Elevated Natriuretic Peptide Levels Research Articles

Death is associated to the type of drug-eluting stent in patients with left ventricular dysfunction and elevated natriuretic peptide levels

As advanced heart failure (HF) with elevated NT-proBNP is characterized by an activated coagulation system, coronary events clinically noticed as sudden or HF death may be more common after treatment with first- compared to newer-generation DES. Our study evaluates (1) if patients with left ventricular dysfunction (LVSD) who underwent percutaneous coronary intervention have a better survival with first- or newer-generation DES, and (2) if the survival benefit is predicted by NT-proBNP. Our observational study evaluated patients with LVSD who were registered in the coronary catheter laboratory database of the Medical University of Vienna. Multivariate Cox regression analyses tested an interaction in the risk of death between those with lower or elevated NT-proBNP levels and the stent-generation. The relative risk of newer- compared to first-generation DES as reference was calculated for patients with low and elevated NT-proBNP levels. In 340 patients (178 newer- and 162 first-generation DES) stent-generation and NT-proBNP were independent predictors of death. When the stent-generation*NTproBNP interaction was forced into a Cox regression model, this term independently predicted death. The relative risk of first- compared to newer-generation DES was similar in patients with lower NT-proBNP (HR 1.02, 95% CI 0.95–1.10, p = 0.560), but was higher in patients with elevated NT-proBNP (HR 1.06, 95% CI 1.01–1.10, p = 0.020). Death is associated to stent-generation. NT-proBNP is a predictor for the stent generation used: elevated levels demonstrated a higher mortality risk when using first- compared to newer-generation DES, while lower levels showed a similar risk when using either DES-generation.

Clinical Characteristics of Patients with Different N-Terminal Probrain Natriuretic Peptide Levels after Hematopoietic Stem Cell Transplantation.

Heart failure (HF) is not uncommon among patients with hematologic malignancies (HM) undergoing hematopoietic stem cell transplantation (HSCT) and is associated with an increased mortality. Among HSCT patients without signs or symptoms of HF, groups with elevated and normal N-terminal probrain natriuretic peptide (NT-proBNP) levels have been poorly characterized in previous literature. Herein, we reviewed consecutive admissions for HM undergoing HSCT (n = 301). Based on NT-proBNP levels and clinical signs or symptoms of HF at follow-up (one month after HSCT), patients were grouped into ENPH (elevated NT‐proBNP > 125 pg/mL, presence of HF symptoms or signs), ENAH (elevated NT‐proBNP > 125 pg/mL, absence of HF symptoms or signs), and NN (normal NT‐proBNP < 125 pg/mL). ENPH, ENAH, and NN were observed in 22.9%, 54.5%, and 22.6% of patients, respectively. ENPH patients had a significantly higher baseline NT-proBNP level, followed by the ENAH and NN groups, respectively (P < 0.001). Frequencies of HLA partially matched related donors, stem cell source (bone marrow+peripheral blood), and utilization of graft-versus-host disease prophylaxis regimens (ciclosporin+methotrexate+antithymocyte globulin±mycophenolate mofetil) were also the highest in the ENPH group, followed by ENAH and NN groups, respectively (all P < 0.05). Uric acid and hemoglobin levels, transplant type, and cyclophosphamide-based conditioning regimens utilized were similar between the ENAH and ENPH groups. We found that ENPH and ENAH are commonly observed in HM hospitalized for HSCT. Serum NT-proBNP levels may allow for earlier identification of HSCT patients at high risk of developing cardiac dysfunction.

Emerging Role of Natriuretic Peptides in Diabetes Mellitus

Prediabetes and diabetes mellitus (DM) are established risk factors for newly occurred heart failure (HF) with reduced and preserved ejection fraction. Natriuretic peptides (NPs) were found to be useful tool for CV risk stratification among patients with prediabetes and type 2 DM (T2DM) regardless of HF phenotype. Previous clinical studies have shown that elevated levels of NPs predicted all-cause mortality and CV mortality, risk of HF occurrence and progression, as well as a risk readmission due to HF. The discriminative potency of NPs for CV death and HF-related clinical events in prediabetes and T2DM populations has not been demonstrated beyond traditional CV risk factors. The aim of the review is to accumulate knowledge regarding predictive value of circulating NPs depending on presentation of prediabetes and established T2DM. It has been found that HFrEF or HFpEF in T2DM patients may require modification of NP cutoff points to primary diagnose HF and determine HF-related risks. There are several controversies between clinical outcomes and dynamic of circulating levels of NPs in diabetics treated with glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors that require to be elucidated in large clinical studies in the future.

