Prevalence of transthyretin cardiac amyloidosis in patients with heart failure with preserved ejection fraction: the PRACTICA study.

INTRODUCTION AND OBJECTIVES: Transthyretin cardiac amyloidosis (ATTR-CA) is a frequent cause of heart failure with preserved ejection fraction (HFpEF). This study aimed to determine the prevalence of ATTR-CA in HFpEF patients in a multicenter nationwide study. METHODS: Consecutive ambulatory or hospitalized patients aged ≥ 50 years with HFpEF and left ventricle hypertrophy ≥ 12 mm were studied at 20 Spanish hospitals. Screening for CA was initiated according to the usual clinical practice at each center. Positive scintigraphs were analyzed centrally. RESULTS: A total of 422 patients were included, of whom 387 underwent further screening for CA. Sixty-five patients (16.8%) were diagnosed with ATTR-CA, and none was younger than 75 years. Prevalence increased with age. Among these patients, 60% were men, with a mean age of 85.3 ± 5.2 years, mean left ventricular ejection fraction of 60.3 ± 7.6%, and a mean maximum left ventricular wall thickness of 17.2 (range, 12-25) mm. Most of the patients were in New York Heart Association class II (48.4%) or III (46.8%). In addition to being older than patients without ATTR-CA, patients with ATTR-CA had higher median NT-proBNP levels (3801 [2266-7132] vs 2391 [1141-4796] pg/mL; P = .003). There was no statistically significant difference in the prevalence of ATTR-CA by sex (19.7% in men and 13.8% in women, P = .085). A genetic variant (ATTRv) was found in approximately 7% (4/56) of the patients. CONCLUSIONS: This multicenter nationwide study found that the prevalence of ATTR-CA was 16.8%, confirming it as a significant contributor to HFpEF in patients of both sexes with left ventricular hypertrophy older than 75 years.

Connective tissue amyloidosis in patients referred for orthopedic surgery. CONNECT-AMY study. / Amiloidosis del tejido conectivo en pacientes referidos a cirugía ortopédica. Estudio CONNECT-AMY.

INTRODUCTION AND OBJECTIVE: Clinical manifestations secondary to amyloid deposition in connective tissue may allow early detection of amyloidosis. We sought to identify the prevalence of connective tissue amyloidosis in patients undergoing orthopedic surgery and evaluate for cardiac involvement. MATERIAL AND METHODS: Descriptive cross-sectional study that included patients >50 years referred for orthopedic surgery at our center. A sample of the affected connective tissue was taken during the intervention to evaluate the presence of amyloid material. Those with confirmed amyloidosis were further evaluated with complementary tests for cardiac involvement. RESULTS: Forty-eight patients were included. Mean age was 65.4 years and 41.7% were women. The most frequent surgery was supraspinatus tendon rupture (50%). Transthyretin amyloid deposits were detected in 2 patients (4.2%). The absence of variants in the protein gene established the diagnosis of ATTRwt in both cases. None of them presented cardiac involvement. CONCLUSIONS: In this study, 4.2% of patients referred for orthopedic surgery presented transthyretin amyloidosis in the affected connective tissue.

Reduced mitochondrial pyruvate carrier expression in hearts with heart failure and reduced ejection fraction patients: ischemic vs. non-ischemic origin.

Introduction and objectives: Mitochondrial pyruvate carrier (MPC) mediates the entry of pyruvate into mitochondria, determining whether pyruvate is incorporated into the Krebs cycle or metabolized in the cytosol. In heart failure (HF), a large amount of pyruvate is metabolized to lactate in the cytosol rather than being oxidized inside the mitochondria. Thus, MPC activity or expression might play a key role in the fate of pyruvate during HF. The purpose of this work was to study the levels of the two subunits of this carrier, named MPC1 and MPC2, in human hearts with HF of different etiologies. Methods: Protein and mRNA expression analyses were conducted in cardiac tissues from three donor groups: patients with HF with reduced ejection fraction (HFrEF) with ischemic cardiomyopathy (ICM) or idiopathic dilated cardiomyopathy (IDC), and donors without cardiac pathology (Control). MPC2 plasma levels were determined by ELISA. Results: Significant reductions in the levels of MPC1, MPC2, and Sirtuin 3 (SIRT3) were observed in ICM patients compared with the levels in the Control group. However, no statistically significant differences were revealed in the analysis of MPC1 and MPC2 gene expression among the groups. Interestingly, Pyruvate dehydrogenase complex (PDH) subunits expression were increased in the ICM patients. In the case of IDC patients, a significant decrease in MPC1 was observed only when compared with the Control group. Notably, plasma MPC2 levels were found to be elevated in both disease groups compared with that in the Control group. Conclusion: Decreases in MPC1 and/or MPC2 levels were detected in the cardiac tissues of HFrEF patients, with ischemic or idiopatic origen, indicating a potential reduction in mitochondrial pyruvate uptake in the heart, which could be linked to unfavorable clinical features.

