Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Early biological therapy within 12 months of diagnosis leads to higher transmural healing rates in Crohn's disease.

BACKGROUND & AIMS: Transmural healing (TH) is emerging as a potential Crohn´s Disease (CD) treatment target. Early biological treatment seems to be associated with improved disease outcomes, but its impact on TH remains unclear. We aimed to assess the impact of early biological treatment initiation on TH and its influence on CD prognosis. METHODS: This multicenter retrospective study included adult CD patients starting biological therapy. TH was assessed using magnetic resonance enterography (MRE) at 12±6 months post-therapy initiation, with radiological examinations reviewed by blinded expert radiologists. TH was defined as complete normalization of all MRE parameters. Timing of biological therapy initiation was analyzed as a continuous variable, with optimal cut-off determined using the Youden index and clinical relevance. Logistic regression with propensity score-adjusted analysis was used to assess the association between early biological therapy initiation and TH. Long-term outcomes (bowel damage progression, CD-related surgery, CD-flare hospitalization, and therapy escalation) were evaluated. RESULTS: Among 154 CD patients, early biological therapy initiation within 12 months of diagnosis was associated with significantly higher TH rates (aOR 3.23, 95% CI 1.36-7.70, p<0.01), which persisted after adjusting for previous biological therapy use (aOR 2.82, 95% CI 1.13-7.06, p=0.03). Time-to-event analysis demonstrated that TH was significantly associated with reduced time until bowel damage progression (aHR 0.28, 95% CI 0.10-0.79, p=0.02), CD-related surgery (aHR 0.21, 95% CI 0.05-0.88, p=0.03) and therapy escalation (aHR 0.35, 95%CI 0.14-0.88, p=0.02), independently of early biological therapy. CONCLUSIONS: Early initiation of biological therapy within 12 months of diagnosis significantly increases TH rates, leading to improved long-term outcomes in CD patients.

Interleukin-6, infection and cardiovascular outcomes in acute heart failure: Findings from the EDIFICA registry.

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 log2 3.69, 95% confidence interval (CI) 1.26-10.8, p =.017) and the composite of HF rehospitalization or cardiovascular death (hazard ratio per log2 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.

Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection.

Hydroxychloroquine sulfate (HCQ) is being scrutinized for repositioning in the treatment and prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This antimalarial drug is also chronically used to treat patients with autoimmune diseases. By analyzing the Portuguese anonymized data on private and public based medical prescriptions we have identified all cases chronically receiving HCQ for the management of diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. Additionally, we have detected all laboratory confirmed cases of SARS-CoV-2 infection and all laboratory confirmed negative cases in the Portuguese population (mandatorily registered in a centrally managed database). Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases of SARS-CoV-2 infection with laboratory confirmed negative cases. Out of 26 815 SARS-CoV-2 positive patients, 77 (0.29%) were chronically treated with HCQ, while 1215 (0.36%) out of 333 489 negative patients were receiving it chronically (P = .04). After adjustment for age, sex, and chronic treatment with corticosteroids and/or immunosuppressants, the odds ratio of SARS-CoV-2 infection for chronic treatment with HCQ has been 0.51 (0.37-0.70). Our data suggest that chronic treatment with HCQ confer protection against SARS-CoV-2 infection.

Management of RAASi-associated hyperkalemia in patients with cardiovascular disease.

Renin-angiotensin-aldosterone system inhibitors (RAASi) reduce morbidity and mortality in heart failure (HF) with reduced ejection fraction in a dose-dependent manner. They also have a positive impact in other cardiovascular diseases (CVDs). However, RAASi may induce hyperkalemia, a potentially life-threatening disorder. This risk is further increased in those with concomitant chronic kidney disease, diabetes mellitus, and/or in patients with hypertension. Current treatment guidelines recommend maximal RAASi dosing to improve clinical outcomes; however, this is often limited by the development of hyperkalemia. When this occurs, current guidelines recommend RAASi down-titration/interruption, which, while improving short-term prognosis, is associated with a negative long-term prognostic impact. At present, the European Society of Cardiology suggests the consideration of novel potassium binders (patiromer and sodium zirconium cyclosilicate) for the management of RAASi-associated hyperkalemia. Both drugs can reduce serum potassium levels and prevent recurrent hyperkalemia. Additionally, patiromer showed enabling of RAASi optimization in high-risk patients. Nevertheless, precise recommendations on the use of these drugs are lacking. Building upon current HF guideline recommendations, a multidisciplinary expert panel convened to design an algorithm providing practical guidance on the use of novel potassium binders/patiromer in patients with HF and/or other CVD. As a result of that effort, we present an evidence-based treatment algorithm for the management of hyperkalemia with novel potassium binders/patiromer in patients with HF and/or other CVD receiving RAASi, including the necessary monitoring to avoid induction of hypokalemia. This algorithm aims to maintain or up-titrate RAASi to optimized doses, while maintaining normokalemia, improved clinical outcomes, and long-term prognosis.

