Autonomic function as indicated by heart rate deceleration capacity and deceleration runs in type 2 diabetes patients with or without essential hypertension
Clinical Interventions in Aging
Autonomic function as indicated by heart rate deceleration capacity and deceleration runs in type 2 diabetes patients with or without essential hypertension
Xing-De Wang 1
li Zhou 1
Chao-Yu Zhu 0
Bin Chen 1
Zhong Chen 1
li Wei 0
0 Department of endocrinology, s hanghai Jiao Tong University Affiliated sixth People's hospital , shanghai 200233 , China
1 Department of Cardiology, s hanghai Jiao Tong University Affiliated s ixth People's hospital , shanghai 200233 , China
8 1 0 2 - l u J - 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r PowerdbyTCPDF(ww.tcpdf.org)
Purpose: Sympathovagal imbalance is a common underlying disorder in hypertension and
diabetes. This study characterized autonomic nervous system function, indicated by heart rate
deceleration capacity (DC) and deceleration runs (DRs), in patients with type 2 diabetes mellitus
(T2DM), with or without concomitant essential hypertension.
Subjects and methods: We recruited 50 healthy subjects, 50 patients with T2DM, and 95
with T2DM and essential hypertension. DC, DRs (DR2, DR4, and DR8, ie, episodes of 2, 4,
or 8 consecutive beat-to-beat heart rate decelerations, respectively), and heart rate variability
were determined by dynamic electrocardiogram. Biochemical markers of glucose and lipid
metabolism, including glycated hemoglobin (HbA1c) and high-density lipoprotein cholesterol
(HDL-C), were measured from blood samples.
Results: Both T2DM groups featured lower DC, SD of all normal-to-normal sinus RR intervals
over 24 h (SDNN), root mean square of the successive normal sinus RR interval difference,
and all DR values, but higher average heart rate (AHR) and acceleration capacity (AC), than
healthy subjects. There were significant associations between the following: DC and HbA1c,
systolic blood pressure (SBP), AHR, age, and HDL-C; DR2 and AHR, SBP, and HbA1c; DR4
and HbA1c, age, SBP, and HDL-C; and DR8 and HbA1c, AHR, and age. In both T2DM groups,
HbA1c correlated negatively with DC, DR2, and SDNN, and positively with AC and AHR;
homeostasis model assessment-insulin resistance index correlated negatively with DC, all DRs,
and SDNN, and positively with AC.
Conclusion: Compared with healthy subjects, T2DM patients with or without essential
hypertension have lower DC and DRs. DC and DRs correlate negatively with blood glucose
and insulin resistance index.
Keywords: autonomic nervous system, deceleration capacity of heart rate, heart rate
deceleration runs, insulin resistance, type 2 diabetes mellitus, hypertension
Autonomic dysfunction is not only an established complication of diabetes,1 but also
a risk factor for the development of diabetes in healthy subjects.2 A study showed that
in randomly selected asymptomatic individuals with diabetes, approximately 20%
had abnormal cardiovascular autonomic function.1 Cardiac autonomic dysfunction
(CAN) ranges from vagus nerve impairment in the early stage to sympathetic nerve
impairment, impairment in both vagus and sympathetic nerves, and loss of cardiac
innervation at the end stage. The reported prevalence of CAN varies substantially, from
Clinical Interventions in Aging 2018:13 1169–1176 1169
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1.6% to 90%, in different studies and populations.3–5 CAN
can cause asymptomatic myocardial ischemia and
myocardial infarction, which in turn increase the risk of malignant
arrhythmia and sudden cardiac death.6–9 Hypertension in
patients with diabetes can damage further the autonomic
nervous system (ANS) and significantly elevate the risk of
malignant arrhythmia and sudden death.
18 The main clinical manifestations of CAN include resting
l-20 tachycardia, exercise intolerance, orthostatic hypotension,
-J3u and syncope. In addition to clinical symptoms, laboratory
no1 tests are often used for the assessment of ANS function and
702 the diagnosis of CAN in patients with diabetes. These tests
..46 include the following: Ewing’s test; assessments of heart
.759 rate variability (HRV), baroreflex sensitivity, heart rate
tury3b bulence (HRT), cardiac tachycardia, and adrenal function;
/om and QT interval analysis and radionuclide imaging. However,
.css each of these has limitations, and there is no uniform gold
re standard to evaluate ANS function, or CAN in particular.10
.vdoepww l.syeonu runs (DRs), proposed as a quantitative assessment of vagal
Heart rate deceleration capacity (DC) and deceleration
/sw laon tone, may be an early indicator of sudden death in patients
tthp rsep with myocardial infarction.11,12 DC refers to extended
from roF deceleration in a cardiac cycle compared with the precedent
de adjacent cycle. Based on the analysis of overall trend and
loda deceleration capability of the 24-h heart rate, it can be used
onw to assess quantitatively the level of vagal tone in subjects.
