Clinical neurocardiology defining the value of neuroscience‐based cardiovascular therapeutics

Shivkumar, Kalyanam; Ajijola, Olujimi A.; Anand, Inder S.; Armour, J. Andrew; Chen, Peng Sheng; Esler, Murray; Ferrari, Gaetano M. De; Fishbein, Michael C.; Goldberger, Jeffrey J.; Harper, Ronald M.; Joyner, Michael J.; Khalsa, Sahib S.; Kumar, Rajesh; Lane, Richard D.; Mahajan, Aman; Po, Sunny S.; Schwartz, Peter J.; Somers, Virend K.; Valderrábano, Miguel; Vaseghi, Marmar; Zipes, Douglas P.

doi:10.1113/jp271870

Cited by 262 publications

(229 citation statements)

References 450 publications

(724 reference statements)

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“…The influence of excess sympathetic activation on cardiovascular dysfunction, arrhythmias, and sudden death is well established (1,2). Modulation of adrenergic signaling via pharmacologic and interventional approaches (3)(4)(5)) is emerging as a major therapeutic strategy in managing ischemic (ICM) and nonischemic cardiomyopathy (NICM), and arrhythmias.…”

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confidence: 99%

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

et al. 2017

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confidence: 99%

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

et al. 2017

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“…This is confirmed ex vivo by experiments showing that CNP decreases neuronal calcium transients and impairs the release of norepinephrine, and in vivo by studies showing that the centrally acting sympatholytic agent clonidine attenuates the hypertension and tachycardia seen in NPR-B transgenic mice. These experiments provide a clear physiological role for CNP in mitigating sympathetic neurotransmission, with direct implications for pathophysiological states such as HF (Figure 1).The rise in CNP levels in HF could act as a 'check' to balance sympathoexcitation and intra-and extra-cardiac neural remodelling driven by a number of mechanisms including spinal and renal afferent activation 5,6 . For instance, CNP exerts protective effects against angiotensin-mediated adverse cardiac remodelling in mice.…”

mentioning

confidence: 99%

“…The rise in CNP levels in HF could act as a 'check' to balance sympathoexcitation and intra-and extra-cardiac neural remodelling driven by a number of mechanisms including spinal and renal afferent activation 5,6 . For instance, CNP exerts protective effects against angiotensin-mediated adverse cardiac remodelling in mice.…”

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confidence: 99%

Natriuretic peptides and peripheral autonomic neurotransmission: back to the A, B, and C’s.

Ajijola¹,

Shivkumar²,

Habecker

2016

Cardiovasc Res

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This editorial refers to 'C-type natriuretic peptide and natriuretic peptide receptor NPR-B signalling inhibits cardiac sympathetic neurotransmission and autonomic function' by J. Buttgereit et al., Natriuretic peptides (NPs) are a family of secretory peptides that have in common a ringed amino-acid structure linked by disulphide bonds 1 which signal via NP receptors (NPRs). Three primary members have been identified: atrial NP (ANP), brain-derived NP (BNP), and C-type NP (CNP), but there is a closely related forth peptide Dendroaspis NP (DNP). ANP and BNP are elevated by atrial stretch; ventricular stretch or stress elevates BNP levels; and all NPs are increased in heart failure (HF). The NPRs are particulate guanylyl-cyclase-coupled receptors which stimulate production of cGMP. Of the seven NPR isoforms known to exist, the majority of NP physiological actions are mediated via NPR-A and -B, while NPR-C mediates NP degradation. ANP, BNP, and DNP activate NP receptor A (NPR-A), which increases natriuresis and vasodilation. In contrast, CNP specifically activates NPR-B and does not possess the potent diuretic actions of the other NPs.Although extensive studies have been performed on BNP in the context of HF, where it has been utilized both as a diagnostic and as a potential therapeutic tool, 2 newer data implicate the peptide in modulating peripheral autonomic neurotransmission. BNP activation of NPR-A inhibits neurotransmission from sympathetic neurons by decreasing the magnitude of intracellular calcium transients, and impairing neurotransmitter release. 3 Phosphodiesterase-2A (PDE2A) levels act as an intracellular switch in this process permitting or preventing the effect of BNP on neurotransmission. CNP, which is present in endothelial cells and ventricular myocardium, is also abundant in the nervous system. CNP levels increase in HF, similar to ANP and BNP, but its physiological relevance has not been well understood.In this issue of the journal Buttgereit et al. 4 extend our understanding of the physiological roles played by CNP, using a rat model overexpressing a neuron-specific dominant negative form of NPR-B. The authors show that inhibition of NPR-B signalling results in sympathoexcitation, analogous to the physiological effect of blocking NPR-A signalling. The heightened sympathetic transmission causes hypertension, tachycardia, and a decrease in heart rate variability. Rats with impaired NPR-B signalling also develop left ventricular dysfunction, likely mediated by excessive sympathoexcitation, analogous to what is clinically observed as Tako-Tsubo syndrome.The authors show in an ex vivo prep that CNP decreases the tachycardia response to nerve stimulation, but not to direct norepinephrine exposure. This suggests that CNP modulates heart rate indirectly via sympathetic innervation rather than a direct effect on the SA node. This is confirmed ex vivo by experiments showing that CNP decreases neuronal calcium transients and impairs the release of norepinephrine, and in vivo by studies showing that the ce...

