Download Impact of Definitions of Left Ventricular Hypertrophy on Left

CKD and LVH
Original Article
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
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
Received: November 29, 2010 Accepted: June 28, 2011
1
Departments 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.
hinet.net
Sources of funding: This study was supported by grant CMRPG
260352 awarded by Chang Gung Memorial Hospital, Keelung, Taiwan.
Acta Cardiol Sin 2012;28:42-52
42
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.
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 ³ 126 mg/dL or use of
hypoglycemic medication. Hypercholesterolemia was
defined as a low-density lipoprotein level ³ 160 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 ³
140 mmHg or a diastolic blood pressure ³ 90 mmHg.
Ischemic heart disease was confirmed by 1) coronary
angiography: ³ 50% diameter stenosis in ³ 1 coronary
vessel after administration of intracoronary nitroglycerin
of 50-100 mg or 2) 201 thallium myocardial perfusion
scanning showing reversible perfusion defects.
MATERIALS AND METHODS
Patients
From November 2007 to August 2009, all ambulatory 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,
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-cham43
Acta Cardiol Sin 2012;28:42-52
Shih-Jen Chen et al.
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.
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 - 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
Acta Cardiol Sin 2012;28:42-52
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).
44
CKD and LVH
RESULTS
phosphorus and intact parathyroid hormone. Hematocrit
level was significantly lower in moderate/severe CKD
patients.
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
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
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)
Mild CKD (n = 36)
Moderate/severe CKD (n = 71)
p value
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
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
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
Data are presented as mean ± SD, number (%), or median (25th, 75th percentiles).
GFR, glomerular filtration rate; hsCRP, high-sensitivity C-reactive protein.
45
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
2
Left atrial volume index, mL/m
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
Mild CKD
Moderate/severe CKD
p value
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
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
Normal
Impaired relaxation
Pseudonormalized filling
Restrictive filling
Mitral E/Em
Mild CKD
Moderate/severe CKD
p value
7.2 ± 1.5
6.1 ± 1.4
9.4 ± 1.6
0.66 ± 0.19
0.57 ± 0.13
95 ± 15
6.7 ± 1.4
5.5 ± 1.6
9.4 ± 1.8
0.60 ± 0.19
0.61 ± 0.19
110 ± 290
0.086
0.076
0.995
0.142
0.247
0.008
< 0.001 <
7
290
0
0
11.6 (9.3, 12.9)
00
58
12
01
13.9 (11.7, 16.3)
< 0.001 <
Data are presented as mean ± SD, median (25 , 75 percentiles).
IVRT, isovolumic relaxation time.
th
th
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 HT 2.7 .
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
Acta Cardiol Sin 2012;28:42-52
46
CKD and LVH
Table 4. LV geometric patterns according to partition values in the mild and moderate/severe CKD groups
Mild CKD
LV geometry
Moderate/severe CKD
2.7
BSA
HT
HT
19
17
08
04
05
09
19
17
10
02
05
07
17
19
05
04
10
14
No remodeling
LV remodeling
Concentric remodeling
Eccentric hypertrophy
Concentric hypertrophy
LVH
BSA
HT
HT2.7
27
44
15
14
15
29
28
43
14
13
16
*29*
19
*52*
10
21
21
*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
No
Concentric Eccentric
remodeling remodeling
LVH
Sm, cm/s
BSA
HT
HT2.7
Em, cm/s
BSA
HT
