Design, Synthesis, and In Vivo Evaluation of Isosteviol Derivatives as New SIRT3 Activators with Highly Potent Cardioprotective Effects.

Cardiovascular diseases (CVDs) persist as the predominant cause of mortality, urging the exploration of innovative pharmaceuticals. Mitochondrial dysfunction stands as a pivotal contributor to CVDs development. Sirtuin 3 (SIRT3), a prominent mitochondrial deacetylase known for its crucial role in protecting mitochondria against damage and dysfunction, has emerged as a promising therapeutic target for CVDs treatment. Utilizing isosteviol, a natural ent-beyerene diterpenoid, 24 derivatives were synthesized and evaluated in vivo using a zebrafish model, establishing a deduced structure-activity relationship. Among these, derivative 5v exhibited significant efficacy in doxorubicin-induced cardiomyopathy in zebrafish and murine models. Subsequent investigations revealed that 5v selectively elevated SIRT3 expression, leading to the upregulation of SOD2 and OPA1 expression, effectively preventing mitochondrial dysfunction, mitigating oxidative stress, and preserving cardiomyocyte viability. As a novel structural class of SIRT3 activators with robust therapeutic effects, 5v emerges as a promising candidate for further drug development.

Resibufogenin: An Emerging Therapeutic Compound with Multifaceted Pharmacological Effects - A Comprehensive Review.

Resibufogenin (RBG), a significant bufadienolide compound found in the traditional Chinese medicine Chansu, has garnered increasing attention in recent years for its wide range of pharmacological effects. This compound has shown promising potential in various therapeutic areas, including oncology, cardiology, and respiratory medicine. Among its notable properties, the anticancer effects of RBG are particularly striking, positioning it as a potential candidate for innovative cancer treatments. The mechanism of action of RBG is diverse, impacting various cellular processes. Its anticancer efficacy has been observed in different types of cancer cells, where it induces apoptosis and inhibits cell proliferation. Beyond its oncological applications, RBG also demonstrates substantial anti-inflammatory and antiviral activities. These properties suggest its utility in managing chronic inflammatory disorders and viral infections, respectively. The compound's cardiotonic effects are also noteworthy, providing potential benefits in cardiovascular health, particularly in heart failure management. Additionally, RBG has shown effectiveness in blood pressure regulation and respiratory function improvement, making it a versatile agent in the treatment of hypertension and respiratory disorders. However, despite these promising aspects, systematic reviews focusing specifically on RBG are limited. This article aims to address this gap by comprehensively reviewing RBG's origin, physiological, and pharmacological effects. The review will serve as a crucial reference for clinicians and researchers interested in the therapeutic applications of RBG, highlighting its potential in various medical domains. By synthesizing current research findings, this review will facilitate a deeper understanding of RBG's role in medicine and encourage further investigation into its clinical uses.

Evaluation of therapeutic and toxic levels of serum digoxin concentration: a cross-sectional study from a tertiary hospital.

OBJECTIVE: Digoxin is a cardiac glycoside for treating heart failure and atrial fibrillation. Despite its limited therapeutic range and complex pharmacokinetic properties, this medication continues to be frequently prescribed. This study aimed to evaluate the serum digoxin concentration (SDC) at therapeutic, subtherapeutic, and toxic levels and explore the factors affecting these levels in patients receiving digoxin therapy for heart failure. PATIENTS AND METHODS: In this descriptive and cross-sectional study, the data were obtained from the electronic system of patients who presented to Afyonkarahisar Health Sciences University. For the SDC, the reference range was accepted as 0.5-0.9 ng/mL, and the upper limit was 2.0 ng/mL. The patient's demographic characteristics, comorbidities, and laboratory findings were evaluated. The Mann-Whitney U test, Chi-square test, and logistic regression analysis were used. p<0.05 was considered statistically significant. RESULTS: The data of 419 patients (mean age: 65.9±16.1 years, 68.5% women) were evaluated. The mean SDC was 1.11±1.01 ng/mL, and it was below 0.5 ng/mL in 24.3% of the patients, 0.5-0.9 ng/mL in 23.4%, 0.9-2 ng/mL in 41.3%, and over 2 ng/mL in 11.1%. Age, male gender, the presence of diabetes mellitus, and high HbA1c values were found to be associated with greater SDC levels, but this was not statistically significant. The presence of renal failure, elevated creatinine and magnesium levels, and potassium, sodium, and calcium levels outside the normal limits significantly increased the SDC. High creatinine and low/high potassium values significantly affected the detection of SDC at the toxic level. CONCLUSIONS: The measurement of SDC levels holds significance not only in the monitoring of toxicity but also in ensuring adherence to the recommended therapeutic range during therapy. It is recommended to exercise caution in terms of risk factors such as age, kidney function test results, and blood electrolyte levels.

