1 Dipartimento di Medicina Interna e di Cardiologia, University of Pisa and 2 Istituto di Fisiologia Clinica, CNR, Pisa, Italy
Correspondence and offprint requests to: Vitantonio Di Bello, MD, Dipartimento di Medicina Interna, Università di Pisa, via Roma, 67, I-56100 Pisa, Italy.
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Abstract |
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Methods. We compared a group of male dialysis patients (D) with two groups: hypertensive patients (H) with comparable left ventricular mass and normotensive healthy subjects as controls (C). The groups (n=15 each) were age- (53±9 years) and gender-matched. Quantitative analysis of echocardiographic digitalized imaging was performed to calculate the mean grey level (MGL) and cyclic variation index (CVI).
Results. The haemodialysis patients had a significantly lower CVI compared with hypertensives and controls both for septum (D): -2.5±17.4% vs (H); 11.8±17% vs (C); 43.2 ±15.4% (P<0.001) and for posterior wall (D): -10.1±261% vs (H); 14.2±14.7% vs (C); 46.6.2±17.2% (P<0.001). A significant inverse relationship was found between intact parathyroid hormone (iPTH) and CVI.
Conclusion. Abnormalities of two-dimensional echocardiographic grey level distribution are present in both haemodialysis patients and hypertensive patients, but seem unrelated to the degree of echocardiographic hypertrophy. These videodensitometric myocardial alterations are significantly higher in dialysis patients than in hypertensive patients with the same extent of left ventricular hypertrophy. The iPTH level may play a role in the development of the ultrasonic myocardial alterations, which probably represent an early stage of uraemic cardiomyopathy.
Keywords: echocardiography; hypertension; uraemic cardiomyopathy; haemodialysis; videodensitometric ultrasonic tissue characterization
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Introduction |
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The purpose of this study was to analyse the myocardial echo density in a group of haemodialysis patients, compared with an age-, gender- and left ventricular mass (LVM)-matched group of hypertensive patients and normal age-matched sedentary controls. We investigated whether videodensitometry is able to detect some early myocardial ultrasonic textural changes in end-stage renal disease maintained with haemodialysis, and if some differences exist between two models of cardiac hypertrophy, `uraemic cardiomyopathy' and essential hypertensive cardiopathy [1416].
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Subjects and methods |
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Haemodialysis group.
Echocardiography was performed within 6 h after the dialysis procedure. The epidemiological and clinicalserological findings of these patients are shown in Table 1. At the time of the study, all patients had been on dialysis for at least 6 months. Chronic renal failure (CRF) was due to chronic glomerulonephritis (n=9), chronic interstitial nephritis (n=4) and polycystic kidney disease (n=2). Eight patients were treated with haemodialysis (blood flow 350 ml/min, dialysate flow 500 ml/min) using synthetic membranes (n 5 PAN and n 3 Polysulphone) and a standard bicarbonate dialysate (NA 140 mmol/l, K 2.0 mmol/l, Ca 1.5 mmol/l, HCO3 35 mmol/l). Seven patients were treated with haemodiafiltration (HDF) with PAN membrane (1.61.8 m2), bicarbonate dialysate as above and a lactate-buffered (42 mmol/l) reinfusate fluid (reinfusate flow 3 l/h). Six patients were treated with antihypertensive medication (four with calcium channel blockers and two with clonidine). The mean intradialysis weight gain was 2.5±1.5 kg. No hypotensive episodes occurred during or after the dialysis procedure on the same day on which echocardiography was performed. Blood samples for biochemical examinations were taken on the day of echocardiography between 8.30 and 9.30 am. Total cholesterol and triglycerides were assayed by enzymatic colorimetric techniques (Boehringer-Mannheim, Mannheim, Germany), white cell count and haematocrit by automated methods (H1 Technicon, Cavenago Brianza, Bayer Diagnostici, Italy), and urea, creatinine and glucose by standard techniques. Total alkaline phosphatase, total calcium and phosphate were determined using standard laboratory methods (Technicon Autoanalyzer). Intact parathyroid hormone (iPTH) was determined by an immunoradiometric assay (Nichols Allegro; normal range 1065 pg/ml) utilizing two different polyclonal antibodies purified by affinity chromography, specific for 3484 and 134 regions, with an intra- and inter-assay coefficient of variability <7%.
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Patients were then excluded if valvular heart disease by Doppler analysis (including only very mild aortic or mitral regurgitation) was present, as well as a history or clinical and instrumental findings of myocardial ischaemia (presence of ECG or echocardiographic findings of myocardial ischaemia, such as echocardiographic segmentary abnormalities of myocardial contraction).
The conventional echocardiogram and tissue characterization were performed on the same day.
