Waiting for a heart,
broker beats the odds

A Connecticut man sets record for survival on heart pump and receives a gift of life.

In his 63 years Robert “Pete” Kenyon has been a Navy officer, an amateur race car driver and, most recently, a reinsurance broker. As someone who makes his living assessing risk, he surely knew the odds as he reached a difficult milestone last year. In August, he became the longest-surviving recipient in the United States of a mechanical pump that replaced the diseased left side of his heart.

At that point he had lived three years on the pump, the outer limits of the manufacturer’s warranty. Novacor’s left ventricular assist system (LVAS) remained in place because none of more than a dozen hearts offered to Kenyon from the organ sharing network had been immunologically compatible.

“We were getting increasingly concerned communications from the engineers at Novacor,” said John A. Elefteriades, M.D. ’76, HS ’83, who implanted the device. By October Kenyon’s physicians decided the pump should be replaced. “The machine was making a lot of abnormal noises, and it was misfiring,” Kenyon said.

He prevailed upon the doctors to wait until the Christmas holidays, when his chances of getting a new heart would increase. On New Year’s Eve, Kenyon went into the operating room, where an expected problem turned out to be even worse than imagined. “The LVAS had been in such a long time that the body’s fibrous tissue had virtually encased it,” Elefteriades said. The device was replaced with an identical, semi-permanent pump.

In a fateful turn of events, another donor heart became available 36 hours later—and this time it matched. Despite having just undergone the ordeal of surgery to implant the new LVAS, Kenyon seized the opportunity. “Dr. Elefteriades felt I was strong enough to undergo surgery, so off we went,” Kenyon said.

From the moment of the donor’s death, a deadline loomed. For the transplant to succeed, the donated heart had to be pumping in the recipient’s chest within four hours. Fortunately, the surgeons had freed the three-year-old LVAS from his tissue the day before. “I do not think we could have gotten everything out fast enough for the heart to be viable,” Elefteriades said.

Three more surgeries followed the heart transplant. A lung infection had to be treated, a pacemaker was installed and Kenyon’s gall bladder had to be removed.

After recuperating from five surgeries in the space of a few weeks, Kenyon is back at work part time, telecommuting from his home office in Darien. “I usually get tossed out of bed at nine o’clock in the morning,” he said with a grin at his wife, Kathy, during an interview in February. “I go down the hall to my office and do my office work. My wife doesn’t like me sitting there for hours at the computer. She wants me up and around. I’m trying to walk as much as possible. I’ll take a nap and read. My appetite is coming back but I can’t eat the quantities of food that I used to.”

He plans to return to a childhood sport learned on frozen ponds—ice hockey. The man whose heart now beats inside Kenyon’s chest was a 30-year-old hockey coach from the Boston area who died of a brain aneurysm. “I want to thank the donor’s family for giving me the gift of life,” Kenyon said.

Even after his death, a skeptic
inspires a legion of scholars

Alvan R. Feinstein, M.D., HS ’54, joked in his 400th scholarly article that he hoped to continue writing until he faced “the ultimate rejection, by adverse pathophysiology.” When Feinstein did die in October—at age 75, while participating in the Gairdner Foundation conference in Toronto—his former student, Peter A. Singer, M.D., M.P.H., found himself taking Feinstein’s place on the podium. Instead of listening to Feinstein speak, Singer delivered a eulogy.

The first part of Singer’s tribute was what one might expect: He described Feinstein’s leadership in establishing the field of clinical epidemiology, in which researchers use scientific principles to study decisions about patient care—what one colleague called “conducting research at the bedside.” And he spoke of Feinstein’s “pattern of challenging orthodoxy.” But then Singer did something unusual: he quoted a comment Feinstein had written on a manuscript that Singer sent him.

“I don’t think your writing is actually bad,” Feinstein wrote to Singer, the Sun Life chair in bioethics at the University of Toronto. “After you fixed the tone and removed most of the sociobabble in this manuscript, the paper could be understood despite its prolixity, verbosity, and subadequate inter- and intra-sentence structure.”

That Singer would affectionately recall the man who offered such criticism reflects Feinstein’s mystique: he had almost impossibly high standards and never minced words, yet his students deeply valued his guidance. Many of those students were young physicians Feinstein supervised as founding director of the Robert Wood Johnson Clinical Scholars Program at Yale, which since 1974 has provided two years of post-residency training in research.

