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1 Original Article CKD and LVH Acta Cardiol Sin 2012;28:42 52 Cardiac Imaging Impact of Definitions of Left Ventricular Hypertrophy on Left Ventricular Remodeling Findings in Patients with Predialysis Chronic Kidney Disease: An Echocardiographic Study Shih-Jen Chen, 1 Ping-Chang Liu, 1 Ning-I Yang, 1 Chi-Wen Cheng, 1 I-Wen Wu, 2 Mai-Szu Wu, 2 Wen-Jin Cherng 1 and Ming-Jui Hung 1 Background: The impact of different definitions of left ventricular hypertrophy (LVH) on the assessment of left ventricular (LV) remodeling in predialysis chronic kidney disease (CKD) remains unclear. Methods: Echocardiography was performed on 107 consecutively enrolled patients with different stages of CKD including 36 patients mild CKD (CKD stages 1 and 2) and 71 patients with moderate/severe CKD (CKD stages 3, 4, and 5). LVH was defined by the following three sets of sex-specific criteria: left ventricular mass (LVM) indexed to body surface area; LVM indexed to height; and LVM indexed to height 2.7. Results: In the mild CKD group, LVM indexed to height 2.7 detected 14 in 15 LVH patients; however, LVM indexed to BSA and height detected 9 and 7 patients, respectively. In the moderate/severe CKD group, LVM indexed to height 2.7 detected 42 in 43 LVH patients; however, LVM indexed to BSA and height both detected 29 patients. In the moderate/severe CKD group, patients with LVH who fulfilled all three criteria at the same time had lower Em and Am and higher mitral E/Em and isovolumic relaxation time (IVRT) than those patients without LVH. Among patients without LVH, moderate/severe CKD patients had significantly higher mitral E/Em and longer IVRT than in mild CKD. In multivariable regression analysis, the independent predictors of septal E/Em > 15 were CKD severity (odds ratio = 3.16, 95% confidence interval = , p = 0.001) and LVH indexed by height 2.7 (odds ratio = 4.10, 95% confidence interval = , p = 0.019). Conclusion: LVH indexed by height 2.7 could detect most of the LVH in predialysis CKD patients. Key Words: Echocardiography Kidney Left ventricular hypertrophy Remodeling INTRODUCTION Received: November 29, 2010 Accepted: June 28, Departments of Cardiology; 2 Nephrology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Keelung, Taiwan. Address correspondence and reprint requests to: Dr. Ming-Jui Hung, Department of Cardiology, Chang Gung Memorial Hospital at Keelung, No. 222, Maijin Road, Keelung 20401, Taiwan. Tel: ext. 3168; Fax: ; miran888@ms61. hinet.net Sources of funding: This study was supported by grant CMRPG awarded by Chang Gung Memorial Hospital, Keelung, Taiwan. Left ventricular hypertrophy (LVH) is a common structural remodeling in patients with end-stage renal disease, and its presence predicts a poor prognosis. 1,2 The characteristics and predictors of LVH in predialysis chronic kidney disease (CKD), however, have not been fully investigated. 3 Echocardiographic diagnosis of LVH is based on cutoff values developed from populationbased studies in which left ventricular (LV) mass was indexed to body surface area (BSA), 4 height 5 or height raised to the power of 2.7, 5 the allometric growth rate of Acta Cardiol Sin 2012;28:

2 CKD and LVH the heart. Based on recent work by Koren et al. 6 and Ganau et al., 7 the combination of left ventricular mass (LVM) and relative wall thickness (RWT) can now be used to identify different forms of LV geometry. Prospective studies have shown that LV geometric patterns have prognostic implications, with the worst prognosis associated with concentric hypertrophy. 8 The methods for the normalization or indexation of LVM have also recently been shown to confer some prognostic value, especially in the obese population. 9,10 Recently, we found that CKD severity without LVH was associated with elevated LV filling pressure and impaired LV relaxation. 