Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway.
PLoS One. 2018 Nov 6;13(11):e0207100. doi: 10.1371/journal.pone.0207100. eCollection 2018.
Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) predisposes to ventricular tachyarrhythmias (VTs) during high heart rates due to physical or psychological stress. The essential role of catecholaminergic effects on ventricular cardiomyocytes in this situation is well documented, but the importance of heart rate per se for arrhythmia initiation in CPVT1 is largely unexplored.
Sixteen CPVT1 patients performed a bicycle stress-test. Occurrence of VT triggers, i.e. premature ventricular complexes (PVC), depended on high heart rate, with individual thresholds. Atrial pacing above the individual PVC threshold in three patients did not induce PVCs. The underlying mechanism for the clinical observation was explored using cardiomyocytes from mice with the RyR2-R2474S (RyR2-RS) mutation, which exhibit exercise-induced VTs. While rapid pacing increased the number of Ca2+ waves in both RyR2-RS and wild-type (p<0.05), β-adrenoceptor (βAR) stimulation induced more Ca2+ waves in RyR2-RS (p<0.05). Notably, Ca2+ waves occurred despite decreased sarcoplasmic reticulum (SR) Ca2+ content in RyR2-RS (p<0.05), suggesting increased cytosolic RyR2 Ca2+ sensitivity. A computational model of mouse ventricular cardiomyocyte electrophysiology reproduced the cellular CPVT1 phenotype when RyR2 Ca2+ sensitivity was increased. Importantly, diastolic fluctuations in phosphorylation of RyR2 and SR Ca2+ content determined Ca2+ wave initiation. These factors were modulated towards increased propensity for arrhythmia initiation by increased pacing rates, but even more by βAR stimulation.
In CPVT1, VT propensity depends on individual heart rate thresholds for PVCs. Through converging data from clinical exercise stress-testing, cellular studies and computational modelling, we confirm the heart rate-independent pro-arrhythmic effects of βAR stimulation in CPVT1, but also identify an independent and synergistic contribution from effects of high heart rate.
儿茶酚胺多形性室性心动过速 1 型（CPVT1）由于身体或心理压力导致心率升高，易发生室性心动过速（VTs）。儿茶酚胺对心室肌细胞的这种情况的重要作用已有充分的文献记载，但 CPVT1 中心律失常起始本身与心率的重要性在很大程度上仍未得到探索。
16 名 CPVT1 患者进行了自行车压力测试。VT 触发的发生，即室性期前收缩（PVC），取决于个体阈值的高心率。在 3 名患者中，高于个体 PVC 阈值的心房起搏并未引起 PVC。使用 RyR2-R2474S（RyR2-RS）突变的小鼠心肌细胞探索临床观察的潜在机制，该突变可引起运动诱导的 VTs。虽然快速起搏增加了 RyR2-RS 和野生型（p<0.05）中的 Ca2+波数量，但β-肾上腺素能受体（βAR）刺激在 RyR2-RS 中诱导更多的 Ca2+波（p<0.05）。值得注意的是，尽管 RyR2-RS 中的肌浆网（SR）Ca2+含量减少（p<0.05），但仍发生 Ca2+波，表明细胞溶质 RyR2 Ca2+敏感性增加。当 RyR2 Ca2+敏感性增加时，复制了小鼠心室肌细胞电生理学的计算模型复制了细胞 CPVT1 表型。重要的是，RyR2 的磷酸化和 SR Ca2+含量的舒张波动决定了 Ca2+波的起始。这些因素通过增加起搏率，甚至通过βAR 刺激来调节，从而更倾向于心律失常的起始。
在 CPVT1 中，VT 倾向取决于 PVC 的个体心率阈值。通过临床运动应激试验、细胞研究和计算模型的收敛数据，我们证实了 CPVT1 中βAR 刺激的独立于心率的致心律失常作用，但也确定了高心率的独立和协同作用。
