ORIGINAL ARTICLE

Endocrine Research

Dysregulation of the Autonomic Nervous System Predicts the Development of the Metabolic Syndrome

Carmilla M. M. Licht, Eco J. C. de Geus, and Brenda W. J. H. Penninx

Department of Psychiatry (C.M.M.L., B.W.J.H.P.), Vrije Universiteit (VU) University Medical Center Amsterdam, The Netherlands; Extramural Medicine Researchϩ Institute (C.M.M.L., E.J.C.d.G., B.W.J.H.P.)

for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; Department Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021 of Biological Psychology (E.J.C.d.G.), VU University, Amsterdam, The Netherlands; Neuroscience Campus Amsterdam (E.J.C.d.G., B.W.J.H.P.), VU University Medical Center, Amsterdam, The Netherlands; Department of Psychiatry (B.W.J.H.P.), Leiden University Medical Center, Leiden, The Netherlands; and Department of Psychiatry (B.W.J.H.P.), University Medical Center Groningen, Groningen, The Netherlands

Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome. Although dysregulation of the autonomic nervous system is found to associate with the metabolic syndrome and its dysregulations, no longitudinal study has been performed to date to examine the predictive value of this stress system in the development of the metabolic syndrome.

Objective: We examined whether autonomic nervous system functioning predicts 2-year devel- opment of metabolic abnormalities that constitute the metabolic syndrome.

Design: Data of the baseline and 2-year follow-up assessment of a prospective cohort: the Neth- erlands Study of Depression and Anxiety was used.

Setting: Participants were recruited in the general community, primary care, and specialized men- tal health care organizations.

Participants: A group of 1933 participants aged 18–65 years.

Main outcome measures: The autonomic nervous system measures included rate (HR), re- spiratory sinus arrhythmia (RSA; high RSA reflecting high parasympathetic activity), pre-ejection period (PEP; high PEP reflecting low sympathetic activity), cardiac autonomic balance (CAB), and cardiac autonomic regulation (CAR). Metabolic syndrome was based on the updated Adult Treat- ment Panel III criteria and included high waist circumference, serum triglycerides, blood pressure, serum glucose, and low high-density lipoprotein (HDL) cholesterol.

Results: Baseline short PEP, low CAB, high HR, and CAR were predictors of an increase in the number of components of the metabolic syndrome during follow-up. High HR and low CAB were predictors of a 2-year decrease in HDL cholesterol, and 2-year increase in diastolic and systolic blood pressure. Short PEP and high CAR also predicted a 2-year increase in systolic blood pressure, and short PEP additionally predicted 2-year increase in diastolic blood pressure. Finally, a low baseline RSA was predictive for subsequent decreases in HDL cholesterol.

Conclusion: Increased sympathetic activity predicts an increase in metabolic abnormalities over time. These findings suggest that a dysregulation of the autonomic nervous system is an important predictor of cardiovascular diseases and diabetes through dysregulating lipid metabolism and blood pressure over time. (J Clin Endocrinol Metab 98: 2484–2493, 2013)

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: ANS, autonomic nervous system; ATC, World Health Organization Ana- Printed in U.S.A. tomical Therapeutic Chemical classification; BP, blood pressure; CAB, cardiac autonomic Copyright © 2013 by The Endocrine Society balance; CAR, cardiac autonomic regulation; CI, confidence interval; ECG, electrocardio- Received August 16, 2012. Accepted March 26, 2013. gram; HDL, high-density lipoproteins; HR, heart rate; IBI, interbeat interval; LV, left ven- First Published Online April 3, 2013 tricle; NESDA, Netherlands Study of Depression and Anxiety study; OR, odds ratio; PEP, pre-ejection period; RSA, respiratory sinus arrhythmia.

2484 jcem.endojournals.org J Clin Endocrinol Metab, June 2013, 98(6):2484–2493 doi: 10.1210/jc.2012-3104 doi: 10.1210/jc.2012-3104 jcem.endojournals.org 2485

