Gender-Adjustment and Cutoff Values of Cornell Product in Hypertensive Japanese Patients
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1 CLINICAL STUDY Gender-Adjustment and Cutoff Values of Cornell Product in Hypertensive Japanese Patients Joji Ishikawa, 1 MD, Yuko Yamanaka, 2 MD, Ayumi Toba, 1 MD, Shintaro Watanabe, 3 MD and Kazumasa Harada, 1 MD Summary In the Japanese population, the electrocardiographic (ECG) Cornell voltage and product predict cardiovascular events at lower values (Cornell voltage of 2.04 mv in males and 1.71 mv in females, and Cornell product of mv msec) than in the guidelines (2.8 mv, 2.0 mv, and 244 mv msec, respectively). We evaluated the ECG criteria for left ventricular hypertrophy (LVH) corresponding to echocardiographic LVH (Echo-LVH) in Japanese patients. We reviewed data on 345 consecutive hypertensive patients who underwent echocardiography, and evaluated the Cornell voltage (S in leads V3 + R in leads avl), Cornell product [(Cornell voltage mv for females) QRS duration], and left ventricular mass index (LVMI) (Echo-LVH: LVMI 116 g/m 2 in males and 96 g/m 2 in females). The mean age was 63.8 ± 12.5 years (174 males/172 females). Echo-LVH was found in 22.7% of males and 37.2% of females. The equations for estimating LVMI from the Cornell voltage were (1) LVMI = 14.5 Cornell voltage for males and (2) LVMI = 21.5 Cornell voltage for females. The Cornell voltage corresponding to Echo-LVH was 2.6 mv in males and 1.6 mv in females, which were below the guideline levels and close to the values indicating cardiovascular risk. The equation for estimating LVMI from the Cornell product was LVMI = 0.15 Cornell product The Cornell product corresponding to Echo-LVH was 170 mv msec (sensitivity: 0.730, specificity: 0.601), which was also close to the cardiovascular risk level. Cornell voltage and product values indicating Echo-LVH are lower than those in the current guidelines and closer to the cardiovascular risk levels. (Int Heart J 2017; 58: ) Key words: Cornell voltage, Sokolow-Lyon voltage, Electrocardiogram, Left ventricular hypertrophy Subjects with left ventricular hypertrophy (LVH) have an increased risk of cardiovascular events and stroke. 1-3) The 2014 Japanese Society of Hypertension (JSH) guidelines recommend evaluation of the Sokolow-Lyon voltage, Cornell voltage, and Cornell product. 4) In our previous study performed in a general Japanese population, 3) subjects with these ECG criteria for LVH (ECG-LVH) had an increased risk of cardiovascular events and stroke, but the values of the Cornell voltage, Cornell product, and Sokolow-Lyon voltage at which cardiovascular events increased were below the cutoff levels in western populations 1,5,6) and in the 2014 JSH guidelines. 4) A cohort study performed in Singapore also suggested that Asian populations might have different ECG- LVH cutoff levels for detecting anatomical LVH, 7) and the ECG-LVH was associated with an increased risk of cardiovascular events. 8) In the present study, we evaluated whether gender adjustment of the Cornell product was appropriate in hypertensive Japanese patients, and also determined the level of ECG-LVH corresponding to anatomical (echocardiographic) LVH. Methods Subjects: We reviewed echocardiography data obtained when screening consecutive hypertensive outpatients for target organ damage at Sano Kosei General Hospital between January 2010 and June There were 345 sets of echocardiographic and ECG data, including annual follow-up data. The exclusion criteria were as follows: (1) significant arrhythmia, (2) complete left or right bundle branch block, (3) were unable to obtain or unclear echocardiographic images, (4) a history of ischemic heart disease, and (5) asynergy of left ventricular wall motion. ECG measurement and interpretation: The ECG was recorded using an automated 12-lead ECG monitor (Fukuda Denshi, Inc., Tokyo, Japan). This monitor auto- From the 1 Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 2 Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi and 3 Department of Cardiology, Sano Kosei General Hospital, Tochigi, Japan. Address for correspondence: Joji Ishikawa, MD, Department of Cardiology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo , Japan. joji_ishikawa@tmghig.jp or george@jichi.ac.jp Received for publication November 14, Revised and accepted February 24, Released in advance online on J-STAGE November 22, doi: /ihj All rights reserved by the International Heart Journal Association. 933
