Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias

Gardner, Ryan T.; Ripplinger, Crystal M.; Myles, Rachel C.; Habecker, Beth A.

doi:10.1161/circep.115.001359

Cited by 72 publications

(73 citation statements)

References 111 publications

(117 reference statements)

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“…Paradoxical increases in AT in the peri-infarct zone may be related to aberrant innervation patterns with preserved parasympathetic but not sympathetic nerve endings, and transdifferentiated neurons to cholinergic phenotype form adrenergic (25). At the level of the myocyte, alterations in ionic properties [e.g., depressed intracellular K ϩ and peak calcium transients (39)] and adrenergic signaling pathways [e.g., adrenergic receptor downregulation (28) and decreased G-protein receptor kinase-2 (GRK2) in cardiomyopathy (64)] in surviving peri-infarct myocytes induced by hyperinnervation or local tissue factors may also play a role (16). These findings may underlie the proarrhythmic risk described in association with peri-infarct zone nerve sprouts (9).…”

Section: Discussionmentioning

confidence: 99%

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Ajijola

Lux

Khahera

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n ϭ 12) or anterior myocardial infarction (MI, n ϭ 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CV L) was increased by RSGS (0.98 Ϯ 0.11 vs. 1.2 Ϯ 0.14m/s, P Ͻ 0.001) but not transverse CV (CV T). This increase was abrogated by ␤-adrenergic receptor and gap junction (GJ) blockade. Neither CV L nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 Ϯ 37 vs. 322 Ϯ 30 ms, P Ͻ 0.001, and 423 Ϯ 36 vs. 398 Ϯ 36 ms, P ϭ 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 Ϯ 1.2 vs. 17.3 Ϯ 1.6 ms, P ϭ 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P Ͻ 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic periinfarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.

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Section: Discussionmentioning

confidence: 99%

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Ajijola

Lux

Khahera

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…; Gardner et al . ). Under normal physiological conditions, NA released from sympathetic nerves impacts cardiac ion channels and Ca 2+ handling to enact prototypical chronotropic and inotropic responses.…”

Section: Neural–cardiac Interactions: Co‐maturation In Developmentmentioning

confidence: 97%

“…Changes in growth factor expression, oxidative stress, and inflammatory cytokines within the heart and vasculature contribute to neuronal remodelling. These issues have been reviewed in detail recently (Kimura et al 2012;Fukuda et al 2015;Gardner et al 2016), and will be summarized here briefly. Sensory nerves.…”

Section: Normal Neurotransmission and Injury-induced Plasticity In Camentioning

confidence: 99%

“…The contributions of sympathetic dysfunction to cardiovascular pathology have been the subject of many reviews (Esler et al 1997;Lefkowitz et al 2000;Gourine & Gourine, 2014;Shen & Zipes, 2014;Fukuda et al 2015;Gardner et al 2016). Under normal physiological conditions, NA released from sympathetic nerves impacts cardiac ion channels and Ca 2+ handling to enact prototypical chronotropic and inotropic responses.…”

Section: Figure 2 Diagram Of the Pathophysiological Interactions Betmentioning

confidence: 99%

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Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

Habecker

Anderson²,

Birren

et al. 2016

The Journal of Physiology

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112

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The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural-cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodelling in cardiovascular disease. The content on each subject was contributed by experts, and we hope that this will provide a useful resource for newcomers to neurocardiology as well as aficionados.

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“…4 The chronically elevated levels of the neurotransmitter norepinephrine that result from this imbalance of parasympathetic and sympathetic influences are cardiotoxic and contribute to the progression of heart failure, including development of left ventricular dilation. 5, 6 Throughout the time course of heart failure, autonomic dysfunction can promote malignant arrhythmias, leading to sudden cardiac death. 7, 8 …”

Section: Introductionmentioning

confidence: 99%

[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

Jung

Jang

et al. 2017

ACS Chem. Neurosci.

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Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In this study, we report an efficient synthesis of 18F-hydroxyphenethylguanidines consisting of nucleophilic aromatic [18F]fluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG, [18F]1) and its structural isomer 3-[18F]fluoro-p-hydroxyphenethylguanidine ([18F]3F-PHPG, [18F]2) with good radiochemical yields. Preclinical evaluations of [18F]2 in non-human primates were performed to compare its imaging properties, metabolism, and myocardial kinetics with those obtained previously with [18F]1. The results of these studies have demonstrated that [18F]2 exhibits imaging properties comparable to those of [18F]1. Myocardial tracer kinetic analysis of each tracer provides quantitative metrics of cardiac sympathetic nerve density. Based on these findings, first-in-human PET studies with [18F]1 and [18F]2 are currently in progress to assess their ability to accurately measure regional cardiac sympathetic denervation in patients with heart disease, with the ultimate goal of selecting a lead compound for further clinical development.

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Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias

Cited by 72 publications

References 111 publications

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

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Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias

Cited by 72 publications

References 111 publications

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

[18F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation

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[¹⁸F]Fluoro-Hydroxyphenethylguanidines: Efficient Synthesis and Comparison of Two Structural Isomers as Radiotracers of Cardiac Sympathetic Innervation