Potena Luciano, Fearon William F, Sydow Karsten, Holweg Cecile, Luikart Helen, Chin Clifford, Weisshaar Dana, Mocarski Edward S, Lewis David B, Valantine Hannah A, Cooke John P
Department of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Transplantation. 2008 Mar 27;85(6):827-33. doi: 10.1097/TP.0b013e318166a3a4.
Cardiac allograft vasculopathy (CAV) is a major cause of death after heart transplantation (HT). The reduced bioavailability of endothelium-derived nitric oxide may play a role in endothelial vasodilator dysfunction and thus in the structural changes characterizing CAV. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. It was hypothesized that ADMA concentrations may influence CAV progression during the first postoperative year.
Thirty-two consecutive HT recipients underwent intravascular ultrasound evaluation at month 1 and year 1 after HT. Immunosuppression included mycophenolate mofetil (MMF, n=16) and sirolimus (n=16). Change in intimal volume greater than the median and vascular remodeling were major outcome measures.
Plasma ADMA levels were associated with subsequent development of intimal hyperplasia (risk ratio [95% confidence interval] =2.72 [1.06-6.94]; P=0.038), and plasma ADMA levels greater than 0.70 micromol/L most accurately identified patients who would have developed intimal hyperplasia. However, ADMA levels did not correlate with negative coronary remodeling. Treatment with sirolimus, as compared with MMF, was associated with significantly lower ADMA levels (0.65+/-0.12 vs. 0.77+/-0.10 micromol/L; P<0.01) and less intimal hyperplasia (risk ratio [95% confidence interval] = 0.08 [0.01-0.56]; P=0.01).
Elevated plasma ADMA is associated with coronary intimal hyperplasia, supporting the importance of nitric oxide synthase inhibition in CAV pathogenesis. Treatment with sirolimus (rather than MMF) is associated with lower ADMA levels and reduced risk of accelerated CAV.
心脏移植血管病变（CAV）是心脏移植（HT）后死亡的主要原因。内皮源性一氧化氮生物利用度降低可能在内皮舒张功能障碍中起作用，进而在CAV特征性的结构变化中起作用。不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶抑制剂，是内皮病理生物学的一个潜在促成因素。据推测，ADMA浓度可能会影响术后第一年CAV的进展。
32例连续的HT受者在HT后第1个月和第1年接受血管内超声评估。免疫抑制包括霉酚酸酯（MMF，n = 16）和西罗莫司（n = 16）。内膜体积变化大于中位数和血管重塑是主要结局指标。
血浆ADMA水平与随后内膜增生的发生相关（风险比[95%置信区间]=2.72[1.06 - 6.94]；P = 0.038），血浆ADMA水平大于0.70 μmol/L最准确地识别出会发生内膜增生的患者。然而，ADMA水平与阴性冠状动脉重塑无关。与MMF相比，西罗莫司治疗与显著更低的ADMA水平（0.65±0.12 vs. 0.77±0.10 μmol/L；P < 0.01）和更少的内膜增生相关（风险比[95%置信区间]=0.08[0.01 - 0.56]；P = 0.01）。
血浆ADMA升高与冠状动脉内膜增生相关，支持一氧化氮合酶抑制在CAV发病机制中的重要性。西罗莫司（而非MMF）治疗与更低的ADMA水平和加速CAV风险降低相关。
