Differential sex-related effect of left ventricular ejection fraction trajectory on the risk of mortality and heart failure readmission following hospitalization for acute heart failure: A longitudinal study.

AIMS: There is limited information on the sex-specific longitudinal changes of left ventricular ejection fraction (LVEF) after an acute heart failure (AHF) hospitalization. We aimed to investigate whether LVEF trajectories over time and their impact on mortality and AHF readmission rates differ between men and women. METHODS AND RESULTS: We conducted a retrospective sex-specific analysis of longitudinal LVEF measurements (n = 9581) in 3383 patients with an index hospitalization for AHF in a single tertiary-level hospital. Statistical techniques suited for longitudinal data analysis were used. The mean age of the sample was 73.8 ± 11.2 years, and 47.9% were women. The mean LVEF was 49.4 ± 15.3%. At a median follow-up of 2.58 years (interquartile range 0.77-5.62), we registered 2197 deaths (64.9%) and 2597 AHF readmissions in 1302 (38.5%) patients. The longitudinal analysis showed that women had consistently higher LVEF values throughout the follow-up with both trajectories characterized by an early peak-approximately at 1 year-followed by decreasing values in men but a plateau in women. Multivariate between-sex comparisons across LVEF categories revealed that women had lower rates of AHF readmissions when LVEF ≤40%. On the contrary, women displayed an excess risk of AHF readmissions when LVEF >60%. A trend in the same direction was found for cardiovascular and all-cause mortality. CONCLUSION: Sex was a significant factor in determining the follow-up trajectory of LVEF and predicting differences in outcomes after an AHF admission. The findings suggest that women have a higher risk of AHF readmissions at higher LVEF values, while men have a higher risk at lower LVEF values. For all-cause and cardiovascular mortality, the same direction of the association was inferred but they were not significant.

ß-Blocker Withdrawal and Functional Capacity Improvement in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: Increasing the patient's heart rate (HR) has emerged as a therapeutic option in patients with heart failure with preserved ejection fraction (HFpEF). However, the evidence is conflicting, and the profile of patients who benefit most from this strategy remains unclear. Objective: To assess the association of ß-blocker treatment withdrawal with changes in the percentage of predicted peak oxygen consumption (VO2) across indexed left ventricular diastolic (iLVEDV) and indexed left ventricular systolic volumes (iLVESV), and left ventricular ejection fraction (LVEF) in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants: This post hoc analysis was conducted using data from the investigator-blinded multicenter, randomized, and crossover clinical trial, PRESERVE-HR, that took place from October 1, 2018, through December 31, 2020, to investigate the short-term effects (2 weeks) of ß-blocker withdrawal on peak oxygen consumption (peak VO2). Patients with stable HFpEF (New York Heart Association functional class II to III) receiving treatment with ß-blocker and chronotropic incompetence were included. Intervention: Participants in the PRESERVE-HR trial were randomized to withdraw vs continue with ß-blocker treatment. After 2 weeks, they were crossed over to receive the opposite intervention. This crossover randomized clinical trial examined the short-term effect of ß-blocker withdrawal on peak VO2. Main Outcomes and Measures: The primary outcome was to evaluate the association between ß-blocker withdrawal and short-term changes in percentage of peak VO2 across iLVEDV, iLVESV, and LVEF in patients with HFpEF and chronotropic incompetence treated with ß-blocker. Results: A total of 52 patients (mean age, 73 [SD, 13] years; 60% female) were randomized. The mean resting HR, peak HR, peak VO2, and percentage of peak VO2 were 65 (SD, 9) beats per minute (bpm), 97 (SD, 15) bpm, 12.4 (SD, 2.9) mL/kg per minute, and 72.4% (SD, 17.7%), respectively. The medians (minimum-maximum) of iLVEDV, iLVESV, and LVEF were 44 mL/m2 (IQR, 19-82), 15 mL/m2 (IQR, 7-32), and 64% (IQR, 52%-78%), respectively. After stopping ß-blocker treatment, the median increase in peak HR was plus 30 bpm (95% CI, 25-35; P < .001). ß-Blocker cessation was differentially associated with change of percentage of peak VO2 across the continuum of iLVESV (P for interaction = .02), indicating a greater benefit in those with lower iLVESV. Conclusions and Relevance: In this study, results showed that in patients with HFpEF and chronotropic incompetence receiving treatment with ß-blocker, lower iLVESV may identify those with a greater short-term improvement in maximal functional capacity after stopping ß-blocker treatment. Further studies are warranted for further investigation. Trial Registration: ClinicalTrials.gov (NCT03871803).

Lipoprotein(a) and Long-Term Recurrent Infarction After an Acute Myocardial Infarction.

