Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms

Background: A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging. Methods: Using circulating placental growth factor (PIGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PIGF measurements (gestational age >= 20 weeks) analyzed on one of four platforms: R & Systems, Alere (R) Triage, Roche (R) Elecsys or Abbott (R) Architect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied. Results: Best reference curves (BRC), based on merged, transformed PIGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PIGF-BRCS was compared to that of platform-specific curves. Conclusions: We demonstrate the feasibility of merging PIGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes. (C) 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.Peer reviewe

Effect of Prenatal Yoga on Heart Rate Variability and Cardio-Respiratory Synchronization: A Prospective Cohort Study

The objective was to assess the effects of prenatal yoga on heart rate variability (HRV) and cardio-respiratory synchronization, used as proxies of autonomic nervous system activity. Sixty-nine healthy pregnant women were included; 33 in a yoga group attending at least one 90-min yoga class weekly throughout pregnancy, and 36 controls not involved in formal pregnancy exercise programs. Measurements of the time domain (SDNN, standard deviation of regular R-R intervals, and RMSSD, square root of mean squared differences of successive R-R intervals) and frequency domain (ln(LF/HF), natural logarithm of low-frequency to high-frequency power) HRV indices, as well as cardio-respiratory synchronization indexes were performed once per trimester before and after yoga or 30-min moderate-intensity walk. A statistical comparison was performed using a three-way analysis of the variance (p < 0.05 significant). Both the time domain and frequency domain HRV indices showed significant shifts towards parasympathetic dominance following yoga when compared to the controls throughout pregnancy (p = 0.002 for SDNN, p < 0.001 for RMSSD, and p = 0.006 for ln(LF/HF), respectively). There was a statistically non-significant trend towards higher synchronization between respiratory frequency and heart rate following yoga vs. controls (p = 0.057). Regular prenatal yoga was associated with enhanced parasympathetic activation persisting throughout pregnancy

Effect of Prenatal Yoga versus Moderate-Intensity Walking on Cardiorespiratory Adaptation to Acute Psychological Stress: Insights from Non-Invasive Beat-to-Beat Monitoring

We recently reported enhanced parasympathetic activation at rest throughout pregnancy associated with regular yoga practice. The present study presents a secondary analysis of data collected within a prospective cohort study of 33 pregnant women practicing yoga once weekly throughout pregnancy and 36 controls not involved in formal pregnancy exercise programs. The objective was to assess the impact of prenatal yoga on the autonomic nervous system stress response. Healthy pregnant women with singleton pregnancies were recruited in the first trimester. There was no significant difference in the maternal body mass index (BMI) between the yoga group and the controls (24.06 ± 3.55 vs. 23.74 ± 3.43 kg/m2, p = 0.693). Women practicing yoga were older (28.6 ± 3.9 vs. 31.3 ± 3.5 years, p = 0.005) and more often nulliparous (26 (79%) vs. 18 (50%), p = 0.001). We studied heart rate variability (HRV) parameters in the time domain (SDNN, standard deviation of regular R-R intervals, and RMSSD, square root of mean squared differences of successive R-R intervals) and frequency domain (ln(LF/HF), natural logarithm of low-frequency to high-frequency power), as well as synchronization indices of heart rate, blood pressure and respiration during and immediately following acute psychological stress of a standardized mental challenge test. Measurements were performed once per trimester before and after yoga or a 30 min moderate-intensity walk. Statistical comparison was performed using three-way analyses of variance (p F = 7.22, p = 0.009 for SDNN and F = 9.57, p = 0.003 for RMSSD, respectively). We observed no significant differences in the yoga group vs. the controls in terms of ln(LF/HF) and synchronization indices. Regular prenatal yoga practice was associated with a significantly reduced sympathetic response to mental challenge and quicker recovery after acute psychological stress. These effects persisted throughout pregnancy with regular practice

Systemic vascular resistance and endogenous inhibitors of nitric oxide synthesis in early- compared to late-onset preeclampsia: preliminary findings

