Characterization of the inflammatory‐metabolic phenotype of heart failure with a preserved ejection fraction: a hypothesis to explain influence of sex on the evolution and potential treatment of the disease

Abstract

Accumulating evidence points to the existence of an inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction (HFpEF), which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, normal-to-mildly increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyte-associated inflammatory mediators. A broad range of adipogenic metabolic and systemic inflammatory disorders-e.g. obesity, diabetes and metabolic syndrome as well as rheumatoid arthritis and psoriasis-can cause this phenotype, independent of the presence of large vessel coronary artery disease. Interestingly, when compared with men, women are both at greater risk of and may suffer greater cardiac consequences from these systemic inflammatory and metabolic disorders. Women show disproportionate increases in left ventricular filling pressures following increases in central blood volume and have greater arterial stiffness than men. Additionally, they are particularly predisposed to epicardial and intramyocardial fat expansion and imbalances in adipocyte-associated proinflammatory mediators. The hormonal interrelationships seen in inflammatory-metabolic phenotype may explain why mineralocorticoid receptor antagonists and neprilysin inhibitors may be more effective in women than in men with HFpEF. Recognition of the inflammatory-metabolic phenotype may improve an understanding of the pathogenesis of HFpEF and enhance the ability to design clinical trials of interventions in this heterogeneous syndrome.

The importance of including uric acid in the definition of metabolic syndrome when assessing the mortality risk

“…Independently on the cause-consequence relationship between SUA and MS, the presence of SUA in patients with MS seems to mark a greater risk of CVM. Indeed, animal models have shown that decreasing uric acid levels can prevent or reverse MS features [20], probably because hyperuricemia can induce endothelial dysfunction [21] and/or oxidative changes in adipocytes [22], which are typical stigmata of MS. Interestingly, all these features are increasingly described in HF with preserved ejection fraction (HFpEF), pointing to the existence of an inflammatory-metabolic phenotype [23]. A recent subanalysis from the PARAGON-HF trial demonstrated that hyperuricaemia was associated with an increased risk of adverse cardiovascular outcomes (CVM and HF hospitalisation) [24], suggesting that SUA may be a relevant therapeutic target also in HFpEF.…”

H2FPEF score predicts atherosclerosis presence in patients with systemic connective tissue disease

“…Besides RA, no other SCTD is currently incorporated into any widely accepted CVD risk calculators 2 . This is not appropriate approach, as accelerated atherosclerosis and heart failure coexist in all distinct phenotypes of SCTD 5,32,34,36 . The mechanisms that contribute to accelerated atherosclerosis are still incompletely understood.…”

“…It has been demonstrated that SCTDs are commonly associated with heart failure preserved ejection fraction (HFpEF) and pulmonary hypertension (PH), 5,6 increasing the risk of death by almost twofold 7 . The synergy amongst HFpEF, systemic inflammatory disorders and atherosclerosis represents a vicious circle leading to very poor survival 5 . As systemic inflammation precedes the onset of HFpEF and atherosclerosis by years, 8 it would be beneficial to conduct early risk prediction in order to prevent future adverse events.…”

<p>Diagnosis and Management of Patients with Heart Failure with Preserved Ejection Fraction (HFpEF): Current Perspectives and Recommendations</p>

“…Additionally, the inflammatory-metabolic phenotype of HFpEF, which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyteassociated inflammatory mediators is primarily seen in women. 81 Therefore, sex differences in cardiac structure, function and metabolism, vascular ageing, and immune system biology are considerable. Future research initiatives of potential sex-specific mechanisms in HFpEF may provide important insights for the optimal prevention and management of HFpEF in both women and men.…”