Association between cardiovascular autonomic neuropathy and left ventricular hypertrophy in diabetic haemodialysis patients

Masato Nishimura1, Tetsuya Hashimoto2, Hiroyuki Kobayashi2, Toyofumi Fukuda2, Koji Okino3, Noriyuki Yamamoto2, Naoto Nakamura4, Toshikazu Yoshikawa4, Hakuo Takahashi5 and Toshihiko Ono2

1 Cardiovascular Division, 2 Division of Urology and 3 Division of Surgery, Toujinkai Hospital, Kyoto, 4 First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto and 5 Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University, Osaka, Japan

Correspondence and offprint requests to: Masato Nishimura, MD, Cardiovascular Division, Toujinkai Hospital, 16 Negoro, Momoyama-cho, Fushimi-ku, Kyoto 612-8024, Japan. Email: tojinkai.hosp{at}dream.com



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Patients with diabetic nephropathy are likely to have neurological complications including cardiovascular autonomic dysfunction, which is related to increased risk of mortality. We investigated whether cardiovascular autonomic neuropathy is associated with left ventricular hypertrophy (LVH) in diabetic haemodialysis patients.

Methods. Holter electrocardiography was carried out for 24 h with time and frequency domain analyses of heart rate variability in 154 diabetic (age 62±11 years) and 63 non-diabetic haemodialysis patients (62±10 years). The left ventricular mass index (LVMI) was determined by echocardiography. We used the percentage of differences exceeding 50 ms between adjacent normal RR intervals (pNN50) in time domain analysis and the power in the high-frequency range (HF: 0.15–0.40 Hz) in frequency domain analysis as indicators of parasympathetic activity.

Results. The mean LVMI was greater in diabetic than in non-diabetic patients (168±63 vs 144±54 g/m2, P<0.01). LVMI inversely correlated with pNN50 (r = –0.270, P = 0.0007, n = 154) and HF (r = –0.277, P = 0.0005, n = 154) in diabetic patients, but not in non-diabetic patients. By multiple logistic analysis, LVH was strongly associated with pNN50 (odds ratio 0.088; 0, <2%; 1, ≥2%) and HF (odds ratio 0.058; 0, <500 ms2; 1, ≥500 ms2) in diabetic patients.

Conclusions. Impaired parasympathetic activity, which indicates cardiovascular autonomic neuropathy, was associated with the presence of LVH in diabetic haemodialysis patients. The co-existence of cardiovascular autonomic neuropathy and LVH may be one of the key factors for the high incidence of cardiovascular events in diabetic haemodialysis patients.

Keywords: diabetes mellitus; haemodialysis; heart rate variability; left ventricular hypertrophy; parasympathetic activity



