Classification Accuracy of Electrocardiographic Criteria for Left Ventricular Hypertrophy in Normal Weight and Overweight Older Adults

Classification Accuracy of Electrocardiographic Criteria for Left Ventricular Hypertrophy in Normal Weight and Overweight Older Adults: The Cardiovascular Health Study

Pentti M. Rautaharju, M.D., Ph.D.,' Teri A. Manolio, M.D.,2 David Siscovick, M.D.? Sophia H. Zhou, Ph.D.,'? Julius M. Gardin, M.D.,5 Curt D. Furberg, M.D., Ph.D.,' Nemat 0. Borhani, M.D., MPH; and Anne Newman, M.D.7 for the CHS Collaborative Research Group. From the 'Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, North Carolina; the 'Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland; the 3Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington; the 4Division of Cardiology, Department of Internal Medicine, S t . Louis University School of Medicine, S t. Louis, Missouri; the 'Department of Medicine, University of California-Irvine, Orange, California; the 6Department of Internal Medicine, University of Calijornia School of Medicine at Davis (UCD), Sacramento, California; and the 'Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Background: We evaluated classification accuracy of ECG criteria at varying levels of left ventricular hypertrophy (LVH) severity according to echocardiographically measured left ventricular mass (LVM) adjusted to body size.

Methods: The test population was derived from the Cardiovascular Health Study (CHS), a population-based sample of 5201 men and women aged 65 and older, and consisted of 1844 women and 11 19 men with adequate quality ECGs and echocardiograms for LVM determination. The criteria evaluated were Sokolow-Lyon, Cornell voltage, Cornell product, Framingham modification of the Cornell voltage, and the left ventricular mass index (LVMI) of the Novacode ECC program.

Results: With LVH thresholds at upper 95% normal limit for weight adjusted LVM for the CHS population and ECG thresholds adjusted for 95% specificity in normal weight and overweight subgroups, the sensitivity of ECG criteria for LVH was relatively low. It was highest (40.8%) for the Novacode LVMI in normal weight men and for the Framingham criteria (30.9%) in normal weight women, but it deteriorated for both of these criteria in the presence of obesity. The overall performance of the Cornell product and Cornell voltage criteria was least influenced by obesity. The Framingham adjustment for the Cornell voltage criteria for obesity substantially reduced their sensitivity.

Conclusion: The choice of echocardiographic standard, LVH severity level and overweight in the test groups have a strong influence on ECG evaluation results. A.N.E. 1996;1(2 Pt. 1):121-132

echocardiogram; left ventricular mass; body size; obesity

Supported by Contracts NO I-HC-85079, NO 1-HC-85080, NO I-HC-85081, NO I-HC-85082, NO I-HC-85083, NO I-HC-85084, NO I-HC-85085, and NO I-HC-85086 from the National Heart, Lung, and Blood Institute, Participating staff from the CHS Collaborative Research Group are listed in the Appendix. Address for reprints: Pentti M. Rautaharju, M.D., Ph.D., EPICARE Center, Piedmont Plaza II, Suite 505, 2000 West First Street, Winston-Salem, NC 271 04. Fax: (91 0) 716-0834.

121

122 A.N.E. April 1996 Vol. 1 , No. 2 , Pt. 1 Rautaharju, et al. Classification of ECG Criteria for LVH

There have been renewed efforts recently to design and evaluate ECG criteria for left ventricular hypertrophy (LVH).’-7 This increasing interest has been stimulated by the reports on excess risk of cardiovascular disease mortality and morbidity as- sociated with LVH8-14 and also by increasing avail- ability of echocardiography as an improved standard for estimation of left ventricular mass (LVM) in clinical and epidemiologic s t~dies . ’~- ’~

A number of conceptual problems have emerged from these recent investigations on ECG classification of LVH. Evaluation results differ widely, de- pending on the selection criteria for the test groups. The severity level and prevalence of L W and echocardiographic methods used, particularly the LVH thresholds chosen and possibly the method of indexing of LVM to body size, are likely to influence test results. These problems have not in general received adequate attention in studies that have addressed LVH classification accuracy. Variations in LVH classification by echocardiographic as well as ECG criteria with relatively minor changes near critical decision boundaries are likely to introduce considerable uncertainty in categorical, dichoto- mous classification of LVH, and thus to influence evaluation results. Some of the recent ECG classification algorithms have attempted to alleviate the above problems by producing estimates for ECG LVM on a continuous ~ c a l e . ’ ~ ~ ’ ~ This facilitates the choice of operating characteristics of the ECG clas- sifiers in terms of sensitivity and specifcity for any particular application with varying prevalence of LVH.

It is well established that ECG patterns undergo a profound evolution with age, and that there are substantial differences in terms of gender, race, and constitutional variables.” ECG criteria for LVH are commonly used in clinical and epidemiologic applications without any adjustment for these variables. However, some of the more recent ECG criteria for LVH involve gender specific r n ~ d e l s , ~ ~ ~ ~ ~ ~ ~ and one new ECG model makes provisions for an adjustment also for age and obesity effect.”

Although the profound evolution of ECG patterns with age is generally r e ~ o g n i z e d , ’ ~ ~ ~ ~ ~ ~ ~ none of the ECG criteria for LVH have been adequately validated in older age groups. The primary purpose of this investigation was to perform such evaluation, and in particular to examine to what extent the choice of the echocardiographic algorithm for indexing LVM to body size and LVH severity level will influence the apparent LVH classification accuracy of various ECG criteria.

