Sympathetic overactivity and sudden cardiac death among hemodialysis patients with left ventricular hypertrophy

International Journal of Cardiology 142 (2010) 80 – 86 www.elsevier.com/locate/ijcard

Sympathetic overactivity and sudden cardiac death among hemodialysis patients with left ventricular hypertrophy Masato Nishimura a,⁎, Toshiko Tokoro b , Masasya Nishida c , Tetsuya Hashimoto c , Hiroyuki Kobayashi c , Satoru Yamazaki c , Ryo Imai d , Koji Okino e , Noriyuki Iwamoto c , Hakuo Takahashi f , Toshihiko Ono c a

Cardiovascular Division, Toujinkai Hospital, Kyoto, Japan Division of Nephrology, Toujinkai Hospital, Kyoto, Japan c Division of Urology, Toujinkai Hospital, Kyoto, Japan d Division of Orthopedics, Toujinkai Hospital, Kyoto, Japan e Division of Surgery, Toujinkai Hospital, Kyoto, Japan Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University, Osaka, Japan b

f

Received 4 September 2008; accepted 13 December 2008 Available online 24 January 2009

Abstract Background: We prospectively investigated whether cardiac autonomic imbalance is associated with sudden cardiac death (SCD) among a group of hemodialysis patients with left ventricular hypertrophy (LVH). Methods: In a prospective cohort study, we enrolled 196 asymptomatic patients on chronic hemodialysis who had LVH as determined by echocardiography and had undergone twenty-four-hour ambulatory Holter electrocardiography between dialysis sessions (males/females, 114/82; mean age, 65 ± 12 years) to analyze heart rate variability. We calculated the percentage difference between adjacent NN intervals more than 50 ms (pNN50) and high-frequency component (HF, 0.15–0.40 Hz) as parameters of cardiac parasympathetic activity, and the low-frequency component (LF, 0.04–0.15 Hz)/HF component ratio as a parameter of sympathetic activity. Results: During 4.5 ± 1.9-year follow-up, 21 patients who had undergone coronary revascularization within 60 days of enrollment were excluded from the analysis. Among the remaining 175 patients (male/female, 105/70; 66 ± 12 years), SCD was recognized in 23 patients. On stepwise Cox hazard analysis, SCD was positively associated with age and LF/HF ratio, and tended to be inversely associated with pNN50. On Kaplan–Meier analysis, SCD-free survival rates at 5 years were 29.4% and 98.1% in patients with LF/HF ratios of 1.9 or more and below 1.9, respectively. Conclusions: The presence of cardiac sympathetic overactivity may predict the occurrence of SCD in the asymptomatic hemodialysis patients with LVH. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Autonomic nervous system; Cardiac arrest; End-stage renal disease; Heart rate variability; Mortality

1. Introduction

⁎ Corresponding author. Cardiovascular Division, Toujinkai Hospital, 83-1, Iga, Momoyama-cho, Fushimi-ku, Kyoto 612-8026, Japan. Tel.: +81 75 622 1991; fax: +81 75 623 0226. E-mail address: [email protected] (M. Nishimura). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.12.104

Patients on chronic hemodialysis are at increased risk of sudden cardiac death (SCD). SCD accounts for approximately one-fourth of all-cause mortality in dialysis patients [1,2]. Advanced kidney dysfunction has recently been reported to be an independent predictor of SCD among women with coronary artery disease [3]. The incidence of

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SCD is significantly higher in dialysis patients than in the general population, irrespective of gender. The death rate due to SCD was 62 per 1000 patient-years in the dialysis population, whereas the overall incidence of out-of-hospital cardiac arrest was 1.89 per 1000 patient-years for the general population [4,5]. The main cause of SCD is believed to be hemodynamic collapse due to malignant arrhythmia such as ventricular fibrillation in the setting of structural heart disease [6]. A triggering event or condition interacts with the underlying structural heart disease to produce the fatal arrhythmia. Left ventricular hypertrophy (LVH), the most frequent cardiac abnormality in dialysis patients [7], causes electrical remodeling of the heart [8–16], and ventricular arrhythmia is increased in frequency in patients with echocardiographically identified LVH compared with those without LVH [17–20]. SCD occurs with increased frequency in patients with LVH; in the Framingham Heart Study, the risk factor-adjusted hazard ratio of SCD was 2.16 in patients with LVH [21]. On the other hand, patients with end-stage renal disease (ESRD) appear to exhibit overactivity of the sympathetic nervous system [22], which plays a role in the generation of spontaneous ventricular ectopy and SCD after myocardial infarction (MI) [23,24]. Interaction between cardiac electrical remodeling and autonomic imbalance is likely to contribute to elicitation of fatal ventricular arrhythmia and SCD. In the present study, we evaluated whether autonomic imbalance including enhanced cardiac

