Correspondence
Endothelial Dysfunction in Microvascular Angina
N Engl J Med 1993; 329:1739-1740December 2, 1993
- Article
To the Editor:
Egashira et al. (June 10 issue)1 described blunted coronary vasodilation in response to acetylcholine infusion in a group of patients with angina pectoris, positive exercise tests, angiographically normal coronary arteries, no coronary-artery spasm, and myocardial lactate production after the administration of intracoronary papaverine. The implications of these results are unclear for other, similar patients in whom the lactate response to papaverine is unknown. What fraction of the patients with angina and normal coronary angiograms had myocardial lactate production after receiving intracoronary papaverine? It seems likely that a number of patients who had no lactate production might have been studied, since the lactate results would not have been available during the conduct of the protocol. If so, what were the findings? In addition, the Methods section indicates that lactate levels in coronary arterial and coronary sinus venous blood were measured after the infusion of acetylcholine as well as after the administration of papaverine. The lactate results obtained after acetylcholine infusion, however, were not presented.
1 ReferencesJames D. Rossen, M.D.
University of Iowa, Iowa City, IA 522421
Egashira K ,Inou T ,Hirooka Y ,Yamada A ,Urabe Y ,Takeshita A . Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med 1993;328:1659-1664
Full Text | Web of Science | Medline
To the Editor:
To assess coronary blood flow, Egashira et al. used multiple angiographic injections (to measure vessel diameter) and continuous Doppler measurements (to determine blood velocity). As recently described, various contrast mediums, including iohexol, which was used in this study, have direct effects on endothelial cells, such as the induction of endothelin synthesis,1,2 and possibly other endothelial factors (including nitric oxide)3. Since these endothelial effects may be prolonged,1 are the data presented truly representative of the basic endothelial function in the patient groups? Perhaps two protocols are needed; the interval between the angiographic study and the Doppler study should probably be sufficient to allow “recovery” of endothelial function.
3 ReferencesYoram Agmon, M.D.
Hadassah University Hospital, Mount Scopus, Jerusalem, Israel 912401
Heyman SN ,Clark BA ,Kaiser N , et al. Radiocontrast agents induce endothelin release in vivo and in vitro. J Am Soc Nephrol 1992;3:58-65
Web of Science | Medline2
Margulies KB ,Hildebrand FL ,Heublein DM ,Burnett JC Jr . Radiocontrast increases plasma and urinary endothelin. J Am Soc Nephrol 1991;2:1041-1045
Web of Science | Medline3
Agmon Y, Levy H, Greenfield Z, et al. Prostanoids and nitric oxide protect the renal outer medulla from radiocontrast toxicity. Presented at the 12th International Congress of Nephrology, Jerusalem, Israel, June 1993. abstract.
To the Editor:
The syndrome discussed by Egashira et al. was first described in 19671. My colleagues and I noted that one third of the patients had lactate production after catecholamine stimulation with or without chest pain. This observation appears to have been lost, even though at the time it was the most telling objective evidence that myocardial ischemia was, indeed, the basis of this obscure syndrome.
What part might papaverine play in the subgroup of patients with lactate production? The authors do not consider the possibility that papaverine infusion may alter oxidative or glycolytic metabolism through enzyme inhibition or enhancement. The fact that normal dogs may have lactate production after papaverine infusion certainly argues against the steal phenomenon. Furthermore, how would a steal explain the findings? I gather the author of the editorial, Dr. Cannon,2 feels the same way.
There seems to be a major dysregulation taking place, with both an endothelial-dependent and an endothelial-independent mechanism. The findings also do not explain whether the reserve capacities (although less than normal) might still meet the demands of ordinary physiologic stress. Were any measurements of flow velocity made during exercise or modest catecholamine stimulation?
2 ReferencesRichard Gorlin, M.D.
Mount Sinai Medical Center, New York, NY 10029-65741
Kemp HG ,Elliott WC ,Gorlin R . The anginal syndrome with normal coronary arteriography. Trans Assoc Am Physicians 1967;80:59-70
Medline2
Cannon RO III . Chest pain with normal coronary angiograms. N Engl J Med 1993;328:1706-1708
Full Text | Web of Science | Medline
To the Editor:
Neither Egashira et al. nor Cannon addressed the vexing problem of nomenclature and the precise definition of the syndrome of chest pain (angina?) with normal coronary vessels. The nonsensical name “syndrome X” has been applied to this clinical problem for decades. To make matters worse, for the past five years endocrinologists and others have been dealing with another syndrome X,1 which brings together glucose intolerance, primary hypertension, dyslipidemia, and central obesity with the common feature of insulin resistance2. The cardiologists' syndrome X may also include insulin resistance if hypertension and diabetes mellitus are excluded3. Others4,5 have noted the confusing nomenclature. Chest pain is not a feature of the metabolic syndrome X, but some patients with that syndrome have microvascular angina (the cardiologists' syndrome X). Thus, a weak link has been suggested1.
