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Comparative Assessment of 2-Dimensional Echocardiography vs Cardiac Magnetic Resonance Imaging in Measuring Left Ventricular Mass in Patients With and Without End-Stage Renal Disease
Canadian Journal of Cardiology 29 (2013) 384 –390
Clinical Research
Comparative Assessment of 2-Dimensional Echocardiography vs Cardiac Magnetic Resonance Imaging in Measuring Left Ventricular Mass in Patients With and Without End-Stage Renal Disease Baruch D. Jakubovic, BA,a Ron Wald, MD, MPH,a,b Marc B. Goldstein, MD,a,b Howard Leong-Poi, MD,a,c Darren A. Yuen, MD, PhD,a,b Jeffrey Perl, MD,a,b Joao A. Lima, MD,d Jerome J. Liu, BSc,a Anish Kirpalani, MD,a,e Niki Dacouris, BSc,b Rachel Wald, MD,a,f Kim A. Connelly, MBBS, PhD,a,c and Andrew T. Yan, MDa,c a
d e
Department of Medicine, University of Toronto, Toronto, Ontario, Canada
b
Division of Nephrology, St Michael’s Hospital, Toronto, Ontario, Canada
c
Division of Cardiology, St Michael’s Hospital, Toronto, Ontario, Canada
Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, USA
Department of Medical Imaging, St Michael’s Hospital, Toronto, Ontario, Canada f
University Health Network, Toronto, Ontario, Canada
ABSTRACT
RÉSUMÉ
Background: While echocardiography (ECHO)-measured left ventricular mass (LVM) predicts adverse cardiovascular events that are common in hemodialysis (HD) recipients, cardiac magnetic resonance imaging (CMR) is now considered the reference standard for determination of LVM. This study aimed to evaluate concordance between LVM measurements across ECHO and CMR among chronic HD recipients and matched controls. Methods: A single-centre, cross-sectional study of 41 chronic HD patients and 41 matched controls with normal kidney function was performed to compare LVM measurements and left ventricular hypertrophy (LVH) designation by ECHO and CMR. Results: In both groups, ECHO, compared with CMR, overestimated LVM. Bland-Altman analysis demonstrated wider agreement limits in LVM measurements by ECHO and CMR in the chronic HD group (mean difference, 60.8 g; limits ⫺23 g to 144.6 g) than in the group with normal renal function (mean difference, 51.4 g; limits ⫺10.5 g to 113.3 g). LVH prevalence by ECHO and CMR in the chronic HD group
Introduction : Bien que la masse ventriculaire gauche (MVG) mesurée par l’échocardiographie (écho) prédise les événements cardiovasculaires indésirables qui sont fréquents chez les patients hémodialysés (HD), l’imagerie par résonance magnétique cardiaque (RMC) est maintenant considérée comme la technique de référence dans la détermination de MVG. Cette étude a pour but d’évaluer la concordance entre les mesures de MVG par l’écho et la RMC chez les patients HD ayant une atteinte chronique et les témoins appariés. Méthodes : Une étude transversale unicentrique de 41 patients HD ayant une atteinte chronique et 41 témoins appariés ayant un fonctionnement rénal normal a été réalisée pour comparer les mesures de MVG, et la détermination de l’hypertrophie ventriculaire gauche (HVG) par l’écho et la RMC. Résultats : Dans les deux groupes, l’écho a surestimé la MVG par rapport à ce qui était déterminé par la RMC. L’analyse Bland-Altman a démontré des limites de concordance plus larges dans les mesures de MVG par l’écho et la RMC du groupe de patients HD ayant une atteinte chronique (différence moyenne, 60,8 g; limites ⫺23 g à 144,6 g) par
Among patients with end-stage renal disease, cardiovascular disease remains the leading cause of mortality, accounting for up to 50% of all deaths.1 Increased left ventricular mass
(LVM), referred to as left ventricular hypertrophy (LVH), is common among patients undergoing maintenance hemodialysis (HD). LVH is associated with myocardial fibrosis2,3 and is a robust predictor of adverse cardiovascular events.4,5 Moreover, regression of LVM has been shown to be associated with favourable outcomes, including a reduced likelihood of developing heart failure6 and lower all-cause mortality.7 As a result, changes in LVM have been used as the primary end point in
Received for publication March 25, 2012. Accepted July 25, 2012. Corresponding author: Dr Andrew T. Yan, Division of Cardiology, St Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B1W8, Canada. E-mail: [email protected] See page 389 for disclosure information.
0828-282X/$ – see front matter © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2012.07.013
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was 37.5% and 22.5%, respectively, while 17.5% and 12.5% had LVH by ECHO and CMR, respectively, in the normal kidney function group. Intermodality agreement in the designation of LVH was modest in the chronic HD patients ( ⫽ 0.42, P ⫽ 0.005) but strong ( ⫽ 0.81, P ⬍ 0.001) in the patients with preserved kidney function. Agreement was strong in assessing LVH by ECHO and CMR only in those with normal kidney function. Conclusions: Our results suggest that the limitations of LVM measurement by ECHO may be more pronounced in patients receiving HD, and provide additional support for the use of CMR in research and clinical practice when rigourous assessment of LVM is essential.
rapport à celles du groupe ayant un fonctionnement rénal normal (différence moyenne, 51,4 g; limites ⫺10,5 g à 113,3 g). La prévalence de l’HVG selon l’écho et la RMC du groupe de patients HD ayant une atteinte chronique a été de 37,5 % et de 22,5 %, respectivement, tandis que la prévalence de l’HVG selon l’écho et la RMC du groupe ayant un fonctionnement rénal normal a été de 17,5 % et 12,5 %, respectivement. La concordance entre les modes dans la détermination d’HVG a été modeste chez les patients HD ayant une atteinte chronique ( ⫽ 0,42, P ⫽ 0,005), mais forte ( ⫽ 0,81, P ⬍ 0,001) chez les patients ayant un fonctionnement rénal préservé. La concordance a été forte dans l’évaluation de l’HVG par l’écho et la RMC seulement chez ceux ayant un fonctionnement rénal normal. Conclusions : Nos résultats suggèrent que les limites de la mesure de la MVG par l’écho peuvent être plus prononcées chez les patients recevant une HD, et apportent un soutien additionnel à l’utilisation de la RMC dans la recherche et la pratique clinique lorsqu’une évaluation rigoureuse de la MVG est essentielle.
recent trials of novel interventions in HD recipients.8,9 This highlights the importance of accurate measurement of LVM and correct designation of LVH. While several imaging modalities are available for assessment of cardiac morphology in patients with chronic kidney disease, LVM is traditionally measured by 2-dimensional echocardiography (ECHO). ECHO is widely available, noninvasive, and has been demonstrated to be of reasonable accuracy in the assessment of LVH.10,11 However, the determination of LVM by ECHO relies on assumptions pertaining to cardiac geometry that are often violated among patients receiving chronic HD.12-14 This makes ECHO-derived LVM particularly susceptible to fluctuations in the patient’s volume status. Cardiac magnetic resonance imaging (CMR) has recently emerged as an accurate and precise modality for the assessment of LVM in patients requiring chronic HD.15,16 Although CMR is contraindicated for patients with certain implanted devices, is more expensive, and not as widely available compared with ECHO, CMR is safe, highly accurate, and reproducible with superior interobserver and intraobserver reliability.17,18 CMR provides measurement of LVM without the need for any geometric suppositions regarding cardiac morphology. Moreover, LVM measurement does not require the use of gadolinium contrast and can thus be safely performed in HD recipients. However, because of its wide availability and universal safety, ECHO remains the dominant cardiac imaging modality in clinical practice. To date, no studies have directly evaluated ECHO and CMR measurements of LVM in both chronic HD patients and those with normal renal function. Therefore, in this study, our aim was to evaluate the agreement between ECHO and CMR in the measurement of LVM and the determination of LVH in chronic HD patients compared with patients with preserved kidney function.
