Download Cardiac Autonomic Nervous Dysfunction in Diabetic

Pathophysiology/Complications
O R I G I N A L
A R T I C L E
Cardiac Autonomic Nervous Dysfunction
in Diabetic Patients With a
Mitochondrial DNA Mutation
Assessment by heart rate variability
YUKIHIKO MOMIYAMA, MD1
YOSHIHIKO SUZUKI, MD2
MASAKO OHTOMO3
YOSHIHITO ATSUMI, MD2
KEMPEI MATSUOKA, MD2
FUMITAKA OHSUZU, MD1
MITSURU KIMURA, MD2
A
OBJECTIVE — To elucidate the degree and characteristics of cardiac autonomic nervous
dysfunction in diabetic patients associated with a mitochondrial DNA mutation at base pair
3243.
RESEARCH DESIGN AND METHODS — We investigated heart rate variability using
24-h Holter monitoring in 10 diabetic patients with the mutation compared with 55 ordinary
diabetic patients and 45 nondiabetic control subjects.
RESULTS — Age and sex were similar in the three groups. Between patients with the mutation
and ordinary diabetic patients, the duration of diabetes and blood glycemic levels were not
different. In the time domain analysis of heart rate variability, patients with the mutation and
ordinary diabetic patients had significantly smaller SDNN index and pNN50 than control subjects. Compared with ordinary diabetic patients, patients with the mutation had smaller SDNN
index (P ⬍ 0.02), but rMSSD and pNN50 were not different. In the frequency domain analysis,
total, low frequency (LF), and high frequency (HF) spectra were significantly smaller in patients
with the mutation and ordinary diabetic patients than in control subjects. Compared with
ordinary diabetic patients, patients with the mutation had smaller total and LF spectra (P ⬍
0.02). However, HF spectra were not significantly different. Notably, the LF/HF spectra ratio was
lower in patients with the mutation than in ordinary diabetic patients and control subjects (P ⬍
0.05), but this ratio was similar in ordinary diabetic patients and control subjects.
CONCLUSIONS — Our results suggest that diabetic patients with the mitochondrial DNA
mutation have more severely impaired cardiac autonomic nervous function with sympathovagal
imbalance, as compared with ordinary diabetic patients.
Diabetes Care 25:2308 –2313, 2002
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
From the 1First Department of Internal Medicine, National Defense Medical College, Saitama, Japan; the
2
Division of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan; and the 3Division of Laboratory Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
Address correspondence and reprint requests to Yukihiko Momiyama, MD, First Department of Internal
Medicine, National Defense Medical College, 3–2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail:
[email protected].
Received for publication 27 September 2001 and accepted in revised form 23 August 2002.
Abbreviations: bp, base pair; DM-Mt3243; diabetes associated with the 3243-bp mutation; HF, high
frequency; HRV, heart rate variability; LF, low frequency; LVH, left ventricular hypertrophy; MELAS,
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MIBG, metaiodobenzylguanidine; PN, peripheral neuropathy; pNN50, the proportion of adjacent R-R intervals varying by ⬎50 ms;
SDANN, the SD of 5-min mean R-R intervals; SDNN, SD of all R-R intervals; RMSSD, the root-mean-square
difference of successive R-R intervals.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion
factors for many substances.
2308
pproximately 1% of type 2 diabetes
is known to be associated with a mitochondrial tRNALeu(UUR) mutation
at base pair (bp) 3243 (1). This 3243-bp
mutation was originally found in patients
with mitochondrial encephalomyopathy,
lactic acidosis, and stroke-like episodes
(MELAS). In MELAS, the involvement of
peripheral nerves, in addition to brain
and muscles, was recently reported to be
common (2). Some patients who had
symptoms of autonomic dysfunction,
such as gastrointestinal dysmotility, were
also reported (3). Left ventricular hypertrophy (LVH) is recognized to be the clinical feature of cardiac involvement in
MELAS (4). However, cardiac autonomic
nervous dysfunction has not been elucidated. It is known that diabetic patients,
especially with peripheral or autonomic
neuropathies, often have cardiac autonomic nervous dysfunction as assessed by
heart rate variability (HRV) (5–7). In diabetes associated with the 3243-bp mutation (DM-Mt3243), cardiac autonomic nervous function may be severely
impaired. To elucidate the degree and
characteristics of cardiac autonomic nervous dysfunction in DM-Mt3243, we assessed HRV using 24-h Holter monitoring
in 10 diabetic patients with the 3243-bp
mutation.
