EDITORIAL COMMENT
Perfusion Abnormality, Normal Coronaries, and Chest Pain*
Dudley J. Pennell, MD, FRCP, FESC, FACC1,*
Imperial College and Royal Brompton Hospital, London, United Kingdom.
* Reprint requests and correspondence: Dr. Dudley J. Pennell, CMR Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom. (Email: d.pennell{at}ic.ac.uk).
The subject of patients with recurrent chest pain but normal coronary arteries provokes controversy. The patients certainly exist, but their characterization and management is discomforting. Such patients are a heterogenous group, and there are difficulties in confidently sub-phenotyping many patients beyond their clinical presentation. Perhaps a majority will have symptoms that are unlikely to be related to the heart in which the coronary angiogram was performed primarily to exclude significant epicardial coronary stenosis. Coronary spasm is well recognized as a cause of chest pain of cardiac origin but is considered uncommon. Microvascular dysfunction occurs in conditions such as left ventricular hypertrophy of pressure or volume overload, cardiomyopathy, and diabetes, and these also might result in chest pain of likely cardiac origin, because of identifiable alterations in arteriolar structure and stress perfusion. And then there is cardiac syndrome X (CSX), in which patients mimic coronary artery disease on exercise testing, but general agreement is lacking over the phenotypic definition and whether the symptoms have a cardiac origin.
The paper by Lanza et al. (1) in this issue of the Journal improves our knowledge in CSX by directly comparing myocardial perfusion and coronary Doppler in the same patients and in the same territories. With cardiovascular magnetic resonance (CMR) with the first pass gadolinium enhancement perfusion technique, they showed that 10 of 18 (56%) patients with CSX (all patients had ST-segment depression and angina during an exercise test) had stress-induced subendocardial perfusion defects on visual analysis, which was a significantly greater proportion than in control subjects (0 of 10, 0%; p = 0.004). In the CSX patients with anterior wall perfusion abnormality, they also showed reduced coronary flow reserve in the left anterior descending artery compared with patients without anterior wall abnormality (1.69 vs. 2.31; p = 0.01). Finally, they showed a significant relation between the perfusion defect score and the coronary flow reserve (r = 0.45; p = 0.019). These results strongly indicate that the perfusion abnormality identified visually by CMR is a substantive finding and are in agreement with the controlled study using CMR by Panting et al. (2), who found visual perfusion abnormality by CMR in 18 of 20 patients with CSX (all patients had ST-segment depression and angina during an exercise test) but only 3 of 10 control subjects (90% vs. 30%; p = 0.002). The results also indicate the presence of microvascular dysfunction and are compatible (but not diagnostic) with the origin of the cardiac symptoms being from the heart. Whether this is combined with an altered pain threshold or problems with other sites of pain perception is not addressed.
Both of these studies are at variance, however, with the results of a recent study by Vermeltfoort et al. (3), in which the visual findings by perfusion CMR were labeled as artifactual. However, closer inspection of this study reveals that their patients and study techniques are not comparable to those of Lanza et al. (1) and Panting et al. (2). Vermeltfoort et al. (3) studied 20 patients with chest pain and normal coronary angiography, with 95% having abnormal perfusion single-photon emission computed tomography (SPECT) but only 25% having ST-segment depression with exercise. Panting et al. (2) and Lanza et al. (1) studied only patients with exercise-induced angina and ST-segment depression. Importantly the selection of patients’ group by abnormal perfusion SPECT might yield a very different group from that selected by abnormal exercise electrocardiography. This strikes at the heart of how CSX is defined, an issue on which there is no universal agreement. Classical diagnosis calls for an abnormal exercise test (4), but more recently some feel that any diagnostic test for ischemia is satisfactory (especially perfusion SPECT) and that CSX might be best relabeled as just 1 cause of microvascular dysfunction (5). There is concern, however, that the criteria for abnormality with perfusion SPECT might be less well defined than the requirement for exercise (0.1 mV horizontal or downsloping ST-segment depression at 80 ms after the J point). Tweddel et al. (6) reported a 98% prevalence of perfusion SPECT abnormality in patients with angina and normal