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Epidemiological Evidence of Altered Cardiac Autonomic Function in Subjects with Impaired Glucose Tolerance But Not Isolated Impaired Fasting Glucose

Departments of Family Medicine (J.-S.W., Y.-C.Y., F.-H.L., C.-J.C.) and Neurology (T.-S.L.), College of Medicine; and Institute of Biomedical Engineering (J.-J.C.), Department of Family Medicine, National Cheng Kung University Hospital (J.-S.W., Y.-C.Y., Y.-H.H., F.-H.L., C.-H.W., C.-J.C.), National Cheng Kung University, 70441 Taiwan, Republic of China

Address all correspondence and requests for reprints to: Chih-Jen Chang, Department of Family Medicine, National Cheng Kung University Hospital, 138, Sheng Li Road, Tainan, 70441, Taiwan, Republic of China. E-mail: em75210{at}email.ncku.edu.tw.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Autonomic dysfunction is present in diabetes mellitus (DM), but no study is available on alteration in cardiac autonomic function (CAF) across different glycemic statuses including normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM.

Objective: Our objective was to examine whether CAF is altered in subjects with IGT and isolated IFG.

Design and Setting: The study was a stratified systematic cluster sampling design within the general community.

Participants: A total of 1440 subjects were classified as NGT (n = 983), isolated IFG (n = 163), IGT (n = 188), and DM (n = 106).

Main Outcome Measure: CAF was determined by 1) standard deviation of normal-to-normal (SDNN) or RR interval, power spectrum in low and high frequency (LF, 0.04–0.15 Hz; HF, 0.15–0.40 Hz), and LF/HF ratio in supine position for 5 min; 2) ratio between 30th and 15th RR interval after standing from supine position (30/15 ratio); and 3) average heart rate change during breathing of six deep breaths for 1 min (HR_DB).

Results: Univariate analysis showed significant differences in SDNN, 30/15 ratio, HR_DB, HF power, and LF/HF ratio among subjects with NGT, isolated IFG, IGT, and DM. In multivariate analysis, none of the indices of CAF was related to isolated IFG in the reference group of NGT. IGT and DM were negatively associated with 30/15 ratio and HF power but positively associated with LF/HF ratio. In addition, DM was also related to a lower SDNN.

Conclusions: DM and IGT subjects had an impaired CAF independent of other cardiovascular risk factors. The risk of altered CAF is not apparent in subjects with isolated IFG.

	Introduction

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DIABETES MELLITUS (DM) is one of the most common causes of autonomic neuropathy, which affects cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor functions (1, 2). Dysfunction of cardiovascular autonomic activity, reflected by reduced heart rate variability (HRV), is strongly associated with the increased risk of cardiac events (3, 4, 5) and overall mortality (3, 6). Diabetic autonomic neuropathy with reduced HRV, even when subclinical, increases the risk of mortality (1, 7, 8).

Traditional tests for cardiac autonomic function (CAF), such as a change in heart rate during deep breathing (HR_DB) and the ratio between 30th and 15th RR interval after standing from supine position (30/15 ratio) have been performed in the past. Both HR_DB and 30/15 ratio are the indices of parasympathetic modulation of the heart. Time and frequency domain methods for HRV assessment have been applied during the last decade (9). The standard deviation of normal-to-normal (SDNN) intervals or RR intervals reflects the cardiac vagal activity in the time domain (9). The frequency components of HRV, derived from power spectral analysis, reflects the cardiac sympathovagal balance (9, 10). The parasympathetic activity is the major contributor to the high-frequency (HF, 0.15–0.40 Hz) component (11), and the low-frequency (LF, 0.04–0.15 Hz) component is suggested as a major quantitative marker of sympathetic modulations (11, 12). The LF/HF ratio is the index of sympathovagal balance (9).

