Review

.2016 Jul 15;594(14):3911-54.

doi: 10.1113/JP271870. Epub 2016 Jun 14.

Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics

Kalyanam Shivkumar¹, Olujimi A Ajijola¹, Inder Anand², J Andrew Armour¹, Peng-Sheng Chen³, Murray Esler⁴, Gaetano M De Ferrari⁵, Michael C Fishbein⁶, Jeffrey J Goldberger⁷, Ronald M Harper⁸, Michael J Joyner⁹, Sahib S Khalsa¹⁰, Rajesh Kumar¹¹, Richard Lane¹², Aman Mahajan¹³, Sunny Po^{14 15}, Peter J Schwartz¹⁶, Virend K Somers⁹, Miguel Valderrabano¹⁷, Marmar Vaseghi¹, Douglas P Zipes¹⁸

Affiliations

¹ UCLA Cardiac Arrhythmia Center and Neurocardiology Research Center of Excellence, Los Angeles, CA, USA.
² Department of Cardiology, University of Minnesota Medical School, Minneapolis, MN, USA.
³ Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
⁵ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁶ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁷ Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA.
⁸ Department of Neurobiology and the Brain Research Institute, University of California, Los Angeles, CA, USA.
⁹ Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
¹⁰ Laureate Institute for Brain Research, Tulsa, OK, USA.
¹¹ Departments of Anesthesiology and Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹² Department of Psychiatry, University of Arizona College of Medicine, Tucson, AZ, USA.
¹³ Department of Anesthesia, UCLA, Los Angeles, CA, USA.
¹⁴ Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹⁵ University of Tulsa Oxley College of Health Sciences, Tulsa, OK, USA.
¹⁶ Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Instituto Auxologico Italiano, c/o Centro Diagnostico e di Ricerrca San Carlo, Milan, Italy.
¹⁷ Methodist DeBakey Heart and Vascular Center and Methodist Hospital Research Institute, Houston Methodist Hospital, Houston, TX, USA.
¹⁸ Indiana University School of Medicine, Indianapolis, IN, USA.

PMID:27114333
PMCID: PMC4945719
DOI: 10.1113/JP271870

Review

Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics

Kalyanam Shivkumar et al. J Physiol.2016.

.2016 Jul 15;594(14):3911-54.

doi: 10.1113/JP271870. Epub 2016 Jun 14.

Authors

Affiliations

¹ UCLA Cardiac Arrhythmia Center and Neurocardiology Research Center of Excellence, Los Angeles, CA, USA.
² Department of Cardiology, University of Minnesota Medical School, Minneapolis, MN, USA.
³ Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
⁵ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
⁶ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁷ Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA.
⁸ Department of Neurobiology and the Brain Research Institute, University of California, Los Angeles, CA, USA.
⁹ Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.
¹⁰ Laureate Institute for Brain Research, Tulsa, OK, USA.
¹¹ Departments of Anesthesiology and Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹² Department of Psychiatry, University of Arizona College of Medicine, Tucson, AZ, USA.
¹³ Department of Anesthesia, UCLA, Los Angeles, CA, USA.
¹⁴ Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹⁵ University of Tulsa Oxley College of Health Sciences, Tulsa, OK, USA.
¹⁶ Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Instituto Auxologico Italiano, c/o Centro Diagnostico e di Ricerrca San Carlo, Milan, Italy.
¹⁷ Methodist DeBakey Heart and Vascular Center and Methodist Hospital Research Institute, Houston Methodist Hospital, Houston, TX, USA.
¹⁸ Indiana University School of Medicine, Indianapolis, IN, USA.

PMID:27114333
PMCID: PMC4945719
DOI: 10.1113/JP271870

Abstract

The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of neuroscience-based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.

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Figures

**Figure 1.Cardiac neurotransmission**
DRG, dorsal root ganglion; ICN, intrinsic nervous system of the heart. Figure modified from W. Jänig (Janig, 2006) with permission.

**Figure 2.Simplified construct of neurohumoral control and functional organization of cardiac innervation**
Aff, afferent; β, β‐adrenergic receptor; C, cervical; DRG, dorsal root ganglion; G_i, inhibitory G‐protein; G_s, stimulatory G‐protein; L, lumbar; LCN, local circuit neuron; M, muscarinic receptor; T, thoracic. Additional pathways, for example nitrergic neurotransmission, are not shown.

**Figure 3.Autonomic influences on cardio‐respiratory interactions**
Recordings of intra‐arterial blood pressure (BP) central venous pressure (CVP), electrocardiogram (ECG), sympathetic nerve activity (SNA) and breathing (RESP) in a healthy young subject during voluntary end expiratory apnoea while awake. Chemoreflex activation during apnoea results in progressively increasing sympathetic outflow to muscle blood vessels, simultaneous with vagally mediated sinus bradycardia with AV block (note the P‐wave with absent QRS). The simultaneous activation of vascular sympathetic outflow and cardiac vagal drive during apnoea represents components of the diving reflex. Reproduced with permission from Somerset al. (1992).

