Inflammation - Cause or Consequence of Heart Failure or Both?

Abstract

Purpose of review: With the intention to summarize the currently available evidence on the pathophysiological relevance of inflammation in heart failure, this review addresses the question whether inflammation is a cause or consequence of heart failure, or both.

Recent findings: This review discusses the diversity (sterile, para-inflammation, chronic inflammation) and sources of inflammation and gives an overview of how inflammation (local versus systemic) can trigger heart failure. On the other hand, the review is outlined how heart failure-associated wall stress and signals released by stressed, malfunctioning, or dead cells (DAMPs: e.g., mitochondrial DNA, ATP, S100A8, matricellular proteins) induce cardiac sterile inflammation and how heart failure provokes inflammation in various peripheral tissues in a direct (inflammatory) and indirect (hemodynamic) manner. The crosstalk between the heart and peripheral organs (bone marrow, spleen, gut, adipose tissue) is outlined and the importance of neurohormonal mechanisms including the renin angiotensin aldosteron system and the ß-adrenergic nervous system in inflammation and heart failure is discussed. Inflammation and heart failure are strongly interconnected and mutually reinforce each other. This indicates the difficulty to counteract inflammation and heart failure once this chronic vicious circle has started and points out the need to control the inflammatory process at an early stage avoiding chronic inflammation and heart failure. The diversity of inflammation further addresses the need for a tailored characterization of inflammation enabling differentiation of inflammation and subsequent target-specific strategies. It is expected that the characterization of the systemic and/or cardiac immune profile will be part of precision medicine in the future of cardiology.

Keywords: Cardiosplenic axis; Heart failure; Monocytopoiesis; Para-inflammation; Sterile inflammation; ß-adrenergic signaling.

Fig. 1

Inflammation and heart failure reciprocally trigger each other. Heart failure (HF) provokes sterile inflammation in the heart itself triggered by wall stress and signals released by stressed, malfunctioning, or dead cells secondary to HF (DAMPs: e.g., mitochondrial (mt) DNA, ATP, matricellular proteins). The released cardiac cytokines and other inflammatory mediators not only affect the heart but also different organs. IL-1ß induces monocytopoiesis via increasing hematopoietic stem cell proliferation in the bone marrow and monocyte proliferation in the spleen. Cytokines particularly, TNF-α, unleashes inflammation in the skeletal muscle and adipose tissue and accelerate atherogenesis. Furthermore, several neurohormonal mechanisms (renin angiotensin aldosteron system (RAAS) and ß-adrenergic nervous system) that become activated in HF to try and sustain cardiac output in the face of decompensating function also affect inflammation in different organs. ß3 agonism and Ang II induce monocytopoiesis in the spleen. As a consequence of chronic vasoconstriction and underperfusion, inflammation is induced in the skeletal muscle. HF-associated decreased cardiac output and redistribution of systemic circulation can further also lead to a decrease in intestinal perfusion and mucosal ischemia and ultimately, a disrupted intestinal mucosa. This disruption can in turn lead to increased gut permeability and subsequent enhanced translocation of bacteria and bacterial toxins in the blood, which can contribute to systemic inflammation. Systemic inflammation, high-grade (e.g., rheumatoid arthritis) and low-grade (e.g., obesity), and cardiac inflammation induce HF involving different pathophysiological mechanisms. Inflammation triggers cardiomyocyte apoptosis, hypertrophy, stiffness, myofibroblast differentiation, collagen production, endothelial dysfunction, endothelial-to-mesenchymal transition, and subsequent cardiac remodeling and left ventricular dysfunction