METHODS Study Population

Source data were derived from the baseline examination of the Cardiovascular Health Study (CHS), a National Heart, Lung, and Blood Institute (NHLBI) sponsored population-based multicenter cohort study of risk factors for coronary heart disease and stroke in men and women 65 years old and older.23 The selection and exclusion criteria of the participants, representing a random sample of older adults, and other aspects of the design of the study have been p~blished.’~ The cohort was 94.7% white, 4.7% African-American, and 0.6% other ethnic groups. Among the 5201 participants enrolled, there were 2239 men with an average age of 73.3 2 5.8 years, and 2962 women with an average age of 72.4 -t 5.4 years.

There were 3236 participants with adequate quality echocardiograms and ECGs with all measurements necessary for LVM estimation by both methods. After exclusion of 273 participants with complete bundle branch blocks (Minnesota codes 7.1,7.2, and 7.41, there were 1844womenand 1119 men remaining in the present study group.

ECG Methods

Five sets of LVH criteria were chosen for comparative evaluation: (1) criteria introduced by Soko- low and Lyon in 1949,= as used, for instance, in Minnesota codez5 (RV5 or RV6 + SV1); (2) Cornell voltage criteria (RaVL + SV3), introduced in 1985 by Casale et al.5; (3) Cornell product criteria, the product of Cornell voltage and QRS duration.’l (In women, 800 pV is added to the Cornell voltage for calculation of this product.); (4) LVM index (LVMI) criteria of the Novacode ECG program26G27 with LVH thresholds adjusted to LVM measurements by the ASE convention; and (5) Framingham modification of the Cornell voltage.” This modification was introduced in order to achieve improved classification accuracy by including body mass index (BMI) and age in the LVH prediction algorithm. The adjusted Cornell voltage V is expressed as:

V = (RaVL + SV3) + C, where

C = 17.4 (Age-49) + 191 (BMI-26.5) for men; and

C = 38.7 (Age-50) + 212 (BMI-24.9) for women.

(The ECG amplitudes and V are in pV and the units for BMI in kg/m2.)

A.N.E. ADril 1996 9 Vol. 1 , No. 2 , Pt. 1 Rautaharju, et al. Classification of ECC Criteria for LVH 123

The threshold values for LVH estimates in the Framingham Study for 95% specificity are V 2 3310 pV for men and V 2 3326 pV for women.

Major ECG findings in the study population have been published previously."

Echocardiographic Methodology

M-mode, two-dimensional, and color Doppler echocardiograms were performed in CHS participants during the baseline examination and re- corded on super-VHS tape using a Toshiba SSH- 160A cardiac ultrasound machine (Toshiba, Tustin, CA, USA) according to a previously published pro- ~ o c o ~ . ~ ~ All studies were sent to a reading center at the University of California, Irvine, where the images were digitized and measurements made using customized computer algorithms. M-mode measurements of the left ventricle were made using standards of the American Society of Echocardiog- r a ~ h y , ~ ' and M-mode LVM was calculated using a formula previously reported by Devereux et al.31

Statistical Methods

In most analyses, the LVH thresholds of ECG criteria were adjusted to 95% specificity. This was done through an iteration process by increasing and decreasing ECG threshold for LVH until a threshold was identified that produced a 95% specificity in the non-LVH group.

In order to facilitate comparisons of LVH classification sensitivity of different ECG criteria according to different echocardiographic methods of indexing LVM to body size, echocardiographic LVH thresholds were adjusted to produce equal LVH severity levels. First, linear regression models were derived for LVM prediction from body surface area and standing height, respectively, and a logarithmic regression model for LVM prediction from body weight. The severity level of LVH was expressed with the aid of an LVH index (LVHI), which is the percentile ratio of the measured LVM to the predicted LVM (LVMp), or (LVM/LVMp) X 100. LVHI value of 150 means that the measured echocardiographic LVM is >50% above the value expected for the subject's body size.

Student's t-test was used to evaluate gender differences in basic anthropometric, ECG, and echocardiographic characteristics of the study groups. Z-test for ratios was used to evaluate the significance of painvise differences in LVH sensitivity of

various ECG criteria after LVH thresholds were adjusted to produce equal specificity (95%).

RESULTS Study Group Characteristics

Selected univariate statistics for various echocardiographic and ECG variables of various LVH models evaluated are listed in Table 1. The mean values of ECG amplitudes are similar to those reported for subgroups of white men and women in age groups 65 - 74 years old in the second National Health and Nutrition Examination Survey (NHANES 11) ." Gen- der differences in ECG amplitudes were relatively minor, although significant (P < 0.001), except for RaVL (P = 0.089). It was also noted that the Cornell product was significantly larger in women than in men (P < 0.001) after the suggested 800 pV adjustment for the RaVL in women. Similarly, the Cornell voltage was considerably larger in women than in men (P < 0.001) after the Framingham adjustment for age and BMI.

Accuracy of ECG Criteria for LVH by Echocardiographic Criteria with

Currently Used Thresholds

Echocardiographic LVH thresholds as originally introduced by various authors were used in these initial comparisons (Table 2). For Framingham criteria and the Novacode LVMI, the thresholds used were those for echocardiographic ASE standards3' for LVM indexed to standing height, and body surface area, respectively. According to these criteria, echocardiographic LVH prevalence in the test group was 4.3% in women and 2.5% in men by the body surface area indexing formula, and 6.9% in women and 3.0% in men by the height formula for LVMI. The specificity levels of different ECG criteria for LVH in men were relatively uniform with both echocardiographic standards for LVH, ranging from 93% - 97%. Specificity levels in women varied more widely, ranging from 81%- 96%. LVH detection sensitivity by different ECG criteria varied widely in men and in women.

