Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Green space exposure and blood DNA methylation at birth and in childhood - A multi-cohort study.

Green space exposure has been associated with improved mental, physical and general health. However, the underlying biological mechanisms remain largely unknown. The aim of this study was to investigate the association between green space exposure and cord and child blood DNA methylation. Data from eight European birth cohorts with a total of 2,988 newborns and 1,849 children were used. Two indicators of residential green space exposure were assessed: (i) surrounding greenness (satellite-based Normalized Difference Vegetation Index (NDVI) in buffers of 100 m and 300 m) and (ii) proximity to green space (having a green space ≥ 5,000 m2 within a distance of 300 m). For these indicators we assessed two exposure windows: (i) pregnancy, and (ii) the period from pregnancy to child blood DNA methylation assessment, named as cumulative exposure. DNA methylation was measured with the Illumina 450K or EPIC arrays. To identify differentially methylated positions (DMPs) we fitted robust linear regression models between pregnancy green space exposure and cord blood DNA methylation and between cumulative green space exposure and child blood DNA methylation. Two sensitivity analyses were conducted: (i) without adjusting for cellular composition, and (ii) adjusting for air pollution. Cohort results were combined through fixed-effect inverse variance weighted meta-analyses. Differentially methylated regions (DMRs) were identified from meta-analysed results using the Enmix-combp and DMRcate methods. There was no statistical evidence of pregnancy or cumulative exposures associating with any DMP (False Discovery Rate, FDR, p-value < 0.05). However, surrounding greenness exposure was inversely associated with four DMRs (three in cord blood and one in child blood) annotated to ADAMTS2, KCNQ1DN, SLC6A12 and SDK1 genes. Results did not change substantially in the sensitivity analyses. Overall, we found little evidence of the association between green space exposure and blood DNA methylation. Although we identified associations between surrounding greenness exposure with four DMRs, these findings require replication.

Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy.

BACKGROUND: Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA. METHODS: To identify DMRs, we employed the bump hunter method in samples from young (9-16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28-33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle. RESULTS: One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring's own adiposity. CONCLUSIONS: Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation.

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.

Impact of a heart failure multidisciplinary clinic on the reduction of healthcare-related events and costs: the GEstIC study.

Introduction: Heart failure (HF) is the leading cause of hospitalization in the elderly in developed countries and significantly impacts public health expenditures. Patients with HF usually have associated comorbidities that require multidisciplinary management. This study aims to demonstrate the benefits of a multidisciplinary clinic in reducing all-cause hospitalizations and HF events (HF hospitalizations and urgent HF visits) in a real-world setting. Finally, the study evaluates the associated costs of HF events. Methods: This observational study included patients admitted to GEstIC, a multidisciplinary Portuguese HF clinic, from January 2013 to February 2019, who had one-year follow-up. Hospitalizations and HF events, total days spent in the hospital during HF hospitalizations, and HF events-related costs, in the year before and the year after GEstIC admission, were compared. Results: Of the 487 patients admitted to the GEstIC, 287 were eligible for the study sample. After one year of HF patients' multidisciplinary management at GEstIC, there was a 53.7% reduction in all-cause hospitalizations (462 vs. 214), a 71.7% reduction in HF hospitalizations (392 vs. 111), and a 39.1% reduction in urgent HF visits (87 vs. 53). As a result, there was a significant decrease of 12.6 days in the length of hospital stay due to HF per patient (15.6 vs. 3.0, p < 0.001). This translated into the release of 9.9 hospital beds in the year following admission to GEstIC. The average total savings associated with the reduction of HF events was €5,439.77 per patient (6,774.15 vs. 1,334.38, p < 0.001), representing a total cost reduction of €1,561,213. Furthermore, the significant reduction in the number of all events was independent of the patient's left ventricular ejection fraction (LVEF). Discussion: Significant reductions in all-cause and HF hospitalizations and urgent HF visits were observed with the implementation of this multidisciplinary clinic for HF patients' management. This was particularly important for patients with LVEF >40%. Before GEstIC, there was no medical intervention to improve the prognosis of these patients. The reduction of over one million euros in health-related costs after only one year of person-centered multidisciplinary management highlights the need to replicate this approach in other national healthcare institutions.

conTemporary reflectiOns regarding heart failure manaGEmenT - How to ovERcome the PorTuguese barriers (TOGETHER-PT).

