The classic theory was that stretching of the ventricular wall caused angina through the mechanical stimulation of pain-sensitive fibers in the myocardium [12]. This theory was elaborated with the suggestion that mechanical dysfunction caused local release of chemical substances, which stimulated pain receptors [13]. Several problems were associated with these theories. First, biochemical phenomena are the initial derangements during ischemia; regional mechanical impairment is also an early finding. Yet pain, if it occurs, occurs late in the temporal sequence of an ischemic episode. Second, substantial myocardial pathology, sometimes associated with mechanical dysfunction, may occur in the complete absence of pain. Specifically, myocarditis, endocarditis, and even endomyocardial biopsy are painless. These facts and others have led to questions about the presence of a specific myocardial nociceptor [14]: Some argue that either the stimulus that conveys cardiac nociception must be subthreshold or that a neuropathy must exist in patients who have ischemia but not chest pain. Neuropathy may be the explanation in some patients with diabetes and some patients after cardiac transplantation, but these represent a minority of those in whom silent ischemia is detected. Subsequent hypotheses that attempt to explain the "missing" pain in silent ischemia have ranged from an inadequate stimulus [15] to altered encoding of painful stimuli at the spinal level [16] to hyperactive pain inhibition mechanisms [17]. Whatever the explanation, it must account for the occurrence of pain during a few ischemic occasions and the absence of pain during many others, which is the pattern in most patients with significant cardiac ischemia.

The actual triggering signal for ischemic pain that is ultimately capable of being perceived by the patient must begin with regional myocellular hypoxia, the result of imbalance between myocardial oxygen demand and supply. Part of this triggering event is the length of time that the affected myocardium remains ischemic. This, in turn, is related to the rate of appearance and disappearance of the deficit in myocellular hypoxia. Episodes of very brief duration (seconds) may not be perceived as painful, but data from ambulatory electrocardiographic monitoring have documented ischemia for long durations (at least 30 minutes) without perception of symptoms [8]. The location and size of the ischemic region is yet another variable that theoretically could be related to the initial triggering sequence. However, the location and magnitude of ischemia-related abnormalities seen on electrocardiography and on wall motion and perfusion studies do not seem to predict episodes likely to be perceived as painful. Similarly, there is no clear association between pain perception and either location or size of the myocardial region made ischemic during angioplasty. Transient balloon inflation in a small right coronary artery may evoke intense pain, whereas a large left anterior descending or circumflex artery may be transiently balloon-occluded without pain. Duration and size of the ischemic region could be important triggering variables under extreme conditions (very brief duration or a very small ischemic region, for example), but these variables are unlikely to explain the presence or absence of pain during most episodes.

Against the background of this information, the work by Rosen and colleagues in this issue [18] is important. It provides, for the first time, direct evidence (from an increase in regional cerebral blood flow) that the brain is activated during painless cardiac ischemia. Their work documents transmission of the ischemia-related signal to the thalamus and frontal region of the nondominant cortex, despite the absence of pain perception by the patient. This finding establishes, in my view, that central processing of the information principally between the thalamus and dominant cortical region is the key to painless ischemia. The findings of Rosen and colleagues also suggest that subsequent investigation must focus on gate control mechanisms at or beyond these levels. Important interactions between behavioral patterns and cognitive processes and the ischemia-related signal are likely to occur at the suprathalamic level. Thus, a patient's "mind-set" about pain (its dangers and its causes, for example) may influence how an ischemic stimulus is perceived [19]. Hostility (principally cynicism), anger, and aggression are well known for their detrimental influences in ischemic heart disease [20]. Coping mechanisms influence pain thresholds and tolerance rates in other types of pain and are also important in ischemic heart disease [21].

The interesting work of Rosen and colleagues [18] raises many important questions for future research. Does the same message reach the thalamus in both the painless and painful ischemic episodes? Why is the hypothalamus activated only in persons with painful ischemia? Considering the extensive referral of visceral pain to somatic locations, why isn't the somatosensory strip labelled? Clearly, we need a better understanding of the mediators controlling transmission of the ischemia-related signal above the thalamus. Is this, in fact, where psychosocial factors such as hostility, anger, and depression link up to influence pain perception as well as morbidity and mortality related to ischemic heart disease? Information about the relation between psychosocial and cardiovascular physiologic interactions is becoming available from the recently completed Psychophysiological Investigations of Myocardial Ischemia (PIMI) [22]. Although a full discussion of learned social responses is not possible here, simply stated, social learning theory assumes that anger and accompanying behavior are "reinforced." For example, persons learn to repeat the responses that they perceive to be most socially desirable. Are these psychosocial-behavioral factors positive reinforcers for diminished sensitivity to the cardiac ischemia signal? Most important is the need for a controlled, long-term interventional trial to assess the influence of psychosocial-behavioral factor modification on the perception of ischemic symptoms and adverse outcomes.

Considering the influence of psychosocial factors on cardiovascular reactivity and pain perception, it may be reasonable to speculate on whether the asymptomatic ischemia that occurs in daily life is a reinforced behavior. Could silent ischemia be a conditioned autonomic response to environmental and psychosocial stressors? This hypothesis assumes that the sequence of events begins with aversive environmental stimuli, including both physical (effort) and psychosocial (mental) stressors and their interactions. These, in turn, constrict dysfunctional coronary arteries to reduce myocardial O₂ supply and increase blood pressure, heart rate, or contractility, augmenting myocardial O₂ demand and producing ischemia. By activating the central nervous system, the resulting ischemia signal would, in its turn, evoke responses that diminish the unpleasantness of the environmental and psychosocial stimulus, thus reinforcing continuation of the ischemia. One response could be an increase in blood pressure, which is known to diminish sensitivity to noxious stimuli [23]. Such a cascade of events could result in more intermittent increases in blood pressure causing more ischemic episodes. This hypothesis also suggests that through such mechanisms, repeated ischemic episodes could blunt the perception of aversive environmental and psychosocial stimuli, as well as the pain response that is traditionally associated with ischemia. The blunting process could involve the endogenous opiate and nonopiate neurochemical analgesia systems in a way that also causes them to moderate the reinforcing ischemia-related signals transmitted to the brain. Such activity could also link silent cardiac ischemia with sudden death arising from arrhythmias. It has been proposed, for example, that diminished baroreceptor sensitivity produces an imbalance in cardiac autonomic output, resulting in reduced cardio-parasympathetic output and enhanced sympathetic output [23]. Cardiac acceleration precedes and continues during the silent ischemic episodes that occur during daily life and is only partially blocked by ß₁-receptor blockade [24]. These findings and recent heart rate variability analyses suggest that increased adrenergic activity may be implicated in silent ischemia in addition to parasympathetic withdrawal. Such a shift in cardiac autonomic balance toward the sympathetic nervous system would tend to promote life-threatening arrhythmias because the increased myocardial electrical excitability and instability due to neurohormones are amplified by ischemia.

Enormous amounts remain to be learned about the ways in which the heart and the brain communicate with each other. But the benchmark work of Rosen and colleagues [18] at least tells us that the brain knows when the heart is ischemic and provides a starting point for future investigation.