These wide differences in ECG criteria specificity in women and in sensitivity in men and women, with the currently used echocardiographic LVH thresholds, complicate comparative evaluation of LVH classification accuracy. It was also of some concern that the echocardiographic methods for indexing LVM to body size may not have been opti-

124 A.N.E. April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju, et al. Classification of ECG Criteria for LVH

Table 1. Mean Values and Standard Deviations (SD) by Gender for the Variables of Various Echocardiographic and ECC Models for LVH Used in Diagnostic Classification Accuracy Evaluation

Variable

Women Men

Mean SD Mean SD (n = 1844) (n = 1119)

Age Body weight (kg) Standing height (cm) Body mass index (kg/m) Echo LVM (g) LVM/BSA (g/m2] LVM/height (g/m) QRS duration (ms) RaVL (pV) RV5 (pv l RV5 + SV1 RaVL + SV3 (pV) RaVL + SV3 (pV) (Framingham adj.) (RaVL + SV3) (QRS dur.) (pVSec)* (RaVL + 800 pV) + SV33 (QRS dur.] (pVsec)#

71.7 66.2

159.1 26.1

133.5 79.5 83.9 91.4

54 1 1390 2066 1257 2356

189 -

5.1 12.7 6.1 4.8

38.8 21.4 24.2 9.3

32 1 53 1 747 503

1190

55 -

72.6 78.7

173.2 26.2

171.1 88.9 98.9 97.6

56 1 1503 2199 151 1 1840

149

5.4 11.8 6.6 3.5

49.7 25.1 28.7

9.6 315 583 824 59 1 953

64

BSA = body surface area: LVH = left ventricular hypertrophy; LVM = echocardiographic left ventricular mass by ASE convention. P < 0.001 for gender difference for all variables except body mass index (P = 0.6761 and RaVL (P = 0.089). * males; #females.

ma1 w h e n used in a n older populat ion l i ke the present study group.

predict ion f r o m body surface area and standing height. This was done because indexing LVM to standing height or body surface area assumes that LVM i s l inear ly proportional t o these variables. In addition, a logarithmic regression model was used for LVM predict ion f r o m body weight in order to

LVM, Body Size, and Obesity As described in the statistical methods section,

linear regression models were derived for LVM

Table 2. Specificity and Sensitivity (%) with Unadjusted Original Thresholds of Five Sets of ECG Criteria for LVH According to Echocardiographic Definitions Based on LVM Indexed to BSA and Standing Height

Echocardiographic Criteria

(LVM/BSA)# (LVM/Ht) # #

LVH < kl 2 kl < k2 2 k2 ECG Criteria Threshold Specificity Sensitivity Specificity Sensitivity

Sokolow-Lyon

Cornell Voltage

Cornell Product

Women 3500 pV 96 19 97 16 Men 3500 pV 95 29 94 24

Women 2000 pv 94 31 95 28 Men 2800 pV 97 21 97 18

Women 243.6 ~ V S 89 41 89 39

Women 3326 pV 81 46 83 59

Men 243.6 ~ V S 93 43 93 36 Framingham

Novacode LVMl Men 3310 pV 93 32 94 30

Women 120 g/m2 85 46 85 42 Men 150 g/m2 95 43 95 39

BSA = body surface area (m’); Ht = standing height (cm); LVH = left ventricular hypertrophy: LVM = left ventricular mass (g); LVMl = left ventricular mass index. # k l = 120 for women, k l = 150 for men. ## k2 = 12 1 for women, k2 = 163 for men.

A . N . E . April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju, et al. Classification of ECG Criteria for LVH 125

Table 3. Three Regression Models for Predicting LVM from BSA, Standing Height and Body Weight by Gender and Obesity Status

Model 1 Model 2 Model 3* LVM = a + bHt LVM = a + bBSA LVM = aWb

GenderANeight Group a b R2 a b R2 a b R2

Women Normal weight 6.4 74.2 0.06 -0.9 0.77 0.02 9.5 0.63 0.09 Overweight -22.3 94.5 0.09 -25.2 1.07 0.02 8.8 0.64 0.1 1 Combined Group# -26.0 95.8 0.13 6.2 0.81 0.01 11.0 0.60 0.17

Normal weight 50.4 63.0 0.02 58.3 0.63 0.01 20.0 0.49 0.04 Overweight 32.3 78.3 0.03 22.5 0.97 0.01 12.3 0.60 0.05 Combined Group# 7.2 87.9 0.06 61.5 0.66 0.01 13.5 0.58 0.09

Men

Pooled LVM prediction formulas for normal weight and overweight groups from Table 3 were used for the adjustment of echocardiographic LVH severity levels. BSA = body surface area [m2); H t = standing height [cm); LVM = left ventricular mass [g); R2 = R- square value; Wt = body weight [kg). * Equation for Model 3 can be reduced to a formula: LVM = aW0.59, where a = 10.8 for women and a = 12.6 for men. # P < 0.001 for regression coefficients (b) for all models in all subgroups except for height in normal weight men [P = 0.0319), overweight men [P = 0.0103), and in combined group of men [P = 0.0051).

derive an optimal power function for this functional relationship. Separate models were derived for normal weight and overweight men and women.

Body size accounted for, at most, 17% of the total LVM variation in women and at most 9% in men, as seen from the R-square values of these LVM prediction models for body weight in the combined normal weight and overweight subgroups of women and men (Table 3). R-square values were lower for the other LVM prediction models; for instance, the model for standing height explained, at most, 2% of LVM variation in women and 1% in men.

The effect of obesity on estimated LVM can be judged by comparing the LVM of overweight subgroups predicted by the formulae derived for the overweight and normal weight subgroups. The average weight of overweight men was 89 kg, the average height 173 cm, and the average body surface area 2.03 m2. In overweight women, the average weight was 74 kg, height 158 cm, and body surface area 1.76 m2. The differences between LVM predicted by the indexing formula for body surface area for overweight and normal weight men were approximately 7% for overweight men and 8% for overweight women. The corresponding differences for the body weight formula were small, approximately 1% for overweight men and 6% for overweight women. These differences appeared larger for the body height indexing formula,

approximately 14% for overweight men and 19% for overweight women.