from January 1, 2005, to June 30, 2010, were eligible. These patients were matched by gender and age (⫾ 3 years) to individuals with normal kidney function (defined as estimated glomerular filtration rate ⬎ 60 mL/min/1.73 m2) who underwent the same requisite imaging. We considered cardiac imaging that was ordered for any clinical indication. Clinical data retrieval Demographics, laboratory values, and comorbidity status were obtained through existing hospital databases and electronic medical records. Additional data for the chronic HD patients, including type of vascular access, time since initiation of HD, and presumed etiology of kidney failure, were obtained through existing hospital databases, administrative files, and in the case of uncertainty, consultation with the primary dialysis physicians. Data on body surface area was missing for 1 patient in each group. ECHO image acquisition and analysis
Methods
Existing hospital databases were used to identify all ECHOs that were performed in the aforementioned period. All ECHO investigations were done with high-quality echocardiographic systems equipped with 2.0- to 2.5-MHz transducers (IE33 Philips Ultrasound; Philips Medical Systems, Best, The Netherlands). Each image was recorded digitally (XCelera Echo, Philips Ultrasound) and interpreted by experienced ECHO readers. Cardiac measurements including left ventricular enddiastolic dimension (LVEDD), left ventricular ejection fraction (LVEF), anteroseptal wall thickness, and inferolateral wall thickness were recorded into the database for LVM calculation. The method for calculating LVM with ECHO measurements is described elsewhere.11,19 In brief, data acquisition was performed by M-mode via a parasternal approach, and LV mass was calculated with the cube function formula, as per the American and Canadian Society of Echocardiography guideline recommendations.19
Study population
CMR image acquisition and analysis
A cross-sectional study was performed with patient health record databases at St Michael’s Hospital, a tertiary care, university-affiliated academic centre in Toronto, Canada. All patients receiving maintenance in-centre HD who had both ECHO and CMR with an interstudy interval of ⬍ 60 days
All patients underwent CMR with a 1.5-T whole-body magnetic resonance imaging scanner (Achieva; Philips Medical Systems) that used a phased-array cardiac coil and retrospective vectorcardiographic gating. Images were obtained during breath holds in end-expiration with the patient in supine posi-
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tion. Depending on the LV long-axis length, 8 to 12 contiguous short-axis cine images were required to cover the entire left ventricle. Segmented, balanced steady-state free-precession imaging sequence was used, typically with the following parameters: repetition time, 4 milliseconds; echo time, 2 milliseconds; slice thickness, 8 mm; field of view, 30 to 34 ⫻ 30 to 34 cm; matrix size, 256 ⫻ 196; temporal resolution of ⬍ 40 milliseconds (depending on heart rate); flip angle, 50°. A blinded experienced cardiac imager (A.Y.) reviewed all the CMR studies and completed the image postprocessing using offline commercial software (ViewForum R 4.2; Philips Medical Systems). The standard methods for determining LV volume, LVEF, and LVM have been described in detail elsewhere.20,21 In brief, to determine stroke volume (SV) and LVEF, manual tracing of endocardial borders at end-diastole (left ventricular end-diastolic volume [LVEDV], which represents the maximum ventricular cavity size) and at end-systole (left ventricular end-systolic volume [LVESV], which represents the minimum ventricular cavity size) via short-axis cine images was performed. These measured values were then used to derive SV (LVEDV ⫺ LVESV) and LVEF (SV/LVEDV ⫻ 100%). Endocardial and epicardial borders in contiguous short-axis slices at end-diastole were also traced, and the difference in area multiplied by the slice thickness. The sum of these differences throughout the entire left ventricle was multiplied by the myocardial specific density (1.05 g/cm3) to yield the LVM. LVM values were subsequently indexed by dividing by body surface area (BSA; height in centimetres ⫻ weight in kilograms/3600). Papillary muscles were not included in the LVM measurement.
Canadian Journal of Cardiology Volume 29 2013
(SAS Institute, Cary, NC) and SPSS 15.0 (SPSS Inc, Chicago, IL) were used to conduct the statistical analyses. The institutional research ethics board approved this study and waived the need for consent. Timing of investigations LVM determination may be sensitive to volume status and therefore modified by the receipt of dialysis. We therefore performed a sensitivity analysis in which we considered only ECHO-CMR pairs that had the same temporal relationship to the dialysis sessions. Dialysis shift was compared with the time of performance of each imaging investigation, and each study was classified according to the following definitions: (1) same day of dialysis, predialysis; (2) same day of dialysis, post dialysis; and (3) interdialytic day. For patients who received incentre nocturnal HD, ECHOs or CMRs done the subsequent day were classified as same day of dialysis, post dialysis. Adjustment of LVM By convention, LVM cutoff values for LVH by CMR usually include the papillary muscle mass in their determination.24,25 However, our CMR measurement protocol excluded the papillary muscle mass, which may be difficult to measure accurately.26,27 Furthermore, LVM measurement by ECHO does not include papillary muscles. Accordingly, we performed a sensitivity analysis in which each LVM value was multiplied by a factor of 1.09, based on data indicating that papillary muscle mass accounts for 8.9% of the total LVM in both sexes.28
Definition of LVH Patients were categorized as having LVH or not based on accepted cutoff values for LVM index (LVMI) for ECHO (men ⬎ 115 g/m2, women ⬎ 95 g/m2)19 and CMR (men ⬎ 81 g/m2, women ⬎ 79 g/m2).20 The measured relative wall thickness (RWT) allowed for further classification of LVH as either concentric hypertrophy (RWT ⬎ 0.42) or eccentric hypertrophy (RWT ⱕ 0.42). Primary analysis Continuous variables are presented as means ⫾ SD unless indicated otherwise. The paired t test was used to assess mean difference between various imaging parameters as measured by ECHO and CMR. Agreement between ECHO and CMR was assessed by the Bland-Altman method,22 which involved comparing mean measurements of LVM [(ECHO ⫹ CMR)/2] to the difference in LVM measurements (ECHO ⫺ CMR). The kappa statistic was used to evaluate the agreement beyond chance in the designation of LVH by ECHO and CMR.23 Pearson correlation was used to evaluate the relationship between ECHO-measured LVEDD and the mean difference in LVM across ECHO and CMR. To determine whether the time lag between ECHO and CMR might have accounted for the discrepancy of LVM measurements, we examined the correlation between absolute time interval between ECHO and CMR performance and the absolute difference in LVM. Intraobserver variability was assessed via a random selection of 10 pairs of matched patients whose LVMs were remeasured by the same reader after a significant time lag. Statistical significance was defined to be P ⬍ 0.05 in all instances. SAS Version 9.1
Results Table 1 summarizes the clinical and demographic characteristics of the study population. A total of 41 patients on chronic HD who underwent ECHO and CMR within the 60-day time interval were identified and matched 1:1 with patients in whom renal function was preserved. The underlying etiologies of renal failure for the chronic HD cohort were as follows: diabetes mellitus (36%), glomerulonephritis (31.7%), ischemic nephropathy (14.6%), polycystic kidney disease (2.4%), other (12.2%), and unknown (2.4%). A tunneled central venous catheter was the mode of vascular access in 53%, an arteriovenous fistula in 44%, and an arteriovenous graft in 2%. Among the HD recipients, mean LVM by ECHO and CMR were 184 ⫾ 65 g and 123 ⫾ 37 g, respectively. LVM measurements in the normal renal function group for ECHO and CMR were 167 ⫾ 57 g and 115 ⫾ 43 g, respectively. These and the other measurements are summarized in Table 2. Bland-Altman analysis (see Figures 1A and 1B) demonstrated that the limits of agreement between ECHO and CMR for measuring LVM were wider in the chronic HD group (⫺23 g to 144.6 g) as compared with those with normal renal function (⫺10.5 g to 113.3 g). In almost all instances, compared with CMR, ECHO overestimated LVM in the chronic HD group, and the difference increased with average LVM (r ⫽ 0.89, P ⬍ 0.01). This trend was similar in the control group, albeit with narrower agreement limits. There was no significant relationship between the time lag between ECHO and CMR and the absolute difference in LVM between these 2 imaging modalities (r ⫽ ⫺0.107).
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mean difference in LVM by ECHO was ⫺4.8 g, with limits of agreement of ⫺56.8 to 47.2 g.
