Viva G3(vi)a

This viva tests Section G3(vi) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the cardiac reflexes".

What is a "cardiac reflex?

"A reflex loop between the heart and central nervous system" which regulates heart rate and peripheral vascular resistance

What are the essential features of  a cardiac reflex?
  • Sensor and stimulus
  • Afferent nerves
  • Processor
  • Efferent nerves
  • Effector
How is stretch sensed in the cardiovascular system?
  • Mechanosensitive receptors which are usually afferent autonomic nerve terminals sitting in the tunica adventitia of large blood vessels 
  • Mechanically sensitive sodium channels (DEG/ENaC, degenerin/epithelial sodium channels).
  • With stretch, the sodium current increases to the point where the membrane potential reaches the threshold of local voltage-gated sodium channels.
What are the pathways of the baroreceptor reflex?
  • Stimulus:  Pressure (stretch)
  • Sensors: Stretch-sensitive mechanoreceptors in the carotid sinus and aortic arch
  • Afferent nerves:
    • Vagus carries afferent fibres from the aortic arch
    • Glossopharyngeal nerve carries fibres from the carotid sinus
  • Processor: Nucleus of the solitary tract and the caudal ventral medulla
  • Efferent nerves: 
    • Sympathetic fibres to the heart and peripheral resistance vessels
    • Vagal efferents to the cardiac ganglion (heart rate)
  • Effector:  Myocardium, SA and AV nodes, vascular smooth muscle
Where are the carotid sinus mechanoreceptors?
  • Small neurovascular structure located at the dilated portion of the common carotid artery (the "carotid bulb"), just at the point of its bifurcation.
  • The sinus itself is just a bundle of nerve endings which is located in an area of thickened adventitia around the carotid bulb
  •  entire surface of the dilatation is well-innervated, i.e. that whole 2-3cm segment of artery is the mechanoreceptor complex, rather than any specific discrete patch
Where are the aortic arch mechanoreceptors?
  • mainly confined to a "saddle-shaped" area between the brachiocephalic trunk and the origin of the left subclavian.  
  • This patch of sensors is not a circumferential area, i.e. it only wraps around about half of the aortic arch.
How are the afferent fibres conducted from these receptors?
  • The carotid sinus nerve, as the name suggests, innervates the carotid sinus barosensors. It courses anteromedially to the internal carotid artery and joins the body of the glossopharyngeal nerve at the base of the skull, where its cell bodies lie in the petrosal ganglion.
  • The aortic branch of the vagus, otherwise known as the "aortic depressor nerve", innervates the aortic bodies and baroreceptors. It is a branch of the vagus or superior laryngeal nerve, and its cell bodies reside in the petrosal ganglion.
  • The nodose and petrosal ganglia lie in the jugular foramen, and represent the last stop before the nerve fibres enter the brainstem. There, the afferent nerves synapse with neurons in the nucleus of the solitary tract. Both types of afferents mainly use glutamate as the neurotransmitter, i.e. the activation of baroreceptor afferents is an excitatory stimulus for this nucleus.
What are the central processing centres for the baroreceptor reflex?
  • The nucleus of the solitary tract (NTS)
    •  GABA neurons
    • Excitatory stimulus from the baroreceptor afferents translate into an inhibitory GABA output from the NTS
  • The rostral ventrolateral medulla (RLVM) 
    • Under resting conditions, this nucleus has a constant tonic output
    • Thus, the excitation of barosensors ultimately leads to an increase in GABA input, which has a depressant effect on the firing rate of RLVM neurons.
What are the efferent fibres involved in the baroreceptor reflex?
  • Sympathetic
    • The rostral ventrolateral medulla communicates with (cholinergic) preganglionic neurons in the spinal cord.
    • These, in turn, communicate with noradrenergic neurons in the sympathetic ganglia  
    • The output of the rostral ventrolateral medulla is distributed widely into the sympathetic nervous system, and has numerous effects, of which the most important is the α-1 mediated tonic control of peripheral vascular resistance. 
  • Parasympathetic
    • The nucleus of the solitary tract depresses heart rate by activating vagal efferents, which communicate with the cardiac ganglion.
    • Increased cholinergic transmission along this efferent pathway inhibits the automaticity of the sinoatrial node, and influences the rate of transmission through the AV node
    • The right vagus does the SA node and the left vagus does the AV node, with enough overlap that the loss of a vagus does not produce total parasympathetic denervation.
    • That means that the right vagus is more important, as the SA node dictates the heart rate, and the AV nodal conduction delay is a minor player.
    • Generally, vagal input into the nodes is described as being more important than sympathetic input.
So, what are the steps in blood pressure regulation by the baroreflex?
  • Decreased blood pressure (eg. upon standing upright from a prostrate position, or the sudden loss of blood volume) results in a decreased baroreceptor firing rate
  • Decreased baroreceptor firing rate decreases the secretion of GABA from the caudal ventrolateral medulla
  • This decreases the inhibition of tonic sympathetic output by the rostral ventrolateral medulla.
  • Thus, sympathetic nervous activity is increased, which results in α-1 mediated peripheral vasoconstriction, including skeletal muscle and the splanchnic circulation
  • At the same time, vagal efferent input into the SA node decreases, which increases the automaticity of the SA node, this increasing the heart rate.
  • Increased heart rate increases cardiac output; with increased peripheral vascular resistance, this translates into an increase in blood pressure.
How fast does the baroreflex activate?
  • Because of the presence of fast myelinated fibres in the afferent and efferent arms of the reflex, control of vascular tone and cardiac output can be very rapid. 
    • about 0.5-0.6 seconds for a change in sinoatrial node rate
