Fig 1.
Central model of cardiac control.
The classical view of the neuronal populations making up the cardiac neuronal hierarchy. In this view the cardiac neuroaxis is made up of two main neuronal groupings based on their anatomic locations: i) higher center neurons, including those in the medulla and spinal cord (C1-T4 primarily) up to the level of the insular cortex. ii) peripheral ganglia—a) neural somata in intrathoracic extracardiac ganglia (adrenergic postganglionic motor neurons) and b) those on the heart (cholinergic postganglionic motor neurons). In this model, these peripheral neuronal populations are under the control of central neuronal command.
Fig 2.
Hierarchical networked model for cardiac control.
Network interactions occur within the local circuit neural (LCN) populations. These integrate activities within and between peripheral ganglia and the central nervous system subserve reflex control of the heart. The intrinsic cardiac nervous system possesses sympathetic (Sympath) and parasympathetic (Parasym) efferent post-ganglionic neurons, local circuit neurons (LCN) and afferent (Aff.) neurons. The intrathoracic extracardiac nervous system is comprised of ganglia containing afferent neurons, LCN and sympathetic efferent post-ganglionic neurons. Cardiovascular heart rate and demand inputs are conveyed centrally via dorsal root (DRG), nodose and petrosal ganglia subserving spinal cord (C-cervical, T-thoracic), brainstem and higher center reflexes for hemostatic maintenance.
Fig 3.
Schematic of mathematical model.
Closed-loop control of cardiac output is shown as a networked 3-level hierarchy.
Fig 4.
In Fig 4 through Fig 14 inclusive the simulation results are depicted as solid lines for four variables: (i) efferent sympathetic activity (red), (ii) heart rate (green), (iii) central drive (black), and (iv) parasympathetic efferent (blue). The simulation timeline definitions described here are further explained in Simulation Design. Each of the red vertical lines Ej, j = 1, 2, 3 indicates the beginning of the jth episode. Three sub-events within each episode are the red, blue, and black vertical lines that respectively correspond to the onset of infarction (or unstable angina), recovery, and demand. The last vertical dashed line indicates the beginning of the aftermath of the recurrent pathology. In this figure, a stratified network with low neural diversity is shown. Local circuit neurons are affected and remain alive. Neurons that transduce heart rate and blood flow demand are affected and remain alive. There is no autonomic derangement.
Fig 5.
A stratified network with high neural diversity is shown.
Local circuit neurons are affected and remain alive. Neurons that transduce heart rate and blood flow demand are affected and living. There is no autonomic derangement.
Fig 6.
A top-down network with low neural diversity.
Local circuit neurons are affected and survive. Neurons that transduce heart rate and blood flow demand are affected and also survive. There is no autonomic derangement.
Fig 7.
A top-down network with high neural diversity.
Local circuit neurons are affected and remain alive. Neurons that transduce heart rate and blood flow demand are affected and survive. There is no autonomic derangement.
Fig 8.
A stratified network with high neural diversity.
Local circuit neurons are affected and remain alive. Neurons that transduce heart rate and blood flow demand are affected and also remain alive. There is autonomic derangement.
Fig 9.
A stratified network with high neural diversity.
Local circuit neurons are unaffected. Neurons that transduce heart rate and blood flow demand are affected and survive. There is autonomic derangement.
Fig 10.
A stratified network with low neural diversity.
During infarction, both local circuit neurons and neurons that transduce heart rate and blood flow demand die. There is no autonomic derangement.
Fig 11.
A stratified network with high neural diversity.
During infarction, both local circuit neurons and neurons that transduce heart rate and blood flow demand die. There is no autonomic derangement.
Fig 12.
A stratified network with high neural diversity.
Local circuit neurons are unaffected. During infarction, neurons that transduce heart rate and blood flow demand die. There is no autonomic derangement.
Fig 13.
A stratified network with high neural diversity.
During infarction, affected local circuit neurons and neurons that transduce heart rate and blood flow demand die. There is autonomic derangement.
Fig 14.
A stratified network with high neural diversity.
During infarction, local circuit neurons survive while neurons that transduce heart rate and blood flow demand die. There is autonomic derangement.
Fig 15.
Changes that occur in this control system in response to ischemic/infarct stress predicate the degree of hyperactivity that cardiac sympathetic efferent neurons undergo.
The transition of the benchmark balance from before (black bars) to the onset of recurrent MI or unstable angina and in the aftermath period of a new normal (white bars) is depicted for stratified networks with high neural diversity. The top half of the figure illustrates this transition for the sympathetic tone and the bottom half for the central drive tone. The first three pairs of bars in the top and bottom halves, starting from the left, represent the benchmark balance without autonomic derangement (’ANS derangement’ labelled ‘N’) while the remaining four pairs of bars refer to the system with autonomic derangement (’Y’). Details of how LCN neurons (’LCN Neurons’) and neurons that transduce heart rate and demand neurons are affected (’Sensory Neurons’) appears in the second and third rows. As a result of the pathology, these neurons are considered to die (’D’), become stressed (’S’), or are unaffected (’N’). In the presence of autonomic derangement (last four pairs of bars) the final state of the system becomes sensitive the extent to which local circuit neurons (’LCN neuron’) versus those transducing heart rate and blood flow demand are influenced by pathology. The vertical scales on the left represent relative neuronal activity states.