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Left ventricular hypertrophy (LVH) is relatively common in end-stage renal disease (ESRD), with a prevalence of nearly 75%. Cross-sectional studies have shown LVH to be an independent risk factor for shortened survival in ESRD patients [1]. Diabetic nephropathy is the leading cause of ESRD requiring renal replacement therapy in Japan. Patients with diabetic nephropathy are likely to have neurological complications of diabetes including cardiovascular autonomic dysfunction [2]. Defined as impairment of the cardiac parasympathetic and sympathetic nervous system, cardiovascular autonomic dysfunction is associated with increased risk of mortality, particularly cardiac deaths, in diabetic patients [3–5]. It would influence the prognosis of diabetic ESRD patients to have cardiovascular autonomic dysfunction as well as LVH as their complications. However, we know of no previous study examining the relationship of cardiovascular autonomic neuropathy to LVH in diabetic haemodialysis patients. Time and frequency domain analyses of heart rate variability have been used extensively for non-invasive assessment of the autonomic nervous control of cardiovascular function. In time domain measures, the percentage of differences between adjacent normal RR intervals exceeding 50 ms over the entire 24 h electrocardiographic (ECG) recording (pNN50) is one of the representative parameters showing cardiac parasympathetic activity [6]. The efferent vagal activity is a major contributor to the power in the high-frequency range (HF: 0.15–0.40 Hz) in frequency domain measures [7,8], while the power in the low-frequency range (LF: 0.04–0.15 Hz) is thought to be a parameter that includes both sympathetic and parasympathetic influences [9,10]. Our present findings showed an association between impaired parasympathetic activity and LVH in diabetic haemodialysis patients by using time and frequency domain analyses of heart rate variability.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects and study protocol
In this study, we enrolled 217 patients who had undergone maintenance haemodialysis for >6 months at Toujinkai Hospital. Patients were excluded if they had (i) a history of angina pectoris, myocardial infarction or moderate to severe congestive heart failure (New York Heart Association grades III–IV); (ii) arrhythmias such as atrial fibrillation, atrial flutter, or premature atrial or ventricular ectopic beats exceeding 100 per day; or (iii) non-compliance with fluid intake restrictions (body weight gain between dialyses exceeding 5% of ‘dry weight’). Of 217 patients, 154 had diabetes mellitus; the other 63 had no present or previous history of diabetes (Table 1). Mean duration of a diabetic history was 20.0±4.8 years. Diabetic nephropathy had been proven to be the cause of ESRD by renal biopsy examination in 126 of 154 diabetic patients (81.8%). In the other 28 patients, diabetes mellitus had been diagnosed before the occurrence of renal insufficiency, but the exact cause of ESRD had not been ascertained by renal biopsy examination. Orthostatic hypotension, a clinical hallmark of cardiovascular autonomic neuropathy, was found in 33 of 154 diabetic patients (21.4%). The Ethics Committee for Human Research of Toujinkai Hospital approved this study, and all patients provided informed consent for participation.


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Table 1. Characteristics of diabetic and non-diabetic patients

 
Haemodialysis was performed three times weekly using a dialysate containing Na+ (140 mEq/l), K+ (2.0 mEq/l), Cl (110 mEq/l), Ca2+ (3.0 mEq/l), Mg2+ (1.0 mEq/l), HCO3 (30 mEq/l) and CH3COO (10–15 mEq/l). Membranes used in the various dialysers included either cellulose triacetate (20% of dialyses in non-diabetic and 20% in diabetic patients; FB-190F, NIPRO, Tokyo), surface-modified regenerated cellulose (19% in non-diabetic and 18% in diabetic patients; AMBC-20X, Asahi Medical, Tokyo), polymethyl methacrylate (22% in non-diabetic and 23% in diabetic patients; FB-2.1F, Toray Medical, Tokyo) or polysulfone (39% in non-diabetic and 39% in diabetic patients; PS-1.9UW, Kawasumi Laboratory, Tokyo). Dialysis filter surface areas ranged from 1.8 to 2.1 m2. Blood pressure was measured hourly during dialysis using a mercury sphygmomanometer. Mean blood pressure and pulse pressure were determined as the means of measurements obtained in eight different midweek haemodialysis sessions in which patients showed essentially the same increase in body weight, including the week in which Holter ECG was performed.

Determination of left ventricular mass index
A two-dimensionally guided M-mode echocardiogram was obtained for each patient using a single ultrasound recorder (UF-8800, Fukuda Denshi, Tokyo) with a 3.5 MHz transducer on the day between midweek dialysis sessions within 2 weeks after the 24 h Holter ambulatory ECG monitoring. Measurements for M-mode-guided calculation of left ventricular mass [LVM; left ventricular internal end-diastolic and end-systolic dimensions (LVIDd and LVIDs), interventricular septal wall thickness (IVST) and left ventricular posterior wall thickness (PWT)] were obtained according to the guidelines of the American Society of Echocardiography [11]. Relative left ventricular wall thickness (rLVWT) was calculated as 2 x PWT/LVIDd. LVM was calculated according to a formula described by Devereux et al. [12]:

LVM was normalized to body surface area as the LVM index (LVMI). Criteria for LVH were an LVMI exceeding 134 g/m2 in men or 110 g/m2 in women [11]. The mean coefficient of variation (CV) of LVMI measurement was 2.14±0.90% (n = 10).