    • about 1.0 second latency for a prolongation of the PR interval (reflective of increased AV nodal conduction delay),
    • 2-3 second latency for the vasodilator response.
  •  The rapid vagal effect is said to be related to the direct activity of acetylcholine on special inward-rectifying potassium channels; whereas other effects (eg. noradrenergic vasoconstriction) rely on the comparatively slower cAMP second messenger system.
What is the threshold for baroreceptor activation?
  • The activity of these receptors is constant and tonic
  • the minimum value for blood pressure change at which the baroreceptors will react with a change in their firing rate is higher in the normal range of pressures
  • the steepest part of the response seems to be around the normal systolic pressure range, i.e. 100-140 mmHg.
  • Carotid sinus baroreceptor reflex threshold  is about 50 mmHg
  • aortic arch baroreceptor reflex threshold is about 110 mm Hg
  • Thus: aortic reflex manages the blood pressure peaks, and the carotid sinus takes care of the troughs
  • it changes over the course of normal ageing (carotid sinus sense threshold is 45mm in your thirties, 80 mmHg in your sixties).
What other cardiac reflexes are there?
What is the Bainbridge reflex?
  • "Atrial stretch reflex"
    • Stimulus:  Pressure (stretch)
      • Not much volume is required: between 50-100ml
    • Sensors: Stretch-sensitive mechanoreceptors in the atria and pulmonary arteries (Type B receptors)
      •  
    • Afferent nerves: Vagus carries afferent fibres 
    • Processor: Nucleus of the solitary tract and the caudal ventral medulla
    • Efferent nerves: 
    • Sympathetic fibres to the heart
    • Vagal efferents to the cardiac ganglion (heart rate)
    • Effector:  SA node and (maybe) AV node
      • Peripheral vascular resistance is not altered by the Bainbridge reflex.
    • Effects:
      • Increased RA pressure produces an increased heart rate;
        unless the patient is hypovolaemic and tachycardic (in which case baroreceptor responses take precedence).
  • Atrial stretch increases the heart rate
  • As you increase the rate of flow into the ventricles, the rate of flow out of the ventricles should also increase.
How does this interact with the baroreceptor reflex?
  • Bainbridge reflex is "weaker" than the baroreceptor reflex, and is overruled when there is hypovolemia, as long as the sympathetic nervous system is intact
  • AWhen it is not intact,  the "reverse Bainbridge" reflex decreases the heart rate in response to decreased preload
  • This can be observed during spinal anaesthesia, where blood pressure cardiac output and venous return are markedly decreased
What is the chemoreceptor reflex?
  • Stimulus:  low PaO2 and/or high PaCO2
  • Sensors: carotid body glomus and aortic body glomus
  • Afferent nerves: 
    • Glossopharyngeal nerve carries afferent fibres from the carotid sinus
    • Vagus (aortic nerve) carries afferent fibres from the aortic glomus
  • Processor: Nucleus of the solitary tract and nucleus ambiguus
  • Efferent nerves: 
    • Sympathetic fibres to the heart and peripheral smooth muscle
    • Vagal efferents to the cardiac ganglion (heart rate)
  • Effector:  SA node, AV node, peripheral vascular smooth muscle
  • Effects: 
    • Primary effects:
      • Vagal effects: bradycardia
      • Sympathetic effects: hypertension
    • Secondary effects: 
      • Increased preload due to increased ventilation, and thus activation of the Bainbridge reflex, which increases heart rate
      • Activation of pulmonary stretch receptors, and thus activation of the Hering-Breuer reflex, which increases heart rate
What is the Cushing reflex?
  • Stimulus:  Intracranial pressure or cerebral ischaemia
    • the threshold of pressure to elicit a sympathetic efferent response was only about 8-20 mmHg
  • Sensors: god knows what; mechanosensors in the rostral medulla?
  • Afferent nerves: 
    • Fibres from the medullary mechanosensory areas, to sympathetic ganglia
    • Fibres from cerebral hemispheres, which exert descending inhibitory control on the medullary vasomotor sensor
  • Processor: Rostral ventrolateral medulla
  • Efferent nerves: 
    • Sympathetic fibres to the heart and peripheral smooth muscle
  • Effector:  SA node, AV node, peripheral vascular smooth muscle
  • Effects: 
    • Primary effects: hypertension and tachycardia
    • Secondary effects: baroreflex-mediated bradycardia
What is the Bezold-Jarisch reflex?
  • Stimulus:  multiple and heterogeneous stimuli, including:
    • Mechanical: pressure and stretch (thus, inotropy preload and afterload)
    • Chemical: veratrum alkaloids, ATP, capsaicin, snake venom, and various other venoms from the animal kingdom
  • Sensors: Heterogeneous sensors distributed in all cardiac chambers
  • Afferent nerves: 
    • Unmyelinated C-fibres of the vagus
  • Processor: Nucleus of the solitary tract, likely involving serotonergic transmission
  • Efferent nerves: 
    • Sympathetic fibres to the heart and peripheral smooth muscle
    • Vagus nerve, via the cardiac ganglion
  • Effector:  SA node, AV node, peripheral vascular smooth muscle
  • Effects: hypotension (vasodilation) and bradycardia
How does this integrate with other cardiac reflexes?
  • This reflex reacts to chamber stretch by slowing the heart rate.
  • This is the exact opposite of what the Bainbridge reflex does.
  • One reflex acts as the physiological restraint of the other.
  • The Bainbridge reflex is dominant, and the Bezold-Jarisch reflex acts as the moderator of the increased heart rate.
What is the oculocardiac reflex?
  • Stimulus:  pressure to the globe of the eye, or traction on the eye muscles
  • Sensors: mechanosensitive stretch receptors in the facial muscles, especially periorbital muscles, and in the globe of the eye
  • Afferent nerves: 
    • Long and short ciliary nerves, to the trigeminal nerve, via the Gasserian ganglion, to the sensory nucleus of the trigeminal nerve, and from there via short internuclear fibres to the NTS.
  • Processor: Nucleus of the solitary tract
  • Efferent nerves: 
    • Vagus nerve, via the cardiac ganglion
  • Effector:  SA node, AV node
  • Effects:
    • Vagal: bradycardia
    • Sympathetic: systemic vasoconstriction, cerebral vasodilation