11 The relationships between the different definitions of LVH, LV geometry and LV function require further delineation. This echocardiographic study aimed to investigate the effects of LVH by different definitions on LV structural and functional changes in patients with predialysis CKD. MATERIALS AND METHODS Patients From November 2007 to August 2009, all ambulatorypatientsaged18to75yearsreferredtothenephrology department with mild to severe CKD, defined according to the National Kidney Foundation Kidney Disease Outcome Quality Initiative Clinical Practice Guidelines, 12 were consecutively enrolled in this study. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD)-4 variable equation in ml/min/1.73 m 2 [186 (serum creatinine) (age) (0.742 if female) (if black)]. 12 CKD stage 1 was defined as GFR > 90 ml/min/1.73 m 2 with structural abnormalities or proteinuria; stage 2 was 60 to 89 ml/min/1.73 m 2 ;stage3 was30to59ml/min/1.73m 2 ; stage 4 was 15 to 29 ml/min/1.73 m 2, and stage 5 was GFR < 15 ml/min/ 1.73 m 2. A GFR partition value of 60 ml/min/1.73 m 2 was used to divide patients into two CKD groups (stages 1 and 2, and stages 3 to 5). 12 Patients with any of the following characteristics or conditions were excluded: history of dialysis and/or renal transplant, currently on dialysis, cor pulmonale, congestive heart failure, in atrial fibrillation or using a pacemaker, bundle branch block, prosthetic valves, mitral annulus calcification, severe valvular regurgitation or stenosis, abnormal wall motion, or inadequate echocardiographic images. This study was conducted in accordance with the Helsinki Declaration and was approved by the Institutional Review Board at Chang Gung Memorial Hospital ( B). Written informed consent was obtained from all patients. Clinical data Current smoking status was defined as at least 0.5 pack years and having smoked at least one cigarette within 3 weeks before enrollment. Diabetes mellitus was defined as a fasting glucose level 126 mg/dl or use of hypoglycemic medication. Hypercholesterolemia was defined as a low-density lipoprotein level 160 mg/dl in a fasting sample or use of statin medication. Hypertension was defined as use of anti-hypertensive medications or a blood pressure > 140/90 mmhg. Uncontrolled hypertension was defined as a systolic blood pressure 140 mmhg or a diastolic blood pressure 90 mmhg. Ischemic heart disease was confirmed by 1) coronary angiography: 50% diameter stenosis in 1 coronary vessel after administration of intracoronary nitroglycerin of g or2) 201 thallium myocardial perfusion scanning showing reversible perfusion defects. Laboratory analysis Blood tests included hematocrit, creatinine, phosphorus, lipids and serum immunoreactive intact parathyroid hormone. Serum high-sensitivity C-reactive protein (hscrp) was measured by enzyme-linked immunosorbent assay using purified protein and polyclonal anti-c-reactive protein antibodies (IMMULITE hscrp, Diagnostic Products Corp., Los Angeles, CA). The lower limit of this assay was 0.10 mg/l, with a coefficient of variation 5% at 0.20 mg/l of C-reactive protein. Echocardiography All echocardiograms were performed by two experienced physicians (NY and MJ) who used second harmonic imaging on an ie33 (Philips Medical Systems, Andover, MA) ultrasonography machine with a multifrequency transducer. Images were obtained with patients in the left lateral decubitus position at end-expiration. All standard measurements were obtained from parasternal long- and short-axis views; apical 4-cham- 43 Acta Cardiol Sin 2012;28:42 52

3 Shih-Jen Chen et al. ber, 2-chamber, and long-axis views. Two-dimensional and color Doppler imaging were performed to screen for wall motion abnormalities, mitral annulus calcification, and valvular stenosis or regurgitation. For pulse tissue Doppler study, a 2-mm sampling volume was used from the apical 4-chamber view in the septal mitral annulus. (1) Assessment of cardiac structure: LV mass was determined by the formula: 0.8[1.04(LVDD + IVST + PWT) 3 LVDD 3 ] 0.6 g, where LVDD = left ventricular end-diastolic diameter, IVST = diastolic interventricular septal thickness, and PWT = diastolic posterior wall thickness. 13 RWT was also determined as (2 PWT)/LVDD. Increased RWT was considered to be present when RWT exceeded This represents the 97.5 th percentile in normal subjects. 