Lipoprotein(a) (Lp[a]) is an emerging risk factor for incident ischemic heart disease. However, its role in risk stratification in in-hospital survivors to an index acute myocardial infarction (AMI) is scarcer, especially for predicting the risk of long-term recurrent AMI. We aimed to assess the relation between Lp(a) and very long-term recurrent AMI after an index episode of AMI. It is a retrospective analysis that included 1,223 consecutive patients with an AMI discharged from October 2000 to June 2003 in a single-teaching center. Lp(a) was assessed during index admission in all cases. The relation between Lp(a) at discharge and total recurrent AMI was evaluated through negative binomial regression. The mean age of the patients was 67.0 ± 12.3 years, 379 (31.0%) were women, and 394 (32.2%) were diabetic. The index event was more frequently non-ST-segment elevation myocardial infarction (66.0%). The median Lp(a) was 28.8 (11.8 to 63.4) mg/100 ml. During a median follow-up of 9.9 (4.6 to 15.5) years, 813 (66.6%) deaths and 1,205 AMI in 532 patients (43.5%) occurred. Lp(a) values were not associated with an increased risk of long-term all-cause mortality (p = 0.934). However, they were positively and nonlinearly associated with an increased risk of total long-term reinfarction (p = 0.016). In the subgroup analysis, there was no evidence of a differential effect for the most prevalent subgroups. In conclusion, after an AMI, elevated Lp(a) values assessed during hospitalization were associated with an increased risk of recurrent reinfarction in the very long term. Further prospective studies are warranted to evaluate their clinical implications.

Índice cronotrópico y eventos adversos a largo plazo en insuficiencia cardiaca con fracción de eyección conservada / Chronotropic index and long-term outcomes in heart failure with preserved ejection fraction

Introducción y objetivos: Poco se sabe sobre la utilidad de la respuesta de la frecuencia cardiaca (FC) al ejercicio para la estratificación del riesgo en la insuficiencia cardiaca con fracción de eyección conservada (ICFEc). El objetivo de este estudio fue evaluar la asociación entre la respuesta de la FC al ejercicio y el riesgo de episodios de descompensación por insuficiencia cardiaca (DIC) en pacientes sintomáticos estables con ICFEc. Métodos: Se trata de un estudio unicéntrico que incluyó a un total de 133 pacientes con ICFEc (NYHA II-III) tras la realización de una prueba de esfuerzo cardiopulmonar máxima. La respuesta de la FC al ejercicio se evaluó mediante la fórmula del índice cronotrópico (IxC). Para el análisis se utilizó un método de regresión binomial negativa. Resultados: La edad media fue de 73,2±10,5 años, el 56,4% eran mujeres y el 51,1% estaban en fibrilación auricular. La mediana de IxC fue de 0,4 (0,3-0,55). Tras una mediana de seguimiento de 2,4 (1,6-5,3) años, se registraron un total de 146 DIC en 58 pacientes y 41 (30,8%) muertes. El IxC no se asoció con eventos adversos (muerte, p=0,319, y DIC, p=0,573) cuando se analizó de forma conjunta toda la muestra. Sin embargo, se encontró un efecto diferencial en función del ritmo electrocardiográfico para DIC (p para interacción=0,002). El IxC se asoció inversa y linealmente con el riesgo de DIC en aquellos pacientes con ritmo sinusal y de forma lineal y positiva con aquellos en fibrilación auricular. Conclusiones: En pacientes con ICFEc, el IxC se asoció diferencialmente con el riesgo de DIC en función del ritmo electrocardiográfico. Un Ixc más bajo surgió como un factor de riesgo para predecir un mayor riesgo de DIC en pacientes en ritmo sinusal. Por el contrario, un IxC más alto identificó un mayor riesgo en aquellos pacientes en fibrilación auricular. (AU)

Introduction and objectives: Little is known about the usefulness of heart rate (HR) response to exercise for risk stratification in heart failure with preserved ejection fraction (HFpEF). Therefore, this study aimed to assess the association between HR response to exercise and the risk of total episodes of worsening heart failure (WHF) in symptomatic stable patients with HFpEF. Methods: This single-center study included 133 patients with HFpEF (NYHA II-III) who performed maximal cardiopulmonary exercise testing. HR response to exercise was evaluated using the chronotropic index (CIx) formula. A negative binomial regression method was used. Results: The mean age of the sample was 73.2± 10.5 years; 56.4% were female, and 51.1% were in atrial fibrillation. The median for CIx was 0.4 [0.3-0.55]. At a median follow-up of 2.4 [1.6-5.3] years, a total of 146 WHF events in 58 patients and 41 (30.8%) deaths were registered. In the whole sample, CIx was not associated with adverse outcomes (death, P=.319, and WHF events, P=.573). However, we found a differential effect across electrocardiographic rhythms for WHF events (P for interaction=.002). CIx was inversely and linearly associated with the risk of WHF events in patients with sinus rhythm and was positively and linearly associated with those with atrial fibrillation. Conclusions: In patients with HFpEF, CIx was differentially associated with the risk of total WHF events across rhythm status. Lower CIx emerged as a risk factor for predicting higher risk in patients with sinus rhythm. In contrast, higher CIx identified a higher risk in those with atrial fibrillation. (AU)

Early glomerular filtration rates changes and risk of mortality in acute heart failure. The modifying role of admission renal function and decongestion.