Timing of intervention in asymptomatic patients with valvular heart disease.

Current management of valvular heart disease (VHD) seeks to optimize long-term outcome by timely intervention. Recommendations for treatment of patients with symptoms due to severe valvular disease are based on a foundation of solid evidence. However, when to intervene in asymptomatic patients remains controversial and decision requires careful individual weighing of the potential benefits against the risk of intervention and its long-term consequences. The primary rationale for earlier intervention is prevention of irreversible left ventricular (LV) myocardial changes that might result in later clinical symptoms and adverse cardiac events. A number of outcome predictors have been identified that facilitate decision-making. This review summarizes current recommendations and discusses recently published data that challenge them suggesting even earlier intervention. In adults with asymptomatic aortic stenosis (AS), emerging risk markers include very severe valve obstruction, elevated serum natriuretic peptide levels, and imaging evidence of myocardial fibrosis or increased extracellular myocardial volume. Currently, transcatheter aortic valve implantation (TAVI) is not recommended for treatment of asymptomatic severe AS although this may change in the future. In patients with aortic regurgitation (AR), the potential benefit of early intervention in preventing LV dilation and dysfunction must be balanced against the long-term risk of a prosthetic valve, a particular concern because severe AR often occurs in younger patients with a congenital bicuspid valve. In patients with mitral stenosis, the option of transcatheter mitral balloon valvotomy tilts the balance towards earlier intervention to prevent atrial fibrillation, embolic events, and pulmonary hypertension. When chronic severe mitral regurgitation is due to mitral valve prolapse, anatomic features consistent with a high likelihood of a successful and durable valve repair favour early intervention. The optimal timing of intervention in adults with VHD is a constantly changing threshold that depends not only on the severity of valve disease but also on the safety, efficacy, and long-term durability of our treatment options.

Heart failure with preserved ejection fraction: insights into diagnosis and pathophysiology.

Heart failure with preserved ejection fraction (HFpEF) accounts for at least half the cases of heart failure, currently diagnosed. There are several cardiac and non-cardiac manifestations of the syndrome. Structure and function abnormalities can include all four cardiac chambers. The left ventricle has abnormal systolic and diastolic functions which can be examined by invasive and non-invasive measurements. In addition, the left atrium enlarges with abnormal left atrial function, pulmonary hypertension occurs, and the right ventricle can develop hypertrophy, enlargement, and systolic dysfunction. There are a paucity of data on calcium handling in HFpEF patients. Growing literature supports the presence of abnormalities in titin and its phosphorylation, and increased interstitial fibrosis contributing to increased chamber stiffness. A systemic inflammatory state causing reduced myocardial cyclic guanosine monophosphate along with defects in the unfolded protein response have been recently reported. Diagnosis relies on signs and symptoms of heart failure, preserved ejection fraction, and detection of diastolic function abnormalities based on echocardiographic findings and abnormally elevated natriuretic peptide levels or invasive measurements of wedge pressure at rest or with exercise. There are currently two diagnostic algorithms: H2FPEF, and HFA-PEFF with limited data comparing their performance head to head in the same patient population. Despite the growing understanding of the syndrome's pathophysiology, there have been little success in developing specific treatment for patients with HFpEF.

Pretransplant NT-proBNP, Dialysis Vintage, and Posttransplant Mortality in Kidney Transplant Recipients.