Objective: To examine systemic vascular resistance index (SVRI), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) levels in preeclampsia at different gestations. Methods: Twenty-four preeclamptic patients (14 at ≥ 34 weeks’) and 72 matched healthy controls were included. SVRI was calculated from impedance cardiography measurements. ADMA and SDMA levels were determined using enzyme-linked immunosorbent assay. Results: SVRI and SDMA were higher in preeclampsia overall, in early onset and late onset compared to controls. SVRI was correlated with ADMA and SDMA, respectively. Conclusions: Early-onset and late-onset preeclampsia are both characterized by increased systemic vascular resistance and elevated levels of nitric oxide synthesis inhibitors

History of Preeclampsia Adds to the Deleterious Effect of Chronic Stress on the Cardiac Ability to Flexibly Adapt to Challenge

Preeclampsia, a pregnancy-specific disorder, presents a major health problem during gestation, but is also associated with increased risk for cardiovascular complications in later life. We aimed to investigate whether chronic stress experience and preeclampsia may have additive adverse effects on the cardiac ability to flexibly adapt to challenge, that is, to mount an appropriately vigorous heart rate response to an acute psychological challenge, or whether they may perhaps have synergistic effects (e.g., mutual augmentation of effects). Blunted cardiac responding to challenge has been linked to poor health outcomes in the longer term. Women previously affected by preeclampsia and women after uncomplicated pregnancies were tested 15–17 weeks post-partum in a standardized stress-reactivity protocol, while cardiovascular variables were simultaneously recorded. Changes in heart rate and blood pressure in response to the stressor were analyzed with regard to the effects of history of preeclampsia and chronic stress experience. Findings indicated blunted cardiac responses in women with higher chronic stress experience (p = 0.020) and, independently from that, in women with a history of preeclampsia (p = 0.018), pointing to an additive nature of the effects of preeclampsia and chronic stress on impaired cardiovascular functioning. Consequently, if both are present, a history of preeclampsia may add to the already deleterious effects of the experience of chronic stress. The additive nature of the effects suggests that stress-reducing interventions, albeit they will not eliminate the heightened cardiovascular risk in patients with a history of preeclampsia, may improve their overall prognosis by avoiding further accumulation of risk

Phase synchronization of hemodynamic variables at rest and after deep breathing measured during the course of pregnancy.

BACKGROUND: The autonomic nervous system plays a central role in the functioning of systems critical for the homeostasis maintenance. However, its role in the cardiovascular adaptation to pregnancy-related demands is poorly understood. We explored the maternal cardiovascular systems throughout pregnancy to quantify pregnancy-related autonomic nervous system adaptations. METHODOLOGY: Continuous monitoring of heart rate (R-R interval; derived from the 3-lead electrocardiography), blood pressure, and thoracic impedance was carried out in thirty-six women at six time-points throughout pregnancy. In order to quantify in addition to the longitudinal effects on baseline levels throughout gestation the immediate adaptive heart rate and blood pressure changes at each time point, a simple reflex test, deep breathing, was applied. Consequently, heart rate variability and blood pressure variability in the low (LF) and high (HF) frequency range, respiration and baroreceptor sensitivity were analyzed in resting conditions and after deep breathing. The adjustment of the rhythms of the R-R interval, blood pressure and respiration partitioned for the sympathetic and the parasympathetic branch of the autonomic nervous system were quantified by the phase synchronization index γ, which has been adopted from the analysis of weakly coupled chaotic oscillators. RESULTS: Heart rate and LF/HF ratio increased throughout pregnancy and these effects were accompanied by a continuous loss of baroreceptor sensitivity. The increases in heart rate and LF/HF ratio levels were associated with an increasing decline in the ability to flexibly respond to additional demands (i.e., diminished adaptive responses to deep breathing). The phase synchronization index γ showed that the observed effects could be explained by a decreased coupling of respiration and the cardiovascular system (HF components of heart rate and blood pressure). CONCLUSIONS/SIGNIFICANCE: The findings suggest that during the course of pregnancy the individual systems become increasingly independent to meet the increasing demands placed on the maternal cardiovascular and respiratory system

Disturbed Cardiorespiratory Adaptation in Preeclampsia: Return to Normal Stress Regulation Shortly after Delivery?

