An angiographic and histologic study of cocaine-induced chest pain

of elderly patients with CAD or systemic hypertension showed that at a mean follow-up of 40 months, new cardiac events occurred in 87% of patients with abnormal LVEF and in 37% of patients with normal LVEF (p
An Angiographic

and Histologic

tachycardia and complex ventricular arrhythmias in predicting new coronary events in patients over 62 years of age. Am J Cardiol 1988,61:1349-1351. 4. Aronow WS, Epstein S. Usefulness of silent myocardial ischemia detected by ambulatory electrocardiographic monitoring in predicting new coronary events in elderly patients. Am J Cardiol 1988,62:1292-1296. 5. Teichholz LE. Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence or absence of asynergy. Am J Cardiol 1976:37:7-11. 6. Spielman SR, Greenspan AM, Kay HR. Discigil KF, Webb CR, Sokoloff N M, Rae AP, Morganroth J, Horowitz LN. Electrophysiologic testing in patients at high risk for sudden cardiac death. 1. Nonsustained ventricular tachycardia and abnormal ventricular function. JACC /985,6;3/-39. 7. Aronow WS. Prevalence of presenting symptoms of recognized acute myocardial infarction and of unrecognized healed myocardial infarction in elderly patients. Am J Cardiol 1987,60:1182. 8. Roberts WC. Sudden cardiac death: definitions and causes. Am J Cardiol 1986;57:1410-1413. 9. Hammermeister KE, DeRouen TA, Dodge HT. Variables predictive of survival in patients with coronary disease. Selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations. Circulation /979;59:421-430. 10. Mock MB, Ringqvist I, Fisher LD, Davis K, Chaitman BR, Kouchoukos NT, Kaiser KC, Alderman E. Survival of medically treated patients in the Coronary Artery Surgery Study (CASS) registry. Circulation 1982,66:562-568. 11. Cohn PF, Brown EJ Jr. Wynne JA, Holman BL, Atkins HL. Global and regional left ventricular ejection fraction abnormalities during exercise in patients with silent myocardial ischemia. JACC /983:/:93/-933. 12. Cohn PF. Detection and prognosis of the asymptomatic patient with silent myocardial &hernia. Am J Cardiol 1988,6/:48-68. 13. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischemia predicts infarction and death during 2 year follow-up of unstable angina. JACC 1987:10:756-760. 14. Nademanee K, Intarachot V, Josephson MA, Rieders D, Mody FV, Singh BN. Prognostic signiticance of silent myocardial ischemia in patients with unstable angina. JACC 1987;10:1-9. 15. Gottlieb SO, Gottlieb SH, Achuff SC, Baumgardner R, Mellits ED, Weisfeldt ML, Gerstenblith G. Silent ischemia on Hotter monitoring predicts mortality in high-risk postinfarction patients. JAMA /988;259:/030-1035. 16. Tzivoni D, Gavish A, Zin D, Gottlieb S, Moriel M, Keren A, Banai S, Stern S. Prognostic significance of ischemic episodes in patients with previous myocardial infarction. Am J Cardiol 1988,62:661-664. 17. Rocco MB, Nabel EG, Campbell S, Goldman L. Barry J, Mead K, Selwyn AP. Prognostic importance of myocardial ischemia detected by ambulatory monitoring in patients with stable coronary artery disease. Circulation /988;78:877-

884.

