Department of Pharmacology (L.M.W., J.-M.D., N.A.H., J.A.K., A.L.G.), The Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL.
Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.Y.B.).
Circ Arrhythm Electrophysiol. 2023 Sep;16(9):e010891. doi: 10.1161/CIRCEP.122.010891. Epub 2023 Aug 17.
Pathogenic variants in genes encoding CaM (calmodulin) are associated with a life-threatening ventricular arrhythmia syndrome (calmodulinopathy). The in vivo consequences of CaM variants have not been studied extensively and there is incomplete understanding of the genotype-phenotype relationship for recurrent variants. We investigated effects of different factors on calmodulinopathy phenotypes using 2 mouse models with a recurrent pathogenic variant (N98S) in or .
Genetically engineered mice with heterozygous N98S pathogenic variants in or were generated. Differences between the sexes and affected genes were assessed using multiple physiological assays at the cellular and whole animal levels. Statistical significance among groups was evaluated using 1-way ANOVA or the Kruskal-Wallis test when data were not normally distributed.
() or () mice exhibited sinus bradycardia and were more susceptible to arrhythmias after exposure to epinephrine and caffeine. Male mice had the most severe arrhythmia phenotype with evidence of early embryonic lethality, greater susceptibility for arrhythmic events, frequent premature beats, corrected QT prolongation, and more heart rate variability after epinephrine and caffeine than females with the same genotype. mice exhibited a less severe phenotype, with female mice having the least severe arrhythmia susceptibility. Flecainide was not effective in preventing arrhythmias in heterozygous CaM-N98S mice. Intracellular Ca transients observed in isolated ventricular cardiomyocytes from male heterozygous CaM-N98S mice had lower peak amplitudes and slower sarcoplasmic reticulum Ca release following in vitro exposure to epinephrine and caffeine, which were not observed in cardiomyocytes from heterozygous female CaM-N98S mice.
We report heterogeneity in arrhythmia susceptibility and cardiomyocyte Ca dynamics among male and female mice heterozygous for a recurrent pathogenic variant in or , illustrating a complex calmodulinopathy phenotype in vivo. Further investigation of sex and genetic differences may help identify the molecular basis for this heterogeneity.
编码钙调蛋白（CaM）的基因中的致病性变异与危及生命的室性心律失常综合征（钙调蛋白病）有关。CaM 变异的体内后果尚未得到广泛研究，对于反复出现的变异，基因型-表型关系的理解也不完全。我们使用携带 或 中反复出现的致病性变异（N98S）的 2 种小鼠模型，研究了不同因素对钙调蛋白病表型的影响。
生成了杂合子 N98S 致病性变异的 或 基因工程小鼠。使用细胞和整体动物水平的多种生理测定来评估性别和受影响基因之间的差异。当数据不呈正态分布时，使用单因素方差分析或 Kruskal-Wallis 检验评估组间的统计学差异。
（）或（）小鼠表现出窦性心动过缓，并且在用肾上腺素和咖啡因处理后更容易发生心律失常。具有相同基因型的雄性 小鼠表现出最严重的心律失常表型，具有早期胚胎致死性、心律失常事件易感性增加、频发早搏、校正 QT 延长和肾上腺素和咖啡因后心率变异性增加的证据，而雌性则较少。 小鼠表现出较轻的表型，其中雌性 小鼠的心律失常易感性最低。氟卡尼不能有效预防杂合子 CaM-N98S 小鼠的心律失常。从雄性杂合子 CaM-N98S 心室肌细胞中观察到的细胞内 Ca 瞬变在体外用肾上腺素和咖啡因处理后，峰值幅度较低，肌浆网 Ca 释放较慢，而在杂合子雌性 CaM-N98S 心肌细胞中则没有观察到。
我们报告了携带 或 中反复出现的致病性变异的杂合子雄性和雌性小鼠心律失常易感性和心肌细胞 Ca 动力学的异质性，说明了体内钙调蛋白病表型的复杂性。对性别和遗传差异的进一步研究可能有助于确定这种异质性的分子基础。