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sympathetic activity could predict the occurrence of SCD in hemodialysis patients with LVH. 2. Materials and methods 2.1. Patients Entry and exclusion criteria for the study are summarized in Fig. 1. The criterion for undergoing 24-hour ambulatory Holter electrocardiography (ECG) was LVH as determined by echocardiography, as described below. Patients who had been noncompliant with fluid intake restriction (body weight gain between dialyses exceeding 5% of dry weight) were excluded from the study. Of 714 patients undergoing maintenance hemodialysis in Toujinkai Hospital, 331 met the criteria. Since 105 patients did not agree to undergo Holter ECG, we performed Holter ECG on the remaining 226 hemodialysis patients between November 1, 2000 and October 31, 2002. Of these, 30 with apparent heart diseases including a history of myocardial infarction (MI), arrhythmias, malignancy, or a history of coronary revascularization such as coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) at the time of Holter ECG were excluded from the study. The criteria for diagnosis of old MI were a history of acute MI, abnormal Q waves on the ECG, or abnormal wall motion and diminished left ventricular wall thickness. Arrhythmias were categorized

Fig. 1. Entry and exclusion of study participants. ECG, electrocardiography; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting.

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as atrial fibrillation, atrial flutter, or premature atrial or ventricular ectopic beats exceeding 100 per day. Of the remaining 196 subjects (male/female, 114/82; 65 ± 12 years) were enrolled in the study and followed up through July 31, 2007, until the end point described below was reached. Smoking habit was defined as 10 or more cigarettes per week. Alcohol consumption was defined as alcohol intake of 20 g or more per week. The Ethics Committee for Human Research of Toujinkai Hospital approved this study, and all patients provided written informed consent to all procedures associated with the study prior to participation in it. The study was performed in accordance with the principles of the Declaration of Helsinki.

2.4. Biochemical and hematological determinations Blood samples (5 ml) were collected before initiating the mid-week hemodialysis sessions and before Holter ECG examination. Blood hemoglobin concentration and serum concentrations of calcium, inorganic phosphorus, and highsensitivity C-reactive protein (hs-CRP) were determined as the means of four measurements within 2 months of Holter ECG. Serum concentrations of albumin, total cholesterol, and triglyceride were determined as the means of four measurements within 4 months before Holter ECG. Serum intact parathyroid hormone concentration was determined within 2 months and plasma B-type natriuretic peptide (BNP) concentration within one month of Holter ECG.

2.2. Analysis of heart rate variability (HRV) 2.5. End point All patients underwent Holter ECG using an ambulatory electrocardiographic monitoring system (FM-100, Fukuda Denshi) for 24 h from the day before the midweek dialysis session to 1 h before the start of dialysis. Holter recordings were scanned with Holter processing equipment (SCM-6000, Fukuda Denshi) and QRS complexes were identified and labeled. HRV parameters were analyzed using a software [HPS-RRLOP (1), Fukuda Denshi]. Special indices of HRV were computed by fast Fourier transformation from 512 consecutive normal RR intervals in the recording, with application of a Hanning window to minimize spatial leakage. Power spectra from sequential prespecified segments were averaged every hour and for the entire 24-h time period. The following frequency-domain measures were assessed: (a) total power or TP, (0.0 to 1.0 Hz); (b) power in low-frequency component or LF (0.04 to 0.15 Hz); (c) power in highfrequency component or HF (0.15 to 0.40 Hz); and (d) LF/HF ratio. Measurement of TP, 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), SDANN, and pNN50. We used pNN50 and HF as parameters of cardiac parasympathetic activity and the LF/HF ratio as a parameter of cardiac sympathetic activity. SDANN was considered a parameter of cardiac parasympathetic activity. Analysis of HRV was performed by highly experienced employees of Fukuda Denshi kept unaware of details of this study. Mean values of CV for measures of HRV were 3.29 ± 0.88% for LF (n = 10), 3.54 ± 0.84% for HF (n = 10), 3.36 ± 0.93% for SDANN (n = 10), and 2.37± 0.84% for pNN50 measurements (n = 10), respectively. 2.3. Echocardiography The patients underwent two-dimensionally-guided Mmode echocardiography using a single ultrasonographic recorder (UF-8800, Fukuda Denshi, Tokyo, Japan) on a midweek non-dialysis day within one month before the Holter ECG. Criteria for LVH were as follows: LV mass index N 134 g/m2 body surface area in men or N 110 g/m2 body surface area in women [25].