ingd A decreasing DC value indicates a decreased vagal tone,
gA which may increase the risk of sudden death in patients.
isnn DRs refer to gradually prolonged RR intervals in the cardiac
iton cycles of the Holter recording, which results from regulation
trvee of negative frequency on sinus rhythm by the vagus nerve in
lIna a short time. Technically, DC and DRs represent quite similar
liicn and complementary physiological processes in heart rate
C regulation. While DC shows the average intensity in a single
heart rate deceleration, DRs reflect regulation by the vagus
nerve of sinus rhythm after continuous deceleration. Bauer
et al11 reported that DC was a strong predictor of mortality
after myocardial infarction, with a higher predictive value
than left ventricular ejection fraction (LVEF) and traditional
measures of HRV. Another study showed that DC could well
discriminate heart failure cases from controls.13
Several studies have shown that heart rate DC and DRs
can quantitatively assess the level of autonomic nervous
tension and may be acceptable as noninvasive indicators of
ANS function.11,12 The DC and DRs are determined over 24 h
using phase-rectified signal averaging. In patients with acute
myocardial infarction, diabetes, and chronic heart failure, the
DC was significantly lower than that of the control group.
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This may indicate ANS dysfunction and a potential risk of
Our previous studies showed a significant reduction in
DC in patients with acute hemispheric ischemic stroke16
and chronic obstructive pulmonary disease with ventricular
arrhythmias.17 Thus, the DC can reflect an imbalance in
ANS function in these patients. Sympathovagal imbalance
and insulin resistance are common underlying disorders in
hypertension and diabetes.18 Sympathetic hyperactivity may
be, either directly or indirectly, a predictor of cardiovascular
morbidity and mortality.19 Sympathovagal imbalance is a
known independent prognostic factor for
cardiovascularrelated morbidity or fatal events in patients with heart
failure, end-stage renal failure, major cardiac arrhythmias,
obstructive pulmonary disease, or acute stroke. The
association between sympathetic activation and insulin resistance
may also be reciprocal. Elevated glucose levels, even in
the nondiabetic range, can damage peripheral nerve fibers,
leading to increased sympathetic activity and reduced
parasympathetic control. Thus, it is possible that an elevated
resting heart rate could be a consequence, and equally, a
marker of insulin resistance. However, little is known of the
DC and DRs of patients with both type 2 diabetes mellitus
(T2DM) and hypertension, and their associations with
glycated hemoglobin (HbA1c) and insulin resistance remains
The primary aim of this study was to characterize ANS
function, indicated by DC and DRs, in T2DM patients with or
without essential hypertension. In addition, we explored
associations between DC and DRs with other clinical markers,
including HbA1c and insulin resistance index.
Subjects and methods
The Ethics Committee of Sixth People’s Hospital affiliated
with Shanghai Jiao Tong University (No 2016004) approved
the study protocol, including monitoring and analysis of
dynamic electrocardiogram data. Each study subject provided
written informed consent.
We consecutively recruited 50 T2DM patients without
hypertension (T2DM group) and 95 T2DM patients with
hypertension (T2DM+HT group), aged 36–74 years, at Shanghai
Jiao Tong University Affiliated Sixth People’s Hospital
from January 20
13 to March 2016
. Diabetes mellitus was
diagnosed in accordance with the American Diabetes
Association criteria:20 HbA1c $6.5%; or fasting plasma glucose
(FPG) $7.0 mmol/L; or 2-h plasma glucose in oral glucose
tolerance test (OGTT) $11.1 mmol/L. Fasting was defined
as no food or drink (except water) for at least 8 h.
Essential hypertension21 is defined as high blood pressure
in which secondary causes such as renovascular disease, renal
failure, pheochromocytoma, and aldosteronism, or other
causes of secondary hypertension, are not present.
