Cellular and Molecular Drivers of Acute Aortic Dissections

  • Dianna MILEWICZ, The University of Texas Health Science Center at Houston (USA)
  • Toru SUZUKI, University of Leicester (UK)
  • Alan DAUGHERTY, University of Kentucky Research Foundation (USA)
  • David DICHEK, University of Washington School of Medicine (USA)
  • Ketan GHAGHADA, Texas Children’s Hospital (USA)
  • Jay HUMPHREY, Yale University (USA)
  • Scott LEMAIRE, Baylor College of Medicine (USA)
  • Ziad MALLAT, The Chancellor, Masters and Scholars of the University of Cambridge (UK)
  • Yvan SAEYS, Ghent University (Belgium)
  • Ying SHEN, Baylor College of Medicine (USA)

The natural history of aneurysms involving the first portion of the aorta is to asymptomatically enlarge over time until a sudden tear in the inner layer of the aortic wall leads to an acute ascending aortic dissection, also called type A dissection. With dissection, blood penetrates the aortic wall and then splits the wall’s layers apart, ultimately causing aortic rupture and other complications. Over 50% of individuals afflicted with type A dissections die suddenly or succumb during emergency aortic surgery. Approximately 7% of out-of-hospital sudden deaths are due to aortic dissections, and the incidence has increased over the past 20 years for unknown reasons. Although the aorta can enlarge prior to a type A dissection, aortic diameter is an unreliable biomarker for predicting dissections. Many individuals present with dissections with little to no aortic enlargement, often driven by high blood pressure. Furthermore, no drugs are proven to prevent dissections. The overarching goal of our Leducq International Network of Excellence (INE) is to prevent dissection-related deaths and disability by identifying molecular changes in the aortic wall that trigger dissections and use these data to discover novel biomarkers and therapeutics that reliably predict and effectively prevent AADs. Based on novel cell-specific analyses of aortic tissue samples from patients with aortic disease and control subjects, our hypothesis is that the major cells in the aortic wall, smooth muscle cells, over-activate cellular motors, which increases energy production by the cells. As additional cell pathways are activated, the cells eventually fail and cannot maintain these compensatory changes, triggering cell death and dissection. Inflammation in the aortic wall also appears to contribute to dissection. Rigorous testing of this hypothesis using several mouse models of dissection that reflect known risk factors for the disease will identify critical changes in cells; these will then be validated in patients’ aortic tissue samples and targeted with therapeutics to prevent dissections. The most promising drugs will be assessed in all dissection mouse models in preparation for clinical trials in patients. Finally, we propose innovative studies to address a critical tool that is missing in the clinical management of at-risk patients: a reliable biomarker to indicate an imminent risk for a dissection. Together, this INE will work to make substantial progress towards preventing premature deaths due to acute aortic dissections.