Heart and Metabolism

The physiology of pain perception in angina pectoris

Robert D. Foreman
Department of Physiology, College of Medicine, University of Oklahoma Health Sciences
Center, Oklahoma City, Okla, USA

Correspondence: Dr Robert D. Foreman, Department of Physiology, College of Medicine,
University of Oklahoma Health Sciences Center, 940 S.L. Young Boulevard, Oklahoma City, OK 73190, USA. Tel: +1 405 271 2226, fax: +1 405 271 3181, e-mail: robert-foreman@ouhsc.edu

Abstract
Retrosternal chest pain with crushing, burning, or squeezing characteristics that may radiate to the left arm, the right arm, and sometimes the neck and jaw, are cardinal signs of angina pectoris. This chapter will review the neurophysiological mechanisms that may underlie these symptoms. The mechanisms providing an explanation for angina pectoris include convergence of nociceptive information from the heart, with afferent input from the overlying somatic structures, cardiac afferent input generally exciting spinothalamic tract cells that receive inputs from proximal somatic fields, and the somatic input originating predominately from muscle. Neck and jaw pain that is occasionally experienced in patients may occur because potent vagal cardiac afferent input converges on upper cervical spinothalamic tract cells that also receive somatic afferent input from the cervical and trigeminal regions. Variations in angina pectoris from patient to patient may result from modulation and processing of cardiac afferent information occurring in the hierarchy of control mechanisms that permit independent intrinsic and extrinsic cardiac and central spinal integration. n Heart Metabol. 2002;16:30–35.

Key words: Ischemic heart disease, muscle pain, spinothalamic tract, viscerosomatic
convergence, vagus

Patients generally experience angina pectoris as a retrosternal chest pain with crushing, burning, or squeezing characteristics. This pain may radiate to the throat, neck, or ulnar aspect of the left arm, the right arm, sometimes reaching to the little finger. Less often, it radiates to the neck and jaw, or either the right or both arms. Intensity and pain location often vary among persons and episodes.
Angina pectoris may also be expressed subjectively as a sensation of anguish and fear of impending death.
The purpose of this chapter is to review the neurophysiological basis for angina pectoris associated with ischemic heart disease. The symptoms experienced by the patients
depend on how the central nervous system processes information received from the heart and somatic structures, the state of the peripheral and central nervous system at the time these events occur, and the psychological state of the person experiencing the sensations. At present our understanding of the supraspinal mechanisms involved with angina pectoris is limited; the scope of this chapter will therefore be limited to spinal cord processing. Detailed reviews related to neurophysiological mechanisms of angina pectoris are available [1–5].

Spinal cord processing of afferent information from the heart
The heart and coronary arteries are innervated by sympathetic afferent fibers that have their cell bodies concentrated in the dorsal root ganglia of the T2 to T6 spinal segments but can extend as far as the C8 to T9 segments [6–8]. Dorsal root ganglion cells have axons that enter the tract of Lissauer and terminate in the same segment, or the axons can ascend and descend a few segments before terminating in the spinal gray matter [7]. An important observation is that the number of sympathetic afferent fibers entering the spinal cord is much less and the afferent fibers are more diffusely distributed than is true for the somatic afferent fibers. This diffuse and extensive organization of the sympathetic afferent fibers most likely contributes to the poorly localized nature of angina pectoris.

