The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists in the Management of Obesity-Related Heart Failure with Preserved Ejection Fraction: Benefits beyond What Scales Can Measure?

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  Figure 1. The pathophysiological mechanisms underlying obesity-related alterations in cardiac structure and function involve a complex interplay of inflammatory processes and cardiovascular remodeling. Obesity triggers a transformation of adipose tissue into a pro-inflammatory state, which can adversely affect the vasculature and various visceral organs. In heart failure with preserved ejection fraction (HFpEF) patients, coronary microvascular endothelial dysfunction is evidenced by elevated expression of endothelial adhesion molecules, such as vascular cell adhesion molecule (VCAM) and E-selectin, observed in myocardial biopsy specimens. Additionally, pro-inflammatory cytokines stimulate the endothelial generation of reactive oxygen species (ROS) through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, leading to increased nitrosative and oxidative stress within the myocardium of HFpEF patients. Obesity, along with increased visceral adiposity, is further associated with significant abnormalities in cardiac structure and function, including increased left ventricular (LV) mass, enhanced LV concentric hypertrophy, and more severe LV diastolic dysfunction. The…

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  Figure 2. The pleiotropic effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and their potential role in management of obesity-related heart failure with preserved ejection fraction (HFpEF).

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  Figure 3. In the context of cardiometabolic heart failure with preserved ejection fraction (HFpEF), significant energetic alterations occur. Under normal physiological conditions, the heart primarily relies on fatty acids (approximately 70%) for adenosine triphosphate (ATP) production, supplemented by glucose, branched-chain amino acids, ketone bodies, and lactate. The healthy heart exhibits metabolic flexibility, enabling it to switch between these energy substrates based on nutrient availability. However, in the setting of obesity-associated HFpEF, an excess influx of fatty acids disturbs the balance among these energy substrates, detrimentally affecting cardiac energy homeostasis—for instance, by inhibiting glucose oxidation (as illustrated in the right portion of the figure). This disruption in the physiological substrate oxidation pattern leads to an imbalance in the redox state and alters metabolite availability, which, in turn, modulates cellular signaling pathways through post-translational modifications (PTMs). This imbalance also increases oxidative and nitrosative stress (e.g., reactive nitrogen/oxygen species (R/NOS) production), fostering a state of cardiac hypoxia or…