[Incidence and causes of hospitalization in patients with transthyretin (ATTR-CA) and light chain (AL-CA) cardiac amyloidosis]. / Incidencia y causas de hospitalización en pacientes con amiloidosis cardiaca por transtiretina (AC-ATTR) y por cadenas ligeras (AC-AL).

INTRODUCTION AND OBJETIVES: Cardiac amyloidosis (CA) is a disorder associated with high number of hospital admissions. Given the scarce information available, we propose an analysis of the incidence and causes of hospitalization in this disease. MATERIAL AND METHODS: One hundred and forty-three patients [128 by transthyretin (ATTR-CA) and 15 by light chains (AL-CA)] included in Registro de Amiloidosis Cardiaca de Galicia (AMIGAL) were evaluated, including all hospitalizations. RESULTS: During a median follow-up of 959 days there were 179 unscheduled hospitalizations [incidence rate (IR) 512.6 admissions per 1000 patients-year], most common due to cardiovascular reasons (n=109, IR 312.2). Most frequent individual cause of hospitalization was heart failure (n=87, TI 249.2). AL-CA was associated with a higher IR of unscheduled hospitalizations than ATTR-CA (IR 781 vs. 483.2; HR 1.62; p=0,029) due to non-cardiovascular admissions (IR 376 vs. 181.2; HR 2.07; p=0.027). Unscheduled admission-free survival at 1 and 3 years in AL-CA was inferior than in ATTR-CA (46.7% and 20.0% vs. 73.4% and 35.2%, respectively; p=0.021). CONCLUSIONS: CA was associated with high incidence of hospitalizations, being heart failure the most frequent individual cause; unscheduled admission-free survival in AL-CA was lower than in ATTR-CA due mostly to non-cardiovascular admissions.

Protocolized Natriuresis-Guided Decongestion Improves Diuretic Response: The Multicenter ENACT-HF Study.

BACKGROUND: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload. METHODS: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms. RESULTS: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P<0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P<0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P<0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P=0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P=0.852). CONCLUSIONS: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay.

Prognostic value of the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio in cardiac amyloidosis.

INTRODUCTION AND OBJECTIVES: The tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/SPAP) ratio is a noninvasive surrogate of right ventricular to pulmonary circulation that has prognostic implications in patients with heart failure (HF) or pulmonary hypertension. Our purpose was to evaluate the prognostic value of the TAPSE/SPAP ratio in patients with cardiac amyloidosis. METHODS: We used the database of the AMIGAL study, a prospective, observational registry of patients with cardiac amyloidosis recruited in 7 hospitals of the Autonomous Community of Galicia, Spain, from January 1, 2018 to October 31, 2022. We selected patients whose baseline TAPSE/SPAP ratio was calculated with transthoracic echocardiography. Long-term survival and survival free of HF hospitalization were assessed by means of 5 different multivariable Cox regression models. Median follow-up was 680 days. RESULTS: We studied 233 patients with cardiac amyloidosis, among whom 209 (89.7%) had transthyretin type. The baseline TAPSE/SPAP ratio correlated significantly with clinical outcomes. Depending on the multivariable model considered, the adjusted hazard ratios estimated per 0.1mm/mmHg increase of baseline TAPSE/SPAP ratio ranged from 0.76 to 0.84 for all-cause mortality. Similarly, the ratios for all-cause mortality of HF hospitalization ranged from 0.79 to 0.84. The addition of the baseline TAPSE/SPAP ratio to the predictive model of the United Kingdom National Amyloidosis Centre resulted in an increase in Harrell's c-statistic from 0.662 to 0.705 for all-cause mortality and from 0.668 to 0.707 for all-cause mortality or HF hospitalization. CONCLUSIONS: Reduced TAPSE/SPAP ratio is an independent adverse prognostic marker in patients with cardiac amyloidosis.

Development and Validation of a Prediction Model and Score for Transthyretin Cardiac Amyloidosis Diagnosis: T-Amylo.

