Empleo de un score semicuantitativo en la valoración de la congestión pulmonar: prevalencia e implicaciones en el manejo diurético tras el alta por insuficiencia cardiaca / Semi-quantitative pulmonary congestion score: prevalence and diuretic management implications after heart failure discharge

Introducción La congestión persistente tras el alta por insuficiencia cardiaca (IC) se asocia a mayor riesgo de reingresos, siendo necesaria su valoración de forma precisa. Material y métodos Un total de 82 pacientes incluidos tras el alta por IC con el objetivo de caracterizar de forma sencilla y semicuantitativa el grado de congestión pulmonar y sus cambios, describiendo la relación entre dichos hallazgos y el manejo diurético. Resultados En la visita postalta, pese a la ausencia de congestión clínica en la mayoría de pacientes, la mitad presentaba algún grado de congestión pulmonar por ecografía. Tras valoración ecográfica y clínica en esta visita inicial se bajó el diurético en 50 pacientes (60%), se mantuvo igual en 16 (20%) y se aumentó en el resto. En los 45 pacientes sin congestión ecográfica, la bajada de diuréticos se intentó en el 80% siendo exitosa esta estrategia en la mayoría de ellos. Conclusiones La ecografía pulmonar, usando métodos de cuantificación sencillos, permite su incorporación real a nuestra práctica clínica ayudándonos en la toma de decisiones. (AU)

Introduction Persistent congestion after heart failure (HF) discharge is associated with a higher risk of readmissions. Material and methods Eighty-two patients included after HF discharge. The aim of the study was to characterize semiquantitatively the degree of pulmonary congestion and its changes, describing the relationship between these findings and diuretic management. Results On the first visit, despite the absence of clinical congestion in the majority of patients, half of the had some degree of pulmonary congestion by ultrasound. After global assessment in this initial visit (clinical and ultrasound) the diuretic was lowered in 50 patients (60%), kept the same in 16 (20%) and it was increased in the rest. In the 45 patients without ultrasound congestion, diuretic reduction was attempted in 80%, being this strategy successful in the majority of them. Conclusions Lung ultrasound, using simple quantification methods, allows its real incorporation into clinical practice, helping us in the decision making process. (AU)

Semi-quantitative pulmonary congestion score: prevalence and diuretic management implications after heart failure discharge.

INTRODUCTION: Persistent congestion after heart failure (HF) discharge is associated with a higher risk of readmissions. MATERIAL AND METHODS: eighty-two patients included after HF discharge. The aim of the study was to characterize semiquantitatively the degree of pulmonary congestion and its changes, describing the relationship between these findings and diuretic management. RESULTS: On the first visit, despite the absence of clinical congestion in the majority of patients, half of the had some degree of pulmonary congestion by ultrasound. After global assessment in this initial visit (clinical and ultrasound) the diuretic was lowered in 50 patients (60%), kept the same in 16 (20%) and it was increased in the rest. In the 45 patients without ultrasound congestion, diuretic reduction was attempted in 80%, being this strategy successful in the majority of them. CONCLUSIONS: Lung ultrasound, using simple quantification methods, allows its real incorporation into clinical practice, helping us in the decision making process.

Colchicine anti-inflammatory therapy for non-intensive care unit hospitalized COVID-19 patients: results from a pilot open-label, randomized controlled clinical trial.