INTRODUCTION AND OBJECTIVES: Heart failure (HF) is a complex clinical syndrome that is a significant burden in hospitalisations, morbidity, and mortality. Although a significant effort has been made to better understand its consequences and current barriers in its management, there are still several gaps to address. The present work aimed to identify the views of a multidisciplinary group of health care professionals on HF awareness and literacy, diagnosis, treatment and organization of care, identifying current challenges and providing insights into the future. METHODS: A steering committee was established, including members of the Heart Failure Study Group of the Portuguese Society of Cardiology (GEIC-SPC), the Heart Failure Study Group of the Portuguese Society of Internal Medicine (NEIC-SPMI) and the Cardiovascular Study Group (GEsDCard) of the Portuguese Association of General and Family Medicine (APMGF). This steering committee produced a 16-statement questionnaire regarding different HF domains that was answered to by a diversified group of 152 cardiologists, internists, general practitioners, and nurses with an interest or dedicated to HF using a five-level Likert scale. Full agreement was defined as ≥80% of level 5 (fully agree) responses. RESULTS: Globally, consensus was achieved in all but one of the 16 statements. Full agreement was registered in seven statements, namely 3 of 4 statements for patient education and HF awareness and 2 in 4 statements of both HF diagnosis and healthcare organization, with proportions of fully agree responses ranging from 82.9% to 96.7%. None of the HF treatment statements registered full agreement but 3 of 4 achieved ≥80% of level 4 (agree) responses. CONCLUSION: This document aims to be a call-to-action to improve HF patients' quality of life and prognosis, by promoting a change in HF care in Portugal.

One-year mortality after hospitalization for acute heart failure: Predicting factors (PRECIC study subanalysis).

INTRODUCTION AND OBJECTIVES: One-year mortality after hospitalization for heart failure (HF) is high. This study aims to identify predictive factors of one-year mortality. METHODS: This is a retrospective, single-center and observational study. All patients hospitalized for acute HF during one year were enrolled. RESULTS: A total of 429 patients were enrolled, mean age of 79 years. The in-hospital and one-year all-cause mortality rates were 7.9% and 34.3%, respectively. In the univariable analysis, the factors significantly associated with higher one-year mortality risk were: age ≥80 years (odds ratio (OR)=2.05, 95% confidence interval (CI) 1.35-3.11, p=0.001); active cancer (OR=2.93, 95% CI 1.36-6.32, p=0.008); dementia (OR=2.84, 95% CI 1.81-4.47, p<0.001); functional dependency (OR=2.63, 95% CI 1.65-4.19, p<0.001); atrial fibrillation (OR=1.86, 95% CI 1.24-2.80, p=0.004); higher creatinine (OR=2.03, 95% CI 1.29-3.21, p=0.002), urea (OR=2.92, 95% CI 1.95-4.36, p<0.001) and red cell distribution width (RDW; 4thQ OR=5.59, 95% CI 3.03-10.32, p=0.001); and lower hematocrit (OR=0.94, 95% CI 0.91-0.97, p<0.001), hemoglobin (OR=0.83, 95% CI 0.75-0.92, p<0.001) and platelet distribution width (PDW; OR=0.89, 95% CI 0.82-0.97, p=0.005). In the multivariable analysis, the independent predictors of higher one-year mortality risk were: age ≥80 years (OR=2.05, 95% CI 1.21-3.48); active cancer (OR=2.70, 95% CI 1.03-7.01); dementia (OR=2.69, 95% CI 1.53-4.74); higher urea (OR=2.97, 95% CI 1.84-4.80) and RDW (4thQ OR=5.24, 95% CI 2.55-10.76); and lower PDW (OR=0.88, 95% CI 0.80-0.97). CONCLUSIONS: Active cancer, dementia, and high values for urea and RDW at admission are predictors of one-year mortality in patients hospitalized for HF. These variables are readily available at admission and can support the clinical management of HF patients.

