Patients with end-stage renal disease (ESRD) have a high mortality rate, primarily due to cardiovascular causes.1 Arterial factors including atherosclerosis and arteriosclerosis2–5 and ventricular remodeling and performance, such us left ventricular (LV) systolic dysfunction6 and LV hypertrophy (LVH), are all major determinants of mortality in ESRD patients.7 There is high prevalence of LVH8 and the association between diastolic dysfunction and LVH has been illustrated in patients with ESRD.9 However, the prognostic significance of diastolic dysfunction in ESRD patients with preserved systolic function is not comprehensively understood.
Tissue Doppler imaging (TDI) is a technique used to assess myocardial motion, which is a sensitive index of ventricular relaxation; it is less dependent on the loading condition and is therefore a more reliable diastolic function index. At present, the early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/E’) ratio is used to evaluate LV filling pressure, and it has been used as a marker for the diagnosis of diastolic heart failure.10,11
In the current study, it was investigated whether the E/E’ ratio and/or E’ could predict the incidence of mortality and hospitalization in ESRD patients receiving regular hemodialysis and who had preserved LV systolic function.
A total of 126 patients were assessed for inclusion in the present study. Patients were eligible for inclusion if they had been on maintenance hemodialysis for at least 3 months on dry body weight, as determined by their physician. Subjects with systolic function impairment, which was defined as left ventricular ejection fraction (LVEF) <50%, were excluded from the study. A total of 103 hemodialysis patients (51 men, 52 women) with a mean age of 51 ± 14 years were consecutively enrolled in the study. Sixteen of the patients (8.7%) had diabetes. All subjects provided written informed consent prior to their inclusion in the study, which had been approved by the institutional review board at the Taipei Veterans General Hospital. All participants received a comprehensive cardiovascular examination and blood tests on a mid-week nondialysis day.
2.2. Echocardiography and cardiac measurements
Two-dimensional echocardiography was performed according to the recommendations of the American Society of Echocardiography.12 LVEF was measured using the two-dimensional guided M-mode method, and the left atrial (LA) volume was measured using the cylinder method with two orthogonal apical views.12 The LV mass index was the LV mass divided by body surface area. The trans-mitral blood flow was measured using pulsed-wave Doppler in an apical four-chamber view. The rate of early diastolic blood flow (peak velocity of the mitral early filling, E), the rate of late diastolic blood flow (peak velocity of the mitral late filling, A), the ratio of E/A, and the deceleration time of the E wave were measured. The early mitral annular velocity (E’) was measured by tissue Doppler at septal site and the E/E’ ratio was calculated.
2.3. Arterial factors
Arterial structure and function were assessed using ultrasound (Philips SONOS 5500, Andover, MA, USA) and arterial tonometry. Supine brachial systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated by taking the average of four measurements obtained using an oscillometric device. Pulse pressure (PP) was the difference between SBP and DBP. Mean blood pressure was DBP + 1/3 PP. The measured arterial structural parameter was carotid intima-media thickness (cIMT). The arterial functional parameters included aortic pulse wave velocity (PWV) and the carotid augmentation index, which were acquired as previously reported.13
The date and causes of death for the deceased patients were collected by both telephone contact and review of hospital charts and death certificates, which were coded according to the International Classification of Disease, Ninth Revision (ICD-9). The ICD-9 codes used for cardiovascular death were 390-459.
2.5. Statistical analysis
Normally distributed continuous variables were presented as the mean ± SD and categorical variables were expressed as absolute numbers and relative frequencies. Student’s t-test or χ2 tests were used to analyze the baseline characteristics where appropriate. Cox proportional hazard models were used to evaluate the independence of the tissue Doppler index in the prediction of outcomes, with adjustments for confounders. The prognostic differences across the subgroups were analyzed using Kaplan–Meier survival analysis. All statistical analyses were performed using SPSS software version 17.0 (SPSS, Inc., Chicago, IL, USA). All tests performed were two-sided and a p-value < 0.05 was considered to indicate a statistically significant difference.
There were 20 deaths and 46 hospitalizations during a follow-up period of 67.9 ± 20.2 months. There were eight cardiovascular and 12 noncardiovascular deaths. Table 1 lists the baseline characteristics of the study population and a comparison of the death and survival groups. The average time after initiation of dialysis was 36.0 ± 24.2 months. The etiologies of ESRD included chronic glomerulonephritis (36.1%), chronic interstitial nephritis (10.4%), diabetes nephropathy (9.5%), and others (including lupus nephritis, hypertensive nephrosclerosis, and polycystic kidney disease; 20%). The remaining cases were of unknown etiology. The death group was characterized by older age, larger LA diameter, lower E’, higher E/E’ ratio, and increased PWV and cIMT, compared with the survival group (Table 1). Underlying comorbidities, including hypertension, diabetes, and cardiovascular disease were similarly distributed across both groups.
3.1. Predictors of mortality and hospitalization
The risk factors associated with all-cause mortality and hospitalization are shown in Table 2. Age, cIMT, PWV, LA diameter, E’, and E/E’ were all significant predictors of all-cause death and/or hospitalization (Table 2). Underlying diseases, such as diabetes or cardiovascular diseases could predict neither morality nor hospitalization. A Kaplan–Meier curve showed that those with high LV end-diastolic pressure (E/E’ ≥ 15) had an increased risk of hospitalization (Fig. 1). In multiple cox proportional hazard models, E’ could predict mortality (hazard ratio [HR] 0.682 and 95% CI 0.472-0.985 per-1SD) after accounting for age, cIMT, and PWV (Table 3). The E/E’ ratio was an independent predictor of the risk of hospitalization (HR 1.235 and 95% CI 1.115-1.368 per-1SD) (Table 3).