End-stage kidney disease and dialysis vintage are characterized by accelerated atherosclerosis, volume overload, and progressive left ventricular hypertrophy, leading to elevated N-terminal probrain natriuretic peptide (NT-proBNP) levels. Pretransplant dialysis vintage is associated with excess mortality after transplantation. We want to study whether pretransplant NT-proBNP is associated with posttransplantation mortality and if it explains the association of dialysis vintage with posttransplantation mortality in kidney transplant recipients (KTR). We measured plasma NT-proBNP on arrival at the hospital before kidney transplantation in 658 KTR between January 1995 and December 2005 in our center. Multivariable Cox regression analyses, adjusted for potential confounders, were used to prospectively study the associations of dialysis vintage and NT-proBNP with all-cause mortality. During median 12.7 (7.8-15.6) years of follow-up after transplantation, 248 (37.7%) KTR died. Dialysis vintage was associated with an increased risk of posttransplant mortality in the fully adjusted model (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.03-1.43; P = 0.02), independent of potential confounders. The association weakened materially and lost significance after further adjustment for NT-proBNP (HR, 1.14; 0.96-1.34; P = 0.14). NT-proBNP was independently associated with all-cause mortality in the fully adjusted model (HR, 1.34; 1.16-1.55; P < 0.001). The association remained independent of adjustment for dialysis vintage (HR, 1.31; 1.13-1.52; P < 0.001). Our study shows that longer dialysis vintage is associated with a higher mortality risk in KTR, and this association might be explained for a considerable part by variation in pretransplant NT-proBNP at the time of transplantation.

Association of β-Blocker Use With Heart Failure Hospitalizations and Cardiovascular Disease Mortality Among Patients With Heart Failure With a Preserved Ejection Fraction

β-Blockers are prescribed to most patients with heart failure (HF) with a preserved ejection fraction (HFpEF), but their effect on HFpEF remains unclear. To determine the association of β-blocker use with HF hospitalizations and cardiovascular disease (CVD) mortality, overall and in strata of patients with an ejection fraction (EF) of 50% or greater or less than 50%. For 1761 participants from North and South America enrolled in the multicenter, double-blinded Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist randomized clinical trial of spironolactone for patients with HFpEF between August 10, 2006, and January 31, 2012, the association of baseline β-blocker use with HF hospitalization and CVD mortality was analyzed using unadjusted and adjusted Cox proportional hazards regression models, overall and in strata of patients with an EF of 50% or greater or less than 50%. Participants had symptomatic HF with a left ventricular EF of 45% or greater, with enrollment based on either hospitalization attributed to decompensated HF in the prior year or elevated natriuretic peptide levels. Statistical analysis was performed from January 31 to May 2, 2019. Use of β-blockers. Incident HF hospitalization and CVD mortality. Among 1761 participants included in the analysis (879 women and 882 men; mean [SD] age, 71.5 [9.6] years), 1394 (79.2%) reported β-blocker use and 1567 (89.0%) had an EF of 50% or greater. Hospitalizations for HF occurred for 399 participants (22.7%), and CVD mortality occurred for 229 participants (13.0%). Use of β-blockers was associated with a higher risk of HF hospitalization among patients with HFpEF with an EF of 50% or greater (hazard ratio, 1.74 [95% CI, 1.28-2.37]; P < .001) but not among patients with an EF between 45% and 49% (hazard ratio, 0.68 [95% CI, 0.28-1.63]; P = .39). There was a significant interaction between β-blocker use and EF threshold for incident HF hospitalizations (P = .03). Use of β-blockers was not associated with a change in CVD mortality. For patients with an EF of 50% or greater, β-blocker use was associated with an increased risk of HF hospitalizations but not CVD mortality. For patients with an EF between 45% and 49%, there was no such association.

