Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure

Background Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF. Methods A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI-MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF. Results After normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p = 0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p = 0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p = 0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to-event in prediction of clinical events in patients with HF (p = 0.0005). Conclusions The results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF

Heart failure and the risk of stroke: the Rotterdam Study

Patients with heart failure used to have an increased risk of stroke, but this may have changed with current treatment regimens. We assessed the association between heart failure and the risk of stroke in a population-based cohort that was followed since 1990. The study uses the cohort of the Rotterdam Study and is based on 7,546 participants who at baseline (1990–1993) were aged 55 years or over and free from stroke. The associations between heart failure and risk of stroke were assessed using time-dependent Cox proportional hazards models, adjusted for cardiovascular risk factors (smoking, diabetes mellitus, BMI, ankle brachial index, blood pressure, atrial fibrillation, myocardial infarction and relevant medication). At baseline, 233 participants had heart failure. During an average follow-up time of 9.7 years, 1,014 persons developed heart failure, and 827 strokes (470 ischemic, 75 hemorrhagic, 282 unclassified) occurred. The risk of ischemic stroke was more than five-fold increased in the first month after diagnosis of heart failure (age and sex adjusted HR 5.79, 95% CI 2.15–15.62), but attenuated over time (age and sex adjusted HR 3.50 [95% CI 1.96–6.25] after 1–6 months and 0.83 [95% CI 0.53–1.29] after 0.5–6 years). Additional adjustment for cardiovascular risk factors only marginally attenuated these risks. In conclusion, the risk of ischemic stroke is strongly increased shortly after the diagnosis of heart failure but returns to normal within 6 months after onset of heart failure

Abnormal shortened diastolic time length at increasing heart rates in patients with abnormal exercise-induced increase in pulmonary artery pressure

<p>Abstract</p> <p>Background</p> <p>The degree of pulmonary hypertension is not independently related to the severity of left ventricular systolic dysfunction but is frequently associated with diastolic filling abnormalities. The aim of this study was to assess diastolic times at increasing heart rates in normal and in patients with and without abnormal exercise-induced increase in pulmonary artery pressure (PASP). Methods. We enrolled 109 patients (78 males, age 62 ± 13 years) referred for exercise stress echocardiography and 16 controls. The PASP was derived from the tricuspid Doppler tracing. A cut-off value of PASP ≥ 50 mmHg at peak stress was considered as indicative of abnormal increase in PASP. Diastolic times and the diastolic/systolic time ratio were recorded by a precordial cutaneous force sensor based on a linear accelerometer.</p> <p>Results</p> <p>At baseline, PASP was 30 ± 5 mmHg in patients and 25 ± 4 in controls. At peak stress the PASP was normal in 95 patients (Group 1); 14 patients (Group 2) showed an abnormal increase in PASP (from 35 ± 4 to 62 ± 12 mmHg; P < 0.01). At 100 bpm, an abnormal (< 1) diastolic/systolic time ratio was found in 0/16 (0%) controls, in 12/93 (13%) Group 1 and 7/14 (50%) Group 2 patients (p < 0.05 between groups).</p> <p>Conclusion</p> <p>The first and second heart sound vibrations non-invasively monitored by a force sensor are useful for continuously assessing diastolic time during exercise. Exercise-induced abnormal PASP was associated with reduced diastolic time at heart rates beyond 100 beats per minute.</p

Heart Rate and Use of Beta-Blockers in Stable Outpatients with Coronary Artery Disease

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Heart rate (HR) is an emerging risk factor in coronary artery disease (CAD). However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods and Findings:&lt;/b&gt; CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of &#62;50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%). Mean (SD) age was 64.2 (10.5) years, HR by pulse was 68.3 (10.6) bpm, and by electrocardiogram was 67.2 (11.4) bpm. Overall, 44.0% had HR&#8805;70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR&#8805;70 bpm. HR&#8805;70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR&#8805;70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.&lt;/p&gt

The Oncoprotein EVI1 and the DNA Methyltransferase Dnmt3 Co-Operate in Binding and De Novo Methylation of Target DNA

EVI1 has pleiotropic functions during murine embryogenesis and its targeted disruption leads to prenatal death by severely affecting the development of virtually all embryonic organs. However, its functions in adult tissues are still unclear. When inappropriately expressed, EVI1 becomes one of the most aggressive oncogenes associated with human hematopoietic and solid cancers. The mechanisms by which EVI1 transforms normal cells are unknown, but we showed recently that EVI1 indirectly upregulates self-renewal and cell-cycling genes by inappropriate methylation of CpG dinucleotides in the regulatory regions of microRNA-124-3 (miR-124-3), leading to the repression of this small gene that controls normal differentiation and cell cycling of somatic cells. We used the regulatory regions of miR-124-3 as a read-out system to investigate how EVI1 induces de novo methylation of DNA. Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. This protein complex targets and binds to a precise region of miR-124-3 that is necessary for repression of a reporter gene by EVI1. Based on our findings, we propose that in cooperation with Dnmt3a/b EVI1 regulates the methylation of DNA as a sequence-specific mediator of de novo DNA methylation and that inappropriate EVI1 expression contributes to carcinogenesis through improper DNA methylation

