of lesions per patient seems to us ple count without any element of also important for risk stratifica- judgment and, thus, essentially betion, because each coronary lesion ing free of bias. It is also available is a risk for myocardial infarction. from all trials. Since 80 to 90% of A patient with 5 new stenosesis cer- deaths in cardiovascular trials are tainly at a higher risk than a patient cardiac, and there are no data to suggest that nifedipine increases with only 1. Hence, if one is performing a the risk of noncardiac deaths, the meta-analysis, all the facts should difference between an overview rebe weighted very carefully. Finally, porting on all-cause or cardiac morif the possibility of an adverseeffect tality is small. We believe that this of a drug on myocardial infarction is worth the price of obtaining comis analyzed, one should primarily plete and bias-free data, especially deal with cardiac and not total mor- in secondary prevention trials. In small trials with few deaths, tality. Paul R. Lichtkn, MD such as INTACT, the play of Hannover, Germany 8 July 1991 chance may give the appearance of a distinction between various modes of deaths. The strength of 1. Yusuf S, Held P, Furberg CD. Update our overview is the inclusion of all of effects of calcium antagonists in myocardial infarction or angina in light of the known trials of calcium antagonists rather than focusing on a specific second Danish Verapamil Infarction Trial trial. The overall data suggest that (DAVIT-II) and other recent studies. Am J Cardiol 1991;67:1295-1297. mortality is increased with the use 2. Lichtlen PR, Hugenholtz PG, Rafflenof dihydropyridine calcium antagobet11W, Hecker H, Jost ST, Deckers JW, nists. However, there may be some on behalf of the INTACT group investiuncertainty concerning the magnigators. Retardation of angiographic protude of the adverse effect. gression of coronary artery disease by The secondissue raised by Lichtnifedipine; results of the International len regards the presentation of anNifedipine Trial on Antiatherosclerotic Therapy (INTACT). Lancer 1990;335: giographic data from his trial. It appears that the primary goal of 1109-1113. his trial was to assessangiographic 3. Lichtlen PR, on behalf of the INTACT study group. Reply to the letter of Drs. progression overall. There is no difM.R. Goldstein and F.W.A. Verheugt as ference between the active and conwell as a letter. from unknown authors trol groups on this end point. The to the article on INTACT, Lancet 1990; claim of an effect on prevention of 335:1109-1113. Lancet 1990;336:172new lesions is data-derived and, 174. moreover, utilizes inappropriate 4. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost ST, Nikutta P, statistical methods. Randomization in this trial is by patient (not by Deckers JW, on behalf of the INTACT group investigators. Retardation of coro- lesion), and therefore, the unit of nary artery disease in humans by the cal- analysis has to be the individual pacium-channel blocker nifedipine: results tient.2 From a physiologic point, the of the INTACT study (International Nirates of lesion changes in different fedipine Trial on Antiatherosclerotic parts of a coronary tree within an Therapy). Cardiovascular Drugs and individual patient are likely to be Therapy 1990;4(suppl 5):1047-1068. correlated. Moreover, the entire coronary tree within an individual is subjected to the same intervenREPLY: We thank Professor Lichtlen for his comments regarding our tion. article. He raises 2 issues:The first Therefore, the analysis of the deissue relates to our use of all-cause velopment of new lesionshasto take instead of cardiac mortality from the unit of randomization (which is the INTACT study.’ The large ma- the individual patient and not each jority of overviews of randomized lesion) into account. In the primary clinical trials in cardiovascular dis- paper,’ the only analysis that utieasehave focused on all-cause mor- lizes such an approach is the comtality, including our original arti- parison of the number of patients in cle* and the recent update.3 All- each group who develop new lesions cause mortality has the distinct (70 of 173 in the active vs 85 of 175 advantage of being based on a sim- in the control). This is not statisti-

cally significant. Furthermore, in 18% of patients, follow-up angiograms were not available. The potential influence of these missing data on the analysis requires clarification. The only analysis that includes all randomized patients and reaches statistical significance in INTACT is the adverse effect of nifedipine on total mortality. Whereas the apparent excessmay be exaggerated by the play of chance in this trial, the adversetrend is consistent with data from other related trials of dihydropyridines calcium antagonists. Therefore, the totality of evidence indicates that on balance these agents are likely to be more harmful than beneficial to patients with ischemic heart disease.There are no data indicating benefit to clinical end points in such patients. SaWm Yusuf, wu8,wee,DpN Bethesda, Maryland Peter Held, PhD

Goteborg. Sweden Curl Furberg,

MD

Winston Salem, North Carolina 20 September 1991

1. Lichtlen RP, Hugenhoitz PG, Rafflenbeul W, Hecker H, Jost S, Deckers JW. Retardation of angiographic progression of coronary artery disease by nifedipine: results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). Lancer 1990;335:11091113. 2. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:1187-1192. 3. Yusuf S, Held P, Furberg CD. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991;67:1295-1297. 4. Yusuf S, Garg R. Randomized trials to assessthe long term effects of therapies on angiographic endpoints. Chest 1991;99: 1243-1247.