Preoperative Levosimendan in Patients With Severe Left Ventricular Dysfunction Undergoing Isolated Coronary Artery Bypass Grafting: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To verify the impact of preoperative levosimendan on patients with severe left ventricular dysfunction (ejection fraction <35%) undergoing isolated coronary artery bypass grafting. DESIGN: A meta-analysis. SETTING: Hospitals. PARTICIPANTS: The authors included 1,225 patients from 6 randomized controlled trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors performed a meta-analysis of trials that compared preoperative levosimendan with placebo or no therapy, reporting efficacy and safety endpoints. Statistical analyses used mean differences and risk ratios (RR), with a random effects model. Six studies were included, comprising 1,225 patients, of whom 615 (50.2%) received preoperative levosimendan, and 610 (49.8%) received placebo/no therapy. Preoperative levosimendan showed a lower risk of all-cause mortality (RR 0.31; 95% CI 0.16-0.60; p < 0.01; I2 = 0%), postoperative acute kidney injury (RR 0.44; 95% CI 0.25-0.77; p < 0.01; I2 = 0%), low-cardiac-output syndrome (RR 0.45; 95% CI 0.30-0.66; p < 0.001; I2 = 0%), and postoperative atrial fibrillation (RR 0.49; 95% CI 0.25-0.98; p = 0.04; I2 = 85%) compared to control. Moreover, levosimendan significantly reduced the need for postoperative inotropes and increased the cardiac index at 24 hours postoperatively. There were no differences between groups for perioperative myocardial infarction, hypotension, or any adverse events. CONCLUSION: Preoperative levosimendan in patients with severe left ventricular dysfunction undergoing isolated coronary artery bypass grafting was associated with reduced all-cause mortality, low-cardiac-output syndrome, acute kidney injury, postoperative atrial fibrillation, and the need for circulatory support without compromising safety.

A review of the contemporary use of inotropes in patients with heart failure.

PURPOSE OF REVIEW: The role of inotropes has evolved with its use now expanding over multiple indications including cardiogenic shock, low cardiac output states, bridging therapy to transplant or mechanical support, and palliative care. There remains no consensus as to the recommended inotrope for the failing heart. We aim to provide an overview of the recent literature related to inotrope therapy and its application in patients with advanced heart failure and hemodynamic compromise. RECENT FINDINGS: In this review, we outline various clinical scenarios that warrant the use of inotrope therapy and the associated recommendations. There remains no mortality benefit with inotrope use. Per American Heart Association recommendations, the choice of the inotropic agent should be guided by parameters such as blood pressure, concurrent arrhythmias, and availability of the medication. Outcome variability remains a heightened concern with inpatient inotropic use in both hemodynamically stable and unstable patients. Finally, inotropic use in palliative care continues to be a recommendation for symptom control and improvement in functional status when the appropriate social support is present for the patient. SUMMARY: In summary, the ideal inotropic agent remains at the discretion of the clinical provider. Different clinical scenarios may favor one agent over another based on the type of cardiogenic shock and mechanism of action of the inotrope. A future shift towards characterizing inotrope use based on subgroup cardiogenic shock profiles may be seen, however further studies are needed to better understand these phenotypes. Inotrope therapy remains a keystone to bridging to advanced therapies and palliative care.

