Divisions of Cardiology (S.H., K.M.K.-S., M.M., D.A.K.)
Divisions of Cardiology (S.H., K.M.K.-S., M.M., D.A.K.).
Circulation. 2018 May 29;137(22):2360-2370. doi: 10.1161/CIRCULATIONAHA.117.033147. Epub 2018 Jan 19.
Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function.
Cardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined.
Myocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (F) was 28% higher in IPAH but 37% lower in SSc-PAH. F in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte F directly correlated with in vivo RV contractility assessed by end-systolic elastance ( =0.46, =0.002) and change in end-systolic elastance with exercise ( =0.49, =0.008) and was inversely related with exercise-induced chamber dilation ( =0.63, <0.002), which also was a marker of depressed contractile reserve.
A primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.
与特发性肺动脉高压（IPAH）相比，系统性硬化症（SSc）相关肺动脉高压（PAH）患者的预后要差得多。在完整的心脏中，与 IPAH 相比，SSc-PAH 表现出静息和储备右心室（RV）收缩力降低。我们检测了这种差异是否涉及肌丝功能的潜在差异。
从 SSc-PAH、IPAH 或 SSc 伴运动性呼吸困难但无静息性 PAH（SSc-d）患者的 RV 间隔心内膜心肌活检中分离心肌细胞。对照 RV 间隔组织取自非病变供心（每组 6-7 个）。确定分离的心肌细胞被动长度-张力和发育张力-钙关系，并与体内 RV 功能和储备相关。还检查了 RV 间隔纤维化。
与对照组相比，IPAH 和 SSc-PAH 的肌细胞被动刚度与长度-张力关系相似增加，尽管 SSc-PAH 活检中存在更多的间质纤维化。在主动力-钙关系之间发现了更显著的差异。与对照组相比，IPAH 的最大钙激活力（F）高 28%，而 SSc-PAH 的 F 低 37%。SSc-d 的 F 介于对照组和 SSc-PAH 之间。一半最大力（EC）所需的钙浓度在对照组、IPAH 和 SSc-d 之间相似，但在 SSc-PAH 中较低。这种差异在用蛋白激酶 A 的活性催化亚单位孵育的心肌细胞中消失。肌细胞 F 与通过收缩末期弹性评估的体内 RV 收缩性直接相关（ =0.46，=0.002），与运动时收缩末期弹性的变化相关（ =0.49，=0.008），与运动诱导的腔扩张呈负相关（ =0.63，<0.002），这也是收缩储备降低的标志物。
人类 SSc-PAH 的主要缺陷在于肌节功能降低，而 IPAH 则增强。这些差异与体内 RV 收缩性和收缩储备相关，与 SSc-PAH 的临床预后较差一致。SSc-d 患者在发生静息性 PAH 之前存在肌节疾病，这表明早期识别和干预可能有用。
