Cardiac dysfunction is common among patients with end-stage renal disease. The aim of this study was to explore the determinants of diastolic dysfunction in patients with end-stage renal disease on maintenance hemodialysis.
Patients with asymptomatic end-stage renal disease undergoing hemodialysis underwent Doppler tissue imaging analysis and two-dimensional speckle-tracking echocardiography with strain analysis. Blood studies included albumin, cardiac troponin T, and procollagen type I C-terminal peptide (PICP).
All enrolled patients had left ventricular (LV) diastolic dysfunction and were stratified into two groups by a cutoff value of 13 for the ratio of early transmitral flow velocity to the average early diastolic annular velocity (E/e′). Seventy-two of the enrolled patients (87%) had grade 1 diastolic dysfunction, and 11 patients (13%) had higher grades of diastolic dysfunction. The study population did not include a representative sample of patients with the pseudonormal or restrictive filling patterns of diastolic dysfunction. There were no significant differences in gender, age, LV geometric change, ejection fraction, global systolic longitudinal strain and strain rate, and prevalence of comorbidities between groups. Patients with average E/e′ ≥ 13 had higher PICP, which was significantly correlated with cardiac troponin T, average E/e′, and systolic circumferential strain rate. By multivariate regression analysis, average E/e′ level was an independent factor of PICP level ( P = .047).
Hemodialysis patients with high average E/e′ ratios showed increased levels of LV filling pressure and higher severity levels of cardiac fibrosis, which occurred before the development of systolic dysfunction. PICP was a potential indicator of diastolic dysfunction and increased LV filling pressure.
Patients with end-stage renal disease (ESRD) have a notoriously high incidence of cardiovascular mortality and morbidities. Abnormal left ventricular (LV) geometry is common in patients with ESRD and is correlated with poor prognosis. Hemodialysis-induced myocardial stunning precipitated by ischemia is a well-known complication. Repetitive subclinical ischemia may gradually reduce cardiac contractility or relaxation. Using two-dimensional speckle-tracking echocardiography with myocardial deformation analysis (also called two-dimensional strain imaging analysis), there is subtle systolic dysfunction in patients with ESRD despite preserved LV ejection fractions (LVEFs; ≥50%). Furthermore, diastolic dysfunction is also common and associated with poor prognosis in patients with ESRD.
Causes of LV diastolic dysfunction are multifactorial. There is evidence that impairment of LV diastolic relaxation develops along with activation of circulating plasminogen activator inhibitor–1. In addition, myocardial fibrosis is a major determinant of diastolic function. The serum level of procollagen type I C-terminal peptide (PICP) has been suggested as a useful marker of cardiac fibrosis. However, the causative factors and plausibly resultant biomarkers associated with LV diastolic dysfunction in patients with ESRD remain unclear.
Thus, we conducted this study to analyze the effect of maintenance dialysis therapy on LV diastolic function and to explore the plausible determinants of diastolic dysfunction among patients undergoing dialysis without decompensated heart failure or excess fluid accumulation.
All enrolled subjects were adults (≥18 years old). The hemodialysis group consisted of consecutive patients with ESRD receiving a maintenance hemodialysis program, 4-hour sessions thrice per week, for >3 months at two community hospitals in Taiwan: National Cheng Kung University Hospital Dou-Liou Branch and Catholic Fu-An Hospital. The study protocol was approved by the human research and ethics committee of National Cheng Kung University Hospital (ER-98-073). Participants gave their informed consent.
The exclusion criteria were (1) moderate to severe valvular heart disease (including mitral or aortic regurgitation or stenosis), (2) an active episode of decompensated heart failure presenting with pulmonary edema, (3) acute coronary syndromes or atrial fibrillation, (4) reduced LVEF (<50%), and (5) inadequate echocardiographic image quality.
It was confirmed that all dialysis patients took their medications regularly and were undergoing dialysis on the basis of prescribed dialysis regimens, frequencies, and dosages. Dialysis adequacy, as measure by Kt/V, and creatinine clearance were evaluated on the basis of the recommendations in the Kidney Disease Outcomes Quality Initiative.
Data were collected through medical history and laboratory findings. Medication compliance was ascertained carefully by questionnaire and personal interviews. Blood samples were collected without anticoagulants, and the samples were separated by centrifugation. Sera were frozen and stored at −80°C until analysis. Sera were thawed to measure the levels of cardiac troponin T, high-sensitivity C-reactive protein, interleukin-6, plasminogen activator inhibitor–1, and PICP. Serum albumin, calcium, phosphate, total cholesterol, and triglyceride levels were determined using an automatic analyzer at National Taiwan University Hospital Yunlin Branch.
