Imbalance of Iron Availability and Demand in Patients With Acute and Chronic Heart Failure.

BACKGROUND: Iron deficiency (ID) is a frequent comorbidity in patients with acute (AHF) and chronic heart failure (CHF) associated with morbidity and death. We aimed to better characterize iron homeostasis in patients with heart failure applying different biomarkers and to evaluate the accuracy of current ID definition by the European Society of Cardiology/American College of Cardiology/American Heart Association to indicate tissue iron availability and demand. METHODS AND RESULTS: We performed a retrospective cohort study investigating 277 patients with AHF and 476 patients with CHF between February 2021 and May 2022. Patients with AHF had more advanced ID than patients with CHF, reflected by increased soluble transferrin receptor and soluble transferrin receptor-ferritin index, and lower ferritin, serum iron, transferrin saturation, hepcidin, and reticulocyte hemoglobin. Decreased iron availability or increased tissue iron demand, reflected by increased soluble transferrin receptor-ferritin index and decreased reticulocyte hemoglobin, was found in 84.1% (AHF) and 28.0% (CHF) with absolute ID and in 50.0% (AHF) and 10.5% (CHF) with combined ID according to the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition. Low hepcidin expression as an indicator of systemic ID was found in 91.1% (AHF) and 80.4% (CHF) of patients with absolute ID and in 32.3% (AHF) and 18.8% (CHF) of patients with combined ID. ID definitions with higher specificity reduce the need for iron supplementation by 25.5% in patients with AHF and by 65.6% in patients with CHF. CONCLUSIONS: Our results suggest that the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition might overestimate true ID, particularly in CHF. More stringent thresholds for ID could more accurately identify patients with heart failure with reduced tissue iron availability who benefit from intravenous iron supplementation.

Ecocardiografía transesofágica intraoperatoria en cirugía cardiovascular. Documento de consenso de la Sociedad Española de Anestesiología y Reanimación (SEDAR) y Sociedad Española de Cirugía Cardiovascular y Endovascular (SECCE) / Intraoperative transesophageal echocardiography in cardiovascular surgery. Consensus document from the Spanish Society of Anesthesia and Critical Care (SEDAR) and the Spanish Society of Endovascular and Cardiovascular Surgery (SECCE)

La ecocardiografía transesfofágica es una técnica semiinvasiva que permite una evaluación de la morfología y función cardiaca a tiempo real y que constituye, a día de hoy, un estándar de calidad en las intervenciones de cirugía cardiovascular. Se ha convertido en una herramienta fundamental tanto de monitorización como de diagnóstico en el perioperatorio que permite la correcta planificación quirúrgica y manejo farmacológico dirigido. El objetivo de este documento es dar respuesta de forma consensuada y avalada por la evidencia científica de cuándo y cómo debe hacerse la ecocardiografía transesfofágica intraoperatoria en cirugía cardiovascular, qué aplicaciones tiene en el intraoperatorio, quién debe realizarla y cómo debe transmitirse la información obtenida durante el estudio. Los autores han hecho una revisión sistemática de las guías internacionales, artículos de revisión y ensayos clínicos para dar respuesta a estas preguntas

Transesophageal echocardiography is a semi-invasive technique that allows an evaluation of cardiac morphology and function in real time and it is a quality standard in cardiovascular surgery. It has become a fundamental tool for both monitoring and diagnosis in the intraoperative period that allows decide the correct surgical planning and pharmacological management. The goal of this document is to answer the questions of when and how the perioperative TEE should be performed in cardiovascular surgery, what are their applications in the intraoperative, who should perform it and how the information should be transmitted. The authors made a systematic review of international guidelines, review articles and clinical trials to answer by consensus to these questions

Intraoperative transesophageal echocardiography in cardiovascular surgery. Consensus document from the Spanish Society of Anesthesia and Critical Care (SEDAR) and the Spanish Society of Endovascular and Cardiovascular Surgery (SECCE). / Ecocardiografía transesofágica intraoperatoria en cirugía cardiovascular. Documento de consenso de la Sociedad Española de Anestesiología y Reanimación (SEDAR) y Sociedad Española de Cirugía Cardiovascular y Endovascular (SECCE).

Transesophageal echocardiography is a semi-invasive technique that allows an evaluation of cardiac morphology and function in real time and it is a quality standard in cardiovascular surgery. It has become a fundamental tool for both monitoring and diagnosis in the intraoperative period that allows decide the correct surgical planning and pharmacological management. The goal of this document is to answer the questions of when and how the perioperative TEE should be performed in cardiovascular surgery, what are their applications in the intraoperative, who should perform it and how the information should be transmitted. The authors made a systematic review of international guidelines, review articles and clinical trials to answer by consensus to these questions.

