ALPK3相关肥厚性心肌病的MRI心肌表型表征。

IF 6.1 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of Cardiovascular Magnetic Resonance Pub Date : 2025-06-26 DOI:10.1016/j.jocmr.2025.101930

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

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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. 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引用次数: 0

摘要

背景：α蛋白激酶3 （ALPK3）最近被确定为肥厚性心肌病（HCM）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的个体的表型。方法：连续575例诊断为HCM的患者接受3次特斯拉心脏磁共振成像（CMR）和全外显子组测序基因检测。携带ALPK3罕见错义变异（小等位基因频率< 0.0005）或截断变异的患者被认为是基因型阳性。结果：575例纳入的患者中，男性占65.0%；中位年龄：50[40-61]岁)，37例（6.43%）显示ALPK3杂合变异。与肌瘤变异携带者相比，ALPK3杂合子显示出更高的根尖肥大患病率（59.5% vs. 20.2%, P < 0.001）和更低的纤维化负担，广泛纤维化发生率降低2倍（左心室[LV]肿块≥15%:8.1% vs. 14.7%, P < 0.001）。单个ALPK3变异的患者更容易出现根尖HCM (ApHCM；80.0% vs. 35.3%， P, 0.006)，晚期钆强化程度较低(LGE；（1.26[0.00-5.77] %比6.00 [3.63-8.50]%，P, 0.011）。截断型和错义型ALPK3变异携带者之间的CMR特征无显著差异。此外，在ApHCM患者中，ALPK3单一变异者更容易出现混合性ApHCM(87.5%比55.2%比14.3%,P < 0.05)， LGE程度较低（0.67[0-5.77]%比6.32[2.39-10.90]%比3.32 [0.00-4.68]%,P < 0.05），游离壁和端LGE受累程度较MYBPC3或MYH7变异者更大（85.7%[6 /7]比41.6%[10 /24]比50%[2 /4]）。结论：ALPK3杂合变异体个体的临床表型具有明显的特点，表现为根尖肥大，尤其是混合性根尖肥大，纤维化程度较低。

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Cardiac Phenotype Characterization at MRI in ALPK3 Associated Hypertrophic Cardiomyopathy.

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.

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来源期刊

Journal of Cardiovascular Magnetic Resonance 医学-核医学

CiteScore

10.90

自引率

12.50%

发文量

审稿时长

6-12 weeks

期刊介绍： Journal of Cardiovascular Magnetic Resonance (JCMR) publishes high-quality articles on all aspects of basic, translational and clinical research on the design, development, manufacture, and evaluation of cardiovascular magnetic resonance (CMR) methods applied to the cardiovascular system. Topical areas include, but are not limited to: New applications of magnetic resonance to improve the diagnostic strategies, risk stratification, characterization and management of diseases affecting the cardiovascular system. New methods to enhance or accelerate image acquisition and data analysis. Results of multicenter, or larger single-center studies that provide insight into the utility of CMR. Basic biological perceptions derived by CMR methods.