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The associations of plasma metabolites with adverse cardiovascular (CV) outcomes are still underexplored and may be useful in CV risk stratification. We performed a systematic review and meta-analysis to establish correlations between blood metabolites and adverse CV outcomes in patients with heart failure (HF). Four cohorts were included, involving 83 metabolites and 37 metabolite ratios, measured in 1158 HF patients. Hazard ratios (HR) of 42 metabolites and 3 metabolite ratios, present in at least two studies, were combined through meta-analysis. Higher levels of histidine (HR 0.74, 95% CI [0.64; 0.86]) and tryptophan (HR 0.82 [0.71; 0.96]) seemed protective, whereas higher levels of symmetric dimethylarginine (SDMA) (HR 1.58 [1.30; 1.93]), N-methyl-1-histidine (HR 1.56 [1.27; 1.90]), SDMA/arginine (HR 1.38 [1.14; 1.68]), putrescine (HR 1.31 [1.06; 1.61]), methionine sulfoxide (HR 1.26 [1.03; 1.52]), and 5-hydroxylysine (HR 1.25 [1.05; 1.48]) were associated with a higher risk of CV events. Our findings corroborate important associations between metabolic imbalances and a higher risk of CV events in HF patients. However, the lack of standardization and data reporting hampered the comparison of a higher number of studies. In a future clinical scenario, metabolomics will greatly benefit from harmonizing sample handling, data analysis, reporting, and sharing.

Background: Recent heart failure (HF) guidelines have re-classified HF patients with left ventricular ejection fraction (LVEF) between 41% and 49% as HF with mildly reduced ejection fraction (HFmrEF). HFmrEF treatment is often considered a grey zone as no randomized controlled trials (RCTs) were conducted exclusively on these patients., Aims: A network meta-analysis (NMA) was performed to compare treatment effect of mineralocorticoid receptor antagonists (MRA), angiotensin receptor neprilysin inhibitor (ARNi), angiotensin receptor blockers (ARB), angiotensin-converting-enzyme inhibitors (ACEi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and beta-blockers (BB) in HFmrEF cardiovascular (CV) outcomes., Methods and Results: RCTs sub-analyses evaluating the efficacy of pharmacological treatment in HFmrEF patients were searched. Hazard ratios (HRs) and their variance were extracted from each RCT for (i) composite of CV death or HF hospitalizations, (ii) CV death, and (iii) HF hospitalizations. A random-effects NMA was performed to compare and assess the treatment efficiency. Six RCTs with subgroup analysis according to participants' ejection fraction, a patient-level pooled meta-analysis of two RCTs, and an individual patient-level analysis of eleven BB RCTs were included, totalling 7966 patients. To our primary endpoint, SGLT2i vs. placebo was the only comparison with significant results, with a 19% risk reduction in the composite of CV death or HF hospitalizations [HR 0.81, 95% confidence interval (CI) 0.67-0.98]. In HF hospitalizations, the impact of the pharmacological therapies was more notorious, and ARNi reduced in 40% the risk of HF hospitalizations (HR 0.60, 95% CI 0.39-0.92), SGLT2i in 26% (HR 0.74, 95% CI 0.59-0.93) and renin-angiotensin system inhibition (RASi) with ARB and ACEi in 28% (HR 0.72, 95% CI 0.53-0.98). Although BBs were globally less beneficial, they were the only class that supported a reduced risk of CV death (HR vs. placebo: 0.48, 95% CI 0.24-0.95). We did not observe a statistically significant difference in any comparison between active treatments. There was a sound reduction with ARNi on the primary endpoint (HR vs. BB: 0.81, 95% CI 0.47-1.41; HR vs. MRA 0.94, 95% CI 0.53-1.66) and on HF hospitalizations (HR vs. RASi 0.83, 95% CI 0.62-1.11; HR vs. SGLT2i 0.80, 95% CI 0.50-1.30)., Conclusions: In addition to SGLT2i, pharmacological treatment recommended for HF with reduced LVEF, namely, ARNi, MRA, and BB, can also be effective in HFmrEF. This NMA did not show significant superiority over any pharmacological class., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Interleukin-6 (IL-6) is upregulated in response to infectious and inflammatory triggers and independently predicts all-cause mortality in acute heart failure (AHF). However, the association of IL-6 with cardiovascular outcomes and its interplay with C-reactive protein and infection, a major precipitating factor in AHF, remains poorly understood., Methods and Results: The association between IL-6 and clinical outcomes (180 days) in AHF was evaluated using a cohort of 164 patients