All patients were examined in the left lateral decubitus position, using a commercially available ultrasound system with a 3.5-MHz probe (Vivid I or Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway). Two-dimensional speckle-tracking echocardiography and Doppler tissue imaging were obtained as described elsewhere. According to the recommendation of the American Society of Echocardiography (ASE), we measured LV mass index, LV volume, LVEF, left atrial volume index, and mitral inflow pattern using pulsed-wave Doppler, positioned at the mitral leaflet tips during diastole at end-expiration. These measurements included the peak early (E) and late (A) diastolic velocities, the E/A ratio, and the deceleration time of E velocity. Furthermore, mitral annular calcification (MAC) was defined as the presence of dense echo structure located at the junction of the atrioventricular groove and the posterior or anterior mitral leaflet on the parasternal long-axis, apical four-chamber, or two-chamber view. With regard to the maximal thickness of the dense echo structure, prescribed previously, the severity of MAC was categorized into two groups: mild to moderate (1–4 mm) and severe (>4 mm).
We used color flow imaging to determine the absence or presence of mitral or aortic regurgitation. According to ASE recommendations, the severity of mitral or aortic regurgitation was graded using the following measurements: jet area, vena contracta width, and structural parameters (i.e., mitral and aortic leaflet, left atrial, and LV size). We also measured the pressure half-time of the regurgitant jet for aortic regurgitation severity grading. The results were averages of three measured values.
Pulse Doppler tissue imaging of mitral annular movement was acquired from the apical four-chamber view when a 2-mm sample volume was placed sequentially at the septal and lateral sides of the mitral annulus. To obtain the peak systolic (s′) and early diastolic (e′) velocities, we measured three end-expiratory beats and averaged these values for further analysis. On the basis of ASE recommendations, we used an average e′ velocity, acquired from the septal and lateral sides of the mitral annulus, to calculate the ratio of mitral inflow E velocity to e′ velocity (average E/e′).
Speckle-tracking echocardiographic images were acquired in the three standard apical views (apical four-chamber, apical two-chamber, and apical long-axis) for three consecutive cardiac cycles at a frame rate of 50 to 90 frames/sec and stored digitally for subsequent offline analysis. Peak systolic longitudinal strain was obtained automatically from the three standard apical views by automated function imaging software, and the average value of peak systolic longitudinal strain from the three apical views was regarded as global longitudinal strain. Additionally, systolic longitudinal strain rate was simultaneously acquired from these three apical views and averaged for further analysis. Also, we assessed the six LV segments on the parasternal short-axis view at the midpapillary level to obtain circumferential and radial strain and strain rate. Two cardiologists performed offline analysis using commercial software (EchoPAC workstation, BT08; GE Healthcare, Haifa, Israel) without knowledge of all clinical information.
Inferior Vena Cava (IVC) Diameter Measurement in Patients with ESRD
To evaluate the fluid status of patients with ESRD, we measured IVC diameter twice at the end of expiration in a subxiphoid location and just proximal to the junction of the hepatic veins that lie approximately 0.5 to 3.0 cm proximal to the ostium of the right atium. The average value of the measured end-expiratory IVC diameter was defined as IVCe. It has been reported that IVCe > 1.53 cm is a marker of overhydration in patients with ESRD. Moreover, on the basis of ASE recommendations, right atrial pressure was estimated by IVC diameter and the presence of inspiratory collapse.
Between-group differences were assessed using Student’s t tests or one-way analysis of variance, as appropriate, or using χ 2 tests for categorical variables to identify the significant parameters of diastolic dysfunction and PICP level. Multivariate linear regression analysis was used to assess the independent factors of PICP level. Two-sided P values < .05 were considered statistically significant.
Initially, 90 patients with ESRD with maintenance hemodialysis were included. After applying the exclusion criteria, we excluded seven patients (8%) because of moderate mitral regurgitation ( n = 2), moderate aortic regurgitation ( n = 1), chronic atrial fibrillation ( n = 2), and a lack of lateral mitral annular e′ velocity because of large angulation (>30°) between the ultrasound beam and the plane of cardiac motion ( n = 2). There was no patient with at least moderate mitral or aortic stenosis among the enrolled patients. All participants presented with LV hypertrophy and diastolic dysfunction. As previously described, diastolic filling patterns were classified as normal in zero patients, impaired relaxation in 72 (87%), pseudonormal in eight (10%), and restrictive in three (3%). Most of the enrolled patients had grade 1 diastolic dysfunction, and the numbers of patients with pseudonormal and restrictive filling patterns were too small to include these patients in comprehensive comparisons of factors influencing the severity of diastolic dysfunction. According to ASE recommendations, the enrolled patients were categorized into two groups by a cutoff value of 13 for average E/e′. Demographic data, concomitant diseases, and medications are shown in Table 1 . The high average E/e′ group (E/e′ ≥ 13) had significantly higher levels of PICP ( Table 2 ). Figures 1 and 2 are echocardiographic images of one individual from each group.
