1Divisions of Baxter Novum and Renal Medicine, Department of Clinical Science and 2Department of Clinical Physiology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
Correspondence and offprint requests to: Astrid Seeberger, MD, PhD, Department of Renal Medicine K56, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. Email: astrid.seeberger{at}klinvet.ki.se
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Abstract |
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Methods. Conventional echocardiographic and TVI images were recorded before and after a single HD session in 13 clinically stable HD patients (62±10 years, six males) and in 13 sex- and age-matched healthy controls. Myocardial tissue velocities (v; cm/s) for isovolumetric contraction (IVC), peak systole (PS), early (E') and late (A') diastolic filling and strain rate (SR) were measured.
Results. Left ventricular hypertrophy (LVH) was present in 12 patients. TVI gave additional information in comparison with conventional echocardiography. Before HD, PS (5.0±0.8 vs 6.0±1.2 cm/s, P<0.05), E' (5.7±1.7 vs 7.3±2.0 cm/s, P<0.05) and A' (6.6±1.7 vs. 8.3±2.9 cm/s, P<0.05) velocities were lower in the patients than in the controls, indicating systolic and diastolic dysfunction. The HD session increased IVCv (4.0±1.7 to 5.5±1.9 cm/s; P<0.001), PSv (5.0±0.8 to 5.7±0.8 cm/s; P<0.05) and SR (0.7±0.2 to 0.9±0.2 1/s; P < 0.05) and decreased E/E' (16.7±7.7 to 12.2±4.0, P<0.05), indicating improved systolic function and decreased LV filling pressure, respectively. Linear regression analysis demonstrated a dependency of systolic contraction (PSv) and contractility (IVCv) upon plasma levels of phosphate (r2 = 0.70, P<0.005, r2 = 0.33, P<0.01).
Conclusions. Using TVI, HD patients demonstrate myocardial dysfunction, which is found less frequently when using conventional echocardiography. The systolic function seems to be impaired by high plasma levels of phosphate and an increased Ca x P product. One single session of HD improved systolic function as indicated by increases in IVCv, PSv and SR. Further studies are needed to clarify if this effect of HD is due to the acute removal of fluid, the removal of solutes or both.
Keywords: diastolic function; end-stage renal disease; haemodialysis; phosphate; systolic function; tissue Doppler echocardiography
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Introduction |
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The prevalence of left ventricular hypertrophy (LVH) is high in dialysis patients and is an important manifestation of uraemic CVD [3], predisposing to ischaemic symptoms by reducing the coronary reserve and inducing systolic and/or diastolic dysfunction. Although LVH can be a normal adaptive response to increased pressure and volume overload, in uraemia, LVH demonstrates pathophysiological characteristics such as capillarycadiomyocyte mismatch, fibrosis and myocardial calcifications [4].
Previous studies have shown that overhydration as well as accumulation of uraemic toxins may influence the development of LVH and LV dysfunction in patients with chronic renal failure [5]. This suggests that haemodialysis (HD) treatment should improve cardiac function; however, studies using conventional echocardiography to examine the acute effects of HD on cardiac function have given conflicting results [6,7]. An explanation for this could be that several factors restrict the possibilities of evaluating changes in systolic and diastolic function in HD patients accurately by conventional Doppler echocardiography. The most important limitation in assessing LV systolic and diastolic function through routine indices from conventional Doppler echocardiography such as cardiac output, fractional shortening (%FS), ejection fraction (EF) and Doppler filling parameters, is the influence of altered conditions of loading on the measurements obtained [8,9]. An increase in blood pressure may cause a reduction of EF in spite of relatively normal contractility, which could be interpreted as a worsening of myocardial function. Conversely, an augmented pre-load may increase the EF, which could be taken as an improvement in the myocardial contractility. In addition, the non-reliability of EF as a good index of myocardial function in patients with LVH, the subjective visual interpretation, the semi-quantitative evaluation of regional systolic LV contraction and the high inter-observer variability [10] complicate the evaluation of cardiac function by conventional echocardiography in ESRD patients.