Analysis of heart rate variability
All patients underwent Holter ambulatory ECG monitoring (FM-100, Fukuda Denshi) for 24 h from the day before the midweek dialysis session to 1 h before the start of dialysis, within 2 weeks before cardiac echocardiography. Holter recordings were scanned with Holter processing equipment (SCM-6000, Fukuda Denshi), and QRS complexes were identified and labelled. Heart rate variability parameters were analysed by use of commercially available software [HPS-RRLOP (1), Fukuda Denshi]. Special indices of heart rate variability were computed by fast Fourier transformation from 512 consecutive normal RR intervals of the recording, with application of a Hanning window to minimize spatial leakage. Power spectra from sequential pre-specified segments were averaged every hour and for the entire 24 h time period. The following frequency domain measures were assessed: (i) total power (0.0–1.0 Hz); (ii) power in the low-frequency component or LF (0.04–0.15 Hz); (iii) power in the high-frequency component or HF (0.15–0.40 Hz); and (iv) the LF/HF ratio. Measurement of total power, LF and HF was carried out in absolute values of power (ms2). As time domain measures, we used the number of total normal RR intervals during the 24 h monitoring period (total NN), the SD of the average normal RR interval for all 5 min segments of a 24 h ECG recording (SDANN) and the percentage of differences between adjacent normal RR intervals exceeding 50 ms over the entire 24 h ECG recoding (pNN50). Analysis of heart rate variability was performed by highly experienced employees of Fukuda Denshi kept unaware of details of this study. Mean values of CV in measures of heart rate variability were 3.29±0.88% in LF (n = 10), 3.54±0.84% in HF (n = 10), 3.36±0.93% in SDANN (n = 10) and 2.37±0.84% in pNN50 measurements (n = 10), respectively.

Biochemical measurements
Blood samples (5 ml) were obtained just before initiation of haemodialysis in the same week as the echocardiographic examination. Plasma B-type natriuretic peptide (BNP) concentration was measured with a sensitive immunoradiometric assay (Shionoria BNP, Shionogi, Osaka). Intra- and inter-assay variations of the assay were 5.3 and 5.9%, respectively. Haematocrit and serum concentrations of haemoglobin and albumin were determined as the mean values of four different measurements within a 2 month period, which included the day of echocardiographic examination.

Ambulatory blood pressure monitoring
Diurnal 24 h ambulatory blood pressures were recorded (FM-200, Fukuda Denshi) between midweek dialysis sessions within 30 days after 24 h Holter ambulatory ECG monitoring, and the data were analysed (SCM-6000) in diabetic or non-diabetic patients with or without LVH. The presence of LVH was determined according to the criteria of echocardiographic measurements as described above. In diabetic patients, the presence of impaired parasympathetic function was taken into account in the selection of the patients. The diabetic LVH group consisted of 30 diabetic haemodialysis patients who had LVH and impaired cardiac parasympathetic activity (pNN50 <1%): 15 male, 15 female; mean age 59±13 years; LVMI 175.8±43.6 g/m2; pNN50 0.3±0.3%; HF 81±89 ms2. The diabetic, non-LVH group consisted of 25 haemodialysis patients who did not have LVH and had apparently intact parasympathetic activity (pNN50 >2%): nine male, 16 female; mean age 64±11 years; LVMI 100.7±16.9 g/m2; pNN50 4.9±3.6%; HF 557±70 ms2. The non-diabetic LVH group consisted of 24 haemodialysis patients (12 male, 12 female; mean age 63±9 years; LVMI 175.3±30.2 g/m2; pNN50 4.4±4.4%; HF 464±404 ms2), and the non-diabetic, non-LVH group consisted of 23 haemodialysis patients (14 male, nine female; mean age 61±12 years; LVMI 100.5±25.0 g/m2; pNN50 3.6±5.4%; HF 377±443 ms2). Antihypertensive drug administration was suspended 2 weeks before the examination. Blood pressure was measured over a 30 min period during the daytime (between 6 a.m. and 8 p.m.) and during a 60 min period at night (between 8 p.m. and 6 a.m.).