Atrial Natriuretic Factor and Transfnural Pressures

Serra et al1 contribute important insights into the physiology of atria1 natriuretic factor (ANF) releaseby demonstrating attenuation in ANF production in patients with right ventricular (RV) infarction complicating inferior wall left ventricular infarction. They suggest plausible mechanisms,including RV necrosis READERS’ COMMENTS

837

and right atria1 ischemia reducing the amount of tissue available for synthesis and storage of ANF. I would like to suggest an additional mechanism: reduction of RV transmural pressure.It is clear that myocardial stretch, dependent on transmural pressure, is the key mechanism in ANF release.2q3 Since RV infarction acts like constrictive pericarditis hemodynamically, producing pressure curves and clinical findings resembling that condition4 one may speculate that increased intrapericardial pressure due to RV dilation, within even a normal pericardium, reducestransmural pressure, thereby attenuating the stimulus for ANF release without blocking ANF entirely, as may happen with zero net transmural pressure in cardiac tamponade.3

from the right sinus of Valsalva. However, in my opinion, the angiographic description of the course of this anomalous coronary artery is incorrect. According to the investigators, “the left main coronary artery coursed posteriorly between the aorta and the pulmonary artery.” The right and left anterior oblique views (Figure 3) show a caudal anterior loop evoking a septal course.2According to Ishikawa and Brandt,2 a caudal initial loop (as observed in Figure 3) is incompatible with an interarterial course (whose angiographic feature is a cranial posterior loop). Another method to delineate the true course of anomalous coronary arteries in adults, using only the right anterior view, was recently described by Serota et aP: the “dot and eye” method (when the course is interarDavid H. Spodick, MD, DSC terial “the contrast column of the Worcester,Massachusetts 30 September 1991 left anterior coronary artery will be seen ‘on end’ anterior to the aorta 1. Serra A, Jimenez W, Ribas M, Bosch and it will appear as a radiopaque X, Pare C, Rivera F, Sanz G, with the dot”). In the case described by technical assistance of Moya P, Mufioz I. Maron et al, the right anterior Impaired response of atria1 natriuretic oblique projection shows an ellipse factor to blood volume expansion in acute (an “eye”), with the left main cororight ventricular infarction. Am J Curdiol nary artery forming the inferior 1991;68:719-724. portion and the circumflex forming 2. Spodick DH. Low atria1 natriuretic factor levels and absent pulmonary edema the superior portion. This aspect evokes a septal course. in pericardial compression of the heart.

Am J Cardiol 1989;63:1271-1272. 3. Wolozin MW, Ortola FV, Spodick DH, Seifter JL. Release of atria1 natriuretic factor following pericardiectomy for chronic constrictive pericarditis. Am J Cardiol 1988;62:1323-1325. 4. Spodick DH. The normal and diseased pericardium: current concepts of pericardial physiology, diagnosis and treatment. J Am Co11Cardiol 1983;1:240-251.

Prospective Identification by Two-Dimensional Echocardiography of Anomalous Origin of the Left Main Coronary Artery from the Right Sinus of Valsalva

Maron et al’ described a young patient in whom a coronary arterial FIGURE 1. Lateral projection from ow anomaly (anomalous origin of the 2l-yoar-oki patient’ showing cowse ot left main coronary artery from the leftcammyartwy.RightJudkins right sinus of Valsalva) was recog- catlletsr seleetiveiy engaged iefl coronized prospectively by echocardiog- lUl~WtS!lyOftEghtSblUS,Md~* dmnsMtrated. raphy. In their report, effectively, opkththofartefyis -w=-Yhckrfy echocardiography allowed the iden- courseofieR uodriortomahmhnonawartew tification of an abnormal origin of the left main coronary artery 838

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69

MARCH 15, 1992

If there is a high incidence of ischemia and sudden death with the interarterial course, the septal course of the left main is probably a benign anomaly.4 Pr. Gilkr

Grdller,

MD

Caen, France 15 August 1991 1. Maron BJ, Leon MB, Swain JA, Cannon RO, Pelliccia A. Prospective identification by two-dimensional echocardiography of anomalous origin of the left main coronary artery from the right sinus of Valsalva. Am J Cardiol 1991;68: 140-142. 2. Ishikawa T, Brandt PWT. Anomalous origin of the main coronary artery from the right anterior aortic sinus: angiographic definition of anomalous course. Am J Cardiol 1985;55:770-776. 3. Serota H, Barth CW, Seuc CA, Vandormael M, Aguirre F, Kern MJ. Rapid identification of the course of anomalous coronary arteries in adults: the “dot and eye” method. Am J Cardiol 1990;65: 891-898. 4. Roberts WC, Dicicco BS, Wailer BF, Kishel JC, McManus BM, Dawson SL, Hunsaker JC, Luke JL. Origin of the left main from the right coronary artery or from the right aortic sinus with intramyocardial tunneling to the left side of the heart via the ventricular septum: the case against clinical significance of myocardial bridge or coronary tunnel. Am Heart J 1982;104:303-305. REPLY: We thank Dr. Grollier for his thoughtful comments and interest in our report of a patient with anomalous origin of the left main coronary artery from the right (anterior) sinus of Valsalva, first identified by two-dimensional echocardiography. We carefully considered the issues raised by Grollier with regard to the angiographic demonstration of coronary artery anatomy in our patient, but upon reflection neverthelessremain convinced that the left main coronary artery originates from the anterior sinus and follows a posterior course between the aorta and pulmonary artery. This conclusion is based on the following evidence: (1) The course of the left coronary between the great vesselswas confirmed by intraoperative inspection. (2) The lateral angiographic view (Figure 1) clearly showsthe left main coronary artery to be situated posterior to the pulmonary artery (the position of the pulmonary artery is identified by