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Progress in proteomic probing for pathogenic pathways in heart failure with preserved ejection fraction

Heart failure (HF) with preserved ejection fraction (HFpEF), a common HF phenotype with an ominous prognosis and scant evidence-based therapeutic options, may be the consequence of common comorbidities which foster a systemic pro-inflammatory state leading to endothelial dysfunction and coronary microvascular dysfunction with abnormal cardiac structure and function. This contrasts somewhat with HF with reduced ejection fraction (HFrEF) where the single most common triggering insult is an acute myocardial infarction and HF most often ensues as a consequence of a defined focal cardiac injury (Figure 1).1,2 The spectrum of comorbidities observed in HFpEF is broad and encompasses hypertension, diabetes, renal impairment and obesity. Obesity is present in up to 80% of cases of HFpEF and this comorbidity is known to be associated with increased circulating volume load and more severe abnormalities in both left and right heart structure and function than observed in non-obese HFpEF. Notably, left ventricular filling pressures are directly related to body mass and plasma volume in obese but not non-obese HFpEF.3 An understanding of the molecular links between comorbidities and HFpEF might offer novel therapeutic targets. On this background, in this issue of the Journal Kresoja et al.4 aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes. Ninety-two circulating serum biomarkers measured by proximity extension assay (PEA) were compared between obese HFpEF, non-obese HFpEF and non-HF participants in the LIFE-Heart study. Adrenomedullin (ADM), galectin-9 (Gal-9), thrombospondin-2 (THBS-2), CD4, and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2)