From Vanderbilt: “Drug developed for arthritis could be first to stop heart valve calcification”

Vanderbilt U Bloc

Vanderbilt University

Jun. 12, 2017
Heidi Hall

The first drug to treat calcification of heart valves may be one originally designed for rheumatoid arthritis.

Today in Circulation, the journal of the American Heart Association, Vanderbilt University researchers published findings that the drug – a monoclonal antibody known as SYN0012 – shows promise in keeping heart valve leaflets supple. About a quarter of Americans suffer hardening of the valves by age 65 and about half by 85, and the only treatment is surgical replacement.

The culprit in the condition, called aortic valve stenosis, is cadherin-11, a binding protein necessary for normal wound healing. Fibroblasts, the most common cell in connective tissue, produce it to ensure cuts and broken bones reconnect, and heart valves are composed of this type of cell. As hearts age and lose elasticity, the fibroblasts become overactive, producing mass amounts of cadherin-11 until the three thin leaflets that make up aortic valves become virtually immobile. The heart pumps harder in an attempt to push blood through the valve, causing the chambers of the heart to enlarge, leading to heart failure if the valve isn’t replaced.

The rheumatoid arthritis drug, an anti-inflammatory, physically binds to cadherin-11 (CDH-11) on the surface of cells so that they can’t bind together.

“Aortic valve stenosis, even though it involves only a little piece of tissue, has a catastrophic effect on the heart,” said W. David Merryman, associate professor of biomedical engineering. “The antibody we’re working with blocks fibroblasts from becoming the active type that leads to disease. It keeps them from becoming inflamed.

“We believe there is potential for using this drug at the first sign of valve disease to prevent the progression,” Merryman said. “You likely cannot reverse the damage, but we believe the drug can prevent it.”

Common disease claims lives

About 750,000 Americans per year suffer heart attacks, and those plus all other varieties of heart disease are the No. 1 killers in America.

Surgeons can replace damaged valves with ones made from either pig or cow tissue or with mechanical versions, said Vanderbilt cardiologist and Assistant Professor of Medicine Mike Baker. Physicians’ only option is to monitor calcifying valves once they’re detected and then operate when symptoms appear, he said.

“Once the patient becomes symptomatic, they start running a significant risk of heart failure or even death,” Baker said. “The exciting thing about this drug’s potential is that it could allow us to consider a strategy of prevention, as we do with other forms of heart disease – like lowering cholesterol or using ACE inhibitors. We don’t have any interventions for aortic valve stenosis that slow its progression.”

The drug is in human clinical trials for treatment of rheumatoid arthritis. After those are complete, Merryman hopes to gain permission to run clinical trials for uses in heart valve disease.

Fluke leads to potential cure

Merryman’s research into CDH-11 dates back to 2013, when two of his Ph.D. students compared two studies of heart valve cellular responses that came to completely different conclusions. One found that a chemical compound caused valve fibroblasts to become active, similar to what is observed during valve disease, but the other study indicated that the same compound prevented the cells from calcifying, indicating that a key piece of the valve disease puzzle was missing. They realized that the teams behind those studies were inadvertently turning CDH-11 production on and off, affecting the outcome.

The Ph.D. students obtained heart valves preserved from surgeries at Vanderbilt University Medical Center and found that patients suffering from calcification had, in some cases, 50 times as much CDH-11 present in their valves as patients without the condition. They completed another study that showed a NOTCH1 genetic mutation likely ensured those carrying it eventually would suffer from heart valve disease because it leads to CDH-11 overproduction.

Merryman’s work is funded by a recent $5.3 million, seven-year R35 Emerging Investigator Award from the National Heart, Lung and Blood Institute. It also funds his research in developing heart valves that may one day be able to grow along with children.

See the full article here .

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Commodore Cornelius Vanderbilt was in his 79th year when he decided to make the gift that founded Vanderbilt University in the spring of 1873.

The $1 million that he gave to endow and build the university was the commodore’s only major philanthropy. Methodist Bishop Holland N. McTyeire of Nashville, husband of Amelia Townsend who was a cousin of the commodore’s young second wife Frank Crawford, went to New York for medical treatment early in 1873 and spent time recovering in the Vanderbilt mansion. He won the commodore’s admiration and support for the project of building a university in the South that would “contribute to strengthening the ties which should exist between all sections of our common country.”

McTyeire chose the site for the campus, supervised the construction of buildings and personally planted many of the trees that today make Vanderbilt a national arboretum. At the outset, the university consisted of one Main Building (now Kirkland Hall), an astronomical observatory and houses for professors. Landon C. Garland was Vanderbilt’s first chancellor, serving from 1875 to 1893. He advised McTyeire in selecting the faculty, arranged the curriculum and set the policies of the university.