All 196 patients were followed at Toujinkai Hospital. The end point was cardiac-derived death, i.e. SCD and death due to acute MI or CHF. SCD was defined as death within 24 h of the time that the victim was last seen alive in a normal state of health, and cardiac diseases such as fatal arrhythmias or acute coronary syndrome were considered the most frequent causes of death of it. Acute MI was diagnosed when new abnormal Q waves appeared on the ECG together with chest pain or discomfort, abnormal left ventricular wall motion was recognized by echocardiography, and serum concentrations of troponin-T and creatine phosphokinase-MB fraction were significantly elevated. 2.6. Statistical analysis Values are expressed as means ± SD. We compared the means of continuous variables using a t-test, while categorical data were analyzed using the chi-square (χ2) test. Receiver operating characteristic (ROC) analysis was performed to define thresholds for continuous variables such as LF/HF ratio. Thresholds were obtained from minimal false-positive and false-negative results, i.e. by minimizing the value of [(1 − specificity)2 + (1 − sensitivity)2]. We used Kaplan–Meier analysis and the log-rank test to examine event-free survival. Hazard ratios and confidence intervals were calculated for each factor by Cox univariate analysis. Further, Cox multivariate regression analysis was used to determine predictors of the end point. Factors with P b 0.1 on the univariate analysis were entered into the multivariate stepwise Cox regression model. A P value of b0.05 was considered significant. Individuals without knowledge of the findings for HRV and patient profiles performed all statistical analyses. 3. Results During follow-up, PCI and CABG were performed within 60 days of enrollment in 19 and 2 of 196 hemodialysis patients, respectively. Data from these 21 patients were not

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Table 1 Clinical characteristics of the study participants.

Age, years Gender; m, f Dialysis duration, months Diabetes mellitus Smoking Alcohol BMI (kg/m2) SBP before dialysis, mm Hg DBP before dialysis, mm Hg Cardiothoracic ratio, % LVEF, % LVMI, g/m2 Blood hemoglobin, g/l Serum albumin, g/l Serum total cholesterol, mmol/l Serum triglyceride, mmol/l Serum high-sensitivity CRP, mg/l Serum calcium, mmol/l Serum inorganic phosphorus, mmol/l Serum intact PTH, pg/ml Plasma BNP, pg/ml

Cardiac death (−) [n = 93]

Cardiac death (+) Acute MI [n = 32]

CHF [n = 27]

SCD [n = 23]

61 ± 10 51, 42 88 ± 8 28/93 (30.1%) 34/93 (36.6%) 43/93 (46.2%) 19.4 ± 3.9 143 ± 18 78 ± 11 51 ± 5 67 ± 11 163 ± 44 99.7 ± 12.0 39.2 ± 3.7 10.1 ± 2.4 1.7 ± 0.8 4.25 ± 3.05 2.3 ± 0.2 1.7 ± 0.4 227 ± 183 493 ± 388

69 ± 12** 21, 11 114 ± 104 13/32 (49.9%) 14/32 (43.6%) 11/32 (34.4%) 18.8 ± 5.0 143 ± 17 70 ± 13* 54 ± 6 60 ± 15 169 ± 36 103.2 ± 14.0 36.8 ± 4.0* 10.0 ± 1.9 1.3 ± 0.4* 3.72 ± 2.54 2.3 ± 0.2 1.7 ± 0.4 302 ± 440 540 ± 333

74 ± 11** 18, 9 94 ± 105 8/27 (29.6%) 7/27 (25.9%) 6/27 (22.2%) 16.4 ± 3.9* 144 ± 19 72 ± 9 54 ± 6 51 ± 18** 159 ± 35 100.9 ± 9.5 36.4 ± 3.9** 9.6 ± 2.0 1.3 ± 0.6 4.15 ± 2.69 2.3 ± 1.3 1.6 ± 0.4 184 ± 108 731 ± 623