Selective SERCA2a activator as a candidate for chronic heart failure therapy.

BACKGROUND: The sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) depression substantially contributes to diastolic dysfunction in heart failure (HF), suggesting that SERCA2a stimulation may be a mechanism-based HF therapy. Istaroxime is a drug endowed with both a SERCA2a stimulatory activity and a Na+/K+ pump inhibitory activity for acute HF treatment. Its main metabolite PST3093 shows a more favorable therapeutic profile as compared to the parent drug, but it is still unsuitable for chronic usage. Novel PST3093 derivatives have been recently developed for oral (chronic) HF treatment; compound 8 was selected among them and here characterized. METHODS: Effects of compound 8 were evaluated in a context of SERCA2a depression, by using streptozotocin-treated rats, a well-known model of diastolic dysfunction. The impact of SERCA2a stimulation by compound 8 was assessed at the cellular level ad in vivo, following i.v. infusion (acute effects) or oral administration (chronic effects). RESULTS: As expected from SERCA2a stimulation, compound 8 induced SR Ca2+ compartmentalization in STZ myocytes. In-vivo echocardiographic analysis during i.v. infusion and after repeated oral administration of compound 8, detected a significant improvement of diastolic function. Moreover, compound 8 did not affect electrical activity of healthy guinea-pig myocytes, in line with the absence of off-target effects. Finally, compound 8 was well tolerated in mice with no evidence of acute toxicity. CONCLUSIONS: The pharmacological evaluation of compound 8 indicates that it may be a safe and selective drug for a mechanism-based treatment of chronic HF by restoring SERCA2a activity.

Impact of vasodilators on diuretic response in patients with congestive heart failure: A mechanistic trial of cimlanod (BMS-986231).

AIM: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide. METHODS AND RESULTS: In this randomized, double-blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 µg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT-proBNP at baseline was 1487 (interquartile range: 847-2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post-furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion. CONCLUSIONS: For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload.

Repeated Levosimendan Infusions in the Management of Advanced Heart Failure: Review of the Evidence and Meta-analysis of the Effect on Mortality.

ABSTRACT: In the latest years, several studies described the impact of repetitive/intermittent i.v. levosimendan treatment in the management of advanced heart failure. For this updated review, we systematically searched the literature for clinical trials, registries , and real-world data and identified 31 studies that we commented in a narrative review: 3814 patients were described, of whom 1744 were treated repetitively with levosimendan. On the basis of the nature of the study protocols and of the end points, out of those studies, we further selected 9 that had characteristics, making them suitable for a meta-analysis on mortality. This short list describes data from 680 patients (of whom 399 received repeated doses of levosimendan) and 110 death events (of which 50 occurred in the levosimendan cohort). In the meta-analysis, repetitive/intermittent therapy with i.v. levosimendan was associated with a significant reduction in mortality at the longest time point available: 50 of 399 (12.5%) versus 60 of 281 (21.4%) in the control arms, with a risk ratio of 0.62 (95% confidence interval, 0.42-0.90; P < 0.01). In a sensitivity analysis, removing each trial and reanalyzing the remaining data set did not change the trend, magnitude, or significance of the results. A visual inspection of the funnel plot did not suggest publication bias. The results provide a very strong rationale for continuing to investigate the repetitive use of levosimendan in patients with advanced heart failure by properly powered regulatory clinical trials. Meanwhile, it seems that the use of repetitive/intermittent i.v. levosimendan infusions has become one of the few effective options for preserving the hemodynamic and symptomatic balance in such patients.

Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study.