coronary angiography, but only a 30% prevalence of an abnormal exercise electrocardiogram (ECG). However, Panting et al. (2) reported that 79% of CSX patients with an abnormal stress ECG had normal perfusion SPECT. This suggests that the population of patients with an abnormal exercise ECG or an abnormal perfusion SPECT is not directly comparable. The second unexplained anomaly in the article by Vermeltfoort et al. (3) is the difficulty in their labeling of all the CMR perfusion results as "artefacts." This was reported in 93% of all the slice series. In 44% of the slice series, it was around the entire subendocardium. This implies that nearly all the reported CMR perfusion scans done are artefactual, which is very much higher than general experience. Certainly, global subendocardial artefact by perfusion CMR in our experience is very uncommon, partly because the spatial resolution of the read-out direction is usually considerably better than that in the phase encode direction, which results in any artefacts predominating in the anteroposterior direction (septum and lateral wall) (7), because this is the phase encode strategy that leads to greatest scanning efficiency. Because no control group was included in the study by Vermeltfoort et al. (3), it is unclear whether the arbitrary assignment of artefact in so many cases is justified.
The paper by Lanza et al. (1) supports the hypothesis that the genesis of chest pain in CSX is from the heart. There are data to support and oppose this position. The Lanza et al. (1) article accords with the findings of Panting et al. (2), who showed subendocardial perfusion abnormality, which is supportive of a cardiac origin of symptoms. Other evidence for ischemia from sophisticated investigative techniques in recent years has come from magnetic resonance spectroscopy (8) and coronary sinus sampling of lipoperoxides as a metabolic marker of ischemia (9). One possible interpretation of the absence of wall motion abnormalities from stress studies in cardiac syndrome X is that if ischemia is indeed present, it has characteristics that are not similar to that found in coronary artery disease. Conceivably, this might reflect diffuse abnormality or insufficient transmural extension. This should not be viewed as solipsistic. We have much to learn about the coronary microcirculation and endothelial function, and such possibilities need to be entertained and tested.
The recent links made between CSX and inflammation and endothelial progenitor cells are opportunities for discovery of mechanisms in CSX. The concept of modulation of chest pain occurrence by inflammation is attractive in CSX, because the clinical condition has clear exacerbations where presentation with unstable symptoms occurs, which might be followed by periods of relative remission. Systemic inflammation has been shown in CSX, with increased levels of C-reactive protein (10–12), interleukin-1 receptor antagonist (9), and interleukin-6 and tumor necrosis factor (TNF)-alpha (10). The relation of C-reactive protein to increased frequency of chest pain and ST-segment depression on exercise testing in patients with normal coronary arteries (13) and the improvement in symptoms, exercise duration, and endothelial function in CSX with the use of statins is consistent with this notion (14–16) and suggests further research could bear fruit. The established link between CSX and endothelial dysfunction (17) has also recently come under new scrutiny. External enhanced counter pulsation (EECP) has recently been evaluated (18); EECP is a novel modulator that improves endothelial function (19) and diastolic coronary flow (20). Impressive responses in the perfusion CMR scans of individuals have been seen with this treatment (Fig. 1), and improvements in symptoms and exercise tolerance have occurred in small patient groups (R. Roberts, personal communication, October 2007). Finally, in patients with CSX (diagnosed by an abnormal exercise ECG), Huang et al. (21) found reduced endothelial progenitor cells as well as attenuated fibronectin adhesion function, which might be consistent with an impaired endothelium repair capacity. The link to statin treatment in CSX was made by the demonstration that the dose dependent suppression of endothelial progenitor cells by TNF-alpha was reversed by pretreatment with simvastatin. This can be interpreted as beneficial, as can the finding that statins mobilize endothelial progenitor cells from the bone marrow and improve endothelial function (22,23). Results from a second study were not concordant however (24), possibly owing to a different cell isolation technique and diagnostic bias from the inclusion of patients with abnormal perfusion SPECT.
