Institute of Experimental Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
Am J Physiol Heart Circ Physiol. 2022 Dec 1;323(6):H1296-H1310. doi: 10.1152/ajpheart.00328.2022. Epub 2022 Nov 11.
cardiomyopathy is an arrhythmogenic form of dilated cardiomyopathy caused by mutations in the splicing factor RBM20. A recent study found a more severe phenotype in male patients with cardiomyopathy patients than in female patients. Here, we aim to determine sex differences in an animal model of cardiomyopathy and investigate potential underlying mechanisms. In addition, we aim to determine sex and gender differences in clinical parameters in a novel cardiomyopathy patient cohort. We characterized an knockout (KO) mouse model, and show that splicing of key RBM20 targets, cardiac function, and arrhythmia susceptibility do not differ between sexes. Next, we performed deep phenotyping of these mice, and show that male and female -KO mice possess transcriptomic and phosphoproteomic differences. Hypothesizing that these differences may influence the heart's ability to compensate for stress, we exposed -KO mice to acute catecholaminergic stimulation and again found no functional differences. We also replicate the lack of functional differences in a mouse model with the -R636Q mutation. Lastly, we present a patient cohort of 33 cardiomyopathy patients and show that these patients do not possess sex and gender differences in disease severity. Current mouse models of cardiomyopathy show more pronounced changes in gene expression and phosphorylation of cardiac proteins in male mice, but no sex differences in cardiac morphology and function. Moreover, other than reported before, male cardiomyopathy patients do not present with worse cardiac function in a patient cohort from Germany and the Netherlands. Optimal management of the cardiac disease is increasingly personalized, partly because of differences in outcomes between sexes. cardiomyopathy has been described to be more severe in male patients, and this carries the risk that male patients are more scrutinized in the clinic than female patients. Our findings do not support this observation and suggest that treatment should not differ between male and female cardiomyopathy patients, but instead should focus on the underlying disease mechanism.
扩张型心肌病是一种心律失常性扩张型心肌病，由剪接因子 RBM20 的突变引起。最近的一项研究发现，扩张型心肌病患者中男性患者的表型比女性患者更严重。在这里，我们旨在确定扩张型心肌病动物模型中的性别差异，并研究潜在的潜在机制。此外，我们旨在确定新型扩张型心肌病患者队列中的临床参数的性别和性别差异。我们对 RBM20 靶点的剪接、心脏功能和心律失常易感性没有性别差异。接下来，我们对这些小鼠进行了深度表型分析，结果表明，雄性和雌性 KO 小鼠具有转录组和磷酸蛋白质组学差异。假设这些差异可能会影响心脏应对压力的能力，我们使 KO 小鼠暴露于急性儿茶酚胺刺激下，结果再次发现没有功能差异。我们还在 KO 小鼠模型中复制了缺乏功能差异的情况。最后，我们提出了一个 33 例扩张型心肌病患者的患者队列，表明这些患者在疾病严重程度方面没有性别和性别差异。目前的扩张型心肌病小鼠模型显示雄性小鼠的心脏蛋白基因表达和磷酸化变化更为明显，但在心脏形态和功能方面没有性别差异。此外，与之前报道的相反，德国和荷兰的患者队列中，男性扩张型心肌病患者的心脏功能并没有更差。心脏疾病的最佳管理越来越个性化，部分原因是性别之间的预后存在差异。扩张型心肌病在男性患者中更为严重，这意味着男性患者在临床中比女性患者受到更严格的检查。我们的发现不支持这一观察结果，并表明治疗不应因男性和女性扩张型心肌病患者而异，而应专注于潜在的疾病机制。