BACKGROUND: Nonintravenous inotropic-delivery options are needed for patients with inotropic-dependent heart failure (HF) to reduce the costs, infections and thrombotic risks associated with chronic central venous catheters and home infusion services. METHODS: We developed a novel, concentrated formulation of nebulized milrinone for inhalation and evaluated the feasibility, safety and pharmacokinetic profile in a prospective, single-arm, phase I clinical trial. We enrolled 10 patients with stage D HF requiring inotropic therapy during a hospital admission for acute HF. Milrinone 60 mg/4 mL was inhaled via nebulization 3 times daily for 48 hours. The coprimary outcomes were adverse events and pharmacokinetic profiles of inhaled milrinone. Acute changes in hemodynamic parameters were secondary outcomes. RESULTS: A concentrated nebulized milrinone formulation was well tolerated, without hypotensive events, arrhythmias or inhalation-related adverse events requiring discontinuation. Nebulized milrinone produced serum concentrations in the goal therapeutic range with a median plasma milrinone trough concentration of 39 (17-66) ng/mL and a median peak concentration of 207 (134-293) ng/mL. There were no serious adverse events. From baseline to 24 hours, mean pulmonary artery saturation increased (60% ± 7%-65 ± 5%; P = 0.001), and mean cardiac index increased (2.0 ± 0.5 mL/min/1.73m2-2.5 ± 0.1 mL/min/1.73m2; P = 0.001) with nebulized milrinone. CONCLUSIONS: In a proof-of-concept study, a concentrated, nebulized milrinone formulation for inhalation was safe and produced therapeutic serum milrinone concentrations. Nebulized milrinone was associated with improved hemodynamic parameters of cardiac output in a population with advanced HF. These promising results require further investigation in a longer-term trial in patients with inotrope-dependent advanced HF.

Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: a systematic review and meta-analysis.

To evaluate milrinone's impact on pediatric cardiac function, focusing on its specific role as an inotrope and lusitrope, while considering its systemic and pulmonary vasodilatory effects. Search of PubMed, EMBASE, and the Cochrane Library up to August 2023. We included all studies that evaluated milrinone in children under 18 years old in neonatal, pediatric, or cardiac intensive care units. We excluded case reports, studies that did not provide tabular information on milrinone's outcomes, and studies focused on non-intensive care populations. We extracted data on the research design, objectives, study sample, and results of each study, including the impact of milrinone and any associated factors. We screened a total of 9423 abstracts and 41 studies were ultimately included. Milrinone significantly improved left ventricular ejection fraction (WMD 3.41 [95% CI 0.61 - 6.21]), left ventricle shortening fraction (WMD 4.25 [95% CI 3.43 - 5.08]), cardiac index (WMD 0.50 [95% CI 0.32 to 0.68]), left ventricle output (WMD 55.81 [95% CI 4.91 to 106.72]), serum lactate (WMD -0.59 [95% CI -1.15 to -0.02]), and stroke volume index (WMD 2.95 [95% CI 0.09 - 5.82]). However, milrinone was not associated with improvements in ventricular myocardial performance index (WMD -0.01 [95% CI -0.06 to 0.04]) and ventricular longitudinal strain (WMD -2.14 [95% CI -4.56 to 0.28]). Furthermore, milrinone was not associated with isovolumetric relaxation time reduction (WMD -8.87 [95% CI -21.40 to 3.66]). CONCLUSION: Our meta-analysis suggests potential clinical benefits of milrinone by improving cardiac function, likely driven by its systemic vasodilatory effects. However, questions arise about its inotropic influence and the presence of a lusitropic effect. Moreover, milrinone's pulmonary vasodilatory effect appears relatively weaker compared to its systemic actions. Further research is needed to elucidate milrinone's precise mechanisms and refine its clinical applications in pediatric practice. WHAT IS KNOWN: • Milrinone is a phosphodiesterase III inhibitor that has been used to treat a variety of pediatric and neonatal conditions. • Milrinone is believed to exert its therapeutic effects by enhancing cardiac contractility and promoting vascular relaxation. WHAT IS NEW: • Milrinone may not have a significant inotropic effect. • Milrinone's pulmonary vasodilatory effect is less robust than its systemic vasodilatory effect.

Benefits and Harms of Continuous Intravenous Inotropic Support as Palliative Therapy: A Single-Institution, Retrospective Analysis.

