Echocardiographic Assessment of Cardiac Dysfunction in Patients of Chronic Renal Failure

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1 ORIGINAL ARTICLE JIACM 2003; 4(4): Echocardiographic Assessment of Cardiac Dysfunction in Patients of Chronic Renal Failure Abstract S Agarwal*, P Dangri**, OP Kalra***, S Rajpal**** Objective : To assess the prevalence of systolic and diastolic dysfunction in patients of chronic renal failure on conservative management. Methods : Sixty patients with varying degree of chronic renal failure (CRF) were subjected to two-dimensional M mode echocardiography for determination of systolic and diastolic dysfunction. These included patients with mild to moderate CRF (n = 30) and advanced CRF (n = 30). Besides these, thirty age and sex matched healthy controls were also studied. The left ventricular ejection fraction (EF) and fractional shortening (FS) were taken as measures of LV systolic function. Diastolic function was determined by measuring E/A ratio by spectral doppler LV inflow velocity. Results : The mean left ventricular ejection fraction (LVEF) in patients with mild/moderate CRF (58.1 ± 6.9%) and severe CRF (55.4 ± 9.8%) was significantly lower than the controls (63.7 ± 5.1%). Although the mean FS in the three groups was similar, 7 (23%) patients with mild/moderate CRF and 5 (16%) patients with severe CRF had FS 25% which was statistically significant. The mean E/A in mild/moderate CRF group (0.92) and severe CRF (0.96) was significantly different from the control group (1.4). In mild/ moderate CRF 20 (66.6%) patients and in severe CRF group 16 (53.2%) patients had evidence of diastolic dysfunction. The prevalence of left ventricular hypertrophy (LVH) alongwith systolic dysfunction in severe CRF group was 30%, which was significantly higher than mild/moderate CRF group (3.3%). The prevalence of LVH along with diastolic dysfunction in severe CRF group was 53.2%, which was significantly higher than mild/moderate CRF group (30%). Conclusion : Patients with chronic renal failure have higher prevalence of diastolic and systolic dysfunction, and diastolic dysfunction appears to occur earlier than systolic dysfunction. Keywords : Chronic renal failure, Cardiac dysfunction. Introduction Chronic renal failure (CRF) is associated with significantly increased morbidity and mortality. Chronic renal failure affects almost every system of the body and results in various functional and structural abnormalities. Among the various causes, infections and cardiovascular causes contribute towards the large proportion of increased morbidity and mortality. Cardiac disease is the major cause of death in dialysis population accounting for 40% of deaths in international registries 1. In the cardiovascular system, left ventricular hypertrophy (LVH) is the most frequent finding 2. The prevalence of left ventricular systolic and diastolic dysfunction is less clear. Cardiac disease frequently predates the start of dialysis and LVH is common in moderate to severe chronic renal failure. Echocardiography should be performed early in the course of CRF and may be valuable in the monitoring of therapy of these patients 3. Cardiac dysfunction is the major impediment to rehabilitation. Patients in developing countries are managed mainly on conservative therapy and therefore, suffer from chronic acidosis, malnutrition, anaemia, and azotaemia. These factors further aggravate the cardiac dysfunction in uraemic patients. Cardiac disease is frequently noted in individuals around the time of commencement of dialysis, but there is little information on the prevalence and natural history of cardiac function in patients with milder degrees of chronic renal failure. The present study was aimed at assessing the prevalence of systolic and diastolic dysfunction by echocardiography in patients with varying degrees of chronic renal failure who had been on conservative management. * Reader, ** Post Graduate Student, *** Professor, **** Medical Specialist, Department of Medicine, University College of Medical Sciences and GTB Hospital, Shahdara, Delhi

