Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

High-intensity care for GDMT titration.

Heart failure (HF) is a systemic disease associated with a high risk of morbidity, mortality, increased risk of hospitalizations, and low quality of life. Therefore, effective, systemic treatment strategies are necessary to mitigate these risks. In this manuscript, we emphasize the concept of high-intensity care to optimize guideline-directed medical therapy (GDMT) in HF patients. The document highlights the importance of achieving optimal recommended doses of GDMT medications, including beta-blockers, renin-angiotensin-aldosterone inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter inhibitors to improve patient outcomes, achieve effective, sustainable decongestion, and improve patient quality of life. The document also discusses potential obstacles to GDMT optimization, such as clinical inertia, physiological limitations, comorbidities, non-adherence, and frailty. Lastly, it also attempts to provide possible future scenarios of high-intensive care that could improve patient outcomes.

Heart failure and sepsis: practical recommendations for the optimal management.

Acute heart failure (AHF) is a common clinical challenge that a wide spectrum of physicians encounters in every practice. In many cases, AHF is due to decompensation of chronic heart failure. This decompensation may be triggered by various reasons, with sepsis being a notable one. Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection and is associated with a very high mortality, which may reach 25%. Alarmingly, the increase in the mortality rate of patients with combined cardiac dysfunction and sepsis is extremely high (may reach 90%). Thus, these patients need urgent intervention. Management of patients with AHF and sepsis is challenging since cornerstone interventions for AHF may be contraindicated in sepsis and vice versa (e.g., diuretic treatment). Unfortunately, no relevant guidelines are yet available, and treatment remains empirical. This review attempts to shed light on the intricacies of the available interventions and suggests routes of action based on the existing bibliography.

Safety and efficacy of up to 60 h of iv istaroxime in pre-cardiogenic shock patients: Design of the SEISMiC trial.

AIMS: Cardiogenic shock (CS) is linked to high morbidity and mortality rates, posing a challenge for clinicians. Interventions to improve tissue perfusion and blood pressure are crucial to prevent further deterioration. Unfortunately, current inotropes, which act through adrenergic receptor stimulation, are associated with malignant arrhythmias and poorer outcomes. Due to its unique mechanism of action, istaroxime should improve haemodynamics without adrenergic overactivation. The SEISMiC study is designed to examine the safety and efficacy (haemodynamic effect) of istaroxime administrated in pre-CS patients. METHODS AND RESULTS: The SEISMiC study is a multinational, multicentre, randomized, double-blind, placebo-controlled safety and efficacy study with two parts (A and B). The study enrols patients hospitalized for decompensated heart failure (pre-CS, not related to myocardial ischaemia) with persistent hypotension [systolic blood pressure (SBP) 70-100 mmHg for at least 2 h] and clinically confirmed congestion, NT-proBNP ≥1400 pg/mL, and LVEF≤40%. Subjects must not have taken intravenous (iv) vasopressors, inotropes or digoxin in the past 6 h. Eligible patients are randomized to receive IV infusion of istaroxime (different doses and regimens in Parts A and B) or placebo for up to 60 h. Central haemodynamics, ECG Holter monitoring, cardiac ultrasound and biomarkers are recorded at predefined time points during the trial. The study's primary efficacy endpoint is the SBP area under the curve from baseline curve from baseline to 6 and 24 h in the combined SEISMiC Parts A and B population. Key secondary efficacy endpoints include haemodynamic, laboratory and clinical measures in SEISMiC B alone in the combined SEISMiC A and B studies. CONCLUSIONS: The study results will contribute to our understanding of the role of istaroxime in pre-CS patients and potentially provide insight into the drug's haemodynamic effects and safety in this population.

Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial.

IMPORTANCE: ß-Blocker therapy may control heart rate and attenuate the deleterious effects of ß-adrenergic receptor stimulation in septic shock. However, ß-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting ß-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P < .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 µg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 µg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P < .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01231698.

Prevalence, clinical characteristics and outcomes of heart failure patients with or without isolated or combined mitral and tricuspid regurgitation: An analysis from the ESC-HFA Heart Failure Long-Term Registry.