BACKGROUND: The pathophysiology of changes in estimated glomerular filtration rate (eGFR) in acute heart failure (AHF) is complex and multifactorial. We evaluated the associated mortality risk of early changes in eGFR across baseline renal function on admission and early changes in natriuretic peptides in patients admitted with AHF. METHODS: We retrospectively evaluated 2,070 patients admitted with AHF. Renal dysfunction on admission was defined as eGFR<60 ml/min/1.73m2 and successful decongestion as NT-proBNP decreased >30% from baseline. We assessed the mortality risk associated with eGFR changes from baseline at 48-72 h after admission (ΔeGFR%) according to baseline renal function, and NT-proBNP changes at 48-72 h through Cox regression analyses. RESULTS: The mean age was 74.4 ± 11.2 years, and 930 (44.9%) were women. The proportion of admission eGFR<60 ml/min/1.73m2 and 48-72 h changes in NT-proBNP>30% were 50.5% and 32.8%, respectively. At a median follow-up of 1.75 years, 928 deaths were registered. In the whole sample, changes in renal function were not associated with mortality (p = 0.208). The adjusted analysis revealed that the risk of mortality related to ΔeGFR% was heterogeneous across baseline renal function and changes in NT-proBNP (p-value for interaction=0.003). ΔeGFR% was not associated with mortality in patients with baseline eGFR≥60 ml/min/1.73m2. In those with eGFR<60 ml/min/1.73m2, a decrease in eGFR was associated with higher mortality, particularly in those with a reduction in NT-proBNP<30%. CONCLUSION: In patients with AHF, early ΔeGFR% was associated with the risk of long-term mortality only in patients with renal dysfunction on admission and no early decline in NT-proBNP.

Short-term Changes in Hemoglobin and Changes in Functional Status, Quality of Life and Natriuretic Peptides After Initiation of Dapagliflozin in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: We aimed to evaluate the effect of dapagliflozin on short-term changes in hemoglobin in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effect of dapagliflozin on functional capacity, quality of life and NT-proBNP levels. METHODS: This is an exploratory analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly allocated to dapagliflozin or placebo to evaluate short-term changes in peak oxygen consumption (peak VO2) (NCT04197635). This substudy evaluated 1- and 3-month changes in hemoglobin levels and whether these changes mediated the effects of dapagliflozin on peak VO2, Minnesota Living-With-Heart-Failure test (MLHFQ) and NT-proBNP levels. RESULTS: At baseline, mean hemoglobin levels were 14.3 ± 1.7 g/dL. Hemoglobin levels significantly increased in those taking dapagliflozin (1 month: + 0.45 g/dL (P = 0.037) and 3 months:+ 0.55 g/dL (P = 0.012)]. Changes in hemoglobin levels positively mediated the changes in peak VO2 at 3 months (59.5%; P < 0.001). Changes in hemoglobin levels significantly mediated the effect of dapagliflozin in the MLHFQ at 3 months (-53.2% and -48.7%; P = 0.017) and NT-proBNP levels at 1 and 3 months (-68.0%; P = 0.048 and -62.7%; P = 0.029, respectively). CONCLUSIONS: In patients with stable HFrEF, dapagliflozin caused a short-term increase in hemoglobin levels, identifying patients with greater improvements in maximal functional capacity, quality of life and reduction of NT-proBNP levels.

Chronotropic index and long-term outcomes in heart failure with preserved ejection fraction.

INTRODUCTION AND OBJECTIVES: Little is known about the usefulness of heart rate (HR) response to exercise for risk stratification in heart failure with preserved ejection fraction (HFpEF). Therefore, this study aimed to assess the association between HR response to exercise and the risk of total episodes of worsening heart failure (WHF) in symptomatic stable patients with HFpEF. METHODS: This single-center study included 133 patients with HFpEF (NYHA II-III) who performed maximal cardiopulmonary exercise testing. HR response to exercise was evaluated using the chronotropic index (CIx) formula. A negative binomial regression method was used. RESULTS: The mean age of the sample was 73.2± 10.5 years; 56.4% were female, and 51.1% were in atrial fibrillation. The median for CIx was 0.4 [0.3-0.55]. At a median follow-up of 2.4 [1.6-5.3] years, a total of 146 WHF events in 58 patients and 41 (30.8%) deaths were registered. In the whole sample, CIx was not associated with adverse outcomes (death, P=.319, and WHF events, P=.573). However, we found a differential effect across electrocardiographic rhythms for WHF events (P for interaction=.002). CIx was inversely and linearly associated with the risk of WHF events in patients with sinus rhythm and was positively and linearly associated with those with atrial fibrillation. CONCLUSIONS: In patients with HFpEF, CIx was differentially associated with the risk of total WHF events across rhythm status. Lower CIx emerged as a risk factor for predicting higher risk in patients with sinus rhythm. In contrast, higher CIx identified a higher risk in those with atrial fibrillation.

