Clin. Cardiol.

15, 122-125 (1992)

Chemotherapy-Induced Myocardial Infarction in a Young Man with Hodgkins Disease

KENNETH

W. HOUSE, D.o., SHERYL R. SIMON, M.D., REGINALD P. PUGH, M.D.

Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA

Summary: A 32-year-old male with stage IIIA nodular

sclerosing Hodgkins disease and no cardiac risk factors presented with chest pain after receiving chemotherapy consisting of multiple drugs, including vinca alkaloids. He completed an uncomplicated anterior wall myocardial infarction. Coronary angiography documented the absence of significant coronary artery disease. Exercise stress testing with gated scan confirmed loss of anterior wall motion and a decreased left ventricular ejection fraction. Vascular toxicity, including, rarely, myocardial infarction, has been reported following antineoplastic regimens containing vinca alkaloids. Hypercoagulable states, cardiac invasion by tumor, and coronary artery spasm are possible etiologies. Of these, coronary artery spasm appears most likely. Management should include discontinuationof the offending drug and supportive care.

ic agents are the anthracyclines,most notably doxorubicin, scattered reports of vinca alkaloid-induced cardiotoxicity* have emerged over the past two decades. A case of acute myocardial infarction following initiation of a standard chemotherapy regimen for Hodgkins disease consisting of nitrogen mustard, vincristine, procarbazine and prednisone, doxorubicin (Adriamycin), bleomycin, and vinblastine (MOPP-ABV) is presented. Possible etiologies to explain this event are discussed in order to emphasize a potential clinical problem.

Case Presentation
A 32-year-old male presented with axillary and supraclavicular adenopathy. He had no fevers, nighttime diaphoresis, or weight loss. He had no history of cardiac disease, hypertension,diabetes mellitus, tobacco use, elevated cholesterol, or family history of premature cardiovascular disease. Biopsy of a left supraclavicular lymph node revealed Hodgkins disease, nodular sclerosis subtype. Computed tomography of the thorax and abdomen revealed mediastinal and left supraclavicular adenopathy. Staging exploratory laparotomy revealed splenic involvement of Hodgkins disease. He received radiation therapy consisting of 40 Gray to the thorax with full mantle technique over 4 weeks and 35 Gray to the para-aortic area and splenic pedicle. Twenty months later the patient noted enlarged left axillary lymph nodes. Biopsy confirmed recurrent nodular sclerosis Hodgkins disease. The patient received MOPP-ABV chemotherapy, a standard treatment for Hodgkins disease. The program consisted of nitrogen mustard and vincristine administered intravenously (IV) on Day 1, with procarbazine and prednisone given orally over 10 and 14 days, respectively. Within 2 hours of receiving nitrogen mustard 10.15 mg IV and vincristine 2.5 mg IV on Day 1, the patient experienced nausea, diaphoresis, and diffuse chest tightness with radiation to bilateral upper extremities. He did not seek medical attention and the discomfortresolved after approximately 2 hours.

Key words: Hodgkins disease, drug therapy, vincristine, vinblastine, myocardial infarction Introduction
Cardiotoxicity following administration of antineoplastic agents is widely recognized.. * Multiple types of cardiac injury have been reported including cardiomyopathy, pericarditis-myocarditis,arrhythmias,angina, and myocardial infarction. Although the most well-known cardiotox-

Address for reprints: Sheryl Simon, M.D. Allegheny General Hospital 320 E. North Avenue Pittsburgh, PA 15212, USA Received September 13, 1991 Accepted: September 27, 1991

K. W. House et al.: MI induced by chemotherapy

123

FIG.1 Electrocardiogram showing acute anterolateral wall myocardial infarction.