Abnormal HRV has been identified in persons with DM (8, 11, 12, 13). The Hoorn Study showed a reduced SDNN in subjects with impaired glucose tolerance (IGT), but they didn’t report the effect of impaired fasting glucose (IFG) on HRV (14). In the Framingham Heart Study, a fasting plasma glucose (FPG) of 6.1–6.9 mmol/liter was used to define IFG, and subjects with IFG had decreased SDNN and LF and HF power compared with normal control subjects (3). The Atherosclerosis Risk in Communities (ARIC) study adopted the American Diabetes Association (ADA) 2004 criteria (15), and their IFG subjects with a FPG of 5.6–6.9 mmol/liter had a lower RR interval, but not a lower SDNN, than subjects with a normal FPG (16). Because some of the IFG subjects may have IGT and even DM (17, 18), both the Framingham Heart Study and the ARIC study didn’t exclude the influence of IGT and DM on IFG subjects (3, 16). There is a paucity of studies that assess the CAF in IGT and IFG subjects (3, 14, 16), and no study is available on HRV change across the different blood glucose levels, including normal glucose tolerance (NGT), isolated IFG, IGT, and DM. Therefore, the aim of this study is to examine whether CAF is altered in community dwellers with IGT and isolated IFG from population-based data in Tainan, Taiwan.

	Subjects and Methods

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Study population

The subjects were recruited for the population-based study for chronic diseases conducted in Tainan, and the details of its results have been described elsewhere (19). A three-stage sampling scheme was used to generate a stratified systemic cluster sample of households throughout the city. First, the city was classified into seven strata according to its administrative districts. In each of the districts, one area was randomly selected from each stratum by adopting a probability proportional to the size of the areas within that specific stratum. Second, every fifth household within each of the seven selected areas was systematically identified. Third, the members of each household aged at least 20 yr old were invited to participate in the study, and a total of 2416 eligible subjects were selected. A total of 1638 subjects, representing a response rate of 67.8%, finished a health screening examination. The nonresponders were slightly younger and consisted of more men as compared with the responders, but the differences were not statistically significant. Written consent was obtained from all participants, and this study was approved by the research committee of National Cheng Kung University Hospital, Taiwan. In the final analysis, a total of 1440 participants were included after excluding 198 subjects who had taken medications known to influence CAF, such as antihypertensive drugs, antiparkinsonism drugs, narcotics, sedatives, antipsychotics, or antidepressants within 2 wk of the study.

Clinical examination

All the subjects were informed of unrestricted diet and usual physical activity at least 3 d before the schedule of examinations by letter and telephone. The subjects were instructed not to consume alcohol, coffee, tea, or cigarettes on the day of the examination. They were interviewed by a well-trained assistant, using a structured questionnaire, which included questions on demographic characteristics, medical history, and use of medications, dietary habits, cigarette smoking, alcohol drinking, and physical activity during the past year. All the subjects received a physical examination by physicians. Measurements of blood pressure when seated, body weight, and height were taken by well-trained nurses. The laboratory tests included blood biochemistry, urine examination, and electrocardiography (ECG) after an overnight fast of at least 10 h. The subjects without a history of DM received a 75-g oral glucose tolerance test after completion of the measurement of their blood pressure and HRV. A blood sample was obtained 2 h after the subject began to drink the glucose solution.

Measurements of blood pressure and HRV

All the subjects were informed of the purpose and procedures of the test. Subjects were resting in a supine position in a quiet ambience, and measurements were obtained in a fasting state between 0800 and 1000 h. Two seated blood pressure readings, separated by intervals of at least 5 min, were taken with an appropriate-sized cuff wrapped around the right upper arm by a DINAMAP vital sign monitor (model 1846SX; Critikon Inc., Irvine, CA) after the subject had rested for 15 min.

The beat-to-beat duration of the cardiac cycle (RR interval) was measured continuously with an ECG monitor (CardiSuny -800; Fukuda M-E Kogyo Inc., Tokyo, Japan) on a personal computer-based data-acquisition system according to the following sequence: 1) normal breathing for 5 min in the supine position, 2) an active change from the lying to the standing position, and then 3) six deep breaths over 1 min while sitting after a 10-min rest. The signal-acquiring and processing system converted the analog signals to digital signals at a sampling rate of 120 Hz per channel with a 12-bit performance by the data acquisition devices for universal serial bus (DAQPad-6020E and SCB-68; National Instruments, Taipei City, Taiwan). The ECG signals were processed to extract the R-peak positions. The procedure for R-peak detection was performed using software with a LabView 6.1 program (National Instruments). A power spectral analysis was used to define the temporal fluctuations of HRV. The total power, very-low-frequency (<0.04 Hz), LF (0.04–0.15 Hz), and HF (0.15–0.4 Hz) components were identified for each subject (9). The CAF included the following: 1) SDNN, LF power, HF power, and LF/HF ratio in the supine position for 5 min; 2) 30/15 ratio; and 3) the average of six HR_DB for 1 min while sitting after a 10-min rest.

