1 Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
2 Department of Cardiology, The People's Hospital of Liaoning Province, Shenyang, China.
J Cardiovasc Pharmacol Ther. 2019 Nov;24(6):575-585. doi: 10.1177/1074248419854749. Epub 2019 Jun 3.
Atrial fibrillation (AF) is an important and growing clinical problem. Current pharmacological treatments are unsatisfactory. Electrical remodeling has been identified as one of the principal pathophysiological mechanisms that promote AF, but there are no effective therapies to prevent or correct electrical remodeling in patients with AF. In AF, cardiac production and circulating levels of B-type natriuretic peptide (BNP) are increased. However, its functional significance in AF remains to be determined. We assessed the hypotheses that chronic BNP treatment may prevent the altered electrophysiology in AF, and preventing AF-induced activation of Ca/calmodulin-dependent protein kinase II (CaMKII) may play a role.
Forty-four rabbits were randomly divided into sham, rapid atrial pacing (RAP at 600 beats/min for 3 weeks), RAP/BNP, and sham/BNP groups. Rabbits in the RAP/BNP and sham/BNP groups received subcutaneous BNP (20 μg/kg twice daily) during the 3-week study period. HL-1 cells were subjected to rapid field stimulation for 24 hours in the presence or absence of BNP, KN-93 (a CaMKII inhibitor), or KN-92 (a nonactive analog of KN-93). We compared atrial electrical remodeling-related alterations in the ion channel/function/expression of these animals. We found that only in the RAP group, AF inducibility was significantly increased, atrial effective refractory periods and action potential duration were reduced, and the density of and decreased, while increased. The changes in the expressions of Cav1.2, Kv4.3, and Kir2.1 and currents showed a similar trend. In addition, in the RAP group, the activation of CaMKIIδ and phosphorylation of ryanodine receptor 2 and phospholamban significantly increased. Importantly, these changes were prevented in the RAP/BNP group, which were further validated by in vitro studies.
Chronic BNP therapy prevents atrial electrical remodeling in AF. Inhibition of CaMKII activation plays an important role to its anti-AF efficacy in this model.
心房颤动（AF）是一个重要且日益严重的临床问题。目前的药物治疗并不令人满意。电重构已被确定为促进 AF 的主要病理生理机制之一，但目前尚无有效的疗法可预防或纠正 AF 患者的电重构。在 AF 中，心脏产生和循环中的 B 型利钠肽（BNP）水平升高。然而，其在 AF 中的功能意义仍有待确定。我们评估了以下假设：慢性 BNP 治疗可能预防 AF 中的电生理学改变，而预防 AF 诱导的钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）激活可能发挥作用。
44 只兔子被随机分为假手术组、快速心房起搏（RAP，以 600 次/分钟起搏 3 周）、RAP/BNP 组和假手术/BNP 组。在 3 周的研究期间，RAP/BNP 和假手术/BNP 组的兔子接受皮下 BNP（20 μg/kg，每天两次）治疗。HL-1 细胞在存在或不存在 BNP、KN-93（CaMKII 抑制剂）或 KN-92（KN-93 的非活性类似物）的情况下接受 24 小时快速场刺激。我们比较了这些动物的离子通道/功能/表达与心房电重构相关的改变。我们发现，只有在 RAP 组中，AF 的可诱导性显著增加，心房有效不应期和动作电位时程缩短，和 密度降低，而 增加。Cav1.2、Kv4.3 和 Kir2.1 的表达变化和电流也表现出相似的趋势。此外，在 RAP 组中，CaMKIIδ 的激活和肌浆网钙释放通道 2 和磷蛋白的磷酸化明显增加。重要的是，这些变化在 RAP/BNP 组中得到了预防，这在体外研究中得到了进一步验证。
慢性 BNP 治疗可预防 AF 中的心房电重构。抑制 CaMKII 激活在该模型中对其抗 AF 疗效起着重要作用。