Table 1. Demographic and clinical characteristics of study population Chronic HD Total number of patients 41 Women, n (%) 19 (46.3) Age, years 52.1 ⫾ 9.9 Body surface area (m2) 1.82 ⫾ 0.29 Comorbidities, n (% of total) Hypertension 33 (80.5) Dyslipidemia 21 (51.2) Smoking Previous 15 (36.6) Current 3 (7.3) Diabetes mellitus 14 (34.1) Angina 6 (14.6) Myocardial infarction 6 (14.6) Heart failure 6 (14.6) Percutaneous coronary intervention 2 (4.9) Coronary bypass surgery 4 (9.8) Stroke 3 (7.3) Peripheral vascular disease 9 (22) Time on dialysis (months), median (interquartile range) 42.7 (11.1-98.9)
Normal kidney function
P value
41 19 (46.3) 51.7 ⫾ 10 1.88 ⫾ 0.24
NA NA 0.28
15 (36.6) 9 (22)
⬍ 0.001 0.011 0.38
12 (29.3) 5 (12.2) 2 (4.9) 6 (14.6) 2 (4.9) 4 (9.8)
0.002 1.0 0.26 0.74
3 (7.3) 0 (0) 2 (4.9) 0 (0)
1.0 0.12 1.0 0.002
NA
NA
HD, hemodialysis; NA, not applicable.
In the chronic HD group, 37.5% of patients met ECHO criteria for LVH (7.5% eccentric LVH, 30% concentric LVH), whereas 22.5% of patients met LVH criteria (7.5% concentric LVH, 15% eccentric LVH) by CMR. In those with normal renal function, LVH was designated by ECHO in 17.5% of patients (7.5% eccentric LVH, 10% concentric LVH) and by CMR in 12.5% (10% eccentric LVH, 2.5% concentric LVH). Table 3 depicts the agreement in LVH designation by ECHO and CMR in both cohorts. The kappa statistic for the chronic HD group was 0.42 (P ⫽ 0.005), reflecting modest agreement. This is in contrast to the kappa value of 0.81 (P ⬍ 0.001) for the patients with normal renal function which indicates strong agreement. The difference in kappa values between the 2 groups was of borderline statistical significance (P ⫽ 0.050). Comparison between ECHO-determined LVEDD and mean difference in LVM by ECHO and CMR demonstrated that as LVEDD increased (corresponding to left ventricular dilatation), so too did the discrepancy in LVM measured by the 2 imaging tests (r ⫽ 0.375, P ⬍ 0.001). In the random group of patients selected to evaluate intraobserver variability, the mean difference in LVM by CMR was ⫺0.54 g, with limits of agreement of ⫺13.3 to 12.3 g, while
Consideration of studies with the same temporal relationship to dialysis session The mean LVM and LVMI measurements were both slightly lower by ECHO and CMR in the chronic HD group when only studies (n ⫽ 17) done with the same temporal relationship to dialysis were considered. Mean LVM was 175 ⫾ 47 g, while mean LVMI was 117 ⫾ 32 g/m2. Prevalence of LVH was 24% by CMR and 35% by ECHO, although agreement beyond chance was still moderate, with ⫽ 0.44 (P ⫽ 0.057). Analyses accounting for estimated papillary muscle mass When the data were analyzed using CMR-generated LVM values that were adjusted to include papillary muscle mass, the prevalence of LVH by CMR increased to 38%. LVH prevalence by CMR also increased slightly in the normal kidney function group. When intermodality agreement was measured, a of 0.30 (P ⫽ 0.060) was observed in the chronic HD group, with stronger agreement ( ⫽ 0.59, P ⬍ 0.001) among patients with normal kidney function. Discussion As compared with CMR, ECHO systematically overestimates LVM in both chronic HD patients and those with preserved renal function. This discrepancy seems to be accentuated in patients receiving chronic HD in whom there is only moderate agreement in the assessment of LVH between ECHO and CMR. Previous studies have compared the measurement of LVM by ECHO and CMR, with varying degrees of discordance identified. While the overestimation of LVM by ECHO has been demonstrated in end-stage renal disease,29 aortic stenosis,24 and hypertension,30,31 underestimation of LVM was seen in another study involving healthy subjects.32 A major contributor to the inaccuracy in LVM measurement by ECHO relates to the presupposition of an ellipsoidshaped heart.10 However, because of pressure and volume overload in chronic HD recipients, the heart may deviate from normal morphology and exhibit varying types and combinations of hypertrophy.13,33 The endocardial border may not be well defined on ECHO, and left ventricular wall thickness is not uniform across all myocardial segments. Furthermore, the ECHO calculation for LVM is based on a formula that relies heavily on the internal diameter of the left ventricle.34 As a
Table 2. Left ventricular measurements of study population Chronic hemodialysis (n ⫽ 41) Parameter measured LVM (g) LVMI (g/m2) LV ejection fraction (%) LV end-diastolic dimension (mm) Anteroseptal wall thickness (mm) Inferolateral wall thickness (mm)
Normal kidney function (n ⫽ 41)
ECHO
CMR
P value
ECHO
CMR
P value
184 ⫾ 65 101 ⫾ 25 67 ⫾ 10 44 ⫾ 7 12 ⫾ 3 11 ⫾ 2
123 ⫾ 37 68 ⫾ 14 61 ⫾ 8 51 ⫾ 7 12 ⫾ 2 9⫾2
⬍ 0.001 ⬍ 0.001 0.012 ⬍ 0.001 ⬍ 0.001 0.015
167 ⫾ 57 89 ⫾ 43 60 ⫾ 15 47 ⫾ 7 10 ⫾ 3 10 ⫾ 2
115 ⫾ 43 61 ⫾ 22 55 ⫾ 12 57 ⫾ 8 8⫾2 7⫾2
⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.005
CMR, cardiac magnetic resonance imaging; ECHO, echocardiography; LV, left ventricular; LVM, LV mass; LVMI, LVM index.
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Figure 1. Bland-Altman plots of the difference in left ventricular (LV) mass measurements against the mean of the 2 measurements. (A) Chronic hemodialysis: The mean difference in LV mass is 60.8 g, and limits of agreement are ⫺23 to 144.6 g. (B) Normal kidney function: The mean difference in LV mass is 51.4 g, and limits of agreement are ⫺10.5 to 113.3 g. Limits of agreement are wider in the chronic hemodialysis group. CMR, cardiac magnetic resonance imaging; ECHO, echocardiography.
result, LVM determined by ECHO can vary considerably between predialytic and postdialytic periods solely because of fluctuations in intravascular volume and the resulting change in intracardiac volume.35,36 By contrast, CMR measures LVM via direct mathematical integration using 3-dimensional data that does not involve assumptions regarding cardiac geometry or reliance on left ventricular diameter.15,21 CMR, unlike ECHO, is therefore less sensitive to changes in intravascular— and by extension intracardiac—volume.37 The limitations of 2-dimensional ECHO may be mitigated by the use of 3-dimensional ECHO, which correlates better with CMR.38 A seminal study by Stewart et al. demonstrated overestimation of LVM by ECHO compared with CMR (using a freegradient echo sequence at 1.0 T) in chronic HD patients.29 However, there was no control group, and free-gradient echo cine imaging is rarely used nowadays. Our study expands on previous work by evaluating paired ECHO and CMR studies in a comparator group with normal kidney function. While the overestimation of LVM in patients with end-stage renal disease and other populations has previously been demonstrated, to our knowledge this is the first instance in which the degree of
mass bias has been shown to be heightened in chronic HD patients compared with those with normal kidney function. This finding is itself novel and provides evidence that it may be even more important for LVM measurements to be performed by CMR instead of ECHO for patients undergoing chronic HD than for those with normal kidney function. We also evaluated a more contemporary cohort of HD patients using a 1.5-T scanner and steady-state free precession imaging, which is the current standard CMR technique that allows for superior delineation between the blood pool and myocardium.39 Our study has several limitations. First, ECHOs and CMRs could have been performed within an interval of up to 60 days. However, considerable changes in left ventricular geometry and LVM are unlikely to occur during this time. This was confirmed by the lack of correlation between the absolute difference in LVM and time interval between ECHO and CMR studies. Furthermore, since changes in left ventricular geometry occur gradually, studies examining LVM regression over time generally require at least 6 months of follow-up.40 There was no predetermined relationship between ECHO and CMR and the timing of dialysis. Hence, LVM results may have been
Table 3. Agreement in the designation of LVH by ECHO and CMR
Group considered for LVH assessment Chronic HD (n ⫽ 40) Normal kidney function (n ⫽ 40) Chronic HD; adjusted for papillary muscle mass (n ⫽ 40) Normal kidney function; adjusted for papillary muscle mass (n ⫽ 40) Chronic HD; dialysis time concordant (n ⫽ 17)
LVH (by ECHO and CMR)
LVH (by ECHO only)
LVH (by CMR only)
No LVH (by ECHO and CMR
n
%
n
%
n
%
n
%
P value
7 5
17.5 12.5
8 2
20 5
2 0
5 0
23 33
57.5 82.5
0.42 0.81
0.005 ⬍ 0.001
8
20
7
17.5
6
15
19
47.5
0.30
0.060
5
12.5
2
5
3
7.5
30
75
0.59
⬍ 0.001
3
17.6
3
17.6
1
5.9
10
58.8
0.44
0.057
CMR, cardiac magnetic resonance imaging; ECHO, echocardiography; HD, hemodialysis; LVH, left ventricular hypertrophy.