Risk of death associated with incident heart failure in patients with known or suspected chronic coronary syndrome.

AIMS: Traditional adverse events in chronic coronary syndrome (CCS) include atherothrombotic events but usually exclude heart failure (HF). Data are scarce about how new-onset HF modifies mortality risk. We aimed to determine the incidence of HF and compare its long-term mortality risk with myocardial infarction (MI) and stroke in patients with known or suspected CCS. METHODS: We prospectively evaluated 5811 consecutive HF-free patients submitted to vasodilator stress cardiac magnetic resonance (CMR) for known or suspected CCS. Ischaemic burden and left ventricular ejection fraction were assessed by CMR. HF included outpatient diagnosis or acute HF hospitalization. The mortality risk for the incident events and their cross-comparisons were evaluated using a Markov illness-death model with transition-specific survival models. RESULTS: The mean age was 55 ± 11 years, and 38.9% were female. At a median follow-up of 5.44 (IQR = 2.53-8.55) years, 591 deaths were registered (1.79 per 100 P-Y). The rates of new-onset HF were higher compared with MI and stroke [1.02, 0.62, and 0.51, respectively (P < 0.05)]. The adjusted association between new-onset HF, MI, and stroke, and subsequent mortality was time dependent. The risk increased almost linearly for HF and became significant by the third year. By Year 10, the mortality risk attributable to new-onset HF was more than 2.5-fold (HR: 2.68, 95% CI = 1.74-4.12). For MI, there was a significant increase in mortality risk up to the second year, followed by a monotonic decrease. For stroke, the mortality risk increased for the entire follow-up but became significant by the third year. A cross-comparison among incident endpoints HF outnumbers risk for those with MI by the sixth year (HRyear6.3 : 1.88, 95% CI = 1.03-3.43). There was no difference in mortality risk between incident HF and stroke. CONCLUSIONS: In patients with CCS, long-term rates of incident HF were higher than MI and stroke. Patients with new-onset HF showed a higher risk of long-term mortality.

Bending oxygen saturation index and risk of worsening heart failure events in chronic heart failure.

AIMS: Bendopnea is a clinical symptom of advanced heart failure with uncertain prognostic value. We aimed to evaluate whether bendopnea and the change in oxygen saturation when bending forward (bending oxygen saturation index [BOSI]) are associated with adverse outcomes in ambulatory chronic heart failure (CHF) patients. METHODS AND RESULTS: We prospectively evaluated 440 subjects with symptomatic CHF. BOSI was defined as the difference between sitting and bending oxygen saturation (SpO2 ). The endpoint was the total number of worsening heart failure (WHF) events (heart failure hospitalization or urgent heart failure visit requiring parenteral diuretic therapy). The mean age was 74 ± 10 years, 257 (58.6%) were male, and 226 (51.4%) had a left ventricular ejection fraction <50%. Bendopnea was present in 94 (21.4%) patients, and 120 (27.3%) patients had a BOSI ≥-3%. The agreement between BOSI ≥-3% and bendopnea was moderate (Gwet's AC 0.482, p < 0.001). At a median (p25%-p75%) follow-up of 2.17 years (0.88-3.16), we registered 441 WHF events in 148 patients. After multivariable adjustment, BOSI was independently associated with the risk for total WHF episodes (overall, p < 0.001). Compared to improvement/no change in SpO2 when bending (BOSI 0%), those with BOSI ≥-3% showed an increased risk of WHF events (incidence rate ratio [IRR] 2.16, 95% confidence interval [CI] 1.67-2.79; p < 0.001). In contrast, bendopnea was not associated with the risk of total WHF episodes (IRR 1.04, 95% CI 0.83-1.31; p = 0.705). CONCLUSIONS: In ambulatory and stable CHF patients, BOSI ≥-3% and not bendopnea was independently associated with an increased risk of total (first and recurrent) WHF episodes. Awareness of SpO2 while assessing bendopnea may be a useful tool for predicting heart failure decompensations.

Incidence, Treatment and Clinical Impact of Iron Deficiency in Chronic Heart Failure: A Longitudinal Analysis.

