Galectin-3, Acute Kidney Injury and Myocardial Damage in Patients With Acute Heart Failure.

BACKGROUND: Galectin-3, a biomarker of inflammation and fibrosis, can be associated with renal and myocardial damage and dysfunction in patients with acute heart failure (AHF). METHODS AND RESULTS: We retrospectively analyzed 790 patients with AHF who were enrolled in the AKINESIS study. During hospitalization, patients with galectin-3 elevation (> 25.9 ng/mL) on admission more commonly had acute kidney injury (assessed by KDIGO criteria), renal tubular damage (peak urine neutrophil gelatinase-associated lipocalin [uNGAL] > 150 ng/dL) and myocardial injury (≥ 20% increase in the peak high-sensitivity cardiac troponin I [hs-cTnI] values compared to admission). They less commonly had ≥ 30% reduction in B-type natriuretic peptide from admission to last measured value. In multivariable linear regression analysis, galectin-3 was negatively associated with estimated glomerular filtration rate and positively associated with uNGAL and hs-cTnI. Higher galectin-3 was associated with renal replacement therapy, inotrope use and mortality during hospitalization. In univariable Cox regression analysis, higher galectin-3 was associated with increased risk for the composite of death or rehospitalization due to HF and death alone at 1 year. After multivariable adjustment, higher galectin-3 levels were associated only with death. CONCLUSIONS: In patients with AHF, higher galectin-3 values were associated with renal dysfunction, renal tubular damage and myocardial injury, and they predicted worse outcomes.

The Influence of Body Mass Index on Clinical Interpretation of Established and Novel Biomarkers in Acute Heart Failure.

BACKGROUND: Body mass index (BMI) is a known confounder for natriuretic peptides, but its influence on other biomarkers is less well described. We investigated whether BMI interacts with biomarkers' association with prognosis in patients with acute heart failure (AHF). METHODS AND RESULTS: B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin I (hs-cTnI), galectin-3, serum neutrophil gelatinase-associated lipocalin (sNGAL), and urine NGAL were measured serially in patients with AHF during hospitalization in the AKINESIS (Acute Kidney Injury Neutrophil gelatinase-associated lipocalin Evaluation of Symptomatic Heart Failure) study. Cox regression analysis was used to determine the association of biomarkers and their interaction with BMI for 30-day, 90-day and 1-year composite outcomes of death or HF readmission. Among 866 patients, 21.2%, 29.7% and 46.8% had normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) or obese (≥ 30 kg/m2) BMIs on admission, respectively. Admission values of BNP and hs-cTnI were negatively associated with BMI, whereas galectin-3 and sNGAL were positively associated with BMI. Admission BNP and hs-cTnI levels were associated with the composite outcome within 30 days, 90 days and 1 year. Only BNP had a significant interaction with BMI. When BNP was analyzed by BMI category, its association with the composite outcome attenuated at higher BMIs and was no longer significant in obese individuals. Findings were similar when evaluated by the last-measured biomarkers and BMIs. CONCLUSIONS: In patients with AHF, only BNP had a significant interaction with BMI for the outcomes, with its association attenuating as BMI increased; hs-cTnI was prognostic, regardless of BMI.

The GUIDE-HF trial of pulmonary artery pressure monitoring in heart failure: impact of the COVID-19 pandemic.

AIMS: During the coronavirus disease 2019 (COVID-19) pandemic, important changes in heart failure (HF) event rates have been widely reported, but few data address potential causes for these changes; several possibilities were examined in the GUIDE-HF study. METHODS AND RESULTS: From 15 March 2018 to 20 December 2019, patients were randomized to haemodynamic-guided management (treatment) vs. control for 12 months, with a primary endpoint of all-cause mortality plus HF events. Pre-COVID-19, the primary endpoint rate was 0.553 vs. 0.682 events/patient-year in the treatment vs. control group [hazard ratio (HR) 0.81, P = 0.049]. Treatment difference was no longer evident during COVID-19 (HR 1.11, P = 0.526), with a 21% decrease in the control group (0.536 events/patient-year) and no change in the treatment group (0.597 events/patient-year). Data reflecting provider-, disease-, and patient-dependent factors that might change the primary endpoint rate during COVID-19 were examined. Subject contact frequency was similar in the treatment vs. control group before and during COVID-19. During COVID-19, the monthly rate of medication changes fell 19.2% in the treatment vs. 10.7% in the control group to levels not different between groups (P = 0.362). COVID-19 was infrequent and not different between groups. Pulmonary artery pressure area under the curve decreased -98 mmHg-days in the treatment group vs. -100 mmHg-days in the controls (P = 0.867). Patient compliance with the study protocol was maintained during COVID-19 in both groups. CONCLUSION: During COVID-19, the primary event rate decreased in the controls and remained low in the treatment group, resulting in an effacement of group differences that were present pre-COVID-19. These outcomes did not result from changes in provider- or disease-dependent factors; pulmonary artery pressure decreased despite fewer medication changes, suggesting that patient-dependent factors played an important role in these outcomes. Clinical Trials.gov: NCT03387813.

Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.

BACKGROUND: Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II-IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation. METHODS: The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II-IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT03387813. FINDINGS: Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74-1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (pinteraction=0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66-1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80-1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70-1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61-0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications. INTERPRETATION: Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group. FUNDING: Abbott.

Comparative Effect of Angiotensin Receptor Neprilysin Inhibition on B-type Natriuretic Peptide Levels Measured by Three Different Assays: The PROVE-HF Study.

BACKGROUND: Several different B-type natriuretic peptide (BNP) assays are used clinically for diagnostic and prognostic evaluation of heart failure (HF). BNP binds weakly to neprilysin and is cleaved in multiple areas adjacent to the binding sites for the antibodies used in these immunoassays. We assessed the changes in BNP following neprilysin inhibition as measured by 3 immunoassays that recognize different epitopes. METHODS: Among 130 participants with HF with reduced ejection fraction, blood was collected prior to treatment with sacubitril/valsartan (sac/val) and then repeatedly measured through 52 weeks of treatment. BNP concentrations were measured with 3 widely used BNP assays (Siemens, Abbott, and Quidel). RESULTS: Study participants had a mean age of 65 ± 13 years and 76% were men. The median BNP concentration at baseline was 133 ng/L by the Siemens assay, 127 ng/L by the Abbott assay, and 141 ng/L by the Quidel assay. Following initiation of sac/val, there were significantly greater declines in BNP measured by Quidel and Abbott (P = 0.009 and P < 0.001), respectively (both with N-terminal capture antibodies), compared to Siemens (with C-terminal capture antibodies). The difference from baseline was not statistically significant until after week 12 (mean -10.1% for Quidel and -14.3% for Abbott) compared to non-significant differences before 12 weeks (mean -4.5% for Quidel and -6.0% for Abbott). CONCLUSIONS: Following initiation of sac/val, BNP measurements may modestly differ depending on the assay method used, particularly after a few months of treatment. Whether these differences relate to neprilysin-mediated degradation of antibody binding sites deserves further study. STUDY REGISTRATION: PROVE-HF ClinicalTrials.gov Identifier: NCT02887183.

Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction.

BACKGROUND: The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cTn assays. However, it remains to be determined how to diagnose, risk-stratify, and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. METHODS: Patients presenting to the emergency department with chest pain, enrolled in the CHOPIN study (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction), were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic curve analysis. The biomarkers analyzed were cTnI, copeptin, MR-proANP (midregional proatrial natriuretic peptide), CT-proET1 (C-terminal proendothelin-1), MR-proADM (midregional proadrenomedullin), and procalcitonin. The prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (a composite of acute myocardial infarction, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. RESULTS: Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, whereas those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the receiver operating characteristic curve for the diagnosis of T2MI was higher for CT-proET1, MR-proADM, and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, P=0.294). Addition of biomarkers to the clinical model yielded the highest area under the receiver operating characteristic curve (0.917). Other biomarkers, but not cTnI, were associated with mortality and major adverse cardiovascular event at 180 days among all patients, with no interaction between the diagnosis of T1MI or T2MI. CONCLUSIONS: Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. All biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of the type of myocardial infarction.

Potential Utility of Cardiorenal Biomarkers for Prediction and Prognostication of Worsening Renal Function in Acute Heart Failure.

BACKGROUND: Multiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure. METHODS AND RESULTS: We retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r ≤ 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitalization. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization. CONCLUSIONS: Biomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury biomarker may prognosticate WRF for heart failure hospitalization.

Clinical Characteristics and Outcomes of Patients With Heart Failure and Methamphetamine Abuse.