Ascending pathways transmitting noxious cardiac information
Noxious cardiac information can be transmitted via cells of origin of ascending pathways, propriospinal neurons, and interneurons in the gray matter of the spinal cord. Of the cells in the upper thoracic gray matter, the spinothalamic tract (STT) cells are the most studied system of the ascending pathways for transmitting visceral afferent information from the heart to the brain [9–11]. The STT axons generally cross to the contralateral side within one or two segments and then ascend in the anterolateral quadrant (Figure 1, a) [9, 12]. These cells usually receive converging information from the heart and from somatic structures and have axons that ascend to the lateral and medial thalamus (Figure 1, b) [10, 11, 13, 14]. The lateral thalamus (Figure 1, c) that receives cardiac information via the STT incorporates the ventroposterolateral, ventroposteromedial, and ventroposteroinferior nuclei. Axons from cells of the lateral thalamus relay information to the primary somatosensory cortex and possibly to the secondary somatic cortex. Some evidence exists to suggest that visceral information projects to the somatosensory cortex [15, 16]. Information processed in this cortical area contributes to sensory discrimination [17, 18].
Cardiac and somatic information also projects via the STT to the medial thalamus (Figure 1, d), consisting primarily of the centralis lateralis and centrum medianum-parafascicularis nuclei [19–21]. The information generated in these nuclei is relayed to the association cortex, including the insular cortex, amygdala, and cingulate gyrus [22–24]. These nuclei may contribute to the emotional components of pain including autonomic adaptations [17, 25–27].
Common pain referral of angina pectoris: chest and arm
Angina pectoris generally has three main clinical characteristics: (1) nociceptive information from the heart is generally felt as pain referred to the overlying somatic structures [28]; (2) this pain is referred to proximal and axial body structures but generally not to distal limbs [29]; (3) the pain is generally deep and aching, and not a superficial or cutaneous pain [30].
This section will address animal studies that provide possible neurophysiological mechanisms to explain angina pectoris.
Convergence
Stimulation of cardiopulmonary afferent fibers strongly excites a majority of the STT cells in the T1 to T5 segments (Figure 1, e) [31] and more than half of the neurons in the C5 to C6 segments (Figure 1, f) [11, 14]. These same cells receive convergent somatic input from the overlying chest and arms. In contrast to thoracic and midcervical STT cells, cells in the cervical enlargement (C7 to C8) receive very little, if any, input from the activity transmitted in cardiopulmonary afferent fibers (Figure 1, g); their somatic innervation originates primarily from the distal forelimb and hand. This minimal activation of cells by stimulation of the cardiac afferents most likely means that pain would not be referred to the distal forelimb and head, which fits, in general, with clinical observations [32–34]. Since cardiopulmonary fibers enter the spinal cord primarily in the upper thoracic segments and they do not excite C7 to C8 STT cells, the afferent input must be dependent on a propriospinal pathway that makes direct or indirect synaptic connection with upper cervical STT cells [35].
In summary, convergence of cardiac and somatic input onto a common pool of STT cells provides a substrate to explain referral of pain to somatic structures.
Proximal and axial referral
Neurophysiological observations support human studies showing that angina pectoris is most commonly felt in the proximal and axial regions of the left arm and chest, and less frequently sensed further down the arm [33, 36, 37]. In animal studies, stimulation of cardiopulmonary afferent fibers strongly excites approximately 80% of the STT cells with proximal somatic receptor fields (Figure 1, h,h’), but only weakly excites 35% of the cells with distal somatic input (Figure 1, i) [31]. Thus, a highly significant relationship exists between cells with excitatory visceral input and proximal axial fields.
Muscle-like pain
Angina pectoris often mimics muscle pain in that both of these types of pain are described as deep, diffuse, dull, and suffering. In contrast, cutaneous pain is usually sharp and localized. Similarities between muscle pain and cardiac pain are shown in patients suffering from angina pectoris [30]. Patients compared pain provoked by a hypertonic saline solution injected into the paraspinal muscles of the left eighth cervical or first thoracic spinal segment with pain that was evoked during angina pectoris. These patients observed that the onset, continuation, segmental localization, and character very closely mimicked angina pectoris [30].
Research on animal models also supports the interaction between muscle and cardiac inputs. The STT cells excited by visceral stimulus are more likely to be excited with input from muscle than from skin [31, 38]. Muscle stimulation most powerfully excited STT cells that receive input primarily from the proximal arm and chest region (Figure 1, h,h’). By contrast, cutaneous stimulation alone elicited only a small response in cells with input from proximal fields. Cells with proximal somatic fields are strongly excited during cardiopulmonary afferent stimulation. However, noxious pinching of the skin alone on the hand and fingers generates the greatest responses in STT cells of C7 to C8 segments, and these responses do not increase when skin and muscle are pinched together (Figure 1, i). The STT cells with distal cutaneous fields were minimally excited by cardiopulmonary afferent fiber stimulation. These results provide evidence that visceral input from cardiopulmonary afferents converged most commonly with muscle afferent input onto the same STT cells, whereas the visceral stimulus has little effect on STT cells with primarily cutaneous input. Since visceral afferents converge on STT cells with afferent input from deep tissue, visceral pain, such as that resulting from myocardial ischemia, mimics muscle pain.
Uncommon pain of angina pectoris: neck and jaw pain
Pain referred to the neck and jaw region is less frequently associated with angina pectoris [33]. Interestingly, this pain sometimes remained or even appeared after surgical sympathectomy was carried out to reduce the incidence of refractory angina pectoris [4, 39]. This pain was attributed to transmission of nociceptive information in vagal afferent fibers, which commonly were thought to transmit innocuous cardiac sensory information. Neurophysiological studies support this supposition by showing that stimulation of vagal and sympathetic afferent fibers from the heart and chemical stimulation of the heart excite STT neurons in the C1 to C3 segments (Figure 1, j) [40, 41]. However, vagal afferent stimulation provided a much more potent activation of the STT cells than activation of cardiopulmonary afferent fibers. Somatic receptive fields for these C1 to C3 STT neurons receiving cardiac input are most commonly located on the neck, jaw, ear, and upper arm (Figure 1, k).

