Elevated resting heart rate is an independent predictor of all-cause death and cardiovascular events in Japanese ambulatory hemodialysis patients.
ABSTRACT BACKGROUND: Elevated heart rate (HR) is an independent risk factor for all-cause death or cardiovascular events in non-hemodialysis subjects; however, the clinical significance of elevated HR in hemodialysis patients is not well studied. METHODS: We prospectively evaluated the relationship between HR and adverse outcome in a total of 229 ambulatory hemodialysis patients (57 % men; mean age 62.2 years) recruited from two dialysis clinics in 2009. Mean (SD) HR of this cohort was 74.1 (11.0) beats per minute (bpm). RESULTS: Receiver operating characteristic curves identified an HR cut-off level of ≥80 bpm for increased adverse outcome. After a mean follow-up of 525 days (range 7-760 days) a total of 30 primary endpoints (21 all-cause deaths, 4 acute coronary syndromes and 8 strokes) and 38 secondary endpoints (30 primary endpoints, 8 congestive heart failures, and 5 other cardiovascular events) were detected. Cox regression analysis revealed that HR >80 bpm was not an independent predictor of primary endpoints [hazard ratio 1.81, 95 % confidence interval (CI) 0.79-4.11, p = NS], but of secondary endpoints (hazard ratio 2.01, 95 % CI 1.01-4.22, p < 0.05) after adjusting for age, sex, hemodialysis duration, and cardiovascular risks. CONCLUSIONS: Elevated HR is an independent predictor of all-cause death and cardiovascular events in Japanese ambulatory hemodialysis patients.
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ABSTRACT: Epidemiologic evidence indicates that an elevated heart rate (HR) is an independent predictor of all-cause and cardiovascular (CV) mortality. Ivabradine, a pure HR-lowering agent, reduces CV events in patients with coronary artery disease (CAD) and chronic heart failure, and indicate that an HR greater than 70 b.p.m. is hazardous. These findings demonstrate not only that an elevated HR is an epiphenomenon of CV risk status but also that an elevated HR itself should be a therapeutic target. In addition, recent epidemiologic evidence demonstrates that the in-treatment HR or HR change predicts subsequent all-cause and CV mortality, independent of the HR-lowering strategy. Characteristics of the in-treatment HR or HR change are also important as possible therapeutic guides for risk management. However, there have been concerns regarding deleterious effects on CV event prevention owing to β-blocker-derived pharmacologic HR reduction. The potential role of HR and its modulation should be considered in future guidance documents.Hypertension Research advance online publication, 22 August 2013; doi:10.1038/hr.2013.98.Hypertension Research 08/2013; · 2.79 Impact Factor
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ABSTRACT: Although a higher heart rate is known to be a risk factor for cardiovascular disease (CVD) events, there have been no reports concerning bradycardia. Whether lower and higher resting pulse rates (RPRs) are associated with cardiovascular risk was investigated in subjects from a community-based, prospective cohort study.Atherosclerosis 07/2014; 236(1):116-120. · 3.71 Impact Factor
Elevated resting heart rate is an independent predictor
of all-cause death and cardiovascular events in Japanese
ambulatory hemodialysis patients
Taku Inoue•Kiyoyuki Tokuyama•
Shinichiro Yoshi•Naoko Nagayoshi•
Chiho Iseki•Kunitoshi Iseki
Received: 2 December 2011/Accepted: 22 April 2012
? Japanese Society of Nephrology 2012
risk factor for all-cause death or cardiovascular events in
non-hemodialysis subjects; however, the clinical signifi-
cance of elevated HR in hemodialysis patients is not well
We prospectively evaluated the relationship
between HR and adverse outcome in a total of 229
ambulatory hemodialysis patients (57 % men; mean age
62.2 years) recruited from two dialysis clinics in 2009.