In patients with heart failure (HF), iron deficiency (ID) is a well-recognized therapeutic target; information about its incidence, patterns of iron repletion, and clinical impact is scarce. This single-centre longitudinal cohort study assessed the rates of ID testing and diagnosis in patients with stable HF, patterns of treatment with intravenous iron, and clinical impact of intravenous iron on HF rehospitalization risk. We included 711 consecutive outpatients (4400 visits) with stable chronic HF from 2014 to 2019 (median [interquartile range] visits per patient: 2 [2−7]. ID was defined as serum ferritin <100 µg/L, or 100−299 µg/L with transferrin saturation (TSAT) < 20%. During a median follow-up of 2.20 (1.11−3.78) years, ferritin and TSAT were measured at 2230 (50.7%) and 2183 visits (49.6%), respectively. ID was found at 846 (37.9%) visits, with ferritin and TSAT available (2230/4400), and intravenous iron was administered at 321/4400 (7.3%) visits; 233 (32.8%) patients received intravenous iron during follow-up. After multivariate analyses, iron repletion at any time during follow-up was associated with a lower risk of recurrent HF hospitalization (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.28−0.88; p = 0.016). Thus, ID was a frequent finding in patients with HF, and its repletion reduced the risk of recurrent HF hospitalizations.

Short-term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA-VO2 ): a randomized clinical trial.

AIMS: This study aimed to evaluate the effect of dapagliflozin on 1 and 3-month maximal functional capacity in patients with stable heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: In this multicentre, randomized, double-blind clinical trial, 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin (n = 45) or placebo (n = 45). The primary outcome was a change in peak oxygen consumption (peakVO2 ) at 1 and 3 months. Secondary endpoints were changes at 1 and 3 months in 6-min walk test (6MWT) distance, quality of life (Minnesota Living with Heart Failure Questionnaire [MLHFQ]), and echocardiographic parameters (diastolic function, left chamber volumes, and left ventricular ejection fraction). We used linear mixed regression analysis to compare endpoint changes. Estimates were adjusted for multiple comparisons. The mean age was 67.1 ± 10.7 years, 69 (76.7%) were men, 29 (32.2%) had type 2 diabetes, and 80 (88.9%) were in New York Heart Association class II. Baseline means of peakVO2 , 6MWT and MLHFQ were 13.2 ± 3.5 ml/kg/min, 363 ± 110 m, and 23.1 ± 16.2, respectively. The median (25th-75th percentile) of N-terminal pro-brain natriuretic peptide was 1221 pg/ml (889-2100). Most patients were on treatment with sacubitril/valsartan (88.9%), beta-blockers (91.1%), and mineralocorticoid receptor antagonists (74.4%). PeakVO2 significantly increased in patients on treatment with dapagliflozin (1 month: +Δ 1.09 ml/kg/min, 95% confidence interval [CI] 0.14-2.04; p = 0.021, and 3 months: +Δ 1.06 ml/kg/min, 95% CI 0.07-2.04; p = 0.032). Similar positive findings were found when evaluating changes from baseline. No significant differences were observed in secondary endpoints. CONCLUSIONS: Among patients with stable HFrEF, dapagliflozin resulted in a significant improvement in peakVO2 at 1 and 3 months. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04197635.

Short-Term Changes in Left and Right Ventricular Cardiac Magnetic Resonance Feature Tracking Strain Following Ferric Carboxymaltose in Patients With Heart Failure: A Substudy of the Myocardial-IRON Trial.

Background The mechanisms explaining the clinical benefits of ferric carboximaltose (FCM) in patients with heart failure, reduced or intermediate left ventricular ejection fraction, and iron deficiency remain not fully clarified. The Myocardial-IRON trial showed short-term cardiac magnetic resonance (CMR) changes suggesting myocardial iron repletion following administration of FCM but failed to find a significant increase in left ventricular ejection fraction in the whole sample. Conversely, the strain assessment could evaluate more specifically subtle changes in contractility. In this subanalysis, we aimed to evaluate the effect of FCM on the short-term left and right ventricular CMR feature tracking derived strain. Methods and Results This is a post hoc subanalysis of the double-blind, placebo-controlled, randomized clinical trial that enrolled 53 ambulatory patients with heart failure and left ventricular ejection fraction <50%, and iron deficiency [Myocardial-IRON trial (NCT03398681)]. Three-dimensional left and 2-dimensional right ventricular CMR tracking strain (longitudinal, circumferential, and radial) changes were evaluated before, 7 and 30 days after randomization using linear mixed-effect analysis. The median (interquartile range) age of the sample was 73 years (65-78), and 40 (75.5%) were men. At baseline, there were no significant differences in CMR feature tracking strain parameters across both treatment arms. At 7 days, the only global 3-dimensional left ventricular circumferential strain was significantly higher in the FCM treatment-arm (difference: -1.6%, P=0.001). At 30 days, and compared with placebo, global 3-dimensional left ventricular strain parameters significantly improved in those allocated to FCM treatment-arm [longitudinal (difference: -2.3%, P<0.001), circumferential (difference: -2.5%, P<0.001), and radial (difference: 4.2%, P=0.002)]. Likewise, significant improvements in global right ventricular strain parameters were found in the active arm at 30 days (longitudinal [difference: -3.3%, P=0.010], circumferential [difference: -4.5%, P<0.001], and radial [difference: 4.5%, P=0.027]). Conclusions In patients with stable heart failure, left ventricular ejection fraction <50%, and iron deficiency, treatment with FCM was associated with short-term improvements in left and right ventricular function assessed by CMR feature tracking derived strain parameters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.