Study of Cocaine-Induced

Chest Pain

Pirzada A. Majid, MBBS, PhD, Bharat Patel, MD, Han-Seob Kim, MD, PhD, Janice L. Zimmerman, and R. Philip -Dellinger, MD hest pain is not an uncommon symptom in patients who abuse cocaine. A small number also develop C acute myocardial infarction.1,2 Most, however, show electrocardiographic ST-segment or T-wave abnormalities as the only objective evidence of myocardial ischemia. Coronary artery spasm has been popularly invoked as the possible cause for chest pain.3*4 However, evidence for spasm is largely circumstantial at present. An alternative source of pain may be myocarditis,5 which has been demonstrated in some patients dying of cocaine abuse.6,7 The following investigations were carried out in 11 men, average age 27 years (range 18 to 35) presenting with prolonged chest pain at rest suggestive of acute myocardial ischemia I to 4 hours after useof cocaineby smoking or intravenous route, electrocardiographic STsegmentelevation or T-wave abnormalities and demonFrom the Sections of Cardiology and Critical Care Medicine, and Departments of Medicine and Pathology, Baylor College of Medicine, One Baylor Plaza, Room 513E, Houston, Texas 77030. Manuscript received September 15,1989; revised manuscript received and accepted November 9,1989.

812

THE AMERICAN

JOURNAL

OF CARDIOLOGY

VOLUME

65

MD,

stration of cocaine or its metabolites in the urine. None had risk factors for coronary artery disease.After acute myocardial infarction was ruled out, informed consent was obtained and coronary arteriography was carried out (within 24 hours of admission) in multiple views using Judkins technique to exclude coronary artery disease.Coronary arteries werefound to be normal in all patients. None showedevidenceof spontaneouscoronary artery spasmor presenceof intraluminal thrombi. In 1 patient, catheter-induced spasmwasseenat the origin of right coronary artery without any symptoms or electrocardiographic changes.Coronary arteriography was repeated in 10patients after 0.4 mg of ergonovinemaleate was given intravenously in divided doses.No focal or diffuse vasoconstrictive responsewas seenon provocation by ergonovine.Ejection fraction calculatedfrom left ventricular angiography was mildly depressedwith an average of 45 f 5%. Only 3 patients had ejectionfractions >500%.Endomyocardial biopsy carried out in all patients failed to show evidenceof myocarditis. In 7 of 11 patients, however, intramyocardial small coronary

arteries, the diameter of which was not more than twice the width of average myoJber (20 to 40 p), were observed to have considerable wall thickening (Figure 1).

Prospective analysis of angiographic data obtained from a group of patients admitted with ischemic chest pain and a history of recurrent cocaine abuse failed to reveal evidence of coronary artery disease, spontaneous coronary artery spasm or presence of intraluminal thrombi to account for symptoms and electrocardiographic abnormalities. An acute myocardial infarction had already been excluded. Attempts at inducing coronary artery spasm, using ergonovine maleate intravenously, were also unsuccessful in all patients. An endomyocardial biopsy ruled out myocarditis as a possible cause of chest pain. However, 7 of the 11 patients demonstrated significant thickening of the small coronary vessel walls. All patients were young and normotensive with no coronary risk factors. All were chronic abusers of cocaine and had been taking the drug for an average of 3 years. The chest pain was typically ischemic in character, localization and radiation. The pain was usually recurrent and temporally related to the use of cocaine; however, the temporal relation of cocaine abuse to the onset of chest pain washighly variable. Electrocardiographic abnormalities were present in all patients and consisted of ST elevation or T-wave abnormalities affecting precordial leads diffusely. None of the patients showed transient elevations of ST segment on electrocardiogram during chest pain as is seen typically in patients with variant angina. In fact, the repolarization abnormalities were persistent in most patients in whom serial electrocardiograms were available for study. The clinical profile of our patients was not consistent with a diagnosis of variant angina. Angiographic findings supported the clinical impression; all patients failed to respond to the ergonovine stimulation test. Other investigators have also reported similar results;‘$2 thus, coronary artery spasm does not appear to be a primary mechanism responsible for acute ischemit syndromes after cocaine use. Other pathophysiologic factors need to be considered. Acute pharmacologic effects of cocaine, such as an increase in heart rate or blood pressure secondary to release of catecholamines, may generate symptoms in patients with underlying coronary artery disease and perhaps induce subendocardial ischemia in patients with significant left ventricular hypertrophy in the absence of coronary artery disease. It is unlikely, however, that increments in heart rate or blood pressure would be responsible for chest pain in our cohort of normotensive patients with normal coronary arteries. In recent years, sporadic reports have stressed the presence of lymphocytic and eosinophilic infiltrates in hearts of patients presumed to have died of cocaine abuse.6%8Very little is known about the origin of cell infiltrates although hypersensitivity reactions to cocaine or adulterants have been implicated from time to time.’ A myocardial inflammatory reaction may also be produced by high concentrations of norepinephrine released after cocaine in a manner similar to that occasionally seen in patients with pheochromocytoma. Eight of our 10 patients demonstrated left ventricular ejection fraction <50%. It is tempting to attribute mild depression of left