14 LVH was assessed using various published partition values. Partition values for LVM normalized for body surface area (BSA) were 116 g/m 2 for men and 104 g/m 2 for women. 4 Partition values for LVM indexed for height were 126 g/m for men and 105 g/m for women. 5 Partition values for LVM indexed for the height allometric growth rate of 2.7 (HT 2.7 ) were 49.2 g/m 2.7 for men and 46.7 g/m 2.7 for women. 5 LV geometry was defined as follows: normal geometry, when left ventricular mass index (LVMI) and RWT were normal; concentric remodeling, when LVMI was normal and RWT increased; eccentric hypertrophy, when LVMI was increased but RWT was normal; and concentric hypertrophy, when both LVMI and RWT were increased. 7 The maximal left atrial volume was determined using the prolate-ellipsoid method: /6 (D1 D2 D3), where D1 = anteroseptal dimension measured from the parasternal long-axis view and D2 and D3 are measurements of short- and long-axis in the apical fourchamber view at ventricular end-systole. 15 (2) Assessment of LV ejection fraction: In each patient, measurements of LV ejection fraction were performed by a quantitative 2-dimensional method as previously described. 16 (3) Assessment of LV diastolic function: Transmitral pulsed-wave Doppler velocities were recorded between the tips of the mitral leaflets. Pulsed-wave Doppler velocities of pulmonary venous flow were obtained in the right upper pulmonary vein. Pulse tissue Doppler imaging of the septal mitral annulus was used to measure myocardial velocities in peak systole (Sm) and in early (Em) and late diastole (Am). Diastolic function was categorized as: normal, impaired relaxation, pseudonormalized filling, and restrictive filling. 17 The time interval from the end to the onset of the mitral annular velocity pattern during diastole (a m ) and the duration of the S-wave (b m ) were measured and used to calculate the myocardial performance index as (a m b m )/b m. Isovolumic relaxation time (IVRT) was calculated as the time interval between Sm and Em. (4) Reproducibility: Intra-observer variability was assessed in 10 patients by repeating the measurements on two occasions under the basal conditions. Interobserver variability was assessed using measurements performed offline from video recordings by a second observer who was unaware of the results of the first examination. Variability was calculated as the mean percent error, derived as the difference between the two sets of measurements, divided by the mean of the observations. Statistical analyses Continuous variables with skewed distributions and p values of < 0.05 by Kolmogorov-Smirnov test were presented as medians (25 th,75 th percentiles), and those not skewed were expressed as means standard deviations. For normally distributed continuous variables, twosample unpaired t-test or analysis of variance was performed. For variables with skewed distribution, Wilcoxon rank sum test and the 2 or Fisher s exact test were used. Log transformation of hscrp was used because of the skewed distribution of the control and CKD groups. As our recent study 11 had shown that septal E/Em is better than IVRT to identify moderate/ severe CKD, we used septal E/Em > 15 to perform receiver-operating characteristic curves and multivariate analyses. To identify variables related to an elevated LV filling pressure (septal E/Em > 15), 18 univariable and multivariable logistic regression analyses were performed including baseline clinical characteristics of all CKD patients. Only variables with p < 0.10 in univariable analysis were entered as covariates in the multivariable model. A p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software version 15.0 for Windows (Chicago, IL). Acta Cardiol Sin 2012;28:

4 CKD and LVH RESULTS Clinical and biochemical characteristics A total of 127 patients were recruited in this study, and 20 of these patients were excluded due to incomplete echocardiography or blood test data. The remaining 107 patients (63 men and 44 women) with different stages of CKD were entered into the final analysis. The patients were categorized into mild or moderate/severe CKD groups according to the estimated GFR by the MDRD equation. The mild CKD group comprised 36 patients (CKD stages, 1 and 2) and the moderate/severe comprised 71 patients (CKD stages 3, 4, and 5). The clinical and laboratory characteristics of the two groups are compared in Table 1. Moderate/severe CKD patients had lower diastolic blood pressure and a higher prevalence of hypertension history. However, the systolic blood pressure and prevalence of uncontrolled hypertension were not significantly different between the two groups. No significant differences were found in other cardiac risk factors between the two groups. As expected, moderate/severe CKD patients had higher serum phosphorus and intact parathyroid hormone. Hematocrit level was significantly lower in moderate/severe CKD patients. Echocardiography The conventional echocardiographic parameters of the two groups are compared in Table 2. Compared to mild CKD patients, patients with moderate/severe CKD had significantly higher LVMI and borderline higher LVMI when LVM was indexed to height and HT 2.7,respectively. The highest prevalence of LVH was found when LVM was indexed to HT 2.7. Compared to patients with mild CKD, mitral E and mitral A velocities were higher in patients with moderate/severe CKD; however, the mitral E/A was not significantly different between the two groups. Analysis using pulse tissue Doppler imaging (Table 3) revealed no significant differences in Sm, Em, Am, Em/Am, and myocardial performance index between the mild and moderate/severe CKD groups. However, patients with moderate/severe CKD had significantly longer IVRT, a higher prevalence of LV diastolic dysfunction, and significantly higher mitral E/Em. Table 1. Comparison of clinical and laboratory characteristics between patients with mild and moderate/severe CKD Mild CKD (n = 36) Moderate/severe CKD (n = 71) p value Age, y 60 (52, 77) 70 (63, 76) Male 17 (47) 46 (65) Body mass index, kg/m Systolic blood pressure, mmhg Diastolic blood pressure, mmhg Heart rate, beats/min Current smoker 09 (25) 20 (28) History of diabetes 16 (44) 39 (55) History of hypertension 21 (58) 55 (77) Uncontrolled hypertension 09 (25) 13 (18) Ischemic heart disease 0 07 (10) Hypercholesterolemia 15 (42) 30 (42) Estimated GFR, ml/min/1.73m < < Hematocrit, % Phosphorus, mg/dl Intact-parathyroid hormone, pg/ml 40 (25, 48) 63 (40, 95) < < Cholesterol, mg/dl Low-density lipoprotein, mg/dl hscrp, mg/l Log (hscrp) Data are presented as mean SD, number (%), or median (25 th,75 th percentiles). GFR, glomerular filtration rate; hscrp, high-sensitivity C-reactive protein. 45 Acta Cardiol Sin 2012;28:42 52

5 Shih-Jen Chen et al. Table 2. Comparison of conventional echocardiographic parameters between patients with mild and moderate/severe CKD Mild CKD Moderate/severe CKD p value Left atrial volume index, ml/m LVMI, g/m LVMI, g/m 97 (85, 114) 116 (91, 138) LVMI, g/m LVH indexed by BSA 9 (25) 29 (41) LVH indexed by HT 7 (19) 29 (41) LVH indexed by HT (39) 42 (59) Relative wall thickness LVEDVI, ml/m LVESVI, ml/m LVEF, % Mitral E, cm/s 61 (57, 74) 75 (62, 89) Mitral A, cm/s 79 (65, 97) 099 (86, 116) < < Mitral E/A Mitral E deceleration time, ms Pulmonary vein S/D Pulmonary vein AR velocity, cm/s Data are presented as mean SD, number (%), or median (25 th,75 th percentiles). A, atrial contraction; AR, atrial reversal; BSA, body surface area; D, diastolic; E, rapid filling; EDVI, end-diastolic volume index; EF, ejection fraction; ESV, end-systolic volume index; HT, height; LV, left ventricular; MI, mass index; S, systolic. Table 3. Comparison of pulse tissue Doppler echocardiographic parameters in septal mitral annulus between patients with mild and moderate/severe CKD Mild CKD Moderate/severe CKD p value Systolic velocity (Sm), cm/s Early diastolic velocity (Em), cm/s Late diastolic velocity (Am), cm/s Em/Am Myocardial performance index IVRT, ms LV diastolic function <0.001< Normal 7 00 Impaired relaxation Pseudonormalized filling 0 12 Restrictive filling 0 01 Mitral E/Em 11.6 (9.3, 12.9) 13.9 (11.7, 16.3) < < Data are presented as mean SD, median (25 th,75 th percentiles). IVRT, isovolumic relaxation time. Effect