β- Adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure?
β- Adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure?
复制标题
DOI：
10.1136/heartjnl-2013-305167
复制
发表时间：
2014-06-01
期刊：
影响因子：
5.7
通讯作者：
Richard, Sylvain
中科院分区：
文献类型：
--
作者：
Thireau, Jerome;Karam, Sarah;Richard, Sylvain
目的 临床研究未能令人信服地证明心力衰竭期间静脉输注奈瑟立肽的有效性，并且有证据表明 B 型钠尿肽 (BNP) 具有促肾上腺素作用。然而，皮下 BNP 疗法最近被提出用于治疗心力衰竭，从而为这种被认为是一种有前途的治疗方法提出了新的观点。我们测试了口服 1-肾上腺素能受体阻滞剂美托洛尔和皮下注射 BNP 联合治疗失代偿性心力衰竭的效果。 方法和结果 在心肌梗死后缺血性心力衰竭实验小鼠模型中，研究了美托洛尔或/和 BNP 对心脏重塑、兴奋-收缩耦合和心律失常的影响。我们确定了抗重构和抗心律失常作用中涉及的细胞和分子机制。主要发现是，该组合在逆转心脏重塑和预防室性心律失常方面比单独使用美托洛尔更有效。两种分子的结合改善了心脏功能，减少了肥厚和纤维化，并纠正了心率、交感迷走神经平衡（低频/高频）和心电图参数（P 到 R 波间隔 (PR)、QRS 持续时间、QTc 间隔）。它还通过使 Ca2+ 处理蛋白水平（S100A1、SERCA2a、RyR2）正常化来改善改变的 Ca2+ 循环，并防止心室心肌细胞中异常 Ca2+ 火花产生的促心律失常 Ca2+ 波。总而言之，这些作用可以减少室性心律失常的发生。 结论 皮下注射 BNP 和口服美托洛尔联用似乎比单独使用美托洛尔更有效。打破 BNP 与心力衰竭中交感神经过度兴奋之间的有害循环可以揭示 BNP 对抗心力衰竭有害损害的效率，并为心力衰竭期间致命性心律失常带来新的潜在方法。
Aims Clinical studies failed to prove convincingly efficiency of intravenous infusion of neseritide during heart failure and evidence suggested a pro-adrenergic action of B-type natriuretic peptide (BNP). However, subcutaneous BNP therapy was recently proposed in heart failure, thus raising new perspectives over what was considered as a promising treatment. We tested the efficiency of a combination of oral 1-adrenergic receptor blocker metoprolol and subcutaneous BNP infusion in decompensated heart failure.Methods and results The effects of metoprolol or/and BNP were studied on cardiac remodelling, excitation-contraction coupling and arrhythmias in an experimental mouse model of ischaemic heart failure following postmyocardial infarction. We determined the cellular and molecular mechanisms involved in anti-remodelling and antiarrhythmic actions. As major findings, the combination was more effective than metoprolol alone in reversing cardiac remodelling and preventing ventricular arrhythmia. The association of the two molecules improved cardiac function, reduced hypertrophy and fibrosis, and corrected the heart rate, sympatho-vagal balance (low frequencies/high frequencies) and ECG parameters (P to R wave interval (PR), QRS duration, QTc intervals). It also improved altered Ca2+ cycling by normalising Ca2+-handling protein levels (S100A1, SERCA2a, RyR2), and prevented pro-arrhythmogenic Ca2+ waves derived from abnormal Ca2+ sparks in ventricular cardiomyocytes. Altogether these effects accounted for decreased occurrence of ventricular arrhythmias.Conclusions Association of subcutaneous BNP and oral metoprolol appeared to be more effective than metoprolol alone. Breaking the deleterious loop linking BNP and sympathetic overdrive in heart failure could unmask the efficiency of BNP against deleterious damages in heart failure and bring a new potential approach against lethal arrhythmia during heart failure.