Heart and Metabolism

Cardiac ischemic pain

Filippo Crea1, Achille Gaspardone2
1Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Rome, Italy
2Cattedra di Cardiochirurgia, Università Tor Vergata, Rome, Italy

Correspondence: Professor Filippo Crea, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, Roma, Italy. Tel: +39 06 3051166, fax: +39 06 3055535, e-mail:f.crea@tiscalinet.it

Abstract
At the turn of this century, Colbeck proposed that ischemic cardiac pain may be related to distension of the ventricular wall (“mechanical hypothesis”). Three decades later, Lewis hypothesized that ischemic pain may be elicited by the intramyocardial release of pain-producing substances induced by ischemia (“chemical hypothesis”). Studies carried out in the last 10 years have lent strong support to the chemical hypothesis, as they have consistently shown that adenosine is a mediator of ischemic cardiac pain. Adenosine-induced ischemic cardiac pain is mainly
mediated by stimulation of A1 receptors located in cardiac nerve endings and is potentiated by substance P. Conversely, the magnitude and rate of left ventricular dilatation during ischemia do not predict the severity of angina. It is worth noting, however, that stretching of epicardial coronary arteries appears to potentiate the severity of angina caused by myocardial ischemia. The nervous activity generated by myocardial ischemia is modulated in intrinsic cardiac, mediastinal, and thoracic ganglia. It is then further modulated in the central nervous system and projects bilaterally to the cortex, as demonstrated in humans using PET, where it is decoded as a painful sensation. The causes responsible for the lack of angina during myocardial ischemia are probably different in patients presenting with either painless or painful myocardial ischemia, in patients with predominantly painless ischemia, and in diabetic patients. n Heart Metabol. 2002;16:5–8.

Keywords: Angina, adenosine, bradykinin, ischemic heart disease

Introduction
Although patients with ischemic heart disease usually consult their doctor because of angina symptoms, transient myocardial ischemia or even necrosis can occur without pain, and, conversely, severe angina-like pain may occur in the absence of detectable myocardial ischemia. Thus the occurrence of pain can serve the useful purpose of eliciting a protective reaction, but can also become a major component of the disease when it is disproportionate to the severity of the ischemic insult.

Causes of cardiac ischemic pain
In 1903, Colbeck proposed that cardiac ischemic pain may be related to distension of the ventricular wall (the “mechanical hypothesis”) [1]. Three decades later, Lewis hypothesized that ischemic pain may be elicited by the intramyocardial release of algogenic substances induced by ischemia (the “chemical hypothesis”) [2].
Mechanical hypothesis
Ventricular dilatation is unlikely to be responsible for anginal pain, as the rate and magnitude of left ventricular dilatation during ergonovine-induced or spontaneous transient ischemic episodes were found to be similar during both painful and painless episodes [3]. Mechanical factors, however, may play a role in activating nociceptors localized at the level of the coronary arteries. The distension of the coronary arterial wall can cause pain: at the end of two sequential balloon inflations during coronary angioplasty, pain severity, normalized for the severity of ischemia, is similar when the two inflations are carried out using the same pressure, yet is more severe during the second inflation when the latter is carried out at a higher pressure [4].
Furthermore, we have recently observed that in a substantial proportion of patients complaining of angina-like chest pain after stent implantation, the pain may be related to a transient increase in vascular tone at the site of the implanted stent which stretches the arterial wall causing nociceptor activation [5].
Chemical hypothesis
Although several substances have been investigated as potential mediators of anginal pain, at present only two molecules have been convincingly demonstrated to be involved in the genesis of cardiac ischemic pain in man: adenosine and bradykinin.
Adenosine
Adenosine is rapidly formed during myocardial ischemia and is released into the vascular bed. The intravenous administration of adenosine causes a dose-dependent angina-like pain in normal subjects [6]. Adenosine-induced pain is increased by dipyridamole, which reduces adenosine cellular uptake, and reduced by theophylline, which is an adenosine antagonist [6]. Infusion of a similar dose of adenosine into the right atrium fails to elicit pain, thus proving that pain elicited by the intracoronary infusion of adenosine originates from the heart [7].
Adenosine-induced cardiac pain is not secondary to myocardial ischemia, as it generally occurs in the absence of ischemic ECG-like changes and it can be induced by infusing adenosine in angiographically normal coronary branches and in vascular beds, such as brachial or femoral arteries, where ischemia caused by steal cannot occur [8–10]. In patients with exercise-induced angina, the severity of anginal pain is significantly reduced by pretreatment with theophylline, a potent nonselective adenosine receptor antagonist, in the presence of a similar severity of myocardial ischemia [11]. This finding indicates that the improvement of anginal pain produced by theophylline is likely to be due also to the direct inhibition of the algogenic effects of adenosine. Adenosine-induced pain is not prevented by b-blockade, atropine, naloxone, nitroglycerine, nifedipine, clonidine, cyclo-oxygenase inhibitors, or steroids [12, 13], and is potentiated by substance P [14].
In humans, the intravenous infusion of bamifylline, a selective A1 receptor antagonist [15], reduces adenosine-induced muscular and cardiac pain without affecting adenosine-induced coronary vasodilatation, which is an A2 receptor-mediated effect [16]. Furthermore, in patients with exercise-induced angina, bamifylline reduces the severity of anginal pain normalized for maximal ST-segment depression, thus suggesting that the improvement in anginal pain produced by bamifylline is likely due to the direct inhibition of the algogenic effect of endogenous adenosine of the A1 adenosine receptors [17]. These findings indicate that in humans the algogenic effects of adenosine are mainly mediated by A1 receptors.
Bradykinin
Among substances released by ischemic myocardium, bradykinin has been in vogue for more than 20 years as a potential mediator of cardiac ischemic pain. Recently, we have shown that the intracoronary infusion of bradykinin in patients with angina and coronary artery disease causes cardiac pain that is similar to their habitual angina [18]. Interestingly, bradykinin-induced pain is abolished or reduced by acetylsalicylate, thus suggesting that acetylsalicylate-sensitive mediators, such as prostaglandins, are involved in the pathogenesis of bradykinin-induced pain. As bradykinin is released in large amounts by the heart during ischemia, it can be a natural stimulus for causing, via arachidonic acid metabolites, excitation of the sensory receptors signaling pain during myocardial ischemia.