t has often been hypothesized that stress leads to the participating universities and all respondents provided written I metabolic syndrome (1–3). Dysregulation of one of the informed consent. Two years after baseline, a face-to-face fol- main stress systems—the autonomic nervous system— low-up assessment was conducted with a response of 2596 of the 2981 respondents (87%). Nonresponders were younger, more could lead to insulin resistance, altered lipid metabolism, often of non-northern European ancestry, and less educated and and increased blood pressure (BP) (4–8). Results of a large more often had major depressive disorder (23). cross-sectional study indeed indicated that dysregulation Of the total follow-up sample, 340 participants had no data of the autonomic nervous system (ANS) is associated with on metabolic abnormalities on 1 of the 2 time points and an several metabolic alterations. Increased heart rate (HR) additional 107 had missing data on all baseline ANS measures. Because of the known effects of antidepressants on the ANS (24) with decreased respiratory sinus arrhythmia (RSA), indic- and the metabolic syndrome (25), we excluded 131 subjects who ative of low parasympathetic activity, and decreased pre- changed antidepressant use during the follow-up period (ie, sub- ejection period (PEP), indicative of high sympathetic ac- jects who started, stopped, or switched to another antidepres- Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021 tivity, were found to associate with high BP, serum sant) because in these individuals changes in metabolic syndrome triglycerides, serum glucose, and waist circumference and also could be due to changes in antidepressant . Use with the presence of the metabolic syndrome and the num- of antidepressants was considered present when taken for at least 1 month and 50% of the time. Using the World Health Orga- ber of its components (9). The metabolic syndrome con- nization Anatomical Therapeutic Chemical (ATC) classifica- sists of a cluster of these metabolic abnormalities and is tion, were classified. Tricyclic antidepressants (ATC thought to be one of the most important risk factors for code N06AA), serotonergic and noradrenergic working antide- cardiovascular diseases (10, 11) and diabetes (12). Our pressants (ATC code N06AF/N06AX), and selective serotonin findings were in line with most other cross-sectional stud- reuptake inhibitors (ATC code N06AB) were included. Simi- ␤ ies investigating the association between metabolic abnor- larly, because of the impact of -blockers on the ANS as well as on metabolic factors (26–31), subjects who stopped or started malities and ANS functioning (3, 13, 14). Elevated the use of a ␤-blocker (ATC code C07, used for at least a month sympathetic nervous system activity and diminished para- and daily or more than 50% of the time) were also excluded (n ϭ sympathetic nervous system activity were found in sub- 85). Subjects who consistently used ␤-blockers or antidepres- jects with metabolic syndrome (15–19). As far as we sants during the 2-year follow-up remained included. The pres- know, only one longitudinal study has been performed ent study sample therefore consisted of 1933 participants. that investigated the predictive value of metabolic syn- Outcome measures drome factors for changes in HR variability (20). How- ever, no longitudinal studies have been performed to Metabolic syndrome test the reverse causality. Therefore, it remains unclear The metabolic syndrome was defined according to the Amer- whether autonomic dysregulation, as a marker of biolog- ican Heart Association and National Heart, Lung, and Blood ical stress activation, leads to metabolic dysregulations Institute’s update of the US National Cholesterol Education Pro- gram–Adult Treatment Panel III criteria (32). The US National and the metabolic syndrome (21). Cholesterol Education Program–Adult Treatment Panel III To examine the relation between (multiple) measures of guidelines define metabolic syndrome as a presence of 3 or more ANS and metabolic components in a large cohort study, of the following criteria: 1) waist circumference Ն102 cm in men we explored whether and which baseline autonomic mea- and Ն88 cm in women; 2) triglycerides Ն1.7 mmol/L (150 mg/ sures predicted worsening of metabolic syndrome com- dL) or medication for hypertriglyceridemia; 3) high-density li- Ͻ ponents over a 2-year time period, while considering pos- poprotein (HDL) cholesterol 1.03 mmol/L (40 mg/dL) in men and Ͻ1.30 mmol/L (50 mg/dL) in