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skewed by transient changes in volume status. Nevertheless, it is reassuring that our findings were largely consistent when we limited our analyses to ECHO-CMR pairs that were performed with the same temporal relationship to dialysis. Our exclusion of papillary muscle mass measurement from LVM determination by CMR may have inflated the mean difference in LVM by ECHO and CMR. However, given that ECHO-based LVM measurements universally exclude papillary muscles, a direct comparison excluding papillary muscles from the CMR protocol is actually more appropriate. Nevertheless, we tried to account for this by performing a sensitivity analysis in which LVM values were adjusted with the best estimate available for papillary muscle. While the prevalence of LVH by CMR increased in the chronic HD group to be almost equivalent to that associated with ECHO, the extent of agreement between ECHO and CMR is similar to the primary analysis. Although our findings suggest that ECHO may lead to an overestimation of LVM and the misclassification of LVH, our data are limited to a cross-section in time. Serial changes in LVM have been shown to be of important prognostic value,6 and whether the significance of such changes depends on imaging modality (ie, CMR vs ECHO) requires further study. Furthermore, although the Bland-Altman analysis demonstrated considerable overlap between the 2 groups, our study was not adequately powered to directly compare the width of the limits of agreement. Despite its limitations, ECHO is advantageous in terms of accessibility and cost. Nevertheless, when it comes to the measurement of LVM and assessment of LVH, the use of ECHO may overestimate the prevalence of LVH in chronic HD recipients. By contrast, CMR—which is less sensitive to volume changes—provides a more accurate LVM measurement irrespective of when it is performed in relation to the dialysis session.37 In recognition of this major drawback of ECHO, clinical trials in which LVM is used as an outcome measure are increasingly relying on CMR. Hence, it is clear that CMR is beginning to emerge as the reference standard in research, particularly in those with left ventricular alterations that may not conform to ECHO geometric assumptions. This study also provides further support for the use of CMR in clinical practice when accurate measurements of LVM are needed. Our findings demonstrate a significant degree of LVM overestimation and increased LVH prevalence by ECHO in chronic HD recipients, compared with individuals with normal renal function. Moreover, the agreement between ECHO and CMR in the designation of LVH is inferior in chronic HD recipients, compared with patients with preserved kidney function. While ECHO will continue to be used in routine clinical practice, evidence is mounting that CMR may afford a more accurate evaluation of cardiac remodelling and associated LVM changes in chronic HD patients, thus providing a superior alternative for cardiac assessment in this population. Funding Sources This study was supported by an operating grant from the Canadian Institutes of Health Research. Baruch Jakubovic was supported by funding from the University of Toronto Faculty of Medicine CREMS Summer Student Program and the Heart and Stroke Foundation of Ontario. Dr Kim Connelly was supported by a Heart and Stroke Foundation of Canada Phase 1
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Clinician Scientist Award. Ron Wald is supported by an unrestricted educational grant from Amgen. Dr Darren Yuen was sponsored by a KRESCENT postdoctoral fellowship and is currently supported by a Canadian Institutes of Health Research fellowship. Dr Andrew Yan is supported by a New Investigator Award from the Heart and Stroke Foundation of Ontario. Disclosures Dr Wald is supported by an unrestricted educational grant from Amgen. The other authors have no conflicts of interest to disclose. References 1. Rostand SG, Brunzell JD, Cannon RO III, Victor RG. Cardiovascular complications in renal failure. J Am Soc Nephrol 1991;2:1053-62. 2. Schietinger BJ, Brammer GM, Wang H, et al. Patterns of late gadolinium enhancement in chronic hemodialysis patients. JACC Cardiovasc Imaging 2008;1:450-6. 3. Mark PB, Johnston N, Groenning BA, et al. Redefinition of uremic cardiomyopathy by contrast-enhanced cardiac magnetic resonance imaging. Kidney Int 2006;69:1839-45. 4. Silberberg JS, Barre PE, Prichard SS, Sniderman SD. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989;36:286-90. 5. Glassock RJ, Pecoits-Filho R, Barbareto S. Increased left ventricular mass in chronic kidney disease and end-stage renal disease: what are the implications? Dial Transplant 2010;39:16-9. 6. Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE. Serial change in echocardiographic parameters and cardiac failure in endstage renal disease. J Am Soc Nephrol 2000;11:912-6. 7. London GM, Pannier B, Guerin AP, et al. Alterations of left ventricular hypertrophy in and survival of patients receiving hemodialysis: follow-up of an interventional study. J Am Soc Nephrol 2001;12:2759-67. 8. Group FHNT, Chertow GM, Levin NW, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010;363: 2287-300. 9. Culleton BF, Walsh M, Klarenbach SW, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA 2007;298:1291-9. 10. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circulation 1977;55:613-8. 11. Devereux RB, Alonso DR, Lutas EM. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450-8. 12. McLntyre CW, Odudu A, Eldehni MT. Cardiac assessment in chronic kidney disease. Curr Opin Nephrol Hypertens 2009;18:501-6. 13. Foley RN, Curtis BM, Randell EW, Parfrey PS. Left ventricular hypertrophy in new hemodialysis patients without symptomatic cardiac disease. Clin J Am Soc Nephrol 2010;5:805-13. 14. McGill RL, Biederman RWW, Getts RT, et al. Cardiac magnetic resonance imaging in hemodialysis patients. J Nephrol 2009;22:367-72. 15. Constantine G, Shan K, Flamm SD, Sivananthan MU. Role of MRI in clinical cardiology. Lancet 2004;363:2162-71.
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16. Lima J, Desai M. Cardiovascular magnetic resonance imaging: current and emerging applications. J Am Coll Cardiol 2004;44:1164-71.
magnetic resonance imaging. J Comput Assist Tomogr 2006;30: 426-32.
17. Grothues F, Smith GC, Moon JCC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 2002;90:29-34.
29. Stewart GA, Foster J, Cowan M, et al. Echocardiography overestimates left ventricular mass in hemodialysis patients relative to magnetic resonance imaging. Kidney Int 1999;56:2248-53.
18. Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000;2:271-8.
30. Missouris CG, Forbat SM, Singer DRJ, Markandu ND, Underwood R, MacGregor GA. Echocardiography overestimates left ventricular mass: a comparative study with magnetic resonance imaging in patients with hypertension. J Hypertens 1996;14:1005-10.
19. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63.
31. Perdrix L, Mansencal N, Cocheteux B, et al. How to calculate left ventricular mass in routine practice? An echocardiographic versus cardiac magnetic resonance study. Arch Cardiovasc Dis 2011;104:343-51.
20. Hudsmith LE, Petersen SE, Francis JM, Robson MD, Neubauer S. Normal human left and right ventricular and left atrial dimensions using steady state free precession magnetic resonance imaging. J Cardiovasc Magn Reson 2005;7:775-82.
33. Nardi E, Palermo A, Mule G, Cusimano P, Cottone S, Cerasola G. Left ventricular hypertrophy and geometry in hypertensive patients with chronic kidney disease. J Hypertens 2009;27:633-41.