For the first 40 years of its existence, Vanderbilt was under the auspices of the Methodist Episcopal Church, South. The Vanderbilt Board of Trust severed its ties with the church in June 1914 as a result of a dispute with the bishops over who would appoint university trustees.

kirkland hallFrom the outset, Vanderbilt met two definitions of a university: It offered work in the liberal arts and sciences beyond the baccalaureate degree and it embraced several professional schools in addition to its college. James H. Kirkland, the longest serving chancellor in university history (1893-1937), followed Chancellor Garland. He guided Vanderbilt to rebuild after a fire in 1905 that consumed the main building, which was renamed in Kirkland’s honor, and all its contents. He also navigated the university through the separation from the Methodist Church. Notable advances in graduate studies were made under the third chancellor, Oliver Cromwell Carmichael (1937-46). He also created the Joint University Library, brought about by a coalition of Vanderbilt, Peabody College and Scarritt College.

Remarkable continuity has characterized the government of Vanderbilt. The original charter, issued in 1872, was amended in 1873 to make the legal name of the corporation “The Vanderbilt University.” The charter has not been altered since.

The university is self-governing under a Board of Trust that, since the beginning, has elected its own members and officers. The university’s general government is vested in the Board of Trust. The immediate government of the university is committed to the chancellor, who is elected by the Board of Trust.

The original Vanderbilt campus consisted of 75 acres. By 1960, the campus had spread to about 260 acres of land. When George Peabody College for Teachers merged with Vanderbilt in 1979, about 53 acres were added.

wyatt centerVanderbilt’s student enrollment tended to double itself each 25 years during the first century of the university’s history: 307 in the fall of 1875; 754 in 1900; 1,377 in 1925; 3,529 in 1950; 7,034 in 1975. In the fall of 1999 the enrollment was 10,127.

In the planning of Vanderbilt, the assumption seemed to be that it would be an all-male institution. Yet the board never enacted rules prohibiting women. At least one woman attended Vanderbilt classes every year from 1875 on. Most came to classes by courtesy of professors or as special or irregular (non-degree) students. From 1892 to 1901 women at Vanderbilt gained full legal equality except in one respect — access to dorms. In 1894 the faculty and board allowed women to compete for academic prizes. By 1897, four or five women entered with each freshman class. By 1913 the student body contained 78 women, or just more than 20 percent of the academic enrollment.

National recognition of the university’s status came in 1949 with election of Vanderbilt to membership in the select Association of American Universities. In the 1950s Vanderbilt began to outgrow its provincial roots and to measure its achievements by national standards under the leadership of Chancellor Harvie Branscomb. By its 90th anniversary in 1963, Vanderbilt for the first time ranked in the top 20 private universities in the United States.

Vanderbilt continued to excel in research, and the number of university buildings more than doubled under the leadership of Chancellors Alexander Heard (1963-1982) and Joe B. Wyatt (1982-2000), only the fifth and sixth chancellors in Vanderbilt’s long and distinguished history. Heard added three schools (Blair, the Owen Graduate School of Management and Peabody College) to the seven already existing and constructed three dozen buildings. During Wyatt’s tenure, Vanderbilt acquired or built one-third of the campus buildings and made great strides in diversity, volunteerism and technology.

The university grew and changed significantly under its seventh chancellor, Gordon Gee, who served from 2000 to 2007. Vanderbilt led the country in the rate of growth for academic research funding, which increased to more than $450 million and became one of the most selective undergraduate institutions in the country.

On March 1, 2008, Nicholas S. Zeppos was named Vanderbilt’s eighth chancellor after serving as interim chancellor beginning Aug. 1, 2007. Prior to that, he spent 2002-2008 as Vanderbilt’s provost, overseeing undergraduate, graduate and professional education programs as well as development, alumni relations and research efforts in liberal arts and sciences, engineering, music, education, business, law and divinity. He first came to Vanderbilt in 1987 as an assistant professor in the law school. In his first five years, Zeppos led the university through the most challenging economic times since the Great Depression, while continuing to attract the best students and faculty from across the country and around the world. Vanderbilt got through the economic crisis notably less scathed than many of its peers and began and remained committed to its much-praised enhanced financial aid policy for all undergraduates during the same timespan. The Martha Rivers Ingram Commons for first-year students opened in 2008 and College Halls, the next phase in the residential education system at Vanderbilt, is on track to open in the fall of 2014. During Zeppos’ first five years, Vanderbilt has drawn robust support from federal funding agencies, and the Medical Center entered into agreements with regional hospitals and health care systems in middle and east Tennessee that will bring Vanderbilt care to patients across the state.

studentsToday, Vanderbilt University is a private research university of about 6,500 undergraduates and 5,300 graduate and professional students. The university comprises 10 schools, a public policy center and The Freedom Forum First Amendment Center. Vanderbilt offers undergraduate programs in the liberal arts and sciences, engineering, music, education and human development as well as a full range of graduate and professional degrees. The university is consistently ranked as one of the nation’s top 20 universities by publications such as U.S. News & World Report, with several programs and disciplines ranking in the top 10.

Cutting-edge research and liberal arts, combined with strong ties to a distinguished medical center, creates an invigorating atmosphere where students tailor their education to meet their goals and researchers collaborate to solve complex questions affecting our health, culture and society.

Vanderbilt, an independent, privately supported university, and the separate, non-profit Vanderbilt University Medical Center share a respected name and enjoy close collaboration through education and research. Together, the number of people employed by these two organizations exceeds that of the largest private employer in the Middle Tennessee region.
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