BACKGROUND: Although transthyretin cardiac amyloidosis (ATTR-CA) is often underdiagnosed, clinical suspicion is essential for early diagnosis. OBJECTIVES: The aim of this study was to develop and validate a feasible prediction model and score to facilitate the diagnosis of ATTR-CA. METHODS: This retrospective multicenter study enrolled consecutive patients who underwent 99mTc-DPD scintigraphy for suspected ATTR-CA. ATTR-CA was diagnosed if Grade 2 or 3 cardiac uptake was evidenced on 99mTc-DPD scintigraphy in the absence of a detectable monoclonal component or by demonstration of amyloid by biopsy. A prediction model for ATTR-CA diagnosis was developed in a derivation sample of 227 patients from 2 centers using multivariable logistic regression with clinical, electrocardiography, analytical, and transthoracic echocardiography variables. A simplified score was also created. Both of them were validated in an external cohort (n = 895) from 11 centers. RESULTS: The obtained prediction model combined age, gender, carpal tunnel syndrome, interventricular septum in diastole thickness, and low QRS interval voltages, with an area under the curve (AUC) of 0.92. The score had an AUC of 0.86. Both the T-Amylo prediction model and the score showed a good performance in the validation sample (ie, AUC: 0.84 and 0.82, respectively). They were tested in 3 clinical scenarios of the validation cohort: 1) hypertensive cardiomyopathy (n = 327); 2) severe aortic stenosis (n = 105); and 3) heart failure with preserved ejection fraction (n = 604), all with good diagnostic accuracy. CONCLUSIONS: The T-Amylo is a simple prediction model that improves the prediction of ATTR-CA diagnosis in patients with suspected ATTR-CA.

Soluble HLA-G levels in heart transplant recipients: Dynamics and correlation with clinical outcomes.

PURPOSE: To describe the evolution of the serum levels of soluble HLA-G (s-HLA-G) during the first 12 months after heart transplantation (HT) and to correlate it with clinical outcomes. METHODS: Observational study based in a single-center cohort of 59 patients who underwent HT between December-2003 and March-2010. Soluble HLA-G levels were measured from serum samples extracted before HT, and 1, 3, 6 and 12 months after HT. The cumulative burden of s-HLA-G expression during the first post-transplant year was assessed by means of the area under the curve (AUC) of s-HLA-G levels over time and correlated with the acute rejection burden -as assessed by a rejection score-, the presence of coronary allograft vasculopathy (CAV) grade ≥ 1 and infections during the first post-transplant year; as well as with long-term patient and graft survival. Mean follow-up was 12.4 years. RESULTS: Soluble HLA-G levels decreased over the first post-transplant year (p = 0.020). The AUC of s-HLA-G levels during the first post-transplant year was higher among patients with infections vs. those without infections (p = 0.006). No association was found between the AUC of s-HLA-G levels and the burden of acute rejection or the development of CAV. Overall long-term survival, long-term survival free of late graft failure and cancer-free survival were not significantly different in patients with an AUC of s-HLA-G levels higher or lower than the median of the study population. CONCLUSIONS: Soluble HLA-G levels decreased over the first year after HT. Higher HLA-G expression was associated with a higher frequency of infections, but not with the burden of acute rejection or the development of CAV, neither with long-term patient or graft survival.

Cancer in patients with heart failure: Incidence, risk factors and prognostic impact.

AIMS: To assess the incidence of cancer diagnosis and cancer-related mortality in patients with heart failure (HF). METHODS: Observational study based in a prospective cohort of patients with HF referred to a specialized Spanish clinic between 2010 and 2019. The observed incidence of malignancies (excluding non-melanoma skin cancer) was compared to that expected for the general Spanish population according to the Global Cancer Observatory. RESULTS: We studied 1909 consecutive patients with HF. Over a median follow-up of 4.07 years, 165 new cases of malignancy were diagnosed. Observed age-standardized incidence rates of cancer were 861 (95% CI 618.4-2159.4) cases per 100,000 patients-years in men and 728.5 (95% CI 451.1-4308.7) cases per 100,000 patients-years in women; while age-standardized incidence rates of cancer expected for the general Spanish population were 479.4 cases per 100,000 patients-years in men (risk ratio = 1.80) and 295.5 cases per 100,000 patients-years in women (risk ratio = 2.46). Both a history of pre-existing malignancy at baseline and the development of new malignancies during follow-up were associated with reduced survival. Observed age-standardized cancer-related mortality was 344.1 (95% CI 202.1-1675) deaths per 100,000 patient-years in men and 217.0 (95% CI 32.8-3949.3) deaths per 100,000 patient-years in women; while age-standardized cancer-related mortality expected for the general Spanish population was 201.4 deaths per 100,000 patients-years in men (risk ratio = 1.71) and 96.2 deaths per 100,000 patients-years in women (risk ratio = 2.26). CONCLUSION: Patients with HF showed higher incidence rates of cancer diagnosis and cancer-related mortality than those expected for the general population.

