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Pathophysiological Mechanisms in HFrEF vs. HFpEF
Study Questions:
What are the biological pathways specifically related to heart failure with reduced ejection fraction (HFrEF) and HF with preserved EF (HFpEF)?
Methods:
The authors studied patients from the BIOSTAT-CHF (BIOlogy Study to TAilored Treatment in Chronic Heart Failure) project. The aim of the BIOSTAT-CHF study was to characterize biological pathways related to response/no-response to guideline-recommended pharmacological therapy for HF. Therefore, patients had to be suboptimally treated at inclusion. The study authors performed a network analysis in HFrEF and HFpEF using 92 biomarkers from different pathophysiological domains in a cohort of 1,544 HF patients. They independently validated data in 804 patients with HF. Networks were enriched with existing knowledge on protein–protein interactions and translated into biological pathways uniquely related to HFrEF, HF with a midrange EF (HFmrEF), and HFpEF.
Results:
In the index cohort (mean age 74 years; 34% female), 718 (47%) patients had HFrEF (left ventricular EF [LVEF] <40%) and 431 (27%) patients had HFpEF (LVEF ≥50%). A total of 8 (12%) correlations were unique for HFrEF and 6 (9%) were unique to HFpEF. Network analysis showed that the central proteins in HFrEF were N-terminal pro–B-type natriuretic peptide, growth differentiation factor-15, interleukin-1 (IL-1) receptor type 1, and activating transcription factor 2, while central proteins in HFpEF were integrin subunit beta-2 and catenin beta-1. In the enriched networks of HFmrEF, they found that plasminogen urokinase receptor, signal transducer and activator of transcription 1, transcription factor AP-1, and IL-1B were possible hubs. Biological pathways in HFrEF were related to DNA binding transcription factor activity, cellular protein metabolism, and regulation of nitric oxide biosynthesis. Unique pathways in patients with HFpEF were related to cytokine response, extracellular matrix organization, and inflammation. Biological pathways of patients with HFmrEF were in between HFrEF and HFpEF.
Conclusions:
Network analysis suggests that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarker profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization. Biological pathways of patients with HFmrEF were in between HFrEF and HFpEF.
Perspective:
This is an important study because it suggests that the molecular expressions are disparate in HFrEF and HFpEF, which in turn emphasizes the fact that therapeutic targets have to be distinct. Given that the natural history of HFrEF varies depending on the underlying etiology (for example, HIV cardiomyopathy has a more relentless course than that associated with excessive consumption of alcohol), it would be interesting to determine whether the biomarker profile is also distinct depending on the underlying cause.
Clinical Topics: Anticoagulation Management, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Acute Heart Failure, Chronic Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Activating Transcription Factor 2, Biomarkers, Extracellular Matrix, Geriatrics, Growth Differentiation Factor 15, Heart Failure, Heart Failure, Systolic, Heart Failure, Diastolic, Inflammation, Stroke Volume, Natriuretic Peptide, Brain, Peptide Fragments, Receptors, Interleukin-1 Type I, Receptors, Urokinase Plasminogen Activator, Transcription Factors
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