Systemic inflammation is a hallmark of severe coronavirus disease-19 (COVID-19). Anti-inflammatory therapy is considered crucial to modulate the hyperinflammatory response (cytokine storm) in hospitalized COVID-19 patients. There is currently no specific, conclusively proven, cost-efficient, and worldwide available anti-inflammatory therapy available to treat COVID-19 patients with cytokine storm. The present study aimed to investigate the treatment benefit of oral colchicine for hospitalized COVID-19 patients with suspected cytokine storm. Colchicine is an approved drug and possesses multiple anti-inflammatory mechanisms. This was a pilot, open-label randomized controlled clinical trial comparing standard of care (SOC) plus oral colchicine (colchicine arm) vs. SOC alone (control arm) in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. Colchicine treatment was initiated within first 48 hours of admission delivered at 1.5 mg loading dose, followed by 0.5 mg b.i.d. for next 6 days and 0.5 mg q.d. for the second week. A total of 96 patients were randomly allocated to the colchicine (n=48) and control groups (n=48). Both colchicine and control group patients experienced similar clinical outcomes by day 14 of hospitalization. Treatment outcome by day 14 in colchicine vs control arm: recovered and discharged alive: 36 (75.0%) vs. 37 (77.1%), remain admitted after 14-days: 4 (8.3%) vs. 5 (10.4%), ICU transferred: 4 (8.3%) vs. 3 (6.3%), and mortality: 4 (8.3%) vs. 3 (6.3%). The speed of improvement of COVID-19 acute symptoms including shortness of breath, fever, cough, the need of supplementary oxygen, and oxygen saturation level, was almost identical in the two groups. Length of hospitalization was on average 1.5 day shorter in the colchicine group. There was no evidence for a difference between the two groups in the follow-up serum levels of inflammatory biomarkers including C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), ferritin, interleukin-6 (IL-6), high-sensitivity troponin T (hs-TnT) and N-terminal pro b-type natriuretic peptide (NT pro-BNP). According to the results of our study, oral colchicine does not appear to show clinical benefits in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. It is possible that the anti-inflammatory pathways of colchicine are not crucially involved in the pathogenesis of COVID-19.

Tocilizumab therapy for severely-ill COVID-19 pneumonia patients: a single-centre retrospective study.

Systemic hyperinflammation is a hallmark of severe coronavirus disease-2019 (COVID-19). Tocilizumab (TCZ) (an interleukin-6 receptor blocker) therapy is currently used as an anti-inflammatory intervention alongside corticosteroids to modulate the hyperinflammatory response (cytokine storm) in hospitalized patients with severe COVID-19 to prevent mortality. There is, however, a wide uncertainty about its pros and cons in patients with COVID-19, particularly, its possible immunosuppressive effect is of serious concern for the clinicians. The present study aimed to report response of a cohort of severely-ill hospitalized COVID-19 pneumonia patients who were treated with tocilizumab after the initial corticosteroids therapy failed to improve the patients' clinical condition. This was a single-arm retrospective study of 100 severely-ill COVID-19 pneumonia patients who were admitted to the specialized COVID-19 units of Mayo Hospital, Lahore, Pakistan from March 12, 2020, to May 25, 2021. These COVID-19 patients had progressed to cytokine storm with persistent hypoxia, associated with pneumonia, and markedly elevated serum levels of inflammatory biomarkers including C-reactive protein (CRP), D-dimer, and ferritin. All the patients had received two separate doses of intravenous 400 mg (4 mg/kg) tocilizumab with an 8-hour interval alongside standard COVID-19 care which includes corticosteroid, antibiotics, and anticoagulants. Following tocilizumab intervention, 75 (75.0%) patients showed clinical improvement, continued to recover, and were safely discharged from the hospital, while in 25 (25.0%) patients, TCZ failed to prevent clinical deterioration, and patients eventually died in the hospital. Amongst the 25 (25.0%) deaths, 8 (32.0%) patients had a single comorbidity, while 9 (36.0%) had two or more comorbidities. The median IQR age for survivors was 57.0 (50.0, 60.0) years, and non-survivors was 60.0 (55.0, 70.0) years; and the period of hospitalization was 25 (20, 40) days and 20 (14, 34) days, respectively. Tocilizumab treatment improved serum inflammatory biomarker levels including CRP, D-dimer, and ferritin, by almost a similar magnitude in both survivors and non-survivors. Development of secondary infections were reported in 25 (25.0%) patients, including 21% patients with bacterial (Pseudomonas, Klebsiella, Acinetobacter) and 4% with fungal (Aspergillus) infection. The emergence of secondary infection was higher in patients who died (72.0%) as compared to those who survived (28.0%). In conclusion: in low- and middle-income countries in the presence of limited therapeutic options, a timely intervention of TCZ alongside corticosteroids may be a suitable anti-inflammatory therapy for severely-ill hospitalized COVID-19 pneumonia patients to prevent mortality. However, patients must be closely monitored for secondary bacterial/fungal infections. Early diagnosis and management of secondary infection can reduce morbidity and mortality.

