Early thromboxane release during pacing-induced myocardial ischemia with angiographically normal coronary arteries

Volume Number

120 6, Part

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2. Seymour J, Emanuel R, Pattinson N. Acquired pulmonary stenosis. Br Heart J 1968;30:776-85. 3. Hatle L, Angelsen B. Doppler ultrasound in cardiology, Philadelphia: Lea & Febiger, 198523. 4. Kuan P, Bernstein S, Ellestad M. Coronary artery bypass surgery morbidity. J Am Co11 Cardiol 1984;3:1391-7. 5. Kutcher M, King S, Alimurung B, Craver J, Logue B. Constrictive pericarditis as a complication of cardiac surgery: recognition of an entity. Am J Cardiol 1982;50:742-8.

Early thromboxane release during pacing-induced myocardial ischemia with angiographically normal coronary arteries G. Montalescot, MD, PhD,B G. Drobinski, MD,a J. Maclouf, PhD,d F. Lellouche, MD,d A. Ankri, MD,b N. Moussallem, MD,* L. Eugene, BS,CD. Thomas, MD,a and Y. Grosgogeat,MD.” Paris, France

The mechanismsof anginapectoris in patients with normal coronary arteries remain unclear. Spasm may cause this type of angina, but the biochemical mediators involved in the development of myocardial ischemiain the absenceof coronary artery stenosisare not known. We report a case of severeangina pectoris with normal coronary angiography in which atria1 pacing causedthe releaseof thromboxane into coronary sinusplasmaassociatedwith myocardial ischemia. A 48-year-old woman whose only cardiovascular risk factor was cigarette smoking wasadmitted to our institution in June 1989 for angina

pectoris.

The patient

com-

plained of typical chest pain occurring both with effort and at rest. The resting electrocardiogram (ECG) was normal. An exercisestresstest induced severechest pain associated with a 3 mm flat ST segment depressionat 91% of the From ‘Service d’Explorations Ul50, HBpital Reprint requests: ital Piti&SalpBtrihre,

de Cardiologie, Fonctionnelles, Lariboisikre.

bService d’HBmatologie, HBpital Pitii! SalpBtrMre;

and CService and dINSERM

G. Montalescot, MD, PhD, Service de Cardiologie, 47 Bl. de YHBpital, 75013 Paris, France.

H6p-

maximal heart rate. Treatment with diltiazem (180 mg) and isosorbidedinitrate (30 mg) started prior to hospitalization was totally ineffective in preventing chest pain. Coronary angiography detected neither an organic obstructive lesion nor coronary spasm.To elucidate the mechanism of angina in this patient, we studied myocardial metabolism during pacing-induced ischemia.After informed consent was obtained from the patient, all antianginal medication except for sublingual nitroglycerin was withdrawn 24 hours before the study. After an overnight fast, a 7F USC1pacing and samplingcatheter (USC1Division of C.R. Bard, Billerica, Mass.) wasintroduced via an antecubital vein into the coronary sinus (CS) and a Cournand needle (Becton, Dickinson and Co., Ltd., Dur Laoghaire, CO., Dublin, Ireland) wasinserted into the brachial artery for arterial blood sampling. The lines were kept patent by intermittent flushing with saline without heparin. A 12lead ECG was continuously recorded. After 10 minutes, coronary sinuspacing wasstarted at the rate of 100beats/ min progressively increasing to 150 beats/min over 1 minute, and then this rate was maintained. No atrioventricular block wasinduced and atropine administration was not required. Chestpain and 2 mm ST segmentdepression occurred after 7 minutes of pacing,which wasthen stopped (Fig. 1). Three setsof blood sampleswere collected: at rest before pacing, during the last minute of pacing, and immediately after pacing. At eachmeasurementinterval, simultaneousblood sampleswere taken from the artery and coronary sinus. Arterial and venous lactate levels were measured on whole blood by enzymatic analysis assay (Boehringer Ingelheim, W. Germany) and we calculated lactate extraction (% L) by substracting the venous from the arterial concentration and dividing by the arterial concentration. At rest and during pacing, the patient showed net cardiac lactate extraction but lactate production occurred immediately after pacing (Fig. 2). To measure thromboxane Bg (TXBz), 4 ml of blood were collected in test tubes containing 0.5 ml of 15% ACD (citric acid, trisodium citrate, Z&O/dextrose) and 10 hmol/L of indomethacin (final concentration). Sampleswere immediately transferred to ice, centrifuged, and plasmawas stored at -70° C. TXB2 analyses were performed by enzyme immunoassay.’ The CS plasma TXB2 level increased to a peak of 4.9 rig/ml

414124338.

Fig.

1.