Syncope in patients with transthyretin amyloid cardiomyopathy: clinical features and outcomes.

BACKGROUND: We aimed to describe the clinical characteristics, underlying causes and outcomes of syncope in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). METHODS: The clinical profile and underlying causes of syncopal episodes were reviewed in a cohort of 128 patients with ATTR-CM enrolled from January 2018 to June 2020 in a prospective multicentre registry in 7 hospitals of Galicia (Spain). After enrollment, patients were followed during a median period of 520 days. The effect of syncope on all-cause mortality was assessed by means of multivariate Cox´s regression. RESULTS: Thirty (23.4%) patients had a history of previous syncope as a clinical antecedent before being enrolled in the prospective phase of the registry, and 4 (3.1%) experienced a first episode of syncope thereafter. The estimated incidence density rate of syncope during the prospective follow-up period after registry enrollment was 71.9 episodes per 1000 patients-year (95% Confidence Interval (CI) 32.8-111.1). The estimated overall prevalence of syncope was 26.6% (95% CI 18.9%-34.2%). Cardiac arrhythmias (n = 11, 32.3%), structural diseases of the heart or great vessels (n = 5, 14.7%), a neurally mediated reflex (n = 6, 17.6%), and orthostatic hypotension (n = 4, 11.8%) were identified as probable underlying causes of syncope; in 8 (23.6%) patients, syncope remained unexplained. Patients with syncope had increased non-adjusted all-cause mortality than patients without it (univariate hazard-ratio 3.37; 95% CI 1.43-7.94). When other independent predictors of survival were added to the survival model, this association was no longer statistically significant (multivariate hazard-ratio 1.81, 95% CI 0.67-4.84). CONCLUSIONS: Syncope is frequent in patients with ATTR-CM. This study could not demonstrate an independent association between syncope and mortality in those individuals.Abbreviations: ATTR-CM: Transthyretin amyloid cardiomyopathy; CI: Confidence Interval; HF: Heart Failure; HR: Hazard Ratio; IQR: Interquartile rank; LVEF: Left Ventricular Ejection Fraction; NTproBNP: N-terminal pro-brain natriuretic peptide; SD: Standard Deviation; 99mTc-DPD: technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid.

Cardiac amyloidosis: Description of a series of 143 cases. / Amiloidosis cardiaca: descripción de una serie de 143 casos.

INTRODUCTION AND OBJECTIVES: Recently, there have been important advances in the diagnosis and treatment of cardiac amyloidosis (CA). Our aim was to provide an updated description of its 2 most frequent types: the transthyretin CA (ATTR-CA) and the light chain CA (AL-CA). METHODS: Prospective registry of patients with CA diagnosed in 7 institutions in Galicia (Spain) between January 1, 2018 and June 30, 2020. Variables related to clinical characteristics, complementary tests, survival and causes of death were collected. RESULTS: One hundred and forty-three patients with CA were consecutively included, 128 ATTR-CA (89.5%) and 15 AL-CA (10.5%). Mean age was 79.6±7.7 years and 23.8% were women. Most patients with ATTR-CA were diagnosed non-invasively (87.5%). On physical examination, 35.7, 35 and 7% had Popeye's sign, Dupuytren's contracture and macroglossia, respectively. Twelve-month and 24-month survival was 92.1 and 76.2% in the ATTR-CA group, and 78.6 and 61.1% in the AL-CA group (P=.152). The cause of death was cardiovascular in 80.8% of the cohort. CONCLUSIONS: ATTR-CA can be diagnosed non-invasively in most cases and it is the most common type of CA in routine clinical practice. Furthermore, an increase in the short-term survival of CA appears to be observed, which could be due to advances related to its diagnosis and treatment.

Real world comparison of spironolactone and eplerenone in patients with heart failure.