Management of patients with heart failure treated in cardiology consultations: IC-BERG Study. / Manejo de los pacientes con insuficiencia cardiaca atendidos en la consulta de cardiología: Estudio IC-BERG.

OBJECTIVE: To determine the perception and management of heart failure with reduced ejection fraction (HFrEF) by clinical cardiologists and to establish a consensus with recommendations. METHODS: We employed the modified Delphi method among a panel of 150 experts who answered a questionnaire that included three blocks: definition and perception of patients with «stable¼ HFrEF (15 statements), management of patients with «stable¼ HFrEF (51 statements) and recommendations for optimising the management and follow-up (9 statements). The level of agreement was assessed with a Likert 9-point scale. RESULTS: A consensus of agreement was reached on 49 statements, a consensus of disagreement was reached on 16, and 10 statements remained undetermined. There was consensus regarding the definition of «stable¼ HF (82%), that HFrEF had a silent nature that could increase the mortality risk for mildly symptomatic patients (96%) and that the drug treatment should be optimised, regardless of whether a patient with HFrEF remains stable in the same functional class (98.7%). In contrast, there was a consensus of disagreement regarding the notion that treatment with an angiotensin receptor-neprilysin inhibitor is justified only when the functional class worsens (90.7%). CONCLUSIONS: Our current understanding of «stable¼ HF is insufficient, and the treatment needs to be optimised, even for apparently stable patients, to decrease the risk of disease progression.

Differences in the Interleukin-1ß/Soluble ST2 Interplay Between Acute and Chronic Heart Failure.

Recently, novel findings about the interleukin 1ß (IL-1 ß) axis in acute decompensated heart failure (ADHF) have been published. There is a positive correlation between IL-1 ß and interleukin-1 receptor like 1 (sST2) in ADHF patients. Is there also a correlation between the values of IL-1 ß and sST2 in chronic heart failure patients?

Yin-Yang 1 transcription factor modulates ST2 expression during adverse cardiac remodeling post-myocardial infarction.

BACKGROUND: The cardioprotective effects of metformin remain poorly defined. Interleukin (IL)-33/ST2L signaling is a novel cardioprotective pathway, which is antagonized by the soluble isoform sST2. No data exist about the regulation of ST2 expression. This study aimed to evaluate the pathophysiological implication of Yin-Yang 1 (Yy1) transcription factor in cardiac remodeling and the expression of the soluble ST2 isoform. METHODS AND RESULTS: Myocardial infarction (MI) was induced in Wistar rats randomly receiving metformin or saline solution by permanent ligation of the left anterior coronary artery. In addition, a model of cardiomyocyte "biochemical strain" was used. Metformin administration improved post-MI cardiac remodeling, an effect that was associated with increased IL-33 and reduced sST2 levels in the myocardium. The anti-remodeling effects of metformin were also associated with a decrease in the transcription factor Yy1 intranuclear level and lower levels of phosphorylated HDAC4 within the cytoplasmic space. These effects were also observed in a cardiomyocyte biochemical strain model, where Yy1 silencing or HDAC4 inhibition blocked sST2 production in cardiomyocytes. Metformin blocked the HDAC4 phosphorylation induced by MI, preventing its export from the nucleus to the cytosol. The presence of dephosphorylated HDAC4 in the nucleus acted as a co-repressor of Yy1, repressing sST2 expression. CONCLUSION: The transcription factor Yy1 regulates sST2 expression, and repression of Yy1 by metformin results in lower levels of sST2 that are associated with favorable myocardial remodeling. The manipulation of YY1 or its co-repressor HDAC4 emerge as new targets to modulate ST2/IL33 signaling and prevent adverse cardiac remodeling.

Galectina-3 as a biomarker of acute kidney injury risk in patients with decompensated heart failure. / Galectina-3 como biomarcador de riesgo de daño renal agudo en pacientes con insuficiencia cardiaca descompensada.