of LV geometry on pulse tissue Doppler echocardiographic parameters To determine the prevalence of LV remodeling in CKD patients, LV remodeling patterns were analyzed using different LVH criteria (Table 4). Compared to mild CKD patients, moderate/severe CKD patients had a significantly higher prevalence of LV remodeling (73% vs. 53%) and LVH (59% vs. 39%) when LVM was indexed to HT 2.7. To further examine the effect of LV remodeling on diastolic function, pulse tissue Doppler parameters were analyzed within and between groups (Table 5). In general, all CKD patients, even those without LV remodeling, had LV diastolic dysfunction as suggested by reduced Em and elevated mitral E/Em. 17 In this study, mild CKD patients with concentric hypertrophy had lower Sm and Am when LVM was indexed to HT 2.7. Acta Cardiol Sin 2012;28:

6 CKD and LVH Table 4. LV geometric patterns according to partition values in the mild and moderate/severe CKD groups Mild CKD Moderate/severe CKD LV geometry BSA HT HT 2.7 BSA HT HT 2.7 No remodeling LV remodeling *52* Concentric remodeling Eccentric hypertrophy Concentric hypertrophy LVH *29* *42* Data are presented as number. * p < 0.05 vs. mild CKD group. BSA, body surface area; HT, height; LV, left ventricular; LVH, left ventricular hypertrophy. Table 5. Effect of different LVH criteria on LV geometry findings of pulse tissue Doppler echocardiography Mild CKD Moderate/severe CKD No remodeling Concentric remodeling Eccentric LVH Concentric LVH p No Concentric remodeling remodeling Eccentric LVH Concentric LVH Sm, cm/s BSA HT HT * * * # * # * * Em, cm/s BSA HT HT * * Am, cm/s BSA HT * * HT * * * * Em/Am BSA HT HT Mitral E/Em BSA * 14 3* HT * HT IVRT, ms BSA * HT HT Within groups: *p < 0.05 and p < 0.01 vs. no remodeling; p < 0.05 and # p = vs. concentric remodeling. Between groups: p < 0.05 and p < 0.01 vs. mild CKD group. Abbreviations as in Tables 3 and 4. p Moderate/severe CKD patients with eccentric hypertrophy had lower Sm, Em, and Am and higher mitral E/Em compared to patients without hypertrophy when LVM was indexed to HT 2.7. When LVM was indexed to BSA and height for patients without LVH, mitral E/Em was higher in the moderate/severe CKD group than in 47 Acta Cardiol Sin 2012;28:42 52

7 Shih-Jen Chen et al. the mild CKD group. When LVM was indexed to HT 2.7 of patients with eccentric LVH, however, mitral E/Em was higher in moderate/severe CKD than in mild CKD. These findings indicate that different LVH criteria provide different information about LV systolic and diastolic function in patients with CKD. Effect of LVH criteria on pulse tissue Doppler echocardiographic parameters To determine the relationship among 3 LVH criteria, we analyzed the prevalence of LVH by three LVH criteria in the mild and moderate/severe CKD groups (Figure 1). In the mild CKD group, LVM indexed to HT 2.7 detected 14 in 15 LVH patients; however, LVM indexed to BSA and height detected 9 and 7 patients, respectively. In the moderate/severe CKD group, LVM indexed to HT 2.7 detected 42 in 43 LVH patients; however, LVM indexed to BSA and height both detected 29 patients. LVH indexed by HT 2.7 could detect most, but not all, of the LVH patients detected by the other two criteria. In addition, 5 patients in mild CKD and 13 patients in moderate/severe CKD turned out to be positive for LVH by sex-specific criterion of LVM indexed to HT 2.7 as compared to LVM indexed to BSA. In these 18 patients, 1, 14, and 3 patients had normal, impaired relaxation and pseudonormalized filling diastolic function, respectively. These findings indicate that use of LVM indexed to HT 2.7 criteria in detecting LVH improves cardiac diastolic function stratification in predialysis CKD management. To determine the effect of LVH criteria on diastolic function, we analyzed pulse tissue Doppler echocardiographic parameters within and between groups (Table 6). In the mild CKD group, patients with LVH fulfilling all three criteria at the same time had higher mitral E/Em than patients without LVH. In the moderate/severe CKD group, patients with LVH fulfilling all three criteria at the same time had