The prognostic impact of uric acid in acute heart failure according to coexistence of diabetes mellitus.

BACKGROUND AND AIMS: Increased uric acid levels predict higher mortality in heart failure (HF) patients. Patients with diabetes mellitus (DM) appear to have increased xanthine oxidase activity. We aimed to study if the association between uric acid and mortality in acute HF was different according to the coexistence of DM. METHODS AND RESULTS: We studied a cohort of patients hospitalized due to acute HF in 2009-2010. Patients with no uric acid measurement upon admission were excluded from the analysis. FOLLOW-UP: 2 years; endpoint: all-cause mortality. Patients with elevated uric acid (>80.0 mg/L) were compared with those with lower values. We used a multivariate Cox-regression analysis to assess the prognostic impact of uric acid (both continuous and categorical variable: cut-off 80.0 mg/L). The analysis was stratified according to coexistence of DM. We studied 569 acute HF patients, 44.6%male, mean age 76 years, 290 were diabetic. Median admission uric acid: 81.2 mg/L and 52.2%had uric acid >80.0 mg/L. Elevated uric acid predicted all-cause mortality in acute HF only in patients with DM. The multivariate-adjusted HR of 2-year mortality was 1.68 (95 % CI: 1.15-2.46) for diabetic HF patients with uric acid>80.0 mg/L compared to those with lower levels (p = 0.008) and 1.10 (95 % CI: 1.03-1.18) per each 10 mg/L increase in uric acid (p = 0.007). In non-diabetic HF patients, uric acid was not associated with mortality. CONCLUSIONS: Increased uric acid predicts ominous outcome in acute HF patients with diabetes, however, it is not prognostic associated in non-diabetics. Uric acid may play a different role in acute HF depending on DM status.

From left ventricular ejection fraction to cardiac hemodynamics: role of echocardiography in evaluating patients with heart failure.

In clinical practice heart failure (HF) patients are generally classified on the basis of left ventricular (LV) ejection fraction. This approach, however, has important limitations. According to the definition of HF as a clinical syndrome that results from any impairment of LV filling or ejection of blood, a more articulated hemodynamic categorization of HF patients taking into account both LV forward flow and filling pressure would be desirable. However, the reliability of hemodynamic measures using echocardiographic techniques, which are the most used in current clinical practice for evaluation of HF patients, needs to be clarified. The aim of this article, therefore, is to verify whether echocardiography has acceptable feasibility, accuracy and reproducibility for the noninvasive evaluation of LV hemodynamics. This evaluation is necessary to progress to a hemodynamic characterization of HF patients that would ultimately overcome the HF classification based on ejection fraction.

Sodium-Glucose Co-transporter 2 Inhibitors in the Failing Heart: a Growing Potential.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new drug class designed to treat patients with type 2 diabetes (T2D). However, cardiovascular outcome trials showed that SGLT2i also offer protection against heart failure (HF)-related events and cardiovascular mortality. These benefits appear to be independent of glycaemic control and have recently been demonstrated in the HF population with reduced ejection fraction (HFrEF), with or without T2D. This comprehensive, evidence-based review focuses on the published studies concerning HF outcomes with SGLT2i, discussing issues that may underlie the different results, along with the impact of these new drugs in clinical practice. The potential translational mechanisms behind SGLT2i cardio-renal benefits and the information that ongoing studies may add to the already existing body of evidence are also reviewed. Finally, we focus on practical management issues regarding SGLT2i use in association with other T2D and HFrEF common pharmacological therapies. Safety considerations are also highlighted. Considering the paradigm shift in T2D management, from a focus on glycaemic control to a broader approach on cardiovascular protection and event reduction, including the potential for wide SGLT2i implementation in HF patients, with or without T2D, we are facing a promising time for major changes in the global management of cardiovascular disease.