HT2.7
Am, cm/s
BSA
HT
HT2.7
Em/Am
BSA
HT
HT2.7
Mitral E/Em
BSA
HT
HT2.7
IVRT, ms
BSA
HT
HT2.7
7.3 ± 1.3
7.2 ± 1.2
7.2 ± 1.2
7.5 ± 2.3
7.6 ± 2.2
*9.1 ± 2.1*
6.4 ± 1.7
6.4 ± 1.7
6.4 ± 1.8
6.0 ± 0.9
5.8 ± 0.9
5.7 ± 0.4
0.6 ± 0.1
0.6 ± 0.1
0.5 ± 0.1
11 ± 20
11 ± 20
11 ± 20
10 ± 20
11 ± 30
10 ± 30
92 ± 14
94 ± 16
96 ± 15
97 ± 17
96 ± 15
95 ± 14
p
Concentric
LVH
No
Concentric
remodeling remodeling
Eccentric
LVH
7.2 ± 0.9
6.3 ± 0.8
0.610
6.8 ± 0.0
6.3 ± 0.8
0.485
6.9 ± 0.3 *#6.2 ± 0.7*# 0.002
6.9 ± 1.4
6.8 ± 1.4
7.2 ± 1.3
6.9 ± 1.1
6.3 ± 0.9
6.7 ± 1.2
6.3 ± 1.0
§
7.0 ± 1.1§ *6.2 ± 1.1*
6.0 ± 1.2
6.5 ± 1.6
6.6 ± 1.0
5.6 ± 1.3
5.7 ± 1.2
6.0 ± 1.0
6.2 ± 1.7
5.1 ± 2.0
5.9 ± 1.1
5.0 ± 2.1
6.3 ± 1.1 *‡5.0 ± 1.8*‡
5.1 ± 0.9
5.1 ± 0.9
5.6 ± 1.2
0.368
0.277
0.389
8.7 ± 1.8
8.7 ± 1.8
‡
8.9 ± 1.3‡
0.471
0.407
0.029
0.6 ± 0.1
0.7 ± 0.3
0.7 ± 0.2
0.6 ± 0.1
0.6 ± 0.1
0.6 ± 0.1
0.408
0.281
0.148
13 ± 2‡0
13 ± 30
11 ± 30
*‡14 ± 3*‡0
14 ± 3*
12 ± 30
0.023
0.090
0.492
98 ± 15
87 ± 40
84 ± 15
102 ± 190
102 ± 190
100 ± 180
0.575
0.644
0.391
9.2 ± 1.6 10.0 ± 1.60 9.8 ± 1.3
9.2 ± 1.6 10.1 ± 1.40 9.5 ± 1.2
9.0 ± 1.6 *11.2 ± 1.1*0 9.9 ± 1.3
0.7 ± 0.2
0.7 ± 0.2
0.7 ± 0.2
Moderate/severe CKD
‡
9.6 ± 1.8 9.6 ± 1.7
9.7 ± 1.8 9.2 ± 1.6
10.0 ± 1.70 9.8 ± 1.3
Concentric
LVH
p
6.4 ± 1.7
6.4 ± 1.7
6.5 ± 1.6
0.537
0.702
0.116
5.0 ± 1.4‡ 0.122
5.4 ± 2.0 0.543
5.3 ± 1.7 0.058
‡
9.0 ± 1.7
*8.5 ± 1.1*
*8.7 ± 1.5*
9.1 ± 2.0
9.7 ± 2.3
9.2 ± 2.2
0.654
0.234
0.130
0.6 ± 0.2
0.6 ± 0.2§
0.6 ± 0.2
0.6 ± 0.1
0.6 ± 0.1
0.6 ± 0.1
0.6 ± 0.1
0.6 ± 0.3
0.6 ± 0.3
0.6 ± 0.1
0.6 ± 0.1
0.6 ± 0.1
0.686
0.686
0.790
||
§
13 ± 3§0
13 ± 3§0
§
12 ± 3§0
15 ± 40
15 ± 70
016 ± 5†‡§
17 ± 70
15 ± 70
16 ± 60
0.301
0.648
0.029
102 ± 200 107 ± 190
102 ± 200 110 ± 180
101 ± 130 108 ± 170
111 ± 280
113 ± 280
110 ± 290
§
||
14 ± 5||0
14 ± 5||0
13 ± 30
§
124 ± 47* 0.147
121 ± 470 0.209
118 ± 410 0.301
Within groups: *p < 0.05 and †p < 0.01 vs. no remodeling; ‡p < 0.05 and #p = 0.001 vs. concentric remodeling.
Between groups: §p < 0.05 and ||p < 0.01 vs. mild CKD group.
Abbreviations as in Tables 3 and 4.
LVM was indexed to HT2.7. 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
Moderate/severe CKD patients with eccentric hypertrophy had lower Sm, Em, and Am and higher mitral
E/Em compared to patients without hypertrophy when
47
Acta Cardiol Sin 2012;28:42-52
Shih-Jen Chen et al.
the mild CKD group. When LVM was indexed to HT2.7
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.
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
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 HT2.7 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
HT2.7 detected 42 in 43 LVH patients; however, LVM
indexed to BSA and height both detected 29 patients.
LVH indexed by HT2.7 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
HT2.7 criteria in detecting LVH improves cardiac diastolic
function stratification in predialysis CKD management.
B
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 HT2.7 (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 HT2.7 detected 42 in 43 LVH patients;
however, LVM indexed to BSA and height both detected 29 patients.
Table 6. Association of LVH with pulse tissue Doppler echocardiographic parameters in patients with mild and moderate/severe
CKD
Mild CKD
Sm, cm/s
Em, cm/s
Am, cm/s
Em/Am
Mitral E/Em
IVRT, ms
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)
7.6 ± 1.7
6.3 ± 1.6
9.5 ± 1.8
0.7 ± 0.2
10 ± 20
94 ± 13
6.6 ± 1.0
6.0 ± 1.2
9.5 ± 1.0
0.6 ± 0.1
11 ± 30
96 ± 20
6.5 ± 0.7
5.5 ± 1.2
9.0 ± 1.8
0.6 ± 0.1
*13 ± 3**
98 ± 17
p
No LVH
(n = 28)
0.101
0.452
0.742
0.626
0.035
0.847
7.0 ± 1.2
6.2 ± 1.0
9.9 ± 1.6
0.6 ± 0.2
†
12 ± 3†0
†
103 ± 15†0
Within groups: *p < 0.05 and **p < 0.01 vs. no LVH.