Mean (SD) HR of this cohort was 74.1 (11.0) beats per
Receiver operating characteristic curves identi-
fied an HR cut-off level of C80 bpm for increased adverse
outcome. After a mean follow-up of 525 days (range
7–760 days) a total of 30 primary endpoints (21 all-cause
deaths, 4 acute coronary syndromes and 8 strokes) and 38
secondary endpoints (30 primary endpoints, 8 congestive
Elevated heart rate (HR) is an independent
heart failures, and 5 other cardiovascular events) were
detected. Cox regression analysis revealed that HR
[80 bpm was not an independent predictor of primary
endpoints [hazard ratio 1.81, 95 % confidence interval (CI)
0.79–4.11, p = NS], but of secondary endpoints (hazard
ratio 2.01, 95 % CI 1.01–4.22, p\0.05) after adjusting for
age, sex, hemodialysis duration, and cardiovascular risks.
Elevated HR is an independent predictor of
all-cause death and cardiovascular events in Japanese
ambulatory hemodialysis patients.
Hemodialysis ? Mortality
Cardiovascular event ? Heart rate ?
Although resting heart rate (HR) fluctuates in response to
different measurement methods or under different mea-
surement conditions, numerous epidemiologic studies indi-
cate that elevated resting HR is closely associated with both
all-cause death and cardiovascular death in a wide range of
subjects, including the general population , those with
hypertension , type II diabetes mellitus , stable coro-
as well as elderly persons  and women . Moreover,
lowering HR reduces mortality in coronary artery disease
renal damage, such as chronic kidney disease  and
albuminuria . The clinical significance of elevated rest-
in the hemodialysis population and elevated restingHR may
be a key predictor of cardiovascular mortality in this popu-
T. Inoue (&)
Center of Residency and Fellowship Program,
Faculty of Medicine, University Hospital of the Ryukyus,
207 Uehara, Nishihara, Okinawa 903-0215, Japan
Tokuyama Clinic, Urasoe, Okinawa, Japan
Yoshi Clinic, Haebaru, Okinawa, Japan
Yoshi Clinic, University Hospital of the Ryukyus,
C. Iseki ? K. Iseki
Dialysis Unit, University Hospital of the Ryukyus,
Clin Exp Nephrol
status  and chronic inflammation . On this basis, the
aim of the present study was to investigate the relationship
between resting HR and survival among chronic hemodial-
Subjects and methods
The studied cohort comprised ambulatory patients recruited
from two hemodialysis clinics in Okinawa, Japan (n = 243)
between January 2008 and December 2009. Patients without
an electrocardiogram recording (n = 2) and having atrial
fibrillation (n = 12) were excluded from the analysis. The
study group comprised 130 men and 99 women (mean age
62.2 ± 12.6 years), and the mean follow-up was 524 days
(range 7–760 days). All patients were dialyzed three times
a week. Blood sampling was performed before and after
hemodialysis. Trained nursesmeasured blood pressure using
position. The arterial pressure values reported in this study
erythropoietin was administered as necessary to maintain a
mean hemoglobin value of 11 g/dl. Standard 12-lead elec-
trocardiography (ECG) was used to calculate HR. An ECG
calculate the left ventricular ejection fraction which was
measured applying the Teichholz rule.
Definition of clinical syndromes
Subjects were diagnosed with hypertension if they were
documented to have a blood pressure of C140/90 mmHg or
were already on antihypertensive therapy. Diabetes melli-
tus was defined as fasting plasma glucose of C126 mg/dl,
glycated hemoglobin (HbA1c) of C6.5 %, and/or clinically
known and treated diabetes mellitus.