RESEARCH DESIGN AND
METHODS — We investigated HRV
in 10 unrelated patients who had type 2
diabetes associated with the 3243-bp mutation. They had no clinical signs of
MELAS but were suspected of having the
mutation because of maternally inherited
diabetes and/or hearing impairment.
They were proved to have the mutation in
blood leukocytes by a molecular test using a restriction endonuclease, ApaI, as
we previously reported (8). Diagnosis of
diabetes had been made according to the
World Health Organization criteria in
1985. All 10 DM-Mt3243 patients underwent 24-h Holter monitoring because of
DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002
Momiyama and Associates
Table 1—Clinical characteristics in the three groups
Age (years)
Sex (male)
Systolic BP (mmHg)
Diabetes duration (years)
Family history of diabetes in mothers
Insulin therapy
Diabetic retinopathy
Diabetic neuropathy (ATR[⫺])
Diabetic nephropathy (proteinuria [⫹])
FPG (mg/dl)
HbA1c (%)
Echocardiography
Wall motion abnormality
LV wall thickness (mm)
LVH (⬎11 mm)
DM-Mt3243
patients
(n ⫽ 10)
DM-Mt3243
versus
ordinary
diabetic
patients
Ordinary
diabetic
patients
(n ⫽ 55)
61 ⫾ 11
6 (60)
130 ⫾ 18
13 ⫾ 8
7 (70)
6 (60)
4 (40)
6 (60)
2 (20)
153 ⫾ 66
7.5 ⫾ 1.3
NS
NS
NS
NS
⬍0.025
NS
NS
NS
NS
NS
NS
64 ⫾ 7
38 (69)
132 ⫾ 16
14 ⫾ 9
13 (24)
19 (35)
18 (33)
20 (36)
8 (15)
152 ⫾ 46
7.5 ⫾ 1.7
0 (0)
10.4 ⫾ 1.5
4 (40)
NS
⬍0.05
NS
0 (0)
9.3 ⫾ 1.2
6 (11)
Ordinary
diabetic
patients
versus
control
subjects
Control
subjects
(n ⫽ 45)
Control
subjects vs
diabetesMt3243
patients
NS
NS
NS
62 ⫾ 6
29 (64)
129 ⫾ 16
NS
NS
NS
⬍0.001
⬍0.001
99 ⫾ 8
5.4 ⫾ 0.5
⬍0.001
⬍0.001
NS
⬍0.05
NS
0 (0)
8.8 ⫾ 1.3
2 (4)
NS
⬍0.002
⬍0.01
Data are presented as means ⫾ SD or n (%). BP, blood pressure; FPG, fasting plasma glucose; ATR, Achilles tendon reflex.
chest pain (5 patients), palpitation (4 patients), and/or DM-Mt3243 (4 patients).
HRV was analyzed, and the results were
compared with those of 55 ordinary diabetes patients and 45 control subjects.
The ordinary diabetes group consisted of
55 consecutive patients with type 2 diabetes (age range 50 –75 years) who underwent Holter monitoring at Tokyo
Saiseikai Central Hospital from 1996 to
1999 for chest pain (15 patients), palpitation (14 patients), suspected arrhythmia
(13 patients), and/or long duration of diabetes (18 patients). The control group
comprised 45 consecutive nondiabetic
subjects (age 50 –75 years) who had
Holter monitoring from 1998 to 1999 for
chest pain (15 patients), palpitation (13
patients), suspected arrhythmia (5 patients), and/or medical checkup (12 patients). All subjects in the three groups
underwent echocardiography. In all subjects, results of stress 201Tl imaging or exercise testing were negative. Any subjects
taking cardioactive drugs, such as ␤adrenergic blockers and antiarrhythmic
drugs, were excluded from the study.
Measurements of HRV
Two-channel Holter monitoring was performed with a Marquette 8500 recorder
(Marquette Electronics, Milwaukee, WI).