These pressure and pain stimuli are cross-talk between sensory fibres, and the reflex appears to be intended to sense immersion in water, i.e. this is an "oxygen-conserving reflex"

What is the diving reflex?
  • Stimulus:  trigeminal nerve sensory distribution
    • Pressure to the globe of the eye, or traction on the eye muscles
    • Pain in the trigeminal nerve distribution
    • Temperature (cold) 
    • Chemical stimulus of the anterior ethmoidal nerve (noxious)
  • Sensors: Pain, temperature, chemical and mechanosensitive stretch receptors in the trigeminal nerve distribution
  • Afferent nerves: 
    • Branches of thee trigeminal nerve, via the Gasserian ganglion, to the sensory nucleus of the trigeminal nerve, and from there via short internuclear fibres to the NTS.
  • Processor: 
    • Nucleus of the solitary tract: vagal response
    • Rostral medulla: sympathetic response
    • Ventral medulla: apnoea
  • Efferent nerves: 
    • Vagus nerve, via the cardiac ganglion
    • Phrenic nerve
  • Effector:  SA node, AV node, respiratory muscles
  • Effects:
    • Vagal: bradycardia
    • Sympathetic: cerebral vasodilation, systemic vasoconstriction
    • Respiratory: apnoea
    • The net effect is to prevent aspiration and to maximise the blood flow to the central nervous system at the expense of the skin, muscle and splanchnic organs.
What is the Barcroft-Edholm reflex?