Colour tissue velocity imaging (TVI) is a new non-invasive Doppler echocardiographic technique that allows quantitative, objective and highly reproducible measurements of LV systolic and diastolic myocardial velocities, duration of the time intervals during the cardiac cycle and LV filling pressure. TVI studies the longitudinal movement of the myocardium, which is generated by subendocardial fibres, which are known to be the first to suffer from myocardial ischaemia and fibrosis. The systolic function can be assessed quantitatively by the measurements of systolic myocardial velocities [11] and strain rate (SR) [12], and the diastolic function is evaluated by the measurement of diastolic myocardial velocities and isovolumetric relaxation time [13]. TVI is a useful diagnostic tool for early detection of LV dysfunction and for the assessment of acute changes in LV function, e.g. during pharmacological or post-exercise stress echocardiography [14].
TVI parameters have also been shown to be less load dependent, especially the isovolumetric phase velocities. This is of particular importance in HD patients in whom both pre-load and after-load change as the hydration status fluctuates. In addition, to our knowledge, there are no previous studies using TVI evaluating not only diastolic function but also regional and global contractility, contraction and LV filling pressure in ESRD patients. Therefore, since TVI appears to be a superior method, in comparison with conventional echocardiography, to study dialysis-induced changes in myocardial function, we investigated HD patients with both methods in order to be able to answer the following questions: (i) can TVI give additional information on global and regional systolic and diastolic LV [and right ventricular (RV)] function in HD patients in comparison with conventional echocardiography?; (ii) does a single HD treatment have an acute effect on LV function?; and (iii) do circulating substances such as phosphate and Ca x P contribute to myocardial dysfunction in HD patients?
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Materials and methods |
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The causes of renal failure were diabetes mellitus (three patients), polycystic kidney disease (three patients), chronic interstitial nephritis (two patients), Wegener's granulomatosis (one patient), crescentic nephritis (one patient), chronic pyelonephritis (one patient), cortical necrosis (one patient) and IgA nephropathy (one patient). Nine patients were receiving anti-hypertensive medications. Calcium antagonists and angiotensin-converting enzyme inhibitors, alone or in combination, were used by four patients; in addition, seven patients were taking ß-adrenergic blockers, five were on diuretics and one was on an angiotenin II receptor antagonist. On the day of the study, no medication was taken before the second TVI investigation was finished.
Thirteen sex- and age-matched subjects (62±10 years; seven women, six men) without CVD, defined as normal echocardiography and stress echocardiography, were studied as a control group.
The study was approved by the Ethics Committee of Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden. The nature and the purpose of the investigation were explained to the subjects, who gave their informed consent.
Haemodialysis parameters
All patients were treated with HD three times per week (time on HD treatment 30±21 months, range 572 months), using polyamide (10 patients) and haemophan (three patients) dialysers. TVI was performed after the long interval (3 days) between two HD sessions. All patients attained their dry weight after the preceding treatment. HD was carried out for 3.04.5 h (blood flow rate 230400 ml/min, dialysate flow rate 500 ml/min) using bicarbonate-buffered dialysate with calcium 1.5 mmol/l, potassium 2±0.2 mmol/l (range 23), sodium 139±12 mmol/l (range 136140) and bicarbonate 33±2.9 mmol/l (range 2538). During the HD session, fluid was removed to achieve the patient's previously clinically determined dry weight (72.4±12 kg). The mean reduction in body weight was 2.3±1.4 kg, and the percentage change in the body weight was 3.1±1.7%. Systolic and diastolic blood pressures were measured before and after each HD session.
Biochemical analysis
Blood samples were collected from the arterial side of the AV fistula just before the start of the HD session. Plasma samples were prepared and frozen (70°C) before analysis. Some analyses were also performed in blood samples obtained immediately after the HD session was stopped and the circulating extracorporeal volume of blood had been given back to the patient (see below).