women or medication for sible important covariates. reduced HDL cholesterol; 4) BP: systolic Ն130 and/or diastolic Ն85 mm Hg or antihypertensive medication; 5) fasting plasma glucose Ն5.6 mmol/L (100 mg/dL) or antidiabetic medication. Materials and Methods The number of metabolic syndrome components was used as an indicator of severity of metabolic abnormalities (25). Study sample Data are from the Netherlands Study of Depression and Anx- Metabolic syndrome components iety (NESDA), a large longitudinal cohort study among 2981 In addition to metabolic syndrome, associations with contin- adults (18–65 y), 95.2% of North-European ancestry (see [22]). uous levels of individual metabolic components were examined, Respondents were recruited from the community, in primary to investigate consistency across components. Waist circumfer- care, through a screening procedure conducted among 65 gen- ence was measured with a measuring tape at the central point eral practitioners, and in specialized mental health care when between the lowest front rib and the highest front point of the newly enrolled at 1 of the 17 participating mental health orga- pelvis, upon light clothing. HDL cholesterol, triglycerides, and nization locations. The baseline assessment comprised a face-to- glucose levels were determined from the fasting blood samples face interview, written questionnaires, and biological measure- using routine standardized laboratorial methods. As has been ments (among which was a blood draw in fasting state). The proposed and applied before (9), the continuous measures were research protocol was approved by the Ethical Committee of adjusted for medication use based on the estimated effects of the 2486 Licht et al Dysregulated ANS Predicts Metabolic Syndrome J Clin Endocrinol Metab, June 2013, 98(6):2484–2493 medication. According to the standards of medical care in dia- al (52). Normalized values of PEP and RSA were computed by betes, the goal of antidiabetic medication should be to lower the dividing the individual raw scores minus the mean of the pop- fasting glucose level to Ͻ7.0 mmol/L (34). In agreement with ulation by the standard deviation of the group. Cardiac auto- these standards, for persons using antidiabetic medication when nomic balance (CAB) was calculated as the difference between glucose level was less than 7.0 mmol/L (126 mg/dL), a value of normalized values of RSA (zRSA) and PEP (zPEP). The formula 7.0 mmol/L (126 mg/dL) was assigned. According to the average is CAB ϭ zRSA Ϫ (ϪzPEP) [because increased sympathetic ac- decline in triglycerides and increases in HDL cholesterol in fi- tivity is associated with shortened PEP values, PEP was multi- brate trials (35–40), 0.10 mmol/L (3.8 mg/dL) was subtracted plied by Ϫ1], such that low values reflect high sympathetic and from the HDL cholesterol level and 0.67 mmol/L (60 mg/dL) was low vagal cardiac activity (unfavorable cardiac pattern) and high added to the triglyceride level of persons using fibrates. Similarly, values reflect low sympathetic and high vagal cardiac activity for persons using nicotinic acid, 0.15 mmol/L (5.8 mg/dL) was (favorable cardiac pattern). Cardiac autonomic regulation subtracted from the HDL cholesterol and 0.19 mmol/L (17 mg/ (CAR) was calculated as the sum of the normalized values of RSA dL) was added to the triglycerides (41–45). Systolic BP and di- and PEP (formula ϭ zRSA ϩ (ϪzPEP)) and low values represent Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021 astolic BP were measured twice during supine rest on the right coinhibition (low sympathetic and low vagal activity) and high arm with the Omron M4-I, HEM 752A (Omron, Healthcare values represent coactivation (high sympathetic and high vagal Europe BV, Hoofddorp, The Netherlands) and were averaged activity) of the 2 cardiac branches. over the 2 measurements. For persons using antihypertensive Because ANS measures served as predictors, only baseline medication, 10 mm Hg was added to the systolic BP and 5 mm values were used. Hg to the diastolic BP according to the average decline in BP in antihypertensive trials (46–48). All metabolic variables were Covariates measured at baseline assessment as well as at 2-year follow-up. Sociodemographic factors included sex, age, and years of at- tained education. Health confounders included cardiovascular Measurements diseases, heart medication, and smoking. Cardiovascular disease Autonomic nervous system (including coronary disease, cardiac arrhythmia, angina, heart failure, and myocardial