Autonomic modulation in gestational diabetes mellitus Raelene E. Maser, M. James Lenhard, Paul Kolm PII: DOI: Reference:
S1056-8727(14)00133-0 doi: 10.1016/j.jdiacomp.2014.05.005 JDC 6269
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
28 February 2014 28 April 2014 17 May 2014
Please cite this article as: Maser, R.E., Lenhard, M.J. & Kolm, P., Autonomic modulation in gestational diabetes mellitus, Journal of Diabetes and Its Complications (2014), doi: 10.1016/j.jdiacomp.2014.05.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI P
T
Autonomic modulation in gestational diabetes mellitus
Raelene E. Maser, Ph.D.a,b,*
SC
M. James Lenhard, M.D.b,c
Department of Medical Laboratory Sciences, University of Delaware, Newark, DE, USA
b
MA
a
NU
Paul Kolm, Ph.D.d
Diabetes and Metabolic Research Center, Christiana Care Health System, Newark, DE, USA
c
Christiana Care Outcomes Research, Christiana Care Health System, Newark, DE, USA
CE
PT
d
ED
Diabetes and Metabolic Diseases Center, Christiana Care Health System, Wilmington, DE, USA
*Address correspondence to: Raelene E. Maser, Ph.D.
AC
Department of Medical Laboratory Sciences 305F Willard Hall Education Building University of Delaware
Newark, DE 19716, USA Phone: 302-831-8400 Fax:
302-831-4180
E-Mail: [email protected]
Funding: Funding for this study was provided by the Clinical Research Committee, Department of Medicine, Christiana Care Health System, Newark, DE, USA.
1
ACCEPTED MANUSCRIPT Abstract Aims: To evaluate the influence of gestational diabetes mellitus (GDM) and positional aortocaval compression on cardiovascular autonomic nervous system (ANS) function in late pregnancy.
T
Methods: Pregnant women with (n=31) and without (n=12) GDM were evaluated at 30-35 weeks
RI P
gestation and 2-3 months postpartum. Measures of ANS function included power spectral analysis (performed sitting) and RR-variation during deep breathing (performed supine). Time-
SC
related changes (late pregnancy vs. 2-3 months postpartum) for measurements of cardiovascular ANS function were analyzed using multivariate analysis of variance for repeated measures.
NU
Results: Baseline characteristics were similar for both groups. Comparing ANS measures for GDM+ vs. GDM- women during pregnancy and postpartum revealed no significant differences.
MA
Time related changes indicated that during late pregnancy total spectral power, low frequency (LF) power, high frequency (HF) power, and RR-variation during deep breathing were significantly reduced (p140 mg/dL on a 50-gram 1-hour glucose challenge test. The challenge test was followed by a 100-gram 3-hour oral glucose tolerance test (OGTT), unless it was determined that
CE
the individual required insulin treatment immediately. Women with two or more glucose values greater than the reference interval at each hour of the 3-hour OGTT were considered to have
AC
GDM. Exclusion criteria included pregnant women with: a) type 1 or known type 2 diabetes mellitus, b) pre-gestational hypertension, c) pre-eclampsia during current pregnancy, d) preterm labor, cervical shortening, premature rupture of membranes or any other obstetric complications that may predispose to preterm labor, e) current multiple fetuses, and f) a history of coronary artery disease or acute ischemia. All women with GDM were counseled by a certified diabetes educator, treated with a standard low carbohydrate GDM diet, advised to exercise, and asked to report blood glucose levels at a minimum of once a week. Seventy-one percent of the GDM women in this study cohort required insulin therapy. Oral hypoglycemic agents were not used, except for one individual with polycystic ovary syndrome who was treated with metformin. Similar inclusion/exclusion criteria were used for women without GDM, with the exception that glucose levels for the 50 gram 1-hour glucose challenge test or the 100-gram 3hour OGTT were normal.