Use of continuous intravenous inotropic support (CIIS) strictly as palliative therapy for patients with ACC/AHA Stage D (end-stage) Heart Failure (HF) has increased significantly. The harms of CIIS therapy may detract from its benefits. To describe benefits (improvement in NYHA functional class) and harms (infection, hospitalization, days-spent-in-hospital) of CIIS as palliative therapy. Methods: Retrospective analysis of patients with end-stage HF initiated on CIIS as palliative therapy at an urban, academic center in the United States between 2014-2016. Clinical outcomes were extracted, and data were analyzed using descriptive statistics. Seventy-five patients, 72% male, 69% African American/Black, with a mean age 64.5 years (SD = 14.5) met study criteria. Mean duration of CIIS was 6.5 months (SD = 7.7). Most patients (69.3%) experienced improvement in NYHA functional class from class IV to class III. Sixty-seven patients (89.3%) were hospitalized during their time on CIIS, with a mean of 2.7 hospitalizations per patient (SD = 3.3). One-third of patients (n = 25) required at least one intensive care unit (ICU) admission while on CIIS therapy. Eleven patients (14.7%) experienced catheter-related blood stream infection. Patients spent an average of 20.6% (SD = 22.8), approximately 40 days, of their time on CIIS admitted to the study institution. Patients on CIIS as palliative therapy report improvement in functional class, survive 6.5 months following initiation, but spend a significant number of days in the hospital. Prospective studies quantifying the symptomatic benefit and the direct and indirect harms of CIIS as palliative therapy are warranted.

Your Heart Function Has Normalized-What Next After TRED-HF?

PURPOSE OF REVIEW: With the widespread implementation of contemporary disease-modifying heart failure therapy, the rates of normalization of ejection fraction are continuously increasing. The TRED-HF trial confirmed that heart failure remission rather than complete recovery is typical in patients with dilated cardiomyopathy who respond to therapy. The present review outlines key points related to the management and knowledge gaps of this growing patient group, focusing on patients with non-ischaemic dilated cardiomyopathy. RECENT FINDINGS: There is substantial heterogeneity among patients with normalized ejection fraction. The specific etiology is likely to affect the outcome, although a multiple-hit phenotype is frequent and may not be identified without comprehensive characterization. A monogenic or polygenic genetic susceptibility is common. Ongoing pathophysiological processes may be unraveled with advanced cardiac imaging, biomarkers, multi-omics, and machine learning technologies. There are limited studies that have investigated the withdrawal of specific heart failure therapies in these patients. Diuretics may be safely withdrawn if there is no evidence of congestion, while continued therapy with at least some disease-modifying therapy is likely to be required to reduce myocardial workload and sustain remission for the vast majority. Understanding the underlying disease mechanisms of patients with normalized ejection fraction is crucial in identifying markers of myocardial relapse and guiding individualized therapy in the future. Ongoing clinical trials should inform personalized approaches to therapy.

Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure.

BACKGROUND: Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have demonstrated that exogenous NADPH exhibits a positive inotropic effect on isolated heart. This study aims to investigate the positive inotropic effects of NADPH in pathological cardiac hypertrophy and heart failure, as well as the underlying mechanisms involved. METHODS: Endogenous plasma NADPH contents were determined in patients with chronic heart failure and control adults. The positive inotropic effects of NADPH were investigated in isolated toad heart or rat heart. The effects of NADPH were investigated in isoproterenol (ISO)-induced cardiac hypertrophy or transverse aortic constriction (TAC)-induced heart failure. The underlying mechanisms of NADPH were studied using SIRT3 knockout mice, echocardiography, Western blotting, transmission electron microscopy, and immunoprecipitation. FINDINGS: The endogenous NADPH content in the blood of patients and animals with pathological cardiac hypertrophy or heart failure was significantly reduced compared with age-sex matched control subjects. Exogenous NADPH showed positive inotropic effects on the isolated normal and failing hearts, while antagonism of ATP receptor partially abolished the positive inotropic effect of NADPH. Exogenous NADPH administration significantly reduced heart weight indices, and improved cardiac function in the mice with pathological cardiac hypertrophy or heart failure. NADPH increased SIRT3 expression and activity, deacetylated target proteins, improved mitochondrial function and facilitated ATP production in the hypertrophic myocardium. Importantly, inhibition of SIRT3 abolished the positive inotropic effect of NADPH, and the anti-heart failure effect of NADPH was significantly reduced in the SIRT3 Knockout mice. INTERPRETATION: Exogenous NADPH shows positive inotropic effect and improves energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. NADPH thus may be one of the potential candidates for the treatment of pathological cardiac hypertrophy or heart failure. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (No. 81973315, 82173811, 81730092), Natural Science Foundation of Jiangsu Higher Education (20KJA310008), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