3.2. Determinants of E’ and the E/E’ ratio
To investigate any correlations between E’ and the E/E’ ratio, stepwise multiple linear regression analysis was performed using age, LV mass index, PWV, LA diameter, and the concentrations of serum calcium and phosphates. PWV, age, and LV mass index formed the maximum predictive model for E’ and the attributable proportions of the total explained variance were 73.4%, 17.3%, and 9.5%, respectively (Fig. 2A). Regarding the E/E’ ratio, it significantly correlated with LA diameter, age, and LV mass index, and the attributable proportions were 65.1%, 20.7%, and 14.1%, respectively (Fig. 2B).
In the present study, it was found that diastolic dysfunction, as evaluated by tissue Doppler, was an independent predictor of hospitalization and all-cause mortality in patients with ESRD receiving regular hemodialysis and with preserved LVEF. It was further illustrated that LA diameter, LV mass, arterial stiffness, and age were major determinants of diastolic dysfunction.
4.1. Arteriosclerosis, atherosclerosis, and LVH in ESRD patients
The mortality rate of ESRD patients remains high despite advances in dialysis facilities and techniques; cardiovascular disease is the leading cause of mortality in these patients. Previous studies have demonstrated that both arteriosclerosis and atherosclerosis are major determinants of outcomes in ESRD patients.2–5 In addition to these arterial factors, LV systolic dysfunction and LVH are also associated with unfavorable outcome in ESRD patients.6,7,14 There is a high prevalence of LVH8 in patients with ESRD; however, the prevalence of LV systolic dysfunction is less frequent.14,15 A significant portion of ESRD patients present with LVH and diastolic dysfunction,9 and the prevalence of diastolic dysfunction increased as renal function deteriorated in patients with autosomal dominant polycystic kidney disease.16
4.2. TDI parameters as clinical risk factors in ESRD
Diastolic function has been shown to be a predictor of mortality and cardiovascular events in patients with chronic kidney disease.9 Han et al17 demonstrated that diastolic dysfunction is an independent predictor of cardiovascular outcomes in dialysis patients with preserved LV systolic function. These studies highlighted the importance of diastolic function in the evaluation and follow-up of ESRD patients; however, they did not consider arterial factors. There is complex ventricular-arterial coupling in ESRD patients.13 Previous studies have demonstrated that LVH and diastolic dysfunction are associated with vascular calcification and arterial stiffness.18,19 The findings of the current study further support that the diastolic function index, as determined by TDI, can independently predict mortality and hospitalization after considering the important arterial factors.
To minimize the effect of volume status on the E/E’ ratio, which was considered to be less preload dependent, an echography was performed after dry weight was achieved and on the next day after hemodialysis. After adjusting for confounding factors, E’ and the E/E’ ratio were still significant predictors of poor outcomes in ESRD patients undergoing hemodialysis. This finding is consistent with previous studies.17,20,21 The E/E’ ratio has been recommended as a noninvasive tool for estimating the LV filling pressure and is widely used in clinical echocardiography.11 It should also be considered during the evaluation of cardiovascular status in ESRD patients.
4.3. Determinants of diastolic dysfunction in ESRD patients
Diastolic dysfunction has a complex presentation in patients with ESRD; it not only involves the myocardium but also age, plasma levels of calcium and phosphate, arterial calcification, aortic stiffness, and volume status.22–24 The present study conducted a multiple linear regression stepwise analysis and revealed that the major determinants of TDI parameters included age, LA diameter, LV mass index and PWV. However, it should be noted that PWV, age and LV mass index explained 35% of the total variance of E’. LA diameter, age and LV mass index could explain 36% of the total variance of E/E’ ratio. These findings further support the idea that diastolic dysfunction is a complex process in patients with ESRD, as not only cardiovascular function but other conditions related to ESRD are involved.22–24 A previous study by the authors also demonstrated that the diastolic function parameters and arterial function are relatively volume dependent.25,26 The effect of volume change was limited by collecting the data on a mid-week nondialysis day. The hematocrit and plasma level of calcium and phosphate during analysis were also considered. However, other ERSD-related factors might play a role but have not been included in the current analysis.
4.4. Study limitations
There were several limitations in the present study. First, there were only a small number of patients enrolled, so the specific causes of death could not be further analyzed. Second, diabetics comprised only 9% of the study population. This might be the reason for the relatively good prognosis in this population; however, it may limit the ability to generalize the findings to the whole ESRD population. Third, sequent follow-up echocardiography data was not available.
In conclusion, diastolic dysfunction, as indexed by TDI, is an independent predictor of mortality and hospitalization in ERSD patients receiving regular hemodialysis and with preserved LV systolic function. The TDI parameters reflected the impairment of arterial function and LV pressure overload with the resultant LV hypertrophy. E’ and the E/E’ ratio should be incorporated in the evaluation of the cardiovascular status of ESRD patients.
This work was supported in part by a grant from the Ministry of Health and Welfare (grant no. MOHW104-TDU-B-211-113-003) and intramural grants from the Taipei Veterans General Hospital (grant nos. VGH94-209, VGH99C1-165).
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