Distinct Profiles and New Pharmacological Targets for Heart Failure with Preserved Ejection Fraction

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial condition with a variety of pathophysiological causes and morphological manifestations. The inclusion criteria and patient classification have become overly simplistic due to the customary differentiation regarding the ejection fraction (EF) cutoff. EF is considered a measure of systolic function; nevertheless, it only represents a portion of the true contractile state and has been shown to have certain limits due to methodological and hemodynamic irregularities.

Methods: As a result, broader randomized clinical trials have yet to incorporate the most recent criteria for HFpEF diagnosis, leading to a lack of data consistency and confusion in interpreting the results. The primary variations between the bigger clinical trials published in this context concerning patient selection and echocardiographic characteristics were analyzed. For all these reasons, we aim to clarify the main features and clinical impact of HFpEF in a study combining imaging, bio-humoral analysis, and clinical history to identify the specific subgroups that respond better to tailored treatment.

Results: Disparate clinical characteristics and a lack of uniform diagnostic standards may cause suboptimal therapeutic feedback. To optimize treatment, we suggest shifting the paradigm from the straightforward EF measurement to a more comprehensive model that considers additional information, such as structural traits, related disorders, and biological and environmental data. Therefore, by evaluating certain echocardiographic and clinical factors, a stepwise diagnostic procedure may be useful in identifying patients at high risk, subjects with early HFpEF, and those with evident HFpEF.

Conclusions: The present assessment underscores the significance of the precision medicine approach in guaranteeing optimal patient outcomes by providing the best care according to each distinct profile.

Keywords: ARNIs; GLP-1; HFpEF phenotype; MRA; SGLT2i; treatment.

Fig. 1.

Different HFpEF phenotypes and clinical scenarios may respond differently to treatment. HFpEF, heart failure with preserved ejection fraction.

Fig. 2.

ARNIs have potential beneficial molecular effects in HFpEF acting through different molecular mechanisms. ARNI, angiotensin receptor–neprilysin inhibitor; HFpEF, heart failure with preserved ejection fraction.

Fig. 3.

MRA potential beneficial mechanisms in HFpEF. MRA, mineralocorticoid antagonists; HFpEF, heart failure with preserved ejection fraction.

Fig. 4.

Potential SGLT2i effects beyond the cardiovascular system on renal, liver, and intestinal districts. SGLT2i, sodium–glucose cotransporter-2 inhibitors; HFpEF, heart failure with preserved ejection fraction; ACE2, angiotensin-converting enzyme 2; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; MASR, mast cell receptor; PKG, protein Kinases G.

Fig. 5.

Metabolic vascular and systemic effects of GLP1RAs potentially reduce the burden of cardiovascular risk and HFpEF deterioration. GLP1RAs act directly on pancreatic beta and alpha cells, the gastrointestinal tract, and the central nervous system to improve glucometabolic homeostasis and indirectly improve circulating lipid profiles by reducing hepatic steatosis. GLP1RAs, synthetic glucagon-like peptide receptor agonists; HFpEF, heart failure with preserved ejection fraction; eGFR, estimated glomerular filtration rate; GI, gastrointestinal.