NDT Advance Access originally published online on January 30, 2008
Nephrology Dialysis Transplantation 2008 23(7):2324-2328; doi:10.1093/ndt/gfm954
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Decreased coronary flow reserve in haemodialysis patients
1 Division of Hypertension and Nephrology 2 Division of Atherosclerosis and Diabetes 3 Division of Cardiology, National Cardiovascular Center, Fujishirodai 5-7-1, Suita 565-8565, Japan
Correspondence and offprint requests to: Hajime Nakahama, Division of Hypertension and Nephrology, National Cardiovascular Center, Fujishirodai 5-7-1, Suita 565-8565, Japan. E-mail: hnakaham{at}hsp.ncvc.go.jp
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Abstract |
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Background. Coronary flow reserve (CFR) reflects the functional capacity of microcirculation to adapt to blood demand during increased cardiac work.
Methods. Forty-one patients who had already undergone coronary angiography were studied. They consisted of 21 haemodialysis patients with no significant left anterior descending coronary artery (LAD) stenosis and 20 non-renal failure patients without LAD stenosis. We performed transthoracic Doppler recording of diastolic coronary flow velocity in the LAD at baseline and after maximal vasodilatation by adenosine triphosphate (ATP) infusion. CFR was defined as the ratio of hyperaemic to basal averaged peak flow velocity.
Results. Although the peak coronary velocities during hyperaemia were similar between the two groups, CFR was smaller in haemodialysis (HD) patients than in control subjects (1.96 ± 04 versus 2.3 ± 0.5, P = 0.001) due to the higher baseline peak coronary velocities in the former.
Conclusions. The elevated baseline peak coronary velocity may be caused by cardiac hypertrophy and anaemia in HD patients.
Keywords: anaemia; coronary flow reserve; echocardiography; haemodialysis; left ventricular
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Introduction |
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Ischaemic heart disease is by far the leading cause of morbidity and mortality in haemodialysis (HD) patients. Since prevention is not easy, early detection of the disease is the key issue. While coronary angiography is a definitive diagnostic tool, its invasiveness makes it not suitable for all patients. Non-invasive exercise thallium single-photon emission computed tomography is expensive and furthermore not available at all facilities. Stress echography, which has gained increasing popularity, requires skilled interpreters. Recently, a method was developed for assessing coronary flow reserve in the left anterior descending coronary artery (LAD) non-invasively using transthoracic Doppler echography [1]. Coronary flow reserve (CFR) reflects the functional capacity of microcirculation to adapt to blood demand during increased cardiac work. It has been shown to be highly sensitive and specific in the general population [2]. It has also been shown to be as effective as Tl-201-SPECT for physiologic estimation of the severity of LAD stenosis [3]. However, there have been few reports on coronary flow reserve in HD patients. The purpose of the present study was to determine the prevalence and mechanism of abnormal CFR in HD patients without significant LAD stenosis.
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Methods |
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Study population
Between 1 June 2003 and 31 August 2003, 196 patients (HD 47, non-HD 149) were hospitalized in our facility because of clinically suspected coronary artery disease. Of the 72 patients who had no significant LAD stenosis on coronary angiography, 41 gave their consent to undergo CFR measurement using transthoracic Doppler echocardiography. The final study population consisted of 21 haemodialysis patients and 20 patients with normal renal function. The exclusion criteria for the present study included the presence of old myocardial infarction, dilated cardiomyopathy, valvular heart disease, hypertrophic cardiomyopathy, congenital heart disease and insufficient echo imaging. Patients with arrhythmias, including atrioventricular blocks or atrial fibrillation, and bronchial asthma were also excluded because the administration of adenosine triphosphate (ATP) might have worsened their symptoms. All subjects gave their informed consent, and the institutional ethics committee approved the study protocol.
CFR measurements by transthoracic Doppler echocardiography
Echocardiographic examinations were performed with a Siemens Sequoia digital ultrasound system (Siemens Medical Solutions Inc., Mountain View, CA, USA) with a frequency of 7.0 MHz. The left ventricular mass index (LVMI) was estimated according to the formula of Devereux et al. [4]. The pulsed Doppler transmitral flow velocity was recorded to measure the ratio of peak mitral E-wave velocity to peak mitral A-wave velocity (E/A ratio) and the deceleration time of mitral E-wave velocity.
The baseline spectral Doppler signals in the distal portion of the LAD were recorded first. ATP was then administered (140 µg/kg/min i.v.) for 3 min to record spectral Doppler signals during hyperaemic conditions. All patients had continuous heart rate and ECG monitoring throughout the study. Blood pressure was recorded at baseline, every minute during ATP infusion, and at recovery.
