Methods:

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.