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Figure 1 Myocardial Perfusion CMR
(A) Myocardial perfusion cardiovascular magnetic resonance (CMR) in patient with cardiac syndrome X (CSX). The perfusion CMR scan is from a 68-year-old woman who presented with a history of disabling angina. The exercise test showed ST-segment depression, and the coronary arteries were smooth, and therefore she was diagnosed with "classical" CSX. There is inferior and septal subendocardial perfusion abnormality with adenosine stress (top row, arrows) at basal and mid levels of the left ventricle, which is not present during the resting perfusion study (bottom row). (B) Myocardial perfusion CMR after treatment. The perfusion CMR scan (identical CMR and stress protocols) on the same patient 9 months later, when the patient had unlimited exercise tolerance. Both stress and rest scans are now unequivocally normal. The intervention after scan A was a program of external enhanced counter pulsation therapy.
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In conclusion, the study of patients with chest pain but normal coronary arteries is in need of rigorous sub-phenotyping. It seems unlikely that this can be achieved by mixing patients with different forms of abnormal noninvasive diagnostic tests, at least until a much clearer picture of comparisons between tests is established. Perfusion CMR has the advantage of much higher spatial resolution than perfusion SPECT, which makes it a good choice for further evaluation; and it would be surprising if perfusion SPECT were positive but perfusion CMR were not. Should abnormal stress perfusion SPECT be pursued as a diagnostic criterion for CSX, it would serve the field well to develop a definition of abnormality that is suitable for noncoronary disease (nearly all the published data on perfusion SPECT are in coronary disease). Agreeing on this definition would not be easy, because the border zone between normal and possibly abnormal is usually blurred in biological tests (for physiological and technical reasons), and low resolution myocardial perfusion SPECT presents particular challenges in specificity. It would be helpful to establish the concordance of such phenotyped patients with those with ST-segment depression and angina on exercise. Should rigorous sub-phenotyping prove possible, genome-wide association studies with achievable sample sizes might be possible with an international multicenter coordination, which might provide new insights into currently unknown mechanisms. This would greatly clarify diagnosis and present rational opportunities for new treatments. The one thing that nearly everyone in the field agrees on is that these patients have significant morbidity from their symptoms with an unrequited need for effective treatment.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
1 Dr. Pennell is a consultant to and receives research support from Siemens. He is a director of CVIS, which makes image analysis software (both >$10,000).
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References
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1. Lanza GA, Buffon A, Sestito A, et al. Relation between stress-induced myocardial perfusion defects on cardiovascular magnetic resonance and coronary microvascular dysfunction in patients with cardiac syndrome X J Am Coll Cardiol 2008;51:466-472.[Abstract/Free Full Text]2. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging N Engl J Med 2002;346:1948-1953.[Abstract/Free Full Text] 3. Vermeltfoort IA, Bondarenko O, Raijmakers PG, et al. Is subendocardial ischaemia present in patients with chest pain and normal coronary angiograms?A cardiovascular MR study. Eur Heart J 2007;28:1554-1558.[Abstract/Free Full Text] 4. Crea F, Lanza GA. Angina pectoris and normal coronary arteries: cardiac syndrome X Heart 2004;90:457-463.[Free Full Text] 5. Lanza GA. Cardiac syndrome X: a critical overview and future perspectives Heart 2007;93:159-166.