BACKGROUND: Despite a global epidemic of methamphetamine abuse, methamphetamine-associated heart failure (MethHF) remains poorly understood. We sought to evaluate characteristics and outcomes for patients with MethHF. METHODS: We reviewed the electronic health records of the University of California, San Diego, from 2005 to 2016. We compared characteristics and outcomes between 896 patients with MethHF and 20,576 patients with heart failure (HF) identified using diagnosis codes, urine toxicology, and natriuretic peptides. RESULTS: Compared with HF, patients with MethHF were younger (50±10 vs 67±16 years), predominantly male (72% vs 54%), and had more psychiatric and substance use comorbidities, including mood/anxiety disorders (29% vs 16%) and opioid use (44% vs 7%). MethHF had a higher 5-year HF readmission rate (64±4% vs 45±1%; hazard ratio [HR] 1.53, P < .001) and a lower 10-year total mortality rate (25±3% vs 28±1%; HR 0.85, P = .09). Predictors of poor outcomes included mood/anxiety disorders (HF readmission HR 1.41, P = .04) and opioid abuse (mortality HR 1.52, P = .04). CONCLUSIONS: Patients with MethHF are frequently encumbered by psychiatric and substance abuse comorbidities, and carry a substantial risk of HF readmission and mortality. Comprehensive efforts are needed to stem this emerging epidemic.

Utility of Urine Neutrophil Gelatinase-Associated Lipocalin for Worsening Renal Function during Hospitalization for Acute Heart Failure: Primary Findings of the Urine N-gal Acute Kidney Injury N-gal Evaluation of Symptomatic Heart Failure Study (AKINESIS).

BACKGROUND: Worsening renal function (WRF) during acute heart failure (AHF) occurs frequently and has been associated with adverse outcomes, though this association has been questioned. WRF is now evaluated by function and injury. We evaluated whether urine neutrophil gelatinase-associated lipocalin (uNGAL) is superior to creatinine for prediction and prognosis of WRF in patients with AHF. METHODS AND RESULTS: We performed a multicenter, international, prospective cohort of patients with AHF requiring IV diuretics. The primary outcome was whether uNGAL predicted development of WRF, defined as a sustained increase in creatinine of 0.5 mg/dL or ≥50% above first value or initiation of renal replacement therapy, within the first 5 days. The main secondary outcome was a composite of in-hospital adverse events. We enrolled 927 patients (mean 68.5 years of age, 62% men). The primary outcome occurred in 72 patients (7.8%). The first, peak and the ratio of uNGAL to urine creatinine (area under curves (AUC) ≤ 0.613) did not have diagnostic utility over the first creatinine (AUC 0.662). There were 235 adverse events in 144 patients. uNGAL did not predict (AUCs ≤ 0.647) adverse clinical events better than creatinine (AUC 0.695). CONCLUSIONS: uNGAL was not superior to creatinine for predicting WRF or adverse in-hospital outcomes and cannot be recommended for WRF in AHF.

Biomarker developments in heart failure: 2016 and beyond.

PURPOSE OF REVIEW: Biomarkers play a fundamental role in the management of heart failure. Both new and old biomarkers are evaluated every year with new information gained for their use in heart failure. Major advancements have been made in the past 2 years in key biomarkers that will surely become part of standard clinical management of heart failure. This review will focus on major developments since 2016. RECENT FINDINGS: Soluble suppression of tumorigenicity 2 has had multiple breakthrough studies solidifying its prognostic use in both acute and chronic heart failure and with multiple studies showing a strong benefit with serial monitoring. High-sensitivity troponin has also recently been demonstrated to be a powerful prognostic biomarker in heart failure. Additionally, it may serve as a novel screening tool to identify patients at high risk for incident heart failure. Natriuretic peptides continue to show their resilience as the main prognostic biomarker in heart failure. Recent studies suggest natriuretic peptides may help identify certain patient populations that benefit from specific therapies and they can predict prognosis beyond in diseases other than heart failure. SUMMARY: Although natriuretic peptides are well-established biomarkers in heart failure, the weight of evidence for soluble suppression of tumorigenicity 2 and high-sensitivity troponin has significantly grown since 2016 that these two biomarkers should be incorporated into regular practice and management of heart failure patients.

Indications and practical approach to non-invasive ventilation in acute heart failure.

In acute heart failure (AHF) syndromes significant respiratory failure (RF) is essentially seen in patients with acute cardiogenic pulmonary oedema (ACPE) or cardiogenic shock (CS). Non-invasive ventilation (NIV), the application of positive intrathoracic pressure through an interface, has shown to be useful in the treatment of moderate to severe RF in several scenarios. There are two main modalities of NIV: continuous positive airway pressure (CPAP) and pressure support ventilation (NIPSV) with positive end expiratory pressure. Appropriate equipment and experience is needed for NIPSV, whereas CPAP may be administered without a ventilator, not requiring special training. Both modalities have shown to be effective in ACPE, by a reduction of respiratory distress and the endotracheal intubation rate compared to conventional oxygen therapy, but the impact on mortality is less conclusive. Non-invasive ventilation is also indicated in patients with AHF associated to pulmonary disease and may be considered, after haemodynamic stabilization, in some patients with CS. There are no differences in the outcomes in the studies comparing both techniques, but CPAP is a simpler technique that may be preferred in low-equipped areas like the pre-hospital setting, while NIPSV may be preferable in patients with significant hypercapnia. The new modality 'high-flow nasal cannula' seems promising in cases of AHF with less severe RF. The correct selection of patients and interfaces, early application of the technique, the achievement of a good synchrony between patients and the ventilator avoiding excessive leakage, close monitoring, proactive management, and in some cases mild sedation, may warrant the success of the technique.

Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction.

IMPORTANCE: In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. OBJECTIVE: To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. DESIGN, SETTING, AND PARTICIPANTS: Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. EXPOSURES: NT-proBNP concentrations among patients treated with sacubitril-valsartan. MAIN OUTCOMES AND MEASURES: The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months. RESULTS: Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%). CONCLUSIONS AND RELEVANCE: In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02887183.

Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure: A Scientific Statement From the American Heart Association.

BACKGROUND AND PURPOSE: Natriuretic peptides have led the way as a diagnostic and prognostic tool for the diagnosis and management of heart failure (HF). More recent evidence suggests that natriuretic peptides along with the next generation of biomarkers may provide added value to medical management, which could potentially lower risk of mortality and readmissions. The purpose of this scientific statement is to summarize the existing literature and to provide guidance for the utility of currently available biomarkers. METHODS: The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through December 2016. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or contemporary clinical practice recommendations. RESULTS: A number of biomarkers associated with HF are well recognized, and measuring their concentrations in circulation can be a convenient and noninvasive approach to provide important information about disease severity and helps in the detection, diagnosis, prognosis, and management of HF. These include natriuretic peptides, soluble suppressor of tumorgenicity 2, highly sensitive troponin, galectin-3, midregional proadrenomedullin, cystatin-C, interleukin-6, procalcitonin, and others. There is a need to further evaluate existing and novel markers for guiding therapy and to summarize their data in a standardized format to improve communication among researchers and practitioners. CONCLUSIONS: HF is a complex syndrome involving diverse pathways and pathological processes that can manifest in circulation as biomarkers. A number of such biomarkers are now clinically available, and monitoring their concentrations in blood not only can provide the clinician information about the diagnosis and severity of HF but also can improve prognostication and treatment strategies.

Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF).

BACKGROUND: Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. METHODS: This 52-week, multicenter, open-label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro-B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro-B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. CONCLUSIONS: Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor-neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183).

Heart Failure With Recovered Ejection Fraction in African Americans: Results From the African-American Heart Failure Trial.

BACKGROUND: Recent studies have described the entity of heart failure with recovered ejection fraction (HFrecEF), but population-specific studies remain lacking. The aim of this study was to characterize patients enrolled in the African-American Heart Failure Trial (A-HeFT) who had significant improvement in their ejection fraction (EF) during the 1st 6 months of follow-up. METHODS AND RESULTS: Subjects with HFrecEF (improvement in EF from <35% to >40% in 6 months; n = 59) were compared with 259 subjects with heart failure and persistently reduced EF (HFrEF), defined as EF ≤40% at 6-month follow-up. The effects of improvement in EF on all-cause mortality and 1st and all hospitalizations were analyzed. Compared with HFrEF, subjects with HFrecEF had a nonsignificant trend toward lower mortality (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.02-1.15; P = .068), fewer 1st HF hospitalizations (HR 0.22, 95% CI 0.07-0.71; P = .011), fewer recurrent HF hospitalizations (HR 0.13, 95% CI 0.05-0.37; P <.001), similar 1st all-cause hospitalizations (HR 0.67, 95% CI 0.39-1.15; P = .150), and fewer recurrent all-cause hospitalizations (HR 0.41, 95% CI 0.24-0.68; P <.001). CONCLUSIONS: These data confirm that, as in other populations, a small subgroup of black patients receiving standard care improve their EF with favorable outcomes. Further studies are required to determine whether myocardial recovery is permanent and the best management strategies in such patients.

Soluble ST2 in end-stage heart failure, before and after support with a left ventricular assist device.