ventricular function in a young group of patients with normal coronary arteries to cocaine abuse. However, none of the patients demonstrated cellular infiltrates in the myocardium. The abnormal coronary resistance vessels in 7 of 11 patients were a surprising finding. Considerable thickening of the walls was observed to encroach upon the lumen of the small blood vessels.Simpson and Edwards* reported a 2 1-year-old patient with no coronary risk factors and a long history of cocaine abuse. They found nonatherosclerotic intimal hyperplasia of smooth muscle cells without deposition of collagen and elastin when epicardial coronary arteries were examined histologically. However, no mention was made of smaller coronary vessels. For obvious reasons, our evaluation of epicardial coronary arteries was limited to contrast angiography. Coronary arteriograms can be interpreted as normal in the presence of significant changes in the vessel wall if the latter is concentric in nature.6 Although not directly visualized, it is conceivable that the changes we observed in smaller coronary vessel walls are part of a generalized pathologic process of the coronary arterial tree and, as such, may represent an important link in the pathogenesis of myocardial ischemia in patients with cocaine abuse. The changes could be anatomic counterparts of increased coronary vascular resistance; yet, the episodic nature of pain and the temporal relation to cocaine use suggest that other factors may be involved. A potential mechanism may be plugging of the abnormal small vessels by platelet thrombi formed either through the direct effect of cocaine on platelets9 or through an cY-adrenergic-mediated increase in platelet aggregability. lo Cocaine directly increases thromboxane production and platelet aggregation when platelets are exposed to arachodonic acid in vitro.9 The vasoconstrictor activity of thromboxane AZ on small to medium sized arteries may also participate in increasing coronary vas-

FIGURE 1. Marked thickening of an intramyocardial coronary artery in a heart biopsy of a 27-year-old cocaine abuser. The vessel appears larger because of thickening of the wall when compared with the sumnmding myotibers. (Hematoxylin and eosin stain, X !500.)

THE AMERICAN

JOURNAL

OF CARDIOLOGY

MARCH

15, 1990

813

cular tone. The sequence of these events would explain the development of acute chest pain soon after cocaine use in patients with preexistent abnormal coronary circulation. Clearly further studies are needed to confirm our hypothesis. Furthermore, the direct effect of cocaine on the coronary circulation in chronic abusers needs to be further characterized. Studies are underway to answer some of these questions.

3. Schachne JS, Roberts BH, Thompson PD. Coronary artery spasm and myocardial infarction associated with cocaine use. N Engl J Med /984;3/0:/665-/666. 4. Ascher EK, Stauffer JE. Gaasch WH. Coronary artery spasm. cardiac arrest, electrocardiographic Q-waves and stunned myocardium in cocaine associated acute myocardial infarction. Am J Cardiol /988;6/:/939-1941, 5. Miklozek CL, Crumpacker CS. Royal HD, Come CC, Sullivan JL. Abelmann WH. Myocarditis presenting as acute myocardial infarction. Am Heart J

1988;115:765-776. 6. Karch SB, Billingham ME. The pathology and etiology heart disease. Arch Pathol Lab Med 198&l 12:225-230.

of cocaine-induced

1. Isner JM, Estes NAM 111, Thompson PD, Costanzo-Nordin MR, Subramanian R, Miller G, Katsas G, Sweeny K, Sturner WQ. Acute cardiac event temporally related to cocaine abuse. N Engl J Med /986;315:1438-1443. 2. Smith HWB III, Liberman HA, Brody SL, Battey LL, Donahue BC, Morris DC. Acute myocardial infarction temporally related to cocaine use. Ann Intern