Definition of clinical measurements

NGT was defined as an FPG of less than 5.6 mmol/liter, a 2-h post-load glucose (PG) of less than 7.8 mmol/liter, and no previous history of DM (15). Isolated IFG was identified as an FPG of 5.6–6.9 mmol/liter and a 2-h PG of less than 7.8 mmol/liter without a DM history. IGT was defined as a 2-h PG of 7.8–11.1 mmol/liter and an FPG of less than 7.0 mmol/liter without a DM history. Subjects with both IFG and IGT were classified as IGT. DM was diagnosed when subjects registered an FPG of at least 7.0 mmol/liter or a 2-h PG of at least 11.1 mmol/liter or reported having a DM history or current use of insulin or an oral hypoglycemic agent (15). Hypertension was defined as the average of two seated systolic/diastolic blood pressure measurements of at least 140/90 mm Hg or a positive history of hypertension (20). Total physical activity, including work, walking, and leisure-time exercise, was measured in metabolic equivalent-hours per week for the past year (21).

Statistical analysis

Data analyses were performed using the Statistical Package for Social Sciences 13.0 for Windows software. Glycemic status was divided into NGT, isolated IFG, IGT, and DM groups. In the univariate analysis, the ANOVA and Bonferroni post hoc test were used to compare continuous variables among the subjects with different glycemic statuses, except that Kruskal-Wallis test was used for comparison of the plasma triglyceride and physical activity level. A square root transformation of LF/HF ratio was used to make the values follow a normal distribution due to its nonnormal distribution. Comparisons of categorical variables were made using the ² or Fisher’s exact test, when the cell size was less than 5.

Multiple linear regression was used to model the links between HRV and different glycemic statuses. Three dummy variables were used to code NGT (0, 0, 0), isolated IFG (1, 0, 0), IGT (0, 1, 0), and DM (0, 0, 1). The outcome variables were HRV including SDNN, 30/15 ratio, HR_DB, LF power, HF power, and the square root of LF/HF ratio, respectively. The predictor variables included age, gender, body mass index (BMI), plasma cholesterol, triglyceride and high-density lipoprotein cholesterol (HDL-C), hypertension, isolated IFG vs. NGT, IGT vs. NGT, DM vs. NGT, and the physical activity levels. To make survey estimates a better representation of population estimates, design weights, which were calculated as the inverse of the sample selection probability, were used in the regression model. A P value of < 0.05 was considered significant.

	Results

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The subjects were classified as NGT (n = 983), isolated IFG (n = 163), IGT (n = 188), and DM (n = 106) according to ADA 2004 criteria (Table 1). Of 106 diabetic subjects, 56 were newly diagnosed with diabetes or no antidiabetic medication, 44 took oral antidiabetic drug, including sulfonylurea and metformin, and six used insulin. Table 2 shows the comparisons of clinical variables among subjects with NGT, isolated IFG, IGT, and DM. There were significant differences in age, BMI, physical activity levels, the average of two seated heart rate measurements, systolic/diastolic blood pressure measurements, FPG, glycosylated hemoglobin (HbA1c), plasma cholesterol, triglyceride, and HDL-C, and the prevalence of hypertension among these four groups (P < 0.001). However, the differences based on gender (P = 0.327) and the prevalence of current smoking (P = 0.501) and alcohol use (P = 0.691) were not significant.