Hypertension was diagnosed in accordance with the 1999 World
Health Organization (WHO) diagnostic criteria for essential
hypertension: systolic blood pressure (SBP) $140 mmHg or
diastolic blood pressure (DBP) $90 mmHg, in the absence
of antihypertensive drugs. Patients who had a past diagnostic
history of hypertension and were currently using
antihypertensive drugs were also classified as hypertensive, even if
their current blood pressure levels were below the WHO
diagnostic cutoff points.
Excluded from this study were patients with the following
conditions: severe liver or renal insufficiency, cancer, or
acute myocardial infarction; using medications that may
affect HRV; and secondary hypertension, and presence of
non-sinus rhythm (eg, atrial fibrillation or atrial flutter) or
using a cardiac pacemaker.
Also enrolled in this study were 50 healthy subjects as
the control group, aged 39–72 years. These participants
had no history of alcohol drinking or smoking and were
without diabetes, hypertension, or other major diseases,
based on results of the 75-g OGTT, blood pressure
measurements, echocardiography, electrocardiogram, X-ray, and
glycemic status assessment
We measured fasting blood glucose (FBG), 2-h postprandial
glucose in OGTT (2hPG), HbA1c, and fasting insulin. The
homeostasis model assessment-insulin resistance index
(HOMA-IR) was calculated by the Matthews et al formula:22
Blood pressure measurement
Blood pressure was measured after at least 5-min rest using
a calibrated mercury sphygmomanometer. The
measurements were performed twice, and the average value was
Dynamic electrocardiogram examination
All subjects received a 24-h long-term electrocardiogram
examination within a week after enrollment. The recorded
data were analyzed using an offline DMS dynamic
electrocardiogram analysis system (DM Software, Stateline, NV, USA).
The average heart rate (AHR), DC, heart rate acceleration
capacity (AC), and DRs were calculated.11,12 DRs included
episodes of 2, 4, or 8 consecutive beat-to-beat heart rate
decelerations (DR2, DR4, and DR8, respectively).12
Indicators of HRV were determined by time-domain
analysis using the DMS analysis software. Specifically, these
were the SD of all normal-to-normal sinus RR intervals over
24 h (SDNN) and the root mean square of the successive
normal sinus RR interval difference (RMSSD).
The LVEF was measured in all subjects within a week after
enrollment by transthoracic echocardiography using the
Philips iE33 Ultrasounds System.
Data were analyzed using SPSS version 19.0 software
(IBM Corporation, Armonk, NY, USA). Each variable was
examined for normal distribution, and any variables that
were significantly skewed were addressed by log
transformation. Continuous variables with normal distribution
were expressed as mean±SD. Continuous variables with
skewed distribution were expressed as median (25%–75%
Comparisons among groups were evaluated using
analysis of variance, with Tukey’s honest significant difference
method for post hoc multiple-comparison analysis. Pearson’s
or Spearman’s partial correlation, as appropriate, was used
to assess correlations between variables. Stepwise multiple
regression, with P#0.05 as entry criteria and P$0.10 as
removal criteria, was used to estimate the association of DC
and DRs with other variables in all subjects. P,0.05 was
There was no significant difference in age or gender ratio
among the T2DM, T2DM+HT, and control groups (P.0.05;
Table 1). Compared with the control group, the T2DM
and T2DM+HT groups had significantly higher levels of
HOMA-IR, FPG, 2hPG, HbA1c, and SBP and DBP. The
triglyceride, SBP, and DBP levels of the T2DM+HT group
were significantly higher than that of the T2DM group
(P,0.05). In addition, use of angiotensin-converting enzyme
inhibitor (ACEI) and angiotensin receptor blocker (ARB) in
the T2DM+HT group was significantly more prevalent than
T2DM group (P,0.001). As expected, diabetes duration was
longer in T2DM patients with hypertension compared with
those without hypertension (P,0.05). Regarding indicators
of ANS function (Table 2), compared with the control group,
Notes: aP,0.05, compared with the T2DM group; bP,0.01, compared with the control group; cP,0.001, compared with the T2DM group; dP,0.05, compared with the
Abbreviations: 2hPg, 2-h postprandial glucose in oral glucose tolerance test; ACeI, angiotensin-converting enzyme inhibitor; AgI, alpha-glucosidase inhibitor;
ArB, angiotensin receptor blocker; BMI, body mass index; Cr, creatinine; DBP, diastolic blood pressure; DM, diabetes mellitus; FBg, fasting blood glucose; hbA1c, glycated
hemoglobin; hDl-c, high-density lipoprotein cholesterol; hOMA-Ir, homeostasis model assessment-insulin resistance index; lDl-c, low-density lipoprotein cholesterol;
lVeF, left ventricular ejection fraction; sBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; T2DM +hT, T2DM and essential hypertension.
the T2DM and T2DM+HT groups had significantly lower
DC, AC, SDNN, RMSSD, DR2, DR4, and DR8 (all P,0.05),
and significantly higher AHR (P,0.01 and P,0.001 in the
T2DM and T2DM+HT groups, respectively). Compared with
the T2DM group, the DC value of the T2DM+HT group was
significantly lower (P,0.05).