Seven days later he received doxorubicin 60 mg IV, bleomycin 18 mg IV, and vinblastine 10.5 mg IV. Five hours later he developed a second episode of chest tightness and did seek medical attention. An electrocardiogram revealed ST-segment elevation in the anterolateral leads consistent with acute myocardial infarction (Fig. 1). His coagulation profile was normal. Cardiac enzymes confirmed infarction and Q waves evolved in the anterolatera1 leads of his electrocardiogram indicating transmural scar. An echocardiogram revealed an ejection fraction of 25% immediately following the myocardial infarction. One week later, coronary angiography revealed widely patent epicardial coronary arteries and akinetic anterolateral and inferoapical walls. He was released from the hospital following routine care of his uncomplicated infarction. A repeat echocardiogram revealed an ejection fraction of 40%. An exercise stress test with radionuclide angiography performed one month following discharge showed decreased motion of the anteroseptal wall which was felt to represent a transmural anterior wall infarction as well as evidence of a nontransmural inferoapical and inferior wall infarction. Left ventricular ejection fraction at that time was 46%. He is currently maintained on a calcium channel blocker and an angiotensin converting enzyme inhibitor and is asymptomatic after 12 months of follow-up. He has received no further chemotherapy and has no evidence of Hodgkins disease.

Discussion
A young man without cardiac risk factors sustained a myocardial infarction after receiving chemotherapy. We believe that the acute infarction was related to vinca alkaloids because of the close temporal association between vincristine and the f i s t episode of chest pain and between vinblastine and the acute myocardial infarction. The other

chemotherapy agents he received, as well as the antiemetics (dexamethasone, triethylperazine,and lorezapam),have not been associated with acute myocardial infarctions. Vincristine and vinblastine, the most commonly used vinca alkaloids, are cytotoxic alkaloid derivatives of the pink periwinkle. They exert their action by binding to the microtubular protein, tubulin, which inhibits formation of the mitotic spindle causing accumulation of cells in mitos ~ sVinca . ~ alkaloids are used primarily in the treatment of leukemias and lymphomas. The most common vincristinerelated toxicity is peripheral neuropathy including decreased deep tendon reflexes, paresthesias of the extremities, motor weakness, and autonomic neuropathy. The doselimiting side effect of vinblastine is myelosuppre~sion.~ Myocardial toxicity due to vinca-containing chemotherapeutic regimens is an infrequent complication. Although there are no case reports in the American cardiology literature, 12 patients have been reported in the world literature who had a myocardial infarction after receiving vincristine or vinblastine (Table Of these, 5 patients were less than 40 years of age; 1 was reported to have no coronary artery disease, and 4 had no cardiac disease risk factors. Five had prior mediastinal radiation therapy. The diagnosis of vinca-induced myocardial infarction is one of exclusion. Other etiologies must be considered including a coincidental myocardial infarction, involvement of the heart by lymphoma, or radiation-induced coronary artery disease. This young man had no cardiac risk factors and his coronary vessels were normal on angiography. Involvement of the heart or pericardium by malignant lymphoma is rare, occurring in 8.7% of patients in one autopsy study.14Rather than acute myocardial infarction,metastases commonly cause pericardial effusion, tamponade, outflow obstruction, and heart fai1~re.l~ Our patient was without these abnormalities both clinically and by echocardiogram. It is unlikely that he had either a coincidental myocardial infarction or lymphomatous involvement of the heart.

124
I TABLE

Clin. Cardiol. Vol. 15, February 1992

Patient
No.
1

Author (ref.) Tavcar et al. (4) Allal et al. (5) Subar and Muggia
(6)

AgeISex
32M

Coronary anatomy Left anterior or descending coronary artery occlusion Unknown Unknown Unknown Normal Unknown Left anterior descending coronary artery thrombosis at autopsy Total left main occulsion with retrograde filling
Unknown

Risk factors None None None Diabetes None

Unknown

Chemo-

therapy Vincristine Vincristine Vincristine Vinblastine Vincristine Vincristine Vinblastine

Mediastinal radiotherapy No
No

Tumor Hodgkins disease Gastric cancer Breast cancer Lung cancer Hodgkins disease Non-Hodgkins lymphoma Hodgkins disease

2 3 4

45F 78/F 62/F 27N 73F 37M

No No
Yes No

5
6 7

Weinstein et al. (7) Somers et al. (8)