High CRP Levels After Critical Illness are Associated With an Increased Risk of Rehospitalization.

PURPOSE: Chronic inflammation, even at subclinical levels, is associated with adverse long-term outcome. PATIENTS AND METHODS: In this prospective, observational study, 66 critically ill patients surviving to hospital discharge were included. C-reactive protein (CRP) levels were determined at hospital discharge, 1, 2, and 6 weeks after hospital discharge. All the patients were repeatedly screened for adverse events resulting in rehospitalization or death for 1.5 years. RESULTS: After hospital discharge, over two-thirds of the patients exhibited elevated CRP levels (>2.0 mg/L). During the first week, CRP decreased compared with hospital discharge (P < 0.001) but did not change after week 1 (P = 0.67). Age (P = 0.24), surgical status (P = 0.95), or sepsis (P = 0.77) did not influence the CRP course. The latter differed between patients with (n = 15) and without (n = 51) adverse events (P = 0.003). CRP levels of patients without adverse events persistently decreased after hospital discharge (P = 0.03), whereas those of patients with adverse events did not (P = 0.86) but rebounded early. CONCLUSIONS: Plasma CRP levels in critically ill patients decreased during the first week after hospital discharge but remained unchanged during the subsequent 5 weeks. Over two-thirds of the patients exhibited elevated CRP levels compatible with chronic sub-clinical inflammation. Persistently elevated CRP levels after hospital discharge are associated with higher risk of rehospitalization.

Protection against Tetanus and Diphtheria in Europe: The impact of age, gender and country of origin based on data from the MARK-AGE Study.

Due to the successful implementation of vaccination strategies early-life morbidity and mortality due to infectious disease has been reduced dramatically. Vaccines against tetanus and diphtheria are among the most frequently used vaccines worldwide, but various studies in different European countries have shown that protection against tetanus and particularly against diphtheria is unsatisfactory in adults and older persons. In this study we analyzed tetanus- and diphtheria-specific antibody concentrations in 2100 adults of different age from 6 selected European countries (Austria, Belgium, Germany, Greece, Italy, Poland) in order to investigate differences in the level of protection against tetanus and diphtheria across Europe. Our data reveal that tetanus- and diphtheria-specific antibody concentrations vary greatly between countries, which is also reflected in the percentage of persons with antibody concentrations below the protective level (0.1IU/ml), which ranged from 2 to 31% percent for tetanus and 28-63% for diphtheria. In most countries, tetanus- and diphtheria-specific antibody concentrations decrease with age. This phenomenon is more pronounced in countries with generally low antibody levels, such as Italy, Poland and Greece. Interestingly, tetanus-specific antibody concentrations are generally higher in males than in females, which is probably due to vaccination during their military service or more frequent booster vaccinations after injuries, whereas no gender-related differences were found for diphtheria-specific antibodies. In conclusion, our study demonstrates that the European population is not fully protected against tetanus and diphtheria. Measures to improve protection should include a life-long perspective on vaccination, more education to increase awareness of and compliance with vaccination guidelines, and a harmonization of recommendations and incentives across Europe.

Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARK-AGE Study.

Gradual changes in the DNA methylation landscape occur throughout aging virtually in all human tissues. A widespread reduction of 5-methylcytosine (5mC), associated with highly reproducible site-specific hypermethylation, characterizes the genome in aging. Therefore, an equilibrium seems to exist between general and directional deregulating events concerning DNA methylation controllers, which may underpin the age-related epigenetic changes. In this context, 5mC-hydroxylases (TET enzymes) are new potential players. In fact, TETs catalyze the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), driving the DNA demethylation process based on thymine DNA glycosylase (TDG)-mediated DNA repair pathway. The present paper reports the expression of DNA hydroxymethylation components, the levels of 5hmC and of its derivatives in peripheral blood mononuclear cells of age-stratified donors recruited in several European countries in the context of the EU Project 'MARK-AGE'. The results provide evidence for an age-related decline of TET1, TET3 and TDG gene expression along with a decrease of 5hmC and an accumulation of 5caC. These associations were independent of confounding variables, including recruitment center, gender and leukocyte composition. The observed impairment of 5hmC-mediated DNA demethylation pathway in blood cells may lead to aberrant transcriptional programs in the elderly.

Age-dependent expression of DNMT1 and DNMT3B in PBMCs from a large European population enrolled in the MARK-AGE study.