lower Em and Am and higher mitral E/Em and IVRT than patients without LVH. Moderate/ severe CKD patients without LVH had significantly higher mitral E/Em and longer IVRT than mild CKD patients without LVH. No significant differences of A Figure 1. Relationships among 3 different LVH criteria in mild CKD (A) and moderate/severe CKD (B) groups. In the mild CKD group, LVM indexed to HT 2.7 (black circle) detected 14 in 15 LVH patients; however, LVM indexed to BSA (dark blue dashed circle) and height (red dashed circle) detected 9 and 7 patients, respectively. In the moderate/severe CKD group, LVM indexed to HT 2.7 detected 42 in 43 LVH patients; however, LVM indexed to BSA and height both detected 29 patients. B Table 6. Association of LVH with pulse tissue Doppler echocardiographic parameters in patients with mild and moderate/severe CKD Mild CKD Moderate/severe CKD No LVH (n = 21) LVH by 1 criterion only or 2 criteria at the same time (n = 8) LVH by all 3 criteria at the same time (n = 7) p No LVH (n = 28) LVH by 1 criterion only or 2 criteria at thesametime (n=16) LVH by all 3 criteria at the same time (n=27) Sm, cm/s Em, cm/s * * ** ** Am, cm/s Em/Am Mitral E/Em *13 3** ** 17 5** * IVRT, ms * Within groups: *p < 0.05 and **p < 0.01 vs. no LVH. Between groups: p < 0.05 and p = vs. mild CKD group. Abbreviations as in Tables 3 and 4. p Acta Cardiol Sin 2012;28:

8 CKD and LVH pulse tissue Doppler echocardiographic parameters were observed between mild CKD with LVH and moderate/ severe CKD without LVH. These findings indicate that fulfilling all three criteria at the same time for LVH tends to have more diastolic dysfunction and LV filling pressure elevation in moderate/severe CKD. Relation of LVH criteria to septal E/Em > 15 in all CKD patients In multivariable regression analysis, the independent predictors of septal E/Em > 15 (a unifying feature of heart failure because of elevated filling pressure) were CKD severity (odds ratio = 3.16, 95% confidence interval = , p = 0.001) and LVH indexed by HT 2.7 (odds ratio = 4.10, 95% confidence interval = , p = 0.019) (Table 7). The more sensitive LVH criteria that predicted the presence of septal E/Em > 15 was LVM indexed to HT 2.7 of > 48 g/m 2.7 by receiver-operating characteristic analysis (area under the curve = , 95% confidence interval = 0.59 to 0.79, p = 0.002) in spite of there being no significant difference among three curves (Figure 2). The sensitivity, specificity, positive predictive, negative predictive, accuracy, positive likelihood ratio, and negative likelihood ratio values for this criteria in detecting septal E/Em > 15 in our cohort were 75%, 57%, 43%, 84%, 62%, 1.76, and 0.84, respectively. Reproducibility Intraobserver and interobserver variabilities were low, with a measured intraobserver variability of 0.7% 2.2% and interobserver variability of 5.8% 10% for mitral E/Em. For LVM, the intraobserver and interobserver variability were 1.2% 3.5% and 3.1% 3.2%, respectively. DISCUSSION This cross-sectional echocardiographic study of Table 7. Multivariable logistic regression analysis for prediction of elevated LV filling pressure (defined as mitral E/Em > 15) in all CKD patients Univariable analysis Multivariable analysis Dependent variable: mitral E/Em > 15 OR (95% CI) p value OR (95% CI) p value Independent variables Age, per 1 y 1.06 ( ) ( ) Male sex 1.68 ( ) BMI, per 1 kg/m ( ) SBP, per 10 mm Hg 0.94 ( ) DBP, per 10 mm Hg 0.52 ( ) ( ) Heart rate, per 10 beats/min 1.24 ( ) Current smoker 1.48 ( ) History of diabetes 2.80 ( ) ( ) History of hypertension 1.68 ( ) Uncontrolled hypertension 1.95 ( ) Ischemic heart disease 0.37 ( ) Hypecholesterolemia 1.08 ( ) CKD, per 1 stage 3.02 ( ) < < 3.16 ( ) Hematocrit, per 1% 1.68 ( ) Phosphorus, per 1 mg/dl 1.67 ( ) ( ) I-PTH, per 1 pg/ml 1.00 ( ) LDL, per 30 mg/dl 0.84 ( ) hscrp, per 1 mg/l 1.10 ( ) ( ) LVH indexed by BSA 1.65 ( ) LVH indexed by HT 1.55 ( ) LVH indexed by HT ( ) ( ) Abbreviations as in Tables 1 and Acta Cardiol Sin 2012;28:42 52