Endpoints and assessment
Follow-up data were obtained through a review of patient
hospital records. Acute coronary syndrome was defined as
acute myocardial infarction and unstable angina, which was
definedas a cardiac eventrequiring admission tothe hospital
with the development of new ECG changes and increased
cardiac enzyme levels. Stroke was defined as the composite
of cerebral infarction and cerebral hemorrhage. Other car-
arteriosclerosis obliterans requiring amputation, bypass sur-
gery, or percutaneous transluminal angioplasty), aortic
dissection, and new-onset or worsening congestive heart
failure. The primary endpoint comprised all-cause death,
acute coronary syndrome, and stroke. The secondary end-
point comprised the primary endpoint and other cardiovas-
cular events, including arteriosclerosis obliterans requiring
intervention (amputation, bypass surgery, or percutaneous
transluminal angioplasty), and aortic dissection and new
onset or worsening of congestive heart failure.
Summary statistics for the continuous variables are pre-
were performed with a one-factor ANOVA or chi-squared
test. Categorical data were summarized as frequencies and
percentages, and comparisons between groups were per-
formed with the two-sided Pearson’s chi-squared test.
Variables with skewed distributions were log-transformed
when used in a multivariate regression analysis. Receiver
operating characteristic curves were used to select optimal
cut-off values for resting HR. To identify significant prog-
nostic variables, their individual association with follow-up
events was assessed by multivariable Cox regression anal-
yses. The following variables were included in the analysis:
atherosclerotic disease indicating coronary artery disease,
stroke and arteriosclerosis obliterans, and ECG-derived HR.
These variables were selected according to their clinical
relevance and potential impact on prognosis, as shown by
earlier studies. The risk associated with a given variable is
expressed by a hazard ratio with corresponding 95 % con-
fidence intervals (95 % CI). Unadjusted survival data are
plotted as Kaplan–Meier curves, and comparisons between
groups were performed using the log-rank statistic. Tests in
the Cox models and log-rank tests were two-sided and
probability values\0.05 were considered statistically sig-
(SAS Institute, Cary, NC, USA).
The present study was conducted in accordance with the
principles defined by the Declaration of Helsinki in 1975,
and revised in 1993. Data for this study were obtained from
the dialysis center of the Tokuyama clinic and the Yoshi
clinic upon approval by the institutional committee on
human research. The patients’ personal information was
excluded from the original registry database.
The hazardous resting HR level in hemodialysis patients
Clin Exp Nephrol
characteristic curve analysis selected an optimal cut-off
value of 80 bpm for prognostically significant mean ECG-
derived HR as the primary endpoint (47 % sensitivity;
71 % specificity; Fig. 1a) and 78 bpm for the secondary
endpoint (55 % sensitivity; 64 % specificity; Fig. 1b). We
therefore used 80 bpm as the hazardous HR cut-off level.
Baseline characteristics of this cohort according to the HR
group are summarized in Table 1. Mean age and hemodi-
alysis duration were 62.2 (12.6) years and 121 (93) months,
respectively. Of these patients, 78 % were diagnosed with
hypertension, 30 % were diagnosed with diabetes mellitus,
21 % had a history of coronary artery disease, and 10 %
had a history of stroke. Mean resting HR was 74.1
(11.0) bpm and subjects had a preserved cardiac function
with an ejection fraction of 68 (11) %. The serum albumin
level was 3.7 (0.3) g/dl. Calcium channel blockers and
angiotensin receptor blockers were frequently used for the
treatment of hypertension and b-blockers were used by
only 24 %.
Events during follow-up and heart rate analysis
During the follow-up period, there were 30 primary end-
points (13 %) including 21 all-cause deaths (9 %), four
acute coronary syndromes (2 %) and eight strokes (3 %),
and 38 secondary endpoints (17 %) including eight con-
gestive heart failures (3 %) and five (2 %) other cardio-
vascular events (Table 2). We therefore performed a
subgroup analysis in patients with a mean resting HR
\80 bpm (157 patients, 68.6 %) and those with a mean
resting HR C80 bpm (72 patients, 31.4 %). Patients with a
higher resting HR did not have a significant increase in
primary endpoints (10 vs. 29 %, p = NS), but had a sig-
nificant increase in secondary endpoints (14 vs. 25 %,
p = 0.0443; Table 2). Kaplan–Meier time to event plots by
baseline resting HR C80 bpm for primary and secondary
endpoints indicated subjects with an elevated resting HR
had lower event-free survival compared with the patients
with a lower resting HR. The statistically significant dif-
ference between the two HR groups was found only in
secondary endpoints but not primary endpoints (Fig. 2a, b).