INTRODUCTION: In decompensated heart failure (HF), both acute kidney injury (AKI) and high Galectina-3 (Gal-3) levels have been associated with poorer outcomes. Plasma Gal-3 levels are affected by renal function; however, the potential role of Gal-3 as a predictor of AKI has not been established. METHODS: We measured Gal-3 concentrations at admission for 175 patients hospitalised for HF and recorded the onset of AKI according to the Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) analytical criteria. RESULTS: During hospitalisation, 44 patients (25.1%) developed AKI, although only 14 (8%) corresponded to more advanced stages. These 14 patients had significantly higher Gal-3 levels at admission, which remained a predictor of AKI after the multivariate adjustment by other predictors and by baseline renal function. CONCLUSIONS: High Gal-3 levels at admission are associated with a higher risk of AKI during hospitalisation for decompensated HF.

Consensus document and recommendations on the use of natriuretic peptides in clinical practice. / Documento de consenso y recomendaciones sobre el uso de los péptidos natriuréticos en la práctica clínica.

Natriuretic peptides are a useful laboratory tool for the diagnosis, prognosis and treatment of patients with heart failure. Natriuretic peptides are used in various healthcare settings (consultations, emergency department, hospitalization, laboratory) and by various primary care and specialised professionals. However, their use in clinical practice is still scare and uneven. Properly using and interpreting natriuretic peptides in clinical practice requires a minimum of prelaboratory (pathophysiology), laboratory (methods) and postlaboratory (interpretation and integration of clinical data) expertise. The objective of this consensus document, developed by several scientific societies, is to update the necessary concepts and expertise on natriuretic peptides that enable its application in the diagnosis, prognosis and treatment of heart failure, in various healthcare environments.

Reformulated meat products protect against ischemia-induced cardiac damage.

The protective effects of the antioxidants present in food are of great relevance for cardiovascular health. This study evaluates whether the extracts from reformulated meat products with a reduction in fat and/or sodium content exert a cardioprotective effect against ischemia-induced oxidative stress in cardiomyocytes, compared with non-meat foods. Ischemic damage caused loss of cell viability, increased reactive oxygen species and lipid peroxidation and decreased the antioxidant activity. Pretreatment for 24 h with digested or non-digested extracts from reformulated meat products led to protection against ischemia-induced oxidative damage: increased cell viability, reduced oxidative stress and restored the antioxidant activity. Similar results were obtained using extracts from tuna fish, but not with the extracts of green peas, salad or white beans. These results suggest that reformulated meat products have a beneficial impact in protecting cardiac cells against ischemia, and they may represent a source of natural antioxidants with benefits for cardiovascular health.

Absence of cystatin C involvement in ventricular remodelling and heart failure.

UNLABELLED: Cystatin C (CysC) is a protease encoded by housekeeping genes. Although its prognostic value in heart failure (HF) is well known, it is debatable whether this value is due to the greater accuracy of CysC in calculating the glomerular filtration rate or to its involvement in pathological ventricular remodelling. The aim of this study was to determine whether CysC expression changes in the myocardium of foetuses of different ages and in the myocardium of adults with various cardiovascular diseases, as well as to analyse the correlation between its serum concentrations and cardiac structure and morphology in a patient group with HF. PATIENTS AND METHODS: We analysed the correlations (Pearson's r and Spearman's test) between the serum CysC levels and echocardiographic parameters of 351 patients with HF. We also performed immunohistochemical staining for CysC, metalloproteinase-9 (MMP-9) and desmin in 9 cardiac tissue samples from autopsies of 4 foetuses of different gestational ages and 5 healthy adults or adults with cardiovascular disease. RESULTS: For the patients with HF, there was no correlation between the CysC concentrations and the cardiac parameters measured by 2D echocardiography. The immunohistochemistry showed a weak background staining for CysC in all samples, regardless of age and the presence or absence of cardiovascular diseases. CONCLUSIONS: Our results suggest that CysC does not have a significant role in the pathological remodelling of the left ventricle in HF.

