Correspondence
Cardiac Syndrome X
N Engl J Med 2002; 347:1377-1379October 24, 2002
- Article
To the Editor:
There may be an alternative explanation for the observations made by Panting et al. (June 20 issue)1 in their elegant study of patients with cardiac syndrome X. Although the heart-rate response to adenosine infusion is not given, the occurrence of “adenosine-induced tachycardia” is mentioned. Huang et al.2,3 showed that cardiac sensory-nerve endings in the canine heart possess specific adenosine receptors that can be activated by endogenous adenosine released from the heart. Exogenous adenosine administered to ventricular sensory-nerve endings greatly stimulates cardiac sensory neurons in the upper thoracic dorsal-root ganglia that project cardiac nociceptive input to the spinal cord in normally perfused hearts.2,3 Thus, adenosine itself is sufficient to induce angina-like chest pain, independently of a myocardial perfusion abnormality.
Furthermore, intracoronary adenosine infusion can induce reflex-mediated cardiovascular sympathetic activation.4 One cannot rule out the possibility that reflex-mediated sympathetic activation — by adenosine or by the severe chest pain due to the well-known increased pain sensitivity in these patients5 — is responsible for the coronary arteriolar vasoconstriction in the subendocardial layer that is richly innervated by sympathetic nerve endings.6 This increased sympathetic vasoconstriction could counterbalance the vasodilative effect of adenosine in the subendocardium, resulting in the secondary, relative hypoperfusion of the subendocardium that Panting et al. observed on magnetic resonance imaging (MRI) in their patients with cardiac syndrome X. Accordingly, the observed defect may be due to increased sympathetic outflow, as indicated by the occurrence of adenosine-induced tachycardia, and may not be related to the mechanism of ischemia in such patients.
6 ReferencesMing-He Huang, M.D., Ph.D.
Gordon A. Ewy, M.D.
University of Arizona Medical Center, Tucson, AZ 85724
mhuang1458@aol.com 1
Panting JR ,Gatehouse PD ,Yang G-Z , et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:1948-1953
Full Text | Web of Science | Medline2
Huang MH ,Sylven C ,Horackova M ,Armour JA . Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. Am J Physiol 1995;269:R318-R324
Web of Science | Medline3
Huang MH ,Horackova M ,Negoescu RM ,Wolf S ,Armour JA . Polysensory response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia. Cardiovasc Res 1996;32:503-515
Web of Science | Medline4
Cox DA ,Vita JA ,Treasure CB ,Fish RD ,Selwyn AP ,Ganz P . Reflex increase in blood pressure during the intracoronary administration of adenosine in man. J Clin Invest 1989;84:592-596
CrossRef | Web of Science | Medline5
Lagerqvist B ,Sylven C ,Waldenstrom A . Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary angiograms. Br Heart J 1992;68:282-285
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Marron K ,Wharton J ,Sheppard MN , et al. Human endocardial innervation and its relationship to the endothelium: an immunohistochemical, histochemical, and quantitative study. Cardiovasc Res 1994;28:1490-1499
CrossRef | Web of Science | Medline
To the Editor:
Panting et al., who suggest that subendocardial ischemia is the cause of chest pain in syndrome X, used a method (contrast-enhanced MRI) with which there has been only minimal experience and obtained a result (ischemia localized to the subendocardium) that is hard to explain anatomically or physiologically, given a disease process that is presumably generalized.
However, I am more troubled by the possibility that this report will increase the already large number of patients with chest pain who, despite normal coronary arteriograms, continue to be treated as if they had heart disease.1 Most of these patients are women, some with but most without all the features of syndrome X. They typically have high scores on psychological inventories that measure anxiety and depression, are very prone to somaticization, and often meet the diagnostic criteria for panic disorder.2,3 Their natural tendency not to be reassured by the news that they have a normal angiogram is all too frequently reinforced by the well-meaning prescription of antianginal drugs and the referral for more tests.1 In general, these patients have noncardiac, usually psychosomatic, chest pain, and they have an excellent prognosis with respect to illness and death from cardiac causes.4,5 They do not have a good response to antianginal therapy5 and will not be well served by the inference that their symptoms have an ischemic origin.
5 ReferencesMayer Bassan, M.D.
Clalit Health Services, Jerusalem 94110, Israel
yoedba@hotmail.com 1
Nijher G ,Weinman J ,Bass C ,Chambers J . Chest pain in people with normal coronary anatomy. BMJ 2001;323:1319-1320
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Katon W ,Hall ML ,Russo J , et al. Chest pain: relationship of psychiatric illness to coronary arteriographic results. Am J Med 1988;84:1-9
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Mukerji V ,Beitman BD ,Alpert MA ,Lamberti JW ,DeRosear L ,Basha IM . Panic disorder: a frequent occurrence in patients with chest pain and normal coronary arteries. Angiology 1987;38:236-240
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Kemp HG ,Kronmal RA ,Vlietstra RE ,Frye RL . Seven year survival of patients with normal or near normal coronary arteriograms: a CASS Registry study. J Am Coll Cardiol 1986;7:479-483
CrossRef | Web of Science | Medline5
Kaski JC ,Rosano GMC ,Collins P ,Nihoyannopoulos P ,Maseri A ,Poole-Wilson PA . Cardiac syndrome X: clinical characteristics and left ventricular function: long-term follow-up study. J Am Coll Cardiol 1995;25:807-814
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To the Editor:
The Perspective by Panza,1 which accompanies the article by Panting et al., should not pass without comment.