AIM: Mitral regurgitation (MR) and tricuspid regurgitation (TR) are common in patients with heart failure (HF). The aim of this study was to investigate prevalence, clinical characteristics and outcomes of patients with or without isolated or combined MR and TR across the entire HF spectrum. METHODS AND RESULTS: The ESC-HFA EORP HF Long-Term Registry is a prospective, multicentre, observational study including patients with HF and 1-year follow-up data. Outpatients without aortic valve disease were included and stratified according to isolated or combined moderate/severe MR and TR. Among 11 298 patients, 7541 (67%) had no MR/TR, 1931 (17%) isolated MR, 616 (5.5%) isolated TR and 1210 (11%) combined MR/TR. Baseline characteristics were differently distributed across MR/TR categories. Compared to HF with reduced ejection fraction, HF with mildly reduced ejection fraction was associated with a lower risk of isolated MR (odds ratio [OR] 0.69; 95% confidence interval [CI] 0.60-0.80), and distinctly lower risk of combined MR/TR (OR 0.51; 95% CI 0.41-0.62). HF with preserved ejection fraction (HFpEF) was associated with a distinctly lower risk of isolated MR (OR 0.42; 95% CI 0.36-0.49), and combined MR/TR (OR 0.59; 95% 0.50-0.70), but a distinctly increased risk of isolated TR (OR 1.94; 95% CI 1.61-2.33). All-cause death, cardiovascular death, HF hospitalization and combined outcomes occurred more frequently in combined MR/TR, isolated TR and isolated MR versus no MR/TR. The highest incident rates were observed in isolated TR and combined MR/TR. CONCLUSION: In a large cohort of outpatients with HF, prevalence of isolated and combined MR and TR was relatively high. Isolated TR was driven by HFpEF and was burdened by an unexpectedly poor outcome.

European Society of Cardiology - Acute Cardiovascular Care Association position paper on safe discharge of acute heart failure patients from the emergency department.

Heart failure is a global public health challenge frequently presenting to the emergency department. After initial stabilization and management, one of the most important decisions is to determine which patients can be safely discharged and which require hospitalization. This is a complex decision that depends on numerous subjective factors, including both the severity of the patient's underlying condition and an estimate of the acuity of the presentation. An emergency department observation period may help select the correct option. Ideally, during an observation period, risk stratification should be carried out using parameters specifically designed for use in the emergency department. Unfortunately, there is little objective literature to guide this disposition decision. An objective and reliable definition of low-risk characteristics to identify early discharge candidates is needed. Benchmarking outcomes in patients discharged from the emergency department without hospitalization could aid this process. Biomarker determinations, although undoubtedly useful in establishing diagnosis and predicting longer-term prognosis, require prospective validation for emergency department disposition guidance. The challenge of identifying emergency department acute heart failure discharge candidates will only be overcome by future multidisciplinary research defining the current knowledge gaps and identifying potential solutions.

BETAWIN-AHF study: effect of beta-blocker withdrawal during acute decompensation in patients with chronic heart failure.

OBJECTIVE: To evaluate the effects of discontinuing chronic beta-blocker (BB) treatment on short-term outcome in patients with chronic heart failure (CHF) during acute decompensation. METHODS: We selected all the patients previously diagnosed with CHF and currently on BB and attended for acute heart failure (AHF) in one of the 35 Spanish emergency departments participating in the EAHFE registry. Patients were classified according to BB maintenance or withdrawal (BBM or BBW, respectively) during the episode. In-hospital mortality was the primary endpoint; and 30-day mortality, 30-day combined endpoint, and prolonged hospitalization were secondary. We used logistic regression for adjustment of results according to the differences between the BBM and BBW groups, and stratified analysis by age, sex, left ventricular ejection fraction, chronic obstructive pulmonary disease, heart rate (HR), and BB type (carvedilol/bisoprolol) was performed. RESULTS: Among 2058 patients receiving chronic BB treatment, 1990 were analyzed: BBM 530 (27 %), BBW 1460 (73 %). Compared to BBM, BBW had a higher in-hospital mortality (5.5 vs 3.0 %; p < 0.05), 30-day mortality (8.7 vs 4.5 %; p < 0.01), and 30-day combined endpoint (29.8 vs 23.4 %; p < 0.05). Multivariate adjustment confirmed an independent direct association between BBW and in-hospital mortality (OR 1.89; 95 % CI 1.09-3.26) and 30-day mortality (OR 2.01; 95 % CI 1.28-3.15). Stratified analysis indicated no interaction by all the subgroups analyzed, except for HR (p = 0.01 for interaction), which showed a greater negative impact of BBW in patients with HR >80 bpm (OR 2.74; 95 % CI 1.13-6.63). CONCLUSIONS: In the absence of clear contraindications, BB treatment should be maintained during AHF episodes in patients already receiving BB at home.

How does a clinical trial fit into the real world? The RELAX-AHF study population into the EAHFE registry.

