A network analysis to compare biomarker profiles in patients with and without diabetes mellitus in acute heart failure

Aims: It is unclear whether distinct pathophysiological processes are present among patients with acute heart failure (AHF), with and without diabetes. Network analysis of biomarkers may identify correlative associations that reflect different pathophysiological pathways. Methods and results: We analysed a panel of 48 circulating biomarkers measured within 24 h of admission for AHF in a subset of patients enrolled in the PROTECT trial. In patients with and without diabetes, we performed a network analysis to identify correlations between measured biomarkers. Compared with patients without diabetes (n = 1111), those with diabetes (n = 922) had a higher prevalence of ischaemic heart disease and traditional coronary risk factors. After multivariable adjustment, patients with and without diabetes had significantly different levels of biomarkers across a spectrum of pathophysiological domains, including inflammation (TNFR-1a, periostin), cardiomyocyte stretch (BNP), angiogenesis (VEGFR, angiogenin), and renal function (NGAL, KIM-1) (adjusted P-value <0.05). Among patients with diabetes, network analysis revealed that periostin strongly clustered with C-reactive protein and interleukin-6. Furthermore, renal markers (creatinine and NGAL) closely associated with potassium and glucose. These findings were not seen among patients without diabetes. Conclusion: Patients with AHF and diabetes, compared with those without diabetes, have distinct biomarker profiles. Network analysis suggests that cardiac remodelling, inflammation, and fibrosis are closely associated with each other in patients with diabetes. Furthermore, potassium levels may be sensitive to changes in renal function as reflected by the strong renal–potassium–glucose correlation. These findings were not seen among patients without diabetes and may suggest distinct pathophysiological processes among AHF patients with diabetes

Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ( guided therapy ) with inconsistent results. Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care. Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01685840

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

Oral anticoagulant use in cardiovascular disorders: a perspective on present and potential indications for rivaroxaban.

BACKGROUND: Four nonvitamin K antagonist oral anticoagulants (NOACs) have been approved for use in various cardiovascular indications. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban are now increasingly used in clinical practice. For some of these agents, available data from real-world studies support the efficacy and safety data in phase III clinical trials. OBJECTIVES: This review aims to summarize the current status of trials and observational studies of oral anticoagulant use over the spectrum of cardiovascular disorders (excluding venous thrombosis), provide a reference source beyond stroke prevention for atrial fibrillation (AF) and examine the potential for novel applications in the cardiovascular field. METHODS: We searched the recent literature for data on completed and upcoming trials of oral anticoagulants with a particular focus on rivaroxaban. RESULTS: Recent data in specific patient subgroups, such as patients with AF undergoing catheter ablation or cardioversion, have led to an extended approval for rivaroxaban, whereas the other NOACs have ongoing or recently completed trials in this setting. However, there are unmet medical needs for several arterial thromboembolic-related conditions, including patients with: AF and acute coronary syndrome, AF and coronary artery disease undergoing elective percutaneous coronary intervention, coronary artery disease and peripheral artery disease, implanted cardiac devices, and embolic stroke of unknown source. CONCLUSION: NOACs may provide alternative treatment options in areas of unmet need, and numerous studies are underway to assess their benefit-risk profiles in these settings

Is There Any Interaction Between Sex and Renal Function Change During Hospital Stay in Patients Hospitalized With Acute Heart Failure?

Background: Renal dysfunction is a strong predictor of outcomes in patients with acute heart failure (AHF). However. less is known about how sex may influence the prognostic import of renal function in AHF. Methods and Results: In a post hoc analysis of the ASCEND-HF trial including 5377 patients with AHF (33% female), patients were categorized into 3 groups based on the changes in renal function during their hospital stay. Worsening. stable, and improving renal functions were defined as a >= 20% decrease, a = 20% increase in the estimated glomentlar filtration rate, respectively. The primary outcome was the composite of 30-day all-cause mortality or HF rehospitalization. The median baseline and discharge estimated glomerular filtration rate were 58.4 and 56.9 mL/min/l.73 m(2), respectively. Worsening, stable, and improving renal function was observed in 31.9%, 63.2, and 4.9% of patients. respectively. Worsening renal function was associated with adverse outcomes at 30 days (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.22-1.76). This association existed in both males and females (aHR 1.42 and aHR 1.56, respectively, both P < .01). There was an interaction between renal function changes and sex (P = .025), because improving renal function was associated with better outcomes in men(aHR 0.29, 95% CI 0.13 0.66) as compared with women (aHR 1.18, 95% CI 0.59 2.35). There was no interaction between the ejection fraction and renal function in association with subsequent outcomes. Conclusions: Irrespective of sex, worsening renal function was associated with poorer outcomes at 30 days in patients with AHF. More studies are warranted to further delineate the possible sex differences in this setting

Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain

Phagocyte recognition and clearance of bacteria play essential roles in the host response to infection. In an on-going forward genetic screen, we identify the Drosophila melanogaster scavenger receptor Croquemort as a receptor for Staphylococcus aureus, implicating for the first time the CD36 family as phagocytic receptors for bacteria. In transfection assays, the mammalian Croquemort paralogue CD36 confers binding and internalization of Gram-positive and, to a lesser extent, Gram-negative bacteria. By mutational analysis, we show that internalization of S. aureus and its component lipoteichoic acid requires the COOH-terminal cytoplasmic portion of CD36, specifically Y463 and C464, which activates Toll-like receptor (TLR) 2/6 signaling. Macrophages lacking CD36 demonstrate reduced internalization of S. aureus and its component lipoteichoic acid, accompanied by a marked defect in tumor necrosis factor-α and IL-12 production. As a result, Cd36−/− mice fail to efficiently clear S. aureus in vivo resulting in profound bacteraemia. Thus, response to S. aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain, which initiates TLR2/6 signaling

Management of Worsening Heart Failure With Reduced Ejection Fraction:<i>JACC </i>Focus Seminar 3/3

Despite worsening heart failure (HF) being extremely common, expensive, and associated with substantial risk of death, there remain no dedicated clinical practice guidelines for the specific management of these patients. The lack of a management guideline is despite a rapidly evolving evidence-base, as a number of recent clinical trials have demonstrated multiple therapies to be safe and efficacious in this high-risk population. Herein, we propose a framework for treating worsening HF with reduced ejection fraction with the sense of urgency it deserves. This includes treating congestion; managing precipitants; and establishing a foundation of rapid-sequence, simultaneous, and/or in-hospital initiation of quadruple medical therapy for HF with reduced ejection fraction, with the top priority being at least low doses of all 4 medications. Moreover, to maximally reduce residual clinical risk, we further propose consideration of upfront simultaneous use of vericiguat (ie, quintuple medical therapy) and administration of intravenous iron for those who are iron deficient.</p

Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial

Background: The prediction of outcomes in patients with heart failure (HF) may inform prognosis, clinical decisions regarding treatment selection, and new trial planning. The VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction included high-risk patients with HF with reduced ejection fraction and a recent worsening HF event. The study participants had a high event rate despite the use of contemporary guideline-based therapies. To provide generalizable predictive data for a broad population with a recent worsening HF event, we focused on risk prognostication in the placebo group. Methods and Results: Data from 2524 participants randomized to placebo with chronic HF (New York Heart Association functional class II–IV) and an ejection fraction of less than 45% were studied and backward variable selection was used to create Cox proportional hazards models for clinical end points, selecting from 66 candidate predictors. Final model results were produced, accounting for missing data, and nonlinearities. Optimism-corrected c-indices were calculated using 200 bootstrap samples. Over a median follow-up of 10.4 months, the primary outcome of HF hospitalization or cardiovascular death occurred in 972 patients (38.5%). Independent predictors of increased risk for the primary end point included HF characteristics (longer HF duration and worse New York Heart Association functional class), medical history (prior myocardial infarction), and laboratory values (higher N-terminal pro-hormone B-type natriuretic peptide, bilirubin, urate; lower chloride and albumin). Optimism-corrected c-indices were 0.68 for the HF hospitalization/cardiovascular death model, 0.68 for HF hospitalization/all-cause death, 0.72 for cardiovascular death, and 0.73 for all-cause death. Conclusions: Predictive models developed in a large diverse clinical trial with comprehensive clinical and laboratory baseline data—including novel measures—performed well in high-risk patients with HF who were receiving excellent guideline-based clinical care. Clinical Trial Registration: Clinicaltrials.gov identifier, NCT02861534. Lay Summary: Patients with heart failure may benefit from tools that help clinicians to better understand a patient's risk for future events like hospitalization. Relatively few risk models have been created after the worsening of heart failure in a contemporary cohort. We provide insights on the risk factors for clinical events from a recent, large, global trial of patients with worsening heart failure to help clinicians better understand and communicate prognosis and select treatment options