2 Material and methods The study population consisted of three groups: group A (n = 30) age and sex-matched healthy controls; group B (n = 30) patients with mild to moderate CRF (S. creatinine mg/dl); and group C (n = 30) patients with advanced CRF (S. creatinine > 6.0 mg/dl) 4. The following patients were excluded from the study: patients with arteriovenous fistula, diabetes mellitus, patients with active or history of recent infection during last three weeks, patients with history of coronary artery disease and other cardiac disorders such as valvular heart disease, congenital heart disease etc., patients on haemodialysis, patients on treatment with erythropoietin, patients with history of smoking and/or alcohol ingestion, and patients with poor echo window. Informed consent was taken from all subjects participating in the study. All subjects underwent various investigations: haemoglobin, total and differential white cell count, renal and liver function tests, urinalysis, urine culture, lipid profile, renal ultrasound, chest skiagram and 12-lead electrocardiography. All patients underwent two dimensional directed M mode echocardiography performed on Hewlett Packard SIM 7000, in left lateral decubitus position using 3.5 MHz transducer by a consultant physician experienced in echocardiography. The left ventricular ejection fraction (EF) and fractional shortening (FS) were taken as measures of LV systolic function. EF was determined by measuring left ventricular volumes in apical 2 - chamber view. Left ventricular volumes were measured by Area-length method 5, both in end diastole (LVVd) and in end-systole (LVVs) : EF = LVVd - LVVs/ LVVd. The mean EF in normal population is taken as 59.2 ± 6% 6,7. EF was considered decreased if it was < 50%. Fractional shortening (FS) was determined by measuring left ventricular internal diameter in diastole (LVIDd) and left ventricular internal diameter in systole (LVIDs) by 2D directed M mode echo at the level of papillary muscle : FS = (LVIDd-LVIDs)/ LVIDd x 100 Normal reference value in adults for FS is 35 ± 8% 8. FS of 25% was taken as index of systolic dysfunction 3. Diastolic function was determined by ratio of peak early diastole velocity (E)/peak atrial filling velocity (A) of LV, i.e., (E/A), measured by spectral doppler LV inflow velocity with sample volume at the level of mitral valve. Normal value of doppler LV diastolic function index was taken as : Peak velocity E (m/sec) : 0.61 m/sec ± 0.14, peak velocity A (m/ sec) : 0.48 m/sec ± 0.14 with a normal E/A ratio : l.40 ± LV diastolic dysfunction was considered if E/A velocity was found to be Statistical analysis Comparison of the three groups was then done by analysis of variance (ANOVA) using F test and t test using SPSS/ PC + package version Results Table I shows age and sex distribution and relevant clinical and biochemical data in the three groups. As evident, all the three groups were well matched. As expected, mean haemoglobin level showed a progressive decline with the severity of renal failure. In patients with mild-moderate CRF, the mean systolic and diastolic blood pressures were ± 9.7 and 96.7 ± 5.0 respectively, while in severe CRF patients the mean systolic and diastolic blood pressures were ± 9.6 and ± 5.7 respectively. The major echocardiographic parameters are given in Table II. As evident, the mean left ventricular internal diameter in diastole (LVIDd) and systole (LVIDs) as well as the mean left ventricular volume in both systole (LVVs) and diastole (LVVd) were higher in patients with mild/ moderate CRF and severe CRF group than the control group. Table III shows indices of left ventricular (LV) systolic function in the three groups. As evident, LV ejection fraction showed a progressive decline with increase in severity of renal failure which was statistically significant in comparison to control (p < 0.05). Further analysis showed that whereas in patients with mild/ moderate CRF only 1/30 (3.3%) patients showed low EF (< 50%), 9/30 (30%) patients with severe CRF had evidence of low EF (Fig. 1). Although mean fractional shortening in the three groups was similar, detailed analysis revealed that 7/30 (23%) patients with mild/ moderate CRF, and 5/30 (16.6%) with severe CRF had impaired fractional shortening (i.e., 25%). Journal, Indian Academy of Clinical Medicine Vol. 4, No. 4 October-December