Significance of cardiac ischemic pain in different coronary syndromes
Cardiac ischemic pain does not provide information on the causes of myocardial ischemia. However, information on the causes of ischemic episodes and on the possible evolution of myocardial ischemia can be obtained from the pattern of pain recurrence and from the circumstances in which the pain occurs. A stable pattern of occurrence of ischemic episodes with pain suggests a stable cause of ischemia. Conversely, a recent onset of ischemic episodes and/or a rapid worsening of their severity and duration, or the presence of pain at rest suggest an unstable cause.
Chronic stable angina
Although this form of angina is characterized by a stable pattern of symptoms over months and years, a detailed history of the circumstances in which anginal attacks develop can provide useful information on the actual cause of ischemia. Attacks that occur predictably only when a certain level of physical activity is exceeded, suggest a fixed impairment of coronary flow reserve. Attacks that occur unpredictably during levels of effort that are usually well tolerated, suggest a variable impairment of coronary flow reserve caused by “dynamic” coronary stenoses [19]. The range of this modulation can be confirmed by assessing the heart rate at which ischemic episodes occur during Holter monitoring or exercise test after acute nitrate administration [20].
Unstable angina
The sudden onset and rapid worsening of angina with more severe and longer lasting attacks, and attacks occurring at rest or during minimal physical effort, are a signal of an unstable cause of ischemia and therefore demand prompt medical attention and aggressive management. The diagnosis of instability is easy when symptoms are rapidly worsening but cannot easily be made only on the basis of the occurrence of angina at rest or angina that occurs unpredictably during a degree of effort well tolerated on other occasions. On the one hand, variability of the anginal threshold and even occasional episodes of angina at rest can occur over periods of months and years in patients with chronic stable, predominantly effort-related, angina [21]. On the other hand, episodes of angina at rest, usually with preserved effort tolerance, are typical of variant angina. In this latter syndrome the attacks are typically nocturnal, or occur in the early morning hours, sometimes associated with palpitation due to arrhythmias. The attacks sometimes occur in clusters within a 30- to 60-min period, leaving the patient angina-free throughout the rest of the day whilst engaged in normal activities [21].
Acute myocardial infarction
In acute myocardial infarction, pain is usually, but not always, more severe and more frequently accompanied by angor animi. The severity of pain is in itself a reason for alarm; but even when symptoms are not severe, it is the persistence of pain that demands prompt attention. Despite the extreme severity of ischemia, which characterizes myocardial infarction, the Framingham study showed that about 34% of acute myocardial infarctions were not associated with pain that could be recognized by the patient. The proportion of painless myocardial infarctions was higher in diabetic and hypertensive patients. In men, but not women, there was a tendency to an increase in the proportion of painless infarctions with age. An intriguing observation of the Framingham study was that 24% of men and 33% of women with painless myocardial infarction had episodes of angina pectoris [22]. As the algogenic stimuli operating during myocardial infarction are likely to be much more powerful than those operating during episodes of transient myocardial ischemia, these findings further emphasize how the central modulation of algogenic messages plays a pivotal role in determining the perception of cardiac ischemic pain.

Conclusions
Mechanical stimuli are unlikely to play a major role in the genesis of anginal pain during daily life, but they may play a role in patients undergoing percutaneous interventions. At present, the clinical evidence indicates that adenosine, via activation of A1 adenosine receptors, and bradykinin, via arachidonic acid metabolites, are algogenic substances involved in the pathogenesis of cardiac ischemic pain.
The relationship between myocardial ischemia and cardiac ischemic pain is rather elusive, as the severity of pain is not necessarily proportionate to the severity of ischemia and as only the pattern and duration of pain can provide clues to the actual causes of ischemia.

REFERENCES
1. Colbeck EH. Angina pectoris: a criticism and a hypothesis. Lancet. 1903;1:793–795.
2. Lewis T. Pain in muscular ischemia — its relation to anginal pain. Arch Intern Med. 1932;49:713–727.

3: Circulation 1988 Aug;78(2):310-9