Impact of Definitions of Left Ventricular Hypertrophy on Left ...

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 Cherng1 and Ming-Jui Hung1

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 height2.7. Results: In the mild CKD group, LVM indexed to height2.7 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 height2.7 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 = 1.64-6.08, p = 0.001) and LVH indexed by height2.7 (odds ratio = 4.10, 95% confidence interval = 1.27-13.32, p = 0.019). Conclusion: LVH indexed by height2.7 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, 2011 1Departments of Cardiology; 2Nephrology, 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: 886-2-24313131 ext. 3168; Fax: 886-2-2433-5342; E-mail: miran888@ms61. Sources of funding: This study was supported by grant CMRPG 260352 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 population-

based studies in which left ventricular (LV) mass was indexed to body surface area (BSA),4 height5 or height raised to the power of 2.7,5 the allometric growth rate of

Acta Cardiol Sin 2012;28:42-52

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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 ambula-

tory patients aged 18 to 75 years referred to the nephrology 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 m2 [186 ? (serum creatinine)-1.154 ? (age)-0.203 ? (0.742 if female) ? 1.212 (if black)].12 CKD stage 1 was defined as GFR > 90 mL/min/1.73 m2 with structural abnormalities or proteinuria; stage 2 was 60 to 89 mL/min/1.73 m2; stage 3 was 30 to 59 mL/min/1.73 m2; stage 4 was 15 to 29 mL/min/1.73 m2, and stage 5 was GFR < 15 mL/min/ 1.73 m2. A GFR partition value of 60 mL/min/1.73 m2 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 (960409B). 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 50-100 mg or 2) 201thallium myocardial perfusion scanning showing reversible perfusion defects.

Laboratory analysis Blood tests included hematocrit, creatinine, phos-

phorus, 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 experi-

enced 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-

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Acta Cardiol Sin 2012;28:42-52

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 deter-

mined by the formula: 0.8[1.04(LVDD + IVST + PWT)3 - LVDD3] + 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 0.43. This represents the 97.5th 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/m2 for men and 104 g/m2 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 (HT2.7) were 49.2 g/m2.7 for men and 46.7 g/m2.7 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: p/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 (am) and the duration of the S-wave (bm) were measured and used to calculate the myocardial performance index as (am - bm)/bm. 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 (25th, 75th 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 c2 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 study11 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;28:42-52

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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 HT2.7, respectively. The highest prevalence of LVH was found when LVM was indexed to HT2.7. 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)

Age, y Male Body mass index, kg/m2 Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Heart rate, beats/min Current smoker History of diabetes History of hypertension Uncontrolled hypertension Ischemic heart disease Hypercholesterolemia Estimated GFR, mL/min/1.73m2 Hematocrit, % Phosphorus, mg/dL Intact-parathyroid hormone, pg/mL Cholesterol, mg/dL Low-density lipoprotein, mg/dL hsCRP, mg/L Log (hsCRP)

60 (52, 77) 17 (47) 26 ? 3 129 ? 14 73 ? 9 078 ? 10 09 (25) 16 (44) 21 (58) 09 (25) 0 15 (42) 098 ? 29 40 ? 6

03.7 ? 0.5 40 (25, 48) 205 ? 50 129 ? 41 02.9 ? 3.7 00.19 ? 0.50

Data are presented as mean ? SD, number (%), or median (25th, 75th percentiles). GFR, glomerular filtration rate; hsCRP, high-sensitivity C-reactive protein.

70 (63, 76) 46 (65) 26 ? 4 127 ? 12 69 ? 9 075 ? 13 20 (28) 39 (55) 55 (77) 13 (18) 07 (10) 30 (42) 037 ? 23 37 ? 6

04.1 ? 0.8 63 (40, 95) 194 ? 38 123 ? 36 03.5 ? 5.5 00.21 ? 0.56

p value

0.061 0.098 0.903 0.526 0.042 0.247 0.820 0.316 0.045 0.457 0.051 1.000 < 0.001 < 0.006 0.009 < 0.001 < 0.234 0.486 0.515

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Acta Cardiol Sin 2012;28:42-52

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/m2 LVMI, g/m2 LVMI, g/m LVMI, g/m2.7 LVH indexed by BSA LVH indexed by HT LVH indexed by HT2.7 Relative wall thickness LVEDVI, mL/m2 LVESVI, mL/m2 LVEF, % Mitral E, cm/s Mitral A, cm/s Mitral E/A Mitral E deceleration time, ms Pulmonary vein S/D Pulmonary vein AR velocity, cm/s

24 ? 8 100 ? 33 97 (85, 114) 048 ? 16

9 (25) 7 (19) 14 (39) 00.46 ? 0.11 048 ? 11 17 ? 4 63 ? 5 61 (57, 74) 79 (65, 97) 00.86 ? 0.27 235 ? 63 01.4 ? 0.3 35 ? 9

24 ? 9 112 ? 34 116 (91, 138) 054 ? 17 29 (41) 29 (41) 42 (59) 00.44 ? 0.12 049 ? 21 018 ? 10

65 ? 8 75 (62, 89) 099 (86, 116) 00.83 ? 0.34 235 ? 70 01.5 ? 0.4

33 ? 9

0.682 0.081 0.039 0.053 0.136 0.031 0.047 0.467 0.621 0.887 0.391 0.006 < 0.001 < 0.667 0.992 0.237 0.173

Data are presented as mean ? SD, number (%), or median (25th, 75th 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

7.2 ? 1.5

Early diastolic velocity (Em), cm/s

6.1 ? 1.4

Late diastolic velocity (Am), cm/s

9.4 ? 1.6

Em/Am

0.66 ? 0.19

Myocardial performance index

0.57 ? 0.13

IVRT, ms

95 ? 15

LV diastolic function

Normal

7

Impaired relaxation

290

Pseudonormalized filling

0

Restrictive filling

0

Mitral E/Em

11.6 (9.3, 12.9)

Data are presented as mean ? SD, median (25th, 75th percentiles).

IVRT, isovolumic relaxation time.

6.7 ? 1.4 5.5 ? 1.6 9.4 ? 1.8 0.60 ? 0.19 0.61 ? 0.19 110 ? 290

00 58 12 01 13.9 (11.7, 16.3)

0.086 0.076 0.995 0.142 0.247 0.008 < 0.001 <

< 0.001 <

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 HT2.7. 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 HT2.7.

Acta Cardiol Sin 2012;28:42-52

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