|Variable||E/e′ < 13 |
( n = 42)
|E/e′ ≥13 |
( n = 41)
|Age (y)||65.5 ± 10.8||68.5 ± 11.7||.23|
|Men||19 (45%)||11 (27%)||.08|
|BMI (kg/m 2 )||22.3 ± 2.6||21.0 ± 3.0||.05|
|SBP (mm Hg)||145.3 ± 17.8||147.7 ± 13.5||.50|
|DBP (mm Hg)||77.2 ± 11.1||77.1 ± 6.9||.97|
|Heart rate||75.3 ± 11.9||75.6 ± 12.5||.89|
|Years on renal replacement therapy||6.0 ± 4.8||6.5 ± 5.6||.66|
|Clinical characteristics (%)|
|CAD||16 (38%)||12 (29%)||.35|
|Diabetes mellitus||18 (43%)||23 (56%)||.23|
|Hypertension||36 (86%)||35 (85%)||.75|
|Hyperlipidemia||9 (21%)||12 (29%)||.49|
|Cardiovascular drugs (%)|
|CCBs||24 (57%)||23 (56%)||.82|
|β-blockers||18 (43%)||21 (51%)||.51|
|ACE inhibitors/angiotensin II antagonists||23 (55%)||24 (59%)||.82|
|Statins||5 (12%)||7 (17%)||.53|
|Variable||E/e′ < 13 |
( n = 42)
|E/e′ ≥13 |
( n = 41)
|Albumin (g/dL)||3.4 ± 0.4||3.2 ± 0.4||.17|
|Calcium (mg/dL)||9.3 ± 0.8||9.2 ± 0.7||.36|
|Phosphate ( mg/dL)||4.5 ± 1.2||4.4 ± 1.4||.63|
|Cholesterol (mg/dL)||165.7 ± 34.7||156.3 ± 37.5||.25|
|Triglyceride (mg/dL)||159.5 ± 23.4||119.6 ± 11.1||.13|
|Cardiac troponin T (ng/mL)||0.042 ± 0.007||0.049 ± 0.009||.55|
|hsCRP (mg/dL)||0.84 ± 0.21||1.32 ± 0.32||.22|
|IL-6 (pg/mL)||12.6 ± 1.6||12.7 ± 1.5||.95|
|PAI-1(ng/mL)||178.6 ± 14.0||201.1 ± 35.1||.56|
|PICP (ng/mL)||753.7 ± 53.0||999.8 ± 67.6||.006|
The results of echocardiography are shown in Table 3 . There were no significant differences in LV systolic function parameters (i.e., LVEF, s′, and systolic strain or strain rate) between these two groups. With regard to diastolic function, both groups had diastolic dysfunction, and most patients had abnormal relaxation. It has been reported that strain rate imaging detects LV diastolic dysfunction accurately but is not superior to the E/e′ ratio. In this present study, we obtained the similar result that there was no significant difference of strain rate in early diastole between groups, but the difference of average E/e′ was significant ( Table 3 ).
|Variable||E/e′ < 13 |
( n = 42)
|E/e′ ≥13 |
( n = 41)
|LVEDV index (mL/m 2 )||69.7 ± 17.5||70.4 ± 21.2||.89|
|LVM index (gm/m 2 )||148.7 ± 51.8||149.6 ± 53.9||.94|
|LVEF (%)||65.5 ± 6.0||63.2 ± 5.6||.08|
|s′ (cm/sec)||8.9 ± 1.8||8.2 ± 1.7||.08|
|LV GLS (%)||−18.5 ± 3.7||−18.0 ± 4.2||.52|
|LSRs (sec −1 )||−1.00 ± 0.21||−0.95 ± 0.23||.26|
|LSRe (sec −1 )||0.83 ± 0.29||0.80 ± 0.30||.65|
|SC (%)||−21.9 ± 6.0||−19.7 ± 6.0||.14|
|CSRs (sec −1 )||−2.0 ± 0.4||−1.9± 0.7||.54|
|CSRe (sec −1 )||1.7 ± 0.6||1.7 ± 0.6||.93|
|SR (%)||39.1 ± 19.2||35.0 ± 17.4||.35|
|RSRs (sec −1 )||2.9 ± 0.9||2.5 ± 1.3||.19|
|RSRe (sec −1 )||−1.8 ± 0.9||−2.2 ± 1.3||.15|
|LAVi (mL/m 2 )||36.1 ± 8.9||35.1 ± 7.2||.67|
|E (m/sec)||0.66 ± 0.16||0.95 ± 0.33||<.001|
|A (m/sec)||0.94 ± 0.21||1.14 ± 0.40||.01|
|E/A ratio||0.70 ± 0.18||0.83 ± 0.53||.01|
|DT (msec)||241.0 ± 91.4||251.0 ± 56.2||.69|
|e′ (cm/sec)||6.2 ± 1.6||4.9 ± 1.5||<.001|
|a′ (cm/sec)||10.1 ± 2.5||9.0 ± 2.6||.29|
|E/e′ ratio||10.6 ± 1.9||19.9 ± 6.9||<.001|
|IVCe (cm)||1.25 ± 0.26||1.32 ± 0.28||.27|
|RA pressure (mm Hg)||3.41 ± 1.38||3.32 ± 1.97||.84|