Int J Cardiovasc Imaging DOI 10.1007/s10554-014-0480-2

ORIGINAL PAPER

Impact of hemodialysis, left ventricular mass and FGF-23 on myocardial mechanics in end-stage renal disease: a three-dimensional speckle tracking study Attila Kova´cs • Miha´ly Tapolyai • Csilla Celeng • Edit Gara • Ma´ria Faludi • Kla´ra Berta • Astrid Apor Andrea Nagy • Andra´s Tisle´r • Be´la Merkely

•

Received: 1 March 2014 / Accepted: 25 June 2014 Ó Springer Science+Business Media Dordrecht 2014

Abstract Left ventricular (LV) hypertrophy and one of its inducers, the fibroblast growth factor-23 (FGF-23) were found to be associated with unfavourable outcome in endstage renal disease (ESRD) patients. We sought to investigate the influence of hemodialysis (HD), increased LV mass and FGF-23 on LV mechanics using three-dimensional (3D) speckle tracking echocardiography. Forty-four ESRD patients on maintenance HD were examined just before and immediately after HD, and were compared to 44 normal controls (NC). Transthoracic 3D recordings were obtained using multi-beat reconstruction from 6 consecutive cardiac cycles. LV mass index (LVMi) was evaluated and 3D speckle tracking analysis was performed to calculate global longitudinal (GLS), circumferential (GCS), area (GAS) and radial (GRS) peak systolic strain. Serum FGF23 levels were also measured. Strain values improved in all directions after HD [pre- vs. post-HD; GLS: -20(3) vs. -21(6), GCS: -20(4) vs. -22(7), GAS: -33(5) vs. -35(10), GRS: 50(12) vs. 53.5(20) %, all p \ 0.01]. LVMi was remarkably increased in our patients [ESRD vs. NC; 136(46) vs. 71(8) g/m2, p \ 0.001]. Elevated FGF-23 levels were associated with increased LV mass (q = 0.581,

A. Kova´cs (&)
C. Celeng
E. Gara
A. Apor
A. Nagy
B. Merkely Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, 68 Va´rosmajor Street, Budapest 1122, Hungary e-mail: [email protected] M. Tapolyai
M. Faludi
K. Berta Fresenius Medical Care, Budapest, Hungary A. Tisle´r 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary

p \ 0.001). LVMi was inversely related to pre-HD GCS (q = 0.626, p \ 0.001) and post-HD GCS (q = 0.761, p \ 0.001), GAS (q = 0.534, p \ 0.05) and GRS (q = -0.639, p \ 0.01). Serum FGF-23 levels correlated with post-HD GAS (q = 0.513, p \ 0.01) and GRS (q = -0.512, p \ 0.05). HD treatment results in immediate improvement in all strain directions. Besides inducing LV hypertrophy, FGF-23 may play a role in the deterioration of LV mechanics in patients with ESRD. Keywords FGF-23
End-stage renal disease
Hemodialysis
3D echocardiography
Speckle tracking

Introduction Left ventricular (LV) hypertrophy has been identified as the strongest predictor of cardiovascular mortality in chronic kidney disease (CKD) [1]. Traditional risk factors for increased LV mass include hypervolemia (volume overload), as well as hypertension (pressure overload) in patients on hemodialysis (HD) [2]. Nevertheless, recent studies have also focused on disorders of mineral and bone metabolism [2, 3]. It has been reported earlier that elevated phosphate levels are associated with increased LV mass [4], however, the potential missing link has just been recently revealed. Fibroblast growth factor-23 (FGF-23) is a 251-amino acid protein secreted by osteoblasts, which reduces phosphate reabsorbtion in renal proximal tubules [5]. Serum concentration of FGF-23 increases with the progression of CKD to maintain phosphate homeostasis, however, as a side effect, it also acts as a potent inducer of pathological LV hypertrophy [6]. FGF-23 has been found to be associated with cardiovascular morbidity and mortality in CKD patients [7].