**Figure 4.Models of Cardiac Interoception**
A, model of cardiovascular neural representation. Cardiovascular information is relayed in ascending fashion via visceral and somatosensory afferent pathways, which project through brainstem and thalamic relay stations, ultimately reaching the insula and somatosensory cortical regions. At each level this sensory information is hierarchically processed, which results in increasingly conceptual representations that are polymodal (i.e. heterogeneous) and can be integrated with emotional states and conscious visceral perceptions. The primary sites where conscious integration typically begins is at the level of cortical regions, including the insula, somatosensory areas, hippocampus and amygdala. These representations are modulated predominantly by the medial, orbital and cingulate regions of the prefrontal cortex, which issues visceromotor commands that propagate back through the system resulting in alterations in cardiovascular tone as well as changes in cardiac prediction signals.B, cardiac interoceptive prediction coding. The brain's active ongoing comparison between incoming and predicted signals results in calculation of an interoceptive prediction error. Disruptions in cardiovascular homeostasis result in large interoceptive prediction error signals, and this can produce illness states if the system is unable to adequately adapt. Boxes with grey outlines indicate neuroanatomical structures, and black arrows indicate anatomical connections. Boxes with blue outlines indicate conceptual processes, and blue arrows indicate information transfer between anatomo‐functional systems and conceptual systems. BNST, bed nucleus of the stria terminalis; BP, blood pressure; dACC, dorsal anterior cingulate cortex; DVN, dorsal motor nucleus of the vagus; HR, heart rate; HRV, heart rate variability; ICNS, intrinsic cardiac nervous system; IML, intermediolateral column; LHA, lateral hypothalamic area; NA, nucleus ambiguous; pACC, pregenual anterior cingulate cortex; PVN, paraventricular nucleus; RAAS, renin–angiotensin–aldosterone system; VM, ventromedial nucleus; VPL, ventroposterior nucleus; pACC, pregenual anterior cingulate cortex; pCC, posterior cingulate cortex; VMPFC, ventromedial prefrontal cortex.

**Figure 5.Intramyocardial neural remodelling following cardiac injury**
A, nerve sprouting in explanted, transplanted heart, with regions of replacement fibrosis due to transplant vasculopathy (S100 immunohistochemical staining, ×400).B, autopsy specimen from a patient dying from coronary artery disease. Note nerve sprouting at junction of healed myocardial infarction (MI) and normal myocardium (NM) (S100 immunohistochemical stain, ×200).C, left atrial appendage from patient with coronary artery disease undergoing coronary artery bypass surgery. Note marked nerve sprouting in atrial tissue (S100 immunohistochemical staining, ×400).D, pulmonary vein from experimental animal with AF. Note pale cell (arrow) that has morphological features of cells of the conduction system (toluidine blue stain, ×400) (the scale bar forA–D is shown inD).E, fluoroscopic location of multi‐electrode catheter (left top and bottom) and electroanatomical map (centre) in a patient with ischaemic cardiomyopathy. On the electroanatomical map, the purple areas represent unscarred tissue with normal voltage while the dense grey represents dense scar. All other colours represent border zones (tissue with bipolar voltage > 0.5 mV but < 1.5 mV). Graph on the right shows change in activation recovery interval (ΔARI) from baseline in normal (NL) and cardiomyopathic (CM) hearts in response to isoproterenol and nitroprusside. The ΔARI is greatest in the CM–NL and scar regions of the cardiomyopathic heart. Border zones within each patient are the least responsive to isoproterenol. In response to nitroprusside, the scar and the CM–NL zones are least responsive, or paradoxically increase ARI compared with the border zone regions.

**Figure 6.Remodelling in higher brain centres induced by chronic heart failure**
A, mean diffusivity, a measure of tissue injury, in a midline and near‐midline sagittal view of the brain in 16 HF patients; injury appears in basal forebrain (a,b), hypothalamic (c), cerebellar (d,e), posterior and mid cingulate (f,g), and dorsal medullary regions.B, axonal injury, indicated by axial diffusivity measures, showing image in axons from the hypothalamus (c), through the medial forebrain bundle (d), to the pons, and from the midline raphe to the cerebellum (a). Injury also appears in the corpus callosum (b).C, averaged functional MRI signals during the course of three Valsalva manoeuvres from 16 HF patients (red)vs. 33 healthy controls (blue); * indicates significance atP < 0.05. HF signals are unable to decline to the challenge, and are phase delayed.D, heart rate responses in 16 HF subjects (red)vs. 33 healthy age‐ and sex‐comparable controls (blue) to three successive Valsalva challenges. The HF subjects show muted and phase‐shifted heart rate changes to the challenges.

**Figure 7.Cardiac sympathetic denervation**
Relationship of stellate and middle cervical ganglia are shown. Both ganglia contain interneurons as well as efferent and afferent neurons that both synapse and traverse through the ganglia. Only the stellate ganglia are anatomically connected to the spinal cord.B, the left sympathetic chain including the left stellate ganglion as well as the T2–T4 ganglia are shown intra‐operatively behind the parietal pleura via video‐assisted thoracoscopic surgery.C, implantable cardioverter defibrillator (ICD) shock free survival is better after bilateral than left cardiac sympathetic denervation (CSD) in patients with refractory ventricular tachycardia (VT) and structural heart disease.D, after CSD, in patient with structural heart disease, the burden of ICD shocks significantly improves at approximately 1 year of follow‐up. Aff, afferent; DH, dorsal horn; Eff, efferent; IML, interomediolateral cell column; MCG, middle cervical ganglia.

**Figure 8.Autonomic dysfunction in obstructive sleep apnoea**
A, recordings of the electrocardiogram (ECG), SNA, RESP and BP in a sleep apnoeic patient undergoing continuous positive airway pressure (CPAP) therapy during REM sleep. The arrow indicates a reduction of CPAP from 8 to 6 mmHg, allowing the development of obstructive apnoea, with consequent increased SNA and BP. Reproduced with permission from Somerset al. (1995).B, recordings of sympathetic nerve activity (SNA) during wakefulness in patients with obstructive sleep apnoea (OSA) and matched controls showing high levels of SNA in patients with sleep apnoea. Reproduced with permission from Somerset al. (1995).

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Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics

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Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics

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