Accuracy of ECG Criteria for LVH at Equal LVH Severity Level by Three

Echocardiographic Standards Pooled LVM prediction formulae for normal

weight and overweight groups from Table 3 were used for the adjustment of LVM by the three echocardiographic standards to LVH severity level 140 in the comparison of ECG criteria performance in Table 4. ECG thresholds shown were obtained by adjusting the specificity to 95% for these comparisons. Severity level 140 is close to the reported upper 95% limit of 147 for echocardiographic weight adjusted LVM in a highly selected subgroup of the CHS considered as a healthy reference group that was used in the assessment of the associations between LVM and anthropometric body size vari- a b l e ~ . ~ ~

In women, the sensitivity levels were highest and approximately equal, between 29% and 31% for the Cornell product, Cornell voltage, and Novacode LVMI criteria when LVM was indexed to body surface area. They were also approximately equal, between 25% and 27%, for these same four criteria when LVM was indexed to body weight. With LVM indexed to standing height, the Framingham modification of the Cornell voltage had the highest sensitivity (31%). It was lower when LVM was indexed to body surface area (22%) or to body weight (16%).

126 A.N.E. April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju, et al. Classification of ECC Criteria for LVH

Table 4. Sensitivity (%) of Five Sets of ECC Criteria for LVH at LVH Severity Level 140* for Three Echocardiographic Methods, with ECC Thresholds Adjusted to 95% Specificity

LVMIBSA LVMIHt (LVM/aW0.59)* 100 2-97 Females 2 102 Females 2 140 Females 2 1 10 Males 2 123 Males 2 140 Males

Criteria Threshold Sensitivity Threshold Sensitivity Threshold Sensitivity

Women Sokolow-Lyon 3238 p V 21 3244 pV 17 3222 p V 19 Cornell Voltage 2048 pV 29 2053 pV 24 2037 pV 25 Cornell Product 299 pVs 31 299 ~ V S 27 296pVs 26 Framingham 4411 pV 22 4298 pV 31 4426 pV 16 Novacode LVMl 138 g/m2 29 138 g/m2 24 137 g/m2 27

Sokolow-Lyon 3515 p V 15 3550 pV 9 3464 p V 16

Cornell Product 277 ~ V S 29 280 ~ V S 24 275 ~ V S 26 Framingham 3527 pV 20 3452 pV 25 3529 pV 15 Novacode LVMl 17 1 g/m2 34 172 g/m2 30 168 g/m2 28

Men

Cornell Voltage 2667 p V 23 2671 p V 21 2614 pV 22

BSA = body surface area (m2]; Ht = standing height (cm); LVH = left ventricular hypertrophy; LVM = left ventricular mass (g]; LVMl = left ventricular mass index. * Measured LVM > 40% higher than that predicted by LVM by formulas for each echocardiographic method in Table 3.

LVH sensitivity levels in men varied more than in women by different ECG criteria at severity level 140 for echocardiographic LVH. It was highest, between 28% and 34%, for the Novacode LVMI by all three LVMI methods.

Obesity and ECG Threshold Adjustment Needed to Achieve 95% Specificity

Indexing of LVM to body weight was chosen for the remaining criteria comparisons because it gave the best adjustment to body size in the CHS population. Final adjustment of ECG thresholds for LVH was made at level 147 for the body weight adjusted LVM. Severity level 147 was the upper 95th percentile limit for echocardiographic weight adjusted LVM in a highly selected subgroup of the CHS that

was considered as a healthy reference group in the assessment of the associations between LVM and anthropometric body size Threshold adjustment was done separately for normal weight and overweight subgroups in order to optimize ECG criteria performance and to evaluate obesity effect on these thresholds [Table 5). LVH prevalence rates at severity level 140 were between 7.2% and 9.2% in women and between 8.2% and 10.3% in men. At severity level 160, LVH prevalence was from 2% - 4% in women, and from 3% - 4% in men. Thus, the echocardiographic LVH prevalence rates at equal estimated severity levels were approximately equal by all echocardiographic methods and approximately equal in men and women. These prevalence rates are considerably lower than the prevalence rates of 18.7% in women and 16% in

Table 5. LVH Thresholds for ECC Criteria at 95% Specificity by Gender and Overweight Status

Women Men

Criteria Normal Weight Overweight Normal Weight Overweight

Sokolow-Lyon (pV) 3339 3142 3606 3240 Cornell Voltage (pV) 2055 2048 2633 2696 Cornell Product (pVs) 289 300 277 286 Framingham (pV) 259 1 4749 2633 3917 Novacode LVMl (g/m2) 138 138 169 172

LVH = left ventricular hypertrophy.

A.N.E. April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju. et al. Classification of ECG Criteria for LVH 127

men reported for the Framingham population, with their thresholds for height indexed echocardiographic LVM.32

The comparison of the LVH thresholds of various ECG criteria adjusted for 95% specificity in Table 5 with the unadjusted thresholds in Table 2 showed some interesting differences. The Cornell voltage limits were close to the desired limits without any adjustment, and the adjustment needed for the No- vacode LVMI and Cornell product were small. Other criteria varied with the obesity status and required gender specific adjustments to a variable degree. The traditional Sokolow-Lyon voltage threshold (3500 pV) was too high in all subgroups except in normal weight men. The recommended Framingham threshold of 3300 pV required scaling down in normal weight women and men by approximately 700 pV and a substantial scaling up in overweight women and men (in women by as much as approximately 1400 pV). The Novacode LVMI thresholds were also scaled up in all subgroups, indicating overestimation of the LVM by this ECG model.

