Correspondence

Plasma Endothelin-1 and Doxorubicin Cardiotoxicity

N Engl J Med 1994; 331:1528-1529December 1, 1994

Article

To the Editor:

Doxorubicin is a widely used and effective antineoplastic agent. However, doxorubicin therapy is limited by dose-dependent cardiotoxicity that may lead to congestive heart failure.1 To optimize doxorubicin therapy, it is important to detect early signs of cardiac toxicity. To measure the severity of myocardial damage and dysfunction, cardiac catheterization and endomyocardial biopsy have been used, as have electrocardiography, echocardiography, and radionuclear angiography. However, these methods all have limitations, are inadequate for the serial monitoring of individual patients, or both.

Levels of endothelin-1 peptide are transiently increased after physical stress.2,3 While studying sequential changes in plasma endothelin-1 levels with a specific radioimmunoassay4,5 during various types of stress, we noticed that the level of plasma endothelin-1 increased progressively in two patients with breast cancer who had received doxorubicin and in whom congestive heart failure subsequently developed (Figure 1Figure 1Sequential Plasma Endothelin-1 Concentrations in Two Patients with Breast Cancer Who Received Doxorubicin Therapy and Subsequently Had Congestive Heart Failure (CHF).). In both patients electrocardiography, echocardiography, and the left ventricular ejection fraction revealed no abnormalities just before the last administration of doxorubicin. By contrast, plasma endothelin-1 levels were increased as compared with the levels before the start of chemotherapy. These patients had received cumulative doses of 490 and 450 mg of doxorubicin per square meter of body-surface area, and clinical congestive heart failure had developed, as manifested by reduced exercise tolerance, resting sinus tachycardia, and reduced left ventricular ejection fraction. In 21 patients with breast cancer who had received doxorubicin therapy in cumulative doses ranging from 380 to 580 mg per square meter but in whom congestive heart failure had not developed, we found no change in plasma endothelin-1 levels during treatment.

Doxorubicin cardiomyopathy is dose-related, and overt congestive heart failure occurs in up to 25 to 30 percent of patients who receive cumulative doses of doxorubicin exceeding 550 mg per square meter.6 However, there is substantial variability in the maximal tolerated dose. In the two patients described here, the cumulative doxorubicin doses were relatively low (490 and 450 mg per square meter). This preliminary report suggests that serial monitoring of plasma endothelin-1 levels may detect subclinical doxorubicin cardiotoxicity. We have started a prospective study of plasma endothelin-1 levels and the doxorubicin-related risk of congestive heart failure.

Jun-ichi Yamashita, M.D.
Michio Ogawa, M.D.
Koichi Nomura, M.D.
Kumamoto University Medical School, Kumamoto 860, Japan

6 References

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Citing Articles (2)

Citing Articles

1. 1

   M Gharib. (2002) Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis. European Journal of Heart Failure 4:3, 235-242
   CrossRef

2. 2

   Jun-Ichi Yamashita, Michio Ogawa, Takayuki Shirakusa. (1995) Plasma endothelin-1 As a marker for doxorubicin cardiotoxicity. International Journal of Cancer 62:5, 542-547
   CrossRef