Is there a C-reactive protein value beyond which one should consider infection as the cause of acute heart failure?

BACKGROUND: Heart Failure (HF) is a low grade inflammatory condition. High sensitivity C-reactive protein (hsCRP) is an established marker of inflammation. A cut-off value of hsCRP beyond which an infection should be sought has never been studied in HF. We aimed to determine the best hsCRP cut-off for infection prediction in acute HF. METHODS: We analyzed patients included in an acute HF registry - EDIFICA (Estratificação de Doentes com InsuFIciência Cardíaca Aguda). Admission hsCRP measurement was available as part of the registry's protocol. Patients with acute coronary syndrome as the cause of acute HF were excluded from the registry. Infection was considered according to the diagnosis registered in the discharge record. A receiver-operating characteristic (ROC) curve was used to determine the best hsCRP cut-off for infection prediction. RESULTS: We studied 615 patients. Mean age was 76 years, 45.2% were male, 60.3% had systolic dysfunction. Median admission hsCRP was 20.3 (9.5-55.5)mg/L; in 41.6% the cause of decompensation was an infection. The area under the ROC curve for admission hsCRP in the prediction of infection was 0.79 (0.76-0.83); the best hsCRP cut-off was 25 mg/L with a sensitivity of 72.7%, specificity 77.2%, positive predictive value 69.4% and negative predictive value 79.9%. Age and elevated hsCRP independently associated with an infection as the precipitant of acute HF. CONCLUSIONS: We suggest 25 mg/L as a cut-off beyond which an infection should be sought underlying acute HF. Almost 80% of the patients with hsCRP< 25 mg/L are not infected and 69.4% of those with higher hsCRP have a concomitant infection.

Prognostic Effect of the Dose of Loop Diuretic Over 5 Years in Chronic Heart Failure.

BACKGROUND: High diuretic doses in chronic heart failure (HF) are potentially deleterious. We assessed the effect of dynamic furosemide dose on all-cause mortality among HF ambulatory patients. METHODS AND RESULTS: A cohort of 560 ambulatory patients from an outpatient clinic specialized in HF, with median age 70 years, 67% male, and 89% with moderate-severely reduced ejection fraction, was retrospectively followed for up to 5 years. Dynamic furosamide exposure was categorized as low (0-59 mg/d), medium (60-119 mg/d), high (120-159 mg/d), and very high (≥160 mg/d). Extended Cox models were used to estimate the association between time-varying diuretic dose and mortality. A dose-dependent crude association between higher doses of furosemide and death (hazard ratio [HR] = 1.34, 95% confidence interval (CI): 1.06-2.16; HR = 2.09, 95% CI: 1.54-2.84, for high and very high dose, respectively) was totally explained by patients' characteristics and disease severity indicators (adjusted HR = 0.94, 95% CI: 0.63-1.38; HR = 1.10, 95% CI: 0.79-1.55, for high and very high dose, respectively). CONCLUSION: In this context, higher doses of diuretic did not impair survival, but rather indicated greater severity of the patient's condition.

Prognostic prediction in acute heart failure patients with extreme BNP values.

BACKGROUND: Some patients have good prognosis despite elevated B-type natriuretic peptide (BNP), while others have ominous outcome with low BNP. We aimed at characterising these groups of patients. METHODS: We analysed patients prospectively included in an acute HF registry. Vital status within 1-year post discharge was ascertained. A receiver-operating characteristic curve was used to define discharge BNP cut-offs for 1-year death prediction. Among survivors, we compared patients with low and not-low BNP (cut-off 400 pg/mL); and among non-survivors those with high vs not-high BNP (cut-off 2000 pg/mL). In the specific subgroups of patients with low and high BNP, mortality predictors were assessed with multivariate Cox-regression analysis. RESULTS: We studied 584 patients, median age 78 years, 62.5% had HF with reduced ejection fraction; and 199 (34.1%) died during the first year. Non-survivors were very homogeneous irrespective of BNP, survivors were substantially different. In patients discharged with BNP <400 pg/mL, increasing age independently predicted death; when BNP ≥2000 pg/mL death predictors were higher NYHA class, and non-use of evidence-based therapy. BNP was outcome associated in both groups. CONCLUSIONS: Different prognostic predictors may play a role in different BNP levels. We suggest that risk stratification in HF would probably be more accurate if made on top of BNP knowledge.