I 445

ST segmentdepressioninduced by atria1 pacing. Arrow

and the C&arterial

difference

indicates the end of pacing.

of TXB2

Brief Communicatiorks

1446

American

December 1990 Heart Journal

Table 1. Coronary sinus arterial differences in platelet concentration, /3-thromboglobulin, and platelet factor 4 at rest, during the last minute of pacing, and 1 minute after pacing

Platelet concentration (Xl000 cells/mm”) fi-thromboglobulin Platelet

factor

(pi/ml)

4 (&ml)

Resting

Pacing

Post pacing

-29

-24

-95

50 13

50 10

222 94

increase of myocardial ventricular vasodilator

0 AEST

PACED

Lactate extraction Coronary sinus-arterial reflecting thromboxane release per milliliter) at rest, during the immediately following the end Fig. 2. Bottom,

Top,

POST-PACED

(measured in percent). gradient of plasma TXBz (measured in nanograms last minute of pacing, and of pacing.

increased threefold and ninefold from baseline at the second and third sampling periods, respectively (Fig. 2). White blood cell concentrations and hematocrits remained identical over the study period in both arterial and venous measurements. In contrast, venous platelet concentrations decreased immediately after pacing, from 251,000 to 181,000, whereas arterial platelet concentrations remained stable, suggesting cardiac platelet sequestration during myocardial ischemia (Table I). Platelet factor 4 and /3thromboglobulin plasma levels (Asserachrom, DiagnosticaStago, Asnieres, France) increased in the last set of samples, demonstrating platelet activation during pacing-induced myocardial ischemia (Table I). In view of these results, the patient was assigned to an aspirin regimen (250mg/day) and this treatment prevented recurrence of chest pain. Patients with chest pain and angiographically normal coronary arteries (a category often designated as syndrome X) present abnormal characteristics that point to microvascular angina. In contrast to the patients without pacinginduced chest pain, those developing pain during atria1 pacing also exhibit a smaller increase of coronary flow, an

myocardial oxygen extraction, a decrease of lactate consumption, and an increase of left end-diastolic pressure, as well as an inadequate response to pharmacologic stimuli and a sensitivity to vasoconstrictor stimuli.’ TXAz is a potent vasoconstrictor agent with platelet aggregating ability. The role of TXAz in myocardial ischemia has been evaluated in animal models of myocardial infarction3 and in patients with acute myocardial infarction and unstable angina.4 Pacinginduced ischemia in patients with severe coronary artery disease is associated with thromboxane release.5 We demonstrated in our patient with severe angina pectoris and normal coronary arteries that atria1 stimulation initiated rapid thromboxane release and myocardial ischemia. During pacing we measured a three-fold increase of TXBz gradient before any lactate production in the CS. Then, following the end of pacing, we demonstrated further TXB2 release into CS plasma, platelet activation, and myocardial platelet sequestration, and the production of lactates in large quantities. In this patient, early thromboxane production may have caused coronary vasoconstriction and exacerbated myocardial ischemia. This initial thromboxane release was not associated with detectable platelet activation, and we cannot be certain that the platelets were the source of the early phase of thromboxane release. Moreover, studies in experimental models of thromboxane-induced vasoconstriction have demonstated that cells other than platelets can release large quantities of thromboxane.6 Myocardial ischemia was probably aggravated by TXA2, causing the aggregation and the myocardial sequestration of platelets we observed immediately after pacing. This platelet activation was associated with a further increase in plasma TXBz levels in the CS and major lactate production. Cyclooxygenase inhibition obtained by assigning our patient to an aspirin regimen was effective in preventing chest pain previously resistant to calcium channel blockers. This suggests that TXAa may play a key role in causing myocardial ischemia in patients suffering from angina pectoris who have normal coronary arteries. REFERENCES

1. Pradelles P, Grassi J, Maclouf J. Enzyme immunoassay of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Anal Chem 1985;57:11’70-3.

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2. Cannon RO III, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol 1988;61:1338-43. 3. Grover GJ, Schumacher W. Effect of the thromboxane receptor antagonist SQ 29,548 on myocardial infarct size in dogs. J Cardiovasc Pharmacol 1988;11:29-35. 4. Hamm CW, Lorenz RL, Bleifeld W, Kupper W, Wober W, Weber PC. Biochemical evidence of platelet activation in patients with persistent unstable angina. J Am Co11 Cardiol 1987;10:998-1006. 5. Lewy RI, Weiner L, Walinsky P, Lefer AM, Silver MJ, Smith JB. Thromboxane relase during pacing-induced angina pectoris. Possible vasoconstrictor influence on the coronary vasculature. Circulation 1980;61:1165-71. 6. Montalescot G, Kreil E, Lynch KE, Greene EM, Torres A, Carvalho A, Fitzgibbon C, Robinson DR, Lowenstein E, Zapol WM. Effect of platelet depletion on lung vasoconstriction in heparin-protamine reactions. J Appl Physiol1989;66:2344-50.