4
ACCEPTED MANUSCRIPT Cardiovascular autonomic function tests Autonomic function (i.e., HRV) was performed after an overnight fast during mid-third trimester pregnancy and 2-3 months postpartum. The women were asked to refrain from taking any prescribed or nonprescription medications, to avoid
T
consuming tobacco products, caffeine-containing or alcoholic beverages, and to refrain from
RI P
engaging in any vigorous exercise 8-10 hours before autonomic function testing. Several assessment modalities are available for measuring HRV. Two widely used
SC
cardiovascular autonomic reflex tests include: RR-variation during deep breathing and the Valsalva maneuver (Spallone et al., 2011). In this study, RR-variation during deep breathing and
NU
the Valsalva maneuver were assessed using the ANS2000 ECG Monitor and Respiration Pacer (DE Hokanson, Inc., Bellevue, WA, USA). For performance of these tests, the participants were
MA
comfortably lying supine in a large reclining chair. The methods for these tests have been previously described (Maser, Lenhard, Peters, Irgau, & Wynn, 2013). Briefly, RR-variation during deep breathing, performed for six minutes, was measured by vector analysis (i.e., mean
ED
circular resultant (MCR)) and by the expiration/inspiration (E/I) ratio of the first six breath cycles. The MCR is more resistant to ectopic beats and not affected by intrinsic heart rate
PT
whereas the E/I ratio is affected by ectopic beats (Schumer, Joyner, & Pfeifer, 1998). Heart rate response to the Valsalva maneuver was determined by having the women expire into the
CE
mouthpiece of a manometer, maintaining a pressure of 40 mmHg for 15 seconds. Heart rate changes during deep breathing and the Valsalva maneuver are indices that mainly assess
AC
parasympathetic function (Spallone et al., 2011). Ectopic beats affected the E/I results for three participants and thus their results were considered incomplete. The results of the Valsalva maneuver were incomplete for eight participants, mainly due to ectopic beats. Heart rate variability was also evaluated by power spectral analysis with and without respiratory analysis (ANX 3.0, ANSAR Medical Technologies, Inc., Philadelphia, PA, USA). For performance of HRV evaluated by power spectral analysis, the women were comfortably seated in a chair. Details of these analyses have been previously published (Maser et al., 2013). Briefly, for power spectral analysis without respiratory analysis, high frequency (HF) power was computed as the area of the frequency spectrum in the range of 0.15-0.40 Hz whereas low frequency (LF) power was computed in the frequency range of 0.04-0.15 Hz. HF power is a measure of parasympathetic function whereas LF power is potentially affected by both sympathetic and parasympathetic activity (Task Force of the European Society of Cardiology
5
ACCEPTED MANUSCRIPT and the North American Society of Pacing and Electrophysiology, 1996). The HF and LF components were also normalized with respect to the total spectral power and reported in normalized units (nu). The LF/HF ratio in this study was considered a measure of autonomic
T
balance as it may mirror sympathovagal balance or reflect sympathetic modulations (Task Force
RI P
of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Spectral analysis of HRV was also combined with spectral analysis of
SC
respiratory activity. Parasympathetic activity that produced respiratory sinus arrhythmia (i.e., respiration frequency area [RFA]) was identified by respiratory analysis. The RFA is found by
NU
locating the peak mode of the respiratory spectrum (i.e., fundamental respiratory frequency (FRF)). The FRF is transferred to the heart rate spectrum and the RFA is computed as the area
MA
under the heart rate spectral curve over a frequency range centered on the FRF. The remaining area under the curve in the LF range is then computed as the low frequency area (LFA). The LFA/RFA ratio was also evaluated. The results for one participant with regard to the power
ED
spectral analyses were labeled as missing owning to excessive ectopic beats during pregnancy. Clinical measurements Weight and height were measured using a stadiometer. Body mass
PT
index (BMI) was calculated as body weight divided by height squared (kg/m2). Blood pressure was monitored electronically in the supine posture using an oscillometric automatic recorder.
CE
The average of four BP readings was used for analysis. Fructosamine levels, measured only for women with GDM, were determined by a colorimetric rate reaction on a Roche Cobas c501
AC
chemistry analyzer (Roche Diagnostics Corporation, Indianapolis, IN, USA). Statisical analysis Distributions of the variables was examined by the Kolmogorov-Smirnov Goodness of Fit test. A natural logarithmic transformation was applied to highly skewed measurements for analysis. Comparisons of clinical characteristics between the GDM+ and GDM- women were made with the Student’s t-test for continuous data. Time-related changes (during late pregnancy vs. 2-3 months postpartum) for measurements of cardiovascular autonomic function were analyzed using multivariate analysis of variance (MANOVA) for repeated measures. The interaction of the group (GDM+ vs. GDM-) by visit (during late pregnancy vs. postpartum) was also tested to assess whether the effect of late pregnancy was the same for both groups.
