Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets “programmed” into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease.

Psychological Stress in Childhood and Susceptibility to the Chronic Diseases of Aging: Moving toward a Model of Behavioral and Biological Mechanisms.

Background: Arginine vasopressin (AVP) is a key regulator of water balance, but its instability makes reliable measurement difficult and precludes routine use. We present a method for quantifying AVP release by use of copeptin, a glycopeptide comprising the C-terminal part of the AVP prohormone.

Methods: We measured copeptin in 50-μL serum and plasma samples from healthy individuals and from critically ill patients with sepsis. Our sandwich immunoluminometric assay used 2 polyclonal antibodies to amino acids 132–164 of pre-provasopressin.

Results: The assay yielded results within 3 h. The analytical detection limit was 1.7 pmol/L, and the interlaboratory CV was 2.25 pmol/L. The assay was linear on dilution of the analyte. Ex vivo copeptin stability (<20% loss of analyte) for at least 7 days at room temperature and 14 days at 4 °C was shown for serum and EDTA-, heparin-, and citrate plasma. Copeptin (median, 4.2 pmol/L; range, 1–13.8 pmol/L) was detectable in 97.5% of 359 healthy individuals and was not associated with age. Median concentrations were considerably higher in men than women, increased significantly after exercise, and were influenced by fasting and water load. Copeptin was significantly ( P <0.001) increased in 60 critically ill patients with sepsis (median, 79.5 pmol/L; range, 10.6–228.0 pmol/L). The correlation between copeptin and AVP for 110 samples was r = 0.78 ( P <0.0001).

Conclusions: Copeptin is stable for days after blood withdrawal and can be quickly and easily measured. The copeptin assay may be a useful alternative to direct measurement of AVP concentration.

/pdf/assay-for-the-measurement-of-copeptin-a-stable-peptide-4q4x135clw.pdf

Assay for the Measurement of Copeptin, a Stable Peptide Derived from the Precursor of Vasopressin

CONTEXT: Prior studies have demonstrated conflicting results regarding how much information novel biomarkers add to cardiovascular risk assessment. OBJECTIVE: To evaluate the utility of contemporary biomarkers for predicting cardiovascular risk when added to conventional risk factors. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 5067 participants (mean age, 58 years; 60% women) without cardiovascular disease from Malmo, Sweden, who attended a baseline examination between 1991 and 1994. Participants underwent measurement of C-reactive protein (CRP), cystatin C, lipoprotein-associated phospholipase 2, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide (N-BNP) and underwent follow-up until 2006 using the Swedish national hospital discharge and cause-of-death registers and the Stroke in Malmo register for first cardiovascular events (myocardial infarction, stroke, coronary death). MAIN OUTCOME MEASURES: Incident cardiovascular and coronary events. RESULTS: During median follow-up of 12.8 years, there were 418 cardiovascular and 230 coronary events. Models with conventional risk factors had C statistics of 0.758 (95% confidence interval [CI], 0.734 to 0.781) and 0.760 (0.730 to 0.789) for cardiovascular and coronary events, respectively. Biomarkers retained in backward-elimination models were CRP and N-BNP for cardiovascular events and MR-proADM and N-BNP for coronary events, which increased the C statistic by 0.007 (P = .04) and 0.009 (P = .08), respectively. The proportion of participants reclassified was modest (8% for cardiovascular risk, 5% for coronary risk). Net reclassification improvement was nonsignificant for cardiovascular events (0.0%; 95% CI, -4.3% to 4.3%) and coronary events (4.7%; 95% CI, -0.76% to 10.1%). Greater improvements were observed in analyses restricted to intermediate-risk individuals (cardiovascular events: 7.4%; 95% CI, 0.7% to 14.1%; P = .03; coronary events: 14.6%; 95% CI, 5.0% to 24.2%; P = .003). However, correct reclassification was almost entirely confined to down-classification of individuals without events rather than up-classification of those with events. CONCLUSIONS: Selected biomarkers may be used to predict future cardiovascular events, but the gains over conventional risk factors are minimal. Risk classification improved in intermediate-risk individuals, mainly through the identification of those unlikely to develop events.

https://jamanetwork.com/journals/jama/articlepdf/184180/joc90055_49_57.pdf

Novel and Conventional Biomarkers for Prediction of Incident Cardiovascular Events in the Community

Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea : results from the BACH (Biomarkers in Acute Heart Failure) trial