One-year rehospitalisation and mortality after acute heart failure hospitalisation: a competing risk analysis.

OBJECTIVE: To identify factors that independently predict the risk of rehospitalisation and death after acute heart failure (AHF) hospital discharge in a real-world setting, considering death without rehospitalisation as a competing event. METHODS: Single-centre, retrospective, observational study enrolling 394 patients discharged from an index AHF hospitalisation. Overall survival was evaluated using Kaplan-Meier and Cox regression models. For the risk of rehospitalisation, survival analysis considering competing risks was performed: rehospitalisation was the event of interest, and death without rehospitalisation was the competing event. RESULTS: During the first year after discharge, 131 (33.3%) patients were rehospitalised for AHF and 67 (17.0%) died without being readmitted; the remaining 196 patients (49.7%) lived without further hospitalisations. The 1-year overall survival estimate was 0.71 (SE=0.02). After adjusting for gender, age and left ventricle ejection fraction, the results showed that the risk of death was higher in patients with dementia, higher levels of plasma creatinine (PCr), lower levels of platelet distribution width (PDW) and at Q4 of red cell distribution width (RDW). Multivariable models showed that the risk of rehospitalisation was increased in patients with atrial fibrillation, higher PCr or taking beta-blockers at discharge. Furthermore, the risk of death without AHF rehospitalisation was higher in males, those aged ≥80 years, patients with dementia or RDW at Q4 on admission (compared with Q1). Taking beta-blockers at discharge and having a higher PDW on admission reduced the risk of death without rehospitalisation. CONCLUSION: When assessing rehospitalisation as a study endpoint, death without rehospitalisation should be considered a competing event in the analyses. Data from this study reveal that patients with atrial fibrillation, renal dysfunction or taking beta-blockers are more likely to be rehospitalised for AHF, while older men with dementia or high RDW are more prone to die without hospital readmission.

Associations of green and blue space exposure in pregnancy with epigenetic gestational age acceleration.

Early life is seen as a particularly sensitive period for environmental exposures. Natural space exposure during pregnancy has been associated with offspring health. Epigenetic gestational age acceleration, a discrepancy between clinical and DNA methylation-based gestational age, may underlie these associations. In 1359 mother-newborn pairs from the population-based Generation R Study, we examined the associations of natural space exposure, defined as surrounding greenness, distance to major green and blue (water) space, and size of the blue space during pregnancy with offspring epigenetic gestational age acceleration. Natural space exposure was based on participants' geocoded addresses, and epigenetic gestational age acceleration was calculated from cord blood DNA methylation using Bohlin's and Knight's epigenetic clocks. Sensitivity analyses were conducted in a subgroup of newborns with optimal pregnancy dating, based on last menstrual period. Surrounding greenness, measured in normalized difference vegetation index values, was intermediate (median 0.4, IQR 0.2), and 84% and 56% of the participants had a major green or blue space near their home address, respectively. We did not observe associations of natural space availability during pregnancy with offspring epigenetic gestational age acceleration. This could imply that epigenetic gestational age acceleration in cord blood does not underlie the effects of residential natural space availability in pregnancy on offspring health. Future studies could investigate whether residential natural space availability during pregnancy is associated with offspring differential DNA methylation at other CpGs than those included in the epigenetic gestational clocks.

DNA Methylation and Gene Expression in Blood and Adipose Tissue of Adult Offspring of Women with Diabetes in Pregnancy-A Validation Study of DNA Methylation Changes Identified in Adolescent Offspring.