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Since the persistent loss of LV systolic function is a major determinant of survival in end-stage renal disease (ESRD) [8], advanced evaluation of myocardial performance may be beneficial, even if ejection fraction is still preserved. Three-dimensional (3D) transthoracic echocardiography allows us to accurately measure LV volumes and mass, and to quantify all aspects of myocardial deformation [9]. Our aim was to compare the LV mechanics before and after the HD treatment in patients with ESRD using 3D speckle tracking echocardiography. We hypothesized that FGF-23 might have an influence on myocardial structure and function even in HD patients without known cardiovascular disease.

Subjects and methods In our cross-sectional study we enrolled 44 prevalent chronic HD patients, who underwent maintenance hemodiafiltration treatment three times a week. All patients were asymptomatic and complaint-free prior to inclusion. Patients with a medical history of diabetes mellitus, known coronary artery disease, any form of cardiac arrhythmias, any cardiomyopathy or severe valvular disease diagnosed by echocardiography were not included. Our study was designed in accordance with the ethical principles of the Declaration of Helsinki and the protocol was also approved by the Semmelweis University Institutional Committee for Science and Research Ethics (TUKEB 175/2012). All participants provided written informed consent before entering the study. After the physical examination, weight, height and blood pressure were recorded. Body surface area (BSA) was calculated by the Mosteller formula [10]. Transthoracic echocardiography and 3D data analysis were performed by an experienced operator (A.K.) of the device and the software environment (GE Vivid E9 ultrasound system, 4V-D probe and EchoPAC v112 software, GE Healthcare, Horten, Norway) [11]. The echocardiographic protocol was carried out before and after the HD treatment. Special care was taken to perform the echocardiography immediately after the end of the patient’s regular dialysis session. ECG-gated subvolumes from six consecutive cardiac cycles were recorded from apical approach at endexspiratory breath-hold for multi-beat reconstruction of the entire LV. Imaging was optimized for the LV by adequate settings of gain, focus position, sector width and also depth to achieve optimal volume rate (32 ± 4 vps). To measure LV volumes, ejection fraction (EF) and mass, and to perform the 3D speckle tracking analysis a dedicated software was used (4D Auto LVQ, GE Healthcare, Horten, Norway) [12]. After adequate alignment of the imaging planes, the semi-automated endo- and epicardial border detection was

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corrected manually in apical four-, two- and long axis views and also in desired short axis planes, both at the timepoint of end-diastole and end-systole. We respectfully followed the tracing proposals described in a recent publication, where the same software was used in a large cohort [13]. 3D derived LV end-diastolic (EDVi) and endsystolic (ESVi) volumes and mass (LVMi) were indexed to BSA. At speckle tracking analysis, acceptance or rejection of LV segments were guided by the software’s recommendations. After careful assessment of the segmental strain curves by the operator, patients who had more than 3 rejected segments were excluded from the study. We defined global longitudinal (GLS), circumferential (GCS), area (GAS) and radial strain (GRS) as the average peak systolic strain value of the 17 LV segments for the corresponding deformation parameters. Three patients were excluded due to inadequate 3D image quality, and further five patients because their speckle tracking analysis did not fulfill the technical criteria. Forty-four patients were eligible to be included in the statistical analysis. Serum FGF-23 levels (Merck Millipore enzyme-linked immunosorbent assay) and standard laboratory tests were assessed from blood collected immediately before the HD. Hemodialysis sessions of our patients lasted at least 4 h targeting a minimum Kt/V of at least 1.30 and the ultrafiltration rates were limited to 12 mL/kg/h. The amount of ultrafiltration was determined prior to the dialysis session by the number of kilograms above the patient’s estimated dry weight. Ultrafiltration and dialysis were performed with a Fresenius 5008 machine (Fresenius Medical Care Ag.; Bad Homburg, Germany), while receiving online hemodiafiltration. Post-HD blood pressure was measured before the termination of the dialysis session. To compare with ESRD patients, 44 healthy, sedentary volunteers were selected from our normal control (NC) database (anthropometric, blood pressure measurements and echocardiographic data are available). For statistical analysis SPSS software version 20 (IBM, Armonk, NY, USA) was used. The majority of our variables failed to show normality using Shapiro–Wilk test, therefore, comparisons of related samples were carried out with Wilcoxon signed-rank test, non-related samples with Mann– Whitney U test. Relationships were calculated with either the Spearman correlation test or multivariate linear regression. Data are presented as median (interquartile range). p values under 0.05 were considered statistically significant.