70 ± 8** 15, 8 64 ± 68 12/23 (52.2%) 11/23 (47.8%) 12/23 (52.2%) 17.7 ± 4.2 144 ± 18 71 ± 13 52 ± 5 65 ± 15‡ 159 ± 27 102.0 ± 9.1 37.7 ± 2.9 9.3 ± 1.9 1.4 ± 0.6 3.36 ± 3.01 2.2 ± 0.2 1.7 ± 0.4 183 ± 113 498 ± 282

MI, myocardial infarction; CHF, congestive heart failure; SCD, sudden cardiac death; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; CRP, C-reactive protein; PTH, parathyroid hormone; BNP, B-type natriuretic peptide. *P b 0.05, **P b 0.01 versus the cardiac death (−) group; ‡P b 0.01 versus CHF death group.

included in the prognostic portion of the analysis. The resulting study cohort comprised the remaining 175 ESRD patients undergoing maintenance hemodialysis for a mean of 90.5 ± 91. 9 months (male/female, 105/70; mean age, 66 ± 12 years). The mean duration of follow-up after 24-hour Holter ECG was 4.5 ± 1. 9 years. The etiologies of renal failure were chronic glomerular disease in 55.4% (97/175), diabetes mellitus in 34.9% (61/175), polycystic kidney disease in 4.6% (8/175), nephropathy due to collagen diseases in 2.3% (4/175), nephrosclerosis in 1.7% (3/175), urolithiasis in 0.6% (1/175), and gouty kidney in 0.6% (1/

175) of the patients. Of the 175 study participants, 82 died of cardiac events [45.7%; acute MI, n = 32; congestive heart failure (CHF), n = 27; SCD, n = 23] during a mean follow-up period of 4.5 ± 1. 9 years. Patients who died due to cardiac events were older than those who did not (Table 1). 3.1. SCD SCD accounted for 28% of all cardiac deaths. Left ventricular ejection fraction (LVEF) was higher in the SCD group than the CHF death group, but did not differ among the

Table 2 Differences in parameters of heart rate variability.

Time-domain measures Total NN (per 24 h) pNN50, % SDANN, ms Frequency-domain measures Total power, ms2 LF, ms2 HF, ms2 LF/HF ratio

Cardiac death (−) [n = 93]

Cardiac death (+) Acute MI [n = 32]

CHF [n = 27]

SCD [n = 23]

100,425 ± 22,999 3.4 ± 4.7 77.5 ± 29.2

98,404 ± 22,382 2.7 ± 3.0 77.4 ± 37.2

103,349 ± 17,610 2.9 ± 4.7 86.0 ± 25.9

102,275 ± 21,622 0.8 ± 1.0 79.9 ± 30.8

1946 ± 2274 393 ± 611 443 ± 707 1.0 ± 0.4

1820 ± 1654 800 ± 1496 530 ± 747 1.3 ± 0.6

2033 ± 1932 683 ± 650 455 ± 666 2.3 ± 1.5**∫

1204 ± 740 789 ± 992 274 ± 288 3.4 ± 2.1**∫∫‡

MI, myocardial infarction; CHF, congestive heart failure; SCD, sudden cardiac death; Total NN, total number of normal RR intervals in a 24-h ECG recording; pNN50, percent difference between adjacent normal RR intervals exceeding 50 ms over the entire 24-h ECG recording; SDANN, standard deviation of the average normal RR interval for all 5-min segments of a 24-h ECG recording; Total power, variance of all NN intervals; LF, power in low-frequency range (0.04 to 0.15 Hz); HF, power in high-frequency range (0.15 to 0.40 Hz). **P b 0.01 versus the cardiac death (−) group; ∫P b 0.05, ∫∫P b 0.01 versus acute MI death group; ‡ P b 0.01 versus CHF death group.

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Table 3 Cox hazard analyses of sudden cardiac death. Univariate analysis

Age (1 year) Diabetes mellitus (1 = yes, 0 = no) DBP before dialysis (1 mm Hg) Serum triglyceride (1 mmol/l) LF/HF ratio pNN50 (1%)

Multivariate analysis

Hazard ratio

95% CI

P value

Hazard ratio

95% CI

P value

1.064 2.084 0.968 0.517 1.574 0.586

1.022–1.198 0.916–4.738 0.939–0.998 0.248–1.078 1.367–1.813 0.394–0.873

0.003 0.080 0.037 0.078 b0.001 0.008

1.064

1.014–1.116

0.011

1.422 0.692

1.216–1.662 0.459–1.044

b0.001 0.079

CI, confidence interval, DBP, diastolic blood pressure; LF, power in low-frequency range (0.04 to 0.15 Hz); HF, power in high-frequency range (0.15 to 0.40 Hz); pNN50, percent difference between adjacent normal RR intervals exceeding 50 ms over the entire 24-h electrocardiography recording.