Measurements were performed off-line by tracing the contour of the spectral Doppler signal using the computer incorporated in the ultrasound system. Peak diastolic velocity was measured at baseline and under peak hyperaemic conditions. The values in three cardiac cycles were averaged. CFR was defined as the ratio of hyperaemic to basal peak diastolic velocity. Inter- and intraobserver variabilities for the measurement of Doppler velocity recordings were 4.1% and 4.2%, respectively.
Coronary angiography and lesion morphology
Coronary angiography was performed following a standard technique. Before angiography, all of the patients received an intracoronary bolus injection of nitroglycerin (0.125– 0.25 mg). Coronary stenosis was evaluated using a computer-assisted quantitative analysis system (CMS-QCA versus 4.0 MEDIS, The Netherlands) based on multiple projections by an experienced investigator who was unaware of the echocardiographic data. A percent diameter stenosis of >50% was defined as significant stenosis [5].
Statistical analysis
For all statistical studies, we used the computer software application StatView (Abacus Concepts Inc., Berkeley, CA, USA). Values are expressed as the means ± SD. Differences were analysed by ANOVA followed by Fisher's protected least significant difference test for continuous variables and with the 
2 test for categorical variables. P < 0.05 was considered statistically significant.
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Results |
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Patient characteristics and clinical findings
The clinical and demographic findings are summarized in Table 1. The percentage of females in the control group was greater than that in the haemodialysis group. There was no significant difference in age or the prevalence of diabetes mellitus between the two groups. The prevalence of hypertension was significantly higher in the haemodialysis group. The prevalence of hyperlipidaemia and the blood haemoglobin level were both significantly lower in the haemodialysis group.
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Coronary angiography results
Table 2 shows the results of coronary angiography. Significant stenosis was found in the LAD in 0 patients, in the LCX in 16 patients (normal 8, HD 8) and in the RCA in 21 patients (normal 10, HD 11). Sixteen patients (normal 8, HD 8) had multivessel disease and no patient had left main trunk stenosis.
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Echocardiographic parameters
The echocardiographic data are summarized in Table 3. The prevalence of left ventricular hypertrophy was significantly greater in the haemodialysis patients.
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Haemodynamics and coronary flow findings
The haemodynamic data and coronary flow data are summarized in Table 4. Both systolic and diastolic blood pressures at baseline were significantly higher in the haemodialysis patients. The average peak coronary flow velocity at baseline in HD patients was significantly greater than that in control subjects. The average peak coronary flow velocity during hyperaemia tended to be greater in the haemodialysis group than in control subjects, but this difference was not statistically significant (Figure 1). Consequently, the coronary flow reserve, defined as the ratio of hyperaemic to basal peak diastolic velocity, was significantly lower in the haemodialysis group than in the control group (Figure 2).
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Relationship between baseline coronary blood flow and left ventricular mass index or blood haemoglobin level
There was a significant positive correlation between left ventricular hypertrophy as assessed by the LVMI and the average peak coronary flow velocity at baseline (Figure 3a). There was a significant negative correlation between the blood haemoglobin level and the average peak coronary flow velocity at baseline (Figure 3b). There was no significant correlation (r = 0.28, P = 0.08) between LVMI and the haemoglobin level.
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Discussion |
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Previous studies have shown that coronary flow reserve is reduced in various disorders. In this study, diminished coronary flow reserve was observed in haemodialysis patients. Diminished coronary flow reserve may account for several symptoms that are often encountered in haemodialysis patients. Chest pain, arrhythmia and hypotension during haemodialysis sessions may be caused by diminished coronary flow reserve.
The impaired coronary flow reserve observed here was caused primarily by an elevation of the peak coronary flow velocity at baseline. The elevated peak coronary flow velocity at baseline may be attributed to an increase in left ventricular mass due to long-standing hypertension and anaemia, which are common in this patient population.
Impaired coronary flow reserve in hypertensive patients has been reported previously. Hamasaki et al. studied coronary flow reserve by intravascular ultrasound examination in hypertensive subjects with normal or mildly diseased coronary arteries at angiography [6]. They demonstrated that coronary blood flow at baseline was enhanced and its response to both acetylcholine and adenosine was significantly reduced in patients with left ventricular hypertrophy. Takiuchi et al. demonstrated that there was a significant negative correlation between coronary flow reserve and the serum concentration of asymmetric dimethylarginine (ADMA) [7]. ADMA is an endogenous competitive inhibitor of nitric oxide synthases, and serum ADMA levels have been suggested to be markers of endothelial dysfunction. Ravani et al. studied the relationship among plasma levels of ADMA, renal function and the risk for progression to end-stage renal disease (ESRD) in 131 patients with chronic kidney disease. They demonstrated that in patients with mild to advanced chronic kidney disease, plasma ADMA was inversely related to glomerular filtration rate and represented a strong and independent risk marker for progression to ESRD and mortality [8]. This study suggests that plasma ADMA level is high in haemodialysis patients. As we demonstrated, anaemia is also associated with high resting basal coronary flow.
