Division of Medicine, Akershus University Hospital, Lørenskog, Norway; Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, Oslo, Norway; Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
J Am Coll Cardiol. 2015 Feb 3;65(4):339-351. doi: 10.1016/j.jacc.2014.10.065.
Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information and influences cardiomyocyte function is unknown.
This study sought to evaluate the merit of SN as a cardiovascular biomarker and assess effects of SN on cardiomyocyte Ca(2+) handling.
We assessed the association between circulating SN levels and mortality in 2 patient cohorts and the functional properties of SN in experimental models.
In 143 patients hospitalized for acute HF, SN levels were closely associated with mortality (n = 66) during follow-up (median 776 days; hazard ratio [lnSN]: 4.63; 95% confidence interval: 1.93 to 11.11; p = 0.001 in multivariate analysis). SN reclassified patients to their correct risk strata on top of other predictors of mortality. In 155 patients with ventricular arrhythmia-induced cardiac arrest, SN levels were also associated with short-term mortality (n = 51; hazard ratio [lnSN]: 3.33; 95% confidence interval: 1.83 to 6.05; p < 0.001 in multivariate analysis). Perfusing hearts with SN yielded markedly increased myocardial levels and SN internalized into cardiomyocytes by endocytosis. Intracellularly, SN reduced Ca(2+)/calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ) activity via direct SN-CaM and SN-CaMKII binding and attenuated CaMKIIδ-dependent phosphorylation of the ryanodine receptor. SN also reduced sarcoplasmic reticulum Ca(2+) leak, augmented sarcoplasmic reticulum Ca(2+) content, increased the magnitude and kinetics of cardiomyocyte Ca(2+) transients and contractions, and attenuated Ca(2+) sparks and waves in HF cardiomyocytes.
SN provided incremental prognostic information to established risk indices in acute HF and ventricular arrhythmia-induced cardiac arrest.
在心力衰竭（HF）患者中，分泌型神经调节蛋白（SN）的水平升高，但 SN 是否提供预后信息并影响心肌细胞功能尚不清楚。
本研究旨在评估 SN 作为心血管生物标志物的价值，并评估 SN 对心肌细胞 Ca（2+）处理的影响。
我们评估了循环 SN 水平与 2 个患者队列死亡率之间的相关性，并评估了 SN 在实验模型中的功能特性。
在因急性 HF 住院的 143 名患者中，SN 水平与随访期间的死亡率（n = 66）密切相关（中位随访时间 776 天；lnSN 的危险比：4.63；95%置信区间：1.93 至 11.11；p = 0.001 在多变量分析中）。SN 在其他死亡率预测因素的基础上，正确地对患者进行了风险分层。在因室性心律失常导致心脏骤停的 155 名患者中，SN 水平也与短期死亡率相关（n = 51；lnSN 的危险比：3.33；95%置信区间：1.83 至 6.05；p < 0.001 在多变量分析中）。用 SN 灌注心脏会导致心肌中 SN 水平显著升高，并且 SN 通过内吞作用进入心肌细胞。在细胞内，SN 通过 SN-CaM 和 SN-CaMKII 结合，降低 Ca（2+）/钙调蛋白（CaM）依赖性蛋白激酶 II δ（CaMKIIδ）的活性，从而减弱 CaMKIIδ 对肌浆网 Ca（2+）释放通道的依赖性磷酸化。SN 还减少肌浆网 Ca（2+）泄漏，增加肌浆网 Ca（2+）含量，增加心肌细胞 Ca（2+）瞬变和收缩的幅度和动力学，并减轻 HF 心肌细胞中的 Ca（2+）火花和波。
SN 为急性 HF 和室性心律失常导致的心脏骤停提供了对既定风险指数的额外预后信息。