[Abstract/Free Full Text] 6. Tweddel AC, Martin W, Hutton I. Thallium scans in syndrome X Br Heart J 1992;68:48-50.[Abstract/Free Full Text] 7. Di Bella EV, Parker DL, Sinusas AJ. On the dark rim artifact in dynamic contrast-enhanced MRI myocardial perfusion studies Magn Reson Med 2005;54:1295-1299.[CrossRef][Web of Science][Medline] 8. 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.[Abstract/Free Full Text] 9. Buchthal SD, den Hollander JA, Bairey Merz N, 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.[Abstract/Free Full Text] 10. Lanza GA, Sestito A, Cammarota G, et al. Assessment of systemic inflammation and infective pathogen burden in patients with cardiac syndrome X Am J Cardiol 2004;94:40-44.[Web of Science][Medline] 11. Arroyo-Espliguero R, Mollichelli N, Avanzas P, et al. Chronic inflammation and increased arterial stiffness in patients with cardiac syndrome X Eur Heart J 2003;24:2006-2011.[Abstract/Free Full Text] 12. Wöhrle J, Nusser T, Merkle N, et al. Myocardial perfusion reserve in cardiovascular magnetic resonance: correlation to coronary microvascular dysfunction J Cardiovasc Magn Reson 2006;8:781-787.[CrossRef][Web of Science][Medline] 13. Cosin-Sales J, Pizzi C, Brown S, Kaski JC. C-reactive protein, clinical presentation, and ischemic activity in patients with chest pain and normal coronary angiograms J Am Coll Cardiol 2003;41:1468-1474.[Abstract/Free Full Text] 14. Kayikcioglu M, Payzin S, Yavuzgil O, Kultursay H, Can LH, Soydan I. Benefits of statin treatment in cardiac syndrome-X Eur Heart J 2003;24:1999-2005.[Abstract/Free Full Text] 15. Fabian E, Varga A, Picano E, Vajo Z, Ronaszeki A, Csanady M. Effect of simvastatin on endothelial function in cardiac syndrome X patients Am J Cardiol 2004;94:652-655.[CrossRef][Web of Science][Medline] 16. Pizzi C, Manfrini O, Fontana F, Bugiardini R. Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cardiac Syndrome X: role of superoxide dismutase activity Circulation 2004;109:53-58.[Abstract/Free Full Text] 17. Lekakis JP, Papamichael CM, Vemmos CN, Voutsas AA, Stamatelopoulos SF, Moulopoulos SD. Peripheral vascular endothelial dysfunction in patients with angina pectoris and normal coronary arteriograms J Am Coll Cardiol 1998;31:541-546.[Abstract/Free Full Text] 18. Bonetti PO, Gadasalli SN, Lerman A, Barsness GW. Successful treatment of symptomatic coronary endothelial dysfunction with enhanced external counterpulsation Mayo Clin Proc 2004;79:690-692.[Abstract/Free Full Text] 19. Bonetti PO, Barsness GW, Keelan PC, et al. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease J Am Coll Cardiol 2003;41:1761-1768.[Abstract/Free Full Text] 20. Michaels AD, Accad M, Ports TA, Grossman W. Left ventricular systolic unloading and augmentation of intracoronary pressure and Doppler flow during enhanced external counterpulsation Circulation 2002;106:1237-1242.[Abstract/Free Full Text] 21. Huang PH, Chen YH, Chen YL, Wu TC, Chen JW, Lin SJ. Vascular endothelial function and circulating endothelial progenitor cells in patients with cardiac syndrome X Heart 2007;93:1064-1070.[Abstract/Free Full Text] 22. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells J Clin Invest 2001;108:399-405.[CrossRef][Web of Science][Medline] 23. Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway J Clin Invest 2001;108:391-397.[CrossRef][Web of Science][Medline] 24. Shmilovich H, Deutsch V, Roth A, Miller H, Keren G, George J. Circulating endothelial progenitor cells in patients with cardiac syndrome X Heart 2007;93:1071-1076.[Abstract/Free Full Text]
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Relation Between Stress-Induced Myocardial Perfusion Defects on Cardiovascular Magnetic Resonance and Coronary Microvascular Dysfunction in Patients With Cardiac Syndrome X
- Gaetano A. Lanza, Antonino Buffon, Alfonso Sestito, Luigi Natale, Gregory A. Sgueglia, Leda Galiuto, Fabio Infusino, Luca Mariani, Antonio Centola, and Filippo Crea
J. Am. Coll. Cardiol. 2008 51: 466-472.
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