Immunometabolic Mechanisms of Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence worldwide, already accounting for at least half of all heart failure (HF). As most patients with HFpEF are obese with metabolic syndrome, metabolic stress has been implicated in syndrome pathogenesis. Recently, compelling evidence for bidirectional crosstalk between metabolic stress and chronic inflammation has emerged, and alterations in systemic and cardiac immune responses are held to participate in HFpEF pathophysiology. Indeed, based on both preclinical and clinical evidence, comorbidity-driven systemic inflammation, coupled with metabolic stress, have been implicated together in HFpEF pathogenesis. As metabolic alterations impact immune function(s) in HFpEF, major changes in immune cell metabolism are also recognized in HFpEF and in HFpEF-predisposing conditions. Both arms of immunity - innate and adaptive - are implicated in the cardiomyocyte response in HFpEF. Indeed, we submit that crosstalk among adipose tissue, the immune system, and the heart represents a critical component of HFpEF pathobiology. Here, we review recent evidence in support of immunometabolic mechanisms as drivers of HFpEF pathogenesis, discuss pivotal biological mechanisms underlying the syndrome, and highlight questions requiring additional inquiry.

Keywords: HFpEF; immune system; metabolism.

Figure 1.

Schematic overview of common HFpEF phenotypes. CKD: chronic kidney disease IBD: inflammatory bowel disease

Figure 2.

Immunometabolic mechanisms involving crosstalk between inflammatory and metabolic events contribute to the pathogenesis of cardiometabolic HFpEF. EAT: epicardial adipose tissue CMs: cardiomyocytes

Figure 3.

Cardiometabolic stress triggers alterations in adaptive immunity in HFpEF. Metabolic stress activates T cells in peripheral organs that, in turn, promote recruitment of other immune cells to the heart and consequent myocardial damage. VAT: visceral adipose tissue Ag: antigen

Figure 4.

Potential contributions of innate immunity to the pathogenesis of cardiometabolic HFpEF. Depicted is a working model in which cardiometabolic risk factors, including visceral adiposity and hypertension, fuel immunometabolic mobilization of innate immune cell subsets. This immune cell mobilization, in turn, activates intercellular crosstalk that also regulates myocardial metabolic pathways. HSPC: hematopoietic stem/progenitor cell Mϕ: macrophages IL-1β: interleukin 1β