Neuroinflammation in heart failure: new insights for an old disease

Abstract

Heart failure (HF) is a complex clinical syndrome affecting roughly 26 million people worldwide. Increased sympathetic drive is a hallmark of HF and is associated with disease progression and higher mortality risk. Several mechanisms contribute to enhanced sympathetic activity in HF, but these pathways are still incompletely understood. Previous work suggests that inflammation and activation of the renin-angiotensin system (RAS) increases sympathetic drive. Importantly, chronic inflammation in several brain regions is commonly observed in aged populations, and a growing body of evidence suggests neuroinflammation plays a crucial role in HF. In animal models of HF, central inhibition of RAS and pro-inflammatory cytokines normalizes Hugo S. Díaz H. S. Díaz and others J Physiol 598.1 sympathetic drive and improves cardiac function. The precise molecular and cellular mechanisms that lead to neuroinflammation and its effect on HF progression remain undetermined. This review summarizes the most recent advances in the field of neuroinflammation and autonomic control in HF. In addition, it focuses on cellular and molecular mediators of neuroinflammation in HF and in particular on brain regions involved in sympathetic control. Finally, we will comment on what is known about neuroinflammation in the context of preserved vs. reduced ejection fraction HF. Abstract figure legendIntegrative physiology of heart failure progression: Heart failure (HF) is characterized by chronic inflammation, renin-angiotensin system (RAS) overactivity, sympathoexcitation and cardiac dysfunction. Sympathoexcitation and RAS activation occur early in HF progression as a compensatory response to haemodynamic challenges. Chronic activation of these compensatory mechanisms becomes maladaptive and has toxic effects on cardiac muscle leading to electrophysiological abnormalities and initiation of fibrotic processes. RAS activation also enhances chemoreflex sensitivity (further exacerbating sympathetic activation) and promotes diffuse inflammation. Both systemic and brain RAS and inflammation feed back to exacerbate sympathoexcitation, generating a vicious cycle that contributes to further cardiac dysfunction.

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…Importantly, neuroinflammation and oxidative stress in the PVN and the rostro-lateral medulla have been reported in rats with HF and neurogenic hypertension [26,64,65]. It is well established that inflammation and activation of the renin-angiotensin system drastically increases sympathetic drive, thereby creating a vicious circle with debilitating effects on affected individuals [66]. Moreover, intracerebroventricular infusions of minocycline, an anti-inflammatory antibiotic that inhibits microglia cell function, resulted in significant attenuation of mean arterial pressure and cardiac hypertrophy [64].…”

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…Importantly, neuroin ammation and oxidative stress in the PVN and the rostro-lateral medulla have been reported in rats with HF and neurogenic hypertension (25,61,62). It is well-established that in ammation and activation of the renin-angiotensin system drastically increases sympathetic drive, thereby creating a vicious circle with debilitating effects on affected individuals (63). Moreover, intracerebroventricular infusions of minocycline, an anti-in ammatory antibiotic that inhibits microglia cell activation, resulted in signi cant attenuation of mean arterial pressure and cardiac hypertrophy (61).…”

A Multi-Gene Synaptic Plasticity Array Identifies Candidate Molecular Underpinnings of Cognitive and Mood Deficits in Rats with Heart Failure

“…Numerous putative mechanisms, not mutually exclusive, could contribute to the disruption of the molecular underpinnings of synaptic plasticity during HF. One obvious candidate is neuroinflammation, a hallmark pathophysiological phenomenon in HF (Diaz et al, 2020).…”