New $11.6 Grant Will Start Center for Study of Often-Fatal Aortic Diseases

HOUSTON—(June 19, 2006)—Dianna Milewicz, M.D., Ph.D., professor and director of the Division of Medical Genetics at The University of Texas Medical School at Houston, will use a new, $11.6 million grant to take the next step in her quest to prevent premature deaths from a stealthy disease that kills people in the prime of their lives.

The five-year grant from the National Heart, Lung and Blood Institute (NHLBI) will create the Specialized Center for Clinically Oriented Research in Thoracic Aortic Aneurysms and Dissections, to be located in the Texas Medical Center.

Milewicz, the George H.W. Bush Chair in Cardiovascular Research, is lead investigator and director of the multi-institutional center.

“This is a first step toward understanding the disease process leading to aortic aneurysms and dissections, so we can go after better biomarkers, better imaging, and better ways to predict outcomes,” said Milewicz, who has extensively researched the genetic basis of thoracic aortic aneurysms and dissections. “The ultimate goal of the grant is to prevent premature deaths due to aortic dissection or rupture and hopefully lead to new therapies to treat the disease.”

Other participating institutions are Baylor College of Medicine and The University of Texas Medical Branch at Galveston (UTMB). Along with the UT Medical School, major sites for patient recruitment and research are Memorial Hermann Hospital-Texas Medical Center, the Texas Heart Institute at St. Luke’s Episcopal Hospital and Texas Children’s Hospital.

Co-directors of the center are Hazim Safi, M.D., professor and chairman of the Department of Cardiothoracic Vascular Surgery at the UT Medical School at Houston, and Joseph Coselli, M.D., professor and chief of the Division of Cardiothoracic Surgery at Baylor College of Medicine.

“This award represents an opportunity for us to link decades of surgical research and management to basic sciences that addresses the fundamental biology of aortic disease,” Safi said. “An NIH-funded effort of this scope is unprecedented in this area of research, and we hold great hope that new findings will lead to rapid development of new therapies.”

“This critically important work effectively builds upon the leadership role the Texas Medical Center has taken in the successful surgical management of aortic pathology, aneurysms and dissection,” Coselli said. “Research programs are focused on the genetics of aortic disease, and the imaging and management of patients with known problems or familial proclivity. They will allow for earlier diagnosis as well as significantly improved management thus reducing morbidity and mortality. Ultimately genetic pathways hopefully make prevention entirely possible.”

The aorta is the main blood vessel leading out of the heart. It supplies blood to the rest of the body. Some people develop a progressive degeneration of the aortic wall, leading to a bulging aneurysm, or to a dissection (a tear in the wall). Thoracic aneurysms tend to be without symptoms until a catastrophic dissection or rupture occurs.

“We don’t know the pathology of the aortic wall degeneration,” Milewicz said. “Understanding the pathological process is crucial in order to develop new therapies and diagnostic tools for the disease. The proposed projects in the grant work toward those goals.”

Thoracic aortic disease is the 15th leading cause of death in the United States, killing up to 20,000 people a year. Famous victims include actor John Ritter (54 years old when he died) and the creator of Broadway hit, “Rent,” Jonathan Larson (who was 35). Untreated high blood pressure and smoking can also lead to the disease in people predisposed to it.

Emergency room doctors unfamiliar with its symptoms sometimes mistake a dissection as a flu virus or muscle pains. Once the aorta begins to dissect, patients may have anywhere from minutes to hours before it ruptures. Even if properly diagnosed, emergency surgery to repair the dissection is risky.

But if caught early enough, when an aneurysm is five centimeters or less, a surgical procedure to replace the diseased portion with a Dacron graft has a high degree of success.

“The Texas Medical Center has a long history of expertise in surgical repair of aneurysms and dissections of the aorta. Drs. DeBakey (Michael E. DeBakey, M.D.) and Cooley (Denton Cooley, M.D.) pioneered successful surgical repair in the late ‘50s,” Milewicz said. “This grant builds on long-standing surgical expertise in the TMC and establishes Houston a national center of expertise in aortic disease research.”

Researchers including Milewicz have identified some of the defective genes that cause the inherited form of the disease, which affects 20 percent of people with aneurysms and dissections. Through DNA testing on family members, early identification of those at risk has led to diagnostic imaging and ultimately to saving lives.

“We’ve come a long way. We’ve identified and mapped genes over the years and have a very well-established research program looking at the genetic basis for this disease. In addition, we have begun to understand how you use that information to manage the disease,” Milewicz said. “We want to take it one step further and discover the biological pathways to this disease, whether it’s people who carry mutated genes or those who don’t but still end up with this disease.”

To that end, the grant includes three projects and six related “cores” to support the research activity.

The first project, led by Milewicz, focuses on transforming growth factor beta (TGF-), a key regulator of vascular smooth muscle cells found in the thick middle layer of the aortic wall. The dysregulation of TGF- may be a pathway to the degeneration of that portion of the wall for people suffering from familial and non-familial forms of the disease.

The second project is led by Allan Brasier, M.D., Professor in Medicine and Associate Director of the NHLBI Proteomics Center at UTMB, one of 10 in the country established by the NHLBI. His team will examine inflammatory biomarkers of aortic aneurysms, especially the role of angiotensin II on vasoconstriction and vascular inflammation. The hope is that this research may lead to anti-inflammatory medications to help treat aortic disease.

“The role of inflammation in aneurysm progression is not well understood,” Brasier said. “Although angiotensin II is normally thought to be a blood pressure regulating hormone, we have found it to be potent inducer of inflammation and structural changes in the aortic wall, activities that may be important in aneurysm progression. Our project will also be coupled with our strength in proteomics research to identify protein patterns associated with vascular remodeling. These studies may significantly impact detection, and risk assessment of aneurysmal diseases.”

Milewicz said information they learn about pathways and inflammation will hopefully lead to the development of biomarkers to develop blood tests. “That’s especially important for people who don’t have an obvious aneurysm or ballooning that appears on an imaging scan, but may have a dissection that will kill them,” she said.

The third project, led by Xing Li Wang, M.D., Ph.D., will look at the 80 percent of people who do not have the familial form of the disease to see what predisposes them to it. His team will explore whether genetic variants of genes associated with an increased risk of developing aortic disease contribute significantly to sporadic thoracic aortic aneurysms and dissections. DNA genetic sequence variations, called single nucleotide polymorphisms (SNP), may be responsible for predisposing people in the general population to aortic disease.

“Identifying genetic variants that determine the susceptibility to the aortic diseases, and specific environmental factors that interact with the genes will be of significant diagnostic and prognostic values,” said Wang, professor and director in the Cardiothoracic Research Laboratory in the Division of Cardiothoracic Surgery of the Michael E. DeBakey Department of Surgery at Baylor College of Medicine. “They may also lead to discoveries of novel molecules with preventive and therapeutic implications.”

The six cores, including administration are: biostatistics and data management; sample banking; pathology; and proteomics. The last core, a physician scientist training core directed by the UT Medical School’s Jon Tyson, M.D., will provide training for junior physician scientists in the area of aortic disease.

“The center takes advantage of the Genome Center at Baylor and the studies they have done there. Galveston has very talented investigators who are participating in one of the projects plus they have a state-of-the-art proteomic center also involved in the grant,” Milewicz said. “We will also be training the next generation of physician-scientists to understand this disease and carry on the research for years to come.”

James T. Willerson, M.D., president of The University of Texas Health Science Center at Houston and director of the Texas Heart Institute, will chair the Internal Advisory Committee.

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