Evaluation of Innate Immunity Biomarkers on Admission and at Discharge From an Acute Heart Failure Episode.

BACKGROUND: The involvement of the immune system in heart failure (HF) has been demonstrated. Evidence shows that innate immunity can have a role in the remodeling process and progression of HF. With previous studies showing the prognostic value of some innate immunity markers and their relevance in this condition, we aim to evaluate how these markers vary on hospitalization due to an acute episode of HF and at discharge. METHODS: About 154 patients admitted with acute HF were prospectively recruited. Patients were evaluated on admission and at discharge from the hospital. Patients with infection were separately analyzed. Innate immunity, inflammatory, and cardiac biomarkers were measured and were compared between groups and between admission and discharge and with reference values of biological variation. RESULTS: Median patients' age was 78 years, and half of the patients were men. The median duration of hospitalization was 6 days. C3 and C4 protein levels significantly increased (P < 0.001) between admission and discharge, as well as eosinophils (P < 0.001) and BNP levels decreased (P < 0.001). Variation in all these variables was independent of infection and biological variation. CONCLUSION: Our results show that innate immunity markers such as C3 and C4 increase after treatment for acute HF, supporting the hypothesis that they can be involved in the resolution of the acute episode.

Diastolic dysfunction in the diabetic continuum: association with insulin resistance, metabolic syndrome and type 2 diabetes.

BACKGROUND: Diabetes increases the risk of heart failure but the underlying mechanisms leading to diabetic cardiomyopathy are poorly understood. Left ventricle diastolic dysfunction (LVDD) is one of the earliest cardiac changes in these patients. We aimed to evaluate the association between LVDD with insulin resistance, metabolic syndrome (MS) and diabetes, across the diabetic continuum. METHODS: Within a population-based study (EPIPorto), a total of 1063 individuals aged ≥45 years (38% male, 61.2 ± 9.6 years) were evaluated. Diastolic function was assessed by echocardiography, using tissue Doppler analysis (E' velocity and E/E' ratio) according to the latest consensus guidelines. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score. RESULTS: The HOMA-IR score correlated to E' velocity (ρ = -0.20;p < 0.0001) and E/E' ratio (ρ = 0.20; p < 0.0001). There was a progressive worsening in E' velocity (p for trend < 0.001) and in E/E' ratio across HOMA-IR quartiles (p for trend <0.001). Individuals in the highest HOMA-IR quartile were more likely to have LVDD, even after adjustment for age, sex, blood pressure and body mass index (adjusted OR: 1.82; 95% CI: 1.09-3.03). From individuals with no MS, to patients with MS and no diabetes, to patients with diabetes, there was a progressive decrease in E' velocity (11.2 ± 3.3 vs 9.7 ± 3.1 vs 9.2 ± 2.8 cm/s; p < 0.0001), higher E/E' (6.9 ± 2.3 vs 7.8 ± 2.7 vs 9.0 ± 3.6; p < 0.0001) and more diastolic dysfunction (adjusted OR: 1.62; 95% CI: 1.12-2.36 and 1.78; 95% CI: 1.09-2.91, respectively). CONCLUSIONS: HOMA-IR score and metabolic syndrome were independently associated with LVDD. Changes in diastolic function are already present before the onset of diabetes, being mainly associated with the state of insulin resistance.

Assessment of cardiovascular physiology using dobutamine stress cardiovascular magnetic resonance reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy.