Influence of Age on Efficacy and Safety of Spironolactone in Heart Failure

ObjectivesThe authors examined efficacy and safety of spironolactone by age in the Americas region (N = 1,767) of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. BackgroundHeart failure with preserved ejection fraction disproportionately affects older adults who may exhibit changes in physiology and variable pharmacokinetics. MethodsTOPCAT enrolled patients with heart failure and a left ventricular ejection fraction ≥45% who were age 50 or older with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 and prior heart failure hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo with a mean follow-up duration of 3.3 years. We assessed treatment effect and safety by protocol-defined age categories (<65, 65 to 74, and ≥75 years). ResultsThe mean age was 72 ± 10 years (range 50 to 97 years) with 41% over the age of 75 years. Participants ≥75 years were more commonly women and white and had a lower body mass index and estimated glomerular filtration rate compared with the younger age categories. Spironolactone reduced the primary composite outcome compared with placebo across all age categories (p interaction = 0.42). However, spironolactone was associated with an increased risk of the safety endpoint (hazard ratio: 2.54; 95% confidence interval: 1.91 to 3.37; p < 0.001), particularly in older age groups (p interaction = 0.02). Findings in the whole TOPCAT cohort were consistent with results from the Americas region. ConclusionsIn this post hoc, exploratory analysis of the TOPCAT trial data from the Americas region, although there was no effect of age on efficacy, there were considerable effects of age on increased rates of adverse safety outcomes. These results should be weighed when considering spironolactone for older heart failure with preserved ejection fraction patients. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302)

Influence of Age on the Efficacy and Safety of Spironolactone in Heart Failure with Preserved Ejection Fraction

Introduction Heart failure with preserved ejection fraction (HFpEF) disproportionately affects older adults. Age-related changes in physiology and variable pharmacokinetics may affect drug efficacy and safety among older individuals. We examined efficacy and safety of spironolactone by age in the Americas region (N=1767) of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Methods TOPCAT was an international, multicenter, prospective, randomized trial that enrolled patients with HF and left ventricular ejection fraction ≥ 45%, age 50 or older with eGFR ≥ 30ml/min/1.73 m2 and prior HF hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo over a mean follow up of 3.3 years. We assessed treatment effect (primary study composite of CV death, aborted cardiac arrest, and hospitalization for HF) and safety (permanent study medication discontinuation due to hyperkalemia, rise in serum creatinine to ≥ 3.0 mg/dL, gynecomastia, or allergic reaction or intolerance) by age categories ( Results Number of participants were 492, 555, and 720 in the Conclusions In patients with HFpEF, the efficacy of spironolactone was consistent across age categories, but treatment-related adverse events were more common in participants age 65 or older. These data support guideline recommendations for use of spironolactone in appropriately selected HFpEF regardless of age, but underscore that closer laboratory surveillance is critical in older individuals.

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Effect of Neladenoson Bialanate on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) lacks effective treatments. Based on preclinical studies, neladenoson bialanate, a first-in-class partial adenosine A1 receptor agonist, has the potential to improve several heart failure-related cardiac and noncardiac abnormalities but has not been evaluated to treat HFpEF. To determine whether neladenoson improves exercise capacity, physical activity, cardiac biomarkers, and quality of life in patients with HFpEF and to find the optimal dose. Phase 2b randomized clinical trial conducted at 76 centers in the United States, Europe, and Japan. Patients (N = 305) with New York Heart Association class II or III HFpEF with elevated natriuretic peptide levels were enrolled between May 10, 2017, and December 7, 2017 (date of final follow-up: June 20, 2018). Participants were randomized (1:2:2:2:2:3) to neladenoson (n = 27 [5 mg], n = 50 [10 mg], n = 51 [20 mg], n = 50 [30 mg], and n = 51 [40 mg]) or matching placebo (n = 76) for 20 weeks of treatment. The primary end point was change in 6-minute walk test distance from baseline to 20 weeks (minimal clinically important difference, 40 m). Key safety measures included bradyarrhythmias and adverse events. To evaluate the effects of varying doses of neladenoson, a multiple comparison procedure with 5 modeling techniques (linear, Emax, 2 variations of sigmoidal Emax, and quadratic) was used to evaluate diverse dose-response profiles. Among 305 patients who were randomized (mean age, 74 years; 160 [53%] women; mean 6-minute walk test distance, 321.5 m), 261 (86%) completed the trial and were included in the primary analysis. After 20 weeks of treatment, the mean absolute changes from baseline in 6-minute walk test distance were 0.2 m (95% CI, -12.1 to 12.4 m) for the placebo group; 19.4 m (95% CI, -10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (95% CI, 3.0 to 55.8 m) for 10 mg of neladenoson group; 13.8 m (95% CI, -2.3 to 29.8 m) for 20 mg of neladenoson group; 16.3 m (95% CI, -1.1 to 33.6 m) for 30 mg of neladenoson group; and 13.0 m (95% CI, -5.9 to 31.9 m) for 40 mg of neladenoson group. Because none of the neladenoson groups achieved the clinically relevant 40-m increase in 6-minute walk test distance from baseline, an optimal dose of neladenoson was not identified. There was no significant dose-response relationship for the change in 6-minute walk test distance among the 5 different dose-response models (P = .05 for Emax; P = .18 for quadratic; P = .21 for sigmoidal Emax 1; P = .39 for linear; and P = .52 for sigmoidal Emax 2). Serious adverse events were similar among the neladenoson groups (61/229 [26.6%]) and the placebo group (21/76 [27.6%]). Among patients with HFpEF, there was no significant dose-response relationship detected for neladenoson with regard to the change in exercise capacity from baseline to 20 weeks. In light of these findings, novel approaches will be needed if further development of neladenoson for the treatment of patients with HFpEF is pursued. ClinicalTrials.gov Identifier: NCT03098979.