Statistical analysis
All values are expressed as mean±SD. Differences between groups were evaluated by one-way analysis of variance, followed by application of Duncan's new multiple range test. Relationships between LVH and clinical parameters in diabetic or non-diabetic patients first were evaluated by univariate logistic analysis; then the association of LVH with other continuous or categorical data collected in patients with or without diabetes mellitus was analysed using a multiple logistic model with a dichotomous response variable for presence/absence of LVH according to LVMI criteria. Selection of covariates included in the final model was carried out using backward elimination, forward selection and stepwise selection. As a measure of relative risks for LVH, odds ratios and their 95% confidence intervals (CIs) were presented in order to summarize the effects of each covariate. All statistical tests were two-sided, with significance accepted at a {alpha} level of 0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Mean duration of haemodialysis was shorter, and mean values of pulse pressure, IVST, PWT, rLVWT or LVMI were greater in diabetic than in non-diabetic patients (Table 1). The two groups did not differ significantly with respect to other parameters including gender, age, mean blood pressure, cardiothoracic ratio, haematocrit, circulating concentrations of haemoglobin, albumin and BNP, left ventricular dimensions or fractional shortening. According to M-mode criteria, LVH was present in 63.3% (19 out of 30) of non-diabetic women and 57.6% (19 out of 33) of non-diabetic men, and in 72.7% (48 out of 66) of diabetic women and 75.0% (66 out of 88) of diabetic men.

Difference in heart rate variability between diabetic and non-diabetic patients
Time domain analysis of heart rate variability showed that mean pNN50 and SDANN were lower in diabetic than in non-diabetic patients, although the total number of NN intervals during 24 h did not differ between the two groups (Table 2). In frequency domain analysis of heart rate variability, mean values of total power, LF and HF were reduced in diabetic patients compared with non-diabetic patients, although the LF/HF ratio did not differ between the two groups. Figure 1 shows typical patterns of power spectra of heart rate variability during 24 h in diabetic and non-diabetic patients.


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Table 2. Differences in parameters of heart rate variability between diabetic and non-diabetic patients

 


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Fig. 1. Typical examples of power spectra of heart rate variability during 24 h. (A) A 56-year-old non-diabetic man: total power (0–1.0 Hz), 6364 ms2; LF (0.04–0.15 Hz), 1535 ms2; HF (0.15–0.40 Hz), 665 ms2. (B) A 64-year-old diabetic woman: total power, 880 ms2; LF, 31 ms2; HF, 21 ms2.

 
Heart rate variability and LVH
In diabetic patients, LVMI correlated negatively with pNN50 or HF (Figure 2), and positively with LF/HF (r = 0.263, P = 0.001, n = 154), but did not correlate with mean blood pressure, pulse pressure or plasma BNP concentration. In contrast, in non-diabetic patients, LVMI correlated positively with pulse pressure after dialysis (r = 0.346, P = 0.006, n = 63) and plasma BNP concentration (r = 0.333, P = 0.007, n = 63), and tended to correlate positively with mean blood pressure before dialysis (r = 0.209, P = 0.099, n = 63) or after dialysis (r = 0.241, P = 0.057, n = 63). LVMI did not correlate with any parameters of heart rate variability in non-diabetic patients.



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Fig. 2. Correlations of left ventricular mass index (LVMI) with the percentage of differences between adjacent normal RR intervals exceeding 50 ms over the entire 24 h ECG recording (pNN50; A) and the power in the HF range (B) in diabetic haemodialysis patients.

 
The results of univariate logistic analysis (Table 3) indicated that LVH in diabetic patients was significantly associated with parameters of heart rate variability such as pNN50, HF and LF/HF, but not with blood pressure, pulse pressure or plasma BNP concentration. In non-diabetic patients, however, LVH tended to be related to mean blood pressure after dialysis, pulse pressure after dialysis, and plasma BNP concentration, but not to parameters of heart rate variability.


