Dilated Cardiomyopathy (DCM) is a myocardial disease characterized by ventricular enlargement and impaired systolic function, leading to heart failure and lethal arrhythmias. Familial DCM, where a causative gene is identified, accounts for 20-40% of idiopathic cases, with higher rates in those with family histories. Guidelines from the Japanese Circulation Society strongly recommend genetic testing and counseling. Key causative genes include TTN (Titin), accounting for 15-25% of familial cases, LMNA (Lamin A/C), MYH7, and TNNT2 (Cardiac Troponin T). These mutations cause structural, contractile, and calcium-handling abnormalities in cardiomyocytes, progressing toward heart failure.

 

Clinical Profile and Diagnosis

Clinical hallmarks include heart failure symptoms like dyspnea and edema, alongside arrhythmias and sudden death risk. LMNA-related cases often present early with conduction disorders and carry a poor prognosis. TNNT2 mutations are noted for early-onset ventricular dilation.Diagnosis involves confirming ventricular dilation via echocardiography or Cardiac MRI, followed by next-generation sequencing (NGS) panels. Cascade screening of relatives allows for early detection and prevention, a priority emphasized in the 2024 JCS guideline updates.

 

Current Treatment and Outlook

Standard care includes pharmacotherapy (Beta-blockers, ARNI, MRA, SGLT2 inhibitors) and devices (ICD, CRT). While heart transplantation remains the definitive cure for severe cases, donor shortages are a critical challenge. Recent shifts toward genotype-stratified medicine show varying risks based on mutation types. Future prospects include genome editing, gene therapy, and personalized drug development.

 

Our Research Approach

At our institute, we focus on the TNNT2 ΔK210 mutation, a three-base deletion encoding lysine identified in familial DCM patients. We developed the world’s first knock-in mouse model to replicate this (Du et al., Circ Res 2007), which faithfully mimics infant-onset dilation and sudden death while pinpointing reduced myofilament Ca²⁺ sensitivity as the core pathology.

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• Pathogenesis: We proved that decreased Ca²⁺ sensitivity triggers compensatory remodeling and arrhythmia substrates. We also analyze exercise intervention, gender differences, and molecular signaling like the CaMKII pathway.

• Therapeutic Discovery: Utilizing this model and iPS cardiomyocytes, we evaluate Ca²⁺ sensitizers, drug repurposing, and gene therapies targeting sarcomere dysfunction.

 

This TNNT2 ΔK210 KI mouse is a global tool for bridging basic research to clinical application. Moving forward, we aim to integrate single-cell analysis and genome editing for precision medicine. Through these innovations, we strive to improve patient QOL and reduce reliance on heart transplantation. Please contact us for inquiries.