Background— Patients with chronic kidney disease (stage 5) who undergo hemodialysis treatment have similarities to heart failure patients in that both populations retain fluid frequently and have excessively high mortality. Volume overload in heart failure is associated with worse outcomes. We hypothesized that in hemodialysis patients, greater interdialytic fluid gain is associated with poor all-cause and cardiovascular survival. Methods and Results— We examined 2-year (July 2001 to June 2003) mortality in 34 107 hemodialysis patients across the United States who had an average weight gain of at least 0.5 kg above their end-dialysis dry weight by the time the subsequent hemodialysis treatment started. The 3-month averaged interdialytic weight gain was divided into 8 categories of 0.5-kg increments (up to ≥4.0 kg). Eighty-six percent of patients gained >1.5 kg between 2 dialysis sessions. In unadjusted analyses, higher weight gain was associated with better nutritional status (higher protein intake, serum...

https://escholarship.org/content/qt6jw460x2/qt6jw460x2.pdf?t=pzxosu

Fluid Retention Is Associated With Cardiovascular Mortality in Patients Undergoing Long-Term Hemodialysis

Background: Adrenomedullin (ADM) is a potent vasodilatory peptide, and circulating concentrations have been described for several disease states, including dysfunction of the cardiovascular system and sepsis. Reliable quantification has been hampered by the short half-life, the existence of a binding protein, and physical properties. Here we report the technical evaluation of an assay for midregional pro-ADM (MR-proADM) that does not have these problems.

Methods: MR-proADM was measured in a sandwich immunoluminometric assay using 2 polyclonal antibodies to amino acids 45–92 of proADM. The reference interval was defined in EDTA plasma of 264 healthy individuals (117 male, 147 female), and increased MR-proADM concentrations were found in 95 patients with sepsis and 54 patients with cardiovascular disease.

Results: The assay has an analytical detection limit of 0.08 nmol/L, and the interassay CV was 0.12 nmol/L. The assay was linear on dilution with undisturbed recovery of the analyte. EDTA-, heparin-, and citrate-plasma samples were stable (<20% loss of analyte) for at least 3 days at room temperature, 14 days at 4 °C, and 1 year at −20 °C. MR-proADM values followed a gaussian distribution in healthy individuals with a mean (SD) of 0.33 (0.07) nmol/L (range, 0.10–0.64 nmol/L), without significant difference between males or females. The correlation coefficient for MR-proADM vs age was 0.50 ( P <0.001). MR-proADM was significantly ( P <0.001) increased in patients with cardiovascular disease [median (range), 0.56 (0.08–3.9) nmol/L] and patients with sepsis [3.7 (0.72–25.4) nmol/L].

Conclusions: MR-proADM is stable in plasma of healthy individuals and patients. MR-proADM measurements may be useful for evaluating patients with sepsis, systemic inflammation, or heart failure.

/pdf/measurement-of-midregional-proadrenomedullin-in-plasma-with-4ran3u31q5.pdf

Measurement of Midregional Proadrenomedullin in Plasma with an Immunoluminometric Assay

The prohormone of atrial natriuretic peptide (proANP) is a polypeptide of 126 amino acids. Mature atrial natriuretic peptide (ANP) consists of amino acids 99–126 and comprises 98% of the natriuretic peptides in the circulation (1). The N-terminal portion of proANP, termed proANP1–98 or NT-proANP, has a much longer half-life than mature ANP and has therefore been suggested to be a more reliable analyte for measurement than mature ANP (2). In addition to other established indications, proANP has recently gained much interest as a potential new marker in the field of sepsis (3), emphasizing the need for a reliable assay for this molecule.

All sandwich immunoassays developed for proANP to date use an antibody against the N-terminal region of proANP1–98 combined with a second antibody against either the midregion (4) or C-terminal region (5)(6). However, under certain conditions, the N-terminal region might be minimally accessible for antibody binding (7)(8). Despite the described long half-life of proANP, results from various competitive immunoassays as well as HPLC analyses indicate that proANP1–98 can be subject to further fragmentation (9)(10).

We developed a new sandwich immunoassay for midregional proANP (amino acids 53–90; Fig. 1A⇓ ). With this assay, which was named B.R.A.H.M.S SERISTRA® (B.R.A.H.M.S AG), we measured proANP values in 325 healthy controls.

EDTA-plasma samples were collected at a blood bank (Red Cross) from 325 consecutive healthy blood donors (age range, 18–67 years; 52.9% male) without clinical evidence of acute disease or a history of chronic illness. Blood donors with risk factors for heart failure were not enrolled in the study. Written consent was obtained from …

Immunoluminometric Assay for the Midregion of Pro-Atrial Natriuretic Peptide in Human Plasma

Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in predicting survival in patients with chronic heart failure.

Oxytocin is a hormone and neurotransmitter found to have anti-inflammatory functions in rodents. Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administ...

Joachim Struck

Papers

Assay for the Measurement of Copeptin, a Stable Peptide Derived from the Precursor of Vasopressin

Measurement of Midregional Proadrenomedullin in Plasma with an Immunoluminometric Assay

Immunoluminometric Assay for the Midregion of Pro-Atrial Natriuretic Peptide in Human Plasma

Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in predicting survival in patients with chronic heart failure.

Oxytocin alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men.