Division of Cardiology, Department of Medicine (M.S., J.A.C.L.), Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Molecular Pharmacology and Experimental Therapeutics (M.W., D.L., N.L.P.), Mayo Clinic, Rochester, MN.
Circ Heart Fail. 2023 Sep;16(9):e010262. doi: 10.1161/CIRCHEARTFAILURE.122.010262. Epub 2023 Aug 1.
Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown.
Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts.
The rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume (0.0002) after adjusting for confounding clinical variables. The rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume (0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of (7.3×10). knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1-mediated α-smooth muscle actin and collagen expression.
Common genetic variation in previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging-based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.
常见的遗传变异与肥厚型心肌病和扩张型心肌病的风险以及左心室（LV）特征有关。这些变异是否与心肌纤维化有关，而心肌纤维化是心肌病的一个重要病理生理介质，目前尚不清楚。
多民族动脉粥样硬化研究（Multi-Ethnic Study of Atherosclerosis）参与者接受了 T1 映射心脏磁共振成像检查，其中评估了细胞外容积，并且可以获得基因分型信息（N=1255）。通过回归分析，将细胞外容积（%）与 50 个候选单核苷酸多态性（先前被确定与肥厚型心肌病、扩张型心肌病和 LV 特征有关）相关联，同时调整年龄、性别、糖尿病、血压和祖系的主成分。通过固定效应荟萃分析汇总了特定祖系的结果。在人心脏成纤维细胞中进行了基因敲低实验。
先前被确定为扩张型心肌病和肥厚型心肌病风险变异的 rs2186370 内含子变异（白种人参与者中的次要等位基因频率为 0.18，黑种人参与者中的次要等位基因频率为 0.50），在调整混杂的临床变量后，与细胞外容积增加显著相关（0.0002）。先前与 LV 壁厚度和质量增加相关的 rs2070458 位点也与细胞外容积增加显著相关（0.0002）。在所有 4 个祖系群体中，效应的方向相似，但在黑种人参与者中效应最强。这些变体是人类 LV 组织中强表达数量基因座，与基因型依赖性的 表达减少相关（7.3×10）。在人心脏成纤维细胞中敲低 导致 TGF-β1 介导的α-平滑肌肌动蛋白和胶原蛋白表达增加。
先前与心肌病和 LV 壁厚度增加风险相关的 常见遗传变异与心脏磁共振成像基于心肌纤维化的增加以及体外 TGF-β1 介导的心肌纤维化增加相关。这些发现是否表明心肌纤维化与心肌病风险之间存在病理生理联系，还有待证实。