Plasma levels of parathyroid hormone (PTH), cholesterol, triglycerides, high-density lipoprotein (HDL), cardiac troponin T (cTnT), high sensitive C-reactive protein (hs-CRP), endothelin-1 (ET-1) and big-endothelin-1 (Big-ET-1) were measured before HD. Intact PTH was measured using a commercial electrochemical immunoassay (Elecsys PTH kit, Roche Diagnostics, Mannheim, Germany). Triglycerides and cholesterol were determined using standard enzymatic techniques (Boehringer Mannheim, Mannheim, Germany). HDL-cholesterol levels were analysed after precipitation of apo B-containing proteins with phosphotungstic acid. cTnT was analysed with the third generation troponin T test (Troponin T STAT, Roche Diagnostics). The third generation TnT test uses the same monoclonal antibodies (M11.7 and M7) as the second generation test but is standardized with human recombinant cTnT instead of bovine cTnT. Serum hs-CRP was measured by nephelometry. ET-1 and Big-ET-1 were quantified by enzyme immunoassay (Biomedica, Vienna, Austria).
Plasma levels of sodium, potassium, creatinine, urea, albumin, Ca2+, pH and phosphate were measured before and immediately after HD using routine methods.
Conventional two-dimensional Doppler echocardiography
All ultrasound examinations were performed before and immediately after HD with a Vivid 7 (General Electric Horten, Norway) linked to a PC workstation with tissue Doppler capabilities. The guidelines of the American Society of Echocardiography (ASE) were applied. All two-dimensional and Doppler parameters were acquired and documented. At least three consecutive heart beats in each view were acquired. Standard echocardiographic measurements included LV end-diastolic and end-systolic dimensions (LVEDd and LVESd, respectively), end-diastolic and systolic wall thickness of the interventricular septum (IVSd and IVSs, respectively) and left ventricular posterior wall (PWTd and PWTs, respectively) from M-mode (MM) images. The EF and %FS were calculated through MM. The LV mass was calculated according to the Penn formula. The LV mass index (LVMI) was calculated by the indexation of mass by height. LVH was diagnosed when the LVMI was >50 g/m2.7 for males and >47 g/m2.7 for females. The relative wall thickness (RWT) [(IVS + PWT)/LV end-diastolic diameter)] was calculated to classify the LV geometric pattern (concentric LVH, RWT >0.45; eccentric LVH, RWT <0.45). Transmitral, pulmonary venous and LV outflow tract flow velocities were acquired with pulse Doppler. The velocities of early diastolic inflow (E) and late atrial inflow (A), its ratio (E/A), and deceleration time were measured. Diastolic dysfunction was defined by the presence of E/A <1 or pulmonary vein systolic/diastolic ratio <1 or a combination of both.
Tissue Doppler
After completion of the conventional echocardiography, apical images (two, three and four chambers) with >100 frames/s were acquired and digitalized for the quantitative analysis of TVI. Off-line measurements were performed. TVI was performed with a 2 mm sampling volume from the apical views at three different regions: mitral annulus, basal and mid-wall (Figure 1). Myocardial velocities recorded with TVI have three main components: systolic, early diastolic and late diastolic velocities (Figure 2). The global LV function was calculated as the average velocities of four LV walls (septal, lateral, inferior and anterior walls). To evaluate the LV filling pressure, tissue Doppler from the apical four chamber view was used to calculate the E/E' ratio, using E' from the lateral wall. Systolic myocardial function was evaluated by measuring the isovolumetric contraction velocity (IVCv = contractility, which is the true inotropic property of the muscle to generate force) and peak systolic velocity (PSv = contraction, which is the translation of force to blood motion generating cardiac output). As measurements of PSv may be affected by heart translation and tethering of adjacent myocardial segments and by the heterogeneous distribution of myocardial velocities, we also used SR as an additional marker of systolic function. Strain is defined as relative deformation, whereas SR describes the rate of deformation, or how quickly a tissue shortens or lengthens. Animal studies, in which SR has been measured simultaneously with invasive catheter evaluation of LV volume and pressure, have shown that SR is a strong non-invasive index of LV contraction. SR was estimated from the velocity gradient divided by the distance between two points with a distance of 14.5 mm. This spatial offset was selected as a compromise between acceptable signal-to-noise ratio and longitudinal resolution.