infarction) was ascertained by self-re- During the visit to the research centers, NESDA subjects were port. Furthermore, it was determined whether subjects were us- wearing the VU Ambulatory Monitoring System. The VU-Am- ing heart medication by copying the names of medicines from the bulatory Monitoring System is a lightweight, unobtrusive device containers brought in by the subjects. Use of heart medication that records the electrocardiogram (ECG) and changes in thorax other than ␤-blockers was ascertained (ATC-codes C01 [cardiac impedance (dZ) from 6 surface electrodes placed at the chest and therapy], C02 [antihypertensives], C03 [], C04 [periph- back of the subjects (49, 50). The interbeat interval (IBI) time eral vasodilators], C05 [vasoprotectives], C08 [calcium channel series was extracted from the ECG signal to obtain HR, an in- blockers], C09 [renin and angiotensin agents], and C10 [lipid- dicator of combined cardiac sympathetic and parasympathetic modifying agents]), and the change in use in any of these med- activity. To index the cardiac effects of both ANS branches sep- ications over the 2-year period was captured in a categorical arately, PEP (high PEP reflects low sympathetic activity) and variable (persistent nonusers, persistent users, discontinuing us- RSA (high RSA reflects high parasympathetic activity) were ex- ers, and new users). Smoking was addressed using a continuous tracted from the combined dZ and ECG signals. variable measuring the mean number of tobacco consumptions The PEP reflects noradrenergic inotropic drive to the left ven- a day. RSA as a proxy for individual differences in cardiac vagal tricle (LV) and was obtained from the ECG and dZ/dt signals, activity suffers from potential confounding by individual differ- with the latter ensemble averaged across 1-minute periods time- ences in respiratory behavior (53, 54). Accordingly, it has often locked to the R-wave of the ECG. Three time points can be scored been suggested that studies investigating RSA should take res- in impedance cardiography ensemble averages: the upstroke or piration rate into account (49, 56). Therefore, respiration rate B-point, the dZ/dt(min) point, and the incisura or X-point. The was included as a covariate as number of breaths per minute. PEP is defined as the interval from the Q-wave onset in the ECG, which is the onset of the LV electrical activity, to the B-point in the impedance cardiography that indicates the beginning of the Statistical analyses blood ejection through the aortic valve. As a more reliably as- Mean baseline characteristics and mean 2-year changes in sessed proxy for the Q-wave onset, the R-wave peak minus a metabolic components were calculated for the whole sample. fixed interval of 48 ms was used (50, 51). The RSA reflects car- Multiple linear regression analyses were used to analyze the re- diac parasympathetic activity and was obtained by combining lationship between baseline ANS measures and the changes in the IBI time series with the filtered (0.1–0.4 Hz) dZ signal, which number of metabolic syndrome components and changes in con- corresponds to the respiration signal. RSA was obtained by sub- tinuous individual metabolic syndrome components during the tracting the shortest IBI during HR acceleration in the inspira- 2-year follow-up period. All changes in metabolic syndrome tional phase from the longest IBI during deceleration in the ex- components were normally distributed. Adjustment for con- pirational phase for all breaths, as described in detail elsewhere founding was done in the following 2 steps: basic adjustment (49). Automated scoring of IBI, RSA, and PEP was checked by (demographic factors and baseline metabolic values) and addi- visual inspection, and valid data were averaged over approxi- tional adjustment for health factors. To exclude potential effects mately 90 minutes to create a single PEP, RSA, and HR value. of persistent antidepressant medication use or psychopathology To investigate additionally whether patterns of cardiac sym- status, additional sensitivity analyses were performed with ad- pathetic and parasympathetic coactivation or parallel reciproc- ditional adjustment for antidepressant medication (yes/no stable ity were related to the metabolic syndrome, 2 measures of au- use during follow-up period) and for psychopathology status tonomic balance were acquired after the approach of Berntson et (yes/no current [6-mo recency] depression at baseline, yes/no doi: 10.1210/jc.2012-3104 jcem.endojournals.org 2487