3 Table I : Age and sex distribution, and biochemical parameters in the three groups. Control Mild/Moderate CRF Severe CRF (n = 30) (n = 30) (n = 30) Age (yrs.) Mean ± SD 37.1 ± ± ± 9.7 Range Sex Male Female Mean blood Systolic ± ± ± 9.6 pressure Diastolic 77.5 ± ± ± 5.7 Biochemical Blood urea (mg/dl) 31.5 ± ± ± 30.2 parameters S. creatinine (mg/dl) 1.0 ± ± ± 3.6 Hb (g/dl) 13.2± ± ± 1.7 Table II : Echocardiographic parameters in the three groups. Control Mild/Moderate CRF Severe CRF LVIDd (cm) 3.4 ± ± ± 0.5 LVIDs (cm) 2.3 ± ± ± 0.5 IVSd (cm) 1.1 ± ± ± 0.3 IVSs (cm) 1.2 ± ± ± 0.3 PWd (cm) 1.0 ± ± ± 0.2 LVVd (cubic ml) 72.7 ± ± ± 28.3 LVVs (cubic ml) 26.5 ± ± ± 15.5 LVIDd Left ventricular internal diameter at end diastole, LVIDs Left ventricular internal diameter at end systole, IVSd Interventricular septal thickness at end diastole, IVSs Interventricular septal thickness at end systole, PWd Posterior wall thickness at end diastole, LVVd Left ventricular volume at end diastole, LVVs Left ventricular volume at end systole. Table III : Left ventricular systolic functions indices (ejection fraction and fractional shortening) in the three groups. Controls (Gp A) Mild/Moderate CRF (Gp B) Severe CRF (Gp C) p-value (n = 30) (n = 30) (n = 30) EF A vs C < 0.05 Mean ± SD 63.7 ± ± ± 9.8 A vs B < 0.05 B vs C > 0.05 No. of patients Nil 1 (3.3%) 9 (30%) A vs B = 0.31 with EF< 50% B vs C = 0.05 A vs C = FS B vs C NS Mean ± SD 33.3 ± ± ± 6.2 A vs B NS A vs C NS No. of patients Nil 7 (23%) 5 (16.6%) A vs B = with FS 25% B vs C = 0.51 A vs C = Journal, Indian Academy of Clinical Medicine Vol. 4, No. 4 October-December 2003

4 Table IV shows diastolic function in the three groups. As evident, the mean E/A was significantly lower in patients with mild/moderate CRF and severe CRF group when compared to controls. In mild/moderate CRF group, 20 (66.6%) patients and in severe CRF group, 16 (53.2%) patients had diastolic dysfunction (E/A 0.8). Thus, the two groups of patients had significantly impaired diastolic function as compared to controls, but impairment was not significantly different from each other. diagnostic modalities, both invasive and non-invasive such as electrocardiography, echocardiography, and radionuclide scans are utilised for diagnosing left ventricular hypertrophy and dysfunction. Echocardiography provides an excellent non-invasive method to delineate details of anatomy of cardiac cavity, wall dimensions, and wall movements. The LV systolic dysfunction appears late in CRF patients. Systolic functions are usually well preserved in Table IV : Diastolic function (E/A) in the three groups. Controls (Gp A) Mild/Moderate CRF (Gp B) Severe CRF (Gp C) (n = 30) (n = 30) (n = 30) E Mean ± SD 0.68 ± ± ± 0.24 A Mean ± SD 0.48 ± ± ± 0.23 E/A Mean No. of patients with E/A 0.8 Nil 20 (66.6%) 16 (53.2%) Significance of E/A: A vs B - < 0.05 S*; B vs C - > 0.05 NS*; A vs C - < 0.05 S*; Significance of prevalence of E/A 0.8: A vs B - < S*; B vs C - > NS**; A vs C - < S* *S = Statistically significant; NS* = Not statistically significant. Table V shows simultaneous occurrence of LVH and systolic or diastolic dysfunction in the three groups. There was only 1 (3.3%) patient in mild/moderate group while there were 9 (30%) patients in severe CRF group with LVH and systolic dysfunction. In mild/moderate CRF group there were 9 (30%) patients and 16 (53.2%) patients in severe CRF group with both LVH and diastolic dysfunction. hypertensive and even diabetic patients with uraemia. In the present study, the mean ejection fraction in patients with mild/moderate CRF and severe CRF groups showed a downward trend but neither of the CRF groups had mean LVEF < 50%. These findings conform to findings of Raj et al (1997) 10 who found mean EF in controls to be 60 ± 12.6%, undialysed CRF patients 55.4 ± 14.4% and in Table V : Prevalence of LVH and systolic (EF < 50%) and diastolic dysfunction (E/A 0.8) in the three groups. Control (Gp A) Mild/Moderate CRF Severe CRF (Gp C) p-value (n = 30) (Gp B) (n = 30) (n = 30) No. of patients with Nil 1 (3.3%) 9 (30.0%) A vs B - = LVH and systolic B vs C- = 0.31 dysfunction A vs C- = No. of patients with Nil 9 (30.0%) 16 (53.2%) A vs B - = LVH and diastolic B vs C- = 0.06 dysfunction A vs C- = Discussion Premature cardiovascular disease is a significant cause of morbidity and mortality among patients with CRF. Various dialysis population 56.8 ± 13.0%. Ayus et al (1981) 11 found that predialysis mean LVEF in end stage renal disease (ESRD) patients was 56 ± 2%. Thus, these studies suggest that LVEF is well maintained in patients with CRF which Journal, Indian Academy of Clinical Medicine Vol. 4, No. 4 October-December