9 Shih-Jen Chen et al. Figure 2. ROC curve analysis set to identify mitral E/Em > 15 by three different LVH criteria. The cutoff value for LVH indexed by HT 2.7 (solid line) to differentiate the presence of E/Em >15 was 48 g/m 2.7, with sensitivity and specificity rates of 75% and 57%, respectively. The area under the curve = , p = For LVH indexed by HT (large dashed line), the best cutoff value was 122 g/m, with sensitivity and specificity rates of 41% and 69%, respectively. The area under the curve = , p = For LVH indexed by BSA (small dashed line), the best cutoff value was 122 g/m 2, with sensitivity and specificity rates of 44% and 68%, respectively. The area under the curve = , p = No significant differences existed among the three curves. predialysis CKD patients had two main findings: 1) fulfillment of all three LVH criteria at the same time provided better assessment of the effects of LVH on diastolic function and E/Em ratios, suggestive of LV filling pressure in patients with moderate/severe CKD; 2) CKD severity alone was positively associated with impaired LV relaxation and increased E/Em ratios, suggestive of elevation of filling pressure. LVH criteria Using the criteria of LVM normalized to HT 2.7,LVH was identified in about one-half of our whole study population. In addition, when indexed to BSA, LVH was identified in 39% of patients with normal LVM. The association between LVH and subclinical vascular and renal damage is clinically relevant, as microalbuminuria and carotid artery intima-media thickening or plaques are associated with an increased risk of fatal and nonfatal cardiovascular events. 19,20 The use of comprehensive echocardiographic detection criteria for LVH is therefore an important issue as it may provide more information about subtle but prognostically adverse LV structural adaptations secondary to hypertension, obesity, and CKD. The Strong Heart study, 9 which included 2400 American Indians from 13 US communities with a high prevalence of cardiometabolic risk factors, found that echocardiographic LVH detection by LVM/HT 2.7 (i.e. > 49.2/46.7 g/m 2.7 in male and female patients, respectively) led to a higher prevalence (27.6% vs. 10.5%) than that defined by LVM/BSA (i.e. > 116/104 g/m 2 ). Cuspidietal. 21 also found a progressive increase in subclinical organ damage at the carotid, renal, and retinal levels in patients with a positive LVH indexed to HT 2.7 only and in patients with a positive LVH indexed tobothbsaandht 2.7 as compared to patients without LVH. Consistent with these reports, the present study found a higher prevalence of LVH patients with moderate/severe CKD compared with mild CKD when the LVM was indexed to HT 2.7. Furthermore, our study showed that when LVM indexed to HT 2.7 detected all LVH but 1 patient in each group when LVM indexed to BSA or HT. When we defined LVH with a more complete set of all three criteria, such that definite LVH patients were included, the association of LVH with LV diastolic function and LV filling pressure became significant. In other words, more subclinical extrarenal cardiac damage was identified when we used more comprehensive LVH diagnostic criteria. These findings indicate that the use of two or three criteria in detecting LVH and may improve cardiac function stratification in CKD management. Accordingly, the use of more comprehensive LVH criteria is suggested to provide better assessment of LV function for predialysis CKD patients. LV function and CKD LV diastolic dysfunction is also associated with CKD patients with LVH who are not undergoing dialysis. 22 A recent study demonstrated that CKD patients had worse diastolic function compared with essential hypertension patients, even in the absence of LVH. 23 In addition, LV systolic asynchrony is also more prevalent in CKD patients. 24 A recent study showed that CKD is associated with worse diastolic function, intracardiac conduction, and prognosis in patients with heart failure; the negative impact on cardiovascular outcome is likely to be stronger in patients with diastolic heart failure. 25 In the present study, moderate/severe CKD patients showed more pronounced LV diastolic dysfunction than Acta Cardiol Sin 2012;28:

10 CKD and LVH did patients with mild CKD, as demonstrated by LV filling pattern and IVRT, without significant impairment of LV systolic function. Patients with moderate/severe CKD without LVH still demonstrated significantly higher LV filling pressure and longer IVRT than did mild CKD patients without LVH. Therefore, CKD severity alone was associated with LV filling pressure elevation and diastolic dysfunction in patients with predialysis moderate/severe CKD. Using more comprehensive criteria for LVH, the within-group analysis showed lower Em, higher mitral E/Em, and longer IVRT in moderate/severe CKD patients with LVH than in those without LVH. In contrast, only higher mitral E/Em was found in mild CKD patients with LVH using the same criteria. This indicates that LVH has a strong positive association with LV relaxation and filling pressure in moderate/severe CKD but is only significantly associated with LV filling pressure in mild CKD. Hemodynamically, elevation of filling pressure is a unifying feature of heart failure regardless of the underlying cause. As LV filling pressure increases, mitral E/Em ratio rises. When Em is obtained from the septal mitral annulus, E/Em > 15 usually indicates pulmonary capillary wedge pressure > 20 mmhg. 18 Wang et al. 26 found that increased LV filling pressure of patients with end-stage renal disease may be partly attributed to extracellular volume expansion. Extracellular fluid excess is also found in the early stages of CKD and it correlated with mitral E/Em. 27 The extracellular fluid excess is an independent determinant of cardiovascular remodeling. This indicates that LV filling pressure is elevated in predialysis CKD and early therapeutic control of extracellular fluid could reduce cardiovascular events in CKD patients. In addition, LVH contributes to an increased LV filling pressure in end-stage renal disease. 26 BasedonhigherprevalenceofLVHandelevation of LV filling pressure in patients with CKD, 3,26-29 it is suggested that both treatment of LVH and control of volume overload are important in CKD management. It is conceivable that drugs affecting myocardial fibrosis (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) may be of interest to slow the progression of cardiac remodeling in CKD. Further studies using pulse-wave flow velocity Doppler or tissue Doppler echocardiography are needed to clarify these points. 30,31 Study limitation Since there is a trade-off between sensitivity and specificity, it is possible that using a more comprehensive criteria-defined LVH for detecting diastolic dysfunction and LV filling pressure elevation will compromise the sensitivity in LVH diagnosis. Because LVH is important with respect to clinical outcomes in CKD patients, additional studies in Taiwan are needed to elucidate the role of LVH criteria in outcomes of CKD patients. CONCLUSION This study found that LVH identified with more comprehensive criteria was associated with impaired LV diastolic function and increased E/Em ratios, suggestive of elevation of LV filling pressure in moderate/severe CKD. CKD severity alone was associated with impaired LV relaxation and increased E/Em ratios, suggestive of elevation of LV filling pressure. These findings provide more information with which to judge the degree of cardiovascular involvement in predialysis CKD patients and may be used to tailor aggressive management. ACKNOWLEDGEMENTS We would like to thank all the investigators and coordinators of this study and all the medical and nursing staff involved in the recruitment of subjects. REFERENCES 1. Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 1995;47: Zoccali C, Benedetto FA, Mallamaci F, et al. Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression. Kidney Int 2004;65: Nardi E, Palermo A, Mule G, et al. Left ventricular hypertrophy and geometry in hypertensive patients with chronic kidney disease. J Hypertens 2009;27: Devereux RB, Dahlof B, Levy D, Pfeffer MA. Comparison of enalapril versus nifedipine to decrease left ventricular hypertrophy in systemic hypertension (the PRESERVE trial). Am J 51 Acta Cardiol Sin 2012;28:42 52

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