ALPK3相关肥厚型心肌病的心脏磁共振成像表型特征

Cardiac Phenotype Characterization at MRI in ALPK3 Associated Hypertrophic Cardiomyopathy.

作者信息

Pu Lutong, Wang Jie, Yu Mengdi, Xu Yuanwei, Wan Ke, Guo Jiajun, Li Yangjie, Han Yuchi, Chen Yucheng

机构信息

Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.

Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK; Cardiac Imaging and Target Therapy Lab, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.

出版信息

J Cardiovasc Magn Reson. 2025 Jun 26:101930. doi: 10.1016/j.jocmr.2025.101930.

DOI:10.1016/j.jocmr.2025.101930

PMID:40581189

Abstract

BACKGROUND

Alpha-protein kinase 3 (ALPK3) was recently identified as a candidate gene associated with hypertrophic cardiomyopathy (HCM). However, clinical data regarding carriers of ALPK3 variants are limited.

OBJECTIVES

To evaluate the prevalence of heterozygous ALPK3 variants in adult patients with HCM through whole-exome sequencing, and to elucidate the phenotypes of individuals harboring these variants.

METHODS

Consecutive 575 patients diagnosed with HCM who underwent 3 Tesla cardiac magnetic resonance imaging (CMR) and whole exome sequencing genetic testing were recruited. Patients harboring ALPK3 rare missense variants (minor allele frequency < 0.0005) or truncating variants were considered genotype-positive.

RESULTS

Among the 575 included patients (65.0% male; median age: 50 [40-61] years), 37 (6.43%) showed heterozygous ALPK3 variants. In comparison with sarcomere variant carriers, ALPK3 heterozygotes showed a higher prevalence of apical hypertrophy (59.5% vs. 20.2%, P < 0.001) and a lower fibrosis burden, with a 2-fold reduction in the incidence of extensive fibrosis (≥15% left ventricle [LV] mass: 8.1% vs. 14.7%, P < 0.001). Patients with single ALPK3 variants were more likely to present with apical HCM (ApHCM; 80.0% vs. 35.3%, P, 0.006) and show a lower extent of late gadolinium enhancement (LGE; 1.26 [0.00-5.77] % vs. 6.00 [3.63-8.50] %, P, 0.011) than those with both ALPK3 and sarcomere variants. CMR characteristics showed no significant differences between carriers with truncating and missense ALPK3 variants. Moreover, among patients with ApHCM, those with single ALPK3 variants were more likely to present with mixed ApHCM (87.5% vs. 55.2% vs. 14.3%, P < 0.05), a lower extent of LGE (0.67 [0-5.77] % vs. 6.32 [2.39-10.90] % vs. 3.32 [0.00-4.68] %, P < 0.05), and greater free-wall and apex LGE involvement (85.7% [six/7] vs. 41.6% [ten/24] vs. 50% [two/4]) than those with MYBPC3 or MYH7 variants.

CONCLUSION

The clinical phenotype of individuals harboring heterozygous ALPK3 variants showed distinct characteristics, characterized by apical hypertrophy, especially mixed apical hypertrophy, and a lower extent of fibrosis.

摘要

背景

α-蛋白激酶3（ALPK3）最近被确定为与肥厚型心肌病（HCM）相关的候选基因。然而，关于ALPK3变异携带者的临床数据有限。

目的

通过全外显子组测序评估成年HCM患者中杂合ALPK3变异的患病率，并阐明携带这些变异个体的表型。

方法

招募了连续575例诊断为HCM且接受了3特斯拉心脏磁共振成像（CMR）和全外显子组测序基因检测的患者。携带ALPK3罕见错义变异（次要等位基因频率<0.0005）或截短变异的患者被视为基因型阳性。

结果

在纳入的575例患者中（男性占65.0%；中位年龄：50[40 - 61]岁），37例（6.43%）表现出杂合ALPK3变异。与肌节变异携带者相比，ALPK3杂合子的心尖肥厚患病率更高（59.5%对20.2%，P<0.001），纤维化负担更低，广泛纤维化（≥15%左心室[LV]质量）的发生率降低了2倍（8.1%对14.7%，P<0.001）。单一ALPK3变异的患者比同时携带ALPK3和肌节变异的患者更易出现心尖肥厚型心肌病（ApHCM；80.0%对35.3%，P<0.006），延迟钆增强（LGE）程度更低（1.26[0.00 - 5.77]%对6.00[3.63 - 8.50]%，P<0.011）。CMR特征显示，截短型和错义型ALPK3变异携带者之间无显著差异。此外，在ApHCM患者中，单一ALPK3变异的患者比携带MYBPC3或MYH7变异的患者更易出现混合型ApHCM（87.5%对55.2%对14.3%，P<0.05），LGE程度更低（0.67[0 - 5.77]%对6.32[2.39 - 10.90]%对3.32[0.00 - 4.68]%，P<0.05），游离壁和心尖LGE累及范围更大（85.7%[6/7]对41.6%[10/24]对50%[2/4]）。