Macrophage depletion in stellate ganglia attenuates cardiac sympathetic overactivation and ventricular arrhythmogenesis by inhibiting neuroinflammation in heart failure

AbstractCardiac 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.

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Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure

Cardiovascular Research ◽

10.1093/cvr/cvaa018 ◽

2020 ◽

Author(s):

Dongze Zhang ◽

Huiyin Tu ◽

Chaojun Wang ◽

Liang Cao ◽

Wenfeng Hu ◽

...

Keyword(s):

Heart Failure ◽

Coronary Artery ◽

Ventricular Arrhythmias ◽

Sympathetic Neurons ◽

Coronary Artery Ligation ◽

Channel Blockers ◽

Artery Ligation ◽

Cell Excitability ◽

Ventricular Arrhythmogenesis

Abstract Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

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Effect of Loss of Heart Rate Variability on T-Wave Heterogeneity and QT Variability in Heart Failure Patients: Implications in Ventricular Arrhythmogenesis

Cardiovascular Engineering and Technology ◽

10.1007/s13239-017-0299-9 ◽

2017 ◽

Vol 8 (2) ◽

pp. 219-228 ◽

Cited By ~ 5

Author(s):

Sachin Nayyar ◽

Muhammad A. Hasan ◽

Kurt C. Roberts-Thomson ◽

Thomas Sullivan ◽

Mathias Baumert

Keyword(s):

Heart Failure ◽

Heart Rate ◽

Heart Rate Variability ◽

Heart Failure Patients ◽

T Wave ◽

Qt Variability ◽

Ventricular Arrhythmogenesis

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136-02: Effect of Loss of Heart Rate Variability on T-wave Heterogeneity and QT Variability in Heart Failure Patients: Implications in Ventricular Arrhythmogenesis

EP Europace ◽

10.1093/europace/18.suppl_1.i89b ◽

2016 ◽

Vol 18 (suppl_1) ◽

pp. i89-i89

Author(s):

Sachin Nayyar ◽

Muhammad Hasan ◽

Kurt Roberts-Thomson ◽

Thomas Sullivan ◽

Mathias Baumert

Keyword(s):

Heart Failure ◽

Heart Rate ◽

Heart Rate Variability ◽

Heart Failure Patients ◽

T Wave ◽

Qt Variability ◽

Ventricular Arrhythmogenesis

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Re‐expression of REST Promotes Ventricular Arrhythmogenesis via Repressing N‐type Calcium Channel in Ventricular Vagal Neurons in Chronic Heart Failure

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.596.1 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Dongze Zhang ◽

Huiyin Tu ◽

Michael C. Wadman ◽

Yu‐Long Li

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Calcium Channel ◽

Ventricular Arrhythmogenesis

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Abstract 389: Human Cardiac Sympathetic Nerves Switch the Neurotransmitter Property from Catecholaminergic to Cholinergic in Patients with Severe Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_297 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Hideaki Kanazawa ◽

Masaki Ieda ◽

Kensuke Kimura ◽

Takahide Arai ◽

Haruko Manabe ◽

...

Keyword(s):

Heart Failure ◽

Interstitial Fibrosis ◽

Severe Heart Failure ◽

Sympathetic Nerves ◽

Cholinergic Neuron ◽

Heart Weight ◽

Control Group ◽

Down Regulation ◽

Stellate Ganglia ◽

Nerve Bundles

[Background] Congestive heart failure (CHF) is characterized by activation of the sympathetic nervous system (SNS) with depletion of norepinephrine (NE) stores, which was initially considered to be the result of excess NE secretion and the loss of noradrenergic nerve terminals. Recent studies however have revealed that it is caused by down regulation of NE synthesis and re-uptake, although the molecular mechanism of down regulation of the sympathetic neuronal function remains unknown. We recently found in an animal model of CHF that the cardiac SNS switches the neurotransmitter property from catecholaminergic to cholinergic, mediated by cytokines LIF and CT-1 secreted from failing myocardium. This study was designed to investigate whether or not this cholinergic transdifferentiation of cardiac SNS occurs in patients with CHF. [Methods & Results] (1) We analyzed 8 samples from patients who died of non-cardiac causes obtained at autopsy (control group), and 8 samples from patients with CHF (CHF group). Five of them died of CHF, and 3 were obtained from native hearts of transplant recipients. (2) The heart weight was significantly higher in the CHF group. (3) The gross morphology of the cardiac SNS did not differ between the two groups. HE and Masson trichrome staining showed disorganized cardiomyocytes and interstitial fibrosis in CHF. (4) Immunostaining for tyrosine hydroxylase (TH, sympathetic nerve marker) revealed that the epicardial nerve bundles and stellate ganglia of the control group had a predominance of TH + nerves, whereas those of CHF group were significantly decreased. (5) Immunostaining for choline transporter (CHT, cholinergic neuron marker) revealed that CHT + neurons were markedly increased in the epicardial nerve bundles of CHF hearts compared with the control group. Some nerves co-expressed both TH and CHT markers. (6) Immunostaining for choline acetyl transferase (ChAT, a cholinergic neuron marker) revealed that stellate ganglia had a lot of ChAT + neurons compared with the control. (7) Nissl staining showed that there was no difference between the two groups in neuron number in the stellate ganglia. [Conclusions] These results indicated that in patients with CHF the cardiac sympathetic nerves also had cholinergic nerve properties.

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