Post-transplant increase in soluble human leukocyte antigen-G associated with non-severe cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is the single most important long-term limitation to heart transplantation. This study aimed to assess the value of monitoring soluble human leukocyte antigen-G (sHLA-G) during the first year post-transplantation to predict the severity of CAV, in 21 out of 77 heart recipients assessed by intravascular ultrasound (IVUS). Serum sHLA-G concentration increased after transplant in recipients free of severe CAV, but decreased in recipients suffering from severe CAV, significant differences between these two groups were found 6 to 12 months post-transplantation. The optimal value of the change in post-transplant sHLA-G for identifying severe CAV was ≥0.062%, which maximized sensitivity (80%) and specificity (100%). Importantly, increases in post-transplant sHLA-G were inversely associated with severe CAV, but directly associated with human cytomegalovirus reactivation. In addition, recipients presenting non-severe CAV or an increased sHLA-G post-transplantation, showed higher numbers of CD8(+)CD28(-) T cells and a down-modulation of CD28 on CD4(+) lymphocytes, which typically identifies CD8(+) regulatory T cells and anergic/tolerogenic T helper cells, respectively. In conclusion, quantification of sHLA-G might offer a complementary non-invasive method for identifying recipients at risk of more severe CAV and who might benefit from earlier preventive therapies, although these results need to be confirmed in larger series.

Serial monitoring of soluble interleukin family member ST2 in patients with acutely decompensated heart failure.

OBJECTIVES: To determine whether serial measures of the interleukin receptor family member soluble ST2 (sST2) provide additional prognostic information to baseline measures for long-term risk stratification of acutely decompensated heart failure (ADHF) patients. METHODS: We prospectively enrolled 72 ADHF patients. Blood samples were collected to measure sST2 concentrations at presentation and on day 4 of hospitalization. All patients were clinically followed, and vital status was registered. RESULTS: Between presentation and day 4, sST2 concentrations decreased from 62 ng/ml (interquartile range 38-105) to 44 ng/ml (interquartile range 26-72; p < 0.001). Both sST2 concentrations at presentation [hazard ratio (HR) 1.011, 95% confidence interval (CI) 1.005-1.016; p < 0.001] and on day 4 (HR 1.015, 95% CI 1.005-1.024; p = 0.003) were independent predictors of mortality. Patients with sST2 ≤ 76 ng/ml at presentation and ≤ 46 ng/ml on day 4 had the lowest mortality rates (3%), whereas those with both sST2 values above these cutoff points had the highest mortality (50%). C index and reclassification analyses demonstrated that the use of serial sST2 measures resulted in an improvement in the accuracy of mortality prediction. CONCLUSIONS: Among ADHF patients, sST2 concentrations tend to decrease following initiation of treatment and are prognostic both at presentation and during hospitalization. Serial sampling of sST2 adds prognostic information and may provide a basis for enhanced clinical decision making.

Soluble TNFα receptor type I and hepcidin as determinants of development of anemia in the long-term follow-up of heart failure patients.

BACKGROUND: Anemia is common in patients with chronic heart failure (CHF) and is associated with a worse prognosis. This study aims to identify the biological mechanisms which reflect evolutionary changes in the hemoglobin concentrations in heart failure patients who are still not anaemic. METHODS: Fifty-nine patients (54 ± 14 years, 83% males) with CHF (LVEF 28 ± 10%), who did not have anemia, and had not received any previous transfusions, were included. The parameters studied were: iron metabolism (ferritin, iron, transferrin, soluble transferrin receptor (sTfR), hepcidin); inflammation (C-reactive protein, soluble TNFα receptor I (sTNFRI), interleukin 6); and myocardial stress (NT-proBNP, high sensitivity TnT, growth differentiation factor 15). All parameters were measured on inclusion and 1 year after inclusion. RESULTS: Baseline hemoglobin (g/dL) was 14.7 ± 1.5 and at 1 year of follow-up it showed a significant decrease of -0.4 (RIC: -0.7 to -0.06) (p=0.02). At baseline, only the sTNFRI was a predictor of a decrease in hemoglobin 1 year later (p=0.007). During follow-up, the increase in sTNFRI (p=0.002, r=-0.39) and hepcidin (p=0.006, r=-0.35) were both associated with a decrease in hemoglobin. Similarly, the patients who became anemic (13%) had higher levels of hepcidin (p=0.001) and sTNFRI (p=0.008). The remaining parameters did not show any relationship with the evolution in the hemoglobin. CONCLUSIONS: In CHF patients without anemia, the increase in the inflammatory state (sTNFRI) and the following deterioration in the iron metabolism (hepcidin) were the main determinants of a decrease in hemoglobin and the appearance of anemia in the long term follow-up period.

