Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model

Jardine, David L.; Charles, Christopher J.; Ashton, R. K.; Bennett, Sinclair I.; Whitehead, M.; Frampton, Christopher M.; Nicholls, M. Gary

doi:10.1113/jphysiol.2004.082198

Cited by 81 publications

(49 citation statements)

References 34 publications

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“…10 In the subacute period after acute MI, rapid VT may result from abnormal automaticity in surviving Purkinje fibers and possibly triggered activity. 9 These delayed arrhythmias may be promoted by increased cardiac sympathetic nerve activity 11 or by increased sensitivity of Purkinje fibers to catecholamines. 9 In the current study, where infarcts were relatively small (mean left ventricular ejection fraction at 55%) and sustained VAs were often difficult to induce at electrophysiological study or terminate with antitachycardia pacing, abnormal automaticity may have been a prominent mechanism.…”

Section: Effect Of Rdn On Spontaneous and Induced Vasmentioning

confidence: 99%

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

Jackson

Gizurarson

Azam

et al. 2017

Circ: Cardiovascular Interventions

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T he therapeutic potential of renal denervation (RDN) for cardiac arrhythmias was previously explored, yielding case reports and small case series that suggested RDN may be an effective adjunctive treatment in addition to medication and cardiac ablation for patients with ventricular tachycardia (VT) storm and atrial fibrillation.1-5 These promising results call for large-scale, well-controlled trials and detailed mechanistic evaluations. However, findings of the SYMPLICITY HTN-3 study (Renal Denervation in Patients With Uncontrolled Hypertension) have raised grave concerns over the benefits from RDN therapy for hypertension. 4 Hence, although RDN-based treatments are being developed for arrhythmias, it is important to reassess and confirm the antiarrhythmic potential of RDN in experiments designed to clearly demonstrate the impacts on cardiac electrophysiology. More importantly, the mechanistic basis of any antiarrhythmic effects should also be determined. See Editorial by Koruth and DukkipatiRDN has been shown to attenuate elevations in left ventricular end-diastolic pressure, suppress spontaneous premature beats, and reduce the incidence of ventricular fibrillation (VF) immediately post-acute coronary occlusion in pigs.6 RDN was also shown to reduce the incidence of ventricular arrhythmias (VAs) immediately after coronary occlusion in a similar acute canine model, in which RDN prolonged the ventricular effective refractory period (ERP) and the ventricular action potential duration, as well as decreased action potential duration dispersion. Although RDN is known to reduce renal sympathetic activity Background-The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium. Methods and Results-Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio-renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (P=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus t...

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Section: Effect Of Rdn On Spontaneous and Induced Vasmentioning

confidence: 99%

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

Jackson

Gizurarson

Azam

et al. 2017

Circ: Cardiovascular Interventions

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“…Sympathoexcitatory action can exaggerate myocardial ischemia further by increasing myocardial oxygen consumption while maintaining cardiac function transiently by enhancing contractility [25,44]. Surgical interventions of sympathetic afferent pathways abolish or relieve angina pectoris [43].…”

Section: Introductionmentioning

confidence: 99%

“…Sympathoexcitatory action in cervical sympathetic ganglia is induced by cardiac afferent activation [4,25,43]. Sympathoexcitatory action can exaggerate myocardial ischemia further by increasing myocardial oxygen consumption while maintaining cardiac function transiently by enhancing contractility [25,44].…”

Section: Introductionmentioning

confidence: 99%

Sensory–sympathetic coupling in superior cervical ganglia after myocardial ischemic injury facilitates sympathoexcitatory action via P2X7 receptor