ECG Classification Accuracy, Obesity, and LVH Severity Level

Although not shown, the specificity levels remained quite stable with the optimized thresholds (Table 5) for 95% specificity at LVHI level 147, which was considered as the upper 95% normal limit in the CHS p~pu la t ion .~~ For instance, with LVHI variations between 140 and 170, the spec&- ity remained within 1% from 95% in all subgroups stratified with respect to gender and obesity in the remaining analyses. In contrast to specificity, the sensitivity level showed some substantial differences between various LVH criteria (Figs. lA, lB, 2A, and 2B).

With LVHI 100 as the echocardiographic threshold, the sensitivity of all ECG criteria was approximately 10% and then increased progressively, in general approximately linearly, with increasing LVH severity level. In normal weight men, the increase was more pronounced for the Novacode LVMI than for the other four criteria (Fig. 1A). Compared with normal weight men, there was no notable change with overweight men in this functional relationship for the Cornell product, Cornell voltage, and Sokolow-Lyon criteria (Fig. 1B). The sensitivity of the Novacode LVMI was reduced with overweight men to approximately the same

n

$+ 40

k .... 0 .... cp

n

$+ 40

k .... 0 .... cp

A

I I I I I I I 100 110 120 130 140 150 160 170

LVHI

B

G- Y I

0 1 I I 1 I I I 4 100 110 120 130 140 150 160 170

LVHI

Figure 1. (A) Progressive, nearly linear increase in sensitivity of five sets of ECG criteria for LVH in normal weight men with increasing echocardiographic LVH index [LVHI). The specificity was adjusted to 95% at LVHl 147, and it remained within 1% from 95% within LVHl range from 140- 170 in this and three other subgroups. Significance levels for painvise differences in sensitivity at LVHl = I 50: NC versus SL, CV, CP, and F: P < 0,00001 for all; CP versus SL: P < 0.01; other differences not significant. (B) Sensitivity of ECG criteria for LVH in overweight men with increasing echocardiographic LVHI. Specificity adjusted to 95% at LVHl 147. Significance levels for pairwise differences in sensitivity at LVHl = 150: CP, CV, NC. and SL versus F: P < 0.0000 1 for all; CP versus SL, CV. F and NC: P < 0.00001 for all; CV and NC versus SL: P < 0.05. CP = Cornell product; CV = Cornell voltage; F = Frarningharn; NC = Novacode LVMI criteria; SL = SOkOlOW-LyOn.

128 A.N.E. April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju, et al. Classification of ECC Criteria for LVH

50

40

30

20

10

C 1 1 1 1 1 ~ 1 ~ 1 1 1 1 1 1 1 00 105 110 115 120 125 130 135 140 145 150 155 160 165 170

LVHI

1Do 110 120 130 140 150 160 170

LVHI

Figure 2. [A) Sensitivity of ECC criteria for LVH in normal weight women with increasing echocardiographic LVH index (LVHI). Specificity adjusted to 95% at LVHl 147. Sig- nificance levels for pairwise differences in sensitivity at LVHl = 150: F versus SL, CV, CP and NC: P < 0.00 1 for all; other differences not significant. [B) Sensitivity of ECC criteria for LVH in overweight women with increasing echocardiographic LVHI. Specificity adjusted to 95% at LVHl 147. Significance levels for pairwise differences in sensitivity at LVHl = 150: CV, CP and NC versus F and versus SL: P < 0.000 1 for all; other differences not significant. CP = Cornell product; CV = Cornell voltage; F = Framingham; NC = Novacode LVMI criteria; SL = So- ko lo w- Lyon .

level as for these three other criteria, and there appeared to be no improvement in the sensitivity of the Framingham criteria with increasing LVH severity level.

In normal weight women, the increase in sensi-

tivity with increasing LVHI appeared relatively uniform and more pronounced than in men (Fig. 2A). Obesity seemed to have little influence on this trend for the Cornell product, Cornell voltage, and Novacode LVMI criteria (Fig. 2B). Compared to normal weight women, the sensitivity increase with increasing LVHI was less pronounced in obese women for the Sokolow-Lyon criteria, and as with overweight men, almost absent for the Framing- ham criteria.

The comparison of the relative accuracy of LVH classification and the significance of the differences seen in the overall trends can perhaps be best judged by testing for the differences in sensitivity at equal specificity using LVHI 150 as the cutpoint for LVH, since this LVHI level in these figures was closest to the upper normal 95% limit for the CHS population. The significance levels for these differences are given in the legends of Figures lA, lB, 2A, and 2B. In normal weight men, the sensitivity of the Novacode LVMI (40.8%) was significantly higher (P < 0.0001) than that of the other criteria. There was no significant difference in the sensitivity of the Cornell product (25.4%), Cornell voltage (22.5%), and the Framingham criteria (22.5%). In overweight men, the Cornell product criteria had a significantly higher sensitivity (32.5%) than the other four criteria (P < O.OOOl) , and the Framing- ham criteria had a significantly lower sensitivity (7.5%) than the other criteria (P < 0.0001). The Framingham criteria had a significantly higher sensitivity (P < 0.001) in normal weight women (38.2%) than Cornell product and Novacode LVMI (22.5% for both) or the Cornell voltage and Soko- low-Lyon criteria (29.1% for both). In contrast with normal weight women, in overweight women the sensitivities of the Framingham criteria (13.9%) and the Sokolow-Lyon criteria (17.7%) were significantly lower (P < 0.0001 for both] than those of the Cornell product (32.5%), Novacode LVMI, and Cornell voltage criteria (25.0% for both).