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Table 3. Univariate logistic analysis between LVH and clinical parameters in diabetic and non-diabetic haemodialysis patients

 
In multiple logistic analysis (Table 4), odds ratios of pNN50 and HF to LVH in diabetic patients were 0.787 and 0.993, respectively when values of pNN50 or HF were treated as continuous variables. The odds ratio of ≥2% pNN50 vs <2% pNN50 to LVH was 0.088, and that of ≥500 ms2 HF vs HF <500 ms2 to LVH was 0.058; in other words, the odds ratio of <2% vs ≥2% pNN50 to LVH was 11.364 (3.690–34.433), and the odds ratio of <500 ms2 vs ≥500 ms to LVH was 17.24 (5.495–55.556) in diabetic patients. LF/HF ratio was not chosen as one of the covariates in multiple logistic models in the diabetic group by the selection procedures. In non-diabetic patients, the odds ratio of plasma BNP concentration to LVH was 1.002, and no significant association was found between LVH and parameters of heart rate variability.


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Table 4. Multiple logistic regression analysis between LVH and cardiac autonomic activity

 
Ambulatory blood pressure in diabetic patients with or without LVH and impaired parasympathetic activity
Mean daytime and night time systolic blood pressures did not differ between diabetic patients with or without LVH (daytime, 140±12 mmHg, n = 30 vs 142±11mmHg, n = 25; night time, 151±9 mmHg, n = 30 vs 153±9 mmHg, n = 25). Mean diastolic blood pressure also did not differ between these two subgroups during the daytime (72±5 mmHg, n = 30 vs 71±5 mmHg, n = 25) or night time (78±6 mmHg, n = 30 vs 76± 5 mmHg, n = 25). Mean systolic and diastolic blood pressures were higher (P<0.001) during the night time than during the daytime in both groups. In non-diabetic patients, both mean systolic and diastolic blood pressure were higher in the LVH group than in the non-LVH group during the night time (141±14 mmHg, n = 24 vs 128±12 mmHg, n = 23, P<0.01; 74± 7 mmHg, n = 24 vs 64±6 mmHg, n = 23, P<0.001). However, neither mean systolic nor diastolic blood pressures during the daytime differed between the two groups (144±14 mmHg, n = 24 vs 138±12 mmHg, n = 23; 71±7 mmHg, n = 24 vs 71±6 mmHg, n = 23).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present study, diabetic haemodialysis patients showed lower mean values than non-diabetic haemodialysis patients in pNN50 and SDANN in time domain analysis of heart rate variability, and in total power, LF and HF in frequency domain analysis. The decrease in heart rate variability in diabetic patients appeared to be derived mainly from reduction of parasympathetic activity, since pNN50 and HF are parameters indicative of such activity and parasympathetic activity is significantly related to components of SDANN, total power and LF [6]. Further, logistic regression analysis showed that reduced parasympathetic activity was related strongly to the presence of LVH in diabetic haemodialysis patients, but not in non-diabetic patients. These results indicate that impaired parasympathetic function, most probably induced by diabetic autonomic neuropathy, is associated with LVH in diabetic haemodialysis patients.

Autonomic neuropathy is a common complication of diabetes mellitus, and the presence of cardiovascular autonomic neuropathy is associated with adverse cardiac outcome. In a study of 120 diabetic patients who had been followed-up for an average of 4.5 years, major cardiac events were significantly more common in patients with than in those without cardiovascular autonomic neuropathy (24 vs 7%) [3]. In addition, a meta-analysis of studies of diabetic patients concluded that the mortality of autonomic neuropathy-free subjects during 5.5 years of observation was ~5%, but this increased to 27% with onset of cardiovascular autonomic neuropathy [5]. When impairment of cardiovascular autonomic function is combined with LVH, an independent risk factor for shortened survival in ESRD patients [1] as well as for cardiovascular diseases including coronary artery disease or arrhythmias [13–15], the mortality of ESRD patients is increased further. To improve prognosis in diabetic haemodialysis patients, mechanisms linking LVH to cardiovascular autonomic neuropathy should be elucidated.

In diabetic patients, the baroreflex dysfunction due to impairment of the afferent limb of the reflex has been well established [16]. Sinoaortic denervation, which results in baroreflex dysfunction, causes persistent apoptosis in myocardiocytes of rats, although the mechanism has not been clarified [17]. Apoptosis in myocardial cells is involved in cardiac remodelling including LVH in human diabetes [18]. The previous study showed a correlation between diminished baroreflex sensitivity and LVH [19], but the precise relationship between them remains to be clarified [20]. Since the baroreceptor–heart rate reflex dysfunction appears to represent an early stage of cardiovascular autonomic neuropathy as a diabetic complication [21], diabetic haemodialysis patients who had shown impaired parasympathetic activity in the analysis of heart rate variability in the present study were likely to have baroreceptor–heart rate reflex dysfunction. It may make a contribution to understanding the association between the cardiovascular autonomic neuropathy and LVH if we were to investigate the relationship between myocardial apoptosis and impaired parasympathetic activity or baroreflex dysfunction in diabetic haemodialysis patients.

