Seino Yoshihiko, Hori Masatsugu, Sonoda Takao
The First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
Cardiovasc Drugs Ther. 2003 Mar;17(2):141-9. doi: 10.1023/a:1025339819051.
To clarify the incidence and pathophysiological mechanism of cardiovascular adverse effects of tacrolimus, the present prospective study performed scheduled cardiovascular examinations at 1, 2, 4, 8, 16, 20, and 24 weeks after starting the tacrolimus therapy in 68 consecutive kidney transplantation recipients enrolled from 26 institutes in Japan. Patients with previous coronary artery disease or congestive heart failure were excluded. The examinations included any subjective symptoms, changes in resting ECG, ambulatory Holter's dynamic ECG, two-dimensional echocardiography, and monitoring of serum drug concentrations and cardiac troponin T levels. Cardiac nuclear imaging and/or coronary angiography were performed in the case of suspicious coronary events. During the investigation, chest pain in 9 (13.2%) and palpitation in 6 patients (8.8%) were reported, both closely related to elevated blood drug concentrations (37.2 +/- 18.7 ng/mL, mean +/- SD). Cardiovascular examinations detected development of resting ECG abnormalities in 12 patients (17.6%), asymptomatic ST depression following increased heart rate in 11 (16.2%) and ventricular arrhythmias in 7 patients (10.3%) on Holter's dynamic ECG. Elevation of troponin T was detected in 3 patients (4.4%), which was also closely related to elevated drug concentrations and interpreted as myocardial damage associated with the therapy. Assessments by thallium(Tl)-201 myocardial scintigraphy and/or coronary angiography in patients with suspicious coronary events revealed only two patients (2.9%) were considered to be myocardial ischemia associated with coronary vasospasm or microcirculatory disturbance. Sequential evaluations on echocardiography revealed significant (p<0.05) decrease in LV end-diastolic dimension (4, 8, 18 and 24 weeks) and LV end-systolic dimension (from 1 to 24 weeks), and significant (p<0.05) increase in LV ejection fraction 1 to 4 weeks after the kidney transplantation. Thickening of LV wall (>2 mm compared with baseline) was detected in only one patient. The present prospective study detected totally 30.9% incidence of cardiovascular adverse events. Symptomatic events and troponin T elevation were closely related to elevated blood drug concentrations (>20 ng/ml). Coronary vasomotor dysfunction seemed to be related to these adverse events especially when the blood drug concentration was exceeding 20 ng/ml.
为阐明他克莫司心血管不良反应的发生率及病理生理机制，本前瞻性研究对来自日本26家机构的68例连续肾移植受者在开始他克莫司治疗后的第1、2、4、8、16、20和24周进行了定期心血管检查。排除既往有冠状动脉疾病或充血性心力衰竭的患者。检查包括任何主观症状、静息心电图变化、动态心电图监测、二维超声心动图以及血清药物浓度和心肌肌钙蛋白T水平监测。对于可疑冠状动脉事件，进行心脏核素成像和/或冠状动脉造影。在调查期间，报告了9例患者（13.2%）出现胸痛，6例患者（8.8%）出现心悸，均与血药浓度升高密切相关（平均±标准差为37.2±18.7 ng/mL）。心血管检查发现12例患者（17.6%）出现静息心电图异常，11例患者（16.2%）在动态心电图监测中出现心率增加后无症状性ST段压低，7例患者（10.3%）出现室性心律失常。3例患者（4.4%）检测到肌钙蛋白T升高，这也与药物浓度升高密切相关，并被解释为与治疗相关的心肌损伤。对可疑冠状动脉事件患者进行铊（Tl）-201心肌闪烁显像和/或冠状动脉造影评估发现，仅2例患者（2.9%）被认为存在与冠状动脉痉挛或微循环紊乱相关的心肌缺血。超声心动图的连续评估显示，肾移植后1至4周左心室舒张末期内径（第4、8、18和24周）和左心室收缩末期内径（第1至24周）显著（p<0.05）减小，左心室射血分数显著（p<0.05）增加。仅1例患者检测到左心室壁增厚（与基线相比>2 mm）。本前瞻性研究检测到心血管不良事件的总发生率为30.9%。有症状事件和肌钙蛋白T升高与血药浓度升高（>20 ng/ml）密切相关。冠状动脉血管舒缩功能障碍似乎与这些不良事件有关，尤其是当血药浓度超过20 ng/ml时。
