A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Genetic Heart Disease

Background:

• Familial cardiomyopathies, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), are often linked to sarcomeric gene variants.
• Recent findings indicate an upregulation of Notch signalling in cardiomyocytes with a specific TNNT2 variant (cTnT-I79N+/-), associated with cardiac hypertrophy and electrical instability.

Purpose of the Study:

• To explore the emerging role of Notch signalling in inherited cardiomyopathies.
• To discuss potential links between Notch signalling and sarcomere mutations in HCM and DCM.
• To highlight the involvement of Notch signalling in disease progression mechanisms like arrhythmias, ischemia, and fibrosis.

Main Methods:

• Literature review and synthesis of current research on Notch signalling and familial cardiomyopathies.
• Analysis of recent findings on Notch pathway upregulation in iPSC-derived cardiomyocytes with a TNNT2 variant.
• Discussion of potential crosstalk between Notch and Hippo signalling pathways.

Main Results:

• Notch signalling is upregulated in cardiomyocytes with a sarcomeric mutation (cTnT-I79N+/-) causing HCM-like features.
• Potential roles for Notch signalling in arrhythmias, microvascular ischemia, and fibrosis in familial cardiomyopathies were identified.
• Evidence suggests Notch signalling interacts with mechano-signalling pathways, including Hippo signalling, in sarcomere-mutant cardiomyopathies.

Conclusions:

• Notch signalling is a potential contributor to the pathogenesis of inherited HCM and DCM.
• Further investigation into Notch signalling is warranted for understanding and potentially treating sarcomere-based familial cardiomyopathies.
• Both cardiac and non-cardiac myocytes may be involved in disease progression influenced by Notch signalling.