By Cox proportional hazards regression analysis, age
(hazard ratio 1.09, 95 % CI 1.05–1.14; p\0.0001), and
hemoglobin (hazard ratio 0.83, 95 % CI 0.76–0.99;
p\0.05), but not resting HR (hazard ratio 1.81, 95 % CI
0.79–4.11; p = NS) were independent determinants of
primary endpoints. Resting HR, however, was an inde-
pendent predictor of secondary endpoints (hazard ratio
2.01, 95 % CI 1.01–4.22; p\0.05) (Table 3).
Epidemiologic results indicate that elevated resting HR is a
predictor of survival in non-hemodialysis subjects [1–7].
To date, only two reports have demonstrated an association
between resting HR and adverse outcome in hemodialysis
patients [13, 14]. Iseki et al.  demonstrated in their
cross-sectional study that survival rate decreased with an
increase in the pre-hemodialysis pulse rate in chronic he-
modialysis patients using a national hemodialysis patient
registry and the survival rate was lowest in patients with a
pulse rate of 60–69 bpm. On the other hand, Cice et al. 
evaluated 407 normotensive hemodialysis patients without
coronary artery disease and demonstrated that 85 bpm was
the hazardous HR cut-off level in this population. Their
finding indicates that resting HR is an independent and
important prognostic factor for hemodialysis patients, even
those at low risk. Real-world hemodialysis patients, how-
ever, comprise a heterogeneous population of patients with
several complications, such as hypertension, diabetes,
(Table 1). The findings of this study indicate that resting
HR is an independent predictor of near-future adverse
Fig. 1 Receiver operating
characteristic curve analysis for
selecting the optimal cut-off
heart rate level for the primary
(a) and secondary (b) endpoints
of this cohort and demonstrating
80 bpm and 78 bpm as a
significant heart rate level,
Clin Exp Nephrol
outcome in ambulatory hemodialysis patients. Further-
more, to the best of our knowledge, this is the first pro-
spective cohort study to evaluate the clinical significance of
resting HR in real-world ambulatory hemodialysis patients.
The mechanism connecting HR and diverse outcome
Heart rate is controlled by sympathetic activity or auto-
nomic imbalance , and an elevated resting HR is
consideredto represent sympatheticdominance.
Sympathetic overactivation is an important mechanism
involved in cardiovascular complications in humans .
Elevated resting HR frequently coexists with cardiometa-
bolic risk factors such as dyslipidemia , glucose
abnormality [20, 21], obesity , and their clustering [22,
23]. Moreover, HR and HR variability are associated with
subclinical inflammation markers [20, 24, 25].