With these criteria, we recruited 15 subjects with hypertension who had completed a full clinical, biochemical and instrumental work-up for secondary hypertension, including fundoscopic examination, urinalysis, renal echo-Doppler examination, up to an angiographic procedure if needed. All patients had clinically uncomplicated essential arterial hypertension (without the major atherosclerotic complications: renal, retinal, carotid, coronary and leg arteries). Twelve patients were not taking any antihypertensive therapy at the time of the study and only three patients were treated with antihypertensive agents including angiotensin-converting enzyme inhibitors and/or diuretics.
Control group.
Fifteen age- and gender-matched normotensive subjects, without any evidence of organic disease, were recruited from the echocardiography laboratory after documentation of normal sonograms. These subjects underwent blood sampling for biochemical examination of the same previously described parameters.
The demographic features of these three groups are reported in Tables 2 and 3. According to institutional guidelines, the study was approved by the local Ethical Committee. Systolic (SBP) and diastolic (DBP) (Korotkoff V phase) blood pressure was measured during the echocardiographic examination [17].
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Image digitization
During echocardiography, the grey scale transfer function was adjusted to be linear for the entire video signal range and no reject, no enhancement or dynamic range were used [2,3]. In general, an amplification of 2530 dB and a depth setting of 18 cm were used. The echocardiographic images were transferred directly to a calibrated video digitization system. Images were converted into 256x256 pixels of 256 grey levels each (0=black, 255=white), with 8 bits of intensity range, by a commercial real-time video-digitizer. One cardiac cycle (RR waves) was divided automatically into 12 frames independently by heart rate. The images corresponding to the end-diastolic and end-systolic phases, all in long axis projection, were selected according to an optimal visualization of the interventricular septum and the left ventricular posterior wall [2023].
Quantitative texture analysis
A trackball-controlled cursor was used to select the same region of interest of the septum (mid-septum) and posterior wall (mid-posterior), always measuring 32x42 pixels. The analysis was performed during the end of systole and the end of diastole and included only the myocardium. The endocardial and epicardial specular echoes were excluded to avoid artefacts. For each region of interest, a histogram of the echocardiographic grey level distribution was generated. The grey level distribution was plotted on the abscissa and the frequency of the occurrence on the ordinate. The intra-class correlation coefficient (ri) was calculated according to Bland and Altman, using a one-way analysis of variance for repeated measurements. One to three values of mean grey level at end diastole and systole were obtained for both the septum and posterior wall. The correlation coefficient (ri) for septum mean grey level was 0.92 for the diastolic and 0.90 for the systolic sample. The posterior wall mean grey level was 0.89 for the diastolic and 0.91 for the systolic sample.
Grey level difference measurements
The mean grey level in each cavity region (background signal) was subtracted from the absolute mean grey level in each tissue region of the same digitized images for the end-systolic and end-diastolic frames (mean grey level, background corrected: MGL). A quantitative analysis of the shape of the distribution was also performed using skewness and kurtosis of each distribution. The cyclic variation index (CVI) of the grey level amplitude was also calculated according to the formula: (MGLEDMGLES)/MGLEDx100) (Figure 1) [2,24].
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Results |
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M-mode, two-dimensional and Doppler echocardiographic findings
Conventional echo-Doppler measurements of the three study groups are displayed in Table 3. End-diastolic volume, parietal thickness and relative LVM were similar both in the dialysis and hypertensive groups, being significantly higher than in controls. Fractional shortening and the diastolic functional indices were similar in all three groups (Table 4
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Discussion |
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Different structural components of the myocardium influence its acoustic properties under physiological and pathological conditions (Rayleigh scattering). Collagen is a primary determinant of both scattering and attenuation of myocardial tissue; a linear relationship was found between integrated backscatter and hydroxyproline content in autopsied human hearts with fibrotic changes associated with remote myocardial infarction [25]. Furthermore, a significant direct correlation was found between collagen content analysed endobioptically and regional echo amplitude [26]. Scatter geometry is another determinant of myocardial reflectivity. In fact, myocardial scattering intensity depends directly on myocyte cellular size; the microstructural arrangement of myocardial cells embedded in a collagen matrix may provide a sufficient local acoustic impedance mismatch to account for the scattering from normal myocardium [27]. The orientation of ventricular muscle fibres might influence myocardial acoustic properties. In fact, the insonification angle might greatly influence the magnitude of both attenuation and backscatter, the backscatter being maximal in a direction perpendicular to fibre orientation. The middle portion of the left ventricular wall is comprised mainly of circumferentially oriented fibre bands. [28] Tissue water content and blood flow both influence myocardial attenuation and scattering. An increase in water content due to tissue oedema and, to a lesser degree, to a reduction in coronary blood flow associated with myocardial ischaemia might influence the acoustic properties of the myocardium. No data are available at the moment regarding the effect of anaemia on the acoustic properties of the myocardium. Some thought must also be given to the dynamic aspect of scattering. According to Wickline et al. [27], peak values occurred at end-diastole and minimal values at end-systole, but these cyclic changes in the echo amplitude are related, although not linearly, to intrinsic myocardial contractile performance.
