the Division of Epidemiology (E.N., D.K.A.), University of Minnesota, Minneapolis, Minn
Boston Medical Center (E.J.B.), Boston University School of Medicine, Boston, Mass
Rush Medical College (P.R.L.), Chicago, Ill
University of Mississippi Medical Center (T.N.S.), Jackson, Miss
The Jackson Heart Study (H.T.), Jackson Medical Mall, Jackson, Miss
Health Effects Laboratory Division (M.A.), National Institute for Occupational Safety and Health, Morgantown, WV.
Abstract
The distribution of echocardiographic left ventricular (LV) mass differs among ethnicities. Because ethnic-specific echocardiographic criteria for LV hypertrophy (LVH) are not established, we determined whether threshold values derived from overwhelmingly white populations are appropriate for blacks, a subgroup having more LVH. Between 1992 and 1994, LV mass was measured echocardiographically in the Jackson, Mississippi, black cohort of the Atherosclerosis Risk in Communities study. Participants free of prevalent cardiovascular disease (CVD) (n=1616; mean±SD, age 59±5.7; 65% women and 57% with hypertension) were included. The optimal LVH threshold value was selected from the continuum of LV mass index (LVMI=LV mass/height2.7) using 3 methods: (1) the best operating point from the area under the resulting receiver-operating characteristic (ROC) curve predicting incident CVD; (2) the value with the smallest probability value associated with incident CVD; and (3) visual inspection of functions of LVMI and CVD in the general additive model (GAM) plot. At a median follow-up of 6.8 years, there were 192 events (coronary heart disease=87, stroke=62, and congestive heart failure=43; incidence=17.6/1000 person-years). The best operating point from the resulting ROC analysis was 51.2 g/m2.7 for sensitivity (53.4%) and specificity (61.5%). The Cox and GAM models adjusted for age, gender, systolic blood pressure, hypertension, diabetes, smoking, total cholesterol-to-high-density lipoprotein ratio, LVH by ECG criterion, and socioeconomic status found 50 to 51 g/m2.7 as the optimal threshold for LVH in middle-aged blacks, corresponding to a minimum probability value and to a log-hazard ratio of zero, respectively. Because these values are close to the 51 g/m2.7 established from predominantly white populations, this cutpoint is appropriate for both groups.
Key Words: epidemiology population echocardiography hypertrophy blacks
Introduction
Left ventricular hypertrophy (LVH) detected by echocardiography is a precursor of premature mortality across all genders, races, and ages,1eC6 beyond the prognostic significance of alterations in LV geometry7 and/or electrocardiographic patterns of LVH.8 Moreover, regression of LVH is a favorable prognostic marker independent of treatment-induced reduction in blood pressure.9
LVH has traditionally been determined as the upper 2.5 to 5 percentiles of LV mass index (LVMI) in a reference population.10eC15 However, it is known that LVMI does not have a Gaussian distribution; thus, the normal range may not contain 95% of the values. Therefore, some authors16,17 have advocated using a risk factor-driven cutpoint as the optimal approach to dichotomize a continuous diagnostic test. Because LVH prevalence12,15,18eC20 and incidence of morbid events21 varies depending on the threshold selected, it is advisable to determine if thresholds obtained from one population apply to others.
To date, LVH thresholds have been derived from overwhelmingly white populations (Table 1) and applied to other ethnic groups.5,23eC32 Because ethnic groups differ in anthropometric measures that correlate with heart size,33 ethnic-specific criteria for LVH may be warranted. The aim of this study is to determine the optimal threshold for LVMI to define LVH in a middle-aged black American population.
Methods
Methods are described in detail in the online supplement available at http://www.hypertensionaha.org.
Study Population
An echocardiographic examination34,35 was performed in blacks aged 51 to 70 years from Jackson, Mississippi. After excluding ineligible participants, 570 men and 1046 women were included.
Echocardiography
The echocardiograph protocol has been reported.34,35 The reliability assessment of the Atherosclerosis Risk in Communities Study (ARIC) echocardiographic reading center reported intraobserver coefficients of variation of 4.6% for interventricular septum, 4.6% for posterior wall, 1.5% for internal diameter, and 6.3% for LV mass.
Echocardiography Measurements
LV measurements were taken according to the American Society of Echocardiography recommendations.36 LV mass was calculated according to Devereux’s validated formula.37,38 As recommended,13 LV mass values were normalized by height2.7 to correct for body size differences. The online supplement also contains LV mass values normalized to body surface area (BSA).
Risk Factors Measurements and Definition of Variables
Risk factors were measured at the echocardiographic examination visit using standardized methods. See Table I, available online, for definitions and measurement procedures.