Maternal gestational diabetes and obesity are associated with adverse outcomes in offspring, including increased risk of diabetes and cardiovascular diseases. Previously, we identified a lower DNA methylation degree at genomic sites near the genes ESM1, MS4A3, and TSPAN14 in the blood cells of adolescent offspring exposed to gestational diabetes and/or maternal obesity in utero. In the present study, we aimed to investigate if altered methylation and expression of these genes were detectable in blood, as well in the metabolically relevant subcutaneous adipose tissue, in a separate cohort of adult offspring exposed to gestational diabetes and obesity (O-GDM) or type 1 diabetes (O-T1D) in utero, compared with the offspring of women from the background population (O-BP). We did not replicate the findings of lower methylation of ESM1, MS4A3, and TSPAN14 in blood from adults, either in O-GDM or O-T1D. In contrast, in adipose tissue of O-T1D, we found higher MS4A3 DNA methylation, which will require further validation. The adipose tissue ESM1 expression was lower in O-GDM compared to O-BP, which in turn was not associated with maternal pre-pregnancy BMI nor the offspring's own adiposity. Adipose tissue TSPAN14 expression was slightly lower in O-GDM compared with O-BP, but also positively associated with maternal pre-pregnancy BMI, as well as offspring's own adiposity and HbA1c levels. In conclusion, the lower DNA methylation in blood from adolescent offspring exposed to GDM could not be confirmed in the present cohort of adult offspring, potentially due to methylation remodeling with increased aging. In offspring adipose tissue, ESM1 expression was associated with maternal GDM, and TSPAN14 expression was associated with both maternal GDM, as well as pre-pregnancy BMI. These altered expression patterns are potentially relevant to the concept of developmental programming of cardiometabolic diseases and require further studies.

Effect of Impulsivity Traits on Food Choice within a Nudging Intervention.

Food choices are often driven by impulsive tendencies rather than rational consideration. Some individuals may find it more difficult resisting impulses related to unhealthy food choices, and low self-control and high impulsivity have been suggested to be linked to these behaviors. Recent shifts have been made towards developing strategies that target automatic processes of decision-making and focus on adjusting the environment, referred to as nudging interventions. Therefore, the purpose of this study was to investigate the effect of impulsivity traits on food choices within a nudging intervention (increased perceived variety). A total of 83 adults participated in an experimental study consisting of a self-service intelligent buffet. Impulsivity traits were measured using the UPPS-P impulsivity scale. General linear models were fitted to evaluate the effect of the five impulsivity traits on the difference of salad consumption (g) between the control and intervention situations. Results showed that impulsivity does not affect food choices in this nudging situation, suggesting that nudging works independently of the participant's impulsivity score. Results also showed a significantly higher consumption of salad in the nudging versus the control setting (17.6 g, p < 0.05), suggesting that nudging interventions can be effective in significantly increasing total vegetable consumption across the whole impulsivity scale.

External Validation of the ELAN-HF Score, Predicting 6-Month All-Cause Mortality in Patients Hospitalized for Acute Decompensated Heart Failure.

Background Our aim was to calibrate and externally revalidate the ELAN-HF (European Collaboration on Acute Decompensated Heart Failure) score, to confirm and improve on a previous external validation of the risk score. Methods and Results The ELAN-HF score predicts 6-month all-cause mortality in patients hospitalized for acute decompensated heart failure using absolute and percentage change of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels in addition to clinical variables. For the external validation, we used the PRIMA II (Can NT-proBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?) trial. For both data sets, observed versus predicted mortality was compared for the 4 risk categories; and the mean predicted mortality was plotted against the observed mortality with calculation of a correlation coefficient and SEE. The model discriminant ability was determined by comparing the C-statistics for both data sets. The predicted versus actual 6-month mortality values in the derivation cohort were 3.7% versus 3.6% for the low-risk category, 9.4% versus 9.2% for the intermediate-risk category, 24.2% versus 23.5% for the high-risk category, and 54.2% versus 51.1% for the very-high-risk category. The correlation between predicted and observed mortality by deciles was 0.92, with an SEE of ±4%. In the validation cohort, predicted versus actual 6-month mortality values were 3.0% versus 2.2% for the low-risk category, 9.4% versus 8.2% for the intermediate-risk category, 25.0% versus 22.9% for the high-risk category, and 56.8% versus 53.6% for the very-high-risk category. The correlation between predicted and actual mortality by quintiles was 0.99, with an SEE of ±2%. There was no significant difference in C-statistic between the derivation cohort (0.78; 95% CI, 0.74-0.82) and the validation cohort (0.77; 95% CI, 0.69-0.84; P=0.693). Conclusions Our study confirms that the ELAN-HF score predicts accurately 6-month mortality in patients hospitalized for acute decompensated heart failure with the use of easily obtained characteristics.