OBJECTIVE: To test how accurate the recently published RELAX-AHF trial was in recruiting real-world patients with acute-decompensated heart failure (ADHF). METHODS AND RESULTS: We compared clinical and outcome data of patients receiving serelaxin in the RELAX-AHF trial (RELAX group, n = 581) with patients included in the EAHFE registry [5497 ADHF from 29 Spanish emergency departments (EDs)]. The EAHFE registry was split into two groups: EAHFE-non-RELAX (patients not fulfilling the RELAX-AHF inclusion criteria; n = 3205, 58.3 %) and EAHFE-RELAX A (patients fulfilling RELAX-AHF inclusion criteria; n = 2292, 41.7 %). The latter group was further refined by also applying exclusion criteria (EAHFE-RELAX B; n = 964, 17.4 %). Both EAHFE-RELAX groups differed from the EAHFE-non-RELAX group in multiple aspects, with the lower the proportion of patients with implantable cardiac defibrillator and with pulmonary diseases the greater the differences found. The RELAX group, compared with the EAHFE-RELAX groups, significantly included fewer females, younger patients, less in NYHA class I/II, less with implantable cardiac defibrillator and on beta-blocker treatment, and patients had lower systolic blood pressure and cardiac and respiratory rates at ED arrival. The EAHFE-RELAX groups had a significantly lower all-cause mortality than EAHFE-non-RELAX group, and qualitative analysis suggested that EAHFE-RELAX groups had a higher mortality than the RELAX group. CONCLUSION: Patients included in the RELAX-AHF trial showed unanticipated differences when compared with a population from the EAHFE registry fulfilling very similar inclusion and exclusion criteria.

[Characteristics and clinical course of patients with acute heart failure and the therapeutic measures applied in Spanish emergency departments: based on the EAHFE registry (Epidemiology of Acute Heart Failure in Emergency Departments)]. / Características clínicas, terapéuticas y evolutivas de los pacientes con insuficiencia cardiaca aguda atendidos en servicios de urgencias españoles: Registro EAHFE (Epidemiology of Acute Heart Failure in Spanish Emergency Departments).

OBJECTIVES: To analyze data recorded in the EAHFE registry (Epidemiology of Acute Heart Failure in Emergency Departments), which collects information on the clinical characteristics and laboratory findings of patients with acute heart failure (AHF) treated in 29 Spanish hospital emergency departments (EDs) as well as therapies used and clinical course. We analyzed changes in management observed over time and compared the results with data recorded in other AHF registries. MATERIAL AND METHODS: Prospective multicenter cohort study of consecutive patients treated in 3 different years: 2007, 2009, and 2011. We collected demographic, clinical, and laboratory data; medications taken prior to the emergency and in the ED; and outcome variables (in-hospital and 30-day and 1-year mortality rates, readmissions within 30 days). Changes in therapy and course in the 3 years were analyzed. The literature was reviewed to find other national and international AHF registries. RESULTS: A total of 5845 patients were included (2007, 948; 2009, 1483; 2011, 3414). The mean age was 79 years and 56% were women. The AHF episode registered was the first experienced by 34.6% of the patients. Comorbidity was high: 82% had hypertension, 42.3% had diabetes mellitus, and 47.7% had atrial fibrillation. Severe or total functional dependence was observed in 21.9%, and 57.3% had systolic dysfunction (left ventricular ejection fraction, 38.3%). The main treatments administered consisted in diuretics (96.8%), endovenous nitroglycerine (20.7%), noninvasive ventilation (6.4%), and inotropic agents or vasopressors (3.6%). The glomerular filtration rate was low in 57%. Troponin and natriuretic peptide levels were measured in the EDs in 49.1% and 42.4% of the cases, respectively. Patients presented as normotensive in 66.4% of the cases, hypertensive in 23.5%, and hypotensive in 4.6% (0.7% in shock); 76.1% were admitted (1.9% to the ICU). The median hospital stay was 7 days and 23.9% were discharged from the ED. In-hospital mortality was 7.6%; 30-day mortality was 9.4% and 1-year mortality 29.5%. Orders for troponin and natriuretic peptide determinations increased over the 3 study periods, and the intravenous infusion of diuretics and inotropic agents and vasoconstrictors decreased (P < 0.001, all comparisons). Revisits within 30 days also decreased (P = 0.004). No changes were observed in in-hospital or 30-day mortality rates between 2007 and 2011. We reviewed 14 previously published registry reports (8 compiled prospectively); only 2 of the registries included ED patients. CONCLUSION: The EAHFE registry describes the characteristics of AHF in a cohort that resembles the universe of our patients with AHF. Significant changes were observed over time in some aspects of AHF management. Revisits decreased, but mortality rates remained unchanged. Only 2 other previously analyzed registries included patients with AHF treated in hospital EDs.

