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Comparisons of traditional electrocardiographic criteria for left and right ventricular hypertrophy in young Asian women

Abstract The performance of electrocardiographic (ECG) voltage criteria to identify left and right ventricular hypertrophy (LVH and RVH) in young Asian female adults have not been clarified so far. In a sample of 255 military young female adults, aged 25.2 years on average, echocardiographic LVH was respectively defined as the left ventricular mass (LVM) indexed by body surface area (BSA) (≥88 g/m2) and by height2.7 (≥41 g/m2.7), and RVH was defined as anterior right ventricular wall thickness >5.2 mm. The performance of ECG voltage criteria for the echocardiographic LVH and RVH were assessed by area under curve (AUC) of receiver operating characteristic (ROC) curve to estimate sensitivity and specificity. For the Sokolow-Lyon (the maximum of SV1 or SV2 + RV5 or RV6) and Cornell (RaVL + SV3) voltage criteria with the LVM/BSA ≥88 g/m2, the AUC of ROC curves were 0.66 (95% confidence intervals [CI]: 0.52–0.81, P = .039) and 0.61 (95% CI: 0.44–0.77, P = .18), respectively. For these 2 ECG voltage criteria with the LVM/height2.7 ≥41 g/m2.7, the AUC of ROC curves were 0.64 (95% CI: 0.52–0.75, P = 0.11) and 0.73 (95% CI: 0.61–0.85, P = 0.0074), respectively. The best cut-off points selected for the Sokolow-Lyon and Cornell voltage criteria with echocardiographic LVH in young Asian females were 26 mm and 6 mm, respectively. In contrast, all the AUC of ROC curves were less than 0.60 and not significant according to the Sokolow-Lyon (the maximum of RV1 + SV5 or V6) and Myers’ voltage criteria (eg, the voltage of R wave in V1 and the ratios of R/S in V1, V5 and V6) with echocardiographic RVH. There was a suggestion that the ECG voltage criteria to screen the presence of LVH should be adjusted for the young Asian female adults, and with regard to RVH, the ECG voltage criteria were found ineffective.


Introduction
The traditional electrocardiographic (ECG) voltage criteria in screening of the presence of left (LVH) and right ventricular hypertrophy (RVH) in the general population have been used for decades. [1][2][3][4] Most of the previous studies using Sokolow-Lyon and Cornell ECG voltage criteria to relate to LVH which was diagnosed by echocardiography or cardiac magnetic resonance imaging (MRI) showed consistent results that the sensitivity was Editor: Michael Masoomi.
The study was supported by the grant from Hualien Armed Forces General Hospital (No. 805C-109-07).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request. very low, estimated merely 20%-30%, whereas the specificity was extremely high, estimated over 95%. [5,6] Similarly, using the ECG voltage criteria for the imaging-based RVH such as the Myers et al and Sokolow-Lyon revealed low sensitivity, commonly lower than 20% and high specificity which was up to 95% or more. [7,8] It is notable that most studies examining the performance of the ECG voltage criteria to relate to the imaging-based LVH and RVH were carried out in White and Black, and middle to old aged persons of the Western world. [9][10][11][12] For the Asian individuals, the studies reporting the ECG criteria performance were relatively rare, [13][14][15] and in the same situation, most of these studies were aimed for the middle to old aged populations with several cardiovascular risk factors such like hypertension. [13,14] To our knowledge, since there have not established standard references with regard to the echocardiographic or other imaging based LVH or RVH for young Asian adults, only a few ECG studies were carried out to investigate the performance of the ECG voltage criteria in this population, particularly a lack of young Asian female adults so far. [8,15] Military personnel are mainly composed of young adults, who have to receive regular exercise training. They are good samples to set standard references of imaging based LVH and RVH for the young adults. Therefore, the purpose of the study was firstly to clarify the standard references of echocardiographic LVH and RVH and then to examine the performance of ECG voltage criteria in a military young Asian female cohort in Taiwan.