CD28 and KIR2D receptors as sensors of the immune status in heart and liver transplantation.

Viral infections and cellular acute rejection (AR) condition immunosuppressive therapy and compromise the evolution of allografts. Immune monitoring can be useful for ascertaining rejection and for differentiating allo-reaction from activation induced by infections. This work analyzes the usefulness of monitoring the expression of CD28 and KIR2D receptors in peripheral blood T lymphocytes by flow cytometry, to ascertain the immune response in heart and liver transplant recipients. In both types of transplant, the up-regulation of CD28 in CD4(+) lymphocytes in the periods of greatest AR frequency indicates an effective allo-response, whereas the post-transplantation emergence of circulating CD8(+)CD28(-) and CD8(+)CD28(-)KIR2D(+) T cells correlates with better early clinical results. Cytomegalovirus (CMV) infection, but not hepatitis C virus (HCV) or other infections, abrogated both CD28 up-regulation and CD8(+)CD28(-)KIR2D(+) T-cell expansion. Our results show that monitoring the expression of CD28 and KIR2D receptors on T lymphocytes might be considered as sensors of the immune status of heart and liver recipients.

Expression of HLA molecules on peripheral blood lymphocytes: a useful monitoring parameter in cardiac transplantation.

During the rejection process of cardiac allografts, the expression of HLA antigens increases on various graft tissues, ie, the myocardium and the interstitial structures. However, in this type of transplant there is a paucity of knowledge about HLA expression on recipient cells, such as peripheral blood mononuclear cells. In the present study expression of HLA class I and class II antigens was monitored on peripheral blood lymphocytes prior to and during a 12-month follow-up, using flow cytometry. In our series, the frequency of acute rejection episodes was greater from the fourth to the ninth month after transplantation, coinciding with a reduction in cyclosporine blood levels. At the same time, expression of HLA class I and class II antigens significantly increased among recipients suffering from more severe acute rejection episodes compared with those showing acceptance of their grafts (P < .01). In conclusion, acute rejection episodes in cardiac transplantation were associated with up-regulation of HLA molecules on recipient peripheral blood cells. Monitoring the expression of HLA molecules on peripheral blood lymphocytes may represent an easy, noninvasive practice to individualize immunosuppressive therapy.

[Impact of diabetes mellitus on the late clinical outcome of coronary revascularization with stents]. / Influencia de la diabetes mellitus en los resultados clínicos tardíos de la revascularización coronaria con stents.

INTRODUCTION: The Influence of diabetes mellitus in the late outcome of coronary stenting remains controversial. AIM: The aim of this study was to determine the late clinical outcome of diabetics in comparison with non diabetics and to establish whether there are subgroups of diabetic patients with a greater need for target lesion revascularization. METHODS: Two hundred sixteen consecutive patients (74 diabetics; 95 stents in 90 lesions and 142 non diabetics) who had successfully undergone coronary stenting were included in the study and followed over 17.6 +/- 10 months. The clinical events evaluated were target lesion revascularization, death and acute myocardial infarction. Independent predictive variables of target lesion revascularization were studied in both groups of patients. RESULTS: The diabetic patients presented greater cardiovascular mortality (6.7% vs 1.4%; p=0.02) but the incidence of infarction was similar in the two groups (2.7% vs. 3.5%; p=0.6). The accumulated rate of target lesion revascularization at two years was 18.2% in diabetics vs 13.3% in non diabetics (p=0.09), respectively. The presence of three vessel disease (p=0.014), history of arterial hypertension ([=0.011) and residual stenosis > 0% (p=0.005) were specific predictive factors of target lesion revascularization for diabetic patients and together with vessel diameter < 3mm (p<0.001) subgroups of diabetics were independently selected with a significantly greater incidence of target lesion revascularization than the non diabetic patients. CONCLUSIONS: Following coronary stenting, diabetic patients show a greater cardiovascular mortality than non diabetics, but only some subgroups of diabetics (small vessels extensive coronary disease, associated arterial hypertension, residual stenosis) show a significantly greater risk of target lesion revascularization.