Biomarker Profiles in Acute HF With Mid-Range EF

Study Questions:

What are the biomarker profiles of patients with acute heart failure with a midrange ejection fraction (HFmrEF) when compared to biomarker profiles of those with HF with reduced (HFrEF) and preserved EF (HFpEF)?


This study was performed in a subcohort of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) trial—a multicenter, randomized, double-blinded, placebo-controlled trial assessing the effect of the selective A1 adenosine receptor antagonist rolofylline in 2,033 patients with a history of HF, who were admitted with acute HF and mild to moderate renal dysfunction. Patients eligible for inclusion had N-terminal pro-brain natriuretic peptide (NT-proBNP) levels of >2000 pg/ml with dyspnea at rest or at mild exertion. In this trial, patients with severe renal dysfunction or potassium levels of <3.1 mmol/L were excluded. The overall results of this trial were neutral. A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 hours in 843 acute HF patients—108 patients had HFpEF (left ventricular EF [LVEF] >50%), 607 patients had systolic HF or HFrEF (LVEF of <40%), and 128 patients with HFmrEF as LVEF of 40-49%. Significant correlation coefficients for HFrEF, HFmrEF, and HFpEF were then displayed graphically as heatmaps with associated disease domains for all biomarkers. The investigators performed network analysis to analyze associations between biomarkers in HFrEF, HFmrEF, and HFpEF.


The investigators noted an upward trend with BNP levels with decreasing LVEF (300 pg/ml [HFpEF]; 397 pg/ml [HFmrEF]; 521 pg/ml [HFrEF]; ptrend <0.001). A similar trend was noted with biomarkers KIM-1, red blood cells, and hemoglobin. On network analysis, the investigators found that in HFrEF, interactions between biomarkers were mostly related to cardiac stretch, and in HFpEF, biomarker interactions were mostly related to inflammation; whereas in HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. Remodeling markers at admission and changes in levels of inflammatory markers across the first 24 hours were predictive for all-cause mortality and rehospitalization at 60 days (pinteraction <0.05), in HFpEF and HFmrEF, but not in HFrEF.


The authors concluded that biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch, and in HFpEF, related to inflammation; whereas in patients with HFmrEF, biomarker profile showed interactions between both cardiac stretch and inflammation markers.


This is an important study because it demonstrates that a panel of biomarkers can be helpful in better distinguishing HFpEF, HFmrEF, and HFrEF. Biomarker profiling, like done in this study, should better help with design of clinical trials evaluating newer therapies for acute HF patients with HFpEF and HFmrEF.

Clinical Topics: Anticoagulation Management, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Stress

Keywords: Adenosine A1 Receptor Antagonists, Biological Markers, Dyspnea, Erythrocytes, Geriatrics, Heart Failure, Hematopoiesis, Hemoglobins, Inflammation, Natriuretic Peptide, Brain, Oxidative Stress, Peptide Fragments, Physical Exertion, Potassium, Renal Insufficiency, Stroke Volume

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