Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Cardiovasc Res. 2013 Jan 1;97(1):171-81. doi: 10.1093/cvr/cvs290. Epub 2012 Sep 12.
Cardiac hypertrophy and fibrosis are associated with potentially lethal arrhythmias. As these substrates often occur simultaneously in one patient, distinguishing between pro-arrhythmic mechanisms is difficult. This hampers understanding of underlying pro-arrhythmic mechanisms and optimal treatment. This study investigates and compares arrhythmogeneity and underlying pro-arrhythmic mechanisms of either cardiac hypertrophy or fibrosis in in vitro models.
Fibrosis was mimicked by free myofibroblast (MFB) proliferation in neonatal rat ventricular monolayers. Cultures with inhibited MFB proliferation were used as control or exposed to phenylephrine to induce hypertrophy. At Day 9, cultures were studied with patch-clamp and optical-mapping techniques and assessed for protein expression. In hypertrophic (n = 111) and fibrotic cultures (n = 107), conduction and repolarization were slowed. Triggered activity was commonly found in these substrates and led to high incidences of spontaneous re-entrant arrhythmias [67.5% hypertrophic, 78.5% fibrotic vs. 2.9% in controls (n = 102)] or focal arrhythmias (39.1, 51.7 vs. 8.8%, respectively). Kv4.3 and Cx43 protein expression levels were decreased in hypertrophy but unaffected in fibrosis. Depolarization of cardiomyocytes (CMCs) was only found in fibrotic cultures (-48 ± 7 vs. -66 ± 7 mV in control, P < 0.001). L-type calcium-channel blockade prevented arrhythmias in hypertrophy, but caused conduction block in fibrosis. Targeting heterocellular coupling by low doses of gap-junction uncouplers prevented arrhythmias by accelerating repolarization only in fibrotic cultures.
Cultured hypertrophic or fibrotic myocardial tissues generated similar focal and re-entrant arrhythmias. These models revealed electrical remodelling of CMCs as a pro-arrhythmic mechanism of hypertrophy and MFB-induced depolarization of CMCs as a pro-arrhythmic mechanism of fibrosis. These findings provide novel mechanistic insight into substrate-specific arrhythmicity.
心肌肥厚和纤维化与潜在致命性心律失常有关。由于这些基质通常同时存在于同一患者中，因此区分致心律失常机制较为困难。这阻碍了对潜在致心律失常机制和最佳治疗方法的理解。本研究在体外模型中研究和比较了心肌肥厚或纤维化的心律失常发生和潜在致心律失常机制。
通过在新生大鼠心室单层中自由成纤维细胞（MFB）增殖来模拟纤维化。抑制 MFB 增殖的培养物用作对照或暴露于苯肾上腺素以诱导肥大。在第 9 天，用膜片钳和光学映射技术研究培养物，并评估蛋白表达。在肥大（n = 111）和纤维化培养物（n = 107）中，传导和复极化减慢。在这些基质中普遍发现触发活动，并导致自发折返性心律失常的高发生率[肥大 67.5%，纤维化 78.5%，对照 2.9%（n = 102）]或局灶性心律失常（39.1%，51.7%，分别）。Kv4.3 和 Cx43 蛋白表达水平在肥大中降低，但在纤维化中不受影响。仅在纤维化培养物中观察到心肌细胞（CMCs）去极化（-48 ± 7 对对照-66 ± 7 mV，P < 0.001）。L 型钙通道阻断在肥大中预防心律失常，但在纤维化中引起传导阻滞。低剂量间隙连接解偶联剂靶向异细胞偶联仅在纤维化培养物中通过加速复极化来预防心律失常。
培养的肥大或纤维化心肌组织产生了类似的局灶性和折返性心律失常。这些模型揭示了 CMC 的电重构是肥厚的致心律失常机制，以及 MFB 诱导的 CMC 去极化是纤维化的致心律失常机制。这些发现为基质特异性心律失常提供了新的机制见解。