21. Bellenger NG, Grothues F, Smith GC, Pennell DJ. Quantification of right and left ventricular function by cardiovascular magnetic resonance. Herz 2000;25:392-9. 22. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307-10. 23. McGinn T, Wyer PC, Newman TB, Keitz S, Leipzig R, Guyatt G. Tips for learners of evidence-based medicine: 3. Measures of observer variability (kappa statistic). CMAJ 2004;171:1369-73. 24. Rajappan K, Bellenger NG, Melina G, et al. Assessment of left ventricular mass regression after aortic valve replacement— cardiovascular magnetic resonance versus M-mode echocardiography. Eur J Cardiothorac Surg 2003;24:59-65. 25. Alfakih K, Plein S, Thiele H, Jones T, Ridgway JP, Sivananthan MU. Normal human left and right ventricular dimensions for MRI as assessed by turbo gradient echo and steady-state free precession imaging sequences. J Magn Reson Imaging 2003;17:323-9. 26. Young AA, Cowan BR, Thrupp SF, Hedley WJ, Dell’Italia LJ. Left ventricular mass and volume: fast calculation with guide-point modeling on mr images. Radiology 2000;216:597-602. 27. van der Geest RJ, Buller VG, Jansen E, m-mode. Comparison between manual and semiautomated analysis of left ventricular volume parameters from short-axis MR images. J Comput Assist Tomogr 1997;21: 756-65. 28. Vogel-Claussen J, Finn JP, Gomes AS, et al. Left ventricular papillary muscle mass: Relationship to left ventricular mass and volumes by
32. Myerson SG, Montgomery HE, World MJ, Pennell DJ. Left ventricular mass: reliability of M-mode and 2-dimensional echocardiographic formulas. Hypertension 2002;40:673-8.
34. Kilickap M, Turhan S, Sayin T, et al. Intravascular volume dependency of left ventricular mass calculation by two-dimensional guided M-mode echocardiography. Can J Cardiol 2007;23:219-22. 35. Martin LC, Barretti P, Cornejo IV, et al. Influence of fluid volume variations on the calculated value of the left ventricular mass measured by echocardiogram in patients submitted to hemodialysis. Ren Fail 2003;25: 43-53. 36. Kilickap M, Turhan S, Sayin T, et al. Intravascular volume dependency of left ventricular mass calculation by two-dimensional guided M-mode echocardiography. Can J Cardiol 2007;23:219-22. 37. Hunold P, Vogt FM, Heemann UW, Zimmermann U, Barkhausen J. Myocardial mass and volume measurement of hypertrophic left ventricles by MRI—study in dialysis patients examined before and after dialysis. J Cardiovasc Magn Reson 2003;5:553-61. 38. Chuang ML, Beaudin RA, Riley MF, et al. Three-dimensional echocardiographic measurement of left ventricular mass: comparison with magnetic resonance imaging and two-dimensional echocardiographic determinations in man. Int J Cardiovasc Imaging 2000;16:347-57. 39. Hundley WG, Bluemke DA, Finn JP, et al. ACCF/ACR/AHA/NASCI/ SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation task force on expert consensus documents. Circulation 2010;121: 2462-508. 40. Devereux RB, Dahlof B, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation 2004;110:1456-62.
Clinical Research
Comparative Assessment of 2-Dimensional Echocardiography vs Cardiac Magnetic Resonance Imaging in Measuring Left Ventricular Mass in Patients With and Without End-Stage Renal Disease Baruch D. Jakubovic, BA,a Ron Wald, MD, MPH,a,b Marc B. Goldstein, MD,a,b Howard Leong-Poi, MD,a,c Darren A. Yuen, MD, PhD,a,b Jeffrey Perl, MD,a,b Joao A. Lima, MD,d Jerome J. Liu, BSc,a Anish Kirpalani, MD,a,e Niki Dacouris, BSc,b Rachel Wald, MD,a,f Kim A. Connelly, MBBS, PhD,a,c and Andrew T. Yan, MDa,c a
d e
Department of Medicine, University of Toronto, Toronto, Ontario, Canada
b
Division of Nephrology, St Michael’s Hospital, Toronto, Ontario, Canada
c
Division of Cardiology, St Michael’s Hospital, Toronto, Ontario, Canada
Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, USA
Department of Medical Imaging, St Michael’s Hospital, Toronto, Ontario, Canada f
University Health Network, Toronto, Ontario, Canada
ABSTRACT
RÉSUMÉ
Background: While echocardiography (ECHO)-measured left ventricular mass (LVM) predicts adverse cardiovascular events that are common in hemodialysis (HD) recipients, cardiac magnetic resonance imaging (CMR) is now considered the reference standard for determination of LVM. This study aimed to evaluate concordance between LVM measurements across ECHO and CMR among chronic HD recipients and matched controls. Methods: A single-centre, cross-sectional study of 41 chronic HD patients and 41 matched controls with normal kidney function was performed to compare LVM measurements and left ventricular hypertrophy (LVH) designation by ECHO and CMR. Results: In both groups, ECHO, compared with CMR, overestimated LVM. Bland-Altman analysis demonstrated wider agreement limits in LVM measurements by ECHO and CMR in the chronic HD group (mean difference, 60.8 g; limits ⫺23 g to 144.6 g) than in the group with normal renal function (mean difference, 51.4 g; limits ⫺10.5 g to 113.3 g). LVH prevalence by ECHO and CMR in the chronic HD group
Introduction : Bien que la masse ventriculaire gauche (MVG) mesurée par l’échocardiographie (écho) prédise les événements cardiovasculaires indésirables qui sont fréquents chez les patients hémodialysés (HD), l’imagerie par résonance magnétique cardiaque (RMC) est maintenant considérée comme la technique de référence dans la détermination de MVG. Cette étude a pour but d’évaluer la concordance entre les mesures de MVG par l’écho et la RMC chez les patients HD ayant une atteinte chronique et les témoins appariés. Méthodes : Une étude transversale unicentrique de 41 patients HD ayant une atteinte chronique et 41 témoins appariés ayant un fonctionnement rénal normal a été réalisée pour comparer les mesures de MVG, et la détermination de l’hypertrophie ventriculaire gauche (HVG) par l’écho et la RMC. Résultats : Dans les deux groupes, l’écho a surestimé la MVG par rapport à ce qui était déterminé par la RMC. L’analyse Bland-Altman a démontré des limites de concordance plus larges dans les mesures de MVG par l’écho et la RMC du groupe de patients HD ayant une atteinte chronique (différence moyenne, 60,8 g; limites ⫺23 g à 144,6 g) par
Among patients with end-stage renal disease, cardiovascular disease remains the leading cause of mortality, accounting for up to 50% of all deaths.1 Increased left ventricular mass
(LVM), referred to as left ventricular hypertrophy (LVH), is common among patients undergoing maintenance hemodialysis (HD). LVH is associated with myocardial fibrosis2,3 and is a robust predictor of adverse cardiovascular events.4,5 Moreover, regression of LVM has been shown to be associated with favourable outcomes, including a reduced likelihood of developing heart failure6 and lower all-cause mortality.7 As a result, changes in LVM have been used as the primary end point in
Received for publication March 25, 2012. Accepted July 25, 2012. Corresponding author: Dr Andrew T. Yan, Division of Cardiology, St Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B1W8, Canada. E-mail: [email protected] See page 389 for disclosure information.
0828-282X/$ – see front matter © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2012.07.013
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was 37.5% and 22.5%, respectively, while 17.5% and 12.5% had LVH by ECHO and CMR, respectively, in the normal kidney function group. Intermodality agreement in the designation of LVH was modest in the chronic HD patients ( ⫽ 0.42, P ⫽ 0.005) but strong ( ⫽ 0.81, P ⬍ 0.001) in the patients with preserved kidney function. Agreement was strong in assessing LVH by ECHO and CMR only in those with normal kidney function. Conclusions: Our results suggest that the limitations of LVM measurement by ECHO may be more pronounced in patients receiving HD, and provide additional support for the use of CMR in research and clinical practice when rigourous assessment of LVM is essential.
rapport à celles du groupe ayant un fonctionnement rénal normal (différence moyenne, 51,4 g; limites ⫺10,5 g à 113,3 g). La prévalence de l’HVG selon l’écho et la RMC du groupe de patients HD ayant une atteinte chronique a été de 37,5 % et de 22,5 %, respectivement, tandis que la prévalence de l’HVG selon l’écho et la RMC du groupe ayant un fonctionnement rénal normal a été de 17,5 % et 12,5 %, respectivement. La concordance entre les modes dans la détermination d’HVG a été modeste chez les patients HD ayant une atteinte chronique ( ⫽ 0,42, P ⫽ 0,005), mais forte ( ⫽ 0,81, P ⬍ 0,001) chez les patients ayant un fonctionnement rénal préservé. La concordance a été forte dans l’évaluation de l’HVG par l’écho et la RMC seulement chez ceux ayant un fonctionnement rénal normal. Conclusions : Nos résultats suggèrent que les limites de la mesure de la MVG par l’écho peuvent être plus prononcées chez les patients recevant une HD, et apportent un soutien additionnel à l’utilisation de la RMC dans la recherche et la pratique clinique lorsqu’une évaluation rigoureuse de la MVG est essentielle.
