Pathophysiology and Biomarkers for Congestion in Heart Failure

Quick Takes

  • Compared with HF patients without congestion, patients with severe congestion had up-regulated pathways involving inflammation, endothelial activation, and response to mechanical stress.
  • Proteins with highest up-regulation included FGF-21, FGF-23, CA-125, soluble ST2, GDF-15, FABP4, IL-6, and BNP.

Study Questions:

Which pathophysiological pathways and biomarkers are associated with congestion in patients with new onset of worsening heart failure (HF)?


A multicenter, prospective cohort that enrolled patients from 11 European countries with signs or symptoms of new or worsening HF was used. The validation cohort was comprised of patients from six European centers. Inpatients and outpatients with left ventricular ejection fraction <40% or N-terminal pro–B-type natriuretic peptide (NT-proBNP) >2000 or BNP >400 pg/mL were enrolled. A congestion score was estimated based on sum of jugular venous pressure, orthopnea, and pedal edema and patients in the lowest quartile (no congestion) were compared to those in the highest quartile of congestion score (severe congestion).


For the derivation cohort, 408 patients had no congestion and 142 had severe congestion. Severely congested patients were older, more symptomatic, and more likely to have atrial fibrillation and renal disease. In the validation cohort, 436 had no congestion and 232 had severe congestion with similar baseline characteristics. Differential protein expression analysis showed that 107/363 regulatory proteins were up-regulated in patients with severe congestion, whereas 6/363 were up-regulated in patients without congestion. The strongest up-regulation was seen for proteins in the inflammation, endothelial activation, and response to mechanical stimulus. The most strongly down-regulated proteins belonged to platelet activation, glioma, and melanoma pathways. Similar findings were noted in the validation cohort. In a Cox regression analysis, higher congestion quartile correlated with increased risk for all-cause mortality (hazard ratio, 3.14).


In a protein expression analysis, congestion in HF patients was associated with up-regulation of pathways related to inflammation, endothelial activation, and response to mechanical stress.


Congestion is the primary cause for symptoms and hospitalizations in most HF patients. More recently, mechanisms for congestion other than reduced cardiac contractility and neurohormonal activation have been proposed. These include increased mechanical stress on blood vessels and venous congestion causing inflammation. Isolated proteins and biomarkers have been individually analyzed as markers of congestion but how these proteins interact with each other is not known.

In this study, the authors perform a comprehensive analysis of a wide array of proteins and biomarkers in HF patients with severe congestion versus no congestion. Their findings suggest up-regulation of inflammation, endothelial dysfunction, and mechanical stress pathways. Proteins with the maximal up-regulation representing these pathways were FGF-21, FGF-23, CA-125, soluble ST2, GDF-15, FABP4, IL-6, and BNP. Some of these proteins have been described as HF biomarkers. Current treatment for HF is based exclusively on neurohormonal blockade and perhaps these alternative pathways may be new targets for treatment. While these proteins correlated with congestion, whether they have a causal association remains to be established.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Atrial Fibrillation, Biomarkers, Edema, Heart Failure, Hyperemia, Inflammation, Melanoma, Natriuretic Peptide, Brain, Stress, Mechanical, Stroke Volume, Up-Regulation, Venous Pressure, Ventricular Function, Left

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