Abstract
Cardiac sympathetic overactivation is involved in arrhythmogenesis in patients with chronic heart failure (CHF). Inflammatory infiltration in the stellate ganglion (SG) is a critical factor for cardiac sympathoexcitation in patients with ventricular arrhythmias. This study aims to investigate if macrophage depletion in SGs decreases cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Surgical ligation of the coronary artery was used for induction of CHF. Clodronate liposomes were microinjected into bilateral SGs of CHF rats for macrophage depletion. Using cytokine array, immunofluorescence staining, and Western blot analysis, we found that macrophage expansion and expression of TNFα and IL-1β in SGs were markedly increased in CHF rats. Flow cytometry data confirmed that the percentage of macrophages in SGs was higher in CHF rats than that in sham rats. Clodronate liposomes significantly reduced CHF-elevated proinflammatory cytokine levels and macrophage expansion in SGs. Clodronate liposomes also reduced CHF-increased N-type Ca2+ currents and excitability of cardiac sympathetic postganglionic neurons and inhibited CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-h, continuous telemetry recording in conscious rats demonstrated that clodronate liposomes not only restored CHF-induced heterogeneity of ventricular electrical activities, but also decreased the incidence and duration of ventricular tachycardia/fibrillation in CHF. Macrophage depletion with clodronate liposomes attenuated CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias through reduction of macrophage expansion and neuroinflammation in SGs.
Highlights
As a common complication in chronic heart failure (CHF), ventricular arrhythmia accounts for nearly 50–60% of mortality in patients with CHF [9]
The data demonstrated that nine cytokines were detectable, and only proinflammatory cytokines including TNFα and IL-1β were elevated in stellate ganglion (SG) from CHF rats, compared to sham rats
There were no significant differences in anti-inflammatory cytokine (IL-10) and other proinflammatory cytokines including cytokine-induced neutrophil chemoattractants (CICN), granulocyte–macrophage colony-stimulating factor (GM-CSF), IL-1α, lipopolysaccharide-induced CXC chemokine (LIX), and vascular endothelial growth factor (VEGF) between sham and CHF rats (Supplemental Fig. 2b, c)
Summary
As a common complication in chronic heart failure (CHF), ventricular arrhythmia accounts for nearly 50–60% of mortality in patients with CHF [9]. Recent studies have revealed an elevation of inflammatory infiltration and macrophage hyperactivation in stellate ganglion (SG) from patients with cardiomyopathy and arrhythmias [1, 40] It remains unclear if and how neuroinflammation in the SG contributes to ventricular arrhythmias. Our recent study has reported that N-type Ca2+ currents and excitability of cardiac sympathetic postganglionic (CSP) neurons located in the SGs are enhanced in CHF rats [58]. Considering that voltage-gated Ca2+ channels could be modulated by proinflammatory cytokines in various tissues and cells [43, 53], it is possible that CHF-enhanced N-type Ca2+ currents in CSP neurons and cardiac sympathoexcitation are attributed to neuroinflammation in the SGs
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