recent trials of novel interventions in HD recipients.8,9 This highlights the importance of accurate measurement of LVM and correct designation of LVH. While several imaging modalities are available for assessment of cardiac morphology in patients with chronic kidney disease, LVM is traditionally measured by 2-dimensional echocardiography (ECHO). ECHO is widely available, noninvasive, and has been demonstrated to be of reasonable accuracy in the assessment of LVH.10,11 However, the determination of LVM by ECHO relies on assumptions pertaining to cardiac geometry that are often violated among patients receiving chronic HD.12-14 This makes ECHO-derived LVM particularly susceptible to fluctuations in the patient’s volume status. Cardiac magnetic resonance imaging (CMR) has recently emerged as an accurate and precise modality for the assessment of LVM in patients requiring chronic HD.15,16 Although CMR is contraindicated for patients with certain implanted devices, is more expensive, and not as widely available compared with ECHO, CMR is safe, highly accurate, and reproducible with superior interobserver and intraobserver reliability.17,18 CMR provides measurement of LVM without the need for any geometric suppositions regarding cardiac morphology. Moreover, LVM measurement does not require the use of gadolinium contrast and can thus be safely performed in HD recipients. However, because of its wide availability and universal safety, ECHO remains the dominant cardiac imaging modality in clinical practice. To date, no studies have directly evaluated ECHO and CMR measurements of LVM in both chronic HD patients and those with normal renal function. Therefore, in this study, our aim was to evaluate the agreement between ECHO and CMR in the measurement of LVM and the determination of LVH in chronic HD patients compared with patients with preserved kidney function.
from January 1, 2005, to June 30, 2010, were eligible. These patients were matched by gender and age (⫾ 3 years) to individuals with normal kidney function (defined as estimated glomerular filtration rate ⬎ 60 mL/min/1.73 m2) who underwent the same requisite imaging. We considered cardiac imaging that was ordered for any clinical indication. Clinical data retrieval Demographics, laboratory values, and comorbidity status were obtained through existing hospital databases and electronic medical records. Additional data for the chronic HD patients, including type of vascular access, time since initiation of HD, and presumed etiology of kidney failure, were obtained through existing hospital databases, administrative files, and in the case of uncertainty, consultation with the primary dialysis physicians. Data on body surface area was missing for 1 patient in each group. ECHO image acquisition and analysis
Methods
Existing hospital databases were used to identify all ECHOs that were performed in the aforementioned period. All ECHO investigations were done with high-quality echocardiographic systems equipped with 2.0- to 2.5-MHz transducers (IE33 Philips Ultrasound; Philips Medical Systems, Best, The Netherlands). Each image was recorded digitally (XCelera Echo, Philips Ultrasound) and interpreted by experienced ECHO readers. Cardiac measurements including left ventricular enddiastolic dimension (LVEDD), left ventricular ejection fraction (LVEF), anteroseptal wall thickness, and inferolateral wall thickness were recorded into the database for LVM calculation. The method for calculating LVM with ECHO measurements is described elsewhere.11,19 In brief, data acquisition was performed by M-mode via a parasternal approach, and LV mass was calculated with the cube function formula, as per the American and Canadian Society of Echocardiography guideline recommendations.19
Study population
CMR image acquisition and analysis
A cross-sectional study was performed with patient health record databases at St Michael’s Hospital, a tertiary care, university-affiliated academic centre in Toronto, Canada. All patients receiving maintenance in-centre HD who had both ECHO and CMR with an interstudy interval of ⬍ 60 days
All patients underwent CMR with a 1.5-T whole-body magnetic resonance imaging scanner (Achieva; Philips Medical Systems) that used a phased-array cardiac coil and retrospective vectorcardiographic gating. Images were obtained during breath holds in end-expiration with the patient in supine posi-
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tion. Depending on the LV long-axis length, 8 to 12 contiguous short-axis cine images were required to cover the entire left ventricle. Segmented, balanced steady-state free-precession imaging sequence was used, typically with the following parameters: repetition time, 4 milliseconds; echo time, 2 milliseconds; slice thickness, 8 mm; field of view, 30 to 34 ⫻ 30 to 34 cm; matrix size, 256 ⫻ 196; temporal resolution of ⬍ 40 milliseconds (depending on heart rate); flip angle, 50°. A blinded experienced cardiac imager (A.Y.) reviewed all the CMR studies and completed the image postprocessing using offline commercial software (ViewForum R 4.2; Philips Medical Systems). The standard methods for determining LV volume, LVEF, and LVM have been described in detail elsewhere.20,21 In brief, to determine stroke volume (SV) and LVEF, manual tracing of endocardial borders at end-diastole (left ventricular end-diastolic volume [LVEDV], which represents the maximum ventricular cavity size) and at end-systole (left ventricular end-systolic volume [LVESV], which represents the minimum ventricular cavity size) via short-axis cine images was performed. These measured values were then used to derive SV (LVEDV ⫺ LVESV) and LVEF (SV/LVEDV ⫻ 100%). Endocardial and epicardial borders in contiguous short-axis slices at end-diastole were also traced, and the difference in area multiplied by the slice thickness. The sum of these differences throughout the entire left ventricle was multiplied by the myocardial specific density (1.05 g/cm3) to yield the LVM. LVM values were subsequently indexed by dividing by body surface area (BSA; height in centimetres ⫻ weight in kilograms/3600). Papillary muscles were not included in the LVM measurement.
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(SAS Institute, Cary, NC) and SPSS 15.0 (SPSS Inc, Chicago, IL) were used to conduct the statistical analyses. The institutional research ethics board approved this study and waived the need for consent. Timing of investigations LVM determination may be sensitive to volume status and therefore modified by the receipt of dialysis. We therefore performed a sensitivity analysis in which we considered only ECHO-CMR pairs that had the same temporal relationship to the dialysis sessions. Dialysis shift was compared with the time of performance of each imaging investigation, and each study was classified according to the following definitions: (1) same day of dialysis, predialysis; (2) same day of dialysis, post dialysis; and (3) interdialytic day. For patients who received incentre nocturnal HD, ECHOs or CMRs done the subsequent day were classified as same day of dialysis, post dialysis. Adjustment of LVM By convention, LVM cutoff values for LVH by CMR usually include the papillary muscle mass in their determination.24,25 However, our CMR measurement protocol excluded the papillary muscle mass, which may be difficult to measure accurately.26,27 Furthermore, LVM measurement by ECHO does not include papillary muscles. Accordingly, we performed a sensitivity analysis in which each LVM value was multiplied by a factor of 1.09, based on data indicating that papillary muscle mass accounts for 8.9% of the total LVM in both sexes.28
Definition of LVH Patients were categorized as having LVH or not based on accepted cutoff values for LVM index (LVMI) for ECHO (men ⬎ 115 g/m2, women ⬎ 95 g/m2)19 and CMR (men ⬎ 81 g/m2, women ⬎ 79 g/m2).20 The measured relative wall thickness (RWT) allowed for further classification of LVH as either concentric hypertrophy (RWT ⬎ 0.42) or eccentric hypertrophy (RWT ⱕ 0.42). Primary analysis Continuous variables are presented as means ⫾ SD unless indicated otherwise. The paired t test was used to assess mean difference between various imaging parameters as measured by ECHO and CMR. Agreement between ECHO and CMR was assessed by the Bland-Altman method,22 which involved comparing mean measurements of LVM [(ECHO ⫹ CMR)/2] to the difference in LVM measurements (ECHO ⫺ CMR). The kappa statistic was used to evaluate the agreement beyond chance in the designation of LVH by ECHO and CMR.23 Pearson correlation was used to evaluate the relationship between ECHO-measured LVEDD and the mean difference in LVM across ECHO and CMR. To determine whether the time lag between ECHO and CMR might have accounted for the discrepancy of LVM measurements, we examined the correlation between absolute time interval between ECHO and CMR performance and the absolute difference in LVM. Intraobserver variability was assessed via a random selection of 10 pairs of matched patients whose LVMs were remeasured by the same reader after a significant time lag. Statistical significance was defined to be P ⬍ 0.05 in all instances. SAS Version 9.1
Results Table 1 summarizes the clinical and demographic characteristics of the study population. A total of 41 patients on chronic HD who underwent ECHO and CMR within the 60-day time interval were identified and matched 1:1 with patients in whom renal function was preserved. The underlying etiologies of renal failure for the chronic HD cohort were as follows: diabetes mellitus (36%), glomerulonephritis (31.7%), ischemic nephropathy (14.6%), polycystic kidney disease (2.4%), other (12.2%), and unknown (2.4%). A tunneled central venous catheter was the mode of vascular access in 53%, an arteriovenous fistula in 44%, and an arteriovenous graft in 2%. Among the HD recipients, mean LVM by ECHO and CMR were 184 ⫾ 65 g and 123 ⫾ 37 g, respectively. LVM measurements in the normal renal function group for ECHO and CMR were 167 ⫾ 57 g and 115 ⫾ 43 g, respectively. These and the other measurements are summarized in Table 2. Bland-Altman analysis (see Figures 1A and 1B) demonstrated that the limits of agreement between ECHO and CMR for measuring LVM were wider in the chronic HD group (⫺23 g to 144.6 g) as compared with those with normal renal function (⫺10.5 g to 113.3 g). In almost all instances, compared with CMR, ECHO overestimated LVM in the chronic HD group, and the difference increased with average LVM (r ⫽ 0.89, P ⬍ 0.01). This trend was similar in the control group, albeit with narrower agreement limits. There was no significant relationship between the time lag between ECHO and CMR and the absolute difference in LVM between these 2 imaging modalities (r ⫽ ⫺0.107).