Aging is associated with alterations in the content and patterns of DNA methylation virtually throughout the entire human lifespan. Reasons for these variations are not well understood. However, several lines of evidence suggest that the epigenetic instability in aging may be traced back to the alteration of the expression of DNA methyltransferases. Here, the association of the expression of DNA methyltransferases DNMT1 and DNMT3B with age has been analysed in the context of the MARK-AGE study, a large-scale cross-sectional study of the European general population. Using peripheral blood mononuclear cells, we assessed the variation of DNMT1 and DNMT3B gene expression in more than two thousand age-stratified women and men (35-75 years) recruited across eight European countries. Significant age-related changes were detected for both transcripts. The level of DNMT1 gradually dropped with aging but this was only observed up to the age of 64 years. By contrast, the expression of DNMT3B decreased linearly with increasing age and this association was particularly evident in females. We next attempted to trace the age-related changes of both transcripts to the influence of different variables that have an impact on changes of their expression in the population, including demographics, dietary and health habits, and clinical parameters. Our results indicate that age affects the expression of DNMT1 and DNMT3B as an almost independent variable in respect of all other variables evaluated.

Secretoneurin gene therapy improves blood flow in an ischemia model in type 1 diabetic mice by enhancing therapeutic neovascularization.

Deficient angiogenesis after ischemia may contribute to worse outcome of peripheral arterial disease in patients with diabetes mellitus. Based on our previous work where we demonstrated that Secretoneurin (SN) is up-regulated under hypoxic conditions and enhances angiogenesis, we analyzed the therapeutic potential of SN gene therapy using a model of severe hind limb ischemia in streptozotocin-induced diabetic mice (STZ-DM). After induction of hind limb ischemia, blood flow was assessed by means of laser Doppler perfusion imaging (LDPI) and increased blood perfusion in the SN-treated animal group was observed. These results were complemented by the clinical observation of reduced necrosis and by an increased number of capillaries and arterioles in the SN-treated animal group. In vitro, we found that SN is capable of promoting proliferation and chemotaxis and reduces apoptosis in HUVECs cultured under hyperglycemic conditions. Additionally, SN activated ERK, eNOS and especially AKT as well as EGF-receptor in hyperglycemic HUVECs. In conclusion, we show that SN gene therapy improves post-ischemic neovascularization in diabetic mice through stimulation of angiogenesis and arteriogenesis indicating a possible therapeutic role of this factor in ischemia-related diseases in diabetic patients.

Heart rate before ICU discharge: a simple and readily available predictor of short- and long-term mortality from critical illness.

PURPOSE: A heart rate >90 bpm serves as one of four characteristics defining the systemic inflammatory response syndrome and is used in scoring systems to predict in-hospital mortality of intensive care unit (ICU) patients. Despite its central role in critical illness, specific data regarding the relationship between heart rate and outcome are rare. METHODS: In this post hoc analysis of a prospectively collected database, we analyzed the value of heart rate averaged from four predefined time points during the last 24 h before ICU discharge as a predictor of post-ICU in-hospital and post-hospital mortality in medical ICU patients. Furthermore, the relationship between heart rate and inflammation, as well as the influence of rate control medications on the association between heart rate and outcome were identified. RESULTS: Among the 702 ICU patients discharged from the ICU, 7.1 % died before hospital discharge. At 4 years of follow-up, post-hospital mortality was 14.4 %. Multivariate Cox proportional hazards models revealed heart rate before ICU discharge (HR 5.95; 95 % CI 1.24-28.63; p = 0.03) as an independent predictor of post-ICU in-hospital mortality. Both heart rate (HR 2.56; 95 % CI, 1.05-6.34; p = 0.04) and the C-reactive protein serum concentration before ICU discharge (HR, 1.26; 95 % CI, 1.09-1.46; p = 0.002) were independently associated with post-hospital mortality. Heart rate control therapy reduced the risk of post-ICU in-hospital (HR 0.38; 95 % CI, 0.18-0.81; p = 0.01) and post-hospital (HR, 0.47; 95 % CI, 0.22-1.00; p = 0.05) mortality. CONCLUSION: Heart rate evaluated 24 h before ICU discharge was independently associated with post-ICU in-hospital and post-hospital mortality. Pharmacological interventions to control heart rate may beneficially influence post-ICU mortality.

Determinants of exercise capacity in dilated cardiomyopathy: a prospective, explorative cohort study.