from the EDIFICA registry. Median IL-6 levels at admission were 17.4 pg/mL. Patients in the higher admission IL-6 tertile presented with lower blood pressure and more congestion, were diagnosed more frequently with infection, and had a longer hospital stay. Higher IL-6 levels were associated with increased risk of HF rehospitalization (hazard ratio per log 2 3.69, 95% confidence interval (CI) 1.26-10.8, p =.017) and the composite of HF rehospitalization or cardiovascular death (hazard ratio per log 2 3.50; 95% CI 1.28-9.57; p =.014), independently of major AHF prognosticators, including B-type natriuretic peptide and renal function. However, no independent associations were found for all-cause rehospitalization or mortality. Despite a moderate correlation of IL-6 with C-reactive protein (CRP) levels (R = .51), the latter were not associated with clinical outcomes in this population., Conclusions: IL-6 levels associate with higher rate of cardiovascular events in AHF, independently of classical prognosticators and evidence of infection, outperforming CRP as an inflammatory outcome biomarker., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Urocortin (Ucn)-2 has shown promising therapeutic effects on heart failure (HF). However, there are still significant knowledge gaps regarding the role and modulation of the endogenous Ucn-2 axis in the cardiovascular system and, specifically, in acute HF. We evaluated Ucn-2 levels in admission serum samples of 80 acute HF patients and assessed their association with clinical, analytical and echocardiographic parameters. Median age was 76.5 years, and 37 patients (46%) were male. Median serum Ucn-2 was 2.3ng/mL. Ucn-2 levels were positively associated with peripheral edemas (P = 0.022), hepatomegaly (P = 0.007) and sodium retention score (ρ = 0.37, P = 0.001) and inversely correlated with inferior vena cava collapse at inspiration (ρ = -0.37, P = 0.001). Additionally, patients with higher Ucn-2 levels had a higher prevalence of right atrial dilation (P = 0.027), right ventricle dilation (P = 0.008), and higher systolic pulmonary artery pressure (ρ = 0.34, P = 0.002). Regarding analytical parameters, Ucn-2 correlated positively with log BNP (r = 0.22, P = 0.055) and inversely with uric acid (r = 0.24, P = 0.029) and total (r = -0.30, P = 0.007) and low-density lipoprotein cholesterol (r = -0.23, P = 0.038). No associations were found between Ucn-2 and age, sex or left heart structure or function. In conclusion, Circulating Ucn-2 was associated with clinical and echocardiographic markers of volume overload and pulmonary hypertension in acute HF patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Rheumatoid arthritis (RA) patients have high risk of heart failure (HF)., Aims: Identifying the risk factors and mechanistic pathways associated with HF in patients with RA., Methods: Cohort study enrolling 355 RA patients. HF was defined according to the ESC criteria. 93 circulating protein-biomarkers (91CVDIIOlink®+troponin-T+c-reactive protein) were measured. Regression modeling (multivariate and multivariable) were built and network analyses were performed - based on the identified relevant protein biomarkers., Results: 115 (32.4%) patients fulfilled the ESC criteria for HF, but only 24 (6.8%) had a prior HF diagnosis. Patients with HF were older (67 vs. 55yr), had a longer RA duration (10 vs. 14yr), had more frequently diabetes, hypertension, obesity, dyslipidemia, atrial fibrillation, and ischemic arterial disease. Several protein-biomarkers remained independently associated with HF, the top (FDR1%) were adrenomedullin, placenta-growth-factor, TNF-receptor-11A, and angiotensin-converting-enzyme-2. The networks underlying the expression of these biomarkers pointed towards congestion, apoptosis, inflammation, immune system signaling and RAAS activation as central determinants of HF in RA. Similar HF-associated biomarker-pathways were externally found in patients without RA. Having RA plus HF increased the risk of cardiovascular events compared to RA patients without RF; adjusted-HR (95%CI)=2.37 (1.07-5.30), p=0.034 CONCLUSION: Age, cardiovascular risk factors, and RA duration increase the HF odds in patients with RA. Few RA patients had a correct prior HF diagnosis, but the presence of HF increased the patients` risk. RA patients with HF largely share the mechanistic pathways of HF patients without RA. Randomized HF trials should include patients with RA. CLINICALTRIALS., Gov Id: NCT03960515., (Copyright © 2020. Published by Elsevier B.V.)