Eco J. de Geus

Contribution of tonic vagal modulation of heart rate, central respiratory drive, respiratory depth, and respiratory frequency to respiratory sinus arrhythmia during mental stress and physical exercise

This study tested various sources of changes in respiratory sinus arrhythmia (RSA). Twenty-two healthy participants participated in three experimental conditions (mental stress, relaxation, and mild physical exercise) that each consisted of three breathing parts (normal breathing, breathing compressed room air, and breathing compressed 5% CO2-enriched air). Independent contributions to changes in RSA were found for changes in tonic vagal modulation of heart rate, central respiratory drive (i.e., PaCO2), respiratory depth, and respiratory frequency. The relative contributions to changes in RSA differed for mental stress and physical exercise. It is concluded that uncorrected RSA will suffice to index within-subject changes in tonic vagal modulation of heart rate in most situations. However, if the central respiratory drive is expected to change, RSA should ideally be corrected for changes in PaCO2, respiratory depth, and respiratory frequency.

Low Birth Weight Is Associated With Increased Sympathetic Activity Dependence on Genetic Factors

Background—Low birth weight may be associated with high blood pressure in later life through genetic factors, an association that may be explained by alterations in sympathetic and parasympathetic activity. We examined the association of birth weight with cardiac pre-ejection period and respiratory sinus arrhythmia (indicators of cardiac sympathetic and parasympathetic activity, respectively) and with blood pressure in 53 dizygotic and 61 monozygotic adolescent twin pairs. Methods and Results—Birth weight of the twins was obtained from the mothers. Pre-ejection period and respiratory sinus arrhythmia were measured with electrocardiography and impedance cardiography at rest, during a reaction time task, and during a mental arithmetic task. In the overall sample, lower birth weight was significantly associated with shorter pre-ejection period at rest, during the reaction time task, and during the mental arithmetic task (P =0.0001, P <0.0001, and P =0.0001, respectively) and with larger pre-ejection period reactivity to the stress tasks (P =0.02 and P =0.06, respectively). In within-pair analyses, differences in birth weight were associated with differences in pre-ejection period at rest and during both stress tasks in dizygotic twin pairs (P =0.01, P =0.06, and P =0.2, respectively) but not in monozygotic twin pairs (P =0.9, P =1.0, and P =0.5, respectively). Shorter pre-ejection period explained approximately 63% to 84% of the birth weight and blood pressure relation. Conclusions—Low birth weight is associated with increased sympathetic activity, and this explains a large part of the association between birth weight and blood pressure. In addition, our findings suggest that the association between birth weight and sympathetic activity depends on genetic factors.

Cardiovascular Reactivity to Psychological Stress and Disease: J. Blascovich and E.S. Katkin (Eds.), APA, Washington, DC, 1993, pp. xv + 242, £35.95. ISBN 1-55798-192-2

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

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 development of metabolic abnormalities that constitute the metabolic syndrome. DESIGN Data of the baseline and 2-year follow-up assessment of a prospective cohort: the Netherlands Study of Depression and Anxiety was used. SETTING Participants were recruited in the general community, primary care, and specialized mental health care organizations. PARTICIPANTS A group of 1933 participants aged 18-65 years. MAIN OUTCOME MEASURES The autonomic nervous system measures included heart rate (HR), respiratory 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 Treatment 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.

Exaggerated perception of normal physiological responses to stress and hypercapnia in young women with numerous functional somatic symptoms

OBJECTIVE This study tested whether functional somatic symptoms are associated with exaggerated increases in self-reported anxiety and somatic complaints in response to stress and CO(2)-enriched air breathing, and whether this association exists in parallel to or in the absence of exaggerated physiological responses. METHODS Out of 499 young somatically healthy undergraduate women, 18 participants high in functional somatic symptoms (HSS group) and 18 participants low in symptoms (LSS) were selected. They were submitted to mental stress, mild physical exercise and relaxation during conditions of normal breathing, breathing compressed normal air, and breathing compressed 5% CO(2)-enriched air. In all conditions, self-reported anxiety and somatic symptoms and respiratory and autonomic responses were assessed. RESULTS HSS participants reported, as compared to LSS, more tenseness, anxiety, and somatic symptoms at baseline and increased responses to mental stress and during 5% CO(2) breathing, but not in response to exercise. However, no evidence was found for a corresponding exaggerated respiratory or autonomic response. CONCLUSIONS A young, female, and nonclinical population with numerous functional somatic symptoms and high levels of anxiety is characterized by an exaggerated perception of a normal physiological response.

