FIGURE 12.

Exploration of arrhythmogenic mechanisms in nonischemic cardiomyopathy. A: flowchart summarizing the study of ventricular arrhythmias in hypertrophic cardiomyopathy (HCM) patients. A combination of late gadolinium enhancement (LGE)-cardiac magnetic resonance (CMR) imaging and postcontrast T1 mapping is used to construct personalized left ventricular (LV) geometrical models with diffuse and dense scar. Incorporating HCM-specific electrophysiological properties (action potential kinetics, conduction velocity) completes the generation of each ventricular model, which is then used to study arrhythmia mechanisms. Modified from Ref. 262, with permission from eLife. B: flowchart summarizing the workflow of using a genotype patient-specific biventricular model, i.e. “digital twin” (Geno-DT) to understand arrhythmogenesis in arrhythmogenic cardiomyopathy in 2 genotype groups, plakophilin-2 (PKP2) and gene-elusive (GE). Orange blocks refer to clinical data, which include genetic testing results and LGE-CMR images for each patient in the cohort. Patient-specific geometrical heart models were reconstructed from the LGE-CMR (top, purple, left and center images). Genotype-specific cell models (green) developed here were incorporated into each heart model based on the patient’s genetic testing result. The integrated multiscale patient-specific Geno-DT models were used to understand the role of remodeling in arrhythmogenesis and to predict ventricular tachycardia (VT) circuits (bottom, gray). Modified from Ref. 461, with permission from eLife. I_Ca,b, background Ca²⁺ current; I_Ca,L, L-type Ca²⁺ current; I_K1, basal inward-rectifier K⁺ current; I_Kr, rapid delayed-rectifier K⁺ current; I_Ks, slow delayed-rectifier K⁺ current; I_leak, Ca²⁺ leak from sarcoplasmic reticulum; I_Na, Na⁺ current; I_Na,b, background Na⁺ current; I_Na,K, Na⁺-K⁺-ATPase current; I_Na,Ca, Na⁺/Ca²⁺ exchange current; I_p,Ca, plasmalemmal Ca²⁺-ATPase current; I_rel, Ca²⁺ release flux from the sarcoplasmic reticulum; I_to, transient outward K⁺ current; I_up, Ca²⁺ uptake flux into the sarcoplasmic reticulum; I_xfer, transfer of Ca²⁺ from subspace to cytosol.