6
ACCEPTED MANUSCRIPT Results Table 1 shows the clinical characteristics of the study cohort. During late pregnancy, women in both groups were similar with regard to age, blood pressure, BMI, and gestational age at the
T
time of autonomic function testing. Glycemic control for the women with GDM, evaluated by
RI P
fructosamine levels at baseline, was 180±15 µmol/L (normal reference range 200-285 µmol/L). Two to three months after delivery the mean fructosamine concentrations were significantly
SC
higher (180±15 vs. 214± 28 µmol/L, p
S1056-8727(14)00133-0 doi: 10.1016/j.jdiacomp.2014.05.005 JDC 6269
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
28 February 2014 28 April 2014 17 May 2014
Please cite this article as: Maser, R.E., Lenhard, M.J. & Kolm, P., Autonomic modulation in gestational diabetes mellitus, Journal of Diabetes and Its Complications (2014), doi: 10.1016/j.jdiacomp.2014.05.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI P
T
Autonomic modulation in gestational diabetes mellitus
Raelene E. Maser, Ph.D.a,b,*
SC
M. James Lenhard, M.D.b,c
Department of Medical Laboratory Sciences, University of Delaware, Newark, DE, USA
b
MA
a
NU
Paul Kolm, Ph.D.d
Diabetes and Metabolic Research Center, Christiana Care Health System, Newark, DE, USA
c
Christiana Care Outcomes Research, Christiana Care Health System, Newark, DE, USA
CE
PT
d
ED
Diabetes and Metabolic Diseases Center, Christiana Care Health System, Wilmington, DE, USA
*Address correspondence to: Raelene E. Maser, Ph.D.
AC
Department of Medical Laboratory Sciences 305F Willard Hall Education Building University of Delaware
Newark, DE 19716, USA Phone: 302-831-8400 Fax:
302-831-4180
E-Mail: [email protected]
Funding: Funding for this study was provided by the Clinical Research Committee, Department of Medicine, Christiana Care Health System, Newark, DE, USA.
1
ACCEPTED MANUSCRIPT Abstract Aims: To evaluate the influence of gestational diabetes mellitus (GDM) and positional aortocaval compression on cardiovascular autonomic nervous system (ANS) function in late pregnancy.
T
Methods: Pregnant women with (n=31) and without (n=12) GDM were evaluated at 30-35 weeks
RI P
gestation and 2-3 months postpartum. Measures of ANS function included power spectral analysis (performed sitting) and RR-variation during deep breathing (performed supine). Time-
SC
related changes (late pregnancy vs. 2-3 months postpartum) for measurements of cardiovascular ANS function were analyzed using multivariate analysis of variance for repeated measures.
NU
Results: Baseline characteristics were similar for both groups. Comparing ANS measures for GDM+ vs. GDM- women during pregnancy and postpartum revealed no significant differences.
MA
Time related changes indicated that during late pregnancy total spectral power, low frequency (LF) power, high frequency (HF) power, and RR-variation during deep breathing were significantly reduced (p140 mg/dL on a 50-gram 1-hour glucose challenge test. The challenge test was followed by a 100-gram 3-hour oral glucose tolerance test (OGTT), unless it was determined that
CE
the individual required insulin treatment immediately. Women with two or more glucose values greater than the reference interval at each hour of the 3-hour OGTT were considered to have
AC
GDM. Exclusion criteria included pregnant women with: a) type 1 or known type 2 diabetes mellitus, b) pre-gestational hypertension, c) pre-eclampsia during current pregnancy, d) preterm labor, cervical shortening, premature rupture of membranes or any other obstetric complications that may predispose to preterm labor, e) current multiple fetuses, and f) a history of coronary artery disease or acute ischemia. All women with GDM were counseled by a certified diabetes educator, treated with a standard low carbohydrate GDM diet, advised to exercise, and asked to report blood glucose levels at a minimum of once a week. Seventy-one percent of the GDM women in this study cohort required insulin therapy. Oral hypoglycemic agents were not used, except for one individual with polycystic ovary syndrome who was treated with metformin. Similar inclusion/exclusion criteria were used for women without GDM, with the exception that glucose levels for the 50 gram 1-hour glucose challenge test or the 100-gram 3hour OGTT were normal.