Prognostic value of NT-proBNP and CA125 across glomerular filtration rate categories in acute heart failure.

BACKGROUND: This study aimed to evaluate whether glomerular filtration rate (eGFR) during admission modifies the predictive value of plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP) and carbohydrate antigen 125 (CA125) in patients hospitalized for acute heart failure (AHF). METHODS: We retrospectively evaluated 4595 patients consecutively discharged after admission for AHF at three tertiary-care hospitals from January 2008 through October 2019. To investigate the effect of kidney function on the association of NT-proBNP and CA125 with 1-year mortality (all-cause and cardiovascular mortality), we stratified patients according to four eGFR categories: <30 mL•min-1•1.73 m-2, 30-44 mL•min-1•1.73 m-2, 44-59 mL•min-1•1.73 m-2, and ≥60 mL•min-1•1.73 m-2. Biomarkers were assessed within the first 24 hours following admission. RESULTS: At 1-year follow-up, 748 of 4595 (16.3%) patients died after discharge (of all deaths, 575 [12.5%] were cardiovascular). After multivariate adjustment, both NT-proBNP and CA125 remained independently associated with a higher risk of death when modeled as main effects (P<0.001). However, we found a differential prognostic effect of NT-proBNP across eGFR categories for both endpoints (all-cause mortality, P-value for interaction=0.002; CV mortality, P-value for interaction=0.001). Whereas NT-proBNP was positively and linearly associated with mortality in the subset of patients with normal or mildly reduced eGFR, its predictive ability progressively decreased at the lower extreme of eGFR (<45 mL•min-1•1.73 m-2). In contrast, the association between CA125 and survival remained consistent across all eGFR categories (all-cause mortality, P-value for interaction=0.559; CV mortality, P-value for interaction=0.855). CONCLUSIONS: In patients with AHF and severely reduced eGFR, CA125 outperforms NT-proBNP in predicting 1-year mortality.

Optimal carbohydrate antigen 125 cutpoint for identifying low-risk patients after admission for acute heart failure.

INTRODUCTION AND OBJECTIVES: Carbohydrate antigen 125 (CA125) has been shown to be useful for risk stratification in patients admitted with acute heart failure (AHF). We sought to determine a CA125 cutpoint for identifying patients at low risk of 1-month death or the composite of death/HF readmission following admission for AHF. METHODS: The derivation cohort included 3231 consecutive patients with AHF. CA125 cutoff values with 90% negative predictive value (NPV) and sensitivity up to 85% were identified. The adequacy of these cutpoints and the risk of 1-month death/HF readmission was then tested using the Royston-Parmar method. The best cutpoint was selected and externally validated in a cohort of patients hospitalized from BIOSTAT-CHF (n=1583). RESULTS: In the derivation cohort, the median [IQR] CA125 was 57 [25.3-157] U/mL. The optimal cutoff value was <23 U/mL (21.5% of patients), with NPVs of 99.3% and 94.1% for death and the composite endpoint, respectively. On multivariate survival analyses, CA125 <23 U/mL was independently associated with a lower risk of death (HR, 0.20; 95%CI, 0.08-0.50; P <.001), and the combined endpoint (HR, 0.63; 95%CI, 950.45-0.90; P=.009). The ability of this cutpoint to discriminate patients at a low 1-month risk was confirmed in the validation cohort (NPVs of 98.6% and 96.6% for death and the composite endpoint). The predicted ability of this cutoff remained significant at 6 months of follow-up. CONCLUSIONS: In patients admitted with AHF, CA125 <23 U/mL identified a subgroup at low risk of short-term adverse events, a population that may not require intense postdischarge monitoring.