Ascertaining Incident Cardiovascular Disease Events
Coronary heart disease (CHD) and stroke incidence were ascertained by annual contact, identifying hospitalizations and deaths during the previous year, and surveying discharge lists from local hospitals and death certificates for potential events.39eC41 For participants with no event, follow-up continued until noncardiovascular death (n=62), December 31, 2001 (n=1405), or date of last contact (n=1). The median follow-up was 6.55 years (interquartile range, 6.13 to 7.51 years).
Statistical Analysis
Comparisons between genders were performed with ManneCWhitney 2-sample statistic for continuous variables and 2 or Fisher exact test for discrete variables.
We followed a 3-step approach to determine the optimal criterion for LVH:16 (1) we used Cox regression analysis to quantify the association between LVMI and incident cardiovascular disease (CVD); (2) we created a general additive model (GAM)42 with Cox extension to uncover the underlying relationship between LVMI and the composite CVD endpoint (Figure 1). We also plotted sensitivity (Se) against 1eCspecificity (Sp) of each value in the continuum of LVMI (Figure 2). The resulting receiver-operating characteristic (ROC) curve43 provided a full range of diagnostic thresholds for all possible combinations of Se and Sp; and (3) all values suggested by the exploratory plots were examined as candidates for optimal cutpoints. Once the range of values of LVMI was selected (45 to 53 g/m2.7), Cox proportional hazard regression models were used to determine the value associated with a minimum probability value or maximum 2 statistic.16,44 Univariate and risk factor-adjusted estimates were computed.
Gaussian Distribution Method
We computed a threshold value corresponding to the 95th percentile of LVMI in a subset of apparently healthy individuals.
Single or Gender-Specific Threshold
To further evaluate the generalizability of the threshold for both sexes, the interaction term of LVH (with a 50 g/m2.7 threshold) with gender was tested in the multivariate analysis, and the value of LVMI corresponding to a log-hazard ratio (HR) of 0 in the GAM curves, in men and women, was also examined.
Results
Clinical and Echocardiographic Findings
Clinical characteristics of the study population are presented online in Table II. Echocardiographic variables are presented in Table 2.
LV mass was higher in men, a difference that disappeared when it was indexed by height2.7 (P=0.08). The prevalence of LVH varied from 40% to 50% in women, but not in men (36%), depending on the criteria used. When using the single partition value currently in use (50 g/m2.7), the difference in LVH prevalence by gender (P=0.05) is attenuated, when compared with the gender-specific criteria, in which women had a greater prevalence than men (P<0.001).
Outcomes and Crude Rates
At the median follow-up, a total of 192 events were identified (Table 3). Under the Poisson assumption, an event rate of 17.6 per 1000 person-years was calculated for the entire population, but men had significantly higher rates than women (25.4 versus 13.4 per 1000 person-years; P<0.001).
GAM
Figure 1 displays the GAM plots. No differences in the optimal threshold were seen between univariate and the multivariate models. Visual inspection of the graph showed that CVD risk increased steadily as LVMI increased, therefore rejecting the null hypothesis of nonlinearity for LVMI (2=4.10; df=4.84; P=0.37). The curve also identified 51 g/m2.7 to be the value of LVMI when the corresponding hazard rate for CVD was zero.
ROC Curve Analyses
Figure 2 shows sensitivity and specificity curves plotted along a range of LVMI values given the reference test (incident CVD); the optimal threshold estimated by the point where the curves cross was 51.2 g/m2.7, with an associated Se of 53.4% (46.7% to 60.3%) and Sp of 61.5% (59.4% to 63.6%)
Cox Proportional Analysis
LVMI (per 10-g/m2.7 increment) predicted incident CVD (HR, 1.36; 95% confidence interval [CI], 1.24 to 1.50; P<0.001), an association that persisted after adjustment for risk factors (HR, 1.19; 95% CI, 1.07 to 1.32; P<0.001). Table III shows that LVH with a threshold at 50 g/m2.7 (P=0.083) best-separated subjects’ outcomes by the minimum probability value approach. The interaction term of LVH with gender was not significant in any of the models tested. As supportive evidence, the same threshold chosen by the adjusted minimum probability value was associated with the highest area under the curve (0.744), indicating the multivariate model defining LVH at 50 g/m2.7 had the highest discriminatory ability for future CVD events. Similar trends in the results from univariate analyses were found after adjusting by multiple comparisons (results not shown).
Diagnostic Test Characteristics
Table 4 depicts the characterization of the LVH modeled as a dichotomous screening test in terms of true and false-positive rates, positive predictive value (PPV) and negative predictive value (NPV), and likelihood ratio (LR). Our criterion for LVH was associated with a sensitivity of 57.1% and specificity of 60.8%. Regarding how accurately LVH predicts future CVD events, the calculated PPV and NPV were 13.3% and 93.1%, respectively.
Gaussian Distribution Method
Demographic and clinical characteristics of the apparently healthy population are displayed in Table II; echocardiographic characteristics are in Table 2. The computed 95th percentile of LVMI was 52.9 g/m2.7 (95% CI, 50.1 to 55.7).