Sympathoexcitation is well-recognized as an indepen-
dent risk for all-cause or cardiovascular death in patients
with end-stage renal disease [26, 27]. Furthermore, HR
Table 1 Baseline
Data shown are mean (SD)
CABG coronary artery bypass
graft, HD hemodialysis, SBP
systolic blood pressure, DBP
diastolic blood pressure, HDL-C
cholesterol, ACE angiotensin
converting enzyme, ARBs
angiotensin receptor blockers,
NS not significant
VariablesAll (n = 229)HR\80 bpm
(n = 157)
HR C80 bpm
(n = 72)
Male sex (%) 57 5560 NS
Age (years)62.2 (12.6) 62.9 (12.9) 60.7 (11.8)NS
Dialysis duration (months)121 (93)111 (90)144 (96)
Diabetes mellitus (%) 3030 29NS
Coronary artery disease (%) 211826 NS
Pre-HD SBP (mmHg)148 (20)148 (19)147 (21) NS
Pre-HD DBP (mmHg) 71 (11)71 (11)72 (12)NS
Heart rate (bpm) 74.1 (11.0)68.4 (7.3) 86.8 (5.9)
Body weight (kg)58.8 (12.6)58.9 (11.4)59.1 (14.7)
Ejection fraction (%)68 (11)67 (12)68 (11)NS
Cardiothoracic ratio (%) 52.3 (6.2)52.3 (6.8)52.4 (4.6)NS
Kt/V 1.36 (0.27)1.37 (0.26)1.34 (0.28) NS
Hemoglobin (g/dl) 10.9 (1.2)11.0 (1.1) 10.8 (1.4) NS
Albumin (g/dl)3.7 (0.3)3.7 (0.3)3.7 (0.3) NS
Total cholesterol (mg/dl)161 (33)159 (33)165 (33) NS
HDL-C (mg/dl) 48 (14)48 (15)48 (13)NS
Triglycerides (mg/dl)123 (81)117 (73)137 (94) NS
Calcium antagonists (%)59 6544
ACE inhibitors (%)887
b-Adrenergic blocker (%)
Anti-platelets (%) 36 31 47
Hypoglycemic agents (%)181622
Statins (%)98 10 NS
Table 2 Incidence of primary
and secondary endpoints
Data shown are numbers of
NS not significant
VariablesAll (n = 229) HR\80 bpm
(n = 157)
(n = 72)
Primary endpoints 30 (13)16 (10)14 (29)NS
All-cause death21 (9)10 (6)11 (15)
Acute coronary syndrome4 (2)3 (2)1 (1)
Stroke8 (3)5 (3)3 (4) NS
Secondary endpoints38 (17)20 (13)18 (25)
Congestive heart failure8 (3)5 (3)3 (4)
Other cardiovascular events5 (2)1 (1)4 (6)
Clin Exp Nephrol
lowering by b-adrenergic blocking agents improves the
prognosis of patients with end-stage renal disease [28, 29].
This evidence, together with our results, demonstrates the
need for HR-lowering therapy in chronic hemodialysis
The upper limits of heart rate
We chose receiver operating characteristic curve analysis
to select the upper limit of normal mean resting HR. This is
an entirely objective statistical way to establish a highly
sensitive and specific cut-off level for abnormal mean
resting HR associated with an increased risk of events,
which avoids the necessity of establishing arbitrary
threshold levels. Using this method, we identified a resting
HR cut-off of 80 bpm for increased risk of adverse out-
come in our hemodialysis patients and this was confirmed
by Cox regression analysis. Evidence from a non-hemod-
ialysis cohort study indicates that the threshold HR level
varies depending on the patient’s background. An HR of
80–90 bpm is a hazardous HR level for low-risk subjects
[2, 7], but patients with cardiovascular disease have a lower
HR cut-off level . Our results together with previous
studies [13, 14] suggest that the hazardous HR level for
hemodialysis patients is between 70 and 80 bpm. Further
analysis is warranted to confirm the hazardous HR level in
chronic hemodialysis patients.
Clinical significance of heart rate in hemodialysis
This has several strengths such as (1) the fact that this is a
prospective cohort study to examine the relationship
between pulse rate and survival in hemodialysis patients,
(2) a mortality rate of 6.6 % per year, which is compatible
with the results of a large Japanese registry and better than
that in other reports , and (3) mean dialysis duration
was 10.2 years—those who had significant ischemic heart
Fig. 2 Kaplan–Meier time-to-event plots by baseline heart rate for
the composite of all-cause death, acute coronary syndrome, and stroke
(a), and composite of primary endpoints, congestive heart failure, and
arteriosclerosis obliterans-related event (b) during follow-up by
resting HR value in the overall population of ambulatory hemodial-
ysis patients. Cumulative survival rate according to the resting HR.