SCD group, acute MI death group, and non-cardiac death group (Table 1). On HRV analysis, the mean LF/HF ratio was higher in the SCD group than in the non-cardiac death group and the acute MI death and CHF death groups (Table 2). The mean pNN50 tended to be lower in the SCD group than in the non-cardiac death group (P = 0.078). On univariate Cox hazard analysis, SCD was significantly associated with age, diabetes mellitus, diastolic blood pressure before dialysis, serum triglyceride concentration, LF/HF ratio, and pNN50. On stepwise Cox hazard analysis among these factors, LF/HF ratio and age were positively associated with SCD, and pNN50 tended to be inversely associated with SCD (Table 3). Kaplan– Meier survival estimation revealed that the event-free rates of SCD at 5 years were 29.4% in patients with LF/HF ratio of 1.9 or higher and 98.1% in patients with LF/HF ratio below 1.9 (Fig. 2), when the cut-off value of the LF/HF ratio was set at 1.9 based on receiver operating characteristic (ROC) analysis. 3.2. Death due to acute MI The subgroup of patients who had died due to acute MI had lower mean values of diastolic blood pressure before

dialysis and serum concentrations of albumin and triglyceride than patients without cardiac death (Table 1). Mean values of parameters of HRV did not differ between the acute MI death group and non-cardiac death group (Table 2). On univariate Cox hazard analysis, acute MI death was significantly associated with age, diastolic blood pressure before dialysis, cardiothoracic ratio, LVEF, and serum concentrations of calcium, albumin, and intact parathyroid hormone. On stepwise Cox hazard analysis among these factors, death due to acute MI was positively associated with age (HR, 1.089; 95% CI, 1.043–1.137; P b 0.0001) and inversely associated with LVEF (HR, 0.967; 95% CI, 0.948– 0987; P = 0.001). 3.3. Death due to CHF The subgroup of patients who had died due to CHF had lower mean values of body mass index, LVEF, and serum albumin concentration than patients without cardiac death (Table 1). On HRV analysis, mean LF/HF ratio was higher in the CHF death group than in non-cardiac death group and the acute MI death group (Table 2). On univariate Cox hazard analysis, CHF death was significantly associated with age, alcohol consumption, body mass index, cardiothoracic ratio, LVEF, serum concentrations of albumin and triglyceride, plasma BNP concentration, and LF/HF ratio. On stepwise Cox hazard analysis among these factors, death due to CHF was positively associated with age (HR, 1.094; 95%CI, 1.046–1.144; P b 0.001) and LF/HF ratio (HR, 1.276; 95% CI, 1.065–1.527; P = 0.008) and inversely associated with LVEF (HR, 0.969; 95%CI, 0.950–0.989; P = 0.003). 4. Discussion

Fig. 2. Kaplan–Meier analysis of sudden cardiac death-free survival rate by LF/HF ratio. LF, power in low-frequency range (0.04 to 0.15 Hz); HF, power in high-frequency range (0.15 to 0.40 Hz).

Of 175 hemodialysis patients with LVH, 81 died of cardiac events during a mean follow-up period of 4.5 ± 1. 9 years. On stepwise Cox hazard analysis, acute MI death was associated with age and LVEF, while CHF death was associated with age, LVEF, and LF/HF ratio. On the other hand, SCD was associated not with LVEF but with age, LF/ HF ratio, and pNN50. In the hemodialysis population with LVH, cardiac autonomic imbalance including sympathetic overactivity appears to play a more important role in SCD