Women with pregnancies complicated by preeclampsia appear to be at increased risk of metabolic and vascular diseases in later life. Previous research has also indicated disturbed cardiorespiratory adaptation during pregnancy. The aim of this study was to follow up on the physiological stress response in preeclampsia several weeks postpartum. A standardized laboratory test was used to illustrate potential deviations in the physiological stress responding to mildly stressful events of the kind and intensity in which they regularly occur in further everyday life after pregnancy. Fifteen to seventeen weeks postpartum, 35 women previously affected by preeclampsia (19 mild, 16 severe preeclampsia), 38 women after uncomplicated pregnancies, and 51 age-matched healthy controls were exposed to a self-relevant stressor in a standardized stress-reactivity protocol. Reactivity of blood pressure, heart rate, stroke index, and systemic vascular resistance index as well as baroreceptor sensitivity were analyzed. In addition, the mutual adjustment of blood pressure, heart rate, and respiration, partitioned for influences of the sympathetic and the parasympathetic branches of the autonomic nervous system, were quantified by determining their phase synchronization. Findings indicated moderately elevated blood pressure levels in the nonpathological range, reduced stroke volume, and elevated systemic vascular resistance in women previously affected by preeclampsia. Despite these moderate abnormalities, at the time of testing, women with previous preeclampsia did not differ from the other groups in their physiological response patterns to acute stress. Furthermore, no differences between early, preterm, and term preeclampsia or mild and severe preeclampsia were observed at the time of testing. The findings suggest that the overall cardiovascular responses to moderate stressors return to normal in women who experience a pregnancy with preeclampsia a few weeks after delivery, while the operating point of the arterial baroreflex is readjusted to a higher pressure. Yet, their regulation mechanisms may remain different

Maternal cardiovascular and endothelial function from first trimester to postpartum

<div><p>Objective</p><p>To explore noninvasively the complex interactions of the maternal hemodynamic system throughout pregnancy and the resulting after-effect six weeks postpartum.</p><p>Methods</p><p>Eighteen women were tested beginning at the 12^th week of gestation at six time-points throughout pregnancy and six weeks postpartum. Heart rate, heart rate variability, blood pressure, pulse transit time (PTT), respiration, and baroreceptor sensitivity were analyzed in resting conditions. Additionally, hemoglobin, asymmetric and symmetric dimethylarginine and Endothelin (ET-1) were obtained.</p><p>Results</p><p>Heart rate and sympathovagal balance favoring sympathetic drive increased, the vagal tone and the baroreflex sensitivity decreased during pregnancy. Relative sympathetic drive (sympathovagal balance) reached a maximum at 6 weeks postpartum whereas the other variables did not differ compared to first trimester levels. Postpartum diastolic blood pressure was higher compared to first and second trimester. Pulse transit time and endothelial markers showed no difference throughout gestation. However, opposing variables PTT and asymmetric dimethylarginine (ADMA) were both higher six weeks postpartum.</p><p>Conclusions</p><p>The sympathetic up regulation throughout pregnancy goes hand in hand with a decreased baroreflex sensitivity. In the postpartum period, the autonomic nervous system, biochemical endothelial reactions and PTT show significant and opposing changes compared to pregnancy findings, indicating the complex aftermath of the increase of blood volume, the changes in perfusion strategies and blood pressure regulation that occur in pregnancy.</p></div

Thoracic impedance variables and baroreflex sensitivity (mean ± SD) of participants and statistical results.

<p>Delta Z_0,RESP = change of thoracic impedance (Z0) driven by respiration; RF = respiratory frequency; BRS = baroreflex sensitivity; DB = deep breathing. Note : Multivariate analyses of variance significant for main effects only.</p

Time course of the phase synchronization index γ of R-R interval and respiration(HF-components; mean ± SD) throughout gestation: Black bars (mean ± SD) depict the values of the variables in rest, grey bars (mean ± SD) show the post stress (deep breathing) condition. (γ = synchronization index; RRI = R-R interval; RESP = respiration; HF = high frequency).

<p>*denotes a significant difference (<i>p<.05) between rest and post DB</i> in case of a significant univariate interaction effect.</p