Myocardial Inflammation in Heart Failure With Reduced and Preserved Ejection Fraction

Abstract

Heart failure (HF) is characterized by a progressive decline in cardiac function and represents one of the largest health burdens worldwide. Clinically, 2 major types of HF are distinguished based on the left ventricular ejection fraction (EF): HF with reduced EF and HF with preserved EF. While both types share several risk factors and features of adverse cardiac remodeling, unique hallmarks beyond ejection fraction that distinguish these etiologies also exist. These differences may explain the fact that approved therapies for HF with reduced EF are largely ineffective in patients suffering from HF with preserved EF. Improving our understanding of the distinct cellular and molecular mechanisms is crucial for the development of better treatment strategies. This article reviews the knowledge of the immunologic mechanisms underlying HF with reduced and preserved EF and discusses how the different immune profiles elicited may identify attractive therapeutic targets for these conditions. We review the literature on the reported mechanisms of adverse cardiac remodeling in HF with reduced and preserved EF, as well as the immune mechanisms involved. We discuss how the knowledge gained from preclinical models of the complex syndrome of HF as well as from clinical data obtained from patients may translate to a better understanding of HF and result in specific treatments for these conditions in humans.

Keywords: heart failure; immune system; inflammation; ventricular function, left; ventricular remodeling.

Figure 1:

Adverse myocardial remodeling at the organ, tissue and cellular levels differs significantly between HFpEF and HFrEF. This illustration reflects gross remodeling processes at the cell and tissue level in both etiologies and does not reflect the actual cell sizes or absolute differences in cell numbers.

Figure 2:

Immune mechanisms contributing to HFrEF. A: The acute inflammatory response to ischemic injury is triggered by the release of danger-associated molecular patterns (DAMP). This early response results in the removal of debris from the injury site and initiates fibrosis and angiogenesis to prevent further damage to the heart. If not resolved, cardiac inflammation becomes chronic resulting in the deposition of an excessive and continuously growing fibrotic scar, which favors the progression to HFrEF over time. B: Non-ischemic heart failure is the result of gradual increase in hypertrophy and fibrosis which is favored by sequential recruitment of innate and adaptive immune cells. HGF, hepatocyte growth factor. TGFβ, transforming growth factor-β. FGF2, fibroblast growth factor-2. VEGF, vascular endothelial growth factor. GrB, granzymeB. αSMA, α-smooth muscle actin. IFNγ, interferon-γ.

Figure 3:

Immune mechanisms contributing to HFpEF. A: In HFpEF patients, systemic inflammation characterized by elevated levels of circulating cytokines, endothelial dysfunction and clonal hematopoiesis leads to alterations of cardiac metabolome and transcriptome that are distinct from HFrEF patients. B: Mechanistic studies based on murine models of HFpEF identified splenic T cell activation, T cell recruitment to the myocardium and clonal hematopoiesis as significant contributors to HFpEF pathology.