Hemodynamic-GUIDEd management of Heart Failure (GUIDE-HF)

BackgroundHemodynamic-guided heart failure (HF) management using pulmonary artery (PA) pressures reduces HF hospitalizations (HFHs) in previously hospitalized HF patients with New York Heart Association (NYHA) class III symptoms. It remains uncertain whether this approach reduces not only HFHs but all-cause mortality and if benefits extend to patients with NYHA class II and IV HF or to those symptomatic patients with elevated natriuretic peptides without recent HFH. MethodsGUIDE-HF is a prospective trial with 2 arms enrolling patients with HF regardless of ejection fraction (EF). The randomized arm is a single-blind, randomized, controlled trial of PA pressure-guided therapy in NYHA class II-IV patients (n = 1,000) with either a previous HFH or elevated natriuretic peptides (B-type natriuretic peptide/NT-pro–B-type natriuretic peptide). All consenting subjects will receive an implantable PA pressure sensor (CardioMEMS HF System) followed by randomization to either a treatment group, managed with provider remote access to the hemodynamic data, or a control group, managed without provider access to these data. Subjects in the control group will receive scheduled, scripted, sham contacts from the study team to maintain blinding as to their study group assignment. The primary study end point is the composite of cumulative HF events and all-cause mortality at 12 months. Secondary end points include quality-of-life and functional assessments. The single arm of the trial is an observational arm in which NYHA class III patients (n = 2,600) with either a previous HFH or elevated natriuretic peptides (but no recent HFH) will be implanted with a PA pressure sensor and observed for occurrence of the primary composite end point of cumulative HF events and mortality at 12 months. This arm will test the hypothesis that hemodynamic-guided care is similarly effective in HF patients enrolled on the basis of elevated natriuretic peptide levels but no recent HFH and those with a recent HFH. ConclusionsGUIDE-HF is the largest clinical trial of hemodynamic-guided HF management across a broad population of HF patients, with a study design and sample size adequate to examine survival, cumulative HF events, quality of life, and functional capacity.

Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis.

AimsPatients with acute pulmonary embolism (PE) classified as low risk by the Pulmonary Embolism Severity Index (PESI), its simplified version (sPESI), or the Hestia criteria may be considered for early discharge. We investigated whether the presence of right ventricular (RV) dysfunction may aggravate the early prognosis of these patients.Methods and resultsWe did a systematic review and meta-analysis of studies including low-risk patients with acute PE to investigate the prognostic value of RV dysfunction. Diagnosis of RV dysfunction was based on echocardiography or computed tomography pulmonary angiography. In addition, we investigated the prognostic value of elevated troponin or natriuretic peptide levels. The primary outcome was all-cause mortality at 30 days or during hospitalization. We included 22 studies (N = 3295 low-risk patients) in the systematic review: 21 were selected for quantitative analysis. Early all-cause mortality rates in patients with vs. without RV dysfunction on imaging were 1.8% [95% confidence interval (CI) 0.9–3.5%] vs. 0.2% (95% CI 0.03–1.7%), respectively, [odds ratio (OR) 4.19, 95% CI 1.39–12.58]. For troponins, rates were 3.8% (95% CI 2.1–6.8%) vs. 0.5% (95% CI 0.2–1.3%), (OR 6.25, 95% CI 1.95–20.05). For natriuretic peptides, only data on early PE-related mortality were available: rates were 1.7% (95% CI 0.4–6.9%) vs. 0.4% (95% CI 0.1–1.1%), (OR 3.71, 95% CI 0.81–17.02).ConclusionsIn low-risk patients with acute PE, the presence of RV dysfunction on admission was associated with early mortality. Our results may have implications for the management of patients who appear at low risk based on clinical criteria alone, but present with RV dysfunction as indicated by imaging findings or laboratory markers.

