Vagal Stimulation, Through its Nicotinic Action, Limits Infarct Size and the Inflammatory Response to Myocardial Ischemia and Reperfusion

Calvillo, Laura; Vanoli, Emilio; Andreoli, Elisa; Besana, Alessandra; Omodeo, Elisabetta; Gnecchi, Massimiliano; Zerbi, Pietro; Vago, Gianluca; Busca, Giuseppe; Schwartz, Peter J.

doi:10.1097/fjc.0b013e31822b7204

Cited by 171 publications

(144 citation statements)

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“…Heart rate-independent effects may include anti-adrenergic effects at ventricular level due to sympathetic-parasympathetic interaction, anti-apoptotic effects and the anti-inflammatory reflex postulated by Tracey [19]. In a model of ischaemia reperfusion in rats, vagal stimulation markedly reduced infarct size and markers of inflammation without changes in heart rate [20].…”

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confidence: 98%

Vagal stimulation for heart diseases: from animals to men. An example of translational cardiology

Schwartz

2012

Neth Heart J

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A significant series of experimental and clinical studies have demonstrated the close association between reduced vagal reflexes (baroreflex sensitivity, BRS) and increased sudden and non-sudden cardiovascular mortality. Subsequently, evidence was provided that, also among chronic heart failure (HF) patients, depressed BRS is associated with a poorer outcome. At the same time, the encouraging results with experimental and clinical attempts to increase cardiac vagal activity led to a few experimental studies with vagal stimulation (VS) in different models for HF. We first performed a pilot study for VS in HF patients, and then in 2011 we reported the results of a small size multicentre clinical trial. The 6-month and 1-year results are encouraging for feasibility, safety and appear to have a favourable clinical effect. An ongoing large clinical trial will provide a definitive assessment of the efficacy and usefulness of chronic VS in HF patients.Keywords Autonomic nervous system . Baroreflex sensitivity . Heart failure . Vagal stimulationThe objective of this essay is to review some aspects of a novel approach to the management of chronic heart failure, a topic recently discussed several times [1][2][3]. Accordingly, it seems reasonable to tackle this issue by reviewing how this concept was developed and how, from a series of experimental studies with a different objective, the end result was the use of chronic vagal stimulation in patients with heart failure.In the early 1980s my interest was largely directed toward the possibility of reducing the risk of developing ventricular fibrillation associated either to arrhythmogenic diseases of genetic origin, such as the long-QT syndrome, or acute myocardial ischaemia. My background, single fibre recording from the sympathetic nerves [4] and from the right cardiac branch of the vagus [5], helped me to develop -with excellent partners such as George Billman and the late Lowell Stone-an animal model for sudden cardiac death that over the years has provided a large number of findings of not minor clinical relevance [6]. We studied conscious dogs with a healed anterior wall myocardial infarction; 1 month after the infarct they performed an exercise stress test and during the last minute we produced a transient episode of acute myocardial ischaemia in conditions of physiologically elevated sympathetic activity, by inflating a balloon occluder previously positioned around the circumflex coronary for 2 min. Under these conditions approximately 50 % of the animals developed ventricular fibrillation (and were defined as 'susceptible' to sudden death) and the remainder did not ('resistant' to sudden death). As the animals were running with defibrillator paddles ligated to the chest, a prompt countershock could re-establish sinus rhythm within seconds and the animals could be studied again over long periods of time. A critical feature of this model is the extremely high reproducibility of the outcome: the susceptible dogs continued to develop ventricular fibrillation wh...

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confidence: 98%

Vagal stimulation for heart diseases: from animals to men. An example of translational cardiology

Schwartz

2012

Neth Heart J

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“…5,6 Evidence is accumulating that vagal nerve activity exerts an immunomodulatory influence, characterized by an anti-inflammatory effect that may be beneficial in a variety of cardiovascular disease states, including myocardial infarction and heart failure. [6][7][8] Indeed, vagal nerve stimulation (VNS) has been reported to limit infarct size in a variety of experimental studies (see Table 4 of Uitterdijk et al 6 ). The exact mechanism by which VNS exerts its cardioprotective effect is not fully understood, but includes nicotinic 8 and muscarinic 7 receptor stimulation as well as activation of nitric oxide synthase, 6 while the VNS-associated bradycardia does not appear to be mandatory for its cardioprotective effects.…”

Section: In This Issue Of Actamentioning

confidence: 99%

“…[6][7][8] Indeed, vagal nerve stimulation (VNS) has been reported to limit infarct size in a variety of experimental studies (see Table 4 of Uitterdijk et al 6 ). The exact mechanism by which VNS exerts its cardioprotective effect is not fully understood, but includes nicotinic 8 and muscarinic 7 receptor stimulation as well as activation of nitric oxide synthase, 6 while the VNS-associated bradycardia does not appear to be mandatory for its cardioprotective effects. [6][7][8] In the present issue of Acta Physiologica, Kiss et al…”