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Statistical analysis
Data were expressed as the mean±SD. Comparisons between HD patients and controls were performed using the MannWhitney U-test. In HD patients, the paired t-test and the Wilcoxon's signed rank test (for non-normally distributed data) were used to assess measurements obtained before and after HD. Furthermore, the Pearson's and Sperman's (for non-normally distributed data) coefficients of correlation were used where appropriate. P<0.05 was considered significant.
To evaluate the dependency of one variable upon another, linear regression analysis was used followed by stepwise multiple regression analysis when more than one variable was significant.
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Results |
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LVH was present in 12 (92%) patients: concentric LVH in 11 and eccentric LVH in one patient. Valvular calcifications were found in five (38%), mild aortic stenosis in two (15%), mild aortic insufficiency in four (30%) and mild mitral insufficiency in three (23%) patients. Slight segmental wall motion abnormalities were noted in three patients (23%): in the apical wall in one patient, in the antero-apical wall in another and in the antero-apical wall as well as the lateral wall in a third patient. The heart rate did not differ significantly between patients and controls (76±9, range 6189 vs 72±7, range 6387, NS). Diastolic dysfunction was present in 10 patients. By visual analysis, global systolic function was considered to be normal in all patients; however, the calculated EF was significantly low in two patients (16%).
TVI variables
Table 1 summarizes the TVI measurements (global function, i.e. the average of measurements in the four walls) in the patients group (before HD) and controls. ESRD patients showed significantly lower PSv before HD compared with controls (5.0±0.8 vs 6.0±1.2, P<0.05), indicating systolic dysfunction. Even when excluding the two patients with low calculated EF, PSv was significantly lower in patients in comparison with controls (5.2±0.7 vs 6.0±1.2, P<0.05). E' (5.7±1.7 vs 7.3±2.0, P<0.05) and A' (6.6±1.7 vs 8.3±2.9, P<0.05) velocities were significantly lower in the ERSD patients compared with controls, indicating altered diastolic filling.
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Regional systolic and diastolic velocities
LV regional contractility improved after HD as demonstrated by an increase in IVCv in the inferior wall (mitral annulus region, 4.1±1.8 to 4.7±2.9 cm/s, P<0.01; basal region, 4.8±2 to 6.2±2.1 cm/s, P<0.05; and mid-wall region, 3.7±1.3 to 5±2.1 cm/s, P<0.05), anterior wall in the mitral annulus region (3.2±1.5 to 4.9±2.6 cm/s, P<0.01), lateral wall in the basal region (2.9±2.7 to 5.4±3.1 cm/s, P<0.01), and posterior wall in the basal region (3.3±2.4 to 5.7±3.1 cm/s, P = 0.001). There was also an improvement in RV free wall contractility (8.1±3.6 to 10.3±4.1 cm/s; P<0.05). LV regional contraction evaluated by PSv increased in the lateral wall in the mid-wall region (3.4±1.8 to 5.7±2.6 cm/s, P<0.01). The regional evaluation of diastolic function demonstrated that after HD there was a significant increase in A' velocities in the inferior (7.3±1.8 to 8.6±2.2 cm/s, P<0.01) and posterior (6.9±2.4 to 8.8±2.4 cm/s, P<0.01) walls in the basal region.
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Discussion |
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Before HD, TVI could demonstrate signs of systolic and diastolic dysfunction in the patients. Whereas systolic function improved after HD, diastolic dysfunction did not. Interestingly, using conventional echocardiography, we could demonstrate neither systolic dysfunction in the majority of HD patients nor a difference in systolic function before and after HD, which both were seen using TVI. Patients with normal systolic function by visual analysis demonstrated a lower PSv than controls, suggesting that this decrease may reflect early systolic dysfunction that could not be detected by conventional echocardiography.