HRV over a 24-h period was analyzed us-
ing a commercially available computerized system (Marquette Electronics). All
tapes were visually processed by an experienced technician with manual imposition of the mean R-R interval for all
ectopic beats. Any tapes that had ⬎5%
ectopic beats in a 24-h record were excluded. In the time domain analysis of
HRV, the SD of all R-R intervals (SDNN),
the SD of 5-min mean R-R intervals
(SDANN), the mean of all 5-min SDs of
R-R intervals (SDNN index), the rootmean-square difference of successive R-R
intervals (RMSSD), and the proportion of
adjacent R-R intervals varying by ⬎50 ms
(pNN50) were calculated. In the frequency domain analysis, the recording
period was divided into 2-min segments,
and total (0.01–1.00 Hz), low frequency
(LF) (0.04 – 0.15 Hz), and high frequency
(HF) (0.15– 0.40 Hz) spectra were calculated at each segment. The Marquette system provides spectral plots as amplitudes
(ms) instead of power (ms2). These values
were computed hourly and averaged over
24 h.
Statistical analysis
Any differences among the three groups
were evaluated by ANOVA with the Fisher’s least significant differences test for
parametric variables, by the KruskalWallis’ test for nonparametric variables,
DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002
and by the ␹2 test for categorical variables.
Any differences between two groups were
evaluated by the unpaired Student’s t test
for parametric variables, by the MannWhitney’s U test for nonparametric variables, and by the ␹2 test for categorical
variables. A P value ⬍0.05 was considered statistically significant. Results are
presented as the means ⫾ SD.
RESULTS — Of the 10 diabetesMt3243 patients, 5 patients (50%) and 4
patients (40%) underwent Holter monitoring because of chest pain and palpitations, respectively, but 4 patients (40%)
had no cardiac symptoms. The percentages of patients having chest pain and palpitations were not different from those
with ordinary diabetes (27 and 25%) and
nondiabetic control subjects (33 and
29%) (P ⫽ NS).
Age, sex, and blood pressure were
similar in the three groups (Table 1). Between DM-Mt3243 and ordinary diabetes
groups, duration of diabetes and blood
glycemic levels were not different. Family
history of diabetes in mothers was present
in 7 of 10 DM-Mt3243 patients (70%)
versus 13 of 55 ordinary diabetic patients
(24%) (P ⬍ 0.025). Hearing impairment
was found in eight DM-Mt3243 patients
(80%), three of whom needed a hearing
aid. Regarding diabetes complications,
2309
Heart rate variability in mitochondrial diabetes
Table 2—HRV data in the three groups
Time domain analysis
Mean R-R interval (ms)
SDNN (ms)
SDANN (ms)
SDNN index (ms)
rMSSD (ms)
pNN50 (%)
Frequency domain analysis
Total spectra (ms)
LF spectra (ms)
HF spectra (ms)
LF/HF ratio
Ordinary
diabetic
patients
(n ⫽ 55)
Ordinary
diabetic
patients
versus
control
subjects
Control
subjects
(n ⫽ 45)
Control
subjects
versus
diabetesMt3243
patients
NS
NS
NS
⬍0.02
NS
NS
834 ⫾ 97
137 ⫾ 39
128 ⫾ 37
44 ⫾ 17
25 ⫾ 14
2.5
NS
NS
NS
⬍0.025
NS
⬍0.005
862 ⫾ 98
145 ⫾ 35
133 ⫾ 35
52 ⫾ 15
28 ⫾ 9
5.7
⬍0.05
NS
NS
⬍0.001
⬍0.02
⬍0.002
⬍0.05
⬍0.02
NS
⬍0.05
25.9 ⫾ 11.5
14.4 ⫾ 7.2
9.1 ⫾ 5.5
1.70 ⫾ 0.46
⬍0.02
⬍0.01
⬍0.05
NS
30.9 ⫾ 8.8
17.9 ⫾ 5.7
11.1 ⫾ 4.0
1.68 ⫾ 0.41
⬍0.001
⬍0.001
⬍0.01
⬍0.05
DM-Mt3243
patients
(n ⫽ 10)
DM-Mt3243
versus
ordinary
diabetic
patients
782 ⫾ 105
127 ⫾ 36
121 ⫾ 35
31 ⫾ 10
18 ⫾ 6
1.2
17.3 ⫾ 5.7
8.8 ⫾ 3.4
6.6 ⫾ 2.4
1.37 ⫾ 0.40
Data are presented as means ⫾ SD, except for pNN50 (the median value).
