Department of Medicine and Pulmonary Hypertension Program, University of Alberta and Mazankowski Alberta Heart Institute, 2C2 WMC, 8440-112 St, Edmonton, Canada.
Circ Res. 2013 Jan 18;112(2):347-54. doi: 10.1161/CIRCRESAHA.111.300448. Epub 2012 Dec 10.
Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin (ET)-1 receptor antagonists (ERAs) are approved therapies for PAH. It is not known whether ERAs have effects on the RV, in addition to their vasodilating/antiproliferative effects in pulmonary arteries.
We hypothesized that the ET axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium.
RV myocardial samples from 34 patients with RVH were compared with 16 nonhypertrophied RV samples, and from rats with normal RV versus RVH attributable to PAH. Confocal immunohistochemistry showed that RVH myocardial ET type A (but not type B) receptor and ET-1 protein levels were increased compared with the nonhypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area; r(2)=0.838 and r(2)=0.818, respectively; P<0.01). These results were recapitulated in the rat model. In modified Langendorff perfusions, ERAs (BQ-123 and bosentan 10(-7,-6,-5) mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner (P<0.01).
Patients and rats with PAH have an upregulation of the myocardial ET axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function, and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERAs on the RV in patients with RVH and PAH.
右心室（RV）功能是肺动脉高压（PAH）发病率和死亡率的最重要决定因素。内皮素（ET）-1 受体拮抗剂（ERAs）是 PAH 的批准治疗药物。尚不清楚 ERAs 是否除了对肺动脉具有舒张/抗增殖作用外，对 RV 还有其他作用。
我们假设 ET 轴在 RV 肥厚（RVH）中上调，并且 ERAs 对 RV 心肌具有直接作用。
将 34 例 RVH 患者的 RV 心肌样本与 16 例非肥厚 RV 样本以及归因于 PAH 的正常 RV 与 RVH 的大鼠进行比较。共聚焦免疫组织化学显示，与非肥厚 RV 相比，RVH 心肌 ET 型 A（而非 B）受体和 ET-1 蛋白水平升高，与 RVH 的程度呈正相关（RV 厚度/体表面积；r(2)=0.838 和 r(2)=0.818，P<0.01）。在大鼠模型中也得到了验证。在改良 Langendorff 灌流中，ERAs（BQ-123 和 bosentan 10(-7,-6,-5) mol/L）以剂量依赖性方式降低肥厚 RV 的收缩性，但对正常 RV 没有影响（P<0.01）。
PAH 患者和大鼠的 RVH 中存在心肌 ET 轴的上调。这可能是一种代偿机制，以在负荷增加时维持 RV 的收缩性。ERAs 的使用可能会潜在地使 RV 功能恶化，这可以解释临床上用这些药物治疗时观察到的一些外周水肿。需要进一步研究评估 ERAs 在 RVH 和 PAH 患者中的 RV 作用。
