. Those patients �17ears of age with concentric LVH (defined as posterior oreptal wall thickness measuring �1.3 cm or the presence ofoncentric LVH specifically noted in report) and normalVEF were identified (n � 855). Technically limited stud-

es (n � 140) and those patients with significant valvularisease (greater than mild aortic regurgitation, aortic steno-is, or mitral regurgitation), asymmetrical septal or posteriorall hypertrophy, complex congenital heart disease, or LV

egional wall motion abnormalities were excluded. Fromhe remaining 555 patients, we included 220 subjects (40%)ho had a follow-up transthoracic echocardiogram (n �10) or other assessment of LVEF such as a transesophagealchocardiogram (n � 6) or multigated acquisition scan (n �) performed �1 year after the index echocardiogram as ofecember 2008. The 3 most common indications for the

ndex echocardiogram were to assess LV function or wallotion, to evaluate the valves or an audible murmur, or a

istory of heart failure. These 3 indications accounted for

5% of the obtained echocardiograms. The institutional

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998 The American Journal of Cardiology (www.ajconline.org)

review board of University of Texas Southwestern MedicalCenter approved the protocol, and informed consent waswaived because the study was retrospective.

The patient demographic and clinical data were reab-stracted through a comprehensive chart review, includingthe electrocardiographic, radiographic, and echocardio-graphic reports generated for clinical purposes. LV functionwas assessed qualitatively as normal or depressed (mildly,moderately, or severely, representing a LVEF of approxi-mately 40% to 50%, 30% to 39%, and �30%, respectively),as previously described.8 The primary outcome variable wasthe development of a qualitatively depressed LVEF (mildly,moderately, or severely) on a follow-up assessment. Wedichotomized the duration of follow-up at the median (7.5years) and classified it as short (�7.5 years) and long (�7.5years) term. An interval myocardial infarction (MI) betweenthe index and follow-up study was identified by clinicalhistory from the chart review. We subsequently reviewedthe available electrocardiograms and cardiac enzyme levelsrelated to the MI. The location of the MI was determined bythe electrocardiographic changes and, if performed, the cul-prit vessel on left heart catheterization. Diastolic parame-ters, such as the mitral filling pattern, were not routinelymeasured on the index echocardiogram. Chest x-rays andlaboratory tests were included if they were obtained withinthe 6 months preceding the index echocardiogram. A com-posite measure of coronary artery disease was defined aseither a history of MI, percutaneous coronary intervention,or coronary artery bypass surgery or the presence of epicar-dial coronary stenoses of �70% with coronary angiogra-phy. Using the hospital electronic coding system, wesearched for all admissions to Parkland Memorial Hospitalwith a primary or secondary diagnosis of heart failure from1992 to 2008. We determined the frequency of the heartfailure admissions that occurred �1 year after the indexechocardiogram among 3 groups: those who had an indexechocardiogram but no follow-up study, those who hadpreserved LVEF on the follow-up echocardiogram, andthose with a low LVEF on the follow-up echocardiogram.

Figure 1. Percentage of patients with progression to low LVEF at follow-up. The median length of follow-up was 7.5 years. Of 45 subjects whodeveloped low LVEF, 20 had mildly, 18 moderately, and 7 severelydepressed LVEF.

The data are expressed as proportions, mean � SD, or 4

median (twenty-fifth to seventy-fifth percentiles). The dif-ferences in the characteristics between the patients who didor did not progress to a depressed LVEF were comparedusing Fisher’s exact test, Student’s t test with equal orunequal variances, or the Wilcoxon rank-sum test, as ap-propriate. The relative wall thickness was defined as [septalwall thickness � posterior wall thickness]/[LV end-dia-stolic dimension (LVEDD)]. Bonferroni’s adjustment wasused to account for multiple comparisons. A multivariatelogistic regression model was developed including the sig-nificant variables (p �0.05) on univariate analysis usingSAS for Windows, release 9.2 (SAS Institute, Cary, NorthCarolina). Odds ratios were calculated for a SD change inthe continuous measurements.

Results

After a median follow-up of 7.5 years, 45 (20%) of 220patients with concentric LVH developed a low LVEF (Fig-ure 1). Of these 45 patients with a reduced LVEF, 20 (44%)had mildly, 18 (40%) moderately, and 7 (16%) severelyreduced LVEF. The baseline (Table 1) clinical and echo-cardiographic characteristics are listed stratified by whetherthere was progression to a low LVEF. Those who did versusdid not progress to a reduced LVEF were more likely tohave a history of coronary artery disease at baseline. Inaddition, those who developed a low LVEF had both alarger LVEDD and LV end-systolic dimension and asmaller relative wall thickness on the index echocardio-gram.