Table 1. Sample Characteristics (n ϭ 1933)

Baseline Follow-up ⌬ Sociodemographics Age, y (mean Ϯ SD) 42.0 Ϯ 13.3 — % Female 67.2 — Education, y (mean Ϯ SD) 12.5 Ϯ 3.3 — Health factors Smoker (mean Ϯ SD) 4.3 Ϯ 8.2 4.1 Ϯ 8.0 % Nonsmoker 29.7 31.3 % Former smoker 35.7 35.1 % Current smoker 34.6 33.6

% Use of heart medication 9.9 12.0 Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021 % Cardiovascular disease 6.1 7.8 % Diabetic medication 2.6 3.6 Body mass index, kg/m2 (mean Ϯ SD) 25.3 Ϯ 4.8 25.6 Ϯ 4.8 Underweight, % 2.2 1.9 Normal weight, % 53.0 51.1 Overweight, % 30.0 31.0 Obese, % 14.8 15.9 Current depressive disorder, % 30.5 19.5 Current anxiety disorder, % 36.7 24.1 Current antidepressant use, % 16.3a 16.3a Autonomic indices RSA, ms (mean Ϯ SD) 44.7 Ϯ 25.3 42.8 Ϯ 22.7 HR, bpm (mean Ϯ SD) 72.0 Ϯ 9.6 72.6 Ϯ 9.5 PEP, ms (mean Ϯ SD) 119.5 Ϯ 17.7 119.7 Ϯ 17.1 CAB (mean Ϯ SD) Ϫ0.022 Ϯ 1.46 0.062 Ϯ 1.49 CAR (mean Ϯ SD) 0.050 Ϯ 1.33 0.037 Ϯ 1.33 Measures of metabolic syndrome No. of metabolic components (mean Ϯ SD) 1.42 Ϯ 1.3 1.48 Ϯ 1.3 0.07 Ϯ 0.9 Elevated waist circumference, % 30.1 32.9 2.8 Elevated blood pressure, % 58.5 53.5 Ϫ5.0 Elevated fasting glucose, % 20.6 25.9 5.3 Reduced HDL cholesterol, % 14.3 17.9 3.6 Elevated triglycerides, % 19.2 20.0 0.8 Waist circumference, cm (mean Ϯ SD) 88.4 Ϯ 13.8 89.0 Ϯ 13.7 0.7 Ϯ 6.0 Systolic BP, mm Hg (mean Ϯ SD) 135.6 Ϯ 19.6 133.1 Ϯ 19.0 Ϫ2.6 Ϯ 12.3 Diastolic BP, mm Hg (mean Ϯ SD) 81.0 Ϯ 10.9 79.2 Ϯ 10.9 Ϫ1.9 Ϯ 7.5 Glucose, mmol/L (mean Ϯ SD) 5.15 Ϯ 0.9 5.31 Ϯ 1.0 0.17 Ϯ 0.6 HDL cholesterol, mmol/L (mean Ϯ SD) 1.64 Ϯ 0.4 1.55 Ϯ 0.4 Ϫ0.09 Ϯ 0.2 Triglycerides, mmol/L (mean Ϯ SD) 1.29 Ϯ 0.9 1.31 Ϯ 0.9 0.02 Ϯ 0.6 Data indicate that since data of the two time points are based on the same sample and follow-up measurement is exactly two years after the baseline assessment for all participants, %female sex, age and education do not change or only in absolute value (ϩ 2 year). Only persistent antidepressant users were included in the present study. Therefore the percentage of users is equal for baseline and follow-up. current anxiety disorder at baseline, yes/no current depression at at baseline, 75.3% still met the criteria at follow-up and of follow-up, yes/no current anxiety disorder at follow-up). the respondents without the metabolic syndrome 10.0% To investigate linear relationships, fully corrected logistic re- developed a new onset of metabolic syndrome. Sample gression analyses were conducted with quartiles of the baseline ANS measure as a predictor of the new onset of metabolic syn- characteristics are presented in Table 1. In general, a mean drome at follow-up. To make sure incident cases were predicted, decrease in BP and HDL cholesterol, and a mean increase subjects with the metabolic syndrome at baseline were excluded in waist circumference, glucose, and triglyceride levels and ϭ Յ (n 352). A P value of .05 was regarded as statistically sig- number of metabolic components were seen over the nificant. All analyses were conducted using SPSS version 20.0 2-year follow-up period, although absolute changes were (SPSS, Chicago, Illinois). rather small. Table 2 shows the results of the predictive value of ANS Results measures for a 2-year increase in the number of metabolic components. Low baseline CAB (indicating high sympa- In our sample, 18.2% met the criteria for the metabolic thetic and/or low parasympathetic activity), short baseline syndrome at baseline and 21.9% met the criteria at 2-year PEP, and high baseline HR predicted a 2-year increase in follow-up. Of the respondents with metabolic syndrome the number of metabolic components. Fully adjusted anal- 2488 Licht et al Dysregulated ANS Predicts Metabolic Syndrome J Clin Endocrinol Metab, June 2013, 98(6):2484–2493

ϭ Table 2. Adjusted Associations Between Baseline P .04, respectively) and short PEP and low CAB addi- Cardiac Autonomic Control and 2-y Change in Number tionally for the 2-year change in diastolic BP (␤ ϭϪ.052, of Metabolic Syndrome Components (n ϭ 1933) P ϭ .02, and ␤ ϭϪ.053, P ϭ .02, respectively). No au- tonomic measure significantly predicted 2-year changes in 2-y Change in Number of Metabolic Syndrome waist circumference, glucose, or triglyceride levels. Sensi- Components, per 1 tivity analyses additionally adjusting for persistent anti- Component Increase depressant use and depressive and/or anxiety disorders at Baseline ANS ␤ P ␤a Pa baseline and at follow-up did not alter our findings. RSA, per 10 ms increase Ϫ.016 .57 Ϫ.016 .59 Finally, we graphically displayed the association be- HR, per 10 bpm increase .057 .02 .056 .02 tween baseline ANS indicators and the development of