NT-proBNP (N-Terminal pro-B-Type Natriuretic Peptide)-Guided Therapy in Acute Decompensated Heart Failure: PRIMA II Randomized Controlled Trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?).

BACKGROUND: The concept of natriuretic peptide guidance has been extensively studied in patients with chronic heart failure (HF), with only limited success. The effect of NT-proBNP (N-terminal probrain natriuretic peptide)-guided therapy in patients with acute decompensated HF using a relative NT-proBNP target has not been investigated. This study aimed to assess whether NT-proBNP-guided therapy of patients with acute decompensated HF using a relative NT-proBNP target would lead to improved outcomes compared with conventional therapy. METHODS: We conducted a prospective randomized controlled trial to study the impact of in-hospital guidance for acute decompensated HF treatment by a predefined NT-proBNP target (>30% reduction from admission to discharge) versus conventional treatment. Patients with acute decompensated HF with NT-proBNP levels >1700 ng/L were eligible. After achieving clinical stability, 405 patients were randomized to either NT-proBNP-guided or conventional treatment (1:1). The primary end point was dual: a composite of all-cause mortality and HF readmissions in 180 days and the number of days alive out of the hospital in 180 days. Secondary end points were all-cause mortality within 180 days, HF readmissions within 180 days, and a composite of all-cause mortality and HF readmissions within 90 days. RESULTS: Significantly more patients in the NT-proBNP-guided therapy group were discharged with an NT-proBNP reduction of >30% (80% versus 64%, P=0.001). Nonetheless, NT-proBNP-guided therapy did not significantly improve the combined event rate for all-cause mortality and HF readmissions (hazard ratio, 0.96; 95% confidence interval, 0.72-1.37; P=0.99) or the median number of days alive outside of the hospital (178 versus 179 days for NT-proBNP versus conventional patients, P=0.39). Guided therapy also did not significantly improve any of the secondary end points. CONCLUSIONS: The PRIMA II trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?) demonstrates that the guidance of HF therapy to reach an NT-proBNP reduction of >30% after clinical stabilization did not improve 6-month outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR3279.

Characteristics and outcomes of heart failure hospitalization before implementation of a heart failure clinic: The PRECIC study.

OBJECTIVE: This study aims to characterize patients hospitalized for acute heart failure (HF) in an internal medicine department and their one-year mortality and rate of rehospitalization for decompensated HF. METHODS: This retrospective observational study enrolled all patients discharged in 2012 after hospitalization for acute HF. Discharge summaries, clinical records and telephone interviews were analysed. The data reports to the year before implementation of a heart failure clinic. RESULTS: Four hundred and twenty-nine patients were enrolled, with a mean age of 79 years, 62.5% female. The most prevalent comorbidity and etiology was hypertension (86.7%) and the most frequent decompensation trigger was infection. HF with preserved ejection fraction (HFpEF) was present in 70.5%. In-hospital mortality was 7.9%. At discharge more than half of the patients were prescribed beta-blockers (52.8%) and angiotensin-converting enzyme inhibitors (52%). Women presented a significantly higher proportion of HFpEF than men (75.3% vs. 62.7%, p=0.01). Patients with diabetes and those with ischemic etiology had significantly higher proportions of HF with reduced ejection fraction (HFrEF) (34.8% vs. 24.3% in non-diabetic patients, p=0.027, and 56.2% vs. 15.6% for other etiologies, p<0.001). The HFrEF group were more frequently discharged under beta-blockers and spironolactone (75.2% vs. 46.4% in the HFpEF group, p<0.001 and 31.2% vs. 12.6% in the HFpEF group, p<0.001, respectively). Mortality was 34.3% and rehospitalization for HF was 30.5% in one-year follow-up. CONCLUSIONS: The population characterized is an elderly one, mainly female and with HFpEF. Nearly a third of patients died and/or were rehospitalized in the year following discharge.