BSA-Normalized Cutpoint
To allow comparison with other studies, the online supplement (Figure I) shows the GAM plot and sensitivity and specificity curves for BSA-normalized LV mass index. The optimum threshold for BSAeCLVH was 105 g/m2. Table IV compares prognostic parameters for LVH indexed by BSA versus height2.7.
Discussion
To our knowledge, this is the first report that determined echocardiographic LVH thresholds in blacks. Previous studies that have focused on comparing black and white patients, or a few of them performed exclusively in blacks, have used the thresholds derived from whites.10eC15 This was performed despite caution raised by the authors regarding the lack of validation with other ethnic groups.10eC12,14 Using the approach recommended by Mazumdar et al,16 our results point to 50 g/m2.7 as the optimal threshold selected on multivariate setting, which is the value that minimizes the probability value relating LVH to cardiovascular disease. This threshold value was further supported by the generalized additive model analysis, which showed graphically that 51 g/m2.7 was the point that the GAM curve crossed a hazard rate of 0, and by the finding that the best operating point derived from the area under the curve points toward a similar value. To make our results comparable with previous studies,10eC15 we also estimated the 95th percentile of LVMI values in our reference subpopulation. Our results based in the percentile method (a single threshold at 52.9 g/m2.7) were slightly higher than previous LVH criteria10eC15 and our prognostically driven estimates. We speculate that differences in exclusion criteria applied as well as the ethnic composition of the reference population in which the criteria were estimated may play an important role. For example, Devereux et al22 used a reference population from 2 different sources, hospital-based series and employed adults, and de Simone et al13,20 from 3 normotensive populations (in New York City; Naples, Italy; and Cincinnati, Ohio), and no mention is made in those studies about the proportion of blacks. The composition of the reference population from the Framingham study is predominantly white.12,14 Nonetheless, the confidence intervals associated with the 95th percentile of LVMI in our analysis included the threshold value estimated by endpoint-driven methods.
Single Threshold for Both Genders
It has been unclear whether gender-specific threshold values are needed to define LVH. For the sake of simplicity, previous investigators11,13,22 have proposed a unique partition value typically estimated by a prespecified percentile and then validated prognostically against morbid CHD events.1,20 To determine the generalizability of the single threshold computed on our cohort, we tested the interaction between LVH and gender in the Cox model. Because no differences were found (P=0.814), our findings support a common threshold of 50 g/m2.7 for both genders. Likewise, a common threshold was supported by visual inspection of the GAM curves, calculated separately in each gender (results not presented).
Characteristics of LVH as a Diagnostic Tool
Relative performance of LVH defined by our single criterion may be evaluated using 2 dimensions of the accuracy scale, namely disease-specific classification probabilities (true positive rate) and false-positive rate, predictive values (PPV and NPV), and diagnostic likelihood ratios (LR+ and LReC). Using our criterion, a TPR of 57.1% and an false-positive rate of 39.2% means testing positive for LVH misses 42.9% of the subjects in whom CVD developed at follow-up and incorrectly identified 39.2% of low-risk subjects as being at high risk for future events. In regard to how well LVH predicted future CVD events, a PPV of 13.3% indicates that among subjects that test positive for LVH, only a few of them had events in the 8-year follow-up period. A NPV of 93.1% showed that only 6.9% of subjects that tested negative were at risk for future events. The likelihood ratios associated with our proposed threshold were: LR+=1.46 (1.28 to 1.67) and LReC=0.71 (0.60 to 0.83). However, the pretest odds of disease, 0.105, were increased to 0.153 by a positive test, and this was decreased to 0.074 by a negative test. Further discussion of the usefulness of LVH as a diagnostic tool is included in the online supplement (Table V, Figure II, and comments).
Limitations of the Study
First, the threshold derived here has been tested only in the data set from which it was derived; it has not been prospectively validated with independent data or in another cohort of blacks. Second, the validity of our results is limited to a CVD-free population of blacks. Third, the lack of a longitudinal assessment of LV mass did not permit us to account for the effects of serial changes in LV mass that may be associated with the incidence of CVD events. Although our threshold for blacks is the same as that recommended generally, we cannot extrapolate this finding to other ethnic groups. Therefore, we recommend future research be performed to establish ethnic-specific LVH thresholds for other groups.
Acknowledgments
The ARIC study was funded by contracts N01 HC55015, N01 HC55016, N01 HC55018, N01 HC55019, N01 HC55020, N01 HC55021, and N01 HC55022 from the US National Heart, Lung, and Blood Institute. The authors thank the staff and their participants in the ARIC study for their important contributions.
Footnotes
This paper was sent to Ernesto Schiffrin, associate editor, for review by expert referees, editorial decision, and final disposition.
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