Figure 1. Schematic diagram outlining the neural organization that could explain the characteristics of referred pain associated with angina pectoris. The spinothalamic tract (STT) (a) cells in the T1 to T5 (e), C5 to C6 (f), C7 to C8 (g), and C1 to C2 (j) spinal segments are represented as a solid black line. The STT ends in the lateral (L, c) and medial (M, d) nuclei of the thalamus (b). Broken lines from figurines represent somatic afferent nerves. The dashed lines are the cardiac afferent fibers that enter the T1 to T5 spinal segments and the ascending pathway that bypasses the C7 to C8 segments and enters the upper cervical segments. The long dash-dot line represents the vagal afferent fibers that synapse in the nucleus tractus solitarius (NTS) of the medulla, which then sends information to the STT cells of the C1 to C2 segments. The black filled areas on the figurines represent primarily muscle input from the chest and upper arm (h,h’) and neck and jaw (k). The stippled area (i) is the cutaneous input from the hand and distal arm. CL, nucleus, centralis lateralis; CMPf, centrum medianum parafascicular nucleus; VPI, ventral posteroinferior nucleus; VPLc, ventral posterolateral nucleus, caudal part; VPM, ventral posteromedial nucleus; VPMpc, ventral posteromedial nucleus,
parvocellular part (Adapted from [43]).

Summary
Afferent input from the heart excites STT cells in the thoracic and upper cervical segments of the spinal cord (Figure 1). These cells receive convergent input from the overlying somatic structures. Thus, this information forms the basis for understanding the pain resulting from ischemic heart disease. However, the huge variations in the expression of pain of overlying somatic structures and in episodes of silent ischemia raise important issues about how information is processed, modulated, and perceived. These variations could occur in the intrinsic and extrinsic cardiac ganglia, the dorsal root ganglia, spinal gray matter, and descending pathways from supraspinal nuclei. Future studies will explore the hierarchy of control mechanisms that permit independent intrinsic cardiac as well as intrathoracic, extracardiac, and central spinal integration of afferent and efferent autonomic influences involved in regional control of normal and stressed hearts [42].

Acknowledgments
The author gratefully acknowledges Julie L. Marley for helping with the manuscript and preparing the illustration. The work of the author was supported by grants HL227321, HL52986, and NS35471 from the National Institutes of Health.

REFERENCES
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