View larger version (22K): [in this window] [in a new window]   FIG. 1. The ß-coefficient and 95% confidence interval (CI) for the effect of IFG, IGT, and DM on CAF with reference group of NGT from multiple linear regression analysis on the basis of weight (inverse of the selection probability). Dependent variables are HRV shown by SDNN, 30/15 ratio, HRDB, LF power, HF power, and square root of LF/HF ratio, respectively. Independent variables are age, gender, BMI, plasma cholesterol, triglyceride, HDL-C, hypertension, isolated IFG vs. NGT, IGT vs. NGT, DM vs. NGT, and physical activity level. *, P < 0.05; , P < 0.01; , P < 0.001.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Population-based study on the CAF in IGT subjects is scarce (14). The Hoorn Study has shown that IGT subjects suffered a higher risk of having a lower 25th percentile of SDNN (14). Based on the multivariate analysis, our study revealed that IGT is associated with a lower 30/15 ratio and HF power but with an increased LF/HF ratio. Both the Hoorn study and our study observed that CAF was altered in IGT subjects, although the indicators of CAF that were used differed. The literature shows that IGT is associated with microvascular complications, such as retinopathy (26), nephropathy (26), and neuropathy (27). In addition, IGT subjects are at great risk of mortality (28, 29) and have an increased incidence of ischemic heart disease and cerebrovascular disease independent of progression to DM (29). Because cardiac autonomic dysfunction is strongly associated with an increased risk of cardiac events (3, 4, 5) and overall mortality (3, 6), the possibility that altered CAF is one of the underlying mechanisms of cardiovascular morbidity and mortality in IGT subjects needs further investigation.

In our study, CAF in subjects with isolated IFG was not different from that identified in NGT subjects after adjustments for other variables. The Framingham Heart Study showed that IFG subjects had a lower SDNN and LF and HF power than NGT subjects (3), but the IFG subjects had a higher FPG criterion (6.1–6.9 mmol/liter) than our subjects. Only FPG, not concomitant with 2-h PG, was used to classify the subjects into NGT, IFG, and DM groups, so the IFG subjects may have IGT and even DM (17, 18). Therefore, the IFG subjects of the Framingham Heart Study may be more hyperglycemic and at an advanced stage of the prediabetes/diabetes course than our isolated IFG subjects. This may explain the inconsistency between our study and the Framingham Heart Study. The ARIC and our study adopted a lower IFG criterion of an FPG of 5.6–6.9 mmol/liter and showed there was no difference in SDNN between those with IFG and NGT, although the ARIC study didn’t exclude the influence of IGT and DM in IFG subjects (16). In addition, our study revealed that NGT and isolated IFG subjects didn’t differ significantly in the frequency domain of HRV, such as HF power, LF power, and LF/HF ratio, although the ARIC study didn’t perform a power spectral analysis of HRV. Therefore, the CAF was not apparently altered in subjects with isolated IFG.

This study provides the epidemiological evidence that an altered CAF is present in both IGT and DM subjects, but not IFG subjects, after carefully controlling for confounding factors. By mapping the CAF across the different glycemic groups, from NGT, then to prediabetes, and finally to DM, our study reveals that IGT subjects had a decreased parasympathetic modulation of the heart, shown by HF power and 30/15 ratio, resulting in a shift toward augmented sympathetic tone shown by an increased LF/HF ratio. This impairment also occurs in subjects with DM. Thus, the parasympathetic tone declined with an autonomic imbalance shifting toward augmented sympathetic tone during the development from NGT to IGT and finally DM. In contrast, the autonomic impairment is not apparent in IFG subjects. In conclusion, DM and IGT subjects had an impaired CAF independent of other cardiovascular risk factors. However, the risk of altered CAF is not significant in subjects with isolated IFG.

	Footnotes

 
This study was supported by grants from the National Science Council, Taiwan, Republic of China (NSC 87-2314-B-006-084, NSC 89-2314-B-006-043, and NSC 92-2314-B-006-117).

Disclosure Statement: The authors have nothing to disclose.

First Published Online July 31, 2007

Abbreviations: ADA, American Diabetes Association; ARIC, Atherosclerosis Risk in Communities; BMI, body mass index; CAF, cardiac autonomic function; DM, diabetes mellitus; ECG, electrocardiography; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; HF, high frequency; HR_DB, heart rate during deep breathing; HRV, heart rate variability; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LF, low frequency; NGT, normal glucose tolerance; PG, post-load glucose; SDNN, standard deviation of normal-to-normal.

Received October 4, 2006.

Accepted July 25, 2007.

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