Results Basic demographic characteristics and the results of relevant laboratory tests of ESRD patients are summarized in Table 1. These patients represent a chronically hemodialyzed but well

Int J Cardiovasc Imaging Table 1 Demographic characteristics of the study groups and laboratory test results of the patients

n

ESRD

NC

44

44

Table 2 Comparison of the three-dimensional volumetric and strain parameters NC 55.9 (13.7)

56.3 (17.2)

55.6 (13.9)#

19.2 (4.3)

19.6 (8.6)

19.3 (5.7)#

63 (9.5)

66 (10)#

48 (24)

48 (23)

Male (%)

55

50

Height (cm)

168 (17)

171 (15)

Pre-dialysis weight (kg)

72 (27)

72 (12)

Left ventricular endsystolic volume index (mL/m2)

BMI (kg/m2)

24 (4)

24 (3)

Ejection fraction (%)

1.8 (0.3) –

1.8 (0.2) 125 (20)

Global longitudinal strain (%)

Pre-dialysis

160 (33)

–

Post-dialysis

134 (46)

–

Global circumferential strain (%)

–

78 (10)

Global area strain (%)

Pre-dialysis

89 (17)

–

Global radial strain (%)

Post-dialysis

80 (23)

–

Data are presented as median (IQR)

BSA (m ) Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Post-HD

Left ventricular enddiastolic volume index (mL/m2)

Age (years)

2

Pre-HD

64 (4)

-20 (3)

-21 (6)#

-21 (3)

-20 (4)*

-22 (7)#

-36 (3)

-33 (5)*

-35 (10)*,#

-20.5 (3)

61 (8)

50 (12)*

53.5 (20)*,#

Weeks on maintenance hemodialysis

51 (68)

Residual urine (mL/day)

0 (450)

NC normal controls, pre-HD patients before hemodialysis, post-HD patients after hemodialysis

Arteriovenous fistula (%)

84

* p \ 0.05 versus NC,

#

p \ 0.05 versus pre-HD values

Antihypertensive medications (%) None

57

One

27

Two

11

Three Creatinine (lmol/L) Blood urea nitrogen (mmol/L)

5 767 (331) 20 (7)

Hemoglobin (g/L)

113 (16)

C-reactive protein (mg/L)

13 (11)

Albumin (g/L)

39 (3)

Parathyroid hormone (pg/mL)

314 (406)

Fluid removal (L)

3.0 (1.8)

Data are presented as median (IQR) BMI body mass index, BSA body surface area, ESRD end-stage renal disease, NC normal controls

treated population with long-standing ESRD. Antihypertensive medications are minimized. The NC group is age- and gender-matched. Anthropometric details were also similar (Table 1). LV mass and mass index were remarkably increased in ESRD patients compared to NC [LV mass: 244(97.5) vs. 130(24) g, LVMi: 136(46) vs. 71(8) g/m2, p \ 0.001]. Serum FGF-23 levels ranged between 34 and 6848 with a median of 687 pg/mL in this patient population. Not surprisingly, the phosphaturic hormone correlated with serum phosphate (q = 0.832, p \ 0.001) and parathyroid hormone (q = 0.556, p \ 0.001) levels. It was also associated with LVMi (q = 0.401, p = 0.025), but even stronger with LV mass without indexing (q = 0.581, p \ 0.001). EDVi and ESVi decreased, whilst EF and strain values improved in all directions after HD (Table 2; Fig. 1). GLS

