Yunli Shen, Chunyu Zeng, Chunyu Zeng, Yingxian Sun, Jian’an Wang, Bo Yu, Xiang Cheng, Xiaogang Guo, Xiaogang Guo, Dao Wen Wang, Yue Li, Yue Li, Wei Han, Bingqing Zhou, Hongzhuan Sheng, Z. Maggie Huang, Yigang Li, Yigang Li, Guosheng Fu, Jidong Zhang, Duanyang Xie, Dandan Liang, Yi Liu, Bing Yang, Qibo Zhang, Ran Duan, Hongxiao Li, Baowei Zhang, Yizhang Wu, Liang Zheng, Jia He, Shenglin Liu, Dechun Yin, Guozhe Sun, Shu Zhang, Xiaofan Guo, Xiaofan Guo, Min Zhang, Yiyi Wang, XiaJun HU, Jing Zeng, Xiaoli Yang, Shufeng Li, Ning Li, Feng Hu, Haifeng Wang, Xinyang Hu, Yaping Wang, Cong Zeng, Cong Zeng, Kai Wang, Jian Yang, Yan Wang, Jinsheng Lai, Luyun Wang, Ke Xiong, Guanghua Wang, Qicheng Zou, Beihua Shao, Zhiwen Chen, Yahan Wu, Junwei Leng, Jun Pu, Changsheng Ma, Yi-Han Chen
BACKGROUND: Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias. METHODS: We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation. RESULTS: Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points; P =0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%; P <0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points; P =0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%; P <0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred. CONCLUSIONS: In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non–ion channel–based therapeutic strategy targeting the cardiac glutamatergic system. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06501638.