Lejonc et al. (9)

Tobacco

Yes

Hanis and Wong (10)

26/M

Tobacco

Vinblastine

Yes

Hodgkins disease Hodgkins disease Non-Hodgkins lymphoma Hodgkins disease Hodgkins disease Hodgkins disease

10 11
12

Mandel et al. (1 1) Dechy et al. ( 12) Barra et al. (1 3)

55M 58M

Moderate generalized atherosclerosis at autopsy

Right coronary

49/M 29N 54N

Vinblastine Tobacco Vincristine Previous myocardial infarction Vincristine Tobacco

Yes No No
Yes No

artery occulsion Unknown Unknown

Tobacco Tobacco

Vincristine Vincristine

The fact that our patient had previously received mediastinal radiation is relevant. In a series of 590 patients who received irradiation for Hodgkins disease, 11 had a myocardial infarction 4 to 144 months after treatment (median 90 months).15 Several other reports have documented myocardial infarction in patients after irradiation, usually as a long-term complication of the radiotherapy.16-18 The possibility of an additive or synergistic effect of chemotherapy with irradiation is difficult to establish. The mechanism by which chemotherapy, specifically vinca alkaloids, cause myocardial infarction is not known. One suggestion is the development of a hypercoagulable diathesis. An increased incidence of thrombosis has been noted in several studies of patients undergoing chemotherapy for turn or^.^^^ 2o It has been postulated that chemotherapeutic agents may produce such hypercoagulable states, through the release of factors from the tumor which modify the coagulation system. But thromboses have also occurred in patients with breast cancer who had no demonstrable tumor and who received adjuvant therapy.21. 22 This suggests that the chemotherapy may have a direct effect on coagulation. Only one patient reported in the literature who had a myocardial infarction following vincristine therapy underwent evaluation of the coagulation system. No effect was found on the parameters tested including platelet

aggregation, fibrinogen, factor III, fibrin stabilization factors, clotting time, euglobulin lysis time, clot retraction, prothrombin time, recalcification time, kaolin-cefalin clotting time, and thromboplastin generation time. This does not exclude vincristine causing a hypercoagulable state. Another proposed mechanism is coronary artery spasm following chemotherapy. This has been among the most prevalent of the possible mechanisms of injury in patients suffering cardiac complications. Reproducible ST-segment elevations reminiscent of Prinzmetals angina were seen in a patient exposed to vindesine, a semisynthetic alkaloid. In this case the ECG normalized and cardiac isoenzymes remained within normal limits without i n t e r ~ e n t i o n . ~ ~ However, Subar reported a 62-year-old woman who developed chest pain and ECG changes during treatment with vinblastine while on verapamil, suggesting that either coronary artery spasm was not responsible or that the calcium channel antagonist was not present in sufficient amounts.6 It is possible that chemotherapeutic compounds may produce cellular hypoxia predisposing the vessel to spasm. Alternatively, a combination of neural, vascular, and thrombotic events may be involved. Although vinca-associated myocardial infarction is rare, the literature evidence supports that this is not coincidental. Two patients had a myocardial infarction after receiving

K. W. House et al.: MI induced by chemotherapy

125

vincristine on two separate occasions.8,I The young age of some of the patients and their lack of predisposing factors for myocardial infarction suggests a causal relationship. There was also a striking temporal relationship between chemotherapy administration and myocardial infarction. Infarction occurs with such rarity that routine monitoring of patients receiving vinca alkaloids is unnecessary. Occurrence of chest pain or other symptoms of myocardial injury warrants inpatient monitoring and aggressive treatment. Thereafter, vinca alkaloids should be avoided in these patients. Patients previously exposed to significant amounts of mediastinal radiation may be at higher risk for cardiovascular events. Awareness of the potential for vinca-induced cardiotoxicity, especially in patients with previous mediastinal radiotherapy, and its timely treatment are at present the best defense.