was not significantly different either before or after HD compared to NC value. Nevertheless, the patients’ baseline GCS, GAS and GRS values were reduced, and after HD only GCS increased enough to reach the normal level (Fig. 1). Pre-HD GCS correlated with pre-HD systolic blood pressure (q = 0.409, p = 0.047), post-HD GCS with post-HD systolic blood pressure (q = 0.585, p = 0.017). Only the improvement in GLS was associated with the changes of LV volumes (DEDVi: q = -0.565, p = 0.022, DESVi: q = -0.525, p = 0.037), the increase of other strain parameters did not show any relation to volumetric changes. Left ventricular mass index was inversely correlated with pre-HD GCS (Table 3). However, after the HD LVMi was strongly associated with GCS, GAS and GRS as well. EF was heavily determined by the deformation parameters, but their values became even more related after HD. GCS was found to be the only independent predictor of EF among strain parameters both before (b = -0.884, adjusted R2 = 0.782, p \ 0.001) and after hemodialysis (b = -0.886, adjusted R2 = 0.785, p \ 0.001). Significant inverse correlations were found between serum FGF-23 levels and post-HD GAS and GRS values (Table 3).

Discussion To the best of our knowledge, this is the first study which has investigated uremic cardiomyopathy both before and after HD by quantifying LV mass and deformation using

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Int J Cardiovasc Imaging Fig. 1 Comparison of threedimensional strain parameters in normal controls (NC, n = 44) and in end-stage renal disease patients (n = 44) before (preHD) and after (post-HD) regular dialysis session. Data are presented as median (IQR). *p \ 0.05 versus NC, #p \ 0.05 versus pre-HD values

Table 3 Correlation matrix between strain parameters, FGF-23 levels, LVMi and EF both before and after HD GLS Pre-HD

GCS Post-HD

Pre-HD

GAS Post-HD

GRS

Pre-HD

Post-HD

Pre-HD

Post-HD

FGF-23

0.281

0.043

0.274

0.385

0.271

0.513*

-0.371

-0.512*

LVMi

0.367

0.459

0.626**

0.761**

0.377

0.534*

-0.329

-0.639*

-0.445*

-0.626*

-0.789**

-0.834**

-0.582*

-0.786**

EF

0.616**

0.695*

Spearman rank-correlation test EF ejection fraction, FGF-23 fibroblast growth factor-23, GAS global area strain, GCS global circumferential strain, GLS global longitudinal strain, GRS global radial strain, LVMi left ventricular mass index, pre-HD before hemodialysis, post-HD after hemodialysis * p \ 0.05, ** p \ 0.001 Italic values indicate key results of the study

3D echocardiography. In addition, we have also measured serum FGF-23 levels and described its correlation with strain parameters for the first time. Uremic cardiomyopathy is first and foremost characterized by increased LV mass [14]. Conventionally, increased pre- and afterload were considered to be responsible for this alteration. Nowadays, we believe that LV hypertrophy is more than just cardiac adaptation with pathological consequences. Cardiomyocytes are directly affected by the chronic uremic state and one of the most important toxins may be the FGF-23. However, substantive investigation of the effects of uremia and HD is difficult, because micro- and macrovascular ischemia significantly deteriorates myocardial

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mechanics and results in LV remodelling [15, 16]. Accordingly, we recruited non-diabetic ESRD patients, with no known history and symptoms of coronary artery disease to minimize this overlap. Imbalance in myocardial perfusion, diastolic and systolic dysfunction, and finally heart failure can all be evident consequences of pathological hypertrophy. Impaired relaxation is usually the first sign of the deterioration of LV mechanics in the presence of increased LV mass [17]. However, even subtle changes in systolic function can also be measured using the speckle tracking technique. In our cohort, no wall motion abnormalities could be detected visually, in line with the preserved EF compared to healthy subjects. Longitudinal strain was similar to control values