The follow-up clinical and echocardiographic character-istics are listed in Table 2, again stratified by whether therewas progression to a low LVEF. There was a more thanthreefold greater rate of interval MI in those who did versusdid not develop a low LVEF. Of the 28 MIs, 18 of thesepatients were admitted to our institution and had cardiacenzyme measurements available. The peak troponin level(n � 14) was 8.5 ng/ml (25th to 75th percentile 5.5 to 37)nd the peak creatine kinase-MB (n � 18) was 23 ng/ml25th to 75th percentile 11 to 55). The electrocardiographichanges at the MI included ST-segment depression (32%),-wave changes only (18%), and ST-segment elevation

18%). With the available information, we were able toocalize only 25% of the MIs (11% anterior, 11% lateral,nd 3% inferior). There was no difference at follow-up inither the posterior wall thickness or septal wall thicknessetween those who did or did not develop a low LVEFTable 2). However, in those who did versus did not develop

low LVEF, the follow-up LVEDD, LV end-systolic di-ension, and change in LVEDD and LV end-systolic di-ension from baseline to follow-up were larger (p �0.001

or each). Additionally, the follow-up relative wall thick-ess was smaller in those who did progress to a low LVEFp � 0.002) but still remained increased (0.5). In the sub-ects who developed a low LVEF after long-term follow-up,he median relative wall thickness when stratified by theccurrence of interval MI was 0.49 with interval MI and.51 without interval MI. The frequency of heart failureospitalizations �1 year after the index echocardiogramas 13.8% for those without a follow-up echocardiogram,

6% for those with preserved LVEF on the follow-up echo-

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999Heart Failure/From LVH to Failure

Table 2Follow-up clinical and echocardiographic characteristics stratified by progression to reduced left ventricular ejection fraction

Variable Progression to Reduced LVEF p Value

No(n � 175)

Yes(n � 45)

Follow-up length (years) 7.5 � 4 8.6 � 4 0.1Age at follow-up (years) 61 � 12 64 � 15 0.3Systolic blood pressure (mm Hg) 147 � 29 140 � 32 0.2Diastolic blood pressure (mm Hg) 81 � 15 82 � 21 1Serum creatinine (mg/dl) 1.1 (0.9–1.4) 1.5 (1–1.8) 0.01Hemodialysis 13% 16% 0.6Interval myocardial infarction 9% 29% �0.001Echocardiographic findings

Posterior wall thickness (cm) 1.3 (1.1–1.5) 1.2 (1.1–1.4) 0.2Septal wall thickness (cm) 1.4 (1.2–1.6) 1.3 (1.2–1.5) 0.4Left ventricular end-diastolic dimension (cm) 4.4 � 0.7 5 � 0.8 �0.001Left ventricular end-systolic dimension (cm) 2.9 � 0.6 3.9 � 0.8 �0.001Relative wall thickness 0.6 (0.5–0.8) 0.5 (0.4–0.6) 0.002Change in left ventricular end-diastolic dimension from baseline (cm) 0.3 � 0.6 0.6 � 0.8 0.004Change in LV end-systolic dimension from baseline (cm) 0.02 � 0.6 0.8 � 0.8 �0.001

Table 1Baseline clinical and echocardiographic characteristics stratified by progression to reduced LVEF

Variable Progression to Reduced LVEF p Value

No(n � 175)

Yes(n � 45)

Age (years) 54 � 12 55 � 15 0.6Women 67% 51% 0.06African American 80% 76% 0.5

iabetes mellitus 41% 51% 0.2ypertension 83% 80% 0.7oronary artery disease* 18% 42% 0.001oronary artery bypass grafting 5% 16% 0.02erebrovascular accident 16% 16% 1ystolic blood pressure (mm Hg) (n � 163) 153 � 28 144 � 21 0.09iastolic blood pressure (mm Hg) (n � 163) 87 � 16 85 � 16 0.6eart rate (beats/min) 80 (72–90) 84.5 (71–92) 0.6edications (n � 158)