Although Singer now studies bioethics rather than the clinical epidemiology in which he immersed himself as a clinical scholar from 1988 to 1990, he says he uses what Feinstein taught him every day. “He didn’t teach us only clinical epidemiology. He taught us how to think,” said Singer in an interview. He said Feinstein also imparted to students “a fundamental irreverence for scientific authority and established beliefs. … He was one of the giants of 20th-century American science. It was really an honor to be able to learn from him.”

The core values that Feinstein established for the clinical scholars program will endure, said Ralph I. Horwitz, M.D., a program scholar from 1975 to 1977 and now chair of internal medicine at the School of Medicine. The scholars—four to five are admitted each year—will continue to study quantitative methods in depth, to think critically not only about methodology but also about the merit of research questions themselves, and to work closely with faculty mentors, said Horwitz, co-director of the program with Harlan M. Krumholz, M.D.

Second-year scholar Thomas M. Morgan, M.D., said that he and fellow scholars learn to recognize hidden assumptions underlying research and to find limitations to methodology. “They want us to be able to think critically about the techniques used rather than just to be able to plug numbers into a computer and get results,” said Morgan. “We deconstruct research and try to build it up from the rubble.” He said the scholars are taught to evaluate whether a question is even worth studying. “The difference between good research and great research, as defined by the mentors of this program, is determined by the quality of the question.”

The clinical scholars program is at a crossroads now: Yale faces unprecedented competition in seeking renewed funding for the 28-year-old program, because The Robert Wood Johnson Foundation will reduce training sites from seven to four beginning in 2005. To win a grant, Yale must successfully argue that its program not only ranks among the best four programs but also outflanks new competitors from top-ranked schools. Lewis Sandy, M.D., the foundation’s executive vice president, said it decided to fund fewer sites for two reasons. First, although the clinical scholars program was unique in 1974, other fellowships now provide similar training. Second, the foundation hopes that through consolidation it can provide more in-depth training in clinical epidemiology and health services research, with an option to extend the fellowship for as long as six years.

Whatever the future of Yale’s program, Singer believes that Feinstein’s model for rigorous research and his “unswerving devotion” to training his students will have a lasting effect. More than 100 clinical scholars studied with Feinstein. Those men and women, said Singer, compose Alvan Feinstein’s “living legacy.”

Yale group launches new effort
to understand why organ transplants fail

By 11 a.m., Yinong Wang, M.D., is performing his fifth transplant procedure of the day. Each one is the same, and not what you would expect: Prepare a snippet of blood vessel from a donor patient and slip it into the aorta of the anesthetized recipient. Suture and close. Repeat.

Though Wang is indeed a surgeon, it would be misleading to call these recipients patients. They are mice. The delicate suturing is part of a long-term study to determine why coronary arteries narrow over time and become blocked. By using so-called severe combined immunodeficiency (SCID) mice that have been bred without the genes necessary to create T and B cells, the study’s designers are able to introduce immune cells from one human and see how they interact with the blood vessels of another. A week after the microsurgery, the study team will introduce T cells and macrophages from the second human into the mouse’s circulation, then watch for signs of inflammation in the transplanted artery. It’s a model that mimics the real-life battle that occurs after the transplantation of a heart, kidney or liver and which can speed the rejection of the organ. Wang, along with George Tellides, M.D., HS ’93, Marc I. Lorber, M.D., and Jordan S. Pober, M.D. ’77, Ph.D. ’76, HS ’78, is interested in seeing how the cytokine interferon gamma may affect that interaction.

The SCID-mouse model for inflammation is one way Yale scientists are exploring common ground between the basic science of the vessel walls and the clinical problems of organ transplantation. Their efforts were formalized at the medical school in 2000 with the establishment of the Interdepartmental Program in Vascular Biology and Transplantation (VBT), a working group of 24 scientists and physicians in 10 departments.

“Our goal is not to become the world’s largest transplant program but to change the ways that transplantation is being done,” said Pober, the program’s director.

VBT has succeeded in attracting new support from the NIH in the form of a $6.4 million program project grant, and is embarking on a collaboration with Cambridge University funded by Britain’s Medical Research Council. The Interdisciplinary Program in Clinical Transplantation (IPCT), the VBT’s companion program, also received $2.5 million last year in the first round of funding from the Yale-New Haven Medical Center’s new Clinical Program Development Fund. More than a dozen visiting scientists have presented their work in the program’s seminar series.

The science in this area is promising, and that’s a good thing. With long waiting lists for organ transplants (4,323 people died last year waiting for a heart, lung, kidney, liver, intestine or pancreas) and a shortage of donors, transplant physicians are eager to find new ways of protecting those scarce organs that are available.