The Role of Pre- and Postnatal Timing of Family Risk Factors on Child Behavior at 36 months

Children growing up in disharmonious families with anxious/depressed mothers are at risk for emotional and behavioral difficulties, however whether these associations reflect postnatal environment, prenatal exposure, or an overall liability is still unclear. This study used prospectively collected data from 24,259 participants of the Norwegian Mother and Child Cohort Study (MoBa). Mothers reported on anxiety/depression and family disharmony twice in pregnancy and twice post pregnancy, as well as on their child’s physical aggression and crying behavior at age 36 months. First, results from an autoregressive cross-lagged model showed a substantial stability in both maternal anxiety/depression and family disharmony from pregnancy to 18 months postnatal, but there was no indication that family disharmony led to maternal anxiety/depression, or the other way around. Second, structural equation models further suggests that the main risk derived from an overall liability, that is, a lasting effect of family risks that spanned the two time periods

Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning.

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.This work was supported by Medical Research Council Grants (G0701500; G0802729), a 503 Wellcome Trust Programme Grant (grant number 089589/Z/09/Z), and by a Core Award 504 from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical 505 21 Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). RLB was supported 506 by a studentship from the Medical Research Council. JA was supported by a Fellowship from 507 the Swedish Research Council (350-2012-230). BJ was supported by Fellowships from the 508 AXA Research Fund and the National Health and Medical Research Council of Australia. 509 Financial support from the Fredrik and Ingrid Thuring Foundation is also acknowledged.This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/npp/journal/vaop/ncurrent/full/npp2014335a.html

Effects of different lower-limb sensory stimulation strategies on postural regulation – A systematic review and meta-analysis

Systematic reviews of balance control have tended to only focus on the effects of single lower-limb stimulation strategies, and a current limitation is the lack of comparison between different relevant stimulation strategies. The aim of this systematic review and meta-analysis was to examine evidence of effects of different lower-limb sensory stimulation strategies on postural regulation and stability. Moderate- to high- pooled effect sizes (Unbiased (Hedges’ g) standardized mean differences (SMD) = 0.31 – 0.66) were observed with the addition of noise in a Stochastic Resonance Stimulation Strategy (SRSS), in three populations (i.e., healthy young adults, older adults, and individuals with lower-limb injuries), and under different task constraints (i.e., unipedal, bipedal, and eyes open). A Textured Material Stimulation Strategy (TMSS) enhanced postural control in the most challenging condition – eyes-closed on a stable surface (SMD = 0.61), and in older adults (SMD = 0.30). The Wearable Garments Stimulation Strategy (WGSS) showed no or adverse effects (SMD = -0.68 – 0.05) under all task constraints and in all populations, except in individuals with lower-limb injuries (SMD = 0.20). Results of our systematic review and meta-analysis revealed that future research could consider combining two or more stimulation strategies in intervention treatments for postural regulation and balance problems, depending on individual need

Sleep and immune function

Sleep and the circadian system exert a strong regulatory influence on immune functions. Investigations of the normal sleep–wake cycle showed that immune parameters like numbers of undifferentiated naïve T cells and the production of pro-inflammatory cytokines exhibit peaks during early nocturnal sleep whereas circulating numbers of immune cells with immediate effector functions, like cytotoxic natural killer cells, as well as anti-inflammatory cytokine activity peak during daytime wakefulness. Although it is difficult to entirely dissect the influence of sleep from that of the circadian rhythm, comparisons of the effects of nocturnal sleep with those of 24-h periods of wakefulness suggest that sleep facilitates the extravasation of T cells and their possible redistribution to lymph nodes. Moreover, such studies revealed a selectively enhancing influence of sleep on cytokines promoting the interaction between antigen presenting cells and T helper cells, like interleukin-12. Sleep on the night after experimental vaccinations against hepatitis A produced a strong and persistent increase in the number of antigen-specific Th cells and antibody titres. Together these findings indicate a specific role of sleep in the formation of immunological memory. This role appears to be associated in particular with the stage of slow wave sleep and the accompanying pro-inflammatory endocrine milieu that is hallmarked by high growth hormone and prolactin levels and low cortisol and catecholamine concentrations

Aging, telomeres and heart failure

During normal aging, the heart undergoes functional, morphological and cellular changes. Although aging per se does not lead to the expression of heart failure, it is likely that age-associated changes lower the threshold for the manifestation of signs and symptoms of heart failure. In patients, the susceptibility, age of onset and pace of progression of heart failure are highly variable. The presence of conventional risk factors cannot completely explain this variability. Accumulation of DNA damage and telomere attrition results in an increase in cellular senescence and apoptosis, resulting in a decrease in the number and function of cells, contributing to the overall tissue and organ dysfunction. Biological aging, characterized by reduced telomere length, provides an explanation for the highly interindividual variable threshold to express the clinical syndrome of heart failure at some stage during life. In this review, we will elaborate on the current knowledge of aging of the heart, telomere biology and its potential role in the development of heart failure