The pain of angina is a phenomenon of conscious perception. The brain integrates sensory information from the periphery with other relevant information (based on previous experiences, situational factors, and social and cultural issues, for example) in order to produce the coherent sensory and emotional experience that we call angina.2 The primary trigger of this symptom is often called cardiac ischemia, but 10 to 20 percent of patients with typical anginal pain have normal coronary angiograms and normal electrocardiograms.3 Thus, discernible cardiac ischemia is not necessary for the experience of angina. In addition, there is little, if any, correlation between objective measures of ischemia and the perception of pain4; 75 percent of ischemic episodes in the community pass unnoticed by the patient.5 Thus, discernible cardiac ischemia is not sufficient for the experience of angina.
With this background, we turn to Panza's Cartesian approach to angina. According to his possible models of heart pain in syndrome X, the problem lies in either an ischemic heart or “abnormally sensitive perception of myocardial pain.” The role of at least two levels of synaptic connections and the most complex object in the known universe (the brain) is relegated to that of passive receptor and reporter of information.
Neuroscientists and cardiologists would do well to work together to begin to unravel the mysteries of heart pain. While the problem is deemed to be only cardiologic, Cartesian dualism will prevail.
5 ReferencesAlf Collins, F.R.C.A.
Musgrove Park Hospital, Taunton TA1 5DA, United Kingdom
alf_collins@hotmail.com 1
Panza JA . Myocardial ischemia and the pains of the heart. N Engl J Med 2002;346:1934-1935
Full Text | Web of Science | Medline2
Mannheimer C ,Camici P ,Chester MR , et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 2002;23:355-370
CrossRef | Web of Science | Medline3
Kemp HG ,Kronmal RA ,Vliestra RE ,Frye RL . Seven-year survival of patients with normal or near normal coronary arteriograms: a CASS Registry study. J Am Coll Cardiol 1986;7:479-483
CrossRef | Web of Science | Medline4
Klein J ,Chao SY ,Berman DS ,Rozanski A . Is `silent' myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases. Circulation 1994;89:1958-1966
Web of Science | Medline5
Deanfield JE ,Maseri A ,Selwyn AP , et al. Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;2:753-758
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Huang and Ewy raise the possibility that the subendocardial perfusion abnormality we observed in patients with syndrome X, when compared with controls, might have arisen from reflex-mediated sympathetic activation of subendocardial nerve fibers. This is a possibility, but one that we did not test in our study. Our hypothesis was that the superior spatial resolution of cardiovascular magnetic resonance would enable a subendocardial perfusion abnormality to be detected, if present, with more certainty than had hitherto been possible because of the limited spatial resolution of nuclear techniques. We were careful in our report not to try to establish a mechanism based on these results. In addition, although we believed that this and other lines of evidence obtained with the use of state-of-the-art investigative techniques increasingly suggest that ischemia occurs in syndrome X,1,2 this conclusion cannot be drawn with certainty on the basis of our study. This is because we demonstrated not an absolute decrease in subendocardial perfusion during stress, but rather a relative failure of subendocardial perfusion (normalized to heart rate) to increase. Because we did not measure microscopic ischemia (in terms of cellular products such as lactate) or macroscopic ischemia (in terms of new wall-motion abnormality), we believe that the best inference is that this relative failure to increase suggests, but does not confirm, the presence of ischemia. Further studies will probably resolve this issue in the near future.
Bassan is concerned about a possible increase in the number of women with chest pain who, as a result of our work based on a technique with which there has been limited experience, will continue to be treated as if they had heart disease. The comments are unfortunately patronizing toward women who have a real clinical syndrome in which the heart is clearly implicated. Although the common occurrence of chest pain from somaticization of psychological problems is not in doubt,3 the point of our report — if it stands the test of time — is that cardiologists will have a diagnostic tool to identify patients with a real perfusion abnormality that may indeed respond to cardiac therapy. The choice of therapy may also eventually be guided by improvements in symptoms as well as subendocardial perfusion, for which there is now the hope of objective measurement. A clear diagnostic strategy thus has the potential to help guide therapy for patients with syndrome X whose symptoms have a possible ischemic origin and those whose symptoms do not.
3 ReferencesDudley J. Pennell, M.D.
Jonathan R. Panting, M.B., M.R.C.P.
Peter Collins, M.D.
Royal Brompton Hospital, London SW3 6NP, United Kingdom
d.pennell@ic. ac. uk 1
Buchthal SD ,den Hollander JA ,Merz CNB , et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med 2000;342:829-835
Full Text | Web of Science | Medline2
Buffon A ,Rigattieri S ,Santini SA , et al. Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X. Am J Physiol Heart Circ Physiol 2000;279:H2627-H2633
Web of Science | Medline3
Bass C ,May S . Chronic multiple functional somatic symptoms. BMJ 2002;325:323-326
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Panza replies:
To the Editor: I entirely agree with Dr. Collins that myocardial ischemia is neither necessary nor sufficient for the provocation of angina pectoris. However, the central message of my Perspective is that myocardial ischemia has not been firmly established as the mechanism of chest pain in patients with cardiac syndrome X. My description of the perception of cardiac pain is not intended to relegate a complex system such as the central nervous system to the role of “passive receptor and reporter of information.” Instead, I used the concept of abnormal perception of cardiac pain to describe an alternative mechanism of angina in patients with cardiac syndrome X that does not involve myocardial ischemia. I concur with Dr. Collins that the brain is the most complex object in the known universe and that neuroscientists and cardiologists should work together to unravel the mysteries of heart pain. The possibility that anginal symptoms in patients with cardiac syndrome X may not be ischemic in origin highlights an area in which such collaboration may yield important clues to unanswered questions.
Julio A. Panza, M.D.
Washington Hospital Center, Washington, DC 20010-2975
julio.a. panza@medstar. net
