LATE CARDIAC EFFECTS OF DOXORUBICIN THERAPY FOR ACUTE LYMPHOBLASTIC-LEUKEMIA IN CHILDHOOD
LATE CARDIAC EFFECTS OF DOXORUBICIN THERAPY FOR ACUTE LYMPHOBLASTIC-LEUKEMIA IN CHILDHOOD
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DOI：
10.1056/nejm199103213241205
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发表时间：
1991-03-21
影响因子：
158.5
通讯作者：
SANDERS, SP
中科院分区：
文献类型：
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作者：
LIPSHULTZ, SE;COLAN, SD;SANDERS, SP
背景。心脏毒性是多柔比星治疗公认的并发症，但多柔比星的长期影响尚未得到充分记录。因此，我们评估了115名在1至15年前因急性淋巴细胞白血病接受多柔比星治疗且疾病持续缓解的儿童的心脏状况。
方法。18名患者接受了一剂多柔比星（每平方米体表面积45毫克），97名患者接受了多剂，总计每平方米228至550毫克（中位数为360毫克）。治疗结束与心脏评估之间的中位间隔为6.4年。我们的评估包括病史、24小时动态心电图记录、运动试验和超声心动图。
结果。57%的患者有左心室后负荷（以收缩末期壁应力衡量）或收缩力（以应力 - 速度指数衡量）异常。多柔比星的累积剂量是心脏功能异常最显著的预测因素（P < 0.002）。接受一剂多柔比星的患者中有17%有年龄校正后的后负荷轻度升高，且无人收缩力下降。相比之下，每平方米至少接受228毫克多柔比星的患者中有65%出现后负荷增加（59%的患者）、收缩力下降（23%）或两者兼有。后负荷增加是由于心室壁厚度减少，而非高血压或心室扩张。在仅限于每平方米至少接受228毫克多柔比星的患者的多变量分析中，唯一显著的预测因素是较高的累积剂量（P = 0.01），其预测收缩力下降，以及治疗时年龄小于4岁（P = 0.003），其预测后负荷增加。在连续评估的34名患者中有24名（71%）后负荷逐渐增加。报告的症状与运动耐量或心室功能指标相关性较差。11名患者在多柔比星治疗后一年内出现充血性心力衰竭；其中5名在完成多柔比星治疗后3.7至10.3年心力衰竭复发，2名需要心脏移植。没有患者出现新发的晚期心力衰竭。
结论。儿童时期的多柔比星治疗以剂量相关的方式损害心肌生长，并导致左心室后负荷逐渐增加，有时伴有收缩力下降。我们假设儿童时期多柔比星治疗过程中肌细胞的丢失可能导致左心室质量不足，并在日后引发具有临床重要性的心脏病。
Background. Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore-assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission.Methods. Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography.Results. Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress-velocity index). The cumulative dose of doxorubicin was the most significant predictor of abnormal cardiac function (P < 0.002). Seventeen percent of patients who received one dose of doxorubicin had slightly elevated-age-adjusted afterload, and none had decreased contractility. In contrast, 65 percent of patients who received at least 228 mg of doxorubicin per square meter had increased afterload (59 percent of patients), decreased contractility (23 percent), or both. Increased afterload was due to reduced ventricular wall thickness, not to hypertension or ventricular dilatation. In multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant predictive factors were a higher cumulative dose (P = 0.01), which predicted decreased contractility, and an age of less than four years at treatment (P = 0.003), which predicted increased afterload. Afterload increased progressively in 24 of 34 patients evaluated serially (71 percent). Reported symptoms correlated poorly with indexes of exercise tolerance or ventricular function. Eleven patients had congestive heart failure within one year of treatment with doxorubicin; five of them had recurrent heart failure 3.7 to 10.3 years after completing doxorubicin treatment, and two required heart transplantation. No patient had late heart failure as a new event.Conclusions. Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload, sometimes accompanied by reduced contractility. We hypothesize that the loss of myocytes during doxorubicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years.