Section: In This Issue Of Actamentioning

confidence: 99%

“…The exact mechanism by which VNS exerts its cardioprotective effect is not fully understood, but includes nicotinic 8 and muscarinic 7 receptor stimulation as well as activation of nitric oxide synthase, 6 while the VNS-associated bradycardia does not appear to be mandatory for its cardioprotective effects. [6][7][8] In the present issue of Acta Physiologica, Kiss et al1 further explore the mechanism by which VNS reduces myocardial infarct size in the setting of an in vivo rat model of 30 min of coronary artery occlusion followed by 2 h of reperfusion. Specifically, the authors set out to test the hypothesis that VNS affords cardioprotection via inhibition of arginase activity.…”

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Arginase – a novel target for cardioprotection by vagal nerve stimulation

Uitterdijk

Duncker

2017

Acta Physiologica

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. 2017. Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and downregulation of cardiac and vascular arginase. Acta Physiol 221, 174-181.The elegant study of Kiss et al. 1 in this issue of Acta Physiologica entitled 'Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and down-regulation of cardiac and vascular arginase' explores the role of arginase in myocardial ischaemia-reperfusion damage, and in the myocardial infarct size limitation produced by vagal nerve stimulation. Although the incidence of acute myocardial infarction has decreased over the last decades, acute myocardial infarction continues to be a major cause of morbidity and mortality, worldwide.2 Moreover, patients that survive an acute myocardial infarction are at increased risk of developing congestive heart failure, with infarct size as a major predictor of post-infarct cardiac remodelling and heart failure. 3 The single most effective therapy to limit infarct size is timely and complete reperfusion. However, despite its overall benefits, reperfusion itself has been shown to result in additional cardiomyocyte death. 4 Hence, adjunctive therapies in addition to reperfusion are still needed to further limit infarct size and improve clinical outcome. 4Myocardial necrosis and microvascular no-reflow are prominent features of ischaemia-reperfusion damage. The mechanisms underlying these events remain incompletely understood, but there is evidence that inflammation plays an important role, including regional influx of neutrophils and macrophages. 5,6 Evidence is accumulating that vagal nerve activity exerts an immunomodulatory influence, characterized by an anti-inflammatory effect that may be beneficial in a variety of cardiovascular disease states, including myocardial infarction and heart failure.6-8 Indeed, vagal nerve stimulation (VNS) has been reported to limit infarct size in a variety of experimental studies (see Table 4 of Uitterdijk et al. 6 ). The exact mechanism by which VNS exerts its cardioprotective effect is not fully understood, but includes nicotinic 8 and muscarinic 7 receptor stimulation as well as activation of nitric oxide synthase, 6 while the VNS-associated bradycardia does not appear to be mandatory for its cardioprotective effects. [6][7][8] In the present issue of Acta Physiologica, Kiss et al.1 further explore the mechanism by which VNS reduces myocardial infarct size in the setting of an in vivo rat model of 30 min of coronary artery occlusion followed by 2 h of reperfusion. Specifically, the authors set out to test the hypothesis that VNS affords cardioprotection via inhibition of arginase activity. This hypothesis was based on the established anti-inflammatory actions of VNS, 8,9 and the critical importance of activation of NO synthase in the cardioprotection by VNS, in conjunction with evidence that inflammation-mediated upregulation of arginase activity contributes to ischaemia-reperfusi...

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“…Initial studies demonstrated that vagal nerve stimulation 49, 50 mimicked the cardioprotective effect of RIC, whereas with bilateral vagotomy this was abrogated 49, 50. An elegant study by Mastitskaya et al.…”

Section: Ric: History and Evolutionmentioning

confidence: 99%

Remote ischaemic conditioning: cardiac protection from afar

2015

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For patients with ischaemic heart disease, remote ischaemic conditioning may offer an innovative, non‐invasive and virtually cost‐free therapy for protecting the myocardium against the detrimental effects of acute ischaemia‐reperfusion injury, preserving cardiac function and improving clinical outcomes. The intriguing phenomenon of remote ischaemic conditioning was first discovered over 20 years ago, when it was shown that the heart could be rendered resistant to acute ischaemia‐reperfusion injury by applying one or more cycles of brief ischaemia and reperfusion to an organ or tissue away from the heart – initially termed ‘cardioprotection at a distance’. Subsequent pre‐clinical and then clinical studies made the important discovery that remote ischaemic conditioning could be elicited non‐invasively, by inducing brief ischaemia and reperfusion to the upper or lower limb using a cuff. The actual mechanism underlying remote ischaemic conditioning cardioprotection remains unclear, although a neuro‐hormonal pathway has been implicated. Since its initial discovery in 1993, the first proof‐of‐concept clinical studies of remote ischaemic conditioning followed in 2006, and now multicentre clinical outcome studies are underway. In this review article, we explore the potential mechanisms underlying this academic curiosity, and assess the success of its application in the clinical setting.

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Vagal Stimulation, Through its Nicotinic Action, Limits Infarct Size and the Inflammatory Response to Myocardial Ischemia and Reperfusion

Cited by 171 publications

References 26 publications

Vagal stimulation for heart diseases: from animals to men. An example of translational cardiology

Vagal stimulation for heart diseases: from animals to men. An example of translational cardiology

Arginase – a novel target for cardioprotection by vagal nerve stimulation

Remote ischaemic conditioning: cardiac protection from afar

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