Is it not time for cardiologists and endocrinologists to work together to clarify this nomenclature? (There already is a fragile X syndrome.) Let us call these entities syndromes of coronary microvascular dysfunction, syndromes of dyslipidemic arterial disease, syndromes of hyperinsulinemia, even Reaven's syndrome, but not syndrome X.
5 ReferencesE.C. Abbott, M.D.
5991 Spring Garden Rd., Halifax, NS B3H 1Y6, Canada1
Reaven GM . Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 1993;44:121-131
CrossRef | Web of Science | Medline2
Foster DW . Insulin resistance -- a secret killer? N Engl J Med 1989;320:733-734
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Dean JD ,Jones CJH ,Hutchison SJ ,Peters JR ,Henderson AH . Hyperinsulinaemia and microvascular angina (“syndrome X”). Lancet 1991;337:456-457
CrossRef | Web of Science | Medline4
Kaplan NM . Syndromes X: two too many. Am J Cardiol 1992;69:1643-1644
CrossRef | Web of Science | Medline5
Conti CR . What is syndrome X? Clin Cardiol 1993;16:1-3
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Author/Editor Response
The authors reply:
To the Editor: Dr. Gorlin raises the possibility that myocardial lactate production with papaverine may result from abnormal glycolytic metabolism induced by papaverine, because this has been reported in normal dogs1. However, in that study, the left coronary artery was perfused by means of an arterial shunt and papaverine infusion caused a pressure gradient of 35 mm Hg across the shunt. It is possible that a flow-limiting stenosis in the shunt system may have altered myocardial perfusion and thus caused lactate production. Since uneven myocardial perfusion in the patients with microvascular angina has been suggested by previous investigators,2,3 we considered the possibility of a steal phenomenon to account for myocardial lactate production during papaverine infusion in the presence of increased coronary blood flow. However, further studies are obviously needed to clarify this issue.
In reply to Dr. Rossen: Most of the patients we have studied thus far had myocardial lactate production with papaverine infusion and a markedly attenuated coronary-blood-flow response to acetylcholine infusion. Consequently, as suggested by Dr. Gorlin, dysregulation of coronary blood flow in our patients was not limited to the endothelium-dependent mechanism. Lactate production was not observed during acetylcholine infusion.
In reply to Dr. Agmon: We compared the results in patients with this syndrome with those in control subjects, since both groups underwent the same angiographic study. It is known that contrast medium has a vasodilating action, but its effect is transient and usually lasts for 10 to 20 seconds in vivo.
We welcome and fully agree with Dr. Abbott's comments about the confusing nomenclature.
Our studies4,5 have elucidated a new pathophysiologic entity, which might be called “syndromes of coronary microvascular endothelial dysfunction.” Since vascular endothelium is known to play a central part in modulating vasomotor tone and regulating vascular homeostasis, it is very likely that defective endothelial function in the coronary microcirculation contributes to an ischemic syndrome.
5 ReferencesKensuke Egashira, M.D.
Akira Takeshita, M.D.
Kyushu University School of Medicine, Fukuoka 812, Japan1
Christensen CW ,Rosen LB ,Gal RA ,Haseeb M ,Lassar TA ,Port SC . Coronary vasodilator reserve: comparison of the effects of papaverine and adenosine on coronary flow, ventricular function, and myocardial metabolism. Circulation 1991;83:294-303
Web of Science | Medline2
Cannon RO III ,Camici PG ,Epstein SE . Pathophysiological dilemma of syndrome X. Circulation 1992;85:883-892
Web of Science | Medline3
Maseri A ,Crea F ,Kaski JC ,Crake T . Mechanism of angina pectoris in syndrome X. J Am Coll Cardiol 1991;17:499-506
CrossRef | Web of Science | Medline4
Egashira K ,Inou T ,Hirooka Y ,Yamada A ,Urabe Y ,Takeshita A . Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med 1993;328:1659-1664
Full Text | Web of Science | Medline5
Egashira K ,Inou T ,Hirooka Y , et al. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993;91:29-37
CrossRef | Web of Science | Medline