PEP, per 10 ms increase Ϫ.065 .005 Ϫ.079 Ͻ.001 new onset of metabolic syndrome to check for linearity of Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021 CAB, per 1 U increase Ϫ.066 .007 Ϫ.077 .002 CAR, per 1 U increase .041 .10 .054 .03 associations. Figure 1 shows the results of multivariable logistic regression analyses associating baseline quartiles Abbreviation: ␤, standardized ␤-coefficient. Based on linear regression analyses adjusted for age, sex, education, and baseline number of of RSA, HR, PEP, CAB, and CAR with new onset of the metabolic syndrome components (RSA was additionally adjusted for metabolic syndrome among subjects without the meta- respiration rate). bolic syndrome at baseline (n ϭ 1581). Compared to sub- a Additionally adjusted for cardiovascular disease, smoking, and jects in the lowest quartile of HR, subjects in 1 of the upper (change in) use of heart medication (other than ␤-blocking agents). 2 quartiles had an increased risk for developing the met- yses showed a similar pattern of results as basic adjusted abolic syndrome during the 2-year follow-up period (odds ϭ analyses, but added a significant positive association with ratio, OR [95% confidence interval, CI] 1.67 [1.01– ϭ ϭ ϭ CAR. Predicting 2-year changes in the continuous mea- 2.86], P .05 and OR 1.96 [1.14–3.37], P .008, sures of individual metabolic syndrome components (Ta- respectively). A similar but reversed pattern was seen for ble 3) indicated that all relationships pointed in the direc- PEP and CAB. Compared to the subjects with the lowest tion that low-parasympathetic and high-sympathetic quartile of PEP (the highest cardiac sympathetic activity), activity predicted increases in metabolic risk factors over those with higher values of PEP had lower odds of devel- time. However, only some of the predictions were signif- oping the metabolic syndrome over time (Second quartile icant after adjustment. High HR predicted decreased HDL : OR [95%CI] ϭ 0.65 [0.40–1.05], P ϭ .08; third quartile: cholesterol (␤ ϭϪ.056, P ϭ .008), increased diastolic BP OR ϭ 0.64 [0.39–1.05], P ϭ .08, and fourth quartile: (␤ ϭ .089, P Ͻ .001), and increased systolic BP (␤ ϭ .056, OR ϭ 0.46 [0.26–0.82], P ϭ .009). Having a higher CAB P ϭ .009). Low RSA predicted a 2-year decrease in HDL (indicating low sympathetic and/or high parasympathetic cholesterol (␤ ϭ .063, P ϭ .02). Also, low baseline CAB activity) was a protective factor against the new onset of was predictive of a decrease in HDL cholesterol over time the metabolic syndrome (Second quartile: OR [95%CI] ϭ (␤ ϭ .056, P ϭ .02). Short PEP, low CAB, and high CAR 0.63 [0.38–1.05], P ϭ .08; third quartile: OR ϭ 0.56 were also predictors of the 2-year change in systolic BP [0.33–0.94], P ϭ .03, and fourth quartile: OR ϭ 0.57 (␤ ϭϪ.055, P ϭ .009, ␤ ϭϪ.044, P ϭ .05, and ␤ ϭ .047, [0.33–0.98], P ϭ .04).

Table 3. Adjusted Associations Between Baseline Autonomic Indices and 2-y Changes in Individual Components of the Metabolic Syndrome (n ϭ 1933)

⌬Waist ⌬HDL Circumference, ⌬Triglycerides, cholesterol, ⌬SBP, per ⌬DBP, per ⌬Glucose, per per1cm per 1 mmol/L per 1 mmol/L 1mmHg 1mmHg 1 mmol/L

ANS BL ␤ P ␤ P ␤ P ␤ P ␤ P ␤ P RSA, ms .010 .71 Ϫ.008 .78 .063 .02 Ϫ.001 .98 Ϫ.014 .60 Ϫ.025 .38 RSA, msa .010 .73 Ϫ.008 .77 .063 .02 Ϫ.002 .94 Ϫ.019 .47 Ϫ.023 .40 HR, bpm .003 .88 .020 .39 Ϫ.052 .02 .053 .01 .082 Ͻ.001 .025 .28 HR, bpma .004 .86 .020 .38 Ϫ.056 .008 .056 .009 .089 Ͻ.001 .020 .39 PEP, ms .002 .92 Ϫ.006 .81 .024 .29 Ϫ.047 .03 Ϫ.046 .03 .009 .70 PEP, msa Ϫ.005 .84 Ϫ.010 .67 .029 .20 Ϫ.055 .009 Ϫ.052 .02 .006 .79 CAB .005 .83 Ϫ.011 .65 .052 .03 Ϫ.037 .10 Ϫ.046 .05 Ϫ.009 .73 CABa .000 .99 Ϫ.014 .57 .056 .02 Ϫ.044 .05 Ϫ.053 .02 Ϫ.009 .71 CAR .002 .94 .002 .92 .016 .52 .041 .07 .030 .19 Ϫ.025 .31 CARa .009 .73 .002 .95 .011 .65 .047 .04 .033 .15 Ϫ.021 .40

Abbreviations: ␤, standardized ␤-coefficient; DBP, diastolic BP; SBP, systolic blood pressure. Based on linear regression analyses adjusted for baseline values of the metabolic component, age, sex, and education (RSA was additionally adjusted for respiration rate). a Additionally adjusted for cardiovascular disease, smoking, and (change in) use of heart medication (other than ␤-blocking agents). doi: 10.1210/jc.2012-3104 jcem.endojournals.org 2489 Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021

Figure 1. Odds ratios (ORs) for incident onset of the metabolic syndrome at follow-up for all autonomic indices (n ϭ 1581). Circles represent ORs; lines represent the 95% confidence intervals. ORs and P values are for comparison with the first quartile. Based on multinomial logistic regression adjusted for age, sex, education, cardiovascular diseases, smoking, and (change in) use of heart medication (other than ␤-blocking agents).