BACKGROUND: The interleukin-33 (IL-33)/suppressor of tumorigenicity 2 (ST2) pathway is suggested to play an important role in fibrosis, remodelling and the progression of heart failure (HF). Increased soluble (sST2) levels are associated with adverse outcome in the average HF population. Less is known about sST2 levels in end-stage HF. Therefore, we studied sST2 levels in end-stage HF and the effect of unloading by left ventricular assist device (LVAD) support on sST2 levels. METHOD AND RESULTS: Serial plasma measurements of sST2 were performed pre-implantation and 1, 3 and 6 months after (LVAD) implantation in 38 patients. sST2 levels were elevated in end-stage HF just prior to LVAD implantation (74.2 ng/mL [IQR 54.7-116.9]; normal <35 ng/mL) and decreased substantially during LVAD support, to 29.5 ng/mL [IQR 24.7-46.6](P < .001). Patients with INTERMACS profile I had significantly higher sST2 levels compared to patients in profile II and profile III. A moderate correlation was found between sST2 and C-reactive protein (r = .580, P < .010). CONCLUSION: Levels of sST2 are elevated in end-stage HF patients with variability that suggests multiple inputs to a pro-inflammatory and pro-fibrotic pathway. Cardiogenic shock and increased C-reactive protein levels are associated with higher sST2 levels. LVAD support results in a significant drop in sST2 levels with normalization within 3 months postimplantation. This suggests that LVAD support leads to lessening of fibrosis and inflammation, which might eventually be used to target medical policy: explantation of the LVAD versus permanent use or cardiac transplantation.

Rationale and design of the IMPACT EU-trial: improve management of heart failure with procalcitonin biomarkers in cardiology (BIC)-18.

OBJECTIVES: To evaluate the effectiveness of procalcitonin (PCT)-guided antibiotic treatment compared to current treatment practice to reduce 90-day all-cause mortality in emergency patients with shortness of breath (SOB) and suspected acute heart failure (AHF). BACKGROUND: Concomitant AHF and lower respiratory tract (or other bacterial) infection in emergency patients with dyspnea are common and can be difficult to diagnose. Early and adequate initiation of antibiotic therapy (ABX) significantly improves patient outcome, but superfluous prescription of ABX maybe harmful. METHODS: In a multicentre, prospective, randomized, controlled process trial with an open intervention, adult emergency patients with SOB and increased levels of natriuretic peptides will be randomized to either a standard care group or a PCT-guided group with respect to the initiation of antibiotic treatment. In the PCT-guided group, the initiation of antibiotic therapy is based on the results of acute PCT measurements at admission, using a cut-off of 0.2 ng/ml. A two-stage sample-size adaptive design is used; an interim analysis was done after completion of 50% of patients and the final sample size remained unchanged. Primary endpoint is 90-day all-cause mortality. CONCLUSIONS: The current study will provide evidence, whether the routine use of PCT in patients with suspected AHF improves outcome.

The Confounding Effects of Non-cardiac Pathologies on the Interpretation of Cardiac Biomarkers.

PURPOSE OF REVIEW: Cardiac biomarkers play important roles in routine evaluation of cardiac patients. But while these biomarkers can be extremely valuable, none of them should ever be used by themselves-without adding the clinical context. This paper explores the non-cardiac pathologies that can be seen with the cardiac biomarkers most commonly used. RECENT FINDINGS: High-sensitivity troponin assay gained FDA approval for use in the USA, and studies demonstrated its diagnostic utility can be extended to patients with renal impairment. Gender-specific cut points may be utilized for high-sensitivity troponin assays. In the realm of the natriuretic peptides, studies demonstrated states of natriuretic peptide deficiency in obesity and in subjects of African-American race. Regardless, BNP and NT-proBNP both retained prognostic utilities across a variety of comorbid conditions. We are rapidly gaining clinical evidence with use of soluble ST2 and procalcitonin levels in management of cardiac disease states. In order to get the most utility from their measurement, one must be aware of non-cardiac pathologies that may affect the levels of biomarkers as although many of these are actually true values, they may not represent the disease we are trying to delineate. A few take-home points are as follows: 1. A biomarker value should never be used without clinical context 2. Serial sampling of biomarkers is often helpful 3. Panels of biomarkers may be valuable.

Natriuretic Peptides in Heart Failure: Atrial and B-type Natriuretic Peptides.

The natriuretic peptides play a vital role in normal physiology and as counter-regulatory hormones in heart failure (HF). Clinical assessment of their levels (for B-type natriuretic peptide [BNP], N-terminal proBNP, and the midregion of N-terminal pro-atrial natriuretic peptide) have become valuable tools in diagnosing patients with HF as well as risk stratifying and guiding therapy. Their roles have further expanded beyond HF to other cardiovascular conditions and for risk stratification in asymptomatic individuals. Understanding the clinical use of these hormones is vital to achieving their full potential.