Solid lines HR C80 bpm; dashed lines HR\80 bpm
Table 3 Adjusted hazard ratios and 95 % confidence intervals for elevated resting heart rate at baseline for primary and secondary endpoints
VariablesPrimary endpoint Secondary endpoint
Hazard ratio95 % CI
Hazard ratio 95 % CI
Age (per 1 year)1.091.05–1.14
NSSex (vs. female)1.190.54–2.70 1.00 0.50–2.06
HD duration (per 1 month) 1.00 0.99–1.01NS 1.000.99–1.01 NS
Diabetes mellitus1.190.47–3.06NS 1.17 0.53–2.65 NS
Atherosclerotic disease2.020.88–4.79 NS2.631.27–5.66
SBP (per 1 mmHg)1.000.88–1.02 NS
Hemoglobin (per 1 mg/dl)0.83 0.76–0.990.890.77–1.07NS
Albumin (per 1 g/dl)
Heart rate (vs.\80 bpm)
1.150.44–2.70 NS0.770.30–1.72 NS
Atherosclerotic disease includes stroke, coronary artery disease, and arteriosclerosis obliterans
CI confidence interval, HD hemodialysis, SBP systolic blood pressure, NS not significant
Clin Exp Nephrol
disease before hemodialysis induction may have died in
The findings of the present study indicate that near-
future prognostic status can be estimated from biologic
information that can be readily obtained without using
complicated or invasive modalities. This method allows us
to stratify patients according to their risk and provide
earlier intervention for high-risk patients. HR-lowering
therapy using b-adrenergic blocking agents is already an
established therapeutic standard in patients with ischemic
heart disease and congestive heart failure. Patients with
end-stage renal disease have elevated sympathetic activity
compared with non-hemodialysis patients, which is asso-
ciated with their prognosis . Moreover, sympathetic
overactivation is a therapeutic target in end-stage renal
disease . Despite the evidence, only 20–30 % of
hemodialysis patients are prescribed b-adrenergic blocking
agents in the United States  and\10 % in Japan .
In our cohort, approximately 24 % of patients were pre-
scribed b-adrenergic blocking agents and only 17 % of
patients with a resting HR [80 bpm used b-adrenergic
blocking agents. Resting HR is considered a useful indi-
cator for managing risk in hemodialysis patients.
The main limitation of this study is the small sample of the
study group. Moreover, the mean follow-up period of
535 days in the present study may not be long enough to
examine the impact of HR on survival. In fact, we could
not demonstrate a statistically significant effect of HR on
the primary endpoint. Another limitation of this study
might be the timing of the ECG examination (e.g., on or off
hemodialysis day), which may differ in each case. Patients
at a pre-hemodialysis session are often volume-overloaded
and concerned about needle puncture which may put them
in a state of sympathoexcitation. Several factors, such as
volume overload, anemia, impaired calcium-phosphate
handling, and uremic toxins, may influence the actual HR.
The results of the present analysis, however, are con-
sistent with the results of previous Japanese cross-sectional
studies . The prognostic significance of treating
elevated resting HR remains to be determined.
Elevated resting HR was an independent predictor of
all-cause death and cardiovascular events in Japanese
ambulatory hemodialysis patients. Our findings support the
notion that elevated resting HR is an independent bio-
marker for cardiovascular events and all-cause death, not
only in non-hemodialysis subjects, but also in hemodialysis
patients. Additional clinical studies are needed to deter-
mine the effect of treatment for elevated resting HR in
appreciation to Mr. Masaki Taira, Ms. Kikue Nakaema (Yoshi
Clinic), and Ms. Miyako Kanoh (Tokuyama Clinic) for retrieving
the data. And the authors also appreciate Dr. Osamu Arasaki,
Dr. Masahiro Tamashiro, Dr. Masahiro Kakazu (Tomishiro Central
Hospital) and Dr. Kazufumi Nagahama (University Hospital of the
Ryukyus) for their assistance.
The authors wish to express their greatest
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