4
ACCEPTED MANUSCRIPT Cardiovascular autonomic function tests Autonomic function (i.e., HRV) was performed after an overnight fast during mid-third trimester pregnancy and 2-3 months postpartum. The women were asked to refrain from taking any prescribed or nonprescription medications, to avoid
T
consuming tobacco products, caffeine-containing or alcoholic beverages, and to refrain from
RI P
engaging in any vigorous exercise 8-10 hours before autonomic function testing. Several assessment modalities are available for measuring HRV. Two widely used
SC
cardiovascular autonomic reflex tests include: RR-variation during deep breathing and the Valsalva maneuver (Spallone et al., 2011). In this study, RR-variation during deep breathing and
NU
the Valsalva maneuver were assessed using the ANS2000 ECG Monitor and Respiration Pacer (DE Hokanson, Inc., Bellevue, WA, USA). For performance of these tests, the participants were
MA
comfortably lying supine in a large reclining chair. The methods for these tests have been previously described (Maser, Lenhard, Peters, Irgau, & Wynn, 2013). Briefly, RR-variation during deep breathing, performed for six minutes, was measured by vector analysis (i.e., mean
ED
circular resultant (MCR)) and by the expiration/inspiration (E/I) ratio of the first six breath cycles. The MCR is more resistant to ectopic beats and not affected by intrinsic heart rate
PT
whereas the E/I ratio is affected by ectopic beats (Schumer, Joyner, & Pfeifer, 1998). Heart rate response to the Valsalva maneuver was determined by having the women expire into the
CE
mouthpiece of a manometer, maintaining a pressure of 40 mmHg for 15 seconds. Heart rate changes during deep breathing and the Valsalva maneuver are indices that mainly assess
AC
parasympathetic function (Spallone et al., 2011). Ectopic beats affected the E/I results for three participants and thus their results were considered incomplete. The results of the Valsalva maneuver were incomplete for eight participants, mainly due to ectopic beats. Heart rate variability was also evaluated by power spectral analysis with and without respiratory analysis (ANX 3.0, ANSAR Medical Technologies, Inc., Philadelphia, PA, USA). For performance of HRV evaluated by power spectral analysis, the women were comfortably seated in a chair. Details of these analyses have been previously published (Maser et al., 2013). Briefly, for power spectral analysis without respiratory analysis, high frequency (HF) power was computed as the area of the frequency spectrum in the range of 0.15-0.40 Hz whereas low frequency (LF) power was computed in the frequency range of 0.04-0.15 Hz. HF power is a measure of parasympathetic function whereas LF power is potentially affected by both sympathetic and parasympathetic activity (Task Force of the European Society of Cardiology
5
ACCEPTED MANUSCRIPT and the North American Society of Pacing and Electrophysiology, 1996). The HF and LF components were also normalized with respect to the total spectral power and reported in normalized units (nu). The LF/HF ratio in this study was considered a measure of autonomic
T
balance as it may mirror sympathovagal balance or reflect sympathetic modulations (Task Force
RI P
of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Spectral analysis of HRV was also combined with spectral analysis of
SC
respiratory activity. Parasympathetic activity that produced respiratory sinus arrhythmia (i.e., respiration frequency area [RFA]) was identified by respiratory analysis. The RFA is found by
NU
locating the peak mode of the respiratory spectrum (i.e., fundamental respiratory frequency (FRF)). The FRF is transferred to the heart rate spectrum and the RFA is computed as the area
MA
under the heart rate spectral curve over a frequency range centered on the FRF. The remaining area under the curve in the LF range is then computed as the low frequency area (LFA). The LFA/RFA ratio was also evaluated. The results for one participant with regard to the power
ED
spectral analyses were labeled as missing owning to excessive ectopic beats during pregnancy. Clinical measurements Weight and height were measured using a stadiometer. Body mass
PT
index (BMI) was calculated as body weight divided by height squared (kg/m2). Blood pressure was monitored electronically in the supine posture using an oscillometric automatic recorder.
CE
The average of four BP readings was used for analysis. Fructosamine levels, measured only for women with GDM, were determined by a colorimetric rate reaction on a Roche Cobas c501
AC
chemistry analyzer (Roche Diagnostics Corporation, Indianapolis, IN, USA). Statisical analysis Distributions of the variables was examined by the Kolmogorov-Smirnov Goodness of Fit test. A natural logarithmic transformation was applied to highly skewed measurements for analysis. Comparisons of clinical characteristics between the GDM+ and GDM- women were made with the Student’s t-test for continuous data. Time-related changes (during late pregnancy vs. 2-3 months postpartum) for measurements of cardiovascular autonomic function were analyzed using multivariate analysis of variance (MANOVA) for repeated measures. The interaction of the group (GDM+ vs. GDM-) by visit (during late pregnancy vs. postpartum) was also tested to assess whether the effect of late pregnancy was the same for both groups.
6
ACCEPTED MANUSCRIPT Results Table 1 shows the clinical characteristics of the study cohort. During late pregnancy, women in both groups were similar with regard to age, blood pressure, BMI, and gestational age at the
T
time of autonomic function testing. Glycemic control for the women with GDM, evaluated by
RI P
fructosamine levels at baseline, was 180±15 µmol/L (normal reference range 200-285 µmol/L). Two to three months after delivery the mean fructosamine concentrations were significantly
SC
higher (180±15 vs. 214± 28 µmol/L, p