OBJETIVO: Presentación de los resultados del Registro EAHFE (Epidemiology of Acute Heart Failure in Emergency Departments) que recoge las características clínicas, de laboratorio, terapéuticas y la evolución de los pacientes con insuficiencia cardiaca aguda (ICA) atendidos en 29 servicios de urgencias hospitalarios (SUH) españoles. Se analizan los cambios de manejo a lo largo del tiempo; y se comparan los resultados con los de otros registros de ICA. METODO: Estudio multicéntrico, de cohortes, prospectivo, de inclusión consecutiva, realizado en tres periodos (2007, 2009 y 2011). Se recogieron datos demográficos, clínicos, de laboratorio, del tratamiento farmacológico previo y el administrado en SUH y variables evolutivas (mortalidad intrahospitalaria y a los 30 días y al año, reingreso a 30 días). Se analizaron los cambios terapéuticos y evolutivos a lo largo de estos 3 periodos. Se revisó la literatura para identificar registros previos de ICA de carácter nacional o internacional. RESULTADOS: Se incluyeron 5.845 pacientes (2007: 948, 2009: 1.483, 2011: 3.414), con edad media de 79 años y 56% mujeres. Un 34,6% era un primer episodio de ICA. Presentaron elevada comorbilidad (82% hipertensión, 42,3% diabetes mellitus, 47,7% fibrilación auricular). Un 21,9% tenía dependencia funcional grave o total. El 57,3% tenía una disfunción sistólica (FEVI 38,3%). Los principales tratamientos administrados en urgencias consistieron en diuréticos (96,8%), nitroglicerina endovenosa (20,7%), ventilación no invasiva (6,4%) y fármacos inotrópicos o vasopresores (3,6%). El 57% presentaba una tasa de filtrado glomerular disminuida. Las troponinas y los péptidos natriuréticos se determinaron en urgencias en un 49,1% y 42,4% de casos, respectivamente. Las formas de presentación se clasificaron como: normotensiva (66,4%), hipertensiva (23,5%), hipotensiva (4,6%, 0,7% con shock). El 76,1% fue ingresado (1,9% en intensivos), con una mediana de estancia hospitalaria de 7 días, y el 23,9% dado de alta desde urgencias. La mortalidad intrahospitalaria fue 7,6%, a 30 días 9,4% y al año 29,5%. A lo largo del periodo estudiado, ha aumentado la solicitud de troponinas (p < 0,001) y péptidos natriuréticos (p <0,001) en urgencias, ha disminuido el uso de diuréticos en perfusión (p < 0,001) y de inotropos/vasoconstrictores (p < 0,001) y ha disminuido el porcentaje de reconsulta a 30 días (p = 0,004). No se observaron cambios en la mortalidad intrahospitalaria y a los 30 días entre el periodo 2007-2011. Se han revisado 14 registros anteriores (8 prospectivos), y solo en 2 la inclusión de pacientes se hizo desde el SUH. CONCLUSIONES: El Registro EAHFE describe las características de la ICA a partir de una cohorte que se aproxima al universo de pacientes con ICA. Con el paso del tiempo se observan cambios significativos en el manejo de la ICA: las revisitas han disminuido aunque la mortalidad no se ha modificado. Aparte del Registro EAHFE, solo existen otros 2 registros en el mundo que incluyan a los pacientes con ICA atendidos en urgencias.

Assessing and grading congestion in acute heart failure: a scientific statement from the acute heart failure committee of the heart failure association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine.

Patients with acute heart failure (AHF) require urgent in-hospital treatment for relief of symptoms. The main reason for hospitalization is congestion, rather than low cardiac output. Although congestion is associated with a poor prognosis, many patients are discharged with persistent signs and symptoms of congestion and/or a high left ventricular filling pressure. Available data suggest that a pre-discharge clinical assessment of congestion is often not performed, and even when it is performed, it is not done systematically because no method to assess congestion prior to discharge has been validated. Grading congestion would be helpful for initiating and following response to therapy. We have reviewed a variety of strategies to assess congestion which should be considered in the care of patients admitted with HF. We propose a combination of available measurements of congestion. Key elements in the measurement of congestion include bedside assessment, laboratory analysis, and dynamic manoeuvres. These strategies expand by suggesting a routine assessment of congestion and a pre-discharge scoring system. A point system is used to quantify the degree of congestion. This score offers a new instrument to direct both current and investigational therapies designed to optimize volume status during and after hospitalization. In conclusion, this document reviews the available methods of evaluating congestion, provides suggestions on how to properly perform these measurements, and proposes a method to quantify the amount of congestion present.