BACKGROUND: Liver cirrhosis has been shown to affect cardiac performance. However cardiac dysfunction may only be revealed under stress conditions. The value of non-invasive stress tests in diagnosing cirrhotic cardiomyopathy is unclear. We sought to investigate the response to pharmacological stimulation with dobutamine in patients with cirrhosis using cardiovascular magnetic resonance. METHODS: Thirty-six patients and eight controls were scanned using a 1.5 T scanner (Siemens Symphony TIM; Siemens, Erlangen, Germany). Conventional volumetric and feature tracking analysis using dedicated software (CMR42; Circle Cardiovascular Imaging Inc, Calgary, Canada and Diogenes MRI; Tomtec; Germany, respectively) were performed at rest and during low to intermediate dose dobutamine stress. RESULTS: Whilst volumetry based parameters were similar between patients and controls at rest, patients had a smaller increase in cardiac output during stress (p = 0.015). Ejection fraction increase was impaired in patients during 10 µg/kg/min dobutamine as compared to controls (6.9 % vs. 16.5 %, p = 0.007), but not with 20 µg/kg/min (12.1 % vs. 17.6 %, p = 0.12). This was paralleled by an impaired improvement in circumferential strain with low dose (median increase of 14.4 % vs. 30.9 %, p = 0.03), but not with intermediate dose dobutamine (median increase of 29.4 % vs. 33.9 %, p = 0.54). There was an impaired longitudinal strain increase in patients as compared to controls during low (median increase of 6.6 % vs 28.6 %, p < 0.001) and intermediate dose dobutamine (median increase of 2.6%vs, 12.6 % p = 0.016). Radial strain response to dobutamine was similar in patients and controls (p > 0.05). CONCLUSION: Cirrhotic cardiomyopathy is characterized by an impaired cardiac pharmacological response that can be detected with magnetic resonance myocardial stress testing. Deformation analysis parameters may be more sensitive in identifying abnormalities in inotropic response to stress than conventional methods.

Impaired resolution of inflammation in human chronic heart failure.

BACKGROUND: Lipoxins (LXs) are proresolving and anti-inflammatory eicosanoids whose role in chronic heart failure (CHF) pathogenesis has never been investigated. This study evaluated levels of LXs in CHF patients, its relationship with disease severity and correlation with established CHF biomarkers. The effect of low-dose aspirin [acetylsalicylic acid (ASA)] on the levels of LXs was also studied. MATERIALS AND METHODS: Lipoxin A4 (LXA4 ), 15-epi-lipoxin A4 (15-epi-LXA4 ) and myeloperoxidase (MPO) concentration and activity were evaluated by immunoenzymatic and spectrophotometric assays in 34 CHF patients [New York Heart Association (NYHA) functional class I to IV]. B-type natriuretic peptide (BNP), troponin, myoglobin, C-reactive protein (CRP) and uric acid (UA) were also analyzed. RESULTS: Patients were stratified into mild-to-moderate CHF (NYHA, classes I and II) and severe CHF (NYHA classes III and IV). Severe patients had lower plasma LXA4 (0·262 ± 0·034 vs. 0·362 ± 0·039 ng/mL, P < 0·05) and decreased urinary 15-epi-LXA4 levels (2·28 ± 0·44 vs. 4·88 ± 1·03 µg/day, P < 0·05) besides exhibiting increased plasma BNP (1464 ± 442 vs. 555 ± 162 pg/mL, P < 0·05) and MPO activity (45·15 ± 11·56 vs. 15·90 ± 2·80 µmol/min/mg protein, P < 0·05). Plasma LXA4 was inversely correlated with BNP, troponin, myoglobin, CRP, UA and MPO activity. ASA treatment was associated with higher urinary excretion of 15-epi-LXA4 (7·70 ± 1·48 vs. 2·06 ± 0·30 µg/day, P < 0·05) in mild-to-moderate CHF patients and lower BNP levels in both groups. CONCLUSIONS: Higher severity of CHF is associated with reduced levels of LXs. Plasma LXA4 appears to be a valuable marker for risk stratification in CHF. Furthermore, the ASA-related increase in urinary 15-epi-LXA4 suggests enhanced renal synthesis of this eicosanoid and may represent a disregarded benefit of ASA.

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.

Elevated Cystatin C Predicts Higher Mortality in Chronic Heart Failure Independently of Renal Function.