AIMS: In the absence of previous direct comparative studies, we aimed to evaluate the effectiveness of spironolactone and eplerenone in patients with heart failure and reduced ejection fraction (HFrEF) in a real-world clinical setting. METHODS: Using Fine-Gray´s competing risk regression, we compared the clinical outcomes of 293 patients with chronic HF and left ventricular ejection fraction <40% treated with eplerenone and 293 propensity-score matched individuals treated with spironolactone. Study subjects were selected from a prospective cohort of 1404 ambulatory patients with HFrEF seen since 2010 to 2019 in a single specialized HF clinic, among which 992 received a mineralocorticoid receptor antagonist at baseline. Median follow-up was 3.95 years. RESULTS: No statistically significant differences between patients treated with eplerenone versus spironolactone were observed with regard to the risk of the primary composite end-point cardiovascular death or HF hospitalization (HR 0.95; 95% CI 0.73-1.23; p= 0.677). However, eplerenone use was associated to lower cardiovascular mortality (HR 0.55; 95% CI 0.35-0.85; p= 0.008) and lower all-cause mortality (HR 0.67; 95% CI 0.47-0.95; p= 0.027). The incidence of drug suspension due to side effects (HR 0.58, 95% CI 0.40-0.85; p= 0.005) and drug suspension due to any reason (HR 0.70, 95% CI 0.51-0.97; p= 0.033) were lower among patients treated with eplerenone. CONCLUSIONS: In this observational, real-world, propensity-score matched study of patients with HFrEF, eplerenone was associated to lower cardiovascular mortality and lower all-cause mortality than spironolactone.

Beta-Blocker Exposure and Survival in Patients With Transthyretin Amyloid Cardiomyopathy.

OBJECTIVE: To investigate a potential association between beta-blocker exposure and survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). METHODS: In this real-world prospective registry of 128 consecutive patients with ATTR-CM recruited in 7 institutions in Galicia (Spain), survival of 65 patients who received beta blockers on registry enrollment was compared with that of 63 untreated controls by means of both unweighted Cox regression and Cox regression with inverse probability of treatment weighting. Tolerance to and adverse effects of beta blockers were recorded. Median study follow-up was 520 days. RESULTS: Patients with ATTR-CM who received beta blockers showed statistically significant lower all-cause mortality than untreated controls as evaluated by either unweighted Cox regression (hazard ratio, 0.31; 95% CI, 0.12 to 0.79) or Cox regression with inverse probability of treatment weighting (hazard ratio, 0.18; 95% CI, 0.08 to 0.41; P<.001). Several sensitivity analyses confirmed the internal validity of these results. The overall frequency of beta-blocker suspension due to adverse effects was 25% (95% CI, 15.5% to 34.5%). CONCLUSION: In this real-world, prospective, multi-institutional registry, patients with ATTR-CM who received beta blockers had lower all-cause mortality than untreated controls.

Characterization of hereditary transthyretin cardiac amyloidosis in Spain.

INTRODUCTION AND OBJECTIVES: Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the transthyretin gene that frequently shows cardiac involvement due to amyloid deposition in the myocardium. Our objective was to identify cardiac involvement in a Spanish cohort. METHODS: Retrospective multicenter study of patients diagnosed with hATTR with cardiac involvement from Spanish centers. We collected demographic, clinical, and genetic data. RESULTS: A total of 181 patients from 26 centers were included (65.2% men, with a median age at diagnosis of 62 years). The most frequent mutations were Val50Met (67.7%) and Val142Ile (12.4%). The main reason for consultation was extracardiac symptoms (69%), mainly neurological. The mean N-terminal pro-B-type natriuretic peptide level was 2145±3586 pg/mL. The most characteristic electrocardiogram findings were a pseudoinfarct pattern (25.9%) and atrioventricular block (25.3%). Mean ventricular thickness was 15.4±4.1mm. Longitudinal strain was reduced in basal segments by 29.4%. Late diffuse subendocardial enhancement was observed in 58.8%. Perugini grade 2 or 3 uptake was observed in 75% of scintigraphy scans. During follow-up, 24.9% of the patients were admitted for heart failure, 34.3% required a pacemaker, and 31.6% required a liver transplant. One third (32.5%) died during follow-up, mainly due to heart failure (28.8%). The presence of non-Val50Met mutations was associated with a worse prognosis. CONCLUSIONS: HATTR cardiac amyloidosis in Spain shows heterogeneous genetic and clinical involvement. The prognosis is poor, mainly due to cardiac complications. Consequently early diagnosis and treatment are vital.

Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study.

AIMS: Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step-wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively. METHODS AND RESULTS: The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) study is an international, multicentre, non-randomized, open-label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N-terminal pro-B-type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in-hospital mortality, and length of hospitalization. CONCLUSIONS: The ENACT-HF study will investigate whether a step-wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.