To our knowledge, there have been only two reports on the effect of renal failure on coronary flow reserve. Ragosta et al. studied coronary flow reserve with a Doppler ultrasound scanning wire in a normal coronary in 32 patients without diabetes mellitus, 11 patients with diabetes mellitus without renal failure and 21 patients with both diabetes mellitus and renal failure [9]. They demonstrated that coronary flow reserve was attenuated in 9% of patients without diabetes mellitus, 18% of patients with diabetes mellitus without renal failure and 57% of patients with diabetes mellitus and renal failure. In the latter cases, abnormal coronary flow reserve was caused by an elevation of baseline coronary flow at baseline. The univariate predictors of abnormal CFR included left ventricular hypertrophy but not the haematocrit level. The baseline heart rate and the presence of diabetes mellitus with renal failure were independent predictors of attenuated coronary flow reserve by multivariate analysis. Their definition of renal failure is ambiguous since they merely state that end-stage renal failure was diagnosed by a nephrologist. Furthermore, they did not have a group of patients with end-stage renal disease who did not have diabetes mellitus. Nevertheless, the notion that elevated coronary flow at baseline is a factor that should always be considered is important. In our present study, there was no difference in the prevalence of diabetes mellitus between the haemodialysis group and the control group. We speculate that an elevation of baseline coronary flow at baseline is independent of diabetes mellitus.
Tok et al. reported that coronary flow reserve was impaired in haemodialysis patients [10]. There was no difference in LVMI between the haemodialysis and control groups. There was also no difference in LVMI between subjects with high and low coronary flow reserve subjects, even among the haemodialysis group. This implies that left ventricular hypertrophy is not a determinant of coronary flow reserve, which contradicts our findings and those in other previous studies. They found a strong inverse correlation between mitral-septal corner mean diastolic velocities during atrial contractions (Am) and coronary flow reserve. In addition, a positive correlation was found between the mitral-septal corner mean diastolic velocity during early diastole (Em):Am ratio, the lateral Em:Am ratio and coronary flow reserve. They concluded that decreased coronary flow reserve might contribute to the impairment of diastolic function, or vice versa. Since no data on baseline coronary flow at baseline were presented, a direct comparison with our study is not possible.
In conclusion, coronary flow reserve was diminished in haemodialysis patients. This impaired coronary flow reserve was caused primarily by an elevation of the peak coronary flow velocity at baseline. The elevated peak coronary flow velocity at baseline may be attributed to an increase in left ventricular mass due to long-standing hypertension and anaemia.
Conflict of interest statement. None declared.
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References |
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- Hozumi T, Yoshida K, Ogata Y, et al. Noninvasive assessment significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color Doppler echocardiography. Circulation (1998) 97:1557–1562.
[Abstract/Free Full Text] - Watanabe N, Akasaka T, Yamaura Y, et al. Noninvasive detection of total occlusion of the left anterior descending coronary artery with transthoracic Doppler echocardiography. J Am Coll Cardiol (2001) 38:1328–1332.
[Abstract/Free Full Text] - Daimon M, Watanabe H, Yamagishi H, et al. Physiologic assessment of coronary artery stenosis by coronary flow reserve measurements with transthoracic Doppler echocardiography: comparison with exercise thallium-201 single-photon emission computed tomography. J Am Coll Cardiol (2001) 37:1310–1315.
[Abstract/Free Full Text] - Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation (1977) 55:613–618.
[Abstract/Free Full Text] - Kataoka Y, Nakatani S, Tanaka N, et al. Role of transthoracic Doppler-determined coronary flow reserve in patients with chest pain. Circ J (2007) 71:891–896.[CrossRef][Web of Science][Medline]
- Hamasaki S, Al Suwaidi J, Higano ST, et al. Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy. J Am Coll Cardiol (2000) 35:1654–1660.
[Abstract/Free Full Text] - Takiuchi S, Fujji H, Kamide K, et al. Plasma asymmetric dimethylarginine and coronary and peripheral dysfunction in hypertensive patients. Am J Hypertens (2004) 17:802–808.[CrossRef][Web of Science][Medline]
- Ravani P, Tripepi G, Malberti F, et al. Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol (2005) 16:2449–2455.
[Abstract/Free Full Text] - Ragosta M, Samady H, Isaacs RB, et al. Coronary flow reserve abnormalities in patients with diabetes mellitus who have end-stage renal disease and normal epicardial coronary arteries. Am Heart J (2004) 147:1017–1023.[CrossRef][Web of Science][Medline]
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Accepted in revised form: 26.12.07
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