Study population
The ancillary cardiorespiratory fitness and hospitalization events in armed forces (CHIEF) Heart study included 1526 military young female adults, aged 18 to 42 years, in eastern Taiwan in 2014 to 2018. [16] All participants carried out a comprehensive health examination, and self-reported a questionnaire for their experience regarding toxic substances use and physical activity in the Hualien Armed Forces General Hospital of Taiwan. Of these, there were 265 subjects receiving a 12-lead ECG and a transthoracic echocardiography on the same day to ensure their cardiac health for the rank promotions and military awards, which were the inclusion criteria in this study, Those with hypertension (systolic/diastolic blood pressure ≥140/90 mm Hg, or on antihypertensive therapy) or an ECG finding of bundle branch block (n = 10) were excluded, leaving a sample of 255 females for the final analyses. The study design of CHIEF study has been described in detail previously. [17][18][19][20][21] 2.1.1. Measurements of 12-lead surface ECG. All 12-lead surface ECGs (Philips PageWriter Trim III) which were recorded at 25 mm/s paper speed and 1 mV/cm were prospectively performed by an experienced technician (Yu YS). The ECG variables including amplitudes of R and S waves in all limb and precordial leads and were retrospectively validated by 2 welltrained technicians (Yu YS and Lin F) and confirmed by a cardiologist (Lin GM) at the Hualien-Armed Forces General Hospital. For female adults, the Sokolow-Lyon voltage criterion for LVH was defined as the maximum of the amplitude (SV 1 or SV 2 + RV 5 or RV 6 ) ≥35 mm, [1] and the Cornell voltage criterion for LVH was defined as the amplitude (RaVL + SV 3 ) ≥20 mm. [2] In addition, the Sokolow-Lyon voltage criterion for RVH was defined as the maximum of the amplitudes (RV 1 + SV 5 or SV 6 ) > 10.5 mm, [3] and the Myers et al voltage criterion for RVH was defined as the R/S ratio of lead V 1 > 1 or the R/S ratio of lead V 5 or V 6 < 1 or the R amplitude in lead V 1 > 6 mm. [4] 2.1.2. Measurements of transthoracic echocardiography. All procedures of echocardiography using a 1 to 5 MHz transducer (iE33; Philips Medical Systems, Andover, MA) were performed by the same experienced technician (Yu YS) after the ECG and verified by a cardiologist (Lin GM) at the Hualien-Armed Forces General Hospital. All participants were examined using parasternal long-axis and short-axis approaches for the apical four and 2-chamber views in supine and left lateral positions. According to the suggestions of American Society of Echocardiography, [22] quantification of left ventricular wall thickness (interventricular septal and posterior walls) and chamber dimension were measured approximately at the onset of the QRS complex of end diastole and tips of the mitral valve by Mmode and 2-dimensional measurements in parasternal long axis view. Left ventricular mass (LVM) was thus calculated according to the corrected formula proposed by Devereux et al. [23] .04 Â [(left ventricular end diastolic diameter (LVIDd) + end diastolic posterior wall thickness + end diastolic interventricular septal thickness] 3 À left ventricular end diastolic diameter 3 } + 0.6. In addition, LVM was indexed for body surface area (LVM/BSA, g/m 2 ), according to the Dubois formula, [24] and alternatively for height 2.7 (LVM/height 2.7 , g/m 2.7 ) suggested by de Simone et al. [25] The cut-off value for echocardiographic LVH was set as LVM/BSA ≥88 g/m 2 and LVM/height 2.7 ≥41 g/m 2.7 which were the 95th percentile in the military young female adults in CHIEF study and according to another study finding for the young Asian female adults. [26,27] Measurements of anterior right ventricular wall thickness (RVWT) were by M-mode and 2dimensional windows at the onset of the QRS complex of end diastole via the parasternal long-axis approaches. [28] Echocardiographic RVH was defined as RVWT > 5.2 mm, which was the 95th percentile in our young female cohort. [29]

Statistical analysis
Baseline characteristics of the CHIEF military female cohort were expressed as mean ± standard deviation (SD) for continuous variables and number (%) for categorical variables, respectively. Pearson correlation coefficient was used to determine the correlation of each ECG voltage criterion with the LVM indexes and RVWT, and was compared by the Fisher z test. Area under curves (AUC) of the receiver-operating characteristics (ROC) curves were used to evaluate and compare the performance of ECG voltage criteria for echocardiographic LVH and RVH. In addition, using the ROC curve to find the maximal sum of sensitivity and specificity was reclassified for each ECG criterion. A two-tailed value of P < .05 was considered significant. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

Ethic statement.
This study was reviewed and approved by the Institutional Review Board of the Mennonite Christian Hospital (No. 16-05-008) in Taiwan, and written informed consent was obtained from all participants.

Results
The baseline characteristics including ECG and echocardiographic data of the military female cohort are shown in Tables 1 and 2  were no correlations between the Sokolow-Lyon criterion-based voltage (the maximal sum of SV 1 or SV 2 + RV 5 or RV 6 ) and the 2 LVM indexes (r = 0.045 and 0.025, respectively). In addition, there were no correlations between RVWT and each ECG voltage criterion for RVH. The greatest correlation coefficients with RVWT were observed in the Myers' voltage criteria for the R/S ratio in lead 5 or 6 (r = -0.124), and in the Sokolow-Lyon criterionbased voltage (the maximum of RV 1 + SV 5 or SV 6 ) (r = 0.017).