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mean difference in LVM by ECHO was ⫺4.8 g, with limits of agreement of ⫺56.8 to 47.2 g.
Table 1. Demographic and clinical characteristics of study population Chronic HD Total number of patients 41 Women, n (%) 19 (46.3) Age, years 52.1 ⫾ 9.9 Body surface area (m2) 1.82 ⫾ 0.29 Comorbidities, n (% of total) Hypertension 33 (80.5) Dyslipidemia 21 (51.2) Smoking Previous 15 (36.6) Current 3 (7.3) Diabetes mellitus 14 (34.1) Angina 6 (14.6) Myocardial infarction 6 (14.6) Heart failure 6 (14.6) Percutaneous coronary intervention 2 (4.9) Coronary bypass surgery 4 (9.8) Stroke 3 (7.3) Peripheral vascular disease 9 (22) Time on dialysis (months), median (interquartile range) 42.7 (11.1-98.9)
Normal kidney function
P value
41 19 (46.3) 51.7 ⫾ 10 1.88 ⫾ 0.24
NA NA 0.28
15 (36.6) 9 (22)
⬍ 0.001 0.011 0.38
12 (29.3) 5 (12.2) 2 (4.9) 6 (14.6) 2 (4.9) 4 (9.8)
0.002 1.0 0.26 0.74
3 (7.3) 0 (0) 2 (4.9) 0 (0)
1.0 0.12 1.0 0.002
NA
NA
HD, hemodialysis; NA, not applicable.
In the chronic HD group, 37.5% of patients met ECHO criteria for LVH (7.5% eccentric LVH, 30% concentric LVH), whereas 22.5% of patients met LVH criteria (7.5% concentric LVH, 15% eccentric LVH) by CMR. In those with normal renal function, LVH was designated by ECHO in 17.5% of patients (7.5% eccentric LVH, 10% concentric LVH) and by CMR in 12.5% (10% eccentric LVH, 2.5% concentric LVH). Table 3 depicts the agreement in LVH designation by ECHO and CMR in both cohorts. The kappa statistic for the chronic HD group was 0.42 (P ⫽ 0.005), reflecting modest agreement. This is in contrast to the kappa value of 0.81 (P ⬍ 0.001) for the patients with normal renal function which indicates strong agreement. The difference in kappa values between the 2 groups was of borderline statistical significance (P ⫽ 0.050). Comparison between ECHO-determined LVEDD and mean difference in LVM by ECHO and CMR demonstrated that as LVEDD increased (corresponding to left ventricular dilatation), so too did the discrepancy in LVM measured by the 2 imaging tests (r ⫽ 0.375, P ⬍ 0.001). In the random group of patients selected to evaluate intraobserver variability, the mean difference in LVM by CMR was ⫺0.54 g, with limits of agreement of ⫺13.3 to 12.3 g, while
Consideration of studies with the same temporal relationship to dialysis session The mean LVM and LVMI measurements were both slightly lower by ECHO and CMR in the chronic HD group when only studies (n ⫽ 17) done with the same temporal relationship to dialysis were considered. Mean LVM was 175 ⫾ 47 g, while mean LVMI was 117 ⫾ 32 g/m2. Prevalence of LVH was 24% by CMR and 35% by ECHO, although agreement beyond chance was still moderate, with ⫽ 0.44 (P ⫽ 0.057). Analyses accounting for estimated papillary muscle mass When the data were analyzed using CMR-generated LVM values that were adjusted to include papillary muscle mass, the prevalence of LVH by CMR increased to 38%. LVH prevalence by CMR also increased slightly in the normal kidney function group. When intermodality agreement was measured, a of 0.30 (P ⫽ 0.060) was observed in the chronic HD group, with stronger agreement ( ⫽ 0.59, P ⬍ 0.001) among patients with normal kidney function. Discussion As compared with CMR, ECHO systematically overestimates LVM in both chronic HD patients and those with preserved renal function. This discrepancy seems to be accentuated in patients receiving chronic HD in whom there is only moderate agreement in the assessment of LVH between ECHO and CMR. Previous studies have compared the measurement of LVM by ECHO and CMR, with varying degrees of discordance identified. While the overestimation of LVM by ECHO has been demonstrated in end-stage renal disease,29 aortic stenosis,24 and hypertension,30,31 underestimation of LVM was seen in another study involving healthy subjects.32 A major contributor to the inaccuracy in LVM measurement by ECHO relates to the presupposition of an ellipsoidshaped heart.10 However, because of pressure and volume overload in chronic HD recipients, the heart may deviate from normal morphology and exhibit varying types and combinations of hypertrophy.13,33 The endocardial border may not be well defined on ECHO, and left ventricular wall thickness is not uniform across all myocardial segments. Furthermore, the ECHO calculation for LVM is based on a formula that relies heavily on the internal diameter of the left ventricle.34 As a
Table 2. Left ventricular measurements of study population Chronic hemodialysis (n ⫽ 41) Parameter measured LVM (g) LVMI (g/m2) LV ejection fraction (%) LV end-diastolic dimension (mm) Anteroseptal wall thickness (mm) Inferolateral wall thickness (mm)
Normal kidney function (n ⫽ 41)
ECHO
CMR
P value
ECHO
CMR
P value
184 ⫾ 65 101 ⫾ 25 67 ⫾ 10 44 ⫾ 7 12 ⫾ 3 11 ⫾ 2
123 ⫾ 37 68 ⫾ 14 61 ⫾ 8 51 ⫾ 7 12 ⫾ 2 9⫾2
⬍ 0.001 ⬍ 0.001 0.012 ⬍ 0.001 ⬍ 0.001 0.015
167 ⫾ 57 89 ⫾ 43 60 ⫾ 15 47 ⫾ 7 10 ⫾ 3 10 ⫾ 2
115 ⫾ 43 61 ⫾ 22 55 ⫾ 12 57 ⫾ 8 8⫾2 7⫾2
⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.005
CMR, cardiac magnetic resonance imaging; ECHO, echocardiography; LV, left ventricular; LVM, LV mass; LVMI, LVM index.