Patient and procedural features predicting early and mid-term outcome after radical surgery for non-small cell lung cancer.

Postoperative cardiovascular and pulmonary complications (PCVCs and PPCs) are frequent and result in prolonged hospital stay. The aim of this study was to update the risk factors associated with major complications and survival after lung cancer surgery. This is a post-hoc analysis of a randomized controlled trial that was designed to assess the benefits of preoperative physical training. After enrollment, clinical, biological and functional data as well as intraoperative details were collected. In-hospital PCVCs and PPCs were recorded and survival data were adjudicated up to 4 years after surgery. Data from 151 patients were analyzed. Thirty-day mortality rate was 2.6% and the incidence of PCVCs and PPCs was 15% and 33%, respectively. Stepwise logistic regression analysis showed that, PCVCs were mainly related to elevated plasma levels of brain natriuretic peptides [odds ratios (ORs) =6.0; 95% confidence interval (CI), 1.3-27.3] and performance of a pneumonectomy (OR =9.6; 95% CI, 2.9-31.5) whereas PPCs were associated with the presence of COPD (OR =5.9; 95% CI, 2.4-14.8), current smoking (OR =2.6; 95% CI, 1.1-6.5) and the need for blood transfusion (OR =5.2; 95% CI, 1.2-23.3). Preoperative physical training was a protective factor regarding PPCs (OR =0.13; 95% CI, 0.05-0.34). Cox proportional hazards regression analysis showed that ventilatory inefficiency during exercise (expressed by a ratio >40 of ventilation to carbon dioxide elimination), coronary artery disease, elevated plasma levels of brain natriuretic peptides and the occurrence of PPCs were all predictive of poor survival after surgery. Besides smoking and the extent of lung resection, preexisting cardiopulmonary disease as evidence by elevated levels of brain natriuretic peptides and inefficient ventilation are associated with poor clinical outcome after lung cancer surgery.

Clinical presentations and hemodynamic parameters in patients hospitalized due to acute heart failure stratified by the left-ventricular ejection fraction

Background: Currently, one of the most common causes of hospitalization, especially in the elderly, is heart failure (HF) exacerbation. In nearly 95% of patients, this is caused by fluid overload. There have been studies comparing the rates of comorbidities and biochemical disturbances in HF patients; however, their hemodynamic parameters have not yet been assessed. Thus, the aim of this study was to compare the clinical presentations and hemodynamic parameters assessed via impedance cardiography (ICG) in patients hospitalized due to acute HF, stratified by the left-ventricular ejection fraction (LVEF). Methods: This study enrolled 102 patients, aged > 18 years, hospitalized due to decompensated HF. Ninety-seven patients (74 men, 23 women) underwent echocardiographic examination. Biochemical and hemodynamic parameters were assessed on the day of admission and, subsequently, every other day during hospitalization. Based on echocardiographic findings and the ESC guidelines the study group was divided into the following subgroups: HFrEF (EF 50%), and HFmrEF (EF 40–49%). Results: The HFrEF group, which constituted 60.8% of patients (n = 58), was predominantly male (P = 0.0005); and most had elevated N-terminal pro-brain natriuretic peptide levels (P = 0.0008). The HFpEF and HFmrEF subgroups, jointly (n = 38), were characterized by higher systolic blood pressure (P = 0.0001), and lower hemoglobin levels (P = 0.003). The hemodynamic assessment showed that HFrEF patients had higher total fluid content (P = 0.005) and lower systolic time ratio (P = 0.0002). Conclusions: Despite similar clinical presentation, patients with HF exhibited different values of hemodynamic and biochemical parameters depending on their LVEF; this indicates non-homogeneity of pathomechanisms and causes of HF decompensation.