INTRODUCTION: Cystatin C (CysC) is a known prognostic marker in cardiovascular diseases and its role in acute heart failure (HF) has been documented. METHODS: We prospectively recruited HF patients followed in a HF clinic. Inclusion criteria: HF diagnosed ≥6 months, optimized evidence-based therapy, and ejection fraction <40% (Heart Failure with reduced ejection fraction). Exclusion criteria: renal replacement therapy and hospitalizations or therapeutic adjustments in the previous 2 months. A venous blood sample and 24-hour urine were collected. Follow-up: 5 years; endpoint: all-cause mortality. CysC was measured and creatinine clearance (CrCl) was calculated using 24-hour urine creatinine excretion. A Receiver operating characteristic curve was used to assess association of CysC with 5-year mortality. The prognostic role of CysC was determined using Cox-regression analysis. The multivariate model included CrCl (24-hour urine). RESULTS: We evaluated 215 chronic stable Heart Failure with reduced ejection fraction patients. Mean age was 68 years, 72.1% were male. Median CysC = 1.15 mg/L, creatinine = 1.20 mg/dL, and CrCl = 63.6 mL/min. During follow-up, 103 (47.9%) patients died. The area under the curve for CysC in predicting mortality was 0.77 (0.70-0.83). Best cut-off value for death prediction = 1.00 mg/L with a sensitivity = 83.5%, specificity = 56.2%, positive predictive value = 63.7%, and negative predictive value = 78.7%. Multivariate-adjusted (age-, B-type natriuretic peptide-, evidence-based therapy, New York Heart Association class, and CrCl) 5-year mortality Hazard ratio = 2.40 (95% Confidence interval, 1.25-4.61), P value = 0.008 when CysC ≥1.00 mg/L. CONCLUSIONS: Patients with CysC <1.00 mg/L have almost 80% probability of being alive at 5 years; If CysC ≥1.00 mg/L, there is almost 2.5-fold higher death risk independently of B-type natriuretic peptide and CrCl.

Biosensors for natriuretic peptides in cardiovascular diseases. A review.

Heart failure (HF) is a complex clinical syndrome associated with high rates of morbidity and mortality. Over the years, it has been crucial to find accurate biomarkers capable of doing a precise monitor of HF and provide an early diagnosis. Of these, it has been established an important role of natriuretic peptides in HF assessment. Moreover, the development of biosensors has been garnering interest as new diagnostic medical tools. In this review we first provide a general overview of HF, its pathogenesis, and diagnostic features. We then discuss the role of natriuretic peptides in heart failure by characterizing them and point out their potential as biomarkers. Finally, we adress the evolution of biosensors development and the available natriuretic peptides biosensors for disease monitoring.

Prognostic association of circulating relaxin-2 in acute heart failure.

BACKGROUND: Despite the increasing interest in the study of the endogenous relaxin system in heart failure (HF), its role as a prognostic marker in acute HF remains unclear. We aimed to evaluate the association of relaxin-2 circulating levels with 6 months' mortality in acute HF. METHODS: We evaluated relaxin-2 serum levels at admission in a cohort of patients with acute HF (n = 202) using an enzyme immunoassay. The ability of relaxin-2 to predict all-cause death (primary outcome) and HF-specific death (secondary outcome) at 6 months was assessed using Cox-regression analysis. RESULTS: The median age was 79 (70-85) years old, 44% of the patients were male, and 43% had preserved ejection fraction (≥50%). Median serum relaxin-2 level was 25 pg/mL. Patients with higher relaxin-2 levels had more peripheral oedemas, higher sodium retention score, higher pulmonary artery pressures, higher prevalence of right ventricle dysfunction and lower inferior vena cava collapse at inspiration. Conversely, there was no association with left chambers parameters or with B-type natriuretic peptide (BNP). Higher relaxin-2 concentrations were associated with a higher risk of all-cause death [HR 1.15; 95%CI 1.01,1.30; P = 0.030] and HF-specific death [HR 1.21; 95% CI 1.03-1.42; P = 0.018], after adjustment for classical prognostic factors such as age, sex and BNP. CONCLUSIONS: In our acute HF population, relaxin-2 circulating levels were associated with clinical and echocardiographic markers of systemic congestion and with 6-months' mortality, independently of BNP. These results lay the groundwork for future investigations on the potential of relaxin-2 as an auxiliary biomarker in HF.