Effect of ß-Blocker Withdrawal on Functional Capacity in Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Chronotropic incompetence has shown to be associated with a decrease in exercise capacity in heart failure with preserved ejection fraction (HFpEF), yet ß-blockers are commonly used in HFpEF despite the lack of robust evidence. OBJECTIVES: This study aimed to evaluate the effect of ß-blocker withdrawal on peak oxygen consumption (peak Vo2) in patients with HFpEF and chronotropic incompetence. METHODS: This is a multicenter, randomized, investigator-blinded, crossover clinical trial consisting of 2 treatment periods of 2 weeks separated by a washout period of 2 weeks. Patients with stable HFpEF, New York Heart Association functional classes II and III, previous treatment with ß-blockers, and chronotropic incompetence were first randomized to withdrawing from (arm A: n = 26) versus continuing (arm B: n = 26) ß-blocker treatment and were then crossed over to receive the opposite intervention. Changes in peak Vo2 and percentage of predicted peak Vo2 (peak Vo2%) measured at the end of the trial were the primary outcome measures. To account for the paired-data nature of this crossover trial, linear mixed regression analysis was used. RESULTS: The mean age was 72.6 ± 13.1 years, and most of the patients were women (59.6%) in New York Heart Association functional class II (66.7%). The mean peakVo2 and peak Vo2% were 12.4 ± 2.9 mL/kg/min, and 72.4 ± 17.8%, respectively. No significant baseline differences were found across treatment arms. Peak Vo2 and peak Vo2% increased significantly after ß-blocker withdrawal (14.3 vs 12.2 mL/kg/min [Δ +2.1 mL/kg/min]; P < 0.001 and 81.1 vs 69.4% [Δ +11.7%]; P < 0.001, respectively). CONCLUSIONS: ß-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence. ß-blocker use in HFpEF deserves profound re-evaluation. (ß-blockers Withdrawal in Patients With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity [PRESERVE-HR]; NCT03871803; 2017-005077-39).

Antigen carbohydrate 125 as a biomarker in heart failure: a narrative review.

Congestion explains many of the signs and symptoms of acute heart failure (AHF) and disease progression. However, accurate quantification of congestion is challenging in daily practice. Antigen carbohydrate 125 (CA125) or mucin 16 (MUC16), a large glycoprotein synthesized by mesothelial cells, has emerged as a reliable proxy of congestion and inflammation in patients with heart failure (HF). In AHF syndromes, CA125 is strongly associated with right-sided HF parameters and a higher risk of adverse clinical events beyond standard prognostic factors, including natriuretic peptides. Furthermore, CA125 has the potential for both monitoring and guide HF treatment following a decompensated HF event. The wide availability of CA125 in most clinical laboratories, together with its standardized measurement and reduced cost, makes this marker attractive for routine use in decompensated HF. Further research is required to understand better its biological role and its promising utility as a tool to guide decongestive therapy in HF.

Clinical utility of antigen carbohydrate 125 for planning the optimal length of stay in acute heart failure.

BACKGROUND: The optimal length of stay (LOS) in patients hospitalized for acute heart failure (AHF) remains controversial. Plasma antigen carbohydrate 125 (CA125) has emerged as a reliable proxy of congestion. We aimed to evaluate whether there is a differential impact of LOS on the risk of 6-month AHF readmission across CA125 levels. METHODS: This is a retrospective study that included 1,387 patients discharged for AHF in two third-level centers. CA125 was measured 48±24 h after admission. The association between CA125 and LOS with the risk of subsequent AHF readmission at 6 months was analyzed by Cox regression analysis accounting for death as a competing event. RESULTS: The median (IQR) age of the sample was 78 (69-83) years, 625 (41.1%) patients were women, and 832 (60%) exhibited preserved left ventricular ejection fraction. The median LOS and CA125 were 6 (4-9) days and 36 (17-83) U/mL, respectively. A total of 707 (51%) patients displayed high CA125 levels (≥35 U/mL). At 6 months, 87 deaths (6,3%) and 304 AHF readmissions (21,9%) were registered, respectively. A multivariate analysis revealed a differential effect of LOS on 6-month AHF readmission across CA125 levels (p-value for interaction=0.010). In those with CA125<35 U/mL, LOS≥7 days did not modify the risk (HR:1.31; 95% CI: 0.92-1.87, p=0.131). Conversely, in those with CA125≥35 U/mL, LOS≥7 days was associated with a lower risk of AHF readmission (HR:0.70; 95% CI: 0.51-0.98, p=0.036). CONCLUSIONS: In patients with AHF, high CA125 levels may identify those patients that benefit from a more prolonged hospitalization in terms of reducing the risk of mid-term AHF readmissions.

Sex differences on new-onset heart failure in patients with known or suspected coronary artery disease.