peripheral neuropathy, which was defined as absence of Achilles tendon reflex,
was found in 6 DM-Mt3243 patients
(60%) versus 20 ordinary diabetic patients (36%) (P ⫽ NS). On echocardiography, thickness of the left ventricular
wall was greater in DM-Mt3243 patients
than in those with ordinary diabetes and
control subjects (10.4 ⫾ 1.5 vs. 9.3 ⫾ 1.2
and 8.8 ⫾ 1.3 mm, respectively; P ⬍
0.05). LVH with wall thickness ⬎11 mm
was found in four DM-Mt3243 patients
(40%) versus six ordinary diabetic patients (11%) and two control subjects
(4%), but none of these patients had
marked LVH (⬎15 mm).
Regarding HRV over a 24-h period
(Table 2), the mean R-R intervals in DMMt3243 patients, ordinary diabetic patients, and control subjects were 782 ⫾
105, 834 ⫾ 97, and 862 ⫾ 98 ms, respectively. The mean R-R interval was shorter
in DM-Mt3243 patients than in control
subjects. In time domain analysis, there
was no difference in SDNN and SDANN
among the three groups. However, DMMt3243 and ordinary diabetic patients
had significantly smaller SDNN index and
pNN50 than control subjects. Compared
with ordinary diabetic patients, those
with DM-Mt3243 had smaller SDNN
index (31 ⫾ 10 vs. 44 ⫾ 17 ms, P ⬍
0.02), but rMSSD and pNN50 were not
different. In frequency domain analysis,
total, LF, and HF spectra were significantly smaller in DM-Mt3243 patients
2310
and those with ordinary diabetes than in
control subjects. Compared with ordinary diabetic patients, DM-Mt3243 patients had smaller total (17.3 ⫾ 5.7 vs.
25.9 ⫾ 11.5 ms) and LF spectra (8.8 ⫾
3.4 vs. 14.4 ⫾ 7.2 ms) (P ⬍ 0.05), but HF
spectra (6.6 ⫾ 2.4 vs. 9.1 ⫾ 5.5 ms) were
not significantly different. Notably, the
LF/HF spectra ratio was lower in DMMt3243 patients than in ordinary diabetic
patients and control subjects (1.37 ⫾
0.40 vs. 1.70 ⫾ 0.46 and 1.68 ⫾ 0.41 ms,
P ⬍ 0.05), but this ratio was not different
between ordinary diabetes patients and
control subjects.
The circadian rhythms of LF and HF
spectra in the three groups are shown in
Fig. 1. LF and HF spectra were significantly smaller throughout the 24-h period in DM-Mt3243 patients and during
the daytime in ordinary diabetic patients
than in control subjects. Compared with
ordinary diabetic patients, those with
DM-Mt3243 had smaller LF during the
daytime and smaller HF spectra only for a
short time in the evening (P ⬍ 0.05).
Figure 1—The circadian rhythms of LF and HF spectra in the three groups. 䡺, significant
differences (P ⬍ 0.05) between DM-Mt3243 patients and control subjects; ‚, P ⬍ 0.05 in DMMt3243 patients versus ordinary diabetic patients; *P ⬍ 0.05 in ordinary diabetic patients versus
control subjects.
DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002
Momiyama and Associates
Table 3—Association between PN and HRV in DM-Mt3243 and ordinary diabetic patients
DM-Mt3243 patients
Age (years)
Diabetes duration (years)
SDNN index (ms)
LF spectra (ms)
HF spectra (ms)
LF/HF ratio
Ordinary diabetic patients
PN(⫹)
(n ⫽ 6)
PN(⫹)
versus (⫺)
PN(⫺)
(n ⫽ 4)
PN(⫹)
(n ⫽ 20)
PN(⫹)
versus (⫺)
PN(⫺)
(n ⫽ 35)
59
12
33
8.5
7.5
1.3
NS
NS
NS
NS
NS
NS
65
10
30*
7.5†
5.0
1.3
64
14
38
12.0
7.0
1.7
NS
NS
NS
NS
NS
NS
66
10
41
13.0
8.0
1.8
Data are median values. *P ⬍ 0.05 and †P ⬍ 0.005 compared with ordinary diabetic patients without PN.