Influence of spironolactone on matrix metalloproteinase-2 in acute decompensated heart failure.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of enzymes important for the resorption of extracellular matrices, control of vascular remodeling and repair. Increased activity of MMP2 has been demonstrated in heart failure, and in acutely decompensated heart failure (ADHF) a decrease in circulating MMPs has been demonstrated along with successful treatment. OBJECTIVE: Our aim was to test the influence of spironolactone in MMP2 levels. METHODS: Secondary analysis of a prospective, interventional study including 100 patients with ADHF. Fifty patients were non-randomly assigned to spironolactone (100 mg/day) plus standard ADHF therapy (spironolactone group) or standard ADHF therapy alone (control group). RESULTS: Spironolactone group patients were younger and had lower creatinine and urea levels (all p < 0.05). Baseline MMP2, NT-pro BNP and weight did not differ between spironolactone and control groups. A trend towards a more pronounced decrease in MMP2 from baseline to day 3 was observed in the spironolactone group (-21 [-50 to 19] vs 1.5 [-26 to 38] ng/mL, p = 0.06). NT-pro BNP and weight also had a greater decrease in the spironolactone group. The proportion of patients with a decrease in MMP2 levels from baseline to day 3 was also likely to be greater in the spironolactone group (50% vs 66.7%), but without statistical significance. Correlations between MMP2, NT-pro BNP and weight variation were not statistically significant. CONCLUSION: MMP2 levels are increased in ADHF. Patients treated with spironolactone may have a greater reduction in MMP2 levels.

Influence of Spironolactone on Matrix Metalloproteinase-2 in Acute Decompensated Heart Failure / Influência da Espironolactona na Metaloproteinase de Matriz 2 na Insuficiência Cadíaca Aguda Descompensada

Background: Matrix metalloproteinases (MMPs) are a family of enzymes important for the resorption of extracellular matrices, control of vascular remodeling and repair. Increased activity of MMP2 has been demonstrated in heart failure, and in acutely decompensated heart failure (ADHF) a decrease in circulating MMPs has been demonstrated along with successful treatment. Objective: Our aim was to test the influence of spironolactone in MMP2 levels. Methods: Secondary analysis of a prospective, interventional study including 100 patients with ADHF. Fifty patients were non-randomly assigned to spironolactone (100 mg/day) plus standard ADHF therapy (spironolactone group) or standard ADHF therapy alone (control group). Results: Spironolactone group patients were younger and had lower creatinine and urea levels (all p < 0.05). Baseline MMP2, NT-pro BNP and weight did not differ between spironolactone and control groups. A trend towards a more pronounced decrease in MMP2 from baseline to day 3 was observed in the spironolactone group (-21 [-50 to 19] vs 1.5 [-26 to 38] ng/mL, p = 0.06). NT-pro BNP and weight also had a greater decrease in the spironolactone group. The proportion of patients with a decrease in MMP2 levels from baseline to day 3 was also likely to be greater in the spironolactone group (50% vs 66.7%), but without statistical significance. Correlations between MMP2, NT-pro BNP and weight variation were not statistically significant. Conclusion: MMP2 levels are increased in ADHF. Patients treated with spironolactone may have a greater reduction in MMP2 levels. .

Fundamento: As metaloproteinases de matriz (MMPs) constituem uma família de enzimas importantes para a reabsorção da matriz extracelular e controle do remodelamento e da reparação vasculares. Demonstrou-se aumento da atividade de MMP2 na insuficiência cardíaca, e, na insuficiência cardíaca agudamente descompensada (ICAD), demonstrou-se uma diminuição nas MMPs circulantes juntamente com o tratamento bem-sucedido. Objetivos: Testar a influência da espironolactona nos níveis de MMP2. Métodos: Análise secundária de estudo prospectivo, intervencionista, incluindo 100 pacientes com ICAD, 50 designados não aleatoriamente para o uso de espironolactona (100 mg/dia) mais terapia padrão para ICAD (grupo espironolactona) e 50 para terapia padrão para ICAD apenas (grupo controle). Resultados: Os pacientes do grupo espironolactona eram mais jovens e tinham níveis mais baixos de creatinina e ureia (todos p < 0,05). Os valores basais de MMP2, NT-pro BNP e peso não diferiram entre os grupos espironolactona e controle. Observou-se tendência para uma redução mais pronunciada na MMP2 do basal para o dia 3 no grupo espironolactona (-21 [-50 a 19] vs 1,5 [-26 a 38] ng/ml, p = 0,06). Os valores de NT-pro BNP e peso também apresentaram maior diminuição no grupo espironolactona. A proporção de pacientes com redução nos níveis de MMP2 do basal para o dia 3 também foi maior no grupo espironolactona (50% vs 66,7%), embora sem significado estatístico. As correlações entre as variações de MMP2, NT-pro BNP e peso não apresentaram significado estatístico. Conclusões: Os níveis de MMP2 acham-se aumentados na ICAD. Pacientes tratados com espironolactona podem apresentar maior redução nos níveis de MMP2. .