DISCUSSION

Echocardiographic LVH as the "Gold Standard": A Methodological Problem

Previous investigations comparing classification accuracy of ECG criteria for LVH have in general performed these comparisons at a fixed threshold for the echocardiographic method chosen for indexing LVM to body size as the standard for evalua-

A.N.E. April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju, et al. Classification of ECG Criteria for LVH 129

tion. This approach is limited in the sense that ECG criteria performance depends strongly on the LVH severity level, as was demonstrated by the results of the present study. This poses problems also in the assessment of LVH prevalence in contrasting populations. A recent study reported that the apparent LVH prevalence in a hypertension clinic population varied from 10% to 47% in women, and from 19% to 39% in men, according to various threshold values recommended for echocardiographic LVH criteria.34

An inherent limitation in the evaluation of ECG criteria for LVH using echocardiographic LVH as the "gold standard'' is the limited accuracy of echocardiographic LVM estimation. A previous report from the CHS documented the overall median in- terreader variability for LVM measurements (per- cent measurement differences) as 17% and 14%, re~pect ively.~~ This imposes a substantial degree of uncertainty in LVH classification accuracy estimation for ECG criteria at any chosen threshold for echocardiographic LVH. The seriousness of this problem can be appreciated by considering proba- bility density functions of echocardiographic LVM and the classification changes induced by random 14% changes (one half of them increases and one half decreases) in LVM measurement (about any given LVH threshold such as severity level 147, which is considered as the upper 95% normal limit for a given body size). If one set of echocardiographic measurements were judged against another paired independent measurements, it appears that, for instance, the specificity of the echocardiographic determination would be approximately 96% in women, 94% in men, and the corresponding sensitivities approximately 69% and 73% in women and men, respectively. The classification instability is even larger if the total biological and technical variation is considered. The Treatment of Mild Hy- pertension Study recently reported that approximately two thirds of subjects initially classified by echocardiographers as LVH would not be so classified on the repeat recording.35 The relatively small differences in the sensitivity of the best ECG criteria at equal specificity have little practical meaning in view of the large degree of uncertainty in the "gold standard" itself, and this should be kept in mind when judging the classification accuracy results of this and other similar studies. However, this does not invalidate the conclusions regarding the trends in classification accuracy with obesity and LVH severity level, and the changes in ECG

thresholds required to improve their performance in older study populations such as the CHS.

Obesity Effect While the obesity effect on echocardiographic

LVM appeared relatively small, overweight status seemed to have a larger influence on the ECG threshold modifications required for some ECG criteria to retain the specificity at the 95% level. The Cornell voltage, and also the Novacode LVMI and Cornell product thresholds were little influenced by obesity. The Sokolow-Lyon LVH threshold in overweight women had to be reduced to approximately 3100 pV and in overweight men to approximately 3000 pV. The biggest change with obesity was for the LVH threshold of the Framingham criteria in women, and in men the upwards adjustment required was also substantial. The Framing- ham criteria contains an adjustment for obesity and age, thereby increasing the Cornell voltage with age and increased BMI." Cornell voltage increases rather than decreases with both age and overweight, reflecting the tendency to left axis shift and concomitant change in the frontal plane ECG amplitudes." Although these thresholds depend on the LVMI method chosen, the drastic changes in the Framingham criteria threshold required to maintain 95% specificity suggest an inappropriate modification for the Cornell voltage with age and obesity by the Framingham model.

Obesity reduced the sensitivity of the Framingham criteria to significantly below those obtained for the other LVH criteria. It also decreased the sensitivity of the Novacode LVMI in men and brought it down to the range of the other LVH criteria. The sensitivity of the Sokolow-Lyon criteria was reduced with obesity in women. The sensitivity of the Cornell voltage and Cornell product criteria was relatively minorly influenced by obesity.

Limitations of the Study The choice of not using the receiver operating char-

acteristics (ROC) curve approach to compare relative performance of ECG criteria may be considered by some as a limitation of the present study. With the ROC curve approach, the performance of ECG criteria is compared for varying ECG thresholds by plot- ting the sensitivity against false-positives ( 100 specificity) over all paired values from 0% - 100%. A limitation of this approach is that the information contained in the ROC curves through a major portion

130 A.N.E. April 1996 Vol. 1, No. 2, Pt. 1 Rautaharju, e t al. Classification of ECC Criteria for LVH

of its range [specificity levels from 0%-90%) is of limited use for most applications because of the pro- hibitively large fraction of false-positives. Another limitation of the ROC curve approach in ECG criteria evaluation is that in reality, one fixed threshold rather than a continuum of thresholds is practically always used for each criterion in usual applications, and thus information provided by the ROC curves is for the most part not relevant.

We chose a different approach in the present study for comparative evaluation of ECG classification accuracy by adjusting echocardiographic cutpoints for varying LVH severity levels and by keeping the adjustments of ECG thresholds to a minimum [gender and overweight status). Since there is no consensus about the method of indexing echocardiographic LVM to body size, we used three different LVMI methods as standards, and we adjusted each method to equal LVH severity level and thus to approximately equal LVH prevalence in the test groups. This was achieved by using regression models to predict echocardiographic LVM and by determining the percentage ratio of the measured and predicted LVM for each LVMI method. This percentage, or LVHI, is a simple expression for the degree by which the measured LVM exceeds the LVM for the subject's body size. In final analysis, LVM adjusted to body weight was chosen as the echocardiographic standard because, compared to indexing to standing height, body weight gave the best adjustment for body size in the CHS population. Standing height explained just 1% - 2% of LVM variance.

One limiting factor not adequately considered in the present study is the limited LVM estimation accuracy of the gold standard itself, the echocardiogram. As mentioned already, this error source may produce a severe estimation bias in ECG criteria evaluation, particularly if the total biological and technical short-term variations in echocardiographic LVM estimation were taken into consideration. This problem warrants serious attention in future studies. Conceptual problems in LVH progression and regression incidence classification are likely to be even more severe than in LVH prevalence cla~sification,~~ and they also warrant serious consideration together with the role of anthropometric factors in future attempts to improve LVH prevalence, and LVH progression and regression incidence estimation algorithms.

