Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States.
Alliance for Cardiovascular Diagnostic and Treatment Innovation, Johns Hopkins University, Baltimore, United States.
Elife. 2023 Oct 18;12:RP88865. doi: 10.7554/eLife.88865.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient's disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (, 8) and gene-elusive (GE, 8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy for patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while in patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC.
致心律失常性右室心肌病 (ARVC) 是一种遗传性心脏病，可导致室性心动过速 (VT)，这是一种危及生命的心律失常。由于涉及结构和电生理 (EP) 重塑的复杂致心律失常机制，治疗 ARVC 仍然具有挑战性。在这里，我们开发了一种新的基因型特异性心脏数字孪生 (Geno-DT) 方法，以研究病理生理重塑在维持 VT 折返环中的作用，并预测不同基因型 ARVC 患者的 VT 环。该方法将来自对比增强磁共振成像的患者疾病引起的结构重塑与基因型特异性细胞 EP 特性相结合。在我们对 16 名具有两种基因型的 ARVC 患者的回顾性研究中：桥粒斑蛋白-2 (, 8) 和基因隐匿型 (GE, 8)，我们发现 Geno-DT 准确且无创地预测了两种基因型的 VT 电路位置 (对于 GE 患者组，敏感性为 100%，特异性为 94%，准确性为 96%，对于 患者组，敏感性为 86%，特异性为 90%，准确性为 89%)，与临床 EP 研究中确定的 VT 电路位置相比。此外，我们的研究结果表明，ARVC 基因型之间的潜在 VT 机制不同。我们确定，在 GE 患者中，纤维化重塑是 VT 电路的主要贡献者，而在 患者中，除了结构底物外，心脏组织的传导速度减慢和复极化特性的改变也是 VT 电路形成的直接原因。我们的新型 Geno-DT 方法有可能提高临床治疗的精确性，并为 ARVC 带来更个性化的治疗策略。