AHR. DR positively correlated with SDNN and RMSSD,
and negatively correlated with SBP, HbA1c, HOMA-IR, and
AHR. DR positively correlated with SDNN and RMSSD,
and negatively correlated with HbA1c, HOMA-IR, and AHR.
DR positively correlated with SDNN and RMSSD, and
negatively correlated with HOMA-IR and AHR.
Spearman’s correlation analysis (Table 3) showed that
A stepwise multiple regression analysis was conducted
DC positively correlated with SDNN and RMSSD, and
negaafter adjusting for gender, DBP, body mass index, FBG,
tively correlated with SBP, FBG, HbA1c, HOMA-IR, and
HOMA-IR, total cholesterol, triglycerides, low-density
lipoprotein cholesterol, blood urea nitrogen, serum
creatinine, and LVEF (Table 4). DC was significantly associated
with age, HbA1c, SBP, AHR, and high-density lipoprotein
cholesterol (HDL-C). DR2 was significantly associated with
AHR, SBP, and HbA1c. DR4 was significantly associated
with age, HbA1c, SBP, and HDL-C. DR8 was significantly
associated with age, HbA1c, and AHR.
This study examined the heart rate DC and DRs of Chinese
patients with T2DM, with or without essential hypertension,
and the association of these parameters with traditional
clinical markers. We observed that patients with T2DM, with or
without hypertension, had significantly lower DC and DRs
compared with the healthy controls. This indicated impaired
ANS function in these patients.
In the present study, T2DM patients, regardless of the
presence of complicated hypertension or acute myocardial
infarction, had autonomic dysfunction; therefore, DC and
DRs may also be applicable in T2DM patients for the
assessment of autonomic function.
Our results showed that DC, DR2, DR4, and DR8 in the
T2DM patients, with and without hypertension, were lower
than that of the healthy subjects, while AC and AHR were
higher. Moreover, DC positively correlated with DR2, DR4,
and DR8 and negatively correlated with AHR. The
reduction of DRs paralleled the reduction in DC, leading to an
increase in heart rate. These findings indicate that T2DM
patients, with or without essential hypertension, may have
a sympathovagal imbalance (ie, decreased vagal tone and
increased sympathetic tone), and the impaired ANS function
may compromise its protective effect on the heart.
This study also showed that AC and AHR were
significantly higher in the T2DM group and T2DM+HT group
compared with the control group. These findings were consistent
with previous studies by Aune et al.23,24 Resting heart rate is
known to be a sensitive indicator of the ANS, and elevation
in resting heart rate has been associated with increased risk of
cardiovascular disease, cancer, and total mortality. Moreover,
elevations in resting heart rate may increase myocardial
oxygen consumption, fatigue, and fracture of elastic fibers
within the arterial wall, further advancing the formation of
atherosclerotic lesions as a consequence.
We also observed that the DC levels of T2DM patients
with hypertension were lower than that of the T2DM patients
without hypertension. This finding, consistent with the
results of the cardiovascular reflex test and the HRV study
by Istenes et al,25 indicates that hypertension may worsen the
impaired autonomic function of patients with T2DM.
In the stepwise multiple regression analysis, we observed
a significant and independent association of DC with age,
HbA1c, SBP, AHR, and HDL-C. DRs were also significantly
associated with most of these markers. Such findings suggest
18 that DC and DRs gradually decrease with increases in age,
l-20 blood glucose, and blood pressure, and AHR and HDL-C
-J3u may also be involved in changes in DC and DRs. Results
no1 from the partial correlation analysis showed that HbA1c
270 may be the most important contributor to the change of DC
..64 and DRs. Hyperglycemia, hypertension, and hyperlipidemia
.957 contribute significantly to the development and progression
yb3 of CAN. Therefore, to prevent or delay the development of
/om CAN in T2DM patients with hypertension, clinicians should
.css pay more attention to controlling blood glucose, blood
presre sure, and blood lipids.9,10
.vdoepw l.syeon with DC, DR2, DR4, and DR8 in the T2DM patients with and
In the present study, HOMA-IR negatively correlated
//:sw laon without complicated hypertension. This indicates that ANS
h ep dysfunction with increased sympathetic tone and decreased
from roF vagal tone may become worse with the progression of insulin
ed resistance. Similar findings were reported by Nakano et al26
loda using a positive glucose hyperinsulinemic clamp technique.