3.2.
Performance of the ECG voltage criteria for LVH and RVH using ROC curves Figure 1A reveals the AUC of ROC curve using the Sokolow-Lyon voltage criterion for LVH ≥35 mm to detect the LVM/BSA index ≥88 g/m 2 higher than that using the Cornell voltage criterion ≥20 mm for LVH (0.66 vs 0.61) in the young Asian females. On the contrary, Figure 1B shows the AUC of ROC curve using the Cornell voltage criterion ≥20 mm for LVH to identify the LVM/height 2.7 index ≥41 g/m 2.7 greater than that utilizing the Sokolow-Lyon voltage criterion ≥35 mm for LVH (0.73 vs 0.64) in the young Asian females. Figure 1C reveals the AUC of ROC curves using the Myers et al and Sokolow-Lyon    Table 4 demonstrates that the prevalence, sensitivity and positive predictive value of the ECG voltage criteria using traditional cut-off values to identify the presence of LVH and RVH in the young Asian females were extremely low, all estimated far less than 20%. In contrast, the specificity and negative predictive value of the ECG voltage criteria to identify the presence of LVH and RVH were extremely high, all estimated much greater than 92% in the young Asian females. When using the AUC of RUC curves to select the best cut-off points for echocardiographic LVH in the young Asian females, the Sokolow-Lyon voltage criterion was

Discussion
Our principal findings were that firstly for the young Asian female adults, we established a standard of echocardiographic LVH as defied by the LVM/BSA index ≥88 g/m 2 and by the LVM/ height 2.7 index ≥41 g/m 2.7 , respectively. In addition, we established a standard of echocardiographic RVH as defined by the RVWT > 5.2 mm. Second, using traditional ECG voltage criteria for LVH and RVH in the young Asian females consistently yielded low sensitivity and high specificity which were in line with the finding of previous studies. Finally, the best cut-off points for the ECG voltage criteria for LVH and RVH in the young Asian females should be lowered to obtain the maximal sum of sensitivity and specificity. It is notable that among the premenopausal women in Asia, the prevalence of metabolic abnormalities such as obesity and hypertension, which are the risk factors of cardiac hypertrophy, is low. [20] In a previous study in Taiwan, the LVM and LVM index were lower in the female adults as compared with the male adults and the values decreased with younger ages. [30] The mean of LVM/ BSA index was 63.6 g/m 2 in women aged 30 years and 67.4 g/m 2 in women aged 31 to 40 years. In addition, in another study for a multiethnic southeast Asian women cohort, [26] those aged <50 years had a mean LVM/BSA index with 64 (standard deviation = 14) g/m 2 and the 95th percentile of the LVM/BSA index was 86 g/m 2 , close to our finding of 88 g/m 2 as the cut-off point for echocardiographic LVH. Moreover, this is the first study clarifying the RVWT > 5.2 mm as echocardiographic RVH for the young Asian females.
As compared with the previous ECG studies for the middleaged females, [14,28] Our findings revealed relevant results that there were low sensitivity and high specificity with regard to using the traditional ECG criteria to identify imaging-based LVH and RVH among the young Asian female adults. These findings were likely due to a very low prevalence of ECG-defined LVH, less than 5% in our subjects, reflecting a need to revise the cut-off values of ECG criteria-defined voltage for LVH. In addition, the correlation coefficients of the Cornell criterion-based voltage were found consistently better than that of the Sokolow-Lyon criterion-based voltage against the two LVM indexes in the young Asian female adults. Unlike the previous study findings for the middle-aged females, [14,31] the AUC of ROC curve was greater for the Sokolow-Lyon voltage criterion to detect the LVM/BSA index ≥88 g/m 2 in the young Asian females, which might be due to a selection of different cut-off value for echocardiographic LVH. On the contrary, neither the Sokolow-Lyon nor the Myers et al criterion-based voltage to correlate with RVWT or to detect echocardiographic RVH was significant in the young Asian female adults. Although the ECG studies for the relationship with RVH in females were rare, the findings in our study were in line with that for males.
Our study had several strengths. First, both the ECG and echocardiographic examinations were performed in a strict manner and the procedures were standardized. Second, the military young females had to participate regular physical training that would modestly increase the level of 95th percentile to define the echocardiographic LVH and RVH compared with that of the age-matched general population of young females and avoid the selection bias. In contrast, this study had some limitations. First, this study was conducted on athletic military young Asian females and thus the results might not be appropriately applied to the general population of young females. Second, the female breast size might be a potential confounder for technicians to put the ECG precordial leads on the standard locations of chests wall, possibly leading to a bias. Third, there might be different results using other imaging diagnostic modalities such as cardiac magnetic resonance imaging for LVH and RVH.

Conclusion
There was a suggestion that the ECG voltage criteria to identify the presence of LVH as defined by echocardiographic LVM indexes should be adjusted for young Asian females, and for RVH as defined by echocardiographic RVWT, the ECG voltage criteria were found ineffective.

Author contributions
Conceptualization: Gen-Min Lin. Data curation: Fang-Ying Su, Yen-Po Lin, Felicia Lin, Henry Horng-Shing Lu, Gen-Min Lin. Table 4 The prevalence, sensitivity, specificity, predictive values and best cut-off point of each electrocardiographic criterion for echocardiographic left ventricular hypertrophy and right ventricular hypertrophy.