5 was also observed in the present study. Among patients in the mild/moderate CRF group, only one patient had LVEF < 50%, while 9/30 (30%) patients in severe CRF group had LVEF < 50% which was significantly different from controls, as well as mild/moderate CRF population. In the present study, there was no significant difference in the mean fractional shortening among the three groups, however, 7 (23%) in mild/moderate CRF group and 5 (16.6%) patients in severe CRF group had fractional shortening 25%. Raj et al (1997) 10 found fractional shortening in CRF patients not on dialysis to be 31.4 ± 1.1% and in dialysis patients to be 33.3 ± 13.0%, while in controls it was 33 ± 9.3. They also did not find significant difference in the mean fractional shortening between the three groups. In a study by Greaves et al (1994) 3 as well, FS showed a trend from being highest in the controls (36.5 ± 5.6%), intermediate in undialysed CRF patients (36.2 ± 7.2%), and lowest in the dialysed patients (29.8 ± 8.9%). They found that LVH is common in moderate to severe renal failure, but LV systolic function is generally preserved. In a group of 218 ESRD patients on dialysis who never developed CHF, Harnett et al (1995) 12 found a mean FS of 35 ± 6 with only 4% patients having evidence of systolic dysfunction. Colan et al (1987) 13 in severe CRF group not on dialysis found mean fractional shortening to be 33.0 ± 9.1%. Thus, all these studies also show that fractional shortening as a function of left ventricular systolic function is well maintained in CRF patients. In the present study, in patients with mild/moderate CRF, the ejection fraction was depressed only in 3.3% whereas FS was depressed in 23%. It is because when the ventricle is stressed by a haemodynamic overload, it first uses its compensatory mechanism to maintain normal mechanical performance and the ejection indices (e.g., ejection fraction) within normal limits. It is only when all the compensatory mechanisms in the form of operation of Frank Starling s mechanism, development of hypertrophy, and endogenous adrenergic stimulation have been maximally used, there is decline in ejection phase indices 14. Ventricular systolic functions have invariably been evaluated using ejection phase indices, viz., ejection fraction, but this is highly sensitive to left ventricular loading conditions (pre load and after load) which are usually abnormal in CRF patients 15. Normalisation of loading conditions is invariably associated with restoration of normal ejection phase indices 13. Fig. 1 : Prevalence of systolic dysfunction as evidenced by EF (< 50%) and FS ( 25%) in the three groups. 300 Journal, Indian Academy of Clinical Medicine Vol. 4, No. 4 October-December 2003

6 Similarly when FS is taken as index of systolic dysfunction, it is assumed that the ventricle must be contracting uniformly for them to reflect global function. FS assesses the status of basal chamber only; it may falsely be normal, depressed, or increased in segmentally depressed left ventricle 16. The number of patients with LVH and systolic dysfunction (ejection fraction < 50%) was 1 (3.3%) in mild/moderate CRF group and 9 (30%) in severe CRF group. In a study by Greaves et al (1994) 3 13% of patients had LVH with systolic dysfunction in the dialysis patients. Thus, in the present study, systolic function was well preserved in patients with mild/moderate and severe CRF which is in concordance with the previous studies done by Greaves et al (1994) 3, Harnett et al (1995) 12, Colan et al (1987) 13, and Raj et al (1997) 10. Left ventricular diastolic dysfunction is an important cause of cardiac morbidity in ESRD patients. Diastolic dysfunction appears to be the initial left ventricular dysfunction and might even precede left ventricular hypertrophy. Diastolic heart function is influenced by numerous factors such as myocardial relaxation and compliance, transvalvular pressure gradient, atrial contraction, pre-load, heart rate, passive elastic properties, respiratory variant, the restraint of pericardium and thoracic wall, and as well as arrhythmias and valve incompetence 17. Diastolic dysfunction develops in three phases: (i) Inversion of ratio of peak early to peak atrial velocity - curve, with reduced early ventricular filling, due