A single haemodialysis treatment reportedly restores the LF component in heart rate variability in non-diabetic ESRD patients [22]. The decrease in blood volume by haemodialysis elicited an increase in heart rate at rest and during sympathetic activation by tilt, and augmented the heart rate response to tilt in patients after dialysis compared with the state before dialysis in non-diabetic ESRD patients [23]. In addition, acute volume expansion of the intrathoracic compartment of the circulation by head-down tilt was able to reduce the overall heart rate and blood pressure variability in healthy subjects [24]. These findings indicate that overhydration may be involved at least partly in reduced heart rate variability before dialysis in non-diabetic ESRD patients, and that the correction of overhydration by ultrafiltration during a haemodialysis treatment is likely to improve the abnormal heart rate variability after dialysis. Because we had carried out Holter ambulatory ECG monitoring for 24 h before a midweek dialysis session, it would be conceivable that overhydration to some extent had affected the results of heart rate variability of non-diabetic haemodialysis patients.

Loss of diurnal variation in blood pressure, with supine hypertension occurring at night, has been noted particularly in diabetic ESRD patients with autonomic neuropathy [25]. In the present study, mean night time systolic and diastolic blood pressures were higher than daytime pressures in diabetic subgroups with or without LVH. On the other hand, mean systolic and diastolic blood pressure did not differ during the daytime or night time between diabetic groups with or without LVH. In contrast, mean systolic and diastolic blood pressures during the night time were higher in non-diabetic patients with LVH than in those without LVH. However, we cannot insist that changes in blood pressure do not seem to be involved in LVH of diabetic haemodialysis patients from the results of the present study. A previous study showed that hypertension was not adequately controlled between dialysis sessions in haemodialysis patients, even though the patients had seemingly ultrafiltration-correctable arterial hypertension [26]. Because ambulatory blood pressure recordings were carried out at 30 min intervals during the daytime and at 60 min intervals at night, it is quite possible that we may have missed the points of high blood pressure during the blood pressure monitoring in patients with LVH. Further investigation would be needed to clarify the precise relationship between hypertension and LVH in diabetic haemodialysis patients.

The results of the present study have shown that cardiovascular autonomic neuropathy may be associated with LVH in diabetic ESRD patients undergoing maintenance haemodialysis, although a cause-and-effect relationship between them is unknown. Co-existence of cardiovascular autonomic neuropathy and LVH, both of which are independent risk factors for major cardiac events such as myocardial infarction or congestive heart failure [1,3–5], is likely to be one of the key factors for poor prognosis in diabetic ESRD patients. We need further investigation to clarify the mechanism linking cardiovascular autonomic neuropathy with LVH in diabetic haemodialysis patients.