Hyperventilation testing for coronary vasospasm: Induction of spontaneous ventricular tachycardia in association with transmural ischemia without obstructive coronary disease Gregory J. Magarian, MD, Sean Jones, MD, and Thomas Calverley, MD. Portland, Ore.

Patients with myocardial ischemic syndromes associated with coronary vasospasmin the absenceof significant obstructive coronary artery disease(CAD) are typically diagnosed by provocation challenge testing with infusions of either ergonovinemaleate’ or, more recently, acetylcholine during coronary arteriography.2 However, becauseof risks associatedwith inducing coronary vasospasmby ergonovine challenge testing,3 patients with angina1 histories but “normal” coronary arteriograms are not always routinely challenged with ergonovine or acetylcholine after significant CAD has been excluded by coronary arteriography. Without useof ergonovine or acetylcholine challengetesting during coronary arteriography of patients with anginalike chest pain but nonobstructive CAD, the diagnosisof myocardial ischemiafrom coronary vasospasmusually remains only presumptive. Recent studies4-6have supported the useof hyperventilation challengetesting asan alternative to ergonovine testing in identifying such patients. In sucha patient, we report a dramatic ischemicresponseassociatedwith a noninvasive hyperventilation challengetest that indicates that this test may be associatedwith potential risk, similar to ergonovine challengetesting. From the Department of Medicine and Division of General Internal Medicine, Oregon Health Sciences University and the Veterans Administration Medical Center. Reprint requests: Gregory J. Magarian, MD, Division of General Medicine, V.A. Medical Center. P.O. Box 1034, Portland, OR 97207. 414124342

Brief Communications

1447

A 62-year-old man presented with a g-month history of substernal,tight chest pain, often with bilateral arm radiation. He denied dyspnea, lightheadedness,palpitations, nausea,or diaphoresiswith the pain episodes.He alsodenied dyspeptic or gastroesophagealreflux symptoms during episodesof chest pain or at other times. The pain regularly occurred in the early morning hours, often while he wasstill in bed. The patient could recall only one episode not occurring during morning hours. Thereafter, as an active outdoorsman, he was unrestricted in all physical activities, which included briskly walking up hills. The episodesof pain were consistently relieved by one sublingual nitroglycerin tablet within 5 minutes. Antacids were without effect. Cardiovascular risk factors included hypercholesterolemiabut not diabetesmellitus, hypertension, smoking in the past 5 years, or a family history of premaurecardiovascular disease. His physical examination was unremarkable, with a blood pressureof 150/68mm Hg and a resting heart rate of 55/min. His cardiovascular and pulmonary examinations were normal. His baselineelectrocardiogram revealed sinusbradycardia and nonspecificST segmentchanges.Two exercisetreadmill stresstests performed during the first 5 months of symptoms at another institution were reported to showno evidenceof ischemia. However, becauseof persistent, recurrent chest pain, he underwent coronary arteriography, which revealed nonobstructive CAD with a maximal obstruction of 30% of the right coronary artery. There were no ventricular wall motion abnormalities, and the ejection fraction was 65%. Neither ergonovinemaleate or acetylcholine infusion challenge testing were performed during coronary arteriography. Forty-eight hours later, at 9:30 AM, after receiving no antianginal medications for over 2 days, the patient underwent a hyperventilation challenge as previously described.5r6He washyperventilated at 30 deep breaths per minute for 6 minutes. Electrocardiograms were obtained just before (Fig. 1) and every 2 minutes during the hyperventilation trial and for 14 minutes thereafter. While we were attempting to draw an arterial blood gas after completing the 6-minute hyperventilatory trial in order to confirm the establishment of a respiratory alkalotic state, the patient developedchest pain identical to that which he had been experiencing. Simultaneously he developed a spontaneous,nonsustainedlo-beat run of ventricular tachycardia (Fig. 2), followed immediately by development of marked ST elevations in leadsVi to Vs (Fig. 3). His chest pain and electrocardiographic changesspontaneously resolvedwithin severalminutes without the useof sublingual nitroglycerin. The patient wasplaced on a regimen of nifedipine, 10 mg three times a day, and was retested in an identical manner 48 hours later at the sametime as the original test during the morning hours. An arterial blood gasobtained at the end of the g-minute trial of hyperventilation confirmed a marked respiratory alkalosiswith a pH of 7.58. During and subsequent to this hyperventilatory challenge, the patient did not develop chest pain or electrocardiographic changesindicative of myocardial ischemia. He was discharged with the diagnosisof Prinzmetal’s variant angina. Becauseof the demonstrated effi-