Heart Failure Syndrome With Preserved Ejection Fraction Is a Metabolic Cluster of Non-resolving Inflammation in Obesity

Abstract

Heart failure with preserved ejection fraction (HFpEF) is an emerging disease with signs of nonresolving inflammation, endothelial dysfunction, and multiorgan defects. Moreover, based on the clinical signs and symptoms and the rise of the obesity epidemic, the number of patients developing HFpEF is increasing. From recent molecular and cellular studies, it becomes evident that HFpEF is not a single and homogenous disease but a cluster of heterogeneous pathophysiology with aging at the base of the pyramid. Obesity superimposed on aging drives the number of inflammatory pathways that intersect with metabolic dysfunction and suboptimal inflammation. Here, we compiled information on obesity-directed macrophage dysfunction that coincide with metabolic defects. Obesity-associated proinflammatory stimuli facilitates heart and interorgan inflammation in HFpEF. Furthermore, diversified mechanisms that drive heart failure urge the need of studying pervasive and unresolved inflammation in animal models to understand HFpEF. A broad and system-based approach will help to study major translational aspects of HFpEF, since no single animal model recapitulates all signs of differential HFpEF stages in the clinical setting. Here, we covered experimental models that target HFpEF and emphasized the advances observed with formyl peptide 2 (FPR2) receptor, a prime sensor that is important in inflammation-resolution signaling. Dysfunction of FPR2 led to the development of spontaneous obesity, impaired macrophage function, and triggered kidney fibrosis, providing evidence of multiorgan defects in HFpEF in an obesogenic aging experimental model.

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets

“…Also, (anti-inflammatory) high density lipoprotein cholesterol/(inflammatory) CRP ratio was shown to be a useful marker for prognostication and correlated with echocardiographic parameters in HFpEF patients (Yano et al, 2021). Moreover, a recent report suggested that the deletion of resolution sensor ALX/FPR2 is associated with the development of diastolic dysfunction related with obesity in mice with HFpEF (Tourki et al, 2020), supporting the concept of nonresolving inflammation in HFpEF (Tourki and Halade, 2021). Besides all this, until now, anti-inflammatory therapies in HFpEF were negative (Murphy et al, 2020), including D-HART2 which failed to improve exercise capacity demonstrated in the pilot study despite lowering CRP and NT-pro-BNP in these patients (Gullestad et al, 2001a;Van Tassell et al, 2018).…”

Role of CD40(L)-TRAF signaling in inflammation and resolution—a double-edged sword

“…In addition to the factors influencing inflammation and its resulting diseases discussed so far, seemingly mundane factors such as unbalanced sleep ( Arnett et al, 2019 ), poor diet, or lack of exercise are also important. They can influence molecular processes in the body and negatively affect the immune system ( Frodermann et al, 2019 ; McAlpine et al, 2019 ; Tourki and Halade, 2021 ). Since the development of inflammation plays a vital role in CVDs, it is crucial to focus on its processes to develop strategies to treat CVDs ( Murphy et al, 2020 ).…”

Cardiovascular Endocrinology: Evolving Concepts and Updated Epidemiology of Relevant Diseases

“…The pathophysiological understanding of HFpEF is still limited. Recent reports have shown that many HFpEF patients exhibit signs of non-resolving inflammation, endothelial dysfunction, insulin resistance, hyperlipidemia, and multiorgan defects ( 14 ). At a cellular level, cardiomyocytes in patients with HFpEF are thicker and shorter than normal cells, collagen content is increased, and recent histologic evaluations have revealed reductions in myocardial capillary density alongside lymphatic dysfunction ( 15 ).…”