National Heart and Lung Institute, Imperial College London, Du Cane Road, London, W12 0NN, UK.
Dipartimento Di Cardiochirurgia, Università Degli Studi Di Verona, Ospedale Borgo Trento, P.le Stefani 1, 37126, Verona, Italy.
Sci Rep. 2021 Mar 1;11(1):4840. doi: 10.1038/s41598-021-84275-w.
Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction (MI)-caused HF. RV myocytes from HF rats show significant cellular hypertrophy accompanied with a disruption of transverse-axial tubular network and surface flattening. Functionally these cells exhibit higher contractility with lower Ca transients. The structural changes in HF RV myocytes correlate with more frequent spontaneous Ca release activity than in control RV myocytes. This is accompanied by hyperactivated L-type Ca channels (LTCCs) located specifically in the T-tubules of HF RV myocytes. The increased open probability of tubular LTCCs and Ca sparks activation is linked to protein kinase A-mediated channel phosphorylation that occurs locally in T-tubules. Thus, our approach revealed that alterations in RV myocytes in heart failure are specifically localized in microdomains. Our findings may indicate the development of compensatory, though potentially arrhythmogenic, RV remodelling in the setting of LV failure. These data will foster better understanding of mechanisms of heart failure and it could promote an optimized treatment of patients.
右心室（RV）功能障碍是心力衰竭（HF）患者生存的独立预测因子。然而，RV 进展为衰竭的机制尚不清楚。我们在左心室心肌梗死（MI）引起的 HF 大鼠模型中研究了 RV 重塑的细胞机制。HF 大鼠的 RV 心肌细胞表现出明显的细胞肥大，同时伴有横轴向管状网络的破坏和表面变平。这些细胞在功能上表现出更高的收缩性和更低的 Ca 瞬变。HF RV 心肌细胞的结构变化与比对照 RV 心肌细胞更频繁的自发性 Ca 释放活动相关。这伴随着位于 HF RV 心肌细胞 T 小管中的超活化 L 型 Ca 通道（LTCC）。管状 LTCC 的开放概率增加和 Ca 火花的激活与蛋白激酶 A 介导的局部发生在 T 小管中的通道磷酸化有关。因此，我们的方法表明，心力衰竭时 RV 心肌细胞的改变特别局限于微域。我们的发现可能表明在 LV 衰竭的情况下 RV 重塑的代偿性，尽管可能有致心律失常性。这些数据将促进对心力衰竭机制的更好理解，并可能促进对患者的优化治疗。