Meta-Analysis of the Efficacy of Levosimendan in the Treatment of Severe Sepsis Complicated with Septic Cardiomyopathy.

INTRODUCTION: Sepsis is a medical condition characterized by acute organ dysfunction and uncontrolled inflammation. Organ dysfunction in sepsis is the primary cause of mortality in patients with myocardial dysfunction. Levosimendan is a vasodilating and inotropic agent used in patients with acute heart failure and has resulted in decreased morbidity and mortality in these patients. Our main objective is to examine levosimendan's efficacy in treating severe sepsis complicated with septic cardiomyopathy. METHODS: We systematically searched five databases, PubMed, Web of Science, Embase, Cochrane Library and BioMed Central, for articles and publications from their inception to 2023. Our study adopted the PICOS approach in identifying suitable publications during the systematic search. Inclusion criteria included randomized, controlled trials utilizing levosimendan in adult patients diagnosed with septic shock or severe sepsis. We excluded non-English publications and non-randomized controlled trials. The Newcastle-Ottawa scale (NOS) scale was used to assess the methodological quality, while the risk of bias was assessed through the Cochrane Risk of bias tool. All statistical analyses were performed using RevMan version 5.4. RESULTS: Eight studies met the eligibility criteria and were included in the analysis. There was a statistically significant positive effect on cardiac input in patients treated with levosimendan compared to those treated with dobutamine (p < 0.001). Similarly, there were positive effects on left ventricular ejection fraction (LVEF) (p < 0.001) and left ventricular stroke work index (LVSWI) (p < 0.001). We observed a significant reduction in mortality (p < 0.01) and serum levels of lactic acid (p < 0.01). DISCUSSION: Levosimendan is a calcium sensitizer associated with an influx of calcium ions and activation of ATP-dependent potassium channels that increases myocardial contractility contractions, enhances vasodilation and improves oxygen supply to the cells and tissues. CONCLUSION: Levosimendan is highly efficacious and safe in the management of sepsis and sepsis-induced cardiomyopathy.

Factores asociados al tratamiento crónico no justificado con digoxina en pacientes con insuficiencia cardiaca aguda y relación con el pronóstico a corto plazo / Factors associated with unjustified chronic treatment with digoxin in patients with acute heart failure and relationship with short-term prognosis

Objetivos Analizar los factores relacionados con el tratamiento crónico inadecuado con digoxina, y si esta inadecuación impacta en la evolución a corto plazo. Método Se incluyeron pacientes diagnosticados de insuficiencia cardiaca aguda (ICA) en tratamiento crónico con digoxina, y se clasificaron como con tratamiento indicado o no indicado, investigándose los factores asociados a este hecho, y si se asociaba a mortalidad intrahospitalaria a 30 días, estancia hospitalaria prolongada (>7 días) y evento adverso combinado (reconsulta a urgencias, hospitalización por ICA o muerte por cualquier causa) durante los 30 días postalta. Resultados Se analizaron 2.366 pacientes en tratamiento crónico con digoxina (mediana=83 años, mujeres=61%): adecuado en 1.373 casos (58,0%), inadecuado en 993 (42,0%). La inadecuación se asoció con mayor edad, menor comorbilidad, menor tratamiento con betabloqueantes e IECA, mejor función ventricular y peor índice de Barthel. La mortalidad intrahospitalaria y a 30 días fue mayor en pacientes con tratamiento inadecuado (9,9 versus 7,6%, p=0,05; y 12,6 versus 9,1%, p<0,001; respectivamente); no hubo diferencias en estancia prolongada (35,7 versus 33,8%) ni en eventos adversos posalta (32,9 versus 31,8%). Ajustando las diferencias basales y del episodio de descompensación, el tratamiento crónico inadecuado con digoxina no se asoció con ningún resultado, con odds ratio de 1,31 (IC 95%: 0,85-2,03) para mortalidad intrahospitalaria, 1,29 (0,74-2,25) para mortalidad a 30 días; 1,07 (0,82-1,40) para estancia prolongada y 0,88 (0,65-1,19) para evento adverso posalta. Conclusión Existe un perfil de paciente que recibe de forma inadecuada tratamiento crónico con digoxina, si bien ello no se asocia con resultados adversos a corto plazo durante los episodios de ICA (AU)