to reduced ventricular relaxation, (ii) Psuedonormalisation of E/A flow pattern, following increased atrial and ventricular filling pressures and decreased ventricular relaxation, (iii) Development of a restrictive pattern with various degrees of early atrial flow velocity involvement. Thus, it may be difficult to interpret whether a normal E/A flow pattern is associated with normal heart function or might in fact be related to progressive diastolic heart dysfunction, with increased filling pressure, unless the pulmonary venous flow is analysed 18. In the present study, the mean E/A ratio in control group was 1.4. It was 0.92 in mild/moderate CRF patients and 0.96 in severe CRF group (the difference being statistically Fig. 2 : Prevalence of diastolic dysfunction dysfunction (E/A 0.8) in three groups. Journal, Indian Academy of Clinical Medicine Vol. 4, No. 4 October-December

7 significant). Similarly, Schroeder et al (1992) 17 had found E/A ratio of velocity time indices to be 1.45 in patients with mild renal impairment as compared to 1.99 in controls. Also, in a study of ESRD patients by Virtanen et al (1998) 19, mean E/A was 1.5 ± 0.5. London et al (1993) 20 reported a significant reduction in E/A ratio in haemodialysis patients as compared to controls. The prevalence of diastolic dysfunction in the present study was found to be 66.6% (20 patients) in mild/moderate CRF group and 53.2% (16 patients) in severe CRF group. Though the mean E/A values in mild/moderate CRF and severe CRF patients have not been 0.8, but most of the patients have diastolic impairment, i.e., E/A < 1. Of the 10 patients with E/A values > 0.8 in mild/moderate CRF group, 5 had E/A ratio of < 1 suggesting diastolic impairment in them. Also, there was 1 patient with low ejection fraction and 1 with pericardial effusion which may account for their E/A ratio to be > 1. In severe CRF group, out of 14 patients who did not have E/A 0.8, 4 patients had low ejection fraction and three had higher left ventricular dimensions. These patients had pseudo-normalisation of E-wave which was confirmed by pulmonary venous flow patterns. Among the rest of patients with E/A > 1, three had mitral valve incompetence and two had pericardial effusion. The number of patients having both LVH and as well diastolic dysfunction (i.e., E/A 0.8) was 9 (30%) in mild/moderate group, whereas it was 16 (53.2%) in severe CRF group. Thus, in comparison to systolic function, diastolic function was deranged in more number of patients suggesting that diastolic dysfunction is first to appear in patients with chronic renal failure. Among the various factors that contribute to diastolic and systolic dysfunction, uncontrolled hypertension and anaemia, which are usually present in CRF, play a significant role. In the present study, 96% had hypertension and anemia was present in all the patients, suggesting that these factors might also have contributed towards development of diastolic and systolic dysfunction. To conclude, patients with chronic renal failure also have higher prevalence of diastolic and systolic dysfunction, and diastolic dysfunction appears to antedate the development of systolic dysfunction. References 1. Fassbinder W, Brunner FP, Brynger H et al. Combined report on regular dialysis and transplant in Europe XX1989. Nephrol Dial Transpl 1991; 6 (Suppl 1): Bullock RE, Hassem AA, Simpson I et al. Cardiac abnormalities and exercise tolerance in patients receiving renal replacement therapy. BMJ 1984; 28: Greaves SC, Gamble GD, Collins JF et al. Determinants of left ventricular hypertrophy and systolic dysfunction in chronic renal failure. Am J Kidney Dis 1994; 24: Guaba C, Agarwal S, Kalra OP, Revathi G. 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8 18. Appleton CP, Hatle LK. The natural history of left ventricular filling abnormalities: assessment by two dimensional and Doppler echocardiography. Echocardiography 1992; 9: Virtanen VK, Saha HST, Groundstroem KWE et al. Calcium infusion and left ventricular diastolic function in patients with chronic renal failure. Nephrol Dial Transplant 1998; 13: London GM, Marchais SJ, Guerin AP et al. Cardiac hypertrophy and arterial alteration in end-stage renal disease: hemodynamic factors. Kidney Int 1993; 41 (Suppl): S42-S49. Journal, Indian Academy of Clinical Medicine Vol. 4, No. 4 October-December