Rannou Fabrice, Scotet Virginie, Marcorelles Pascale, Monnoyer Roxane, Le Maréchal Cédric
Physiology Department-EA 4324, CHRU Cavale Blanche, Brest, France.
Institut National de la Santé et de la Recherche Médicale - UMR 1078, Brest, France.
PLoS One. 2017 Nov 2;12(11):e0187266. doi: 10.1371/journal.pone.0187266. eCollection 2017.
Current evidence indicates that the common AMPD1 gene variant is associated with improved survival in patients with advanced heart failure. Whilst adenosine has been recognized to mediate the cardioprotective effect of C34T AMPD1, the precise pathophysiologic mechanism involved remains undefined to date. To address this issue, we used cardio-pulmonary exercise testing data (CPX) from subjects with myoadenylate deaminase (MAD) defects.
From 2009 to 2013, all the patients referred in our laboratory to perform a metabolic exercise testing, i.e. a CPX with measurements of muscle metabolites in plasma during and after exercise testing, were prospectively enrolled. Subjects that also underwent an open muscle biopsy for diagnosis purpose were finally included. The metabolic-chronotropic response was assessed by calculating the slope of the linear relationship between the percent heart rate reserve and the percent metabolic reserve throughout exercise. MAD activity was measured using the Fishbein's technique in muscle biopsy sample. The common AMPD1 mutation was genotyped and the AMPD1 gene was sequenced to screen rare variants from blood DNA.
Sixty-seven patients were included in the study; 5 had complete MAD deficiency, 11 had partial MAD deficiency, and 51 had normal MAD activity. Compared with normal MAD activity subjects, MAD deficient subjects appeared to have a lower-than-expected metabolic-chronotopic response during exercise. The metabolic-chronotropic relationship is more closely correlated with MAD activity in skeletal muscle (Rs = 0.57, p = 5.93E-7, Spearman correlation) than the presence of the common AMPD1 gene variant (Rs = 0.34, p = 0.005). Age-predicted O2 pulse ratio is significantly increased in MAD deficient subjects, indicating a greater efficiency of the cardiovascular system to deliver O2 (p < 0.01, Scheffé's post hoc test).
The metabolic-chronotropic response is decreased in skeletal muscle MAD deficiency, suggesting a biological mechanism by which AMPD1 gene exerts cardiac effect.
目前的证据表明，常见的AMPD1基因变异与晚期心力衰竭患者生存率的提高有关。虽然腺苷已被认为可介导C34T AMPD1的心脏保护作用，但迄今为止，所涉及的确切病理生理机制仍不明确。为解决这一问题，我们使用了患有肌腺苷酸脱氨酶（MAD）缺陷的受试者的心肺运动测试数据（CPX）。
从2009年到2013年，前瞻性纳入了所有转诊至我们实验室进行代谢运动测试的患者，即进行CPX并在运动测试期间和之后测量血浆中的肌肉代谢物。最终纳入了那些也接受了开放性肌肉活检以进行诊断的受试者。通过计算整个运动过程中心率储备百分比与代谢储备百分比之间线性关系的斜率来评估代谢变时反应。使用Fishbein技术在肌肉活检样本中测量MAD活性。对常见的AMPD1突变进行基因分型，并对AMPD1基因进行测序以筛选血液DNA中的罕见变异。
67名患者纳入研究；5名完全缺乏MAD，11名部分缺乏MAD，51名MAD活性正常。与MAD活性正常的受试者相比，MAD缺乏的受试者在运动期间的代谢变时反应似乎低于预期。代谢变时关系与骨骼肌中的MAD活性相关性更强（Rs = 0.57，p = 5.93E - 7，Spearman相关性），而不是与常见的AMPD1基因变异的存在相关性强（Rs = 0.34，p = 0.005）。MAD缺乏的受试者中年龄预测的氧脉搏比率显著增加，表明心血管系统输送氧气的效率更高（p < 0.01，Scheffé事后检验）。
骨骼肌MAD缺乏时代谢变时反应降低，提示AMPD1基因发挥心脏作用的生物学机制。