Plasma natriuretic peptide levels in fetuses with congenital heart defect and/or arrhythmia.

Diagnosing fetal heart failure remains challenging because it is difficult to know how well the fetal myocardium will perform as loading conditions change. In adult cardiology, natriuretic peptides (NPs) are established markers of heart failure. However, the number of studies investigating NP levels in fetuses is quite limited. The aim of this study was to evaluate the significance of plasma NP levels in the assessment of heart failure in fetuses with a congenital heart defect (CHD) and/or arrhythmia. This was a prospective observational study conducted at a tertiary pediatric cardiac center. A total of 129 singletons with CHD and/or arrhythmia and 127 controls were analyzed between 2012 and 2015. Umbilical cord plasma atrial NP, brain NP and N-terminal pro-brain NP levels at birth were compared with ultrasonography findings indicating fetal heart failure, such as cardiovascular profile (CVP) score and morphological characteristics. Fetuses with CHD and/or arrhythmia had higher NP levels than did controls (P < 0.01). NP levels of fetuses with CHD and/or arrhythmia were correlated inversely with CVP score (P for trend < 0.01). No differences in NP levels were found in fetuses with CHD and/or arrhythmia and a CVP score of ≥ 8 in comparison to controls. Multivariate analysis showed that a CVP score of ≤ 5, tachy- or bradyarrhythmia at birth, preterm birth and umbilical artery pH < 7.15 were associated independently with high NP levels (P < 0.01). Among fetuses with a CVP score of ≤ 7, abnormal venous Doppler sonography findings were significantly more common and more severe in fetuses with tachy- or bradyarrhythmia than in those with CHD, and those with tachy- or bradyarrhythmia had higher NP levels than did those with CHD (P = 0.01). Fetuses with right-heart defect and moderate or severe tricuspid valve regurgitation had significantly higher NP levels than did fetuses with other types of CHD (P < 0.01). Plasma NP levels in fetuses with CHD and/or arrhythmia are correlated with the severity of fetal heart failure. Elevated NP levels are attributed mainly to an increase in central venous pressure secondary to arrhythmia or atrioventricular valve regurgitation due to CHD, rather than to the morphological abnormality itself. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

1215P - Sequential blockade of PD-1 and PD-L1 causes fulminant cardiotoxicity: From case report to mice model validation

Background: In clinical practice, the sequential use of shifting from a programmed cell death 1 (PD-1) inhibitor to its ligand 1 (PD-L1) inhibitors in consideration of ineffectiveness or toxicity is becoming more common due to prolonged survival. We report a patient in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. To validate this finding, a syngeneic tumor-bearing mice model was used. Methods: A 61-year-old woman with metastatic lung adenocarcinoma, who had received 5 doses of nivolumab (3 mg/kg) and then 1 dose of atezolimumab (1200 mg), complained of chest tightness and dyspnea 4 weeks later. The workup revealed sinus tachycardia, a normal Troponin I level (< 0.01 ng/mL), an elevated creatine kinase-myocardial band (CK-MB) level (10 ng/mL), and an elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) level (2960 ng/mL). Serial echocardiograms revealed left ventricular ejection fractions declining from 66.3 to 59.2 %. Under a diagnosis of myocarditis, she was treated with intravenous methylprednisolone at 5 mg/kg/day and oral mycophenolate mofetil at 1000 mg/day. The progressive clinical deterioration was noted with serial elevation of Troponin I, CK-MB and NT-proBNP levels up to 1.3, 24 and 15738 ng/mL, respectively. Cardiac arrest was noted later. The Balb/c mice bearing lung metastasis of CT26 colon cancer cells were treated with PD-1 and PD-L1 inhibitors for pathological and immuohistochemical studies. Results: The pathology shows that the combination of anti-PD-1 and anti-PD-L1, either sequentially or simultaneously administered, caused myocarditis lesions with myocyte injury and patchy mononuclear infiltrates in the myocardium in all combination group mice (n = 3 for each). The myocarditis lesions were not seen in mice treated with anti-PD-1 or anti-PD-L1 alone. Marked expression of PD-L1 in infiltrating lymphocytes and expression of PD-1 in myocytes was noted only in mice with combination blockade, implying a possible role for pathogenesis of myocarditis. Conclusions: The combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, and such usage should be cautious. Legal entity responsible for the study: Mackay Memorial Hospital, Taipei, Taiwan. Funding: Mackay Memorial Hospital, Taipei, Taiwan. Disclosure: All authors have declared no conflicts of interest.

