Metabolic inflammation in heart failure with preserved ejection fraction

Abstract

One in 10 persons in the world aged 40 years and older will develop the syndrome of HFpEF (heart failure with preserved ejection fraction), the most common form of chronic cardiovascular disease for which no effective therapies are currently available. Metabolic disturbance and inflammatory burden contribute importantly to HFpEF pathogenesis. The interplay within these two biological processes is complex; indeed, it is now becoming clear that the notion of metabolic inflammation-metainflammation-must be considered central to HFpEF pathophysiology. Inflammation and metabolism interact over the course of syndrome progression, and likely impact HFpEF treatment and prevention. Here, we discuss evidence in support of a causal, mechanistic role of metainflammation in shaping HFpEF, proposing a framework in which metabolic comorbidities profoundly impact cardiac metabolism and inflammatory pathways in the syndrome.

Keywords: HFpEF; Immunity; Inflammation; Metabolism; Obesity.

Figure 1

Metabolism and Immunity Coupling in HFpEF. Metainflammation is a chronic low-grade systemic state of inflammation associated with obesity. Systemic inflammation has been recognized as a cause of HFpEF through: (i) microvascular dysfunction and downregulation of NO/cGMP signalling; (ii) nitrosative stress and protein quality control impairment, altering the dynamic state of cardiomyocyte molecular constituents. In addition, nutrient overload in obesity has immune and metabolic consequences on insulin sensitivity. Insulin resistance limits cardiac metabolic flexibility and hampers energy provision (iii).

Figure 2

Overview of HFpEF pathophysiology: metabolic inflammation moves centre stage. Metabolic dysregulation is coupled with immune dysregulation. Systemic disruption of metabolic homoeostasis in obesity elicits a chronic low-grade inflammatory response (i.e. metainflammation). In the heart, cytokines and other inflammatory mediators modulate cardiac metabolism. Downstream, these alterations contribute to structural and functional remodelling in HFpEF.

Figure 3

How to fill an empty toolbox? Potential targets and approaches in HFpEF therapy. A promising therapeutic rationale is targeting the stressors prevalent in HFpEF. Possible approaches are shown in association with the prevalent forms of stress they are able to tackle, together with the clinical efficacy they have demonstrated so far. Whereas we still lack evidence of effective HFpEF treatments from large clinical trials, encouraging evidence suggests that targeting metabolic and inflammatory stress, limiting nutrient overload, and antagonizing key inflammatory mediators hold promise and warrant further study. RAAS (Renin–Angiotensin–Aldosterone System).