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Figure 1. Bland-Altman plots of the difference in left ventricular (LV) mass measurements against the mean of the 2 measurements. (A) Chronic hemodialysis: The mean difference in LV mass is 60.8 g, and limits of agreement are ⫺23 to 144.6 g. (B) Normal kidney function: The mean difference in LV mass is 51.4 g, and limits of agreement are ⫺10.5 to 113.3 g. Limits of agreement are wider in the chronic hemodialysis group. CMR, cardiac magnetic resonance imaging; ECHO, echocardiography.
result, LVM determined by ECHO can vary considerably between predialytic and postdialytic periods solely because of fluctuations in intravascular volume and the resulting change in intracardiac volume.35,36 By contrast, CMR measures LVM via direct mathematical integration using 3-dimensional data that does not involve assumptions regarding cardiac geometry or reliance on left ventricular diameter.15,21 CMR, unlike ECHO, is therefore less sensitive to changes in intravascular— and by extension intracardiac—volume.37 The limitations of 2-dimensional ECHO may be mitigated by the use of 3-dimensional ECHO, which correlates better with CMR.38 A seminal study by Stewart et al. demonstrated overestimation of LVM by ECHO compared with CMR (using a freegradient echo sequence at 1.0 T) in chronic HD patients.29 However, there was no control group, and free-gradient echo cine imaging is rarely used nowadays. Our study expands on previous work by evaluating paired ECHO and CMR studies in a comparator group with normal kidney function. While the overestimation of LVM in patients with end-stage renal disease and other populations has previously been demonstrated, to our knowledge this is the first instance in which the degree of
mass bias has been shown to be heightened in chronic HD patients compared with those with normal kidney function. This finding is itself novel and provides evidence that it may be even more important for LVM measurements to be performed by CMR instead of ECHO for patients undergoing chronic HD than for those with normal kidney function. We also evaluated a more contemporary cohort of HD patients using a 1.5-T scanner and steady-state free precession imaging, which is the current standard CMR technique that allows for superior delineation between the blood pool and myocardium.39 Our study has several limitations. First, ECHOs and CMRs could have been performed within an interval of up to 60 days. However, considerable changes in left ventricular geometry and LVM are unlikely to occur during this time. This was confirmed by the lack of correlation between the absolute difference in LVM and time interval between ECHO and CMR studies. Furthermore, since changes in left ventricular geometry occur gradually, studies examining LVM regression over time generally require at least 6 months of follow-up.40 There was no predetermined relationship between ECHO and CMR and the timing of dialysis. Hence, LVM results may have been
Table 3. Agreement in the designation of LVH by ECHO and CMR
Group considered for LVH assessment Chronic HD (n ⫽ 40) Normal kidney function (n ⫽ 40) Chronic HD; adjusted for papillary muscle mass (n ⫽ 40) Normal kidney function; adjusted for papillary muscle mass (n ⫽ 40) Chronic HD; dialysis time concordant (n ⫽ 17)
LVH (by ECHO and CMR)
LVH (by ECHO only)
LVH (by CMR only)
No LVH (by ECHO and CMR
n
%
n
%
n
%
n
%
P value
7 5
17.5 12.5
8 2
20 5
2 0
5 0
23 33
57.5 82.5
0.42 0.81
0.005 ⬍ 0.001
8
20
7
17.5
6
15
19
47.5
0.30
0.060
5
12.5
2
5
3
7.5
30
75
0.59
⬍ 0.001
3
17.6
3
17.6
1
5.9
10
58.8
0.44
0.057
CMR, cardiac magnetic resonance imaging; ECHO, echocardiography; HD, hemodialysis; LVH, left ventricular hypertrophy.
Jakubovic et al. Echocardiography vs CMR for Measuring LV Mass
skewed by transient changes in volume status. Nevertheless, it is reassuring that our findings were largely consistent when we limited our analyses to ECHO-CMR pairs that were performed with the same temporal relationship to dialysis. Our exclusion of papillary muscle mass measurement from LVM determination by CMR may have inflated the mean difference in LVM by ECHO and CMR. However, given that ECHO-based LVM measurements universally exclude papillary muscles, a direct comparison excluding papillary muscles from the CMR protocol is actually more appropriate. Nevertheless, we tried to account for this by performing a sensitivity analysis in which LVM values were adjusted with the best estimate available for papillary muscle. While the prevalence of LVH by CMR increased in the chronic HD group to be almost equivalent to that associated with ECHO, the extent of agreement between ECHO and CMR is similar to the primary analysis. Although our findings suggest that ECHO may lead to an overestimation of LVM and the misclassification of LVH, our data are limited to a cross-section in time. Serial changes in LVM have been shown to be of important prognostic value,6 and whether the significance of such changes depends on imaging modality (ie, CMR vs ECHO) requires further study. Furthermore, although the Bland-Altman analysis demonstrated considerable overlap between the 2 groups, our study was not adequately powered to directly compare the width of the limits of agreement. Despite its limitations, ECHO is advantageous in terms of accessibility and cost. Nevertheless, when it comes to the measurement of LVM and assessment of LVH, the use of ECHO may overestimate the prevalence of LVH in chronic HD recipients. By contrast, CMR—which is less sensitive to volume changes—provides a more accurate LVM measurement irrespective of when it is performed in relation to the dialysis session.37 In recognition of this major drawback of ECHO, clinical trials in which LVM is used as an outcome measure are increasingly relying on CMR. Hence, it is clear that CMR is beginning to emerge as the reference standard in research, particularly in those with left ventricular alterations that may not conform to ECHO geometric assumptions. This study also provides further support for the use of CMR in clinical practice when accurate measurements of LVM are needed. Our findings demonstrate a significant degree of LVM overestimation and increased LVH prevalence by ECHO in chronic HD recipients, compared with individuals with normal renal function. Moreover, the agreement between ECHO and CMR in the designation of LVH is inferior in chronic HD recipients, compared with patients with preserved kidney function. While ECHO will continue to be used in routine clinical practice, evidence is mounting that CMR may afford a more accurate evaluation of cardiac remodelling and associated LVM changes in chronic HD patients, thus providing a superior alternative for cardiac assessment in this population. Funding Sources This study was supported by an operating grant from the Canadian Institutes of Health Research. Baruch Jakubovic was supported by funding from the University of Toronto Faculty of Medicine CREMS Summer Student Program and the Heart and Stroke Foundation of Ontario. Dr Kim Connelly was supported by a Heart and Stroke Foundation of Canada Phase 1
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Clinician Scientist Award. Ron Wald is supported by an unrestricted educational grant from Amgen. Dr Darren Yuen was sponsored by a KRESCENT postdoctoral fellowship and is currently supported by a Canadian Institutes of Health Research fellowship. Dr Andrew Yan is supported by a New Investigator Award from the Heart and Stroke Foundation of Ontario. Disclosures Dr Wald is supported by an unrestricted educational grant from Amgen. The other authors have no conflicts of interest to disclose. References 1. Rostand SG, Brunzell JD, Cannon RO III, Victor RG. Cardiovascular complications in renal failure. J Am Soc Nephrol 1991;2:1053-62. 2. Schietinger BJ, Brammer GM, Wang H, et al. Patterns of late gadolinium enhancement in chronic hemodialysis patients. JACC Cardiovasc Imaging 2008;1:450-6. 3. Mark PB, Johnston N, Groenning BA, et al. Redefinition of uremic cardiomyopathy by contrast-enhanced cardiac magnetic resonance imaging. Kidney Int 2006;69:1839-45. 4. Silberberg JS, Barre PE, Prichard SS, Sniderman SD. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989;36:286-90. 5. Glassock RJ, Pecoits-Filho R, Barbareto S. Increased left ventricular mass in chronic kidney disease and end-stage renal disease: what are the implications? Dial Transplant 2010;39:16-9. 6. Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE. Serial change in echocardiographic parameters and cardiac failure in endstage renal disease. J Am Soc Nephrol 2000;11:912-6. 7. London GM, Pannier B, Guerin AP, et al. Alterations of left ventricular hypertrophy in and survival of patients receiving hemodialysis: follow-up of an interventional study. J Am Soc Nephrol 2001;12:2759-67. 8. Group FHNT, Chertow GM, Levin NW, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010;363: 2287-300. 9. Culleton BF, Walsh M, Klarenbach SW, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA 2007;298:1291-9. 10. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circulation 1977;55:613-8. 11. Devereux RB, Alonso DR, Lutas EM. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450-8. 12. McLntyre CW, Odudu A, Eldehni MT. Cardiac assessment in chronic kidney disease. Curr Opin Nephrol Hypertens 2009;18:501-6. 13. Foley RN, Curtis BM, Randell EW, Parfrey PS. Left ventricular hypertrophy in new hemodialysis patients without symptomatic cardiac disease. Clin J Am Soc Nephrol 2010;5:805-13. 14. McGill RL, Biederman RWW, Getts RT, et al. Cardiac magnetic resonance imaging in hemodialysis patients. J Nephrol 2009;22:367-72. 15. Constantine G, Shan K, Flamm SD, Sivananthan MU. Role of MRI in clinical cardiology. Lancet 2004;363:2162-71.
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