Angiotensin converting enzyme inhibitors 31% 38% 0.4� Blockers 18% 21% 0.8Diuretics 35% 41% 0.6erum creatinine (mg/dl) (n � 115) 1 (0.8–1.2) 1.1 (0.9–1.2) 0.1emodialysis 11% 16% 0.5hest x-ray findings (n � 75)Pulmonary edema 38% 47% 0.6Cardiomegaly 33% 47% 0.4lectrocardiographic findingsLeft ventricular hypertrophy (n � 95) 29% 47% 0.3Duration of QRS complex (ms) (n � 89) 88 (80–98) 88 (82–96) 0.9Left ventricular strain pattern (n � 92) 14% 25% 0.3chocardiographic findingsPosterior wall thickness (cm) 1.3 (1.3–1.5) 1.3 (1.2–1.5) 0.4Septal wall thickness (cm) 1.4 (1.3–1.6) 1.4 (1.3–1.5) 0.5Left ventricular end-diastolic dimension (cm) 4.1 � 0.6 4.4 � 0.6 0.01Left ventricular end-systolic dimension (cm) 2.9 � 0.5 3.1 � 0.6 0.007Relative wall thickness 0.7 (0.6–0.8) 0.6 (0.6–0.7) 0.02

Data are presented as mean � SD, median (25th to 75th percentiles), or percentages.* Coronary artery disease defined as a history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery or the

Data are presented as mean � SD and median (25th to 75th percentiles) or percentages.

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1000 The American Journal of Cardiology (www.ajconline.org)

cardiogram, and 62% for those with a low LVEF on thefollow-up echocardiogram (p �0.001).

The frequency of progression to a depressed LVEF isshown in Figure 2 stratified by the presence of an interval MInd duration of follow-up. During the short-term follow-uperiod (median 4.2 years), a low LVEF developed in 13% ofhe subjects without interval MI and 50% of the subjects withnterval MI (p � 0.008). During long-term follow-up, theutcome in these groups was 20% and 44% (p � 0.09) after a

follow-up of 11 years (25th to 75th percentile 9.9 to 13) and 12years (25th to 75th percentile 11 to 14).

On multivariate analysis (Table 3), interval MI and

Figure 2. Frequency of progression to low LVEF stratified by interval MI.†p � 0.008 for comparison between subjects with and without interval MIwith follow-up of �7.5 years; §p � 0.09 for comparison between subjectswith versus without interval MI in subjects with follow-up �7.5 years.

Table 3Multivariate models of progression to reduced left ventricular ejectionfraction

Model Variable Odds Ratio 95% CI p Value

1 Coronary artery disease 2.1 0.88–5 0.09Interval myocardial

infarction2.9 1.2–7.2 0.02

Coronary artery bypassgrafting

1.5 0.4–5.4 0.5

2 Coronary artery disease 2.3 1.1–5.1 0.04Interval myocardial

infarction3.9 1.5–10 0.006

Baseline LV end-diastolic dimension

1.6 1–2.4 0.048

3 Baseline posterior wallthickness

0.7 0.4–1.0 0.06

Interval myocardialinfarction

8.4 3.1–23 �0.001

Baseline LV end-diastolic dimension

2.1 1.3–3.2 0.001

4 Baseline relative wallthickness

0.5 0.3–0.7 0.002

Interval myocardialinfarction

7.6 2.8–20 �0.001

CI � confidence interval.

baseline LVEDD or relative wall thickness remained s

significantly associated with the development of a re-duced LVEF.

In a sensitivity analysis, we attempted to assess theLVEDD as an outcome variable. However, only 7 subjectshad an enlarged LVEDD (�6 cm) at follow-up. Next, weattempted to use an interval change in LVEDD �2 SDs ofthe baseline LVEDD (SD 1.01 cm) as an outcome, but only2 subjects reached that criterion.

Discussion

The natural history of concentric LVH in humans re-mains ill characterized,6,9,10 with few longitudinal studiesavailable.7,8 In the present study of a cohort of predomi-antly African American hypertensive patients with concen-ric LVH and a normal LVEF, we found that only 20%eveloped a low LVEF after a median of 7.5 years ofollow-up (Figure 1). Interval MI was associated with a riskf transition to low LVEF (Figure 2). In subjects without annterval MI, a group whose natural history remains uncer-ain,6,10 the absolute event rate was relatively low, given the

long duration of follow-up (median 11 years), such that theoverwhelming majority (80%) still had a preserved LVEF.Furthermore, even among those with concentric LVH atbaseline who developed a low LVEF during follow-up, theLV geometry remained of a concentric phenotype.

The results of the present study support and substantiallyextend most of the findings from our previous analysis ofthis cohort.8 In that initial study, 18% of 159 subjectsdeveloped a low LVEF at 4 years of follow-up. Now, withthe present study, we found that 20% of 220 subjects de-veloped a low LVEF at 7.5 years of follow-up. Just as in thepresent study (Table 3), both a baseline history of coronaryartery disease and an interval MI were associated with thedevelopment of a low LVEF in the initial study.