Previous studies in HD patients using conventional echocardiography are conflicting, demonstrating either an HD-induced improvement of systolic function or unchanged myocardial performance [7] after HD. Several factors limit the possibilities to evaluate LV function accurately with traditional echocardiography in patients with ESRD during HD. First, the measurements depend on visual and semi-quantitative assessment of wall motion and are subjected to a considerable inter-observer variability [10] Most importantly, altered loading conditions may profoundly influence the most commonly used indices of cardiac function, such as EF and %FS.
In the present study, we did not find any significant changes in EF and %FS after HD when all patients were analysed together. However, when we looked at the patients individually, we found that the calculated EF and %FS decreased in seven patients and increased in five. These divergent results could be explained by the changes in LVESd which depends, among others, on the systolic blood pressure, i.e. after-load. Indeed, five out of five patients in whom HD was observed to increase the calculated EF and %FS had reduced systolic blood pressure following HD, whereas systolic blood pressure increased in five out of seven patients in whom the calculated EF and %FS decreased following HD. In contrast to the ambiguous results of conventional echocardiography, in the present study, TVI examinations showed signs of systolic dysfunction before HD and significant rises in IVCv, PSv and SR after HD, indicating improvements in myocardial contractility and contraction.
Using conventional Doppler echocardiography, 77% of the patients showed signs of diastolic dysfunction. This method evaluates diastolic function by measurements of transmitral blood flow velocity which is related to transmitral pressure gradient and is affected by the LV relaxation and left atrial pressure and consequently by changes in pre-load [8], whereas TVI measures the velocities of the myocardial movement during diastole and has been shown to be less affected by changes in load [15]. In accordance with other studies [16], we found that LV diastolic function is altered in HD patients as reflected by significantly lower E' and A' velocity measurements in HD patients compared with age- and sex-matched controls. Using TVI, HD had no influence on global and regional E' velocities. In contrast, conventional echocardiography showed that HD elicited significant changes in the early diastolic filling wave (Doppler E) which correlated with changes in weight. These findings indicate that the changes in diastolic performance seen in conventional echocardiography are not due to a change in cardiac muscle diastolic properties but to alterations in the pressure gradient between the left atrium and LV. Therefore, TVI appears to be a superior method for assessment of both systolic and diastolic cardiac muscle function.
Three previous studies in ESRD patients utilizing TVI as a method to evaluate diastolic function have demonstrated different responses of regional E' velocity measurements after HD. Both Dincer et al. [17] and Agmon et al. [18] demonstrated that there was a significant decrease in regional E' velocities after HD. On the other hand, Bauer et al. [15] demonstrated that diastolic velocity measurements were not significantly affected by HD. The different responses of E' velocity measurements between the studies of Dincer et al. [17], Agmon et al. [18] and ours could be related to differences in the methodology, changes in heart rate and the patients sample studied.
These previous studies [17,18] used pulsed wave tissue Doppler, which has been shown to give higher velocity measurements because it includes the spectral velocity from all points and may overestimate the true velocity value. We used extraction of velocity information from colour Doppler myocardial imaging which measures the mean values of velocity measurements from all points. In addition, the previous studies analysed only regional diastolic velocity measurements that were evaluated in different regions and different walls, which could result in different responses to pre-load changes, because myocardial velocity measurements are different from one wall to another. Further, changes in heart rate may influence E' and A' velocity measurements but, in the present study, in contrast to the others, no significant changes in heart rate were seen after HD. It should also be remembered that load sensitivity of LV relaxation may differ in relation to cardiac contractility as failing hearts have being shown to be more sensitive to load changes [19]. Agmon et al. [18] demonstrating load sensitivity of E' velocities in their study, investigated patients with a high prevalence of coronary artery disease (CAD) (69%) and heart failure (15%, mean EF in all patients 47±17%), while none of our patients had evidence of CAD or signs of heart failure, and the mean EF was 61±15%.