   Acknowledgments
 
The authors are indebted to Takashi Koshimizu, PhD, at Bayer Yakuhin, Ltd, for statistical support. The authors greatly appreciate the efforts of the staff at Fukuda Denshi Co. for their precise analyses of heart rate variability.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Silberberg J, Barre PE, Prichard SS, Sniderman AD. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989; 36: 286–290[ISI][Medline]
  2. Zander E, Schulz B, Heinke P, Grimmberger E, Zander G, Gottschling HD. Importance of cardiovascular autonomic dysfunction in IDDM subjects with diabetic nephropathy. Diabetes Care 1989; 12: 259–264[Abstract]
  3. Valensi P, Sachs R-N, Harfouche B et al. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care 2001; 24: 339–343[Abstract/Free Full Text]
  4. Gerritsen J, Dekker JM, Ten Voorde BJ et al. Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease. Diabetes Care 2001; 24: 1793–1798[Abstract/Free Full Text]
  5. Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Rev 1999; 17: 342–357
  6. Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 1996; 17: 354–381[ISI][Medline]
  7. Pomeranz M, Macaulay RJB, Caudill MA. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985; 248: H151–H153[ISI][Medline]
  8. Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation 1991; 84: 1482–1492
  9. Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat to beat cardiovascular control. Science 1981; 213: 220–222[ISI][Medline]
  10. Appel ML, Berger RD, Saul JP, Smith JM, Cohen RJ. Beat to beat variability in cardiovascular variables: noise or music? J Am Coll Cardiol 1989; 14: 1139–1148[ISI][Medline]
  11. Sahn DJ, DeMaria A, Kisso J, Weyman A. The Committee on M-mode Standardization of the American Society of Echocardiography: recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–1083[Abstract]
  12. Devereux RB, Koren MJ, de Simone G, Okin PM, Kligfield P. Methods for detection of left ventricular hypertrophy: application to hypertensive heart disease. Eur Heart J 1993; 14 [Suppl D]: 8–15[Medline]
  13. Kannel WB, Dannenberg AL, Levy D. Population implications of electrocardiographic left ventricular hypertrophy. Am J Cardiol 1987; 60: 85I–93I[Medline]
  14. Brown DW, Giles WH, Croft JB. Left ventricular hypertrophy as a predictor of coronary heart disease mortality and the effect of hypertension. Am Heart J 2000; 140: 848–856[CrossRef][ISI][Medline]
  15. Levy D, Anderson KM, Savage DD et al. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol 1987; 60: 560–565[ISI][Medline]
  16. Gouty S, Regalia J, Helke CJ. Attenuation of the afferent limb of the baroreceptor reflex in streptozotocin-induced diabetic rats. Auton Neurosci 2001; 89: 86–95[CrossRef][ISI][Medline]
  17. Tao X, Zhang SH, Shen FM, Su DF. High-level apoptosis is persistent in myocardiocytes of sinoaortic-denervated rats. J Hypertens 2004; 22: 557–563[CrossRef][ISI][Medline]
  18. Frustaci A, Kajstura J, Chimenti C et al. Myocardial cell death in human diabetes. Circ Res 2000; 87: 1123–1132[Abstract/Free Full Text]
  19. Head GA. Baroreflexes and cardiovascular regulation in hypertension. J Cardiovasc Pharmacol 1995; 26: S7–S16[ISI][Medline]
  20. Malpas SC, Groom AS, Head GA. Baroreflex control of heart rate and cardiac hypertrophy in angiotensin II-induced hypertension in rabbits. Hypertension 1997; 29: 1284–1290[Abstract/Free Full Text]
  21. Ziegler D, Laude D, Akila F, Elghozi J-L. Time- and frequency-domain estimation of early diabetic cardiovascular autonomic neuropathy. Clin Auton Res 2001; 11: 369–376[ISI][Medline]
  22. Forsström J, Forsström J, Heinonen E, Valimaki I, Antila K. Effects of haemodialysis on heart rate variability in chronic renal failure. Scand J Clin Lab Invest 1986; 46: 665–670[ISI][Medline]
  23. Weise F, London GM, Pannier BM, Guerin AP, Elghozi J-L. Effect of hemodialysis on cardiovascular rhythms in end-stage renal failure. Kidny Int 1995; 47: 1443–1452
  24. Weise F, London FM, Guerin AP, Pannier BM, Eoghozi JL. Effect of head-down tilt on cardiovascular control in healthy subjects: a spectral analytic approach. Clin Sci 1995; 88: 87–93[ISI][Medline]
  25. Hornung RS, Mahler RF, Raftery EB. Ambulatory blood pressure and heart rate in diabetic patients: an assessment of autonomic function. Diabetes Med 1989; 6: 579–585[ISI][Medline]
  26. Cheigh JS, Milite C, Sullivan JF, Rubin AL, Stenzel KH. Hypertension is not adequately controlled in hemodialysis patients. Am J Kidney Dis 1992; 19: 453–459[ISI][Medline]
Received for publication: 5. 3.04
Accepted in revised form: 19. 5.04