Nomenclature in heart failure: a call for objective, reproducible, and biologically‐driven terminology

Contemporary clinical trials in heart failure (HF) enroll patients largely based on acuity of presentation, left ventricular ejection fraction (EF), and functional status. These trial programs variably employ certain enrichment criteria such as prior hospitalization for HF or elevated natriuretic peptide levels to reaffirm the HF diagnosis and identify patients at higher risk of clinical events. This approach has yielded heterogenous patient cohorts with distinct biological substrates and varying levels of clinical risk. Indeed, patients with HF have variable clinical trajectories that often depend on comorbidities, congestion, hemodynamics, and underlying etiology. In the past decade, progress has been made in identifying imaging- and biomarker-based signatures of HF and the development of risk scores for prognosis. Although these parameters have advanced the promise of precision-based therapeutic approaches, such tools have been variably incorporated alongside traditional eligibility criteria in contemporary trial design. Over the past 3 decades, since the initial publication of the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) trial in 1987 (1), enrollment criteria have remained relatively stagnant and have not evolved in parallel with progress in defining HF as an entity. Similarly, patients early or late in their HF journey are loosely defined and have variable approaches to care. We explore complexities in the interpretation and application of traditional HF-related nomenclature in clinical practice and in clinical trials (Table 1). Table 1. Complexities with Current HF Nomenclature

Heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) represents a heterogeneous collection of conditions that are unified by the presence of a left ventricular ejection fraction ≥50%, evidence of impaired diastolic function and elevated natriuretic peptide levels, all within the context of typical heart failure signs and symptoms. However, while HFpEF is steadily becoming the predominant form of heart failure, disease-modifying treatment options for this population remain sparse. This review provides an overview of the diagnosis, management and prevention of HFpEF for general physicians.

Hospitalization and medical cost of patients with elevated serum N-terminal pro-brain natriuretic peptide levels.

BackgroundPatients with heart failure (HF) are reportedly at high risk for ‘all-cause’ re-hospitalization. A biomarker for HF, N-terminal pro-brain natriuretic peptide (NT-proBNP), enables to simply detect patients with possible HF (pHF). We examined the hospitalization and medical cost of Japanese patients detected by an elevated serum NT-proBNP, and also evaluated the effects of institutional team approaches for HF on their all-cause hospitalizations.MethodsWe retrospectively extracted all adult patients with serum NT-proBNP ≥400 pg/ml measured between January and March 2012 in Hiroshima University Hospital as pHF-positive patients. We studied their all-cause hospitalization records during the past 3-year period. We also extracted all pHF-negative patients with NT-proBNP <400 pg/ml and studied as well. In the pHF-positive patients followed for 3 years after starting interprofessional team approaches to prevent the onset and exacerbation of HF in the hospital, we compared the hospitalization and medical cost between the 3-year periods before and after the start of the team approaches.ResultsWe enrolled 432 pHF-positive and 485 pHF-negative patients with one or more hospitalization records. Compared to the pHF-negative patients, the pHF-positive patients had longer total hospitalization days (median [interquartile range], 30 [13–58] versus. 18 [8–39], p <0.0001) and higher total medical cost for hospitalizations (2.42 [1.07–5.08] versus. 1.80 [0.79–3.65] million yen, p <0.0001). A subset of 303 pHF-positive patients was followed for 3 years after starting the team approaches, and we found that both total hospitalization days (30 [13–57] to 8 [0–31]) and medical cost for hospitalizations (2.59 [1.37–5.05] to 0.76 [0–2.38] million yen) showed marked reduction in them.ConclusionsPatients with an elevated serum NT-proBNP have longer hospitalizations and higher costs for all-cause hospitalizations than those without. Institutional team approaches for HF may reduce them.