The results of the present study confirm our previous studies in essential hypertension in which we have demonstrated that chronic pressurevolume overload of hypertension caused an altered pattern of ultrasonic texture [8,9]. In fact, prolonged pressurevolume overload due to arterial hypertension could be responsible for an increase in LVM with an increase in collagen content which probably alters the physiological collagen/myocardium ratio, as demonstrated in experimental and autopsy studies [1416,2931).
The high prevalence of left ventricular hypertrophy (LVH) in dialysis patients, in the absence of a history of arterial hypertension and without an association with the aetiology of CRF, represents the result of complex humoral and haemodynamic stimuli which lead to an increase in LVM. The acute and the chronic effects of haemodialysis on cardiac function and structure were well differentiated in our study. We focused on the chronic modifications induced by dialysis and for this reason we observed patients 6 h after the dialysis session under resting conditions. After removal of fluid from the circulating blood volume by ultrafiltration, refilling occurs from the extravascular compartment. This compensatory mechanism may alter cardiac contractility and rate. However, it has been established that in patients affected by CRF undergoing ultrafiltration [32], most of the redistribution of extracellular fluid loss after haemodialysis occurs in the first 2 h after haemodialysis. At 6 h after the end of dialyisis, most of the electrolyte variations occurring during haemodialysis (including ionized calcium increase) are stabilized.
Different risk factors have been ascribed to echocardiographic abnormalities found in dialysis patients [33]; Nowack et al. [34] demonstrated the role of PTH in the development of LVH in dialysis patients. Experimental studies have shown that PTH affects myocardial function [35] and structure. Furthermore, PTH has been considered to be a major uraemic toxin [36] which promotes activation of myocardial fibroblasts and, therefore, the genesis of cardiac fibrosis found in the dialysis population [37]. Autopsy studies have shown pronounced diffuse non-coronary inter-myocardiocytic fibrosis in uraemic patients which is clearly distinct from perivascular fibrosis observed in arterial hypertension and from patchy scars typical of coronary artery disease or myocarditis [38]. Mall et al. [10] documented that the inter-myocardiocytic fibrosis in uraemic patients was significantly more pronounced than that in hypertensive or diabetic type II patients. Kuzela et al. [11] demonstrated soft tissue calcification in the myocardium of uraemic patients undergoing chronical dialysis. Myocardial fibre degeneration, interstitial calcium deposits and dense interstitial fibrosis were predominantly observed. The most severe autopsy lesions consisted of dense fibrous connective tissue containing large irregular calcium deposits.
Previous studies suggest that all biological, experimental and autopsy observations could explain the high incidence of heart failure in dialysis patients, and the worst prognosis of uraemic heart in comparison with essential hypertensive cardiopathy with the same degree of LVM.
With videodensitometry, we documented that dialysis patients have a significantly lower septal and posterior wall CVI compared with hypertensive patients and controls. It is well known that the major determinants of the alteration of videodensitometric patterns are the presence of excess collagen with respect to a normal collagen/myocyte ratio and intramyocardial calcification. These elements have a significantly higher level of acoustic reflection compared with normal structures of the myocardium. The higher degree of myocardial fibrosis and calcification in dialysis patients compared with hypertensive subjects could explain the alteration in myocardial textural parameters in dialysis patients detected by the videodensitometric method.
The systolic and diastolic left ventricular functions were still within the normal range in both the hypertensive and dialysis patients. For this reason, the altered videodensitometric findings in our dialysis patients could represent an early index of altered myocardial textural patterns, which potentially might evolve toward so-called `uraemic cardiomyopathy'. Furthermore, the individual analysis of CVI permitted clear differentiation of dialysis and hypertensive patients even though they had similar LVM. In fact, the CVI is altered in the entire dialysis population, less than the 95th percentile of the normal distribution (Figure 2).
The strength of this casecontrol study was the recruitment of subjects similar in age and cardiac mass and of the same gender, thereby excluding important confounding factors. Furthermore, stringent clinical criteria avoided major confusion due to co-existent coronary artery disease which might per se influence the videodensitometric signal. However, the study is limited by the lack of histological determination of cardiac structure, but the use of this invasive technique was not ethically acceptable.
In conclusion, videodensitometry might represent a non-invasive, feasible ultrasound tissue characterization method which could integrate the conventional echo-Doppler analysis of the uraemic heart, and give us new insights into primary cardiomyopathies. Further studies are needed to understand completely the clinical and prognostic significance of the myocardial ultrasonic textural alterations.
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References |
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