High-sensitivity troponin T: a biomarker for diuretic response in decompensated heart failure patients.

Background. Patients presenting with acutely decompensated heart failure (ADHF) and positive circulating cardiac troponins were found to be a high-risk cohort. The advent of high-sensitive troponins resulted in a detection of positive troponins in a great proportion of heart failure patients. However, the pathophysiological significance of this phenomenon is not completely clear. Objectives. The aim of this study is to determine the early evolution and clinical significance of high-sensitivity troponin T (hsTnT) in ADHF. Methods. Retrospective, secondary analysis of a prospective study including 100 patients with ADHF. Results. Globally, high-sensitivity troponin T decreased from day 1 to day 3 (P = 0,039). However, in the subgroup of patients who remained decompensated no significant differences in hsTnT from day 1 to day 3 were observed (P = 0,955), whereas in successfully compensated patients a significant reduction in hsTnT levels was observed (P = 0,025). High-sensitivity troponin T decrease was correlated with NTproBNP reduction (P = 0,007). Patients with hsTnT increase had longer length of stay (P = 0,033). Conclusions. Episodes of ADHF are associated with transient increases in the blood levels of hsTnT that are reduced with effective acute episode treatment. The decrease in hsTnT can translate less myocardial damage along with favourable ADHF treatment.

The role of albuminuria as a non-invasive marker for congestive acutely decompensated chronic heart failure and the spironolactone effect in elderly Portuguese: a non-randomized trial.

BACKGROUND/OBJECTIVES: Albuminuria is a robust, validated cardiovascular risk factor. It is a simple and widely available test that was shown to be a powerful and independent predictor of prognosis in chronic heart failure. Mineralocorticoid receptor antagonists may reduce the acute and chronic harmful effects of mineralocorticoid receptor activation on the kidney. The objectives of the trial were to compare the effect of spironolactone versus standard acutely decompensated heart failure (ADHF) therapy on albuminuria and to investigate the role of albuminuria as a prognostic marker in patients with ADHF. METHODS: Secondary analysis of a prospective, interventional study including 100 patients with ADHF. Fifty patients were non-randomly assigned to spironolactone 100 mg/day plus standard ADHF therapy (intervention group) or standard ADHF therapy alone (control group). RESULTS: Patients in control group were older, had higher creatinine and urea levels, and had higher proportion of microalbuminuria (all, P < 0.05). Paired comparison of baseline and day 3 log albuminuria within each group, showed a more pronounced decrease in the intervention group (1.79 ± 0.75 to 1.59 ± 0.67, P = 0.003 vs 1.89 ± 0.70 to 1.79 ± 0.74, P = 0.096). In addition, the proportion of patients with normoalbuminuria increased from baseline to day 3 in spironolactone group (20 (40%) to 27 (54%), P < 001), accordingly the number of patients in the micro and macroalbuminuria groups was reduced. Day 1 albuminuria was positively correlated with day 1 N-terminal pro-brain natriuretic peptide (0.260 [0.105-0.758], P = 0.009). CONCLUSIONS: High-dose spironolactone added to standard ADHF therapy is likely to induce a more pronounced albuminuria decrease and a significant reduction in the proportion of micro and macroalbuminuria.

Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failure.