2 934 Ishikawa, ET AL November 2017 Table. Characteristics of the Patients Variable Age, years 63.8 ± 12.5 Male, % 50.3 Body mass index, g/m ± 4.2 Systolic blood pressure, mmhg ± 23.7 Diastolic blood pressure, mmhg 85.0 ± 14.8 Pulse rate, beat/minute 72.2 ± 11.9 Antihypertensive drug use, % 69.3 Calcium channel blockers, % 55.2 Angiotensin converting enzyme inhibitors or Angitotensin II receptor blockers, % 48.1 Diuretics, % 12.2 Beta blockers, % 12.2 Alpha blockers, % 3.2 Current smokers, % 15.6 Regular alcohol drinkers, % 37.0 Diabetes, % 13.3 Diabetic drug use, % 8.7 Dyslipidemia, % 41.2 Statin use, % 20.9 Data are shown as mean ± standard deviation or percentage. matically measured the QRS duration, S in leads V1, and R in lead V5 (Sokolow-Lyon criteria), while R in lead avl and S in lead V3 (i.e., Cornell voltage) were measured manually. Then the Cornell product was calculated as Cornell voltage (+ 0.6 mv in females) QRS duration. A Cornell voltage 2.8 mv in males and 2.0 mv in females, Cornell product 244 mv msec, or Sokolow- Lyon voltage 3.5 mv were defined as diagnosing ECG- LVH in the 2014 JSH Guidelines for the Management of Hypertension, 4) while a Cornell product 244 mv msec and Sokolow-Lyon voltage 3.8 mv were used to diagnose ECG-LVH in the Losartan Intervention For Endpoint Reduction in Hypertension Study. 5) Echocardiography: The first author performed most of the echocardiography examinations using an Altida (Toshiba, Japan) with a 3.5-MHz transducer. The absence of apparent asynergy of LV wall motion was confirmed in all patients. Two-dimensional B-mode images were recorded according to the guidelines of the American Society of Echocardiology. 9,10) Then LV mass was calculated by the following formula: [(IVS + LVID + PW) 3 -(LVID) 3 ] 0.6, where IVSd is the diastolic interventricular septal diameter, LVDd is the diastolic LV dimension, and PWd is the diastolic posterior wall diameter. LVMI was calculated as LV mass divided by body surface area. The mean inter-observer difference of LVMI was 6.6 ± 19.5 g/ m 2. Informed consent: The institutional review board of Sano Kosei General Hospital approved this study. We did not obtain written informed consent because this was a retrospective analysis of routine clinical data. Statistical analysis: Results are shown as the mean ± SD for continuous variables or as percentages for categorical variables. Relations between electrocardiographic measures of LVH and LVMI were evaluated by calculating Pearson s correlation coefficients. The predictive value of ECG-LVH for echocardiographic LVH (Echo-LVH) was determined by receiver operating characteristics (ROC) analysis with calculation of the area under the curve (AUC). SPSS statistical software (version 18.0, Chicago, IL, USA) was used for all analyses and P < 0.05 was considered to be statistically significant. Results Subjects: The characteristics of the subjects (n = 346) are shown in the Table. The mean age was 63.8 ± 12.5 years (174 males/172 females). There were 39 males (22.7%) and 64 females (37.2%) with Echo-LVH. Relationship of the Cornell voltage to LVMI in males and females: Scatter plots of the relation between the Cornell voltage and LVMI are shown in Figures 1A (males), 1B (females). According to linear regression analysis, the equations for estimating LVMI from the Cornell voltage are as follows: (1) LVMI = 14.5 Cornell voltage in males and (2) LVMI = 21.5 Cornell voltage in females. The voltage corresponding to Echo-LVH (LVMI 116 g/m 2 in males and 96 g/m 2 in females) was 2.6 mv in males and 1.6 mv in females. Sensitivity and specificity at different cutoff Cornell voltages are shown in Figures 2A (males), 2B (females). The cutoff levels listed in the 2014 guidelines of the JSH (2.8 mv in males and 2.0 mv in females) 4) showed high sensitivity, but very low specificity. Relationship of the Sokolow-Lyon voltage to LVMI in males and females: Scatter plots of the relation between the Sokolow-Lyon voltage and LVMI are shown in Figure 1C (males) and 1D (females). According to linear regression analysis, the equations for estimating LVMI from the Sokolow-Lyon voltage are as follows: (1) LVMI = 12.2 Sokolow-Lyon voltage in males and (2) LVMI = 13.1 Sokolow-Lyon voltage in females. The voltage corresponding to Echo-LVH was 3.8 mv in males and 2.8 mv in females. Although cardiovascular risk levels of the Sokolow-Lyon voltage (i.e., 3.0 mv) were lower than the 2014 guideline levels of the JSH (i.e., 3.5 mv), 3) these relationships to the Sokolow-Lyon voltage corresponding to Echo-LVH were inconsistent between males and fe-