AIMS: The impact of sex in patients with CAD has been widely reported, but little is known about the influence of sex on the risk of new-onset HF in patients with known or suspected CAD. We aimed to examine sex-related differences and new-onset heart failure (HF) risk in patients with known or suspected coronary artery disease (CAD) undergoing vasodilator stress cardiac magnetic resonance (CMR). METHODS AND RESULTS: We prospectively evaluated 5899 consecutive HF-free patients submitted to stress CMR for known or suspected CAD. Ischaemic burden (number of segments with stress-induced perfusion deficit) and left ventricular ejection fraction (LVEF) were assessed by CMR. The association between sex and new-onset HF (including outpatient diagnosis or acute HF hospitalization) was evaluated using a Cox proportional hazards regression model adjusted for competing events [death, myocardial infarction (MI), and revascularization]. A total of 2289 (38.8%) patients were women. During a median follow-up of 4.5 years, 610 (10.3%) patients died, 191 (3.2%) suffered an MI, 905 (15.3%) underwent revascularization, and 314 (5.3%) developed new-onset HF. Unadjusted new-onset HF rates were higher in women than in men (1.25 vs. 0.83 per 100 person-years, P = 0.001). After comprehensive multivariate adjustment, women showed an increased risk of new-onset HF (hazard ratio 1.58, 95% confidence interval 1.18-2.10; P = 0.002). We found a sex-differential effect along the continuum of LVEF (P-value for interaction = 0.007). At lower LVEF, there was an increased risk in both sexes. However, compared with men, the risk of new-onset HF was higher in women with LVEF >55%. CONCLUSION: Women with known or suspected CAD are at a higher risk of new-onset HF. Further studies are needed to unravel the mechanisms behind these sex-related differences.

Long-term prognostic implications of revascularization in patients with known or suspected chronic coronary syndromes without ischemia in vasodilator stress cardiovascular magnetic resonance.

AIMS: In this study, we evaluated the association between symptoms-guided revascularization occurred within three months following a negative vasodilator stress cardiovascular magnetic resonance (negative stress-CMR) and long-term adverse events in patients with known or suspected chronic coronary syndrome (CCS). METHODS: We retrospectively evaluated 3517 patients in which the stress first-pass perfusion imaging revealed no ischemia. The primary endpoint was the composite of death, spontaneous myocardial infarction, heart failure (HF), or stroke. The association between symptoms-guided revascularization after a negative stress-CMR and the endpoint was assessed using the multivariable Cox proportional hazard regression model. RESULTS: The mean age was 64.7 ± 11.9 years and 45.4% were females. Coronary angiography and revascularization following a negative stress-CMR were performed in 176 (5%) and 59 (1.7%) patients. At a median follow-up of 4.8 years (2.0-8.2), 529 (15%) patients experienced the primary endpoint (2.0 per 100 person-years). Revascularization following a negative CMR was associated with a higher incidence of the composite (4.85 vs. 1.96 per 100 person-years, p < 0.001) and each of the isolated components of the endpoint, except for the HF endpoint, in which differences were borderline significant. After multivariate adjustment, revascularization remained associated with an excess of risk (HR = 2.01, 95% CI:1.21-3.30; p = 0.007). CONCLUSIONS: In CCS patients with persistent symptoms but without evidence of ischemia in vasodilator stress CMR, revascularization was associated with a higher risk of adverse clinical events.

CA125 but not NT-proBNP predicts the presence of a congestive intrarenal venous flow in patients with acute heart failure.

BACKGROUND: Intrarenal venous flow (IRVF) measured by Doppler ultrasound has gained interest as a potential surrogate marker of renal congestion and adverse outcomes in heart failure. In this work, we aimed to determine if antigen carbohydrate 125 (CA125) and plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) are associated with congestive IRVF patterns (i.e., biphasic and monophasic) in acute heart failure (AHF). METHODS AND RESULTS: We prospectively enrolled a consecutive cohort of 70 patients hospitalized for AHF. Renal Doppler ultrasound was assessed within the first 24-h of hospital admission. The mean age of the sample was 73.5 ± 12.3 years; 47.1% were female, and 42.9% exhibited heart failure with preserved ejection fraction. The median (interquartile range) for NT-proBNP and CA125 were 6149 (3604-12 330) pg/mL and 64 (37-122) U/mL, respectively. The diagnostic performance of both exposures for identifying congestive IRVF patterns was tested using the receiving operating curve (ROC). The cut-off for CA125 of 63.5 U/mL showed a sensibility and specificity of 67% and 74% and an area under the ROC curve of 0.71. After multivariate adjustment, CA125 remained non-linearly and positively associated with congestive IRVF (P-value = 0.008) and emerged as the most important covariate explaining the variability of the model (R2: 47.5%). Under the same multivariate setting, NT-proBNP did not show to be associated with congestive IRVF patterns (P-value = 0.847). CONCLUSIONS: CA125 and not NT-proBNP is a useful marker for identifying patients with AHF and congestive IRVF patterns.