Although, using TVI, we were not able to detect an HD-induced improvement in diastolic myocardial function, we found that, due to fluid removal, LV filling pressure decreased after HD, measured as the ratio of transmitral E flow velocity to E' (E/E'), which has been shown to correlate strongly with direct simultaneous high fidelity measurements of LV pressure and also with pulmonary capillary wedge pressure (PCWP) [20]. The present study also demonstrated that average A' velocity measurements at the basal region increased after HD. This could be related to alterations in pre-load, changing the diastolic pattern from a restrictive pattern before HD, when there is higher left atrial and LV pressure, to an impaired relaxation pattern after HD when these pressures are reduced.
The abnormalities in myocardial function in HD patients can only partly be explained by LVH, which was present in the majority of the patients. In view of the marked improvement in systolic function following HD, it is likely that other reversible factors contributed to the impaired ventricular function. Although decreased after-load is one possible explanation of improved contractility following HD, blood pressure changed in different directions in the individual patients and improved contractility was also observed in patients with increased systolic blood pressure after HD. The HD treatment was associated with fluid removal and, as a consequence, a decrease in LV filling pressure or pre-load, which, at least theoretically, could result in improvement of ventricular function, if the heart is operating at or close to the maximum of the FrankStarling curve, as in the presence of failing heart [21]. Normally, however, a decrease in pre-load will give a reduction of LV contraction. Therefore, as none of the patients had clinical signs or symptoms of heart failure and/or severe heart dilatation (mean LVEDd 46.9±5.2) and, in addition, as the HD-induced reduction in body weight did not correlate with changes in myocardial contractility and contraction (r between 0.02 and 0.2), it is unlikely that the improvement of systolic function was caused only by changes in loading conditions.
The contractility of the heart is also influenced by sympathetic activity, heart rate and biochemical factors, such as inorganic phosphate and pH. Previous studies have shown that although the sympathetic system is activated during the early phase of HD, it is restored to pre-dialysis levels at the end of treatment [22]. We did not measure plasma levels of catecholamines or any other index of sympathetic activity. Still, regarding the fact that heart rate did not change, it seems unlikely but cannot be excluded that enhanced sympathetic activity contributed substantially to the enhanced LV contractility after HD.
Interestingly, however, we found a strong inverse correlation between plasma levels of phosphate and Ca x P, respectively, and systolic contraction measured as PSv in all three different regions (r = 0.80) and systolic contractility measured as IVCv in the mitral annulus region. These observations are compatible with results of studies in vitro showing that isometric force in isolated myocytes declines in the presence of increasing concentrations of inorganic phosphate [23]. Hyperphosphataemia and increased Ca x P appear to play a role in cardiovascular calcification and cardiac fibrosis, and have been found to increase the risk of cardiovascular and all-cause mortality in HD patients [1]. Our results suggest that even moderate hyperphosphataemia may also have an inhibitory effect on LV function. However, contrary to what could be expected, given the strong correlation between serum phosphate concentrations and systolic contraction before HD, we did not observe any correlation between the changes in inorganic phosphate and changes in LV function parameters following HD, possibly because of the rather uniform decreases in serum phosphate concentrations in the individual patients. Blood pH was fairly homogenous in the individual patients before HD and increased similarly in the individual patients after HD, rendering a relationship between pH and myocardial function before and after HD difficult to evaluate.
Although we did not find any correlations between plasma urea, plasma creatinine, PTH, cTnT, ET-1 and Big-ET-1 concentrations and ventricular function, it is natural to speculate that some other factors, in addition to phosphate, could have negative effects on the myocardium and that their removal by dialysis could result in an enhancement of ventricular contractility. However, the present study does not allow any further speculations on this matter.
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Summary and conclusions |
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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