DNA Modification Study of Major Depressive Disorder: Beyond Locus-by-Locus Comparisons

BACKGROUND Major depressive disorder (MDD) exhibits numerous clinical and molecular features that are consistent with putative epigenetic misregulation. Despite growing interest in epigenetic studies of psychiatric diseases, the methodologies guiding such studies have not been well defined. METHODS We performed DNA modification analysis in white blood cells from monozygotic twins discordant for MDD, in brain prefrontal cortex, and germline (sperm) samples from affected individuals and control subjects (total N = 304) using 8.1K CpG island microarrays and fine mapping. In addition to the traditional locus-by-locus comparisons, we explored the potential of new analytical approaches in epigenomic studies. RESULTS In the microarray experiment, we detected a number of nominally significant DNA modification differences in MDD and validated selected targets using bisulfite pyrosequencing. Some MDD epigenetic changes, however, overlapped across brain, blood, and sperm more often than expected by chance. We also demonstrated that stratification for disease severity and age may increase the statistical power of epimutation detection. Finally, a series of new analytical approaches, such as DNA modification networks and machine-learning algorithms using binary and quantitative depression phenotypes, provided additional insights on the epigenetic contributions to MDD. CONCLUSIONS Mapping epigenetic differences in MDD (and other psychiatric diseases) is a complex task. However, combining traditional and innovative analytical strategies may lead to identification of disease-specific etiopathogenic epimutations.

A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder

Major depressive disorder (MDD) is a psychiatric disorder that is characterized -amongst others- by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r2>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P = 6.8E−7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P = 1.2E−6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P = 9.9E−7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833.

Ambulatory measurement of the ECG T-wave amplitude.

Ambulatory recording of the preejection period (PEP) can be used to measure changes in cardiac sympathetic nervous system (SNS) activity under naturalistic conditions. Here, we test the ECG T-wave amplitude (TWA) as an alternative measure, using 24-h ambulatory monitoring of PEP and TWA in a sample of 564 healthy adults. The TWA showed a decrease in response to mental stress and a monotonic decrease from nighttime sleep to daytime sitting and more physically active behaviors. Within-participant changes in TWA were correlated with changes in the PEP across the standardized stressors (r = .42) and the unstandardized naturalistic conditions (mean r = .35). Partialling out changes in heart rate and vagal effects attenuated these correlations, but they remained significant. Ambulatory TWA cannot replace PEP, but simultaneous recording of TWA and PEP provides a more comprehensive picture of changes in cardiac SNS activity in real-life settings.

Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10−4), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

LPAR1 and ITGA4 regulate peripheral blood monocyte counts.

We recently mapped a quantitative trait locus for monocyte counts to chromosome 9q31 (rs7023923). Here we extend this work by showing with two independent approaches that rs7023923 regulates the expression levels of the nearby LPAR1 gene (P<0.0001), specifically implicating this gene in monocyte development. Furthermore, we tested 10 additional loci identified in the original analysis for replication in 1,122 individuals and confirm that rs6740847 near the alpha‐4‐integrin gene (ITGA4) associates with variation in monocyte counts (combined P=2.7×10−10). This variant is in complete linkage disequilibrium (r2=1) with a previously reported eQTL for ITGA4 (rs2124440), indicating that this is the likely causal gene in the region. Our results indicate that rs7023923 and rs6740847 respectively upregulate LPAR1 and downregulate ITGA4 expression and this increases the number of monocytes circulating in the peripheral blood. Further studies that investigate the downstream mechanism involved and the impact on immune function are warranted. Hum Mutat 32:1–4, 2011.