onw ANS dysfunction and insulin resistance are underlying
comingd mon mechanisms of T2DM and essential hypertension.18,27
gA Insulin resistance can induce activation of the sympathetic
isnn nerve, which subsequently leads to the development of
iton hypertension. T2DM and hypertension may aggravate insulin
trvee resistance, which is negatively correlated with DC and DRs.
lIan The exact mechanisms of these pathophysiological processes
iilcn are still to be elucidated.
C HRV is the coefficient of variation of the RR intervals
between successive cardiac cycles and can be used to evaluate
the tension and balance of the cardiac sympathetic vagus
nerve and their effect on cardiovascular activities. A
reduction in HRV indicates impaired cardiac autonomic function
and increased risk of sudden death.28,29 The present study
showed that T2DM patients with and without hypertension
had significantly lower SDNN and RMSSD, indicating that
these patients may suffer from impaired cardiac autonomic
function. This is consistent with previous studies.25,29 In
addition, the DC levels of T2DM patients with hypertension
positively correlated with SDNN and RMSSD. This indicates
that DC may be linked with traditional markers of autonomic
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CAN is a common complication of diabetes. The lack
of specific symptoms makes the clinical diagnosis of CAN
challenging, in particular at an early stage. At present, many
methods are available to assess ANS function in T2DM,
but there is no gold standard.10 DC and DRs are reliable,
sensitive, and specific measures of the quantitative intensity
of the vagal and sympathetic nerves, respectively.11,12 The
measurement of DC and DRs can be performed with the
dynamic electrocardiogram examination, without the need
of additional equipment or facilities. Therefore, DC and DRs
can be used as noninvasive indicators for the assessment of
ANS function in patients with T2DM and may have great
value for clinical application.
Although several other techniques are available for
assessing ANS function, most of them have important
shortcomings. First, most techniques usually target indirect
regulation, such as HRV and HRT, which are indicators of
indirect reflex regulation of blood pressure and heart rate.
Second, some methods mix the assessment of sympathetic
nerves with vagus nerves and can only provide qualitative but
not quantitative assessment or do not differentiate the results
as normal or pathological. In addition, some techniques are
usually performed under specific conditions. For example,
HRT detection requires ventricular premature beat, and
baroreflex sensitivity needs an injection with phenylephrine.
In comparison, the DC detection technology has obvious
advantages because it is simple and easy to implement, does
not require specific conditions, can quantitatively measure
vagal and sympathetic nerve intensity, and is highly reliable,
sensitive, and specific.
This study has some limitations. First, some of the
patients may have been taking medications such as ACEIs,
ARBs, or statins that may affect ANS function, and it has
been reported that ACEI/ARB can ameliorate autonomic
dysfunction in patients with diabetes.30 However, there is
no evidence that these drugs specifically influence the DC
or DRs. More research is warranted in this regard. Second,
we excluded patients with atrial fibrillation, atrial flutter, and
cardiac pacemakers in this study. Therefore, our findings
may not be directly generalized to these patients. Third, the
sample size of this study is small. Large-scale, multicenter
prospective studies are needed to confirm our findings.
T2DM patients with or without essential hypertension have
lower levels of DC and DRs compared with healthy
subjects, impaired autonomic function, and increased insulin
resistance. HbA1c, SBP, AHR, age, and HDL-C are the main
determinants of DC and DRs, and they may be contributing
factors in the development and progression of CAN. DC and
DRs can be used as noninvasive markers for quantitative
assessment of ANS function in T2DM patients.
This study was funded by the Key Disciplines Group
Construction Project of Pudong Health Bureau of Shanghai
(No. PWZxq2014-07) and the Pudong New Area Science
and Technology Development Fund (No PKJ2013-Y70).
The funders had no role in the study design, data
collection and analysis, decision to publish, or preparation of the
manuscript. The authors thank Drs Shaojun Yin and Weixing
Zhang for their help with participant recruitment and writing
of the manuscript.
The authors report no conflicts of interest in this work.
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