The posterior wall thickness and septal wall thickness onthe index echocardiogram were increased similarly in thosewho did or did not progress to a low LVEF (Table 2). Incontrast, those who developed a reduced LVEF at follow-uphad a larger LVEDD and LV end-systolic dimension and asmaller relative wall thickness at baseline versus those who didnot develop a reduced LVEF (Table 2). These data suggest thatsubtle differences in LV volume and geometry at baseline wereassociated with the progression to a reduced LVEF.

It is also worthwhile to consider the LV geometry evi-dent on the follow-up echocardiogram in those who devel-oped a reduced LVEF (Table 2). Although at follow-up suchsubjects had both a larger LVEDD and LV end-systolicdimension and a smaller relative wall thickness compared tothose who did not develop a low LVEF, their LV chamberwas not grossly dilated, with few reaching the upper limitsof normal for our laboratory (�6 cm). These patients wouldstill be classified as having concentric instead of eccentricLVH.11 Even in those who developed a low LVEF afterong-term follow-up, the LV geometry remained of a con-entric phenotype (relative wall thickness 0.5). Such find-ngs suggest that patients with concentric LVH might notrequently develop a dilated, thin-walled left ventricle evenhen their LVEF is reduced.The present study was retrospective and had a relatively

mall sample size. Nevertheless, to our knowledge, these are

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1001Heart Failure/From LVH to Failure

the longest longitudinal data to be brought forth to addressthis important question. Because the imaging studies (bothat baseline and follow-up) were obtained for clinical indi-cations, the reported association of interval MI with thedevelopment of low LVEF might be biased. The patientcohort was selected for having a substantially increased LVwall thickness (�1.3 cm) and might represent a subgroupwith a different natural history than that of many othersubjects with less extreme LVH. Additionally, only 40% ofsubjects with concentric LVH at baseline had a follow-upassessment of LVEF, and the estimated rate of progressionto a reduced LVEF might have been affected in eitherdirection by this incomplete follow-up. However, becausethe frequency of subsequent heart failure hospitalizations(13.8%) was significantly lower among those subjects withconcentric LVH who did not have a follow-up echocardio-gram, while it was greatest (62%) among the subjects whohad progressed to a reduced LVEF, we hypothesize that thefrequency of progression to a low LVEF in those without afollow-up echocardiogram might be lower than that re-ported for the 220 subjects with paired echocardiograms.Furthermore, we note that the increase in the number ofsubjects who had a follow-up echocardiogram (n � 61, 38%of the initial study cohort) since our initial study8 did notqualitatively change its conclusions. Another limitation wasthat 11 years of follow-up might not be long enough forpatients to progress to a reduced LVEF. However, the meanage at which subjects with concentric LVH progressed to areduced LVEF was 64 years, data that suggest that thispathway might not be operative in young African Ameri-cans who developed a dilated cardiomyopathy commonlyattributed to hypertension.6 The echocardiographic datawere based on the clinical reports and the qualitative changein LVEF might not be accurate. However, in those with aqualitatively reduced LVEF, there were concomitantchanges in quantitatively measured LV dimensions, provid-ing independent supportive evidence that the LVEF diddecrease. We determined interval MI by comprehensivechart review and might have misclassified the subjects with

LVH into the “no interval MI” group if an MI occurred at a

different facility. If so, the reported frequency of progres-sion to a low LVEF in those without interval MI groupmight be an overestimate. Finally, we were unable to ana-lyze the change in the LVEDD as an outcome variablebecause few subjects developed LV dilation. A larger studyusing cardiac magnetic resonance imaging to assess thechange in LV volumes might be helpful in this regard.

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4. Pfeffer JM, Pfeffer MA, Mirsky I, Braunwald E. Regression of leftventricular hypertrophy and prevention of left ventricular dysfunctionby captopril in the spontaneously hypertensive rat. Proc Natl Acad SciU S A 1982;79:3310–3314.

5. Rapaport E. Natural history of aortic and mitral valve disease. Am JCardiol 1975;35:221–227.

6. Drazner MH. The transition from hypertrophy to failure: how certainare we? Circulation 2005;112:936–938.

7. Drazner MH, Rame JE, Marino EK, Gottdiener JS, Kitzman DW,Gardin JM, Manolio TA, Dries DL, Siscovick DS. Increased leftventricular mass is a risk factor for the development of a depressed leftventricular ejection fraction within five years: the CardiovascularHealth Study. J Am Coll Cardiol 2004;43:2207–2215.

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9. Berenji K, Drazner MH, Rothermel BA, Hill JA. Does load-inducedventricular hypertrophy progress to systolic heart failure? Am J PhysiolHeart Circ Physiol 2005;289:H8–H16.

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