Approximately 1% of type 2 diabetes

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1 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, MD 1 YOSHIHIKO SUZUKI, MD 2 MASAKO OHTOMO 3 YOSHIHITO ATSUMI, MD 2 KEMPEI MATSUOKA, MD 2 FUMITAKA OHSUZU, MD 1 MITSURU KIMURA, MD 2 OBJECTIVE To elucidate the degree and characteristics of cardiac autonomic nervous dysfunction in associated with a mitochondrial DNA mutation at base pair RESEARCH DESIGN AND METHODS We investigated heart rate variability using 24-h Holter monitoring in 10 with the mutation compared with 55 ordinary and 45 non control. RESULTS Age and sex were similar in the three groups. Between with the mutation and ordinary, the duration of diabetes and blood glycemic levels were not different. In the time domain analysis of heart rate variability, with the mutation and ordinary had significantly smaller SDNN index and pnn50 than control. Compared with ordinary, 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 with the mutation and ordinary than in control. Compared with ordinary, 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 with the mutation than in ordinary and control (P 0.05), but this ratio was similar in ordinary and control. CONCLUSIONS Our results suggest that with the mitochondrial DNA mutation have more severely impaired cardiac autonomic nervous function with sympathovagal imbalance, as compared with ordinary. Diabetes Care 25: , 2002 Approximately 1% of type 2 diabetes is known to be associated with a mitochondrial trna Leu(UUR) mutation at base pair (bp) 3243 (1). This 3243-bp mutation was originally found in 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 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, 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 (), cardiac autonomic nervous function may be severely impaired. To elucidate the degree and characteristics of cardiac autonomic nervous dysfunction in, we assessed HRV using 24-h Holter monitoring in 10 with the 3243-bp mutation. From the 1 First Department of Internal Medicine, National Defense Medical College, Saitama, Japan; the 2 Division of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan; and the 3 Division 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 , Japan. momiyama@me.ndmc.ac.jp. Received for publication 27 September 2001 and accepted in revised form 23 August Abbreviations: bp, base pair; ; 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. RESEARCH DESIGN AND METHODS We investigated HRV in 10 unrelated 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 All 10 underwent 24-h Holter monitoring because of 2308 DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002

2 Momiyama and Associates Table 1 Clinical characteristics in the three groups (n 10) ordinary (n 55) control (n 45) vs diabetes- Mt3243 Age (years) NS 64 7 NS 62 6 NS Sex (male) 6 (60) NS 38 (69) NS 29 (64) NS Systolic BP (mmhg) NS NS NS Diabetes duration (years) 13 8 NS 14 9 Family history of diabetes in mothers 7 (70) (24) Insulin therapy 6 (60) NS 19 (35) Diabetic retinopathy 4 (40) NS 18 (33) Diabetic neuropathy (ATR[ ]) 6 (60) NS 20 (36) Diabetic nephropathy (proteinuria [ ]) 2 (20) NS 8 (15) FPG (mg/dl) NS HbA 1c (%) NS Echocardiography Wall motion abnormality 0 (0) NS 0 (0) NS 0 (0) NS LV wall thickness (mm) LVH ( 11 mm) 4 (40) NS 6 (11) NS 2 (4) 0.01 Data are presented as means SD or n (%). BP, blood pressure; FPG, fasting plasma glucose; ATR, Achilles tendon reflex. chest pain (5 ), palpitation (4 ), and/or (4 ). HRV was analyzed, and the results were compared with those of 55 ordinary diabetes and 45 control. The ordinary diabetes group consisted of 55 consecutive with type 2 diabetes (age range years) who underwent Holter monitoring at Tokyo Saiseikai Central Hospital from 1996 to 1999 for chest pain (15 ), palpitation (14 ), suspected arrhythmia (13 ), and/or long duration of diabetes (18 ). The control group comprised 45 consecutive non (age years) who had Holter monitoring from 1998 to 1999 for chest pain (15 ), palpitation (13 ), suspected arrhythmia (5 ), and/or medical checkup (12 ). All in the three groups underwent echocardiography. In all, results of stress 201 Tl imaging or exercise testing were negative. Any 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 using 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 ( Hz), low frequency (LF) ( Hz), and high frequency (HF) ( Hz) spectra were calculated at each segment. The Marquette system provides spectral plots as amplitudes (ms) instead of power (ms 2 ). 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 Kruskal- Wallis test for nonparametric variables, 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 Mann- Whitney 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 diabetes- Mt3243, 5 (50%) and 4 (40%) underwent Holter monitoring because of chest pain and palpitations, respectively, but 4 (40%) had no cardiac symptoms. The percentages of having chest pain and palpitations were not different from those with ordinary diabetes (27 and 25%) and non control (33 and 29%) (P NS). Age, sex, and blood pressure were similar in the three groups (Table 1). Between 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 (70%) 13 of 55 ordinary (24%) (P 0.025). Hearing impairment was found in eight (80%), three of whom needed a hearing aid. Regarding diabetes complications, DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER

3 Heart rate variability in mitochondrial diabetes Table 2 HRV data in the three groups (n 10) ordinary (n 55) control (n 45) diabetes- Mt3243 Time domain analysis Mean R-R interval (ms) NS NS SDNN (ms) NS NS NS SDANN (ms) NS NS NS SDNN index (ms) rmssd (ms) 18 6 NS NS pnn50 (%) 1.2 NS Frequency domain analysis Total spectra (ms) LF spectra (ms) HF spectra (ms) NS LF/HF ratio NS 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 (60%) 20 ordinary (36%) (P NS). On echocardiography, thickness of the left ventricular wall was greater in than in those with ordinary diabetes and control ( vs and mm, respectively; P 0.05). LVH with wall thickness 11 mm was found in four (40%) six ordinary (11%) and two control (4%), but none of these had marked LVH ( 15 mm). Regarding HRV over a 24-h period (Table 2), the mean R-R intervals in DM- Mt3243, ordinary, and control were , , and ms, respectively. The mean R-R interval was shorter in than in control. In time domain analysis, there was no difference in SDNN and SDANN among the three groups. However, DM- Mt3243 and ordinary had significantly smaller SDNN index and pnn50 than control. Compared with ordinary, those with had smaller SDNN index (31 10 vs ms, P 0.02), but rmssd and pnn50 were not different. In frequency domain analysis, total, LF, and HF spectra were significantly smaller in and those with ordinary diabetes than in control. Compared with ordinary, had smaller total ( vs ms) and LF spectra ( vs ms) (P 0.05), but HF spectra ( vs ms) were not significantly different. Notably, the LF/HF spectra ratio was lower in DM- Mt3243 than in ordinary and control ( vs and ms, P 0.05), but this ratio was not different between ordinary diabetes and control. 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 and during the daytime in ordinary than in control. Compared with ordinary, those with 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., significant differences (P 0.05) between and control ;, P 0.05 in DM- Mt3243 ordinary ; *P 0.05 in ordinary control DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002

4 Momiyama and Associates Table 3 Association between PN and HRV in and ordinary (n 6) ( ) (n 4) (n 20) ( ) (n 35) Age (years) 59 NS NS 66 Diabetes duration (years) 12 NS NS 10 SDNN index (ms) 33 NS 30* 38 NS 41 LF spectra (ms) 8.5 NS NS 13.0 HF spectra (ms) 7.5 NS NS 8.0 LF/HF ratio 1.3 NS NS 1.8 Data are median values. *P 0.05 and P compared with ordinary without PN. To evaluate the association between peripheral neuropathy (PN) and HRV, and ordinary were divided into two subgroups according to the presence or absence of PN (absent Achilles tendon reflex) (Table 3). Among the, HRV parameters were not different between with and without PN. However, SDNN index and LF spectra tended to be smaller in with PN than in ordinary diabetes with PN. In without PN, SDNN index and LF spectra were smaller than in ordinary without PN (P 0.05). DM- Mt3243 and ordinary were also divided into two subgroups by the presence or absence of LVH (Table 4). Among, SDNN index and LF spectra tended to be smaller in with LVH than in those without LVH. Notably, HF spectra were smaller in with LVH than in those without LVH (P 0.02). Compared with ordinary with LVH, with LVH had smaller SDNN index and LF spectra (P 0.05). Although without LVH tended to have smaller SDNN index and LF spectra than ordinary without LVH, the LF/HF ratio was smaller in without LVH than in ordinary without LVH (P 0.02). CONCLUSIONS The 3243-bp mutation was originally detected in MELAS. In addition to brain and muscles, the involvement of peripheral nerves was reported to be common in 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 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 and diabetes in others remains unclear. In the heart, we recently reported that diabetes- Mt3243 have LVH more often than ordinary, but marked LVH, like hypertrophic cardiomyopathy, is rare (9). Regarding cardiac autonomic nervous function, Ishida et al. (10) reported two with marked LVH who showed no uptake of 123 I-metaiodobenzylguanidine (MIBG) in myocardium. Imaging with 123 I-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 compared with 19 without the mutation. They suggested that the 3243-bp mutation would cause cardiac sympathetic nervous dysfunction in DM- Mt3243. 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 and ordinary (n 4) ( ) (n 6) (n 6) ( ) (n 49) Age (years) 61 NS NS 64 Diabetes duration (years) 12 NS NS 12 LV wall thickness (mm) SDNN index (ms) 25* NS NS 39 LF spectra (ms) 7.5* NS NS 12.0 HF spectra (ms) NS 7.0 LF/HF ratio 1.5 NS NS 1.7 Data are median values. *P 0.05 compared with ordinary with LVH. P 0.02 compared with ordinary without LVH. DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER

5 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. 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 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 diabetes- Mt3243 compared with ordinary and control. We found that had significantly smaller SDNN index and LF spectra than with ordinary diabetes, which suggests that cardiac autonomic nervous function is more severely impaired in than in ordinary diabetes. Regarding the parasympathetic parameters, RMSSD and pnn50 were not different between diabetes-mt3243 and those with ordinary diabetes, but HF spectra were smaller in DM- Mt3243 only for a short time during the day. Notably, had a lower LF/HF ratio than ordinary and control. This ratio was similar in ordinary and control. Therefore, sympathovagal imbalance in is different than in ordinary and control. Cardiac autonomic dysfunction in may be more severe in sympathetic nerves than in parasympathetic nerves. In our study, LVH was present in 4 of 10 (40%) compared with 11% of ordinary and 4% of control. As we previously reported (9), are more likely to have LVH than with ordinary diabetes. Our study also showed that HRV parameters, especially HF spectra, were smaller in with LVH than in those without LVH. Cardiac autonomic dysfunction in seems to be more severe in with LVH than in those without LVH. Reduced HRV was reported to be predictive of cardiovascular death in as well as with myocardial infarction (12,16). LVH is recognized to be associated with cardiovascular morbidity (17). Therefore, DM- Mt3243, 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 with, a further study with long-term follow-up is needed. Our study was not without limitations. First, due to the small number of, further studies in a large number of are needed to confirm our data. Moreover, our data in Japanese may not be applicable to 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, 6 underwent Holter monitoring for chest pain and/or palpitations. Although the percentages of having chest pain and palpitations were not different from those in ordinary and control, these may have caused some selection bias and may have confounded the results. We conclude that with diabetes associated with the 3243-bp mutation have more severely impaired cardiac autonomic nervous function than with ordinary diabetes. Moreover, they have sympathovagal imbalance that is different from that in with ordinary diabetes. References 1. Odawara M, Sasaki K, Yamashita K: Prevalence and clinical characterization of Japanese diabetes mellitus with an A-to-G mutation at nucleotide 3243 of mitochondrial trna Leu(UUR) gene. 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Diabetes Care 21: , Freeman MR, Newman D, Dorian P, Barr A, Langer A: Relation of direct assessment of cardiac autonomic function with metaiodobenzyl guanidine imaging to heart rate variability in diabetes mellitus. Am J Cardiol 80: , Kadowaki T, Kadowaki H, Mori Y, Tobe K, Sakuta R, Suzuki Y, Tanabe Y, Sakura H, Awata T, Goto Y, Hayakawa T, Matsuoka K, Kawamori R, Kamada T, Horai S, Nonaka I, Hagura R, Akanuma Y, Yazaki Y: A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 330: , Momiyama Y, Suzuki Y, Ohsuzu F, Atsumi Y, Matsuoka K, Kimura M: Left ventricular hypertrophy and diastolic dysfunction in mitochondrial diabetes. Diabetes Care 24: , Ishida Y, Ueno H, Yoshida R, Hozumi T, Shiotani H, Matsunaga K, Kasuga M, Kazumi T: Cardiac sympathetic nervous dysfunction in mitochondrial cardiomyopathy and diabetes (Letter). Diabetes Care 18: , Ueno H, Shiotani H: Cardiac abnormalities in with mutation in mitochondrial trna Leu(UUR) gene. Jpn Circ J 63: , Kleiger RE, Miller JP, Bigger JT, Moss AJ: Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 59: , Pomeranz B, Macaulay RJB, Caudill MA, Kutz I, Adam D, Gordon D, Kilborn KM, Barger AC, Shannon DC, Cohen RJ, Benson H: Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 248:H151 H153, Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN: Correlations among time and frequency domain measures of heart period variability two weeks after acute myocardial infarction. Am J Cardiol 69: , Task Force of the European Society of 2312 DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER 2002

6 Momiyama and Associates Cardiology and the North American Society of Pacing and Electrophysiology: Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 3: , Ewing DJ, Martin CN, Young RJ, Clarke BF: The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 8: , Casale PN, Devereux RB, Milner M, Zullo G, Harshfield GA, Pickering TG, Laragh JH: Value of echocardiographic measurement of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med 105: , 1986 DIABETES CARE, VOLUME 25, NUMBER 12, DECEMBER