Objectives To analyze the factors related to inadequate chronic treatment with digoxin and whether the inadequacy of treatment has an impact on short-term outcome. Method Patients diagnosed with AHF who were in chronic treatment with digoxin were selected. Digoxin treatment was classified as adequate or inadequate. We investigated factors associated to inadequacy and whether such inadequacy was associated with in-hospital and 30-day mortality, prolonged hospital stay (>7 days) and combined adverse event (re-consultation to the ED or hospitalization for AHF or death from any cause) during the 30 days after discharge. Results We analyzed 2366 patients on chronic digoxin treatment (median age=83 years, women=61%), which was considered adequate in 1373 cases (58.0%) and inadequate in 993 (42.0%). The inadequacy was associated with older age, less comorbidity, less treatment with beta-blockers and renin–angiotensin inhibitors, better ventricular function, and worse Barthel index. In-hospital and 30-day mortality was higher in patients with inadequate digoxin treatment (9.9% vs. 7.6%, p=0.05; and 12.6% vs. 9.1%, p<0.001, respectively). No differences were recorded in prolonged stay (35.7% vs. 33.8%) or post-discharge adverse events (32.9% vs. 31.8%). In the model adjusted for baseline and decompensation episode differences, inadequate treatment with digoxin was not significantly associated with any outcome, with an odds ratio of 1.31 (95% CI=0.85-2.03) for in-hospital mortality; 1.29 (0.74-2.25) for 30-day mortality; 1.07 (0.82-1.40) for prolonged stay; and 0.88 (0.65-1.19) for post-discharge adverse event. Conclusion There is a profile of patients with AHF who inadequately receive digoxin, although this inadequateness for chronic digitalis treatment was not associated with short-term adverse outcomes (AU)

Use of levosimendan in hemodynamic management of heart failure in two neonates with intracranial arteriovenous shunts: a case series.

BACKGROUND: The hemodynamic status of newborns with intracranial arteriovenous shunts (AVSs) may be extremely complex. Mini-invasive hemodynamic monitoring through innovative techniques such as Near-Infrared Spectroscopy (NIRS) and Pressure Recording Analytical Method (PRAM) may help in understanding hemodynamics in newborns with AVSs. Levosimendan is a calcium sensitizer and inodilator, and it is known to improve ventricular function, but its use in newborns is limited. In our cases, we evaluated the effect of levosimendan on hemodynamics through NIRS and PRAM. CASE PRESENTATION: Herein, we report the cases of two neonates with intracranial arteriovenous shunts, in whom we used levosimendan to manage cardiac failure refractory to conventional treatment. Levosimendan was used at a dosage of 0.1 mcg/kg/min for 72 h. Combined use of NIRS and PRAM helped in real-time monitoring of hemodynamic effects; in particular, levosimendan determined significant improvement in myocardium contractility as well as a reduction of heart rate. CONCLUSION: In two neonatal cases of AVSs, levosimendan led to an overall hemodynamic stabilization, documented by the combination of NIRS and PRAM. Our results suggest introducing levosimendan as a second-line treatment in cases of severe cardiac dysfunction due to AVSs without improvement using standard treatment strategies. Future prospective and larger studies are highly warranted.