The new generation of immunosuppressive drugs that emerged during the past decade has greatly reduced the threat of acute rejection immediately following a transplant. Solving the problems of chronic rejection, which leads to the failure of transplanted organs within the first year, is the next step in the effort to reduce demand and stretch supply. Creating a new source of organs through the creation of engineered pig organs, or xenografts, is another. Yale scientists are working in both areas, as well as searching for ways to create artificial tissues or synthetic skin to improve graft viability.

Applying the rapidly unfolding science of immunology to clinical problems will make a huge difference, said Lorber, director of the IPCT. “Most organs that fail do so not because of the failure of immunosuppression in the early post-transplant period. Rather they fail over a period of months to years from the process of chronic rejection,” said Lorber. “We believe that understanding this process may dramatically improve the long-term outlook.” Toward that end, the group’s research is focused on the possibility that chronic rejection may result from an attack by the immune system on the blood vessels, Lorber added. The same process that causes coronary artery disease and heart attacks may be similar to the events leading to chronic organ rejection.

Hence, the group’s interest in SCID mice and the “vascular remodeling” they’ve observed in the studies of transplanted vessels. After doing more than 100 of the procedures, they reported last May in Nature that interferon gamma actually contributed to a thickening of the vessel wall and sped the division of smooth muscle cells, contrary to the conventional wisdom. Both factors contribute to the narrowing of the arteries that supply blood to transplanted organs.

For Tellides, chief of cardiac surgery at the Veterans Administration hospital in West Haven, the finding is an important step. “By knowing which molecules exacerbate vascular disease, we can improve diagnosis and eventually treatment,” he said. “Right now we can only bypass the blockages.”

Alcohol and the brain

Since the 1950s, when Yale scientist E.M. Jellinek pioneered the notion that alcoholism is a disease, investigators have discovered links between certain genes and problem drinking. Now, with a $9 million grant from the National Institute on Alcohol Abuse and Alcoholism, investigators at Yale, the University of Texas and Columbia University will explore the biochemistry of a brain circuit that appears to make some people more likely to become alcoholics; they will also look for ways to apply that knowledge to the treatment of the disease. “With new imaging tools to look at brain chemicals, and molecular genetics studies, we now have an opportunity to observe broad clinical implications from molecular neuroscience,” said John H. Krystal, M.D. ’84, HS ’88, the Albert E. Kent Professor of Psychiatry. Krystal, the principal investigator on the five-year grant, said it will fund the new Center for Translational Neuroscience of Alcoholism at Yale.

Et Cetera

Clear guidance on conflicts

Since the Bayh-Dole Act of 1980, technology transfer has brought thousands of academic inventions to the private sector. For almost as long, universities have struggled with the conflicts of interest that could arise if investigators held a financial stake in the outcome of their research. When an Association of American Medical Colleges task force issued guidelines on conflicts of interest in December, it all but ruled out participation by scientists who might profit from the research. The panel, which included Yale Vice President and General Counsel Dorothy K. Robinson, urged institutions to presume that individuals with a financial interest in a clinical study may not conduct it and to enforce that view through close scrutiny of research proposals. “Transparency,” the task force members agreed, “must be the watchword.”

Community minded

Libraries at the School of Medicine have teamed up with the New Haven Free Public Library to offer health information to the public. Located at the main public library on Elm Street and three branches throughout New Haven, the Consumer Health Information Center (CHIC) will provide workstations with computers, consumer health books and access to health resources on the Web. The partners in the CHIC are the public library, the School of Medicine, the Harvey Cushing/John Hay Whitney Medical Library and the Epidemiology and Public Health Library. A $43,885 grant from the National Network of Libraries of Medicine will fund the program for 18 months.

Sign of compassion

Emotions have a legitimate place in the practice of medicine, according to Associate Dean for Student Affairs Nancy R. Angoff, M.P.H. ’81, M.D. ’90, HS ’93. Writing in JAMA: The Journal of the American Medical Association last fall, Angoff reported that of 182 Yale students surveyed, 133 said they had cried at least once during their first year of clinical rotations. Thirty had been on the verge of crying and only 19 said they didn’t cry even once. In her JAMA essay, “Crying in the Curriculum,” Angoff wrote that “medical educators who fail to look for or listen to stories of crying may be missing an opportunity to have an impact on students’ emotional [development as doctors]. … We should let [students] know that not only is it normal and okay, but it may be a sign of a valuable capacity for compassion.”


			Originally published in Yale Medicine, Spring 2002. Copyright © 2002 Yale University School of Medicine. All rights reserved.

Waiting for a heart, broker beats the odds