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

Habecker, Beth A.; Anderson, Mark E.; Birren, Susan J.; Fukuda, Keiichi; Herring, Neil; Hoover, Donald B.; Kanazawa, Hideaki; Paterson, David J.; Ripplinger, Crystal M.

doi:10.1113/jp271840

Cited by 88 publications

(115 citation statements)

References 250 publications

(451 reference statements)

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“…This has been based on mechanistic evidence from models of sympathetic hyperactivity at the level of the organ in animals (Habecker et al, 2016), and more recently from human studies (Shivkumar et al, 2016). …”

Section: The Effects Of Sympathetic Stimulation On Cardiac Electrophymentioning

confidence: 99%

Cardiac sympatho-vagal balance and ventricular arrhythmia

Kalla¹,

Herring²,

Paterson³

2016

Autonomic Neuroscience

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A hallmark of cardiovascular disease is cardiac autonomic dysregulation. The phenotype of impaired parasympathetic responsiveness and sympathetic hyperactivity in experimental animal models is also well documented in large scale human studies in the setting of heart failure and myocardial infarction, and is predictive of morbidity and mortality. Despite advances in emergency revascularisation strategies for myocardial infarction, device therapy for heart failure and secondary prevention pharmacotherapies, mortality from malignant ventricular arrhythmia remains high. Patients at highest risk or those with haemodynamically significant ventricular arrhythmia can be treated with catheter ablation and implantable cardioverter defibrillators, but the morbidity and reduction in quality of life due to the burden of ventricular arrhythmia and shock therapy persists. Therefore, future therapies must aim to target the underlying pathophysiology that contributes to the generation of ventricular arrhythmia. This review explores recent advances in mechanistic research in both limbs of the autonomic nervous system and potential avenues for translation into clinical therapy. In addition, we also discuss the relationship of these findings in the context of the reported efficacy of current neuromodulatory strategies in the management of ventricular arrhythmia.

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Section: The Effects Of Sympathetic Stimulation On Cardiac Electrophymentioning

confidence: 99%

Cardiac sympatho-vagal balance and ventricular arrhythmia

Kalla¹,

Herring²,

Paterson³

2016

Autonomic Neuroscience

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“…However, emerging clinical evidence suggests that removal of sympathetic nerves that innervate the heart (cardiac stellectomy) improves morbidity and mortality caused by arrhythmias and sudden cardiac death3, although the ability of the neuron to drive the myocyte phenotype in disease has not been firmly established. Nevertheless cardiac sympathetic hyperactivity is a well established early hallmark of heart failure45, post myocardial infarction6 and hypertension, both in humans7891011 and in the spontaneously hypertensive rat (SHR)1213. In the pro-hypertensive SHR, the sympathetic stellate neurons that predominantly innervate the heart14 show increased membrane Ca 2+ currents1516, intracellular Ca 2+ transients17 and significant impairment of the noradrenaline reuptake transporter (NET)18 that all contribute to enhanced noradrenaline (NA) release131920.…”

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confidence: 99%

Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease

Larsen

Lefkimmiatis

Paterson

2016

Sci Rep

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Many therapeutic interventions in disease states of heightened cardiac sympathetic activity are targeted to the myocytes. However, emerging clinical data highlights a dominant role in disease progression by the neurons themselves. Here we describe a novel experimental model of the peripheral neuro-cardiac axis to study the neuron’s ability to drive a myocyte cAMP phenotype. We employed a co-culture of neonatal ventricular myocytes and sympathetic stellate neurons from normal (WKY) and pro-hypertensive (SHR) rats that are sympathetically hyper-responsive and measured nicotine evoked cAMP responses in the myocytes using a fourth generation FRET cAMP sensor. We demonstrated the dominant role of neurons in driving the myocyte ß-adrenergic phenotype, where SHR cultures elicited heightened myocyte cAMP responses during neural activation. Moreover, cross-culturing healthy neurons onto diseased myocytes rescued the diseased cAMP response of the myocyte. Conversely, healthy myocytes developed a diseased cAMP response if diseased neurons were introduced. Our results provide evidence for a dominant role played by the neuron in driving the adrenergic phenotype seen in cardiovascular disease. We also highlight the potential of using healthy neurons to turn down the gain of neurotransmission, akin to a smart pre-synaptic ß-blocker.

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“…However, in the setting of structural heart disease, the electrophysiological effects of sympathetic activation predispose to sudden death. 27 The calcium loading effects on the sarcoplasmic reticulum can create delayed after depolarizations that can initiate ventricular arrhythmias. 28 Action potential duration (APD) is shortened in areas of dense sympathetic innervation, and due to the heterogeneity of sympathetic innervation, APD dispersion increases.…”

Section: Autonomic Nervous System and Cardiac Pathophysiologymentioning

confidence: 99%

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death

Huang¹,

Boyle²,

Vaseghi³

2017

Cardiac Electrophysiology Clinics

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Summary Neural remodeling in the autonomic nervous system contributes significantly to sudden cardiac death. The fabric of cardiac excitability and propagation are controlled by autonomic innervation. Heart disease predisposes to malignant ventricular arrhythmias by causing neural remodeling at the level of the myocardium, the intrinsic cardiac ganglia, extra-cardiac intrathoracic sympathetic ganglia, extra-thoracic ganglia, spinal cord, and the brainstem, as well as the higher centers and the cortex. Therapeutic strategies at each of these levels aim to restore the balance between the sympathetic and parasympathetic branches. Understanding this complex neural network will provide further important therapeutic insights into the treatment of sudden cardiac death.

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

Cited by 88 publications

References 250 publications

Cardiac sympatho-vagal balance and ventricular arrhythmia

Cardiac sympatho-vagal balance and ventricular arrhythmia

Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death

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