Between groups: †p < 0.05 and ‡p = 0.005 vs. mild CKD group.
Abbreviations as in Tables 3 and 4.
Acta Cardiol Sin 2012;28:42-52
48
LVH by 1 criterion LVH by all 3
only or 2 criteria at criteria at the
same time
the same time
(n=16)
(n=27)
6.5 ± 1.4
*5.2 ± 1.8*
9.0 ± 2.0
0.6 ± 0.1
**‡17 ± 5**‡0
105 ± 250
6.4 ± 1.4
**5.0 ± 1.8**
9.1 ± 1.8
0.6 ± 0.3
16 ± 6*
119 ± 39*
p
0.153
0.020
0.110
0.582
0.007
0.094
CKD and LVH
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.
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 = 1.64-6.08, p = 0.001) and LVH indexed by HT2.7
(odds ratio = 4.10, 95% confidence interval = 1.2713.32, p = 0.019) (Table 7). The more sensitive LVH criteria that predicted the presence of septal E/Em > 15 was
LVM indexed to HT2.7 of > 48 g/m2.7 by receiver-operating characteristic analysis (area under the curve = 0.69 ±
0.05, 95% confidence interval = 0.59 to 0.79, p = 0.002)
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
Dependent variable: mitral E/Em > 15
Independent variables
Age, per 1 y
Male sex
BMI, per 1 kg/m2
SBP, per 10 mm Hg
DBP, per 10 mm Hg
Heart rate, per 10 beats/min
Current smoker
History of diabetes
History of hypertension
Uncontrolled hypertension
Ischemic heart disease
Hypecholesterolemia
CKD, per 1 stage
Hematocrit, per 1%
Phosphorus, per 1 mg/dL
I-PTH, per 1 pg/mL
LDL, per 30 mg/dL
hsCRP, per 1 mg/L
LVH indexed by BSA
LVH indexed by HT
LVH indexed by HT2.7
Multivariable analysis
OR (95% CI)
p value
OR (95% CI)
p value
1.06 (1.02-1.11)
1.68 (0.73-3.87)
1.00 (0.89-1.12)
0.94 (0.65-1.37)
0.52 (0.31-0.86)
1.24 (0.83-1.86)
1.48 (0.56-3.93)
2.80 (1.17-6.72)
1.68 (0.64-4.43)
1.95 (0.73-5.19)
0.37 (0.04-3.21)
1.08 (0.47-2.49)
3.02 (1.81-5.06)
1.68 (0.64-4.43)
1.67 (0.94-2.95)
1.00 (1.00-1.01)
0.84 (0.58-1.22)
1.10 (0.99-1.21)
1.65 (0.71-3.87)
1.55 (0.66-3.65)
04.03 (1.60-10.13)
0.009
0.225
0.996
0.943
0.011
0.287
0.428
0.021
0.293
0.181
0.368
0.859
< 0.001 <
0.293
0.083
0.104
0.350
0.066
0.247
1.547
0.003
1.04 (0.98-1.11)
0.229
0.81 (0.42-1.58)
0.541
1.57 (0.48-5.12)
0.457
3.16 (1.64-6.08)
0.001
0.78 (0.38-1.69)
0.556
1.12 (0.96-1.31)
0.247
04.10 (1.27-13.32)
0.019
Abbreviations as in Tables 1 and 2.
49
Acta Cardiol Sin 2012;28:42-52
Shih-Jen Chen et al.
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/m2.7 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/m2).
Cuspidi et al. 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
HT2.7 only and in patients with a positive LVH indexed
to both BSA and HT2.7 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.
Figure 2. ROC curve analysis set to identify mitral E/Em > 15 by
three different LVH criteria. The cutoff value for LVH indexed by HT2.7
(solid line) to differentiate the presence of E/Em >15 was 48 g/m2.7, with
sensitivity and specificity rates of 75% and 57%, respectively. The area
under the curve = 0.69 ± 0.05, p = 0.002. 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 = 0.67 ± 0.05, p = 0.006. For LVH indexed by BSA (small dashed
line), the best cutoff value was 122 g/m2, with sensitivity and specificity
rates of 44% and 68%, respectively. The area under the curve = 0.67 ±
0.05, p = 0.005. 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.
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
LVH criteria
Using the criteria of LVM normalized to HT2.7, 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
Acta Cardiol Sin 2012;28:42-52
50
CKD and LVH
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.
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 Based on higher prevalence of LVH and elevation 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
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.
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