Discussion nents irrespective of vagal activity. Lower RSA with higher HR was found to predict a decrease in HDL cholesterol. In this large longitudinal study, we found that short base- These findings suggest that diminished parasympathetic line PEP, low CAB, high HR, and high CAR were associ- activity was predictive for future HDL cholesterol dys- ated with an increase in number of metabolic syndrome regulation. To our knowledge, we are the first to report components over a 2-year time period. These findings sug- gest that increased sympathetic nervous system activity this. Increases in systolic BP over a 2-year period were predicts an increase in number of metabolic components. mainly predicted by high baseline sympathetic activity, Results on CAB and CAR (52) showed us that this holds reflected by high HR and short PEP. High diastolic BP was true in situations in which parasympathetic nervous sys- also predicted by high sympathetic control, reflected by tem activity is reciprocally decreased but also when it is high HR and short PEP. For prediction of 2-year changes coactivated. In other words, increased sympathetic activ- in other measures of the metabolic syndrome (waist cir- ity predicts an increase in number of metabolic compo- cumference, triglycerides, and glucose levels), autonomic 2490 Licht et al Dysregulated ANS Predicts Metabolic Syndrome J Clin Endocrinol Metab, June 2013, 98(6):2484–2493 nervous system measures appeared to be less firm predic- which are independent dysregulators of the lipid metab- tors. In addition, tests for linearity in relations showed that olism and BP (4, 6, 7, 13, 68–73). In addition, HDL cho- for HR, PEP, and CAB a “dose-response effect” was seen lesterol has an antiatherogenic function and low HDL in the prediction of new onset of the metabolic syndrome. cholesterol might deteriorate (diastolic) LV function. In In other words, for higher baseline values of HR and lower this way low HDL itself might also cause or worsen high baseline values of PEP and CAB, higher odds for new onset BP and hypertension (74–77). Clearly, dysregulation of of the metabolic syndrome at follow-up were seen. the ANS can cause decreases in HDL cholesterol levels and These findings extend the previous findings by adding increases in BP in different ways. a prospective design, which gives a good indication of An important contribution of the present study is the which autonomic indices are predictive for later metabolic finding that previous cross-sectional findings are now abnormalities. Our longitudinal findings are consistent (partly) confirmed in longitudinal analyses, making a Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021 with our prior cross-sectional findings that indicated a causal pathway more plausible. Our study has other negative association between the number of metabolic strengths as well: a large sample size and multiple mea- syndrome components and RSA, PEP, and CAB (and a sures of sympathetic as well as parasympathetic activity. positive association with HR) (9). Results are also largely In addition to the presence of metabolic syndrome itself, congruent with other cross-sectional studies such as Ko- all separate components that constitute the metabolic syn- skinen et al, Liao et al, and Min et al, who found that drome were analyzed. Finally, our sample size enabled us diminished parasympathetic and increased sympathetic to consider important confounders. However, some lim- activity were associated with higher numbers of metabolic itations must be acknowledged as well. First, because the abnormalities (17–19). BP findings were rather consistent follow-up period was rather short (2 y), time to develop a with our previous cross-sectional results that indicated an new onset of the metabolic syndrome and observe clini- association between high systolic BP and high sympathetic cally important changes in continuous measures might be activity. These findings are not unexpected because the limited. This limitation might explain why we found little role of the sympathetic nervous system in the control of BP predictive value for changes in waist circumference and has already been known for decades (57, 58). However, glucose levels, which might need more time to develop. the lack of a relationship between parasympathetic activ- Future follow-up measurements will allow us to investi- ity and BP is in contrast with our cross-sectional results. gate these relationships over a more robust period. In ad- Our results are also in disagreement with some other stud- dition, because several studies have indicated that auto- ies that suggested vagal involvement in the development of nomic dysregulation becomes apparent specifically during hypertension (59–61). A likely explanation is the fol- stress, it would be valuable to investigate the predictive low-up duration of 2 years only (in contrast to4yinthe value of autonomic stress reactivity (78–80). Finally, we Framingham study), which may have been too short to need to consider the fact that differences in adrenergic and allow lasting effects of decreased vagal tone on BP. Al- muscarinergic