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“…In the worst case scenario, imbalances in autonomic control coupled with regional variations in cardiac electrical/mechanical function set the stage for arrhythmias leading to sudden cardiac death or heart failure [3][4][5]. Through a mechanistic understanding of neurohumoral-cardiac processes, a rationale for therapies designed to maintain cardiovascular homeostasis [6] can be defined. Neuromodulation is at the forefront of novel therapies that are establishing new frontiers for effective treatments of cardiac disease.…”

mentioning

confidence: 99%

“…Concept 2: there are inherent & acquired factors that impact the progression of cardiac disease Remodeling of autonomic reflexes in response to cardiac pathology, while necessary to maintain homeostasis, can also accelerate the progression of disease [2,6]. A hyperdynamic sympathetic response is a key adverse effect which contributes to the increased risk of sudden cardiac death [4] and progression into heart failure [3,5].…”

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Foundational Concepts for Cardiac Neuromodulation

Ardell

Shivkumar

2017

Bioelectron. Med.

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" It is only through an improved mechanistic understanding of structure/function that rationale neuromodulation-based therapies of cardiac control will advance. The twofold objectives are: do no harm and develop a better understanding of the nuances governing structure/function of the cardiac control hierarchy; and, develop therapies that account for the biological complexity of the system. " Heart disease remains the primary cause of morbidity and mortality in the world with its impact cutting across all segments of the population [1]. The field of neurocardiology incorporates all aspects of cardiology with important elements of autonomic neuroscience to define cellular physiology/pathophysiology [2]. The fundamental premise of neurocardiology is that it is the dynamic interactions between autonomic control and the heart that ultimately determines how closed-loop control of cardiac function evolves in response to cardiovascular stressors including those leading to cardiac disease [2]. In the worst case scenario, imbalances in autonomic control coupled with regional variations in cardiac electrical/mechanical function set the stage for arrhythmias leading to sudden cardiac death or heart failure [3][4][5]. Through a mechanistic understanding of neurohumoral-cardiac processes, a rationale for therapies designed to maintain cardiovascular homeostasis [6] can be defined. Neuromodulation is at the forefront of novel therapies that are establishing new frontiers for effective treatments of cardiac disease. A conceptual framework for bioelectronic medicine, as related to cardiac disease, is presented via three key concepts of neurocardiology. Concept 1: neural control of cardiac function involves a multitier hierarchy of interdependent reflexesCardiac control depends on interactions between intrathoracic and central aspects of the cardiac nervous system. Peripheral neural networks for cardiac control include intrinsic cardiac and extracardiac-intrathoracic (e.g., stellate and middle cervical) ganglia. These ganglia contain all the necessary neural machinery for reflex control of the heart (afferent, efferent and local circuit interneurons for information processing) [2].Centrally located neural networks involved in cardiac control include elements of the spinal cord, brainstem and higher centers up to and including the insular cortex [7][8][9]. These top-down contributions to control involve projections from preganglionic soma located in the brainstem (parasympathetic) and spinal cord (sympathetic) toward the heart with both regions (nucleus Ambiguus and intermediolateral cell column) impacted by interconnections with brainstem (e.g., nucleus tractus solitaries) and higher centers (e.g., hypothalamus, limbic system). Bottom-and middle-level cardio-centric contributions to control include intrathoracic ganglia (intrinsic cardiac and stellate/middle cervical) receiving cardiac-related afferent projections and central neurons (spinal cord and brainstem) receiving cardiovascular-related afferent inputs via primary sensory...

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Clinical neurocardiology defining the value of neuroscience‐based cardiovascular therapeutics

Cited by 262 publications

References 450 publications

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

Natriuretic peptides and peripheral autonomic neurotransmission: back to the A, B, and C’s.

Foundational Concepts for Cardiac Neuromodulation

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