3 November 2017 CORNELL VOLTAGE AND PRODUCT FOR Echo-LVH 935 Figure 1. A: Scatter plot of Cornell voltage and LVMI in males. The regression line was LVMI = 14.5 (Cornell voltage) , r = 0.309, P < A Cornell voltage of 2.0 mv (cardiovascular risk) estimates an LVMI of 108 g/m 2 and a Cornell voltage of 2.8 mv (guideline value) estimates an LVMI of 120 g/m 2. B: Scatter plot of Cornell voltage and LVMI in females. The regression line was LVMI = 21.5 (Cornell voltage) , r = 0.523, P < A Cornell voltage of 1.7 mv (cardiovascular risk) estimates an LVMI of 98 g/m 2 and a Cornell voltage of 2.0 mv (guideline value) estimates an LVMI of 105 g/m 2. C: Scatter plot of Sokolow-Lyon voltage and LVMI in males. The regression line was LVMI = 12.2 (Sokolow-Lyon voltage) , r = 0.365, P < A Cornell voltage of 3.0 mv (cardiovascular risk) estimates an LVMI of g/m 2 and a Cornell voltage of 3.5 mv (guideline value) estimates an LVMI of g/m 2. D: Scatter plot of Sokolow-Lyon voltage and LVMI in females. The regression line was LVMI = 13.1 (Sokolow-Lyon voltage) , r = 0.364, P < A Cornell voltage of 3.0 mv (cardiovascular risk) estimates an LVMI of 99.0 g/m 2 and a Cornell voltage of 3.5 mv (guideline value) estimates an LVMI of g/m 2. males. Gender adjustment of the Cornell product: AUCs obtained for detecting Echo-LVH with different genderadjusted values of the Cornell product are shown in Figure 3. The AUC for the unadjusted Cornell product was and it increased to for the gender-adjusted Cornell product (0.6 mv added to Cornell voltage in females). There was a small increase of the AUC using adjusted values of mv. Relationship of the Cornell product to LVMI: Based on the scatter plot in Figure 4, the equation for estimating LVMI from the gender-adjusted Cornell product is as follows: LVMI = 0.15 Cornell product According to ROC analysis (Figure 5), the optimum value of the Cornell product for predicting Echo-LVH was 170 mv msec (sensitivity: 0.730, specificity: 0.601). Discussion The present study showed that the Cornell voltage and product values in the current 2014 JSH guidelines (a Cornell voltage of 2.8 mv in males and 2.0 mv in females or a Cornell product of 244 mv msec) 4) have a high specificity for detecting Echo-LVH in hypertensive Japanese patients, but have a very low sensitivity. The ECG-LVH values corresponding to Echo-LVH (anatomical LVH) in the present study were a Cornell voltage of 2.6 and 1.6 mv (i.e., an LVMI of 116 g/m 2 for males and 96 g/m 2 for females, respectively), which were lower than the values in the guidelines and closer to those reported to in-
4 936 Ishikawa, ET AL November 2017 Figure 2. A: Receiver operating characteristics analysis curve of the Cornell voltage for detecting Echo-LVH (LVMI > 116 g/m 2 ) in males. B: Receiver operating characteristics analysis curve of the Cornell voltage for detecting Echo-LVH (LVMI > 116 g/m 2 ) in females. Figure 3. Area under the curve (AUC) for detecting Echo-LVH with the Cornell product using different gender adjustment values. Echo-LVH was defined as LVMI > 116 g/m 2 in males and LVMI > 96 g/m 2 in females. dicate an increased risk of cardiovascular events and stroke (i.e., a Cornell voltage of 2.04 mv in males and 1.71 mv in females or a Cornell product of mv msec). 3) Gender adjustment of the Cornell product (by adding 0.6 mv to the Cornell voltage in females) improved detection of Echo-LVH in our study population of hypertensive Japanese patients. Our findings suggested that the cutoff values for ECG-LVH should be lower than those in the current Japanese guidelines. A previous meta-analysis has shown that ECG-LVH Figure 4. Scatter plot of the Cornell product versus LVMI. The regression line was LVMI = 0.15 (Cornell product) , r = 0.409, P < A Cornell product of 159 mv msec (cardiovascular risk) estimates an LVMI of 93 g/m 2 and a product of 244 mv msec (guideline value) estimates an LVMI of 105 g/m 2. is a poor predictor of Echo-LVH (sensitivity of % and specificity of 89-99%), 11) and similar results were obtained in a study that evaluated LVH using cardiac MRI. 12) The results of this study performed in Japan supported these reports from western countries. On the other hand, racial differences of Cornell values were reported between white and African American populations, 13) or between white and Singaporean populations. 7) Additionally, the Cornell voltages detecting Echo-LVH in Korean patients