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than left ventricular dysfunction, compared with deaths due to acute MI or CHF. The frequency and complexity of ventricular arrhythmia are related to the severity of LVH as well as chamber volume and indices of left ventricular contractility [18,19]. LVH causes electrical remodeling including lengthening and increase in dispersion of the action potential duration [10– 12], reduction in action potential upstroke velocity and impulse conduction velocity [13,14], or early and delayed afterdepolarizations [15,16]. These electrical changes are associated with increased vulnerability to ventricular arrhythmias. However, LVH alone cannot spontaneously cause fatal arrhythmias and SCD. A number of studies using experimental models of ventricular fibrillation have shown that artificial triggers such as electrical stimulation or drugs are needed to induce ventricular fibrillation in addition to the structural or electrical left ventricular remodeling seen in association with acute MI or complete arterioventricular block [26–28]. In a previous study of 53 native hearts of transplant recipients [29], regional increase in sympathetic innervation was observed around the diseased myocardium and blood vessels in patients with histories of ventricular tachycardia and SCD. Since many ESRD patients exhibit overactivity of the sympathetic nervous system [22], enhanced cardiac sympathetic activity might function as a trigger of malignant arrhythmias in hemodialysis patients with LVH. Decrease in HRV has been reported to predict cardiac death and the occurrence of fatal arrhythmias after acute MI [30–32]. An association between reduced HRV and all-cause mortality was also found in the Framingham Heart Study [33]. However, few studies have examined the relationship between autonomic imbalance and cardiac death in the dialysis population with or without diabetes. Hayano et al. [34] reported that reduced HRV increased the risk for both all-cause and sudden death in hemodialysis patients; however, their sample size was small (n = 31), and many participants (over 80%) had significant cardiac disease at baseline such as CHF, old MI, or coronary stenosis. In the present study, the LF/HF ratio was more strongly associated with SCD than other parameters of HRV including cardiac parasympathetic activity. In asymptomatic hemodialysis patients with LVH, cardiac sympathetic overactivity is likely to more strongly contribute to the occurrence of SCD than impaired parasympathetic activity. In this study, we could not eliminate the possibility of myocardial ischemia as a cause of SCD, although we excluded patients who had been diagnosed with death due to acute MI from those with death due to SCD. The density of myocardial capillaries is reduced in the heart with LVH. The enlarged muscle mass limits the ability of the coronary arteries to dilate in response to decreased perfusion or vasodilatory stress by compressing the endocardial capillaries [35]. These factors can lead to decrease in coronary reserve. Patients with hypertension and LVH who died suddenly reportedly had less extensive coronary disease and

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were less likely to have thrombi in the coronary vessels than those without LVH who suffered SCD [36]. ESRD patients with LVH may be more susceptible to ischemia than those without LVH, and myocardial ischemia, which does not usually cause severe damage to the heart, might induce SCD in those hemodialysis patients with LVH. This study has several limitations. The mean age of the study participants was relatively high, at 65 years. Advanced age is generally an independent risk factor for cardiac death [5,37], and age was significantly associated with SCD in the present study. In statistical analysis, the variable selection procedure for multivariate models is not likely to be specified a priori, and might be unable to detect other significant variables on univariate analysis that are of relatively low significance. Finally, our sample size was relatively small, and limited to patients with LVH as evaluated by echocardiography. LVH is a strong and independent risk factor for cardiovascular morbidity and mortality in patients with ESRD [38]. Worsening of LVH has been reported to be predictive of SCD in hemodialysis patients [39]. In the present study, the LF/HF ratio, a parameter indicating enhanced cardiac sympathetic activity, was strongly associated with SCD. The combination of sympathetic overactivity with LVH may increase the risk of SCD in hemodialysis patients without apparent coronary artery disease. In our recent study [40], we reported that myocardial fatty acid imaging could identify groups at high risk for myocardial ischemia and cardiac death among asymptomatic hemodialysis patients. Assessment of cardiac autonomic imbalance by analysis of HRV in hemodialysis patients with LVH may help decrease cardiac death in this population. Acknowledgements The authors thank the staff of Fukuda Denshi Co. for their precise analyses of heart rate variability. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [41]. References [1] Cheung AK, Sarnak MJ, Yan G. Cardiac diseases in maintenance hemodialysis patients: results of the HEMO study. Kidney Int 2004;65: 2380–9. [2] Wanner C, Krane V, Marz W. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353: 238–48. [3] Deo R, Lin F, Vittinghoff E, Tseng ZH, Hulley SB, Shlipak MG. Kidney dysfunction and sudden cardiac death among women with coronary heart disease. Hypertension 2008;51:1578–82. [4] Collins AJ, Kasiske B, Herzog C, et al. United States Renal Data System 2006 annual data report: morbidity & mortality. Am J Kidney Dis 2007;49(Suppl 1):S129–46. [5] Rea TD, Pearce RM, Raghunathan TE. Incidence of out-of-hospital cardiac arrest. Am J Cardiol 2004;93:1455–60. [6] Demirovic J, Myerburg RJ. Epidemiology of sudden coronary death: an overview. Prog Cardiovasc Dis 1994;37:39–48.

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