To evaluate the association between
peripheral neuropathy (PN) and HRV,
DM-Mt3243 and ordinary diabetic patients were divided into two subgroups
according to the presence or absence of
PN (absent Achilles tendon reflex) (Table
3). Among the DM-Mt3243 patients,
HRV parameters were not different between patients with and without PN.
However, SDNN index and LF spectra
tended to be smaller in DM-Mt3243 patients with PN than in ordinary diabetes
patients with PN. In DM-Mt3243 patients
without PN, SDNN index and LF spectra
were smaller than in ordinary diabetic patients without PN (P ⬍ 0.05). DMMt3243 and ordinary diabetic patients
were also divided into two subgroups by
the presence or absence of LVH (Table 4).
Among DM-Mt3243 patients, SDNN index and LF spectra tended to be smaller in
patients with LVH than in those without
LVH. Notably, HF spectra were smaller in
patients with LVH than in those without
LVH (P ⬍ 0.02). Compared with ordinary
diabetic patients with LVH, DM-Mt3243
patients with LVH had smaller SDNN index and LF spectra (P ⬍ 0.05). Although
DM-Mt3243 patients without LVH
tended to have smaller SDNN index and
LF spectra than ordinary diabetic patients
without LVH, the LF/HF ratio was smaller
in DM-Mt3243 patients without LVH
than in ordinary diabetic patients without
LVH (P ⬍ 0.02).
CONCLUSIONS — T h e 3 2 4 3 - b p
mutation was originally detected in
MELAS. In addition to brain and muscles,
the involvement of peripheral nerves was
reported to be common in patients with
MELAS (2). Sural nerve biopsy showed
axonal degeneration and marked loss of
myelinated fibers. Markedly increased
mitochondria with abnormal configuration of cristae were shown in Schwann
cells (2). Some patients with symptoms of
autonomic dysfunction, such as gastrointestinal dysmotility, were also reported
(3). In the heart, LVH is recognized to be
the clinical feature of cardiac involvement
in MELAS (4), but cardiac autonomic nervous dysfunction has not been elucidated.
Approximately 1% of type 2 diabetes
is associated with the 3243-bp mutation
(1). The mechanism of this mutation that
causes MELAS in some patients and diabetes in others remains unclear. In the
heart, we recently reported that diabetesMt3243 patients have LVH more often
than ordinary diabetic patients, but
marked LVH, like hypertrophic cardiomyopathy, is rare (9). Regarding cardiac
autonomic nervous function, Ishida et al.
(10) reported two DM-Mt3243 patients
with marked LVH who showed no uptake
of 123I-metaiodobenzylguanidine (MIBG)
in myocardium. Imaging with 123I-MIBG,
a norepinephrine analog, can be used to
assess cardiac sympathetic nervous function. The same group (11) recently
showed reduced myocardial uptake of
123
I-MIBG in 10 DM-Mt3243 patients
compared with 19 diabetic patients without the mutation. They suggested that the
3243-bp mutation would cause cardiac
sympathetic nervous dysfunction in DMMt3243 patients. However, parasympathetic nervous function has not been
evaluated.
HRV is another common tool to assess cardiac autonomic nervous function
in various diseases, such as diabetes and
myocardial infarction (12). Among HRV
parameters, SDNN index and the LF component correlate with each other and
reflect both the sympathetic and para-
Table 4—Association between LVH and HRV in DM-Mt3243 and ordinary diabetic patients
DM-Mt3243 patients
Age (years)
Diabetes duration (years)
LV wall thickness (mm)
SDNN index (ms)
LF spectra (ms)
HF spectra (ms)
LF/HF ratio
Ordinary diabetic patients
LVH(⫹)
(n ⫽ 4)
LVH(⫹)
versus (⫺)
LVH(⫺)
(n ⫽ 6)
LVH(⫹)
(n ⫽ 6)
LVH(⫹)
versus (⫺)
LVH(⫺)
(n ⫽ 49)
61
12
12.1
25*
7.5*
4.5
1.5
NS
NS
⬍0.02
NS
NS
⬍0.02
NS
63
12
9.4
33
9.0
9.0
1.1†
70
16
12.0
48
13.5
7.0
1.8
NS
NS
⬍0.02
NS
NS
NS
NS
64
12
8.9
39
12.0
7.0
1.7
Data are median values. *P ⬍ 0.05 compared with ordinary diabetic patients with LVH. †P ⬍ 0.02 compared with ordinary diabetic patients without LVH.
DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002
2311
Heart rate variability in mitochondrial diabetes
sympathetic modulations; RMSSD,
pNN50, and the HF component reflect
primarily the parasympathetic modulation (13,14). The LF/HF ratio is a measure
of sympathovagal balance and may reflect
the sympathetic modulation (15). In our
study, ordinary diabetes had significantly
smaller SDNN index, pNN50, and LF and
HF spectra than control subjects. However, the LF/HF ratio was not different.
These results are compatible with those of
the study by Pagani et al. (5) and suggest
that cardiac autonomic function in patients with diabetes is impaired in both
sympathetic and parasympathetic nerves.
Aso et al. (6) also documented that sympathetic nervous damage in diabetes occurs
much earlier than previously believed
and runs parallel with parasympathetic
damage.
Using HRV, we investigated cardiac
autonomic nervous function in diabetesMt3243 patients compared with ordinary
diabetic patients and control subjects. We
found that DM-Mt3243 patients had significantly smaller SDNN index and LF
spectra than patients with ordinary diabetes, which suggests that cardiac autonomic nervous function is more severely
impaired in DM-Mt3243 than in ordinary
diabetes. Regarding the parasympathetic
parameters, RMSSD and pNN50 were not
different between diabetes-Mt3243 patients and those with ordinary diabetes,
but HF spectra were smaller in DMMt3243 patients only for a short time during the day. Notably, DM-Mt3243
patients had a lower LF/HF ratio than ordinary diabetic patients and control subjects. This ratio was similar in ordinary
diabetic patients and control subjects.
Therefore, sympathovagal imbalance in
DM-Mt3243 patients is different than in
ordinary diabetic patients and control
subjects. Cardiac autonomic dysfunction
in DM-Mt3243 patients may be more severe in sympathetic nerves than in parasympathetic nerves.
In our study, LVH was present in 4 of
10 DM-Mt3243 patients (40%) compared
with 11% of ordinary diabetic patients
and 4% of control subjects. As we previously reported (9), DM-Mt3243 patients
are more likely to have LVH than patients
with ordinary diabetes. Our study also
showed that HRV parameters, especially
HF spectra, were smaller in DM-Mt3243
patients with LVH than in those without
LVH. Cardiac autonomic dysfunction in
DM-Mt3243 seems to be more severe in
2312
patients with LVH than in those without
LVH. Reduced HRV was reported to be
predictive of cardiovascular death in diabetic patients as well as patients with
myocardial infarction (12,16). LVH is
recognized to be associated with cardiovascular morbidity (17). Therefore, DMMt3243 patients, especially those with
LVH, may be at much higher risk for cardiovascular death than ordinary diabetes.
However, to elucidate the prognosis and
the clinical usefulness of HRV in patients
with DM-Mt3243, a further study with
long-term follow-up is needed.
Our study was not without limitations. First, due to the small number of
DM-Mt3243 patients, further studies in a
large number of patients are needed to
confirm our data. Moreover, our data in
Japanese may not be applicable to patients of other ethnicities. Second, cardiac
autonomic function was evaluated only
by HRV. Classic bedside procedures such
as Valsalva maneuver were not used in
our study. Peripheral neuropathy was
also diagnosed only by the absence of
Achilles tendon reflex. Other signs, such
as pain and numbness, were not evaluated. Finally, of the 10 DM-Mt3243 patients, 6 underwent Holter monitoring for
chest pain and/or palpitations. Although
the percentages of patients having chest
pain and palpitations were not different
from those in ordinary diabetic patients
and control subjects, these may have
caused some selection bias and may have
confounded the results.
We conclude that patients with diabetes associated with the 3243-bp mutation have more severely impaired cardiac
autonomic nervous function than patients with ordinary diabetes. Moreover,
they have sympathovagal imbalance that
is different from that in patients with ordinary diabetes.
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