receptor sensitivity as well as differences in though the predictive value for HDL cholesterol is not cardiac afterload and preload can influence PEP and RSA, entirely in line with our previous results—we only found independently of the actual cardiac ANS activity. These a cross-sectional relationship between HDL cholesterol parameters therefore do not unequivocally reflect sympa- and HR—it does match with other cross-sectional results thetic and parasympathetic activity. Nonetheless, various (17, 19, 62). Our BP and HDL cholesterol findings per- studies have shown that PEP and RSA do reflect the ex- fectly match those of Palatini et al. (6). In a study on hy- pected individual differences in cardiac autonomic activity pertension and lipid abnormalities, they reported that sub- across a wide range of paradigms including pharmacolog- jects with sympathetic predominance (high sympathetic ical blockade (81), chronic stress (82), or chronic exercise activity relative to low parasympathetic activity) showed exposure (83), making it useful parameters to answer our increased BP (systolic as well as diastolic) and total cho- research questions. lesterol levels at 6-year follow-up compared to the subjects Taken together, these results suggest that increased without autonomic dysregulations. sympathetic activity is a predictor of an increase in the ANS dysregulation is reported to have a direct effect on number of metabolic syndrome components and high BP BP regulation and lipid metabolism via circulating (nor) and a decrease in HDL cholesterol over time, whereas epinephrine (63–67). However, also more indirect ways decreased parasympathetic activity only predicts a de- are reported, for instance, via insulin resistance and the crease in HDL cholesterol over time. Especially these met- effects of adipokines. Increased sympathetic and de- abolic factors have been associated with hypertension, ar- creased parasympathetic activity are (bidirectionally) terial stiffness, diabetes, and stroke (77, 84–88). Because linked to increased levels of leptin and insulin (resistance), several prospective studies indicated that decreased para- doi: 10.1210/jc.2012-3104 jcem.endojournals.org 2491 sympathetic activity and increased sympathetic activity with metabolic abnormalities. J Clin Endocrinol Metab. 2010;95(5): are important risk factors for cardiovascular diseases (33, 2458–2466. 10. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk 55, 89–95), our results suggest that part of this relation- of incident cardiovascular events and death: a systematic review and ship may be explained by ANS effects on the development meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007; of the metabolic syndrome. 49(4):403–414. 11. Guize L, Pannier B, Thomas F, Bean K, Jégo B, Benetos A. Recent advances in metabolic syndrome and cardiovascular disease. Arch Cardiovasc Dis. 2008;101(9):577–583. Acknowledgments 12. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care. 2008;31(9):1898– 1904. Address all correspondence and requests for reprints to: Carmilla 13. Tentolouris N, Argyrakopoulou G, Katsilambros N. Perturbed au- M.M. Licht, PhD, Department of Psychiatry/Extramural Med- ϩ tonomic nervous system function in metabolic syndrome. Neuro- Downloaded from https://academic.oup.com/jcem/article/98/6/2484/2537184 by guest on 30 September 2021 icine Research Institute, VU University Medical Center, AJ molecular Med. 2008;10(3):169–178. Ernststraat 1087, 1081 HL Amsterdam, The Netherlands. E- 14. Brunner EJ, Hemingway H, Walker BR, et al. Adrenocortical, au- mail: [email protected]. tonomic, and inflammatory causes of the metabolic syndrome: The infrastructure for the NESDA study (www.nesda.nl)is nested case-control study. Circulation. 2002;106(21):2659–2665. funded through the Geestkracht program of the Netherlands 15. Huggett RJ, Burns J, Mackintosh AF, Mary DA. Sympathetic neural Organisation for Health Research and Development (Zon-Mw, activation in nondiabetic metabolic syndrome and its further aug- mentation by hypertension. Hypertension. 2004;44(6):847–852. Grant Number 10-000-1002) and is supported by participating 16. Grassi G, Quarti-Trevano F, Seravalle G, Dell’Oro R, Dubini A, universities and mental health care organizations (VU University Mancia G. Differential sympathetic activation in muscle and skin Medical Center, Geestelijke Gezondheidszorg inGeest, Arkin, neural districts in the metabolic syndrome. Metabolism. 2009; Leiden University Medical Center, GGZ Rivierduinen, Univer- 58(10):1446–1451. sity Medical Center Groningen, Lentis, GGZ Friesland, GGZ 17. Koskinen T, Kähönen M, Jula A, et al. Metabolic syndrome and Drenthe, Scientific Institute for Quality of Healthcare [IQ health- short-term heart rate variability in young adults. The cardiovascular care], Netherlands Institute for Health Services Research risk in young Finns study. Diabet Med. 2009;26(4):354–361. [NIVEL], and Netherlands Institute of Mental Health and Ad- 18. Liao D, Sloan RP, Cascio WE, et al. Multiple metabolic syndrome diction [Trimbos]). 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