BACKGROUND: Exercise capacity in patients with dilated cardiomyopathy has low correlation to resting left ventricular function. Dysfunctional autonomic activity, cardiomechanics and inflammation are associated with exercise capacity but were investigated under inhomogeneous situations. It remains essentially unclear which factor mainly determines exercise capacity in dilated cardiomyopathy. METHODS: In a prospective, observational study in a narrow time frame we assessed clinically, inflammatory, hemodynamic and, autonomic parameters as well as echocardiographic measures to explore independent determinants of exercise capacity in 28 treated patients with dilated cardiomyopathy. RESULTS: Right ventricular end-diastolic diameter, tricuspid regurgitation velocity, and sympathovagal balance were independent determinants of exercise capacity (B coefficient, 69; CI 95 %, 15-122; p = 0.004); (B coefficient, - 226; CI 95 %, - 374 to - 79; p = 0.007) and (B coefficient, - 104; CI 95 %, - 172 to - 37), respectively. C-reactive protein, serum creatinin and body mass index were independently associated with right ventricular end-diastolic diameter (B coefficient, 0.34; CI 95 %, 0.12-0.56; p = 0.004); (B coefficient, 0.9; CI 95 %, 0.34-1.455; p = 0.003); and (B coefficient, 0.09; CI 95 %, 0.02-0.15; p = 0.01), respectively. CONCLUSIONS: In stable patients with dilated cardiomyopathy, autonomic modulation, and right ventricular dysfunction may be the most important determinants of exercise capacity, whereas inflammation, kidney dysfunction, and body mass index are independently associated with right ventricle remodeling.

C-reactive protein levels and post-ICU mortality in nonsurgical intensive care patients.

BACKGROUND: There are no data on the association between acute inflammation during critical illness and long-term mortality in ICU patients. METHODS: Nonsurgical patients with an ICU length of stay > 24 h surviving until ICU discharge were included into this prospective, observational, follow-up study. Demographics, chronic diseases, admission diagnosis, the Simplified Acute Physiology Score (SAPS) II, length of ICU stay, maximum C-reactive protein (CRP) levels during the ICU stay (CRPmax), and CRP levels at ICU discharge (CRPdis) were documented. After a follow-up time of 1.88 ± 1.16 years (range, 0.5-4 years), the survival status was determined. RESULTS: Seven hundred sixty-five patients were enrolled into the study protocol. One hundred fifty-eight patients (20.7%) died within 0.62 ± 0.88 years after ICU discharge. Cumulative survival rates differed between patients grouped into the CRPmax and CRPdis quartiles. Patients in the first and second CRPmax quartiles had better cumulative survival rates than those in higher CRPmax quartiles (all P < .001). Patients in the first CRPdis quartile had better cumulative survival rates than those in higher CRPdis quartiles (all P < .001). Using adjusted Cox proportional hazards models, both CRPmax and CRPdis were independently associated with post-ICU mortality (both P < .001). Furthermore, the number of chronic diseases (P < .001), age (P < .001), and the SAPS II (P = .03) were associated with post-ICU mortality in both Cox models. CONCLUSIONS: CRP levels during critical illness seem independently associated with post-ICU survival in nonsurgical ICU patients. Future research focusing on the association between acute systemic inflammation and post-ICU outcome is warranted in order to improve long-term survival of critically ill patients.

Gene therapy with the angiogenic cytokine secretoneurin induces therapeutic angiogenesis by a nitric oxide-dependent mechanism.

RATIONALE: The neuropeptide secretoneurin induces angiogenesis and postnatal vasculogenesis and is upregulated by hypoxia in skeletal muscle cells. OBJECTIVE: We sought to investigate the effects of secretoneurin on therapeutic angiogenesis. METHODS AND RESULTS: We generated a secretoneurin gene therapy vector. In the mouse hindlimb ischemia model secretoneurin gene therapy by intramuscular plasmid injection significantly increased secretoneurin content of injected muscles, improved functional parameters, reduced tissue necrosis, and restored blood perfusion. Increased muscular density of capillaries and arterioles/arteries demonstrates the capability of secretoneurin gene therapy to induce therapeutic angiogenesis and arteriogenesis. Furthermore, recruitment of endothelial progenitor cells was enhanced by secretoneurin gene therapy consistent with induction of postnatal vasculogenesis. Additionally, secretoneurin was able to activate nitric oxide synthase in endothelial cells and inhibition of nitric oxide inhibited secretoneurin-induced effects on chemotaxis and capillary tube formation in vitro. In vivo, secretoneurin induced nitric oxide production and inhibition of nitric oxide attenuated secretoneurin-induced effects on blood perfusion, angiogenesis, arteriogenesis, and vasculogenesis. Secretoneurin also induced upregulation of basic fibroblast growth factor and platelet-derived growth factor-B in endothelial cells. CONCLUSIONS: In summary, our data indicate that gene therapy with secretoneurin induces therapeutic angiogenesis, arteriogenesis, and vasculogenesis in the hindlimb ischemia model by a nitric oxide-dependent mechanism.