CONCLUSIONS (1) Echocardiographic LVH thresholds and the

method of adjusting LVM to body size can have

an important effect on the results of ECG criteria accuracy assessment. Body weight dominates the body size-LVM relationship, and this functional relationship is nearly identical in normal weight and overweight subjects. After adjustment for weight [approximately an inverse square root relationship), standing height does not improve LVM prediction. The sensitivity of ECG criteria for LVH is relatively low. With echocardiographic LVH threshold at upper 95% normal limit for weight adjusted LVM for this test group of older subjects, it was highest (40.8%) for the Novacode LVMI criteria in normal weight men, and for the Framingham criteria (30.9%) in normal weight women. The sensitivity of the Cornell voltage and Cor- nell product criteria is not influenced by obesity. Obesity reduces sensitivity of the Nova- code LVMI criteria, and Framingham adjustment of the Cornell voltage criteria for age and obesity substantially deteriorates their performance in overweight men and women.

ADDENDUM

After submission of this manuscript for publica- tion, the Framingham Study group recently published new equations37 for the adjustment of the Cornell voltage with a substantially lower slope for the overall correction than produced by the original equations, and also considerably lower weights for the adjustment for obesity and age, and lower LVH thresholds. The article also contains equations for the adjustment of the Cornell product for obesity and age. These new LVH criteria were not evaluated in the present report.

APPENDIX

Participating Institutions and Principal Staff

Forsyth County, NC: Bowman Gray School of Medicine, Wake Forest University: Gregory L. Burke, Walter H. Ettinger, Alan Elster, Curt D. Furberg, Edward Haponik, Dalane Kitzman, Ge- rardo Heiss, H. Sidney Klopfenstein, David S. Lef- kowitz, Mary F. Lyles, Maurice B. Mittelmark, Ward Riley, Grethe S. Tell, James F. Toole, Cathy Nunn.

A.N.E. April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju, e t al. Classification of ECG Criteria for LVH 131

Sacramento County, CA: University o f California, Davis: William Bommer, Marshall Lee, John Rob- bins, Marc Schenker.

Washington County, MD: The Johns Hopkins University: R. Nick Bryan, Trudy L. Bush, Joice Chabot, George W. Comstock, Linda P. Fried, Pearl S. German, Joel Hill, Steven J. Kittner, Shiriki Kumanyika, Neil R. Rowe, Thomas R. Price, Rob- ert Rock, Moyses Szklo.

Allegheny County, PA: University of Pittsburgh: Janet Bonk, Laurie Knepper, Diana G. Ives, Charles A. Jungreis, Lewis H. Kuller, Robert H. McDonald Jr, Elaine Meilahn, Peg Meyer, Anne Newman, Gale H. Rutan, Richard Schulz, Vivienne E. Smith, Sidney K. Wolfson.

Echocardiography Reading Center: University o f California, Irvine: Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, Nathan Wong.

Ultrasound Reading Center: Geisinger Medical Center: Daniel H. O'Leary, Joseph F. Polak, Laurie Funk.

Central Blood Analysis Laboratory: University o f Vermont: Edwin Bovill, Elaine Cornell, Paula Howard, Russel P. Tracy.

Respiratory Sciences: University o f Arizona, Tucson: Paul Enright.

Electrocardiography Reading Center: Bowman Gray School o f Medicine, Wake Forest University: Teresa Alexander, Beverly Benton, Stacey Gustaf- son, Margaret Mills, Larry Park, Farida Rautaharju, Pentti Rautaharju, Daniel Tesfaye, Martha Smith.

Coordinating Center: University of Washington, Seattle: Annette L. Fitzpatrick, Richard A. Kron- mal, Bonnie K. Lind, Bruce M. Psaty, David S. Sis- covick, Lynn Shemanski, Lloyd Fisher, Will Longs- treth, Trivellore Ragunathan, Patricia W. Wahl, David Yanez.

University of California School o f Medicine at Davis {UCD): Nemat 0. Borhani.

NHLBI Project Office: Diane E. Bild, Teri A. Ma- nolio, Peter J. Savage, Patricia Smith.

REFERENCES 1. Reichek N, Devereux RB. Left ventricular hypertrophy: Re-

lationship of anatomic, echocardiographic and electrocardiographic findings. Circulation 1981; 63:1391- 1398.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Wgytgaler JN, Singer SL, Kwan L, et al. Accuracy of echocardiography versus electrocardiography in detecting LVH: Comparison with postmortem mass measurements. J Am Coll Cardiol 1983; 2306-311. Kansal S, Roitman DI, Sheffield LT. A quantitative relationship of electrocardiographic criteria of left ventricular hypertrophy with echocardiographic left ventricular mass: A multivariate approach. Clin Cardiol 1983; 6:456 -463. Devereux RB, Casale PN, Eisenberg RR, et al. Electrocardio- graphic detection of left ventricular hypertrophy using echocardiographic determinants of left ventricular mass as the reference standard. J Am Coll Cardiol 1984; 3:82-87. Casale PN, Devereux RB, Kligfield P, et al. Electrocardio- graphic detection of left Ventricular hypertrophy: Develop- ment and prospective validation of improved criteria. J Am Coll Cardiol 1985; 6:572-580. Casale PN, Devereux RB, Alonso DR, et al. Improved sex- specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: Valida- tion with autopsy findings. Circulation 1987; 75:565- 572. Levy D, Labib SB, Anderson KM, et al. Determinants of sensitivity and specificity of electrocardiographic criteria for left ventricular hypertrophy. Circulation 1990; 81:815 - 820. Kannel WB, Gordon T, Offat D. Left ventricular hypertrophy by electrocardiogram: Prevalence, incidence, and mortality in the Framingham Study. Ann Intern Med 1969;