BACKGROUND/OBJECTIVES: Mineralocorticoid receptor antagonist (MRA) use in acutely decompensated chronic heart failure (ADCHF) may improve congestion through diuretic effect and prevent neurohormonal activation. We aimed to evaluate the clinical effect and safety of spironolactone in ADCHF. METHODS: Prospective, experimental, single-center, and single-blinded trial. Patients were treated with: standard ADCHF therapy or oral spironolactone 50-100mg/d plus standard ADCHF therapy. RESULTS: During a 1year period, 100 patients were enrolled, 50 included in the treatment group. Mean (SD) spironolactone dose (mg) at day 1 was 94.5±23.3 and at day 3 was 62.7±24.3. Worsening renal function (increase in pCr≥0.3mg/dL from day 1 to day 3) was more likely to occur in control group (20% vs. 4%; p=0.038), serum potassium did not differ between groups, and plasma NTproBNP had a significant decrease in spironolactone group at day 3 (median [IQR], 2488 [4579] vs. 1555 [1832]; p=0.05). Furthermore, a greater proportion of patients in the treatment group were free of congestion at day 3: less edema, rales, jugular venous pressure (JVP) and orthopnea (all, p<0.05). In addition, a significantly higher proportion of patients were on oral furosemide at day 3 (44% vs. 82%; p<0.001). CONCLUSIONS: Our study supports the safety of high dose spironolactone in ADCHF and suggests a positive impact in the resolution of congestion. The important findings of our pilot study need to be confirmed in larger trials.

Tailoring diuretic therapy in acute heart failure: insight into early diuretic response predictors.

BACKGROUND/OBJECTIVES: Few data exist to help physicians in the use of diuretics to provide the greatest symptomatic benefit with the least adverse effect to patients and to select the subset of patients who require a more aggressive diuretic strategy and monitoring. The aim of this study is to identify early predictors of diuretic response in a selected group of patients with acutely decompensated chronic heart failure (ADCHF). METHODS: This was an observational, retrospective secondary analysis of a study including 100 patients with ADCHF. RESULTS: The mean ± standard deviation (SD) of age was 76.0 ± 10.9 years. Sixty-one patients were female. After three days of inpatient treatment, 16 (16 %) patients maintained or increased i.v. furosemide dose (slow diuretic response, SDR). This group of patients had more indirect signs of fluid overload, including greater body mass index increment. The other 84 patients had greater congestion relief and had decreased i.v. furosemide dose or were switched furosemide to oral route (fast diuretic response, FDR). Admission day factors predicting SDR were: higher levels of pUr (mean ± SD, 69.6 ± 20.9 vs. 52.5 ± 19.8, p = 0.002), higher levels of pUr/pCr ratio (mean ± SD, 58.3 ± 15.2 vs. 49.6 ± 15.1, p = 0.036), higher levels of albuminuria [median (IQR), 131.5 (396.9) vs. 47.1 (143.6), p = 0,011], higher levels of red cell distribution width (RDW) [median (IQR), 16.0 (1.9) vs. 15.1 (1.5), p = 0.039], lower levels of HgB (mean ± SD, 11.5 ± 1.8 vs. 12.6 ± 2.1, p = 0.04) and higher levels of hsTnT [median (IQR), 0.05 (0.05) vs. 0.03 (0.03), p = 0,026]. By multivariate analysis, the strongest independent early predictors of SDR were: pUr [OR (95 % CI), 1.04 [1.01-1.07], p = 0.006] and RDW [OR (95 % CI), 1.47 (1.07-2.02), p = 0.018]. During the first 3 days of hospitalization, the strongest independent factor associated with SDR was NTproBNP increase or decrease by less than 30 % from day 1 to day 3 [OR (95 % CI), 4.84 (1.14-20.55), p = 0.032]. Use of high-dose spironolactone was associated with FDR [OR (95 % CI), 0.17 (0.03-0.85), p = 0.031]. CONCLUSIONS: High RDW and high levels of pUr at admission are strong predictors of slower diuretic response. No change or increase in NTproBNP in the first 3 days of treatment is associated with slower diuretic response. On the other hand, the use of high-dose spironolactone is associated with faster diuretic response.