7. Virmani R, Robinowitz M, Smialek JE, Smyth DF. Cardiovascular effects of cocaine: an autopsy study of 40 patients. Am Heart J /988://5:/068-1076. 8. Simpson RW, Edwards WD. Pathogenesis of cocaine-induced ischemic heart disease. Arch Pathol Lab Med 1986;110:479-484. 9. Togna G, Tempesta E, Togna AR, Dolci N. Cebo B, Caprino 1. Platelet responsiveness and biosynthesis of thromboxane and prostacyclin in response to in vitro cocaine treatment. Haemostasis 1985:/5:/00-107. 10. Schnetzer GW. Platelet and thrombogenesis-current concepts. Am Heart J

Med

1972:83:552-564.

1987;107:13-18.

Xamoterol

in Autonomic

and Intrinsic

Sinus Node Dysfunction

Maarten P. van den Berg, MD, Jan Willem Viersma, MD, Wiek H. van Gilst, PhD, and Kong I. Lie, MD a recent study, pindolol, due to its intrinsic symactivity or partial agonism, appeared to Ibe npathomimetic of some benefit in the treatment of sinus node (SN)

rhythmias on 24-hour Holter monitoring (sinus bradycardia [<40 beats/min] and/or sinusarrest [>3 s]). No rate responsivesystems were used. Sinus tachycardia dysfunction. * Xamoterol is a cardioselective /3-adreno- wasdefined assinusrhythm >lOO beatslminfor at least ceptor partial agonist. However, the degree of partial 1 minute. As part of the SN dysfunction 8 patients had agonism is substantially higher in xamoterol than in pin- episodesof supraventricular tachyarrhythmia, mostly dolol; 43 versus 30%.* In this study the effect of xamoterol paroxysmal atria1 ftbrillation. Baseline characteristics on heart rate and pacemaker activity was evaluated in are listed in Table I. After informed consentwas giuen, patients with SN dysfunction in whom a VVI pacemaker patients entered a j-week, randomized, double-blind, was implanted previously because of incapacitating placebo-controlled cross-over study. At entry the pacesymptoms. In addition, autonomic blockade with pro- maker was programmed to intervene after a pause of pranolol and atropine3 was carried out to determine the 1,200 ms. Medication known to influence the sinusnode, underlying pathophysiologic mechanism (intrinsic or the atrioventricular node or sympathetic tone was autonomic SN dysfunction) and to relate these findings stopped (except diuretics in 2 patients). After a run-in to the effect of xamoterol. period of 2 weeksonplacebo a baseline24-hour ambulaThirteen consecutive patients (6 women,7 menrang- tory electrocardiogram wasrecorded. Patients werethen ing in age from 44 to 70 years [mean 631) with SN treated with xamoterol200 mg twice daily orplacebofor dysfunction were entered into the study. In all these 1 week and a second24-hour ambulatory electrocardiopatients a WI pacemaker had beenimplanted because gram wasrecordedduring the last day of treatment. A Iof incapacitating symptoms associated with bradyar- week wash-out period preceded the second treatment period. The final 24-hour ambulatory electrocardioFrom the Department of Cardiology, Thoraxcenter, University Hospi- gram was recorded during the last day of the second tal, Oostersingel 59, 9713 EZ, Groningen, The Netherlands, and the treatment period, which also lasted 1 week(Figure 1). At Institute of Clinical Pharmacology, University of Groningen, Groningen. Manuscript received July 24, 1989; revised manuscript received and the end of the wash-out period the patients underwent autonomic blockade. Autonomic blockade was peraccepted November 14,1989. STUDY 0

I 814

1

PACEMAKER 50 beats/mm

THE

AMERICAN

DESIGN

2

3

DECG

DECG

4

AUTONOMIC BLOCKADE

JOURNAL

OF CARDIOLOGY

VOLUME

65

S WEEKS

DECG