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首页> 外文期刊>ESC Heart Failure >Acute molecular effects of pressure‐controlled intermittent coronary sinus occlusion in patients with advanced heart failure
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Acute molecular effects of pressure‐controlled intermittent coronary sinus occlusion in patients with advanced heart failure

机译：压力控制性间歇性冠状动脉窦阻塞对晚期心力衰竭的急性分子影响

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Aims Cardiac repair has steered clinical attention and remains an unmet need, because available regenerative therapies lack robust mechanistic evidence. Pressure‐controlled intermittent coronary sinus occlusion (PICSO), known to induce angiogenetic and vasoactive molecules as well as to reduce regional ischemia, may activate endogenous regenerative processes in failing myocardium. We aimed to investigate the effects of PICSO in patients with advanced heart failure undergoing cardiac resynchronization therapy. Methods and results Eight out of 32 patients were treated with PICSO, and the remainder served as controls. After electrode testing including left ventricular leads, PICSO was performed for 20?min. To test immediate molecular responses, in both patient groups, coronary venous blood samples were taken at baseline and after 20?min, the time required for the intervention. Sera were tested for microRNAs and growth factors. To test the ability of up‐regulated soluble factors on cell proliferation and expression of transcription factors [e.g. Krüppel‐like factor 4 (KLF‐4)], sera were co‐cultured with human cardiomyocytes and fibroblasts. As compared with controls, significant differential expression (differences between pre‐values and post‐values in relation to both patient cohorts) of microRNA patterns associated with cardiac development was observed with PICSO. Importantly, miR‐143 ( P ??0.048) and miR‐145 ( P ??0,047) increased, both targeting a network of transcription factors (including KLF‐4) that promote differentiation and repress proliferation of vascular smooth muscle cells. Additionally, an increase of miR‐19b ( P ??0.019) known to alleviate endothelial cell apoptosis was found, whereas disadvantageous miR‐320b ( P ??0.023) suspect to impair expression of c‐myc, normally provoking cell cycle re‐entry in post‐mitotic myocytes and miR‐25 ( P ??0.023), decreased, a target of anti‐miR application to improve contractility in the failing heart. Co‐cultured post‐PICSO sera significantly increased cellular proliferation both in fibroblasts ( P ??0.001) and adult cardiomycytes ( P ??0.004) sampled from a transplant recipient as compared with controls. Adult cardiomyocytes showed a seven‐fold increase of the transcription factor KLF‐4 protein when co‐cultured with treated sera as compared with controls. Conclusions Here, we show for the first time that PICSO, a trans‐coronary sinus catheter intervention, is associated with an increase in morphogens secreted into cardiac veins, normally present during cardiac development, and a significant induction of cell proliferation. Present findings support the notion that epigenetic modifications, that is, haemodynamic stimuli on venous vascular cells, may reverse myocardial deterioration. Further investigations are needed to decipher the maze of complex interacting molecular pathways in failing myocardium and the potential role of PICSO to reinitiate developmental processes to prevent further myocardial decay eventually reaching clinical significance.
机译：目的心脏修复已引起临床关注，但仍未满足需求，因为可用的再生疗法缺乏可靠的机制证据。压力控制间歇性冠状动脉窦闭塞（PICSO），已知可诱导血管生成和血管活性分子，并减少局部缺血，可激活衰竭心肌的内源性再生过程。我们旨在研究PICSO在接受心脏再同步治疗的晚期心力衰竭患者中的​​作用。方法和结果32例患者中有8例接受PICSO治疗，其余作为对照。电极测试包括左心室导线后，进行PICSO 20分钟。为了测试即时的分子反应，在两个患者组中，均在基线和干预时间20分钟后采集了冠状静脉血样。测试血清中的microRNA和生长因子。测试上调可溶性因子对细胞增殖和转录因子表达的能力[例如将血清与类Krüppel因子4（KLF-4），人心肌细胞和成纤维细胞共培养。与对照相比，PICSO观察到与心脏发育相关的微小RNA模式的显着差异表达（相对于两个患者队列的前值和后值之间的差异）。重要的是，miR-143（P <？0.048）和miR-145（P？<0.047）都增加了，它们都针对促进分化并抑制血管平滑肌细胞增殖的转录因子网络（包括KLF-4）。此外，发现已知可减轻内皮细胞凋亡的miR-19b（P <？0.019）增加，而不利的miR-320b（P <？0.023）可能会损害c-myc的表达，通常会引起细胞周期的恢复。有丝分裂后心肌细胞和miR-25的进入（P？<？0.023）减少，这是应用抗miR的目标，以改善衰竭心脏的收缩力。与对照组相比，PICSO共培养后血清在成纤维细胞（P <0.001）和成年心肌细胞（P <0.004）中均显着提高了细胞增殖。与对照血清共培养时，成人心肌细胞的转录因子KLF-4蛋白增加了7倍。结论在这里，我们首次证明了经冠状动脉窦导管介入术PICSO与心脏发育中通常存在的分泌到心脏静脉的形态发生子增加以及细胞增殖的显着诱导有关。目前的发现支持以下观点：表观遗传修饰，即对静脉血管细胞的血流动力学刺激，可以逆转心肌退化。需要进一步的研究来破译心肌衰竭中复杂的相互作用分子途径的迷宫，以及PICSO在重新启动发育过程以防止进一步的心肌衰退最终发挥临床意义方面的潜在作用。

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