The aorta in Marfan syndrome: from molecular mechanisms to mechanobiological dysfunction

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Research
• Connective Tissue Disorders

Background:

• Marfan syndrome (MFS) is an autosomal dominant disorder impacting cardiovascular, musculoskeletal, and ocular systems.
• Pathogenic variants in FBN1, encoding fibrillin-1, are the primary cause of MFS, affecting elastic fiber integrity.
• Thoracic aortic dissection is a frequent cause of premature mortality in MFS patients.

Purpose of the Study:

• To review recent advancements in understanding the progression of aortic disease in Marfan syndrome.
• To explore insights from genetics, histology, mechanobiology, and biomechanics.
• To highlight the role of mouse models and computational approaches in developing novel therapies.

Main Methods:

• Review of existing literature on Marfan syndrome and thoracic aortic disease.
• Focus on studies utilizing genetically modified mouse models to investigate disease mechanisms.
• Analysis of data from genetic, histological, mechanobiological, and biomechanical perspectives.

Main Results:

• Significant progress has been made in understanding the genetic and molecular underpinnings of MFS aortic disease.
• Mouse models reveal complex gene expression changes in the aorta, with cell-specific alterations.
• Pharmacological treatments and genetic modifications in models offer insights into therapeutic strategies.

Conclusions:

• Despite 35 years since FBN1 discovery, a complete understanding of variant-disease links and definitive treatments for MFS aortic disease is still lacking.
• Delineating compensatory versus pathological gene expression changes is crucial for targeted therapies.
• Data-driven computational models are essential for integrating multimodal data to advance MFS therapeutic development.