Peng

et al. 2013

Purinergic Signalling

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P2X receptors participate in cardiovascular regulation and disease. After myocardial ischemic injury, sensorysympathetic coupling between rat cervical DRG nerves and superior cervical ganglia (SCG) facilitated sympathoexcitatory action via P2X 7 receptor. The results showed that after myocardial ischemic injury, the systolic blood pressure, heart rate, serum cardiac enzymes, IL-6, and TNF-α were increased, while the levels of P2X 7 mRNA and protein in SCG were also upregulated. However, these alterations diminished after treatment of myocardial ischemic (MI) rats with the P2X 7 antagonist oxATP. After siRNA P2X 7 in MI rats, the systolic blood pressure, heart rate, serum cardiac enzymes, the expression levels of the satellite glial cell (SGC) or P2X 7 were significantly lower than those in MI group. The phosphorylation of ERK 1/2 in SCG participated in the molecular mechanism of the sympathoexcitatory action induced by the myocardial ischemic injury. Retrograde tracing test revealed the sprouting of CGRP or SP sensory nerves (the markers of sensory afferent fibers) from DRG to SCG neurons. The upregulated P2X 7 receptor promoted the activation of SGCs in SCG, resulting in the formation of sensory-sympathetic coupling which facilitated the sympathoexcitatory action. P2X 7 antagonist oxATP could inhibit the activation of SGCs and interrupt the formation of sensory-sympathetic coupling in SCG after the myocardial ischemic injury. Our findings may benefit the treatment of coronary heart disease and other cardiovascular diseases.

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“…In rats, direct recordings from cardiac sympathetic nerves demonstrate that cardiac sympathetic nerve activity (CSNA) increased twofold within hours after MI (40). In conscious sheep, CSNA was significantly increased by the second hour post-MI and remained elevated for at least 1 wk (14).…”

mentioning

confidence: 99%

Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade

Drobysheva

Ahmad

White

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Drobysheva A, Ahmad M, White R, Wang H, Leenen FH. Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade. Am J Physiol Heart Circ Physiol 305: H1817-H1829, 2013. First published October 11, 2013; doi:10.1152/ajpheart.00445.2013.-Central mechanisms involving mineralocorticoid receptor (MR) activation contribute to an increase in sympathetic tone after myocardial infarction (MI). We hypothesized that this central mechanism also contributes to cardiac sympathetic axonal sprouting and that central MR blockade reduces cardiac sympathetic hyperinnervation post-MI. Post-MI, tyrosine hydroxylase (TH) and norepinephrine transporter protein content in the noninfarcted base of the heart remained unaltered. In contrast, protein gene product (PGP)9.5 protein was increased twofold in the base of the heart and sixfold in the peri-infarct area at 1 wk post-MI and was associated with increased ubiquitin expression. These changes persisted to a lesser extent at 4 wk post-MI and were no longer present at 12 wk. Cardiac myocytes rather than sympathetic axons were the main source of this elevated PGP9.5 expression. At 7-10 days post-MI, in the peri-infarct area, sympathetic hyperinnervation was observed with a fourfold increase in growth-associated protein 43, a twofold increase in TH, and a 50% increase in PGP9.5-positive fibers compared with the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone markedly attenuated these increases in nerve densities but did not affect overall cardiac PGP9.5 and ubiquitin protein overexpression. We conclude that central MR activation contributes to sympathetic hyperinnervation, possibly by decreasing cardiac sympathetic activity post-MI, or by affecting other mechanisms, such as the expression of nerve growth factor. Marked PGP9.5 expression occurs in cardiomyocytes early post-MI, which may contribute to the increase in ubiquitin. myocardial infarction; cardiac sympathetic hyperinnervation; brain mineralocorticoid receptors; eplerenone; ubiquitin; protein gene product 9.5 CARDIAC REMODELING after myocardial infarction (MI) affects both infarcted and noninfarcted areas of the heart and contributes to the impairment of ventricular performance (19,43,44). Cardiac sympathetic hyperactivity enhances maladaptive cardiac remodeling post-MI and plays a major role in the development of chronic heart failure (CHF) (5, 31). In humans with mild CHF, there is a selective increase in cardiac sympathetic activity, which is followed by augmented sympathetic outflow to skeletal muscle and the kidneys as CHF progresses (16,38). In rats, direct recordings from cardiac sympathetic nerves demonstrate that cardiac sympathetic nerve activity (CSNA) increased twofold within hours after MI (40). In conscious sheep, CSNA was significantly increased by the second hour post-MI and remained elevated for at least 1 wk (14).Increased CSNA may also contribute to the development of cardiac sympathetic hyperi...

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Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model

Cited by 81 publications

References 34 publications

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

Sensory–sympathetic coupling in superior cervical ganglia after myocardial ischemic injury facilitates sympathoexcitatory action via P2X7 receptor

Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade

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