Researchers at Johns Hopkins Medicine have made important advances in exploring the reasons why those with Loeys-Dietz syndrome, an inherited connective tissue disorder, face an increased risk for developing aneurysms at the aortic root—the vital section of the main artery that transports blood from the heart to the rest of the body.
Understanding Loeys-Dietz Syndrome
Loeys-Dietz syndrome affects multiple bodily systems, including craniofacial structures, the skeletal system, skin, the gastrointestinal tract, and the cardiovascular system.
One of the most serious complications associated with this condition is the formation of aneurysms, which are dilations of an artery’s diameter that exceed 50% of its normal size.
These aneurysms can lead to catastrophic events, such as dangerous tears (dissections) or ruptures.
While this syndrome can provoke aneurysm development in various arteries, researchers have pinpointed the aortic root as particularly vulnerable.
Research Findings on Aneurysm Formation
In a study released on November 20 in *Nature Cardiovascular Research*, the research team discovered that vascular smooth muscle cells in the aortic root of genetically modified mice show elevated levels of a protein called Gata4, heightening their risk of aneurysm formation.
These mice carry a mutation in the Tgfbr1 gene, which is one of seven genes commonly altered in individuals diagnosed with Loeys-Dietz syndrome.
Hal Dietz III, M. D. , a leading researcher in this area, emphasized the significance of these findings, noting previous identification of the TGFBR1 mutation in affected individuals.
He highlighted that understanding this mutation’s role could provide valuable insights into the disease mechanism and potential therapeutic targets.
Additionally, researchers have begun exploring the effects of neuropilin2 gene disruption in mice, aiming to determine whether similar pathways are involved in connective tissue disorders.
These studies may further clarify the complex genetic interactions underlying Loeys-Dietz syndrome.
Elena MacFarlane, Ph.D., highlighted that identifying the risk factors for aortic aneurysms in those with Loeys-Dietz syndrome has emerged as a central focus of research.
She pointed out that the aortic root often acts as an early indicator of structural weaknesses in the artery.
Understanding these mechanisms could not only help in tracking the progression of Loeys-Dietz syndrome but also potentially lead to interventions that delay or prevent its effects.
Significance and Future Directions
The disorder was first identified in 2005 by researchers Bart Loeys and Hal Dietz, who also investigated Marfan syndrome, a related condition.
According to their research, Loeys-Dietz syndrome affects roughly one in 50,000 individuals.
Treatment options for patients may include angiotensin II receptor blockers (ARBs), which are regularly prescribed for hypertension and have shown promise in slowing aneurysm progression based on studies involving both mouse models and people with Marfan syndrome.
The implications of these recent findings could significantly enhance our understanding of why the aortic root tends to dilate more readily in patients with Loeys-Dietz syndrome, leading to improved treatment strategies not only for this disorder but also for other vascular connective tissue diseases.
To conduct their research, Emily Bramel, Ph.D., a postdoctoral fellow at the Broad Institute in Boston, analyzed genetically engineered mice that demonstrate features of Loeys-Dietz syndrome, particularly the formation of aortic root aneurysms.
Her analysis incorporated data from aortic cells collected from consenting patients, working alongside Stanford University cardiac surgeons Albert Pedroza, M.D., Ph.D., and Michael Fischbein, M.D., Ph.D.
Using an innovative tool developed by Johns Hopkins computational biologist Genevieve Stein-O’Brien, Ph.D., M.H.S., the researchers effectively compared gene expression patterns in both human and mouse tissues.
The study revealed a significant increase in cells expressing high levels of Gata4 in the aortic roots of both mice and human participants with Loeys-Dietz syndrome.
This finding raised intriguing questions about the role of Gata4 in contributing to the risk of aneurysm formation, as noted by MacFarlane.
It appeared that smooth muscle cells harboring the Tgfbr1 mutation failed to break down excess Gata4 protein, leading to its accumulation.
While Gata4 is crucial for numerous physiological functions, an overabundance can result in harmful effects, including heightened levels of angiotensin II receptors, which are the targets of ARB medications.
The researchers acknowledged that directly modifying Gata4 through pharmacological means may pose safety challenges due to its essential role in development; however, they expressed optimism that forthcoming studies might uncover the mechanisms behind Gata4 accumulation, potentially unveiling new therapeutic targets.
In addition to Bramel, MacFarlane, Dietz, Stein-O’Brien, Pedroza, and Fischbein, contributors to this research included Wendy Espinoza Camejo, Tyler Creamer, Leda Restrepo, Muzna Saqib, Rustam Bagirzadeh, Anthony Zeng, and Jacob Mitchell from Johns Hopkins University.
This research received funding from the National Institutes of Health, with grants S10OD023548, R01HL147947, and F31HL163924, as well as support from the Marfan Foundation, the Loeys-Dietz Syndrome Foundation, and the Johns Hopkins Broccoli Center for Aortic Diseases.
Source: ScienceDaily