Int J Cardiovasc Imaging

both before and after HD, suggesting the absence of relevant subendocardial ischemia [18]. There are conflicting data in the literature regarding longitudinal function, albeit most of the studies reported its decrease in similar populations [19–21]. It has been also shown that longitudinal strain is lower in moderate-advanced CKD patients compared to ESRD patients undergoing maintenance HD, whose GLS was similar to the control group [22]. These results may refer to the heterogeneity of patient selection, timepoint of the evaluation, comorbidities, or even the pattern of LV hypertrophy [19]. Prior to HD, global circumferential, radial and area strains were all lower in our patients. However, HD resulted in immediate improvement in all analyzed directions of myocardial deformation, which points to the relief from overhydration gained during the interdialytic period. Although this improvement is scant, the long-term effects of such overhydration burden can not only be detectable, but also clinically significant, even in this population with no other cardiovascular disorders. Careful monitoring of systolic dysfunction may help in the selection of the type of renal replacement therapy and also in the optimal timing of transplantation to improve survival [23–25]. Closer relationships between EF and strains may indicate that post-HD evaluation can reveal the real state of LV mechanics, free from the volume- and pressure overload. Nevertheless, after the HD treatment only global circumferential strain increased enough to be similar compared to controls (Fig. 1), while exclusively correlating with the actual blood pressure. As GCS is found to be the only independent predictor of EF both before and after HD, its increase may be responsible for the majority of the systolic improvement reflected by the higher EF. Altekin and coworkers also confirmed the superiority of circumferential shortening in generating EF in a less selected HD population using 2D speckle tracking [26]. Despite increasing EF and overall improvement of LV mechanics after HD, global area and radial strains remained significantly depressed compared to the values of healthy volunteers. We may hypothesize that deformation in these directions is mostly determined by the chronic effects and not by the actual overload. Long-standing uremia and ensuing increase of LV mass can be the causes, as it can be presumed from the strong correlations found between strain values and LVMi (Table 3). These two components were found to be also heavily affected in a recent study involving patients with hypertension-induced hypertrophy [27]. Elevated serum FGF-23 levels correlated well with the increase of LV mass in our patients. Wald and coworkers have recently published an elegant cardiac MRI study about prevalent HD recipients in the Journal and surprisingly could not observe the same relationship [28]. However, this association is well-known from previous studies,

and is also supported by our own work [29]. Differences in patient selection and the significant LV hypertrophy existing in our population may lie behind the disagreement between our results. Furthermore, we found significant correlations between elevated serum FGF-23 levels and reduced area and radial strains. FGF-23 induced LV hypertrophy can be an unequivocal explanation of this association, but direct effects of the hormone can also play a remarkable role as a mediator of injury. Touchberry et al. demonstrated that FGF-23 also regulates calcium homeostasis and contractility in cardiomyocytes [30]. Well-conducted experiments proved that FGF-23 acutely increases intracellular calcium, however, the authors hypothesized that chronic effects could be similar to stress hormones leading to contractile dysfunction and cardiac remodelling. This corresponds well with a follow-up study, where increasing FGF-23 levels were independently associated with decreasing EF in a large chronic HD population [31]. Accordingly, FGF-23 may be an important uremic toxin of the myocardium for multiple reasons: by inducing LV hypertrophy and also by directly deteriorating myocardial mechanics.

Limitations An obvious limitation of our study is its cross-sectional, single center approach. A strict selection had to be made in our HD population to exclude diabetic and ischemic cardiomyopathy patients. Both pathologies significantly interfere with myocardial deformation [15, 32], but our aim was to investigate uremic cardiomyopathy per se. This resulted in a reduced sample size and less generalizability. We did not perform coronary angiography to exclude coronary artery disease. Our data could be biased by the phenomenon of hemodialysis-induced wall motion abnormalities, although it is also reported that such myocardial dysfunction is more frequent in patients with diabetes or other history of cardiovascular disease [33]. Instability of body fluid distribution after HD may affect cardiac load [34].

Conclusions Myocardial deformation improved in all directions after the HD treatment. While longitudinal strain was found to be preserved, area and radial strains are significantly affected by the LV hypertrophy and potentially by the endocrine effects of FGF-23 in patients with ESRD. Acknowledgments Authors are grateful to GE Healthcare for equipment support and to Fresenius Medical Care for allowing our

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Int J Cardiovasc Imaging study. This work was supported by the Hungarian Scientific Research Fund (Grant Number 105555). 14. Conflict of interest

None. 15.

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