Kannel WB, Gordon T, Castelli WP, et al. Electrocardio- graphic left ventricular hypertrophy and the risk of coronary heart disease: The Framingham Study. Ann Intern Med 1970; 72813-822. Kannel WB, Abbott RD. A prognostic comparison of asymp- tomatic left ventricular hypertrophy and unrecognized myocardial infarction: The Framingham Study. Am Heart

Kannel WB, Dannenberg AL, Levy D. Population implica- tions of electrocardiographic left ventricular hypertrophy. Am J Cardiol 1987; 60:851-931. Kreger BE, Cupples LA, Kannel WB. The electrocardiogram in prediction of sudden death: Framingham Study experi- ence. Am Heart J 1987; 113:377-382. Rautaharju PM. Electrocardiogram in epidemiology and clinical trials. Chapter in PW MacFarlane, TDV Lawrie (eds): Comprehensive Electrocardiology. Pergamon Books Ltd., New York, 1988, pp. 1219-1266. Rautaharju PM, LaCroix AZ, Savage DD, et al. Electrocar- diographic estimate of left ventricular mass versus radio- graphic cardiac size and the risk of cardiovascular disease mortality in the epidemiologic follow-up study of the First National Health and Nutrition Examination Survey. Am J Cardiol 1988; 62:59-66. Levy D, Savage DD, Garrison RJ, et al. Echocardiographic criteria for left ventricular hypertrophy: The Framingham Heart Study. Am J Cardiol 1987; 59:956-960. Levy D, Garrison RJ, Savage DD, et al. Prognostic implica- tions of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;

Casale PN, Devereux RB, Milner M, et al. Value of echocardiographic left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med

Savage DD. Overall risk of left ventricular hypertrophy sec-

71~89- 105.

j 1986; 111:391-397.

32211561 - 1566.

1987; 105:173-178.

132 A.N.E. April 1996 Vol. 1 , No. 2, Pt. 1 Rautaharju, et al. Classification of ECG Criteria for LVH

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

ondary to systemic hypertension. Am J Cardiol 1987; 60:81- 121. Wolf HK, Burggraf GW, Cuddy E. Prediction of left ventricular mass from the electrocardiogram. J Electrocardioll991;

Rautaharju PM, Zhou SH, Calhoun HP. Ethnic differences in ECG amplitudes in North American White, Black, and Hispanic men and women: Effect of obesity and age. J Elec- trocardiol 1995; 2720- 31. Malloy JM, Okin PM, Devereux RB, et al. Electrocardio- graphic detection of left ventricular hypertrophy by the simple QRS voltage-duration product. J Am Coll Cardiol 1992;

Norman JE, Levy D, Campbell G, et al. Improved detection of echocardiographic left ventricular hypertrophy using a new electrocardiographic algorithm. J Am Coll Cardiol

Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: Design and rationale. Ann Epidemiol 1991; 1263-276. Sokolow M, Lyon TP. Ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949; 37:161- 186. Blackburn H, Keys A, Simonson E, et al. The electrocardiogram in population studies. A classification system. Circula- tion 1960; 21:1160- 1175. Rautaharju PM, MacInnis PJ, Warren JW, et al. Methodol- ogy of ECG interpretation in the Dalhousie Program. Nova- code ECG classification procedures for clinical trials and population health surveys. Methods Infor Med 1990;

Rautaharju PM, Calhoun HP, Chaitman BR. Novacode se- rial ECG classification system for clinical trials and epidemi- ological studies. J Electrocardiol 1992; 24: 163- 172. Furberg CD, Manolio TA, Psaty BM. Major ECG abnormali-

24:121- 127.

511180- 1186.

1993; 2111680-1686.

29:362 - 374.

ties in persons aged 65 years and older: The Cardiovascular Health Study. Am J Cardiol 1992; 69:1329-1335.

29. Gardin JM, Wong ND, Bommer W, et al. Echocardiographic design of a multicenter investigation of free-living elderly subjects. The Cardiovascular Health Study. J Am SOC Echo- cardiol 1992; 1:63-72.

30. Sahn DJ, DeMaria A, Kisslo J, et al. The Committee on M- mode Standardization of the American Society of Echocardi- ography- Results of a survey of echocardiographic methods. Circulation 1978; 58:1072- 1083.

31. Devereux RB, Alonso DR, Lutas EM. Echocardiographic assessment of left ventricular hypertrophy: Comparison with necropsy findings. Am J Cardiol 1986; 57:450-458.

32. Levy D, Savage DD, Garrison RJ, et al. Echocardiographic criteria for left ventricular hypertrophy: The Framingham Heart Study. Am J Cardiol 1987; 59:956-960.

33. Gardin JM, Siscovick D, Anton-Culver H, et al. Sex, age and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly. The Cardio- vascular Health Study. Circulation 1995; 91:1739- 1748.

34. Abergel E, Tase M, Boblender J, et al. Which definition for echocardiographic left ventricular hypertrophy? Am J Cardiol 1995; 75:498-502.

35. Crow RS, Prineas RJ, Rautaharju P, et al. Relation between electrocardiography and echocardiography for left ventricular mass in mild systemic hypertension. (Results from Treat- ment of Mild Hypertension Study). Am J Cardiol 1995;

36. Zhou SH, Rautaharju PM, Prineas RJ. Improved accuracy of ECG models for estimation of left ventricular hypertrophy progression and regression incidence by proper consideration of ECG variability. J Electrocardiol 1993; 26: 108 - 113.

37. Norman JE, Levy D. Improved electrocardiographic detection of echocardiographic left ventricular hypertrophy: Re- sults of a correlated data base approach. J Am Coll Cardiol

75:1233- 1238.

1995; 26:1022- 1029.

Documents

Classification Accuracy of Electrocardiographic Criteria for Left Ventricular Hypertrophy in Normal Weight and Overweight Older Adults