Antiproliferative treatment of myofibroblasts prevents arrhythmias in vitro by limiting myofibroblast-induced depolarization
Antiproliferative treatment of myofibroblasts prevents arrhythmias in vitro by limiting myofibroblast-induced depolarization
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DOI：
10.1093/cvr/cvr011
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发表时间：
2011-05-01
影响因子：
10.8
通讯作者：
Pijnappels, Daniel A.
中科院分区：
文献类型：
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作者：
Askar, Said F. A.;Ramkisoensing, Arti A.;Pijnappels, Daniel A.
目的 心脏纤维化与心律失常发生率增加有关，但其潜在的致心律失常机制仍不完全清楚，抗心律失常治疗仍不理想。本研究验证了肌成纤维细胞 (MFB) 增殖通过改变心肌细胞 (CMC) 的兴奋性导致快速心律失常的假设，并且抑制 MFB 增殖会降低此类心律失常的发生率。 方法和结果 新生大鼠 CMC 培养物中的内源性 MFB 自由增殖或在不同剂量的抗增殖剂（丝裂霉素-C 和紫杉醇）的控制下增殖。在第 4 天和第 9 天，通过光学和多电极标测研究这些培养物的心律失常发生性。还研究了培养物的蛋白质表达和电生理特性。 MFB 增殖使传导速度从 15.3 +/- 3.5 cm/s（第 4 天）减慢至 8.8 +/- 0.3 cm/s（第 9 天）（n = 75，P < 0.01），而 MFB 数量增加至 37.4 +/- 1.7 和 62.0 +/- 2%。第 9 天，81.3% 的培养物显示出持续的自发折返性心律失常。然而，只有 2.6% 的丝裂霉素 C 处理培养物（n = 76，P < 0.0001）表现出快速心律失常，异位活性降低。心律失常的发生率与药物剂量相关，并且与 MFB 增殖密切相关。紫杉醇治疗产生了类似的结果。 CMC 在功能上与 MFB 偶联，并且在 MFB 持续增殖的培养物中去极化程度更高，其中仅 L 型 Ca(2+) 通道阻断可终止 100% 的折返性心律失常，而 Na(+) 阻断则可终止 (36%，n = 12)。结论 MFB 在心肌培养物中的增殖会引起自发性、持续性折返性快速心律失常。对此类培养物进行抗增殖治疗可通过限制 MFB 诱导的去极化、传导减慢和异位活动来预防心律失常的发生。这项研究可以为心律失常的新治疗方案提供理论依据。
Aims Cardiac fibrosis is associated with increased incidence of cardiac arrhythmias, but the underlying proarrhythmic mechanisms remain incompletely understood and antiarrhythmic therapies are still suboptimal. This study tests the hypothesis that myofibroblast (MFB) proliferation leads to tachyarrhythmias by altering the excitability of cardiomyocytes (CMCs) and that inhibition of MFB proliferation would thus lower the incidence of such arrhythmias.Methods and results Endogenous MFBs in neonatal rat CMC cultures proliferated freely or under control of different dosages of antiproliferative agents (mitomycin-C and paclitaxel). At Days 4 and 9, arrhythmogeneity of these cultures was studied by optical and multi-electrode mapping. Cultures were also studied for protein expression and electrophysiological properties. MFB proliferation slowed conduction from 15.3 +/- 3.5 cm/s (Day 4) to 8.8 +/- 0.3 cm/s (Day 9) (n = 75, P < 0.01), whereas MFB numbers increased to 37.4 +/- 1.7 and 62.0 +/- 2%. At Day 9, 81.3% of these cultures showed sustained spontaneous reentrant arrhythmias. However, only 2.6% of mitomycin-C-treated cultures (n = 76, P < 0.0001) showed tachyarrhythmias, and ectopic activity was decreased. Arrhythmia incidence was drug-dose dependent and strongly related to MFB proliferation. Paclitaxel treatment yielded similar results. CMCs were functionally coupled to MFBs and more depolarized in cultures with ongoing MFB proliferation in which only L-type Ca(2+)-channel blockade terminated 100% of reentrant arrhythmias, in contrast to Na(+) blockade (36%, n = 12).Conclusion Proliferation of MFBs in myocardial cultures gives rise to spontaneous, sustained reentrant tachyarrhythmias. Antiproliferative treatment of such cultures prevents the occurrence of arrhythmias by limiting MFB-induced depolarization, conduction slowing, and ectopic activity. This study could provide a rationale for a new treatment option for cardiac arrhythmias.