MYH11 variants in thoracic aortic aneurysm pathophysiology: From bench to bedside

Area of Science:

• Cardiovascular Genetics
• Vascular Biology
• Smooth Muscle Cell Biology

Background:

• Thoracic aortic aneurysms and dissections (TAAD) are life-threatening conditions affecting the aortic wall's medial layer.
• MYH11 gene variants, encoding smooth muscle cell myosin heavy chain (SM-MHC), represent a rare but significant cause of familial TAAD (FTAAD).
• Current understanding of MYH11-associated disease mechanisms, clinical presentation, and treatment options remains incomplete.

Purpose of the Study:

• To review and synthesize current knowledge on the pathophysiological mechanisms of MYH11-associated TAAD.
• To evaluate phenotypic variability, extrathoracic vascular involvement, and potential gene therapy strategies.
• To highlight the clinical significance of MYH11 in vascular disorders.

Main Methods:

• Literature review of existing evidence on MYH11 variants and associated diseases.
• Analysis of data from mouse models, patient-derived cells, and human tissue studies.
• Evaluation of emerging therapeutic strategies, including RNA-based therapies.

Main Results:

• MYH11 variants often affect C-terminal dimerization, impairing thick filament assembly, force generation, and ECM remodeling.
• Clinical manifestations include FTAAD and patent ductus arteriosus (PDA), with reduced penetrance and variable expression.
• RNA-therapy strategies show promise but face challenges in vascular delivery and long-term safety.

Conclusions:

• MYH11 is a clinically relevant gene associated with TAAD and PDA, characterized by contractile dysfunction and increased aortic stiffness.
• Further research is needed for mechanistic studies, genotype-phenotype correlations, and evaluation of targeted gene therapies.
• Understanding gene-environment interactions is crucial for risk prediction and clinical management.