This is the reflex that generates bradycardia in response to blood loss or extreme stress, producing vasovagal syncope.

  • Description:
    • ​​V​​​​asovagal syncope, or neurocardiogenic syncope, is a transient loss of consciousness due to global cerebral hypoperfusion, which occurs as the result of an autonomic reflex response to various stimuli
  • Stimulus:  
    • For "true" vasovagal syncope:
      • Emotional distress
      • Orthostatic changes (decreased preload with changes in posture)
    • For "situational" neurocardigenic syncope:
  • Sensors: Central (descending) as well as peripheral
    • Mechanoreceptors located in the wall of the left ventricle, the aorta, atria and the pulmonary trunk
    • Numerous other strecth receptors, eg. splanchnic, bowel, 
  • Afferent nerves: Unknown! Presumably, both central nervous system and peripheral sensory nerves are involved
  • Processor: Unknown! Presumably at some stage the nucleus of the solitary tract and the nucleus ambiguus are involved.
  • Efferent nerves: 
    • Vagus nerve, via the cardiac ganglion
    • Sympathetic nervous system
  • Effector:  SA node, AV node, peripheral smooth muscle
  • Effects:
    • Vagal: bradycardia
    • Sympathetic: systemic vasodilation (mainly muscles)
    • Vasovagal syncope is thought to have four distint phases:
      • phase 1: early stabilization (by normal baroreceptor reflex)
      • phase 2: circulatory instability (baroreflex vasoconstriction)
      • phase 3: terminal hypotension (bradycardia, cerebral hypoperfusion, systemic vasodilation)
      • phase 4: recovery
What is the mechanism of respiratory sinus arrhythmia?
  • Normal variation in heart rate which occurs cyclically in response to normal respiration.
  • The primary reason for this heart rate fluctuation is an interaction between the medullary respiratory and cardiac centres.
  • The heart rate slows immediately as the breath starts, before any of the other reflexes have had time to react
  • This is a coordinated reflex, driven by the interaction of central control organs, and it does not rely on pressure data from the lungs

In summary:

  • Stimulus: presumably, the Pre-Bötzinger complex ("respiratory pacemaker")
  • Sensors: none (unless you count respiratory control chemoreceptors)
  • Afferent nerves: interneurons between Pre-Bötzinger complex and nucleus ambiguus
  • Processor: nucleus ambiguus? 
  • Efferent nerves: Vagus nerve, via the cardiac ganglion
  • Effector:  SA node, AV node
  • Effects: cyclical decrease of vagal output during inspiration

References

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Somers, Virend K., Allyn L. Mark, and Francois M. Abboud. "Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans." The Journal of clinical investigation 87.6 (1991): 1953-1957.

Wan, Wei Hwang, Beng Ti Ang, and Ernest Wang. "The Cushing Response: a case for a review of its role as a physiological reflex." Journal of Clinical Neuroscience 15.3 (2008): 223-228.

Warltier, David C., Jason A. Campagna, and Christopher Carter. "Clinical relevance of the Bezold–Jarisch reflex." Anesthesiology: The Journal of the American Society of Anesthesiologists 98.5 (2003): 1250-1260.

Dewar, Kirsteen MS, and H. Y. Wishart. "The oculocardiac reflex." (1976): 373-374.

Van, MD Brocklin, R. R. Hirons, and R. L. Yolton. "The oculocardiac reflex: a review." Journal of the American Optometric Association 53.5 (1982): 407-413.

Michael Panneton, W. "The mammalian diving response: an enigmatic reflex to preserve life?." Physiology 28.5 (2013): 284-297.

Jardine, David L., et al. "The pathophysiology of the vasovagal response." Heart Rhythm 15.6 (2018): 921-929.

Berntson, Gary G., John T. Cacioppo, and Karen S. Quigley. "Respiratory sinus arrhythmia: autonomic origins, physiological mechanisms, and psychophysiological implications." Psychophysiology 30.2 (1993): 183-196.