References
1 . Doll DC, Ringenberg QS, Yarbro J W Vascular toxicity associated with antineoplastic agents. J Clin Oncol 4, 1405-1417

(1986) 2. Perry MC: Effects of chemotherapy on the heart. In Cancer and the Heart (Ed. Kapoor AS). Springer-Verlag, New York (1986) 223-226 3. Bender RA, Hamel E, Hande KR: Plant alkaloids. In Cancer Chemotherapy: Principles and Practice (Eds. Chabner BA, Collins JM). Lippincott, Philadelphia ( 1990) 253-275 4. Tavcar I, Malesevic M, Ciko Z: Myocardial infarction after treatment of Hodgkins disease with vincristine. SRPSKIArch ZA CelakupnoLekarstvo 108, 1325-1331 (1980) 5 . Allal J, Becq-Giraudon B, Pouget-Abadie JF, Sudre Y,Barraine R: Two new cases of myocardial infarction following the injection of vincristine. Ann Cardiol Angio/33,469470 (1984) 6. Subar M, Muggia FM: Apparent myocardial ischemia associated with vinblastine administration. Cancer Treat Rep 70, 690-691 (1986) 7. Weinstein P, Greenwald ES, Grossman J: Unusual cardiac reaction to chemotherapy following mediastinal irradiation in a patient with Hodgkins disease. A m J Med 60, 152-156 (1976)

8. Somers G , Abramow M, Wittek M, Naets JP: Myocardial infarction: A complication of vincristine treatment? Lancer 2,690 ( 1976) 9. Lejonc JL, Vernant JP, Macquin I, Castaigne A: Myocardial infarction following vinblastine treatment. Lancet 2,692 (1980) 10. Harris AL, Wong C: Myocardial ischaemia, radiotherapy, and vinblastine. Lancet 1,787 (1981) 11. Mandel EM, Lewinski U, Djaldetti M: Vincristine-induced myocardial infarction. Cancer 36, 1979-1982 (1975) 12. Dechy H, Debain P, Levy R, Dorra M: Myocardial infarction after vincristine treatment. Nouv Prase Med 7,2657 (1978) 13. Barra M, Brignole M, Sartore B, Bertulla A: Vincristine induced myocardial infarction in two patients with Hodgkins disease. GZtalCardiol 15, 107-111 (1985) 14. McDonnell PJ, Mann RB, Bulkley BH: Involvement of the heart by malignant lymphoma: A clinicopathologic study. Cancer 49,944-95 1 (1982) 15. Tarbell NJ, Thompson L, Mauch P: Thoracic irradiation in Hodgkins disease: Disease control and long-term complications. Int J Rad Oncol Biol Phys 18,275-281 (1990) 16. Gustavsson A, Eskilsson J, Landberg T, Svahn-Tapper G , White T, Wollmer P, Akerman M: Late cardiac effects after mantle radiotherapy in patients with Hodgkins disease. Ann Oncol I , 355-363 (1990) 17. Rodgers DL: Precocious myocardial infarction after radiation treatment for Hodgkins disease. Chest 70, 675-677 (1976) 18. McReynolds RA, Gold GL. Roberts WC: Coronary heart disease after mediastinal irradiation for Hodgkins disease. Am J Med 60,3945 ( 1976) 19. Seifter EJ, Young RC, Longo DL: Deep venous thrombosis during therapy for Hodgkins disease. Cancer Treat Rep 69, 10111013 (1985) 20. Goodnough LT, Saito H, Manni A, Jones PK, Pearson OH: Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-drug chemotherapy regimen: A study of 159 patients. Cancer 54, 1264-1268 (1984) 21. Weiss RB, Tormey DC, Holland JF, Weinberg VE: Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat Rep 65,677-679 (1981) 22. Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, De Pauw S: The thrombogenic effect of anticancer drug therapy in women with stage I1 breast cancer. N Engl J Med 3 18,404-407 (1988) 23. Yancey RS, Talpaz M: Vindesine-associated angina and ECG changes. Cancer Treat Rep 66,587-589 (1982)