5 November 2017 CORNELL VOLTAGE AND PRODUCT FOR Echo-LVH 937 Conclusion The sensitivity of the Cornell voltage and Cornell product values recommended by the 2014 JSH guidelines was very low in hypertensive Japanese patients. Thus, these ECG-LVH criteria did not correspond to Echo-LVH. In addition, Cornell voltage and product values indicating cardiovascular risk were lower than those in the JSH guidelines or those reported in western populations, suggesting that lower Cornell cutoff values for ECG-LVH may be more appropriate in Japanese patients. Disclosures Conflicts of interest: None. Figure 5. Receiver operating characteristics analysis curves of different ECG-LVH criteria for detecting Echo-LVH. Echo-LVH was defined as LVMI > 116 g/m 2 and LVMI > 96 g/m 2 in females. (2.0 mv in males and 1.6 mv in females) 14) were similar to those indicating cardiovascular risk in the general Japanese population. To our knowledge, this was the first study, in a Japanese population, that showed the levels of Cornell voltages and product to estimated anatomical LVH. It was reported that ECG-LVH predicts future cardiovascular events without predicting Echo-LVH (anatomical LVH), 15) suggesting that these two types of LVH might be slightly different risk markers. Because LVH involves both enlargement of cardiomyocytes and interstitial fibrosis, electronic and anatomical hypertrophy would not necessarily be identical. Therefore, it might be better to set cutoff values for ECG-LVH so as to detect cardiovascular risk, rather than set values corresponding to anatomical LVH. Limitations: This study was performed at a single center and most of the echocardiography studies were performed by the first author. Accordingly, the results should be confirmed by a multicenter study using cardiac CT or MRI. Additionally, LVMI could be affected by age, gender, body mass index, systolic blood pressure, antihypertensive drug use, and alcohol intake. 16) References 1. Okin PM, Devereux RB, Jern S, et al. LIFE Study Investigators. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA 2004; 292: Ishikawa J, Ishikawa S, Kabutoya T, et al. for the Jichi Medical School Cohort Study Investigators G. Cornell product left ventricular hypertrophy in electrocardiogram and the risk of stroke in a general population. Hypertension 2009; 53: Ishikawa J, Ishikawa S, Kario K. Levels of cornell voltage and cornell product for predicting cardiovascular and stroke mortality and morbidity in the general Japanese population. Circ J 2014; 78: Shimamoto K, Ando K, Fujita T, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res 2014; 37: Okin PM, Devereux RB, Gerdts E, et al. LIFE Study Investigators. Impact of diabetes mellitus on regression of electrocardiographic left ventricular hypertrophy and the prediction of outcome during antihypertensive therapy: the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study. Circulation 2006; 113: Schillaci G, Battista F, Pucci G. A review of the role of electrocardiography in the diagnosis of left ventricular hypertrophy in hypertension. J Electrocardiol 2012; 45: (Review). 7. Xu CF, Tan ES, Feng L, et al. Electrocardiographic criteria for left ventricular hypertrophy in Asians differs from criteria derived from western populations community-based data from an Asian population. Ann Acad Med Singapore 2015; 44: Santhanakrishnan R, Wang N, Larson MG, et al. Racial differences in electrocardiographic characteristics and prognostic significance in whites versus Asians. J Am Heart Assoc 2016; 5: e Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two- Dimensional Echocardiograms. J Am Soc Echocardiogr 1989; 2: (Review). 11. Pewsner D, Juni P, Egger M, Battaglia M, Sundström J, Bachmann LM. Accuracy of electrocardiography in diagnosis of left ventricular hypertrophy in arterial hypertension: systematic review. BMJ 2007; 335: 711. (Review). 12. Jain A, Tandri H, Dalal D, et al. Diagnostic and prognostic utility of electrocardiography for left ventricular hypertrophy defined by magnetic resonance imaging in relationship to ethnicity: the Multi-Ethnic Study of Atherosclerosis (MESA). Am Heart J 2010; 159: Okin P, Wright J, Nieminen MS, et al. Ethnic differences in electrocardiographic criteria for left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint. Am J Hypertens 2002; 15: Park JK, Shin JH, Kim SH, et al. A comparison of cornell and sokolow-lyon electrocardiographic criteria for left ventricular hypertrophy in korean patients. Korean Circ J 2012; 42:
6 938 Ishikawa, ET AL November Sundström J, Lind L, Arnlöv J, Zethelius B, Andrén B, Lithell HO. Echocardiographic and electrocardiographic diagnoses of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men. Circulation 2001; 103: Yoshimura A, Adachi H, Hirai Y, et al. Serum uric acid is associated with the left ventricular mass index in males of a general population. Int Heart J 2014; 55:
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